👤 Sarfuddin Azmi

Obesity is a global health challenge characterized by significant heterogeneity in causes and treatment responses, complicating sustainable management. This narrative review explores the genomic architecture of obesity and its implications for personalized interventions, focusing on how genetic variations influence key biological pathways and treatment outcomes. A comprehensive literature search, guided by the authors' expertise, was conducted to identify key publications on the genomics of obesity and personalized approaches. The selection of articles prioritized those that provided direct insights into the genomic basis of obesity and its potential for informing tailored strategies. Genomic studies reveal both monogenic and polygenic influences on obesity, identifying numerous susceptibility loci. Genome-wide association studies (GWASs) have linked common variants in genes like Show less

Alzheimer's disease (AD) is a leading neurodegenerative disorder recognized by progressive cognitive decline and behavioral changes. The pathology of AD is characterized by the accumulation of amyloid-β (Aβ) plaques and the hyperphosphorylation of tau protein, which leads to synaptic loss and subsequent neurodegeneration. Additional contributors to disease progression include metabolic, vascular, and inflammatory factors. Glycogen synthase kinase-3β (GSK-3β) is also implicated, as it plays a crucial role in tau phosphorylation and the progression of neurodegeneration. This review provides a comprehensive analysis of various phytomolecules and their potential to target multiple aspects of AD pathology. We examined natural products from diverse classes, including stilbenes, flavonoids, phenolic acids, alkaloids, coumarins, terpenoids, chromenes, cannabinoids, chalcones, phloroglucinols, and polycyclic polyprenylated acylphloroglucinols (PPAPs). The key mechanisms of action of these phytomolecules include modulating tau protein dynamics to reduce aggregation, inhibiting acetylcholinesterase (AChE) to maintain neurotransmitter levels and enhance cognitive function, and inhibiting β-secretase (BACE1) to decrease Aβ production. Additionally, some phytomolecules were found to influence GSK-3β activity, thereby impacting tau phosphorylation and neurodegeneration. By addressing multiple targets, Aβ production, tau hyperphosphorylation, AChE activity, and GSK-3β, these natural products offer a promising multi-targeted approach to AD therapy. This review highlights their potential to develop effective treatments that not only mitigate core pathological features but also manage the complex, multifactorial aspects of AD progression. Show less

Several KRASG12D inhibitors (KRASG12Di) are under clinical evaluation for pancreatic ductal adenocarcinoma (PDAC). However, as seen with other first generation KRAS inhibitors, resistance may limit their long-term efficacy, necessitating combination strategies to enhance therapeutic outcomes. Exportin 1 (XPO1), a nuclear transport protein overexpressed in PDAC, represents a therapeutic vulnerability in KRAS-mutant cancers. Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. We generated KRASG12Di-resistant PDAC cells and assessed their response to Eltanexor. The antiproliferative effects of MRTX1133 and Eltanexor combinations were evaluated in 2D and 3D Eltanexor sensitized MRTX1133-resistant PDAC cells to growth inhibition. In both 2D and 3D culture models, the combination of Eltanexor and MRTX1133 significantly reduced cell viability. Mechanistically, the combination treatment suppressed key KRAS downstream signaling molecules, including p-ERK, mTOR, p-4EBP1, DUSP6, and cyclin D1. Kinome analysis further revealed reduced MAPK-related kinase activity. Combining subtherapeutic doses of Eltanexor and MRTX1133 resulted in significant tumor regression and prolonged survival in PDAC xenograft and immunocompetent orthotopic allograft models. Moreover, maintenance therapy with Eltanexor prevented tumor relapse, yielding a durable antitumor response. This study demonstrates that Eltanexor overcomes resistance to MRTX1133 and enhances its efficacy in PDAC. The combination regimen may provide a durable therapeutic response while reducing the required dose of KRASG12D inhibitors, potentially delaying resistance and improving patient outcomes. Show less

In the past decade, researchers have been focused on discovering protein biomarkers for diabetic kidney disease. This paper aims to search for, analyze, and synthesize current updates regarding the development of these efforts. We systematically searched the ScienceDirect, SpringerLink, and PubMed databases for observational studies of protein biomarkers in patients with diabetes mellitus. We included studies published between January 2018 and April 2020, that were based on a population of patients with type-1 or type-2 diabetes mellitus aged ⩾18 years, with an observational design such as cross-sectional, case-control, or cohort studies. The dependent variable of the research results was in the form of protein biomarkers from urine, plasma, or serum. Following the screening process, 20 research articles with available full text met the inclusion criteria. These could be categorized as glomerular biomarkers (ANGPTL4, beta-2 microglobulin, Smad1, and glypican-5); inflammatory biomarkers (MCP-1 and adiponectin); and tubular biomarkers (NGAL, VDBP, megalin, sKlotho, and KIM-1). The development of a panel of biomarkers showed more promising results than those for a single biomarker in diagnosing diabetic kidney disease. All the biomarkers discussed in this review showed promising results for predicting diabetic kidney disease because they correlate with albuminuria, eGFR, or both. However, of the 11 protein biomarkers, none have prognostic value beyond albuminuria and eGFR. Show less