👤 Sameena Khan

Cognitive impairment and mood disturbances are increasingly linked to underlying mechanisms such as oxidative stress, neurotransmitter dysregulation, and reduced neurotrophic support. As conventional pharmacological treatments often provide limited efficacy or are associated with tolerability concerns, there is growing scientific interest in botanical supporting strategies that may modulate the above pathways and provide complementary support for cognitive function and emotional well-being. This study aimed to investigate the mechanistic basis of a botanical association consisting of a standardized Show less

Growing evidence highlights that long-term orbital flight may lead to structural changes in brains and cognitive impairments in astronauts. However, effective strategies to counteract these effects remain limited. Compound Gastrodia elata Formula (CGEF), composed of Gastrodia elata Bl., Polygonatum sibirium Red., and Poria cocos (Schw.) Wolf has been shown to improve learning and memory. The present study aimed to evaluate the effects and underlying mechanisms of CGEF in attenuating cognitive deficiency induced by simulated weightlessness in mice. A cognitive impairment model was induced in mice using Hindlimb unloading (HU) method. Cognitive function was assessed through Object recognition test (ORT), the Morris water maze (MWM), and the Step-down Test (SDT). Serum and hippocampus levels of inflammatory markers, including Interleukin-1 beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α), and Interleukin-6 (IL-6) were evaluated using ELISA. Neurotransmitter concentrations in the hippocampus and cortex were measured using LC-MS/MS. While Brain-derived neurotrophic factor (BDNF) / Tropomyosin receptor kinase B (TrkB) protein expression signaling pathway in hippocampus was evaluated by western blot. Results showed that CGEF treatment significantly reversed the memory deficits induced by four weeks of HU exposure. Furthermore, CGEF treatment markedly suppressed the production of inflammatory factors. It also assisted in the recovery of neurotransmitter balance and regulated tryptophan metabolism to improve cognitive disorder. Western blotting analysis revealed that CGEF treatment upregulated the expression of Synaptophysin, Postsynaptic density 95 proteins, while also activating the brain-derived neurotrophic factor-Tropomyosin receptor kinase B pathway. These findings suggest that CGEF has substantial potential for development as an aerospace health product to improve memory decline associated with spaceflight. Show less

Diabetic nephropathy (DN) is a chronic renal complication characterized by persistent proteinuria, glomerular hypertrophy, impaired filtration capacity, and progressive renal fibrosis, ultimately leading to a gradual decline in kidney function. DN remains one of the leading causes of end-stage renal disease worldwide, contributing substantially to morbidity and mortality. Although the precise etiology of DN is not fully elucidated, its development is closely linked to prolonged hyperglycemia, renal hyperfiltration, accumulation of advanced glycation end products (AGEs), activation of pro-inflammatory cytokines, and oxidative stress-mediated injury. These pathogenic events involve multiple diabetes-associated pathways, including protein kinase C activation and increased reactive oxygen species (ROS) generation. O-linked β-N-acetylglucosamine (O-GlcNAc) modification is a dynamic post-translational protein modification that is significantly upregulated in DN and plays a critical role in regulating cellular signaling pathways associated with disease initiation and progression. This review summarizes current evidence on the role of O-GlcNAcylation in modulating molecular mechanisms underlying DN. Furthermore, Angiopoietin-like 4 (ANGPTL4) has emerged as a key regulator of lipid metabolism through inhibition of lipoprotein lipase and interactions with integrins, influencing vascular permeability, oxidative stress, and tissue remodeling. Increasing evidence suggests that ANGPTL4 plays a pivotal role in DN onset and progression. Show less

Self-collection of biospecimens at-home, without specialized equipment or training, are increasingly being adopted in clinical practice due to convenience and patient preferences. However, sample instability during shipment means that remote access to common blood tests remains challenging. We hypothesized that the inaccuracy and imprecision in test results that develop because of sample instability could be modeled and controlled using knowledge of transit conditions captured by environmental sensors. We subjected 2685 blood samples from 65 participants to temperature cycles derived from real-world transit conditions. Training a model called Remote Control to predict change enabled accurate calibration of test results to approximate the time zero value at the point of collection, despite sample degradation. With calibration, unprocessed whole blood could be transported, for up to 9 days under ambient conditions and exposed to temperatures between 3.4 and 47.4 °C. Under these conditions, agreement with CLIA TEa ranged between 98.1 and 100%, with a |%bias| of 0.1-1.6%, a %CV of 2.2-4.9%, and a minimum sigma metric between 3 and 8.8σ for lipids (Cholesterol, HDL, LDL, Triglycerides, APO-A1, and APO-B). Performance was linear across measurement intervals (R Show less

