👤 Ami S Bhatt

Unilateral vocal fold paralysis (UVFP) due to recurrent laryngeal nerve (RLN) injury is a common cause of dysphonia. No biotherapeutic injectable exists that directs laryngeal reinnervation after RLN injury. Placental-derived connective tissue matrix (pd-CTM) could fill this need, as it contains a plethora of cytokines with potential UVFP therapeutic benefits. This study aimed to identify and quantify the factors in a commercially available pd-CTM (CTM Flow, CTM Biomedical, Lake Worth, Florida) and to study the effects of pd-CTM on vocal fold microenvironment and glottic function in a mouse model of unilateral RLN injury. Cytokine expression (ng/mL) in pd-CTM was characterized using a cytokine array and ELISA. In a separate experiment, C57/BL6 mice were divided into three groups: uninjured negative controls (n = 12), RLN transection with ipsilateral saline thyroarytenoid (TA) injection (n = 16), and RLN transection with ipsilateral pd-CTM TA injection. Outcomes included laryngeal electromyography (L-EMG) and video laryngoscopy after 7 and 28 days, with larynges then harvested and analyzed via immunohistochemistry (IHC) and qPCR. pd-CTM characterization showed moderate-to-high levels of neurotrophic (BDNF, CNTF, GDNF, NTF-3), angiogenic (Angiogenin, VEGF-D), tissue remodeling (bFGF, IGF-1, HGF, TGF-β3), and anti-inflammatory factors (IL-10, IL-1Rα). L-EMG demonstrated increased mean normalized area under the curve ratio in pd-CTM treated mice compared to saline treated mice at the 28-day time point indicating reinnervation (p < 0.001). IHC detected innervated neuromuscular junctions 28 days after pd-CTM treatment. pd-CTM may be a novel treatment option for patients with UVFP based on the neurotrophic, angiogenic, tissue remodeling, and anti-inflammatory factors present. NA. Show less

Although familial hypercholesterolemia (FH) is a US Centers for Disease Control and Prevention tier 1 condition for genetic testing, the impact of testing on clinical outcomes is unclear. We aimed to assess whether genetic testing alters lipid management in HeartCare participants. For participants with pathogenic/likely pathogenic variants for FH observed at Baylor College of Medicine cardiology clinics, data on laboratory values, medication prescriptions, and diagnoses were collected and compared before and after genetic testing. In the 20 participants with APOB/LDLR variants and complete data, low-density lipoprotein cholesterol (LDL-C) was numerically lower but not significantly different before vs after genetic testing (103 vs 79.5 mg/dL). Sixteen (80%) participants were from the lipid clinic; the majority had a preexisting FH diagnosis. LDL-C levels were numerically lower, and more patients received proprotein convertase subtilisin/kexin type 9 inhibitor prescriptions after genetic testing; however, the difference was not statistically significant. The majority of patients with FH achieved LDL-C <100 mg/dL after genetic testing; however, most patients with APOB/LDLR variants were from the lipid clinic and had been diagnosed with FH by clinical criteria. Show less

Determining apolipoprotein E (APOE) ε4 allele status, a key genetic risk factor for Alzheimer's disease (AD), requires molecular genotyping infrastructure not widely accessible beyond specialized centers. A fully automated high-throughput apoE E4 proteotyping immunoassay was evaluated for clinical performance (460 participants across three cohorts) and analytical validity. Concordance with polymerase chain reaction (PCR)-based genotyping and measures of analytical validity were reported. The apoE E4 immunoassay demonstrated 99.6% (95% confidence interval [CI]: 98.4% to 99.9%) concordance with PCR-based APOE ε4 genotype results across the pooled clinical cohort; 100.0% (95% CI: 97.1% to 100.0%) in those with AD (N = 127) and 99.4% (95% CI: 97.8% to 99.8%) in those without AD (333). The assay met analytical validity criteria for E4 isoform specificity, interference, precision, and stability. The apoE E4 immunoassay demonstrated high concordance with PCR-based genotyping and robust analytical validity, offering an accessible alternative for APOE ε4 zygosity assessment. A novel high-throughput plasma-based proteotyping immunoassay for APOE ε4 zygosity classification was developed and evaluated for clinical performance and analytical validity. The apoE E4 immunoassay demonstrated high concordance (99.6%) with PCR-based APOE ε4 genotyping across a diverse international cohort, and a robust analytical profile. An apoE E4 immunoassay may offer a more cost-effective and accessible alternative to DNA genotyping approaches currently used for AD risk evaluation and anti-amyloid treatment decisions. Show less

