👤 Mrinal K Ghosh

Complex progressive neurodegenerative Alzheimer's disease is characterized by cognitive decline, memory impairment, and accumulation of amyloid and tau pathologies, along with aggravation of neuroinflammatory and oxidative stress pathways. In our previous studies, the potential of azilsartan, a widely used angiotensin receptor blocker (ARB), was demonstrated to possess neuroprotective action when administered through intranasal route, improving memory and cognition through modulation of central renin-angiotensin signalling in a demented animal model. With the intranasal administration, azilsartan nanoemulgel offers the ability to bypass the BBB due to the use of the olfactory and trigeminal neural pathways, achieving direct brain targeting of the therapeutics. In the present study, the neuroprotective effect of azilsartan (5 mg/kg via intranasal route consequently for 45 days) was further validated in an AlCl Show less

'Small extracellular vesicles (sEVs) are nanosized, membrane-enclosed sacs released by diverse cell types. They play a critical role in cell-cell communication through their cargo, which includes a wide range of proteins, lipids, and nucleic acids. Physiologically, sEVs circulate in various body fluids such as blood, urine, and saliva, making them accessible for diagnostic via non-invasive isolation techniques. Recent advances in high-throughput proteomics have significantly enhanced our ability to characterize the protein content of sEVs. Importantly, multiple studies on human fluids have identified specific protein markers across different cancer types, encompassing molecules involved in inflammation, cellular adhesion, immunity, and lipoprotein regulation. Interestingly, some of these proteins are consistently detected across multiple cancer types and sample sources, suggesting the existence of a shared "oncogenic signature" that may be transferred via sEVs. Among body fluids, urine and saliva are particularly promising for easy, non-invasive diagnostics. However, these sample types remain underexplored as compared to the serum, leaving substantial opportunities for future research. Taken together, these findings position sEVs as a powerful tool with significant potential for advancing precision cancer care. SIGNIFICANCE: Living cells release nanosized membrane-enclosed vesicles called small extracellular vesicles (sEVs) into the extracellular environment. sEVs contain protein cargo molecules that critically take part in cell-cell communications. Quantitative proteomics identified potential sEV associated biomarkers for early cancer diagnosis and therapy. sEV Proteins associated with cell adhesion and inflammation, lipoproteins and immunoglobulins are potential molecules that were majorly identified. Interestingly, some of these proteins such as APOA4, SAA4, ITIH4, SERPINC1 and VWF were consistently identified across multiple cancer types and sample sources, highlighting their potential as future biomarkers. Show less

Single-cell RNA-sequencing has identified that Alzheimer's disease (AD) pathology in humans is associated with activation of disease-associated microglia (DAM). Microglial signatures of human AD have not been consistently identified in AD mouse models. Since the inflammatory response of rats is more like humans, we profiled microglial transcriptomes in aging TgF344-AD rats, which overexpress two human AD risk genes. Classic DAM gene activation ( Show less

Depletion of TRF2 from chromosome ends causes telomeric fusions and genome instability in mammals, but in mouse neural stem cells (mNSCs), Trf2's role is non-telomeric. Although essential for mNSC proliferation and survival, Trf2 does not protect telomeres, aligning with findings that Trf2 is dispensable for telomere protection in pluripotent stem cells. In Trf2-deficient adult mNSCs (Trf2fl/fl; Nestin-Cre), proliferation decreased and neuronal differentiation was impaired, yet no telomere dysregulation or DNA damage response was observed. Similarly, TRF2 depletion in SH-SY5Y cells induced differentiation without telomere dysfunction. Mechanistically, non-telomeric TRF2 directly binds to the promoters of key genes that regulate differentiation, recruiting the polycomb repressor complex (PRC2) for H3K27 trimethylation, repressing differentiation genes to maintain NSC identity. G-quadruplex (G4) motifs are crucial for TRF2 binding; disrupting this interaction via G4-binding ligands or the G4-specific helicase DHX36 induces differentiation genes, promoting neurogenesis. These findings highlight TRF2's non-telomeric role in NSC survival, offering insights into neurogenesis and aging-related neurodegeneration. Show less

