👤 Niraj Kumar Singh

Dysregulated actions of the bone-derived phosphaturic hormone, fibroblast growth factor-23 (FGF23), underlie the pathophysiology of several diseases. FGF23 is synthesized primarily in osteocytes in response to various endogenous molecules; however, the mechanisms governing FGF23 production are incompletely understood. Glycerol-3-phosphate (G3P), a glycolytic by-product originating from the kidney, critically controls skeletal FGF23 synthesis via its conversion in bone to lysophosphatidic acid (LPA), which stimulates osteocyte FGF23 production. The bioactive vitamin D, 1,25-dihydroxyvitamin D (1,25D), also promotes FGF23 production in osteocytes. We herein demonstrated that LPA requires 1,25D action to raise FGF23 levels in mouse bone explants and mice. RNA sequencing of osteocyte-like Ocy454 cells identified differentially expressed genes (DEGs) uniquely induced by LPA/1,25D co-treatment. These unique DEGs were enriched for the ribosome biogenesis pathway. DEGs concurrently induced by individual LPA and 1,25D treatments were enriched for MAPK signaling, and inhibiting this pathway obliterated LPA/1,25D-induced FGF23 production. DEGs following LPA/1,25D co-treatment were enriched for the cytokine-cytokine receptor interaction pathway. Moreover, LPA/1,25D co-treatment, but not individual LPA and 1,25D treatments, rapidly induced the expression of Il12a, the gene encoding the pro-inflammatory cytokine interleukin-12 alpha-subunit, which responded solely to 1,25D at later times and required MAPK-ERK1/2 signaling. Inhibiting cytokine signaling or knocking down Il12a inhibited, while overexpressing Il12a enhanced LPA/1,25D-induced FGF23 production. However, challenging Ocy454 cells with recombinant bioactive interleukin-12 failed to enhance FGF23 production, suggesting that Il12a plays a noncanonical role. Our results reveal a mechanism of skeletal FGF23 synthesis involving synergistic actions of LPA and 1,25D, advancing our understanding of FGF23 regulation. Show less

Lipoprotein(a) [Lp(a)] and PCSK9 are emerging lipid biomarkers implicated in atherogenesis and residual cardiovascular risk, but their relationship with coronary disease complexity in acute coronary syndrome (ACS) is unclear. This study evaluates their serum levels in first-episode ACS patients versus controls and explores their relationship with SYNTAX score-defined coronary severity. This single-centre observational study enrolled 160 patients presenting with their first episode of ACS (aged 18-75) and 40 age-matched healthy controls. All participants were free from lipid-lowering therapy and major comorbidities. Fasting serum samples were collected to measure the standard lipid profile, Lp(a), and PCSK9 levels. The severity of coronary artery disease was quantified using the SYNTAX score after coronary angiography. The ACS cohort (mean age 55.7 years; 73.1 % male) most frequently presented with STEMI (53.7 %). Traditional risk factors included smoking/tobacco use (48.8 %), diabetes (40.0 %), and hypertension (38.1 %). Median SYNTAX score was 19.4. Compared with controls, ACS patients had significantly lower HDL-C and higher LDL/HDL and cholesterol/HDL ratios. Lp(a) (38.9 vs. 15.9 mg/dL, p < 0.001) and PCSK9 (272.3 vs. 169.6 ng/mL, p < 0.001) were markedly elevated in ACS patients. Neither Lp(a) nor PCSK9 correlated with SYNTAX score. LDL-C showed a modest positive correlation with Lp(a) (r = 0.163, p = 0.040). Higher SYNTAX scores were associated with more extensive multivessel disease. Patients with ACS exhibited significantly higher Lp(a) and PCSK9 levels compared with healthy controls, but these biomarkers did not reflect angiographic disease complexity. Their role may lie more in underlying cardiovascular risk assessment than in predicting anatomical severity. Show less

