Tumor-related factor complement Clq/TNF-related protein 6 affects the development of digestive system tumors through the phosphatidylinositol 3-kinase pathway.

In this editorial, we review the work of Razali et al published in World J Gastroenterology, with a particular focus on the effect of rs10889677 variation in the phosphatidylinositol 3-kinase (PI3K) pathway and buparlisib on colitis-associated cancer. The role of PI3K in promoting cancer progression has been widely recognized, as it is involved in regulating the survival, differentiation, and proliferation of cancer cells. The complement Clq/TNF-related protein 6 (CTRP6) is a newer tumor-associated factor. Recent studies have revealed the pro-tumor effect of CTRP6 in gastric cancer, hepatocellular carcinoma, colorectal cancer, and other gastrointestinal tumors through the PI3K pathway. This article attempts to reveal the mechanism through which the CTRP6 affects the development of digestive system tumors through the PI3K pathway by summarizing recent research.

Switching within versus out of class following first-line TNFi failure in ulcerative colitis: real-world outcomes from a German claims data analysis.

Background: Biologic agents have demonstrated efficacy in treating ulcerative colitis (UC); however, treatment failure to tumor necrosis factor inhibitors (TNFi) is common in the real world. Data on preferential sequencing in clinical practice after failure remain limited. Objectives: This study aimed to evaluate real-world outcomes of patients cycling to TNFis or switching to non-TNFi biologics following first-line failure with TNFis. Design: Retrospective cohort study in Germany. Methods: Adult patients with UC were identified using administrative claims data from 1 May 2014 to 30 June 2022 provided by a statutory sickness fund. Patients newly initiating first-line therapy with TNFis and then switching to another agent were identified. Patients were defined as within-class switched (WCS), if they cycled to another TNFi, or outside-class switchers (OCS), if they switched to a non-TNFi biologic [ustekinumab (UST) or vedolizumab (VDZ)] and followed from index (switch date) to death, insurance end, or study end on 30 June 2022. Inverse probability of treatment weighting (IPTW) was performed to adjust for differences in baseline characteristics between groups, and weighted Cox regression models were used to compare primary (time to discontinuation and second treatment switch) and secondary outcomes (corticosteroid-free drug survival). Results: We identified 166 patients initiating TNFis and switching to a subsequent treatment (mean age: 42.9 years, 49.4% female). Following IPTW, there were 71 and 76 patients in the WCS and OCS groups, respectively. Compared to OCS, WCS were more likely to discontinue the new therapy [hazard ratio (HR), 1.82, 95% confidence interval (CI), 1.14-2.89, p = 0.012], and switch a second time (HR, 3.46, 95% CI, 1.89-6.36, p < 0.001). Moreover, WCS showed an increased likelihood of initiating prolonged corticosteroid therapy (HR, 1.42, 95% CI, 0.77-2.59, p = 0.260); however, the results were not significant. Conclusion: Following first-line TNFi failure, this study suggests that real-world outcomes among patients with UC are less favorable when cycling to another TNFi, compared to switching to a non-TNFi such as UST or VDZ.

Measuring serum and drainage fluid interleukin-6 and tumor necrosis factor-α levels for early detection of infectious complications after minimally invasive surgery for gastric cancer.

OBJECTIVE: Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are inflammatory cytokines produced in response to biological invasion or infection. Their levels are elevated in the blood and locally. We examined whether measuring IL-6 and TNF-α levels in serum or drainage fluid on postoperative day (POD) 1 could detect infectious complications after minimally invasive surgery for gastric cancer. METHODS: This cohort study included 205 consecutive patients who underwent laparoscopic or robot-assisted gastrectomy for gastric cancer between November 2020 and July 2023. We measured serum and drainage fluid IL-6 and TNF-α levels on POD 1 after gastrectomy. Receiver operating characteristic (ROC) curves were created to compare the diagnostic values of each cytokine and serum C-reactive protein levels for detecting postoperative infectious complications. RESULTS: IL-6 and TNF-α levels in the serum or drainage fluid were significantly higher in patients with an infectious complication. In addition, drainage fluid IL-6 levels were significantly different in patients with versus without intra-abdominal abscess. In the ROC curve analysis, serum and drainage fluid IL-6 had the highest AUC values for any infectious complication and intra-abdominal abscess, respectively. POD 1 serum IL-6 level above 47 pg/mL could detect any infectious complication with sensitivity of 74.1 % and specificity of 71.8 %. POD 1 drainage fluid IL-6 level above 14,750 pg/mL had 100 % sensitivity for detecting intra-abdominal abscess with specificity of 56.0 %. CONCLUSIONS: Measurement of IL-6 levels in blood and drainage fluid on POD 1 is valuable for early detection of postoperative infectious complications or intra-abdominal abscess after gastric cancer surgery.

