Iranian Journal of Pharmaceutical Research
Volume:23 Issue: 1, Winter 2024

This study aimed to develop a microemulsion (ME)-based skin delivery platform containing sildenafil citrate (SC)-ME and evaluate its in vitro skin permeability.

Accurate MEs were prepared using pseudo-ternary phase diagrams and a full factorial design with three variables at two levels. After the design phase, suitable ratios of oil, water, and a mixture of surfactant (S) and cosurfactant (CS) were selected to prepare various SC-ME formulations. These SC-MEs were analyzed for stability, droplet size, in vitro SC release, skin permeability, and viscosity properties.

The droplet size of the ME samples ranged from 6.24 to 32.65 nm, with viscosities between 114 to 239 cps. Release profiles indicated that 26 to 60% of SC was released from the different SC-MEs within 24 hours. All ME formulations significantly enhanced the permeability coefficient (P) through rat skin. Specifically, the flux (Jss) in SC-ME7 increased by approximately 117 times (Jss = 0.0235 mg/cm2.h) compared to the control sample (0.0002 mg/cm2.h).

The study concluded that the proportions of the water or oil phase and the S/CS mixture in the MEs significantly influenced the physicochemical characteristics and permeation parameters. The selected MEs improved both the permeability coefficient and the rate of permeation through rat skin. The enhanced drug delivery through and into deep skin layers is a key attribute of an ideal dermal ME. These findings suggest that MEs could serve as effective transdermal delivery systems for SC and similar drugs. However, in vivo assays and clinical research are needed to confirm the therapeutic efficacy of MEs.

Cisplatin, an anti-cancer chemotherapy drug, has nephrotoxic effects. Thymus caramanicus Jalas (TCJ) has antioxidant effects due to its main components.

In the current research, we assessed the impact of TCJ extract and its main compound on cisplatin-induced nephrotoxicity in mice.

Forty-two male mice were used in the study. Depending on their group, the animals received saline, carvacrol (10 mg/kg), or TCJ extract (50, 100, and 150 mg/kg) for 10 days. On the fifth day, mice received cisplatin (7.5 mg/kg, i.p.). After 10 days, serum creatinine (Cr) and blood urea nitrogen (BUN) levels were measured. Additionally, malondialdehyde (MDA) and glutathione (GSH) contents, as well as the activity levels of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), and total antioxidant capacity (TAC) were measured in the kidney tissues. The western blotting method was used to determine the kidney's expression of cleaved caspase-3, Bax, Bcl-2, nuclear factor kappa-B (NF-κB), and tumor necrosis factoralpha (TNF-α). Kidney tissue damage score (KTDS) was assessed using the hematoxylin-eosin (H&E) staining method.

Cisplatin significantly increased serum Cr, KTDS, MDA, BUN levels, NF-κB, TNF-α, cleaved caspase-3, and Bax protein expression in the cisplatin group compared to the control group (P < 0.01). Additionally, cisplatin significantly decreased the kidney tissue's TAC and GSH content, activity levels of SOD, catalase, and GPx indicators, and expression of Bcl-2 protein (P < 0.05). TCJ and carvacrol significantly ameliorated these indicators in the cisplatin + TCJ (150 mg/kg) and cisplatin + carvacrol (10 mg/kg) groups compared to the cisplatin group (P < 0.05).

TCJ (150 mg/kg) and its main component, carvacrol, could somewhat reduce cisplatin-induced nephrotoxicity through their anti-inflammatory, antioxidant, and anti-apoptotic effects.

This study assessed the acute and sub-chronic toxicity of Camelina oil, a well-known oil rich in polyunsaturated fatty acids that enhance cellular immunity and human health, in Wistar rats. Wistar rats, 5 per sex per group, were randomly assigned to three groups for acute (14 days) toxicity studies and five groups for sub-chronic (90 days) toxicity studies. In the acute study, Camelina sativa oil was administered orally at a single dose of 5000 mg/kg of body weight (BW). The positive control group received a single dose of 5 000 mg/kg BW Canola oil by gavage. In the sub-chronic study, Groups III-V received 250, 500, and 1 000 mg/kg BW of Camelina oil, while Groups I and II received ultra-pure water and Canola oil at a dose of 500 mg/kg BW, respectively. Throughout the experiment, clinical signs, mortality, and body weight were monitored. At the end of the sub-chronic study, hematological, biochemical, and histopathological investigations were conducted. Administration of Camelina oil and Canola had no significant effect on daily weight gain (P > 0.05) of the test rats. Serum calcium levels decreased while phosphorous levels increased in male rats treated with Camelina oil. Other hematological and biochemical parameters showed no significant differences or dose-response effects between control and seed oil groups in both sexes (P < 0.05). Moreover, in animal necropsy, there were no apparent lesions in the liver, heart, and kidney organs in any of the doses administered. In conclusion, the results suggest that oral administration of Camelina oil is unlikely to be toxic. Therefore, the possibility for the development of future human nutrition should be considered.

Cassia angustifolia Vahl. ( Senna) is a medicinal plant containing anthraquinone compounds such as sennoside. Senna is primarily valued for its laxative properties. In Persian medicine, this plant has been also used to treat various disorders such as diabetes and skin hyperpigmentation. Previous studies have shown that different species of senna, such as C. articulata, C. alata, C. Siamea, C. Surattensis inhibit alpha-amylase and α-glucosidase enzymes. To the best of our knowledge, no previous evidence is available on tyrosinase and α-glucosidase inhibitory effects of the extract and different fractions of C. angustifolia leaves.

The purpose of this study was to investigate the inhibitory effect of the methanol-water extract and different fractions (hexane, chloroform, ethyl acetate, and remaining crude extract) of senna against tyrosinase and α-glucosidase and to investigate their total phenolic and sennoside B contents.

Our findings depicted that the methanol-water extract and fractions had no significant anti-tyrosinase activity; however, some fractions were active toward α-glucosidase. The hexane fraction and the remaining crude extract demonstrated the highest inhibition on α-glucosidase compared to acarbose (positive control). In addition, the ethyl acetate fraction contains high phenolic and hydroxy anthraquinone derivatives based on the amount of sennoside B contents equivalent to 382.25 μg/mL of gallic acid and 1.525% of sennoside B, respectively. Moreover, no correlation was observed between the phenolic and sennoside contents of different fractions and their α-glucosidase inhibitory effect.

Considering the α-glucosidase inhibition results, the hexane fraction of C. angustifolia can be a valuable fraction for in vitro and in vivo antidiabetic studies as well as further phytochemical studies. Further studies to identify the active substances and the exact mechanism of the bioactive ingredients on the inhibitory effects of α-glucosidase can provide promising results in the future.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive deterioration, including deficits in memory and other cognitive functions. Oxidative stress and free radical damage play significant roles in its pathogenesis. This study aimed to investigate the potential anti-inflammatory and neuroprotective effects of Pistacia atlantica gum (administered at doses of 50 and 100 mg/kg for 14 days) in a rat model of AD induced by aluminum chloride (AlCl3). Behavioral changes were assessed using open field, passive avoidance, and elevated plus maze tests. Additionally, nitrite levels, nuclear factor-kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), and immunostaining were evaluated. Administration of P. atlantica gum significantly increased step-through latency in the passive avoidance test (P < 0.01 and P < 0.001), enhanced mobility in the open field test (P < 0.01 and P < 0.001), and reduced anxiety-like behaviors in the elevated plus maze (P < 0.001) compared to the AlCl3 group. Treatment with the gum partially normalized the elevated levels of NF-κB and the decreased levels of BDNF caused by AlCl3 exposure. Our findings suggest that P. atlantica gum administration may alleviate oxidative stress, neuroinflammation, and cognitive impairment in AD rats.

Benzo(a)pyrene (BaP), an environmental toxicant and endocrine disruptor, has been shown to exacerbate atherosclerosis when combined with a high-fat diet. Fibroblast Growth Factor-21 (FGF21), a novel hormone with antiatherosclerotic properties, is associated with the presence of atherosclerosis and reduces plaque formation in experimental animals.

The present study aimed to investigate the chronic effect of BaP injection on hepatic FGF21 expression, as an antiatherosclerotic hormone, in mice fed with or without an atherogenic diet (AtD).

Eighteen C57BL/6J male mice (6 weeks) were randomly divided into six groups based on the dosage and diet. Blood samples were collected, and serum cholesterol, triglyceride, HDL-C, LDL-C, and glucose levels were measured. FGF21 expression was assessed by quantitative real-time PCR. Atherosclerotic lesions in mice were studied with Oil Red O (ORO) staining.

Benzo(a)pyrene causes a significant increase in liver FGF21 expression in a dose-dependent manner, and BaP coexposure with AtD leads to a further increase in FGF21 expression. Additionally, the addition of BaP to AtD significantly increased the serum glucose, cholesterol, and LDL-C levels and accelerated the formation of atherosclerotic lesions. Besides, our findings showed that there is a significant positive correlation between FGF21 expression and glucose, cholesterol, LDL-C, and OROpositive areas.

Our findings revealed that BaP increases the expression of endogenous FGF21 in treated animals as a compensatory response to protect the heart from atherosclerosis induced by BaP and AtD.

Polycystic ovary syndrome (PCOS) is the most common gynecological endocrine disorder.

This study evaluated the therapeutic effects of Pimpinella anisum L. (P. anisum) fruit on pro-inflammatory cytokines, oxidative stress markers, and ovarian tissue structure in a rat model of PCOS.

After inducing PCOS, female Wistar rats were randomly divided into control and PCOS groups. They orally received daily doses of normal saline or hydro-alcoholic extract of P. anisum at two doses (200 and 400 mg/kg) for 21 days. At the end of the treatment period, ovarian and liver tissues were collected to measure lipid peroxidation, antioxidant status, TNF-, IL-6 mRNA expression, and its content. Additionally, histopathological examinations of the ovarian tissue were conducted.

Our findings revealed a dose-dependent change in the biochemical and histopathological parameters. Treatment with P. anisum resulted in a significant decrease in TNF-and IL-6mRNAexpression levels and their content in the ovarian and liver tissues. It also reduced MDA levels while increasing SOD and GPx activity in both ovarian and liver tissues of PCOS rats. Furthermore, the number of follicular cysts in the PCOS rat model was significantly reduced.

The beneficial effects of P. anisum in PCOS rats are partly attributed to the inhibition of inflammatory and oxidative stress markers in ovarian tissue. These findings suggest that P. anisum could be a potential candidate for the treatment of PCOS disorders

Cancer remains the leading cause of death globally, with breast cancer being the foremost cause among women and lung cancer ranking second for both women and men.

This study aimed to identify the metabolomic content of Coleus amboinicus leaves and evaluate their anticancer activities against breast and lung cancer cells, thereby providing insights into potential alternative treatments for these cancers and initiating research on active isolates from C. amboinicus leaves.

The research methodology involved maceration using ethanol, followed by multistage partitioning with solvents nhexane, chloroform, and ethyl acetate. Phytochemical screening was performed using standard reagents to detect the presence of alkaloids, phenolics, polyphenols, flavonoids, steroids/triterpenoids, and saponins. Metabolomic profiling was conducted using LC/HRMS, and the anticancer activities against lung cancer cells (A549) and breast cancer cells (MCF-7) were assessed using the MTT assay.

The results showed that the C. amboinicus extract contains various secondary metabolite groups such as alkaloids, phenolics and polyphenols, flavonoids, steroids, triterpenoids, and saponins.

The diverse metabolomic profile of the C. amboinicus leaf extract demonstrated potential activity against cancer, as evidenced by in vitro tests on lung (A549) and breast (MCF-7) cancer cells. C. amboinicus leaf extract shows promise as an active ingredient in the prevention and alternative natural treatment of lung and breast cancer. Further research and testing, both in vivo and clinically, are warranted.

The utilization of amorphous silica nanoparticles (SiNPs) is gaining popularity in various applications, but it poses a potential risk to human and environmental health. However, the underlying causes and mechanisms of SiNPs-induced kidney damage are still largely unknown.

This study aimed to investigate the SiNPs-induced damage in the kidney and further explore the possible mechanisms of SiNPs-induced nephrotoxicity.

Thirty adult male rats were divided into 3 different groups. Rats in groups 2 and 3 were administered SiNPs at 2 dosage levels (25 and 100 mg/kg of body weight), while the rats in the control group received no treatment for 28 days. Reactive oxygen species (ROS), antioxidant enzyme activities (glutathione peroxidase [GPx], superoxide dismutase [SOD], and catalase [CAT]), glutathione (GSH) levels, and oxidation markers (such as lipid peroxidation [malondialdehyde (MDA)] and protein oxidation [protein carbonyl (PCO)]) were analyzed in the kidney tissue. Additionally, renal fibrogenesis was studied through histopathological examination and the expression levels of fibrotic biomarkers.