Injectable PCSK9 inhibitors effectively lower LDL-C levels in patients with hypercholesterolemia; however, their high cost and requirement for parenteral administration limit their widespread use. Oral PCSK9 inhibitors have emerged as a convenient alternative. This review and meta-analysis of the literature evaluate the effectiveness and safety of oral PCSK9 inhibitor treatment for adults with hypercholesterolemia. PubMed, Embase, Cochrane CENTRAL, and Scopus were searched through September 2025 for randomized controlled trials comparing oral PCSK9 inhibitors with placebo. The primary outcome was percentage change in LDL-C, with secondary lipid and safety outcomes. We used Cochrane RoB 2.0 tool to assess risk of bias, and pooled estimates were calculated using a random-effects model. Certainty of evidence was evaluated with GRADE. From 1253 records, 3 trials were included. Participants were mostly men, aged 61-65 years, with elevated baseline LDL-C. Oral PCSK9 inhibitors significantly reduced LDL-C and ApoB in a dose-dependent manner and achieved modest reductions in triglycerides (MD -6.56 mg/dL; 95% CI, -12.30 to -0.83) and total cholesterol (MD -25.25 mg/dL; 95% CI, -30.67 to -19.83). Effects on lipoprotein(a) were inconsistent. Adverse events (RR 1.06; 95% CI, 0.91-1.23) and serious adverse events (RR 1.32; 95% CI, 0.41-4.26) were comparable with placebo. According to our review, oral PCSK9 inhibitors are a promising therapeutic option for treating hypercholesterolemia because of their potent lipid-lowering effects and an overall favorable safety profile. However, more trials are needed to confirm their impact on cardiovascular outcomes. Show less

Von Willebrand factor (VWF) and ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, 13) are linked to dementia risk, and limited evidence suggests Vanderbilt Memory and Aging Project cohort participants (n=332, 73±7 years, 59% male) completed serial blood draw, neuropsychological assessment, and brain magnetic resonance imaging over 6.4 years (range 1.4-9.7 years). Baseline plasma VWF and ADAMTS13 levels were quantified using mass spectrometry and Olink. Fully adjusted linear mixed-effects models related Lower baseline ADAMTS13 predicted faster declines in language (β=0.11, ADAMTS13 shows promise as a potential plasma biomarker for brain aging outcomes, but additional research is warranted to understand the performance of VWF in the presence versus absence of an Show less

Globally, Alzheimer's disease (AD) is the leading cause of dementia. Key symptoms include extracellular amyloid β (Aβ) accumulation, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and BBB disruption. Integrative solutions are needed because conventional medicines merely relieve symptoms and cannot stop disease progression. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in Aβ efflux, tau control, neuroinflammatory signaling, and neurovascular unit maintenance, making it a promising but unexplored therapeutic target. In AD and aging, LRP1 deficiency worsens clearance, vascular impairment, and neurodegeneration. Ligand-functionalized nanocarriers, antibodies, and gene manipulation show preclinical promise, but lower receptor expression, systemic off-target effects, and BBB penetration are challenges. Recent advances suggest innovative strategies, such as upregulating hepatic LRP1 for peripheral Aβ storage, modulating cofactors like ANKS1A (ankyrin repeat and SAM domain containing protein 1A) for receptor trafficking, using engineered nanoparticles or extracellular vesicles as Aβ decoys, preventing negative apolipoprotein E: ApoE4 and LRP1 interactions, and promoting neuroprotective pathways through LRP1 modulation. Endothelial-targeted gene therapy and dual transport rebalancing, which increases LRP1-mediated efflux and decreases RAGE-driven influx, are complementary. These precision strategies reposition LRP1 as a multifaceted therapeutic gateway rather than a clearance receptor, combining biomarker-driven patient stratification with next-generation delivery systems to transform AD disease-modifying therapies. Show less