Can treatment with chondroitin and glucosamine sulphate prevent changes in the articular disc caused by temporomandibular joint osteoarthritis?

BACKGROUND: Chondroitin and glucosamine sulphates (CGS) are considered structure-modifying drugs and have been studied in the prevention, delay or reversal of structural morphological changes in joints caused by osteoarthritis. OBJECTIVE: The aim of the present study was to investigate the action of CGS on the progression of chemically induced osteoarthritis in the temporomandibular joint (TMJ) of rabbits by evaluating the serum levels of tumour necrosis factor (TNF-α) and collagen in the articular discs. MATERIALS AND METHODS: A sample of 36 male rabbits was divided into three groups: control (CG), osteoarthritis (OG) and treatment (TG). The disease was induced by intra-articular injection of sodium monoiodoacetate (10 mg/mL) in the OG and TG groups bilaterally. After 10 days, the TG animals received subcutaneous injection of chondroitin sulphates and glucosamine (7.5 mg/kg) and the OG and CG received saline solution (50 µL). Euthanasia times were subdivided into 40 and 100 days. Collagen quantification was performed by biochemical and histological analysis and for the quantification of serum levels of TNF-α, an enzyme immunoassay was used. RESULTS: The TG showed an increase in the collagen area of the articular disc when compared to the CG and the OG. The increase collagen concentration in the discs did not show a statistically significant difference between the groups. Post-treatment TNF-α levels were significantly lower in TG compared to OG. CONCLUSIONS: The results indicate that CGS treatment delayed the degeneration of the collagen in the TMJ articular disc and reduced serum TNF-α levels, indicating a preventive effect on OA progression.

Association of serum biomarkers level transforming growth factor-ß and tumor necrosis factor-α with diabetic neuropathy.

BACKGROUND: Many studies have examined the role of inflammation in the development of diabetic neuropathy (DPN). OBJECTIVE: Evaluate the relation of the serum level of Transforming Growth Factor-ß and Tumor Necrosis Factor-α and development of diabetic peripheral neuropathy DPN. METHODS: In a case-control study, randomly selected 140 diabetic patients were included, the randomly selected patients were divided equally and matched into a case group who have diabetic peripheral neuropathy and diabetic neuropathy-free patients as a control group. For both groups whole blood sample was examined to compare for (TGF-ß), and (TNF-α) levels determination by ELISA technique. RESULTS: The age of the study samples ranged from 25 to 80 years with a male ratio of 1.45:1 although the sex differences between both groups were not significant. The mean levels of (TNF-α) and (TGF-ß) was significantly higher among cases group than that of controls group (254.86 ± 75.9 vs158.01 ± 50.600) for TNF-α and for TGF- ß (312.85 ± 62.27 vs. 217.82 ± 52.95) respectively. Both TNF-α and TGF-ß have high sensitivity and specificity in detection of DPN. The sensitivity of TNF-α was 95.7% and specificity of 61.4% area under the ROC curve (AUC) of 0.870 ± 0.029, while the sensitivity of TGF-ß was 91.4%, and specificity of 67.1 with good area under the ROC curve (AUC) of 0.891 ± 0.026 (P=0.000). CONCLUSIONS: TNF-α and TGF -ß are significantly elevated levels in patients with DPN, these cytokines could be used as indicators for the development of DPN.

Diagnostic value of 8-OHdG, 8-iso-PGF2α and TNF-α levels in blood for early carcinogenesis of erosive oral lichen planus.

