1,2,4-trimethoxybenzene exerts multi-target effects against ulcerative colitis by inhibiting the NLRP3 inflammasome and remodeling the gut microbiota-metabolism axis.

Pulmonary tuberculosis in humans is characterised by features of immunopathology, which influence both antimycobacterial therapy and the long-term prognosis. In the blood of tuberculosis patients, immunopathology manifests itself in reduced immune responses to mitogenic substances. Previous studies have demonstrated the influence of tuberculosis serum on T-cell and monocyte function, but the exact mechanisms remain unclear. Here, we performed a case/control study to analyse the influence of tuberculosis serum milieu changes on (i) T-cell stimulation (using Staphylococcal Enterotoxin B), (ii) monocyte stimulation (using the Toll-like receptor agonist Pam3CSK4), (iii) T-cell/monocyte interaction characterised by the response against the lectin phytohemagglutinin, by using a novel peripheral blood mononuclear cell invitro assay. Cell-specific activation marker and cytokine expression were determined by multicolor flow cytometry. Staphylococcal Enterotoxin B mainly induced cytokine expression by T cells, while Pam3CSK4 stimulated monocytes to secrete distinct cytokine signatures. Phytohemagglutinin induced activation and cytokine expression in both T cells and monocytes. Notably, tuberculosis patient serum samples affected exclusively phytohemagglutinin stimulated T-cell responses and particularly activation marker as well as CD40L/IL-2 positive CD4+ T-cell subsets were decreased as compared to serum from healthy contacts. Neither Staphylococcal Enterotoxin B-mediated T-cell stimulation nor phytohemagglutinin or Pam3CSK4 induced monocyte cytokines (i.e., Interleukin-6, Interleukin-8, Tumour Necrosis Factor-α) were affected by the tuberculosis patients' serum samples. These results highlight the immunosuppressive influence of the tuberculosis serum milieu, which specifically reduced T-cell responses to phytohemagglutinin, probably through impaired function of the accessory monocytes required for stimulation.

Neuroinflammation, driven by microglia activation and the production of pro-inflammatory cytokines, has been implicated in several neurological diseases and neuropathic pain. MicroRNAs (miRNAs) have emerged as important regulators of neuroinflammatory processes. Prior studies identified elevated levels of circulating miR-19a and miR-19b in individuals living with chronic pain following spinal cord injury (SCI). In this study, we wanted to determine whether miR-19a and miR-19b have a direct effect on microglia activation, specifically pro-inflammatory activation, associated with neuroinflammation. Microglia were activated by inflammatory stimuli in the presence of miR-19a or miR-19b mimics, and assessed for the expression of cytokines, chemokines, and effector molecules. The results show that miR-19a or miR-19b mimics increased the expression of pro-inflammatory cytokines, chemokines, and effector molecules in microglia. The results also showed decreased expression of suppressor of cytokine signaling (SOCS) proteins, namely SOCS1 and SOCS3, in activated microglia with miR-19a and miR-19b mimics. Additionally, enhanced signaling through the NFκB and Jak pathways was observed with increased NFkB-p65 and JAK1 phosphorylation in the presence of miR-19a and miR-19b mimics. Further results show that miR-19a and miR-19b inhibitors reversed these effects on activated microglia. Overall, our results demonstrate that miR-19a or miR-19b increased the expression of pro-inflammatory cytokines, chemokines, and effector molecules in activated microglia. These results indicate that miR-19a and miR-19b can enhance microglia activation and associated inflammatory responses, which may have implications for conditions associated with neuroinflammation.

Clonal hematopoiesis driven by somatic mutations is an emerging cardiovascular risk factor, and the DNA damage response gene PPM1D is among the most frequently mutated genes. Mutations in PPM1D are enriched in cancer patients and survivors, where cytotoxic therapies promote the expansion of mutant clones, a condition termed therapy-related clonal hematopoiesis. Although PPM1D-mutant clonal hematopoiesis has been associated with increased risk and poorer prognosis of atherosclerotic cardiovascular disease in humans, it remains unclear whether these mutations, or their expansion under cytotoxic stress, causally contribute to atherosclerosis. We modeled PPM1D-mutant clonal hematopoiesis in Ldlr-/- mice through bone marrow transplantation strategies. Conventional transplantation approaches were used to generate mice with complete or partial hematopoietic reconstitution by cells carrying monoallelic or biallelic gain-of-function Ppm1dR451X mutations. To mimic therapy-related clonal hematopoiesis, we used a nonconditioned adoptive transfer model in which a small fraction of mutant hematopoietic cells was introduced into recipients, followed by fractionated low-dose γ-radiation to promote clonal expansion. All mice were fed a Western diet to induce atherosclerosis. Clonal dynamics, plaque size and characteristics, and macrophage functions were evaluated using flow cytometry, histopathology, and in vitro assays. Ppm1d-mutant cells expanded in blood and bone marrow after low-dose radiation, but not in nonirradiated mice. Across all transplantation strategies, Ppm1d mutations did not affect plasma cholesterol, atherosclerotic plaque size, or composition. In vitro, mutant macrophages showed no alterations in proliferation, cytokine expression, or cholesterol handling, although apoptosis in response to genotoxic stress was modestly reduced (≈20%). Ppm1d-mutant hematopoietic cells expand predominantly under genotoxic stress and do not promote atherosclerosis in mice under the conditions tested. These findings raise the possibility that the association of PPM1D mutations with atherosclerotic cardiovascular disease may, at least in part, reflect exposure to DNA damage response-activating stressors that independently promote clonal expansion and atherosclerosis, rather than direct causality.

