Elevated Tumor Necrosis Factor-alpha Research Articles

Effects of Polyvinyl Chloride (PVC) Microplastic Particles on Gut Microbiota Composition and Health Status in Rabbit Livestock

The widespread use of polyvinyl chloride (PVC) and its entry into humans and livestock is of serious concern. In our study, we investigated the impact of PVC treatments on physiological, pathological, hormonal, and microbiota changes in female rabbits. Trend-like alterations in weight were observed in the spleen, liver, and kidney in both low (P1) and high dose (P2) PVC treatment groups. Histopathological examination revealed exfoliation of the intestinal mucosa in the treated groups compared to the control, and microplastic particles were penetrated and embedded in the spleen. Furthermore, both P1 and P2 showed increased 17-beta-estradiol (E2) hormone levels, indicating early sexual maturation. Moreover, the elevated tumor necrosis factor alpha (TNF-α) levels suggest inflammatory reactions associated with PVC treatment. Genus-level analyses of the gut microbiota in group P2 showed several genera with increased or decreased abundance. In conclusion, significant or trend-like correlations were demonstrated between the PVC content of feed and physiological, pathological, and microbiota parameters. To our knowledge, this is the first study to investigate the broad-spectrum effects of PVC microplastic exposure in rabbits. These results highlight the potential health risks associated with PVC microplastic exposure, warranting further investigations in both animals and humans.

Diacerein ameliorates amiodarone-induced pulmonary fibrosis via targeting the TGFβ1/α-SMA/Smad3 pathway.

This study is aimed at investigating the possible protective effect of diacerein (DIA) against AMD-induced pulmonary fibrosis in rats. Rats were classified into 4 groups: a normal group that received distilled water, control group that received AMD (100 mg/kg, p.o.) for 21 days to induce pulmonary fibrosis, and 2 treatment groups that received diacerein, in 2 dose levels (50 and 100 mg/kg, p.o., respectively) in addition to AMD (100 mg/kg, p.o.), for 21 days. Lung function test was assessed using a spirometer; serum and tissue were collected. Biochemical, real-time PCR, histopathological, and immunohistopathological analyses were carried out. AMD reduced tidal volume (TV), peripheral expiratory rate (PER), forced vital capacity (FVC), serum reduced glutathione (GSH) levels, Beclin, and LCII, while it elevated transform growth factor (TGF-β1) gene expression, serum malondialdehyde (MDA) level, alpha-smooth muscle actin (α-SMA), Smad3, phosphorylated signal transducer and activator of transcription (p-STAT3), and p62 lung content. Also, AMD elevated tumor necrosis factor-alpha (TNF-α) and caspase-3 protein expression. DIA elevated TV, PER, FVC, serum GSH level, Beclin, and LCII, while it reduced TGF-β1 gene expression, serum MDA level, α-SMA, Smad3, p-STAT-3, and p62 lung content. Moreover, DIA reduced TNF-α and caspase-3 protein expression. DIA attenuated AMD-induced pulmonary fibrosis via alleviating the TGF1/α-SMA/Smad3 pathway, reducing STAT-3 activation, and combating oxidative stress and inflammation in addition to promoting autophagy and abrogating apoptosis.

Association Between Elevated Serum Histidine Decarboxylase and Tumor Necrosis Factor-Alpha Levels and High Risk in tic Disorder Children

Background: Children with tic disorder (TD) have been reported to exhibit abnormal levels of certain peripheral proteins, but none of these abnormalities have been established as biomarkers for diagnosis. Objectives: The purpose of this study is to evaluate serum histidine decarboxylase (HDC) and tumor necrosis factor-alpha (TNF-α) levels in children with TD, assess their relationship with TD development, and provide reliable biomarkers for prediction and risk management in clinical settings. Methods: In the present study, serum HDC and TNF-α levels from 118 no-comorbid and medication-naive TD patients and 111 age-matched healthy controls were measured using enzyme-linked immunosorbent assay (ELISA) kits. Tic severity was assessed using the Yale Global Tic Severity Scale (YGTSS). Binary logistic regression analysis was used to evaluate the relationship between serum HDC and TNF-α levels and TD development. Results: An increase in serum HDC and TNF-α levels was observed in TD patients compared with controls. Further analysis revealed a significant association between elevated HDC and TNF-α levels and TD development, with a significant ROC curve for HDC and TNF-α as potential risk factors. Conclusions: This study identified a high prevalence of elevated serum HDC and TNF-α levels in children with TDs and provides evidence that elevated blood HDC and TNF-α may be potential risk factors for TD development.

