Tumor Necrosis Factor-alpha Receptor Research Articles

EXPRESS: Advanced cancer perineural invasion induces profound peripheral neuronal plasticity, pain, and somatosensory mechanical deactivation, unmitigated by the lack of TNFR1. Part. 1: Behavior and single-cell in vivo electrophysiology.

Patients with cancer perineural invasion (PNI) report greater spontaneous pain and mechanical allodynia. Here, we examine the impact of the disease on the peripheral sensory system, the excitability changes induced by PNI at the dorsal root ganglia, and the potential protective role of the absence of Tumor Necrosis Factor-α Receptor 1 (TNFR1). To study these effects, we use a murine model generated by injecting mouse oral cancer squamous cell carcinoma (MOC2) into the sciatic nerve (MOC2-PNI) in both male and female mice. We found that MOC2-PNI induces a profound change in the somatosensory landscape by deactivating/blocking the peripheral inputs while modulating the afferent's sensibility (tactile desensitization with concurrent nociceptive sensitization) and demyelination without inducing spontaneous activity. All these changes caused by MOC2-PNI are unmitigated by the absence of TNFR1. We conclude that MOC2-PNI induces an aberrant neuronal excitability state and triggers extreme gender-specific neuronal plasticity. These data allow us to speculate on the role of such plasticity as a powerful defense mechanism to prevent terminal sensory dysfunction, the rise of chronic pain, and extend animals' survivability.

Integrated analysis of genetic, proteinic, and metabolomic alterations in Behcet’s disease

Numerous studies have investigated the alterations of genes, proteins, and metabolites in Behcet’s disease (BD). By far, little is known about the depiction of panoramic changes underlying this disease. This study purposed to assess the consistently dysregulated genes, proteins, and metabolites in BD across publications using the vote-counting approach. This study was based on 745 studies that identified a collection of 2354 differential molecules with 3574 molecule entries in blood, peripheral blood mononuclear cells, CD4+T cells, and aqueous humor samples from patients with BD. In this study, the results of binomial analysis showed that the circulating levels of 38 molecules, including interferon-γ and interleukin 17, were consistently upregulated, whereas high density lipoprotein cholesterol, apolipoprotein A, hemoglobin, and glutathione were consistently downregulated. The levels of interferon-γ, tumor necrosis factor-α and toll like receptor 4 in peripheral blood mononuclear cells, and interferon-γ and interleukin-17 in CD4+T cells were consistently upregulated. Additionally, the levels of interferon-γ, tumor necrosis factor-α and C-X-C motif chemokine ligand 8 in aqueous humor were consistently upregulated. Collectively, this study showed that the hyperactivity of Th1 and Th17 responses played an essential role in the pathogenesis of BD, and the progression of this disease was associated with enhanced neutrophil chemotaxis, vascular endothelial injury, activation of haemostatic system, and oxidative stress.

Clinical efficacy of donepezil combined with nerve growth factor in the treatment of patients with Parkinson’s disease dementia and its impact on adiponectin and soluble tumor necrosis factor-alpha receptor-1

Objective: To explore clinical efficacy of donepezil combined with nerve growth factor (NGF) in the treatment of Parkinson’s disease dementia (PDD) and its potential impact on serum levels of adiponectin (APN) and soluble tumor necrosis factor receptor-1 (sTNFR-1). Methods: Clinical data of 140 patients with PDD treated in Taizhou First People’s Hospital from March 2021 to December 2023 were retrospectively analyzed. Patients were grouped based on the treatment received. Patients who received donepezil alone (n=68) comprised the Donepezil group, and patients who were treated with a combination of donepezil and NGF (n=72) were assigned into the Donepezil & NGF group. Treatment effects, symptom improvement before and after the treatment, APN and sTNFR-1 levels, and incidence of adverse reactions were compared between two groups. Results: The overall efficacy of the combination therapy was higher than that of donepezil regimen alone (P<0.05). After treatment, symptom improvement in the Donepezil & NGF group was significantly better than that in the Donepezil group (P<0.05). Post-treatment serum levels of APN in the Donepezil & NGF group were significantly higher than that of Donepezil group, while the level of sTNFR-1 was significantly lower (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion: Combined regimen of donepezil and NGF is more effective than donepezil monotherapy in improving cognitive function, neurological function, and severity of the condition of patients with PDD, and is associated with the suppression of the inflammatory response without a significant increase in the incidence of adverse reactions. The study provides a basis for the clinical application of the combined regimen, but it still needs to be confirmed by more basic and clinical research. doi: https://doi.org/10.12669/pjms.41.2.11191 How to cite this: Hu M, Ye J. Clinical efficacy of donepezil combined with nerve growth factor in the treatment of patients with Parkinson’s disease dementia and its impact on adiponectin and soluble tumor necrosis factor-alpha receptor-1. Pak J Med Sci. 2025;41(2):372-377. doi: https://doi.org/10.12669/pjms.41.2.11191 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