Zerumbone from Zingiber zerumbet (L.) Roscoe ex Sm. ameliorates atopic dermatitis by regulating the MAP kinase/NF-κB, Akt, and STAT pathways.

Impact of spray-dried Lactiplantibacillus plantarum CIDCA 83114 on a murine model of giardiasis.

Hydrogen nanobubble water reduces cochlear inflammation and oxidative stress in noise-induced hearing loss via the gut-inner ear axis.

Acetaminophen (APAP) overdose is a leading cause of acute liver injury and is associated with high mortality. G protein-coupled receptor kinase 2 (GRK2) is a widely expressed serine/threonine kinase involved in the regulation of multiple cellular signaling pathways. Dysregulation of GRK2 expression has been linked to numerous pathological states, highlighting its potential contribution to disease mechanisms. However, its involvement in drug-induced acute liver injury is yet to be elucidated. This study explored the hepatoprotective effects of paroxetine, a GRK2 inhibitor, in the context of APAP-induced liver injury. Male C57BL/6 mice received an intraperitoneal injection of APAP (300 mg/kg), followed by oral administration of paroxetine (10 mg/kg) 30 min afterward. Paroxetine markedly decreased serum alanine aminotransferase and aspartate aminotransferase concentrations and reduced APAP-induced hepatocellular apoptosis and inflammation. Paroxetine also diminished hepatic neutrophil accumulation and decreased the expression of pro-inflammatory cytokines and chemokines. Furthermore, GRK2 inhibition alleviated oxidative stress, as evidenced by lower hepatic malondialdehyde concentrations and a partially restored glutathione (GSH)/GSH disulfide ratio. Importantly, inhibition of GRK2 resulted in a decrease in hepatic phosphorylation of extracellular signal-regulated kinase (ERK). Collectively, these results indicate that pharmacological inhibition of GRK2 by paroxetine confers protection against APAP-induced hepatotoxicity through anti-inflammatory and antioxidant actions, potentially mediated by modulation of ERK signaling.

Carcinogenesis is a dynamic, multistep process in which the initiation stage represents a critical and irreversible event that determines cellular fate. Although genetic alterations play a central role in tumor development, dysregulation of intracellular organelles such as the endoplasmic reticulum (ER) has emerged as an important contributor to cancer initiation. In the present study, we aimed to evaluate how modulation of ER stress affects the initiation phase of hepatocarcinogenesis. The initiation-stage hepatocarcinogenic model was developed by administering a single dose of N-nitrosodiethylamine (NDEA) (50 mg/kg b.w, i.p.) to male Wistar rats. To modulate ER activity, the endogenous chaperone inducer 1-(3,4-dihydroxyphenyl)-2-thiocyanatoethanone (BIX) was administered intraperitoneally (0.1 mg/kg body weight) for 2 weeks prior to NDEA treatment. The effect of ER modulation on pro-tumorigenic events was assessed in terms of oxidative DNA damage, expression of inflammatory cytokines, p53, and cellular proliferation. Modulation of UPR by BIX was evaluated based on expression levels of PERK, ATF6, CHOP, and p-PERK/PERK ratio. BIX treatment demonstrated marked attenuation of pro-tumorigenic events as evidenced by significantly decreased levels of 8-OHdG, TNF-α, IL-6, PCNA, and p53, which were upregulated in the NDEA-treated group. Histopathological analysis further confirmed the preservation of hepatic architecture in the BIX-treated group as compared with the NDEA group. In addition, significantly decreased expression of UPR markers in the BIX-treated group, as compared to the NDEA group, confirmed inhibition of UPR activation. Collectively, these findings demonstrated that BIX-mediated ER-stress modulation effectively inhibited the initiation of NDEA-induced hepatocarcinogenesis.

