Plausible Mechanism Of Action Research Articles

Synthesis of novel 6-substituted-3-formyl chromone derivatives as anti-leishmanial agents and their possible mechanism of action in Leishmania donovani

Eleven new compounds, including the hydrazones 4a-h, pyrazole 5, and pyrazole-oximes 7b-c, were synthesized by condensation reaction between 6-substituted (-H, -Me, -F) 3-formylchromones 1a-c with N-substituted hydrazines 2a-d and hydroxylamine hydrochloride 3. The synthesized compounds were evaluated for their in vitro antileishmanial activity to determine the IC50 values. Compounds 4b, 4c and 4e exhibited the strongest antileishmanial activity with IC50 values between 1.6 – 4.7 µm. A plausible mechanism of action is proposed for the antileishmanial activity of the above-mentioned compounds. We also studied the effect of these three compounds on macrophages, which represent the mammalian host-cell. The results obtained on this system were about one order of magnitude larger when compared to those of L. donovani, thus supporting these compounds potential as precursors of antileishmanial drugs.

Antimycobacterial Compound of Cynoglossum lanceolatum Forsk.: Bioassay Guided Isolation, Molecular Docking, Synthesis of Analogs, and a Plausible Mechanism of Action.

Tuberculosis (TB) remains a major threat to human health. Due to the prevalence of drug-resistant Mycobacterium tuberculosis (Mtb), it is urgent to discover drugs with new mechanisms of action (MOA) to ensure effectiveness against strains that are resistant to existing TB drugs. Cynoglossum lanceolatum Forsk was used to treat TB in Traditional Chinese Medicine. In this article, shikonin, the anti-Mtb active component, was obtained from the whole herb extract of C. lanceolatum by bioassay-guided isolation. Using the microplate alamar blue assay (MABA), the minimum inhibitory concentration (MIC) of shikonin against Mtb was determined to be 128 μg/mL. In order to obtain a more efficient anti-Mtb molecule, (E)-1-(6-bromo-2,3-dihydrochromen-4-ylidene)thiosemicarbazide was synthesized based on the scaffold of shikonin, which exhibited potent activity against Mtb (MIC=4 μg/mL). These results highlight that both naphthalene-1,4-dione and chroman-4-one are pharmacophores with activities against Mtb. To investigate a plausible mechanism of action, the molecular docking was firstly performed against catalase-peroxidase enzyme (KatG) of Mtb using AutoDock 4 software. The results demonstrated that both shikonin and (E)-1-(6-bromo-2,3-dihydrochromen-4-ylidene)thiosemicarbazide could bind to the active site of Mtb KatG. KatG enzyme activity and intracellular reactive oxygen species (ROS) levels in Mtb cells were then measured by ultraviolet spectrophotometric method and fluorescence microplate reader assay, respectively. The experiments confirmed that above compounds could inhibit the catalytic activity of Mtb KatG, and cause the ROS accumulation in Mtb cells. Therefore, inhibition of KatG may be a novel mechanism of action for these two compounds to fight against Mtb.

Antihypertensive effects of pentacyclic triterpenoid from Convolvulus pluricaulis and its plausible mechanism of action hypothesizing its selectivity targeting Mineralocorticoid receptor of RAAS.

