A Convenient Synthesis of the Substituted 2,3-Diarylindole the Potent Selective COX-2 Inhibitors

Phenyl sulfone-containing 2, 3-diarylindole derivatives were designed and identified to be selective COX-2 inhibitors. A convenient synthetic route was also developed for the synthesis of the novel inhibitors.

Anti-cancer effects of COX-2 inhibitors and their correlation wit angiogenesis and invasion in gastric cancer

AIM- To observe the anti-cancer effects of COX-2 inhibitors and investigate the relationship between COX-2 inhibitors and angiogenesis, infiltration or metastasis in SGC7901 cancer xenografts.METHODS: Thirty athymic mice xenograft models with human stomach cancer cell SGC7901 were established and divided randomly into 3 groups of 10 each. Sulindac, one non-specific COX inhibitor belonging to non-steroidal antiinflammatory drugs (a series of COX inhibitors known as NSAIDs) and celecoxib, one selective COX-2 inhibitor (known as SCIs) were orally administered to mice of treatment groups. Immunohistochemistry was used to examine the expression of PCNA, CD44v6 and microvessel density (MVD).Apoptosis was detected by using TUNEL assay.RESULTS: Tumors in sulindac and celecoxib groups were significantly smaller than those in control group from the second week after drug administration (P<0.01). In treatment group, the cell proliferation index was lower (P<0.05) and apoptosis index was higher (P<0.05) than those in control groups. Compared with the controls,microvessel density was reduced (P<0.01) and expression of CD44v6 on tumor cells was weakened (P<0.05) in treatment groups.CONCLUSION: COX-2 inhibitors have anticancer effects on gastric cancer. They play important roles in angiogenesis and infiltration or metastasis of stomach carcinoma. The anticancer effects of COX-2 inhibitors may include inducing apoptosis, suppressing proliferation, reducing angiogenesis and weakening invasiveness.

Clinical benefit of COX-2 inhibitors in the adjuvant chemotherapy of advanced non-small cell lung cancer: A systematic review and metaanalysis

BACKGROUND Lung cancer is a major cause of death among patients,and non-small cell lung cancer(NSCLC)accounts for more than 80%of all lung cancers in many countries.AIM To evaluate the clinical benefit(CB)of COX-2 inhibitors in patients with advanced NSCLC using systematic review.METHODS We searched the six electronic databases up until December 9,2019 for studies that examined the efficacy and safety of the addition of COX-2 inhibitors to chemotherapy for NSCLC.Overall survival(OS),progression free survival(PFS),1-year survival rate(SR),overall response rate(ORR),CB,complete response(CR),partial response(PR),stable disease(SD),and toxicities were measured with more than one outcome as their endpoints.Fixed and random effects models were used to calculate risk estimates in a meta-analysis.Potential publication bias was calculated using Egger’s linear regression test.Data analysis was performed using R software.RESULTS The COX-2 inhibitors combined with chemotherapy were not found to be more effective than chemotherapy alone in OS,progression free survival,1-year SR,CB,CR,and SD.However,there was a difference in overall response rate for patients with advanced NSCLC.In a subgroup analysis,significantly increased ORR results were found for celecoxib,rofecoxib,first-line treatment,and PR.For adverse events,the increase in COX-2 inhibitor was positively correlated with the increase in grade 3 and 4 toxicity of leukopenia,thrombocytopenia,and cardiovascular events.CONCLUSION COX-2 inhibitor combined with chemotherapy increased the total effective rate of advanced NSCLC with the possible increased risk of blood toxicity and cardiovascular events and had no effect on survival index.

Health Related Quality of Life among Osteoarthritis Patients: A Comparison of Traditional Non-Steroidal Anti-Inflammatory Drugs and Selective COX-2 Inhibitors in the United Arab Emirates Using the SF-36