Variants of uncertain significance represent the biggest challenge for genomics-based precision oncology. Activated fibroblast growth factor receptors (FGFRs) frequently drive tumorigenesis by different genetic aberrations. However, it remains unknown which of the many point mutations affecting FGFR1, FGFR2, FGFR3 or FGFR4 in cancer are druggable, that is, activating signaling while not mediating FGFR inhibitor resistance. Here we implemented a saturation mutational scanning platform to screen all 11,520 possible point mutations covering the kinase domains of FGFR1-4. Pooled positive selection screens identified 474 activating and 738 mutations mediating resistance to the FGFR inhibitors pemigatinib and futibatinib, together revealing 301 druggable FGFR mutations analogous to a strong PS3/BS3 evidence level. The screens also identified loss-of-function mutations and an association of gain-of-function mutations with hydrophobic changes. The functional screens identified 97% of acquired resistance mutations in clinical trials. Our comprehensive catalog of every druggable mutation in the FGFR kinase domains is readily available for clinical decision support. Show less

Dendritic cells (DCs) encounter Leishmania differentially, and the conflict can restrict or disseminate the parasite infection, either by activating or dampening the protective T cell responses and inducing the regulatory T cells. The outcome of this conflict depends on the species of Leishmania, infection tenure, DC subtypes, and, importantly, the DC-stimulating chemical and physical mediators. The critical balance between splenic cDC1 (CD8α Show less

Many older adults with chronic obstructive pulmonary disease (COPD) are inactive and moderate-to-vigorous physical activity (MVPA) can be too strenuous for long-term maintenance. We examined effects of an intervention to increase light physical activity (LPA). Primary outcomes were physical activity (PA) and sedentary behavior (SB). Active for Life with COPD (Active-Life) is a self-efficacy-based intervention designed to increase LPA. Chair Exercises with Health Education (Chair-HE) served as an active control. PA and SB were measured with ActivPAL and ActiGraph accelerometers. We randomized 159 people with COPD to 10 weeks of Active-Life or Chair-HE. 128 people completed the intervention; 105 completed 1-year follow-up. The sample was 45% female, mean (SD) age was 69.6 (8.2), FEV Active-Life produced significant, sustained increases in PA for 12 months. Further work is needed to reduce SB and establish longer-term PA effects. Show less

Copyright: © 2026 Adeyika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Aberrant DNA methylation changes lead to abnormal gene expression that contributes to the development and progression of prostate cancer (PCa). Inquiry of genome-wide DNA methylation dataset, we identified the homeodomain pancreatic and duodenal homeobox 1 (PDX1) gene as differentially hypermethylated in PCa compared to normal prostate tissues. Immunohistochemical analysis of matched PCa and normal prostate tissues using tissue microarray showed a significant 2.33-fold (p = 0.0001) higher PDX1 protein expression in the PCa compared to the normal prostate tissues. In PCa cell lines (PC-3 and LNCaP) engineered to stably overexpress or knockdown PDX1, the ectopic PDX1 expression significantly enhanced cell proliferation and migration, whereas PDX1 knockdown suppressed these phenotypic processes. Quantitative RT-PCR and Western blot analysis demonstrated that PDX1 overexpression was associated with increased expression of key metabolic regulators; INSR, IGF1R, CXCR4, CDH2, TWIST1, and SNAI1, whereas there is decreased expression of ESR2, and TNFα. Conversely, PDX1 knockdown led to the opposite effect in expression profiles of these metabolites. Notably, these effects were more pronounced under high-glucose conditions compared to low-glucose environments. Overall, our findings suggest that PDX1 plays a tumor-promoting role in human PCa cells by influencing expression of metabolites in insulin, inflammatory, and epithelial-mesenchymal transition (EMT) signaling pathways. Given its potential role in metabolic regulation, full insights into the function of PDX1 in PCa could contribute to improved treatment and prevention strategies, particularly for men with PCa and comorbidities such as obesity and diabetes. Show less

Self-labelling proteins like SNAP- and HaloTag have advanced imaging in life sciences by enabling live-cell labeling with fluorophore-conjugated substrates. However, the typical one-fluorophore-per-protein system limits signal intensity. To address this, we developed a strategy using the ALFA-tag system, a 13-amino acid peptide recognized by a bio-orthogonal and fluorescently labelled nanobody, for signal amplification. We synthesized a pentavalent ALFA Show less