BACKGROUND: Oral cancer has a high worldwide incidence and mortality rate showing an upward trend year by year, predominantly occurring in emerging countries. Oral squamous cell carcinoma (OSCC) is one of the main types of oral cancer, accounting for more than 90% of all cases in oral cancer. OBJECTIVE: To evaluate the diagnostic value of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-iso-Prostaglandin F2alpha (8-iso-PGF2α) and tumor necrosis factor (TNF)-α as biomarkers in the early carcinogenesis of erosive oral lichen planus (EOLP) by measuring their levels in the blood of patients with EOLP and oral squamous cell carcinoma (OSCC). METHODS: A total of 69 patients were enrolled in this case-control study [including an OSCC group (n= 23), an EOLP group (n= 23), and an age- and gender-matched healthy control group (n= 23)]. Blood levels of 8-OHdG, 8-iso-PGF2α and TNF-α were measured using enzyme-linked immunosorbent assay (ELISA). Statistical differences in these indicators among the three groups were analyzed. RESULTS: Plasma levels of 8-OHdG and 8-iso-PGF2α in the OSCC group were significantly higher than those in both the EOLP group and the control group (all P< 0.05); no significant statistical difference was found between the EOLP group and the control group. Serum levels of TNF-α in both the OSCC and EOLP groups were elevated compared with the control group, showing significant differences among all three groups (all P< 0.05). Receiver operating characteristic (ROC) curves revealed that plasma 8-OHdG and 8-iso-PGF2α levels and serum TNF-α levels had diagnostic effects on early carcinogenesis in EOLP patients. When these indicators were combined for diagnosis, the diagnostic effect was enhanced, with an area under the ROC curve (AUC) values of 0.819. CONCLUSION: 8-OHdG, 8-iso-PGF2α and TNF-α may serve as biological indicators for monitoring the early carcinogenesis of EOLP, and the diagnostic effect was augmented when these indicators were combined.

Comparative risk of serious infections and tuberculosis in Korean patients with inflammatory bowel disease treated with non-anti-TNF biologics or anti-TNF-α agents: a nationwide population-based cohort study.

Background: The risk of serious infection and active tuberculosis in patients with inflammatory bowel disease (IBD) has not been concurrently evaluated based on the use of anti-tumor necrosis factor (TNF)-α agents versus non-anti-TNF biologics (vedolizumab/ustekinumab) in the Korean population. Objectives: We compared the risk of serious infection and active tuberculosis in Korean patients with IBD treated with non-anti-TNF biologics (vedolizumab/ustekinumab) or anti-TNF-α agents. Design: This study was a population-based cohort analysis of nationwide administrative claims data. Methods: Health Insurance Review and Assessment Service claims data (representing 97% of the South Korean population) from between January 2007 and February 2021 were reviewed, and adults with IBD who initiated vedolizumab/ustekinumab or anti-TNF-α treatment (n = 6123) between 2017 and 2020 were enrolled. Intergroup differences in the risk of serious infection requiring hospitalization/emergency department visits or active tuberculosis during the follow-up period were analyzed. Results: In the patients treated with anti-TNF-α agents or vedolizumab/ustekinumab during a mean follow-up of 1.55 ± 1.05 and 0.84 ± 0.69 years, the incidence rates of serious infection were 9.43/100 and 6.87/100 person-years, respectively. Multivariable analysis showed no significant intergroup difference in the risk of serious infection with vedolizumab/ustekinumab or anti-TNF-α treatment; the adjusted relative risk of vedolizumab/ustekinumab compared with anti-TNF-α agents was 0.81 (95% confidence interval 0.46-1.44, p = 0.478). Among patients treated with anti-TNF-α agents and vedolizumab/ustekinumab, the incidence rates of active tuberculosis were 0.87 and 0.37 per 100 person-years, respectively. The relative risk of vedolizumab/ustekinumab compared with anti-TNF-α agents was 0.31 (95% confidence interval 0.07-1.26, p = 0.101). In a subset analysis comparing vedolizumab and ustekinumab with anti-TNF-α agents, similar results were observed. Conclusion: In Korean patients with IBD, non-anti-TNF biologics (vedolizumab/ustekinumab) tended to be associated with a lower risk of serious infection or active tuberculosis than anti-TNF-α agents.

Comparative Safety and Effectiveness of Ustekinumab and Anti-TNF in Elderly Crohn's Disease Patients.

