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24Z-Masticadienonic acid (MNA) and 24Z-isomasticadienonic acid (IMNA) are the major triterpenic acids in Chios Mastic Gum (CMG), a resin derived from Pistacia lentiscus var. Chia. Despite their promising pharmacological potential, limited information is available due to the complexity of isolating them in pure form. This study developed a chemo-selective method for isolating MNA and IMNA and investigated their chemical transformation through isomerization of the external double bond and A-ring contraction of the triterpene scaffold. A rapid method for isolating MNA from CMG was first established, followed by a high-yield acid-catalyzed procedure to obtain both 24Z and 24E isomers of IMNA. Additionally, a basic catalyzed isomerization of IMNA led to the formation of two new compounds with A-ring contraction, which could serve as novel scaffolds for the design of new triterpene analogs. The mixture of MNA/IMNA, along with the individual compounds and their semi-synthetic analogs, exhibited significant anti-inflammatory activity. Notably, 24E-isomasticadienonic acid and 24Z-2-hydroxy-3-oxotirucalla-1,8,24-trien-26-oic acid, a previously unreported compound, significantly reduced the mRNA expression levels of Tnf, Il6, and Nfkb1 in RAW 264.7 macrophage cells. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study aimed to evaluate the prognostic significance of serum inflammatory factor levels in patients with acute ischemic stroke undergoing revascularization therapy. METHODS: The study included 94 patients with acute ischemic stroke who underwent revascularization therapy at our hospital. The primary outcome was the modified Rankin scale (mRS) score assessed three months post-treatment. Patients were categorized into two groups: those with a poor prognosis (mRS score > 2) and those with a good prognosis (mRS score≤2). The patients were divided into two groups based on the type of revascularization treatment received: thrombus extraction or intravenous thrombolysis. Logistic regression analysis was used to identify independent risk factors associated with the prognosis of patients treated with recanalization for acute ischemic stroke. RESULTS: Among the 94 patients, 59 had a good prognosis, and 35 had a poor prognosis. At admission, the patients in the good prognosis group exhibited lower NIHSS scores, shorter hospital stays, fewer previous cardiac events, lower LDL levels, fasting glucose, IL-6, and TNF-a compared to those in the poor prognosis group (all P < 0.05). Logistic regression analysis identified TNF-a (odd ratio (OD), 1.623; 95% confidence interval (CI), 1.282–1.933; P = 0.035) and IL-6 (OD, 1.055; 95% CI, 1.024–1.088, P = 0.023) as independent risk factors for poor prognosis in patients after revascularization. Additionally, pre-hospital NIHSS scores, IL-6, and TNF-a levels were significantly lower in the good prognosis group compared to the poor prognosis group, with these differences being statistically significant. CONCLUSION: IL-6 and TNF-α may serve as prognostic markers for outcomes following revascularization therapy in patients with acute ischemic stroke, including those receiving intravenous thrombolysis. [ABSTRACT FROM AUTHOR]

Uterine leiomyomas (UL) are benign uterine tumors. Hypertrophic increase in muscle mass in LM is accompanied by development of vascular networks, which are regulated by the balance of pro-angiogenic factors, e.g., VEGF-A. Moreover, a number of inflammatory molecules exert pro-angiogenic effects, especially, IL-1β, IL-8, etc. The spectrum of their activity may overlap, being regulated by other cytokines. The aim of our work was to assess serum concentrations of cytokines actively involved in vascular network growth in the patients with multiple uterine fibroids, as compared with data obtained in conditionally healthy women. The survey included 178 females: 89 women (23-60 years old) with uterine fibroids, and 89 conditionally healthy age-matched women (22-61 years old). The levels of TNFα, IL-1β, IL-4, IL-6, IL-8, IL-10 and VEGF-A were detected by ELISA technique (Vector-Best, Russia). Statistical analysis was carried out using the IBM SPSS Statistics 23 (USA). Serum levels of IL-6, TNF and IL-8, were higher among patients compared with healthy women. The dependence of VEGF level on the number of myoma nodes has been established: VEGF serum level was higher in patients with multiple tumor nodes. In healthy women, an increase in TNFα level showed direct correlation with higher serum level of IL-6. Correlation with VEGF level was weakly negative. In leiomyoma, these relationships persist for IL-6, IL-8, VEGF levels. The obtained data are of practical importance not only as potential prognostic criteria for development of the uterine myoma at preclinical stage, but also as additional laboratory indexes for differential diagnostics, in particular when discerning uterine leiomyoma, the most common benign myomatous tumor of uterus, from malignant uterine leiomyosarcomas.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing b-cells in the pancreas. This destruction leads to chronic hyperglycemia, necessitating lifelong insulin therapy to manage blood glucose levels. Typically diagnosed in children and young adults, T1D can, however, occur at any age. Ongoing research aims to uncover the precise mechanisms underlying T1D and to develop potential interventions. These include efforts to modulate the immune system, regenerate b-cells, and create advanced insulin delivery systems. Emerging therapies, such as closed-loop insulin pumps, stem cell-derived b-cell replacement and disease-modifying therapies (DMTs), offer hope for improving the quality of life for individuals with T1D and potentially moving towards a cure. Currently, there are no disease-modifying therapies approved for stage 3 T1D. Preserving b-cell function in stage 3 T1D is associated with better clinical outcomes, including lower HbA1c and decreased risk of hypoglycemia, neuropathy, and retinopathy. Tumor Necrosis Factor alpha (TNFa) inhibitors have demonstrated efficacy at preserving b-cell function by measurement of C-peptide in two clinical trials in people with stage 3 T1D. However, TNF-a inhibitors have yet to be evaluated in a pivotal trial for T1D. To address the promising clinical findings of TNF-a inhibitors in T1D, Breakthrough T1D convened a panel of key opinion leaders (KOLs) in the field. The workshop aimed to outline an optimal clinical path for moving TNF-a inhibitors to a pivotal clinical trial in T1D. Here, we summarize the evidence for the beneficial use of TNF-a inhibitors in T1D and considerations for strategies collectively identified to advance TNF-a inhibitors beyond phase 2 clinical studies for stage 3 T1D. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Cardiovascular disease is the main cause of mortality in patients with chronic kidney disease stage 5 on dialysis (CKD-5D). High sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-a (TNF-a), and neutrophil-lymphocyte ratio (NLR) are several inflammatory parameters associated with high cardiovascular events in CKD-5D. The main aim of this study was to evaluate the effect of reduced L-glutathione supplementation on serum hs-CRP, TNF-a, and NLR in patients with CKD-5D. PATIENTS AND METHODS: This study is a quasi-experimental research with one group pretest-posttest design. Subjects included were patients with CKD-5D who routinely underwent hemodialysis therapy two times a week in Hasan Sadikin General Hospital. Serum hs-CRP, TNF-a, and NLR levels were obtained before and after the intervention of reduced L-glutathione supplementation dosing of one thousand milligrams a day for four weeks. Statistical analysis was then conducted using the Wilcoxon test. RESULTS: There were 26 hemodialysis patients included in the study, with a median age of 43 years and a male predominance. There was a significant decrease in serum TNF-a level after reduced L-glutathione supplementation for 4 weeks, 5.40 (-10.80-0.00) pg/mL, p = 0.002. However, there was no statistically significant decrease in either serum hs-CRP level, 0.40 (-0.70-0.80) mg/L (p = 0.656), or NLR with a difference of 0.55 (0.30-1.00) p = 0.055. CONCLUSIONS: Exogenous oral reduced glutathione supplementation for four weeks significantly reduced TNF-a level, but no significant decrease in hs-CRP level and NLR in patients with CKD-5D. [ABSTRACT FROM AUTHOR]

Background: The association between cytokines in peripheral blood and clinical symptoms of multiple system atrophy (MSA) has been explored in only a few studies with small sample size, and the results were obviously controversial. Otherwise, no studies have explored the diagnostic value of serum cytokines in MSA. Methods: Serum cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF-a), were measured in 125 MSA patients and 98 healthy controls (HCs). Correlations of these serum cytokines with clinical variables were analyzed in MSA patients. Diagnostic value of cytokines for MSA was plotted by receiver operating curves. Results: No significant differences were found in sex and age between the MSA group and the HCs. TNF-a in MSA patients were significantly higher than those in HCs (area under the curve (AUC) 0.768), while IL-6 and IL-8 were not. Only Hamilton Anxiety Scale (HAMA) has a positive correlation between with TNF-a in MSA patients with age and age at onset as covariates. Serum IL-6 was associated with HAMA, Hamilton Depression Scale (HAMD), the Unified MSA Rating Scale I (UMSARS I) scores, the UMSARS IV and the Instrumental Activity of Daily Living scores. However, IL-8 was not associated with all clinical variables in MSA patients. Regression analysis showed that HAMA and age at onset were significantly associated with TNF-a, and only HAMA was mild related with IL-6 levels in MSA patients. Conclusion: Serum TNF-a and IL-6 levels in MSA patients may be associated with anxiety symptom; however, only TNF-a was shown to be a useful tool in distinguishing between MSA and HCs. [ABSTRACT FROM AUTHOR]