Polycystic ovary syndrome (PCOS) is associated with increased cardiometabolic risk in young women of reproductive age. There are limited studies on atherogenic dyslipidemia, inclusive of triglycerides (TG), Apolipoprotein (apo) B-lipoproteins and remnant-cholesterol (C), atherosclerotic cardiovascular disease (ACVD), cardiac function and remodeling in young women with and without PCOS. The aim of this pilot study was to investigate the relationship of atherogenic dyslipidemia and other cardiometabolic risk factors with ACVD, cardiac function-remodeling in high-risk young overweight-obese PCOS women compared to non-PCOS and healthy-weight controls. Women with and without PCOS (non-PCOS control) aged 18 - 45 years who were overweight and obese (>25kg/m PCOS (n=48) and non-PCOS control overweight-obese age-BMI matched groups (n=19) were shown to have significantly higher fasting and non-fasting lipids including TG, remnant-C, total ApoB and ApoB48, compared to healthy-weight non-PCOS controls (n=10). PCOS and non-PCOS control overweight-obese groups had significantly higher SBP, DBP, cIMT and evidence of cardiac dysfunction and remodeling, with reduced Mitral E/A ratio, intraventricular (IV) relaxation time and increased Left ventricle (LV) end diastolic and systolic diameter, LV posterior wall thickness and IV septal thickness, compared to healthy-weight non-PCOS controls. Individuals with PCOS had significantly higher fasting plasma TG and remnant-C compared to the non-PCOS overweight-obese control group. The PCOS group tended to have 25% higher carotid plaque height, although this was not significant, compared to the non-PCOS overweight-obese control group. DBP, HOMA-IR and ApoB predicted 40% of the variability in cIMT and ApoB was shown to predict 14% of the variability in carotid plaque height, independent of age and BMI. A 1mg/ml increase in ApoB was associated with a 0.041mm increase in cIMT and a 0.75mm increase in carotid plaque height in all young women. Our pilot results supports the potential of apoB-dyslipidemia, cIMT, carotid plaque height and left ventricular diastolic dysfunction and remodeling to be used in screening for CVD risk in high-risk populations such as overweight-obese women with and without PCOS. ApoB may be useful to predict atherosclerotic vascular burden and progression of cIMT and carotid plaque, and could be used to develop a female specific algorithm for ACVD risk in high-risk young women with and without PCOS. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by synaptic dysfunction and neuronal loss, with glutamate excitotoxicity playing a central role in its pathology. The astrocytic glutamate transporter EAAT2, responsible for maintaining synaptic glutamate homeostasis, is significantly downregulated in AD. Restoration of EAAT2 expression presents a promising therapeutic strategy. This study explores the potential of modulating the Wnt/β-catenin signaling pathway to enhance EAAT2 levels by targeting the Axin-1/β-catenin interaction. Through virtual screening of 120,993 compounds from the Asinex-CNS database, five lead candidates were identified based on molecular docking, MMGBSA scores, and drug-likeness parameters. Advanced in-silico analyses-including Principal Component Analysis, Dynamic Cross-Correlation Mapping, molecular dynamics simulations, and MM/PBSA binding free energy calculations-highlighted BAS 04937103 as the most promising compound for disrupting β-catenin degradation. In vitro validation using C6 glioma cells and primary astrocytic cultures demonstrated that BAS 04937103 enhanced β-catenin stabilization and nuclear translocation, reduced Axin-1 expression, and significantly upregulated EAAT2 levels. These molecular effects corresponded with decreased extracellular glutamate concentrations, improved glutamate uptake, and reduced oxidative stress. Collectively, these findings establish BAS 04937103 as a novel modulator of the Axin/β-catenin interaction with therapeutic potential in mitigating glutamate-mediated neurotoxicity in Alzheimer's disease. Show less

Soybean-based foods enhance cognitive functions by influencing hippocampal mechanisms. These salutary effects have so far been attributed to isoflavones present in soybeans. Considering cellular senescence contributes to cognitive decline and that no specific soy-derived peptides are known for their potential to mitigate senescence, we examined the efficacy of a thirteen amino acid soy-derived peptide, Soymetide, on a doxorubicin-induced senescence mice model. Soymetide pretreatment lowered the senescence markers p53, p21 and p16, pro-inflammatory cytokines, and Senescence β-Galactosidase staining while enhancing the mature neuronal marker NeuN in the hippocampus. This anti-senescent effect was comparable with that of a well-known senolytic combination (dasatinib and quercetin). Research indicates that Wnt signaling influences cellular senescence, and our findings here demonstrate that doxorubicin decreased hippocampal Wnt3a, p-LRP6, Frizzled, Dishevelled, Axin1, and β-catenin levels and increased GSK-3β, while Soymetide mitigated these effects. Additionally, upon inhibition of the Wnt/β-catenin pathway, Soymetide's ability to reduce senescence markers and restore NeuN expression was reduced. We validated the anti-senescence impact on hippocampal neurons by co-immunostaining Wnt/β-catenin and senescence indicators alongside NeuN in mice and assessed it in primary hippocampal neurons. Further examining the neuronal survival and functions revealed that Soymetide blocked the doxorubicin-induced loss in Nissl-stained surviving neurons and learning-memory performances, measured by Y-Maze and Passive Avoidance tests, which Wnt/β-catenin inhibitors could counteract. In conclusion, our study identifies a novel Wnt/β-catenin-linked mechanism of doxorubicin-induced senescence in the hippocampal neurons and demonstrates Soymetide's effectiveness in reversing this process. Hence, this suggests Soymetide's potential therapeutic application in addressing cognitive decline associated with cellular aging. Show less

