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There is evidence that hypoglycemic stress can interact with other stressors, and that ketamine can mitigate the impact of these stressors on behavior and physiology. The current study in male Sprague-Dawley rats investigated whether pre-treatment with 0, 10, or 20 mg/kg ketamine could modulate the interaction between hypoglycemia induced by 0 or 300 mg/kg 2-deoxy-D-glucose (2-DG) and the psychophysical stress of forced swimming (FSS; 6 sessions, 10 min/session) on serum concentrations of corticosterone (CORT) and the pro-inflammatory cytokine, tumor necrosis factor (TNF)-α. It was found that 2-DG enhanced the CORT response to an initial session of FSS, and this effect dissipated after multiple sessions. More importantly, animals displayed significantly higher levels of CORT and lower levels of TNF-α in response to a drug-free test swim conducted 1 week after exposure to the combined stressors, and these responses were not observed in rats that were pre-treated with ketamine. Overall, these findings indicate that ketamine has the potential to reduce the negative impact of interacting stressors on the biological reactivity of the hypothalamic-pituitary-adrenal axis and the immune system.

Over the past two decades, tumor necrosis factor-α (TNF-α) inhibitors became one of the most important drugs in the treatment of patients with psoriatic arthritis. Unfortunately, some of the patients exhibit unwanted side effects of the treatment. We describe a patient with psoriasis, psoriatic arthritis and uveitis who was treated with adalimumab and after 4 months of the treatment developed clinical and neuroradiological signs of demyelinating disease of the central nervous system. She experienced no signs and symptoms of neurological disease prior to adalimumab administration. After a detailed neurological work-up she was diagnosed with relapsing-remitting type of multiple sclerosis and treated with oral and pulse glucocorticoids and later with dimethyl fumarate. Adalimumab was discontinued. The question remains was the demyelination induced by the TNF-α blockade or was it unmasked by the introduction of the cytokine blocking agent. In patients suffering from inflammatory arthritis, treating disease to target as well as a close follow- up and knowledge of potential side effects of treatment remains crucial in good clinical practice.

Jing Xu, Xiaomin Shi, Youjin Pan Department of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaCorrespondence: Youjin PanDepartment of Endocrinology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Lucheng District, Wenzhou, Zhejiang Province, People’s Republic of ChinaTel +86 15068256508Fax +86 577-85678813Email panyj6190@163.comPurpose: To investigate the relationship between aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT) and diabetic nephropathy (DN).Patients and Methods: A total of 402 patients with type 2 diabetes mellitus were divided into three groups, such as normoalbuminuria (n = 196), microalbuminuria (n = 131) and macroalbuminuria (n = 75) groups. Basic information and laboratory results were collected. Serum AST/ALT, tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-4, IL-6, IL-10 and interferon- γ (INF- γ) were also measured. DN was defined as microalbuminuria or macroalbuminuria. The estimated glomerular filtration rate (eGFR) was calculated using the following formula: 186 × (serum creatinine)− 1.154× (age)− 0.203× (0.742 if female).Results: The AST/ALT in the macroalbuminuria group was higher than in the microalbuminuria and normoalbuminuria groups. The concentrations of tumor necrosis factor-α (TNF-α), IL-2, IL-4, IL-10 and INF-γ in the macroalbuminuria group were significantly higher than those in the two other groups. Multivariate logistical analysis showed that after adjusting confounding factors, TNF-α and high AST/ALT were independent risks for DN and macroalbuminuria. Furthermore, the AST/ALT had significantly positive correlation with TNF-α (r = 0.101, P = 0.048), IL-4 (r = 0.185, P = 0.005) and IL-6 (r = 0.274, P < 0.001) levels.Conclusion: This study showed that high AST/ALT was an independent risk factor for the DN. Additionally, AST/ALT was positively correlated with inflammation cytokines, such as TNF-α, IL-4 and IL-6 levels.Keywords: AST/ALT, diabetic nephropathy, inflammatory factors, tumor necrosis factor-&#x03B1

Background Our recent studies have identified that the red nucleus (RN) dual-directionally modulates the development and maintenance of mononeuropathic pain through secreting proinflammatory and anti-inflammatory cytokines. Here, we further explored the action of red nucleus IL-33 in the early development of mononeuropathic pain. Methods In this study, male rats with spared nerve injury (SNI) were used as mononeuropathic pain model. Immunohistochemistry, Western blotting, and behavioral testing were used to assess the expressions, cellular distributions, and actions of red nucleus IL-33 and its related downstream signaling molecules. Results IL-33 and its receptor ST2 were constitutively expressed in the RN in naive rats. After SNI, both IL-33 and ST2 were upregulated significantly at 3 days and peaked at 1 week post-injury, especially in RN neurons, oligodendrocytes, and microglia. Blockade of red nucleus IL-33 with anti-IL-33 neutralizing antibody attenuated SNI-induced mononeuropathic pain, while intrarubral administration of exogenous IL-33 evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 generated an algesic effect in the early development of SNI-induced mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3, suppression of NF-κB, ERK, p38 MAPK, and JAK2/STAT3 with corresponding inhibitors markedly attenuated SNI-induced mononeuropathic pain or IL-33-evoked mechanical hypersensitivity in naive rats. Red nucleus IL-33 contributed to SNI-induced mononeuropathic pain by stimulating TNF-α expression, which could be abolished by administration of inhibitors against ERK, p38 MAPK, and JAK2/STAT3, but not NF-κB. Conclusions These results suggest that red nucleus IL-33 facilitates the early development of mononeuropathic pain through activating NF-κB, ERK, p38 MAPK, and JAK2/STAT3. IL-33 mediates algesic effect partly by inducing TNF-α through activating ERK, p38 MAPK and JAK2/STAT3.

Objective Acute lung injury (ALI) is characterized by inflammation and oxidative stress. Nuclear factor-kappaB (NF-κB) mediates the expression of various inflammation-related genes, including the NADPH oxidase family. This study aimed to identify the potential regulatory role of NF-κB on NADPH oxidases in tumor necrosis factor-α (TNF-α)-induced oxidative stress in human alveolar epithelial cells. Methods A549 cells were treated with TNF-α for 24 h to establish ALI cell models. RT-PCR, western blot, assessment of oxidative stress, Alibaba 2.1 online analysis, electrophoretic mobility shift assays and luciferase reporter analysis were employed to identify the potential regulatory role of NF-κB on NADPH oxidases in TNF-α-induced oxidative stress in human alveolar epithelial cells. Results The expression of NF-κB/p65 was notably upregulated in TNF-α-stimulated A549 cells. NF-κB knockdown by siRNA significantly inhibited the TNF-α-induced oxidative stress. Moreover, NF-κB/p65 siRNA could inhibit the activation of NOX1, NOX2 and NOX4 mRNA and protein expression in TNF-α-stimulated A549 cells. The next study demonstrated that NF-κB activated the transcription of NOX1 by binding to the -261 to -252 bp (NOX1/κB2, TAAAAATCCC) region of NOX1 promoter in TNF-α-stimulated A549 cells. Conclusion Our data demonstrated that NF-κB can aggravate TNF-α-induced ALI by regulating the oxidative stress response and the expression of NOX1, NOX2 and NOX4. Moreover, NF-κB could promote the NOX1 transcriptional activity via binding its promoter in TNF-α-stimulated A549 cells.

During biologic treatments, attention should be paid to adverse reactions, particularly infectious diseases. Furthermore, drug-induced interstitial lung disease is also known to be associated with biologic therapies. We retrospectively reviewed serum Krebs von den Lungen-6 (KL-6) levels in psoriatic patients who underwent treatment with seven different biologics. A total of 67 patients who received 80 biologic treatments were evaluated. The 31 anti-tumor necrosis factor (TNF)-alpha treatments consisted of 17 infliximab (IFX) and 14 adalimumab. The 23 anti-interleukin (IL)-23 treatments consisted of 14 ustekinumab and nine guselkumab. The 26 anti-IL-17 treatments consisted of nine secukinumab, six ixekizumab and 11 brodalumab. The IFX showed significantly increased mean serum KL-6 (170.9%), but none of the other treatments showed significant increases. Thirteen of the 17 (75.6%) patients in the IFX and 17 of the 31 (54.8%) patients in the total anti-TNF-alpha group demonstrated at least a 25% increase in serum KL-6. Levels exceeding the cut-off (500 U/mL) were detected in three patients before treatment and in seven patients after treatment. This study showed that anti-IL-17 and anti-IL-23 treatments have no significant impact on serum KL-6 level. In addition to the influence of IFX, a significantly large number of patients in the IFX group had a history of methotrexate administration associated with psoriatic arthritis, which might have influenced the KL-6 level. None of the patients with elevated serum KL-6 showed pulmonary changes by computed tomography and/or X ray.