Objective: To evaluate levels of physiological parameters (Testosterone, follicle stimulating hormone FSH, luteinizing hormone LH, leptin and tumor necrosis factor TNF-a, Adipsin and Ghrelin), Total antioxidant capacity-TAC, Glutathione S transfers -GST in sera of patients with endometriosis. Methods: This study involved (85) women within reproductive age (25-40) years, who were distributed into two groups: patients' group (55) women diagnosed with endometriosis, and (30) healthy control women. The study was carried out at Al-Karkh Maternity Hospital/Baghdad and extended from 20/4/2024 to 20/5/2024. The pathological cases of patients were diagnosed by clinical examinations and confirmed by specialist physician with ultrasound examination. Blood samples were taken from both groups, serum was separated for each individual by a centrifuge. Results: A significant rise in the (FSH, Leptin, TNF-a, Adipisin) while a significant decrease in levels of (Testosterone, LH, GST, TAC, Ghrelin) concentration were found in the sera of patients compered to healthy women, with a probability of P = 0.05. According to Receiver operating characteristic (ROC) statistical analysis, Area under curve (AUC) for LH, leptin, TNF-a, adipsin, ghrelin, GST, TAC were closely or equal to (1) for patients. Conclusion: Serum levels of LH, Leptin, Adipisin, Gherlin, TNF-a and GST can be dependable as prognostic indicator markers that reflect the degree of oxidative stress accompanying endometriosis. [ABSTRACT FROM AUTHOR]

Community-acquired pneumonia (CAP) is a common respiratory disease in children. This prospective cohort study of 110 children with CAP and 100 healthy children investigated the relationship between the levels of vitamin A, D and E and inflammatory markers, such as tumour necrosis factor (TNF-a), interleukin-1 (IL-1), interleukin-10 (IL-10), neutrophils (NE) and C-reactive protein (CRP), in CAP. The haemoglobin, leukocyte concentration, NE, monocytes and CRP concentration in the CAP group showed significant differences (P < 0.05). The levels of vitamin A, D and E in the CAP group were lower than those in the control group, while the levels of TNF-a and IL-1 were higher than in the control group; the differences were statistically significant (P < 0.05). The IL-10 levels showed no significant differences (P > 0.05). Pearson analysis revealed that the vitamin A, D and E levels were all correlated with the TNF-a, IL-10 and CRP levels (P < 0.05). The vitamin A, D and E levels of the CAP children were lower than those of the healthy children. Thus, the content of fat-soluble vitamins is correlated with the secretion of TNF-a and IL-10. The research provides a new direction for the prevention, diagnosis and treatment of CAP.

Introduction: There is growing evidence indicating that being overweight and obese has a negative impact on the central nervous system. It was also demonstrated that excessive body fat coincides with lower levels of cognitive functions. The potential mechanism by which the excessive adipose tissue can negatively influence cognitive performance is unclear. However, it is generally accepted that the negative impact of body fat on cognitive function may be mediated by inflammatory cytokines. The current study examines the impact of body fat on cognitive performance in young, healthy people. The authors also attempt to determine the potential mechanism of such an impact. Material and methods: 38 women, age 21.65 ± 1.45 took part in this study. To evaluate the cognitive performance of the present subjects, standard cognitive tests were used: the Face/name Association Test, Stroop Test, and Trail Making Test. The level of fat tissue was determined by a body composition analyzer (Tanita, type BC-418MA). The levels of IL-6 and TNF-alpha were determined in serum using an enzyme-linked immunosorbent assay (ELISA) kit (LDN GmbH & Co., Nordhorn, Germany). Results: A statistically significant relationship was observed between the percentage of body fat tissue and the level of TNF-a as well as waist-hip ratio and IL-6. A negative correlation was demonstrated between the level of IL-6 and cognitive performance. A statistically significant correlation between the level of TNF-a and the results of cognitive tests was not observed. Conclusions: This study confirms that an increase in body fat content leads to a decreasing level of cognitive performance. Also, demonstrated was a negative correlation between the level of IL-6 and the results of cognitive tests in young people. [ABSTRACT FROM AUTHOR]

A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). The study analysed articles published in JCR journals from 2019 to 2024. The search strategy comprised the MESH, free terms of "Neuroinflammation", and selective searches for the following single biomarkers that had previously been selected from the relevant literature: "High mobility group box 1/HMGB1", "Toll-Like-Receptor 4/TLR-4", "Interleukin-1/IL-1", "Interleukin-6/IL-6", "Transforming growth factor beta/TGF-β", and "Tumour necrosis factor-alpha/TNF-α". These queries were all combined with the MESH terms "Epileptogenesis" and "Epilepsy". We found 243 articles related to epileptogenesis and neuroinflammation, with 356 articles from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 55 evaluated by the authors. A total of 21 articles were included in the qualitative evaluation, including 18 case–control studies, 2 case series, and 1 prospective study. As conclusion, this systematic review provides acceptable support for five biomarkers, including TNF-α and some of its soluble receptors (sTNFr2), HMGB1, TLR-4, CCL2 and IL-33. Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control of epileptic seizures. Their value will be better defined by future studies. [ABSTRACT FROM AUTHOR]

Objective: The present study investigated the effects of Andaliman fruit extract on tumor necrosis factor-alpha (TNF-α) and transient receptor potential ankyrin-1 (TRPA-1) levels in type 2 diabetes mellitus (T2DM) mouse models induced with streptozocin (STZ) and a high-fat diet (HFD). Materials and Methods: In this research, mice were allocated into six distinct groups: normal, negative control (HFD and STZ), positive control (metformin, HFD, and STZ), and three treatment groups (HFD, STZ, and Andaliman extract at varying dosages of 100, 300, and 500 mg/kg, respectively). Body weight and blood glucose levels (BGLs) were recorded at weeks 1 (baseline), 8, 12, and 16. The levels of TNF-α and TRPA-1 were measured during the 16th week. Results: Phytochemical screening of the Andaliman extract revealed the presence of flavonoids, alkaloids, tannins, saponins, and glycosides. The one-way ANOVA revealed significantly elevated BGL at week 16 in the negative control group in comparison to the other groups (p < 0.05). The Kruskal-Wallis test followed by Bonferroni-corrected pairwise comparisons showed that the negative control had significantly higher TNF-α levels than the Andaliman-groups (z = 22.11, p < 0.01). TRPA-1 was significantly higher in the negative control group compared to the treatment groups (p < 0.05). Furthermore, Spearman's rho analysis revealed a statistically significant positive association between BGL and both TNF-α and TRPA-1, as well as between TNF-α and TRPA. Conclusion: Andaliman extract potentially serves as a therapy for diabetic neuropathy in T2DM by lowering BGL and inhibiting the expression of TNF-α and TRPA-1. [ABSTRACT FROM AUTHOR]