Alzheimer's disease (AD) represents a significant global health challenge due to its complex pathophysiology and limited therapeutic options. Traditional drug discovery methods have had limited success, highlighting the need for innovative strategies. This systematic review evaluates the role of molecular docking, virtual screening, and molecular dynamics simulations in the early stages of AD drug discovery. This study reviewed 100 studies published between 2000 and 2024, focusing on computational approaches to identify and optimize drug candidates targeting key AD-related proteins, including acetylcholinesterase (AChE), β-secretase (BACE1), and tau. Both natural and synthetic compounds were examined, emphasizing studies integrating in silico methods with in vitro and in vivo validations. AChE was the most frequently targeted protein (23 studies), followed by BACE1 and multi-target approaches. The compounds investigated varied, with 35 studies focusing on natural products (e.g., quercetin, huperzine A) and 54 on synthetic analogs (e.g., tacrine derivatives). Integrating computational and experimental methods enhanced the validation process, providing comprehensive insights into the pharmacodynamics and pharmacokinetics of potential therapeutics. Computational approaches significantly expedite the identification and optimization of AD drug candidates by enabling the rapid screening of extensive compound libraries. These methods, when combined with experimental validations, offer deeper molecular-level insights into drug interactions and mechanisms. However, challenges such as predictive accuracy and data quality remain, necessitating further advancements in computational models and data integration to improve the predictability and effectiveness of AD therapeutics. Show less

Histone deacetylases (HDACs) play a critical role in chromatin remodelling and modulating the activity of various histone proteins. Aberrant HDAC functions has been related to the progression of breast cancer (BC), making HDAC inhibitors (HDACi) promising small-molecule therapeutics for its treatment. Hydroxamic acid (HA) is a significant pharmacophore due to its strong metal-chelating ability, HDAC inhibition properties, MMP inhibition abilities, and more. They were found to increase the efficacy of the approved drugs when used in combination. In this review we presented bioinformatic analysis using available data from the Cancer Genome Atlas and Genotype-Tissue Expression databases, outlined the recent advancements in the application of HA-based HDACi for BC during preclinical investigation and clinical trials, tried to offer the rationale for targeting HDAC in BC with HA-based HDACi, summarised the challenges faced in the successful clinical application of HDACi, and proposed potential strategies to address these challenges, aiming to enhance treatment outcomes in BC. Abbreviations: ABCG2, ATP-binding cassette super-family G member 2; ABC, ATP-binding cassette; ADP, Adenosine diphosphate; APC, Antigen presenting cell; AML, Acute myeloid leukemia; ARH1, Aplysia ras homolog 1; BCRP, Breast cancer resistance protein; BRCA, Breast invasive carcinoma; Bax, B-cell lymphoma associated X; CK5, Cytokeratin 5; CK14, Cytokeratin 14; CK17, Cytokeratin 17; CoRESTMiDAC, Co-repressor for element-1-silencing transcription factor; CRM1, Chromosomal maintenance 1; CTCL, Cutaneous T-cell lymphoma; DNMT, DNA methyltransferase; DFS, Disease-free survival; ER, Oestrogen receptor; EMT, Epithelial-mesenchymal transition; FGFR1, Fibroblast growth factor receptor 1; GEPIA, Gene Expression Profiling Interactive Analysis; GTEx, Genotype tissue expression; HAT, Histone acetylase; HDAC, Histone deacetylase; HDF, Human dermal fibroblast; HER2, Human epidermal growth factor receptor 2; HDLP, Histone deacetylase-like protein; Hsp90, Heat shock protein 90; HSF1, Heat shock factor 1; HeLa, Henrietta Lacks; HER1, Human epidermal growth factor receptor 1; IARC, International Agency for Research on Cancer; IL-10, Interleukin-10; KAP1, KRAB associated protein 1; MDM2, Mouse double minute 2 homolog; MDR, Multidrug resistance; MCF-7, Michigan cancer foundation-7; MEF-2, Myocyte enhancer factor-2MMP- Matrix metalloproteinase; NAD, Nicotinamide adenine dinucleotide; NuRD, Nucleosome remodelling and deacetylation; NF- κ B, Nuclear factor kappa light chain enhancer of activated B cell; NES, Nuclear export signal; NLS, Nuclear localization signal; NCoR, Nuclear receptor corepressor; NCT, National clinical trial; OS, Overall survival; PR, Progesterone receptor; PI3K, Phosphoinositide 3-kinase; PAX3, Paired box gene 3; P-gp, P-glycoprotein; ROS, Reactive oxygen species; SIRT, Sirtuin; SMRT, Silencing mediator for retinoid and thyroid receptor; STAT3, Signal transducer and activator of transcription-3; SAR, Structure-activity relationship; SHP1, Src homology region 2 domain-containing phosphatase 1; SAHA, Suberoylanilide hydroxamic acid; SMEDDS, Self micro emulsifying drug delivery system; TNBC, Triple-negative breast cancer; TSA, Trichostatin A; ZBG, Zinc binding group. Show less