Endothelial to mesenchymal transition (EndMT), the transformation of endothelial cells into a mesenchymal-like state, is regulated by various factors, including transcription factors such as activator protein 1 (AP-1). While recent studies have confirmed the role of EndMT in atherosclerosis, the involvement of AP-1 in EndMT, particularly in the context of human diabetes, remains unclear. This study aimed to elucidate the role of the AP-1 transcription factor complex in EndMT associated with atherosclerosis in diabetes, utilising both an in vivo preclinical model and an ex vivo model using patient-derived serum for translational relevance. Additionally, it sought to profile gene expression changes following AP-1 inhibition in an EndMT model under high glucose conditions. Serum from patients with and without type 2 diabetes mellitus (T2DM) was used to assess EndMT in primary human aortic endothelial cells (HAECs) in the presence and absence of the AP-1 inhibitor T-5224. EndMT was evaluated through immunofluorescent staining of these cells and of aortic sections from a murine model of diabetes-associated atherosclerosis in a preclinical early intervention study. Furthermore, HAECs were used to explore the effects of AP-1 inhibition on the transcriptional signature of EndMT. Patient-derived serum induced EndMT in HAECs, which T-5224 effectively prevented, as confirmed by immunofluorescent staining. Immunofluorescent analysis of the aortic sinus also revealed that T-5224 treatment inhibited EndMT, leading to reduced atherosclerosis in Apoe This study identifies AP-1 inhibition with T-5224 as a potential therapeutic approach for EndMT resulting in reduced atherosclerosis in diabetes. The use of human serum underscores the translational relevance of these findings. Show less

The genetic basis of sporadic early-onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late-onset Alzheimer's disease (LOAD) polygenic risk in EOAD. A LOAD polygenic score (PGS) was calculated in the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset (p = 0.106) or with cognitive performance (p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal-associated protein 25 (SNAP-25) (p = 2.3 × 10 While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal-associated protein 25 (SNAP-25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD. 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

Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC Show less

For a long time, noncoding RNAs (ncRNAs) were considered irrelevant fragments of the genome, dismissed as genetic noise. However, recent breakthroughs have unveiled their crucial Role in regulating gene expression, influencing fundamental biological processes such as chromatin remodeling, epigenetic modifications, and cellular communication. Among them, long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have drawn considerable attention due to their strong association with neurodegenerative disorders and cardiovascular diseases (CVDs). Despite their apparent differences, these conditions share molecular regulatory networks that ncRNAs help orchestrate. LncRNAs, like ANRIL and MEG3, play a Role in vascular integrity and cardiac fibrosis, while MIAT and MALAT1 are implicated in heart failure and ischemic injury. In Alzheimer's disease, BACE1-AS and BC200 contribute to the buildup of amyloid plaques and tau protein tangles, worsening cognitive decline. The ability of ncRNAs to act as molecular sponges-binding to miRNAs and modulating gene expression-demonstrates their intricate Role in disease progression. With advances in sequencing technologies and computational biology, ncRNAs are emerging as promising biomarkers and therapeutic targets. New approaches, including CRISPR-based gene editing and RNA therapeutics, present exciting possibilities for intervention. However, challenges such as stability, precise delivery, and potential side effects must be addressed before these treatments can be translated into clinical practice. This chapter delves into the expanding field of ncRNA research, highlighting its potential to reshape the future of precision medicine and targeted therapies. Show less

SARS-CoV-2 is the causative agent of COVID-19, and although vaccines have reduced disease severity, emerging variants remain a significant public health issue. Broadly effective therapeutics, particularly those targeting host pathways essential for coronavirus infection, are still needed. Here, we used a CRISPR knockout screen to identify druggable host factors required for SARS-CoV-2 infection. The screen revealed NAE1 and FGFR1 as key contributors to infection. Inhibitors, either FDA-approved or those in clinical trials, of these pathways reduced replication of both ancestral and contemporary viral variants. Mechanistic studies showed that FGFR1 promotes viral replication through downstream MEK/ERK signaling, while neddylation appears to support viral entry or infectivity rather than replication itself. In a murine model of severe COVID-19, inhibitors of NAE1 and FGFR1 significantly decreased viral load and lung pathology. These findings support the development of host-targeted antiviral strategies. Show less

