Pharmaceutical Sciences
Volume:29 Issue: 1, Jan 2023

Despite the tremendous progress in breast cancer diagnosis and treatment, the mortality rate is expected to increase due to the emergence of drug resistance. Pro-inflammatory markers are thought to contribute to drug resistance by activation of its naive receptors and its downstream signaling pathways. Elevation of pro-inflammatory markers leads to an increase in the biosynthesis of estrogen which can promote the proliferation of estrogen receptor (ER)+ breast cancer. Inflammation also results in obesity which is one of the key risk factors. Estrogen receptor-beta (ER-β) is an important target that has been widely studied and accepted to possess anti-cancer activity in a number of cancers including breast cancer. ER-β elicits its action through genomic and non-genomic pathways. The genomic pathway increases the transcription of potent cyclin-dependent kinase inhibitor (p21), and tumor suppressor genes such as melanoma differentiation associated gene 7 and tumor protein (p53). The non-genomic pathway works through protein-protein interaction and phosphorylation. Here, we propose that the activation of ER-β might enhance the activation of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) via estrogen receptor-alpha (ER-α) repression. The activation of Nrf2 increases the transcription of antioxidant genes such as NADH quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), etc., and decreases the expression of pro-inflammatory genes such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), etc. This review hypothesizes and suggests that ER-β agonists could play a beneficial role to overcome inflammation-related drug resistance by modulation of the Nrf2/antioxidant response element (Nrf2/ARE) pathway.

The immune system plays an essential role in cancer pathogenesis through providing an inflammatory immune response. Chronic inflammation causes tumor growth, angiogenesis, and metastasis facilitated by interactions between tumor, immune, and stromal cells in the tumor microenvironment (TME). Various inflammatory mediators and growth factors secreted by cells in the TME exert a synergistic effect on cancer promotion. Thus, the development of cancer therapies that lead to inhibition of the activity of immune cells, cytokines, chemokines, and cancer-inducing growth factors is a promising therapeutic strategy. Andrographis paniculata (A. paniculata) is an ethnomedicinal plant with immunomodulatory and anticancer activity. A. paniculata can also inhibit the resistance of chemotherapy agents associated with TME as adjuvant chemotherapy. This review focuses on the mechanism of A. paniculata in suppressing cancer-associated chronic inflammation, angiogenesis, and metastasis through modulation of the immune response. The results show that A. paniculata exerts anticancer effects directly targeting cancer cells, inhibiting cancer growth by modulating immune responses. A. paniculata exerts anticancer effects by inhibiting the production of cytokines, growth factors, and chemokines via the nuclear factor-kappa B (NF-ĸB), mitogen-activated protein kinase (MAPK), Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways. In addition, this review provides a new hypothesis regarding the potential of A. paniculata to serve as an anticancer agent that can inhibit cancer cell proliferation at the angiogenesis and metastatic stages through regulating inflammation due to interactions between cancer cells, immune cells, and stromal cells in the TME.

Researchers have mentioned many beneficial effects for the compounds present in the toothbrush tree (Miswak) (Salvadora persica: SP); such as anti-inflammatory, antioxidant and antimicrobial activities. The current study aimed to evaluate the effect of aqueous-alcoholic extract of toothbrush tree on the wound healing of second-degree skin burns in BALB/c mice.

In this study, 60 mature mice (8 weeks) were used. The mice were divided into 5 groups of twelve. Groups 1 and 2 were respectively treated with concentrations of 5% and 10% of aqueous-alcoholic extract of the toothbrush plant, group3 was treated with silver sulfadiazine ointment (positive control), group4 was treated with Vaseline (negative control), and group 5 (sham) received no treatment. A second-degree circular burn wound with a diameter of 1 cm was made on the back of the animal. The first to fourth groups were dressed twice a day. On days 4, 7, 10 and 14, sampling was performed from the wounded site and wound healing was evaluated histopathologically.

