Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Prevalence and risk factors of osteoporosis detected by dual-energy X-ray absorptiometry among Chinese patients with primary biliary cholangitis.

BACKGROUND: Osteoporosis is an extrahepatic complication of primary biliary cholangitis (PBC) that increases the risk of fractures and mortality. However, Epidemiological studies of osteoporosis in patients with PBC in China and the Asia-Pacific region is lack. AIM: To assess the prevalence and clinical characteristics of osteoporosis in Chinese patients with PBC. METHODS: This retrospective analysis included consecutive patients with PBC from a tertiary care center in China who underwent bone mineral density (BMD) assessment using dual-energy X-ray absorptiometry between January 2013 and December 2021. We defined subjects with T-scores ≤ -2.5 in any sites (L1 to L4, femoral neck, or total hip) as having osteoporosis. Demographic, serological, clinical, and histological data were collected. Independent risk factors for osteoporosis were identified by multivariate logistic regression analysis. RESULTS: A total of 268 patients with PBC [236 women (88.1%); mean age, 56.7 ± 10.6 years; 163 liver biopsies (60.8%)] were included. The overall prevalence of osteoporosis in patients with PBC was 45.5% (122/268), with the prevalence of osteoporosis in women and men being 47.0% and 34.4%, respectively. The prevalence of osteoporosis in postmenopausal women was significantly higher than that in premenopausal women (56.3% vs 21.0%, P < 0.001). Osteoporosis in patients with PBC is associated with age, fatigue, menopausal status, previous steroid therapy, body mass index (BMI), splenomegaly, gastroesophageal varices, ascites, Mayo risk score, histological stage, alanine aminotransferase, albumin, bilirubin, platelet and prothrombin activity. Multivariate regression analysis identified that older age, lower BMI, previous steroid therapy, higher Mayo risk score, and advanced histological stage as the main independent risk factors for osteoporosis in PBC. CONCLUSION: Osteoporosis is very common in Chinese patients with PBC, allowing for prior screening of BMD in those PBC patients with older age, lower BMI, previous steroid therapy and advanced liver disease.

Gut microbiota dysbiosis with hepatitis B virus liver disease and association with immune response.

Background and aims: Given hepatitis B virus (HBV)-related hepatocellular carcinoma (HBV-HCC) exhibits unique gut microbiota characteristics and a significant immunosuppressive tumor microenvironment. Thus, a better understanding of the correlation between gut microbiota and the immunosuppressive response may help predict occurrence and prognosis of HBV-HCC. Methods: Here, in a cohort of ninety adults (healthy control n=30, HBV-cirrhosis n=30, HBV-HCC n=30) with clinical data, fecal 16S rRNA gene sequencing, matched peripheral blood immune response with flow cytometry analysis. Correlation between the gut microbiome of significantly different in HBV-HCC patients and clinical parameters as well as the peripheral immune response was assessed. Results: We found that community structures and diversity of the gut microbiota in HBV-CLD patients become more unbalanced. Differential microbiota analysis that p:Acidobacteriota, p:Proteobacteria, p:Campilobacterota, f:Streptococcaceae, g:Klebsiella associated with inflammation were enriched. The beneficial bacteria of f:Clostridia UCG-014, f:Oscillospiraceae, f:_Rikenellaceae, g:_Barnesiella, g:Prevotella, g:Agathobacter were decreased. Functional analysis of gut microbiota revealed that lipopolysaccharide biosynthesis, lipid metabolism, butanoate metabolism were significantly elevated in HBV-CLD patients. Spearman's correlation analysis showed that Muribaculaceae, Akkermaniacaeae, [Eubacterium]_coprostanoligenes_group, RF39, Tannerellaceae have positive correlation with CD3+T, CD4+T and CD8+T cell counts while negatively correlated with liver dysfunction. Furthermore, paired peripheral blood showed a decreased proportion of CD3+T, CD4+T and CD8+T cells, while an increased T (Treg) cells. The immunosuppressive response of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), immune receptor tyrosine based inhibitor motor (ITIM) domain (TIGIT), T-cell immune domain, and multiple domain 3 (TIM-3) of CD8+T cells were higher in HBV-HCC patients. They were positively correlated with harmful bacteria, such as Actinobaciota, Myxococota, Streptococcaceae and Eubacterium coprostanoligenes. Conclusions: Our study indicated that gut beneficial bacteria, mainly Firmicutes and Bacteroides appeared dysbiosis in HBV-CLD patients. They have negative regulation of liver dysfunction and T cell immune response. It provides potential avenues for microbiome-based prevention and intervention for anti-tumor immune effects of HBV-CLD.