BACKGROUND: Biologic therapies are associated with increased infection risk among elderly patients with inflammatory bowel disease (IBD). However, there are few data on the safety and effectiveness of ustekinumab compared with anti-tumor necrosis factor (anti-TNF) agents in the elderly. METHODS: The study sought to compare the safety and effectiveness of ustekinumab and anti-TNF agents in elderly Crohn's disease (CD) patients. Patients ≥60 years of age who commenced ustekinumab or an anti-TNF agent for CD were included in this retrospective multicenter cohort. The primary outcome was incidence of serious infections requiring hospitalization. Effectiveness was assessed by clinical remission, clinical response, and treatment persistence rates at 6 months. We adjusted for confounders using inverse probability of treatment weighting (IPTW) and performed a logistic regression analysis to assess factors associated with serious infections, clinical remission, and treatment persistence. RESULTS: Eighty-three patients commencing ustekinumab and 124 commencing anti-TNF therapy were included. There was no difference in serious infection rates between anti-TNF agents (2.8%) and ustekinumab (3.1%) (P = .924) after propensity adjustment. Clinical remission rates were comparable at 6 months for ustekinumab (55.9%) and anti-TNF agents (52.4%) (P = .762). There was a significant reduction in HBI at 6 months in both groups. Treatment persistence was comparable between ustekinumab (90.6%) and anti-TNF agents (90.0%) at 6 months. Cox regression analysis did not show differences in treatment persistence (hazard ratio, 1.23; 95% confidence interval, 0.57-2.61; P = .594) and serious infection incidence (hazard ratio, 1.38; 95% confidence interval, 0.25-7.57; P = .709) by 6 months. CONCLUSIONS: We observed comparable safety and effectiveness for ustekinumab and anti-TNF agents in treating elderly CD patients.

In this retrospective multicenter cohort study, we report equal safety and effectiveness for ustekinumab and anti-tumor necrosis factor agents in treating older adults with Crohn's disease over a 6-month period.

A comprehensive review of phase 2/3 trials in osteoarthritis: an expert opinion.

INTRODUCTION: Osteoarthritis (OA) is a chronic, degenerative, and debilitating disease associated with significant long-term morbidity and disability. The pathogenesis of OA is not completely understood but involves an interplay between environmental risk factors, joint mechanics, abnormal pain pathways and upregulation of inflammatory signaling pathways. Current therapeutic options for patients are limited to conservative management, minimal pharmacological options or surgical management, with significant caveats to all approaches. AREAS COVERED: In this review, we have set out to investigate current phase II/III clinical trials by undertaking a PubMed search. Examined clinical trials have explored a myriad of potential therapeutics from conventional disease-modifying anti-rheumatic drugs and biologics usually used in the treatment of inflammatory arthritides, to more novel approaches targeting inflammatory pathways implicated in OA, cartilage degeneration or pain pathways. EXPERT OPINION: Unfortunately, most completed phase II/III clinical trials have shown little impact on patient pain scores, with the exception of the traditional DMARD methotrexate and Sprifermin. Methotrexate has been shown to be beneficial when used in the correct patient cohort (MRI proven synovitis). Sprifermin has the longest follow-up data of 5 years and has been shown to reduce loss of MRI-measured cartilage thickness and pain scores.

Prenatal arsenic exposure alters EZH2-H3K27me3 occupancy at TNF-α promoter leading to insulin resistance and metabolic syndrome in a mouse model.