Targeting dendritic cell-specific TNFR2 improves skin and joint inflammation by inhibiting IL-12/ IFN-γ pathways in a mouse model of psoriatic arthritis.

Psoriasis (PsO) and Psoriatic arthritis (PsA) are immune-mediated inflammatory diseases affecting the skin and joints. Approximately, 30% of patients with PsO develop PsA over time with both conditions being associated with elevated tumor necrosis factor-alpha (TNF-α) expression. TNF-α mediates its effect through two membrane receptors, TNFR1 and TNFR2. While current TNF-α-neutralizing agents, targeting both TNFR1 and TNFR2 receptors, constitute the primary treatment for psoriatic diseases, their long-term use is limited due to an increase in opportunistic infections, tuberculosis reactivation and malignancies likely attributed to TNFR1 inactivation. Recent findings suggest a pivotal role of TNFR2 in psoriatic disease, as evidenced by its amelioration in global TNFR2-knockout (TNFR2KO) mice, but not in TNFR1KO mice. The diminished disease phenotype in TNFR2KO mice is accompanied by a decrease in DC populations. However, the specific contribution of TNFR2 in dendritic cells (DCs) remains unclear. Here, utilizing a mannan-oligosaccharide (MOS)-induced PsA model, we demonstrate a significant reduction in PsA-like skin scaling and joint inflammation in dendritic cell-specific TNFR2 knockout mice (DC-TNFR2KO). Notably, MOS treatment in control mice (TNFR2 fl/fl) led to an increase in conventional type 1 dendritic cells (cDC1) population in the spleen, a response inhibited in DC-TNFR2KO mice. Furthermore, DC-TNFR2KO mice exhibited reduced levels of interleukin-12 (IL-12), a Th1 cell activator, as well as diminished Th1 cells, and interferon-gamma (IFN-γ) levels in the serum compared to controls following MOS stimulation. In summary, our study provides compelling evidence supporting the role of TNFR2 in promoting PsA-like inflammation through cDC1/Th1 activation pathways.

Mechanistic Association of Hepatoblastoma with Cerebral Palsy: A Narrative Review.

Hepatoblastoma is a rare liver cancer that occurs most often in children who present with lower birth weight. Cerebral palsy (CP) is a neurodevelopmental disorder distinguished by irregularities in muscle tone, movement, and motor skills. CP is caused by damage to the developing brain and is often associated with secondary complications such as severe constipation. Clinicians must be aware of sudden worsening constipation occurring in CP children because it can also be a sign of hepatoblastoma. The aim of this review is to summarize the current understanding of the risks for hepatoblastoma development in children with CP. Cancer risks likely include dysfunction of the immune system surveillance in CP children. Elevated C-reactive protein and tumor necrosis factor-alpha levels may be higher in children with CP, which weakens their innate immune system. Metabolic disruption increases the risk of some cancers, and poor nutrition and reduced growth that occur in CP patients may have an impact on cancer development through a loss in immune function. Increased mobility and physical activity can increase the T-cell, natural killer cell, and neutrophil population. Children with CP tend to engage poorly in physical activity, and consequently, their immune system is affected. There are multiple factors associated with CP that increase the risk of childhood cancers such as hepatoblastoma.