The GramAdapt Social Contact Dataset is a curated dataset of 34 language pairs with qualitative and quantifiable data on social interaction and aspects of societal multilingualism. The language pairs were sampled globally to represent the world's linguistic diversity. The dataset can be used to interrogate the social dimensions of language contact independently or in conjunction with appropriate linguistic data. The data were collected by distributing a questionnaire to experts who have experience with either one or both of the language communities of a pair. The data represent subjective expert assessments based on choices from predetermined answers which can be quantified. Authors 1, 2 and 3 manually checked the response to identify possible misjudgments or misunderstandings. This results in a dataset containing 13,493 data points. This dataset is a first of its kind in the field of linguistics, built upon wide findings from sociolinguistics, historical linguistics, psycholinguistics, and linguistic anthropology. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD), the hepatic manifestation of obesity and type 2 diabetes, can progress to metabolic dysfunction-associated steatohepatitis and fibrosis. MASLD is characterized by elevated hepatic lipid accumulation (steatosis) and insulin resistance. The ketogenic diet (KD), a high-fat, low-carbohydrate diet, induces hepatic insulin resistance and steatosis in animal models through unknown mechanisms. Herein, we investigated the mechanisms behind KD-induced metabolic dysfunction-associated steatohepatitis and fibrosis at thermoneutrality, identifying upregulated inflammatory and lipogenic pathways, including Il-6, Tnf, Mapk13, Lpl, and Pparg. Given the substantial increase in IL-6 during MASLD progression, we investigated IL-6-gp130 signaling using liver- and adipocyte-specific knockout mice. Liver-specific gp130 deletion failed to prevent KD-induced hepatic steatosis and glucose intolerance. In contrast, adipocyte-specific gp130 deletion significantly reduced KD-induced hepatic steatosis by suppressing lipolysis in white adipose tissue and reducing p-JNK and p-p38 signaling in the liver. In agreement, adipocyte-specific deletion of gp130 protected mice from KD-induced hepatic steatosis in response to recombinant IL-6 treatment. Our studies demonstrate the importance of adipose tissue-liver crosstalk in mediating MASLD progression and identify adipocyte IL-6-gp130 as a potential therapeutic target. Show less

Many traditional treatments include honey owing to its magnificent health beneficiary effects. Recent studies have demonstrated the potent anti-diabetic activity of honey. However, its actual mechanism of action remains elusive. Moreover, being rich in sugar (75%-80%), its role in maintaining glucose homeostasis remains questionable. Although the polyphenol content of honey aids its hypoglycaemic activity, the small quantity of bioactive compounds in honey (0.5%-1.0%) may not be solely responsible for this. In the current study, an attempt was made to understand the role of Indian lychee honey (LyH) in regulating blood glucose levels under diabetic conditions. This study investigated whether LyH, although rich in sugars, can be used as an alternative to regulate glucose and lipid homeostasis under insulin-resistant conditions by regulating the ChREBP/Glut4 signalling pathway. This study was first performed Show less