The findings revealed that in vivo treatment with SiNPs significantly triggered oxidative stress in kidney tissues in a dose-dependent manner. This was characterized by increased production of ROS, elevated levels of MDA, PCO, and nitric oxide (NO), along with a significant decline in the activities of SOD, CAT, GPx, and reduced GSH. These changes were consistent with the histopathological analysis, which indicated interstitial fibrosis with mononuclear inflammatory cell aggregation, tubular degeneration, glomerulonephritis, and glomerular atrophy. The fibrosis index was confirmed using Masson’s trichrome staining. Additionally, there was a significant upregulation of fibrosis-related genes, including transforming growth factor-beta 1 (TGF-B1), matrix metalloproteinases 2 and 9 (MMP-2/9), whereas the expression of tissue inhibitor of metalloproteinase 2 (TIMP2) was downregulated.

This study provided a new research clue for the role of ROS and deregulated TGF-B signaling pathway in SiNPs nephrotoxicity.

Warfarin is the only approved anticoagulant for antithrombotic treatment in patients with mechanical prosthetic heart valves (MPHV). However, dosing warfarin is challenging due to its narrow therapeutic window and highly variable clinical outcomes. Both low and high doses of warfarin can lead to thrombotic and bleeding events, respectively, with these complications being more severe in individuals with sensitive genetic polymorphisms. Incorporating genetic testing could enhance the accuracy of warfarin dosing and minimize its adverse events.

This study aims to evaluate the utilities and cost-effectiveness of pharmacogenomics-guided versus standard dosing of warfarin in patients with MPHV in Iran.

In this economic evaluation study, a cost-effectiveness analysis was conducted to compare pharmacogenomicsguided versus standard warfarin dosing. Data related to quality of life (QoL) were collected through a cross-sectional study involving 105 randomly selected MPHV patients using the EuroQol-5D (EQ-5D) Questionnaire. Costs were calculated with input from clinical experts and a review of relevant guidelines. Additional clinical data were extracted from published literature. The pharmacoeconomic threshold set for medical interventions within Iran's healthcare system was $1,500. A decision tree model was designed from the perspective of Iran's healthcare system with a one-year study horizon. Sensitivity analyses were also performed to assess the uncertainty of input parameters.

The utility scores derived from the questionnaire for standard and pharmacogenomics-guided warfarin treatments were 0.68 and 0.76, respectively. Genotype-guided dosing of warfarin was more costly compared to the standard dosing ($246 vs $69), and the calculated incremental cost-effectiveness ratio (ICER) was $2474 per quality-adjusted life year (QALY) gained. Oneway sensitivity analyses showed that our model is sensitive to the percentage of time in the therapeutic range (PTTR), the cost of genetic tests, and the utility of both pharmacogenomics-guided and standard dosing arms. However, the probabilistic sensitivity analysis demonstrates the robustness of our model.

Warfarin dosing with pharmacogenomics testing is currently not cost-effective. However, if the cost of genotyping tests decreases to $118, the ICER would become cost-effective.

Antibiotic-resistant Escherichia coli is one of the major opportunistic pathogens that cause hospital-acquired infections worldwide. These infections include catheter-associated urinary tract infections (UTIs), ventilator-associated pneumonia, surgical wound infections, and bacteraemia.

To understand the mechanisms of resistance and prevent its spread, we studied E. coli C91 (ST38), a clinical outbreak strain that was extensively drug-resistant. The strain was isolated from an intensive care unit (ICU) in one of Kuwait’s largest hospitals from a patient with UTI.

This study used whole-genome sequencing (Illumina, MiSeq) to identify the strain’s multi-locus sequence type, resistance genes (ResFinder), and virulence factors. This study also measured the minimum inhibitory concentrations (MIC) of a panel of antibiotics against this isolate.

The analysis showed that E. coli C-91 was identified as O99 H30 ST38 and was resistant to all antibiotics tested, including colistin (MIC > 32 mg/L). It also showed intermediate resistance to imipenem and meropenem (MIC = 8 mg/L). Genome analysis revealed various acquired resistance genes, including mcr-1, blaCTX-M-14, blaCTX-M-15, and blaOXA1. However, we did not detect blaNDM or blaVIM. There were also several point mutations resulting in amino acid changes in chromosomal genes: gyrA, parC, pmrB, and ampC promoter. Additionally, we detected several multidrug efflux pumps, including the multidrug efflux pump mdf (A). Eleven prophage regions were identified, and PHAGE Entero SfI NC was detected to contain ISEc46 and ethidium multidrug resistance protein E (emrE), a small multidrug resistance (SMR) protein family. Finally, there was an abundance of virulence factors in this isolate, including fimbriae, biofilm, and capsule formation genes.

This isolate has a diverse portfolio of antimicrobial resistance and virulence genes and belongs to ST38 O99 H30, posing a serious challenge to treating infected patients in clinical settings.

Crocin is a water-soluble carotenoid compound present in saffron (Crocus sativus L.), known for its wide range of pharmacological activities, including cardioprotective, hepatoprotective, anti-tumorigenic, anti-atherosclerosis, and anti-inflammatory effects.

The instability of crocin, its low miscibility with oils, and poor bioavailability pose challenges for its pharmaceutical applications. This study aimed to design and prepare a crocin-phospholipid complex (CPC) and assess its physicochemical properties.

The study investigated the formation of the complex and its binding affinity through molecular docking. Molecular dynamics (MD) simulations were conducted to find the optimal molar ratio of crocin to phospholipid for the complex’s preparation. TheCPCwasproduced using the solvent evaporation method. Techniques such as X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), field-emission scanning electron microscopy (FE-SEM), nuclear magnetic resonance (NMR), and solubility studies were utilized to characterize and confirm the formation of CPC. Additionally, the in vitro antioxidant activity of crocin and CPC was evaluated.

Molecular dynamic simulations explored molar ratios of 1: 1, 1: 1.5, and 1: 2 for crocin to phospholipid. The ratio of 1: 2 was found to be the most stable, exhibiting the highest probability of hydrogen bond formation. Molecular docking, FTIR, and NMR studies indicated hydrogen bond interactions between crocin and phospholipid, confirming CPC’s formation. XRD and FE-SEM analyses showed a decrease in crocin’s crystallinity within the phospholipid complex. Furthermore, the solubility of crocin in n-octanol was enhanced post-complexation, indicating an increase in crocin’s lipophilic nature.

Phospholipid complexation emerges as a promising technique for enhancing the physicochemical characteristics of crocin.

Insulin resistance is an important pathological hallmark of Parkinson’s disease (PD). Proinflammatory cytokines during neuroinflammation decrease insulin sensitivity by suppressing insulin signaling elements. Toll-like receptor 4 (TLR4), the main receptor involved in neuroinflammation, is also associated with the pathogenesis of PD.

The present study evaluated the effect of insulin, an insulin receptor antagonist, and a TLR4 inhibitor on behavioral deficits and insulin resistance induced by 6-hydroxydopamine (6-OHDA).

Male Wistar rats were divided into nine groups: (1) sham (normal saline [NS] in the medial forebrain bundle [MFB]); (2) 6-OHDA (20 μg in the MFB); (3) 6-OHDA + NS; (4) 6-OHDA + dimethyl sulfoxide (DMSO); (5) 6-OHDA + insulin (2.5 IU/day, intracerebroventricular ([ICV]); (6) 6-OHDA + insulin (5 IU/day, intranasal [IN]); (7) 6-OHDA + insulin receptor antagonist (S961; 6.5 nM/kg, ICV); (8) 6-OHDA + TLR4 inhibitor (TAK242; 0.01 μg/rat, ICV); (9) 6-OHDA + insulin + TLR4 inhibitor. All treatments were administered for seven consecutive days. Motor performance was evaluated using apomorphine-induced rotation and cylinder tests. Gene expression and protein levels of α-synuclein, TLR4, insulin receptor substrate (IRS) 1, IRS2, and glycogen synthase kinase 3β (GSK3β) were measured by real-time PCR and western blotting, respectively, in the striatum.

Insulin, alone and with TAK242, improved motor deficits induced by 6-OHDA. Administration of the insulin receptor antagonist had no effect on motor deficits. The increased expression of α-synuclein and TLR4 following 6-OHDA was attenuated by insulin and TAK242. GSK3β levels, both mRNA and protein, were significantly increased by 6-OHDA and attenuated with insulin and TAK242.

The findings suggest that 6-OHDA induces neurodegeneration via activation of TLR4 and GSK3β, indicating insulin resistance, and that insulin can improve these impairments. Moreover, TLR4 inhibition prevents insulin signaling dysfunction and improves behavioral and molecular impairments, highlighting the critical role of TLR4 in the development of insulin resistance in PD pathology.

Heracleum species are commonly used as spices, flavorings, and food additives. Members of the genus Heracleum offer many medicinal benefits but may also pose adverse effects on human health.

To prepare a crude leaf extract of Heracleum lasiopetalum and assess its toxicity profile towards healthy rats.

The H. lasiopetalum leaf extract was prepared using pure methanol and ethyl acetate (1:10) at room temperature over a period of 72 hours. After filtration, the crude extract was obtained using a rotary evaporator at 40 - 45°C. Subsequently, various doses of the H. lasiopetalum extract were administered orally to healthy Sprague Dawley rats at three doses (300, 600, and 900 mg/kg body weight) for four weeks to test for toxicity. Blood samples were examined for hematologic and biochemical changes, while the liver, kidneys, and heart were examined for histopathological changes.

The toxicity study revealed no mortality at low and medium doses, as well as no clinical toxicity indicators. Additionally, there were no significant alterations observed in the haematological, biochemical, and histopathological profiles of the treated animals throughout the 28-day experiment. However, at high doses, the mortality rate was significantly elevated, accompanied by notable histopathological changes.

Continuous administration of high doses of H. lasiopetaum may induce potential toxic effects in the treated animals.

Endometriosis is a chronic gynecological disorder characterized by the ectopic growth of endometrial tissue outside the uterus, leading to debilitating painandinfertility in affectedwomen. Despite its prevalenceandclinical significance, the molecularmechanismsunderlying the progression of endometriosisremainpoorly understood. This studyemploys bioinformatics toolsandmolecular docking simulations to unravel the intricate genetic and molecular networks associated with endometriosis progression.

The primary objectives of this research are to identify differentially expressed genes (DEGs) linked to endometriosis, elucidate associated biological pathways using the Database for Annotation, Visualization, and Integrated Discovery (DAVID), construct a Protein-Protein Interaction (PPI) network to identify hub genes, and perform molecular docking simulations to explore potential ligand-protein interactions associated with endometriosis.

Microarray data from Homo sapiens, specifically Accession: GDS3092 Series = GSE5108 (Platform: GPL2895), were retrieved from the NCBI Gene Expression Omnibus (GEO). The data underwent rigorous preprocessing and DEG analysis using NCBI GEO2. Database for Annotation, Visualization, and Integrated Discovery analysis was employed for functional annotation, and a PPI network was constructed using the STITCH database and Cytoscape 3.8.2. Molecular docking simulations against target proteins associated with endometriosis were conducted using MVD 7.0.

A total of 1 911 unique elements were identified as DEGs associated with endometriosis from the microarray data. Database for Annotation, Visualization, and Integrated Discovery analysis revealed pathways and biological characteristics positively and negatively correlated with endometriosis. Hubgenes, including BCL2, CCNA2, CDK7, EGF, GAS6, MAP3K7, and TAB2, were identified through PPI network analysis. Molecular docking simulations highlighted potential ligands, such as Quercetin-3-o-galactopyranoside and Kushenol E, exhibiting favorable interactions with target proteins associated with endometriosis.

This study provides insights into the molecular signatures, pathways, and hub genes associated with endometriosis. Utilizing DAVID in this study clarifies biological pathways associated with endometriosis, revealing insights into intricate genetic networks. Molecular docking simulations identified ligands for further exploration in therapeutic interventions. The consistent efficacy of these ligands across diverse targets suggests broad-spectrum effectiveness, encouraging further exploration for potential therapeutic interventions. The study contributes to a deeper understanding of endometriosis pathogenesis, paving the way for targeted therapies and precision medicine approaches to improve patient outcomes. These findings advance our understanding of the molecular mechanisms in endometriosis (EMS), offering promising avenues for future research and therapeutic development in addressing this complex condition.

The incidence of colorectal cancer is increasing globally. Daunorubicin (DNR), an anthracycline antibiotic, is effective against various cancers. The PI3K/AKT/mTOR signaling pathway is crucial in regulating cell growth and cancer growth.

This study aims to evaluate the effects of liposomal daunorubicin (Lip-DNR) on cell proliferation and cell death induction in HCT116 cells compared to free daunorubicin.