Background Intradialytic hypotension (IDH) is a common complication in maintaining hemodialysis (MHD) patients. Immune activation might be part of the mechanisms. However, the association between pro-inflammatory cytokines and blood pressure (BP) has not been deeply explored. So we aim to evaluate the potential role of pro-inflammatory cytokines in IDH. Methods MHD patients starting hemodialysis before January 2016 were enrolled in our retrospective study. Patients' characteristics, laboratory results, and intradialytic BP were collected. IDH was defined as nadir systolic BP ≤ 90 mmHg during hemodialysis. The definition of IDH group was that those who suffered from more than one hypotensive event during one month after the enrollment (10% of dialysis treatments). Spearman correlation analysis and logistic regression were employed to explore the relationship between pro-inflammatory cytokines and IDH. Results Among 390 patients, 72 were identified with IDH (18.5%). High levels of serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were observed in the IDH group (p

Purpose: Investigating the effects of intraperitoneal carvacrol administration in rats using the oxygen-induced retinopathy (OIR) model. Methods: A total of 28 newborn Sprague Dawley rats were used and the OIR model was created using the 50/10% oxygen model. The study composed of four groups in total. While the OIR model was not used in Group I (control group), it was created for Groups II, III, and IV. About 0.01 mL carvacrol, bevacizumab, or 0.9% NaCl was administered intraperitoneal (IP) to the rats in all groups on postnatal day (PND) 14 as follows: Group I and Group II were administered 0.9% NaCl, Group III was administered bevacizumab, and Group IV was administered carvacrol. On PND 18, rats were sacrificed and their right eyes were enucleated. Results: Histopathological and immunohistochemical studies showed that the number of vascular endothelial cells (VECs), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha) decreased similarly in Group III and Group IV compared with Group II. VECs values for Group I, Group II, Group III, and Group IV were measured as 0 +/- 0, 26.45 +/- 4.57, 7.75 +/- 1.98, and 5.78 +/- 1.72, respectively, and it differed significantly between groups (P < 0.001). Likewise, VEGF levels were observed as 0.06 +/- 0.01, 3.31 +/- 0.53, 2.47 +/- 0.44, and 2.49 +/- 0.52, respectively, and it differed significantly between groups (P < 0.001). TNF-alpha levels were recorded as 0.06 +/- 0.01, 3.58 +/- 0.38, 2.46 +/- 0.49, and 2.29 +/- 0.25, respectively, and it differed significantly between groups (P < 0.001). VECs, VEGF, and TNF-alpha were similar between Group III and IV (range of P values were 0.486-0.998). Conclusion: The study demonstrated that carvacrol significantly reduced retinal pathological angiogenesis, NV, VEC nuclei count, VEGF, and TNF-alpha levels. Moreover, the observed effects were comparable to those of bevacizumab.

AIM: To find a new concept to show whether or not apoptosis of retinal ganglion cells (RGCs) can be determined in the histology of acute hyperglycemia in the role of expressed Brn3b gene related to nitric oxide (NO), caspase-3, nuclear factor kappa-B (NF-κB), and tumor necrosis factor-α (TNF-α) as an early predictor of primary open angle glaucoma (POAG) eyes and their associations. METHODS: Experimental in vivo study was carried out using adult male, white Sprague-Dawley rats aged ≥2mo, weighing 150-200 g. The animals were divided into two groups, one group receiving intraperitoneal injection of streptozotociz 50 mg/kg in 0.01 mol/L citric buffer and pH 4.5 and a comparison made with the control group. Retinal tissue was divided into two parts (both experimental and control groups respectively): a) right retina for immunohistochemistry (IHC; caspase-3 and TNF-α); b) left retina was divided into two parts for the purpose of real-time polymerase chain reaction (PCR) test (RNA extraction for Brn3b gene expression analysis) and ELISA test (NO and NF-κB). RESULTS: The experimental group showed a decrease in Brn3b gene expression compared to the control group (1.3-fold lower in 2nd month; 1.1-fold lower in 4th month and 2.5-fold lower in 6th month). However, there was a decrease of NO, caspase-3, and an increase of NF-κB and TNF-α quantity. CONCLUSION: The expression of mRNA Brn3b gene is inversely proportional to apoptosis in RGCs. The quantity of NO, caspase-3, NF-κB and TNF-α is influential in expression of Brn3b in RGCs caused by hyperglycemia in diabetic rats.

Background To investigate the association between blood biomarkers and disease activity of Takayasu’s arteritis (TAK) in a follow-up cohort. Methods Disease activity was assessed by clinical manifestations and repeated vascular Doppler examinations. The association between erythrocyte sedimentation rate (ESR), serum levels of high-sensitive C-reactive protein (hsCRP), interleukin-6(IL-6), and tumor necrosis factor-α (TNFα) and disease activity were analyzed by logistic regression and survival analysis. Kaplan-Meier method was used to estimate the cumulative remission rate curve, log-rank tests for group comparison, and Cox regression for estimating hazard ratios of these parameters for disease activity. Results 428 patients were included. 188 patients were in active disease, and 240 patients were in inactive disease at baseline. Elevation of ESR, hsCRP, and IL-6 were associated with active disease at baseline and during follow-up. Cox regression and Kaplan-Meier analysis showed that lower possibility and longer time to remission were associated with elevated ESR (hazard ratio [HR] = 0.32, 80 vs 33 weeks, p p p p p p p Conclusions Elevated ESR, CRP, and IL-6 are associated with active disease, lower possibility, and longer time to achieve disease remission. Elevation of any among ESR, CRP, IL-6, and TNFα is associated with high risk and short time for relapse during follow-up.

Graphical abstract, Introduction and aim Considering the magnitude of giardiasis problem, the side-effects of the used anti-giardia drugs and the resistance posed against them, the current study aimed to evaluate the in-vivo giardicidal effect of Psidium guajava leaf extract (PGLE). Methods For fulfilling this aim, five Swiss-albino mice groups were included; GI: non-infected, GII: Giardia-infected and non-treated, GIII: Giardia-infected and metronidazole-treated, GIV: Giardia-infected and PGLE-treated, and GV: Giardia-infected and treated with both metronidazole and PGLE. Treatment efficacy was assessed via; Giardia cyst viability and trophozoite count, trophozoite electron microscopic ultrastructure, duodenal histopathological scoring, immunohistochemistry for TNF-α and duodenal scanning electron microscopy. Moreover, mice serum liver enzymes, total bilirubin, albumin, lipid profile including; total cholesterol, HDL, LDL and triglycerides were assessed. Additionally, hepatic oxidative stress markers including; malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH) and superoxide dismutase (SOD) were measured. Results Results showed that PGLE whether alone or combined with metronidazole has induced significant trophozoite count reduction and major architectural changes. Duodenal histological improvement, and local protective anti-inflammatory effect were confirmed. PGLE has also helped in healing of Giardia-induced gut atrophy. Thus, offered a comprehensive therapy for both the pathogen and the resultant pathological sequalae. Serum markers showed favorable hepatoprotective effect. Total cholesterol, LDL and triglycerides levels were less in PGLE-treated group than in metronidazole-treated group. Hepatic oxidative stress markers revealed the promising extract antioxidant effect. This study highlights, the promising in-vivo giardicidal PGLE activity, that was comparable to metronidazole, thus, the extract would be an ideal strongly recommended treatment for giardiasis. When combined with metronidazole, the extract potentiated its therapeutic effect. Besides, having hepatoprotective, anti-inflammatory, and antioxidant properties, the extract can combat the major side effects of metronidazole therapy.

Purpose: To report a case with rapid regression of scleral melting associated with tumor necrosis factor-α (TNF-α) in a surgically induced necrotizing scleritis (SINS) patient treated with local steroid therapy. Case Presentation: An 85-year-old male patient presented with conjunctival tumor in his right eye. Complete resection of the tumor lesion and conjunctival re-construction were performed. Local steroid drops were administered until 1 month after surgery, and a good clinical course was achieved. However, after stopping the local steroid, scleral melting to the uvea occurred on the center of the tumor-resected sclera. After diagnosing SINS, we immediately restarted his local steroid. After 2 weeks, there was a complete and rapid regression of the scleral melting. Following this episode, only local steroid therapy was continued for the treatment of SINS, with no recurrence observed after 6 months. Histopathological analysis revealed the infiltration of inflammatory cells during the acute phase, with TNF-α immune reactivity observed in the center of the melting site near the resected conjunctiva. Conclusion: We speculate that the observed changes were associated with the TNF-α that was present during the pathological state of SINS. Local steroid therapy may play a key role in the local immune balance in SINS.