Effects of adjuvant huaier granule therapy on survival rate of patients with hepatocellular carcinoma.

Objective: Clinical trials have reported that Huaier granule inhibits the recurrence of hepatocellular carcinoma (HCC) after resection. However, its efficacy in patients at different clinical stages of HCC remains unknown. We investigated the effects of Huaier granule on the 3-year overall survival (OS) rate of patients at different clinical stages. Design: This cohort study included 826 patients with HCC, screened between January 2015 and December 2019. The patients were divided into Huaier (n = 174) and control groups (n = 652), and the 3-year OS rates were compared between the two groups. To eliminate bias caused by confounding factors, propensity score matching (PSM) was performed. We used the Kaplan-Meier method to estimate OS rate and tested the difference using the log-rank test. Results: Multivariable regression analysis revealed that Huaier therapy was an independent protective factor for 3-year survival rate. After PSM (1:2), the Huaier and control groups comprised 170 and 340 patients, respectively. The 3-year OS rate was remarkably higher in the Huaier group than in the control group (adjusted hazard ratio [aHR]: 0.36; 95% confidence interval: 0.26-0.49; p < 0.001). The aHR for Huaier use for 3-12, 12-24, and >24 months was 0.48, 0.23, and 0.16, respectively, indicating a dose-response pattern. For the 3-12-, 12-24-, and >24-month groups, the 3-year OS rate was 54.1%, 68.6%, and 90.4%, respectively. Multivariate stratified analysis confirmed that the mortality risk in Huaier users was lower than that in non-Huaier users in most subgroups. Conclusion: Adjuvant Huaier therapy improved the OS rate in patients with HCC. However, these findings require further verification through prospective clinical studies.

Neutrophil-to-high-density-lipoprotein-cholesterol ratio and mortality among patients with hepatocellular carcinoma.

Background: Inflammatory responses and lipid metabolism disorders contribute to the development and prognosis of hepatocellular carcinoma (HCC). This study aimed to investigate the prognostic value of lipid-related inflammatory parameters in patients with HCC. Methods: From January 2010 to June 2017, we enrolled 1,639 patients with HCC at Beijing Ditan Hospital. Multivariate Cox regression analysis and area under the receiver operating characteristic (AUC) analysis were used to evaluate and compare the predictability and reliability of high-density lipoprotein cholesterol (HDL-C), neutrophil-to-HDL-C ratio (NHR), monocyte-to-HDL-C ratio (MHR), and lymphocyte-to-HDL-C ratio (LHR) values. A restricted cubic spline was used to explore the association between the NHR and 3-year mortality in patients with HCC. Differences in survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. The results were validated in an internal cohort between July 2017 and October 2019 (n = 373). Results: After adjusting for confounding variables, NHR was independently associated with 3-year mortality, both as a continuous and categorical variable (both p < 0.05). The correlation between the mortality and the MHR and LHR was not statistically significant. The NHR showed a suitable prognostic value (AUC at 3 years: 0.740), similar to that of the Model for End-stage Liver Disease (MELD) (AUC at 3 years: 0.761). In the validation cohort, the AUC of the NHR was 0.734 at 3 years. The optimal cut-off values of NHR and MELD were 3.5 and 9, respectively. The 3-year survival rates in the low- (NHR < 3.5 and MELD <9) and high-risk (NHR ≥ 3.5 and MELD ≥9) groups were 81.8 and 19.4%, respectively, in the training cohort, and 84.6 and 27.5%, respectively, in the validation cohort. Conclusion: Baseline NHR is a promising prognostic parameter for mortality in patients with HCC and patients with NHR ≥ 3.5 and MELD ≥9 have a high mortality rate.

Curative effect of anti-fibrosis Chinese patent medicines combined with ursodeoxycholic acid for primary biliary cholangitis: A systematic review and meta-analysis.

