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Yi-Sheng He,1,2,* Gui-Hong Wang,3,* Qian Wu,1,2,* Zheng-Dong Wu,1,2 Yue Chen,1,2 Jin-Hui Tao,4 Xin-Yu Fang,1,2 Zhiwei Xu,5 Hai-Feng Pan1,2 1Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, People’s Republic of China; 2Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, People’s Republic of China; 3Department of Rheumatology, Anqing Hospital Affiliated to Anhui Medical University, Anqing, Anhui, People’s Republic of China; 4Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, People’s Republic of China; 5School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia*These authors contributed equally to this workCorrespondence: Zhiwei Xu; Hai-Feng Pan Email xzw1011@gmail.com; panhaifeng1982@sina.comObjective: Gout is a chronic disease caused by the deposition of sodium urate (MSU) crystals. Available data on the association between environmental hazards and gout are scarce. The present study was present to investigate the relationship between short-term exposure to air pollution and hospitalizations for acute gout from 2016 to 2020 in Anqing City, China.Methods: Daily records of hospital admissions for acute gout in Anqing from 1 January 2016 to 31 December 2020 were retrieved from the tertiary first-class hospitals in Anqing. Air pollutants and meteorological data were obtained from the China Environmental Monitoring Station and China Meteorological Data Service Center respectively. We used a time-series analysis to explore the association between air pollution (NO2, O3, and CO) and hospitalizations for acute gout, and conducted stratified analyses by gender, age and season.Results: We observed an association between NO2 and hospitalizations for gout (lag 0, relative risk (RR):1.022, 95% confidence interval (CI):1.004– 1.041). For every 1 mg/m3 increase in CO concentration, hospitalizations for gout increased by 3.9% (lag 11 days, RR=1.039, 95% CI: 1.004– 1.076). Intriguingly, there was a negative association between O3 and hospitalizations for gout (lag0, RR=0.986, 95% CI: 0.976– 0.996). Stratified analyses showed that exposure to high levels of NO2 was considered to be more vulnerable to gout in cold season.Conclusion: Our study showed that short-term exposure to NO2 and CO has a significant effect on hospitalizations for acute gout.Keywords: gout, air pollutants, carbon monoxide, nitrogen dioxide, ozone

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp 3 )-rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza-BCHs) by an enantioselective zinc-catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2-acyl imidazole group and a diverse array of alkynyl- and aryl-substituted imines. The target aza-BCHs, which consist of α-chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94 % and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring-opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid-catalyzed cycloadditions of BCBs., (© 2024 Wiley-VCH GmbH.)

In recent years, cell therapy has emerged as an innovative treatment method for the management of clinical tumors following immunotherapy. Among them, Natural killer (NK) cell therapy has achieved a significant breakthrough in the treatment of hematological tumors. However, the therapeutic effectiveness of NK cells in the treatment of solid tumors remains challenging. With the progress of gene editing and culture techniques and their application to NK cell engineering, it is expected that NK cell therapy will revolutionize the treatment of solid tumors. In this review, we explore the discovery and biological properties of NK cells, their role in the tumor microenvironment, and the therapeutic strategies, clinical trials, challenges, and prospects of NK cells in the treatment of solid tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The apoptosis resistance of myofibroblasts is a hallmark in the irreversible progression of pulmonary fibrosis (PF). While the underlying molecular mechanism remains elusive. In this study, we unveiled a previously unrecognized mechanism underlying myofibroblast apoptosis resistance during PF. Our investigation revealed heightened expression of mesenchyme homeobox 1 (MEOX1) in the lungs of idiopathic pulmonary fibrosis (IPF) patients and bleomycin-induced PF mice. Silencing MEOX1 significantly attenuated PF progression in mice. In vitro, we found a notable increase in MEOX1 expression in transforming growth factor-β1 (TGF-β1)-induced myofibroblasts. Silencing MEOX1 enhanced apoptosis of myofibroblasts. Mechanistically, we identified G-protein signaling pathway regulatory factor 4 (RGS4) as a critical downstream target of MEOX1, as predicted by bioinformatics analysis. MEOX1 enhanced apoptosis resistance by upregulating RGS4 expression in myofibroblasts. In conclusion, our study highlights MEOX1 as a promising therapeutic target for protecting against PF by modulating myofibroblast apoptosis resistance., (© 2024 Wiley Periodicals LLC.)