This phase 3 multicenter study, including 26‐week treatment and extension periods, evaluated the efficacy and safety of adalimumab in Japanese patients with active ulcers due to pyoderma gangrenosum. Patients received adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every week starting at week 4. Of the 22 enrolled patients, 12 (54.5%, P

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by intestinal inflammation. Increased intestinal levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) are associated with disease activity and severity. Anti-TNF-α therapy is administered systemically and efficacious in the treatment of IBD. However, systemic exposure is associated with adverse events that may impede therapeutic treatment. Clinical studies show that the efficacy correlates with immunological effects localized in the gastrointestinal tract (GIT) as opposed to systemic effects. These data suggest that site-specific TNF-α inhibition in IBD may be efficacious with fewer expected side effects related to systemic exposure. We therefore reviewed the available literature that investigated the efficacy or feasibility of local TNF-α inhibition in IBD. A literature search was performed on PubMed with given search terms and strategy. Of 8739 hits, 48 citations were included in this review. These studies ranged from animal studies to randomized placebo-controlled clinical trials. In these studies, local anti-TNF-α therapy was achieved with antibodies, antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA) and genetically modified organisms. This narrative review summarizes and discusses these approaches in view of the clinical relevance of local TNF-α inhibition in IBD.

Cutaneous malignant melanoma (CMM) is one of the most immunogenic types of cancer, with a 6-fold higher rate of spontaneous regression than any other malignancy. In addition to responsiveness to different immunotherapies, the immunogenicity of CMM highlights the important role of the host immune system in the response to CMM. The present study aimed to explore the role of two functional promoter polymorphisms [IL6 -174G>C (rs1800785) and TNFA -308G>A (rs1800629)] in the regulation of the genes encoding the pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor-α, specifically in patients with CMM. A total of 76 patients with CMM and 200 control subjects were genotyped using PCR-restriction fragment length polymorphism. The genotype frequencies for both single nucleotide polymorphisms (SNPs) did not differ significantly between the patients and controls (P=0.358 and P=0.810 for IL6 and TNFA, respectively). However, compared with carriers of C-allele genotypes (CG+CC), patients with the IL6 -174GG genotype exhibited more advanced melanoma (Clark scale ≥3; P=0.037) and shorter survival times, particularly those who worked outdoors (in conditions with increased sunlight exposure; P=0.016). Furthermore, the serum IL-6 levels of patients with CMM were significantly higher than those of the control subjects, which were associated with unfavorable blood and serum characteristics and tumor progression (development of new distant metastases; P=0.004), and with a shorter overall survival time (P=0.042). Using a Cox proportional hazard model, the IL6 -174GG genotype was found to be an independent prognostic factor for reduced survival time (P=0.030), together with sex (being male; P=0.004) and occupations with higher exposure to sunlight (P=0.047). In conclusion, the results of the present study indicated that the promoter polymorphisms IL6 -174G>C and TNFA -308G>A are not predisposing factors for CMM. However, the IL6 -174G>C SNP and IL-6 serum concentrations are likely to influence the progression of the disease, and the GG genotype and higher IL-6 serum levels may indicate shorter survival.

Background Vascular inflammation plays a key role in the progression of hypertension. Progranulin (PGRN), an anti-inflammatory growth factor, mediated inhibition of tumor necrosis factor-α (TNF-α), a pleiotropic cytokine, activity has been well-established. Despite the role of chronic low-grade inflammation in hypertension, serum levels of PGRN and PGRN/TNF-α ratio and, their association with systolic and diastolic blood pressure has not been determined in hypertensive patients till now. This study aims to find and correlate the serum levels of pro-inflammatory cytokine (TNF-α), anti-inflammatory growth factor (PGRN), and PGRN/TNF-α ratio with the blood pressure in systolic-diastolic hypertension (SDH) and isolated systolic hypertension (ISH) patients. Results A cross-sectional study was conducted on SDH patients (mean age, 52.95 ± 12.6 years; male/female (M/F) number = 15/10) and ISH patients (mean age, 55.80 ± 9.40 years; M/F number = 12/13) (n = 25 each). Twenty-five age and body mass index (BMI)-matched healthy subjects (mean age, 56.00 ± 8.55 years; male/female number = 11/14) were considered as control. All patients and healthy subjects were overweight (BMI, 25–30 kg/m2). Overnight fasting blood samples of subjects were taken and levels of PGRN and TNF-α were measured using ELISA diagnostic kits. PGRN and TNF-α levels were found significantly high, whereas PGRN/TNF ratio was found very low, in SDH and ISH patients as compared to healthy subjects. Reduced PGRN/TNF-α ratio and pulse pressure were found as independent predictors of SBP both in SDH and ISH patients. Conclusions Findings of elevated PGRN levels in response to raised TNF-α levels depict the counter regulation by PGRN to neutralize TNF-α. Findings of reduced PGRN/TNF ratio, and it being an independent predictor of SBP, ascertain the key role of imbalance in pro- and anti-inflammatory environment in hypertension. Thus, it strengthens the cross-link between the concept of immunity–adiposity–inflammation–blood pressure¸ a vicious network. Further, this cross-link of SBP and progranulin must be explored in longitudinal studies. New researches should be focused not only on impact of pro-inflammatory environment rather to find on a balance between pro- and anti-inflammatory status, so that new target sites could be explored for therapeutic management of hypertension.

PURPOSE Chemokines are involved in the pathogenesis of various autoimmune diseases, including Graves' orbitopathy (GO), but comprehensive analyses of the dynamics of these cytokines and their receptors in such diseases remain lacking. In this study, we investigated the expressions of chemokines and their receptors during adipogenesis and inflammation in primary cultured orbital fibroblasts from patients with GO. METHODS The messenger RNA (mRNA) expression levels of chemokines were compared between GO (n = 6) and non-GO (n = 5) orbital tissues by real-time polymerase chain reaction. After adipogenesis was induced in primary cultured orbital fibroblasts from patients with GO (n =5) and following stimulation with interleukin (IL)-1β and tumor necrosis factor (TNF)-α, the mRNA expression levels of chemokines and their receptors were analyzed. RESULTS Chemokines were significantly downregulated in GO orbital tissues compared to non-GO orbital tissues (p < 0.05). Adipogenesis resulted in a strong increase in mRNA expression levels of chemokines and their receptors at an early stage (day 1); however, expression levels started to decrease thereafter and, eventually, decreased to below basal levels at the end of adipogenesis (day 10). Following stimulation with IL-1β and TNF-α, the mRNA expression levels of chemokines and their receptors increased, showing different responses to various proinflammatory cytokines. CONCLUSIONS Chemokines were strongly upregulated in the early phase of adipogenesis before decreasing continuously until the end of adipogenesis. Also, overt mature GO tissues showed reduced mRNA expression of chemokines compared to controls, which might indicate the existence of a shorter window for effective medical inflammatory treatment. The heightened levels of chemokines and their receptors observed after stimulation with IL-1β and TNF-α suggest a crucial role of proinflammatory cytokines in the pathogenesis of GO and, further, support the idea that chemokines could be used as biomarkers of GO activity.

Background Though accumulated evidence has demonstrated visceral organ involvement in acute graft-versus-host disease (aGVHD), how aGVHD influences the bone marrow (BM) niche and the reconstitution of hematopoiesis post-hematopoietic stem cell transplantation remains largely unknown. Methods In the current study, the cell morphology, immunophenotype, multi-differentiation capacity, self-renewal capacity, and hematopoiesis promotion of the MSCs from aGVHD and non-aGVHD patients were investigated. Additionally, the stemness and hematopoiesis-promoting property of healthy donor-derived MSCs were evaluated in the presence of BM supernatant from aGVHD patients. Mechanistically, antibodies targeting inflammatory cytokines involved in aGVHD were added into the MSC culture. Furthermore, a recombinant human tumor necrosis factor (TNF-α) receptor-Ig fusion protein (rhTNFR:Fc) was used to protect healthy donor-derived MSCs. Moreover, mRNA sequencing was performed to explore the underlying mechanisms. Results The aGVHD MSCs exhibited morphological and immunophenotypic characteristics that were similar to those of the non-aGVHD MSCs. However, the osteogenic and adipogenic activities of the aGVHD MSCs significantly decreased. Additionally, the colony formation capacity and the expression of self-renewal-related genes remarkably decreased in aGVHD MSCs. Further, the hematopoiesis-supporting capacity of aGVHD MSCs significantly reduced. The antibody neutralization results showed that TNF-α contributed to the impairment of MSC properties. Moreover, rhTNFR:Fc exhibited notable protective effects on MSCs in the aGVHD BM supernatants. The mRNA sequencing results indicated that the TNF-α pathway and the Toll-like receptor pathway may be activated by TNF-α. Conclusions Thus, our data demonstrate MSCs as cellular targets of aGVHD and suggest a potential role of TNF-α blockage in maintaining the BM niche of aGVHD patients.