Objective: To delineate the curative effect and safety of anti-fibrosis Chinese patent medicines (CPMs) combined with ursodeoxycholic acid (UDCA) for primary biliary cholangitis (PBC). Methods: A literature search was conducted using PubMed, Web of Science, Embase, Cochrane Library, Wanfang database, VIP database, China Biology Medicine Database, and Chinese National Knowledge Infrastructure from their inception until August 2022. Randomized controlled trials (RCTs) of the treatment of PBC with anti-fibrotic CPMs were collected. The eligibility of the publications was assessed using the Cochrane risk-of-bias tool. The evaluation indicators were the clinical efficacy rate, liver fibrosis, liver function, immune function, and symptom score. Meta-analysis and subgroup analysis were conducted to evaluate the effectiveness of anti-fibrosis CPMs. Risk ratio (RR) was used to assess dichotomous variables, and continuous variables with a 95% confidence interval were calculated using mean difference. Results: Twenty-two RCTs including 1,725 patients were selected. The findings demonstrated that anti-fibrotic CPMs combined with UDCA improved the efficacy rate, liver function, liver fibrosis, immunological indicators, and clinical symptoms compared with UDCA alone (all p < 0.05). Conclusion: This study demonstrates that the combination of anti-fibrotic CPMs and UDCA can improve both clinical symptoms and outcomes. Nevertheless, more high-quality RCTs are needed to assess the effectiveness of anti-fibrosis CPMs for PBC.

Development of a nomogram to predict the risk of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis on antivirals.

Objective: Patients with compensated hepatitis B-related cirrhosis receiving antivirals are at the risk of hepatocellular carcinoma (HCC). This study aimed to develop and validate a nomogram for predicting the incidence of HCC in patients with hepatitis-B related cirrhosis. Design: A total of 632 patients with compensated hepatitis-B related cirrhosis treated with entecavir or tenofovir between August 2010 and July 2018 were enrolled. Cox regression analysis was used to identify independent risk factors for HCC and a nomogram was developed using these factors. The area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analyses were used to evaluate the nomogram performance. The results were validated in an external cohort (n = 324). Results: In the multivariate analysis, age per 10 years, neutrophil-lymphocyte ratio > 1.6, and platelet count < 86×109/L were independent predictors of HCC occurrence. A nomogram was developed to predict HCC risk using these three factors (ranging from 0 to 20). The nomogram showed better performance (AUC: 0.83) than that of the established models (all P < 0.05). The 3-year cumulative HCC incidences in the low- (scores < 4), medium- (4-10), and high-risk (> 10) subgroups were 0.7%, 4.3%, and 17.7%, respectively, in the derivation cohort, and 1.2%, 3.9%, and 17.8%, respectively, in the validation cohort. Conclusion: The nomogram showed good discrimination and calibration in estimating HCC risk in patients with hepatitis-B related cirrhosis on antivirals. High-risk patients with a score > 10 points require close surveillance.

A novel prognostic model for predicting the risk of first variceal hemorrhage in patients with HBV-related cirrhosis.

Background: Variceal hemorrhage (VH) is a life-threatening complication of cirrhosis. An accurate VH risk evaluation is critical to determine appropriate prevention strategies. We aimed to develop an individualized prediction model to predict the risk of first VH in hepatitis B virus (HBV)-related cirrhotic patients. Methods: A nomogram was developed based on a retrospective analysis of 527 consecutive HBV-related cirrhotic patients with gastroesophageal varices (GEVs). The nomogram evaluation was performed using the area under the receiver operating characteristic curve (AUC), concordance index (C-index), calibration plot, and decision curve analysis (DCA). The results were verified using an external cohort (n = 187). Results: We developed a nomogram based on clinical and endoscopic features, including the size of varices, red wale marks, ascites, spleen thickness, γ-glutamyltransferase, and hematocrit. The C-index of the nomogram in the derivation and validation cohort was 0.806 and 0.820, respectively, and the calibration plot fitted well. Compared with those of the North Italian Endoscopic Club (NIEC) and revised NIEC indexes, the AUC (derivation cohort: 0.822 vs. 0.653 vs. 0.713; validation cohort: 0.846 vs. 0.685 vs. 0.747) and DCA curves of this nomogram were better. Further, based on the risk scores, patients were classified into low-, medium-, and high-risk groups, and significant differences were noted in VH incidence among the three risk groups (P <0.001 for each cohort). Conclusions: An effective individualized nomogram to predict the risk of first VH in HBV-related GEV patients was established, which can assist clinicians in developing more appropriate prevention strategies.

Evaluation of LiangXue JieDu Therapy in Combination With Western Medicine for Acute-On-Chronic Liver Failure: A Systematic Review and meta-Analysis.