SEX-SPECIFIC BIOMARKER PREDICTION OF FEMORAL NECK BONE LOSS AFTER HIP FRACTURE

Abstract Hip fracture exacerbates age-related inflammation and metabolic dysfunction, which could accelerate bone loss post-fracture. This study aimed to develop biomarker prediction models for declines in femoral neck bone mineral density (BMD) after hip fracture. Participants were Caucasian men (n=99) and women (n=75) from the Baltimore Hip Studies 7th cohort with a hip fracture who were not receiving glucocorticoids, sex-hormone therapy, or bone-active medications. Data were collected at baseline (within 15 days of admission) and 2-, 6-, and 12-months later. Biomarkers were categorized into tertiles: interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), soluble tumor necrosis factor-alpha (TNF-alpha) receptor type 1, estradiol (E), testosterone (T), intact parathyroid hormone (iPTH), sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), C-terminal telopeptide of type I collagen (CTX), and procollagen type I N-propeptide (PINP). Femoral neck BMD was measured using dual energy x-ray absorptiometry. Mixed-effects models adjusted for age, height, and weight estimated 1-year changes in femoral neck BMD after hip fracture. Bone loss was classified as accelerated for intra-individual changes that exceeded the mean decline. Logistic regression models were stratified by biological sex and implemented using stepwise selection. The area under the curve (AUC) estimate among men was 0.68, and biomarkers related to bone loss were E, IGF-1, SHBG, and CTX. Similarly, the AUC metric among women was 0.69, but identified biomarkers were IL-6, iPTH, IGF-1, and SHBG. Findings indicate that both inflammatory and hormonal biomarkers relate to accelerated bone loss post-fracture; however, there are differential associations in physiological mechanisms between men and women.

Bushen Huoxue Recipe inhibits endometrial epithelial-mesenchymal transition through the transforming growth factor-β/nuclear factor kappa-B pathway to improve polycystic ovary syndrome-mediated infertility

Objective To investigate the target and mechanism of action of Bushen Huoxue Recipe (BSHX) for the treatment of infertility in polycystic ovary syndrome (PCOS), to provide a basis for the development and clinical application of herbal compounds. Methods Prediction and validation of active ingredients and targets of BSHX for the treatment of PCOS by using network pharmacology-molecular docking technology. In an animal experiment, the rats were randomly divided into four groups (control group, model group, BSHX group, metformin group, n = 16 in each group), and letrozole combined with high-fat emulsion gavage was used to establish a PCOS rat model. Body weight, vaginal smears, and number of embryos were recorded for each group of rats. Hematoxylin-eosin (HE) staining was used to observe the morphological changes of ovarian and endometrial tissues, and an enzyme-linked immunosorbent assay (ELISA) was used to detect the serum inflammatory factor levels. Expression levels of transforming growth factor-β (TGF-β), transforming growth factor beta activated kinase 1 (TAK1), nuclear factor kappa-B (NF-κB), Vimentin, and E-cadherin proteins were measured by western blot (WB). Results Ninety active pharmaceutical ingredients were obtained from BSHX, involving 201 protein targets, of which 160 were potential therapeutic targets. The active ingredients of BSHX exhibited lower binding energy with tumor necrosis factor-α (TNF-α), TGF-β, TAK1, and NF-κB protein receptors (< −5.0 kcal/mol). BSHX significantly reduced serum TNF-α levels in PCOS rats (p < .01), effectively regulated the estrous cycle, restored the pathological changes in the ovary and endometrium, improved the pregnancy rate, and increased the number of embryos. The results of WB suggested that BSHX can down-regulate protein expression levels of TGF-β and NF-κB in endometrial tissue (p < .05), promote the expression level of E-cadherin protein (p < .001), intervene in the endometrial epithelial-mesenchymal transition (EMT) process. Conclusions TGF-β, TAK1, NF-κB, and TNF-α are important targets of BSHX for treating infertility in PCOS. BSHX improves the inflammatory state of PCOS, intervenes in the endometrial EMT process through the TGF-β/NF-κB pathway, and restores endometrial pathological changes, further improving the pregnancy outcome in PCOS.