The global prevalence of Metabolic Syndrome (MetS) is continuously rising and exposure to environmental toxicants such as arsenic could be contributing to this rapid surge. In this study, we have assessed the effects of prenatal arsenic exposure on insulin resistance and MetS parameters in a mouse model, and an underlying mechanism was identified. We found that prenatal arsenic exposure promotes insulin resistance and adipocyte dysfunction which leads to the early onset of MetS in male offspring. Primary adipocytes isolated from 20-week-old arsenic-exposed offspring showed hypertrophy, elevated basal lipolysis, and impaired insulin response along with enhanced expression of Tumor necrosis factor-alpha (TNF-α). TNF-α levels were consistently high at gestational day 15.5 (GD15.5) as well as primary adipocytes of 6-week-old arsenic-exposed male offspring. Along with TNF-α, downstream p-JNK1/2 levels were also increased, which led to inhibitory phosphorylation of IRS1and reduced GLUT4 translocation upon insulin stimulation in adipocytes. Insulin response and downstream signaling were restored upon TNF-α inhibition, confirming its central role. The persistent overexpression of TNF-α in adipocytes of arsenic-exposed mice resulted from diminished EZH2 occupancy and reduced H3K27me3 (gene silencing histone marks) at the TNF-α promoter. This further led to chromatin relaxation, recruitment of c-Jun and CBP/p300, formation of an enhanceosome complex, and TNF-α expression. Our findings show how prenatal arsenic exposure can epigenetically modulate TNF-α expression to promote adipocyte dysfunction and insulin resistance which contributes to the early onset of MetS in offspring.

Expression analysis of microRNAs and cytokine mRNAs in pregnancies complicated by gestational hypertension.

OBJECTIVES: Gestational hypertension (GH1) is one of the most common pregnancy-related complications, however, there is still insufficient knowledge about its development and molecular changes. The aim of our study was to examine the expression of miR-17, miR-29a and miR-181a, as well as TNF-α, IL-1ß, IL-6 and IL-17 in women with GH and to investigate possible correlations between these parameters. STUDY DESIGN: The study included 64 pregnant women, placed either in the control or the GH group. Quantitative real-time PCR (qPCR2) was used to determine expression levels of microRNAs and cytokines' mRNAs. MAIN OUTCOME MEASURES: Expression levels of miRNAs (miR-17, miR-29a and miR-181a) and proinflammatory cytokines mRNAs (TNF-α, IL-1ß, IL-6 and IL-17) in women with gestational hypertension were compared to the control group (healthy pregnant women). RESULTS: No significant changes in microRNAs expression level were found between compared groups. TNF-α was significantly upregulated in the GH group compared to controls. Expression levels of other investigated cytokines did not differ between examined groups. ROC curve analysis indicated that TNF-α does not show sufficient ability to discriminate between CG and GH patients. TNF-α was significantly positively correlated with IL-1ß and IL-17 and negatively correlated with miR-181a. CONCLUSIONS: Our results point to the involvement of proinflamatory cytokines in gestational hypertension. Although increased expression of TNF-α was found in the GH group, this cytokine did not show sufficient ability to discriminate between GH and healthy pregnancies.

Gene expression-phenotype association study reveals the dual role of TNF-α/TNFR1 signaling axis in confined breast cancer cell migration.

AIMS: While enhanced tumor cell migration is a key process in the tumor dissemination, mechanistic insights into causal relationships between tumor cells and mechanical confinement are still limited. Here we combine the use of microfluidic platforms to characterize confined cell migration with genomic tools to systematically unravel the global signaling landscape associated with the migratory phenotype of breast cancer (BC) cells. METERIALS AND METHODS: The spontaneous migration capacity of seven BC cell lines was evaluated in 3D microfluidic devices and their migration capacity was correlated with publicly available molecular signatures. The role of identified signaling pathways on regulating BC migration capacity was determined by receptor stimulation through ligand binding or inhibition through siRNA silencing. Downstream effects on cell migration were evaluated in microfluidic devices, while the molecular changes were monitored by RT-qPCR. KEY FINDINGS: Expression of 715 genes was correlated with BC cells migratory phenotype, revealing TNF-α as one of the top upstream regulators. Signal transduction experiments revealed that TNF-α stimulates the confined migration of triple negative, mesenchymal-like BC cells that are also characterized by high TNFR1 expression, but inhibits the migration of epithelial-like cells with low TNFR1 expression. TNFR1 was strongly associated with the migration capacity and triple-negative, mesenchymal phenotype. Downstream of TNF/TNFR1 signaling, transcriptional regulation of NFKB seems to be important in driving cell migration in confined spaces. SIGNIFICANCE: TNF-α/TNFR1 signaling axis reveals as a key player in driving BC cells confined migration, emerging as a promising therapeutic strategy in targeting dissemination and metastasis of triple negative, mesenchymal BC cells.

Analysis of PANoptosis-related ceRNA network reveals lncRNA MIR17HG involved in osteogenic differentiation inhibition impaired by tumor necrosis factor-α.

