The central amygdala corticotropin releasing factor system regulates anxiety-like behavior in an age- and sex- dependent manner in rats.

A mitochondria-targeted nanoantioxidant restores alveolar bone homeostasis in periodontitis by quenching ROS and suppressing the cGAS-STING pathway.

Group 3 innate lymphoid cells (ILC3s) play an essential role in maintaining intestinal barrier immunity. Dysfunction of ILC3s contributes to the pathogenesis of inflammatory bowel disease (IBD), whereas the mechanisms underlying ILC3 regulation remain incompletely understood. Here, we report that the transcription factor BTB domain and CNC homolog 2 (BACH2) represents an important regulator of intestinal ILC3s. ILC3s from IBD patients exhibited reduced BACH2 expression compared with those from healthy donors. Conditional ablation of BACH2 in ILC3s impaired their function, thereby exacerbating the severity of murine colitis. Mechanistically, BACH2 enhanced mitochondrial oxidative phosphorylation in ILC3s in a peroxisome proliferator-activated receptor γ (PPARγ)-dependent manner. PPARγ was identified as a direct transcriptional target of BACH2 in ILC3s. Notably, pharmacological activation of PPARγ with rosiglitazone restored ILC3 function and ameliorated colitis in BACH2-deficient mice. These observations demonstrate that the presence of BACH2-PPARγ signaling in ILC3s protects against colitis.

A Se-content-controlled selenylation strategy unravels the function of Se in the enhanced anti-tumor activity of polysaccharides.

Frankincense improves motor symptoms and attenuates the progression of Paraquat (PQ)-induced Parkinson's disease in mice by attenuating oxidative stress, inflammation, and apoptotic cell death and improving nerve growth factor gene expression.

1,2,3,6-Tetragalloylglucose inhibits hnRNPA2B1/TRAIL Axis to attenuate apoptosis and barrier dysfunction in intestinal epithelial cells: A potential therapeutic avenue for IBD.

Zn2+-dependent modulation of the mitochondrial Ca2+ uniporter underlies resveratrol-mediated protection against myocardial ischemia-reperfusion injury.

The metabolic regulation in embryos is distinct from that in somatic cells. Early mammalian embryos obtain nutrients from the maternal environment to fulfill the energy requirements of growth and development, and lactate is one of the major substrates of embryonic energy metabolism. To interrogate metabolic regulation during early embryogenesis, we transiently inhibited maternally supplied Lactate dehydrogenase B (LDHB) in early embryos, and found that inhibition led to developmental arrest during the 4- to 8-cell transition, reduced ATP levels, impaired mitochondrial readouts and a decreased NAD+/NADH ratio. Aspartate supplementation rescued developmental progression and restored the NAD+/NADH balance in a malate-aspartate shuttle (MAS)-dependent manner. Together, these data suggest that maternal LDHB is important during the 4- to 8-cell transition to maintain LDH-linked redox homeostasis, and that MAS activity contributes to redox restoration during the rescue. Our study highlights a link between metabolic flexibility, redox homeostasis, and developmental competence during mammalian preimplantation development.

Parkinson's disease is a progressive and severe neurodegenerative disease with loss of dopaminergic neurons of substantia nigra. Sigma-1 receptor activation by ligand/agonist has shown neuroprotective effect in various diseases including Parkinson's disease. Present study aimed to investigate the neuroprotective potential of 1,3-di-o-tolylguanidine, a Sigma-1 receptor agonist in rat model of Parkinson's disease. Male Wistar rats underwent intraperitoneal administration of rotenone with simultaneous treatment of 1,3-di-o-tolylguanidine for 28 days. After 28 days, behavioural tests were conducted for assessing motor symptoms. Sigma 1 receptor, dopamine, alpha synuclein, IL-6, glutamate levels were measured in brain homogenate. Histopathological studies were performed for assessing neurodegeneration. Rotenone treated disease control group showed significant bradykinesia, impaired grip strength and motor incoordination compared to normal control group. Further, brain sigma 1 receptor, dopamine, alpha synuclein, IL-6, glutamate levels as well as histological features were significantly compromised. Treatment with 1,3-di-o-tolylguanidine significantly improved behavioural parameters, biochemical parameters and histological features in dose dependent manner. These findings suggest that 1,3-di-o-tolylguanidine has neuroprotective effects in rotenone-induced model of Parkinson's disease in rats.