Inflammation and infiltration of neutrophils and lymphocytes, being compared to the negative and sham control groups, were significantly reduced in the group treated with 10% SP extract (P<0.01); besides, on days 10 and 14 in the group treated with 10% and 5% SP extracts, the number of fibroblasts, followed by collagen production, epithelialization and formation of new hair follicles in the wound margins significantly increased compared to the negative control and sham group (P<0.05). The number of fibroblasts and collagen fiber density in the group treated with 10% SP extract, compared to the 5% extract group and silver sulfadiazine, showed a significant increase (P<0.05).

The findings showed that using extract of toothbrush plant accelerates the healing process of burn wounds.

The success of Staphylococcus aureus as an important human pathogen is probably due to possession of various virulence determinants. Attachment and biofilm formation is considered the main step in any infection. The present study aimed to determine the presence of S. aureus surface (sas) genes and their association with biofilm formation and antibiotic resistance.

S. aureus isolates collected were analyzed for biofilm formation using polystyrene microtitre plates. All S. aureus isolates were also examined for the determination of sas genes by PCR assays and antibiotic susceptibility assay by disk diffusion method.

Biofilm formation assay revealed that 29 S. aureus isolates were weak biofilm producers, 57 had moderate biofilm production, while only five isolates showed strong biofilm formation. The biofilm production was not revealed among nine isolates. The frequency of sas genes were 95 (88%), 94 (87%), 94 (87%), 92 (85.2%), 98 (90.7%), 93 (86.1%), 97 (89.8%), 87 (80.6%), and 85 (78.7%) for sasF, sasA, sasC, sasE, sasG, sasH, sasI, sasJ, and sasK genes, respectively.

High incidence of biofilm production was noticed in S.aureus strains positive for sas genes indicating the precise role of them as virulence-associated genes. Moreover, phenotypically weak or moderate biofilm formation can be well managed by antibiotic therapeutics and allow timely elimination of planktonic cells prior biofilm production.

 Neonatal respiratory distress syndrome (NRDS) affects approximately up to 7% of all term newborns. This study aimed to assess the efficacy and safety of investigational beractant (BeraksurfTM, Tekzima Company) in comparison with poractant alfa (Curosurf®, Chiesi Pharmaceuticals) as surfactant replacement therapy in NRDS.

 This trial was a randomized, controlled, single-blind, phase III study of two natural surfactants which was conducted in NICU of Alzahra hospital in Tabriz for 8 months. 220 infants were enrolled in 2 groups to receive either 100 mg/kg BeraksurfTM or 200 mg/kg Curosurf® as an initial dose endotracheally. Additional doses were given if needed. Infants’ gestational age, birth weight, discharge weight and other demographic information were recorded. Efficacy outcomes were changes in fraction of inspired oxygen (FiO2) and the number of infants who reached FiO2 less than 0.3 (treatment success rate) which were compared between both groups with analysis of covariance (ANCOVA).

 The results showed that the treatment success rate was 92% and 72% in BeraksurfTM and Curosurf® groups, respectively (P-value< 0.001). In addition, no difference was observed in the efficacy of these two treatments in terms of binary outcomes and incidence of complications such as mortality.

 The result analysis of current study implies BeraksurfTM has same beneficial impact on clinical management of RDS as Curosurf® among infants below 32 weeks. However, larger studies are needed to evaluate further efficacy and safety outcomes of this surfactant in comparison with the reference products in other subgroups.

Thrombolytic therapy is a key in the management of ST elevated myocardial infarction (STEMI). Metformin implies a series of cardioprotective effects. We aimed to investigate how pretreatment with metformin could affect cardiac troponin I (cTnI) levels following reteplase therapy amid STEMI patients.

A pilot randomized clinical trial was carried out in 80 STEMI patients undergoing thrombolytic therapy with reteplase. The metformin group (n = 40) received a single dose of 1000 mg metformin orally before receiving reteplase, while the control group (n = 40) received only reteplase. The serum level of cTnI was measured at baseline, 8, 16, 24, and 32 hours after the admission to assess myocardial damage.

