👤 Dur E Shahwar Afzal

Huntington's Disease (HD) is a neurodegenerative ailment characterized by progressive motor, cognitive, and psychiatric decline, linked with mitochondrial dysfunction, oxidative stress, and neuroinflammation. Few effective treatments are available for Huntington's. Additionally, the therapeutic effects of natural polysaccharides against neurodegenerative disorders have not yet been fully explored. This study aimed to investigate the neuroprotective potential of Aloe Polysaccharides (APs) against 3-Nitropropionic Acid (3- NPA)-initiated HD-like symptoms in rats. Adult male rats were allocated to control, 3-NPA-treated, and APs-treated groups (100 and 200 mg/kg orally) following 3-NPA administration. Behavioral assessments (rotarod, open field, narrow beam walking) and biochemical analyses, including neurotransmitters [Acetylcholinesterase (AChE), Acetylcholine (ACh), Dopamine (DA), Norepinephrine (NE), Serotonin (5-HT), Gamma-Aminobutyric Acid (GABA), Glutamate (Glu)], oxidative/nitrative stress markers [Malondialdehyde (MDA, Nitric Oxide (NO)], antioxidant enzymes [Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH)], mitochondrial enzyme [Succinate Dehydrogenase (SDH)], inflammatory mediators [Nuclear Factor Kappa B (NF-κB), Tumor Necrosis Factor Alpha (TNF-α), Interleukin- 1 Beta (IL-1β), Cyclooxygenase-2 (COX-2)], neurotrophic factor [Brain-Derived Neurotrophic Factor (BDNF)], and apoptotic markers (caspase-3, caspase-9, B-Cell Lymphoma 2 (Bcl-2), Bcl-2-Associated X Protein (Bax)] were performed. Additionally, the impact of APs on regulators of mitochondrial biogenesis and antioxidant response [Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), Sirtuin 1 (Sirt1), Heme Oxygenase-1 (HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-1α), Adenosine Monophosphate-Activated Protein Kinase (AMPK), Uncoupling Protein 1 (UCP1), Uncoupling Protein 2 (UCP2)] was evaluated. Histopathological examination of the striatum was conducted. Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test. 3-NPA administration induced significant motor deficits, neurotransmitter imbalance, elevated oxidative stress, inflammation, mitochondrial impairment, BDNF depletion, apoptosis, and striatal degeneration (P < 0.01). APs treatment significantly (P < 0.01; P < 0.001) reversed 3-NPA effects and improved behavioral performance (rotarod latency, OFT exploratory activity, and beam walk score); restored neurotransmitter balance; improved antioxidant enzymes (SOD, CAT, and GSH); mitigated MDA and NO effects; suppressed NF-κB, TNF-α, IL-1β, and COX-2; elevated BDNF and SDH activities; mitigated apoptosis (caspase-3 and 9, BAX, and BCl-2); and preserved striatal structure. APs showed neuroprotective potential in 3-NPA-induced HD rats by modulating the BDNF/NF-κB/Nrf2 pathway, controlling oxidative stress and neuroinflammation, restoring neurotransmitter function, and arresting striatal damage. Treatment with Aps markedly upregulated the levels of mitochondrial biogenesis-related proteins (Sirt1, PGC-1α, AMPK, UCP1, and UCP2) and antioxidant defense mediators (HO-1 and NQO1). In addition to behavioral and biochemical improvements, this study uniquely demonstrates that APs upregulate genes central to the mitochondrial biogenesis pathway, suggesting a new mechanistic basis for their neuroprotective effects in 3-NPA-induced HD. The study results showed that Applied Physiology Solution (APS) enhanced behavioural characteristics and neurotransmission function while simultaneously reducing the inflammatory response and cell stress and preserving striatal tissue structure. These findings reveal that APs promote neuroprotection not only by modulating oxidative stress, neuroinflammation, neurotransmission, and apoptosis, but also by specifically upregulating genes in the mitochondrial biogenesis pathway, highlighting their potential as a natural therapeutic candidate for HD management. Show less