BACKGROUND: Inflammatory cytokines such as Interleukin 1ß(IL1ß), IL6,Tumor Necrosis Factor-α (TNF-α) can inhibit osteoblast differentiation and induce osteoblast apoptosis. PANoptosis, a newly identified type of programmed cell death (PCD), may be influenced by long noncoding RNA (lncRNAs) which play important roles in regulating inflammation. However, the potential role of lncRNAs in inflammation and PANoptosis during osteogenic differentiation remains unclear. This study aimed to investigate the regulatory functions of lncRNAs in inflammation and apoptosis during osteogenic differentiation. METHODS AND RESULTS: High-throughput sequencing was used to identify differentially expressed genes involved in osteoblast differentiation under inflammatory conditions. Two lncRNAs associated with inflammation and PANoptosis during osteogenic differentiation were identified from sequencing data and Gene Expression Omnibus (GEO) databases. Their functionalities were analyzed using diverse bioinformatics methodologies, resulting in the construction of the lncRNA-miRNA-mRNA network. Among these, lncRNA (MIR17HG) showed a high correlation with PANoptosis. Bibliometric methods were employed to collect literature data on PANoptosis, and its components were inferred. PCR and Western Blotting experiments confirmed that lncRNA MIR17HG is related to PANoptosis in osteoblasts during inflammation. CONCLUSIONS: Our data suggest that TNF-α-induced inhibition of osteogenic differentiation and PANoptosis in MC3T3-E1 osteoblasts is associated with MIR17HG. These findings highlight the critical role of MIR17HG in the interplay between inflammation, PANoptosis, and osteogenic differentiation, suggesting potential therapeutic targets for conditions involving impaired bone formation and inflammatory responses.

Update on non-infectious uveitis treatment: anti-TNF-alpha and beyond.

Non-infectious uveitis (NIU) encompasses a range of conditions marked by inflammation within various layers of the eye. NIU is a significant contributor to irreversible vision loss among the working-age population in developed countries. The aim of treating uveitis is to manage inflammation, prevent its recurrences and to restore or salvage vision. Presently, the standard treatment protocol for NIU involves initiating corticosteroids as the primary therapeutic agents, although more aggressive approaches and steroid sparing agent may be necessary in certain cases. These advanced treatments option include synthetic immunosuppressants like antimetabolites, calcineurin inhibitors and alkylating agents. For patients who exhibit an intolerance or resistance to corticosteroids and conventional immunosuppressive therapies, biologic agents have emerged as a promising alternative. Notably, among the biologic treatments evaluated, TNF-α inhibitors, anti-CD20 therapy and alkylating agents have shown considerable efficacy. In this review, we delve into the latest evidence surrounding the effectiveness of biologic therapy and introduce novel therapeutic strategies targeting immune components as potential avenues for advancing treatment of NIU.

Tear cytokines as potential markers of inflammation in feline conjunctivitis.

INTRODUCTION: Conjunctivitis is a prevalent feline ocular surface disorder, often accompanied by inflammation. Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), play a crucial role in the pathogenesis of conjunctival inflammation. This study aimed to evaluate the levels of TNF-α and IL-6 in the tears of cats with conjunctivitis and compare them with healthy controls, thereby enhancing our understanding of the inflammatory processes in feline conjunctivitis. METHODS AND MATERIALS: Tear samples were collected from cats of various breeds diagnosed with conjunctivitis (n = 15) and healthy control cats (n = 5) using Schirmer strips. The levels of TNF-α and IL-6 were measured using the enzyme-linked immunosorbent assay (ELISA) method. Protein concentration were measured using Bradford assay and data were expressed as pg/mg protein of tear sample. RESULTS: Our results revealed a statistically significant increase in the levels of both TNF-α and IL-6 in cats with conjunctivitis compared to the control group (p < .0001). Positive correlation were observed between tear IL-6 (p < .001, r = 0.902) and TNF-α (p < .001, r = 0.919) with clinical grades of conjunctivitis. CONCLUSION: The results demonstrated a significant elevation in the levels of TNF-α and IL-6 in the tears of cats with conjunctivitis, suggesting that these cytokines are involved in the inflammatory response of feline conjunctivitis. These findings could pave the way for new diagnostic and therapeutic approaches, focusing on cytokine modulation, to manage feline conjunctivitis more effectively.