Multipotent mesenchymal stromal cells (MSC) play an increasing role in the treatment of immune-mediated diseases and inflammatory processes. They regulate immune cells via cell-cell contacts and by secreting various anti-inflammatory molecules but are in turn influenced by many factors such as cytokines. For MSC culture, platelet lysate (PL), which contains a variety of cytokines, is a promising alternative to fetal bovine serum (FBS). We aimed to analyze if PL with its cytokines improves MSC immunoregulatory characteristics, with the perspective that PL could be useful for priming the MSC prior to therapeutic application. MSC, activated peripheral blood mononuclear cells (PBMC) and indirect co-cultures of both were cultivated in media supplemented with either PL, FBS, FBS+INF-g or FBS+IL-10. After incubation, cytokine concentrations were measured in supernatants and control media. MSC were analyzed regarding their expression of immunoregulatory genes and PBMC regarding their proliferation and percentage of FoxP3+ cells. Cytokines, particularly IFN-g and IL-10, remained at high levels in PL control medium without cells but decreased in cytokine-supplemented control FBS media without cells during incubation. PBMC released IFN-g and IL-10 in various culture conditions. MSC alone only released IFN-g and overall, cytokine levels in media were lowest when MSC were cultured alone. Stimulation of MSC either by PBMC or by PL resulted in an altered expression of immunoregulatory genes. In co-culture with PBMC, the MSC gene expression of COX2, TNFAIP6, IDO1, CXCR4 and MHC2 was upregulated and VCAM1 was downregulated. In the presence of PL, COX2, TNFAIP6, VCAM1, CXCR4 and HIF1A were upregulated. Functionally, while no consistent changes were found regarding the percentage of FoxP3+ cells, MSC decreased PBMC proliferation in all media, with the strongest effect in FBS media supplemented with IL-10 or IFN-g. This study provides further evidence that PL supports MSC functionality, including their immunoregulatory mechanisms. The results justify to investigate functional effects of MSC cultured in PL-supplemented medium on different types of immune cells in more detail. [ABSTRACT FROM AUTHOR]

Objective: To detect the continuous blood purification (CBP)'s application value in patients with urosepsis caused by ureteral calculi and heart failure after catheterization. Methods: This is a clinical comparative study. Sixty patients with ureteral calculi complicated with heart failure and urosepsis were admitted at Affiliated Hospital of Hebei University from January 2021 to March 2023 randomly split into control and experimental group(n=30). Based on conventional treatment after indwelling the DJ tube, the experimental group was treated with CBP therapy. The control group dealt with conventional anti-inflammatory, oxygen inhalation and other treatments only. Compared and analyzed in terms of alterations in blood inflammatory factors, cardiac function, BNP prior to and after therapy, blood pressure, blood WBC recovery time, and so on. Results: TNF-a, CRP, and PCT levels in the control and experimental groups were substantially more prominent than the average reference value prior to treatment. They decreased considerably at distinct time points after therapy, with substantial distinctions (p< 0.05). A more meaningful decrease was noticed in the experimental group in comparison with the control group (p< 0.05). BNP and cardiac function were improved in both groups prior to and after therapy, and the amelioration of indexes in the experimental group was more substantial than that in the control group after therapy, with statistically considerable distinctions. The improvement time in experimental group was earlier than in the control group, with statistically substantial differences. Conclusion: Patients with urosepsis complicated with heart failure after indwelling DJ tube have their inflammatory factors improved significantly, with more thorough excretion by using conventional treatment combined with CBP therapy. [ABSTRACT FROM AUTHOR]

Adequate diet, physical activity, and dietary supplementation with muscle-targeted food for special medical purposes (FSMP) or dietary supplement (DS) are currently considered fundamental pillars in sarcopenia treatment. The aim of this study is to evaluate the effectiveness of a DS (containing hydroxy-methyl-butyrate, carnosine, and magnesium, for its action on muscle function and protein synthesis and butyrate and lactoferrin for their contribution to the regulation of gut permeability and antioxidant/anti-inflammation activity) on muscle mass (assessed by dual X-ray absorptiometry (DXA)), muscle function (by handgrip test, chair test, short physical performance battery (SPPB) test, and walking speed test), inflammation (tumor necrosis factor-alpha (TNF-a), C-reactive protein (CRP), and visceral adipose tissue (VAT)) and gut axis (by zonulin). A total of 59 participants (age 79.7 ± 4.8 years, body mass index 20.99 ± 2.12 kg/m2) were enrolled and randomly assigned to intervention (n = 30) or placebo (n = 28). The skeletal muscle index (SMI) significantly improved in the supplemented group compared to the placebo one, +1.02 (CI 95%: −0.77; 1.26), p = 0.001; a significant reduction in VAT was observed in the intervention group, −70.91 g (−13.13; −4.70), p = 0.036. Regarding muscle function, all the tests significantly improved (p = 0.001) in the supplemented group compared to the placebo one. CRP, zonulin, and TNF-alpha significantly decreased (p = 0.001) in intervention, compared to placebo, −0.74 mg/dL (CI 95%: −1.30; −0.18), −0.30 ng/mL (CI 95%: −0.37; −0.23), −6.45 pg/mL (CI 95%: −8.71; −4.18), respectively. This DS improves muscle mass and function, and the gut muscle has emerged as a new intervention target for sarcopenia. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress (ERS) and Toll-like receptor 2 (TLR2) signaling play an important role in inflammatory bowel disease (IBD); however, the link between TLR2 and ERS in IBD is unclear. This study investigated whether Thapsigargin (TG) -induced ER protein expression levels contributed to TLR2-mediated inflammatory response. The THP-1 cells were treated with TLR2 agonist (Pam3CSK4), ERS inducer Thapsigargin (TG) or inhibitor (TUDCA). The mRNA expressions of TLR1-TLR10 were detected by qPCR. The production and secretion of inflammatory factors were detected by PCR and ELISA. Immunohistochemistry was used to detect the expressions of GRP78 and TLR2 in the intestinal mucosa of patients with Crohn's disease (CD). The IBD mouse model was established by TNBS in the modeling group. ERS inhibitor (TUDCA) was used in the treatment group. The expression of TLRs was detected via polymerase chain reaction (PCR) in THP-1 cells treated by ERS agonist Thapsigargin (TG). According to the findings, TG could promote TLR2 and TLR5 expression. Subsequently, in TLR2 agonist Pam3CSK4 induced THP-1 cells, TG could lead to increased expression of the inflammatory factors such as TNF-α, IL-1β and IL-8, and ERS inhibitor (TUDCA) could block this effect. However, Pam3CSK4 did not significantly impact the GRP78 and CHOP expression. Based upon the immunohistochemical results, TLR2 and GRP78 expression were significantly increased in the intestinal mucosa of patients with Crohn's disease (CD). For in vivo experiments, TUDCA displayed the ability to inhibit intestinal mucosal inflammation and reduce GRP78 and TLR2 proteins. ERS and TLR2 is upregulated in inflammatory bowel disease, ERS may promote TLR2 pathway-mediated inflammatory response. Moreover, ERS and TLR2 signaling could be novel therapeutic targets for IBD. [ABSTRACT FROM AUTHOR]

Background: Cancer-related anemia (CRA) occurs in a significant proportion of cancer patients and affects disease progression, treatment efficacy, and survival. The chronic inflammatory state associated with cancer is believed to be a major cause of CRA. Tumor necrosis factor alfa (TNF-a) plays a crucial role in the pathogenesis of cancer-related anemia (CRA). Aim: To evaluate TNF-a level, erythropoietin (EPO), and iron status in children with newly diagnosed solid tumors. Methods: This cross-sectional study included 42 children with newly diagnosed solid tumors, recruited from the Pediatric Oncology Clinic at Ain Shams University Children's Hospital by random sampling during the period from June 2022 to February 2023. Twenty-five age- and sexmatched children were enrolled as hospital-based controls. All study participants were subjected to full history taking, through clinical examination and assessment of CBC, iron profile, serum TNF-a and EPO levels. Results: Out of 42 cancer patients, 48%(n=20) were non-anemic (group 1) and, 52%(n=22) were anemic (group 2) with 54.5% (n=12) having functional iron deficiency (FID) anemia. In both patient groups, significantly higher TNFa and lower EPO levels were found compared to controls. Among the anemic group, TNFa negatively correlated with both EPO level and reticulocyte count (p= 0.024) and (p= 0.211) respectively. Conclusion: Patients with CRA have evident state of FID anemia, elevated TNFa and reduced EPO levels. [ABSTRACT FROM AUTHOR]