This study presents the phylogenetic and antimicrobial susceptibility characterization of Mycobacterium monacense, a rare nontuberculous mycobacterium (NTM), cultured from clinical extrapulmonary samples. Eight Mycobacterium monacense isolates were identified between 2019 and 2023 in the Western Cape province of South Africa. Whole-genome sequencing (WGS) was applied to assess phylogenetic relatedness, identify virulence factors, and characterize the resistome of the isolates. Antimicrobial susceptibility testing (AST) was performed using the GenoType NTM-DR line probe assay (LPA), Sensititre minimum inhibitory concentrations (MIC) plates, and the proportional method based on critical concentrations. Spatial distribution of cases was mapped using ArcGIS software. Spatiotemporal distribution patterns indicated the presence of circulating clones confined within specific geographical areas. Plasmids coding for ferredoxin and cytochrome P450 genes were identified in one cluster, which notably lacked the chromosomal mbtH gene involved in siderophore biosynthesis for iron acquisition. In contrast, isolates grouped in a second cluster harbored the mbtH chromosomal gene but lacked these plasmid-associated elements. LPA and broth microdilution showed that all Mycobacterium monacense isolates were susceptible to aminoglycosides, fluoroquinolones, and macrolides, but generally exhibited elevated MICs against β-lactam antibiotics. Phenotypic AST indicated that drugs commonly used to treat Mycobacterium tuberculosis complex (MTBC), namely bedaquiline, linezolid, and rifampicin, are effective against Mycobacterium monacense. Mycobacterium monacense in extrapulmonary cultures accentuates the need for improved diagnostics and enhanced clinical awareness of infections with rare NTM. WGS highlights the potential significance provided by plasmid-encoded genes. Current treatment regimens for MTBC exhibit therapeutic efficacy against Mycobacterium monacense isolates. Show less

Endothelial lipase (EL) is a key regulator of high-density lipoprotein (HDL) metabolism. Many aspects of EL function remain incompletely understood due to challenges in purifying active EL. This study identifies apolipoprotein J (ApoJ) as a novel chaperone for EL, crucial for its solubility and activity. Using an optimized purification protocol that yields active EL, we discovered that ApoJ consistently co-purifies with EL, maintaining its activity. We further show that knocking down ApoJ decreases the activity of EL. We demonstrate that ApoJ interacts with EL via its hydrophobic lid and tryptophan loop regions, and that mutating these regions abolishes the effect of ApoJ on the solubility and activity of EL. We show that ApoJ, EL, and ApoA1 (the defining lipoprotein of HDL particles) colocalize in HDL particles in mouse plasma. However, we find that ApoJ is not a direct carrier for EL to HDL particles. Instead, our data suggest that ApoJ primarily serves to enhance EL activity through its role as a chaperone, even when incorporated into lipid substrates. Our findings suggest a model in which ApoJ protects EL in plasma and enhances its hydrolysis of lipoprotein substrates. We propose that ApoJ is an accessory protein for EL, analogous to GPIHBP1 for LPL and co-lipase for PL. Further study of the interaction between EL and ApoJ will promote a better understanding of HDL metabolism. Show less

The chronic unpredictable mild stress (CUMS) paradigm is a well-known preclinical model used to investigate the pathophysiology of stress-induced neuropsychiatric disorders. This review integrates recent findings to elucidate how chronic stress initiates a multifaceted cascade involving neuroendocrine dysregulation, metabolic dysfunction, immune activation and synaptic impairment. Persistent stimulation of hypothalamic-pituitary adrenal (HPA) axis results in hypercortisolaemia, insulin resistance and compromised neuroplasticity through dysregulated BDNF-TrkB signalling, oxidative stress and activation of inflammatory pathways. Compelling evidence highlights both the Gut brain axis (GBA) and epigenetic alterations as central to stress-induced neuropathology. Stress-mediated microbial dysbiosis and intestinal barrier disruption amplify central inflammation through altered tryptophan metabolism and immune neurotransmitter signalling. Simultaneously, epigenetic modification including DNA methylation, histone remodelling and microRNAs encodes transcriptional changes that results in behavioural and cognitive deficits. While, CUMS model offers strong face and predictive validity but its translational relevance is constrained by protocol validity and limited modelling of psychological stressors. Nonetheless, it remains instrumental for evaluating pharmacological and non-pharmacological interventions targeting inflammatory, neurotrophic and metabolic pathways. Future refinement should incorporate biomarker discovery and gene-environment interaction paradigms. In synthesizing these diverse mechanistic insights, this review underscores the value of the CUMS model in identifying system-level therapeutic targets and advancing translational research in stress-related brain disorder. Show less