Lip-DNR was synthesized, and its shape and size were analyzed using FE-SEM imaging. HCT116 cells were treated with Lip-DNR concentrations of 0 (control), 0.125, 0.25, 0.5, 1, and 2 μm for 48 hours to determine the IC50. The effects of free (0.5 μm) and liposomal DNR (IC50 of 0.43 μm) on PI3K mRNA levels were assessed using real-time PCR. The cell cycle was analyzed by flow cytometry.

FE-SEM imaging showed that the liposomes are spherical and range from 50 - 100 nm in size. Lip-DNR induced cell death in HCT116 cells in a dose-dependent manner, with 0.5 μm Lip-DNR causing more cell death than an equivalent concentration of free DNR. Analysis of PI3K gene expression showed that DNR decreases PI3K gene transcription in HCT116 cells, with Lip-DNR having a more substantial effect than the free form. Both forms reduced the proportion of G2/M phase cells, but Lip-DNR was more effective at inhibiting cell proliferation in HCT116 cells.

DNR inhibits the proliferation of HCT116 cells by downregulating PI3K gene expression and enhancing cell death, with the liposomal form demonstrating stronger effects than the free form.

The abnormal expression of microRNA (miRNA) influences RNA transcription and protein translation, leading to tumor progression and metastasis. Today, reliably identifying aberrant miRNA expression remains challenging, especially when employing quick, simple, and portable detection methods.

This study aimed to diagnose and detect the miR-21 biomarker with high sensitivity and specificity.

Our detection approach involves immobilizing ROX dye-labeled single-stranded DNA probes (ROX-labeled ssDNA) onto MWCNTs to detect target miRNA-21. Initially, adsorbing ROX-labeled ssDNA onto MWCNTs causes fluorescence quenching of ROX. Subsequently, introducing its complementary DNA (cDNA) forms double-stranded DNA (dsDNA), which results in the desorption and release from MWCNTs, thus restoring ROX fluorescence.

The study examined changes in fluorescence intensities before and after hybridization with miRNA-21. The fluorescence emission intensities responded linearly to increases in miR-21 concentration from 10-9 to 3.2  10-6 M. The developed fluorescence sensor exhibited a detection limit of 1.1210-9 M.

This work demonstrates that using a nano-biosensor based on carbon nanotubes offers a highly sensitive method for the early detection of colorectal cancer (CRC), supplementing existing techniques.

Context: 

Breast cancer poses significant challenges due to its high incidence and prevalence, necessitating heightened attention. Understanding how patients prioritize different treatment options based on various attributes can assist healthcare decision-makers in maximizing patient utility. The discrete choice experiment, a conjoint method, facilitates preference elicitation by presenting different attributes and choices. This systematic review aims to identify key factors in patient preference research related to adjuvant treatment for early breast cancer characterized by hormone receptor-positive, HER2- negative status.

Evidence Acquisition: 

PubMed, Embase, Web of Science, and Scopus were searched from 01.01.2000 to 31.03.2023. Original English articles reporting patient preferences in adjuvant breast cancer treatment were retrieved based on predefined inclusion and exclusion criteria. Included studies were examined through a narrative synthesis approach, with descriptive statistics employed for analysis.

Out of 1163 articles reviewed, four met the inclusion criteria and were conducted in the USA, Canada, and the Netherlands. Attributes extracted from all studies included alopecia, sensory neuropathy, motor neuropathy, myalgia/arthralgia, nausea, vomiting, fatigue, neutropenia, mucositis/stomatitis, hand-foot syndrome, diarrhea, prevention of breast cancer recurrence, osteoporosis, risk of endometrial cancer, joint and muscle pain, fluid retention, libido decrease, hot flashes, ECG monitoring, efficacy, treatment regimen, 5-year invasive disease-free survival (iDFS), dosing schedule, and treatment duration. The most frequently reported attributes were side effects, efficacy, and treatment regimen. Systematic review was commonly used to determine which attributes and levels to include. The minimum number of attributes identified per study was seven, and the maximum was 12. Sample sizes ranged from 102 to 300, with none of the studies mentioning the method of sample size estimation. Ordinary Least Squares, logistic regression, and hierarchical Bayes regression were the most frequent analysis methods.

Side effects, 5-year iDFS, and treatment regimen are three attributes identified for conducting discrete choice experiment studies. Utilizing conjoint analysis to assess patient preferences for breast cancer treatment can aid in selecting optimal treatment regimens and improving patient adherence. Moreover, adhering to guidelines for developing experimental designs and conducting data analysis is essential for yielding robust results when employing preference elicitation methods.

Molecular imaging is a highly effective method for diagnosing cancer and evaluating treatment. A molecular tracer often consists of two segments: A targeting segment, which can be antibodies, antibody fragments, or VHH (nanobody), and a detection segment, such as radioisotopes. The small size of VHH allows for excellent tissue penetration and fast clearance, resulting in minimal nonspecific background, which makes them appealing for use as imaging agents. 99m-technetium (99mTc), one of the well-known radioisotopes, is particularly useful in routine clinical imaging.

This study aims to construct 99mTc-anti-placenta growth factor (PlGF) nanobody and assess its radiochemical purity (RCP).

The mutant form of anti-PlGF nanobody was expressed in E. coli TG1 and purified using Ni-NTA column affinity chromatography. The purified nanobodies were confirmed by SDS-PAGE and western blotting. A 99mTc-tricarbonyl solution was added to phosphate-buffered saline (PBS) containing the mutant nanobody for labeling, and the mixture was purified using a PD-10 column.

The RCP of 99mTc-tricarbonyl is > 98%. After the addition of radioisotopes to the mixture of nanobodies, purity reached 70% in 2 hours and remained constant during incubation. After purifying the labeled nanobody, activity was measured, and the highest amount of labeled nanobodies was collected in the second part. The stability of the labeled nanobody in PBS and in competition with histidine for 4 hours was checked by thin-layer chromatography (TLC).

The findings of this study reveal that the RCP of the labeled nanobody was above 95% after 4 hours, indicating the labeled antibody's stability. These results are promising and could be utilized in future in vitro and in vivo studies.

Lately, there has been increasing interest in the benefits of metal-organic frameworks, and among them, zeolitic imidazolate frameworks (ZIF - 8) stand out as one of the most commonly employed systems owing to their unique characteristics.

Given that properties like particle size play a key role in biomedical applications of nanoparticles, optimizing the synthesis conditions becomes crucial. Additionally, it is essential to label these nanoparticles to track them effectively within the body.

Zeolitic imidazolate frameworks nanoparticles were synthesized under various conditions, including high and room temperature, using two different solvents: Water and methanol. Modifications were made to the reaction temperature and the ratio of reactants to improve the outcomes. Particle size and size distribution were assessed in all conditions. Additionally, the radiolabeling of nanoparticles was examined using four different methods to identify the method with the highest efficiency and radiochemical purity.

The optimum conditions for ZIF-8 synthesis were determined at 50°C using methanol as the solvent. A reactant weight ratio of 1: 2 (zinc nitrate to 2-methylimidazole) was utilized. The most effective radiolabeling approach involved using tin chloride as a reducing agent, with the reaction mixture maintained at a temperature of 70°C for 30 minutes.

In this study, the optimum conditions were successfully identified for synthesizing and labeling ZIF-8 nanoparticles. These nanoparticles have the potential to serve as effective carriers for diagnostic and therapeutic agents.

Femoral head necrosis (FHN) is a debilitating bone disease affecting an estimated 8 million people worldwide. Although specific drugs for FHN have limitations, targeted therapies have shown promising results. The significance of this study is underscored by the high prevalence of FHN, the limitations of current treatments, and the potential of targeted drugs and natural compounds for effective therapeutic interventions.

This study aimed to explore the genetic landscape and associated pathways of FHN through bioinformatics analysis of Gene Expression Omnibus (GEO) data and molecular docking simulations targeting specific enzymes implicated in FHN.

Differentially expressed genes (DEGs) in FHN samples were identified from GEO datasets, specifically accession number GSE123568 (Platform: GPL15207). Functional enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) to identify enriched pathways and Gene Ontology (GO) terms. Additionally, a protein-protein interaction (PPI) network was constructed using the STITCH (search tool for interaction of chemicals) database, which helped identify top hub genes and proteins. Molecular docking was conducted against key proteins using compounds from the topical chinese herbal medicine (TCHM) database associated with FHN.

The study provided a comprehensive bioinformatics analysis of key candidate genes and pathways associated with FHN, which may serve as potential therapeutic targets. It was found that FHN is associated with mitogen-activated protein kinases (MAP4K4/ MAPK8/ MAPK9) and interleukins (IL1b/ IL19/ IL26). Molecular docking results showed strong interactions of traditional Chinese herbal compounds through hydrogen bonding and electrostatic interactions at the active sites of the top ten target proteins associated with FHN.

The study confirmed that FHN is linked with enzymes such as mitogen-activated protein kinases (MAPKs), interleukins, tumor necrosis factors (TNFs), and VEGFA (vascular endothelial growth factor A). Molecular docking simulations demonstrated that hesperidin, naringin, and curcumin exhibit potent inhibition against key proteins involved in FHN. Future research will focus on elucidating the specific roles of genes associated with FHN and exploring potential therapeutic targets using natural compounds.

The increasing recreational use of ecstasy (MDMA) poses significant risks to human health, including reports of fatal renal failure due to its adverse renal effects. While MDMA-induced renal toxicity might result from systemic effects, there is also substantial evidence of direct harm to renal tissues by MDMA or its metabolites. The precise mechanisms underlying renal toxicity remain unclear. This study explored the impact of a single intraperitoneal dose of MDMA (20 mg/kg) on rat kidneys. Serum BUN and creatinine levels were evaluated to assess renal function, while TNF-α and TGF-β protein concentrations were measured using ELISA. mRNA levels of Bax, Bcl-xl, and Bcl-2 were quantified using quantitative RT-PCR. Additionally, apoptosis and histopathological changes in renal tissue were examined. Results showed a transient increase in serum BUN and creatinine in MDMA-treated rats. There were decreases in TNF-α and TGF-β levels in the renal tissue. Both pro-apoptotic Bax and antiapoptotic Bcl-xl gene expressions were significantly reduced, whereas Bcl-2 expression and apoptosis did not show significant changes. No structural alterations were observed in the renal tissues. Overall, this study suggests that the renal adverse effects of MDMA may be mediated through the disruption of cytokine pathways, with notable reductions in TGF-β possibly linked to decreased TNF-α levels.

Poultry red mites, or Dermanyssus gallinae, pose a threat to the welfare and productivity of laying hens. Moreover, the increasing resistance of these mites to conventional miticides highlights the urgent need for alternative treatment options. There are also documented cases of poultry red mite infestations in humans.

The primary objective of this study was to evaluate the efficacy of fluralaner against Dermanyssus gallinae infestation in hens.

Fluralaner was selected as a novel treatment for poultry red mite due to its effectiveness and safety profile. The presence of live mites in the drinking water tank served as the indicator of infestation. Live mites were counted on nine occasions throughout the study. Fluralaner was administered at three doses of 0.5 mg/kg in drinking water with a seven-day interval between each dose. The efficacy of fluralaner was assessed, with an efficacy percentage exceeding 90% considered indicative of antiparasitic efficacy.

The overall efficacy of Fluralaner in the current study exceeded 90% by day 5 and reached 100% by day 17.

This study demonstrates that fluralaner is an effective alternative treatment, achieving efficacy rates exceeding 90% against poultry red mite infestation in laying hens.

To investigate the mechanisms of exercise therapeutics in preclinical animal models of chronic kidney disease (CKD), PAG (D, L-propargylglycine), an inhibitor of hydrogen sulfide production, was used to examine the protective effects of physical activity on oxidative stress and inflammation levels during CKD.

Male Wistar rats with CKD, induced by the 5/6 nephrectomy procedure and subjected to 8 weeks of exercise training, received injections of PAG, a cystathionine γ-lyase (CSE) inhibitor, at a dose of 19 mg/kg, i.p., twice a week during those 8 weeks. The systolic blood pressure (BP) and renal sympathetic nerve activity (RSNA) were assessed. Additionally, plasma creatinine, BUN, renal hydrogen sulfide (H2S) levels, oxidative stress, and inflammatory markers were evaluated.

In the PAG group, inhibition of H2S production significantly reversed the improvements in plasma creatinine, BUN, renal malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, TNF-α, and IL-6 that were achieved by exercise. Additionally, high RSNA and high BP, which were also reversed in the PAG group, compared to the CKD group subjected to exercise training.

The results suggest that the improvement in BP, oxidative stress, and inflammation status by exercise in CKD may be at least partially due to CSE/H2S signaling.