BackgroundThe renin-angiotensin-aldosterone system (RAAS) is important in maintaining blood pressure and malfunction of this system leads to the main cause of hypertension. Though a variety of synthetic inhibitors have been used to treat hypertension and related disorders, chronic use of these inhibitors causes undesirable side effects. To eliminate this problem, several scientific studies have proved that plant based and food derived products could be used as an alternative strategy to treat high blood pressure. PurposeWe intend to isolate the major bioactive compound from the medicinal plant Convolvulus pluricaulis as it is reported to possess anti-hypertensive activity. We also aimed to address the mechanism of action of taraxerol and to hypothesize its selectivity targeting RAAS. Study designThe study was designed to isolate the phytoconstituent from C. pluricaulis and characterization by XRD, NMR, FT-IR, and UV–Vis. To further elucidate the activity of isolated molecules, we have designed a two-way approach using in-silico and in-vitro methodologies. MethodsThe roots of Convolvulus pluricaulis were dried, powdered and the extract was purified by repeated column chromatography. The purified compound was characterized by UV–Vis, IR, NMR, and single crystal X-ray diffraction. The high quality single crystal was grown from the mixture of hexane ethyl acetate. Molecular docking was done to identify the interaction pattern and binding efficacy of isolated compounds against various receptors of RAAS and the stability of the molecule was analyzed by molecular dynamic simulations. The cytotoxicity of the molecule was checked using the MTT assay and the IC50 value was also calculated against the AngII-induced cardiac hypertrophy in H9c2 cells. Tanimoto coefficient was calculated to check the similarity indices with the already reported antihypertensives from plants/herbs. ResultsThe crystal structure of taraxerol solved by crystallography has been deposited with the Cambridge Crystallographic Data Centre (CCDC: 2,180,265). Taraxerol had an IC50 at 20 μM concentration against AngII-induced cardiac hypertrophy in H9c2 cells, indicating that it suggestively increased the cell viability as compared to positive control. In-silico molecular docking analysis of taraxerol found that taraxerol binds to mineralocorticoid receptor with the binding energy of −11.03 kcal/mol. Molecular Dynamics (MD) simulations were further done to check the stability of MR-taraxerol complex to unravel the structure activity relationship of taraxerol. Furthermore, SAR studies show that taraxerol had the highest degree of molecular similarity (0.78% – 0.93%) with reported antihypertensive oleanane triterpenoids highlighting its efficacy. ConclusionOur findings corroborate taraxerol as a potential anti-hypertensive agent and leads to the hypothesis of its specificity towards Mineralocorticoid receptor than other receptors in RAAS.

Glycyrrhizin prevents 3-nitropropionic acid-induced neurotoxicity by downregulating HMGB1/TLR4/NF-κB p65 signaling, and attenuating oxidative stress, inflammation, and apoptosis in rats

AimsGlycyrrhizin (Glyc) is a saponin triterpenoid that has signified its efficacy against Huntington's disease (HD). Nonetheless, its mechanism has not been fully clarified. Accordingly, this study was designed to evaluate the plausible mechanism of action of Glyc against 3-nitropropionic acid (3-NP)-induced HD. Main methodsRats were treated with Glyc (50 mg/kg, i.p.) for 3 weeks and 3-NP (10 mg/kg, i.p.) was administered at the latter 2 weeks alongside to induce HD. Key findingsAnimals exposed to 3-NP revealed a reduction in body weight, neurobehavioral abnormalities, and various deleterious effects related to overexpression of HMGB1 such as oxidative stress, apoptosis, and inflammation. Promisingly, Glyc administration provided valuable effects by reversing the decline in body weight with improved neurobehavioral deficits. Ameliorating oxidative stress via restoring GSH, SOD, and Nrf2 alongside with MDA suppression was evident. Furthermore, Glyc switched the HMGB1/TLR4/NF-κB p65 signaling off, reduced IL-6, IL-β, TNF-α, caspase-3, and increased Bcl-2 as well as BDNF. All these beneficial effects were mirrored by a better histopathological picture upon using Glyc that suppressed gliosis by reducing GFAP expression as observed in the immunohistochemistry results. SignificanceAccordingly, the current study demonstrated a promising neuroprotective effect of Glyc against experimentally induced HD through alleviating deleterious events by diverse mechanisms.

Wireless technology is an environmental stressor requiring new understanding and approaches in health care.

Electromagnetic signals from everyday wireless technologies are an ever-present environmental stressor, affecting biological systems. In this article, we substantiate this statement based on the weight of evidence from papers collated within the ORSAA database (ODEB), focusing on the biological and health effects of electromagnetic fields and radiation. More specifically, the experiments investigating exposures from real-world devices and the epidemiology studies examining the effects of living near mobile phone base stations were extracted from ODEB and the number of papers showing effects was compared with the number showing no effects. The results showed that two-thirds of the experimental and epidemiological papers found significant biological effects. The breadth of biological and health categories where effects have been found was subsequently explored, revealing hundreds of papers showing fundamental biological processes that are impacted, such as protein damage, biochemical changes and oxidative stress. This understanding is targeted toward health professionals and policy makers who have not been exposed to this issue during training. To inform this readership, some of the major biological effect categories and plausible mechanisms of action from the reviewed literature are described. Also presented are a set of best practice guidelines for treating patients affected by electromagnetic exposures and for using technology safely in health care settings. In conclusion, there is an extensive evidence base revealing that significant stress to human biological systems is being imposed by exposure to everyday wireless communication devices and supporting infrastructure. This evidence is compelling enough to warrant an update in medical education and practice.

Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) exhibit incretin activity, meaning that they potentiate glucose-dependent insulin secretion. The emergence of GIP receptor (GIPR)-GLP1 receptor (GLP1R) co-agonists has fostered growing interest in the actions of GIP and GLP1 in metabolically relevant tissues. Here, we update concepts of how these hormones act beyond the pancreas. The actions of GIP and GLP1 on liver, muscle and adipose tissue, in the control of glucose and lipid homeostasis, are discussed in the context of plausible mechanisms of action. Both the GIPR and GLP1R are expressed in the central nervous system, wherein receptor activation produces anorectic effects enabling weight loss. In preclinical studies, GIP and GLP1 reduce atherosclerosis. Furthermore, GIPR and GLP1R are expressed within the heart and immune system, and GLP1R within the kidney, revealing putative mechanisms linking GIP and GLP1R agonism to cardiorenal protection. We interpret the clinical and mechanistic data obtained for different agents that enable weight loss and glucose control for the treatment of obesity and type 2 diabetes mellitus, respectively, by activating or blocking GIPR signalling, including the GIPR-GLP1R co-agonist tirzepatide, as well as the GIPR antagonist-GLP1Ragonist AMG-133. Collectively, we update translational concepts of GIP and GLP1 action, while highlighting gaps, areas of uncertainty and controversies meriting ongoing investigation.

Synthesis, Biological Evaluation and Computational Studies of New Hydrazide Derivatives Containing 1,3,4-Oxadiazole as Antitubercular Agents

To extend our screening for novel antimycobacterial molecules, we have designed, synthesized, and biologically evaluated a library of 14 new hydrazide derivatives containing 1,3,4-oxadiazole core. A variety of mycobacterial strains, including some drug-resistant strains, were tested for antimycobacterial activity. Among the compounds tested, five showed high antimycobacterial activity (MIC values of 8 μg/mL) against M. tuberculosis H37Ra attenuated strain, and two derivatives were effective (MIC of 4 µg/mL) against pyrazinamide-resistant strains. Furthermore, the novel compounds were tested against the fungal C. albicans strain, showing no antimycotic activity, and thus demonstrating a good selectivity profile. Notably, they also exhibited low cytotoxicity against human SH-SY5Y cells. The molecular modeling carried out suggested a plausible mechanism of action towards the active site of the InhA enzyme, which confirmed our hypothesis. In conclusion, the active compounds were predicted in silico for ADME properties, and all proved to be potentially orally absorbed in humans.

Sodium-Glucose Co-transporter 2 Inhibitors/Gliflozins: A New Miracle Therapy for Heart Failure Patients Irrespective of Diabetes Status?

Despite the existence of effective medicines, heart failure continues to be the largest cause of illness and death worldwide. As a prospective family of drugs with potential cardiovascular advantages in non-diabetic patients, sodium-glucose co-transporter 2 inhibitors (SGLT2-I) have recently come to the forefront. In this comprehensive study, we assessed the favorable cardiovascular outcomes of SGLT2-I in three sizable, randomized trials with both diabetic and non-diabetic populations. The results from these studies revealed a substantial reduction in heart failurehospitalizations and cardiovascular and all-cause deaths. To further support our assertion that SGLT2-I has the potential to be a novel addition to the standard treatment plan for heart failure, we also tried to assemble several post hoc and prespecified studies of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. The details of two clinical investigations that supported their use in acute decompensated heart failure were also examined, along with the most plausible mechanism of action generating their cardioprotective effects. Additionally, positive cardiovascular advantages were addressed in chronic heart failure with both preserved and reduced ejection fractions. The role of SGLT2-I in ST-elevation myocardial infarction (STEMI) and hypertrophic cardiomyopathy (HOCM) patients is currently being studied, and this research has the potential to be revolutionary. The purpose of this systematic review is to compile all information that supports the use of this life-saving drug in patients who do not have diabetes so that cardiac care can be improved globally.