Objectives: Osteoarthritis (OA) has a dramatic impact on patients’ health related quality of life (HRQoL). Chronic use of analgesics and anti-inflammatory medications for pain management may improve symptoms but on long term may affect HRQoL negatively. The objective of the present study was to compare the impact of two different classes of analgesics, traditional non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclo-oxygenase-2 (COX-2) inhibitors on HRQoL among osteoarthritis patients using the SF-36 questionnaire. Methods: Clinic based cross-sectional study conducted at Al-Qassimi Hospital, Sharjah, United Arab Emirates (UAE), over a period of six months. Ethical Approval was obtained from the ethics committee at Al-Qassimi Clinical Research Center. Total of 200 osteoarthritis patients fulfilling the inclusion and exclusion criteria were involved in the study. Patients’ demographics were collected from their medical records. The Medical Outcome Study Short-Form 36 (SF-36) questionnaire was used to measure patients’ HRQoL. SF-36 data were scored using health outcomes scoring software 4.5. Results: Mean age of the subjects was 62.19 ± 9.81 years with females constituting 151 (75.5%) of the patients. In general, females scored lower in most of the HRQoL domains compared to males and there was significant difference between the two groups in the mental health (p = 0.005) & mental component (p = 0.042) domains. Compared to selective COX-2 inhibitors, patients on NSAIDs scored higher on all domains of SF-36 except physical functioning. There was significant difference in mental health domain for patients treated with NSAIDs (p = 0.02). Celecoxib was only better than NSAIDs in osteoarthritis patients with more than one musculoskeletal disorders in the domain of bodily pain (p = 0.009). Conclusion: NSAIDs-treated patients did not differ significantly from celecoxib-treated patients in all domains of the SF-36 except for the mental health domain.

NSAIDs and the Gastrointestinal Tract： will COX-2 Inhibitors Make this a thing of the Past？

Aspirin has been marketed for just over 100 years and for, an evolving set of clinical indications, has been the world's first and most successful mass marketed pharmaceutical compound. However, by 1937 it was clear that aspirin could cause acute gastric erosions and chronic ulcers. Attempts to develop aspirin like compounds that would avoid of aspirin's topical toxicity did not result in avoidance of the same side effects. This is probably because aspirin and non-aspirin NSAIDs inhibit prostaglandin synthesis, a central component of both their therapeutic and toxic activity.

Recent development on COX-2 inhibitors as promising anti-inflammatory agents:The past 10 years

Cyclooxygenases play a vital role in inflammation and are responsible for the production of prostaglandins.Two cyclooxygenases are described,the constitutive cyclooxygenase-1 and the inducible cyclooxygenase-2,for which the target inhibitors are the non-steroidal anti-inflammatory drugs(NSAIDs).Prostaglandins are a class of lipid compounds that mediate acute and chronic inflammation.NSAIDs are the most frequent choices for treatment of inflammation.Nevertheless,currently used anti-inflammatory drugs have become associated with a variety of adverse effects which lead to diminished output even market withdrawal.Recently,more studies have been carried out on searching novel selective COX-2 inhibitors with safety profiles.In this review,we highlight the various structural classes of organic and natural scaffolds with efficient COX-2 inhibitory activity reported during 2011-2021.It will be valuable for pharmaceutical scientists to read up on the current chemicals to pave the way for subsequent research.

Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure

BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.

Proton pump inhibitors and all-cause mortality risk among cancer patients

BACKGROUND Proton pump inhibitors(PPIs)are widely used,including among cancer patients,to manage gastroesophageal reflux and other gastric acid-related disorders.Recent evidence suggests associations between long-term PPI use and higher risks for various adverse health outcomes,including greater mortality.AIM To investigate the association between PPI use and all-cause mortality among cancer patients by a comprehensive analysis after adjustment for various confounders and a robust methodological approach to minimize bias.METHODS This retrospective cohort study used data from the TriNetX research network,with electronic health records from multiple healthcare organizations.The study employed a new-user,active comparator design,which compared newly treated PPI users with non-users and newly treated histamine2 receptor antagonists(H2RA)users among adult cancer patients.Newly prescribed PPIs(esomeprazole,lansoprazole,omeprazole,pantoprazole,or rabeprazole)users were compared to non-users or newly prescribed H2RAs(cimetidine,famotidine,nizatidine,or ranitidine)users.The primary outcome was all-cause mortality.Each patient in the main group was matched to a patient in the control group using 1:1 propensity score matching to reduce confounding effects.Multivariable Cox regression models were used to estimate hazard ratios(HRs)and 95% confidence interval(CI).RESULTS During the follow-up period(median 5.4±1.8 years for PPI users and 6.5±1.0 years for non-users),PPI users demonstrated a higher all-cause mortality rate than non-users after 1 year,2 years,and at the end of follow up(HRs:2.34-2.72).Compared with H2RA users,PPI users demonstrated a higher rate of all-cause mortality HR:1.51(95%CI:1.41-1.69).Similar results were observed across sensitivity analyses by excluding deaths from the first 9 months and 1-year post-exposure,confirming the robustness of these findings.In a sensitivity analysis,we analyzed all-cause mortality outcomes between former PPI users and individuals who have never used PPIs,providing insights into the long-term effects of past PPI use.In addition,at 1-year follow-up,the analysis revealed a significant difference in mortality rates between former PPI users and non-users(HR:1.84;95%CI:1.82-1.96).CONCLUSION PPI use among cancer patients was associated with a higher risk of all-cause mortality compared to non-users or H2RA users.These findings emphasize the need for cautious use of PPIs in cancer patients and suggest that alternative treatments should be considered when clinically feasible.However,further studies are needed to corroborate our findings,given the significant adverse outcomes in cancer patients.