Inflammatory Indices and Their Associations With Postoperative Delirium.

Although the pathogenesis of delirium is poorly understood, increasing evidence supports a role for inflammation. Previously, individual inflammatory biomarkers have been associated with delirium. Aggregating biomarkers into an index may provide more information than individual biomarkers in predicting certain health outcomes (eg, mortality); however, inflammatory indices have not yet been examined in delirium. Four inflammatory markers, C-reactive protein, interleukin-6, soluble tumor necrosis factor alpha receptor-1, and chitinase-3 like protein-1, were measured preoperatively and on postoperative day 2 in 548 adults aged 70+ undergoing major noncardiac surgery (mean age 76.7 [standard deviation 5.2], 58% female, 24% delirium). From these markers, 4 inflammatory indices were considered: (i) quartile summary score, (ii) weighted summary score, (iii) principal component score, and (iv) a well-established inflammatory (least absolute shrinkage and selection operator-derived) index associated with mortality. Delirium was assessed using the Confusion Assessment Method, supplemented by chart review. Generalized linear models with a log-link term were used to determine the association between each inflammatory index and delirium incidence. Among the inflammatory indices, the weighted summary score demonstrated the strongest association with delirium: participants in the weighted summary score quartile (Q)4 had a higher risk of delirium versus participants in Q1, after clinical variable adjustment (relative risk, 95% confidence interval for preoperatively: 3.07, 1.80-5.22; and postoperative day 2: 2.65, 1.63-4.30). Theweighted summary score was more strongly associated with delirium than the strongest associated individual inflammatory marker (preoperatively chitinase-3 like protein-1 [relative risk 2.45, 95% confidence interval 1.53-3.92]; postoperative day 2 interleukin-6 [relative risk 2.39, 95% confidence interval 1.50-3.82]). A multi-protein inflammatory index using a weighted summary score provides a slight advantage over individual inflammatory markers in their association with delirium.

Role of trigeminal ganglion satellite glial cells in masseter muscle pain hypersensitivity.

The underlying mechanism of masseter muscle pain hypersensitivity by sustained masseter muscle contraction (SMMC) is not well understood. This study aimed to examine whether the activation of satellite glial cells in the trigeminal ganglion (TG) contributes to masseter muscle pain hypersensitivity induced by SMMC. Electrodes were placed on the masseter muscle fascia of rats to induce strong contractions, by daily electrical stimulation. Pain sensitivity in the masseter muscle was measured and the activation level of satellite glial cells in the TG was examined. The localization of P2Y12 and the effects of P2Y12 receptor inhibition on SMMC-induced pain hypersensitivity were evaluated. The amount of tumor necrosis factor alpha (TNF-α) and TNF-α receptor localization were determined in the TG. SMMC induced masseter muscle pain hypersensitivity and activation of satellite glial cells. P2Y12 receptors were expressed in satellite glial cells and masseter muscle pain hypersensitivity was suppressed by intra-TG P2Y12 receptor antagonism. TG neurons innervating the sustained-contracted masseter muscle expressed TNF-α receptor and SMMC increased TNF-α levels in TG. SMMC-induced activation of satellite glial cells though the P2Y12 receptor signaling may contribute to masseter muscle pain hypersensitivity via the TNF-α signaling pathway.