Alzheimer's Disease (AD) is associated with reduced laryngeal sensation, decreased pharyngeal strength, and silent aspiration. Aspiration pneumonia is a leading cause of death in advanced AD. Superior laryngeal nerve(SLN) dysfunction is hypothesized to be responsible for poor laryngeal sensation and aspiration pneumonia. The purpose of this study was to compare SLN neurophysiology in an AD rat model to control animals. SLN-evoked studies were performed via stimulation of the main trunk in 4-month-old adult apolipoprotein-E4 (ApoE4-KI) rats (n = 8) versus wild-type rats (n = 10). Recording electrodes were placed on the internal branch of the SLN (iSLN) and cricothyroid muscles. Stimulated swallow force measurements from hyoid elevation were compared between groups. Outcome measures included both sensory and motor evoked responses. Additionally, force and frequency of electrically and tactile stimulated swallow reflexes were analyzed. Sensory nerve action potential duration was significantly longer in APOE-KI rats than controls with a mean difference (95% CI) of 2.24 ms (1.08-3.41). Both compound motor action potential latency and total duration were significantly longer in the APOE4-KI rats than controls with a mean difference (95% CI) of 0.22 (0.115-0.33) and 2.18 (0.90-3.4) respectively. Tactile-stimulated swallow frequency was significantly lower in the AD cohort vs. controls with a mean difference of -5.4 swallows/10 s (-7.6, -3.2). SLN evoked responses were significantly longer with a decrease in swallow frequency in an AD rat model compared to age-matched controls. This work suggests differences in SLN signaling between the cohorts. This work may provide a mechanistic understanding of SLN dysfunction and a tractable model to test new treatments for swallow dysfunction. N/A. Show less

Depletion of TRF2 from chromosome ends causes telomeric fusions and genome instability in mammals, but in mouse neural stem cells (mNSCs), Trf2's role is non-telomeric. Although essential for mNSC proliferation and survival, Trf2 does not protect telomeres, aligning with findings that Trf2 is dispensable for telomere protection in pluripotent stem cells. In Trf2-deficient adult mNSCs (Trf2fl/fl; Nestin-Cre), proliferation decreased and neuronal differentiation was impaired, yet no telomere dysregulation or DNA damage response was observed. Similarly, TRF2 depletion in SH-SY5Y cells induced differentiation without telomere dysfunction. Mechanistically, non-telomeric TRF2 directly binds to the promoters of key genes that regulate differentiation, recruiting the polycomb repressor complex (PRC2) for H3K27 trimethylation, repressing differentiation genes to maintain NSC identity. G-quadruplex (G4) motifs are crucial for TRF2 binding; disrupting this interaction via G4-binding ligands or the G4-specific helicase DHX36 induces differentiation genes, promoting neurogenesis. These findings highlight TRF2's non-telomeric role in NSC survival, offering insights into neurogenesis and aging-related neurodegeneration. Show less

Non-olfactory G-protein-coupled receptors (GPCRs) regulate vital physiological functions and are targets for ∼34% of US Food and Drug Administration (FDA)-approved drugs. While small-molecule-activated GPCRs are well studied, there is growing interest in peptide GPCRs, particularly the melanocortin-4 receptor (MC4R), a key regulator of energy balance and appetite. Activation of MC4R by β-melanocyte-stimulating hormone (β-MSH) reduces food intake, and pathway dysfunction leads to obesity. However, current methods to study GPCR-peptide interactions are resource intensive and low throughput. To address this, we developed a high-throughput cell surface peptide display platform with a β-arrestin-based MC4R reporter to screen over 2,000 β-MSH point mutants. This approach identified peptide variants that significantly impact MC4R activation, including a novel D5H mutant with enhanced receptor activation. Our results demonstrate a scalable method to directly link GPCR activation to peptide variants, offering insights for therapeutic peptide design. Show less

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT001747 and NCT01663402. Show less