Despite the preweaning period being critical for immune system development, heat abatement for calves in summer is often overlooked during this early-life period. Herein, we evaluated selected markers of innate and adaptive immunity development in outdoor hutch-housed Holstein dairy heifers with 2 types of ventilation during a Midwestern summer. Heifer calves were housed in outdoor hutches with passive (PASS; 0.07 m/s natural air speed, n = 16) or active ventilation (ACT; 1.1 m/s air speed via solar-powered fans, n = 16) from birth to 28 d of life. At d 28, fans were turned off, and all heifers were naturally ventilated. Heifers were weaned at 49 d and monitored until 56 d of age. Blood samples were collected at various stages of the preweaning period (d 1-56) to assess IgG, glucose, blood hematology, gene expression, and functional assays. At birth, circulating IgG, glucose, and hematology parameters were not different between groups. Relative to heifers exposed to PASS, ACT heifers had reduced white blood cell, monocyte, neutrophil, and lymphocyte counts, particularly the first 28 d. The ACT heifers had a greater percentage of neutrophils with phagocytic activity on d 28 and 42 of life, and tended to have neutrophils with greater percentage of oxidative burst on d 42. The mRNA expression of haptoglobin, IL-6, IL-8, IFN-γ, and NFKβ1 was downregulated in peripheral blood leukocytes of PASS heifers, relative to ACT. Providing active ventilation to heifers during the first 4 wk of life in summer enhances neutrophil phagocytic capacity, reduces circulating neutrophil and lymphocyte counts, and downregulates the expression of key pro-inflammatory cytokine and interleukin genes in peripheral leukocytes.

Sphingosine-1-phosphate drives astrocyte pyroptosis via activation of NLRC4 inflammasome in autism spectrum disorder.

Dissection of crucial components of Chinese medicinal formula for COPD treatment by combining cell-based assays, animal studies, and lung organoid platforms.

Teleost bone morphogenetic protein 2 (BMP2): Dynamic responses to infection and negative feedback regulation of inflammatory cytokines in gills of flounder (Paralichthys olivaceus).

Co-infection with Anatid herpesvirus-1 and Newcastle disease virus in chicken embryonic fibroblast cells drives differential cytokine expression and viral interplay.

Gentamicin (GET) is a commonly prescribed aminoglycoside antibiotic used to treat severe bacterial infections, but its therapeutic effectiveness is limited by its cardiotoxicity, which is mainly caused by oxidative damage and inflammation. This study investigated the cardioprotective role of vincamine (VIN) against GET-induced cardiac injury. Adult male rats were divided into four groups and treated for 7 days with either CMC (control), VIN, GET, or a combination of GET and VIN. Measurements included oxidative stress markers (TAC and MDA), gene expression of inflammatory cytokines and apoptosis markers (TNF-α, IL-6, Bax, Bcl-2) by qRT-PCR, protein levels of signaling molecules (Nrf2/HO-1, WNT-4, pGSK-3β, β-catenin, pERK, Klotho) by qRT-PCR and ELISA, and NF-κB protein quantification via Western blot. Cardiac tissue was also examined histologically for structural changes. Results demonstrated that VIN significantly reduced GET-induced cardiac damage by modulating crucial signaling pathways and markedly diminished the tissue structural alterations caused by GET. These findings suggest that VIN may serve as a promising cardioprotective agent against GET-induced toxicity through the regulation of pathways including Nrf2/HO-1, pERK/NF-κB, WNT-4/pGSK-3β/β-catenin, and Bax/Bcl-2.

Chronic exposure to environmentally relevant Bisphenol F induces hepatic injury and inflammation in Zebrafish.

Spatiotemporal 4D-printed shape-memory scaffold with a triple-acting liposomal strategy for the treatment of infectious bone defects.

Determination of urinary and serum myeloperoxidase and interleukin-6, -8 -10 in dogs with subclinical bacteriuria and urinary tract infections.

Early life stress, caused by maternal separation (MS), increases hippocampal inflammatory markers in neonates. However, the effects of MS on hypothalamic neuroimmune development and the peripheral immune response have not yet been assessed. This study examined the effect of MS on neuroimmune and synaptic development by evaluating the expression of pro- and anti-inflammatory cytokines and their association with synaptic plasticity markers in the hypothalamus and hippocampus throughout postnatal development. Microglial activation was analyzed in both brain regions at postnatal day 15 (P15), and the systemic immune response was measured through hemolytic capacity. Cytokine and synaptophysin expression showed dynamic, region-specific changes across postnatal development. MS reduced hypothalamic interleukin 6 expression at P6 and P12, enhanced microglial activation at P15, and blunted the developmental increase in hemolytic capacity seen in controls at P21. While control animals exhibited region-specific associations between cytokines and synaptic markers, these relationships were attenuated in the MS group, including a differential interleukin 6-synaptophysin association. These results suggest that MS alters hypothalamic neuroimmune relationships and systemic immune responses during critical developmental windows. Additionally, increased microglial activation at P15 suggests that MS induced proinflammatory, region-specific changes. These alterations may contribute to heightened vulnerability to mental disease later in life.

Enhanced efficacy of methyl ferulate upon pentanoylation in ameliorating psoriasis via Nrf2/NF-κB pathway regulation and HDACs downregulation.