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer‑related deaths globally. Epithelial‑to‑mesenchymal transition (EMT) is a cellular process that confers HCC tumor cells with the ability to evade the immune system. Immune escape in most tumors, including HCC, is controlled by immune checkpoint molecules. The aim of the present study was to investigate the association between EMT and immune checkpoint in HCC, and identify novel therapeutic targets for HCC. An in vitro model of reversible EMT was utilized based on cytokine tumor necrosis factor (TNF)‑α treatment of HCC cell lines Hep3B and PLC/PRF/5. Hep3B and PLC/PRF/5 cells were treated with TNF‑α, and the EMT status and the expression of immune checkpoint molecules was assessed by reverse transcription‑quantitative PCR, western blotting and immunofluorescence. To confirm an association between EMT and immune modulators, cells were exposed to culture medium with TNF‑α for 3 days to induce EMT, following which a reversal assay was performed. The expression of immune modulators and mesenchymal‑to‑epithelial transition (MET) status was investigated upon reversal of EMT. Furthermore, SurvExpress, a web‑based platform was utilized to analyze survival and recurrence in a dataset of patients with HCC. TNF‑α treatment for 3 days induced EMT in Hep3B and PLC/PRF/5 cells, as demonstrated by the downregulation of epithelial markers along with upregulation in mesenchymal markers. An EMT reversal assay was able to induce MET by increasing epithelial markers and decreasing mesenchymal markers. TNF‑α‑induced EMT led to the upregulation of immune modulators, including programmed death receptor ligand (PD‑L)1, PD‑L2, CD73 and B7‑H3. In contrast, reversal of EMT suppressed the expression of PD‑L1, PD‑L2, CD73 and B7‑H3. In addition, high expression of TNF‑α and PD‑L1 in 422 patients with HCC was associated with poor overall survival. The coordinate expression of TNF‑α with PD‑L2 in this patient cohort was associated with increased HCC recurrence. In conclusion, the present study demonstrated a close association between immune modulator expression and EMT induction/reversal driven by TNF‑α.

Objectives Childhood tuberculosis (TB) accounts for 10–20% of all TB cases, with tuberculous meningitis (TBM) being the leading cause of severe morbidity and mortality. Pathophysiology of TBM still remains obscure. Tumor necrosis factor-α (TNF-α) induces fever and activation of hypothalamus–pituitary–adrenal axis, and serum TNF-α level has been shown to be significantly raised and has a positive correlation with severity of disease in TBM. We aimed to assess serum TNF-α level in pediatric patients with TB in association with clinicoradiological and microbiological features, with special reference to TBM. Materials and methods Serum TNF-α level was estimated using enzyme-linked immunosorbent assay in clinically diagnosed (clinical history and Mantoux and/or contact history and/or radiological evidence) or microbiologically confirmed (≥1 of smear/culture/catridge-based nucleic acid amplification test) pediatric TB cases up to 12 years and healthy controls. Results Among 60 pediatric TB cases, 19 were TBM. Median serum TNF-α level among pediatric TB, TBM, and healthy controls was 53.10, 74.2, and 79.2 pg/ml, respectively, with the difference among the three being insignificant. Median TNF-α level in pulmonary TB cases was slightly higher (64.10 pg/ml) as compared with extrapulmonary TB (52.90 pg/ml), with the difference being statistically insignificant (P=0.816). Levels did not vary significantly with clinical features, microbiological diagnosis, and radiological features. Conclusion TNF-α level was not significantly associated with pediatric TB, which may be owing to ineffective immune response in children and also the resulting increased susceptibility to TB in children. Further studies comparing TNF-α level in cerebrospinal fluid of affected patients are required to look for local inflammation and rise in cytokine levels, thus contributing to lower levels in serum.

Anemia is considered one of the manifistations of many neoplasms affecting the overall survival and reducing the quality of life of patients. The prevalence of anemia varies from 20 to 90% depending on the nosology, the stage of the disease, antitumor treatment. The pathogenesis of anemia in cancer patients is complex. Among pathogenetic factors, such factors are distinguished as tumor infiltration of the bone marrow by malignant cells, inhibition of erythroid growth by cytokines of inflammation, decreased sensitivity of receptors to erythropoietin and its production, increased levels of hepcidin, defects of nutrition, increased deposition and sequestration of blood cells in the spleen, excessive bone fibrosis, hemorrhagic syndrome, antitumor therapy. The article presents the pathogenesis of anemia in oncological disease with a detailed description of the suppressive effect on hematopoiesis of a number of proinflammatory cytokines (interleukin-1, interleukin-6, tumor necrosis factor-, interferon-) produced by cells of the immune system. The mechanism of influence of cytokines on erythropoiesis, synthesis of erythropoietin as well as on the enhancement of hepcidin production in the body is presented in detail. The article also describes the mechanism of impairment of iron kinetics in the body in patients with cancer and subsequent development of functional deficiency. This review of the literature contains up-to-date information about the factors involved in the pathogenesis of anemia in cancer patients, understanding of which will allow the clinical physician to choose a rational way of pathogenetic or substitution correction of anemic syndrome, taking into account the personalized approach to treatment and prevention, especially in patients receiving surgical, chemotherapy, radiation treatment.

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract that have been linked to microbiome dysbiosis and immune system dysregulation. We investigated the longitudinal effect of anti-TNF therapy on gut microbiota composition and specific immune response to commensals in IBD patients. The study included 52 patients tracked over 38 weeks of therapy and 37 healthy controls (HC). To characterize the diversity and composition of the gut microbiota, we used amplicon sequencing of the V3V4 region of 16S rRNA for the bacterial community and of the ITS1 region for the fungal community. We measured total antibody levels as well as specific antibodies against assorted gut commensals by ELISA. We found diversity differences between HC, Crohn’s disease, and ulcerative colitis patients. The bacterial community of patients with IBD was more similar to HC at the study endpoint, suggesting a beneficial shift in the microbiome in response to treatment. We identified factors such as disease severity, localization, and surgical intervention that significantly contribute to the observed changes in the gut bacteriome. Furthermore, we revealed increased IgM levels against specific gut commensals after anti-TNF treatment. In summary, this study, with its longitudinal design, brings insights into the course of anti-TNF therapy in patients with IBD and correlates the bacterial diversity with disease severity in patients with ulcerative colitis (UC).

Objective This study aimed to analyze the changes in serum inflammatory cytokines and anti-inflammatory cytokines in patients with gouty arthritis (GA). Methods The clinical data and serum samples in patients with gouty arthritis and those in healthy volunteers were collected in China-Japan Friendship Hospital from July 2018 to January 2019. Serum cytokine concentrations in patients with GA and volunteers (controls) were determined by a chemiluminescence method. The differences in cytokine concentrations were compared between the two groups. Results Concentrations of serum interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), IL-6, IL-8, and IL-4 were significantly higher in patients with acute GA than in controls. Serum concentrations of IL-1ß, TNF-α, IL-6, IL-8, and immunoglobulin E in patients with remission of GA were significantly lower, whereas concentrations of IL-10 and interferon-γ were significantly higher, compared with those in patients with acute GA. Conclusion This study shows that serum concentrations of IL-1ß, TNF-α, IL-6, IL-8, and IL-4 are significantly elevated in patients with GA, and may be involved in the pathogenesis of GA.

The purpose of this study was to determine serum levels of sleep-related cytokines in patients with rotator cuff tear (RCT) who were experiencing pain-related sleep disturbance. Peripheral blood samples before surgery were collected from 63 study participants and divided into three groups: RCT with sleep disturbance group; SD group (n = 21), RCT with normal sleep group; NS group (n = 21), and patients with chronic shoulder instability; control group (n = 21). Serum concentration levels of interleukin-1α (IL-1α), IL-1β, IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) were measured via ELISA. The associations between serum levels of sleep-related cytokines and clinical scores and the Pittsburgh Sleep Quality Index (PSQI) were analyzed. Serum concentration levels of TNF-α were significantly higher in the SD group compared with those of the NS and control groups (p = < 0.001 and 0.05). Serum levels of IL-8 and IL-10 were significantly higher in the SD group compared with those of control group (p = 0.01 and = 0.05), but did not differ significantly from that of the NS group. There were no associations between serum levels of sleep-related cytokines and all clinical scores. The current findings suggest that TNF-α may be associated with sleep disturbance in patients with RCT.

Objective Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by inflammatory synovitis. We developed a new disease activity evaluation system using important cytokines to help doctors better evaluate disease activity in patients with RA. Methods Flow cytometry was used to detect the levels of seven cytokines. Then, the results were analyzed using an R language decision tree. Results The levels of six cytokines, namely interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ, were significantly different between the active disease and remission stages. Decision tree analysis of the six cytokines with statistical significance identified two judgment rules for the remission stage and three judgment rules for the active disease stage. Conclusion We proposed the use of the decision tree method to analyze cytokine levels in patients with RA and obtain a more intuitive and objective RA disease activity scoring system. This method revealed the relationships of IL-6 and TNF-α levels with inflammatory characteristics in patients with RA, which can help predict disease activity.