Angiopoietin-like protein 8 (Angptl8), expressed in the liver and adipocytes, forms a complex with Angptl3 or Angptl4, which regulates lipoprotein lipase and triglyceride metabolism. However, the precise functions of adipocyte Angptl8 remain elusive. Here we report that adipocyte-specific inducible Angptl8-knockout (AT-A8-KO) male mice on normal diet showed minor phenotypic changes, but after a high-fat high fructose (HFHF) diet, exhibited decreased body weight gain and glycemia, elevated rectal temperature and early dark phase energy expenditure compared to the Cre controls. AT-A8-KO mice also displayed improved glucose tolerance, a trend for better insulin sensitivity, improved insulin-stimulated glucose uptake in adipose tissues, and reduced visceral adipose tissue crown-like structures, plasma MCP-1 and leptin levels. The results indicate the importance of adipose Angptl8 in the context of nutri-stress and obesity, as its deletion in mice promotes a metabolically healthy obese phenotype by slightly ameliorating obesity, improving glucose and energy homeostasis, and mitigating inflammation. Show less

ANGPTL8, expressed mainly in the liver and adipose tissue, regulates the activity of lipoprotein lipase (LPL) present in the extracellular space and triglyceride (TG) metabolism through its interaction with ANGPTL3 and ANGPTL4. Whether intracellular ANGPTL8 can also exert effects in tissues where it is expressed is uncertain. ANGPTL8 expression was low in preadipocytes and much increased during differentiation. To better understand the role of intracellular ANGPTL8 in adipocytes and assess whether it may play a role in adipocyte differentiation, we knocked down its expression in normal mouse subcutaneous preadipocytes. ANGPTL8 knockdown reduced adipocyte differentiation, cellular TG accumulation and also isoproterenol-stimulated lipolysis at day 7 of differentiation. RNA-Seq analysis of ANGPTL8 siRNA or control siRNA transfected SC preadipocytes on days 0, 2, 4 and 7 of differentiation showed that ANGPTL8 knockdown impeded the early (day 2) expression of adipogenic and insulin signaling genes, PPARγ, as well as genes related to extracellular matrix and NF-κB signaling. Insulin mediated Akt phosphorylation was reduced at an early stage during adipocyte differentiation. This study based on normal primary cells shows that ANGPTL8 has intracellular actions in addition to effects in the extracellular space, like modulating LPL activity. Preadipocyte ANGPTL8 expression modulates their differentiation possibly via changes in insulin signaling gene expression. Show less

Alzheimer's disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around the globe. Currently, there is no cure or effective treatment. The majority of drug development efforts to date have targeted reduction of amyloid-β peptide (Aβ). Drug development through inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), resulted in promising early clinical studies. However, nearly all small molecule BACE1 inhibitor drugs failed to live up to expectations in later phase clinical trials, due to toxicity and efficacy issues. This commentary aims to provide a brief review of over two decades of BACE1 inhibitor drug development challenges and efforts for treatment of AD and prospects of future BACE1-based drugs. Show less

Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) have revolutionized cancer treatment by enabling the restoration of suppressed T-cell cytotoxic responses. However, resistance to single-agent ICIs limits their clinical utility. Combinatorial strategies enhance their antitumor effects, but may also enhance the risk of immune related adverse effects of ICIs. Prostaglandin (PG) E Show less

We have extracted and characterized Phasa fish (Setipinna phasa) oil for the first time to evaluate the anti-obesity and related anti-inflammatory effects on obese mice. Inbred male albino BALB/c mice were segregated into three categories: control (C), Obese control group (OC), and Phasa fish oil treated group (TX). To establish the potentiality of Setipinna phasa oil for its anti-obesity and anti-inflammatory properties, it was extracted and characterized using GC-MS method. To evaluate the anti-obesity effect, different parameters were considered, such as body weight, lipid composition, obesity, and obesity associated inflammation. The physicochemical characteristics of Phasa fish oil revealed that the oil quality was good because acid value, peroxide value, p-anisidine value, Totox value, refractive index, and saponification value were within the standard value range. The GC-MS study explored the presence of fatty acids beneficial to health such as Hexadec-9-enoic acid; Octadec-11-enoic acid; EPA, DHA, Methyl Linolenate, etc. The application of Setipinna phasa oil on the treated mice group acutely lowered body weight and serum lipid profile compared to the obese group. In connection with this, leptin, FAS, and pro-inflammatory cytokines TNF-α genes expression were downregulated in the treated group compared to the obese group. The Phasa oil treated group had an elevated expression of PPAR-α, adiponectin, LPL gene, and anti-inflammatory markers IL-10 and IL-1Ra compared to the obese group. This study suggests that Phasa fish oil, enriched with essential fatty acid, might be used as an anti-obesity and anti-inflammatory supplement. Show less

