Biology subjects

Al-Mulla, F.

Publications and source records attributed to Al-Mulla, F..

9 recordsLinked to original sources

bioRxiv2025

Comparative Machine Learning Analysis of Saliva and Plaque Microbiomes in Children with Type 1 Diabetes

BackgroundType 1 diabetes (T1D) is associated with microbial dysbiosis. While most research has focused on the gut microbiome, limited data address the role of the oral microbiome in T1D. The oral and gut microbiomes overlap substantially, and the oral cavity may influence the gut microbial composition. Saliva and dental plaque represent two distinct oral niches with unique microbial communities, but it remains unclear which better reflects systemic disease states such as T1D. This study compared the performance of salivary and plaque microbiomes in classifying pediatric T1D status. MethodsPaired saliva and plaque samples were collected from 46 children (23 with T1D and 23 healthy controls). Microbial DNA was extracted and sequenced to target the 16S rRNA gene. The data were processed via QIIME 2 for taxonomic classification and centered log-ratio transformation. Alpha diversity, microbial abundance, and clustering analyses were performed to compare the oral microbiome between the T1D and control groups. Random forest classifiers were used to evaluate and compare the predictive accuracy of saliva- and plaque-based models, both with and without clinical metadata. ResultsSaliva samples presented lower alpha diversity than plaque samples did but presented significantly greater bacterial loads and total microbial abundances. Saliva-based models outperformed plaque-based models, achieving a classification accuracy of 94.2% with or without clinical metadata, compared with 73.3% accuracy for plaque-based models. ROC curve analysis further supported this difference, with saliva models reaching an AUC of approximately 0.94 versus 0.75 for plaque, indicating superior discriminative performance. UMAP clustering revealed more distinct separation of the T1D and control groups in terms of the salivary profiles than in the plaque profiles. Feature importance analysis revealed both unique and shared taxa predictive of T1D in each niche. The incorporation of clinical and demographic metadata did not enhance model performance, underscoring the robustness and predictive strength of microbiome data alone. ConclusionThe salivary microbiome is a more effective biospecimen than dental plaque for detecting T1D-associated microbial profiles in children. It offers superior classification accuracy and greater sensitivity in distinguishing T1D status, supporting salivas potential as a noninvasive, scalable medium for future microbiome-based monitoring.

microbiology↗

bioRxiv2025

Eicosapentaenoic Acid (EPA) Alleviates LPS-Induced Oxidative Stress via the PPARa-NF-kB Axis

Metabolic-endotoxemia, characterized by the translocation of lipopolysaccharide (LPS) from Gram-negative bacteria into the bloodstream, is a key contributor to chronic low-grade inflammation associated with obesity and type 2 diabetes. This condition exacerbates metabolic disruptions by activating Toll-like receptor 4 (TLR4) on macrophages, leading to the release of pro-inflammatory cytokines and subsequent insulin resistance. Eicosapentaenoic acid (EPA/C20:5), an omega-3 polyunsaturated fatty acid, has demonstrated anti-inflammatory and antioxidative properties, but its precise mechanisms of action in mitigating LPS-induced stress remain unclear. This study investigates the pathways through which EPA/C20:5 alleviates LPS-induced oxidative stress and inflammation in macrophages. EPA pretreatment significantly reduced LPS-induced inflammatory responses, decreasing IL-1{beta} and IL-6 expression and IL-1{beta} secretion, and lowering the percentage of HLA-DR macrophages. EPA also attenuated ER stress, evidenced by reduced expression of ATF4, DDIT3, HSPA5/GRP78, BIP, and CHOP at both gene and protein levels. Oxidative stress was mitigated, as shown by decreased HIF1 expression, reduced ROS levels, and preservation of mitochondrial membrane potential. Importantly, EPA increased the expression of PPAR and FABP5 while inhibiting NF-{kappa}B activation independently of the TLR4-IRF5 pathway. The protective effects of EPA were abolished by PPAR inhibition with GW9662, indicating that EPAs action is PPAR-dependent. This study highlights the modulatory role of EPA in alleviating LPS-induced oxidative stress and inflammation in macrophages through activation of the FABP5/PPAR/NF-{kappa}B axis, independently of TLR4-IRF5 signaling. These findings reveal a novel mechanism for EPAs anti-inflammatory effects and suggest that targeting the FABP5/PPAR pathway may offer therapeutic potential for treating metabolic disorders associated with chronic inflammation.

molecular biology↗

bioRxiv2023

Glucose intolerance induces anxiety-like behaviors independent of obesity and insulin resistance in a novel model of nutritional metabolic stress

