Iranian Journal of Pharmaceutical Research
Volume:20 Issue: 2, Spring 2021

Drug-induced cholestasis is the main type of liver disorder accompanied by high morbidity and mortality. Evidence for the role of hepatobiliary pumps in the cholestasis patho-mechanism is constantly increasing. Recognition of the interactions of chemical agents with these transporters at the initial phases of drug discovery can help develop new drug candidates with low cholestasis potential. This review delivers an outline of the role of these transport proteins in bile creation. It addresses the pathophysiological mechanism for drug-induced cholestasis. In-vitro models, including cell-based and membrane-based approaches and In-vivo models such as genetic knockout animals, are considered. The benefits and restrictions of each model are discussed in this review. Current understandings into the cellular and molecular process that control the activity of hepatobiliary pumps have directed to a better understanding of the pathophysiology of drug-induced cholestasis. A combination of in-vitro monitoring for transport interaction, in-silico predicting systems, and consideration of and metabolic and physicochemical properties must cause more effective monitoring of possible liver problems.

Stress-dependent disorders cause severe harm to human health and trigger the risk of neurodegenerative disorder. Corticotropin-releasing factor-1 receptor was found to be a potent drug target.We evaluate the essential structural residues for pharmacophore identification through 2D and 3D QSAR analysis and identify the binding residues for a possible mechanism of CRF-1 binding with 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives through molecular docking and molecular dynamics simulations. The best 2D QSAR model was obtained through the MLR method with an r2 value of 0.8039 and a q2 value of 0.6311. Also,a 3D QSAR model was generated through the KNN MFA method with a q2 value of 0.6013 and a q2_se value of 0.3167.Further, docking analysis revealed that residue Glu196 and Lys334 were involved in hydrogen bonding and Trp9 in Π- Π stacking. Simulation analysis proves that target protein interactions with ligands were stable, and changes were acceptable for small and globular proteins. Compound B18, a benzimidazole derivative, has an excellent binding affinity towards CRF-1 protein compared to reference molecules; hence, this compound could be a potential drug candidate for stress-dependent disorders. Based on findings, 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives could be a novel class of corticotropin-releasing factor 1 receptor antagonists for stress-related disorders. All benzimidazole derivatives were found to be within the acceptable range of physicochemical properties. Hence, these observations could provide valuable information for the design and development of novel and potent CRF-1 receptor antagonists.

Cholestasis is associated with the accumulation of bile acids and bilirubin in the hepatocytes and leads to liver injury. Pregnane X Receptor (PXR) coordinates protective hepatic responses to toxic stimuli, and this receptor was reported to stimulate bile secretion by increasing MRP2 expression. Since PXR activators were reported to be anti-inflammatory in the liver, PXR was proposed as a drug target for the treatment of chronic inflammatory liver diseases. We investigated the potential protective effect of spironolactone (SPL), an enzyme inducer, in hepatotoxicity induced by bile duct ligation in rats. Wistar Albino (250-300 g) rats were divided into the control group and the bile duct ligated (BDL) group. BDL group was divided into three subgroups; following BDL, for 3 days, the first group received propylene glycol (vehicle of SPL) (blinded), the second subgroup received spironolactone (SPL) (200 mg/kg oral), and the third subgroup received SPL for 3 days, starting 3 days after the bile duct ligation, in order to investigate if it has a healing effect after hepatitis had developed. The control group was sham-operated and received saline. At the end of the experiment, blood and tissue samples were collected. Serum TNF-α, NF-ĸB, bilirubin, IL-6 levels, ALT, AST, ALP activities and tissue MPO activity and oxidant damage increased after the bile duct ligation was significantly decreased following SPL administration. PXR and MRP2 activity showed an increase in the hepatocytes as a result of the treatment. In conclusion, it was observed that SPL administration significantly decreases liver inflammation and damage related to BDL.

Colon cancer is one of the most prominent causes of cancer-related morbidity and mortality and curable if detected in the early stages. TNF-related apoptosis-inducing ligand (TRAIL) is a therapeutic protein and has a potential anti-cancer activity that is widely used for the treatment of several cancers. In this study, we aimed to develop a silver nanoparticle system conjugated with TRAIL and coated with PEG (AgCTP NPs) to improve the therapeutic effects of colon cancer. AgCTP NPs were characterized by UV spectrum, FTIR and zetasizer. Cytotoxicity, hemolysis assay and apoptotic effects of nanoparticles were investigated using a colon cancer cell line (HT-29) in-vitro. Treatment with AgCTP NPs effectively inhibited proliferation and colony formation of HT-29 cells. The apoptotic effects of nanoparticles on HT-29 cells were determined as Bax, Bcl-2, PARP and clv-PARP protein expression levels using Western blot. Apoptotic proteins were upregulated by AgCTP NPs. In this study, we demonstrated that AgCTP NPs had an anti-cancer effect by activating cell death. Thus, we have confirmed that silver nanoparticles can be selected as a good carrier for TRAIL therapeutic proteins that can be used to treat colon cancer.

Annona muricata L. extract (AME) exhibits cytotoxic activities on various types of cancercells. This study aims to unveil the anticancer activity of AME as a cotreatment agent with doxorubicin (dox) on 4T1 cells and AME’s relation to senescence. AME was obtained by maceration using 96% ethanol. AME was then subjected to qualitative analysis using TLC compared to quercetin (hRf = 75). Spectrophotometry analysis of AME resulted in a total flavonoid content of 2.3% ± 0.05%. Cytotoxic evaluation using the MTT assay revealed that AME showed an IC50 value of 63 µg/mL, while its combination (25 µg/mL) with dox (10 nM) decreased the viability of 4T1 cells to 58 % (CI = 0.15). Flowcytometry using propidium iodide staining confirmed that AME (13 and 25 µg/mL) caused cell cycle arrest in the G1 phase as a single treatment and G2/M arrest in combination with dox. However, by using the dichloro dihydrofluorescein diacetate staining assay, it turned out that AME at concentrations of 13 and 25 µg/mL decreased intracellular reactive oxygen species (ROS) levels both as a single treatment and in combination with dox. Senescence-associated β-galactosidase assay showed that AME decreased dox-induced senescence. AME alone and in combination with dox (cotreatment) showed cytotoxic effect synergistically on 4T1 cells, but this was not caused by an increase in intracellular ROS levels as well as senescence induction. Therefore, AME showed its potential to be a cotreatment agent with antioxidant property on triple-negative breast cancer cells.