During endoscopic endonasal surgery (EES), inferolateral trunk (ILT) sacrifice may be required to efficiently and safely achieve tumor resection within the lateral compartment (LC) of the cavernous sinus (CS). The authors investigated the surgical anatomy and variations of the ILT, aiming to provide practical information to safely expose, coagulate, and transect this artery during EES. In this anatomical study, 24 postmortem, lightly embalmed, colored silicone-injected human head specimens were dissected and 41 sides were examined. The origin, course, branching pattern, and relation of the ILT with surrounding structures were investigated. Clinical charts of patients surgically treated for pituitary adenomas (PAs) with LC invasion from July 2018 to April 2023 at the authors' institution were also retrospectively analyzed. Illustrative cases are provided. The ILT was found in 93% (38/41) of sides, mainly arising from the inferolateral aspect (91%, 30/33 sides) of either the middle or posterior third (82%, 27/33 sides) of the horizontal segment of the internal carotid artery. After a short common trunk (mean length 3 mm), the artery divided into 2 (21%, 8/38) or, more frequently, 3 (74%, 28/38) branches, supplying blood to cranial nerves (CNs) III, IV, V1, V2, V3, and VI and the Gasserian ganglion. While the sympathetic plexus was always located anterior to the ILT, CN VI was found anterior to the ILT in 82% (31/38) of sides. The lateral parasellar ligament (LPL) enwrapped the ILT and its branches in 43% (15/35) of sides. In the coronal plane, the ILT origin was found at the level of the sellar floor (0 ± 1 mm) and the LPL (0 ± 2 mm), both of which can serve as surgical landmarks during lateral transcavernous EES. In the case series of 25 EESs for PAs with LC invasion, the ILT was sacrificed in 5 cases (20%) without any permanent postoperative CN deficits. This study served as a detailed anatomical investigation of the ILT, which is crucial when accessing the LC of the CS. The authors proposed two reliable landmarks to identify the ILT intraoperatively: the sellar floor and the LPL. Furthermore, investigations confirmed that the ILT can be sacrificed without causing permanent CN deficits given the existence of a collateral supply. Show less

Plin4 is transcriptionally regulated by peroxisome proliferator-activated receptor gamma and is primarily expressed in white adipose tissue (WAT). We found that expression of Plin4 is elevated in the liver upon prolonged feeding with an obesogenic diet containing saturated fat, fructose, and cholesterol (Western diet). To investigate the functional role of Plin4 in energy metabolism, we generated Plin4 Show less

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that affects the human blood glucose levels. Previous studies have confirmed the role of the gastric inhibitory polypeptide receptor (GIPR) gene in T2DM, obesity, and other human diseases. This study aimed to identify the molecular role of 5 SNPs (rs1800436, rs1800437, rs2302382, rs10423928, and rs34125392) in the GIPR gene in patients with T2DM in the Saudi population. This prospective case-control study enrolled 118 T2DM cases and 118 control participants based on the inclusion and exclusion criteria. Serum was collected from peripheral blood for biochemical tests, while EDTA blood was used for HbA1c and molecular analysis. In this study, T2DM cases were compared with control population to study the baseline characteristics along with molecular data. Genotyping and allelic association analysis showed that rs2302382, (OR-2.757 and OR-2.303) and rs10423928 (OR-3.859 and 2.206) are associated, while genotyping analysis alone showed rs34125392 (OR-1.776) is associated. The co-dominant model (OR-2.226) was associated with obese vs. non-obese participants among T2DM cases (p = 0.039). Females showed a positive association with rs2302382 (OR-3.701; p = 0.003) and rs10423928 (OR-2.343; p = 0.033) SNPs, while males showed a positive association with rs1800437 (OR-1.849; p = 0.040) rs2302382 (OR-2.418; p = 0.016), and rs10423928 (OR-3.641; p = 0.019) SNPs. ANOVA analysis and linkage disequilibrium exhibited a positive association along with gene-gene interaction in GMDR analysis. Linear regression, haplotype analysis and Frutcherman-Reingold, circle, and Kamada-Kawali models showed negative association. Our findings confirm a strong and significant association between rs2302382, rs10423928 and rs34125392 SNPs in T2DM. Additional analyses, such as ANOVA, haplotype analysis, gene-gene interaction, and graphical depiction models revealed genetic interactions among the studied SNPs. Show less