The present study was conducted in order to study the detailed molecular mechanism of tumor necrosis factor (TNF)-α in chronic obstructive pulmonary disease (COPD). The rats were treated with cigarette smoke (CS) and lipopolysaccharide (LPS) to establish the COPD model. Next, the changes in lung injury in COPD rats with TNF-α knockdown was tested. Meanwhile, the regulation of TNF-α on MAPK pathway and its downstream molecules (SOCS3/TRAF1) was determined by western blotting. On this basis, the activation of MAPK and inhibition of SOCS3/TRAF1 was also examined. Subsequently, the lung function was tested with the plethysmograph, the cells of bronchoalveolar lavage fluid was counted and classified. Furthermore, lung tissue sections were stained with hematoxylin and eosin to verify whether the treatment of MAPK pathway and downstream molecules affected the effect of TNF-α knockdown on COPD. The present study showed that TNF-α knockdown could alleviate the decrease in the function and inflammatory injury of the lungs of rats with COPD. Western blot analysis verified that TNF-α knockdown could inhibit the activation of MAPK pathway and increase the expression of SOCS3/TRAF1. The following experimental results showed that the relief of lung injury caused by TNF-α knockdown could be deteriorated by activating MAPK pathway. It was also found that the symptom of COPD was decreased following transfection with sh-TNF-α but worsened by SOCS3/TRAF1 knockdown. Overall, TNF-α knockdown inhibited the activation of MAPK pathway and increased the expression of SOCS3/TRAF1, thus delaying the process of COPD.

Background: Considering the association of inflammation with suicide and acute coronary syndrome (ACS), we investigated the individual and interactive effects of serum tumor necrosis factor-alpha (sTNFα) levels and two polymorphisms (−850 C/T and −308 G/A) on suicidal ideation (SI) after ACS.Methods: The SI status using items on the Montgomery–Åsberg Depression Rating Scale (MADRS), related covariates including sociodemographic and clinical characteristics, sTNFα levels, and tumor necrosis factor-alpha (TNF-α) polymorphisms were evaluated in 969 patients within 2 weeks after ACS. Of the patients, 711 were evaluated 1 year later for SI. Multivariate logistic regression models were used to calculate individual and interactive associations after adjusting for the covariates.Results: Higher (vs. lower) sTNFα levels and the −850 C/T or T/T (vs. C/C) polymorphism were significantly associated with SI 2 weeks after ACS, while only higher sTNFα levels were significantly associated with SI after 1 year. Significant interactive effects were detected between sTNFα (higher) levels and the −850 C/T (C/C or C/T) polymorphism on SI 2 weeks after ACS and between the two (−850 CC or CT and −308 G/A or AA) polymorphisms on SI 1 year after ACS.Conclusions: The sTNFα level and two polymorphisms (−850C/T and −308 G/A), separately or in combination, could be time-specific biomarkers for SI in ACS. Focused interventions for ACS patients at risk of SI might reduce the suicidal burden in patients with ACS.

Cardiovascular complications are a well-documented limitation of conventional cancer chemotherapy. As a notable side effect of cisplatin, cardiotoxicity represents a major obstacle to the treatment of cancer. Recently, it has been reported that cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) signaling pathway was associated with the occurrence and development of cardiovascular diseases. However, the effect of STING on cardiac damage caused by cisplatin remains unclear. In this study, cisplatin was shown to activate the cGAS-STING signaling pathway, and deficiency of STING attenuated cisplatin-induced cardiotoxicity in vivo and in vitro. Mechanistically, the STING-TNF-α-AP-1 axis contributed to cisplatin-induced cardiotoxicity by triggering cardiomyocyte apoptosis. In conclusion, our results indicated that STING might be a critical regulator of cisplatin-induced cardiotoxicity and be considered as a potential therapeutic target for preventing the progression of chemotherapy-associated cardiovascular complications.

Endolymphatic hydrops is a characteristic pathological manifestation of Meniere's disease (MD) that has been previously associated with autoimmunity. Interest in the circulating immune complex (CIC) has increased due to its reported role in the occurrence of MD. The present study aimed to investigate the potential value of serum CIC concentration in the diagnosis of MD and the therapeutic potential of cyclophosphamide (CTX) for the treatment of MD. In the present study, guinea pigs were immunized with isologous crude inner ear antigens to establish an autoimmune MD model. Pure tone audiometry, Vestibular-evoked myogenic potential test, electrocochleography test and auditory brainstem response was applied in this study for assessing the severity of MD in guinea pigs. ELISA was applied to measure CIC, tumor necrosis factor α (TNF-α) and heat shock protein 70 (HSP70) expression levels in the serum samples of different groups of patients. Western blotting was applied to detect the protein expression of HSP70 in inner ear tissues in guinea pigs. Hematoxylin and eosin staining was applied to visualize the spiral ganglions in spiral ganglions models. CIC expression in the inner ear was detected by immunohistochemistry. In vivo experiments were performed to confirm the therapeutic effects of CTX in MD. Serum concentrations of CIC, TNF-α and HSP70 were found to be significantly higher in patients with MD, which were also associated with increases in hearing classification and the severity of endolymphatic hydrops. Using a guinea pig MD model, ELISA results revealed significantly increased serum CIC, TNF-α and HSP70 concentrations compared with those in the control group. ABR results showed that the thresholds in the CTX group were notably decreased compared with that in the dexamethasone group, whereas CIC concentrations in the serum were reduced following dexamethasone and CTX treatments compared with those after saline treatment. In the inner ear tissues, the CIC concentration in CTX group was lower than that in the dexamethasone group. Similarly, reductions in HSP70 and TNF-α concentrations was also observed in a similar manner. Immunohistochemistry staining found notably lower CIC deposition in the inner ear tissues following CTX treatment than that in dexamethasone group. Taken together, higher CIC expression can be used as a biomarker for MD diagnosis. The efficacy of CTX in MD was found to be higher compared with that in dexamethasone, which may be associated with the effective inhibition of CIC, HSP70 and TNF-α generation.

Background: Cardiovascular events (CVEs) are the first cause of death in patients with psoriatic arthritis (PsA). Depression is a recognized risk factor in cardiovascular events and is frequently associated with PsA. Flow-mediated dilatation (FMD) is a widely used method for assessing endothelial dysfunction, a parameter with strong prognostic implications for CVEs. The study aims to explore the relationship between FMD, depressive symptoms and serum cytokines in a cohort of patients with PsA.Patients and Methods: FMD was assessed in 50 consecutive PsA patients aged between 30 and 75 years without known cerebrovascular and coronary heart disease or diabetes. Depressive symptoms were reported using the related subscale of the Hospital Anxiety and Depression Scale (HDS). Disease features, activity indexes, and adjusted Framingham risk score (aFRS) were calculated. Serum level of IL-6, TNF-α, and IL-17A were also assessed.Results: In PsA patients (age 50.7 ± 10.2 years, male 42%, disease duration 5.9 ± 3.3 years, Disease Activity in PSoriatic Arthritis (DAPSA) score 14.0 ± 9.4) FMD inversely correlated with the severity of depressive symptoms according to HDS (ρ = −0.339, p = 0.016), age (ρ = −0.507, p = 0.001), aFRS (rs = −0.453, p < 0.001), duration of PsA (ρ = −0.507, p = 0.001), intensity of pain (ρ = −0.507, p = 0.001), and DAPSA (ρ = −0.507, p = 0.001). No statistically significant correlation was found between FMD or HDS and serum cytokines concentrations. HDS predicted FMD in a model adjusted for age, aFRS, PsA duration, and pain intensity (β = −0.271, p = 0.008), with depressive symptoms contributing directly to 6.4% of the variance.Conclusions: Depressive symptoms correlate with endothelial dysfunction with an exposure-response pattern in our cohort of PsA patients.