Providing data on the superior efficacy of vancomycin administered based on the area under the curve over 24 hours to the minimum inhibitory concentration of vancomycin (AUC24/MIC) is crucial. However, data on dosing and monitoring of vancomycin pharmacokinetics in the pediatric population are limited. Previous findings have showed that intermittent infusion of vancomycin (IIV) may not achieve the desired levels, continous infusions of vancomycin (CIV) reach the desired serum concentration faster than IIV and are associated with reduced nephrotoxicity.

This study aimed to compare the serum concentrations, AUC24, clinical variables, and adverse effects of two vancomycin administration methods in the pediatric population.

This study was a double-blind, randomized, controlled clinical trial conducted at a tertiary children's teaching hospital. Inclusion criteria were age between 2 months and 15 years and weight less than 67 kilograms, with exclusion criteria including renal impairment. Participants were divided into CIV and IIV groups following distinct administration protocols. Demographic, clinical, and laboratory data, including vancomycin serum concentrations, were compiled. Assessments included pediatric mortality risk, pediatric sequential organ failure assessment, and regular temperature monitoring. Pharmacokinetic analysis was conducted using Monolix software 2023R1. Primary endpoints were vancomycin serum levels and AUC24 between cohorts on day three, with nephrotoxicity and additional adverse drug responses evaluated.

Sixty-eight patients in the pediatric intensive care unit (PICU) were allocated to either CIV (33) or IIV (35) for vancomycin treatment. In the CIV group, 82% of patients achieved an AUC24 ≥ 400 mg.h/L, compared to 23% in the IIV group. Continuous infusions of vancomycin demonstrated a greater AUC24 (587.7 ± 184.4 mg.h/L vs. 361.9 ± 113.2 mg.h/L, P < 0.05) compared to IIV. Two cases of nephrotoxicity were reported, one in each group, with mortality and adverse events being comparable between the two groups.

This study demonstrated that continuous vancomycin infusion has a higher success rate in safely achieving therapeutic vancomycin levels in PICU patients compared to intermittent vancomycin infusion.

Migraine is a prevalent, chronic neurovascular disorder that incurs significant indirect costs due to productivity loss. Preventive therapy is an effective way to alleviate the societal and healthcare burden of migraine. Approximately 14% of both the global and Iranian populations are affected by migraine, which has substantial economic implications.

To determine the cost-effectiveness of Erenumab compared to Topiramate for migraine treatment in Iran.

A three-state Markov model was used to evaluate the cost-effectiveness of Erenumab. The model considered both direct and indirect costs from a societal perspective. The incremental cost-effectiveness ratio (ICER) was calculated by determining the cost per quality-adjusted life year (QALY) gained. Costs and QALYs were discounted annually at 5.8% and 5%, respectively. Deterministic and probabilistic sensitivity analysis (PSA) were performed to assess the robustness of the model.

The average cost for patients using the Erenumab strategy was 16,836 USD over five years, whereas the average cost for the Topiramate strategy was estimated to be 2,660 USD. Additionally, the average QALYs for the Erenumab and Topiramate strategies were 3.64 and 3.46, respectively. The ICER for the Erenumab strategy was 78,923 USD/QALY. This ICER is significantly higher than the fixed Iranian willingness-to-pay (WTP) threshold of 2,456 USD.

The study concludes that preventive treatment of migraine with Erenumab, compared to Topiramate, is not costeffective in Iran based on current prices. Therefore, for Erenumab to be considered cost-effective, a significant price reduction is necessary for its entry into the Iranian pharmaceutical market.

Doxorubicin (DOX) is used in the treatment of various cancers and has good effectiveness. However, its therapeutic use is limited due to its effects on various organs and healthy cells. Doxorubicin can affect the kidneys and cause toxicity. Evidence shows that DOX induces nephrotoxicity through oxidative stress.

In this research, we examined the effect of mitochondrial transplantation on improving mitochondrial and cellular toxicity caused by DOX on renal proximal tubular cells (RPTCs).

The research measured 7 toxicity parameters, including cell lysis, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) decline, GSH and GSSG content, lipid peroxidation (LPO), adenosine triphosphate (ATP) content, and Caspase-3 activity (the final mediator of apoptosis). Active fresh mitochondria were prepared from Wistar rat kidney.

The findings indicated that DOX caused cytotoxicity in RPTCs. Additionally, DOX induced oxidative stress by increasing the level of reactive oxygen species, reducing glutathione content, and elevating lipid peroxidation. Moreover, it led to damage to the mitochondrial membrane, increased caspase-3 activity, and decreased ATP content. Mitochondrial transplantation, as a new therapeutic approach, reduced oxidative stress, mitochondrial membrane damage, and apoptosis caused by DOX in RPTCs. Furthermore, this therapeutic approach increased the ATP content in RPTCs.

Our study suggests that this therapeutic approach could be helpful in the treatment of drug-induced nephrotoxicity.

Osbeckia opipara, a traditional Miao medicine, is commonly used by the renowned national-level Chinese Traditional Medicine practitioner Zhengshi Wu for the treatment of diarrhea due to its strong antioxidative, anti-inflammatory, and antidiarrheal effects. This study aimed to establish a high-performance liquid chromatography (HPLC) fingerprint for O. opipara to provide new evidence and technical means for the scientific evaluation and effective quality control of O. opipara. The procedure involved isolation with a Nano ChromCore C18 column (250 mm × 4.6 mm, 5 μm), using a gradient elution of 0.1% formic acid in water and 0.1% formic acid in acetonitrile as the mobile phase, with a flow rate of 1.0 mL/min, a column temperature of 30°C, an injection volume of 10 μL, and detection at a wavelength of 254 nm. Under these chromatographic conditions, fingerprint analysis was conducted on 11 batches of O. opipara collected from different origins. The National Pharmacopoeia Committee developed the 'Chromatographic Fingerprint Similarity Evaluation System' (2004A version) for automated comparison, similarity computation, and analysis of chromatographic data. The results revealed 13 common peaks across the 11 batches of O. opipara samples, with a similarity to the automatically generated reference spectrum exceeding 0.9. SPSS 26.0 software was used to conduct cluster analysis on the peak areas of the 13 common peaks. The observations indicated that the reference spectrum generated from the 11 batches could serve as the standard fingerprint profile for O. opipara, providing sufficient characteristic information extraction.

Despite the availability of tetanus-diphtheria (TD) vaccines in Iran, the seroconversion rate of these products as a booster dose is unknown.

This study evaluates the seroconversion rate of the Iranian Td vaccine in adults who have not been vaccinated in the past decade.

In this study, 20 adult volunteers aged 18 to 60 who had not received the Td vaccine in the past decade received a booster dose of the Iranian Td vaccine. Twenty-eight days after vaccination, the seroconversion rate was evaluated using the ELISA method. Vaccine adverse events were monitored at three time points after vaccination.

Seroconversion rates with the Iranian Td vaccine boosters were 75% and 90%, respectively, based on a 4-fold increase in anti-tetanus toxoid antibody titers and a 2- and 4-fold combination. Significant associations were found between the demographic data, specifically female gender and age 43 years and older, with seroconversion rates. Injection-site pain was the most common adverse reaction, with a frequency of 35%. No adverse events were reported between one week and one month after vaccination.

Results showed that a booster dose of the Iranian Td vaccine produced a protective titer (> 0.1 IU/mL) and a longterm protective titer (> 1.0 IU/mL) in 100% of participants. The seroconversion rate of the Iranian Td vaccine was comparable to other common tetanus vaccines, including Tenivac®, Adacel®, Infanrix ®, Tetavax ®, and Vacteta®. The proportion of suitable candidates for plasma donation, based on minimum (2 IU/mL) and maximum (10 IU/mL) anti-tetanus toxoid antibody titers, was 100% and 45%, respectively.

Calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors are essential for maintaining transplanted organs. However, determining the appropriate dosage and predicting blood concentrations of these drugs based solely on net body weight may be inadequate. Previous studies have presented contradictory results regarding the impact of obesity on drug concentrations and transplant success.

This study aims to evaluate various weight indices to identify the most reliable indicator of weight that correlates with the blood levels of drugs used in organ transplantation.

This retrospective descriptive study included patients from nephrology clinics affiliated with Isfahan University of Medical Sciences who were taking calcineurin and/or mTOR inhibitor drugs. Data extracted from medical records included demographic and clinical information, such as height, weight, and various weight indices (total/ideal/adjusted body weight, lean body mass (LBM), Body Mass Index, and predicted normal weight), as well as blood levels of immunosuppressive drugs at each patient's visit. The dosages of each drug (mg/kg) were analyzed to determine which weight indices best correlated with the obtained blood concentrations, using the Generalized Estimating Equation (GEE) model with logistic regression, an independent correlation matrix, and a binary distribution for data analysis.

The study analyzed the medical records of 71 patients. Trough (C0) concentrations of drugs were evaluated in relation to each weight index, and odds ratios (OR) were calculated for statistical comparison. All weight indices increased the likelihood of achieving appropriate concentrations for cyclosporine, tacrolimus, and sirolimus. Drug dosing based on LBM (OR: 1.028), ideal body weight (OR: 1.075), and total body weight (OR: 1.041) showed the strongest correlations with achieving proper blood levels for cyclosporine, tacrolimus, and sirolimus, respectively.

Integrating various weight indices for calculating individualized doses (mg/kg) of each immunosuppressive drug increases the likelihood of achieving appropriate blood concentrations. However, the optimal weight index varies for each drug. Further studies, particularly those incorporating therapeutic drug monitoring (TDM) plans in transplant centers, are warranted to validate and generalize these findings, providing a potential avenue for improving immunosuppressive therapy and enhancing transplant outcomes.

Alprazolam, a commonly prescribed benzodiazepine, poses risks of toxicity and severe withdrawal symptoms. There is an urgent need for a rapid and sensitive diagnostic method for detecting alprazolam poisoning.

This study aimed to detect alprazolam poisoning through Fourier-transform infrared (FTIR) analysis of saliva, addressing the need for a quick, cost-effective, and sensitive diagnostic method for poison control and differential diagnosis.

Saliva samples were collected from 45 individuals with benzodiazepine toxicity, therapeutic consumption, and normal health status, as well as from a control group. The samples were analyzed using FTIR spectroscopy. The resulting spectra were processed with OriginPro software, and statistical analyses were performed using receiver operating characteristic (ROC) and analysis of variance (ANOVA).

The average age of the studied population was approximately 45 years, with women being the most affected by poisoning. Fourier-transform infrared analysis revealed significant differences in the structure of lipids between poisoned individuals, therapeutic receivers, and healthy individuals (P < 0.0001).

Fourier-transform infrared analysis of saliva is a fast and accurate method for diagnosing alprazolam poisoning within minutes, enabling prompt and appropriate treatment during critical life-threatening situations. This non-invasive technique has the potential to guide treatment staff toward effective treatment options.

Vaccine adjuvants are components that enhance immune responses to an antigen. Given the importance of adjuvants, research on novel adjuvants with higher efficacy and fewer adverse effects remains crucial. Spirulina (Arthrospira sp.), an aqueous, photosynthetic, filamentous, spiral, multicellular microalga also classified as a cyanobacterium, is well known for its high protein content, vitamins, essential fatty acids, and amino acids. Cphycocyanin (C-PC) is one of the most significant proteins in Spirulina.

This study aimed to investigate the adjuvant capabilities of three Spirulina-derived substances—Spirulina extract, C-phycocyanin (C-PC), and phycocyanobilin (PCB)—in conjunction with the Hepatitis B surface antigen (HBsAg).

Vaccine groups received the vaccine and adjuvants three times at two-week intervals, administered either orally or by injection in encapsulated or naked forms. To use the injectable form while preventing antigenic effects from the C-PC protein portion, the PCB portion was isolated and used as an injectable adjuvant.

The highest levels of interferon gamma (IFN-γ) and interleukin 4 (IL-4) stimulation were observed in the naked PCB form with the vaccine. In both oral and injectable forms of PCB and C-PC, results indicated an increased expression of Hepatitis B surface antibodies (HBsAb) in response to the antigen. The absence of a significant difference between C-PC and Spirulina extract in oral form suggested that the adjuvant effect of this microalga was primarily due to the C-PC compound. Additionally, the injectable form of PCB led to the highest HBsAb expression level. This enhancement of the humoral immune response indicated that these compounds have potential as adjuvants in both oral and injectable forms.

These findings suggest the potential for improved Hepatitis B vaccine efficacy with this novel adjuvant, paving the way for further evaluation with other vaccines.

Malaria parasites have gradually developed resistance to commonly used antimalarial drugs. For decades, chloroquine was the most widely used drug to eradicate malaria. However, with the spread of chloroquine resistance, many countries have adopted combination therapies that utilize two drugs acting synergistically instead of monotherapy. In this study, the synergistic effect of chloroquine and the semipolar extract of Artemisia kopetdaghensis. Semipolar extract (SPE) was investigated in vivo through pathological and parasitological studies on mouse model.