Pancreatic islets undergo coordinated cellular remodeling during obesity-induced insulin resistance (IR). However, the associated molecular changes across endocrine and non-endocrine compartments remain largely unexplored. Here, using longitudinal single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on islets from C57BL/6 mice subjected to high-fat diet (HFD) feeding for 8, 16, and 24 weeks, along with age-matched controls on regular chow, we mapped dynamic changes in islet cell composition and transcriptional states. Beta cells demonstrated pronounced stress-induced reprogramming, with the emergence of proliferative and dysfunctional subsets. Alpha and delta cell fractions declined under HFD, despite increased polyhormonal biosynthesis, suggesting functional rather than numerical adaptation. Immune profiling showed robust expansion of proinflammatory M1 macrophages and upregulation of NF-κB and chemotaxis pathways, particularly at 16 weeks. Notably, cell-cell communication analyses revealed diet-specific disruption in signaling networks. Under HFD conditions, intercellular communication among beta cells, macrophages, and delta cells was markedly altered, leading to the disruption of key signaling pathways such as the gastric inhibitory polypeptide receptor (GIPR) and major histocompatibility complex-I (MHC-I). Notably, C-C motif chemokine ligand 27A ( Show less

Olezarsen (Tryngolza) is a next-generation, N-acetylgalactosamine (GalNAc)-conjugated antisense oligonucleotide that selectively inhibits hepatic ApoC-III, a key regulator of triglyceride metabolism. By inhibiting ApoC-III, olezarsen increases triglyceride clearance through both lipoprotein lipase (LPL)-dependent and -independent pathways. In the Phase 3 BALANCE trial, olezarsen reduced fasting triglycerides by approximately 60% at 12 months in patients with familial chylomicronemia syndrome (FCS), with a marked decrease in pancreatitis events versus placebo. Consistent triglyceride reductions (around 50%) were also observed in moderate and severe hypertriglyceridemia, along with improvements in ApoB-containing lipoproteins and high-density lipoprotein (HDL) profiles. In completed trials, olezarsen demonstrated a favorable safety profile, with most adverse events limited to mild injection-site reactions and no clinically significant thrombocytopenia. Ongoing Phase 3 trials (ESSENCE, CORE, and CORE2) will further define its role in cardiovascular risk reduction and pancreatitis prevention in broader hypertriglyceridemic populations. Olezarsen represents a precision medicine advance, offering effective triglyceride lowering with improved tolerability compared with earlier antisense therapies. Show less

Inclisiran, a small interfering RNA (siRNA), reduces the levels of low-density lipoproteins (LDL) in the body by preventing the hepatic synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9). However, there is limited pooled data regarding the efficacy and safety of inclisiran in patients with hypercholesterolemia. PubMed/MEDLINE, Embase and the Cochrane Library were searched by investigators from inception till July 2024 to identify randomised controlled trials (RCTs) that investigated inclisiran in patients with hypercholesterolemia. Weighted mean differences (MDs) for continuous outcomes and risk ratios (RRs) for the dichotomous outcomes were pooled. The analysis was conducted using the random effects model, and a p-value of < 0.05 was considered statistically significant. A total of 8 RCTs reporting data for 5016 patients were included in the pooled analysis. Our pooled analysis demonstrated that inclisiran was associated with a significant decline in the % of LDL-C levels (MD = -50.42, 95% CI: -56.15 to -44.70), % of PCSK9 levels (MD = -78.57, 95% CI: -81.64 to -75.50), % of total cholesterol levels in the body (MD = -31.22, 95% CI: -33.08.15 to -29.37), and apo B levels (MD = -41.47, 95% CI: -44.83 to -38.11) when compared with the control group. The risk of all-cause death, cardiovascular death, major adverse cardiovascular events, myocardial infarction, stroke, and serious adverse events remained comparable (p > 0.05) across the two groups. Inclisiran reduces LDL-C, PCSK9, cholesterol and apo-B levels in the body without increasing the risk of serious adverse events. Show less