Type 2 diabetes (T2D) and its comorbidities are a major public health concern. In addition to peripheral tissues, T2D also impacts the central nervous system leading to neurocognitive impairments, including memory deficits, anxiety, and depression. The metabolic determinants of these neurocognitive impairments remain unidentified. Here, we used a novel proprietary high-fat diet, in which glucose intolerance precedes weight gain, to decipher the metabolic determinants of neurocognitive affects. We show that this model exhibits anxiety-like behaviors, without eliciting depression nor recognition memory deficits. Long-term feeding leads to weight gain, brain glucose hypometabolism and impaired recognition memory alongside the early onset anxiety-like behavior. Using an established genetic model of T2D (db/db) and of diet-induced obesity we show that additional insulin resistance and obesity are associated with depressive-like behaviors and recognition memory deficits. Our findings indicate that glucose intolerance alone can elicit anxiety-like behaviors. Through this study we also provide a novel nutritional model to characterize the discrete effects of glucose intolerance on cognition, behavior, and the physiology of metabolic disease.

animal behavior and cognition↗

bioRxiv2023

ANGPTL8 R59W variant influences inflammation through modulating NF-κB pathway under TNFα stimulation

BackgroundANGPTL8 is known to regulate lipid metabolism and inflammation. It interacts with ANGPTL3 and ANGPTL4 to regulate LPL activity, and with IKK/{beta} to modulate NF-{kappa}B activity. Further, a SNP leading to ANGPTL8 R59W variant associates with reduced LDL/HDL and increased FBG in Hispanic and Arab individuals, respectively. In this study, we investigate the impact of R59W variant on the inflammatory activity of ANGPTL8. MethodsANGPTL8 R59W variant was genotyped in a discovery cohort of 867 Arab individuals from Kuwait. Plasma levels of ANGPTL8 and inflammatory markers were measured and tested for associations with the genotype; the associations were tested for replication in an independent cohort of 278 Arab individuals. Impact of the ANGPTL8 R59W variant on NF-{kappa}B activity was examined using approaches including overexpression, luciferase assay, and structural modeling of binding dynamics. ResultsThe ANGPTL8 R59W variant was associated with increased circulatory levels of TNF and IL7. NF-{kappa}B activity, as assessed by the increased in the phosphorylation of IKK-/{beta} protein, I{kappa}B, and NF-{kappa}B p-65 in R59W variant compared to wild type, and TNF stimulation further elevated it. This finding was substantiated by increased luciferase activity of NF-{kappa}B p65 with the R59W variant. Modeled structural and binding variation due to R59W change in ANGPTL8 agreed with the observed increase in NF-{kappa}B activity. ConclusionANGPTL8 R59W is associated with increased circulatory TNF, IL7 and NF-{kappa}B p65 activity. Weak transient binding of ANGPTL8 R59W variant explains its regulatory role on the NF-{kappa}B pathway and inflammation.

biochemistry↗

bioRxiv2021

A glycerol shunt functions as a glucose excess security valve in pancreatic β-cells

The recently identified glycerol-3-phosphate (Gro3P) phosphatase (G3PP) in mammalian cells, encoded by the PGP gene, was shown to regulate intermediary metabolism by hydrolyzing Gro3P and to control glucose-stimulated insulin secretion (GSIS) in {beta}-cells, in vitro. We now examined in inducible {beta}-cell specific G3PP-KO (BKO) mice, the role of G3PP in the control of insulin secretion in vivo, {beta}-cell function and glucotoxicity. BKO mice, compared to MCre controls, showed increased body weight, adiposity, fed insulinemia, GSIS, reduced plasma triglycerides and mildly altered glucose tolerance. Isolated BKO mouse islets at high (16.7 mM) but not low or intermediate glucose (3-8 mM) showed elevated GSIS, Gro3P, metabolites reflecting {beta}-cell activation, O2 consumption, ATP production and reduced glycerol release. BKO islets chronically exposed to elevated glucose showed increased apoptosis, reduced insulin content and expression of Pdx-1, MafA and Ins-2 genes. As G3PP channels glucose carbons towards glycerol formation and release, the results demonstrate that {beta}-cell are endowed with a "glycerol shunt" acting as a glucose excess security valve. We propose that the glycerol shunt plays a role in glucodetoxification, the prevention of insulin hypersecretion, acts as a defense against excess body weight gain and contributes to {beta}-cell mass preservation in the face of hyperglycemia.

biochemistry↗

bioRxiv2020

Fine-scale population structure reveals high genetic heterogeneity of the Kuwaiti population in the Arabian Peninsula

Recent studies have showed the diverse genetic architecture of the highly consanguineous populations inhabiting the Arabian Peninsula. Consanguinity coupled with heterogeneity is complex and makes it difficult to understand the bases of population-specific genetic diseases in the region. Therefore, comprehensive genetic characterization of the populations at the finest scale is warranted. Here, we revisit the genetic structure of the Kuwait population by analyzing genome-wide single nucleotide polymorphisms data from 583 Kuwaiti individuals sorted into three subgroups. We envisage a diverse demographic genetic history among the three subgroups based on drift and allelic sharing with modern and ancient individuals. Furthermore, our comprehensive haplotype-based analyses disclose a high genetic heterogeneity among the Kuwaiti populations. We infer the major sources of ancestry within the newly defined groups; one with an obvious predominance of sub-Saharan/Western Africa mostly comprising Kuwait-B individuals, and other with West Eurasia including Kuwait-P and Kuwait-S individuals. Overall, our results recapitulate the historical population movements and reaffirm the genetic imprints of the legacy of continental trading in the region. Such deciphering of fine-scale population structure and their regional genetic heterogeneity would provide clues to the uncharted areas of disease-gene discovery and related associations in populations inhabiting the Arabian Peninsula.