Objectives: To assess the efficacy of LiangXue JieDu (LXJD) therapy in combination with Western medicine (WM) for acute-on-chronic liver failure (ACLF). Methods: Articles on randomized controlled trials of LXJD therapy for ACLF were obtained from PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure, VIP, Wanfang, and China Biology Medicine databases, with the search range from database inception to March 2022. We evaluated the quality of data from these articles using the Cochrane risk-of-bias tool. Evaluation indicators were total effective rate, mortality rate, complications, liver and coagulation function, and Traditional Chinese medicine (TCM) syndrome score. We then calculated the risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables with a 95% confidence interval (CI). Results: The meta-analysis included 18 studies with moderate quality and totaling 1,609 patients. Compared with WM alone, LXJD therapy plus WM improved total effective rate [RR = 1.34, 95% CI: (1.24, 1.45)], while reducing mortality rate [RR = 0.54, 95% CI: (0.42, 0.70)] and complications [RR = 0.43, 95% CI: (0.26, 0.71)]. The combined treatment also improved prothrombin activity [MD = 1.30, 95% CI: (1.02, 1.59)], prothrombin time [MD = -0.90, 95% CI: (-1.40, -0.39)], international normalized ratio [MD = -0.59, 95% CI: (-0.93, -0.25)], alanine aminotransferase [MD = -0.92, 95% CI: (-1.30, -0.55)], aspartate aminotransferase [MD = -0.57, 95% CI: (-0.93, -0.21)], total bilirubin [MD = -1.07, 95% CI: (-1.38, -0.76)], and TCM syndrome score [MD = -1.70; 95% CI: (-2.03, -1.37)]. Conclusions: This study suggests that LXJD therapy plus WM can significantly improves ACLF clinical symptoms and short-term outcomes. However, more high-quality trials are required to confirm the efficacy of LXJD therapy.

Sugar-Sweeten Beverage Consumption Is Associated With More Obesity and Higher Serum Uric Acid in Chinese Male Gout Patients With Early Onset.

Background: Early onset gout has received increasing interest from researchers. Previous studies have reported that serum urate (sUA) levels and prevalence of obesity are higher in early onset gout patients than in later-onset gout patients. We explored the dietary habits of early onset and later-onset gout patients and their association with clinical features. Materials and Methods: Gout patients completed a 10-item food frequency questionnaire. Early onset gout patients were defined as gout onset before the age of 40, and onset after age 40 was classified as later-onset. Associations between dietary factors, obesity, and sUA level of ≥600 µmol/L were assessed using logistic regression. Results: Among the 655 gout patients, 94.6% were males, and 59.1% presented with early onset gout. All early onset patients were males. sUA level was significantly higher in the early onset group than in the later-onset group (550.7 vs. 513.4 µmol/L). The proportion of patients with a sUA level of ≥ 600 µmol/L (40.3 vs. 26.2%) and obesity (27.6 vs. 10.7%) was higher in the early onset group than in the later-onset group (all p < 0.05). The early onset group consumed more red meat (101-200 g/day: 43.6 vs. 26.0%), sugar-sweetened beverages (>4 times/week: 27.9 vs. 7.7%), and milk and milk products (1-2 times/week: 28.5 vs. 16.6%), but less alcohol (>84 g/day: 8.5 vs. 21.5%) and tea (>4 times/week: 35.7 vs. 52.4%; all p < 0.05). Sugar-sweetened beverage intake was positively correlated with sUA level of ≥600 µmol/L (compared with 4 times/week: adjusted odds ratio = 2.2, 95% confidence interval: 1.4, 3.7) and obesity (compared with 4 times/week: adjusted odds ratio = 2.2, 95% confidence interval: 1.2, 3.7). These correlations remained significant for early onset gout patients. Conclusion: Sugar-sweetened beverage intake replaced alcohol as the main dietary risk factor for gout in early onset patients, and this change was associated with a greater prevalence of obesity and higher sUA level. Clinicians should provide specific dietary education for different generations of gout patients. The epidemic of sugar-sweetened beverage consumption should be considered for the development of public health policies for the prevention of gout.

A dynamic nomogram to predict transplant-free mortality in patients with hepatitis B-related cirrhosis and overt hepatic encephalopathy.