ISG15 negatively regulates RIPK3-mediated cell death and viral pathogenesis.

Dose-dependent neurotoxic effects of anastrozole via disrupting NLRP3 inflammasome and α-synuclein pathways.

Leukocyte trafficking is a critical step in the development of chronic intestinal diseases such as Crohn's disease. While strategies that block gut homing have yielded partial success, this disease remains uncurable leaving an unmet clinical need. This is the first paper to describe a role for cannabinoid receptor 2 (CB2R) signaling in promoting retinoic acid-mediated induction of the gut homing associated integrin heterodimer α4β7. Using in vitro and in vivo models, we characterized the effects of pharmacological CB2R agonists and inverse agonists on T cell homing receptor expression and transmigration across gut-associated endothelial barriers. This extracellular signal-regulated kinase-dependent process coincides with increased T cell adherence in response to CB2R agonism with JWH-133. These effects were reversed with an inverse agonist GP-1a in a CB2R dependent manner. Selective deletion of CB2R using CRISPR in vitro or CD4Cre/+ floxed mice in vivo resulted in impaired endothelial cell adherence and decreased diapedesis into the ileal lamina propria. T cell-specific deletion of CNR2, the gene encoding CB2R, attenuated chronic murine ileitis characterized by decreased naïveT cell infiltration and loss of tissue architecture in 20-week-old TNFΔARE/+ mice. This study supports further therapeutic development of CB2R-targeting drugs for the treatment of inflammatory bowel disease.

SENP3 promotes PDPK1 deSUMOylation to inhibit the PI3K-Akt signaling pathway and induce apoptosis in intestinal ischemia/reperfusion.

Prolyl hydroxylase domain enzyme 1 (PHD1) is a key regulator of hypoxic adaptation and metabolic homeostasis, playing an important role in tissue damage and repair. To enable precise pharmacological interrogation of PHD1 function, we developed the first PHD1 degrader using proteolysis-targeting chimera (PROTAC) technology. Our lead compound, SH-26, a cereblon (CRBN)-recruiting PROTAC, induced PHD1 degradation in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner across multiple cell lines. In an acetaminophen (APAP)-induced acute liver injury (ALI) model, SH-26 demonstrated protective effects, attenuating hepatic inflammation and necrosis without detectable cytotoxicity. Mechanistically, SH-26-mediated PHD1 degradation attenuated APAP-triggered reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and NLRP3 inflammasome activation, leading to robust in vivo protection against ALI. Collectively, our work identifies SH-26 as the first effective PHD1 degrader and demonstrates its utility as a chemical tool to dissect the pathological role of PHD1 in ALI.

Objective:Pulse pressure (PP) calculated as systolic minus diastolic blood pressure is a surrogate measure of arterial stiffness that may affect executive function; however, this relationship could be moderated by age and genetic risk for Alzheimer’s disease (AD). We therefore examined relationships among PP, age, AD risk (i.e., APOE genotype) and executive function measured by the NIH Toolbox Cognition Battery (NIHTB-CB) in older adults.Method:PP was determined in 216 older adults without dementia (mean age: 77.5 ± 7.9 years, education: 16.8 ± 2.4 years, 55% women, 34.8% APOE ɛ4+) who were tested with the NIHTB-CB as part of the Advancing Reliable Measurement of Alzheimer’s Disease and Cognitive Aging (ARMADA) study.Results:Multiple linear regression revealed PP X Age X APOE genotype interaction effects for List Sorting Working Memory (β=.04; p=.007) and Picture Sequence Memory (β=.04; p=.006); higher PP was associated with worse scores in younger APOE ɛ4+ older adults (same pattern for fluid and total cognition composite scores). Higher PP was associated with lower Picture Vocabulary scores in ApoE ɛ4+ (PP X APOE interaction: β=−.19; p=.022). Higher PP was associated with lower Flanker Inhibitory Control scores (β=−.13; p=.005) across all participants.Conclusions:Arterial stiffness measured by PP in older adults is associated with worse performance on NIHTB-CB tests of executive function, working memory, and episodic sequence memory, particularly in younger APOE ɛ4 carriers. Arterial stiffness and AD risk may work synergistically in an age dependent manner to adversely affect cognition.