Engrailed-2 and inflammation convergently and independently impinge on cerebellar Purkinje cell differentiation

Autism spectrum disorders (ASD) have a complex pathogenesis thought to include both genetic and extrinsic factors. Among the latter, inflammation of the developing brain has recently gained growing attention. However, how genetic predisposition and inflammation might converge to precipitate autistic behavior remains elusive. Cerebellar structure and function are well known to be affected in autism. We therefore used cerebellar slice cultures to probe whether inflammatory stimulation and (over)expression of the autism susceptibility gene Engrailed-2 interact in shaping differentiation of Purkinje cells, key organizers of cerebellar histogenesis and function. We show that lipopolysaccharide treatment reduces Purkinje cell dendritogenesis and that this effect is enhanced by over-expression of Engrailed-2 in these cells. The effects of lipopolysaccharide can be blocked by inhibiting microglia proliferation and also by blocking tumor necrosis factor alpha receptor signaling, suggesting microglia and tumor necrosis factor alpha are major players in this scenario. These findings identify Purkinje cells as a potential integrator of genetic and environmental signals that lead to an autism-associated morphology.

The association between TNF-receptors (TNFR1 and TNFR2) and mortality as well as kidney function decline in patients with chronic kidney disease.

Higher circulating levels of tumor necrosis factor (TNF) alpha receptors 1 (TNFR1) and 2 (TNFR2) are associated with increased long-term mortality and impaired kidney function. To study associations between levels of TNFR1 and TNFR2 and all-cause mortality as well as estimated glomerular filtration rate (eGFR) decline. Patients with chronic kidney disease (CKD) stages 3-5 in the Salford Kidney Study were included. Associations between one standard deviation increase in plasma TNFR1 and TNFR2 and mortality were estimated by Cox regression models with hazard ratios (HRs) and 95% confidence intervals adjusted for age, sex, eGFR based on creatinine and cystatin C, urine-protein, C-reactive protin, cardiovascular comorbidity, smoking habits, and diabetes. Differences in eGFR decline in relation to plasma TNFR1 and TNFR2 were estimated by both linear and logistic regression models, with regression coefficients and odds ratios (ORs). Univariate models showed significant associations between TNFR1 (n = 985) and TNFR2 (n = 988) and all-cause mortality based on 7424 person-years at risk, but in the fully adjusted models with continuous variables significant only for TNFR2 HR 1.17 (1.03-1.34), but with a borderline value for TNFR1 HR 1.15 (1.00-1.31). For rapid decliners, that is, eGFR decline in highest TNFR-receptor quartile versus quartiles 1-3, the decline was 1.60% per month (interval 0.78-10.99). For eGFR decline in continuous models, the fully adjusted ORs were for TNFR1 1.29 (0.92-1.81) and for TNFR2 1.33 (0.90-1.98). TNFR2 was associated with mortality, but TNFR1 was not, although showing a borderline value. Neither TNFR1 nor TNFR2 predicted decline in kidney function. TNFR1 and TNFR2 portray interesting aspects in patients with CKD, but the clinical utility seems limited.

Changes to inflammatory markers during 5 years of viral suppression and during viral blips in people with HIV initiating different integrase inhibitor based regimens.

Heightened levels of inflammatory markers are linked to increased morbidity/mortality in people with HIV (PWH) and often remain elevated after virologic suppression by antiretroviral therapy (ART). As new combinations of ART become available, an evaluation of their effects on immune activation and inflammation is warranted. Additionally, it remains unknown whether transient increases in viral load ("blips") during ART are associated with increases in inflammation. We utilized cryopreserved samples from treatment-naïve PWH enrolled in two Phase 3 clinical trials investigating the efficacy and safety of bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) or dolutegravir, abacavir, and lamivudine (DTG/ABC/3TC) or DTG + F/TAF over a 5-year window (GS-US-380-1489/1490). At week 144, participants were offered the option to switch to open label B/F/TAF for an additional 96 weeks. We measured levels of interleukin-6 (IL-6), C-reactive protein (hsCRP), D-dimer, soluble CD14 (sCD14), and tumor necrosis factor-α receptor 1 (TNFR1) from available baseline, week 24, 48, 144, and 240 samples (B/F/TAF, N=123; DTG/ABC/3TC, N=62; DTG+F/TAF, N=58). Additional samples from PWH who experienced a viral blip (n=44, defined as a single HIV-1 RNA >50c/mL) were also analyzed and paired with the most recent available suppressed sample before the blip. Longitudinal biomarker changes were assessed using a constrained mixed effects linear regression model adjusting for covariates. Baseline demographics and selected laboratory characteristics were similar across groups. Levels of D-dimer, sCD14, and TNFR1 decreased significantly from baseline in all treatment arms, with no significant differences between arms at any timepoint. Biomarker levels also remained stable following ART-switch at week 144. No significant changes in hsCRP or IL-6 were observed versus baseline in any arm at any timepoint. A significant association was observed between sCD14 and increasing viral load (p=0.022) in viral blips; D-dimer also increased with blips in the B/F/TAF arm. Viral suppression was associated with reductions in most inflammatory markers in PWH, with no significant differences among the three ART regimens during the 144-week randomized period. These decreases were sustained after the open label switch to B/F/TAF. Viral blips were associated with increases in monocyte activation (sCD14). Further analysis is needed to confirm these findings and determine the potential impact on clinical outcomes.