Sixty female Balb/c mice infected with the Plasmodium berghei (P. berghei) parasite were treated with different concentrations of the semipolar extract of Artemisia kopetdaghensis (SPE) according to the protocol. The mean percentage of parasitemia, the mean survival time of the mice, the serum levels of IFN-γ, IL-4, IL-17, and TGF-β, and the effects of the SPE on the kidney, spleen, and liver tissues were investigated and compared across different treatment groups. The data were analyzed using Bonferroni, ANOVA, and Tukey tests.

The semipolar extract of Artemisia kopetdaghensis (SPE) demonstrated better therapeutic effects in both synergistic and monotherapy conditions compared to chloroquine alone. The combination of chloroquine and SPE resulted in the lowest parasitemia rate, the highest percentage of parasite inhibition, and the longest average survival time. Pathological studies showed no signs of acute toxicity in the organs.

This study demonstrated that using chloroquine in combination with Artemisia kopetdaghensis semipolar extract has synergistic effects in reducing parasitemia, enhancing the inhibitory effect on parasite growth and reproduction, and balancing the host immune system.

High mobility group box 1 (HMGB1) plays an essential role in various pathological conditions, including inflammation, fibrosis, autoimmune diseases, and carcinogenesis. The quantification of HMGB1 in body fluids holds promise for clinical applications.

This study aimed to isolate high-affinity single-stranded DNA (ssDNA) aptamers that target HMGB1.

In this study, ssDNA aptamers were selected using Systematic Evolution of Ligands by Exponential Enrichment (SELEX). The affinity and specificity of the aptamers were evaluated through South-Western blot analysis, enzyme-linked aptamer sorbent assay (ELASA), and aptamer-based histochemistry staining. The impact of the aptamers on the biological activity of HMGB1 was tested in the human acute monocytic leukemia cell line, THP-1.

An aptamer (H-ap25, dissociation constant = 8.20 ± 0.53 nmol/L) with high affinity for the HMGB1 B box was generated. Further experiments verified that H-ap25 can be used to detect HMGB1 in South-Western blot analysis, ELASA, and aptamer-based histochemistry staining. Moreover, H-ap25 significantly augmented HMGB1-induced expression of tumor necrosis factor-α (TNF- α), interleukin (IL)-1β, IL-6, Toll-like receptor 9 (TLR9), and activation of NF-κB in THP-1 cells.

Our results demonstrated that H-ap25 can be used both as an enhancer of HMGB1 and as a probe in research.

This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and their potential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated from Euphorbia malleata and explore their cytotoxic properties.

Euphorbia malleata was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract was chromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected based on 1H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. The isolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of the isolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both in mono and combination treatments with cisplatin.

Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two new premyrsinane diterpenes (Malleatin A and Malleatin B) alongside two known compounds (beta-sitosterol and loliolide). Malleatin A exhibited cytotoxicity against A2780 wild and A2780 R-CIS cells, with an IC50 range of 50 - 65 μM in the MTT assay. While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIS cells due to their resistance. However, the combination therapy of Malleatin A and cisplatin exhibited a synergistic effect, significantly increasing the mortality rate of the resistant cells compared to monotherapy. The Combination Index (CI) of 0.58 indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatin needed, potentially reducing its associated side effects.

Chronic kidney disease (CKD), which progresses to end-stage renal disease (ESRD) and requires maintenance hemodialysis (MHD), is a global health issue. Inflammation in MHD patients is associated with increased mortality and cardiovascular events. Zinc, essential for immune function and possessing anti-inflammatory properties, is frequently deficient in these patients and could potentially help mitigate inflammation.

This study aims to assess the impact of zinc supplementation on inflammatory biomarkers, specifically (CRP) and the neutrophil-to-lymphocyte ratio (NLR), in MHD patients.

In a double-blind, randomized controlled crossover trial conducted at Labafinejad Hospital, Tehran, MHD patients with zinc deficiency were initially allocated to either a zinc supplementation group or a placebo group. After 30 days, the groups were crossed over, with patients initially receiving zinc now receiving a placebo and vice versa. The primary outcome was changes in serum zinc levels, while secondary outcomes focused on CRP and NLR levels.

Significant changes in serum zinc levels were observed in both groups from baseline to Month 2 (drug-placebo group: Mean change -15.9±10.33 μg/dL, P < 0.05; placebo-drug group: Mean change -14.70 ± 12.58 μg/dL, P < 0.05). A significant initial reduction in CRP levels at Month 1 (P = 0.045) was not sustained at Month 2 (P = 0.812). No statistically significant changes in NLR were noted. Improvements in quality of life, including reductions in muscle pain and skin dryness, were significant in the drugplacebo group (P < 0.05).

Zinc supplementation in MHD patients significantly improved serum zinc levels and initially reduced CRP levels, highlighting its potential role in managing inflammation. Although the impact on NLR was not significant, overall patient outcomes and quality of life showed promising improvements.

Diabetes mellitus (DM) is a chronic metabolic disorder that disrupts normal bone remodeling.

This study aimed to investigate how the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (LIR) addresses bone metabolism imbalances induced by type-II diabetes.

Type-II diabetic rat models were established through a single intraperitoneal injection of streptozotocin (STZ). Blood glucose levels were measured using a blood glucose meter, and insulin levels were assessed using an assay kit. Bone formation markers [alkaline phosphatase (ALP), osteocalcin (OCN), and procollagen I N-terminal propeptide (PINP)] and bone resorption markers [tartrate-resistant acid phosphatase (TRACP) and CTX-1] were monitored using assay kits. Bone marrow mesenchymal stem cells (BMSCs) were cultured in vitro under high-fat and high-glucose (HFHS) conditions to mimic diabetic bone metabolism dysregulation. Neutrophil extracellular traps (NETs) formation was examined through immunofluorescent staining and Western blot analysis.

Liraglutide was found to reduce STZ-induced NETs formation, as indicated by decreased expression of cit-H3 by 36.90% - 53.57%, myeloperoxidase (MPO) by 55.81% - 65.12%, NE by 53.95% - 65.17%, and PAD4 by 46.81% - 63.83%, alongside increased Sirtuin-1 (SIRT1) expression in femur tissue (70.71% - 91.19%). In vitro, LIR enhanced osteogenesis and inhibited apoptosis, effects that were partially reversed by SIRT1 knockdown. Additionally, SIRT1 knockdown partially restored LIR-induced reductions in oxidative stress, inflammation, and NETs formation.

LIR mitigates diabetes-induced bone metabolism imbalance by inhibiting NETs formation through SIRT1 mediation.

Helicobacter pylori is a significant contributor to a range of gastrointestinal conditions, with conventional treatment methods primarily relying on antibiotics. However, the rise of antibiotic-resistant strains has necessitated the exploration of alternative therapeutic approaches.

To determine the in vitro antibacterial potential of probiotic bacteria (Lacticaseibacillus rhamnosus BLRH 260 and Limosilactobacillus reuteri) and four propolis extracts against H. pylori and to analyze their impacts on body weight index and histopathological changes in H. pylori-challenged Wistar rats.

The inhibitory effects of probiotic bacteria (L. rhamnosus BLRH 260 and L. reuteri) and propolis extracts on the growth of H. pylori were evaluated using an agar well diffusion assay. In vivo analysis involved fifty-four male Wistar rats (200 - 250 g) infected with an H. pylori suspension (108 CFU/mL) and orally administered propolis or probiotics (108 CFU/mL) via gavage for 21 days. The effects of different treatments on body weight and histopathological changes in gastric tissue samples were assessed, and the results were statistically analyzed.

The tested propolis extracts and the supernatant fluids from the mentioned probiotic strains showed significant antibacterial activity against H. pylori in the agar well diffusion assay, with notable variations. In vivo, the findings demonstrated that oral administrations of propolis and probiotics, either separately or in combination, led to significant increases in body weight and amelioration of histopathological changes in gastric tissue samples, particularly in terms of erosion depth, hemorrhagic inflammation, and apoptosis in the infected animals. Histopathological differences between antibiotic-treated animals and those receiving other treatments were observed, with significant differences.

The results of this study underscore the potential therapeutic benefits of propolis and probiotics in addressing H. pylori-induced gastropathy. Additional research is necessary to clarify the mechanisms involved and to refine dosage and treatment protocols for optimal effectiveness.

Hormonal imbalances related to women's health, physical activity, and fluctuations are prevalent metabolic disorders in several nations and have significantly impacted women's health for an extended period. The application of individual or combined botanical extracts in traditional, alternative, and complementary medicine is employed to manage and alleviate these issues.

The objective of this study is to examine the suppressive properties of horehound (Marrubium vulgare L.) on pivotal hormones associated with feminine disorders.

The horehound plant was exposed to ultrasonic radiation while five different solvents (methanol, ethyl acetate, nhexane, acetone, and water) were used to extract its components. The individuals were isolated using high-performance thinlayer chromatography (HPTLC). The most powerful compounds were analyzed using a direct antioxidant assay (DPPH test) and a hormone inhibitory assay (Oestrogen, Progesterone, Estradiol, and Testosterone) on the HPTLC plate. The compounds that had a significant effect were then identified using LC-ESI/MSMS.

The antioxidant properties of the extracts and hormone inhibitors were evaluated, and the substances were separated from the HPTLC plate and analyzed using mass spectrometry. The results showed strong antioxidant capabilities, with an IC50 range of 8.24 - 12.42 μg/mL. Moreover, the plant extract showed beneficial effects on hormones associated with female health issues.

The extract was subjected to chemical and molecular analysis using the HPTLC technique, followed by LCESI/ MSMS. The study revealed the presence of vulgarole, marrubiin, and marrubenol chemicals.

Herbal compounds sourced from various plants are becoming targeted therapies for breast cancer.

This study aims to explore the potential of focusing on herbal compounds as targeted therapies for breast cancer using computational techniques.

A total of 129 herbal compounds linked with breast cancer were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. Molecular docking and MD simulation were carried out against three protein targets linked with breast cancer. Network pharmacology was used to identify the common plant sources for the bioactive compounds, and interaction networks were constructed. The ADME-toxicity profiles and density functional theory (DFT) analysis were calculated for the top docking hits.

Dipiperitylmagnolol and sophoranone were identified as the top docking hits and lead compounds. Network pharmacology analysis revealed Magnolia species as the common plant sources having multiple bioactive compounds. MD simulation analysis revealed conformational stability of the top docking hits. The analyses underscore the robust binding potential of dipiperitylmagnolol and its possible therapeutic relevance in targeting breast cancer pathways. ADME-toxicity and DFT analysis provided insights into the pharmacokinetic and electronic behavior of the top docking hit. Combinatorial study of herbal therapies with conventional treatments will increase the therapeutic efficacy for breast cancer treatment.

The study provides insights into the implications of herbal compounds as targeted therapy for breast cancer. Therefore, the study recommends further experimental validation and development of herbal-based compounds for the treatment of breast cancer.

The positive effects of growth hormone (GH) on the endometrium, including increased endometrial blood supply and enhanced expression of cytokines associated with endometrial receptivity, have been noted. However, data on the effect of GH on the endometrium remain limited.

This study aimed to investigate the effect of intrauterine administration of GH on the IVF success rate in women with recurrent implantation failure (RIF).

This randomized double-blind clinical trial was conducted on 60 infertile women under 40 years old with a Body Mass Index (BMI) below 30 kg/m², all diagnosed with RIF—defined as at least three failed pregnancies after transferring a minimum of four good-quality embryos due to unknown causes. Women with uterine malformations, Asherman syndrome, cavity-distorting lesions, severe endometriosis, or other underlying diseases were excluded. After six days of estrogen therapy, transvaginal ultrasound (TVS) was performed to measure and compare the thickness and quality of the endometrium. Participants were divided into two groups. In the intervention group, 10 units of GH were administered using an IUI catheter positioned one centimeter above the cervical os. Study outcomes included changes in endometrial thickness (ET) and quality, as well as pregnancy rates. Primary endpoints were changes in ET and quality, while secondary endpoints were pregnancy rates. Adverse drug responses were also evaluated.

The mean age was 34.96 ± 4.04 years, and the mean BMI was 24.89 ± 2.91 kg/m², with no significant differences in baseline variables between the study groups. The average ET on the 8th day of the cycle was 5.38 ± 0.96 mm in the intervention group and 5.20 ± 0.80 mm in the control group, showing no significant difference (P = 0.467). The ET on the day of initiating progesterone was 7.60 ± 1.03 mm in the intervention group and 7.40 ± 0.60 mm in the control group, with no significant difference (P = 0.264). The odds ratio for achieving a high-quality endometrium was 2.37 (95% CI 0.80 - 6.98, P = 0.116) for the GH group compared to the non-GH group. The odds ratio for achieving a clinical pregnancy was 3.06 (95% CI 0.54 - 17.37, P = 0.205) for the GH group compared to the non-GH group. Two cases of cervicitis were reported in the GH group.