Mitochondrial Fragmentation Increases with Aging in Rats

The diaphragm muscle (DIAm) is the major pump muscle for breathing. Neural control of the DIAm involves recruitment of phrenic motor neurons (PhMNs) comprising motor units that vary in their mechanical and fatigue properties. Smaller PhMNs innervating fatigue resistant DIAm fibers are highly active being recruited during breathing, while larger PhMNs are infrequently recruited during more forceful expulsive behaviors. Previously, we found that to support their higher activity levels, smaller PhMNs have higher mitochondrial volume density and are less fragmented compared to larger PhMNs. With aging, larger PhMNs are more vulnerable and ~30% are lost, and those surviving display greater mitochondrial fragmentation. We also found that older rats exhibit elevated levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFa), which in other tissue has been linked to mitochondrial fragmentation via activation of the IRE1a S724-mediated endoplasmic reticulum (ER) stress pathway. Accordingly, we hypothesized that in 24-month-old rats, increased TNFa levels activate the pIRE1aS724-mediated ER stress pathway, leading to XBP1s splicing, which transcriptionally increases expression of cyclin-dependent kinases (CDK1 and CDK5) that mediate phosphorylation of DRP1 at Serine 616 (pDRP1S616), and ultimately mitochondrial fragmentation. We found that serum TNFa levels increased ~3.5 fold in 24-month rats compared to 6-month rats. Consistent with elevated TNFa, we found increased pIRE1aS724 and XBP1s splicing in the cervical ventral horn of 24-month rats. In retrogradely labeled PhMNs, we found XBP1s was localized to the nucleus, consistent with transcriptional activation of gene expression. Bioinformatic analysis and ChIP assay confirmed XBP1s binding to the CDK1 and CDK5 promoter regions in rat cervical ventral horn. Both CDK1 and CDK5 mRNA and protein were elevated in the cervical ventral of 24-month rats. In aged rats, pDRP1S616 phosphorylation increased with a corresponding increase in mitochondrial fragmentation. Our results support our hypothesis that chronic inflammation (elevated TNFa levels) in older rats activate the pIRE1aS724-mediated ER stress pathway, leading to XBP1s splicing, which transcriptionally targets CDK1 and CDK5 expression mediating pDRP1S616 phosphorylation and mitochondrial fragmentation. Research Supported by NIH R01 grant AG44615. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Protective effect of Petroselinum crispum methanolic extract against acrylamide-induced reproductive toxicity in male rats through NF-ĸB, kinesin, steroidogenesis pathways

This study examined the protective effects of a Petroselinum crispum (P. crispum) methanolic extract on reproductive dysfunction induced by acrylamide in male rats. A total of 40 rats were divided into four groups (n=10). The control group received distilled water, the acrylamide group received 10 mg/kg of acrylamide, the P. crispum group received 100 mg/kg of P. crispum extract, and the combined group was pretreated with P. crispum for two weeks before co-administration of P. crispum and acrylamide. All administrations were administered orally using a gastric tube for eight weeks. Acrylamide decreased testosterone levels but did not affect levels of FSH or LH. It also increased testicular levels of (MDA) malondialdehyde and reduced activity of (SOD) superoxide dismutase and impairment of sperm parameters. Furthermore, the administration of acrylamide resulted in an elevation of tumor necrosis factor-alpha (TNF-α) levels and a reduction in the levels of steroidogenic acute regulatory protein (STAR) and cytochrome P450scc (P450scc). Acrylamide negatively affected the histopathological outcomes, Johnsen's score, the diameter of seminiferous tubules, and the thickness of the germinal epithelium. It also upregulated the expression of NF-ĸB P65 and downregulated the expression of kinesin motor protein. In contrast, treatment with P. crispum extract restored the levels of antioxidant enzymes, improved sperm parameters, and normalized the gene expression of TNF-α, IL-10, IL-6, iNOS, NF-ĸB, STAR, CYP17A1, 17β-HSD and P450scc. It also recovered testicular histological parameters and immunoexpression of NF-ĸB P65 and kinesin altered by acrylamide. P. crispum showed protective effects against acrylamide-induced reproductive toxicity by suppressing oxidative damage and inflammatory pathways.