Abstract 11150: The Effect of Eicosapentaenoic Acid and Docosahexaenoic Acid on Neutrophil/Lymphocyte Ratio, a Marker of Inflammation, in Subjects With Coronary Artery Disease: Results of a Randomized Trial

Background: The neutrophil/lymphocyte (N/L) ratio increases with the systemic inflammatory response due to an increase in neutrophils and decrease in lymphocytes with systemic inflammation. An elevated N/L ratio has been associated with an increased risk of cardiovascular disease (CVD), cancer and mortality. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease levels of high sensitivity C-reactive protein (hs-CRP), the gold standard inflammatory marker, when levels of hs-CRP are elevated. Randomized trials have also reported a decrease in CVD events with EPA. The mechanism for this benefit is unclear. Objective: To examine the effect of high-dose EPA and DHA supplementation on inflammation as measured by the N/L ratio in the setting of low levels of hs-CRP. Methods: A total of 242 subjects with stable coronary artery disease on statin treatment were randomized to 3.36 g EPA+DHA daily or none. N/L ratio and the monocyte to lymphocyte (M/L) ratio were measured at baseline and 1 year. Results: Mean (SD) age was 63.1 years (7.7); mean (SD) LDL-C: 77.8 mg/dL (27.3); median [IQR] TG: 117.5 mg/dL [81.3,166.8] and median [IQR] hs-CRP: 0.75 mg/L [0.40,2.5]. Those on EPA+DHA had a 2.2% reduction in N/L ratio (P=0.014) at 1 year compared to those not on EPA+DHA who had a 12.2% increase (Figure) (between group P= 0.007). There was a trend toward benefit with the M/L ratio (P=0.078). Conclusion: High-dose EPA+DHA decreases systemic inflammation as reflected in the N/L ratio even with low hs-CRP levels. This is a new finding which suggests that under conditions of generally low levels of inflammation in terms of hs-CRP levels, the N/L ratio may be a more sensitive measure of underlying inflammation than hs-CRP and should be considered as an additional marker in future studies of omega-3 fatty acids. If a decrease in inflammation by N/L ratio were accompanied by a clinical decrease in CVD events, this would assist in determining a plausible mechanism of action.

Investigation of the Anti-inflammatory potential of Mono-carbonyl Analogues of Curcumin

In the present investigation, we report the synthesis, anti-inflammatory activity and molecular docking of monocarbonyl analogues of curcumin. The anti-inflammatory activity of the synthesized compounds was gauzed using the protein denaturation assay using Diclofenac sodium as reference standard. Among the tested compounds, 3d, 3e, 3f, 3j, 3k, 3l and 3m displayed excellent anti-inflammatory activity by exhibiting good range of percentage inhibition as compared to the standard DFS. In silico binding affinity study against Cyclooxygenase (COX-2) enzyme could provide valuable insight into their plausible mechanism of action. Also, in silico ADME prediction of synthesized monocarbonyl curcumin analogues showed excellent pharmacokinetic parameters by not violating Lipinski’s rule of five.

Emergency Contraception: Access and Challenges at Times of Uncertainty.

The UN Commission on Life-Saving Commodities for Women and Children identified emergency contraceptive pills as 1 of the 13 essential underused, low-cost, and high-impact commodities that could save the lives of millions of women and children worldwide. In the US, 2 emergency contraceptive regimens are currently approved, and their most plausible mechanism of action involves delaying and/or inhibiting ovulation. Abortion and contraception are recognized as essential components of reproductive health care. In the US, in the wake of the Dobbs v. Jackson Women's Health Organization Supreme Court decision on June 24, 2022, 26 states began to or are expected to severely restrict abortion. It is anticipated that these restrictions will increase the demand for emergency contraception (EC). Several obstacles to EC access have been described, and these include cost, hurdles to over-the-counter purchase, low awareness, myths about their mechanisms of action, widespread misinformation, and barriers that special populations face in accessing them. The politicization of EC is a major factor limiting access. Improving sex education and health literacy, along with eHealth literacy, are important initiatives to improve EC uptake and access. PubMed, The Guttmacher Institute, Society of Family Planning, American College of Obstetricians and Gynecologists, the World Health Organization, The United Nations. A randomized noninferiority trial showed that the 52 mg levonorgestrel intrauterine device was noninferior to the copper intrauterine device when used as an EC method in the first 5 days after unprotected intercourse. This is a promising and highly effective emergency contraceptive option, particularly for overweight and obese patients, and a contraceptive option with a different bleeding profile than the copper intrauterine device. EC represents an important facet of medicine and public health. The 2 medical regimens currently approved in the US are very effective, have virtually no medical contraindications, and novel formulations are actively being investigated to make them more convenient and effective for all patient populations. Barriers to accessing EC, including the widespread presence of contraception deserts , threaten to broaden and accentuate the already existing inequities and disparities in society, at a time when they have reached the dimensions of a public health crisis.