Intrauterine administration of GH appears to enhance endometrial receptivity in women with RIF.

Hormone therapy is commonly used to treat breast cancer but can cause mood disorders and sleep disturbances, negatively impacting patients' well-being.

This trial aimed to evaluate the effects of melatonin on sleep problems and mood changes in breast cancer patients undergoing hormone therapy.

The study was conducted at Omid Hospital in Isfahan, Iran, using a randomized, double-blinded, placebo-controlled design. Participants were assessed using the Hospital Anxiety and Depression Scale (HADS) and were randomly assigned to receive either 6 mg of melatonin or a placebo daily for 4 weeks. Sleep quality, depression levels, and mood states were measured using the Pittsburgh Sleep Quality Index (PSQI), the Center for Epidemiological Studies-Depression Scale (CES-D), and the Profile of Mood States (POMS) Questionnaires at the beginning and end of the 4-week follow-ups.

Sixty participants (34 in the melatonin group and 26 in the placebo group) completed the study. Melatonin administration significantly improved sleep quality, latency, duration, and reduced the use of sleep-promoting medication, according to the PSQI scores. However, there were no significant improvements in depression severity or mood disorders, as assessed by the CES-D and POMS questionnaires, in either group following the 4-week melatonin supplementation period.

Melatonin supplementation effectively alleviated sleep disturbances caused by hormone therapy in breast cancer patients. However, the study did not find substantial evidence supporting the use of melatonin for improving mood disorders or depression in this specific context.

Biliverdin reductase (BVR) plays a central role in bile pigment metabolism by reducing biliverdin (BV) to bilirubin (BR), a potent antioxidant that scavenges reactive oxygen species (ROS) under normal and pathological conditions. Elevated oxidative stress activates extracellular signal-regulated protein kinases 1/2 (ERK1/2) signaling, which strongly interacts with BVR’s C and D motifs, forming the BVR/ERK1/2 axis. In pathological states, increased ERK1/2 activity inhibits BVR’s ability to convert BV to BR, exacerbating oxidative damage and contributing to cardiovascular disease. Therefore, the interaction between BVR and ERK1/2 is critical in modulating oxidative stress.

This study aimed to evaluate the effects of BR and the ERK1/2 inhibitor PD-98059, both individually and in combination, on ROS levels, ERK1/2 activity, and vascular responses under normoxic and hypoxia-reoxygenation (H-R) injury conditions.

Aortic rings from rats were subjected to equal distending pressure after oxidative stress induction using 22'-Azobis (2-amidinopropane) dihydrochloride (ABAP) in an organ bath. Different doses of BR were administered in combination with the ERK1/2 inhibitor PD-98059 to assess their impact on ROS depletion, vascular relaxation, and maximal effect (Emax).

The combination of BR and PD-98059 significantly enhanced aortic relaxation and Emax under both normoxic and H/R conditions compared to either treatment alone. Inhibiting ERK1/2 with PD-98059 appeared to upregulate BVR activity, increasing BR synthesis and reducing oxidative damage in aortic rings.

Biliverdin reductase plays a vital role in defending against oxidative stress and endothelial dysfunction through its dual-specificity kinase activity and interaction with ERK1/2. ERK1/2 inhibition further enhances BR’s ROS-scavenging ability and vascular protective effects. Targeting the interaction between BVR and ERK1/2 holds potential as an effective therapeutic strategy for conditions characterized by excessive ROS levels, such as cardiovascular diseases.

Cerebral ischemia/reperfusion (I/R) injury is the most prevalent form of brain stroke, affecting many patients worldwide. It is believed that oxidative stress and inflammation play major roles in the damage that occurs after the initiation of the disease.

Therefore, for the first time, the current study aimed to investigate the neuroprotective effects of bupropion against cerebral I/R damage in a rat model.

Forty male rats were divided into four groups: Control, cerebral I/R, and two diseased groups that received 60 and 100 mg/kg of bupropion. One day after induction of the disease, behavioral tests, including grid walking, novel object recognition, and modified neurological severity score (mNSS), were performed on the rats. The levels of inflammatory cytokines, including IL-1β, TNF-α, IL-6, and IL-10, were measured in the rats' brain homogenates. Additionally, the levels of MDA, catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), and NO2 - were measured.

Bupropion administration was associated with improved performance in the novel object recognition and grid walking behavioral tests, as well as in the neurological disorder scores, in cerebral I/R rats. Moreover, BCAAO-induced inflammation was reduced by the administration of this drug, evidenced by reduced levels of cytokines IL-1β, TNF-α, and IL-6 and upregulation of IL-10. Additionally, membrane lipid peroxidation was reduced in the cerebral I/R rats receiving 100 mg/kg bupropion, and the level of SOD activity was improved in these animals. Finally, the administration of bupropion prevented the increase in NO2 - levels induced by BCAAO.

In conclusion, bupropion has neuroprotective effects against cerebral I/R damage by reducing inflammation and oxidative stress in the brain.

Obesity, a rising global health issue, is linked to numerous disorders, including cognitive impairment.

This study investigates the effects of coenzyme Q10 (Co-Q10) on cognitive performance, antioxidant defense,cholinergic activity, and hippocampal neuron damage in rats rendered obese by monosodium glutamate (MSG) exposure.

Forty-eight neonatal male Wistar rats were randomly assigned to one of four groups: Control, MSG, MSG + Q10-10,and MSG + Q10-20. Monosodium glutamate (4 g/kg BW) was administered subcutaneously into the cervical region frompostnatal day (PND) 2 to PND 10. Coenzyme Q10 (10 mg/kg BW and 20 mg/kg BW) was administered intraperitoneally from PND30 to PND 42. At the end of the treatment period, working memory and avoidance learning tests were conducted.Anthropometric data were collected, followed by evaluations of hippocampal catalase (CAT), superoxide dismutase (SOD),acetylcholinesterase (AChE), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels. The density of apoptotic/darkneurons (DN) in the CA₁ and CA₃ regions of the hippocampus was also assessed.

Monosodium glutamate treatment increased Body Mass Index (BMI) and Lee Index, impaired working memory andavoidance learning, and reduced CAT, SOD, and GPx activities. Additionally, MSG exposure led to elevated MDA levels, increasedAChE activity, and higher DN density in the CA₁ and CA₃ hippocampal regions. Treatment with Co-Q10 resulted in a decrease inBMI, enhanced memory and learning, noteworthy increases in CAT, SOD, and GPx activities in the hippocampus, and reductionsin MDA levels, AChE activity, and DN density in the CA₁ and CA₃ regions.

Coenzyme Q10 mitigates hippocampal neuronal damage and improves cognitive function in MSG-inducedobesity, primarily through its antioxidant and AChE inhibitory properties.

Cancer is a devastating disease with varying mortality rates and severe treatment side effects. Researchers are exploring alternative treatments that target cancer cells with high selectivity and minimal side effects. Photothermal therapy has shown promise as one such treatment option.

Single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) can penetrate cellular membranes and convert near-infrared light into heat for photothermal therapy (PTT).

In a recent study, carbon nanotubes (CNTs) were used in combination with PTT to treat HT29 and PCL/PRF/5 cancerous cells for different durations (6, 12, 24, 48, and 72 hours). The cytotoxicity of each treatment was evaluated through MTT assay, reactive oxygen species (ROS) analysis, lipid peroxidation, lysosomal membrane integrity, and protein carbonyl analysis.

The study found that SWCNTs, MWCNTs, and PTT each individually had a significant cytotoxic effect on cancer cells. However, when used together, they were even more effective in destroying cancer cells. Combining SWCNTs with PTT resulted in the highest level of cytotoxicity.

These findings suggest that using CNTs, especially SWCNTs, in combination with PTT shows promise for treating cancer.

The inefficiency of some medications to cross the blood-brain barrier (BBB) is often attributed to their poor physicochemical or pharmacokinetic properties. Recent studies have demonstrated promising outcomes using machine learning algorithms to predict drug permeability across the BBB. In light of these findings, our study was conducted to explore the potential of machine learning in predicting the permeability of drugs across the BBB. We utilized the B3DB dataset, a comprehensive BBB permeability molecular database, to build machine learning models. The dataset comprises 7,807 molecules, including information on their permeability, stereochemistry, and physicochemical properties. After preprocessing and cleaning, various machine learning algorithms were implemented using the Python library Pycaret to predict permeability. The extra trees classifier model outperformed others when using Morgan fingerprints and Mordred chemical descriptors (MCDs), achieving an area under the curve (AUC) of 0.93 and 0.95 on the test dataset. Additionally, we conducted an experiment to train a voting classifier combining the top three performing models. The best-blended model, trained on MCDs, achieved an AUC of 0.96. Furthermore, Shapley additive exPlanations (SHAP) analysis was applied to our best-performing single model, the extra trees classifier trained on MCDs, identifying the Lipinski rule of five as the most significant feature in predicting BBB permeability. In conclusion, our combined model trained on MCDs achieved an AUC of 0.96, an F1 Score of 0.91, and an MCC of 0.74. These results are consistent with prior studies on CNS drug permeability, highlighting the potential of machine learning in this domain.

Breast cancer is the most common cancer among women worldwide, impacting not only the patients but also their families and communities. Tournefortia mutabilis vent. is a plant endemic to Mexico, traditionally used in Zapotec medicine for the treatment of cancer.

This study aims to evaluate the effects of the chloroformic extract of T. mutabilis vent. leaves on cell proliferation and cell death in MCF-7 cells.

The effect of the extract on MCF-7 cell proliferation was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) and crystal violet staining. Apoptosis was evaluated through fluorescein diacetate/propidium iodide staining and caspase-3, -6, and -9 activity assays.

The half-maximal inhibitory concentration (IC50) of the T. mutabilis vent. extract on MCF-7 cell proliferation at 48 hours and 72 hours after treatment was 86.4 μg/mL and 2.74 μg/mL, respectively. We observed that the extract and its semi-purified fractions induced cell death through the activation of caspases 3, -6, and -9.

Tournefortia mutabilis vent. is a potential source of compounds with antiproliferative and pro-apoptotic activities on the MCF-7 cell line, primarily through the intrinsic pathways of apoptosis.

Dry eye disease (DED) is a multifactorial condition characterized by ocular surface inflammation, tear film instability, and corneal epithelial damage. Current treatments often provide temporary relief without addressing the underlying inflammatory mechanisms.

This study examined the therapeutic potential of crocin and nobiletin, two naturally derived compounds with wellknown antioxidant and anti-inflammatory properties, in a mouse model of DED induced by lacrimal gland excision (LGE).

Thirty female Balb/c mice were divided into five groups (n = 6 each): Control (sham surgery), untreated DED, nobiletin-treated DED (32.75 μM), crocin-treated DED (34 μM), and 1% betamethasone-treated DED. Treatments were administered three times daily for 28 days. Ocular tissues were evaluated using Hematoxylin and Eosin (H&E) staining and fluorescein staining. Conjunctival inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α), were measured by enzyme-linked immunosorbent assay (ELISA).

Histological analysis showed that the crocin and nobiletin treatment groups exhibited reduced epithelial disruption, keratinization, and inflammatory cell infiltration compared to the untreated DED group. The ELISA assay revealed that both compounds efficiently inhibited the production of the pro-inflammatory cytokines IL-6, TNF-α, and IL-1β, which are key mediators of DED pathogenesis. Fluorescein staining further confirmed the protective impact of crocin and nobiletin on corneal epithelial integrity. Moreover, the anti-inflammatory and epithelial-preserving effects of these compounds were comparable to those of the corticosteroid betamethasone.

Overall, these findings suggest that crocin and nobiletin have therapeutic potential for DED management by modulating inflammatory responses and enhancing ocular surface healing. These naturally derived compounds offer promising avenues for the development of safer and more effective treatments for this challenging condition. However, further investigations, including clinical trials, are essential to elucidate the underlying mechanisms of action and optimize therapeutic approaches.

Hepatic fibrosis is a biological response characterized by the accumulation of extracellular matrix (ECM) during the wound healing process. Hepatic stellate cells (HSCs) play a pivotal role in fibrogenesis, transitioning from quiescent to myofibroblast cell types and leading to excessive ECM production. Platelet-derived growth factor (PDGF), a potent mitogen, is produced by activated HSCs, stimulating cell proliferation and migration.

This study aims to analyze the impact of Wharton's jelly mesenchymal stem cell (WJ-MSC)-derived exosomes on HSC activation induced by PDGF during liver fibrosis.