The development of simple, fast, cheap and reliable analytical methods for tracing biological indicators is demanded through clinical investigations. Herein, we developed, for the first time, a cheap and specific method for the extraction and quantification of p-cresol (pC) in real plasma samples of chronic kidney disease (CKD). Plasma samples were prepared by hydrolyzing in an acidic medium to convert pCS (p-cresol sulfate) and p-Cresol glucuronide (pCG) to pC. Next, proteins of plasma samples were precipitated and then pC was extracted by acetonitrile (ACN) and saturated NaCl (as salting-out agent). Finally, fluorescence emissions were measured at λex/λem = 280/310 nm. The specificity of the method was checked by testing various possible interfering agents. The obtained results revealed a specific determination of pC. Under optimal conditions, a linear range was detected from 0.5 to 30 µg/mL of pC with a lower limit of detection (LLOQ) of 0.5 µg/mL. The reliability of the method was checked by calculating the repeatability, selectivity, and accuracy of the developed method for pC determination in plasma samples. The application of the developed method was investigated for the detection of pC in a number of CKD patients. Due to the simplicity and selectivity, the developed method could be applied for routine analysis of pC concentrations in the plasma samples of CKD patients. In addition, the developed method showed great potential for developing a point-of-care testing (POCT) device.

Alzheimer's disease is the most common form of dementia among the elderly. This progressive neurodegenerative disorder affects brain regions that control cognition, memory, language, speech, and awareness. As a potent antioxidant, crocin has been proposed to effectively manage the neurodegenerative disease.In this study, the recovery effects of crocin on the memory deficits caused by the intra-hippocampal injection of amyloid beta1-42 (Aβ1-42) were evaluated in rats. We also considered the protective effects of crocin on the mitochondrial damage caused by Aβ1-42. We examined the memory deficits of rats with the help of the Morris water maze. Then, we determined different mitochondrial toxicity endpoints caused by Aβ1-42, including mitochondrial ROS formation, lipid peroxidation, mitochondrial membrane potential collapse, mitochondrial outer membrane integrity, and cytochrome c release. Our results demonstrated that the behavioral signs of memory deficiency caused by Aβ1-42 significantly (P < 0.01) reduced by both pretreatment and post-treatment with crocin (30 mg/kg). Furthermore, crocin prevented all the Aβ1-42 induced above referenced mitochondrial upstream toxic events leading to neuronal apoptosis.These results demonstrated that crocin is a promising preventive candidate for the potential treatment of Alzheimer's disease. Furthermore, it seems that the antioxidant and neuroprotective effects of crocin are better seen when the compound is pretreated beforehand rather than introduced afterward in Aβ1-42 exposed mitochondria.

Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration of nerve cells. Due to the complexity of conditions in neurodegenerative diseases, combination therapy including cell therapy and drug therapy is important as a new therapeutic strategy. Epidermal neural crest stem cells (EPI-NCSCs) are as one of the best option in cell therapy for various neurological diseases. In this study, the effect of Lithium carbonate and Crocin, with considering of their effects on cellular signaling pathways and neuroprotective properties were investigated on expression of neurotrophic factors BDNF and GDNF in EPI-NCSCs.EPI-NCSCs were isolated from hair follicle and after 72 hours of treatment with different concentration of drugs [Lithium, Crocin and lithium + Crocin], and trial doses were selected by MTT assay. The cells were treated with selected concentration (Lithium 1 mM, Crocin 1.5 mM, and for co-treatment Lithium 1mM and Crocin 1 mM) for 7 days.The Real Time PCR results indicated an increasing in expression of BDNF and GDNF in treated cells as compared with control (*p

Onion or Allium cepa (A. cepa) is one of the most important condiment plants grown and consumed all over the world. This plant has various therapeutic effects attributed to its constituents, such as quercetin, thiosulphinates and phenolic acids. In the present article, various pharmacological and therapeutic effects of A. cepa were reviewed. Different online databases using keywords such as onion, A. cepa, therapeutic effects, and pharmacological effects until the end of December 2019 were searched for this purpose. Onion has been suggested to be effective in treating a broad range of disorders, including asthma, inflammatory disorders, dysentery, wounds, scars, keloids and pain. In addition, different studies have demonstrated that onion possesses numerous pharmacological properties, including anti-cancer, anti-diabetic and anti-platelet properties as well as the effect on bone, cardiovascular, gastrointestinal, nervous, respiratory, and urogenital systems effects such as osteoporosis, anti-hypertensive, antispasmodic, anti-diarrheal, neuro-protective, asthma and diuretic effects. The present review provides detailed the various pharmacological properties of onion and its constituents and possible underlying mechanisms. The results of multiple studies suggested the therapeutic effect of onion on a wide range of disorders.

Methamphetamine (METH) is a potent central nervous system (CNS) stimulant and frequently used illegal drugs. Repeated exposure to METH can induce degenerative changes in dopaminergic and serotonergic axons. There is no standard medical treatment for METH’s neurotoxic effects. Cinnamaldehyde is an important compound of cinnamon and has activities against neurological disorders. The present study was designed to examine the neuroprotective effect of trans-cinnamaldehyde (TCA) on METH-induced cytotoxicity. PC12 cells were treated with METH (2.5 mM) 24 h after treated with different concentrations of TCA (3.75- 50 μM). The percentage of cell survival was evaluated by MTT assay and the following parameters were measured to detect apoptosis and oxidative stress responses: DNA fragmentation, ROS production and GSH content. Exposure to 2.5 mM METH decreased the cell viability and GSH levels, caused the generation of reactive oxygen species and ultimately induced apoptosis. Pretreatment with TCA at 3.125-25 μM significantly attenuated cell viability loss. TCA, especially at a concentration of 12.5 and 25 μM, decreased the apoptosis and ROS generation and increased the GSH level compared with the METH group. The findings of the present study suggested that TCA exerted a protective effect against METH-induced neurotoxicity through mechanisms related to antioxidant and anti-apoptosis. It is suggested that TCA may be useful for the prevention and treatment of harmful effects of METH on the brain.