Residual cardiovascular risk remains, despite achieving low-density lipoprotein cholesterol targets with high-intensity statins. Traditional risk scores are suboptimal. This study evaluated the prognostic utility of a 9-plex apolipoprotein panel in recent patients with acute coronary syndrome on statins and its role in predicting treatment benefit by alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, enabling precision medicine. Baseline serum samples from 11 843 participants in the ODYSSEY OUTCOMES trial (https://www.clinicaltrials.gov; Unique identifier: NCT01663402) were analyzed using mass spectrometry to measure Apo(a), ApoA-I, ApoA-II, ApoA-IV, ApoB, ApoC-I, ApoC-II, ApoC-III, and ApoE. Using logistic regression, probabilities of major adverse cardiovascular events (MACE) and all-cause death over a median follow-up of 2.9 years were estimated based on baseline apolipoproteins and lipid concentrations. Clinical performance was assessed by comparing the area under the curve (AUC) of 3 models: the apolipoprotein panel, the lipid panel (total cholesterol, high-density lipoprotein cholesterol, and triglycerides), and a combination. In addition, prediction models estimating the treatment benefit of alirocumab by the apolipoprotein panel were developed. The prognostic performance of the apolipoprotein panel for MACE showed an AUC (95% CI) of 0.648 (0.626-0.670), compared with 0.579 (0.557-0.602) for the lipid panel. For all-cause death, the apolipoprotein panel had an AUC of 0.699 (0.664-0.733), while the lipid panel had an AUC of 0.599 (0.564-0.635). Adding the apolipoprotein panel significantly improved the performance of the conventional lipid panel ( A multiplex apolipoprotein panel led to better prediction of MACE and all-cause death, beyond lipids, in patients with postacute coronary syndrome on optimized statin therapy. The panel also predicts the treatment benefit of alirocumab. Further validation of this approach is now needed, and if confirmed and improved, it could lead to better disease prediction and management in the future. Show less

Elevated lipoprotein(a) [Lp(a)] levels increase cardiovascular (CV) risk. Lp(a) contains oxidized phospholipids that may promote lipid oxidation more than other lipoproteins. The highly unsaturated omega-3 fatty acid eicosapentaenoic acid (EPA) has multiple double bonds that can trap free radicals in resonance structures. Purified ethyl-EPA reduced CV events in high-risk patients with elevated Lp(a) despite Lp(a)-associated risk elevation. Since Lp(a) is enriched in oxidized lipids, we hypothesized that Lp(a)-enriched plasma undergoes more rapid oxidation than other apolipoprotein B (ApoB)-containing particles and that EPA limits oxidation of Lp(a)-enriched plasma more effectively than less-unsaturated fatty acids or other lipid-lowering treatments. This property could limit the cellular stress responses in endothelial cells (ECs). Lp(a) was enriched to >50% total ApoB content to resemble an Lp(a)-associated 'high-risk' phenotype and compared with matching levels of small-dense LDL (sdLDL) and very-low-density lipoprotein by isopycnic centrifugation. Samples were then incubated with EPA (50 µM) or equivolume vehicle at 37°C for 30 min. Oxidation was initiated with copper sulfate and monitored by malondialdehyde formation. We also subjected EPA to oxidation before measuring its antioxidant activity when compared with other long chain, less saturated fatty acids and lipid-lowering agents. Human umbilical vein ECs (HUVECs) were incubated with Lp(a)-enriched plasma following oxidation in the absence and presence of EPA. Cell lysate samples were then analysed by global liquid chromatography-mass spectroscopy (LC/MS)-based proteomics for significant changes in protein expression (>1-fold). Lp(a)-enriched plasma contained the highest baseline oxidized lipid (P < 0.05) and underwent the most rapid oxidation. EPA, but neither the less-unsaturated fatty acids nor lipid agents attenuated oxidation of each fraction through 4 h (P < 0.01). Oxidized EPA had diminished antioxidant capacity corresponding to the extent of oxidation. Attenuation of Lp(a) oxidation with EPA also mitigated pro-inflammatory and cellular stress response changes in protein expression. Lp(a)-enriched plasma underwent more rapid oxidation than other ApoB-containing lipoproteins and promoted inflammatory changes in EC protein expression, a process attenuated by EPA. This action may contribute to reduced CV risk by EPA in those with elevated Lp(a) levels. Show less