Objective: Tumor necrosis factor-a (TNF-a) inhibitors are used extensively in the treatment of inflammatory diseases in rheumatology, ophthalmology, and neurology. Despite their therapeutic benefits, inflammatory demyelinating lesions or relapses have been observed following TNF-a inhibitor use. Materials and Methods: Of the 295 patients who were screened, 258 were included in the study. The demographic characteristics, diagnoses, accompanying diseases, TNF-a agent(s) used, drug usage, and exposure times were recorded. The neurological symptoms and clinical visits were also documented. Results: The study included 142 females and 116 males, with a mean age of 43.82±11.81 years. Twenty-eight patients used three or more TNF-a inhibitors for an average of 72.42 months. Fifty-eight patients used two TNF-a inhibitors for 55.7 months, and 172 patients used a single TNF-a inhibitor for 45.27 months. During the follow-up, a brain magnetic resonance imaging (MRI) was obtained in 63 patients. Most of these MRIs showed asymptomatic lesions that met one Barkhof criteria and scored one on Fazekas scale for deep and periventricular white matter lesions. One patient with idiopathic uveitis exhibited symptoms of a demyelinating lesion. Conclusion: TNF-a inhibitors appear to be mostly safe with regards to the induction of inflammatory demyelinating diseases/lesions. However, patients with idiopathic uveitis may be predisposed to developing or presenting with inflammatory/demyelinating lesions of the central nervous system. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the impact of continuous blood purification in conjunction with reduced glutathione on endotoxin levels, inflammatory mediators and the severity of liver injury in septic shock patients. Methods: A cohort of 100 septic shock patients admitted at The Second Affiliated Hospital of Hainan Medical University, China between May 2020 and May 2023 were enrolled in this study. They were randomly divided into study and control groups, each comprising 50 patients. Both groups received standard interventions. In addition, control group underwent continuous blood purification, while study group received reduced glutathione therapy for two weeks. Acute physiology score + age point + chronic health point (APACHE II) and sequential organ failure assessment (SOFA) scores, intensive care unit (ICU) and mechanical ventilation duration, oxygenation levels, 28-day mortality, organ injury, serum endotoxin levels, inflammatory markers, as well as serum aspartate aminotransferase (AST) and glutamate aminotransferase (ALT) levels were determined before and after treatment. Adverse events during treatment were documented. Results: Both groups exhibited a significant decrease in APACHE II and SOFA scores, with greater decreases observed in study group (p < 0.05). The study group had shorter ICU stays and mechanical ventilation durations. The groups had no significant differences in 28-day mortality or organ injury (p > 0.05). Study group demonstrated significantly lower levels of endotoxin, tumor necrosis factor (TNF-a), procalcitoninogen (PCT), ALT and AST in comparison to control group (p < 0.05). Adverse reactions were similar between the two groups (p > 0.05). Conclusion: Combining continuous blood purification with reduced glutathione therapy reduces endotoxin and inflammatory mediator levels, mitigates liver injury and supports patient recovery in septic shock, with a favorable safety profile. Future studies to accommodate the diverse profiles of septic shock patients from multiple centers will be needed to validate the outcomes of this study. [ABSTRACT FROM AUTHOR]

Background: To study the changes in intestinal flora in patients with ulcerative colitis (UC), and to explore its correlations with micro ribonucleic acid (miR)-21 and serum tumor necrosis factor-a (TNF-a). Methods: A total of 150 patients with UC were selected and divided into remission group and seizure group according to the severity of disease. At the same time, 150 healthy people receiving physical examination in the hospital during the same period were selected as control group. The levels of fecal miR-21 and TNF-a in all subjects were determined via reverse transcription-polymerase chain reaction (RT-PCR). The correlation between miR-21 and TNF-a and their associations with the changes in intestinal bacteria in UC were analyzed using Pearson correlation analysis. The risk factors affecting the occurrence of UC were explored via multivariate logistic regression analysis. Results: The levels of fecal miR-21 and TNF-a in patients with UC were significantly higher than those in control group, and they were also significantly higher in seizure group than those in remission group. There was a positive correlation between the levels of miR-21 and TNF-a. The number of fecal intestinal flora (Bifidobacterium, Lactobacillus, Enterobacterium and Enterococcus) was different in patients with varying degrees of disease. MiR-21 and TNF-a were negatively correlated with the content of Bifidobacterium and Lactobacillus, but positively correlated with the content of Enterobacterium and Enterococcus. According to multivariate logistic regression analysis, miR-21 and TNF-a were risk factors for the seizure of UC. Conclusion: MiR-21 can promote the expression of TNF-a, and lead to the alteration of intestinal flora, thereby enhancing the occurrence and development of UC. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by multi-organ multi-system inflammation, causing severe damage to various organs or systems. Recent studies have shown that miR-155 can affect the progression of Lupus Nephritis via regulating TNF-a. The present study aims to explore the roles of MIR155HG and TNF-a in the evaluation of prognosis of patients with SLE, so as to provide a basis for clinical work. Methods: A total of 130 patients with SLE admitted to our hospital were selected, were selected from June 2015 to December 2017., and the SLE disease activity index (SLEDAI) score was given. 1 he expressions of MIR155HG and 1 NF-a were detected via quantitative reverse transcription-polyme-rase chain reaction (qRT-PCR), the incidence of complications during treatment was observed, and the associations of MIR155HG and TNF-a with SLEDAI before treatment and complications were analyzed. All patients were followed up after discharge, and the related factors to the prognosis of patients were analyzed via Cox regression analysis. Results: The levels of MIR155HG and TNF-a were higher in patients with an SLEDAI score of 10-14 points than those in patients with an SLEDAI score of 5-9 points and 0-4 points. MIR155HG and TNF-a were positively correlated with the incidence of infection, renal damage and cardiac damage (r=0.623, 0.533 and 0.621; r=0.431, 0.498 and 0.552) (P<0.05). Moreover, there was also a positive correlation (r=0.3398, PcO.001) between the expressions of serum MIR155HG and TNF-a in SLE patients. SLEDAI score Ž10 points, complications during hospitalization, and highly-expressed MIR155HG and TNF-a were risk factors related to the prognosis of patients. Conclusions: MIR155HG and TNF-a affect the activity of SLE, and the high expressions of them promote the occurrence of such complications as infection, renal damage and cardiac damage, harming the prognosis. [ABSTRACT FROM AUTHOR]

Introduction: 7,12-dimethylbenz (a) anthracene (DMBA) is a harmful polycyclic aromatic hydrocarbon derivative known for its cytotoxic, carcinogenic, and mutagenic effects in mammals and other species. Annona muricata, L. (Graviola; GRV) is a tropical fruit tree traditionally well-documented for its various medicinal benefits. This investigation is the first report on the potential antioxidant and antinfammatory reno-protective impact of GRV against DMBAinduced nephrotoxicity in rats. Methods: Forty male albino rats were allocated into four equal groups (n = 10). The 1st group served as the control, the 2nd group (GRV) was gastro-gavaged with GRV (200 mg/kg b.wt), the 3rd group (DMBA) was treated with a single dose of DMBA (15 mg/kg body weight), and the 4th group (DMBA + GRV) was gastrogavaged with a single dose of DMBA, followed by GRV (200 mg/kg b.wt). The GRV administration was continued for 8 weeks. Results and Discussion: Results revealed a significant improvement in renal function, represented by a decrease in urea, creatinine, and uric acid (UA) in the DMBA + GRV group. The antioxidant potential of GRV was confirmed in the DMBA + GRV group by a significant decline in malondialdehyde (MDA) and a significant increase in catalase (CAT), superoxide dismutase (SOD), glutathione S transferase (GST), and reduced glutathione (GSH) compared toDMBA-intoxicated rats; however, it was not identical to the control. Additionally, the antiinflammatory role of GRV was suggested by a significant decline in mRNA expression of cytochrome P450, family 2, subfamily e, polypeptide 1 (CYP2E1), tumor necrosis factor-alpha (TNF-a), and interleukin 1 beta (IL-1ß) in the DMBA + GRV group. Moreover, GRV improved the histopathologic and immunohistochemical expression of TNF-a, CYP450, and IL1ß in DMBA-intoxicated kidney tissue. Conclusively, GRV is a natural medicinal product that can alleviate the renal injury resulting from environmental exposure to DMBA. The reno-protective effects of GRV may involve its anti-inflammatory and/or antioxidant properties, which are based on the presence of phytochemical compounds such as acetogenins, alkaloids, and flavonoids. [ABSTRACT FROM AUTHOR]

