Current Pharmaceutical Design - Volume 29, Issue 24, 2023

The pathophysiology of hypertension is often associated with endothelial dysfunction and the impairment of endothelium-dependent vasodilation mechanisms, as well as alterations in vascular smooth muscle (VSM) tone. Natural products, particularly alkaloids, have received increased attention in the search for new vasodilator agents. This review aims to summarize the noteworthy results from ex-vivo and in-vitro studies that explored the vasodilatory effects of some selected alkaloids (Berberine, Sinomenine, (S)-Reticuline, Neferine, Nuciferine, Villocarine A, 8-Oxo-9-Dihydromakonakine, Harmaline, Harman, and Capsaicin) and the underlying mechanisms implicated. The results obtained from the literature revealed that these selected alkaloids exhibited vasodilation in various vascular models, including mesenteric, carotid, and coronary arteries, thoracic aorta, and cultured HUCECs and VSMCs. Furthermore, most of these alkaloids induced vasodilation through endothelium- dependent and endothelium-independent mechanisms, which were primarily mediated by activating eNOS/NO/sGC/cGMP pathway, opening various potassium (K⁺) channels, or modulating calcium (Ca2⁺) channels. Additionally, several alkaloids exerted vasodilatory effects through multiple mechanism pathways. Moreover, different alkaloids demonstrated the ability to protect endothelial function by reducing oxidative stress, endoplasmic reticulum and inflammation. In conclusion, this class of secondary metabolites holds interesting therapeutic potential in the prevention and treatment of cardiovascular diseases (CVD), particularly hypertension.

Many nanodrug delivery systems used with various routes of administration have been developed recently. These may be dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, or polymeric nanoparticles. The nanodrug delivery systems may improve effectiveness, safety, physicochemical qualities, and pharmacokinetic/pharmacodynamic profile. Functionalized nanodrug delivery systems can increase the half-life, improve the bioavailability of orally administered pharmaceuticals, and target tissue distribution. By decreasing the number of dosage intervals required, increasing the magnitude of the intended pharmacological effects, and decreasing the severity of undesirable systemic side effects, nanodrug systems show promise for improving treatment adherence and clinical results. Nanodrugs have been demonstrated to exhibit cytotoxicity, oxidative stress, inflammation, and genotoxicity in vitro and in vivo; however, this attention has recently been refocused on their potentially harmful potential owing to their beneficial pharmacokinetic features for the treatment of cancer. Researchers require a more profound knowledge of the pharmacokinetic and safety aspects of nanodrugs and the limits of each administration route to continue creating safe and efficacious nanodrugs with high therapeutic potential. The benefits and risks associated with pharmacokinetics have been highlighted in this article, which describes the current state of nanodrug system development.

Purpose: Acute kidney injury (AKI) accounts for up to 29% of severe COVID-19 cases and increases mortality among these patients. Viral infections participate in the pathogenesis of diseases by changing the expression profile of normal transcriptome. This study attempts to identify LncRNA-miRNA-gene and TF-gene networks as gene expression regulating networks in the kidney tissues of COVID-19 patients. Methods: In this analysis, four kidney libraries from the GEO repository were considered. To conduct the preprocessing, Deseq2 software in R was used for the purpose of data normalization and log2 transformation. In addition, pre- and post-normalization, PCA and box plots were developed using ggplot2 software in R for quality control. The expression profiles of the kidney samples of COVID-19 patients and control individuals were compared using DEseq2 software in R. The considered significance thresholds for DEGs were Adj P value < 0.05 and |logFC| >2. Then, to predict molecular interactions in lncRNA-miRNA-gene networks, different databases, including DeepBase v3.0, miRNATissueAtlas2, DIANA-LncBase v3, and miRWalk, were used. Furthermore, by employing ChEA databases, interactions at the TF-Gene level were obtained. Finally, the obtained networks were plotted using Stringdb and Cytoscape v8. Results: Results obtained from the comparison of the post-mortem kidney tissue samples of the COVID-19 patients with the healthy kidney tissue samples showed significant changes in the expression of more than 2000 genes. In addition, predictions regarding the miRNA-gene interaction network based on DEGs obtained from this meta-analysis showed that 11 miRNAs targeted the obtained DEGs. Interestingly, in the kidney tissue, these 11 miRNAs interacted with LINC01874, LINC01788, and LINC01320, which have high specificity for this tissue. Moreover, four transcription factors of EGR1, SMAD4, STAT3, and CHD1 were identified as key transcription factors regulating DEGs. Taken together, the current study showed several dysregulated genes in the kidney of patients affected with COVID-19. Conclusion: This study suggests lncRNA-miRNA-gene networks and key TFs as new diagnostic and therapeutic targets for experimental and preclinical studies.