Hepatic stellate cells-T6 cells were treated with PDGF-BB for 24 hours to induce activation, followed by treatment with varying concentrations of WJ-MSC-derived exosomes (0, 25, and 50 μg/mL) for another 24 hours. The effects of exosome treatment on HSC activation were evaluated through flow cytometry, differentiation assays, dynamic light scattering (DLS), transmission electron microscopy (TEM), RT-PCR, and western blot analysis.

Our study yields promising results, highlighting the potential therapeutic effects of WJ-MSC-derived exosomes on liver fibrosis. The dose-dependent decrease in fibrotic markers such as α-SMA, COLA1, and phosphorylated AKT protein in PDGFBB- treated HSC-T6 cells suggests that WJ-MSC exosomes exert an anti-fibrotic effect by inhibiting HSC activation.

These findings suggest that exosomes derived from WJ-MSCs hold therapeutic promise for liver fibrosis treatment by targeting key pathways involved in HSC activation and fibrogenesis. Further investigation into the underlying mechanisms of this anti-fibrotic effect and the potential clinical applications of WJ-MSC-derived exosomes in liver fibrosis management is warranted.

Non-small-cell lung cancer (NSCLC) remains a deadly malignancy worldwide. Resistance to cisplatin (DDP) is a significant obstacle that limits the therapeutic efficacy in NSCLC patients.

This study investigated the role and mechanism of 24-dehydrocholesterol reductase (DHCR24) in DDP resistance in NSCLC cells.

24-dehydrocholesterol reductase levels, ferroptosis-related molecules, and proteins involved in the PI3K/AKT/GSK3β pathway were measured. The growth capacity of the cells was evaluated, and ferroptosis was assessed by measuring MDA, GSH, Fe2+, and ROS levels. The impact of DHCR24 on NSCLC DDP resistance was analyzed using a tumor xenograft assay in vivo. Ki-67 and DHCR24 expression in tumors were evaluated through immunohistochemical staining.

24-dehydrocholesterol reductase expression was elevated in DDP-resistant cells, indicating a poorer prognosis for NSCLC patients. Down-regulation of DHCR24 inhibited the growth of DDP-resistant cells and induced ferroptosis. Inhibition of DHCR24 led to the inactivation of the PI3K/AKT/GSK3β pathway and subsequent induction of ferroptosis. Inhibition of ferroptosis or activation of the PI3K/AKT/GSK3β pathway counteracted the increased DDP sensitivity induced by DHCR24 knockdown in NSCLC cells. Additionally, DHCR24 deficiency improved NSCLC DDP resistance in vivo.

24-dehydrocholesterol reductase contributes to DDP resistance in NSCLC cells by suppressing ferroptosis through the activation of the PI3K/AKT/GSK3β pathway.

Invasive cervical cancer is recognized as the second most common malignancy in women after breast cancer.

This study investigates, for the first time, the effect of gold nanoparticle-doped graphene oxide (GO) nanosheets on the human epithelial carcinoma (HeLa) cell line in the presence of heliox cold plasma.

Graphene oxide nanosheets were synthesized using the Hummer method and then doped with gold nanoparticles. The nanoparticles were characterized by transmission electron microscopy (TEM), and the diffraction peaks of GO and gold nanoparticles were confirmed through X-ray diffraction (XRD) analysis. Additionally, the optical absorbance of the nanoparticles was measured in the range of 200 - 900 nm using UV-Visible spectroscopy. A plasma generator was fabricated to produce cold plasma using helium (He) and oxygen (O₂) gases at a 99:1 ratio. The radicals generated by the cold plasma were analyzed via optical emission spectroscopy (OES). Cell treatment was conducted by applying various concentrations of GO and GO/Au nanoparticles. Cellular phenotype was monitored through optical microscopy, and biocompatible concentrations of both nanoparticles were determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Subsequently, cold plasma at varying distances and durations was applied to the nanoparticle-treated cells. The generated radicals and the expression of apoptotic genes in treated cells were assessed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and realtime PCR, respectively.

The width of the bacillus-like gold nanoparticles was 15.13 ± 0.96 nm. The cold plasma generated radicals such as N2I2⁺, N2II1⁻, He•, and O⁻•. XRD analysis confirmed the successful coupling of gold onto the GO nanosheets. The biocompatible concentrations of GO and GO/Au nanoparticles were found to be 30 μg/100 μL and 20 μg/100 μL, respectively, as determined by the MTT assay. Radical formation increased as incubation time was extended from 30 to 60 seconds. Furthermore, real-time PCR analysis demonstrated the highest levels of p53, Bax, and caspase 3/8 expression at a plasma exposure time of 60 seconds in the composite-treated group, while Bcl2 expression was significantly reduced.

The findings suggest that the parameters of heliox cold plasma and the concentrations of GO/Au nanoparticles must be optimized to effectively induce apoptosis in cervical cancer cells.

Toxoplasma gondii transmission can occur during pregnancy if the mother contracts the infection for the first time. Treatment strategies include the use of antimicrobial medications and providing supportive care. Spiramycin is commonly used to treat toxoplasmosis in pregnant women and to hinder the disease's transmission. However, its ability to treat the fetus is questionable due to its limited capacity to cross the placental barrier. Additionally, economic constraints and sanctions may impede access to this medication.

Consequently, in search of an effective treatment, for the first time in Iran, the effectiveness of clindamycin in preventing abortion and vertical transmission of the PRU strain of T. gondii infection in pregnant mice was evaluated.

On the twelfth day of gestation, pregnant mice were exposed to T. gondii and subsequently received treatment with either clindamycin or spiramycin. This resulted in the establishment of four distinct groups: A normal control group, an infected group without treatment, an infected group treated with clindamycin, and another infected group treated with spiramycin. Following these interventions, a series of parasitological evaluations (including microscopic examination and realtime PCR), histopathological evaluations, and immunological assessments were conducted.

The findings showed a significant reduction in the number of cysts in the eye and brain (ranging from 77.32% to 90.72%) among the groups treated with clindamycin and spiramycin compared to the control group. Furthermore, treatment with clindamycin, like treatment with spiramycin, was able to suppress inflammatory changes, prevent cell death, and reduce vascular cuffs in the brain, as well as decrease bleeding, placental thrombosis, and the accumulation of inflammatory cells in the placenta. Clindamycin was also effective in diminishing retinal folds, tiny retinal bleeds, and cell vacuolation in eye tissues. Immunologically, treatment in both the spiramycin and clindamycin groups resulted in a decrease in the level of the cytokine TNF-α, indicating an increase in the cellular immune response. In addition, increased levels of IL-10 in the treated infected groups could contribute to the reduction of TNF-α production.

Typically, spiramycin is the first choice for treating congenital toxoplasmosis, but clindamycin can be a useful substitute or additional treatment when resistance to primary medications occurs, when there is intolerance, or when access to the main drugs is restricted.

Artificial intelligence (AI) has revolutionized the pharmaceutical industry, improving drug discovery, development, and personalized patient care. Through machine learning (ML), deep learning, natural language processing (NLP), and robotic automation, AI has enhanced efficiency, accuracy, and innovation in the field. The purpose of this review is to shed light on the practical applications and potential of AI in various pharmaceutical fields. These fields include medicinal chemistry, pharmaceutics, pharmacology and toxicology, clinical pharmacy, pharmaceutical biotechnology, pharmaceutical nanotechnology, pharmacognosy, and pharmaceutical management and economics. By leveraging AI technologies such as ML, deep learning, NLP, and robotic automation, this review delves into the role of AI in enhancing drug discovery, development processes, and personalized patient care. It analyzes AI's impact in specific areas such as drug synthesis planning, formulation development, toxicology predictions, pharmacy automation, and market analysis. Artificial intelligence integration into pharmaceutical sciences has significantly improved medicinal chemistry, drug discovery, and synthesis planning. In pharmaceutics, AI has advanced personalized medicine and formulation development. In pharmacology and toxicology, AI offers predictive capabilities for drug mechanisms and toxic effects. In clinical pharmacy, AI has facilitated automation and enhanced patient care. Additionally, AI has contributed to protein engineering, gene therapy, nanocarrier design, discovery of natural product therapeutics, and pharmaceutical management and economics, including marketing research and clinical trials management. Artificial intelligence has transformed pharmaceuticals, improving efficiency, accuracy, and innovation. This review highlights AI's role in drug development and personalized care, serving as a reference for professionals. The future promises a revolutionized field with AI-driven methodologies.

The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 interacts with the angiotensinconverting enzyme 2 (ACE2) receptor in humans. To date, numerous SARS-CoV-2 variants, particularly those involving mutations in the RBD, have been identified. These variants exhibit differences in transmission, pathogenicity, diagnostics, and vaccine efficacy.

Although therapeutic agents are currently available to inhibit SARS-CoV-2, most provide supportive and symptomatic relief. Moreover, different variants may exhibit resistance to these treatments. This study aimed to identify a potential compound with favorable antiviral effects against SARS-CoV-2 variants.

The study explored drug discovery through structure-based virtual screening of natural products (NPs) from the StreptomeDB database, targeting the ACE2-binding pocket of the SARS-CoV-2 RBD protein. The analysis included the wild-type protein (PDB ID: 6VW1) as well as the Alpha, Beta, Delta, Lambda, Omicron/BA.1, and Omicron/BA.2 variants.

In silico screening identified ‘Stambomycin B’ as a potential compound with the highest binding affinity. Molecular dynamics simulations of the complexes, conducted over 100 ns, confirmed the prediction that ‘Stambomycin B’ could inhibit different SARS-CoV-2 variants effectively.

This study concludes that ‘Stambomycin B’, a macrolide compound produced by Streptomyces ambofaciens, may be a candidate NP for effectively combating all mutants that occur in the binding of SARS-CoV-2 RBD to ACE2, even those that may arise in the future.

Combining natural compounds with chemotherapeutic agents has emerged as a promising approach for cancer treatment. Curcumin (Cur), a natural polyphenol, is known for its anti-cancer properties, including the ability to induce apoptosis and arrest cell cycle progression.

This study aimed to evaluate the effects of Cur and etoposide (ETO), both individually and in combination, on the induction of apoptosis in breast cancer (BC) cell lines.

The impact of Cur and ETO on cell proliferation was assessed using MTT viability assays. Apoptosis induction by these drugs was evaluated through Annexin V flow cytometry and caspase-3 and caspase-9 activity assays. Quantitative real-time PCR was employed to measure Bax and Bcl-2 gene expression levels. Western blotting was conducted to determine protein levels of p53, p21, Bax, and Bcl-2.

A non-significant dose of ETO was selected based on MTT assay results and combined with 75 μM of Cur. Curcumin enhanced ETO’s pro-apoptotic effect by increasing caspase activities. The combination of Cur and ETO significantly reduced Bcl-2 gene expression while upregulating Bax expression. Furthermore, treatment with this combination elevated the protein levels of p53, p21, and Bax, compared to ETO or Cur alone, while significantly decreasing Bcl-2 protein levels.

Cur has the potential to amplify ETO-induced apoptosis in BC cells. This combination may offer a promising therapeutic approach for BC.

Cyclooxygenases (COX) play a pivotal role in inflammation and are responsible for the production of prostaglandins (PGs). Two types of COXs have been identified as key biological targets for drug design: Constitutive COX-1 and inducible COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) target COX-1, while selective COX-2 inhibitors are designed for COX-2. These COX isoforms are involved in multiple physiological and pathological pathways throughout the body. Overproduction of tumor necrosis factor-alpha (TNF-α) plays a role in COX-2's inflammatory activity. Tumor necrosis factor-alpha can contribute to cardiac fibrosis, heart failure, and various cancers by upregulating the COX-2/PGE2 axis. Therefore, suppressing COX activity has emerged as a potentially effective treatment for chronic inflammatory disorders and cancer. This review explores the mechanisms of TNF-α-induced COX-2/PGE2 expression, a significant pathophysiological feature of cancer development. Furthermore, we summarize chemical compounds with dual COX-2/TNF-α inhibitory actions, providing an overview of their structure-activity relationship. These insights may contribute to the development of new generations of dual-acting COX-2/TNF- α inhibitors with enhanced efficacy.

Atherosclerosis remains the leading cause of mortality worldwide, highlighting the urgent need for innovative treatments targeting chronic inflammation. Recent research indicates that quercetin (QCT) and curcumin, two naturally occurring compounds, have potential therapeutic benefits in cardiovascular diseases.

This study focuses on the novel synthesis of nano-quercetin (N-QCT) encapsulated in solid lipid nanoparticles (SLNs) and investigates the synergistic cardioprotective effects of N-QCT and curcumin on human vascular smooth muscle cells (VSMCs). The underlying molecular mechanisms, particularly the involvement of the TGF-β signaling pathway in VSMCs, are explored.