Background: Changes in both circulating cytokines and neurochemical concentrations have been observed in aging. Patterns of change across these factors are associated with age-related pathologies, including neurodegenerative disease. More evidence to define patterns of change that are characteristic of healthy aging is needed, as is an investigation into how age-related changes in blood cytokines and brain neurochemicals may relate to one another in a healthy older adult population.Methods: Single voxel 1H-proton magnetic resonance spectroscopy was collected in medial frontal and medial parietal regions. Phosphocholine and glycerophosphocholine (Cho), myo-inositol (MI), N-acetylaspertate and N-acetylasperglutamate (NAA), creatine and phosphocreatine (Cr), and glutamate and glutamine (Glx) were measured in a sample of 83 healthy, cognitively normal adults aged 52–89. Blood data were collected to quantify 12 cytokines: interleukins (IL-) 2, 5, 6, 7, 8, 10, 12, 13, IL-1 β, tumor necrosis factor α (TNF-α), interferon γ (IFN-γ), and IL-17 α. Correlation analyses were performed to assess age relationships between each of these factors. Backward linear regressions were performed. Cytokine data and age were used as predictors of each cerebrospinal fluid (CSF)-corrected metabolite concentration in both voxels.Results: Associations were identified between a variety of cytokines and concentrations of frontal NAA, Cr, and Glx, and of parietal MI, Cho, NAA, and Cr. In the frontal voxel, NAA was predicted by more IL-1B and less TNF-α, Cr by less TNF-α and more IL-5, and Glx by less TNF-α. In the parietal voxel, MI was predicted by more IL-10 and IL-8 and less IL-2, Cho by more TNF-α and less IL-2, NAA by more IL-1B and TNF-α and less IL-13, IL-2, and IL-7, and Cr by more IL-10 and less IL-2.Conclusions: Associations were identified between circulating cytokines and neurometabolite concentrations in this sample of older adults. The present results serve as the initial evidence of relationships between circulating cytokines and neurophysiology. Findings invite further investigation to understand the physiological consequences of aging, and how peripheral inflammatory markers may relate to neurochemical concentrations in healthy aging.

Background and Objectives: Muscle strengthening exercise is suggested to beneficial for patients with knee osteoarthritis (OA) and electrical muscular stimulation is reported to be effective in improvement of muscle strength. This study examined whether isometric exercise combined with whole body-electromyostimulation (WB-EMS) can improve serum cytokine levels, muscle strength, and knee function in elderly women with early knee OA.Materials and Methods: This randomized controlled study included 75 participants assigned into three groups: the control group (CON), isometric exercise group (ISOM), and isometric exercise and electromyostimulation group (ISOM + EMS). The two exercise groups performed their respective programs for 8 weeks, 3 days a week, 30 min a day. The main exercises for both groups were performed continuously during the 20 min in an alternation of a 6-s contraction with a 4-s break. At pre- and post-intervention, anthropometric variables, muscle strength, Knee Injury and Osteoarthritis Outcome Score (KOOS), and blood sampling for biomarkers including interleukin-6, tumor necrosis factor-α, C-reactive protein, and resistin were performed.Results: All variables at pre-intervention showed no significant differences among the three groups. However, there were significant differences between groups for body composition, muscle strength, KOOS subscale scores, and biomarkers. ISOM + EMS group resulted in a significant reduction in body weight, fat mass, fat percentage, inflammatory cytokine levels, and increased muscle strength. An ISOM + EMS group had the best KOOS score among all groups.Conclusion: Isometric exercise combined with WB-EMS resulted in the best overall improvements in knee function and alleviating the pain and symptoms of patients with early knee OA. Further, reduced levels of inflammatory cytokines were observed. These non-pharmacologic, non-invasive interventions should be considered by healthcare specialists for elderly patients with early knee OA.

Qianbo Cui,1,&ast; Jing Li,1,&ast; Jing Wang2 1Department of Otorhinolaryngology Head and Neck Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430000, People’s Republic of China; 2Department of Otorhinolaryngology Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing WangDepartment of Otorhinolaryngology Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Road, Wuhan, 430030, Hubei Province, People’s Republic of ChinaEmail lijing32979@163.comBackground: Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of the nasal mucosa that is mainly mediated by IgE after exposure to allergens. Tumor necrosis factor-α has been found to be involved in inflammation response. In the present study, we screened several SNPs of TNF-α gene and analyzed the associations between target SNPs polymorphism and AR.Methods: Using an unmatched case–control design, 600 AR patients and 600 healthy controls were enrolled. General characteristics were collected including IgE expression. Univariate and multivariate logistic regression were used to estimate the odds ratio (OR) and 95% confidence interval (CI) of TNF–α gene for AR in dominant model, additive model, recessive model and allele model. The haplotype analyses were performed using rs1799964, rs1800630 and rs769178. Stratified analyses were also performed in gender, age, overweight, smoking, drinking, family history, and asthma history.Results: Our multivariate logistic regression indicated that rs1799964, rs1800630 and rs769178 locus polymorphisms are not associated with AR. For rs769178, the GT (OR=2.35, 95% CI:1.82– 3.03, P< 0.001) and GT+TT (OR=1.89, 95% CI: 1.50– 2.38, P< 0.001) genotypes present an increased risk for AR compared to GG. The C-G-A-T (OR=2.04, 95% CI: 1.21– 3.44, P=0.007) and C-G-C-T (OR=1.29, 95% CI: 1.04– 1.62, P=0.024) haplotypes are associated with the increased risk of AR, and the C-G-C-G haplotypes decreased risk of AR (OR=0.75, 95% CI: 0.63– 0.88, P=0.001). Stratified analyses shown a significant association between recessive model of rs769178 locus and AR risk in the subgroup of age≤ 60, overweight and smoking. Cross-over analysis indicated that the effects of TT+GT of genotype combined with smoking or drinking related with AR were associated with AR risk.Conclusion: The rs769178 locus polymorph of TNF-α was associated with an increased risk of AR. The haplotypes (C-G-A-T and C-G-C-T) of TNF-α can significantly increase the risk of AR, and C-G-C-G haplotype decreased the risk of AR. There are interactions between rs769178 polymorphism and smoking/drinking for AR risk.Keywords: allergic rhinitis, tumor necrosis factor-α, gene polymorphism, interaction

Ventilator-induced lung injury (VILI) is an important critical care complication. Nuclear factor-κB (NF-κB) activation, a critical signaling event in the inflammatory response, has been implicated in the tracking of the lung injury. The present study aimed to determine the effect of simultaneous pretreatment with enteral aspirin and omega-3 fatty acid on lung injury in a murine VILI model. We compared the lung inflammation after the sequential administration of lipopolysaccharides and mechanical ventilation between the pretreated simultaneous enteral aspirin and omega-3 fatty acid group and the non-pretreatment group, by quantifying NF-κB activation using an in vivo imaging system to detect bioluminescence signals. The pretreated group with enteral aspirin and omega-3 fatty acid exhibited a smaller elevation of bioluminescence signals than the non-pretreated group (p = 0.039). Compared to the non-pretreated group, the pretreatment group with simultaneous enteral aspirin and omega-3 fatty acid showed reduced expression of the pro-inflammatory cytokine, tumor necrosis factor-α, in bronchoalveolar lavage fluid (p = 0.038). Histopathological lung injury scores were also lower in the pretreatment groups compared to the only injury group. Simultaneous pretreatment with enteral administration of aspirin and omega-3 fatty acid could be a prevention method for VILI in patients with impending mechanical ventilation therapy.

Purpose: The role of tumor necrosis factor-α (TNFα) and toll-like receptor 4 (TLR 4) in the pathogenesis of alcoholic liver disease (ALD) has been widely entrenched. We investigated the profitable effects of Bifidobacterium bifidum YRT3115 and Bifidobacterium animalis subsp. lactis KV9 on tumor necrosis factor-α (TNFα) expression and injury response to acute alcohol gavage in mice. Methods: Ninety-six C57BL/6 mice were classified into 4 groups: control, intragastric administration of white spirit, intragastric administration of white spirit + YRT3115 and intragastric administration of white spirit + KV9. The mice were treated daily with probiotics and white spirit until 15 days. The body weight, food intake, liver weight and liver index of mice were measured. Duration of alcohol-induced loss of righting reflex (LORR) was also evaluated. The concentration of ethanol (EtOH) and acetaldehyde (AcH) in mice blood were performed by a head-space GC. The activity of aspartate transaminase (AST) and alanine transaminase (ALT) in mice serum, activity of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in mice liver were performed by commercial kits. The liver mRNA levels of TNF-α, CYP2E1 and TLR 4 were evaluated by RT-PCR. The protein level of TNF-α was evaluated by Western-blot. Results: After intragastric administration white spirit, B. animalis subsp. lactis KV9 reduced duration of LORR, recovery of loss of righting reflex (RORR) and was significantly reduced the concentration of EtOH in blood of mice, by 15.69% at 30 min, 15.01% at 60 min and 45.01% at 120 min (p

Objective To evaluate the effect of thrombin (TM) injection via the cerebellomedullary cistern on cerebral vessels in rats with subarachnoid hemorrhage (SAH). Methods Eighteen rats were randomly divided into three groups. In the A1 group, physiological saline was injected via the cerebellomedullary cistern; in the A2 group, 3 U of TM was injected into the subarachnoid space; and in the A3 group, SAH models were established and 3 U of TM was injected with the first injection of whole blood. Three days later, basilar artery specimens were collected for pathological examination. Results The basilar arterial lumen cross-sectional area was significantly smaller in the A2 versus the A1 group, and proteinase-activated receptor (PAR)-1 and tumor necrosis factor (TNF)-α average optical densities were significantly higher (all P Conclusions There was no significant difference in the extent of cerebral vasospasm between SAH and non-SAH model groups following TM injection into the subarachnoid space, so TM was considered to be an independent factor affecting cerebral vasospasm.