137 Light-mediated Vagus Nerve Stimulation Inhibits Pro-inflammatory Cytokine Production in Acute Endotoxemia

INTRODUCTION: Vagus nerve stimulation (VNS) is a form of neuromodulation being explored to treat chronic inflammatory conditions by activating the inflammatory reflex, an arc reducing proinflammatory cytokine release through efferent cholinergic signaling. Current VNS approaches are primarily invasive and use electricity, but alternatives may improve vagal fiber specificity and eliminate surgical risks. Red-light optogenetics, a biological tool utilizing red light-activatable channelrhodopsins (ReaChR), can selectively activate genetically-modified neurons transdermally with light. Here, we show that ReaChR activation of cholinergic vagal fibers reduces cytokine production in a model of acute inflammation. METHODS: Vagus nerve cholinergic fibers were selectively activated using ReaChR expressed on choline acetyltransferase-expressing (ChAT) fibers in transgenic ChAT-ReaChR mice. Sensory afferent vagal fibers were activated in a separate cohort of transient receptor potential vanilloid subfamily member 1 (TRPV1)-ReaChR mice. Lipopolysaccharide (LPS) was injected intraperitoneally under anesthesia to induce acute endotoxemia, as measured by elevated tumor necrosis factor-alpha (TNFa). A 635nm fiber optic was targeted onto an isolated, cervical vagus for optogenetic VNS post-LPS administration. RESULTS: Selective ReaChR activation of cholinergic fibers in the cervical vagus nerve stimulates the inflammatory reflex to inhibit splenic TNFa production to bacterial LPS (ChAT-ReaChR: 1.27 ± 1.44 pg/ug; control: 4.26 ± 0.97 pg/ug, p < 0.001), but no significant differences were observed in serum (ChAT-ReaChR: 538 ± 216 pg/ml; littermate: 447 ± 206 pg/ml, p = 0.81). In contrast to efferent activation, ReaChR stimulation of afferent subsets (TRPV1+) failed to show cytokine regulation in splenic nor in serum .Approximate 20% baseline heart rate drop was seen during both ChAT+ and TRPV1+ fiber excitation, but only cholinergic activation sustained bradycardia throughout the stimulation period. CONCLUSIONS: Red-light optogenetic activation of cholinergic vagal fibers reduces splenic inflammatory cytokine production in murine endotoxemia and holds potential as a non-invasive, light-mediated VNS approach.

Elevated tumor necrosis factor alpha and vascular endothelial growth factor in intermediate age-related macular degeneration and geographic atrophy.

Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine implicated in pathological changes to the retinal pigment epithelium that are similar to changes in geographic atrophy (GA), an advanced form of age related macular degeneration (AMD). TNF-α also modulates expression of other cytokines including vascular endothelial growth factor (VEGF), leading to choroidal atrophy in models of AMD. The purpose of this study was to investigate systemic TNF-α and VEGF in patients with GA and intermediate AMD (iAMD) compared to controls without AMD. We examined plasma levels of TNF-α and VEGF in patients with GA, iAMD, and controls without AMD from the University of Colorado AMD registry (2014 to 2021). Cases and controls were characterized by multimodal imaging. TNF-α and VEGF were measured via multiplex immunoassay and data were analyzed using a non-parametric rank based linear regression model fit to plasma biomarkers. There were 97 GA, 199 iAMD patients and 139 controls. TNF-α was significantly increased in GA (Median:9.9pg/ml, IQR:7.3-11.8) compared to iAMD (Median:7.4, IQR:5.3-9.1) and in both GA and iAMD compared to controls (Median:6.4, IQR:5.3-7.8), p<0.01 for all comparisons. VEGF was significantly increased in iAMD (Median:8.9, IQR:4.8-14.3) compared to controls (Median:7.7, IQR:4.6-11.1), p<0.01. There was a significant positive correlation between TNF-α and VEGF in GA (0.46, p<0.01), and iAMD (0.20, p=0.01) with no significant interaction between TNF-α and VEGF in any group. These findings suggest TNF-α and VEGF may contribute to systemic inflammatory processes associated with iAMD and GA. TNF-α and VEGF may function as systemic biomarkers for disease development.

Modulation of myocardial injury in polymicrobial sepsis: The dual role of interleukin-13 in cardiac inflammation and stress.

Polymicrobial sepsis is associated with a poor prognosis due to severe type-1 innate inflammation triggered by immune cells, such as dendritic cells and macrophages. This immune response frequently leads to damage in the heart. Although interleukin (IL)-13 is thought to play a protective role in organ inflammation, its function in polymicrobial sepsis remains unclear. We aimed to investigate the role of IL-13 in modulating myocardial injury during cecal ligation and puncture (CLP)-induced sepsis using a murine model. Cardiac troponin I (cTnI), a biomarker for myocardial damage, was measured in both IL-13-deficient (KO) and wild type (WT) mice subjected to CLP. Contrary to the conventional view of IL-13 as a protective cytokine, IL-13-competent mice exhibited significantly higher serum cTnI levels than IL-13-deficient mice, indicating exacerbated myocardial injury. Elevated cardiac tumor necrosis factor-alpha (TNF-α) levels and IL-1β in WT CLP mice corroborated this finding, suggesting IL-13's role in enhancing the inflammatory response. In vitro assays with bone marrow-derived dendritic cells (BMDCs) stimulated with lipopolysaccharide and Group A Streptococcus revealed a dose-dependent suppression of TNF-α and IL-6 production by recombinant IL-13. These findings indicate a complex role of IL-13 in sepsis, modulating inflammation but potentially increasing myocardial stress.