In order to find new drugs with potent antiproliferative effect, a series of novel barbituric acid derivatives containing azoles at the C-5 position were designed, synthesized, and evaluated for antiproliferative activity against three human cancer cell lines (BEL-7402, MCF-7, and HCT-116) using MTT assay. Several of the synthesized compounds exhibited potent antiproliferative effects. The most promising compound was 5-((1-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-4-yl) methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (3s), which showed considerably high antiproliferative activity in the BEL-7402 cell line, with a half-maximal  inhibitory concentration of 4.02 µM and 20.45-fold higher selectivity for BEL-7402 cells than for normal L02 cells. The apoptosis experiment showed that compound 3s induced apoptosis and cell necrosis in a concentration-dependent manner and exert its anti-proliferative activity. Therefore, compound 3s exhibited better therapeutic activity and specificity compared with the positive control 5-fluorouracil.

In this study, the protective effect of crocin on malathion (MTN) induced cardiotoxicity in rats in subacute exposure was evaluated. Rats were divided into 6 groups; control (normal saline); MTN (100 mg/kg); MTN + crocin (10, 20 and 40 mg/kg) and MTN + vitamin E 200 IU/kg. Treatments were continued for two weeks. Creatine phosphokinase MB (CK-MB), malondialdehyde (MDA) and glutathione (GSH) levels were evaluated in heart tissue at the end of treatments. The effect of crocin and MTN on histopathological changes in rat cardiac tissue was also investigated. The alteration of protein profile in the heart of the animals exposed to MTN was evaluated by proteomic approach through two-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) software. MTN induced histopathological damages and elevated the level of cardiac marker CK-MB (P < 0.01). The level of MDA increased and the level of GSH reduced (P < 0.001). MDA levels were reduced in all crocin plus MTN groups (P < 0.001) and vitamin E plus MTN (P < 0.001) groups as compared to MTN groups. However, in the crocin (10 mg/kg) + MTN group, the content of GSH compared to MTN treated rats increased (P < 0.001). Protein abundance analysis identified proteins implicated in cardiac necrosis, tricarboxylic acid cycle, cellular energy homeostasis, arrhythmias, heart development, heart failure and cardiovascular homeostasis to be affected by MTN. In summary, MTN may induce damage in the heart tissue of rats following subacute exposure and crocin, as an antioxidant, showed protective effects against MTN cardiotoxicity.

Since 1980 after introducing the concept of live cell encapsulation by Lim et al., this technology has received enormous attention. Several studies have been conducted to improve this technique; different polymers, either natural or synthetic, have been used as microcapsules` making materials and different substances as coating layers. Literature review leads us to the conclusion that alginate (Alg) multilayer microcapsules and, in particular, alginate-poly l-lysine (PLL)-alginate (APA) are the most used structures for live cell encapsulation. Although, disadvantages of PLL (e.g., weak mechanical strength and low biocompatibility) made researchers work on other cationic polymers to find an alternative. This review aims to discuss more popularly suggested cationic polymers such as poly l-ornithine (PLO), chitosan, etc. As alternatives for PLL and, more importantly, we want to take a closer look to see which one of these systems are closer to clinical applications.

Aimed to improve the dissolution profile of risperidone and increase the compliance of psychotic patients, we designed a fast dissolution tablet (FDT) containing nanoparticles. Risperidone nanoparticles were prepared by the acid-alkali neutralization method, and their size and stability were evaluated. Spray freeze-drying (SFD) process was then employed to fabricate the nanoaggregates using sugars. The physicochemical properties of the dried powders were assessed. Finally, nanoaggregates were compressed into tablets, and their properties were evaluated.The results show that the synergic effect of cremophore EL and hydroxypropyl methyl cellulose E15 can give rise to the formation of risperidone nanosuspension with the particle size of 188 nm. Moreoevr, it is shown that the fabrication of risperidone nanoaggregate enhanced the drug dissolution and decreased that to 2 min, which is faster than coarse risperidone powder (with dissolution time of 60 min). The formulations of FDT containing 9.5% of sodium starch glycolate and 83.2% microcrystalline cellulose were selected with a disintegration time of less than 30 seconds and a dissolution time of 10 minutes. This investigation shows that the preparation of FDT containing nanoparticles using SFD is an easy and feasible method for improving the dissolution profile of many drugs with low solubility.

Ulcerative colitis (UC) is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon. The exact etiology of UC is unknown, but the role of autoimmunity and activated inflammatory cascade is quite clear. Melatonin possesses anti-inflammatory and immune-modulative properties in animal and clinical trials. The aim of the present study was to evaluate the efficacy and safety of oral melatonin as an adjudicative therapy in clinical, biochemical, and quality of life in UC patients. Thirty patients diagnosed with mild to moderate UC, were randomly allocated to either receive melatonin (3 mg/d) or the placebo group for three months. Simple clinical colitis activity index (SCCAI), fecal calprotectin (FC), C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR), and Sf-36 questionnaire have been used for assessment at the baseline and the end of the trial. Melatonin significantly improve SCCAI score, FC, role-emotional, energy and general health relative to placebo (p = 0.03, 0.05, 0.002, 0.032, 0.004 respectively). Regarding CRP, ESR, and the other components of SF-36 there is not any significant difference between melatonin and placebo group. Melatonin supplementation over a three-month period is effective and safe in improving clinical index, FC, and some quality of life in patients with mild to moderate UC.

