👤 O Sadiq

Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, significantly increasing the risk of premature cardiac events and mortality. In Pakistan, despite the potential burden of FH, comprehensive studies evaluating its genetic characteristics, cascade screening significance, and lipoprotein (a) [Lp(a)] levels remain scarce. Understanding these factors is crucial for effective diagnosis, risk assessment, and management of FH in the Pakistani population. After the identification of index case with clinical homozygous FH, characterized by high LDL-C and high Lp(a) levels together with a positive personal and family history of cardiovascular disease, a cascade screening of 66 relatives from a consanguineous family was performed. Blood samples were obtained from all subjects for biochemical and genetic analysis. Simon Broome criteria was applied on children for clinical FH diagnosis. Dutch Lipid Clinic Network scores were calculated for individuals aged ≥16years. Genetic screening was performed using next-generation sequencing to analyse all coding regions and exon-intron borders of the following genes: ALMS1, APOA1, APOB, APOA5, APOC2, APOC3, APOE, ABCA1, ABCG5, ABCG8, CREB3L3, GPIHBP1, LDLR, LDLRAP1, LIPA, LMF1, LPL, and PCSK9. The identified variants were confirmed using Sanger sequencing. Cascade screening identified seven homozygous and 25 heterozygous FH patients with pathogenic variant in the LDLR gene (NM₀₀₀₅₂₇.5: c.2416dupG: p. Val806GlyfsTer11). Additionally, heterozygous variants of uncertain significance were identified in 4 other subjects. This study underscores the high effectiveness of cascade screening in consanguineous families and societies that could lead to early detection and prevention. Show less

Alzheimer's disease (AD) is among the highly prevalent neurodegenerative disorder of the aging brain and is allied with cognitive and behavioral abnormalities. Unfortunately, there is very limited drug discovery for the effective management of AD, and the clinically approved drugs have limited efficacy. Consequently, there is an immediate demand for the development of new compounds that have the ability to act as multitarget-directed ligands (MTDLs). As major pathological targets of the disease, the current study aimed to investigate lead natural bioactive compounds including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol for their inhibitory potentials against β-amyloid cleaving enzyme-1 (BACE1) and monoamine oxidase-B (MAO-B) enzymes. The study compounds were docked against the target enzymes (MAO-B and BACE1) using MOE software and subsequent molecular dynamics simulations (MDS) studies. The molecular docking analysis revealed that these phytochemicals (MTDLs) showed good interactions with the target enzymes as compared to the reference inhibitors. Among these eight phytocompounds, the epigallocatechin-3-gallate compound was an active inhibitor against both drug targets, with the highest docking scores and good interactions with the active residues of the enzymes. Furthermore, the docking result of the active one inhibitor in complex with the target enzymes (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 and reference/MAO-B) were further validated by MDS. According to the findings of our study, epigallocatechin-3-gallate has the potential to be a candidate for use in the treatment of neurological illnesses like AD. This compound has MTDL potential and may be exploited to create new compounds with disease-modifying features.Communicated by Ramaswamy H. Sarma. Show less

Hypertriglyceridemia (HTG) is a complex disorder caused by genetic and environmental factors that frequently results from loss-of-function variants in the gene encoding lipoprotein lipase (LPL). Heterozygous patients have a range of symptoms, while homozygous LPL deficiency presents with severe symptoms including acute pancreatitis, xanthomas, and lipemia retinalis. We described the clinical characteristics of three Slovenian patients (an 8-year-old female, an 18-year-old man, and a 57-year-old female) and one Pakistani patient (a 59-year-old male) with LPL deficiency. We performed next-generation sequencing (NGS) targeting all coding exons and intron-exon boundaries of the Two Slovenian patients with a heterozygous pathogenic variant NM₀₀₀₂₃₇.3:c.984G>T (p.Met328Ile) were diagnosed within the first three years of life and had triglyceride (TG) values of 16 and 20 mmol/L. An asymptomatic Pakistani patient with TG values of 36.8 mmol/L until the age of 44 years, was identified as heterozygous for a pathogenic variant NM₀₀₀₂₃₇.3:c.724G>A (p.Asp242Asn). His TG levels dropped to 12.7 mmol/L on dietary modifications and by using fibrates. A Slovenian patient who first suffered from pancreatitis at the age of 18 years with a TG value of 34 mmol/L was found to be homozygous for NM₀₀₀₂₃₇.3:c.337T>C (p.Trp113Arg). Patients with LPL deficiency had high TG levels at diagnosis. Homozygous patients had worse outcomes. Good diet and medication compliance can reduce severity. Show less

Alzheimer's disease (AD) is a complex, multifactorial and most prevalent progressive neurodegenerative ailment. Its multifactorial and complex nature causes the lack of disease modifying drugs. Hence, multi-target drug design strategies have been adopted to halt the progression of AD. In current research, we applied multitarget strategy to tackle multifactorial nature of AD. Rational design and synthesis of framework of hybrids containing Pyrimidine/pyrrolidine-sertraline scaffolds were carried out. The synthesized compounds were further evaluated for their in-vitro enzyme inhibition potential against cholinesterases, monoamine oxidases and β-site amyloid precursor protein cleaving enzyme-1 (BACE-1). Compound 19 emerged as an optimal multipotent hybrid with IC Show less

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD. Show less

Huntington's disease is caused by expansion of a polyglutamine tract found in the amino-terminal of the ubiquitously expressed protein huntingtin. Well studied in its mutant form, huntingtin has a wide variety of normal functions, loss of which may also contribute to disease progression. Widespread transcriptional dysfunction occurs in brains of Huntington's disease patients and in transgenic mouse and cell models of Huntington's disease. To identify new transcriptional pathways altered by the normal and/or abnormal function of huntingtin, we probed several nuclear receptors, normally expressed in the brain, for binding to huntingtin in its mutant and wild-type forms. Wild-type huntingtin could bind to a number of nuclear receptors; LXRalpha, PPARgamma, VDR and TRalpha1. Over-expression of huntingtin activated, while knockout of huntingtin decreased, LXR mediated transcription of a reporter gene. Loss of huntingtin also decreased expression of the LXR target gene, ABCA1. In vivo, huntingtin deficient zebrafish had a severe phenotype and reduced expression of LXR regulated genes. An LXR agonist was able to partially rescue the phenotype and the expression of LXR target genes in huntingtin deficient zebrafish during early development. Our data suggest a novel function for wild-type huntingtin as a co-factor of LXR. However, this activity is lost by mutant huntingtin that only interacts weakly with LXR. Show less