Lipid-lowering therapy is typically initiated at high low-density lipoprotein(LDL) cholesterol marked by elevated apolipoprotein B(apoB). We tested the hypothesis that elevated apoB alternatively due to high remnant cholesterol confers equally high risk of atherosclerotic cardiovascular disease(ASCVD) but less initiation of lipid-lowering therapy, compared to elevated apoB due to high LDL cholesterol. From the Copenhagen General Population Study, 94 299 lipid-lowering therapy naïve adults without a history of ASCVD were included in 2003-2015. Discordance groups were formed by median levels of remnant cholesterol, LDL cholesterol and apoB. In the national Danish health registries, individuals were followed for a prescription of lipid-lowering therapy and for incident ASCVD until December 2021. During a median follow-up of 12 years, 9269 developed ASCVD. Compared to individuals with concordant low values of remnant cholesterol, apoB, and LDL cholesterol, those with high remnant cholesterol and high apoB but low LDL cholesterol had a hazard ratio(HR) of 1.45 (95% confidence interval: 1.34-1.56) for ASCVD and an odds ratio(OR) of 3.0 (2.5-3.6) for starting lipid-lowering therapy within one year. Correspondingly, those with low remnant cholesterol but high apoB and high LDL cholesterol had a HR of 1.20 (1.11-1.30) for ASCVD and an OR of 5.1 (4.3-5.9) for starting lipid-lowering therapy. In a primary prevention setting, elevated apoB due to high remnant cholesterol confers high risk of ASCVD but less initiation of lipid-lowering therapy compared to elevated apoB due to high LDL cholesterol, representing a guideline-based limitation and an unmet medical need. Show less

Hypertriglyceridemia is a prevalent lipid disorder that considerably increases the risk of cardiovascular diseases, pancreatitis, and metabolic syndrome. Existing treatment options, including lifestyle changes and medications, often show limited effectiveness and may cause side effects. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (APOC3), represents a novel therapeutic strategy for lowering triglyceride levels. This systematic review and meta-analysis assess the efficacy and safety of olezarsen in comparison to a placebo for managing hypertriglyceridemia. A systematic literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines across databases such as PubMed, Google Scholar, and the Cochrane Library, incorporating clinical trials and conference proceedings. Studies that compared olezarsen with a placebo and reported outcomes related to triglyceride levels, APOC3, and other lipid parameters were included. Two independent reviewers conducted data extraction and quality assessment. Statistical analyses were performed using RevMan, employing risk ratios for dichotomous variables and standard mean differences for continuous variables, with a random-effects model. Three randomized controlled trials, comprising 334 participants, were included in the analysis. Olezarsen significantly lowered triglyceride levels at both 6 months (standard mean difference [SMD]: -1.69, 95% CI -2.22 to -1.17) and 12 months (SMD: -1.64, 95% CI -2.22 to -1.07). Very low-density lipoprotein (VLDL) levels also declined at 6 months (SMD: -1.95, 95% CI -2.38 to -1.51) and 12 months (SMD: -0.83, 95% CI -1.13 to -0.53). Additional lipid profile improvements included reductions in total cholesterol, non-HDL cholesterol, and apoB levels, along with increases in HDL cholesterol and apoA-1. The incidence of adverse events was similar between the olezarsen and placebo groups. Olezarsen effectively reduces triglyceride and VLDL levels while enhancing lipid profiles in patients with hypertriglyceridemia. Although serious adverse events were more frequent, the overall safety profile remains acceptable. Further long-term research is required to validate these findings and optimize treatment regimens. Show less

Randomized clinical trials of remnant cholesterol lowering drugs show 50 % and 80 % reduction in remnant cholesterol with apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) inhibitors. However, how many of atherosclerotic cardiovascular disease(ASCVD) cases that could be prevented lowering remnant cholesterol by these therapies is unknown. The aim of the study was to estimate the potential of APOC3 and ANGPTL3 inhibitors to reduce the ASCVD burden through lowering of remnant cholesterol. Of 98,311 individuals from the Copenhagen General Population Study without ASCVD at study entry 8,506 were statin users and 89,805 were statin non-users. Cause-specific Cox regression was used to model rates of ASCVD and non-cardiovascular death conditional on remnant cholesterol and risk factors. Based on these models the potential 10-year absolute risk reduction of ASCVD in individuals with remnant cholesterol >1 mmol/L (>39 mg/dL) for 15 %, 30 %, 50 %, and 80 % lower remnant cholesterol was predicted. The predicted average 10-year absolute risk of ASCVD was 20 % for statin users and 11 % for statin non-users with remnant cholesterol >1 mmol/L (>39 mg/dL). The predicted 10-year absolute risk reduction of ASCVD in individuals with remnant cholesterol >1 mmol/L (>39 mg/dL) for 50 % and 80 % lower remnant cholesterol were 2.7 % (95 % confidence interval: 2.2-3.2 %), and 4.1 % (3.4-4.8 %) for statin users and 1.4 % (1.3-1.5 %), and 2.1 % (2.0-2.3 %) for statin non-users. We have shown that significant ASCVD risk reductions are expected for remnant cholesterol lowering drugs in at-risk populations, if intervention trials with novel remnant cholesterol lowering drugs show expected reductions in remnants in large cardiovascular outcomes trials. Show less