Trazodone, an antidepressant, may play a potential role in enhancing long-term memory by combining anxious behavior deficits induced by scopolamine. The current study proposes the potential novel mechanistic insights between oxidative stress and memory biomarkers, including BNDF and CREB pathways, to modulate the pathogenesis of AD-like symptoms. Behavioral deficits were studied in terms of biochemical determination of lipid peroxidation and acetylcholinesterase activities. In addition, the study looked at the immunohistochemistry of BDNF and CREB against scopolamine-induced AD-like symptoms. Moreover, histopathological alterations were also performed against an AD-like model. Aβ The present study findings showed that administration of TRAZ considerably improved cognitive impairments as validated by NOR and display of anti-anxiety behavior, as verified by EPM. In addition, biochemical findings confirmed that TRAZ lowered oxidative stress through LPO, reduced Aβ deposition, and decreased the AChE. Furthermore, there was a notable upregulation of BDNF and CREB signaling expression, as confirmed by the IHC. Overall, the study findings confirmed that TRAZ could be useful in mitigating the negative effects of scopolamine-induced cognitive impairment and lowering oxidative stress by enhancing memory indicators. Show less

Glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y receptors (NPYRs) are expressed in reproductive tissues contributing to the regulation of gonadal function. This exploratory study examines the potential impact of their modulation by assessing the effects of exendin-4 (Ex-4) and peptide YY (PYY) (3-36) on endocrine ovaries and adrenals in high-fat diet (HFD) mice. Ex-4 and PYY(3-36) reduced blood glucose and energy intake, with no effects on body weight. While HFD did not impact the estrous cycle, Ex-4 increased metestrus frequency and decreased diestrus frequency resulting in 0% mice experiencing repeated diestrus or becoming acyclic. Luteinizing hormone levels were significantly higher in the Ex-4 and PYY(3-36) groups compared to the normal diet and HFD controls. In the adrenals, reduced capsule and zona glomerulosa thickness caused by HFD was reversed after peptide treatments. Within the ovaries, HFD increased the number of atretic follicles, an effect that disappeared after Ex-4 and PYY(3-36) treatments. Ex-4 also increased the number of corpora lutea owing to the prolonged metestrus phase. Gene expression analysis within the adrenals revealed the upregulation of Insr and the downregulation of Prgtr in HFD mice, while Ex-4 downregulated the expression of Gipr. The ovarian gene expression of Gipr, Npy1r and Prgtr was downregulated by Ex-4 treatment, while PYY(3-36) significantly downregulated the Prgtr expression compared to HFD mice. These data indicate that manipulating GLP-1R and NPY2R leads to changes in the reproductive physiology of mice. In addition, the observed alterations in the morphology and gene expression in the adrenals and ovaries imply a direct impact of these peptides on female reproductive function. Show less

Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases. Show less

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) have similar clinical characteristics in the brain and islet, as well as an increased incidence with ageing and familial susceptibility. Therefore, in recent years there has been a great desire for research that elucidates how anti-diabetic drugs affect AD. This work attempts to first elucidate the possible mechanism of action of DPP-IV inhibitors in the treatment of AD by employing techniques from network pharmacology, molecular docking, molecular dynamic simulation, principal component analysis, and MM/PBSA. A total of 463 targets were identified from the SwissTargetPrediction and 784 targets were identified from the SuperPred databases. 79 common targets were screened using the PPI network. The GO and KEGG analyses indicated that the activity of DPP-IV against AD potentially involves the hsa04080 neuroactive ligand-receptor interaction signalling pathway, which contains 17 proteins, including CHRM2, CHRM3, CHRNB1, CHRNB4, CHRM1, PTGER2, CHRM4, CHRM5, TACR2, HTR2C, TACR1, F2, GABRG2, MC4R, HTR7, CHRNG, and DRD3. Molecular docking demonstrated that sitagliptin had the greatest binding affinity of -10.7 kcal/mol and established hydrogen bonds with the Asp103, Ser107, and Asn404 residues in the active site of the CHRM2 protein. Molecular dynamic simulation, PCA, and MM/PBSA were performed for the complex of sitagliptin with the above-mentioned proteins, which revealed a stable complex throughout the simulation. The work identifies the active component and possible molecular mechanism of sitagliptin in the treatment of AD and provides a theoretical foundation for future fundamental research and practical implementation. Show less

This study investigates how sorafenib induces toxicity in glomerular cells and examines the protective role of 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs in reducing this kidney damage. Human renal mesangial cells (HRMCs) and podocytes were treated with no treatment, sorafenib alone, or sorafenib combined with 8,9-EET analogs. Cell viability and apoptosis were measured in both cell types. Sorafenib (1-10 µM) lowered cell viability and increased caspase 3/7 activity in a dose-dependent way in HRMCs and podocytes. Five of twenty 8,9-EET analogs significantly enhanced cell survival and decreased apoptosis. RNA sequencing showed that sorafenib altered 1244 genes, including those involved in cell cycle and the Raf/MEK/ERK pathway. The 8,9-EET analog MDB-52a raised ANGPTL4 levels, linked to metabolism and vascular health, and reduced ACTA2, which could activate protective pathways. Nephroseq data correlated these gene changes with glomerulosclerosis. MDB-52 appears to counteract gene disruptions and protect against sorafenib-induced kidney damage. Overall, 8,9-EET analogs targeting glomerular cells could be potential therapeutic agents to lessen sorafenib-related nephrotoxicity. Show less

