👤 Abdullah N Alotaibi

Drug-induced hyperpigmentation (DIH) represents a significant subset of acquired pigmentation disorders and poses diagnostic challenges due to delayed onset and polypharmacy. This systematic review and meta-analysis aimed to identify medications significantly associated with DIH and evaluate their reported incidence. A systematic search was conducted across PubMed, Scopus, Web of Science, and Cochrane Library for studies published between 2002 and June 2024. Eligible studies reported DIH as an outcome with incidence or descriptive data. Pooled proportions were calculated using a random-effects model, and heterogeneity was assessed via the I Twenty-two studies met the inclusion criteria. The overall pooled incidence of DIH was 36.7% (95% CI: 0.291-0.444). Subgroup analyses revealed the highest incidences with tyrosine kinase inhibitors (89.2%) and MC4R agonists (71.4%), followed by antibiotics (52.0%), antineoplastic agents (35.5%), and antimalarials (29.0%). Commonly implicated agents included minocycline, hydroxychloroquine, and hydroxyurea. DIH is a prevalent adverse drug reaction with considerable variation in incidence across drug classes. Recognition of high-risk medications is essential for prompt diagnosis and clinical management. The study protocol was pre-registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42024529250). Show less

Microplastic (MPs) pollution is widespread in the environment and poses growing risks to food safety and human health. In a 60-day oral exposure study, male Swiss mice received MPs (10 mg/kg b.wt), and the neuroprotective potential of taurine (Tau, 200 mg/kg b.wt) was evaluated. MPs exposure induced pronounced anxiety-like behavior, evidenced by increased peripheral zone activity in the open field test (+ 81.1%) and elevated anxiety index in the elevated plus maze (+ 75.9%), along with significant memory and spatial learning impairments in the Y-maze (increased trials + 31.6% and latency + 75.2%). Neurochemically, MPs increased acetylcholinesterase (AChE) activity (+ 89.4%) while reducing dopamine (-29.4%) and γ-aminobutyric acid (GABA) (-17.9%) levels. MPs also triggered marked oxidative stress, as shown by elevated reactive oxygen species (+ 107.6%) and malondialdehyde (+ 249.0%), accompanied by reduced total antioxidant capacity (-26.2%). At the molecular level, MPs downregulated CREB1 (-82.2%) and BDNF (-80.2%) while markedly upregulating AKT1 (~ fivefold) and pro-inflammatory cytokines (TNF-α, IL-6, CXCL-10, and IL-1β; 5.2-7.2-fold). Histopathological analysis revealed severe neurodegenerative alterations across the cerebrum, hippocampus, and cerebellum. Tau co-treatment significantly ameliorated MPs' induced neurotoxicity by reducing anxiety and memory deficits, lowering AChE activity (- 17.3%), restoring dopamine (+ 28.8%) and GABA (+ 14.2%) levels, attenuating oxidative stress (ROS -45.4% and MDA -44.7%), suppressing inflammatory gene expression (-51.0 to -68.1%), and partially normalizing CREB1 and BDNF expression (+239% and +240%, respectively). Collectively, these findings identify Tau as a promising natural neuroprotective agent against MPs' induced neurotoxicity. Show less

Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second-generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease-modifying therapies for AD treatment. Show less

Alzheimer's disease (AD) is characterized by the gradual deterioration of cognitive functions, speech impairment, and memory loss. It can potentially be treated by targeting the beta-site amyloid precursor protein cleavage enzyme 1 (BACE1), which plays a key role in amyloid plaque formation, neurofibrillary tangles, and hyperphosphorylated tau protein. Current drugs have limitations in terms of safety, efficacy, and blood-brain barrier permeability. In view of this, this study was designed to determine the potential inhibitors of the BACE1 enzyme by virtual screening using a curated library of 415 natural products including terpenoids, phenolic compounds, and alkaloids from different medicinal plants. Based on the docking score and interaction analysis, 50 compounds were selected for the downstream analysis, such as ligand binding interactions, pharmacokinetics, druglikness and physicochemical parameters. Among the lead compounds, Palmatine (compound 45) and Berberine (compound 49), demonstrated optimal drug-likeness and blood-brain barrier permeability among the top compounds. 2-[(9Z,12Z)-heptadeca-9,12-dienyl]-6-hydroxybenzoic acid (compound 4) was inactive in most toxicity parameters. Pharmacophore analysis revealed that Palmatine and Berberine share similar features with the standard, highlighting their potential as effective compounds. Furthermore, structural chemistry analysis provided insights on their shared isoquinoline alkaloid framework, illustrating their structural similarities. Molecular dynamics simulations confirmed the stability of the Palmatine-BACE1 and Berberine-BACE1 complexes during a 50 ns production run. Overall, these findings highlighted the potential of Palmatine and Berberine as promising candidates for the experimental validation and the development of the drugs for the treatment of AD. Show less