PANoptosis is an inflammatory programmed cell death (PCD) regulated by multifaceted PANoptosome complexes with major features of pyroptosis, apoptosis, and/or necroptosis that cannot be accounted for by any of these PCD pathways alone. The aim of this study was to investigate the role of PANoptosis on the occurrence and development of abdominal aortic aneurysm (AAA). Clinical samples of patients with AAA, angiotensin II (ANG II)-induced AAA mouse model, and ANG II-induced vascular smooth muscle cells (VSMCs) in vitro model were used for investigation on PANoptosis features. The expressions of ZBP1, AIM2, and other markers related to pyroptosis, apoptosis, and necroptosis elevated obviously in aortic wall tissues of patients with AAA, mice with AAA, and ANG II-treated VSMCs. ANG II treatment increased inflammatory cytokines levels in VSMCs. The stimulation of tumor necrosis factor-a (TNF-a) or interleukin-1b (IL-1b) alone promoted VSMCs death, and the effect of TNF-a combined with IL-1b is more obvious. The expressions of ZBP1, AIM2, and related markers of pyroptosis, apoptosis, and necroptosis were increased by TNF-a and IL-1b combined treatment. Inhibition of TNF-a and/or IL-1b in mice with AAA improved the AAA pathology, reduced the loss of VSMCs, decreased the expression of ZBP1 and AIM2, and markers associated with pyroptosis, apoptosis, and necroptosis. PANoptosis features were observed in aortic wall tissues of patients with AAA, mice with AAA, and ANG IItreated VSMCs. The inhibition of TNF-a and IL-1b can alleviate PANoptosis in mice with AAA, which provides a new strategy for the prevention and treatment of AAA. NEW & NOTEWORTHY Early detection, diagnosis, and treatment are very important to improve the quality of life and prognosis of patients with abdominal aortic aneurysm (AAA). Based on the findings of apoptosis, necroptosis, and pyroptosis (PANoptosis) in AAA clinical samples, this study further explored the molecular mechanism in vivo and in vitro. Specifically, inhibition of tumor necrosis factor-a and interleukin-1b can reduce PANoptosis in vascular smooth muscle cell and thus alleviate the process of AAA. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress and inflammation play an important role in cataracts' causal network. In this study, we used the Dietary Inflammatory Index (DII) and Dietary Antioxidant Index (DAI) to comprehensively examine the nutritional status related to inflammation and oxidative stress and investigate their association with the odds of cataracts. We hypothesize that higher DII scores (a pro-inflammatory diet) and lower DAI (a pro-oxidant diet) are associated with related serum biomarkers and increase the odds of cataracts. Methods: The study included 263 patients with cataracts and 326 healthy controls. A valid 168-item food frequency questionnaire (FFQ) evaluated the participants' dietary intake over the past year. DII and DAI were calculated based on FFQ, and blood/serum indicators, e.g., hs-CRP, TNF-a, etc., were extracted from patients' records. Results: Based on the multivariable linear regression models, there was a significant association between DII and hs-CRP (Beta = 0.095, CI95 %: 0.001–0.189) and between DAI and TNF-a (Beta = 0.494, CI95 %: 0.121–0.866) and LDL-C (Beta = 1.037, CI95 %: 0.159–1.915). In addition, in logistic regression models, after adjusting for multiple confounders, there was a significant association between DII (continuous variable) (OR = 1.27, CI95 %: 1.08–1.50) and DAI (continuous variable) (OR = 0.93, CI95 %: 0.87–0.99) and odds of cataracts. Conclusion: This study confirms the association between pro-inflammatory and pro-oxidant diets, as indicated by higher DII scores and lower DAI, with serum biomarkers of inflammation and oxidative stress. Our study supports the notion that dietary interventions targeting inflammation and oxidative stress may have a potential role in preventing or delaying the onset of cataracts.

Introduction: The clinical manifestations of acute severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) suggest a dysregulation of the host immune response that leads to inflammation, thrombosis, and organ dysfunction. It is less clear whether these dysregulated processes persist during the convalescent phase of disease or during long COVID. We sought to examine the effects of SARS-CoV-2 infection on the proportions of classical, intermediate, and nonclassical monocytes, their activation status, and their functional properties in convalescent COVID-19 patients. Methods: Peripheral blood mononuclear cells (PBMCs) from convalescent COVID-19 patients and uninfected controls were analyzed by multiparameter flow cytometry to determine relative percentages of total monocytes and monocyte subsets. The expression of activation markers and proinflammatory cytokines in response to LPS treatment were measured by flow cytometry and ELISA, respectively. Results: We found that the percentage of total monocytes was decreased in convalescent COVID-19 patients compared to uninfected controls. This was due to decreased intermediate and non-classical monocytes. Classical monocytes from convalescent COVID-19 patients demonstrated a decrease in activation markers, such as CD56, in response to stimulation with bacterial lipopolysaccharide (LPS). In addition, classical monocytes from convalescent COVID-19 patients showed decreased expression of CD142 (tissue factor), which can initiate the extrinsic coagulation cascade, in response to LPS stimulation. Finally, we found that monocytes from convalescent COVID-19 patients produced less TNF-a and IL-6 in response to LPS stimulation, than those from uninfected controls. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the nephroprotective effect of vildagliptin against cisplatin-induced nephrotoxicity in rats. Methods: Twenty-eight male rats have been divided into four groups: Control (received distal water), cisplatin treated group (received single dose of cisplatin (7 mg/kg) intraperitoneally (IP) on day eight), vildagliptin plus cisplatin treated group (received vildagliptin 10 mg/kg/day orally for 14 days, seven days before and seven days after the dose of cisplatin on day eight), and vildagliptin treated group (received the same dose and duration of vildagliptin mentioned previously). At the end, blood samples were collected to evaluate tumor necrotic factor-a (TNF-a), caspase-3, total antioxidant capacity (TAOC), urea, and creatinine. The serum levels of these biomarkers were expressed as mean ± standard error of mean. Additionally, kidneys were fixed in formalin for histopathological examination. Results: Vildagliptin treatment significantly reduced the serum levels of TNF-a, caspase-3, urea, and creatinine as well as increased the TAOC level in rats treated with vildagliptin plus cisplatin when compared with cisplatin treated group. Histopathological examination further supported the nephroprotective effect of vildagliptin in rats with cisplatin induced nephrotoxicity. Conclusion: Vildagliptin improved kidney function and reduced cisplatin nephrotoxicity which may highlight the nephroprotective effect of this DPP-4 inhibitor against cisplatin-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Aim: investigate the possible anti-psoriatic effect of ivermectin in mice based on observational and histopathological outcomes and biomarkers. Methods: Sixty male Swiss Albino Mice were divided into six groups (Groups I-VI); each group contained ten mice with shaved dorsal skin. The clinical, pathological, and laboratory effects were measured. Results: Topical Ivermectin significantly decreased vascular endothelial growth factor levels. At the same time, the combination of ivermectin plus Clobetasol showed a more significant reduction in tumor necrosis factor-alpha (TNF-α) and Interleukin-17 (IL-17) levels. Regarding the Interleukin-10 (IL-10) level, the Ivermectin and Ivermectin/Clobetasol combination groups showed a significant increase in IL-10. Conclusion: Topical Ivermectin's anti-psoriasis activity increases IL-10 levels and could be used efficiently to alleviate psoriatic symptoms. Its combination treatment with Clobetasol holds promise for the management of psoriasis. [ABSTRACT FROM AUTHOR]

Background: Peptic Ulcer Disease is characterized by acid-induced ulcers in the stomach and duodenum. Their denuded mucosa with the distortion which extends into the submucosa or muscularis propria distinguishes them. The rationale behind this study was that long-term use of aspirin reduces Prostaglandins levels, due to which the protective mechanism of the gastric layer gets affected and results in sore formation and cytokine infiltration at the site of damage along with the inflammation. The study objective was to investigate the combination of curcumin (40 mg/kg) and flaxseed oil (5 mL/kg) compared to disease control and ranitidine hydrochloride (standard 50 mg/Kg) in an NSAID-induced gastric ulcer model. Materials and Methods: Male Wistar rats were given standard, curcumin, and flaxseed oil individually and in combination for 10 days before being given aspirin. Body weight, macroscopic evaluation, ulcer index, percentage ulcer inhibition, gastric pH, volume, total acidity, and free acidity were studied. Histamine content, RBCs, and WBCs were also determined. Furthermore, an examination of antioxidant levels, histopathology, TNF-a, and IL-1ß was done. Conclusion: The combination resulted in a gradual increase in body weight (11th day). Clinically significant RBC and WBC counts were observed. In the estimation of the ulcer index, the combination was found to be highly significant. The combination demonstrated a significant change in inflammatory cell infiltration, gastric juice parameters, and minimal histamine content, indicating satisfactory ulcer-protective effects. Additionally, the combination increased GSH levels while decreasing lipid peroxidation. TNF-a and IL-1ß levels were found to be significant. Anti-inflammatory and ulcer-protective potential was shown by the combination. [ABSTRACT FROM AUTHOR]