BACKGROUND: Overt hepatic encephalopathy (OHE) is a serious complication of liver disease. We aimed to develop a dynamic nomogram for estimating the probability of 30-day transplant-free mortality in patients with OHE and hepatitis B-related cirrhosis (HBC). METHODS: We identified 402 patients with OHE and HBC at the Beijing Ditan Hospital between January 2011 and July 2016. Independent risk factors were determined using multivariate Cox proportional hazards regression analysis. A dynamic nomogram was established to predict the probability of 30-day transplant-free mortality. The discrimination and clinical usefulness of the nomogram were estimated using the area under the receiver operating characteristic (AUC) and calibration curves, and decision curve analysis. A prospective cohort of 208 patients was enrolled for validation. RESULTS: The model for end-stage liver disease (MELD) score and neutrophil-to-lymphocyte ratio (NLR) were independently associated with the 30-day transplant-free mortality. The AUC values of the nomogram were 0.881 and 0.879 in the derivation and validation cohorts, respectively, and the discrimination ability was superior to that of the established models. The calibration plot fitted the predicted survival and observed probabilities well. The incidence of mortality was 2.0% (3/151) in patients with MELD scores < 23 and NLR < 4, and 55.4% (41/92) in those with MELD scores ≥ 23 and NLR ≥ 4. CONCLUSIONS: The dynamic nomogram can predict the risk of 30-day transplant-free mortality in patients with OHE and HBC. Patients with MELD scores ≥ 23 and NLR ≥ 4 have a high mortality rate and should be admitted to intensive care.

Association between probiotic therapy and the risk of hepatocellular carcinoma in patients with hepatitis B-related cirrhosis.

Objective: Probiotics may offer cancer-prevention benefits, based on experimental investigation results. This study aimed to determine the potential association between probiotics and hepatocellular carcinoma (HCC) in patients with hepatitis B-related cirrhosis (HBC) receiving antiviral therapy. Design: This retrospective study included 1267 patients with HBC treated with entecavir or tenofovir between January 2013 and December 2017. The risk of developing HCC was compared between two cohorts of 449 probiotic users (taking a cumulative defined daily doses [cDDD] of ≥ 28) and 818 non-probiotic users (< 28 cDDD). To eliminate the bias caused by confounding factors, propensity score matching (PSM) was used. Results: On multivariate regression analysis, probiotic consumption was an independent protective factor for HCC occurrence. After PSM, the incidence of HCC was significantly lower in the probiotic users than that in the nonusers (adjusted hazard ratio [aHR]: 0.70, 95% confidence interval: 0.59-0.83, P < 0.001). The aHRs for probiotics with 28-89, 90-180, and >180 cDDD were 0.58, 0.28, and 0.12, respectively, indicating a dose-response pattern. In 28-89, 90-180, and >180 cDDD, the 3-year cumulative incidence of HCC was 8.7%, 4.7%, and 3.0%, respectively. A multivariate stratified analysis confirmed that the administration of probiotics could help patients. Conclusion: Adjuvant probiotic therapy may reduce the risk of HCC in patients receiving antiviral medication for HBC. However, further clinical research is required to confirm these findings.

TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity.

TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPß activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway.

Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis.

OBJECTIVE: Tumour necrosis factor alpha (TNF-α) signalling plays a central role in the pathogenesis of various autoimmune diseases, particularly inflammatory arthritis. This study aimed to repurpose clinically approved drugs as potential inhibitors of TNF-α signalling in treatment of inflammatory arthritis. METHODS: In vitro and in vivo screening of an Food and Drug Administration (FDA)-approved drug library; in vitro and in vivo assays for examining the blockade of TNF actions by fexofenadine: assays for defining the anti-inflammatory activity of fexofenadine using TNF-α transgenic (TNF-tg) mice and collagen-induced arthritis in DBA/1 mice. Identification and characterisation of the binding of fexofenadine to cytosolic phospholipase A2 (cPLA2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, information field dynamics and molecular dynamics; various assays for examining fexofenadine inhibition of cPLA2 as well as the dependence of fexofenadine's anti-TNF activity on cPLA2. RESULTS: Serial screenings of a library composed of FDA-approved drugs led to the identification of fexofenadine as an inhibitor of TNF-α signalling. Fexofenadine potently inhibited TNF/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signalling in vitro and in vivo, and ameliorated disease symptoms in inflammatory arthritis models. cPLA2 was isolated as a novel target of fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished fexofenadine's anti-TNF activity. CONCLUSION: Collectively, these findings not only provide new insights into the understanding of fexofenadine action and underlying mechanisms but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly inflammatory rheumatic diseases.