Although total carbon (TC) is an important component of fine particulate matter (PM 2.5 : particulate matter with aerodynamic diameter of <2.5 μm); its sources remain partially unidentified, especially in coastal urban areas. With ongoing development of the global economy and maritime activities, ship-generated TC emissions in port areas cannot be neglected. In this study, from September 11, 2017 to August 31, 2018, we collected 355 p.m. 2.5 samples in Qingdao, China, to determine the water-soluble ion concentrations, TC concentrations, and stable carbon isotopes (δ 13 C TC ). During the open fishing season (OFS; September 11, 2017 to April 30, 2018) and the closed fishing season (CFS; May 1, 2018 to August 31, 2018), the TC concentrations were 9.30 ± 5.38 μg/m 3 and 3.36 ± 2.10 μg/m 3 respectively, and the corresponding δ 13 C TC values were -24.53‰ ± 1.17‰ and -27.03‰ ± 0.91‰, respectively, indicating significant differences (p < 0.05) between the two periods. The differences in TC concentrations and the δ 13 C TC values between the OFS and CFS reflect changes in the source of contamination. Bayesian model was used to quantify the contributions of different TC sources, revealing that ship emissions accounted for approximately 35.3% of the total, which was close to the contribution from the largest source, i.e., motor vehicles (39%). Using the ship emission inventory, Qingdao's ship emissions were further quantified at 455 metric tons, representing 35%-40% of the total TC emissions around Qingdao. Notably, fishing ships contributed approximately 40% of the total ship emissions. These findings underscore the considerable impact of ship emissions, particularly those from fishing ships, on TC concentrations in coastal urban areas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cyclin-dependent kinases (CDKs) are overexpressed in tumor cells, and their aberrant activation can promote the progression of non-small-cell lung cancer (NSCLC). We utilized structure-based virtual screening and experimental validation to screen for potential CDKs antagonists among TargetMol natural products. Molecular docking and molecular dynamics simulation results indicate that Dolastatin 10 exhibits strong interactions with multiple subtypes of CDKs (CDK1, CDK2, CDK3, CDK4, and CDK6), forming stable CDKs-Dolastatin 10 complex compounds. Furthermore, in vitro experiments demonstrate that Dolastatin 10 significantly inhibits the viability, migration, and invasion of H1299 cells in a concentration-dependent manner, arresting the cell cycle at the G2/M phase by inducing cell senescence. These findings suggest that Dolastatin 10 may serve as a potential CDKs antagonist deserving further investigation., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Herb couple Rehmannia glutinosa Libosch and Cornus officinalis Sieb (RC), originated from "Liuwei Dihuang Pill" which recorded in Key to Therapeutics of Children's Diseases. Traditionally, they have been used widely for their ability to nourish yin and energize the kidneys. Our previous study indicated that the RC could protect against adenine induced Chronic kidney disease (CKD) rats. Nevertheless, there is still no clear explanation of the mechanisms by which RC affects renal interstitial fibrosis in CKD rats., Aim of the Study: Current Work aims to explore the amelioration and potential mechanism of RC on renal interstitial fibrosis in CKD rats., Materials and Methods: CKD rats were induced by adenine. Two weeks after administration, blood, urine, and kidney tissue were collected for biochemical analysis. Observing the physiological state of rats through the changes of rat body weight and renal index. The pro-inflammatory cytokines were measured by enzyme linked immunosorbent assay (ELISA), while renal tissue damage and fibrosis were assessed with Hematoxylin-eosin staining (H&E) and Masson's trichrome staining. In order to determine the levels of indicators and proteins associated with fibrosis signaling pathways, real time PCR (Rt-PCR), Western blot (WB), and immunofluorescence were employed., Results: The renal interstitial fibrosis led to impaired cellular functions with increased the levels of Blood Urea Nitrogen (BUN), Urine protein (UP), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor alpha (TNF-α). and simultaneous up-regulated collagenⅠ(COL-1), fibronection (FN), α-smooth muscle actin (a-SMA), transforming growth factor-β1 (TGF-β1), c-Jun N-terminal kinase (JNK), p38 and extracellular regulated protein kinases (ERK), down-regulated the expression of the E-cadherin proteins. RC notably improved renal dysfunction in CKD rats as indicated by decreases in BUN, UP, and renal index. In addition, consistent with the morphological changes of renal tissue, renal interstitial fibrosis in CKD rats after RC intervention was significantly improved, mainly manifested by a decrease in the positive expression of COL-1, FN, and a-SMA, and increased levels of E-cadherin protein. Meanwhile, RC reduced the classical pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in adenine-induced CKD rats. Additionally, RC administration also down-regulated TGF-β1, JNK, p38 and ERK., Conclusion: In conclusion, RC may reduce inflammation in adenine induced CKD rats, improve extracellular matrix (ECM) components deposition, and diminish epithelial-mesenchymal transition (EMT) marker protein levels. Furthermore, RC intervention significantly reduces the release of inflammatory cytokines and inhibits the TGF-β1/MAPK signaling pathway. Based on the results, RC might be useful in the treatment of adenine induced renal fibrosis., Competing Interests: Declaration of competing interest We declare that the results presented in this paper have not been published previously, either in whole or part. The authors have declared that no competing interest exists., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The blood-retinal barrier (BRB), homeostasis, neuronal integrity, and metabolic processes are all directly influenced by Müller cells, the most important retinal glial cells. We isolated primary Müller cells from Sprague-Dawley (SD) neonatal rats and treated them with glucose at varying doses. CCK-8 was used to quantify cellular viability, and a TUNEL assay was performed to detect cell apoptosis. ELISA, immunofluorescence, and western blotting were used to assess cAMP/PKA/CREB signaling, Kir4.1, AQP4, GFAP, and VEGF levels, respectively. H&E staining was used to examine histopathological alterations in diabetic retinopathy (DR)-affected retinal tissue in rats. As glucose concentration increases, gliosis of Müller cells became apparent, as evidenced by a decline in cell activity, an increase in apoptosis, downregulation of Kir4.1 level, and overexpression of GFAP, AQP4, and VEGF. Treatments with low, intermediate, and high glucose levels led to aberrant activation of cAMP/PKA/CREB signaling. Interestingly, blocking cAMP and PKA reduced high glucose-induced Müller cell damage and gliosis by a significant amount. Further in vivo results suggested that cAMP or PKA inhibition significantly improved edema, bleeding, and retinal disorders. Our findings showed that high glucose exacerbated Müller cell damage and gliosis via a mechanism involving cAMP/PKA/CREB signaling., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