Considering the diversified pharmacological importance of thiazole and triazole heterocyclic moieties, a unique series of S-aralkylated bi-heterocyclic hybrids, 7a-l, was synthesized in a convergent manner. The structures of newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, IR, and EI-MS spectral studies. The structure-activity relationship of these compounds was envisaged by analyzing their inhibitory effects against tyrosinase, whereby all these molecules exhibited potent inhibitory potentials relative to the standard used. The Kinetics mechanism was ascertained by Lineweaver-Burk plots, which revealed that 7g inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0057µM. These bi-heterocyclic molecules also disclosed good binding energy values (kcal/mol) when assessed computationally. So, these molecules can be considered promising medicinal scaffolds for the treatment of skin disorders.

Polymeric micelles (PMs) are one of Nanoscale delivery systems with high stability, loading capacity, and biocompatibility. PMs are nano-sized and spherical particles with a hydrophilic shell and hydrophobic core or reverse depending on their applications. Polymeric micelles could be synthesized by different methods, such as direct dissolution, dialysis method, and lyophilization. Microfluidics is also a relatively modern approach for this purpose, in which chemical reactions are carried out in the microchannels. Compared with conventional preparation methods, the microfluidic technique produces homogeneous polymeric micelles with desirable features, tunable particle size, and relatively high drug loading. These advantages are originated from the ability of microfluidics in precise control over the streamlines of reactants without chaotic turbulence. Although the synthesis of polymeric micelles by the microfluidic platform is advantageous, little or no review has been conducted to provide a clear image of the different PMs preparation by the microfluidic approach. Thus, in this review, the production of the PMs, utilizing microfluidic procedures to enhance their favorable characteristics is investigated. For this purpose, an electronic search is conducted on PubMed, Web of Science, Scopus, and Embase databases for retrieval of relevant papers. Seven papers are included in this systematic review. Preparation of PMs by the microfluidic approach and the effect of different parameters, such as the flow rate ratio, channel dimensions, drug concentration, and organic solvent type on PMs characteristics is obtained from the included papers.

The treatment of melanoma is still challenging and therefore identification of novel agents is needed for its better management. Our previous study suggested that cyclooxygenase-2 (COX-2) would be a novel target for treatment of several cancers. In the present study, we searched selective cytotoxicity and mitochondria mediated apoptosis of novel synthesized chalconeferrocenyl derivative (1-Ferrocenyl-3-(dimethylamino)-3-(4-methylsulfonylphenyl) propan-1-one) (FDMPO) as a COX-2 inhibitor on normal and melanoma cells and their mitochondria. For this purpose, we evaluated the cellar parameters such as cytotoxicity, apoptosis% versus necrosis%, activation of caspase-3 and ATP content, and also mitochondrial parameters such as reactive oxygen species formation, mitochondrial swelling, mitochondrial membrane potential decline, mitochondrial membrane integrity, and cytochrome C release. Our results showed FDMPO could selectively induce cellular and mitochondrial toxicity (up to 50 µM) on melanoma cells and mitochondria without any toxic effects on normal  fibroblast and their mitochondria. Taken together, the results of this study suggest that mitochondria are a potential target for the melanoma. Selective inhibition of mitochondrial COX-2 could be an attractive therapeutic option for the effective clinical management of therapy-resistant melanoma.

Chemoprevention with natural products may provide important alternatives in the search for new drugs to treat cancer. Thus, the ethanol extract of Bomarea setacea and its secondary metabolite (chromone) were evaluated in-vitro in SW480 and SW620 human adenocarcinoma colon cells to identify a possible effect on cell growth, antiproliferative and/or proapoptotic activity. The ethanol extract did not show growth inhibition of these cell lines 48 h after treatment; besides, it required higher concentration and time to have an antiproliferative effect. On the other hand, although the chromone was not as active as the reference drug (5-FU), it displayed a greater selectivity, being 156-fold more selective against SW480 cells (SI => 100) and 255-fold against SW620 cells (SI => 86,9). Additionally, the chromone caused an important arrest in G2/M (44.18%) with an important accumulation in subG0/G1 phase in SW620 cells, inducing loss in mitochondrial membrane potential and damage in the cell membrane of both cell lines, with activation of caspase 3, suggesting an apoptotic process independent of ROS production and p53 activation.

Origanum vulgare L. (O. vulgare) is an important medicinal herb of the family Lamiaceae. In the current study, we explained the critical evaluation of traditional uses, the phytochemistry and the antimicrobial properties of O. vulgare and its subspecies, with a focus on the mechanisms of actions of the most important phytochemicals from O. vulgare subspecies. The most important phytochemicals of O. vulgare are volatile (essential oil) and non-volatile phenolic compounds (phenolic acids & flavonoids). The constituents of the O. vulgare essential oil (EO) include high percentages of thymol and carvacrol with excellent antimicrobial activity alone or in combination with other antibiotics. Interesting results have been reported the remarkable antimicrobial activities of infusion or tea products of O. vulgare with a high amount of EO against multidrug‐resistant bacterial and fungal microorganism (such as Escherichia coli, Staphylococcus aureus, Candida albicans and Pseudomonas aeruginosa). The most important antibacterial mechanisms of O. vulgare are enzyme inhibition, efflux pump inhibition, ATP depletion, biofilm formation inhibition and cytoplasmic membrane damage. The antimicrobial activity of the hirtum subspecies has been confirmed in different in-vitro and in-vivo studies. The present review confirms the clinical and preclinical research showing the O. vulgare and its subspecies antimicrobial effects.