Quantitative assessments of white matter hyperintensities and plasma biomarkers can predict cognitive impairment and cerebral microbleeds in cerebral small vessel disease patients

The objective of this study is to examine the efficacy of magnetic resonance imaging (MRI) features and peripheral blood biomarkers in assessing cognitive function in patients with cerebral small vessel disease (CSVD). A total of 58 CSVD patients were recruited. Six features of white matter hyperintensities (WMHs) were derived from MRI scans. Additionally, five neurodegenerative biomarkers (Aβ40, Aβ42, t-tau, p-tau181, NfL) and 13 serum inflammatory cytokines (VILIP-1, CCL2, IL-6, IL-18, TNF-α, CX3CL, sTREM-1/2, VEGF, s-RAGE, BNDF, TGF-β1, β-NGF) were quantified. Cognitive assessments were conducted using standardized neuropsychological scales. Spearman analysis revealed that the volumetric characteristics (absolute area, upper area, bottom area, absolute area percentage, upper percentage, and bottom percentage) of WMHs were negatively correlated with performance on all cognitive scale measures except the verbal fluency test (VFT) (r<-0.3, p>0.05), while they were positively correlated with plasma neurofilament light (NFL) levels (r>0.4, p<0.05). Additionally, serum tumor necrosis factor-α (TNF-α) and soluble receptor for advanced glycation end-products (s-RAGE) showed significant correlations with scales of speech function. An integrated model incorporating WMHs features, neurodegenerative biomarkers, and neuroinflammatory markers was developed, demonstrating high predictive accuracy for cognitive impairment with an area under the curve (AUC) of 0.95 (accuracy 0.88, sensitivity 0.87, specificity 0.89). Another integrated model that includes features of WMHs and inflammatory cytokines for predicting cerebral microbleeds (CMBs) achieved an AUC of 0.95 (accuracy 0.88, sensitivity 0.82, specificity 0.92). Our findings suggest that these markers have the potential to be used for the early detection of cognitive decline and CMBs in patients with CSVD.

TNFR2 blockade promotes antitumoral immune response in PDAC by targeting activated Treg and reducing T cell exhaustion

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor α receptor 2 (TNFR2)...

Inflammation, physical activity, and disease-free survival in stage III colon cancer: Cancer and Leukemia Group B-Southwest Oncology Group 80702 (Alliance).

