👤 A R Nour El Huda

Schizophrenia is a complex mental disorder involving genetic, environmental, and neurodevelopmental factors. Despite significant progress in identifying several genetic contributors to schizophrenia, the role of apolipoprotein in lipid metabolism, neurodevelopment, and neuroprotection remains underexplored. This systematic review aims to synthesise existing genetic studies on apolipoproteins associated with schizophrenia to clarify their potential role in the disorder's pathogenesis. A comprehensive literature review was conducted using the PubMed and Scopus databases, involving studies published from 2004 to 2023, and limited to English. Keywords included "schizophrenia," "apolipoprotein," "genetic," and "genetics." Non-research publications such as books, reviews, editorials, letters to editors, short communications, book series, chapters, and conference proceedings were excluded from this review. Only peer-reviewed journal articles were selected to ensure the reliability and credibility of the systematic review. A total of 41 articles were included in the review, with four key themes identified. The themes addressed specific aspects of apolipoproteins in schizophrenia, including their role in schizophrenia susceptibility, lipid metabolism, and cognitive functions within the disorder. This review presents a novel synthesis of these studies, focusing on the underexplored roles of apolipoprotein genes, including APOE, APOL, APOD, APOA, APOC, APOER2, and APOBEC, in schizophrenia. This systematic review provides a comprehensive understanding of the genetics of apolipoprotein in schizophrenia, particularly in relation to lipid metabolism. The findings suggest future research directions to enhance the understanding of schizophrenia pathogenesis and highlight the importance of targeted research to identify specific genetic biomarkers for therapeutic interventions. Show less

Chronic inflammation constitutes a well-established driver of colorectal carcinogenesis, yet the molecular circuitry linking inflammatory receptor signalling to tumour cell survival remains incompletely delineated. Here we demonstrate that the HMG-CoA reductase inhibitors atorvastatin and rosuvastatin modulate inflammatory survival pathways in colorectal cancer cells in a manner consistent with targeted interference with the protease-activated receptor 2 (PAR-2)-extracellular signal-regulated kinase (ERK)-tumour necrosis factor-α (TNF-α) signalling axis. Using lipopolysaccharide-stimulated HT-29 and Caco-2 cells as complementary models of inflammatory colorectal malignancy, we show that both statins selectively attenuate PAR-2 expression at the protein and transcript levels while leaving structurally related PAR-1 unaffected. This pattern of receptor modulation is accompanied by suppression of total ERK1/2 expression, ERK1/2 phosphorylation, and the transcriptional target DUSP6, together with attenuation of TNF-α secretion. Importantly, these signaling shifts are associated with dual apoptotic programs; the extrinsic pathway, reflected by transcriptional upregulation and proteolytic activation of caspase-8; and the intrinsic mitochondrial pathway, evidenced by reciprocal modulation of Bcl-2 family proteins favoring Bax over Bcl-2. Both pathways converge upon activation of executioner caspase-3 and an increase in Annexin V-defined apoptotic fractions, indicating re-engagement of programmed cell death under inflammatory stress. Notably, rosuvastatin consistently demonstrates superior potency across signaling endpoints, achieving comparable biological effects at lower concentrations than atorvastatin. Collectively, these data indicate that clinically deployed statins target the PAR-2-ERK axis and are associated with re-activation of apoptotic pathways in inflammatory colorectal cancer models, while leaving open the possibility that additional statin-responsive networks contribute to their pro-apoptotic effects. This mechanistic framework provides biological plausibility for epidemiologic observations linking statin use with reduced colorectal cancer risk and improved outcomes, and supports further translational evaluation of PAR-2-directed statin strategies in colorectal malignancy. Show less

Atherogenesis is an insipidus but precipitating process leading to serious consequences of many cardiovascular diseases (CVD). Numerous genetic loci contributing to atherosclerosis have been identified in human genome-wide association studies, but these studies have limitations in the ability to control environmental factors and to decipher cause/effect relationships. To assess the power of hyperlipidemic Diversity Outbred (DO) mice in facilitating quantitative trait loci (QTL) analysis of complex traits, we generated a high-resolution genetic panel of atherosclerosis susceptible (DO-F1) mouse cohort by crossing 200 DO females with C57BL/6J males carrying two human genes: encoding apolipoprotein E3-Leiden and cholesterol ester transfer protein. We examined atherosclerotic traits including plasma lipids and glucose in the 235 female and 226 male progeny before and after 16 weeks of a high-fat/cholesterol diet, and aortic plaque size at 24 weeks. We also assessed the liver transcriptome using RNA-sequencing. Our QTL mapping for atherosclerotic traits identified one previously reported female-specific QTL on Chr10 with a narrower interval of 22.73 to 30.80 Mb, and one novel male-specific QTL at 31.89 to 40.25 Mb on Chr19. Liver transcription levels of several genes within each QTL were highly correlated with the atherogenic traits. A majority of these candidates have already known atherogenic potential in humans and/or mice, but integrative QTL, eQTL, and correlation analyses further pointed Ptprk as a major candidate of the Chr10 QTL, while Pten and Cyp2c67 of the Chr19 QTL in our DO-F1 cohort. Finally, through additional analyses of RNA-seq data we identified genetic regulation of hepatic transcription factors, including Nr1h3, contributes to atherogenesis in this cohort. Thus, an integrative approach using DO-F1 mice effectively validates the influence of genetic factors on atherosclerosis in DO mice and suggests an opportunity to discover therapeutics in the setting of hyperlipidemia. Show less