The aim of this study was to investigate in-vitro antibacterial and antibiofilm effect of colistin, imipenem, gentamicin, and fosfomycin alone and the various combinations against carbapenem-resistant Pseudomonas aeruginosa (P. aeruginosa). Eight carbapenem-resistant and biofilm-forming P. aeruginosa isolates from burn patients were collected. The mechanisms of resistance to carbapenem were determined by the phenotypic, PCR, and Real-Time PCR assays. The minimum inhibitory concentration (MIC) of antimicrobial agents was determined by the broth micro dilution. To detect any inhibitory effect of antibiotics against the biofilm, the biofilm inhibitory concentration was determined. To detect synergetic effects of the combinations of antibiotics, the checkerboard assay and the fractional inhibitory concentration (FIC) were used. The highest synergic effect was observed in colistin/fosfomycin and gentamicin/fosfomycin (5 of 8 isolates), and the lowest synergic effect was found in gentamicin/imipenem and colistin/gentamicin (1 of 8 isolates). Colistin/fosfomycin, imipenem/fosfomycin, colistin/imipenem, gentamicin/fosfomycin, and gentamicin/imipenem were shown synergic effect for 3, 2, 2, 2 and 1 isolates, respectively. The combination of antibiotics had different effects on biofilm and planktonic forms of P. aeruginosa. Therefore, a separate determination of inhibitory effects of the antibiotic in the combination is necessary. Fosfomycin/colistin and fosfomycin/gentamicin were more effective against planktonic form and fosfomycin/colistin against biofilm forms.

Changes in plasma concentration of taurine during hospitalization of acetaminophen poisoned patients have not been studied. Hepatotoxicity is a common consequence of acetaminophen overdose that may lead to acute liver failure. Numerous biomarkers for drug-induced liver injury have been explored. All biomarkers are usually obtainable 48 h following acetaminophen overdose. We have already introduced taurine as a non-specific early biomarker of acetaminophen overdose. This study aimed to follow up changes in plasma concentration of taurine during the first three days of acetaminophen overdose. Sixty-four male patients suffering from acetaminophen overdose were selected for the study. Four blood samples were taken from the patients every 12 h. Sixty blood samples were also taken from sixty healthy humans. The plasma concentration of taurine in both groups was analyzed an already developed HPLC method. Analysis of regression showed a significant correlation between means of plasma concentrations of taurine and acetaminophen, aspartate aminotransferase, Alanine aminotransferase, glutathione peroxidase, and prothrombin time during hospitalization. The high plasma concentration of taurine, 6 h or more after acetaminophen overdose, could be a useful early indicator of liver damage.

A group of Novel phenylhydrazone derivatives of ethyl acetoacetate was synthesized and evaluated for their antiplatelet activities. Fourteen ethyl acetoacetate phenylhydrazone derivatives were synthesized using the diazonium salt of various aromatic primary amines with good yields and purity. The structure of the final compounds was confirmed and approved by spectroscopic techniques such as 1HNMR, FTIR, and ESI-Mass. We examined the antiplatelet activity of the derivatives against Arachidonic Acid (AA) and Adenosine Diphosphate (ADP) as platelet aggregation inducers. The final results indicated the acceptable potency for different derivatives. In this regard, the para-hydroxyphenylhydrazine derivative of ethyl acetoacetate has the best activity among all derivatives, both on AA and ADP pathways. It seems that the derivatives with electron-releasing substituents (hydroxyl, methoxy, and methyl group) have better inhibition activities against the aggregation induced by AA. In contrast, those with an electron-withdrawing group showed a significant decrease in their potency. Based on the results of this study, we would proceed with further assessments both in-vitro and in-vivo to get success in introducing some new antiplatelet agents to the clinic.

Cardiovascular diseases (CVD) affect millions of people and spend a lot of medical costs around the world each year. Taxifolin is a natural anti-oxidative reagent obtained from multiple plants and exhibits a wide range of pharmacological effects. High mobility group box protein 1 (HMGB1) is expressed in multiple types of cells in the extracellular environment, regulating the pro-inflammatory process. Here, we detected the viability of cells using MTT assay, and the expression of each target protein was detected using western blotting analysis. The expression of each target mRNA was detected using the qPCR method, and the concentration of each cytokine in serum samples was detected using the ELISA method. In this study, we found that taxifolin could decrease the expression of hypoxia-inducible factor-1α (HIF-1α) while increasing the expression of endothelial nitric oxide synthase (eNOS), presented a protective role. Besides, taxifolin could also increase the expression of vascular endothelial growth factor-α (VEGF-α), transforming growth factor-β (TGF-β) and fibroblast growth factor21 (FGF21), resulting in viability rate increasing. And these effects were mediated by phosphatidylinositol 3-hydroxy kinase (PI3K)/AKT/mTOR signaling pathway; a similar trend was also observed in HMGB1 knockdown mice. We also found that inhibition of HMGB1 could enhance the cardioprotective effect of taxifolin and might be a new therapeutic strategy for cardiovascular disease.

The significant threat to humanity is HIV infection, and it is uncertain whether a definitive treatment or a safe HIV vaccine is. HIV-1 is continually evolving and resistant to commonly used HIV-resistant medications, presenting significant obstacles to HIV infection management. The drug resistance adds to the need for new anti-HIV drugs; it chooses ingenious approaches to fight the emerging virus. Highly Active Antiretroviral Therapy (HAART), a multi-target approach for specific therapies, has proved effective in AIDS treatment. Therefore, it is a dynamic system with high prescription tension, increased risk of medication reactions, and adverse effects, leading to poor compliance with patients. In the HIV-1 lifecycle, two critical enzymes with high structural and functional analogies are reverse transcriptase (RT) and integrase (IN), which can be interpreted as druggable targets for modern dual-purpose inhibitors. Designed multifunctional ligand (DML) is a new technique that recruited many targets to be achieved by one chemical individual. A single chemical entity that acts for multiple purposes can be much more successful than a complex multidrug program. The production of these multifunctional ligands as antiretroviral drugs is valued with the advantage that the viral-replication process may end in two or more phases. This analysis will discuss the RT-IN dual-inhibitory scaffolds' developments documented so far.