With the deepening of research on the correlation between meteorological factors and autoimmune diseases, the relationship between climate change and dermatomyositis (DM) has come to our attention. This study aimed to explore the short-term correlation between meteorological factors and DM outpatient visits. Daily records of hospital outpatient visits for DM, air pollutants, and meteorological factor data in Hefei from January 1, 2018 to December 31, 2021 were obtained. The mean temperature (MT), relative humidity (RH), diurnal temperature range (DTR), and temperature change between neighboring days (TCN) were used to quantify environmental temperature and humidity and their variations. And we performed a time series analysis using a generalized linear model (GLM) in combination with a distributed lag nonlinear model (DLNM). Furthermore, gender and age were further stratified for the analysis. The sensitivity analysis was also performed. A total of 4028 DM outpatient visits were recorded during this period. There were statistically significant associations of low temperature (5th, 1.5 °C), low RH (1st, 48.6%), high RH (99th, 99%), high DTR (75th, 12.6°c), and low TCN (10th, -2.7 °C) that were associated with risk of DM outpatient visits, with lag days of 30, 16, 16, 10, and 14, respectively. Moreover, women were more susceptible to high RH exposure and low TCN exposure, while the elderly were more susceptible to low temperature. This study concluded that exposure to low temperature, extreme RH, and temperature changes (especially high DTR and low TCN) was associated with an increased risk of DM outpatient visits., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In recent years, a growing number of studies have found that air pollution plays critical roles in the onset and development of autoimmune diseases, but few studies have shown an association between air pollutants and dermatomyositis (DM). We sought to investigate the relationship between short-term exposure to air pollution and outpatient visits for DM and to quantify the burden of DM due to exposure to air pollutants in Hefei, China. Daily records of hospital outpatient visits for DM, air pollutants and meteorological factors data in Hefei from January 1, 2018 to December 31, 2021 were obtained. We used a distributed lag non-linear model (DLNM) in conjunction with a generalized linear model (GLM) to explore the association between air pollution and outpatient visits for DM, and conducted stratified analyses by gender, age and season. Moreover, we used attributable fraction (AF) and attributable number (AN) to reflect the burden of disease. A total of 4028 DM clinic visits were recorded during this period. High concentration nitrogen dioxide (NO 2 ) exposure was associated with increased risk of DM outpatient visits (relative risk (RR) 1.063, 95% confidence interval (CI) 1.015-1.114, lag 0-5). Intriguingly, exposure to high concentration ozone (O 3 ) was associated with reduced risk of outpatient visits for DM (RR 0.974, 95% CI 0. 0.954-0.993, lag 0-6). The results of stratified analyses showed that the cold season (vs. warm season) were more susceptible to outpatient visits for DM associated with NO 2 and O 3 exposure. In addition, we observed that an increased risk of DM outpatient visits was attributable to high concentration NO 2 exposure, while high concentration O 3 exposure was associated with a decreased risk of DM outpatient visits. This study provided a scientific basis for the etiology research and health protection of DM., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Patients with chronic kidney disease (CKD) undergoing coronary angiography (CAG) are at high risk of contrast-associated acute kidney injury (CA-AKI) and mortality. Therefore, there is a clinical need to explore safe, convenient, and effective strategies for preventing CA-AKI., Objectives: This study sought to assess whether simplified rapid hydration is noninferior to standard hydration for CA-AKI prevention in patients with CKD., Methods: This multicenter, open-label, randomized controlled study was conducted across 21 teaching hospitals and included 1,002 patients with CKD. Patients were randomized to either simplified hydration (SH) (SH group, with normal saline from 1 hour before to 4 hours after CAG at a rate of 3 mL/kg/h) or standard hydration (control group, with normal saline 12 hours before and 12 hours after CAG at a rate of 1 mL/kg/h). The primary endpoint of CA-AKI was a ≥25% or 0.5-mg/dL rise in serum creatinine from baseline within 48 to 72 hours., Results: CA-AKI occurred in 29 of 466 (6.2%) patients in the SH group and in 38 of 455 (8.4%) patients in the control group (relative risk: 0.8; 95% CI: 0.5-1.2; P = 0.216). In addition, the risk of acute heart failure and 1-year major adverse cardiovascular events did not differ significantly between the groups. However, the median hydration duration was significantly shorter in the SH group than in the control group (6 vs 25 hours; P < 0.001)., Conclusions: In CKD patients undergoing CAG, SH is noninferior to standard hydration in preventing CA-AKI with a shorter hydration duration., Competing Interests: Funding Support and Author Disclosures This study was funded by the Beijing Lisheng Cardiovascular Health Foundation (LHJJ20141751), Guangdong Provincial Science and Technology Project (2020B1111170011 and KJ022021049), and Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention (No. Y0120220151), Multi-center study on key techniques for prevention, diagnosis, and treatment of high-risk coronary artery disease (DFJH2020026). The funders were not involved in study design, data collection, analysis, interpretation, or reporting. All authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Our previous study has shown that ATP action on P2X7R could be the second signal to induce the onset of gouty arthritis. However, the functional changes of P2X7R single nucleotide polymorphisms (SNPs) on the effects of ATP-P2X7R-IL-1β signaling pathway and uric acid remained unknown. We aimed to investigate the association between the functional change of P2X7R containing the Ala 348 to Thr polymorphisms (rs1718119) and the pathogenesis of gout. First, 270 gout patients and 70 hyperuricemic patients (without gout attack history in recent 5 years) were recruited for genotyping. In addition, the changes of ATP-induced pore formation were assessed in HEK-293T cells overexpressing different mutants in P2RX7, and the effects on P2X7R-NLRP3-IL-1β pathway activation were explored in P2RX7 overexpression THP-1 cells. The risk allele for gout was A at rs1718119, and the AA and AG genotypes exhibited a higher risk of gout. Furthermore, Ala 348 to Thr mutants increased P2X7-dependent ethidium + bromide uptake, upregulated IL-1β and NLRP3 levels as compared to the wild-type. We suggest that genetic polymorphisms of P2X7R containing the Ala 348 to Thr are associated with the increased risk of gout, showing an enhanced gain-of-function effect on the development of this disease., (© 2023. The Author(s).)

Objective: Gut fungi, as symbiosis with the human gastrointestinal tract, may regulate physiology via multiple interactions with host cells. The plausible role of fungi in systemic lupus erythematosus (SLE) is far from clear and need to be explored., Methods: A total of 64 subjects were recruited, including SLE, rheumatoid arthritis (RA), undifferentiated connective tissue diseases (UCTDs) patients and healthy controls (HCs). Fecal samples of subjects were collected. Gut fungi and bacteria were detected by ITS sequencing and 16S rRNA gene sequencing, respectively. Alpha and beta diversities of microbiota were analyzed. Linear discriminant analysis effect size analysis was performed to identify abundance of microbiota in different groups. The correlation network between bacterial and fungal microbiota was analyzed based on Spearman correlation., Results: Gut fungal diversity and community composition exhibited significant shifts in SLE compared with UCTDs, RA and HCs. Compared with HCs, the alpha and beta diversities of fungal microbiota decreased in SLE patients. According to principal coordinates analysis results, the constitution of fungal microbiota from SLE, RA, UCTDs patients and HCs exhibited distinct differences with a clear separation between fungal microbiota. There was dysbiosis in the compositions of fungal and bacterial microbiota in the SLE patients, compared to HCs. Pezizales, Cantharellales and Pseudaleuria were enriched in SLE compared with HCs, RA and UCTDs. There was a complex relationship network between bacterial and fungal microbiota, especially Candida which was related to a variety of bacteria., Conclusion: This study presents a pilot analysis of fungal microbiota with diversity and composition in SLE, and identifies several gut fungi with different abundance patterns taxa among SLE, RA, UCTDs and HCs. Furthermore, the gut bacterial-fungal association network in SLE patients was altered compared with HCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Wang, Li, Zhang, Huang, Wu, Wang, Li, Chu, Cao, Zhou, Fang, Leng, Fan, Tao, Shuai and Ye.)

Objective: Previous observational studies demonstrated that a subset of patients with systemic lupus erythematosus (SLE) have markedly short telomere length in leukocytes. This study was undertaken to test whether leukocyte telomere length is causally associated with risk of SLE., Methods: A 2-sample Mendelian randomization (MR) analysis was conducted to estimate causality of telomere length on SLE in European populations. A replication 2-sample MR study using Asian genetic data was also conducted. A reverse MR analysis was then performed to test the effects of SLE on telomere length. The autoantibodies targeting telomere-associated protein (telomeric repeat-binding factor 1 [TERF1] autoantibodies) were detected in patients with SLE, healthy controls, and patients with rheumatoid arthritis., Results: The results of the inverse variance-weighted method (odds ratio [OR] 2.96 [95% confidence interval (95% CI) 1.58-5.55], P < 0.001) showed strong evidence for a causal relationship between longer telomere length and risk of SLE in people with European ancestry. The outcomes of MR-Egger regression analysis (OR 29.46 [95% CI 3.02-287.60], P = 0.033) and MR pleiotropy residual sum and outlier analysis (OR 3.62 [95% CI 2.03-6.46], P = 0.002) also showed that longer telomere length was significantly associated with increased risk of SLE in a European population. Sensitivity analyses using different methods and summary data sets showed that the results were still broadly consistent. A replication MR study using Asian genetic data yielded similar findings. However, the reverse MR analysis showed that genetically predicted SLE was not causally associated with telomere length. In addition, we found that TERF1 autoantibodies were present in 2 of 40 SLE patients (5.0%)., Conclusion: In contrast with previous observational studies, MR analyses show that longer telomere length is significantly associated with increased risk of SLE., (© 2022 American College of Rheumatology.)