There was no significant difference in cTnI levels at baseline (p = 0.657), 8 (p = 0.93), 16 (p = 0.690), 24 (p = 0.217), and 32 (p = 0.517) hours after STEMI diagnosis between two groups. The mean differences were also not significant for changes of cTnI at baseline and other time frames.

The results of the present study demonstrated that early use of 1000 mg metformin prior to reteplase could not reduce the level of cTnI in STEMI patients.

 Intestinal absorption of levofloxacin (LFX) is decreased by the concomitant administration of antacids due to the formation of insoluble chelate complexes with various metal cations.

 The following four ester prodrugs of LFX—cilexetil ester (LFX-CLX), medoxomil ester (LFX-MDX), ethoxycarbonyl 1-ethyl hemiacetal ester (LFX-EHE) and pivaloyloxymethyl ester (LFX-PVM)—were synthesized. Then, the lipophilicity, in vitro chelate formation with aluminum chloride (AlCl3), chemical and enzymatic stability, minimum inhibitory concentrations (MICs) against some bacteria, and the efficacy in preventing chelate formation of prodrugs with aluminum hydroxide (Al(OH)3) in rabbits were evaluated.

 The synthesized ester prodrugs of LFX exhibited high purity and higher lipophilicities than LFX depending on the ester moieties. MICs of the prodrugs against S. aureus, E. coli, and P. aeruginosa were more than 10 times higher than those of LFX. Prodrugs were stable chemically but unstable enzymatically and generated LFX in biological specimens. When AlCl3 solution was mixed with LFX solution in vitro, insoluble chelate complex was formed immediately. In rabbits, co-administration of Al(OH)3 with LFX reduced the oral bioavailability of LFX by approximately 40%. In contrast, no precipitation was observed when AlCl3 solution was mixed with each prodrug solution in vitro, and co-administration of Al(OH)3 exerted no significant effect on the oral bioavailability of LFX when each prodrug was administered in rabbits.

 The ester prodrug approach of LFX could be a feasible strategy for avoiding chelate formation with aluminum ion in vivo.

The JAK-STAT pathway has been revealed to play a crucial role in the dysregulation of immune responses in autoimmune skin disorders. Ruxolitinib, a selective inhibitor of JAK1 and JAK2, potently suppresses cytokine signaling.

A topical emulgel containing ruxolitinib nanoliposome (RuxoLip) was prepared by thin film hydration method. Then, its physicochemical characteristics were evaluated at 25±2 ̊C/60±5% RH for 12 months. RuxoLip was assessed based on particle characteristics, Scanning Electron Microscopy (SEM), entrapment efficiency (EE), drug loading (DL), and Differential Scanning Calorimetry (DSC). The pH, density, viscosity, microbial assessment, in vitro drug release, and in vivo tape stripping test were evaluated on the emulgel of RuxoLip. Validating the analysis method was performed by UV spectroscopy.

Nanoliposomal preparation was successfully formulated with a good particle size (218±2 nm), an EE of 67% and a DL of 8%. The formulation was stable in a long-term condition. SEM showed that liposomes had a regular spherical surface. Moreover, in vitro drug release and the in vivo tape stripping test revealed good absorption and permeation, respectively.

The liposome dosage form is anticipated to be a perfect carrier for the topical drug delivery system of ruxolitinib in autoimmune skin disorders.

Enoxaparin is low-molecular-weight heparin administered by subcutaneous/intravenous injection. The oral bioavailability of enoxaparin is restricted by its low absorption through the intestine. In this study cell-penetrating peptide-surface functionalized liposomes (CPPs-L) were prepared to improve the intestinal absorption of enoxaparin.

Liposomal formulations were prepared by the ethanol injection method and the intestinal absorption of the formulation was evaluated using the single-pass intestinal perfusion (SPIP) technique in rats. Meanwhile, the human fraction dose absorbed value (Fa (human)) of the formulations was predicted based on the calculated effective intestinal permeability (P effect (rat)) values obtained from the SPIP study.