The VSMCs, including TGF-β-stimulated VSMCs, were treated with N-QCT, curcumin, or a combination of both. The MTT assay was performed to evaluate the cytotoxic effects of these treatments. The cytotoxicity of various concentrations of curcumin and QCT was used to calculate the Combination Index (CI), with CI analysis quantifying synergy or antagonism. Furthermore, following TGF-β stimulation, antioxidant enzyme activity, nuclear transcription factor erythroid 2-related factor (Nrf2) mRNA expression, reactive oxygen species (ROS) production, NADPH oxidases (NOX) expression, and extracellular signalregulated kinase (Erk)1/2 phosphorylation were measured in the treated VSMCs.

The N-QCT and curcumin significantly influenced Nrf2 mRNA expression and upregulated downstream antioxidant enzymes, including HO-1, GPx, and SOD1. The combination treatment further enhanced Nrf2 protein expression and modulated Erk1/2 phosphorylation. Notably, the synergistic effect of the combination produced pronounced cardioprotective outcomes, characterized by reduced ROS production and decreased phosphorylation of Erk1/2 via the TGF-β/NOX/Erk1/2 and ROS/Nrf2 signaling pathways.

The findings demonstrate that the combination of QCT encapsulated in SLNs and curcumin synergistically reduces oxidative stress and inflammation in TGF-β-stimulated VSMCs. This effect is achieved through the inhibition of ROS/Erk1/2 signaling and the activation of Nrf2 and antioxidant enzymes. These natural compounds, when used together, represent a promising therapeutic approach for mitigating the inflammatory processes associated with atherosclerosis.

Context: 

Dipeptidyl peptidase 4 (DPP-4) is a serine exopeptidase enzyme that hydrolyzes the amide bond at the N-terminal of peptides. This enzyme converts incretins, such as glucagon-like peptide I and glucose-dependent insulinotropic peptide, into their inactive forms, thereby preventing them from stimulating insulin secretion. Numerous studies have confirmed the role of DPP-4 in the pathophysiology of type 2 diabetes, leading to the development of various DPP-4 inhibitors. In recent years, research on DPP-4 inhibitors has expanded significantly, resulting in the creation of both non-peptidomimetic heterocyclic compounds and peptidomimetic scaffolds.

Evidence Acquisition: 

This systematic review summarizes all recent advances related to DPP-4 inhibitors up to 2024. It begins by outlining the biochemical characteristics of DPP-4 and general pharmacological principles of DPP-4 inhibition, followed by an overview of the latest developments from recent publications. The review provides valuable insights into the pharmacophores necessary for ligand-protein interactions, aimed at understanding the structure-activity relationship of novel DPP-4 inhibitors. Data for this review was collected from sources including ScienceDirect, PubMed, and Scopus.

This review highlights various chemical scaffolds that have been explored in the development of novel DPP-4 inhibitors. It emphasizes scaffolds with significant DPP-4 inhibitory activity, including azoles, azines, sulfonamides, and quinolone motifs. The article also details the structure-activity relationships of newly developed analogs, providing a comprehensive overview of recent advancements in this area.

Despite moderate progress in the development of novel DPP-4 inhibitors, emerging molecular aspects of DPP-4 intervention show great promise for future therapeutic developments.

Mutations in the p53 gene have been linked to the initiation and progression of breast cancer, as well as resistance to chemotherapy. Therefore, the development of novel treatment approaches is essential to combat this disease.

This study aimed to evaluate the effects of dendrosomal curcumin (DNC) on the breast cancer cell line MDA-MB231.

MDA-MB231 cells were treated with 20 μM DNC, and the apoptosis rate and cell proliferation cycles were assessed using flow cytometry. Additionally, after RNA extraction and cDNA synthesis, the expression levels of Lnc-DANCR, EZH2, Noxa, bcl- 2, bax, PUMA, p21, and p53 genes were analyzed using RT-PCR. Protein expression levels of P53, P21, Bcl-2, and Bax were evaluated through western blotting.

Dendrosomal curcumin induced apoptosis in MDA-MB231 cells and caused cell cycle arrest at the SubG1 phase. Dendrosomal curcumin treatment downregulated Lnc-DANCR, EZH2, bcl-2, and p53 gene expression, while upregulating bax, Noxa, PUMA, and p21 gene expression in a time-dependent manner. Bax and P21 protein levels were significantly upregulated following DNC treatment, whereas Bcl-2 and P53 protein levels were downregulated in DNC-treated breast cancer cells.

In summary, dendrosomal nanocurcumin demonstrated potent anti-tumor effects against breast cancer cells, suggesting its potential as a therapeutic agent in breast cancer treatment.

Folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and oxaliplatin and capecitabine (XELOX) are the most widely used chemotherapy regimens for treating metastatic colorectal carcinoma (CRC). These regimens are associated with various adverse reactions, including neuropathy and hand-foot syndrome (HFS). Silymarin, a flavonoid derived from Silybum marianum, has a wide range of biological activities. It has been used to counteract chemotherapy side effects due to its antioxidant, anti-apoptotic, and anti-inflammatory properties.

The purpose of this study was to assess the preventive effect of nano-silymarin on neuropathy and HFS induced by the FOLFOX6 and XELOX regimens.

A randomized, triple-blinded, placebo-controlled clinical trial was conducted on 60 patients who were randomly assigned to receive 70 mg capsules containing 15% silymarin nano micelles twice a day after meals, starting from the first day of the first chemotherapy course and continuing for six courses of the XELOX or m-FOLFOX6 regimen. The severity of adverse effects was assessed after the third and sixth courses based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.

The median CTCAE scores for HFS and neuropathy were significantly lower in the nano-silymarin group at the end of the third course (P < 0.001). However, the difference remained significant only for HFS at the end of the sixth course (P = 0.022). Additionally, the scores increased significantly in both the placebo and nano-silymarin groups during the therapy (P < 0.05).

Nano-silymarin may be considered an adjuvant medication for the prevention of certain chemotherapy-induced adverse reactions. Further research with larger sample sizes and various doses of nano-silymarin is recommended for a more comprehensive evaluation.

The pharmaceutical supply chain (PSC) faced numerous challenges, particularly during the COVID-19 crisis. Due to the supply chain (SC) 's vulnerabilities, it requires enhanced capabilities to address these challenges. In Iran, specific economic and political issues have intensified the vulnerabilities of the PSC.

This study investigates the issues caused by the COVID-19 crisis in the PSC, identifies and characterizes these issues, and recommends appropriate courses of action to address future SC disruptions.

This study is a qualitative-quantitative analysis conducted in Iran during the COVID-19 crisis. Qualitative thematic analysis was performed from July 2022 until May 2023. Semi-structured, in-depth, face-to-face interviews with 23 Iranian PSC specialists were conducted until saturation was reached. The qualitative phase was analyzed using MAXQDA 2021. The quantitative phase included a survey of 547 individuals working in pharmaceutical manufacturing in Iran, with the questionnaires analyzed using SPSS 26.

In the qualitative phase, the research identified two main themes: (1) vulnerabilities and (2) capabilities, along with 15 subthemes providing solutions to enhance the resilience of the PSC. In the quantitative phase, findings from 64 questionnaires highlighted major vulnerabilities and capabilities necessary to create a resilient SC. The median score for vulnerabilities was 5.12, while the median score for capabilities was 5.39.

According to the questionnaire results, the quantitative findings indicate that capabilities received a higher score, suggesting that this sector of the PSC demonstrated better resilience against the pandemic. This study, with its contextual focus, mixed-method approach, comprehensive analysis of vulnerabilities and capabilities, and sector-specific insights, offers a novel contribution to the understanding of SC resilience within Iranian pharmaceutical manufacturing. It also has the potential to promote further research in other sectors of the PSC.

Advanced glycation end products (AGEs) are complex compounds that play a critical role in neurological disorders, including the pathogenesis of Alzheimer's disease. Methylglyoxal (MG) is recognized as the primary precursor of AGEs. Methylglyoxal is produced endogenously and also introduced through dietary exposures.

This study aimed to investigate and compare the effects of aminoguanidine (AG), semicarbazide (SC), and thiosemicarbazide (TSC) on MG-induced neurological toxicity in rats.

Male Wistar rats were exposed orally to MG, MG + AG, MG + SC, and MG + TSC for 70 days. Neurobehavioral, biochemical, and histopathological changes were evaluated.

The findings indicated that oral administration of MG for 70 days resulted in memory impairment and increased anxiety in neurobehavioral tests. Additionally, MG elevated protein carbonylation in brain tissues. Semicarbazide was found to prevent MG-induced memory problems, while both SC and AG reduced carbonyl content in brain tissues. Aminoguanidine and TSC were effective in alleviating anxiety induced by MG exposure. Histopathological analysis revealed that MG caused cell damage and neuronal necrosis in the hippocampus, particularly in the cornu ammonis 1 and 3 (CA1 and CA3) and AG, SC, and TSC improved neuronal survival specifically in the CA1 and DG areas.

The data suggest that SC, AG, and TSC may offer neuroprotective effects against MG-induced neurobehavioral toxicity. Further studies are required to explore the mechanisms of action of these compounds.

Chemotherapy remains a primary approach to cancer treatment, widely applied in bladder cancer (BC). However, the various side effects and resistance associated with chemotherapeutic drugs pose significant challenges in BC therapy, prompting interest in natural compounds like luteolin. Studies focus on its effects on key biological processes involved in BC, including metastasis, apoptosis, and autophagy.

This study investigated the regulation of mRNA expression of genes associated with apoptosis (BCL2, P53), autophagy (ULK1, ATG12), and metastasis (MMP2, MMP9) in malignant BC cells treated with luteolin.

This was an in vitro experimental study. EJ138 BC cells were treated with various concentrations of luteolin, and its impact on cell viability, proliferation, and gene expression was assessed. The cytotoxic effect of luteolin on EJ138 BC cells was evaluated using the MTT assay after 24- and 48-hour treatments with different luteolin concentrations. Flow cytometry was performed to examine luteolin’s anti-proliferative effect, and RT-PCR was used to analyze mRNA expression of BCL2, P53, ULK1, ATG12, MMP2, and MMP9 genes.

MTT assay results confirmed that luteolin reduced the proliferation rate of BC cells. Flow cytometry indicated increased cell death in EJ138 BC cells following luteolin treatment. RT-PCR findings demonstrated that luteolin upregulated P53, ULK1, and ATG12 expression while downregulating BCL2 mRNA expression. However, luteolin treatment in EJ138 cells did not significantly alter MMP2 and MMP9 expression levels.

These findings indicate that luteolin exerts cytotoxic effects on EJ138 BC cells by dysregulating mRNA expression of genes involved in apoptosis and autophagy. Therefore, luteolin shows potential as an effective anti-cancer agent for BC therapy.

Breast cancer is one of the most common types of cancer in women, and its incidence is increasing in Iran. HER- 2-positive breast cancer is invasive and often associated with poorer outcomes. Patients with this type of breast cancer can develop resistance to medications like trastuzumab. Trastuzumab-emtansine (TDM1) is a medication developed to reduce cancer cell resistance to trastuzumab. The TDM1 has been shown to decrease the incidence of death and recurrence in breast cancer.

This study aimed to evaluate the cost-utility and calculate the budget impact of TDM1 versus trastuzumab for the treatment of residual invasive HER-2-positive breast cancer.

A Markov model with a lifetime horizon was developed, incorporating four health states. Women aged 45 with residual invasive HER-2-positive breast cancer entered the model. The study adopted a healthcare system perspective, with costs reported in 2021 US dollars. Discount rates of 7% for costs and 3% for utility values were applied. Utility values and transition probabilities were derived from published literature. Costs were estimated based on guidelines, expert opinions, and Iranian tariffs. Iran’s pharmacoeconomic threshold of 1085$ was used for comparison. The incremental cost-effectiveness ratio (ICER) and budget impact of TDM1 were calculated, and sensitivity analyses were conducted to assess the robustness of the model.

The model indicated that treatment with TDM1 resulted in a 1.59 quality-adjusted life year (QALY) increase, with an additional cost of 1408$. This was deemed cost-effective, considering Iran’s pharmacoeconomic threshold of 1085$ (calculated ICER: 886$ per QALY gained). One-way sensitivity analysis revealed that the model was sensitive to the costs of TDM1 and trastuzumab, the discount rates for utility values and costs, and the probability of achieving invasive disease-free survival (IDFS). Probabilistic sensitivity analysis showed that 59.61% of simulations fell below Iran’s pharmacoeconomic threshold, supporting the model's robustness. The budget impact analysis revealed that the additional budget required for TDM1 treatment over a three-year period was 1,120,546$ compared to trastuzumab.

Although TDM1 imposes higher costs, it is more cost-effective than trastuzumab for the treatment of residual invasive HER-2-positive breast cancer in Iran