Introduction: Inflammation, oxidative stress (OS), and obesity are documented to play key roles in the pathogenesis of cardiovascular diseases (CVDs). Accordingly, tumor necrosis factor-α (TNF-α) and hydrogen peroxide (H2 O2 ), as a main innate immunity pro-inflammatory cytokine and a main free radical, respectively, are the main risk factors for CVDs. The present study aimed to evaluate the effects of OS, regular aerobic exercise (RAE), and vitamin D3 (VD3) on the expression of TNF-α in the myocardial cells in a rat model. Methods: In this experimental study, 48 male Wistar rats were divided into 8 groups (6 in each group) including healthy controls, sham (injected with dimethyl sulfoxide [DMSO] + saline), H2 O2 (either 1 or 2 mmol/kg), H2 O2 (1 mmol/kg) + VD3, H2 O2 (2 mmol/kg) + VD3, H2O2 (1 mmol/kg) + RAE, and H2 O2 (2 mmol/kg) + RAE. TNF-α level of myocardial cells was evaluated after 8 weeks using the ELISA technique. Results: The results of the study demonstrated that exposure to 2 mmol/kg of H2 O2 significantly increased TNF-α level of myocardial cells compared to the rats which were exposed to one mmol/ kg H2 O2 (P=0.039). Furthermore, RAE (P=0.040), and the combination of RAE+VD3 (P=0.049) significantly reduced the expression of myocardial TNF-α. Conclusion: In general, VD3 and RAE were found to suppress TNF-α expression induced by H2 O2 in the rat myocardium. Therefore, they can be considered as potential therapeutic interventions for reducing OS-induced inflammation in the damaged myocardial cells.

Herein we describe four patients with acquired hemophilia A (AHA) caused by factor VIII (FVIII) inhibitor and histories of dipeptidyl peptidase-4 inhibitor (DPP4-I) treatment for diabetes mellitus (DM). Drug exposure can cause a breakdown of immune tolerance to FVIII associated with CD4 T cells, resulting in the induction of autoantibodies against FVIII. In patient 1 in the present series, FVIII inhibitor disappeared after DPP4-I treatment. The DPP4-I treatment was stopped faster in patient 1 than it was in patient 2, whose FVIII inhibitor titer was higher than patient 1’s. Two patients died: patient 3 due to brain infarction after recurrence associated with the development of sigmoid colon rupture, and patient 4 due to multiple organ failure associated with Clostridium difficile colitis. DPP4-I treatment may create an ideal environment for the induction of new antibodies and AHA onset associated with tumor necrosis factor-α reduction. These are the first reported cases of the potential development and/or prolonging of AHA after DDP4-I treatment for DM, and they suggest possible disease associations. Electronic supplementary material The online version of this article (10.1007/s13300-019-0609-3) contains supplementary material, which is available to authorized users.

Background This study aimed to investigate the association of pre-treatment inflammatory status with survival time and to develop a prognostic nomogram incorporating inflammatory cytokines in non-Hodgkin's lymphoma. Methods A total of 228 patients with diffuse large B-cell lymphoma (DLBCL) received R-CHOP-based regimens from a prospective randomized study (NCT01852435) were included as a training cohort. Other cohorts of 886 lymphoma patients were served as validation cohorts. Lymphocyte-monocyte ratio (LMR), serum levels of soluble interleukin s(IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α), were assessed before treatment. Least absolute shrinkage and selection operator (LASSO) regression were used to select variables for nomogram of overall survival (OS). The predictive accuracy of the nomogram was determined by concordance index (C-index). Findings The nomogram included lactate dehydrogenase (LDH), sIL-2R, TNF-α and decreased LMR. The C-index of the nomogram for OS prediction were range from 0.61 to 0.86 for training cohort of DLBCL and validation cohorts of DLBCL, PTCL, NKTCL and ASCT, which were superior to the predictive power of International Prognostic Index (IPI, 0.67 to 0.84) or NCCN-IPI (0.59 to 0.78), but not in those of indolent lymphoma like FL and MALT. Interpretations The nomogram incorporating inflammatory cytokines provides a useful tool for risk stratification in aggressive non-Hodgkin's lymphomas. Fund National Natural Science Foundation of China, the Shanghai Commission of Science and Technology, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of SHDC, and Chang Jiang Scholars Program.

Objective To investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on serum levels of brain-derived neurotrophic factor (BDNF), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α in elderly patients with refractory depression. Methods A total of 58 elderly patients diagnosed with refractory depression between January 2015 and December 2016 were divided randomly into two groups: 29 patients who received rTMS and 29 controls without rTMS. Thirty healthy individuals were also enrolled and all received rTMS. Serum levels of BDNF, IL-1β, and TNF-α were measured before the study (0 days), and at 48 hours and 1, 2, 3, and 4 weeks after the first TMS treatment. Results BDNF levels gradually increased with treatment duration in the rTMS group and were significantly higher compared with the control group. In contrast, IL-1β and TNF-α levels gradually decreased and were significantly lower than in the control group. None of the serum factors were affected by rTMS in the healthy individuals. BDNF levels were negatively correlated and IL-1β and TNF-α levels were positively correlated with Hamilton Depression Rating Scale-24 scores. Conclusion These results suggest that rTMS may increase BDNF and decrease IL-1β and TNF-α serum levels in elderly patients with refractory depression.

To compare serum inflammatory cytokines between laparoscopic-assisted and open radical gastrectomy in the perioperative period, 80 cases of advanced gastric cancer were chosen for the study. They were divided into laparoscopy group (40 cases) and abdominal open surgery group (40 cases), performed laparoscopic-assisted radical gastrostomy and conventional open radical gastrectomy, respectively. Serum Heme oxygenase-1 (HO-1), TNF-α, IL-6 and CRP were measured by ELISA on preoperative day 1, post-operative day 1 and post-operative day3. Serum HO-1, TNF-α, IL-6 and CRP had no significant difference between the laparoscopy group and the open group on pre-operative day 1. Serum HO-1, IL-6 and CRP of the laparoscopy group were significantly lower than that of the open group on post-operative day 1 and day 3 except for Serum TNF-α which had no significant difference. Laparoscopic-assisted radical gastrectomy was minimally invasive compared with conventional open radical gastrectomy in advanced gastric cancer patients.

Introduction. Obesity is becoming one of the leading risk factors of coronary heart disease, hypertension, cerebrovascular disease. Despite the presence of a large number of antihypertensive agents and scientific substantiation of antihypertensive treatment principles it would be wrong to assume that the problem is completely solved. Development of endothelial dysfunction is one of the key pathogenic mechanisms in hypertension. This process is proven to have contributed by immune inflammation activation which is mediated by pro-inflammatory cytokines and oxidative stress. Aims. To investigate the additional benefits of the combined antihypertensive therapy with lacidipine and candesartan on the basis of studying their antioxidant properties, impact on endothelial function and pro-inflammatory cytokines activity in hypertensive patients with overweight and obesity. Methods. A combination of a calcium channel blocker and angiotensin receptor blocker (lacidipine 2 mg, 4 mg, and candesartan 4mg, 8mg, 16mg) was prescribed to 30 patients with essential hypertension of grades 1-3, 30 to 65 years old (mean age - 54.7 ± 5.8 years), who previously have not been receiving regular antihypertensive therapy. Results. During the course of combined antihypertensive therapy with lacidipine and candesartan, a significant reduction in i-NOS activity, TNF-α to its type I soluble receptor ratio (TNF- α/sTNF-αRI), and oxidative stress marker - 8-iso-PgF2α has been observed. Activity of e-NOS, levels of SOD and catalase, in contrast, have increased by the end of observation period. Conclusion. The improvement of endothelial function due to lower level of oxidative stress and a significant decrease of immune activation has been observed in hypertensive patients with overweight and obesity under the influence of combined antihypertensive therapy with lacidipine and candesartan.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology, in which different parts of the immune system and other tissues are involved and joint destruction also occurs. Current therapy methods are aimed at suppressing inflammation and reducing pain; however, they do not affect the pathophysiological and biochemical mechanisms involved in joint destruction. Moreover, RA patients are an exclusively heterogeneous group, so not all of them respond equally well to treatment. In this regard, there is a need for personalized therapy. However, the patient's assessment, including clinical, immunological, and radiological parameters, does not currently allow the response to anti-rheumatic treatment to be predicted in about half of the cases. Just the same, recent studies suggest that patient stratification according to the blood level of proinflammatory genes can help predict a response to antirheumatic therapy.