Design, synthesis, antimicrobial evaluation, and in‐silico studies of some 4‐thiazolidinone hybrids bearing coumarin and pyridine moieties

AbstractAntimicrobial resistance is a major threat to mankind. Many frontline medications are ineffective against antimicrobial‐resistant strains which are also responsible for the high mortality rate worldwide. The urgency to create new sets of antimicrobial agents is a priority in present circumstances. In continuation to this, we have strategically designed and synthesized some novel hybrids of 4‐thiazolidinone bearing coumarin and pyridine cores for the evaluation of antimicrobial efficacy. A three‐step multicomponent reaction was performed via imine formation, cyclization, and Knoevenagel condensation for the synthesis of titled compounds (5a‐o). The synthesized entities were characterized through different analytical techniques, that is, IR, 1H NMR, 13C NMR, and mass spectra. On evaluating the potency of our synthesized hybrids, we received some promising results. Compound 5m was identified as the most potent component possessing 50 μg/ml (minimum inhibitory concentration [MIC] value) against S. aureus and 250 μg/ml (MIC value) against C. albicans strains. Further, a molecular docking study against microbial DNA gyrase was carried out to understand the binding profile of synthesized molecules, which supported their in‐vitro antimicrobial activity. These data helped to gain an insight into their plausible mechanism of action. Their binding affinity scores correlated well with the in‐vitro antimicrobial activities while their binding modes proposed the involvement of steric, electrostatic, and hydrogen‐bonding interactions with the active site.

Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer’s disease risk in the general population: a Mendelian randomisation study

Aims/hypothesisMetformin use has been associated with reduced incidence of dementia in diabetic individuals in observational studies. However, the causality between the two in the general population is unclear. This study uses Mendelian randomisation (MR) to investigate the causal effect of metformin targets on Alzheimer’s disease and potential causal mechanisms in the brain linking the two.MethodsGenetic proxies for the effects of metformin drug targets were identified as variants in the gene for the corresponding target that associated with HbA1c level (N=344,182) and expression level of the corresponding gene (N≤31,684). The cognitive outcomes were derived from genome-wide association studies comprising 527,138 middle-aged Europeans, including 71,880 with Alzheimer’s disease or Alzheimer’s disease-by-proxy. MR estimates representing lifelong metformin use on Alzheimer’s disease and cognitive function in the general population were generated. Effect of expression level of 22 metformin-related genes in brain cortex (N=6601 donors) on Alzheimer’s disease was further estimated.ResultsGenetically proxied metformin use, equivalent to a 6.75 mmol/mol (1.09%) reduction on HbA1c, was associated with 4% lower odds of Alzheimer’s disease (OR 0.96 [95% CI 0.95, 0.98], p=1.06×10−4) in non-diabetic individuals. One metformin target, mitochondrial complex 1 (MCI), showed a robust effect on Alzheimer’s disease (OR 0.88, p=4.73×10−4) that was independent of AMP-activated protein kinase. MR of expression in brain cortex tissue showed that decreased MCI-related gene (NDUFA2) expression was associated with lower Alzheimer’s disease risk (OR 0.95, p=4.64×10−4) and favourable cognitive function.Conclusions/interpretationMetformin use may cause reduced Alzheimer’s disease risk in the general population. Mitochondrial function and the NDUFA2 gene are plausible mechanisms of action in dementia protection.Graphical abstract

Synthesis of fluoro-rich pyrimidine-5-carbonitriles as antitubercular agents against H37Rv receptor

Abstract The purpose of this study was to prepare various derivatives of 4-amino-2-(3-fluoro-5-(trifluoromethyl)phenyl)-6-arylpyrimidine-5-carbonitrile (6a–6h) using a three-step procedure. The derivatives were screened in vitro for activity against Mycobacterium tuberculosis strain H37Rv. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL (μM). Eight compounds showed activity against Mtb H37Rv, and among them, 6f showed the best value of MIC, IC50 (53 μM) and IC90 (62 μM). Minimum bactericidal concentration of compound 6f was higher than its MIC and was more time-dependent than the concentration. Compound 6f was more active against M. tuberculosis H37Rv under low oxygen than metronidazole and did not show good potency in different treatments and non-tuberculous mycobacteria. Furthermore, a molecular docking study against mycobacterial enoyl-ACP reductase (InhA) could provide valuable insights into the plausible mechanism of action, which could set the theme for lead optimization.