In pancreatic ductal adenocarcinoma, hypoxia is a crucial component of the tumour microenvironment and is associated with worse clinical outcomes. Adaptation to extreme hypoxic settings is based on abnormal lipid metabolism, but insights into how hypoxia-regulated lipid changes link with aggressive migratory potential in pancreatic cancer are lacking. This study investigates the molecular processes, pathways, and critical proteins involved in hypoxia-induced lipidic and polyunsaturated fatty acid alterations in pancreatic cancer. Our findings elucidate increased multilayer unsaturation in FA chains of major lipid classes associated with greater migration and invasion, as well as higher abundances of particular desaturases. The expression of these proteins was verified in clinical tumour samples by unsaturated fatty acid biosynthesis-related gene enrichment score. High unsaturated fatty acid clusters were shown to be associated with a low survival rate. Pathway correlation and protein-protein interaction analysis indicated that the PPAR-hypoxia axis and SCD/FADS2/APOC3-HDLBP protein network are implicated in mediating the observed alterations in lipid pools and poly-unsaturation levels in pancreatic cancer under hypoxia. These results provide novel therapeutic targets in pancreatic cancer while improving our understanding of hypoxia-induced migratory potential in pancreatic cancer. Show less

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder influenced by genetic, metabolic, and lifestyle factors. Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, notably C677T and A1298C, may increase AD susceptibility through disruptions in one-carbon metabolism and homocysteine accumulation. This study examined the association of MTHFR C677T and A1298C variants with metabolic alterations, cognitive decline, and AD risk. A case-control study was conducted with 120 AD patients and 120 cognitively healthy controls. Cognitive function was assessed using the Hindi Mini-Mental State Examination (HMMSE) and Hindi Mattis Dementia Rating Scale (HMDRS). MRI evaluated white matter hyperintensities and cortical atrophy. Biochemical markers, including homocysteine, folate, and vitamin B12, were measured. Genotyping was performed via TaqMan SNP assays. Functional enrichment and protein-protein interaction analyses were conducted to investigate molecular mechanisms. AD cases demonstrated elevated homocysteine and blood glucose, reduced folate, and impaired cognition. Both MTHFR C677T and A1298C polymorphisms were significantly associated with AD risk under dominant and over-dominant models (ORs 3.41-4.09). Risk-allele carriers exhibited pronounced metabolic alterations. Bioinformatics analyses revealed disruption in one-carbon metabolism, oxidative stress defense, and vascular pathways, with indirect interactions between MTHFR and key AD genes (APP, PSEN1/2, MAPT, APOE, CLU, PICALM, SORL1). MTHFR C677T and A1298C variants contribute to AD susceptibility through metabolic and vascular mechanisms that exacerbate cognitive decline. Integrating genetic, biochemical, and cognitive assessments highlights potential targets for early prevention and therapeutic interventions. Show less

Early identification of markers of cognitive decline in cognitively normal older adults is essential for dementia prevention strategies. Sensorimotor measures, such as gait speed, grip strength, and reaction time, may provide sensitive indicators of current and future impairment. This study examined associations between baseline sensorimotor function and cognitive decline in cognitively normal older adults. In this prospective cohort, 246 cognitively normal older adults from the DRIVES Project completed baseline assessments of grip strength, gait speed, simple reaction time, and the Preclinical Alzheimer Cognitive Composite (PACC). Participants were followed for a mean of 4 years. Linear mixed-effects models adjusted for demographics, APOE ε4 status, and neighborhood deprivation. Cross-sectional analyses evaluated the associations between sensorimotor measures and cerebrospinal fluid (CSF) biomarkers of amyloid, tau, and plasma neurofilament light chain (NfL). Participants (mean age: 74.9 ± 5.17 years; 48.8% female) had a mean baseline PACC score of 1.06 ± 0.50. Cross-sectionally, slower gait speed was associated with higher CSF tau/Aβ Show less