The evolutionarily conserved apical Crumbs (CRB) complex, consisting of the core components CRB3a (an isoform of CRB3), PALS1 and PATJ, plays a key role in epithelial cell-cell contact formation and cell polarization. Recently, we observed that deletion of one Pals1 allele in mice results in functional haploinsufficiency characterized by renal cysts. Here, to address the role of PALS1 at the cellular level, we generated CRISPR/Cas9-mediated PALS1-knockout MDCKII cell lines. The loss of PALS1 resulted in increased paracellular permeability, indicating an epithelial barrier defect. This defect was associated with a redistribution of several tight junction-associated proteins from bicellular to tricellular contacts. PALS1-dependent localization of tight junction proteins at bicellular junctions required its interaction with PATJ. Importantly, reestablishment of the tight junction belt upon transient F-actin depolymerization or upon Ca2+ removal was strongly delayed in PALS1-deficient cells. Additionally, the cytoskeleton regulator RhoA was redistributed from junctions into the cytosol under PALS1 knockout. Together, our data uncover a critical role of PALS1 in the coupling of tight junction proteins to the F-actin cytoskeleton, which ensures their correct distribution along bicellular junctions and the formation of tight epithelial barrier. Show less

Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34-the regulator of endosome identity and sorting-through oxidation of key cysteines, pointing to a redox checkpoint in sorting. Testing MSB in a myotubular myopathy model that is driven by loss of Show less

Mitochondrial dysfunction in astrocytes has been implicated in the development of various neurological disorders. Mitophagy, mitochondrial autophagy, is required for proper mitochondrial function by preventing the accumulation of damaged mitochondria. The importance of mitophagy, specifically in the astrocytes of the optic nerve (ON), has been little studied. We introduce an animal model in which two separate mutations act synergistically to produce severe ON degeneration. The first mutation is in Show less

Clinical triage in coronavirus disease 2019 (COVID-19) places a heavy burden on senior clinicians during a pandemic situation. However, risk stratification based on serum biomarker bioprofiling could be implemented by a larger, nonspecialist workforce. Measures of Complement Activation and inflammation in patientS with CoronAvirus DisEase 2019 (CASCADE) patients ( The LDA models distinctly discriminated between deteriorators, nondeteriorators, and HC, with IL-27, IP-10, MDC, ferritin, C5, and sC5b-9 among the key predictor variables during deterioration. C3a and C5 were elevated in all severity classes vs. HC ( Distinct immunological fingerprints from serum biomarkers exist within different severity classes of COVID-19, and harnessing them using machine learning enabled the development of clinically useful triage and prognostic tools. Complement-mediated lung injury plays a key role in COVID-19 pneumonia, and preliminary results hint at the usefulness of a C5 inhibitor in COVID-19 recovery. Show less

Alzheimer's disease (AD) is a severe neurodegenerative disorder of the brain that manifests as dementia, disorientation, difficulty in speech, and progressive cognitive and behavioral impairment. The emerging therapeutic approach to AD management is the inhibition of β-site APP cleaving enzyme-1 (BACE1), known to be one of the two aspartyl proteases that cleave β-amyloid precursor protein (APP). Studies confirmed the association of high BACE1 activity with the proficiency in the formation of β-amyloid-containing neurotic plaques, the characteristics of AD. Only a few FDA-approved BACE1 inhibitors are available in the market, but their adverse off-target effects limit their usage. In this paper, we have used both ligand-based and target-based approaches for drug design. The QSAR study entails creating a multivariate GA-MLR (Genetic Algorithm-Multilinear Regression) model using 552 molecules with acceptable statistical performance ( Show less