Wnt signaling plays a critical role during embryogenesis and is responsible for regulating the homeostasis of the adult stem cells and cells fate via a multitude of signaling pathways and associated transcription factors, receptors, effectors, and inhibitors. For this review, published articles were searched from PubMed Central, Embase, Medline, and Google Scholar. The search terms were Wnt, canonical, noncanonical, signaling pathway, β-catenin, environment, and heavy metals. Published articles on Wnt signaling pathways and heavy metals as contributing factors for causing diseases via influencing Wnt signaling pathways were included. Wnt canonical or noncanonical signaling pathways are the key regulators of stem cell homeostasis that control many mechanisms. There is an adequate balance between β-catenin dependent and independent Wnt signaling pathways and remain highly conserved throughout different development stages. Environmental heavy metal exposure may cause either inhibition or overexpression of any component of Wnt signaling pathways such as Wnt protein, transcription factors, receptors, ligands, or transducers to impede normal cellular function via negatively affecting Wnt signaling pathways. Environmental exposure to heavy metals potentially contributes to diseases via deregulated Wnt signaling pathways.

The treatment of Cutaneous Leishmaniasis (CL) is complex, and the search for safer, more efficient, and cost-effective treatments is ongoing. This study aimed to evaluate the efficacy of the combination of liposomal and oral azithromycin as the first clinical study against CL. This assessor-blind, randomized clinical trial was conducted in out-patients Leishmaniasis clinic of Skin Diseases and Leishmaniasis. The cutaneous lesions of eligible participants were randomized to receive either oral azithromycin or the combined oral and topical liposomal azithromycin. All participants received 250 mg of azithromycin twice daily or 8 mg/per kg for 4 weeks. In the combination group, a topical liposomal formulation of 0.04 mmol/mL of azithromycin was administered as 0.2-0.5 cc twice daily according to the lesion size in order to make a thin layer of the drug on the surface of the lesion. The size and induration changes from baseline to the end of the study were analyzed. Twenty-one lesions of 13 patients in the combination group and 20 lesions of 14 patients in the oral group were recruited. The mean ± SD of improvement was significantly different between two groups after 12 weeks (3.89 ± 0.46 vs. 3.15 ± 1.23 P = 0.02 combination group vs. oral group respectively). The patients did not experience any systemic adverse effects related to azithromycin and the only adverse effects related to topical treatment were mild pruritus in 2 cases. In conclusion, the combination of oral and topical liposomal formulation of azithromycin is safe and effective to treat CL.

The antihyperglycemic effect of the polyherbal combination of the leaves of Momordica balsamina Linn (MB) and Leptadenia hastata (pers) Decne (LH) have been reported in our previous study in addition to its documented dietary usages. However, the bioactive principles are yet to be fully elucidated. In the present study, bioactive antidiabetic compounds from the leaf extracts of Momordica balsamina Linn and Leptadenia hastata (pers) Decne were isolated and characterized. The plant leaves were fractionated with solvents in ascending order of polarity (hexane-chloroform-ethylacetate-methanol) using microwave assisted extraction method. The ethylacetate (MBE) and methanolic (LHM) leaf extracts of MB and LH, having the highest antihyperglycemic effects were purified by column chromatography and preparative thin layer chromatography. The antihyperglycemic activity of the isolated compounds was evaluated in streptozotocin (STZ)-induced diabetic rats and the structures of the most bioactive compounds were elucidated by 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy in comparison with reported literature. A pentacyclic triterpenoid (H3) and an isoflavone (LH2b) isolated from MBE and LHM with significant (p < 0.05) antihyperglycemic effects were identified as betulinic acid and 5-methyl genistein respectively. Our study isolated for the first time a triterpenoid and an isoflavone with potential antidiabetic effects from these indigenous antidiabetic plants. This further validates the traditional multi-therapeutic usage of the combination for the management of Diabetes Mellitus (DM) and its complications.

ACE- inhibitors, angiotensin receptor blockers, beta-blockers, Ca- antagonists are recommended as first-line monotherapy for hypertension. The aim of the current study is to analyze expenditures paid by the National Health Insurance Fund (NHIF) after introducing the budget cap cost-containment measure and its impact on affordability and utilization. The study is a retrospective, observational analysis of expenditure on main groups' antihypertensive medicines: beta blockers, calcium channel blockers, ACE- inhibitors, and AT receptor blockers. The cost paid by the NHIF two years before (2016-2017), and after (2018-2019) the introduction of the budget cap measure was evaluated. Utilization and affordability data covering antihypertensive therapy were retrospectively calculated and analyzed during 2016-2019. The reimbursed expenditures on sartans, ACE-inhibitors, and β-blockers decreased in absolute terms in 2019 compared to that in 2016. There are no statistically significant differences, excluding the group of sartans. The result reveals decreasing utilization of ACE-inhibitors and β-blockers, which is the most significant for enalapril and bisoprolol. Affordability increases during the observed period because less than a working day income is sufficient for monthly therapy.  Patients with hypertension in Bulgaria have access to affordable first-line antihypertensive medicines. Despite the stable and low prices, utilization mainly decreases. The reimbursed amount is reduced with a low rate or remains similar to that found at the beginning of the observed period. The results of the implemented budget cap as a measure to control NHIF cost are not evident and not fully expressed on the market for the first-line antihypertensive therapy.

In phytochemical analysis, Jacein derivatives: 5,7,4''-trihydroxy-3,6,3''-trimethoxyflavone-7(β)-D-glucopyranoside (1), and 3-demethyljacein: 3,5,7,4''-tetrahydroxy-6,3''-dimethoxyflavone-7(β)-D-glucopyranoside (2) were isolated from Campylopus schmidii (C. schmidii) for the first time. The structures were determined by interpretation of NMR, UV, and Mass spectra. To check the roles of ER stress and consequent apoptosis in MCF-7 cell by these compounds, UPR signaling pathway was further examined by analysis of expression of ER stress-related genes. In MTT assay, compounds 1-2 showed cytotoxicity activity against MCF-7 (A) and MDA-MB cells (B) with IC50 values (μM) of 1) 60.04 ± 7.98 (A), and > 200 (B); 2) 42.89 ± 1.91 (A), and 85.31 ± 2.68 (B). The Annexin/PI flow cytometry apoptosis of tested compounds 1-2 was increased significantly in a dose-dependent manner. For example, MCF-7 treatment at the concentration of 100 μM of compounds 1, 2 resulted in total apoptosis (early + late) of 42.04 (18.1 + 24.0), and 66.49 (2.7 + 63.8)%, respectively.  Fluorescence microscopy analysis detected an increased protein aggregation, indicating induced ER stress with a marked increase in XBP-1, sXBP-1, ATF-4, and CHoP compared to untreated cells. In-silico characterization, suggested that Adenosine diphosphate site (A-site) and quercetin site (Q-Site) in IRE1a enzyme are both available interacting sites of a target for the investigated ligands but with different strengths of interactions. The results indicated that the ligand∼A-Site complexes are stronger than the ligand∼Q-Site complexes, but the already available ADP ligand in cells does not allow other ligands to interact with the A-Site and cause them to bond in Q-Site.