Early detection of preclinical Alzheimer's disease (AD) could expand preventative care. Current biomarkers are costly, invasive, or lack generalizability. Driving and sensorimotor performance may reveal prodromal changes. We tested whether features from high-frequency driving trips detect preclinical AD and whether demographic, genetic, or sensorimotor data improve accuracy. Drivers aged ≥ 65 (n = 254) from Driving Real-World In-Vehicle Evaluation System (DRIVES) completed cerebrospinal fluid Aβ The top-performing model (driving, age, A high-frequency trip's driving telemetry, combined with age and Show less

Driving integrates multiple cognitive, sensory, and motor systems and may serve as a real-world indicator of functional decline in aging. Older adults with mild cognitive impairment (MCI) often experience subtle driving changes before formal dementia diagnosis, but longitudinal, real-world evidence is limited. This study examined whether naturalistic driving data can differentiate older adults with MCI from those with normal cognition (NC) over time and evaluated the discriminative ability of driving features compared with conventional risk factors. We conducted a prospective, observational cohort study of community-dwelling older drivers enrolled in the Driving Real-World In-Vehicle Evaluation System Project at Washington University. Participants underwent annual Clinical Dementia Rating assessment, neuropsychological testing, and apolipoprotein ε4 (APOE ε4) genotyping. Driving behaviors were captured daily for up to 40 months using global positioning system-enabled in-vehicle dataloggers, recording trip frequency, duration, distance, time of day, speeding, hard braking, and spatial mobility (entropy, maximum distance, radius of gyration). Longitudinal changes were analyzed using linear mixed-effect models, adjusting for age, sex, race, education, and APOE ε4. Logistic regression with reciever operator curve analysis evaluated discrimination between older adults with MCI and those with NC, compared with conventional sociodemographic and genetic markers. Among 298 participants (MCI, n = 56; NC, n = 242; mean age 75.1 years; 45.6% female), the groups were similar in age, sex, race, and APOE ε4 status at baseline, as well as in most driving behaviors. Over time, drivers with MCI showed greater reductions in monthly trip count (MCI: -0.501, standard error [SE]: 0.21, 95% CI [-0.923 to -0.083] vs NC: -0.523, SE: 0.09, 95% CI [-0.709 to -0.337]; MCI was associated with progressive declines in driving frequency, complexity, and spatial range, supporting naturalistic driving data as a potential unobtrusive digital biomarker for early cognitive decline. Limitations of the study include a predominantly White, highly educated sample and a lack of external validation, warranting cautious interpretation. Continuous monitoring could augment clinical assessments, inform driving safety decisions, and guide interventions to preserve mobility in aging. Show less

Innate immunity, the primary defence mechanism, encompasses a range of protective processes like anatomical barriers, cytokine secretion, and the action of various immune cells. Cattle breeds might differ in these processes because of their genetic differences such as copy number variations (CNVs). Therefore, the present investigation employed an array comparative genomic hybridisation (aCGH) approach on breed representative pooled DNA samples to evaluate CNVs across six cattle breeds: four indigenous Indian breeds, Kangayam (KNG), Tharparkar (TP), Sahiwal (SW), Gir (GIR), one crossbred Karan Fries (KF), and one exotic breed, Holstein Friesian (HF). In aCGH, HF DNA was used as control, while test DNA was from the other breeds. Each pooled test DNA sample was a representative of 18 animals belonging to three distinct geographical locations of India. The study using Aberration Detection Method 2 (ADM-2) of Agilent Genomic Workbench revealed the highest number of duplications in KNG (1189 genes), followed by TP (534 genes), and the greatest number of deletions in SW (774 genes). Among these genes, 183 and 76 innate immune genes with hub genes TGF-β1, CD79A, and IL4 showed duplications in KNG and TP, respectively. In SW, 113 innate immune genes with hub genes PSMC5, MAPK1, and AXIN1 showed deletions. In contrast, KF and HF showed no genes with deletions and fewer duplicated innate immunity genes, reflecting either lower genetic variability in their immune gene repertoire or a potential bias due to HF DNA as a control in aCGH. Functional enrichment of innate immune genes revealed duplications in KNG enriched in interleukin-1 receptor (IL1R) activity (p = 9.9 × 10 Show less