Photoaffinity labeling (PAL) utilizes photoreactive molecules to derivatize proteins in a solvent-accessible dependent manner. The site and frequency of the products of this reaction can be used to garner insights into the conformation of the protein. In this work, we document and characterize a novel oxidation process instigated by UV irradiation of aromatic diazirines. Diazirine is an increasingly utilized reagent for probing protein conformations, and this product has yet to be documented. We initially assess the selectivity of the chemical reaction and find that it is highly selective to methionine (Met) and tryptophan (Trp) residues. We next examine whether this oxidative labeling can be utilized to evaluate protein conformation. We assess native and urea-denatured ubiquitin and cytochrome c, holo- and apo-myoglobin, and native and copper-bound β-2-microglobulin. In all surveyed protein systems but ubiquitin, this diazirine-promoted oxidation readily differentiates between the two protein conformations.

Although immune checkpoint blockade therapy has generated dramatic responses in certain cancer types, breast tumors are largely unresponsive. Epithelial-mesenchymal plasticity leads to the assembly of an immunosuppressive tumor microenvironment and drives resistance of breast tumors to immunotherapies. Importantly, targeting CD73 completely sensitizes quasi-mesenchymal breast tumors to anti-CTLA4 immune checkpoint blockade therapy. However, the mechanism(s) of sensitization remained unknown. We demonstrate that targeting CD73 in quasi-mesenchymal breast tumors sensitizes them to anti-CTLA4 immune checkpoint blockade therapy in a CD4+ T-cell dependent manner. Moreover, epithelial-mesenchymal plasticity results in elevated expression of cancer cell-intrinsic CD73 in human triple negative breast cancers. Given the ability of quasi-mesenchymal cancer cells to metastasize and resist multiple therapies, these findings can instruct the formation of translational strategies for the treatment of human breast cancers. These findings also bring to the forefront the attractive possibility of utilizing the phenotypic plasticity of cancer cells along with CD73 and CD4+ T-cells as a predictive criterion for immunotherapy responsiveness.

In this work, we investigated the safety characteristics and probiotic proprieties of Enterococcus faecium (E. Faecium) strains isolated from raw milk of indigenous Brown Atlas cows reared in the Tafoughalt region (Berkane, Morocco). Eleven isolates were identified as E. faecium by 16S rRNA gene sequencing and subjected to an in-vitro evaluation approach including antibiotic susceptibility, safety related enzymatic activities, tolerance to gastrointestinal stress conditions, antioxidant capacity, and antibacterial activity against selected foodborne pathogens. All isolates were susceptible to clinically relevant antibiotics, such as ampicillin, vancomycin, gentamicin, tetracycline, and chloramphenicol, and none exhibited evidence of acquired or transferable antibiotic resistance. Safety assessment revealed the absence of haemolytic, DNase, and gelatinase activities in all strains. The isolates demonstrated marked tolerance to acidic conditions (pH 2.0-3.0) and bile salt concentrations (0.15%-0.30%), indicating their ability to survive simulated gastrointestinal environments. All strains inhibited the growth of Staphylococcus aureus ATCC 29213 in a strain and concentration dependent manner, while moderate inhibitory activity was observed against Escherichia coli ATCC 25922. Neutralisation and enzymatic treatments indicated that the antibacterial activity was primarily associated with organic acid production and, to a lesser extent, with proteinaceous compounds, suggesting the involvement of bacteriocin like substances. In addition, the isolates exhibited moderate, strain dependent antioxidant activity, ranging from approximately 15% to 27%. Among the evaluated strains, E. faecium EF89 displayed the most favourable combination of safety attributes and probiotic properties. Collectively, these results show that E. faecium strains isolated from Brown Atlas cow milk in Eastern Morocco are safe and promising candidates for use in functional foods and food biopreservation, supporting the valorisation of indigenous dairy resources.

Biochemical and structural analysis of -AtN-Myc down regulated like-1 reveals phosphatidic acid regulated esterase function.

Extracellular 70kDa heat shock protein in blood plasma binds insulin and modulates glycaemic control in vivo.