Objective: Treatment with TNF-α inhibitors improve psoriasis with minimize/minor neutrophils infiltration and CXCL-1/8 expression in psoriatic lesions. However, the fine mechanism of TNF-α initiating psoriatic inflammation by tuning keratinocytes is unclear. Our previous research identified the deficiency of intracellular galectin-3 was sufficient to promote psoriasis inflammation characterized by neutrophil accumulation. This study aims to investigate whether TNF-α participated in psoriasis development through dysregulating galectin-3 expression. Methods: mRNA levels were assessed through quantitative real-time PCR. Flow cytometry was used to detect cell cycle/apoptosis. Western blot was used to evaluate the activation of the NF-κB signaling pathway. HE staining and immunochemistry were used to detect epidermal thickness and MPO expression, respectively. Specific small interfering RNA (siRNA) was used to knock down hsa-miR-27a-3p while plasmids transfection was used to overexpress galectin-3. Further, the multiMiR R package was utilized to predict microRNA-target interaction. Results and discussion: We found that TNF-α stimulation altered cell proliferation and differentiation and promoted the production of psoriasis-related inflammatory mediators along with the inhibition of galectin-3 expression in keratinocytes. Supplement of galectin-3 could counteract the rise of CXCL-1/8 but not the other phenotypes of keratinocytes induced by TNF-α. Mechanistically, inhibition of the NF-κB signaling pathway could counteract the decrease of galectin-3 and the increase of hsa-miR-27a-3p expression whereas silence of hsa-miR-27a-3p could counteract the decrease of galectin-3 expression induced by TNF-α treatment in keratinocytes. Intradermal injection of murine anti-CXCL-2 antibody greatly alleviated imiquimod-induced psoriasis-like dermatitis. Conclusion: TNF-α initiates psoriatic inflammation by increasing CXCL-1/8 in keratinocytes mediated by the axis of NF-κB-hsa-miR-27a-3p-galectin-3 pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: Stem cell therapy plays a therapeutic role in tissue regeneration in vivo, and its use is increasing for the treatment of incurable diseases. However, stem cells from aged individuals exhibit lower activity, characterized by a high population doubling time and deficient secretion of growth factors. Thus, the transplantation of stem cells with poor activity has shown disappointing results, and we need a strategy to improve the cellular activity of stem cells from aged or diseased individuals. The application of endogenous peptide, substance P, could restore the proliferation rate and paracrine potential of aged stem cells under inflammatory conditions. This suggests the potential use of substance P as a preconditioning factor before stem cell transplantation. Aging leads to a decline in stem cell activity by reducing the repopulation rate and paracrine potential, ultimately diminishing efficacy in vivo. TNF-α can exert inflammatory and cell death actions via Erk by binding to TNFR-1, and survival and tissue repair actions via Akt by binding to TNFR-2. Aged cells are reported to have insufficient expression of TNFR-2, indicating that aged adipose-derived stem cells (ADSCs-E) lack the ability for cell survival and immune control compared to young ADSCs (ADSCs-Y). This study aims to assess the preconditioning effect of SP on the response of ADSCs-E to inflammation. ADSCs-E were treated with SP and then exposed to a high dose of TNF-α for 24 h. Consequently, ADSC-E exhibited weaker viability and lower TNFR2 levels compared to ADSC-Y. In response to TNF-α, the difference in TNFR2 expression became more pronounced in ADSC-E and ADSC-Y. Moreover, ADSC-E showed a severe deficiency in proliferation and paracrine activity. However, preconditioning with SP significantly enhanced the viability of ADSCs-E and also restored TNFR2 expression and paracrine potential, similar to ADSC-Y under inflammatory conditions. Our findings support the idea that preconditioning with SP has the potential to restore the cellular function of senescent stem cells before transplantation. [ABSTRACT FROM AUTHOR]

The active season of hibernators corresponds to rapid adiposity in preparation for the next hibernation season. We have previously shown that this dramatic increase in adipose mass is associated with metabolic inflammation similar to what is seen in obesity and metabolic disease. We next sought to determine whether curbing this inflammation at its source (i.e., the gut) would attenuate weight gain in fattening 13-lined ground squirrels (Ictidomys tridecemlineatus). We fed active yearling ground squirrels a diet containing the gut-specific nonsteroidal anti-inflammatory drug mesalazine (5-aminosalicylic acid) for 10 wk. Mesalazine treatment had slight effects on microbial community diversity in the cecum and colon. Not surprisingly, mesalazine treatment decreased inflammatory cytokine levels in the ileum and colon. Mesalazine also decreased proinflammatory and increased antiinflammatory cytokines in omental white adipose tissue (oWAT). Despite this, body mass was unaffected, and caloric intake increased in mesalazine-treated squirrels, mainly in males. Mass of the primary WAT depot, intra-abdominal WAT (iaWAT), or the highly metabolic oWAT were unaltered by treatment, as was adiposity index. Together, these results suggest that mesalazine treatment has some effects on adiposity in fattening ground squirrels, but this treatment needs to be modified to overcome the strong drive to fatten in this species. NEW & NOTEWORTHY Adiposity and obesity are caused, at least in part, by inflammation of metabolic tissues. Hibernators, like ground squirrels, undergo this same metabolic inflammation during their summer fattening period. We attempted to curb this inflammation, and thus fattening, using mesalazine. We found that mesalazine did curb the inflammation but did not affect fattening, likely due to the strong drive to fatten in hibernators. [ABSTRACT FROM AUTHOR]

Omega-3 fatty acids are potential anti-inflammatory agents that may exert beneficial outcomes in diseases characterised by increased inflammatory profile. The purpose of this study was to comprehensively evaluate the existing research on the effectiveness of n-3 fatty acid supplementation in lowering levels of circulating inflammatory cytokines in patients with heart failure (HF). From the beginning until October 2022, randomised controlled trials (RCTs) were the subject of PubMed, Scopus, Web of Science, and Cochrane Library literature search. Omega-3 fatty acid supplementation vs. placebo were compared in eligible RCTs to see how they affected patients with HF in terms of inflammation, primarily of tumour necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), and c-reactive protein (CRP). A meta-analysis employing the random effects inverse-variance model and standardised mean differences was performed to assess group differences. Ten studies were included in this systematic review and meta-analysis. Our main analysis (k = 5) revealed a beneficial response of n-3 fatty acid supplementation on serum TNF-a (SMD: − 1.13, 95% CI: − 1.75– − 0.50, I2 = 81%, P = 0.0004) and IL-6 levels (k = 4; SMD: − 1.27, 95% CI: − 1.88– − 0.66, I2 = 81%, P < 0.0001) compared to placebo; however, no changes were observed in relation to CRP (k = 6; SMD: − 0.14, 95% CI: − 0.35–0.07, I2 = 0%, P = 0.20). Omega-3 fatty acid supplementation may be a useful strategy for reducing inflammation in patients with HF, but given the paucity of current studies, future studies may increase the reliability of these findings. [ABSTRACT FROM AUTHOR]

IntroductionCytokines and chemokines play an important role in shaping innate and adaptive immunity in response to infection and vaccination. Systems serology identified immunological parameters predictive of beneficial response to the BNT162b2 mRNA vaccine in COVID-19 infection-naïve volunteers, COVID-19 convalescent patients and transplant patients with hematological malignancies. Here, we examined the dynamics of the serum cytokine/chemokine responses after the 3rd BNT162b2 mRNA vaccination in a cohort of COVID-19 infection-naïve volunteers.MethodsWe measured serum cytokine and chemokine responses after the 3rd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in COVID-19 infection-naïve individuals by a chemiluminescent assay and ELISA. Anti-Spike binding antibodies were measured by ELISA. Anti-Spike neutralizing antibodies were measured by a pseudotype assay.ResultsComparison to responses found after the 1st and 2nd vaccinations showed persistence of the coordinated responses of several cytokine/chemokines including the previously identified rapid and transient IL-15, IFN-γ, CXCL10/IP-10, TNF-α, IL-6 signature. In contrast to the transient (24hrs) effect of the IL-15 signature, an inflammatory/anti-inflammatory cytokine signature (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CXCL8/IL-8, IL-1Ra) remained at higher levels up to one month after the 2nd and 3rd booster vaccinations, indicative of a state of longer-lasting innate immune change. We also identified a systemic transient increase of CXCL13 only after the 3rd vaccination, supporting stronger germinal center activity and the higher anti-Spike antibody responses. Changes of the IL-15 signature, and the inflammatory/anti-inflammatory cytokine profile correlated with neutralizing antibody levels also after the 3rd vaccination supporting their role as immune biomarkers for effective development of vaccine-induced humoral responses.ConclusionThese data revealed that repeated SARS-Cov-2 BNT162b2 mRNA vaccination induces both rapid transient as well as longer-lasting systemic serum cytokine changes associated with innate and adaptive immune responses.Clinical trial registrationClinicaltrials.gov, identifier NCT04743388.