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2, or APC, and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations. Show less

Brain metastasis occurs in up to 40% of patients with non-small cell lung cancer (NSCLC). Considerable genomic heterogeneity exists between the primary lung tumor and respective brain metastasis; however, the identity of the genes capable of driving brain metastasis is incompletely understood. Here, we carried out an in vivo genome-wide CRISPR activation screen to identify molecular drivers of brain metastasis from an orthotopic xenograft model derived from a patient with NSCLC. We found that activating expression of the Alzheimer's disease-associated beta-secretase 1 (BACE1) led to a substantial increase in brain metastases. Furthermore, genetic and pharmacological inhibition of BACE1 blocked NSCLC brain metastasis. Mechanistically, we identified that BACE1 acts through epidermal growth factor receptor to drive this metastatic phenotype. Together, our data highlight the power of in vivo CRISPR activation screening to unveil molecular drivers and potential therapeutic targets of NSCLC brain metastasis. Show less

Alzheimer's disease (AD) is a degenerative neurological disease characterized by a loss of memory and cognitive ability. One of the main factors influencing the development of AD is the accumulation of amyloid β (Aβ) plaque in the brain. The sequential production of Aβ is mediated by two enzymes: gamma-secretase and β-secretase (BACE1). The goal of beta-secretase inhibitors is to prevent the initial cleavage of amyloid precursor protein (APP), which reduces the production of (Aβ) peptides by limiting the substrate available for gamma-secretase. Simultaneously, gamma-secretase modulators are engineered to specifically modify enzyme performance, reducing the synthesis of the harmful Aβ42 isoform while maintaining vital physiological processes. Targeting both secretases reduces amyloidogenic processing synergistically. Selective inhibitors, which have been recently developed, have also shown good clinical development. They can reduce Aβ levels effectively with minimal side effects. The therapeutic strategy also underlines the importance of early therapy intervention in the preclinical AD phase for an optimum effect. Although there are some problems in the optimization of drug delivery and the alleviation of side effects, targeting beta and gamma secretases remains a promising direction. However, all these strategies still need more research and clinical testing to improve existing treatments and develop new, efficient Alzheimer's disease therapies. This review seeks to examine the therapeutic promise of β- and γ-secretase inhibition in Alzheimer's disease and review recent progress, challenges, and new dual-inhibition approaches. Show less

Flavonoids are an important class of natural products, particularly, belong to a class of plant secondary metabolites having a polyphenolic structure. They are widely found in fruits, vegetables, and certain beverages. Hispidulin and diosmin are naturally occurring flavonoids recognized for their potential health benefits, such as antioxidant, anti-inflammatory, and neuroprotective properties. Hispidulin is present in several plants, including Arnica montana, Salvia officinalis (sage), and Eupatorium arnottianum. Diosmin is mainly extracted from citrus fruits like lemons and oranges and can also be synthesized from hesperidin, another flavonoid found in citrus fruits. Neurodegenerative diseases are characterized by complex signaling pathways that contribute to neuronal deterioration. The JAK/STAT pathway is involved in inflammatory responses, while the NF-κB/NLRP3 pathway is associated with metabolic stress and inflammation, both facilitating neurodegeneration. Conversely, the AMPK/pGSK3β pathway is crucial for neuroprotection, regulating cellular responses to oxidative stress and promoting neuronal survival. Additionally, the BACE/Aβ pathway exacerbates neuronal damage by triggering inflammatory and oxidative stress responses, highlighting critical targets for therapeutic strategies. Hispidulin and diosmin have emerged as promising agents in the modulation of mediators involved in neuroinflammation and neurodegenerative diseases. Oxidative stress and inflammatory pathways, including those driven by Aβ/BACE1 and JAK/STAT signaling, are central to neuronal damage and disease progression. Recent studies highlight that hispidulin and diosmin exhibit notable neuroprotective effects by targeting these mediators. Hispidulin has been shown to impact key inflammatory cytokines and adhesion molecules, while diosmin influences proinflammatory cytokine production and inflammasome activation. Both compounds offer potential therapeutic benefits by modulating crucial mediators linked to neuroinflammation and neurodegeneration. This review article is designed to explore the intricate mechanistic interplay underlying the neuroprotective effects of hispidulin and diosmin. Show less