Liposomal enoxaparin revealed an increased intestinal absorption by ten-time compared with the free drug solution. Meanwhile, CPPs-L formulation revealed an enhanced intestinal absorption compared with the un-modified liposomal formulation. Regarding Fa (human), it is predicted that liposomal formulations could have the potential to improve the fraction dose absorbed of enoxaparin from low to intermediate levels.

Overall, the liposomal formulation can be considered as a mighty drug carrier for the oral delivery of enoxaparin.

 Type 1 diabetes is an autoimmune disorder characterized by the loss of pancreatic islets. Islet allotransplantation is a potentially beneficial therapeutic approach for diabetes. Islets suffer a variety of cellular insults including ischemia and partial vascular loss during isolation, resulting in a significant reduction in viability prior to transplantation. The present study aimed to investigate the effect of angiogenic microRNA (miRNA)-126 and -210 on islet function and viability in an indirect way.

 Poly Ethylenimine (PEI)-miRNA-126 and -210 polyplexes were constructed at various Nitrogen/Phosphate (N/P) ratios. After confirmation by gel retardation and ethidium bromide dye exclusion assay, its cytotoxicity and transfection efficiency were analyzed by MTT and fluorescent assays, respectively. After that, the selected polyplexes were used to transfect Human Umbilical Vein Endothelial Cells (HUVECs) in vitro and were indirectly co-cultured with islet cells for three days. Real-time polymerase chain reaction and enzyme-linked immunoassay were conducted to verify the regulation of target genes and the functionality of the islets.

 The findings showed that PEI could condense miRNAs at N/P=5. The viability of the HUVECs was decreased by increasing the amount of PEI. Additionally, ployplex-126 and -210 led to a decrease in the expressions of target genes, phosphoinositol-3 kinase regulatory subunit 2, sprouty-related EVH1 domain-containing protein 1, and ephrin-A3 in the islets. Moreover, the expressions of Bax and Bcl2 and their ratio in the treated groups by polyplex-126 and -210 led to better survival and function of the islets, with a higher expression of insulin and response to glucose stimulations. Furthermore, polyplex-210 could downregulate the anti-angiogenic protein, thrombospondin 1, compared to the other groups. Finally, the secretion of C-peptide was higher in polyplex-210 than in the other groups, adjusted for insulin secretion.

 The results indicated that angiogenic miRNAs could promote the survival and function of islet cells by interacting with their targets.

 Tea (Camellia sinensis L.O. Kuntze) is one of the most commonly consumed beverages globally, with several beneficial health effects. The composition of leaves is affected by different factors such as climate and tea cultivar.

 In this study, the total phenolic, flavonoid, and tannin contents, and antioxidant activities of eight cultivars of tea growing in Iran were determined. The epigallocatechin gallate (EGCG) contents were measured by high-performance liquid chromatography (HPLC) analysis. The Fourier-transform infrared (FT-IR) spectra were used to construct a supervised pattern recognition model using a genetic algorithm-support vector machine (GA-SVM) for the classification of cultivars.

 The results indicated a wide variation of total phenolic content (178.04 to 316.09 mg gallic acid equivalents (GAE)/g extract). Also, the flavonoid contents ranged from 25.54 to 41.1 mg quercetin equivalents )QE(/g extract. All the samples had close tannin amounts (ranging from 40.32 to 45.90 mg as tannic acid equivalent (TAE)/g extract). There was a significant linear relationship among total phenolic and flavonoid contents and antioxidant properties. The cultivars DN, PK2, and C.Y.9 had the highest content of phenolic and flavonoid content as well as the best antioxidant activity. The EGCG contents were from 2.66 to 4.12%. The highest amount of EGCG was found in cultivars 282, PK2, and C.Y.9. The discriminative region of FT-IR spectra (1350-1650 cm-1) was selected using a GA-SVM. This model showed 100% sensitivity and specificity for training and test sets.