TNFa inhibitors, which include adalimumab, infliximab, etanercept, certolizumab, and golimumab, and IL12/23 inhibitor, ustekinumab, have been widely used as a U.S. Food and Drug Administration (FDA) approved for the treatment of psoriasis. Outside of psoriasis, high levels of TNFa had also been found in several skin diseases including hidradenitis suppurativa. IL12 and IL23 play important role in the pathogenesis of SLE, alopecia areata, and vitiligo. This paper reviews the off-label uses of TNFa inhibitors and IL12/23 inhibitors in skin disorders.

Introduction: Hypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/ Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation in vivo. Methods: In vivo, following a 5-day supracalvarial injection of LPS or tumor necrosis factor-alpha (TNF-a) with or without azilsartan, the proportion of bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)- positive multinucleated cells, which are identified as osteoclasts on mice calvariae were counted. The mRNA expression levels of TRAP, cathepsin K, receptor activator of NF-kB ligand (RANKL), and TNF-a were also evaluated. In vitro, the effect of azilsartan (0, 0.01, 0.1, 1, and 10 mM) on RANKL and TNF-atriggered osteoclastogenesis were investigated. Also, whether azilsartan restrains LPS-triggered TNF-a mRNA and protein expression in macrophages and RANKL expression in osteoblasts were assessed. Furthermore, western blotting for analysis of mitogen-activated protein kinases (MAPKs) signaling was conducted. Results: Azilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone. In vivo, LPS with azilsartan administration resulted in lower levels of receptor activator of RANKL and TNF-a mRNA expression than LPS administration alone. Nevertheless, azilsartan did not show inhibitory effect on RANKL- and TNF-a-triggered osteoclastogenesis in vitro. Compared to macrophages treated with LPS, TNF-a mRNA and protein levels were lower in macrophages treated by LPS with azilsartan. In contrast, RANKL mRNA and protein expression levels in osteoblasts were the same in cells co-treated with azilsartan and LPS and those exposed to LPS only. Furthermore, azilsartan suppressed LPS-triggered MAPKs signaling pathway in macrophages. After 5-day supracalvarial injection, there is no difference between TNF-a injection group and TNF-a with azilsartan injection group. Conclusion: These findings imply that azilsartan prevents LPS-triggered TNF-a production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption in vivo. [ABSTRACT FROM AUTHOR]

Cigarette smoke contains a large number of oxidants and plays an important role in disturbing the oxidative balance due to the content of free radicals in it, which is responsible for many adverse effects in the oral cavity. Chronic inflammation accompanied by increased TNF-a can lead to increased production of free radicals in the body. A high total antioxidant capacity can help neutralize free radicals and reduce oxidative stress, which in reducing TNF-a production. This study aimed to evaluate the effect of switching from tobacco smoking to using non-combustion products on gingival health in terms of TNF-a levels in saliva, and total antioxidant capacity in saliva in smokers with gingivitis. This study was a randomized controlled trial. A total of 34 subjects (17 smokers and 17 switching to non-combustion products) were involved in the study according to the inclusion criteria. Saliva samples were taken at month 0 and month 3 to examine TNF-a levels and total antioxidant capacity (TAOC). TAOC in the switch group increased after 3 months (p=0.006) compared to the smoker group. TNF-a in the switch group decreased after 3 months compared to the smoker group, but there was no significant difference (p=0.473). Switching smoking behavior from conventional cigarettes to non-combustion products has the potential to increase TAOC levels and decrease TNF-a after 3 months. [ABSTRACT FROM AUTHOR]

Introduction: SARS-CoV-2 infection (COVID-19) induces dysregulated production of pro- and anti-inflammatory cytokines, called the cytokine storm, leading to the development of severe pneumonia and ARDS. We aimed to examine the dynamic cytokine response on different days of the disease in adult COVID-19 patients. Methodology: Our study included 142 patients (with SARS-CoV-2 PCR-positive nasopharyngeal samples) with varying disease severity and admitted on different days of the disease. We examined the presence and mean levels of TNF-a and IL-10 and did a correlation and logistic regression analysis. Results: TNF-a levels were high in all patients, with mean levels being the highest on day 5 of the disease. IL-10 was high only in a quarter of the patients. The levels of IL-10 were also the highest on day 5, which was significantly different from the mean levels on the other days of the disease. Average IL-10 levels were not any higher than the normal range on the other days. We found a significant positive correlation between the levels of TNF-a and IL-10 during the first week of the infection. In the second week, the positive correlation was no longer significant, and starting from day 10, there was even a slight negative correlation. IL-10 level increase showed prognostic significance for severe, but not the critical forms of the disease. Conclusions: The uncontrolled immune response to SARS-CoV-2 in the second week of the disease can be the result of dysregulated production of endogenous anti-inflammatory cytokines. This leads to a severe disease course and a possible unfavorable outcome. [ABSTRACT FROM AUTHOR]

Background and Aim: The purpose of this study was to investigate the hepatoprotective effects of quercetin, a potent antioxidant, against hepatotoxicity caused by cyclophosphamide (CYC) in the rat liver using histopathological parameters. Materials and Methods: Thirty female rats were divided into five groups - control, quercetin (Q), CYC, Q+CYC, and CYC+Q. At the end of the study, the liver tissues were removed and stained with routine histological hematoxylin and eosin, Periodic acid-Schiff, and Masson's trichrome. Caspase-3 (Cas-3), B-cell lymphoma protein 2-associated X (Bax), tumor necrosis factor alpha (TNF-a), and interleukin 1 beta (IL-1ß) levels were investigated in immunohistochemically stained liver tissues. Results: Histopathological examination showed that CYC caused impairment and degeneration in the structure of the hepatocyte cordon, necrosis in the periportal space, sinusoidal dilatation (p=0.000), congestion and edema (p=0.000), mononuclear cell infiltration, and increased connective tissue density (p=0.000). Cas-3, Bax, TNF-a, and IL-1ß immunoreactivities were significantly higher in the CYC group (for all, p=0.000). Q administration gradually reduced histopathological structural damage and Cas-3, Bax, TNF-a (p=0.000), and IL-1ß (p=0.000) intensity in the rat liver. Conclusion: The administration of Q protected the liver tissue against CYC-induced damage, and successfully protected the liver against apoptosis, inflammation, and histopathological changes. [ABSTRACT FROM AUTHOR]

Memory B cells are comprised of unswitched (CD27+IgD+) and switched (CD27 +IgD-) subsets. The origin and function of unswitched human memory B cells are debated in the literature, whereas switched memory B cells are primed to respond to recurrent infection. Unswitched memory B cells have been described to be reduced in frequency with severe SARS-CoV2 infection and here we characterize their activation status, BCR functionality, and contribution to virally-induced cytokine production. Analyses of whole blood from healthy individuals, people immunized against SARS-CoV2, and those who have had mild and severe SARS-CoV2 infection, confirm a reduction in the frequency of unswitched memory B cells during severe SARS-CoV2 infection and demonstrate this reduction is associated with increased levels of systemic TNFα. We further document how severe viral infection is associated with an increased frequency of 'IgD+' only memory B cells that correlate with increased IgG autoantibody levels. Unswitched and switched memory B cells from severe SARS-CoV2 infection displayed evidence of heightened activation with a concomitant reduction in the expression of the inhibitory receptor CD72. Functionally, both populations of memory B cells from severe SARS-COV2 infection harbored a signaling-competent BCR that displayed enhanced BCR signaling activity in the unswitched population. Finally, we demonstrate that B cells from mild SARS-CoV2 infection are poised to secrete pro-inflammatory cytokines IL-6 and TNFα. Importantly, unswitched memory B cells were a major producer of IL-6 and switched memory B cells were a major producer of TNFα in response to viral TLR ligands. Together these data indicate that B cells contribute to the inflammatory milieu during viral infection. [ABSTRACT FROM AUTHOR]