Aspirin attenuates the detrimental effects of TNF-α on BMMSC stemness by modulating the YAP-SMAD7 axis.

BACKGROUND: Bone marrow mesenchymal stem cells (BMMSCs) are commonly used for cell transplantation to treat refractory diseases. However, the presence of inflammatory factors, such as tumour necrosis factor-alpha (TNF-α), at the transplantation site severely compromises the stemness of BMMSCs, thereby reducing the therapeutic effect of cell transplantation. Aspirin (AS) is a drug that has been in use for over a century and has a wide range of effects, including the regulation of cell proliferation, multidirectional differentiation, and immunomodulatory properties of stem cells. However, it is still unclear whether AS can delay the damaging effects of TNF-α on BMMSC stemness. METHODS: This study investigated the effects of AS and TNF-α on BMMSC stemness and the molecular mechanisms using colony formation assay, western blot, qRT-PCR, and overexpression or knockdown of YAP and SMAD7. RESULTS: The results demonstrated that TNF-α inhibited cell proliferation, the expression of stemness, osteogenic and chondrogenic differentiation markers of BMMSCs. Treatment with AS was shown to mitigate the TNF-α-induced damage to BMMSC stemness. Mechanistic studies revealed that AS may reverse the damage caused by TNF-α on BMMSC stemness by upregulating YAP and inhibiting the expression of SMAD7. CONCLUSION: AS can attenuate the damaging effects of TNF-α on BMMSC stemness by regulating the YAP-SMAD7 axis. These findings are expected to promote the application of AS to improve the efficacy of stem cell therapy.

A diagnostic dilemma: cytomegalovirus colitis as an uncommon comorbidity in inflammatory bowel disease: a case report.

BACKGROUND: The role of cytomegalovirus infection as an opportunistic pathogen in exacerbating ulcerative colitis and its response to treatment remain a topic of ongoing debate. Clinicians encounter numerous challenges, including the criteria for differentiating between an acute ulcerative colitis flare and true cytomegalovirus colitis, the diagnostic tests for identifying cytomegalovirus colitis, and determining the appropriate timing for initiating antiviral therapy. CASE PRESENTATION: A 28-year-old Syrian female with a seven-year history of pancolitis presented with worsening bloody diarrhea, abdominal pain, and tenesmus despite ongoing treatment with azathioprine, mesalazine, and prednisolone. She experienced a new flare of acute severe ulcerative colitis despite recently completing two induction doses of infliximab (5 mg/kg) initiated four weeks prior for moderate-to-severe ulcerative colitis. She had no prior surgical history. Her symptoms included watery, bloody diarrhea occurring nine to ten times per day, abdominal pain, and tenesmus. Initial laboratory tests indicated anemia, leukocytosis, elevated C-reactive protein (CRP) and fecal calprotectin levels, and positive CMV IgG. Stool cultures, Clostridium difficile toxin, testing for Escherichia coli and Cryptosporidium, and microscopy for ova and parasites were all negative. Sigmoidoscopy revealed numerous prominent erythematous area with spontaneous bleeding. Biopsies demonstrated CMV inclusions confirmed by immunohistochemistry, although prior biopsies were negative. We tapered prednisolone and azathioprine and initiated ganciclovir at 5 mg/kg for ten days, followed by valganciclovir at 450 mg twice daily for three weeks. After one month, she showed marked improvement, with CRP and fecal calprotectin levels returning to normal. She scored one point on the partial Mayo score. The third induction dose of infliximab was administered on schedule, and azathioprine was resumed. CONCLUSION: Concurrent cytomegalovirus infection in patients with inflammatory bowel disease presents a significant clinical challenge due to its associated morbidity and mortality. Diagnosing and managing this condition is particularly difficult, especially regarding the initiation or continuation of immunosuppressive therapies.

The implications of the TNFα-TNFR2 immune checkpoint signaling pathway in cancer treatment: From immunoregulation to angiogenesis.