Comparative efficacy of sodium glucose cotransporter-2 inhibitors in the management of type 2 diabetes mellitus:A real-world experience

BACKGROUND Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are a class of drugs with modest antidiabetic efficacy,weight loss effect,and cardiovascular benefits as proven by multiple randomised controlled trials(RCTs).However,real-world data on the comparative efficacy and safety of individual SGLT-2i medications is sparse.AIM To study the comparative efficacy and safety of SGLT-2i using real-world clinical data.METHODS We evaluated the comparative efficacy data of 3 SGLT-2i drugs(dapagliflozin,canagliflozin,and empagliflozin)used for treating patients with type 2 diabetes mellitus.Data on the reduction of glycated hemoglobin(HbA1c),body weight,blood pressure(BP),urine albumin creatinine ratio(ACR),and adverse effects were recorded retrospectively.RESULTS Data from 467 patients with a median age of 64(14.8)years,294(62.96%)males and 375(80.5%)Caucasians were analysed.Median diabetes duration was 16.0(9.0)years,and the duration of SGLT-2i use was 3.6(2.1)years.SGLT-2i molecules used were dapagliflozin 10 mg(n=227;48.6%),canagliflozin 300 mg(n=160;34.3%),and empagliflozin 25 mg(n=80;17.1).Baseline median(interquartile range)HbA1c in mmol/mol were:dapagliflozin-78.0(25.3),canagliflozin-80.0(25.5),and empagliflozin-75.0(23.5)respectively.The respective median HbA1c reduction at 12 months and the latest review(just prior to the study)were:66.5(22.8)&69.0(24.0),67.0(16.3)&66.0(28.0),and 67.0(22.5)&66.5(25.8)respectively(P<0.001 for all comparisons from baseline).Significant improvements in body weight(in kilograms)from baseline to study end were noticed with dapagliflozin-101(29.5)to 92.2(25.6),and canagliflozin 100(28.3)to 95.3(27.5)only.Significant reductions in median systolic and diastolic BP,from 144(21)mmHg to 139(23)mmHg;(P=0.015),and from 82(16)mmHg to 78(19)mmHg;(P<0.001)respectively were also observed.A significant reduction of microalbuminuria was observed with canagliflozin only[ACR 14.6(42.6)at baseline to 8.9(23.7)at the study end;P=0.043].Adverse effects of SGLT-2i were as follows:genital thrush and urinary infection-20(8.8%)&17(7.5%)with dapagliflozin;9(5.6%)&5(3.13%)with canagliflozin;and 4(5%)&4(5%)with empagliflozin.Diabetic ketoacidosis was observed in 4(1.8%)with dapagliflozin and 1(0.63%)with canagliflozin.CONCLUSION Treatment of patients with SGLT-2i is associated with statistically significant reductions in HbA1c,body weight,and better than those reported in RCTs,with low side effect profiles.A review of large-scale real-world data is needed to inform better clinical practice decision making.

Sodium-Glucose Cotransporter-2 Inhibitors: Who, When & How? Guidance for Use from a Multidisciplinary Practical Approach