 The leaves’ phytochemical compositions and antioxidant effect are deeply dependent on the type of tea cultivars. The cultivars PK2 and C.Y.9 can be considered richer sources of polyphenols, especially EGCG. The eight different cultivars can be classified based on chemical components using the recorded FT-IR spectra.

 An eco-friendly approach for the synthesis of noble metal nanoparticles employing various plant extracts has become of great interest in the field of nanotechnology. In the present study, the efficacy of Grewia tiliifolia leaf extract in reducing 1 mM silver nitrate to silver nanoparticles (AgNPs) has been reported for the first time. We also investigated the anticancer, antituberculosis and antioxidant activity.

 Characterization of biosynthesized AgNPs using G. tiliifolia leaf extract was evaluated by different techniques. Efficacy of biosynthesized AgNPs using G. tiliifolia leaf extract was tested for cytotoxicity against A549 Lung cancer cell lines by MTT Assay and against the infectious agent Mycobacterium tuberculosis using MABA assay. Further antioxidant activity was evaluated by DPPH radical scavenging assay.

 The biosynthesis of AgNPs was evident by a color change of the reaction mixture from dark yellow to reddish-brown. Biofabricated AgNPs were further confirmed by characteristic surface plasmon absorption peak at 409 nm by UV-vis analysis. FTIR data reveals the presence of phytochemicals involved in bioreduction and biocapping of AgNPs, XRD analysis depicted the crystallographic nature of AgNPs. Further, size, charge, and polydispersity nature were studied using DLS (40.2 nm with polydispersity index 0.361) and Zeta potential (-35.8 mV). The morphology of AgNPs was determined by TEM analysis with a size ranging from 11-34 nm. The plant-derived AgNPs exhibited a cytotoxic effect on the lung cancer cell line with an IC50 value of 23.45 µg/ml and were also found to be effective against M. tuberculosis with a MIC of 6.25 µg/ml in comparison to the leaf extract (MIC 50 µg/ml). Antioxidant activity observed by AgNPs was moderate with IC50 value of 49.60 µg/ml.

 The findings indicate that the AgNPs synthesized from leaf extract of G. tiliifolia are eco-friendly, cost-effective, non-toxic and can be effective natural anticancer, antituberculosis and antioxidant agents.

 The study of medicinal plants has made it possible to develop products and drugs for the treatment of different diseases. Several plants in Colombia have a history of popular use for the treatment of malaria. The objective of this work was to provide information on the antiplasmodic and phytochemical activity of five neotropical native plants with a folk use for the treatment of malaria.

 The ethanolic extract of each species was obtained by percolation method and characterized by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and hydrogen nuclear magnetic resonance (1H-NMR). The in vitro antiplasmodial activity was evaluated against Plasmodium falciparum (strain FCR-3, chloroquine-resistant).

 Ethanolic extracts of Ambelania duckey, Cecropia metensis, Cecropia membranacea, and Verbena littoralis showed no activity. However, Curarea toxicofera extract exhibited an IC50 of 7.6 ± 3.9 μg/mL and was classified as moderately active. Most extracts show hemolytic concentration (CH50) > 1000 μg/ mL). A preliminary phytochemical study was carried out using tube analysis, TLC, HPLC, and 1H-NMR. Steroids or triterpenes, and phenolic compounds were detected by TLC in all extracts. These findings were confirmed by characteristic aliphatic and aromatic signals in 1H-NMR spectra, corresponding to triterpenes and phenolics, respectively. Additionally, alkaloids were extracted from C. toxicofera and detected by aromatic signals in 1H-NMR spectra.

 Ethanolic extract of C. toxicofera showed antiplasmodial activity (IC50 of 7.6 ± 3.9 μg/mL); this activity may be due to the bisbenzylisoquinoline alkaloids. The ethanol extracts of A. duckey, C. membranacea, C. metensis, and V. littoralis did not present antiplasmodial activity.