BCG revaccination in adults enhances pro-inflammatory markers of trained immunity along with anti-inflammatory pathways

This study characterized mechanisms of Bacille Calmette-Guérin (BCG) revaccination-induced trained immunity (TI) in India. Adults, BCG vaccinated at birth, were sampled longitudinally before and after a second BCG dose. BCG revaccination significantly elevated tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 in HLA-DR+CD16-CD14hi monocytes, demonstrating induction of TI. Mycobacteria-specific CD4+ Tcell interferon (IFN) γ, IL-2, and TNF-α were significantly higher in re-vaccinees and correlated positively with HLA-DR+CD16-CD14hi TI responses. This, however, did not translate into increased mycobacterial growth control, measured by mycobacterial growth inhibition assay (MGIA). Post revaccination, elevated secreted TNF-α, IL-1β, and IL-6 to "heterologous" fungal, bacterial, and enhanced CXCL-10 and IFNα to viral stimuli were also observed concomitant with increased anti-inflammatory cytokine, IL-1RA. RNA sequencing after revaccination highlighted a BCG and LPS induced signature which included upregulated IL17 and TNF pathway genes and downregulated key inflammatory genes:CXCL11, CCL24, HLADRA, CTSS, CTSC. Our data highlight a balanced immune response comprising pro- and anti-inflammatory mediators to be a feature of BCG revaccination-induced immunity.

Bioactivity of Eriocephalus africanus essential oil against concanavalin A-induced hepatitis via suppressing immune cell infiltration, inhibiting TNF-α/NF-κB and IFN-γ/STAT1 signaling pathways

Ethnopharmacological relevanceEriocephalus africanus infusion is used as a diuretic and a diaphoretic and is also used in the treatment of gastrointestinal disorders and gynaecological conditions, inflammation and dermal disorders, asthma, coughs, fevers, and painful ailments. The plant has been used traditionally as a medication to cure inflammation and skin problems. Aim of the studyStudying E. africanus essential oil (EAEO) as a potential hepatoprotective measure against concanavalin (Con) A-induced hepatitis in mice and investigating its underlying mechanism. Materials and methodsHydro-distilled oil of the fresh plant aerial shoots is subjected to GC/MS analysis. Autoimmune hepatitis (AIH) was induced in mice by intravenous injection of Con A (15 mg/kg). EAEO was administered orally before Con A injection to test its hepatoprotective activity. ResultsGC/MS analysis revealed the presence of 22 compounds representing 99.43% of the oil components. The monoterpene artemisia ketone (41.02%) and the sesquiterpene juniper camphor (14.17%) are the major components. The in vivo study showed that the oil suppressed Con A-induced neutrophil and CD4+T cell infiltration into the liver, restored hepatic redox balance, inhibited Con A-induced elevation of tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), and interferon-gamma (IFN-γ) hepatic levels which were correlated with its ability to suppress nuclear factor kappa B (NF-κB) and Signal Transducer and Activator of Transcription (STAT1) activation in the liver. ConclusionEAEO showed hepatoprotective potential against Con A-induced hepatitis in mice collectively through selective anti-oxidant, anti-inflammatory, and anti-necrotic effects.

Extensive diet-induced atherosclerosis in scavenger receptor class B type 1-deficient mice is associated with substantial leukocytosis and elevated vascular cell adhesion molecule-1 expression in coronary artery endothelium.