Sodium-glucose cotransporter-2 inhibitors (SGLT-2 inhibitors) have transformed diabetes management by targeting renal glucose reabsorption. Designed initially as antidiabetic agents, their ability to lower blood glucose levels independently of insulin is well-documented. Beyond glycemic control, emerging research has unveiled their profound cardiorenal benefits. By inhibiting SGLT-2 protein, these drugs enhance glucose excretion in urine, reducing blood glucose levels. This mechanism has translated into significant cardiovascular and renal protection, establishing SGLT-2 inhibitors as pivotal in managing not only diabetes but also cardiovascular and renal diseases. Recent studies have illuminated the broader therapeutic potential of SGLT-2 inhibitors beyond diabetes. Evidence indicates their efficacy in managing heart failure, chronic kidney disease (CKD), and cardiovascular complications in individuals with or without diabetes. This expanded therapeutic landscape has catalyzed a paradigm shift in SGLT-2 inhibitor use, positioning them as key agents in the cardiorenal metabolic continuum. Moreover, their role in the secondary prevention of cardiovascular events and slowing CKD progression in T2DM patients has garnered considerable attention. This consensus-based review aims to offer practical guidance in an algorithmic approach to primary care healthcare professionals to optimize SGLT-2 inhibitors utilization and maximize their benefits. The review seeks to empower clinicians to effectively manage patients who may benefit from SGLT-2 inhibitor therapy by addressing common initiation barriers and optimizing treatment strategies. Additionally, it aims to raise awareness among primary care physicians regarding the multifaceted benefits of these medications and overcome clinical inertia in their adoption into routine clinical practice.

Sodium glucose cotransporter-2 inhibitors and heart disease:Current perspectives

Sodium glucose cotransporter-2 inhibitors(SGLT-2i)are antidiabetic medications with remarkable cardiovascular(CV)benefits proven by multiple randomised controlled trials and real-world data.These drugs are also useful in the prevention of CV disease(CVD)in patients with diabetes mellitus(DM).Although DM as such is a huge risk factor for CVD,the CV benefits of SGLT-2i are not just because of antidiabetic effects.These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well.There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated.Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases.This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

Sodium-Glucose Cotransporter 2 Inhibitors in Adult and Pediatric Congenital Heart Disease: Review of Emerging Data and Future Directions

Heart failure(HF)is common in patients with congenital heart disease(CHD)and there are limited medical therapies.Sodium-glucose cotransporter 2 inhibitors(SGLT2i)are a proven medical therapy in patients with acquired HF,though data are limited in patients with CHD.The aim of this review is to summarize the current evidence for use of SGLT2i in patients with CHD and identify future directions for study.In available publica-tions,SGLT2i in patients with CHD seem to be well tolerated,with similar side effect profile to patients with acquired HF.Improvement in functional capacity and natriuretic peptides are mixed,though there is a signal for potential reduction in HF hospitalizations.One prospective study in patients with systemic right ventricles showed an improvement in systolic function for patients already on maximal HF medical therapy.Though lim-ited,there is emerging data on use of SGLT2i in pediatric patients with CHD and HF.Future prospective studies are needed to evaluate for clinically meaningful endpoints,including HF hospitalization,as well as evaluate the hemodynamic impact in subtypes of CHD at high risk for HF.

Sodium-dependent glucose transporter 2 inhibitors:Transforming diabetic cardiomyopathy management

This article addresses the substantial findings of a study on sodium-dependent glucose transporter 2 inhibitors(SGLT2is)and their effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure.The editorial explores the broader implications of the study findings for clinical practice,thus highlighting the pivotal role of SGLT2is in improving cardiac function,reducing oxidative stress,and attenuating inflammation.It emphasizes the importance of early intervention with SGLT2is in preventing the progression of diabetic cardio-myopathy;hence,these inhibitors have the potential to transform the manage-ment of asymptomatic heart failure in patients with diabetes.

BET inhibitors potentiate melanoma ferroptosis and immunotherapy through AKR1C2 inhibition

Dear Editor,Ferroptosis,an iron-dependent form of cell death driven by overwhelming lipid peroxidation,represents a vulnerability in cancers,and therapeutic strategies to further potentiate ferroptosis hold great potential for melanoma treatment.

Effects of sodium-dependent glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus and asymptomatic heart failure

Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have been increa-singly used with proven efficacy in patients with heart failure(HF),regardless of diabetes status.GrubićRotkvićet al recently published an observational study on SGLT2i therapy in patients with type 2 diabetes mellitus and asymptomatic HF.They found that the use of SGLT2i led to reduced cardiac load and improved cardiovascular performance,reinforcing the evolving paradigm that SGLT2i are not merely glucose-lowering agents but are integral to the broader management of cardiovascular risk in patients with type 2 diabetes mellitus.The study by GrubićRotkvićet al contributes to the growing body of literature supporting the early use of SGLT2i in patients with diabetic cardiomyopathy,offering a potential strategy to mitigate the progression of HF.Future larger studies should be con-ducted to confirm these findings,and explore the long-term cardiovascular bene-fits of SGLT2i,particularly in asymptomatic patients at risk of developing HF.