Inflammation and insufficient physical inactivity contribute to individual-level risk of disease recurrence and death in stage III colon cancer. The extent to which increased inflammatory risk can be offset by sufficient physical activity remains unknown. This cohort study was nested within the Cancer and Leukemia Group B (now part of the Alliance for Clinical Trials in Oncology) and Southwest Oncology Group randomized trial. Inflammatory burden was quantified by high-sensitivity C-reactive protein, interleukin-6, and soluble tumor necrosis factor-α receptor 2 after recovery from tumor resection. Physical activity was measured during and after postoperative chemotherapy. The primary endpoint was disease-free survival. The 3-year disease-free survival rate was 88.4% among patients with low inflammation and sufficient physical activity (referent group for all comparisons), 84.9% with low inflammation and insufficient physical activity (absolute risk difference = -3.5 percentage points, 95% confidence interval [CI] = -11.3 to 4.3; P = .38), 78.0% with intermediate inflammation and insufficient physical activity (absolute risk difference = -10.4 percentage points, 95% CI = -17.4 to -3.3; P = .007), and 79.7% with high inflammation and insufficient physical activity (absolute risk difference = -8.7 percentage points, 95% CI = -15.7 to -1.6; P = .022). In contrast, the 3-year disease-free survival rate was 87.3% among patients with intermediate inflammation and sufficient physical activity (absolute risk difference = -1.1 percentage points, 95% CI = -7.5 to 5.3; P = .74) and 84.4% with high inflammation and sufficient physical activity (absolute risk difference = -4.0 percentage points, 95% CI = -12.3 to 4.3; P = .34). In this observational study of stage III colon cancer patients, physical activity was associated with improved disease-free survival despite high inflammation. Patients with intermediate or high inflammation who were physically active had disease-free survival rates that were not statistically significantly different from those with low inflammation.

Relationship between plasma TNF-α levels and agitation symptoms in first episode patients with schizophrenia

BackgroundIncreasing evidence suggested that immune abnormalities involved in the pathophysiology of schizophrenia. However, the relationship between immunity and clinical features has not been clarified. The aim of this study was to measure the plasma levels of tumor necrosis factor alpha (TNF-α) and soluble TNF-α receptor 1 (sTNF-α R1) and to investigate their association with agitation in first episode patients with schizophrenia (FEPS).MethodsThe plasma TNF-α and sTNF-α R1 levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA) in the FEPS with (n = 36) and without agitation (n = 49) symptoms, and healthy controls (HCs, n = 54). The psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS), and the agitation symptoms were evaluated by the PANSS excitatory component (PANSS-EC).ResultsThe plasma TNF-α levels in patients with and without agitation symptoms were significantly higher than those in HCs. The patients with agitation had significantly higher plasma TNF-α levels compared to the patients without agitation. There were no significant differences in the sTNF-α R1 levels among the three groups. Furthermore, the plasma TNF-α levels were positively correlated with the PANSS total score, Positive and General psychopathological subscores, and PANSS-EC score in the FEPS, but the relationships were not found for the plasma sTNF-α R1 levels.ConclusionsThese results suggested that TNF-α might play an important role in the onset and development of agitation symptoms of schizophrenia.

Dietary Clostridium autoethanogenum protein has dose-dependent influence on the gut microbiota, immunity, inflammation and disease resistance of abalone Haliotis discus hannai

Clostridium autoethanogenum protein (CAP) is an eco-friendly protein source and has great application potential in aquafeeds. The present study aimed to investigate the effects of dietary CAP inclusion on the anti-oxidation, immunity, inflammation, disease resistance and gut microbiota of abalone Haliotis discus hannai after a 110-day feeding trial. Three isonitrogenous and isolipidic diets were formulated by adding 0% (control), 4.10% (CAP4.10) and 16.25% (CAP16.25) of CAP, respectively. A total of 540 abalones with an initial mean body weight of 22.05±0.19g were randomly distributed in three groups with three replicates per group and 60 abalones per replicate. Results showed that the activities of superoxide dismutase and glutathione peroxidase in the cell-free hemolymph (CFH) were significantly decreased and the content of malondialdehyde in CFH was significantly increased in the CAP16.25 group. The diet with 4.1% of CAP significantly increased the activities of lysozyme and acid phosphatase in CFH. The expressions of pro-inflammatory genes such as tumor necrosis factor-α (tnf-α), nuclear factor-κb (nf-κb) and toll-like receptor 4 (tlr4) in digestive gland were downregulated, and the expressions of anti-inflammatory genes such as β-defensin and mytimacin 6 in digestive gland were upregulated in the CAP4.10 group. Dietary CAP inclusion significantly decreased the cumulative mortality of abalone after the challenge test with Vibrio parahaemolyticus for 7 days. Dietary CAP inclusion changed the composition of gut microbiota of abalone. Besides, the balance of the ecological interaction network of bacterial genera in the intestine of abalone was enhanced by dietary CAP. The association analysis showed that two bacterial genera Ruegeria and Bacteroides were closely correlated with the inflammatory genes. In conclusion, the 4.10% of dietary CAP enhanced the immunity and disease resistance as well as inhibited the inflammation of abalone. The 16.25% of dietary CAP decreased the anti-oxidative capacity of abalone. The structure of the gut microbiota of abalone changed with dietary CAP levels.