High levels of low density lipoprotein (LDL) cholesterol and low levels of high density lipoprotein (HDL) cholesterol are risk factors for cardiovascular disease. Mice that lack genes involved in the clearance of LDL from the bloodstream, such as the LDL receptor and apolipoprotein E, are widely used models of experimental atherosclerosis. Conversely, mice that lack the HDL receptor, scavenger receptor class B type I, and therefore have disrupted HDL functionality, also develop diet-inducible atherosclerosis but are a seldom-used disease model. In this study, we compared atherosclerosis and associated phenotypes in scavenger receptor class B type I knockout mice with those of wild type, LDL receptor knockout, and apolipoprotein E knockout mice after 20weeks of being fed an atherogenic diet containing sodium cholate. We found that while scavenger receptor class B type I knockout mice had substantially lower plasma cholesterol than LDL receptor and apolipoprotein E knockout mice, they developed atherosclerotic plaques with similar sizes and compositions in their aortic sinuses, and more extensive atherosclerosis in their descending aortas and coronary arteries. This was associated with elevated tumor necrosis factor alpha levels in scavenger receptor class B type I knockout mice compared to wild type and LDL receptor knockout mice, and lymphocytosis, monocytosis, and elevated vascular cell adhesion molecule expression in coronary artery endothelial cells compared to the other mice examined. We conclude that extensive atherosclerosis in arteries that are not generally susceptible to atherosclerosis in scavenger receptor class B type I knockout mice is driven by factors in addition to hypercholesterolemia, including inflammation, dysregulation of the immune system and increased sensitivity of endothelial cells in arteries that are normally resistant to atherosclerosis. Scavenger receptor class B type I knockout mice fed a cholate containing atherogenic diet may prove to be a useful model to study mechanisms of atherosclerosis and evaluate treatments that rely on intact LDL clearance pathways.

IGF1 deficiency integrates stunted growth and neurodegeneration in Down syndrome

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by stunted growth, cognitive impairment, and increased risk of diverse neurological conditions. Although signs of lifelong neurodegeneration are well documented in DS, the mechanisms underlying this phenotype await elucidation. Here we report a multi-omics analysis of neurodegeneration and neuroinflammation biomarkers, plasma proteomics, and immune profiling in a diverse cohort of more than 400 research participants. We identified depletion of insulin growth factor 1 (IGF1), a master regulator of growth and brain development, as the top biosignature associated with neurodegeneration in DS. Individuals with T21 display chronic IGF1 deficiency downstream of growth hormone production, associated with a specific inflammatory profile involving elevated tumor necrosis factor alpha (TNF-α). Shorter children with DS show stronger IGF1 deficiency, elevated biomarkers of neurodegeneration, and increased prevalence of autism and other conditions. These results point to disruption of IGF1 signaling as a potential contributor to stunted growth and neurodegeneration in DS.

MiR-495-3p depletion contributes to myocardial ischemia/reperfusion injury in cardiomyocytes by targeting TNC.

BackgroundTenascin-C (TNC) has been found to abnormally express in myocardial ischemia/reperfusion injury (MI/RI), but its effect on cardiomyocytes apoptosis is unknown and is worthy of investigation.MethodsH9C2 cells were given hypoxia/reoxygenation (H/R) treatment to obtain the replica of MI/RI in vitro. The effect of H/R on viability, apoptosis and inflammation was studied by CCK-8 assay, flow cytometry, mitochondrial membrane potential (MMP) and Ca2+ measurements as well as enzyme linked immunosorbent assay. We applied bioinformatics analysis and luciferase reporter assay to screened and validated TNC-targeting miR-495-3p which was then mechanistically investigated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. With the assistance of cell transfection, rescue assays were conducted.ResultsH9C2 cells showed diminished viability, accelerated apoptosis, elevated tumour necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), and TNC overexpression in response to H/R induction, while silencing of TNC partially reversed the effect of H/R treatment on the H9C2 cells. TNC silencing reduced Ca2+ level and enhanced MMP level in the H/R-stimulated cells. MiR-495-3p targeted TNC and showed a low expression in the H/R-stimulated cells. The expression of TNC was negatively regulated by miR-495-3p. Inhibition of miR-495-3p repressed viability and MMP level, and facilitated apoptosis and levels of Ca2+, TNF-α and IL-1β in the H/R-stimulated cells. The effect of TNC silencing and miR-495-3p depletion on H/R-induced cardiomyocyte injury was mutually reversed in vitro.ConclusionMiR-495-3p targeted TNC to regulate the apoptosis and inflammation of cardiomyocytes in H/R induction, which was associated with Ca2+ overload.