To compare the level of pro and anti-inflammatory cytokines, and angiogenic mediators between Rheumatoid arthritis (RA) patients with and without subclinical synovitis (SS) in remission state, to find the correlation of these mediators with Greyscale synovitis (GSS) and power Doppler (PD) scores, and to find the probable predictor/s of SS. 52 RA patients in remission state were recruited and subdivided into with and without SS group by Ultrasonography (USG) of 14 joints. Total GSS and PD scoring was done. The serum levels of the pro/anti-inflammatory cytokines and angiogenic mediators were compared between groups, and correlation and regression analysis were done with GSS and PD scores. 63.46% patients had USG evidence of SS. Patients with SS had significantly higher levels of pro-inflammatory and angiogenic mediators [matrix-metalloproteinase -3 (p = 0.0001), Tumour necrosis factor-α (p = 0.0001), Interleukin (IL)-6 (p = 0.001), IL-1b (p = 0.0001), IL-17 (p = 0.0005), IL-33 (p = 0.0003), Tie-2 (p = 0.0001), vascular endothelial growth factor (VEGF (p = 0.03)], and lower anti-inflammatory cytokines [IL-27 (p = 0.0003), IL-10(p = 0.0001)]. A strong positive correlation of GSS score was noted with IL-17(r = 0.7), IL-6 (r = 0.7), IL-1b (r = 0.7), and IL-33 (r = 0.6). Multiple linear regression model identified IL-17 and IL-6 as predictors of GSS score, and TNF-α and VEGF as predictors of PD score. IL-17 level > 249 picogram/millilitre (pg/ml) could predict the SS with high specificity (89.5%). Patients with SS in the remission state of RA showed altered expression of some of the pro/anti-inflammatory/angiogenic markers compared to those not having SS. IL-17, IL-6, VEGF, and TNF-α could be the predictors of USG synovial scores. Show less

Selective degradation of protein aggregates by macroautophagy/autophagy is an essential homeostatic process of safeguarding cells from the effects of proteotoxicity. Among the ubiquitin-like proteins, NEDD8 conjugation to misfolded proteins is prominent in stress-induced protein aggregates, albeit the function of neddylation in autophagy is unclear. Here, we report that polyneddylation functions as a post-translational modification for autophagic degradation of proteotoxic-stress induced protein aggregates. We also show that HYPK functions as an autophagy receptor in the polyneddylation-dependent aggrephagy. The scaffolding function of HYPK is facilitated by its C-terminal ubiquitin-associated domain and N-terminal tyrosine-type LC3-interacting region which bind to NEDD8 and LC3 respectively. Both NEDD8 and HYPK are positive modulators of basal and proteotoxicity-induced autophagy, leading to protection of cells from protein aggregates, such as aggregates of mutant HTT exon 1. Thus, we propose an indispensable and additive role of neddylation and HYPK in clearance of protein aggregates by autophagy, resulting in cytoprotective effect during proteotoxic stress. Show less

Combinatorial gut hormone therapy is one of the more promising strategies for identifying improved treatments for metabolic disease. Many approaches combine the established benefits of glucagon-like peptide-1 (GLP-1) agonism with one or more additional molecules with the aim of improving metabolic outcomes. Recent attention has been drawn to the glucose-dependent insulinotropic polypeptide (GIP) system due to compelling pre-clinical evidence describing the metabolic benefits of antagonising the GIP receptor (GIPR). We rationalised that benefit might be accrued from combining GIPR antagonism with GLP-1 agonism. Two GIPR peptide antagonists, GIPA-1 (mouse GIP(3-30)NH2) and GIPA-2 (NαAc-K10[γEγE-C16]-Arg18-hGIP(5-42)), were pharmacologically characterised and both exhibited potent antagonist properties. Acute in vivo administration of GIPA-1 during an oral glucose tolerance test (OGTT) had negligible effects on glucose tolerance and insulin in lean mice. In contrast, GIPA-2 impaired glucose tolerance and attenuated circulating insulin levels. A mouse model of diet-induced obesity (DIO) was used to investigate the potential metabolic benefits of chronic dosing of each antagonist, alone or in combination with liraglutide. Chronic administration studies showed expected effects of liraglutide, lowering food intake, body weight, fasting blood glucose and plasma insulin concentrations while improving glucose sensitivity, whereas delivery of either GIPR antagonist alone had negligible effects on these parameters. Interestingly, chronic dual therapy augmented insulin sensitizing effects and lowered plasma triglycerides and free-fatty acids, with more notable effects observed with GIPA-1 compared to GIPA-2. Thus, the co-administration of both a GIPR antagonist with a GLP1 agonist uncovers interesting beneficial effects on measures of insulin sensitivity, circulating lipids and certain adipose stores that seem influenced by the degree or nature of GIP receptor antagonism. Show less