Human exposure to polycyclic aromatic hydrocarbons (PAHs) is known as a carcinogen risk factor. In this study, a gas chromatography-mass spectrometry (GC-MS) technique combined with the QuEChERS extraction method was developed for concurrent analysis of 10 polycyclic aromatic hydrocarbons (PAHs) in Iranian traditional Sangak bread samples. The method was validated by determining different parameters, including; linearity, accuracy, precision, limit of detection (LOD) and limit of quantitation (LOQ). Calibration curves showed a linear relationship in the concentration range of 10-500 ng/g with a coefficient of determination (R2) ranged between 0.994 and 0.999. The obtained mean recoveries were 92-106% with the relative standard deviations (RSDs) in the range of 3-7% with an acceptable precision (RSD < 20%). The Limit of detections (LODs) for different PAHs were between 0.14-0.78 ng/g, while the limit of quantitation (LOQ) was 0.46-2.60 ng/g. Matrix effect studies showed that the analytes concluded signal suppressions or enhancements. Therefore, spiked calibration curves were used for overcoming this issue. The result of Sangak bread samples analysis using the validated method showed that 9 (19.4%) out of 47 Sangak bread samples were contaminated with phenanthrene (PHE) and anthracene (ANT) at the mean level of 10.08 ± 6.38 ng/g which were higher than the permissible limit of European Commission regulatory control value for BaP (1 μg/kg of wet weight) in processed cereal-based foods and baby foods for infants and young children.

Reperfusion therapies are recommended for patients with hemodynamic instability or high-risk acute pulmonary embolism (PE). Lower doses of tissue plasminogen activator (rt-PA) could be considered to improve bleeding complications. The aim of this study was to evaluate the efficacy and safety of a reduced dose of rt-PA for the treatment of acute PE, compared with anticoagulation and standard dose. PubMed Central, Scopus, Web of Science and Embase were searched for all relevant randomized studies and prospective observational studies that compared reduced dose of rt-PA with anticoagulation alone or standard dose of rt-PA in patients with acute PE. The risk ratios (RR, with 95% CI) were calculated according to the value of I2. Outcomes were described as bleeding events, all-cause death, and recurrence of PE. Thirteen articles, including four observational studies (4223 patients) and nine RCTs (780 patients), were included. In comparing reduced dose of rt-PA with anticoagulant, a greater incidence of total bleeding events in low dose was showed (RR, 5.08 (95% CI, (1.39–18.6), I2  =  0.0%). In the standard dose rt-PA vs. reduced dose, there was a greater incidence of total bleeding events in the standard dose of rt-PA, RR 1.48 (95% CI, (1.00–2.19), I2 = 0.0%) was shown. There were no statistical differences in recurrent PE or all-cause mortality. It concluded that in the absence of the benefit of a standard dose of rt-PA in comparison with dose reduction, a reduced dose of rt-PA showed a lower rate of total bleeding events and similar efficacy regarding mortality and PE recurrence rate.

Irrational use of antibiotics as a global health concern has led to excessive treatment costs, failure of treatments, and antimicrobial resistance. Parents’ knowledge of and practice regarding antibiotics are two important factors contributing to the (ir) rational use of antibiotics. This study aimed to evaluate ill children’s parents’ knowledge and practice of prescribed antibiotics. Our subjects included only parents with children up to 12 (inclusive) years of age in Tehran, Iran’s capital. A prospective cross-sectional survey was conducted at 203 health care centers in Tehran. Parents’ knowledge was evaluated using a 37-item researcher-made questionnaire, and their practice about antibiotics was measured with a self-stated questionnaire, followed by an observational method to gain a real insight into their practice. SPSS 22 was used to analyze the data.A total of 401 randomly selected parents were enrolled in the study. The average score of parents’ knowledge of antibiotics regarding administration, indications, storage, and antimicrobial resistance was found to be 9.72 out of 17.00. In the self-stated method, an appropriate practice of antibiotic use was reported in 49.4% of participants who also got an average score of 3.95 points out of a total 8. In the observational method, most parents’ practice (68.4%) regarding antibiotic use was found to be acceptable; their average score was 5.93 points out of a total of 10. The findings of this study showed that half of the parents had adopted an acceptable practice regarding antibiotic use.

Pruritus is one of the disturbing complications induced by chronic liver disease (CLD), bearing a negative impact on patient quality of life and potentially resulting in early liver transplants. Given the main role of the autotaxin enzyme in pruritus induced by CLD and the suppressive effects of melatonin on the expression of the autotaxin gene, this study was designed to evaluate the antipruritic effect of melatonin in patients with CLD. A double-blind, cross-over, randomized, placebo-controlled pilot trial was conducted on patients with CLD -induced pruritis. Patients were randomly assigned to two groups where they received melatonin 10-mg at night or placebo for 2 weeks. After a 2-week washout period, patients were then crossed over to the other group. The Visual Analog Scale (VAS) and the 12-Item Pruritus Severity Score (12-PSS) were used to assess patient response to therapy as the co-primary outcomes, while liver function tests were assayed too. Forty patients completed the study. The VAS score showed alleviation of 3.21 ± 2.24 (in pruritus) with melatonin (p-value <0.05). The study goal (a reduction of at least 20% in VAS) was achieved in 33 (82%) of study participants. In patients who received melatonin, the 12-PSS and Body Surface Area (BSA) affected by pruritus decreased on average 46.57% and 51.71%, respectively, with mood, sleep pattern and daily activity levels also demonstrating significant improvement (p-value < 0.05). Melatonin was found to be effective for managing pruritus in patients with CLD.