Hypertriglyceridemia (HTG), which arises from defects in triglyceride-rich lipoprotein (TRL) metabolism, is associated with increased morbidity and mortality from pancreatitis and atherosclerotic cardiovascular disease. Traditional therapies, including fibrates and omega-3 fatty acids, have shown limited efficacy in controlling triglyceride (TG) levels and cardiovascular risk. This review explores the role of emerging therapies that target TG and TRL metabolism via novel biochemical pathways. Apolipoprotein C-III inhibitors appear most effective for patients with variants of severe HTG, particularly multifactorial and familial chylomicronemia syndromes, by enhancing TRL metabolism through both lipoprotein lipase-dependent and independent mechanisms. Angiopoeitin-like proteins 3 and 4 inhibitors appear most useful for mixed hyperlipidemia, with favorable effects across the entire spectrum of apoB-containing atherogenic lipoproteins. For patients with HTG and concomitant complications of insulin resistance, including metabolic associated steatotic liver disease and type 2 diabetes mellitus, fibroblast growth factor-21 analogs may provide significant benefit. HTG is a diverse condition. Apolipoprotein C-III inhibitors, angiopoeitin-like proteins 3 and 4 inhibitors, and fibroblast growth factor-21 analogs represent significant advancements in the treatment of HTG, offering new hope for effectively managing this condition across its full spectrum of disease. Show less

Apolipoprotein (Apo) C3 has been associated with incident coronary heart disease and major adverse cardiovascular events (MACE). Whether ApoC3 levels predict risk in patients with acute coronary syndrome (ACS) on optimized statin treatment is unknown. ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months' treatment (M4; n=11 176) with alirocumab or placebo in the ODYSSEY OUTCOMES trial. Patients with fasting triglycerides >400 mg/dL were excluded. The association of baseline ApoC3 with risk of MACE or death was assessed in post hoc adjusted Cox regression models and spline analyses adjusted for treatment and ApoB. In adjusted models in the alirocumab group we determined association of ApoC3 change from baseline to M4 with subsequent risk of MACE and death. Median (Q1, Q3) baseline ApoC3 concentration was 85 (65, 113) mg/L. With adjustment for ApoB, baseline ApoC3 showed no clinically meaningful relationship to risk of MACE or death in spline analyses and no association with MACE (P=0.89) or death (P=0.70) in Cox regression analyses. Alirocumab reduced ApoC3 modestly by median -10 (-27, -5) mg/L (P<0.0001) and reduced MACE (10.1% vs 12.1%; P=0.0006) and death (3.5% vs 4.2%; P=0.045) versus placebo. However, the change in ApoC3 on alirocumab did not predict subsequent MACE or death. In patients with recent ACS on optimized statins without severe hypertriglyceridemia, neither baseline ApoC3 (accounting for ApoB) nor ApoC3 change with alirocumab predicted MACE or death. It is uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk. Show less

Pathological tau aggregates form distinct polymorphic species across diseases and even across Alzheimer's disease (AD) patients. However, tau aggregate polymorphism across the apolipoprotein E isoforms (APOE ε2, ε3, ε4), the strongest predictors of late-onset AD development, is unknown. This study assessed the conformational and bioactivity properties of tau oligomers from 14 patients with varying APOE genotypes. Tau oligomers differ in proteolytic stability and cleavage site profiles across the APOE isoforms, indicating conformationally distinct polymorphs. APOE isoform-associated tau oligomers affect synaptic plasticity differently, with ε4-associated oligomers having the highest potency and strongest impact on synaptic functioning. Bioactivity assays reveal that ε4-associated oligomers demonstrate particularly high seeding activity. Interestingly, tau oligomer synaptotoxicity and seeding activity are independent characteristics. The APOE isoforms are associated with distinct tau oligomer polymorphs with varying bioactivity, underscoring the importance of considering APOE status when generating AD therapies. Polymorph-specific targeting of pathological tau species could provide a novel method of combating AD. Conformational and bioactivity distinctions of tau oligomers have not yet been investigated across the APOE isoforms (ε2, ε3, ε4). Tau oligomers differ in conformational properties across the APOE isoforms. APOE ε4-relevant tau oligomers strongly impair synaptic plasticity and demonstrate high tau seeding activity. APOE ε4-relevant tau oligomers exist as a particularly toxic species, making them an ideal target for tau-based AD therapies. Show less