To evaluate the diagnostic performance of APOA4, CEACAM1, CD147, DJ-1/PARK7, Gamma-synuclein, S100A1, and Stathmin-1 in urothelial carcinoma and establish optimal immunohistochemical cutoffs for their use as diagnostic markers. This cross-sectional study included 141 histologically confirmed urothelial carcinoma cases and controls. Immunohistochemical staining was optimized for each biomarker, and semiquantitative scoring was applied. Diagnostic validity was assessed using receiver operating characteristic (ROC) analysis, comparing sensitivity and specificity across several cutoffs and biomarker panels. Among seven biomarkers, APOA4, DJ-1/PARK7, Gamma-synuclein, and Stathmin-1 demonstrated high diagnostic accuracy (≥80% sensitivity and specificity). Using an Allred score ≤2 as a cutoff, the sensitivity/specificity were as follows: APOA4, 96%/100%; DJ-1/PARK7, 97%/94%; Gamma-synuclein, 98%/84%; and Stathmin-1, 98%/90%. A combined panel of these four biomarkers achieved near-perfect diagnostic performance, reaching almost 100% sensitivity and specificity. A biomarker panel comprising Stathmin-1, DJ-1/PARK7, Gamma-synuclein, and APOA4 reliably distinguished urothelial carcinoma from benign urothelium. These markers, when integrated with cytology, could enhance the diagnostic precision and reduce dependence on invasive cystoscopy. The proposed cutoffs (10%-20% positive cells or Allred score ≤2) offer clinically actionable threshold for histopathological practice. Show less

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

Coronary artery calcium (CAC) scoring is widely used to screen for coronary artery disease (CAD) in asymptomatic individuals. However, it detects calcified plaques and may miss non-calcified or soft plaques. This study compared the diagnostic accuracy of CAC scoring with coronary computed tomography angiography (CCTA) for detecting CAD in asymptomatic individuals with risk factors. Eighteen asymptomatic adults with a CAC score of 0 underwent CCTA to evaluate for subclinical CAD. Clinical, biochemical, and lifestyle risk factors were assessed. Diagnostic agreement between CAC and CCTA was analyzed using the Wilcoxon signed rank test. The cohort had a mean age of 51.4 ± 10.6 years, 88.8% were male, and mean body mass index (BMI) was 27.7 ± 3.6 kg/m CCTA detected non-calcified atherosclerosis missed by CAC and demonstrated superior sensitivity for early CAD detection in asymptomatic individuals. Show less

Dried blood spot sampling offers a scalable strategy to close diagnostic gaps and improve global surveillance for cardiovascular-kidney-metabolic syndrome. However, assay performance and the extent of validity vary widely between biomarkers used in cardiovascular-kidney-metabolic health assessment under different settings and have not been well described. To fill this gap, we conducted a systematic search of the literature and a narrative synthesis through April 2024 and included reports with laboratory or field validation measuring biomarkers that can be used in cardiovascular-kidney-metabolic health assessment. We categorized assays into categories based on laboratory validation: excellent performance (r>0.95 with gold standard methods and coefficients of variation <5%), very good performance (r>0.90 and coefficients of variation <10%), reasonable performance (r>0.80 and coefficients of variation <15%), and poor performance (r<0.80 or coefficients of variation >15%). The extent of validation was determined by the total number of field validation studies with strong agreement. Hemoglobin A1c has strong laboratory and field validation and should be considered for expansion into clinical testing in low-resource settings. Traditional lipid biomarkers showed poor performance in field validation studies, but apoB (apolipoprotein B), creatinine, cystatin C, and NT-proBNP (N-terminal prohormone of brain natriuretic peptide) showed promising initial laboratory validation results and deserve greater attention in field validation studies. High-sensitivity C-reactive protein has strong laboratory and field validation but has limited clinical utility. Dried blood spot assays have been developed for biomarkers that offer mechanistic insights including inflammatory and vascular injury markers, fatty acids, malondialdehyde, asymmetric dimethylarginine, trimethylamine N-oxide, carnitines, and omics. Show less