Poisoning, as a well-known medical condition, puts everyone at risk. As a data management tool, a registry plays an important role in monitoring the poisoned patients. Having a poisoning minimum data set is a major requirement for creating a poisoning registry. Therefore, the present systematic review was conducted in 2019 to identify the minimum data set for a poisoning registry. Searches were performed in four scientific databases, i.e., PubMed, Scopus, Web of Science, and Embase. The keywords used in the searches included minimum data set, “poison”, and “registry”. Two researchers independently evaluated the titles, abstracts, and texts of the papers. The data were collected from the related papers. Ultimately, the minimum data set was identified for the poisoning registry. Data elements extracted from the sources were classified into two general categories: administrative data and clinical data. Ninety-eight data elements in the administrative data category were subdivided into three sections: general data, admission data, and discharge data. One-hundred and thirty-one data elements in the clinical data category were subdivided into five sections: clinical observation data, clinical assessment data, past medical history data, diagnosis data, and treatment plan data. The minimum data set is a prerequisite for creating and using a poisoning registry and data system. It is suggested to evaluate and use the poisoning minimum data set in accordance with the national laws, needs, and standards based on the opinion of the local experts.

Currently, most of the developed and developing countries are facing the problem of infectious diseases. The genius way of an exaggerated application of antibiotics led the infectious agents to respond by bringing a regime of persisters to resist antibiotics attacks prolonging their survival. Persisters have the dexterity to communicate among themself using signal molecules via the process of Quorum Sensing (QS), which regulates virulence gene expression and biofilms formation, making them more vulnerable to antibiotic attack. Our review aims at the different approaches applied in the ordeal to solve the riddle for QS inhibitors. QS inhibitors, their origin, structures and key interactions for QS inhibitory activity have been summarized. Solicitation of a potent QS inhibitor molecule would be beneficial, giving new life to the simplest antibiotics in adjuvant therapy.

Postoperative cognitive dysfunction is a common postoperative neurological complication in elderly patients, and has some relationship with neuroinflammation. some studies have shown ability of dexmedetomidine to improve cognitive performance in elderly individuals who underwent thoracic surgery. Therefore, our study hypothesized that dexmedetomidine treatment may reduce the incidence of POCD in elderly patients.In addition,this study detected the antineuroinflammatory effects of dexmedetomidine by β-amyloid aggregation inhibitors and release of cytokines in elderly patients . The results show that dexmedetomidine used during operation can inhibit the postoperative release of Aβ and cytokines in elderly patients, and dexmedetomidine used during operation can reduce the incidence of postoperative cognitive dysfunction, with dose-dependence. These results provide a clinical application direction for clinical anesthesiologists and ICU physicians.

Glyco-engineering has attracted lots of interest in studies dealing with the pharmacokinetics of therapeutic proteins. Based on our previous in-silico studies, two sites were selected in the N-terminal gamma-carboxy glutamic acid-rich (Gla) domain of the human clotting factor IX (hFIX) to add new N-glycosylation sites. Site-directed mutagenesis was employed to conduct K22N and R37N substitutions and introduce new N-glycosylation sites in the mature hFIX. The expression efficiencies of the mutants, in parallel with the wild-type hFIX (hFIXwt), were assessed in suspension adapted Chinese hamster ovary (CHO-s) cells at transcriptional, translational, and post-translational levels. The transcription levels of both N-glycosylation mutants were significantly lower than that of the hFIXwt. In contrast, at the protein level, the two hFIX mutants showed higher expression. The occurrence of hyper-glycosylation was only confirmed in the case of the hFIXR37N mutant, which decreased the clotting activity. The higher expression of the hFIX mutants at protein level was evidenced, which could be attributed to higher protein stability, via omitting certain protease cleavage sites. The coagulation activity decline in the hyper-glycosylated hFIXR37N mutant is probably due to the interference of the new N-glycan with protein-protein interactions in the coagulation cascade.

A series of aminoguanidine derivatives containing an acylhydrazone moiety was designed based on combination principles to find new antibacterial agents with wide spectra and high activities. The synthesized compounds were characterized by spectral methods and screened for their antibacterial activity. The results showed that several compounds provided great antimicrobial activities against Gram-positive bacteria (including the multidrug-resistant clinical isolates). Especially, this series of compounds presented high potency against Staphylococcus aureus, among which the derivative 3f was the most promising one with a MIC value of 4 μg/mL. Compound 3d, with a tertiary butyl group, was found to have the broad spectrum inhibitory capacity, which is effective to eight strains and showed the most potent inhibitory activity against B. subtilis CMCC 63501 with a MIC value of 4 μg/mL. What’s more, compound 3d also presented high activities against four multidrug-resistant strains, which were comparable or potent to oxacillin and penicillin. Molecular docking studies revealed that H-bond interaction with amino acid residue THR81 and alkyl hydrophobic interaction with residue ALA246 of FabH were crucial for their binding force and in-vitro antimicrobial activities.

Novel 1,2,3-triazole-tethered 9-bromonoscapine derivatives were synthesized by the propargylation of N-nornoscapine followed by Huisgen’s 1,3-dipolar cycloaddition of the terminal alkynes with different azides. Cytotoxicity of the products was studied by MTT assay against the MCF-7 breast cancer cell line. Most of the compounds revealed a better cytotoxicity than N-nornoscapine and 9-bromonornoscapine as the parent compounds. Among the synthesized compounds, those with a hydroxylated aliphatic side chain (5p, 5q, and 5r) showed the highest activities (IC50s: 47.2, 37.9, and 32.3 μg/mL, respectively). Molecular docking studies showed that these compounds also had the highest docking scores and effective interactions with binding sites equal to -8.074, -7.425 and -7.820 kcal/mol, respectively.