The 2025 American Society for Preventive Cardiology meeting highlighted evolving strategies in cardiovascular disease prevention, spanning risk models based on traditional risk factors, emerging biomarkers, novel therapeutics, and digital health innovations. Key discussions addressed lipoprotein(a) [Lp(a)] and inflammation as a causal risk factor, their clinical management, and readiness for targeted therapies; optimal systolic blood pressure targets informed by recent randomized controlled trials; and ongoing debate regarding apolipoprotein B versus low-density lipoprotein cholesterol (LDL-C) as the primary lipid target. Advances in digital health emphasized prevention through artificial intelligence, health equity in technology, and the growing role of wearables. Imaging emerged as a central theme, with sessions highlighting its role in risk assessment, monitoring treatment response, and refining prevention strategies, especially in young adults. Sessions on women's cardiovascular health underscored female-specific risk enhancers and limitations of current risk prediction models. Additional debates addressed the use of polygenic risk scores in young adults and strategies for universal screening with LDL-C, hsCRP, and Lp(a). Heart failure prevention was highlighted as a critical frontier, with emphasis on stage-based risk stratification, early identification of subclinical disease, and targeted interventions to avert progression to symptomatic heart failure. Updates on renal denervation reaffirmed its safety, efficacy, and durability as an adjunctive therapy in resistant hypertension. Collectively, these highlights emphasize the rapid evolution of preventive cardiology, integrating precision risk stratification, digital tools, and novel therapies into routine care. Show less

Both lipoprotein(a) [Lp(a)] and peripheral artery disease (PAD) are associated with ischaemic events. We sought to assess the association between Lp(a) and major adverse cardiovascular events (MACE) and major lower extremity events (MALE) among patients with baseline PAD. The Mass General Brigham (MGB) Lp(a) registry includes all individuals with Lp(a) measured at two tertiary care centres from 2000 to 2019. Those with PAD were grouped according to Lp(a) percentile: 1st-25th [Q1, Lp(a) ≤ 14 nmol/L], 26th-50th (Q2, 14-<42 nmol/L), 51st-75th (Q3, 42-<132 nmol/L), and 76th-100th (Q4, 132-855 nmol/L). Outcomes were MACE [composite of cardiovascular (CV) death, myocardial infarction, or coronary revascularization] and MALE (composite of peripheral revascularization, acute limb ischaemia, or major lower extremity amputation). Cox proportional hazard modelling was used to assess the association between Lp(a) and the outcomes of interest after adjusting for traditional risk factors. Among 3757 individuals with PAD [39% female, median age 68 (IQR: 58-77)], individuals with Lp(a) levels in the third and fourth quartiles had a 24 and 30% increased hazard of MACE, respectively [adj. hazard ratio (HR): 1.24, P = 0.005; adj. HR: 1.30, P = 0.001] when compared with those in the first quartile. Individuals in the fourth quartile had a 19% greater hazard of MALE (adj. HR: 1.19, P = 0.043). Elevated Lp(a) in patients with PAD was associated with an increased risk of both MACE and MALE. Accordingly, measurement of Lp(a) may convey important prognostic value and allow for further risk stratification within this high-risk population. Show less

The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Show less

Metabolic syndrome (MetSyn) is associated with high risk of cardiovascular (CV) events, irrespective of statin therapy. In the overall REDUCE-IT study of statin-treated patients, icosapent ethyl (IPE) reduced the risk of the primary composite endpoint (CV death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or unstable angina requiring hospitalization) and the key secondary composite endpoint (CV death, non-fatal myocardial infarction, or non-fatal stroke). REDUCE-IT was an international, double-blind trial that randomized 8179 high CV risk statin-treated patients with controlled LDL cholesterol and elevated triglycerides, to IPE 4 g/day or placebo. The current study evaluated the pre-specified patient subgroup with a history of MetSyn, but without diabetes at baseline. Among patients with MetSyn but without diabetes at baseline ( In statin-treated patients with a history of MetSyn, IPE significantly reduced the risk of first and total CV events in REDUCE-IT. The large relative and ARRs observed supports IPE as a potential therapeutic consideration for patients with MetSyn at high CV risk. Show less