Aging is a major risk factor associated with increased morbidity and mortality rates observed during respiratory infections. In this study, we investigated the role of influenza virus infections in the establishment of premature cellular senescence and paracrine macrophage-activated inflammation. We observed in our murine model a premature aging by the appearance of senescent cells in the lungs after 21 d of influenza A virus infection. By using murine ex vivo lung models, the influence of TNF-a on the establishment of cellular senescence was detectable. Our findings were proven by using conditioned media of infected human monocytederived macrophages on primary lung fibroblasts. Here, a distinct expression of senescence-associated parameters could be confirmed. Furthermore, senescent cells in the lungs strongly influenced subsequent viral infections. Our data demonstrated a higher viral load in senescent primary lung fibroblasts, indicating an intracellular effect on viral replication. Transcriptomic data revealed an increased regulation of JAK/STAT signaling in senescent IAVinfected cells accompanied with increased TRAIL expression. Additionally, senescent cells indicating low pH values, accelerating viral replication. Our study provides new insights into pathomechanisms of virus-induced cellular senescence. Hence, IAV infection induces premature senescence and subsequent infections in senescent cells lead to an increased viral replication. [ABSTRACT FROM AUTHOR]

Background Obesity is an abnormal amount of fats in the body that can result from several factors majorly including environmental and genetic fac- tors. The worldwide prevalence of obesity has increased tremendously in the last three decades and is now considered a global epidemic. Despite the negative impacts of obesity on human health and its majorly associated risk factors such as heart disease, diabetes, and certain types of cancers, no effective strategies have been employed to bring down its rate which can reach an alarming level in the next few years. Objective Previously, various studies have reported the high serum concentrations of two cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in obese patients. These genes (TNF-α and IL-6) are released from the adipose tissues stimulated by obesity. Considering their pivotal association with obesity, this study has been designed to investigate the relationship between SNPs of TNF-α and IL-6 and their high serum lev- els in obesity. Results Here, we utilized R language to perform statistical analyses such as correlation, normality testing, ROC, and regression analysis on serum levels of TNF-α and IL-6 between obese and control groups. Furthermore, the frequencies of clinical data and Hardy-Weinberg Equilibrium tests for allele and the genotypes analysis of the cytokines were performed. Conclusion The results of this study indicate that serum levels of TNF-α and IL-6 were significantly correlated with obesity SNPs.

Background: To investigate the expression levels of blood biomarkers interleukin-6 (IL-6), tumour necrosis factor (TNF-a), and intestinal fatty acid binding protein (iFABP) in patients with post-stroke depression (PSD), and their correlation with PSD occurrence. Methods: Clinical data of stroke patients admitted to the First People's Hospital of Wenling from December 2017 to December 2022 were retrospectively analyzed. Patients were classified into two groups based on their Hamilton Depression Rating Scale (HAMD) scores: PSD and nonPSD groups. The blood levels of IL-6, TNF-a, and iFABP were compared between the two groups, and their association with PSD occurrence was analyzed. Results: The PSD group had significantly higher levels of IL-6, TNF-a, and iFABP. The combined detection of these biomarkers demonstrated a greater predictive value for PSD occurrence compared to the individual detection of each biomarker. Conclusions: The study indicates that the levels of IL-6, TNF-a, and iFABP in the blood are significantly increased in patients with PSD. The combined detection of these biomarkers can effectively predict the occurrence of PSD, indicating high clinical value.

Background: Currently the responses of peripheral cytokine-secreting cells in the natural course of human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection haven’t been fully elucidated. Methods: The function of peripheral proinflammatory, regulatory and cytotoxic cytokine-secreting cells were investigated by direct intracellular cytokine staining (ICS) and flow cytometry, additionally, the absolute numbers of different cytokine-secreting cells were measured among patients with HIV/TB co-infection (HT group), and compared them with the healthy controls (HC group), patients with TB (TB group) and patients with HIV infection (HIV group). After one week’s anti-TB treatment, the changes of the percentages of cytokine-secreting cells were further evaluated in TB and HT groups. Results: Totally 26 individuals in the HC group, 51 in the TB group, 26 in the HIV group and 29 in the HT group were enrolled. The HT. HT group exhibited significantly lower absolute numbers of IFN-γ+CD4+, IFN-γ+CD8+, TNF-α+CD4+, IL17A+CD4+ T cells and TNF-α+CD14+ monocytes than the TB and HIV groups. Compared with the TB group, the percentages of CD8+ T cells secreting IFN-γ and perforin (p=0.010; p=0.043) were significantly lower among the HT group. Compared with the HIV group, the percentages of CD4+, CD8+ T cells and CD14+ monocytes secreting TNF-α (p=0.013; p=0.001; p<0.001) were significantly decreased, and the percentage of CD8+ T cells secreting IL-17A (p=0.015) was significantly increased among the HT group. Both the percentages of CD4+ T cells secreting TGF-β (p<0.001; p=0.001), and CD4+ and CD8+ T cells secreting granzyme A (all p<0.001), were significantly higher among the HT group than among the TB group and HIV group. After one week’s anti-TB treatment, an increased percentage of CD4+ T cells secreting TNF-α (p=0.003) was found in the TB group, and an increased percentage of CD8+ T cells secreting TNF-α (p=0.029) was found in the HT group. Conclusion: Significantly different functional profiles of peripheral proinflammatory, regulatory, and cytotoxic cytokine-secreting cells were observed in the natural course of HIV/TB co-infection compared to TB and HIV infection alone, even though the absolute numbers of those cells were significantly lower in HIV/TB co-infection. TNF-α-secreting CD8+ T cells may be a more sensitive marker for early evaluation of anti-TB treatment efficacy in patients with HIV/TB co-infection. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) is one of the most prevalent, chronic diseases affecting majority of world population. Objective: The aim of this study was to explore the correlation between TNF-a serum levels and TNF-308 gene polymorphisms in a group of diabetic Iraqi patients. Subjects and Methods: A blood sample was taken from fifty patients suffered from type2 diabetes (T2DM), and fifty healthy volunteers as a control. TNF-a serum level was detected by ELISA and TNF-308G/A (rs1800629) gene polymorphism was assessed by high resolution melting real time PCR technique. Results: The results of estimation TNF-a level showed high elevation in patients' group (52.69±4.48 pg/ml) with high significant difference (P=0.01) as compared with control group (23.35±1.67 pg/ml). While detection of TNF-a-308 polymorphism in patients revealed that the wild genotype GG was 1 (2%), heterogeneous genotype GA was 19 (38%), and homogeneous genotype AA was 30 (60%) with significant difference (P=0.001) and even as in control GG genotype was 35(70%), GA genotype was 10 (20%), AA genotype was 5 (10%) with considerable difference (P=0.01). The findings of correlation between TNFa level and TNFa-308 genotype in T2DM patients, revealed that a substantial increase at AA genotype patients (P=0.01) in TNFa serum level (46.17±4.64 pg/ml) followed by GA patients genotype (29.21±2.74 pg/ml) and finally GG genotype (5.11±9.15 pg/ml). Conclusion: The result revealed that patients with (A) allele had a higher risk for T2DM; also the genotype of TNFa-308 and the serum level of TNF-a in people with T2DM and healthy control were significantly different. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a highly reactive molecule involved in a variety of physiological and pathophysiological processes, such as inflammation. eNOS-produced NO has anti-inflammatory properties and play a role in vascular homeostasis. Through a variety of mechanisms, tumor necrosis factor alpha (TNF-a) has been shown to induce inflammation in HUVECs. The purpose of this study was to investigate the role of NO in HUVEC cells under inflammatory conditions induced by TNF-a. To identify TNF-a induction mechanisms, the phosphorylation of ERK, Akt, and eNOS was investigated. Sildenafil and L-NAME used to examine the role of NO in this process. In TNF-a-induced HUVEC cells, cell viability, nitrite/nitrate production, phosphorylated and total ERK, Akt, and eNOS levels were measured with or without sildenafil and L-NAME. At 20 and 40 ng/ml concentrations, TNF-a increased nitrite/nitrate and decreased cell viability (p<0.05). Sildenafil and L-NAME had no effect on cell viability and they both decreased nitrite/nitrate in HUVEC that had been stimulated by TNF-a. TNF-a had no effect on the phosphorylation of ERK, Akt, and eNOS, but it did increase total eNOS levels. The phosphorylation of ERK, Akt, and eNOS was unaffected by sildenafil and L-NAME; however, L-NAME decreased total eNOS. According to our findings, there is no known direct relationship between TNF-a, sildenafil, or L-NAME and protein phosphorylation. [ABSTRACT FROM AUTHOR]