Introduction: Electrical vagal nerve stimulation is known to decrease gut permeability and alleviate gut injury caused by traumatic hemorrhagic shock. However, the specific mechanism of action remains unclear. Glycocalyx, located on the surface of the intestinal epithelium, is associated with the buildup of the intestinal barrier. Therefore, the goal of our study was to explore whether vagal nerve stimulation affects enterocyte glycocalyx, gut permeability, gut injury, and remote lung injury. Materials and methods: Male Sprague Dawley rats were anesthetized and their cervical nerves were exposed. The rats underwent traumatic hemorrhagic shock (with maintenance of mean arterial pressure of 30–35 mmHg for 60 min) with fluid resuscitation. Vagal nerve stimulation was added to two cohorts of animals before fluid resuscitation, and one of them was injected with methyllycaconitine to block the cholinergic anti-inflammatory pathway. Intestinal epithelial glycocalyx was detected using immunofluorescence. Intestinal permeability, the degree of gut and lung injury, and inflammation factors were also assessed. Results: Vagal nerve stimulation alleviated the damage to the intestinal epithelial glycocalyx and decreased intestinal permeability by 43% compared with the shock/resuscitation phase (P

Adalimumab, as a TNF inhibitor biologic for the treatment of rheumatoid arthritis, is one of the top-selling drugs worldwide. As its various patents have gradually expired, experiments on its biosimilars are constantly being implemented. In this review, we summarized clinical trials of seven biosimilars currently approved by the FDA and/or EMA for the treatment of rheumatoid arthritis, namely: ABP 501 (Amjevita/Amgevita/Solymbic), BI 695501 (Cyltezo), SB5 (Imraldi/Hadlima), GP2017 (Hyrimoz/Hefiya/Halimatoz), MSB11022 (Idacio), FKB327 (Hulio), and PF-06410293 (Abrilada). Overall, these biosimilars showed similar efficacy, safety, and immunogenicity to adalimumab. All biosimilar switching trials indicated that switching from adalimumab to a biosimilar does not have a significant impact on efficacy, safety, and immunogenicity.

Background: Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. As apelin is an adipocytokine closely associated with diabetes, this study explored the clinical significance of serum apelin levels in patients with type 2 DPN before and after treatment. Methods: In total, 44 patients with T2DM without DPN (non-DPN group), 41 patients with DPN who received antihyperglycemic treatment (DPN-A group), 44 patients with DPN who received antihyperglycemic treatment combined with nutritional neurotherapy (DPN-B group), and 40 healthy control individuals (NC group) were selected continuously enrolled in the present study. Enzyme-linked immunosorbent assays (ELISA) were performed to determine serum levels of apelin and tumor necrosis factor-α (TNF-α). Related apelin, fasting blood glucose (FBG), glycosylated hemoglobin A1c, TNF-α, body mass index, fasting C peptide, and nerve conduction velocity (NCV) were recorded in each group before and after treatment. Results: Serum levels of apelin and TNF-α were higher in patients with diabetes than those in the NC group, as well as in the DPN group as compared to the non-DPN group; furthermore, some NCV values were significantly reduced in the DPN group. After treatment, the serum levels of apelin, TNF-α, and FBG reduced in patients with diabetes; moreover, apelin levels were found significantly lower in the DPN-B group as compared to the DPN-A group, while some NCV values significantly increased in the DPN-B group. Apelin was negatively correlated with part of NCV values and positively correlated with TNF-α and FBG (P

Aims To analyze expression of members of the Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB signaling pathway in the heart and liver in a rat model of type 2 diabetes mellitus (T2DM). Our overall goal was to understand the underlying pathophysiological mechanisms. Methods We measured fasting blood glucose (FBG) and insulin (FINS) in a rat model of T2DM. Expression of members of the TLR4/MyD88/NF-κB signaling pathway as well as downstream cytokines was investigated. Levels of mRNA and protein were assessed using quantitative real-time polymerase chain reaction and western blotting, respectively. Protein content of tissue homogenates was assessed using enzyme-linked immunosorbent assays. Results Diabetic rats had lower body weights, higher FBG, higher FINS, and higher intraperitoneal glucose tolerance than normal rats. In addition, biochemical indicators related to heart and liver function were elevated in diabetic rats compared with normal rats. TLR4 and MyD88 were involved in the occurrence of T2DM as well as T2DM-related heart and liver complications. TLR4 caused T2DM-related heart and liver complications through activation of NF-κB. Conclusions TLR4/MyD88/NF-κB signaling induces production of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, leading to the heart- and liver-related complications of T2DM.

Fifty-six head of cattle, 28 animals with bovine respiratory disease complex (BRDC), and 28 healthy animals that were matched by treatment, sale barn of origin, day, and interactions among these variables, were identified from a population of 180 animals (60 each purchased at three sale barns located in Missouri, Tennessee, and Kentucky) enrolled in a study comparing animals receiving metaphylaxis to saline-treated controls. Cattle were transported to a feedlot in KS and assigned to treatment group. Blood samples were collected at Day 0 (at sale barn), Day 1, Day 9, and Day 28 (at KS feedlot), and transported to the US Meat Animal Research Center in Clay Center, NE where plasma was harvested and stored at −80°C until assayed for the cytokines IFN-γ, IL-1β, IL-6, and TNF-α, and the acute stress protein haptoglobin (HPT). Our objectives were to determine if cytokine and haptoglobin profiles differed between control and metaphylaxis treatment groups over time, and if profiles differed between animals presenting with BRDC and those that remained healthy. There was no difference between the treated animals and their non-treated counterparts for any of the analytes measured. Sale barn of origin tended to affect TNF-α concentration. Differences for all analytes changed over days, and on specific days was associated with state of origin and treatment. The Treatment by Day by Case interaction was significant for HPT. The analyte most associated with BRDC was HPT on D9, possibly indicating that many of the cattle were not exposed to respiratory pathogens prior to entering the feedlot.

Idiopathic interstitial pneumonia (IIP) entails a variable group of lung diseases of unknown etiology. Idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, interstitial lung diseases related to connective tissue disease (CTD-ILD), and hypersensitivity pneumonitis (HP) can manifest with similar clinical, radiological, and histopathological features. In a differential diagnosis, biomarkers can play a significant role. We assume that levels of specific cyto- or chemokines or their receptors can signal pathogenetic processes in the lungs. Eighty patients with different types of idiopathic interstitial pneumonia were enrolled in this study. Cell counts and concentrations of tumor necrosis factor (TNF)-α, interleukin-4 receptor α, proteinase-activated receptor (PAR)-2, matrix metalloproteinase (MMP)-7, and B cell-activating factor were measured in bronchoalveolar lavage fluid using commercial ELISA kits. High resolution computer tomography results were evaluated using alveolar and interstitial (IS) score scales. Levels of TNF-α were significantly higher in HP compared to fibrosing IIP (p &lt, 0.0001) and CTD-ILD (p = 0.0381). Concentrations of IL-4Rα, PAR-2, and MMP-7 were positively correlated with IS (p = 0.0009, p = 0.0256, p = 0.0015, respectively). Since TNF-α plays a major role in inflammation, our results suggest that HP is predominantly an inflammatory disease. From the positive correlation with IS we believe that IL-4Rα, PAR-2, and MMP-7 could serve as fibroproliferative biomarkers in differential diagnosis of IIP.

Endothelial cells (EC) have dynamic properties and high plasticity in response to microenvironmental change. A proinflammatory cytokine such as tumor necrotizing factor-α (TNF-α) can induce EC phenotype shift to osteoinduction properties by releasing a potent osteogenic cytokine, namely bone morphogenetic protein 2 (BMP2). Normally BMP2 acts as an osteoblast stimulating factor in bone and cartilage tissue. BMP2 activation in vascular tissue will invite osteoblast recruitment and mineralization and generated pathological vascular stiffening and calcification. Recently, endoplasmic reticulum stress (ERS) has been emerging as a new target therapy in many vascular diseases such as vascular stiffening and calcification. Some short-chain fatty acid like 4-phenyl butyric acid has been shown had anti-ERS properties. However, the role of 4-phenyl butyric acid in BMP2 inhibition in endothelial cells is still poorly understood. Hence, we investigated the role of 4-phenyl butyric acid in inflammation-induced BMP2 expression in human vein derived endothelial cells. Endothelial cells obtained from a baby born umbilical vein were cultured and pre-treated with TNF-α (5 ng/ml) as inflammation precondition. Multiple doses of 4-phenyl butyrate acid (4- PBA) 1 nM/mL, 2 nM/mL, and 3 nM/m were used as ERS inhibitors. The expression of two ERS biomarkers, glucose-related protein-8 (GRP78) and activating transcription factor-6 (ATF6), were measured. Statistical analysis was done using one-way ANOVA and Kruskal Wallis tests, and P