South Asians (SAs) represent ∼25% of the world's population and account for >50% of global cardiovascular (CV) deaths, yet they continue to be underrepresented in contemporary clinical trials. The REDUCE-IT study demonstrated in a high-risk and predominantly White population that icosapent ethyl (IPE) lowered major adverse cardiovascular events by 25%. We sought to determine the generalizability of these results to a high-risk population of SAs with established CV disease living in Canada. This was a cross-sectional observational study of 200 statin-treated SAs (≥45 years) with atherosclerotic CV disease (ASCVD) (NCT05271591). SA ethnicity was self-identified as being of Anglo-Indian, Bangladeshi, Bengali, Bhutanese, Goan, Gujarati, Indian, Jatt, Kashmiri, Maharashtrian, Malayali, Nepali, Pakistani, Punjabi, Sindhi, Sinhalese, Sri Lankan, Tamil, Telugu, or other SA. ASCVD was defined as the presence of coronary, carotid, or peripheral atherosclerosis. Mean age of the cohort was 67 years, where 82% were men and 57% had diabetes. The predominant ASCVD phenotype was coronary artery disease (94%). Mean (SD) baseline LDL-C and triglycerides were 1.70 (0.8) mmol/L and 1.42 (1.0) mmol/L, respectively. Three-quarters were on high-intensity statin therapy. According to the Health Canada/Canadian Cardiovascular Society Guidelines and FDA-approved indication, 33% and 25% of the participants were, respectively, eligible for IPE. A large proportion of high-intensity, statin-treated, high-risk patients with ASCVD and of self-reported SA ethnicity are eligible for IPE. These data have important translational implications for SAs who are at a disproportionately higher risk of CV morbidity and mortality. This study was funded by an unrestricted grant provided by HLS Therapeutics Inc, Canada. Show less

Natural products have significantly contributed to drug discovery for neurodegenerative diseases. Caffeine is one of the well-known central nervous system(CNS)-active natural products. Besides its CNS stimulant properties, it is a mild inhibitor of acetylcholinesterase (AChE) and possesses memory-enhancing properties. The present work aimed to improve the AChE inhibition activity of the caffeine. The rationally designed caffeine-based triazoles were synthesized and evaluated in vitro for cholinesterase and β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitory activities. The attachment of triazole to the caffeine enhances its AChE inhibition activity from half-maximal inhibitory concentration (IC Show less

Alzheimer's Disease (AD) impairs memory and cognitive functions in the geriatric population and is characterized by intracellular deposition of neurofibrillary tangles, extracellular deposition of amyloid plaques, and neuronal degeneration. Literature suggests that latent viral infections in the brain act as prions and promote neurodegeneration. Memantine possesses both anti-viral and N-methyl-D-aspartate (NMDA) receptor antagonistic activity. This research was designed to evaluate the efficacy of antiviral agents, especially valacyclovir, a prodrug of acyclovir in ameliorating the pathology of AD based on the presumption that anti-viral agents targeting the Herpes Simplex Virus (HSV) can have a protective effect on neurodegenerative diseases like Alzheimer's disease. Thus, we evaluated acyclovir's potential activity by in-silico computational docking studies against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1). These findings were further evaluated by in-vivo scopolamine-induced cognitive impairment in rats. Two doses of valacyclovir, a prodrug of acyclovir (100 mg/kg and 150 mg/kg orally) were tested. Genetic Optimisation for Ligand Docking scores and fitness scores of acyclovir were comparable to donepezil. Valacyclovir improved neurobehavioral markers. It inhibited AChE and BuChE (p<0.001) enzymes. It also possessed disease-modifying efficacy as it decreased the levels of BACE-1 (p<0.001), amyloid beta 1-42 (p<0.001), amyloid beta 1-40 (p<0.001), phosphorylatedtau (p<0.001), neprilysin (p<0.01), and insulin-degrading enzyme. It ameliorated neuroinflammation through decreased levels of tumour necrosis factor α (p<0.001), nuclear factor-kappa B (p<0.001), interleukin 6 (p<0.001), interleukin 1 beta (p<0.001), and interferon-gamma (p<0.001). It also maintained synaptic plasticity and consolidated memory. Histopathology showed that valacyclovir could restore cellular density and also preserve the dentate gyrus. Valacyclovir showed comparable activity to donepezil and thus can be further researched for the treatment of Alzheimer's disease. Show less

Triple-negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial-to-mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)-approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan-MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance. Show less