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

Tyrosine kinase inhibitors (TKIs) have transformed outcomes in chronic myeloid leukemia (CML) and FLT3-mutated acute myeloid leukemia (AML), yet durable remissions are curtailed by the emergence of drug resistance. This review summarizes the principal mechanisms that underlie that resistance. In CML, the most common mechanism is the development of point mutations in the BCR::ABL1 kinase domain (KD). Additional layers of resistance arise when imatinib, a substrate for the P-glycoprotein (P-gp) efflux pump, is shunted out of the intracellular space and when leukemic cells engage alternative signaling pathways such as the SIRT1 and JAK2-STAT5. Up-regulation of the WNT/β-catenin pathway and epigenetic changes such as HOXA4 and PDLIM4 promoter hypermethylation have likewise been linked to TKI resistance. FLT3-mutated AML shows a parallel yet distinct pattern. One of the most common mechanisms of acquired resistance to FLT3 inhibitors is point mutations in FLT3 itself; the gatekeeper F691L, N676K and K429E substitutions cause resistance to clinically used FLT3 inhibitors. Resistance is also driven by activation of alternative signaling cascades: RAS/MAPK and IDH2-associated pathways frequently emerge and make FLT3 inhibition less effective. After initial therapy, clonal selection allows inhibitor-insensitive subclones to dominate, while bone-marrow stromal factors, high CYP3A4 activity together with FGF2/FGFR1-mediated MAPK signaling, protect blasts from FLT3 inhibitors. It is important to study the mechanisms of resistance responsible for treatment failure to develop therapeutic strategies to overcome this resistance. This paper aims to review the important mechanisms of resistance to TKIs, both in CML and AML. Show less

Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicated in the development of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), a fatal and progressive lung vascular disease. Transforming growth factor β Show less

Dyslipidemia is frequently linked to various disorders, and its clinical relevance is now recognized. The role of inflammation and oxidative stress (OS) in dyslipidemia has been acknowledged. This study assessed the potential of arbutin (ARB) to prevent dyslipidemia and its associated OS and inflammation in rats with acute hyperlipidemia. Rats received ARB orally for 14 days and a single intraperitoneal injection of poloxamer-407 on day 15. Poloxamer-407 elevated circulating cholesterol (CHOL), triglycerides (TG), very low-density lipoprotein (vLDL), and LDL, and reduced high-density lipoprotein (HDL)-C and lipoprotein lipase (LPL). ARB ameliorated the circulating lipids and LPL, and suppressed 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) in rat liver and in vitro. Fatty acid synthase (FAS) in rat liver and its in vitro activity were suppressed by ARB, which also upregulated the LDL receptor (LDL-R) and ABCA1, and had no effect on ABCG5 and ABCG8 mRNA. ARB ameliorated liver malondialdehyde and nitric oxide and enhanced antioxidants in rats with dyslipidemia. Liver NF-κB p65 and blood inflammatory cytokines were increased in dyslipidemic rats, effects that were reversed by ARB. Moreover, ARB effectively suppressed lymphocyte E-NTPDase and E-ADA activities in dyslipidemic rats. The biochemical findings were supported by in silico data showing the affinity of ARB to bind LDL-R PCSK9 binding domain, HMGCR, FAS, and E-NTPDase. ARB possessed anti-dyslipidemia, anti-inflammatory, and antioxidant effects mediated via the modulation of CHOL and TG synthesis, LPL, lymphocyte E-NTPDase and E-ADA, and cytokine release in rats. Thus, ARB could be an effective agent to attenuate dyslipidemia and its associated OS and inflammation, pending further studies as well as clinical trials. Show less

Endothelial-to-mesenchymal transition (EndMT) is a biological process that converts endothelial cells to mesenchymal cells with increased proliferative and migrative abilities. EndMT has been implicated in the development of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), a fatal and progressive lung vascular disease. Transforming growth factor β EndMT has been reported to contribute to the pathogenesis of PH. In this study we aimed to determine the role of Ca Show less

Eicosanoids are biologically active derivatives of polyunsaturated fatty acids with broad relevance to health and disease. We report a genome-wide association study in 8406 participants of the Atherosclerosis Risk in Communities Study, identifying 41 loci associated with 92 eicosanoids and related metabolites. These findings highlight loci required for eicosanoid biosynthesis, including FADS1-3, ELOVL2, and numerous CYP450 loci. In addition, significant associations implicate a range of non-oxidative lipid metabolic processes in eicosanoid regulation, including at PKD2L1/SCD and several loci involved in fatty acyl-CoA metabolism. Further, our findings highlight select clearance mechanisms, for example, through the hepatic transporter encoded by SLCO1B1. Finally, we identify eicosanoids associated with aspirin and non-steroidal anti-inflammatory drug use and demonstrate the substantial impact of genetic variants even for medication-associated eicosanoids. These findings shed light on both known and unknown aspects of eicosanoid metabolism and motivate interest in several gene-eicosanoid associations as potential functional participants in human disease. Show less

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations. Show less