BACE-1 is an encouraging target for the development of AD therapeutics. However, many BACE-1 inhibitors failed clinical trials due to their non-selectivity towards BACE-2 or adverse effects. Herein, a set of 96 benzothiazoles were designed based on the structural features of Atabecestat and Riluzole to find a promising selective BACE-1 inhibitor. Out of the 96 designed compounds, compound Show less

Identifying new genetic variants linked to plasma lipoprotein-lipid concentrations is of significant public health importance, as it can aid in developing genetic markers for CVD risk assessment, diagnosis, and prognosis. Our work aimed to investigate the relationship between lipoprotein lipase (LPL) genetic polymorphisms and hyperlipidemia in Pakistani population. To achieve this goal, 400 blood samples were obtained. DNA was extracted for the measurement of biochemical variables and genetic profiling. A lipid lowering agent, fibrate (200mg/day) is administered to the patients for two months. The online genetic epidemiology tool (http/www.oege.org) was used to determine the allelic and genomic frequencies. Odds ratio (OR) and 95% CI were calculated by chi-square. Single nucleotide polymorphism (SNP) in LPL gene, rs258 (T > C) and rs268 (A>G) were genotyped in 300 hypertriglyceridemia patients and 100 healthy/control individuals. The LPL gene showed a significant association with a high risk of hyperlipidemia diseases when differentiate the genotype evaluations between treated and untreated patients. Lipid levels were significantly (p<0.05) reduced after treatment. LPL SNP rs258 and rs268 were observed to be associated to hypertriglyceridemia in the Pakistani patients. Fibrate therapy showed a positive effect on the serum lipid levels after treating the patients with 200mg/day for two months. Show less

A 63-year-old woman presented with plaques covering 60 % body-surface-area and leonine facies. Blood work showed no diagnostic aberrancies. Skin biopsy contained a malignant CD4+/CD56+ mononuclear cell population concerning for blastic plasmacytoid dendritic cell neoplasm. A later bone marrow biopsy confirmed AML with Show less

The balance between the potential long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency, mimicking pharmacologic CETP inhibition, is unknown. To assess the relative benefits and harms associated with genetic CETP deficiency. This study examined 2 similar prospective cohorts of the Danish general population, with data on a total of 102 607 participants collected from October 10, 1991, through December 7, 2018. Weighted CETP allele scores. Incident cardiovascular mortality, ischemic heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, vascular dementia, Alzheimer disease, all-cause mortality, and age-related macular degeneration (AMD). The study first tested whether a CETP allele score was associated with morbidity and mortality, when scaled to genetically lower levels of non-high-density lipoprotein (HDL) cholesterol (ie, 17 mg/dL), corresponding to the reduction observed for anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the study assessed how much of the change in morbidity and mortality was associated with genetically lower levels of non-HDL cholesterol. Finally, the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency was quantified. For AMD, the analyses also included higher levels of HDL cholesterol associated with genetic CETP deficiency. Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77 [95% CI, 0.62-0.95]), ischemic heart disease (HR, 0.80 [95% CI, 0.68-0.95]), myocardial infarction (HR, 0.72 [95% CI, 0.55-0.93]), peripheral arterial disease (HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]) and an increased risk of AMD (HR, 2.33 [95% CI, 1.63-3.30]) but was not associated with all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]), ischemic stroke (HR, 1.05 [95% CI, 0.81-1.36]), or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger. A considerable fraction of the lower risk of cardiovascular end points was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol. Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol. This study suggests that genetic CETP deficiency, mimicking pharmacologic CETP inhibition, was associated with a lower risk of cardiovascular morbidity and mortality, but with a markedly higher risk of AMD. Show less

Both the apolipoprotein A5 and C3 genes have repeatedly been shown to play an important role in determining plasma triglyceride concentrations in humans and mice. In mice, transgenic and knockout experiments indicate that plasma triglyceride levels are strongly altered by changes in the expression of either of these 2 genes. In humans, common polymorphisms in both genes have also been associated with plasma triglyceride concentrations. These similar findings raised the issue of the relationship between these 2 genes and altered triglycerides. To address this issue, we generated independent lines of mice that either overexpressed ("double transgenic") or completely lacked ("double knockout") both apolipoprotein genes. We report that both "double transgenic" and "double knockout" mice display normal triglyceride concentrations compared with overexpression or deletion of either gene alone. Furthermore, we find that human ApoAV plasma protein levels in the "double transgenic" mice are approximately 500-fold lower than human ApoCIII levels, supporting ApoAV as a potent triglyceride modulator despite its low concentration. Together, these data support that APOA5 and APOC3 independently influence plasma triglyceride concentrations but in an opposing manner. Show less