Objective: To elucidate the mechanism of Lizhong Decoction (LZD) in treating dextran sodium sulfate (DSS)-induced colitis in mice based on metabonomics., Methods: Thirty-six mice were randomly divided into 6 groups, including normal, model, low- (1.365 g/kg), medium- (4.095 g/kg) and high dose (12.285 g/kg) LZD and salazosulfadimidine (SASP) groups, 6 mice in each group. Colitis model mice were induced by DSS admistration for 7 days, and treated with low, medium and high dose LZD extract and positive drug SASP. Metabolic comparison of DSS-induced colitis and normal mice was investigated by using ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass (UPLC-Q-TOF/MS) combined with Metabolynx™ software., Results: The metabolic profiles of plasma and urine in colitis mice were distinctly ameliorated after LZD treatment (P<0.05). Potential biomarkers (9 in serum and 4 in urine) were screened and tentatively identified. The endogenous metabolites were mainly involved in primary bile acid, sphingolipid, linoleic acid, arachidonic acid, amino acids (alanine, aspartate, and glutamate), butanoate and glycerophospholipid metabolism in plasma, and terpenoid backbone biosynthesis, glycerophospholipid and tryptophan metabolism in urine. After LZD treatment, these markers notably restored to normal levels., Conclusions: The study revealed the underlying mechanism of LZD on amelioration of ulcerative colitis based on metabonomics, which laid a foundation for further exploring the pathological and physiological mechanism, early diagnosis, and corresponding drug development of colitis., (© 2021. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Necroptosis is the major cause of death in alveolar epithelial cells (AECs) during acute lung injury (ALI). Here, we report a previously unrecognized mechanism for necroptosis. We found an accumulation of mitochondrial citrate (citrate mt ) in lipopolysaccharide (LPS)-treated AECs because of the downregulation of Idh3α and citrate carrier (CIC, also known as Slc25a1). shRNA- or inhibitor-mediated inhibition of Idh3α and Slc25a1 induced citrate mt accumulation and necroptosis in vitro. Mice with AEC-specific Idh3α and Slc25a1 deficiency exhibited exacerbated lung injury and AEC necroptosis. Interestingly, the overexpression of Idh3α and Slc25a1 decreased citrate mt levels and rescued AECs from necroptosis. Mechanistically, citrate mt accumulation induced mitochondrial fission and excessive mitophagy in AECs. Furthermore, citrate mt directly interacted with FUN14 domain-containing protein 1 (FUNDC1) and promoted the interaction of FUNDC1 with dynamin-related protein 1 (DRP1), leading to excessive mitophagy-mediated necroptosis and thereby initiating and promoting ALI. Importantly, necroptosis induced by citrate mt accumulation was inhibited in FUNDC1-knockout AECs. We show that citrate mt accumulation is a novel target for protection against ALI involving necroptosis., (© 2022. The Author(s).)

Background: Epoxyeicosatrienoic acids (EETs), the metabolite of arachidonic acid by cytochrome P450 (CYP), reportedly serve as a vital endogenous protective factor in several chronic diseases. EETs are metabolized by soluble epoxide hydrolase (sEH). We have observed that prophylactic blocking sEH alleviates bleomycin- (BLM-) induced pulmonary fibrosis (PF) in mice. However, the underlying mechanism and therapeutic effects of EETs on PF remain elusive., Objective: In this study, we investigated the effect of CYP2J2/EETs on the activation of murine fibroblasts and their mechanisms., Results: we found that administration of the sEH inhibitor (TPPU) 7 days after the BLM injection also reversed the morphology changes and collagen deposition in the lungs of BLM-treated mice, attenuating PF. Fibroblast activation is regarded as a critical role of PF. Therefore, we investigated the effects of EETs on the proliferation and differentiation of murine fibroblasts. Results showed that the overexpression of CYP2J2 reduced the cell proliferation and the expressions of α -SMA and PCNA induced by transforming growth factor- (TGF-) β 1 in murine fibroblasts. Then, we found that EETs inhibited the proliferation and differentiation of TGF- β 1-treated-NIH3T3 cells and primary murine fibroblasts. Mechanistically, we found that 14,15-EET disrupted the phosphorylation of Smad2/3 murine fibroblasts by activating PPAR γ , which was completely abolished by a PPAR γ inhibitor GW9662., Conclusion: our study shows that EETs inhibit the activation of murine fibroblasts by blocking the TGF- β 1-Smad2/3 signaling in a PPAR γ -dependent manner. Regulating CYP2J2-EET-sEH metabolic pathway may be a potential therapeutic option in PF., Competing Interests: The authors declared no conflict of interest., (Copyright © 2022 Jia-Hao Tao et al.)

Objective: Systemic lupus erythematosus (SLE) has been observationally associated with endometrial cancer, but the causality remains unclear. Here, we investigated for the first time the causal links between SLE and endometrial cancer risk., Methods: Univariable and multivariable Mendelian randomization (MR) analyses were conducted to disentangle the causality of SLE with endometrial cancer. Apart from the inverse-variance weighted (IVW) method as the primary MR estimate, three complementary MR techniques including weighted median, weighted mode, and MR-Egger regression in univariable MR were conducted to clarify the robustness of the causal estimate and mediation effects of the body mass index (BMI) and were investigated within multivariable MR-IVW and MR-Egger analyses., Results: All univariable MR analyses consistently suggested that SLE has a protective effect on the risk of overall endometrial cancer (IVW: OR = 0.956, 95% CI = 0.932-0.981, P = 0.001) and endometrioid endometrial cancer (IVW: OR = 0.965, 95% CI = 0.933-0.999, P = 0.043). More compelling, after adjustment for BMI within the multivariable MR setting, the association between SLE and decreased risk of overall endometrial cancer was significantly stronger (IVW: OR = 0.952, 95% CI = 0.931-0.973, P = 9.58E-06)., Conclusions: Our findings provide evidence of a significant causal relationship between SLE and decreased endometrial cancer risk. Further understanding of the underlying mechanisms linking SLE with endometrial cancer is therefore needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wan, Zhao and Tao.)

CKD is a clinical syndrome with slow development and gradual deterioration of renal function. At present, modern medicine still lacks an ideal treatment method for this disease, while TCM has accumulated rich clinical experience in the treatment of CKD, which can effectively improve renal function and delay renal failure, and has unique advantages. RC is widely used in clinical practice to treat CKD, especially the "Kidney-Yin" deficiency syndrome. However, the compatibility mechanisms responsible for its effects in experimental studies, including preclinical and clinical research studies, are still not fully understood. Adenine-induced CKD rats were used to investigate the preventive effect of RC on CKD rats. Based on the high-throughput 16S rRNA gene sequencing results from Illumina, we discussed the intestinal flora abundance in rats in different treatment groups. According to a PCA and a PCoA based on a distance matrix, there was a clear separation of gut microbiome profiles between normal rats and model rats in terms of beta diversity. The abundance of Firmicutes in CKD rats was relatively increased, while that of Bacteroidetes was decreased. It is clear that the plot for the RC group was closer to that of the normal group, suggesting that the RC group had higher similarities among bacterial members with N rats. Ussing chamber, Western blot, and PCR assays were used to investigate the effects of RC on intestinal barrier function and its molecular mechanism in model animals. The results indicated that the protein expressions of ZO-1, claudin-1, and occludin-1 were decreased significantly in chronic kidney disease rats with the induction of adenine. With the treatment of RG, CO, and RC, the intestinal barrier was repaired due to the upregulated expressions of the aforementioned proteins in CKD rats. Based on our findings, RC appears to strengthen the intestinal barrier and modulate gut microbiota in adenine-induced CKD rats. This project revealed the compatibility mechanism of RC in regulating the intestinal microecology and barrier function to intervene in CKD and provided the basis and ideas for the clinical application of RC and the development of innovative drugs for CKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhu, Jiang, Ma and Tao.)