Perilla frutescens: A Rich Source of Pharmacological Active Compounds.

Perilla frutescens (L.) Britton, an important pharmaceutical and nutraceutical crop, is widely cultivated in East Asian countries. In this review, we present the latest research findings on the phytochemistry and pharmacological activities of P. frutescens. Different databases, including PubMed, Scopus, CNKI, Agricola, Scifinder, Embase, ScienceDirect, DOAJ, and Web of Science, were searched to present the best review. In this review, we clearly represent the active constituents responsible for each and every pharmacological activity, plausible mechanism of action, and maximum inhibitory concentrations, as well as IC50 values. Approximately 400 different bioactive compounds, including alkaloids, terpenoids, quinines, phenylpropanoids, polyphenolic compounds, flavonoids, coumarins, anthocyanins, carotenoids, neolignans, fatty acids, polycosanols, tocopherols, and sitosterols, have been reported in the leaves, seeds, roots, and aerial parts of P. frutescens. The bioactive constituents of P. frutescens exhibited different enzyme-inhibition properties, including antihyaluronidase effects and aldose reductase inhibitory, α-glucosidase inhibitory, xanthine oxidase inhibitory, and tyrosinase inhibitory properties. P. frutescens showed strong anti-inflammatory, antidepressant, anti-spasmodic, anticancer, antioxidant, antimicrobial, insecticidal, neuroprotective, and hepatoprotective effects. Hence, the active constituents of P. frutescens used in the treatment of diabetes and diabetic complications (retinopathy, neuropathy, and nephropathy), prevention of hyperuricemia in gout patients, hyper pigmentation, allergic conditions, skin inflammation, skin allergy, atopic dermatitis, periodontosis, androgenic alopecia, gastric inflammation, oesophagitis, carcinogenesis, cardiovascular, Alzheimer’s, Parkinson’s, and cerebral ischemic disorders. Furthermore, we revealed the most active constituents and possible mechanisms of the pharmacological properties of P. frutescens.

Eryngium Species as a Potential Ally for Treating Metabolic Syndrome and Diabetes.

Medicinal plants possess natural compounds that can be used as an alternative for synthetic medicines that may cause long-term side effects on patients such as neurocognitive effects, muscular and hepatic toxicity. Metabolic Syndrome is associated with increased risk of several diseases such as diabetes, cardiovascular disease, dyslipidemia, and hypertension thus, becoming the greatest challenge as a growing public health concern worldwide. Latin-American countries possess a wide diversity of medicinal plants that have been used to treat different health conditions since pre-Hispanic times. Eryngium spp. has been studied due to their beneficial properties mainly to treat diabetes, dyslipidemia, blood pressure, and digestive problems. This review gives an update mainly on the pharmacological activities of the Eryngium spp., summarizing the biological activities and plausible mechanism of action of their bioactive components toward metabolic syndrome. For instance, flavonoids and tannins proved to increase the levels of HDL and reduced the levels of VLDL, LDL. On the other hand, phenolic acids improved glucose metabolism through the inhibition of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase (G6Pase) and reestablished the impaired activity of enzymes related to glucose oxidation and glycogen synthesis. The terpenes and sesquiterpenes like β-farnese, β-pinene, and calamenene exhibited a protective effect by reducing the oxidizing damage by the regulation of the Reactive Oxygen Species (ROS). Saponins controlled the dyslipidemia by reducing the serum concentrations of lipids, triglycerides and total cholesterol. Finally, the aerial parts of Eryngium had the capacity of inhibiting dietary carbohydrate digestive enzymes, thus controlling glucose levels. The Eryngium plant is normally consumed as an infusion to obtain the benefits of the plants, however novel technologies such as cavitation, ultrasound assisted, microwave assisted, and supercritical fluid have been applied to improve the extraction yields and selectivity of bioactive compounds. The common treatment to control diabetic dyslipidemia are synthetic medicines such as metformin and ezetimibe, which allows the regulation of glucose, cholesterol and insulin resistance. However, patients that take these medications may present side effects such as muscular toxicity, hepatic toxicity, neurocognitive effects, just to name a few. More studies regarding the efficacy and safety of the use of traditional medicinal herbs are required. However, these materials may be used in the treatment of diabetes related conditions to ensure life quality and reduce side effects among the diabetic population

Mechanistic Insights for Drug Repurposing and the Design of Hybrid Drugs for Alzheimer's Disease.