Tumor necrosis factor α receptor 1A transduces the inhibitory effect on axon regeneration triggered by IgG anti-ganglioside GD1a antibodies

Anti-ganglioside antibodies (anti-Gg Abs) have been linked to delayed/poor clinical recovery in both axonal and demyelinating forms of Guillain-Barrè Syndrome (GBS). In many instances, the incomplete recovery is attributed to the peripheral nervous system's failure to regenerate. The cross-linking of cell surface gangliosides by anti-Gg Abs triggers inhibition of nerve repair in both in vitro and in vivo axon regeneration paradigms. This mechanism involves the activation of the small GTPase RhoA, which negatively modulates the growth cone cytoskeleton. At present, the identity/es of the receptor/s responsible for transducing the signal that ultimately leads to RhoA activation remains poorly understood. The aim of this work was to identify the transducer molecule responsible for the inhibitory effect of anti-Gg Abs on nerve repair. Putative candidate molecules were identified through proteomic mass spectrometry of ganglioside affinity-captured proteins from rat cerebellar granule neurons (Prendergast et al., 2014). These candidates were evaluated using an in vitro model of neurite outgrowth with primary cultured dorsal root ganglion neurons (DRGn) and an in vivo model of axon regeneration. Using an shRNA-strategy to silence putative candidates on DRGn, we identified tumor necrosis factor receptor 1A protein (TNFR1A) as a transducer molecule for the inhibitory effect on neurite outgrowth from rat/mouse DRGn cultures of a well characterized mAb targeting the related gangliosides GD1a and GT1b. Interestingly, lack of TNFr1A expression on DRGn abolished the inhibitory effect on neurite outgrowth caused by anti-GD1a but not anti-GT1b specific mAbs, suggesting specificity of GD1a/transducer signaling. Similar results were obtained using primary DRGn cultures from TNFR1a-null mice, which did not activate RhoA after exposure to anti-GD1a mAbs. Generation of single point mutants at the stalk region of TNFR1A identified a critical amino acid for transducing GD1a signaling, suggesting a direct interaction. Finally, passive immunization with an anti-GD1a/GT1b mAb in an in vivo model of axon regeneration exhibited reduced inhibitory activity in TNFR1a-null mice compared to wild type mice. In conclusion, these findings identify TNFR1A as a novel transducer receptor for the inhibitory effect exerted by anti-GD1a Abs on nerve repair, representing a significant step forward toward understanding the factors contributing to poor clinical recovery in GBS associated with anti-Gg Abs.

Sustained IL-6 and sTNF-αR1 levels after hip fracture predict 5-year mortality: A prospective cohort study from the Baltimore Hip Studies.

Persistent inflammation is associated with adverse health outcomes, but its impact on mortality has not been investigated previously among hip fracture patients. This article aims to investigate the influence of changes in levels of cytokines in the 2 months after a hip fracture repair on 5-year mortality. This is a prospective cohort study from the Baltimore Hip Studies (BHS) with 191 community-dwelling older men and women (≥65 years) who had recently undergone surgical repair of an acute hip fracture, with recruitment from May 2006 to June 2011. Plasma interleukin-6 (IL-6), soluble tumor necrosis factor alpha receptor1 (sTNFα-R1), and interleukin-1 receptor agonist (IL-1RA) were obtained within 22 days of admission and at 2 months. All-cause mortality over 5 years was determined. Logistic regression analysis tested the associations between the cytokines' trajectories and mortality over 5 years, adjusted for covariates (age, sex, education, body mass index, lower extremity physical activities of daily living, and Charlson comorbidity index). High levels of IL-6 and sTNFα-R1 at baseline with small or no decline at 2 months were associated with higher odds of 5-year mortality compared with those with lower levels at baseline and greater decline at 2 months after adjustment for age, and other potential confounders (OR = 4.71, p = 0.01 for IL-6; OR = 15.03, p = 0.002 for sTNFα-R1). Similar results that failed to reach significance were found for IL-1RA (OR = 2.40, p = 0.18). Those with higher levels of cytokines at baseline with greater decline did not have significantly greater mortality than the reference group, those with lower levels at baseline and greater decline. Persistent elevation of plasma IL-6 and sTNFα-R1 levels within the first 2 months after hospital admission in patients with hip fracture is associated with higher 5-year mortality. These patients may benefit from enhanced care and earlier intensive interventions to reduce the risk of death.