Fibrosis is a common pathological outcome of chronic injuries, characterized by excessive deposition of extracellular matrix components in organs, as seen in most chronic inflammatory diseases. At present, there is an increasing tendency of the morbidity and mortality of diseases caused by fibrosis, but the treatment measures for fibrosis are still limited. Fibroblast growth factor 21 (FGF21) belongs to the FGF19 subfamily, which also has the name endocrine FGFs because of their endocrine manner. In recent years, it has been found that plasma FGF21 level is significantly correlated with fibrosis progression. Furthermore, there is evidence that FGF21 has a pronounced antifibrotic effect in a variety of fibrotic diseases. This review summarizes the biological effects of FGF21 and discusses what is currently known about this factor and fibrosis disease, highlighting emerging insights that warrant further research., Competing Interests: The authors declare that they have no conflict of interest., (Copyright © 2022 Min-Qi Jia et al.)

The bud of Vaccinium dunalianum Wight has been traditionally consumed as health herbal tea by "Yi" people in Yunnan Province, China, which was locally named "Que Zui tea". This paper studied the chemical constituents of five fractions from Vaccinium dunalianum , and their enzyme inhibitory effects of α-glucosidase and pancreatic lipase, antioxidant activity, and cytoprotective effects on H 2 O 2 -induced oxidative damage in HepG2 cells. The methanol extract of V. dunalianum was successively partitioned with petroleum ether (PF), chloroform (CF), ethyl acetate (EF), n -butanol (BF), and aqueous (WF) to obtain five fractions. The chemical profiling of the five fractions was analyzed by ultra-high-performance liquid chromatography coupled with a tandem mass spectrometry (UHPLC-MS/MS), and 18 compounds were tentatively identified. Compared to PF, CF, BF and WF, the EF revealed the highest total phenols (TPC) and total flavonoids (TFC), and displayed the strongest enzyme inhibition ability (α-glucosidase and pancreatic lipase) and antioxidant capacity (DPPH, ABTS and FRAP). Furthermore, these five fractions, especially EF, could effectively inhibit reactive oxygen species (ROS) production and cell apoptosis on H 2 O 2 -induced oxidative damage protection in HepG2 cells. This inhibitory effect might be caused by the up-regulation of intracellular antioxidant enzyme activity (CAT, SOD, and GSH). The flavonoids and phenolic acids of V. dunalianum might be the bioactive substances responsible for enzyme inhibitory, antioxidant, and cytoprotective activities.

Background: Colorectal cancer (CRC) is a common malignant tumor of the gastrointestinal tract. Lipid metabolism, as an important part of material and energy circulation, is well known to play a crucial role in CRC., Aim: To explore the relationship between serum lipids and CRC development and identify aberrantly expressed cholesterol metabolism genes in CRC., Methods: We retrospectively collected 843 patients who had confirmed CRC and received surgical resection from 2013 to 2015 at the Cancer Hospital of the Chinese Academy of Medical Sciences as our research subjects. The levels of serum total cholesterol (TC), triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C and clinical features were collected and statistically analyzed by SPSS. Then, we used the data from Oncomine to screen the differentially expressed genes (DEGs) of the cholesterol metabolism pathway in CRC and used Gene Expression Profiling Interactive Analysis to confirm the candidate DEGs. PrognoScan was used to analyze the prognostic value of the DEGs, and Search Tool for the Retrieval of Interacting Genes was used to construct the protein-protein interaction network of DEGs., Results: The serum HDL-C level in CRC patients was significantly correlated with tumor size, and patients whose tumor size was more than 5 cm had a lower serum HDL-C level (1.18 ± 0.41 mmol/L vs 1.25 ± 0.35 mmol/L, P < 0.01) than their counterparts. In addition, TC/HDL (4.19 ± 1.33 vs 3.93 ± 1.26, P < 0.01) and LDL-C/HDL-C (2.83 ± 1.10 vs 2.61 ± 0.96, P < 0.01) were higher in patients with larger tumors. The levels of HDL-C ( P < 0.05), TC/HDL-C ( P < 0.01) and LDL-C/HDL-C ( P < 0.05) varied in different stages of CRC patients, and the differences were significant. We screened 14 differentially expressed genes (DEGs) of the cholesterol metabolism pathway in CRC and confirmed that lipoprotein receptor-related protein 8 (LRP8), PCSK9, low-density lipoprotein receptor (LDLR), MBTPS2 and FDXR are upregulated, while ABCA1 and OSBPL1A are downregulated in cancer tissue. Higher expression of LDLR (HR = 3.12, 95%CI: 1.77-5.49, P < 0.001), ABCA1 (HR = 1.66, 95%CI: 1.11-2.48, P = 0.012) and OSBPL1A (HR = 1.38, 95%CI: 1.01-1.89, P = 0.041) all yielded significantly poorer DFS outcomes. Higher expression of FDXR (HR = 0.7, 95%CI: 0.47-1.05, P = 0.002) was correlated with longer DFS. LDLR, ABCA1, OSBPL1A and FDXR were involved in many important cellular function pathways., Conclusion: Serum HDL-C levels are associated with tumor size and stage in CRC patients. LRP8, PCSK9, LDLR, MBTPS2 and FDXR are upregulated, while ABCA1 and OSBPL1A are downregulated in CRC. Among them, LDLR, ABCA1, OSBPL1A and FDXR were valuable prognostic factors of DFS and were involved in important cellular function pathways., Competing Interests: Conflict-of-interest statement: The authors declare that there are no conflicts of interest related to this study., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Previous studies have found that non-optimal temperature influences the development of gout, but the results have been inconsistent. The present study aimed to explore the effects of high temperature and high temperature variation on hospitalizations for gout in Anqing, China. We collected daily data on air pollutants, meteorological factors, and hospitalizations for gout between 1January 2016 and 31 December 2020 in Anqing City, China. We used Poisson generalized linear regression model and a distributed lag non-linear model (DLNM) to explore the relationship of high temperature, diurnal temperature range (DTR), and temperature change between neighboring days (TCN) with hospitalizations for gout. Stratified analysis by gender (male, female) and age (<65 years, ≥65 years) was conducted. Hospitalizations for gout attributed to high temperature, high DTR, and high TCN were also quantified. A total of 8675 hospitalized patients with gout were reported during the study period. We observed that exposure to high temperature was linked with an increased risk of hospitalizations for gout (lag 0, RR: 1.081, 95% confidence interval (CI): 1.011, 1.155). Exposure to high DTR was also associated with increased risk of hospitalizations for gout (lag9, RR: 1.017, 95% CI: 1.001,1.035). A large drop in temperature between neighboring days was associated an increased risk of hospitalizations for gout (lag 0-2 days, RR: 1.234, 95% CI: 1.017, 1.493). Stratified analysis results revealed that older adults and men were more sensitive to high-level DTR exposure than their counterparts. Nearly 15% of hospitalizations for gout could be attributable to high temperature (attributable fraction: 14.93%, 95% CI: 5.99%, 22.11%). This study suggests that high temperature and high temperature variation may trigger hospitalizations for gout, indicating that patients with gout need to take proactive actions in the face of days with non-optimal temperature., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Citrate has a prominent role as a substrate in cellular energy metabolism. Recently, citrate has been shown to drive inflammation. However, the role of citrate in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Here, we aimed to clarify whether extracellular citrate aggravated the LPS-induced ALI and the potential mechanism. Our findings demonstrated that extracellular citrate aggravated the pathological lung injury induced by LPS in mice, characterized by up-regulation of pro-inflammatory factors and over-activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in the lungs. In vitro, we found that citrate treatment significantly augmented the expression of NLRP3 and pro-IL-1β and enhanced the translocation of NF-κB/p65 into the nucleus. Furthermore, extracellular citrate plus adenosine-triphosphate (ATP) significantly increased the production of reactive oxygen species (ROS) in primary murine macrophages. Inhibiting the production of ROS with a ROS scavenger N-acetyl-L-cysteine (NAC) attenuated the activation of NLRP3 inflammasome. Altogether, we conclude that extracellular citrate may serve as a damage-associated molecular pattern (DAMP) and aggravates LPS-induced ALI by activating the NLRP3 inflammasome., (Copyright © 2021. Published by Elsevier B.V.)