SGLT2 inhibitors in the prevention of diabetic cardiomyopathy:Targeting the silent threat

Heart failure(HF)is a major global health challenge,particularly among indi-viduals with type 2 diabetes mellitus(T2DM),who are at significantly higher risk of developing HF.Diabetic cardiomyopathy,a unique form of heart disease,often progresses silently until advanced stages.Recent research has focused on sodium-dependent glucose transporter 2 inhibitors(SGLT2i),originally developed for hyperglycemia,which have shown potential in reducing cardiovascular risks,including HF hospitalizations,irrespective of diabetic status.In this editorial we comment on the article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.The investigators examined the effects of SGLT2i on myocardial function in T2DM patients with asymptomatic HF,finding significant improvements in stroke volume index and reductions in systemic vascular resis-tance,suggesting enhanced cardiac output.Additionally,SGLT2i demonstrated anti-inflammatory and antioxidant effects,as well as blood pressure reduction,though the study’s limitations—such as small sample size and observational design—necessitate larger randomized trials to confirm these findings.The study underscores the potential of early intervention with SGLT2i in preventing HF progression in T2DM patients.

Effectiveness and mechanisms of sodium-dependent glucose transporter 2 inhibitors in type 2 diabetes and heart failure patients

We comment on an article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and their impact on comorbidities.SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys,lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine.Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control.In addition,SGLT2i has been shown to be effective in anti-apoptosis,weight loss,and cardiovascular protection.Accordingly,it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.

Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes:A systematic review with multiple network meta-regressions

BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.

In Silico Screening of Potential Inhibitors against dPLA2 from Named Chinese Herbs for Identification of Compounds with Antivenom Effects Due to Deinagkistrodon acutus Snake Bites

Phospholipase A2 (PLA2) is the key enzyme to the venom from Deinagkistrodon acutus which is one of the highly venomous snakes in China. In addition to being a catalyst for the hydrolysis of phospholipases A2 from snake venom, its well known that it possesses a broad spectrum of pharmacological activities, such as myotoxicity, neurotoxicity, cardiotoxicity, and hemolytic, anticoagulant and antiplatelet activities. However, snakebites are not efficiently treated by conventional serum therapy. Acute wounds can still cause poisoning and death. In order to find effective inhibitors of Deinagkistrodon venom acid phospholipase A2 (dPLA2), we obtained 385 compounds in 9 Chinese herbs from the TCMSP. These compounds were further performed to virtual screen using in silico tools like ADMET analysis, molecular docking and molecular dynamics (MD) simulation. After Pharmacokinetics analysis, we found 7 candidate compounds. Besides, analysis of small molecule interactions with dPLA2 confirmed that the amino acid residues HIS47 and GLY29 are key targets. Because they bind not only to the natural substrate phosphatidylcholine and compounds known for having inhibitory functions, but also for combining with potential antidote molecules in Chinese herbal medicine. This study is the first to report experience with virtual screening for possible inhibitor of dPLA2, such as the interaction spatial structure, binding energy and binding interaction analysis, these experiences not only provide reference for further experimental research, but also have a guideline for the study of drug molecular mechanism of action.

Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways:Experimental and clinical evidence

Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and inflammation.Angiotensin II,the main mediator of the renin-angiotensin-aldosterone system,also contributes to CVD by promoting ROS production.Reduced activity of sirtuins(SIRTs),a family of proteins that regulate cellular metabolism,also worsens oxidative stress.Reduction of energy production by mitochondria is a common feature of all metabolic disorders.High SIRT levels and 5’adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta,which promotes ketosis.Ketosis,in turn,increases autophagy and mitophagy,processes that clear cells of debris and protect against damage.Sodiumglucose cotransporter-2 inhibitors(SGLT2i),a class of drugs used to treat type 2 diabetes,have a beneficial effect on these mechanisms.Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events.SGLT2i also increase mitochondrial efficiency,reduce oxidative stress and inflammation,and strengthen tissues.These findings suggest that SGLT2i hold great potential for the treatment of CVD.Furthermore,they are proposed as anti-aging drugs;however,rigorous research is needed to validate these preliminary findings.