Nesfatin-1 treatment preserves antioxidant status and attenuates renal fibrosis in rats with unilateral ureteral obstruction.

Nesfatin-1 (NES-1), an anorexigenic peptide, was reported to have anti-inflammatory and anti-apoptotic actions in several inflammation models. To elucidate potential renoprotective effects of NES-1, unilateral ureteral obstruction (UUO) was induced in male Sprague Dawley rats by ligating left ureters. The rats were injected intraperitoneally with either saline (SL) or NES-1 (10µg/kg/day) for 7 or 14 days (n=8 in each group). On the 7th or 14th day, obstructed kidneys were removed for the isolation of leucocytes for flow-cytometric analysis and the assessments of biochemical and histopathological changes. Opposite to glutathione levels, renal myeloperoxidase activity in the SL-treated UUO group was significantly increased compared with the sham-operated group, while NES-1 treatment abolished the elevation. The percentages of CD8+/CD4+ T-lymphocytes infiltrating the obstructed kidneys were increased in the SL-treated groups but treatment with NES-1 did not prevent lymphocyte infiltration. Elevated tumour necrosis factor-alpha (TNF-α) levels in SL-treated UUO group were decreased with NES-1. Although total degeneration scores were similarly increased in all UUO groups, tubular dilatation scores were significantly increased in UUO groups and lowered by NES-1 only in the 7-day treated group. Elevated interstitial fibrosis scores in the SL-treated groups were decreased in both 7- and 14-day NES-1 treated groups, while alpha-smooth muscle actin (α-SMA) and apoptosis scores were depressed in both NES-1 treated groups. The present data demonstrate that UUO-induced renal fibrosis is ameliorated by NES-1, which appears to involve the inhibition of neutrophil infiltration and thereby amelioration of oxidative stress and inflammation. These data suggest that NES-1 may have a regulatory role in protecting the kidneys against obstruction-induced renal injury.

MtROS Induced via TLR-2-SOCE Signaling Plays Proapoptotic and Bactericidal Role in Mycobacterium fortuitum-Infected Head Kidney Macrophages of Clarias gariepinus.

The mechanisms underlying Mycobacterium fortuitum-induced mycobacteriosis remain unexplored. Using head kidney macrophages (HKM) from catfish (Clarias gariepinus), we report that Ca2+ surge across mitochondrial-Ca2+ uniporter (MICU), and consequent mitochondrial ROS (mtROS) production, is imperative for mycobactericidal activity. Inhibition of mtROS alleviated HKM apoptosis and enhanced bacterial survival. Based on RNA interference (RNAi) and inhibitor studies, we demonstrate that the Toll-like receptor (TLR)-2–endoplasmic reticulum (ER) stress–store-operated calcium entry (SOCE) axis is instrumental for activating the mt-Ca2+/mtROS cascade in M. fortuitum-infected HKM. Additionally, pharmacological inhibition of mtROS attenuated the expression of CHOP, STIM1, and Orai1, which suggests a positive feedback loop between ER-stress-induced SOCE and mtROS production. Elevated tumor necrosis factor alpha (TNF-α) levels and caspase-8 activity were observed in HKM consequent to M. fortuitum infection, and our results implicate that mtROS is crucial in activating the TNF-mediated caspase-8 activation. Our results for the first time demonstrate mitochondria as an innate immune signaling center regulating mycobacteriosis in fish. We conclude that M. fortuitum-induced persistent SOCE signaling leads to mtROS production, which in turn activates the TNF-α/caspase-8 axis culminating in HKM apoptosis and bacterial clearance.

Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis

Evidence of NF-ΚB Pathway Activation in Patients with Advanced, High Molecular Risk Myelofibrosis

Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model.