Vasoactive intestinal peptide (VIP) is an intrapulmonary neuropeptide with multi-function, including anti-fibrosis. However, the exact role of VIP in pulmonary fibrosis has not been documented. Here, we investigated the protective effect of VIP against pulmonary fibrosis in a murine model induced by bleomycin (BLM). We found that the overexpression of VIP mediated by the adenoviral vector significantly attenuated the lung tissue destruction, reduced the deposition of the extracellular matrix, and inhibited the expression of alpha-smooth muscle actin (α-SMA) in the lungs of mice received BLM. Mechanismly, we found that VIP significantly suppressed the transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) and inhibited the matrix-producing ability of alveolar epithelial cells in vitro. Furthermore, we found that TGF-β1 depressed the autophagy and an autophagy inductor partly reversed the TGF-β1-induced EMT in alveolar epithelial cells. The impaired autophagy was also observed in the lungs of BLM-treated mice, which was restored by VIP treatment. And VIP treatment enhanced autophagy in TGF-β1-stimulated alveolar epithelial cells, contributing to its anti-EMT effect. In summary, our data, for the first time, show that VIP attenuates BLM-induced pulmonary fibrosis in mice with anti-EMT effect through restoring autophagy in alveolar epithelial cells. This study provides a possibility that inhaled long-acting VIP may be an anti-fibrotic drug in the treatment of pulmonary fibrosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with complex genetic predisposing factors involved. PU.1 is an important member of the ETS transcription factors family which has diverse functions such as regulating the proliferation, differentiation of immune cells and multiple inflammatory cytokines. Previous studies preliminary explored the relation between PU.1 and SLE. To further explain the potential role of PU.1 in the pathogenesis of SLE, 40 SLE patients and 20 age-sex matched healthy controls (HC) were recruited in this study. Flow cytometry was used to test the percentages of CD4 + PU.1 + T cells in peripheral blood mononuclear cells (PBMCs) from patients with SLE and HC. Expression levels of PU.1 mRNA in CD4 + T cells from SLE patients and HC were analyzed by real-time transcription-polymerase chain reaction. Expression levels of plasma IL-1β, IL-9, IL-18, IL-6, IFN-α, TNF-α, IL-10 and TGF-β1 were measured by enzyme-linked immunosorbent assay. The percentage of CD4 + PU.1 + T cells in PBMCs from patients with SLE was significantly higher than that from HC (P < 0.001). In addition, the PU.1 mRNA expression in CD4 + T cells from SLE patients was increased than that from HC (P = 0.002). In SLE patients, no significant correlation was found between the percentage of CD4 + PU.1 + T cells and the expression of PU.1 mRNA in CD4 + T cells (P > 0.05). Associations of PU.1 mRNA expression in CD4 + T cells with major clinical and laboratory parameters of SLE patients were also analyzed, but no significant correlations were found. Consistent with previous studies, SLE patients had increased IL-1β, IL-18, IL-6, IFN-α, TNF-α and IL-10 plasma concentrations than HC (P < 0.01). The expression level of plasma TGF-β1 was significantly decreased in SLE patients than in HC (P < 0.001). In SLE patients, the expression level of IL-1β was positive correlated with PU.1 mRNA expression in CD4 + T cells (P = 0.001). Our study first time evaluated the expression profile of PU.1 in CD4 + T cells from SLE patients confirming that PU.1 may participate in the pathogenesis of SLE., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: The skin is the second most affected organ after articular involvement in systemic lupus erythematosus (SLE) patients. Cutaneous involvement occurs in approximately 80% of patients during the course of SLE. Interaction between the host and skin microorganism is a complex process. There are few studies on the diversity of skin microbes in SLE patients. Therefore, this study aims to explore the relationship between skin microorganisms and SLE., Methods: A total of 20 SLE patients, 20 controls with rosacea and 20 healthy controls were selected as study subjects. Both the skin microbiota of rash region and non-rash region for each SLE patient were collected.16S rRNA gene sequencing was used to detected skin microbiota from 80 specimens. α-Diversity and β-diversity of skin microbiota were analyzed based on operational taxonomic units (OTUs) and minimal entropy decomposition (MED). Using Wilcoxon test and Linear Discriminate Analysis Effect Size (LEfSe), skin microbial diversity and composition were analyzed. Functional capabilities of microbiota were estimated through Kyoto Encyclopedia of Genes and Genomes database., Results: Compared to rash region of SLE, diversity and richness were increased in healthy controls, and decreased in non-rash region of SLE and rash region of controls with rosacea. Additionally, changes of skin microbial composition were found at different taxonomic levels between four groups. For example, genus Halomonas was increased and genera Pelagibacterium , Novosphingobium , and Curvibacter were decreased in rash region compared to non-rash region of SLE based on OTUs and MED. Based on OTUs, metabolic pathways were also found differences in SLE patients, such as Xenobiotics Biodegradation and Metabolism., Conclusion: Compositions and diversity of skin microbiota in SLE patients are changed. This pilot study provides some suggestive evidence for further exploration of skin microbiota in SLE patients with cutaneous involvement.