We test the hypothesis that high levels of neuroplasticity in the context of Alzheimer's disease (AD) risk factors are involved in AD pathogenesis by investigating interactions between cerebrospinal fluid (CSF) levels of growth-associated protein-43 (GAP-43) and AD risk factors (female sex, cerebrovascular risk, mild cognitive impairment, apolipoprotein E [APOE] ε4 genotype, amyloid positivity) on CSF biomarkers of AD pathology (amyloid beta 42/40[Aβ42/40], phosphorylated tau (p-tau)) and neurodegeneration (tau). Baseline GAP-43 levels in 161 non-demented older adults were related to cross-sectional and longitudinal (mean follow-up = 4 years) CSF biomarkers of AD, adjusting for covariates, with GAP-43 x AD risk factor interaction terms. Higher GAP-43 was cross-sectionally related to all AD biomarkers (p-values < 0.0001) and predicted longitudinal reductions in Aβ42 (p < 0.0001). Associations were stronger in AD risk groups. We found strong support linking increased levels of neuroplasticity in the context of AD risk factors to the pathological cascade of AD over a 4-year mean follow-up period. Cerebrospinal fluid growth-associated protein-43 (GAP-43) is associated with Alzheimer's disease (AD) biomarkers cross-sectionally and longitudinally. GAP-43 interacts with AD risk factors to predict AD biomarkers. Increased neuroplastic activity may play a role in AD pathogenesis. Show less

Dysferlin direct protein-protein interactions (PPI) previously have been elucidated with surface plasmon resonance (SPR) and predicted to underlie membrane repair in mechanotransducing myofibrils. In mechanotransducing inner ear hair cells, dysferlin is detected with Z-stack confocal immunofluorescence in the stereocilia and their inserts in the tectorial membrane (TM) co-localizing with FKBP8, consistent with the SPR determination of tight, positively Ca Show less

Neurodegenerative diseases, particularly Alzheimer's disease (AD), represent a significant public health challenge due to their increasing prevalence and the lack of effective treatments. In this study, we explored the neuroprotective effects of beta-carotene, a naturally occurring carotenoid, by investigating its ability to inhibit or reduce apoptosis and inflammation while enhancing antioxidant potential in SH-SY5Y neuroblastoma cells. Beta-carotene was extracted from Chlorella vulgaris using high-performance liquid chromatography (HPLC). We utilized SH-SY5Y cells, a widely employed in vitro model for studying neurodegenerative processes, to evaluate these therapeutic effects. A combination of colorimetric assays, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time PCR (qRT-PCR) was used to assess the impact of beta-carotene on enzyme activity, cytokine production, and gene expression. The caspase assay results demonstrated that beta-carotene effectively reduced the activity of pro-apoptotic caspases and downregulated the expression of pro-apoptotic genes such as Bax, Bak and caspases, thereby inhibiting apoptosis in SH-SY5Y cells. Additionally, beta-carotene exhibited potent antioxidant properties by upregulating NRF2 and superoxide dismutase (SOD), along with enhancing ABTS and DPPH radical scavenging activities.showed antiinflamatory effects reduce the concentrations of proinflamatory cytokines TNFα, IL-1 β and IFN-γ, and supress the inflamtion patway by supressing the expression of Akt, PIK3, STAT1 and NF-kB, Akt etc. Importantly, beta-carotene treatment led to the suppression of β-secretase (BACE1), γ-secretase and acetylcholinesterase (AChE) activities, and the downregulation of genes involved in amyloid-beta production, including BACE1, and PECN1 eventualy resulted in dcerase concentration o Aβ peptides. These findings suggest that β-carotene could be a promising therapeutic candidate for the prevention and treatment of neurodegenerative diseases, particularly Alzheimer's disease, however further investigations are recomended in animal models and clinical trials before incorporating beta-cerotene into pharmaceutical formulations for AD treatment. Show less

Poly(ADP-ribose) (PAR) polymerase-1 (PARP1) has been implicated in DNA damage responses and neuroinflammation in Alzheimer's disease (AD), yet its role in amyloid-β (Aβ) pathology remains unclear. Here, we show that PARP1 activation drives Aβ pathology and neurodegeneration. Using a sensitive ELISA, we observed significantly elevated PAR levels in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD compared to controls. Show less