Introduction: Cannabis sativa L. is a well-recognized medicinal plant. Cannabis regulations in Argentina are insufficient to solve the problem of patient access to full-spectrum cannabis-based products. So, the market of artisanal products with unknown quality and dosage of cannabinoids is increasing, and so is the local demand and need for analyzing these products. However, much of the latest validated methodologies for cannabinoid quantification include expensive instrumentation that is not always available in laboratories of health institutions in Argentina. Methods: The aim of this work was to develop and validate a simple and rapid HPLC-UV method for the identification and quantification of principal cannabinoids in cannabis resins, inflorescences, and medicinal oils using standard HPLC equipment. The cannabinoids selected for validation were cannabidiol acid (CBDA), cannabigerol (CBG), cannabidiol (CBD), cannabinol (CBN), delta-9-tetrahydrocannabinol (Δ9-THC), cannabichromene (CBC), and tetrahydrocannabinol acid (THCA). A method for the simultaneous identification and quantification of these 7 main cannabinoids was developed and then validated. Some data parameters were comparable to other reports with more sophisticated analytical instruments for the analysis of cannabis. The assessed limits of detection and the limits of quantitation ranged from 0.9 to 3.66 μg/mL and 2.78 to 11.09 μg/mL, respectively. The concentration-response relationship of the method indicated a linear relationship between the concentration and peak area with R² values of > 0.99 for all 7 cannabinoids. Results: The relative standard deviation (RSD%) varied from 2.34 to 4.82 for intraday repeatability and from 1.16 to 3.15 for interday repeatability. The percentage of recovery values was between 94 to 115% (resins) and 80 to 103% (inflorescence extract). The cannabis industry is growing rapidly, and there is a need for reliable testing methods to ensure the safety and efficacy of cannabis products. In addition, current methods for cannabinoid analysis are often time-consuming and expensive, while the HPLC-UV method herein reported is a simple, rapid, accurate, and cost-effective alternative for the analysis of cannabinoids in cannabis resins, inflorescences, and medicinal oils. Conclusion: This method will be proposed to be included in the Cannabis sativa L. monograph of the Argentine Pharmacopoeia.

Background: Polycystic ovary syndrome (PCOS), the most prevalent reproductive disorder, is accompanied by hyperandrogenism (HA), ovulatory dysfunction (OD), and insulin resistance (IR). A number of reports indicate that adipokines play a vital role in the pathophysiology of PCOS. One of these adipokines is chemerin, which is engaged in metabolic disorders, especially obesity, diabetes, and PCOS. Based on the data, the circulating levels of chemerin and the expression of chemokine-like receptor-1 (CMKLR1) in white adipose tissue (WAT) of women with PCOS are significantly higher than in healthy ones. Currently, several scholars have emphasized the therapeutic capacities of stem cells, notably mesenchymal stem cells (MSCs), for the treatment of PCOS. Objective: In this study, for the first time, the impacts of 2-(α-naphthoyl) ethyltrimethylammonium iodide (α- NETA), an antagonist of CMKLR1, adipose-derived stem cells (ADSCs), and their combinations on metabolic and endocrine aberrancies were assessed in the WAT and ovarian tissues of the letrozole (LET)-induced PCOS rats. Methods: In the current study, 30 Wistar rats were randomly divided into five groups: control (n = 6), LET-induced PCOS (1.5 mg/kg p.o., n = 6), LET + ADSCs (10⁶ ADSCs i.v., n = 6), LET + α-NETA (10 mg/kg p.o., n = 6), and LET + ADSCs + α-NETA (n = 6). The blood samples and adipose and ovarian tissues were obtained to evaluate the effects of ADSCs and α-NETA on hormonal and metabolic parameters in the PCOS rats. Results: Our findings showed that the administration of α-NETA, ADSCs, and the combination of both favorably restored the irregular estrus cycle and considerably modulated the endocrine parameters in PCOS rats. In addition, these therapeutic factors remarkably regulated steroidogenic and adipogenic gene expressions, as well as the genes related to glucose metabolism and brown adipose tissue (BAT) markers in these animals. Conclusion: These findings indicate that the combination of ADSCs and α-NETA can successfully ameliorate metabolic and endocrine dysfunction in LET-induced PCOS rats, and this strategy could be a new therapeutic choice for patients with PCOS.

Background: Myricitrin is a flavonol glycoside possessing beneficial effects on obesity, a rising global health issue that affects millions of people worldwide. However, the involving target and mechanism remain unclear. Objective: In the present study, the anti-obesity targets and molecular mechanisms of Myricitrin, along with another flavanol Epigallocatechin gallate (EGCG), were explored through network pharmacology, bioinformatics, and molecular docking. Methods: The potential targets for Myricitrin and EGCG were obtained from Pharmmaper, SwissTargetPrediction, TargetNet, SEA, Super-PRED, TCMSP, and STICH databases. Meanwhile, DEG targets were retrieved from GEO datasets, and obesity targets were collected from DrugBank, TTD, DisGeNet, OMIM, GeneCards, PharmGKB, and CTD databases. GO and KEGG pathway enrichment analyses were conducted through Metascape online tool. Protein-protein interaction (PPI) networks were also constructed for compound, DEG, and obesity targets to screen the core targets through MCODE analysis. The further screened-out key targets were finally verified through the compound-target-pathway-disease network, mRNA expression level, target-organ correlation, and molecular docking analyses. Results: In total, 538 and 660 targets were identified for Myricitrin and EGCG, respectively, and 725 DEG targets and 1880 obesity targets were retrieved. GO and KEGG analysis revealed that Myricitrin and EGCG targets were enriched in the pathways correlating with obesity, cancer, diabetes, and cardiovascular disease. Furthermore, the intersection core targets for Myricitrin and EGCG function mainly through the regulation of responses to hormones and involving pathways in cancer. Above all, androgen receptor (AR), cyclin D1 (CCND1), early growth response protein 1 (EGR1), and estrogen receptor (ERS1) were identified as key targets in the compound-target-pathway-disease network for both Myricitrin and EGCG, with significant different mRNA expression between weight loss and control groups. Target-organ correlation analysis exhibited that AR and CCND1 showed high expression in adipocytes. Molecular docking also revealed good binding abilities between Myricitrin and EGCG, and all four receptor proteins. Conclusion: The present research integrated network pharmacology and bioinformatics approach to reveal the key targets of Myricitrin and EGCG against obesity. The results provided novel insights into the molecular mechanism of Myricitrin and EGCG in obesity prevention and treatment and laid the foundations for the exploitation of flavonoid-containing herbal resources.