Objective: To investigate the clinical characteristics and prognosis of myelin oligodendrocyte glycoprotein (MOG) antibody-positive optic neuritis (ON). Methods: The data of 39 patients with MOG antibody-positive ON in the Department of Neurology of Beijing Tongren Hospital, Capital Medical University from January 1, 2017 to October 31, 2019 were retrospectively collected. There were 25 males and 14 females, aged from 15 to 80 (40±16) years. According to the recurrence, the patients were divided into two groups: the recurrence group ( n =12) and the non-recurrence group ( n =27). The clinical manifestations, relapse-related factors, magnetic resonance imaging (MRI) manifestations, treatment and prognosis of the two groups were analyzed. Results: A total of 63 eyes were involved, including 30 cases of optic perineuritis (OPN), accounting for 47.6% (30/63). The number of attacks ranged from 1 to 9, among which 12 patients had more than 2 attacks. There were 37 eyes [58.7% (37/63)] with severe visual loss (SVL) at the time of onset, and 7 eyes [11.1% (7/63)] with SVL at the final follow-up. Forty-eight eyes [76.2% (48/63)] had optic disc edema. Forty seven eyes [74.6% (47/63)] showed long-segment disease on optic nerve MRI. One case was complicated with aseptic meningitis and encephalitis. The recurrence group was younger than the non-recurrence group [(28.5±9.8) years vs (43.3±16.4) years, P =0.001]. There were no statistically significant differences between the two groups in gender, bilateral onset, initial visual acuity, final visual acuity, optic disc edema, head and spinal cord lesions, and immunosuppressant (all P >0.05). All patients were treated with methylprednisolone (MP) pulse therapy during the acute attack, and 16 of them were additively treated with immunosuppressive agents; the pain was alleviated or relieved significantly after the application of glucocorticoids. Conclusions: MOG antibody-positive ON often occurred in both eyes at the same time, often manifesting as OPN, often accompanied by optic disc edema, and SVL at the beginning of the disease, but most of the visual recovery was good, might be associated with meningitis and encephalitis. MRI of the optic nerve showed that the lesions often manifested as long-segment lesions. Glucocorticoids could alleviate pain and promote the recovery of visual function.

Background: Double kissing (DK) crush approach for patients with coronary bifurcation lesions, particularly localized at distal left main or lesions with increased complexity, is associated with significant reduction in clinical events when compared with provisional stenting. Recently, randomized clinical trial has demonstrated the net clinical benefits by intravascular ultrasound (IVUS)-guided implantation of drug-eluting stent in all-comers. However, the improvement in clinical outcome after DK crush treatment guided by IVUS over angiography guidance for patients with complex bifurcation lesions have never been studied in a randomized fashion., Trial Design: DKCRUSH VIII study is a prospective, multicenter, randomized controlled trial designed to assess superiority of IVUS-guided vs angiography-guided DK crush stenting in patients with complex bifurcation lesions according to DEFINITION criteria. A total of 556 patients with complex bifurcation lesions will be randomly (1:1 of ratio) assigned to IVUS-guided or angiography-guided DK crush stenting group. The primary end point is the rate of 12-month target vessel failure, including cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization. The secondary end points consist of the individual component of primary end point, all-cause death, myocardial infarction, and in-stent restenosis. The safety end point is the incidence of definite or probable stent thrombosis. An angiographic follow-up will be performed for all patients at 13 months and clinical follow-up will be continued annually until 3 years after the index procedure., Conclusions: DKCRUSH VIII trial is the first study designed to evaluate the differences in efficacy and safety between IVUS-guided and angiography-guided DK crush stenting in patients with complex true bifurcation lesions. This study will also provide IVUS-derived criteria to define optimal DK crush stenting for bifurcation lesions at higher complexity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To obtain a reliable estimation on the sleep quality in patients with systemic lupus erythematosus (SLE) and identify the main sleep problems, a meta-analysis was performed., Methods: Up to March 21, 2020, PubMed, EMBASE, and Cochrane Library were searched; quality evaluation were conducted with Newcastle-Ottawa Scale; statistical analyses were performed by stata14.0 software; results were expressed by weighted mean difference or standardized mean difference (WMD/SMD) and 95% confidence interval (CI)., Results: Eighteen case-control studies were included in meta-analysis, 1086 SLE patients and 2866 controls were collected. The score of sleep quality in the case group was higher than that in the control group (SMD = 1.03, 95% CI: 0.80-1.27), and so was the Pittsburgh Sleep Quality Index (PSQI) (WMD = 3.45, 95% CI: 2.49-4.42). The first three complaints of sleep problems in PSQI were daytime dysfunction (WMD = 0.64, 95% CI: 0.36-0.92), subjective sleep quality (WMD = 0.62, 95% CI: 0.40-0.84), and habitual sleep efficiency (WMD = 0.54, 95% CI: 0.37-0.72). Subgroup analyses showed that the score of sleep quality in SLE patients were higher than controls among different regions, races, and disease duration. The sleep quality score of SLE patients with fibromyalgia (FM) was higher than that in general control, but no significant difference as compared with SLE patients without FM., Conclusions: Our meta-analysis indicates that the sleep quality of SLE patients is worse than that of the general population; thus, more attention should be paid to the sleep status among this disease. Key Points •The sleep quality of SLE patients is worse than that of the general population. •Region, race, and disease duration are correlated with sleep quality in SLE patients.

Objectives: To explore the associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid (GC) efficacy, anxiety, depression, and health-related quality of life (HRQOL) in systemic lupus erythematosus (SLE) patients., Methods: All subjects were collected from the First and the Second Affiliated Hospital of Anhui Medical University in Hefei, China, during 2011 to 2015. In the case-control study, 541 SLE patients and 543 controls were recruited. In the follow-up study, 466 patients completed the 12-week follow-up and then were divided into GC-sensitive and GC-insensitive groups. Genotyping was determined using Multiplex SNaPshot technique. Data were analyzed using chi-square test and univariate and multivariate logistic regression analyses., Results: rs4713904, rs9368878, and rs7757037 of FKBP5 were associated with depression in SLE patients (rs4713904, P BH  = 0.037; rs9368878, P BH  = 0.001; rs7757037, P BH  = 0.003). Moreover, rs4713904 was associated with GC efficacy in males with SLE (P BH  = 0.011). The rs755658 of FKBP5 was associated with improvement in social function (P BH  = 0.022) and mental component summary (P BH  = 0.028). The rs4713907 of FKBP5 was related to improvement in total score of SF-36, bodily pain, and mental component summary score (all P BH  = 0.018). Furthermore, the rs12582595 of FKBP4 was correlated with general health improvement (P BH  = 0.033). No associations were seen between FKBP4/FKBP5 gene polymorphisms and SLE susceptibility and anxiety., Conclusions: FKBP5 gene polymorphisms may be associated with depression and GC efficacy of SLE patients. Meanwhile, the genetic polymorphisms of FKBP4 and FKBP5 genes may be associated with HRQOL improvement in SLE patients. Key Points • FKBP5 gene polymorphisms were associated with depression of SLE patients. • FKBP5 gene polymorphisms were associated with GC efficacy of SLE patients. • FKBP5 gene polymorphisms were associated with HRQOL improvement in SLE patients. • FKBP4 gene polymorphisms were associated with HRQOL improvement in SLE patients.