Pinocembrin's protective effect against acute pancreatitis in a rat model: The correlation between TLR4/NF-κB/NLRP3 and miR-34a-5p/SIRT1/Nrf2/HO-1 pathways

Acute pancreatitis (APS) is a prevalent acute pancreatic inflammation, where oxidative stress, inflammatory signaling pathways, and apoptosis activation contribute to pancreatic injury. Pinocembrin, the predominant flavonoid in propolis, was explored for its likely shielding effect against APS provoked by two intraperitoneal doses of L-arginine (250 mg / 100 g) in a rat model. Pinocembrin ameliorated the histological and immunohistochemical changes in pancreatic tissues and lowered the activities of pancreatic amylase and lipase that were markedly elevated with L-arginine administration. Moreover, pinocembrin reinstated the oxidant/antioxidant equilibrium, which was perturbed by L-arginine, and boosted the pancreatic levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Pinocembrin markedly reduced the elevation in serum C-reactive protein (CRP) level induced by L-arginine. Additionally, it decreased the expression of high motility group box protein 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and NOD-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in the pancreas. Furthermore, it also reduced myeloperoxidase (MPO) activity. Pinocembrin markedly downregulated miR-34a-5p expression and upregulated the protein levels of peroxisome proliferator-activated receptor alpha (PPAR-α) and Sirtuin 1 (SIRT1) and the gene expression level of the inhibitor protein of NF-κB (IκB-α), along with normalizing the Bax/Bcl-2 ratio. Pinocembrin notably improved L-arginine-induced APS by its antioxidant, anti-inflammatory, and anti-apoptotic activities. Pinocembrin exhibited a protective role in APS by suppressing inflammatory signaling via the TLR4/NF-κB/NLRP3 pathway and enhancing cytoprotective signaling via the miR-34a-5p/SIRT1/Nrf2/HO-1 pathway.

Tumor Necrosis Factor-alpha (TNFα) receptor type 1 (TNFR1) activation during severe inflammation; Can it be a therapeutic target in hypervolemic hyponatremia?

Hyponatremia is a life-threatening situation in severe inflammatory disorders. Managing this disorder is seriously hampered because its underlying pathophysiology has remained elusive. An increase in tumor necrosis factor-alpha (TNFα) during systemic inflammation may be involved in this hyponatremic mechanism as it is known that circulating TNFα exerts potent natriuresis via its action on receptor type 1 (TNFR1). Systemic inflammation also induces non-osmotic release of Antidiuretic Hormone (ADH), commonly known as ‘Syndrome of Inappropriate ADH’ (SIADH), that would cause water retention to increase in Extracellular Fluid Volume (ECV). Thus, the inflammation-induced TNFR1 activation and sodium loss coupled with SIADH-induced increases in ECV, would lead to the serious condition of hypervolemic hyponatremia. In this brief review, some experimental evidence will be provided that indicates TNFR1 activation during the inflammatory process can be targeted therapeutically to prevent such critical conditions of hypervolemic hyponatremia. The importance of these co-morbidities also extends to several other clinical scenarios of hyponatremia observed in patients with heart failure, liver disease, and renal disease. Besides the pathophysiological insights, the recognition of the propensity for both antidiuresis and natriuresis during inflammation is critically important in selecting the appropriate intravenous fluid regimens in patients with this disorder such as in the coronavirus disease of 2019 (COVID-19).

The role of PANoptosis in renal vascular endothelial cells: Implications for trichloroethylene-induced kidney injury

The role of PANoptosis in renal vascular endothelial cells: Implications for trichloroethylene-induced kidney injury