The heterogeneity and complex nature of Alzheimer's disease (AD) is attributed to several genetic risk factors and molecular culprits. The slow pace and increasing failure rate of conventional drug discovery has led to the exploration of complementary strategies based on repurposing approved drugs to treat AD. Drug repurposing (DR) is a cost-effective, low-risk, and efficient approach for identifying novel therapeutic candidates for AD treatment. Similarly, hybrid drug design through the integration of distinct pharmacophores from known or failed drugs and natural products is an interesting strategy to target the multifactorial nature of AD. In this Perspective, we discuss the potential of DR and highlight promising drug candidates that can be advanced for clinical trials, backed by a detailed discussion on their plausible mechanisms of action. Our article fosters research on the hidden potential of DR and hybrid drug design with the goal of unravelling new drugs and targets to tackle AD.

Blockade of M4 muscarinic receptors on striatal cholinergic interneurons normalizes striatal dopamine release in a mouse model of TOR1A dystonia

Trihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is commonly used for the treatment of dystonia associated with TOR1A, otherwise known as DYT1 dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. We previously found that THP normalizes the deficit in striatal dopamine (DA) release in a mouse model of TOR1A dystonia (Tor1a+/ΔE knockin (KI) mice), revealing a plausible mechanism of action for this compound, considering that abnormal DA neurotransmission is consistently associated with many forms of dystonia. However, the mAChR subtype(s) that mediate the rescue of striatal dopamine release remain unclear. In this study we used a combination of pharmacological challenges and cell-type specific mAChR conditional knockout mice of either sex to determine which mAChR subtypes mediate the DA release-enhancing effects of THP. We determined that THP acts in part at M4 mAChR on striatal cholinergic interneurons to enhance DA release in both Tor1a+/+ and Tor1a+/ΔE KI mice. Further, we found that the subtype selective M4 antagonist VU6021625 recapitulates the effects of THP. These data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that subtype selective M4 mAChR antagonists may be effective therapeutics with fewer side effects than THP for the treatment of TOR1A dystonia.

Repurposing Lansoprazole and Posaconazole to treat leishmaniasis: Integration of in vitro testing, pharmacological corroboration, and mechanisms of action.

Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing of compounds against Leishmania amastigotes and selected the most promising active compounds, Lansoprazole and Posaconazole. We identified possible Leishmania drug targets of Lansoprazole and Posaconazole using several available servers. Our in-silico screen identified likely Lansoprazole targets as the closely related calcium-transporting ATPases (LdBPK_352080.1, LdBPK_040010.1, and LdBPK_170660.1), and the Posaconazole target as lanosterol 14-alpha-demethylase (LdBPK_111100.1). Further validation showed LdBPK_352080.1 to be the most plausible target based on induced-fit docking followed by long (100ns) MD simulations to confirm the stability of the docked complexes. We present a likely ion channel-based mechanism of action of Lansoprazole against Leishmania calcium-transporting ATPases, which are essential for parasite metabolism and infectivity. The LdBPK_111100.1 interaction with Posaconazole is very similar to the known fungal orthologue. Herein, we present two novel anti-leishmanial agents, Posaconazole and Lansoprazole, already approved by the FDA for different indications and propose plausible mechanisms of action for their antileishmanial activity.

Design, synthesis of anticancer and anti-inflammatory 4-(1-methyl-1H-indol-3-yl)-6-(methylthio) pyrimidine-5-carbonitriles

A novel series of 4-(1-methyl-1H-indol-3-yl)-6-(methylthio) pyrimidine-5-carbonitriles (4a–i) was synthesized and evaluated for anticancer potential against cell lines for breast cancer. Compounds 4b, 4e, and 4h exhibited prominent cytotoxicity against human breast carcinoma MCF-7 cell line with GI50 of 2.0, 0.5, and 0.5 µM, respectively. Molecular docking study against EGFR tyrosine kinase could provide valuable insights into the plausible mechanism of action. The compounds could bind with significantly high binding affinity and their binding affinity scores could correlate well with the observed anticancer activity. Furthermore, compounds 4a, 4c, 4e, 4g, and 4i exhibited significant inflammatory activities as well which could expand the therapeutic domain of this novel series.