genomics↗

bioRxiv2020

A comprehensive germline variant and expression analyses of ACE2, TMPRSS2 and SARS-CoV-2 activator FURIN genes from the Middle East: Combating SARS-CoV-2 with precision medicine

The severity of the new COVID-19 pandemic caused by the SARS-CoV-2 virus is strikingly variable in different global populations. SARS-CoV-2 uses ACE2 as a cell receptor, TMPRSS2 protease, and FURIN peptidase to invade human cells. Here, we investigated 1,378 whole-exome sequences of individuals from the Middle Eastern populations (Kuwait, Qatar, and Iran) to explore natural variations in the ACE2, TMPRSS2, and FURIN genes. We identified two activating variants (K26R and N720D) in the ACE2 gene that are more common in Europeans than in the Middle Eastern, East Asian, and African populations. We postulate that K26R can activate ACE2 and facilitate binding to S-protein RBD while N720D enhances TMPRSS2 cutting and, ultimately, viral entry. We also detected deleterious variants in FURIN that are frequent in the Middle Eastern but not in the European populations. This study highlights specific genetic variations in the ACE2 and FURIN genes that may explain SARS-CoV-2 clinical disparity. We showed structural evidence of the functionality of these activating variants that increase the SARS-CoV-2 aggressiveness. Finally, our data illustrate a significant correlation between ACE2 variants identified in people from Middle Eastern origins that can be further explored to explain the variation in COVID-19 infection and mortality rates globally.

genetics↗

bioRxiv2020

Neutral sphingomyelinase 2 regulates inflammatory responses in monocytes/macrophages induced by TNF-α

Obesity is associated with elevated levels of TNF- and proinflammatory CD11c monocytes /macrophages. TNF- mediated dysregulation in the plasticity of monocytes/macrophages is concomitant with pathogenesis of several inflammatory diseases, including metabolic syndrome, but the underlying mechanisms are incompletely understood. Since neutral sphingomyelinase 2 (nSMase2; product of the sphingomyelin phosphodiesterase 3 gene, SMPD3) is a key enzyme for ceramide production involved in inflammation, we investigated whether nSMase2 contributed to the inflammatory changes in the monocytes/macrophages induced by TNF-. In this study, we demonstrate that the disruption of nSMase activity in monocytes/macrophages either by chemical inhibitor GW4869 or small interfering RNA (siRNA) against SMPD3 results in defects in the TNF- mediated expression of CD11c. Furthermore, blockage of nSMase in monocytes/macrophages inhibited the secretion of inflammatory mediators IL-1b and MCP-1. In contrast, inhibition of acid SMase (aSMase) activity did not attenuate CD11c expression or secretion of IL-1b and MCP-1. TNF--induced phosphorylation of JNK, p38 and NF-{kappa}B was also attenuated by the inhibition of nSMase2. Moreover, NF-kB/AP-1 activity was blocked by the inhibition of nSMase2. SMPD3 was elevated in PBMCs from obese individuals and positively corelated with TNF- gene expression. These findings indicate that nSMase2 acts, at least in part, as a master switch in the TNF- mediated inflammatory responses in monocytes/macrophages.

immunology↗

bioRxiv2019

Genome-wide selection scan in the Kuwaiti population identifies a TNKS haplotype linked to metabolic traits and hypertension

Despite the extreme and varying environmental conditions prevalent in the Arabian Peninsula, it has experienced several waves of human migrations following the out-of-Africa diaspora. Eventually, the inhabitants of the peninsula region adapted to the hot and dry environment. The adaptation and natural selection that shaped the extant human populations of the Arabian Peninsula region have been scarcely studied. In an attempt to explore natural selection in the region, we analyzed 662,750 variants in 583 Kuwaiti individuals. We searched for regions in the genome that display signatures of positive selection in the Kuwaiti population using an integrative approach in a conservative manner. We highlight a haplotype overlapping TNKS that showed strong signals of positive selection based on the results of the multiple selection tests conducted (integrated Haplotype Score, Cross Population Extended Haplotype Homozygosity, Population Branch Statistics, and log-likelihood ratio scores). Notably, the TNKS haplotype under selection potentially conferred a fitness advantage to the Kuwaiti ancestors for surviving in the harsh environment while posing a major health risk to present-day Kuwaitis.

evolutionary biology↗