Proinflammatory cytokines, especially interleukin-17 A (IL-17 A) have been found to be significantly associated with AD patients. IL-17 A amplifies neuroinflammation during AD pathology. This study highlighted the ability of IL-17 A to exacerbate amyloid-beta-induced pathology in animals. The AD pathology was induced with repeated intranasal administration of Aβ along with recombinant mouse IL-17 A (rmIL-17) at 1, 2 and 4 µg/kg for seven alternate days. Although, the combination of rmIL-17 and Aβ did not have severe effects on memory of the animals, but it drastically increased the IL-17 A mediated signaling, level of proinflammatory cytokines, oxidative stress and reduced antioxidants in the hippocampus and cortex regions of the animal brains. Interestingly, combining rmIL-17 with Aβ also triggered the expression of AD structural markers like pTau, amyloid-beta and BACE1 in the brain regions. Furthermore, rmIL-17 with Aβ exposure stimulated astrocytes and microglia leading to activation of proinflammatory signaling in the brain of the animals. These results showed the propensity of IL-17 A to promote severity of AD pathology and suggest IL-17 A as potent therapeutic target to control AD progression. Show less

The multi-target directed ligands (MTDLs) strategy has been evolved as the propitious approach for the development of therapeutics for Alzheimer's disease (AD). In an earlier report, we described the novel series of chalcone derivatives bearing N-aryl piperazine scaffold as MTDLs for the treatment of AD. Herein, we report the lead optimization of the series culminating in potent, multi-targeting compounds (32-57), evaluated through in-vitro and in-vivo biological studies. The optimal compound 48 exhibited potent inhibitory activities against AChE (IC Show less

Alzheimer's Disease (AD), a prevalent neurodegenerative disorder, poses a significant global health challenge with complicated pathogenesis. Pathological characteristics of AD include increasing loss of cholinergic neurons, oxidative stress, mitochondrial dysfunction, and amyloid beta accumulation. Due to the limited availability of effective therapeutic options with only symptomatic relief and their severe adverse effects, there is a significant need to search and explore new agents for the management of AD. Recently, natural products and/or phytoconstituents of plants have gained notable attention as potential sources of neuroprotective agents due to their diverse chemical constituents, mechanism of action, and relatively safe profiles. In view of this, Glycyrrhiza glabra has been recognized for its several therapeutic properties in traditional medicine systems for centuries. Further, neuroactive phytoconstituents of this plant, including glycyrrhizin, liquiritigenin, isoliquiritigenin, glabridin, and glycyrrhizic acid, exhibit significant pharmacological advantages along with potential neuroprotective effects against AD. Show less

Alzheimer's Disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive function, including memory loss, reasoning difficulties, and disorientation. Its hallmark features include the formation of neurofibrillary tangles and neuritic plaques in the brain, disrupting normal neuronal function. Neurofibrillary tangles, composed of phosphorylated tau protein and neuritic plaques, containing amyloid-β protein (Aβ) aggregates, contribute to the degenerative process. The discovery of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in 1999 revolutionized our understanding of AD pathogenesis. BACE1 plays a crucial role in the production of Aβ, the toxic protein implicated in AD progression. Elevated levels of BACE1 have been observed in AD brains and bodily fluids, underscoring its significance in disease onset and progression. Despite setbacks in clinical trials of BACE1 inhibitors due to efficacy and safety concerns, targeting BACE1 remains a promising therapeutic strategy for early-stage AD. Natural flavonoids have emerged as potential BACE1 inhibitors, demonstrating the ability to reduce Aβ production in neuronal cells and inhibit BACE1 activity. In our review, we delve into the pathophysiology of AD, highlighting the central role of BACE1 in Aβ production and disease progression. We explore the therapeutic potential of BACE1 inhibitors, including natural flavonoids, in controlling AD symptoms. Additionally, we provide insights into ongoing clinical trials and available patents in this field, shedding light on future directions for AD treatment research. Show less