BackgroundElevated tumor necrosis factor alpha (TNF-α) expression is correlated with the progression of intervertebral disc degeneration (IVDD). Progranulin binding to tumor necrosis factor receptor (TNFR) and its derivative Atsttrin are effective for treating inflammatory arthritis. We hypothesize that Atsttrin has a protective effect in IVDD through different roles of TNFR receptor type 1 (TNFR1) and TNFR receptor type 2 (TNFR2) in degenerated discs.MethodsIVDD models were established in TNFR1−/−, TNFR2−/− mice and their control littermates. Nucleus Pulpous (NP) samples from human patients and IVDD murine models were evaluated by X-ray, micro-MRI, μCT, histological staining and immunofluorescence staining. NP cells isolated from wild-type (WT), TNFR1−/− and TNFR2−/− mice were treated with TNF-α or Atsttrin and then assayed by Western blotting, qRT–PCR, and ELISA.ResultsTNFR1 and TNFR2 expression was significantly elevated in the disc tissues of both human patients and IVDD murine models. TNFR1 knockout contributed to reduced disc degeneration. In contrast, TNFR2 knockout was associated with enhanced IVDD severity, including degraded cellular composition, increased cell apoptosis and elevated vertebral destruction. Atsttrin protected against IVDD in WT and TNFR1−/− mouse models but had no effect in TNFR2−/− IVDD models. Additionally, in vitro NP cell-based assays demonstrated that TNF-α-stimulated catabolism and Atsttrin-activated anabolism depended on TNFR1 and TNFR2, respectively.ConclusionTNFR1 is associated with the degenerative progression of IVDD, while TNFR2 contributes to the protective effect on the discs. Atsttrin protects against IVDD at least partially by inhibiting the TNFα/TNFR1 inflammatory/catabolic pathway and activating the TNFR2 protective/anabolic pathway.The translational potential of this articleThis study demonstrates that TNFR1 and TNFR2 have disparate roles in disc degeneration and hlights the potential use of Atsttrin as a therapeutic agent against IVDD in mice.

TNF-alpha Concentrations in Serum and Human Milk of Mothers With Insufficient Versus Sufficient Milk Production

ObjectivesObesity and poor metabolic health are associated with poor lactation outcomes, potentially driven by elevated tumor necrosis factor alpha (TNF-α) from chronic inflammation. TNF-α reduces lipoprotein lipase (LpL) activity, limiting triglyceride (TG) uptake by the mammary gland for milk synthesis. Our objective here is to determine if TNF-α concentrations in serum and milk are higher in mothers with severely low compared to sufficient milk production and if TNF-α is associated with plasma TG. MethodsMothers screened for low milk production were categorized into very low (VL; 177 [87,219] mL/d; n = 23) and moderately low/normal (ML; Median [IQR]: 467 [373,655] mL/d; n = 20) milk production. An external control group had sufficient milk production (EC; 783 [717,818] mL/d; n = 18). Mothers provided a spot milk sample at a morning clinic visit, where fasting blood samples were taken for clinical metabolic health measures. TNF-α concentrations were measured in duplicate by high-sensitivity ELISA in serum and aqueous milk. Group differences were assessed by Wilcoxon Rank Sums Tests or Fisher’s Exact Chi Square Test (α = 0.05). Correlations were assessed by Spearman rank order. ResultsMothers were 31.3 [27.3, 34.1] years old, delivered at gestational age of 39.4 [38.6, 40.3] weeks, and were 43 [35, 56] days postpartum, with no significant differences among groups. Milk TNF-α was detected in 47% of samples (1.3 [0.8, 2.2] pg/mL). The proportion of detectable TNF-α (D-TNF) in milk was higher in VL compared with ML and EC (71%, 32%, 33% respectively; p = 0.02). Compared to undetected (U-TNF), subjects with D-TNF in milk had higher plasma TG (D-TNF: 94 [68,140] mg/dL; U-TNF: 60 [49, 84] mg/dL; p = 0.001). Serum TNF-α was not significantly different by group (VL: 6.3 [5.8, 7.0] pg/mL; ML: 6.1 [5.6, 6.5]; EC: 5.8 [5.3, 6.6]; p = 0.31), but was correlated with plasma TG (ρ = 0.40, p = 0.002). ConclusionsIn this exploratory cohort, TNF- α levels were higher in milk from mothers with low milk production, and both milk and serum TNF- α was associated with higher plasma TG. This suggests that proximal TNF-α expression is more associated with reduced mammary LpL activity than circulating serum TNF-α, leading to low milk production. Funding SourcesNIH and USDA.