Obesity plays a pivotal role in the development of metabolic syndrome-excessive body fat, spikes in blood glucose levels and hypertension-and ultimately leads to cardiovascular diseases and type 2 diabetes (T2D), if left unattended. The present study aimed to investigate the associated risk of T2D with obesity risk alleles of fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes. The study includes 400 subjects (300 T2D diabetic cases and 100 healthy controls). Genetic analysis was done by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. The findings of the study show no significant increase in odds of diabetes associated with the prevalence of FTO and MC4R minor alleles. Rare allele frequencies for "A" of FTO rs9939609 were 0.34 and 0.30 in cases and controls, respectively. Rare allele frequencies for A of MC4R rs12970134 were found to be more common in controls (0.45) than cases (0.41), but the difference was insignificant (p 0.246); however, an increase in body weight with the presence of allele "A" of the FTO gene (p value < 0.001) was found, indicating indirect involvement in the development of T2D. In addition, these were also correlated with the demographic/lifestyle and clinico-pathological parameters between T2D cases and controls. We found that T2D patients with a history of smoking and high consumption of alcohol, fast foods and sweetened beverages are at high risk of T2D compared to healthy controls (p  < 0.01*). The present study concludes that there is no direct association of rs9939609 of the FTO gene with the occurrence of diabetes in the Indian population, but its role in T2D development cannot be overlooked altogether. Furthermore, we conclude that the rs9939609 of FTO carries a potential risk of obesity and because of this FTO rs9939609 T > A is widely considered an obesity-associated allele/single-nucleotide polymorphism (SNP). Show less

Triple-negative breast cancers (TNBCs) represent 15% to 20% of all breast cancers and are often associated with poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Aberrations in the phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. While the crosstalk between PI3K and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways has been characterized in several systems, new evidence suggests that MEK5/ERK5 signaling is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/protein kinase B (Akt) and MEK5/ERK5 in the MDA-MB-231, BT-549, and MDA-MB-468 TNBC cell lines. We used the Akt inhibitor ipatasertib, ERK5 inhibitors XMD8-92 and AX15836, and the novel MEK5 inhibitor SC-1-181 to investigate the effects of dual inhibition. Our results indicated that dual inhibition of PI3K/Akt and MEK5/ERK5 signaling was more effective at reducing the proliferation and survival of TNBCs than single inhibition of either pathway alone. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. In addition, the dual inhibition strategy was determined to be synergistic in MDA-MB-231 and BT-549 cells and was relatively nontoxic in the nonneoplastic MCF-10 cell line. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs. Show less

Mutations in sarcomeric genes are common genetic cause of cardiomyopathies. An intronic 25-bp deletion in cardiac myosin binding protein C (MYBPC3) at 3' region is associated with dilated and hypertrophic cardiomyopathies in Southeast Asia. However, the frequency of sarcomeric gene polymorphisms and associated clinical presentation have not been established with left ventricular dysfunction (LVD). Therefore, the aim of the present study was to explore the association of MYBPC3 25-bp deletion, titin (TTN) 18 bp I/D, troponin T type 2 (TNNT2) 5 bp I/D and myospryn K2906N polymorphisms with LVD. This study includes 988 consecutive patients with angiographically confirmed coronary artery disease (CAD) and 300 healthy controls. Among the 988 CAD patients, 253 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as LVD. MYBPC3 25-bp deletion, TTN 18 bp I/D and TNNT2 5 bp I/D polymorphisms were determined by direct polymerase chain reaction method, while myospryn K2906N polymorphism by TaqMan assay. Our results showed that MYBPC3 25-bp deletion polymorphism was significantly associated with elevated risk of LVD (LVEF <45) (healthy controls versus LVD: OR=3.85, P <0.001; and nonLVD versus LVD: OR=1.65, P = 0.035), while TTN 18 bp I/D, TNNT2 5 bp I/D and myospryn K2906N polymorphisms did not show any significant association with LVD. The results also showed that MYBPC3 25-bp deletion polymorphism was significantly associated with other parameters of LV remodelling, i.e. LV dimensions (LV end diastole dimension, LVEDD: P = 0.037 and LV end systolic dimension, LVESD: P = 0.032). Our data suggests that MYBPC3 25-bp deletion may play significant role in conferring LVD as well as CAD risk in north Indian population. Show less

Myelin regeneration is indispensably important for patients suffering from several central nervous system (CNS) disorders such as multiple sclerosis (MS) and spinal cord injury (SCI), because it is not only essential for restoring neurophysiology, but also protects denuded axons for secondary degeneration. Understanding the cellular and molecular mechanisms underlying remyelination is critical for the development of remyelination-specific therapeutic approaches. As remyelination shares certain common mechanisms with developmental myelination, knowledge from study of developmental myelination contributes greatly to emerging myelin regeneration therapies, best evidenced as the recently developed human anti-Nogo receptor interacting protein-1 (LINGO-1) monoclonal antibodies to treat MS patients in clinical trials. Show less