The Sahiwal are among the most prominent international transboundary dairy cattle distributed in large numbers between India and Pakistan. With the elapse of more than seven decades after the independence and limited cross-border exchange of Sahiwal germplasm, one thought-provoking question arises as to whether natural and artificial selection could alter the genomic signature patterns in the Sahiwal, reared for different purposes in these two countries. Deciphering the genetic mechanisms that underlie economic traits is essential for advancement and long-term breeding plans that are reflected in the distinct selection signatures they carry. To identify these genomic signatures, three medium-density SNP datasets of Sahiwal from three geographical locations of India and Pakistan were analyzed, using De-Correlated Composite of Multiple Selection Signals technique to identify the major candidate genes. In the genome of Sahiwal, a total of 70 genomic regions with 261 protein-coding genes were found. Milk production (NEK11, HMGCS1, BTN1A1,KCNH3), reproduction (SH3BGR, PSMG1, BRWD1,B3GALT5) and immune response genes (BPIFB1, MCOLN2) were more closely related to the Indian Sahiwal. Pakistani Sahiwal had genes closely linked with the dual-purpose meat (RALGAPA2, RIN2, CFAP61), and milk (SLC24A3 GALNT17, BACH2) traits. Our findings revealed differential patterns of selection signatures in transboundary Sahiwal cattle. Show less

Disruption of photoreceptor-retinal pigment epithelium (RPE) interface with loss of photoreceptor outer segments (POSs) in the retina is a pathological hallmark of several neurodegenerative and retinal diseases including lysosomal storage disorder's like CLN3 disease. However, the retina is a functional composite Acid ceramidase deficiency and consequently altered sphingolipid signaling promotes disease phenotype(s) in a lysosomal storage disorder, CLN3 disease. Show less

CLN3 disease or juvenile neuronal ceroid lipofuscinosis (Batten disease), is a progressive, severe, neurodegenerative, lysosomal storage disorder. Previous studies have demonstrated that network-level excitability differences are present in mouse models prior to significant lysosomal storage accumulation. Here we sought to identify the earliest biochemical and functional markers of disease in the hippocampus, a brain region important in learning and memory and implicated in CLN3 disease. Using targeted hydrophilic interaction liquid chromatography high resolution mass spectrometry (LC-HRMS), we quantified levels of glycerophosphodiesters (GPDs), recently-described biomarkers of CLN3 disease, in early postnatal hippocampus. In addition, we assessed hippocampal excitability via in vitro voltage-sensitive dye imaging (VSDI) across the period of postanal hippocampal maturation (p7, p14, p21). Finally, we completed longitudinal electroencephalogram (EEG) recordings to evaluate in vivo hippocampal circuit dynamics once the hippocampal circuit was matured. Intriguingly, glycercophosphoinositol (GPI or GroPIns), but not other GPDs, were significantly elevated in CLN3 disease hippocampus in early development at p11, further supporting the hypothesis that GPI plays a key role in disease pathogenesis. Functionally, the hippocampus was significantly hypoexcitable as early as p7 and showed a very atypical pattern of maturation across early development. This aberrant development resulted in abnormal in vivo circuit function, with pathologic slowing observed on EEG recordings at p30. Collectively these data underscore the potential link between pathologic metabolism of GPI and functional defects in CLN3 disease. In addition, this work highlights that CLN3 disease is an early neurodevelopmental, and not just neurodegenerative, disorder. Show less

Three single component Dy(iii) complexes featuring β-diketone ligand TTBD (4,4,4-trifluoro-1-(2-thienyl)-1,3-butanedione) were studied for their potential as white-light emitters. The complexes include a water-containing species (DyA) and two anhydrous species (DyM and DyD) incorporating the auxiliary bidentate ligand pyrazine (pyz). The coordination geometry and ligand environment, particularly the nuclearity and presence of sensitizing co-ligands, significantly influence the relative intensities of the characteristic Dy(iii) yellow Show less