Despite the tremendous advances that have been made in biomedical research, cancer remains one of the leading causes of death worldwide. Several therapeutic approaches have been suggested and applied to treat cancer with impressive results. Immunotherapy based on targeting immune checkpoint signaling pathways proved to be one of the most efficient. In this review article, we will focus on the recently discovered TNFα-TNFR2 signaling pathway, which controls the immunological and pro-angiogenic properties of many immunoregulatory and pro-angiogenic cells such as endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs), and regulatory T cells (Tregs). Due to their biological properties, these cells can play a major role in cancer progression and metastasis. Therefore, we will discuss the advantages and disadvantages of an anti-TNFR2 treatment that could carry two faces under one hood. It interrupts the immunosuppressive and pro-angiogenic behaviors of the above-mentioned cells and interferes with tumor growth and survival.

Saponins from Dolichos lablab seeds with anti-inflammatory activity.

As one of a traditional Chinese medicine with dual applications in both medicinal treatment and dietary consumption, the mature seeds of D. lablab were reported to be rich in saponins and have a good effect on inflammatory related diseases. However, the substance basis for its anti-inflammatory activity remains unclear. Thus, a comprehensive phytochemical investigation on triterpenoid saponins from D. lablab seeds was carried out, resulting in the isolation and identification of twenty-one new triterpenoid saponins including dolilabsaponins A1-A4, B, C, D1-D3, E-M, N1, N2 and O (1-21) along with thirteen known analogs (22-34). Notably, the known saponins, 31, 32, and 34 were obtained from Leguminosae family for the first time. The 1H and 13C NMR data of saponins 24 and 28 were firstly reported here. Additionally, lipopolysaccharide (LPS)-stimulated RAW264.7 cells model was utilized to assess inhibitory activities of compounds 1-34 on nitric oxide (NO) production. The results revealed that compounds 1-3, 9, 10, 13-15, 18, 22, 23 and 28-34 significantly suppressed the elevation of NO levels in LPS-induced RAW264.7 cells at the concentration of 30 µM, exhibiting a concentration-dependent manner at 3, 10, and 30 µM. The results suggested that compounds 1-3, 9, 10, 13-15, 18, 22, 23, and 28-34 possessed potential anti-inflammatory activity. Further western blot assay demonstrated that 1, 9, 10, 13, 14, and 18 suppressed inflammatory response via down-regulated the expression levels of inflammatory factors, tumor necrosis factor-alpha and interleukin-6.

Nrf1 Reduces COX-2 Expression and Maintains Cellular Homeostasis After Cerebral Ischemia/Reperfusion By Targeting IL-6/TNF-α Protein Production.

Neuroinflammation has been considered involved in the process of cerebral ischemia-reperfusion injury (CIRI). Transcription factors play a crucial role in regulating gene transcription and the expressions of specific proteins during the progression of various neurological diseases. Evidence showed that transcription factor nuclear factor erythroid 2-related factor 1 (NFE2L1, also known as Nrf1) possessed strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in CIRI remain unclear. In our study, we observed a significant elevation of Nrf1 in the cerebral cortex following cerebral ischemia-reperfusion in rats. The Nrf1 downregulation markedly raised COX-2, TNF-α, IL-1ß, and IL-6 protein levels during middle cerebral artery occlusion/reperfusion in rats, which led to worsened neurological deficits, higher cerebral infarct volume, and intensified cortical histopathological damage. In subsequent in vitro studies, the expression of Nrf1 protein increased following oxygen-glucose deprivation/reperfusion treatment on neurons. Subsequently, Nrf1 knockdown resulted in a significant upregulation of inflammatory factors, leading to a substantial increase in the cell death rate. Through analyzing the alterations in the expression of inflammatory factors under diverse interventions, it is indicated that Nrf1 possesses the capacity to discern variations in inflammatory factors via specific structural domains. Our findings demonstrate the translocation of the Nrf1 protein from the cytoplasm to the nucleus, thereby modulating the protein expression of IL-6/TNF-α and subsequently reducing the expression of multiple inflammatory factors. This study signifies, for the first time, that during cerebral ischemia-reperfusion, Nrf1 translocases to the nucleus to regulate the protein expression of IL-6/TNF-α, consequently suppressing COX-2 expression and governing cellular inflammation, ultimately upholding cellular homeostasis.