Epoxyeicosatrienoic acids (EETs) derived from arachidonic acid exert anti-inflammation effects. We have reported that blocking the degradation of EETs with a soluble epoxide hydrolase (sEH) inhibitor protects mice from lipopolysaccharide (LPS)-induced acute lung injury (ALI). The underlying mechanisms remain essential questions. In this study, we investigated the effects of EETs on the activation of nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome in murine macrophages. In an LPS-induced ALI murine model, we found that sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl), TPPU, profoundly attenuated the pathological injury and inhibited the activation of the NLRP3 inflammasome, characterized by the reduction of the protein expression of NLRP3, ASC, pro-caspase-1, interleukin precursor (pro-IL-1β), and IL-1β p17 in the lungs of LPS-treated mice. In vitro, primary peritoneal macrophages from C57BL/6 were primed with LPS and activated with exogenous adenosine triphosphate (ATP). TPPU treatment remarkably reduced the expression of NLRP3 inflammasome-related molecules and blocked the activation of NLRP3 inflammasome. Importantly, four EETs (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) inhibited the activation of NLRP3 inflammasome induced by LPS + ATP or LPS + nigericin in macrophages in various degree. While the inhibitory effect of 5,6-EET was the weakest. Mechanismly, EETs profoundly decreased the content of reactive oxygen species (ROS) and restored the calcium overload in macrophages receiving LPS + ATP stimulation. In conclusion, this study suggests that EETs inhibit the activation of the NLRP3 inflammasome by suppressing calcium overload and ROS production in macrophages, contributing to the therapeutic potency to ALI., (© 2020 Wiley Periodicals LLC.)

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), which are characterized by self-perpetuating inflammation and tissue/organ damage, resulting from the failure of lymphocyte auto-tolerance, cause morbidity and mortality worldwide. The current drugs or therapies including conventional non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs), as well as several biologic therapies such as B cell-targeted, T cell-targeted, cytokines-targeted and cytokines receptors-targeted therapy, cannot completely cure SLE and RA, and are always accompanied by unexpected side effects. Therefore, more studies have explored new methods for therapy and found that the herbal medicine as well as its natural products (NPs) exhibited promising therapeutic value through exerting effects of immunomodulation, anti-inflammation, anti-oxidation, and anti-apoptosis, etc. via regulating abnormal responses in kidney, innate and adaptive immune systems, intestine, synoviocytes, as well as bone system including chondrocytes, osteoclasts, joints and paw tissues. In the present review, we will elucidate the current mainstream drugs and therapies for SLE and RA, and summarize the efficacy and mechanisms of NPs in the treatment of SLE and RA based on available findings including in vitro and in vivo animal models, as well as clinical studies, and further analyze the existing challenges, in order to provide comprehensive evidence for improvement of SLE and RA therapy by NPs and to promote management of these two autoimmune diseases., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: To obtain a novel pullulanase with synthetic ability from a microorganism and characterize its substrates specificity., Results: A novel pullulanase, PulY103A, from Bacillus megaterium Y103 was purified, characterized and expressed in Escherichia coli. PulY103A contained the signature sequences of type I pullulanases and showed 94.7% identity with a type I pullulanase (BmPul) from B. megaterium WW1210, showing similar molecular weight (110.8 kDa) and optimal pH (6.5). However, PulY103A had an optimal temperature of of 45 °C and exhibited relatively higher activity toward amylose (48.3%) compared with pullulan (100%), soluble starch (67.5%), and amylopectin (23.1%). The thin-layer chromatography results showed that the major pullulan hydrolysis products were maltotriose and maltohexaose, which differed from those reported in other pullulanases. On the basis of enzyme specificity, PulY103A was an amylopullulanase, which presented transglycosylation activity by forming α-1,4-glucosidic linkages., Conclusions: A novel amylopullulanase with transglycosylation activity was characterized. The features of this enzyme suggested its potential to produce maltohexaose.

Introduction: The present study aimed to investigate the prevalence and influential factors of thrombocytopaenia in systemic lupus erythematosus (SLE) patients among the Chinese population in order to provide evidence for improving the treatment and nursing of SLE patients., Methods: A retrospective analysis of 3140 SLE patients admitted to two large tertiary hospitals was conducted in Anhui, China, from 2011 to 2018. In addition, the influential factors related to SLE with thrombocytopaenia were analysed through univariate and multivariate analysis., Results: A total of 804 SLE patients had thrombocytopaenia (25.6%). The top 5 clinical manifestations of SLE inpatients were proteinuria (51.0%), lupus nephritis (45.9%), new rash (38.4%), haematuria (36.7%) and pyuria (32.2%). The incidence of neurological manifestations, oral mucosal ulceration, pleurisy, pericarditis, hyperglycaemia, leucocytopaenia, urinary casts, haematuria, pyuria and high disease activity in the thrombocytopaenia group were higher than those in the non-thrombocytopaenia group ( p  < 0.05). Multivariate analysis showed age (odds ratio (OR) = 1.009, p  = 0.005), neurological manifestations (OR = 1.373, p  = 0.048), pericarditis (OR = 1.394, p  = 0.048), hyperglycaemia (OR = 1.717, p  < 0.001), leucocytopaenia (OR = 2.551, p  < 0.001), haematuria (OR = 1.582, p  < 0.001), serum C3 level <0.85 g/L (OR = 1.525, p  = 0.001), serum C4 concentration <0.10 g/L (OR = 1.287, p  = 0.020), serum CRP concentration <8 ng/L (OR = 1.314, p  = 0.005), prothrombin time >15.30 seconds (OR = 1.479, p  = 0.032), activated partial thromboplatin time >45 seconds (OR = 1.924, p  < 0.001) and thrombin time >21 seconds (OR = 1.629, p  = 0.015) were associated with thrombocytopaenia., Conclusion: Thrombocytopaenia has a high prevalence in SLE patients and is related to some baseline, clinical and laboratory characteristics, affecting multiple organs and systems.

Objectives: The aim of this study is to investigate whether heat shock protein 70 (Hsp70) gene polymorphisms are implicated in systemic lupus erythematous (SLE) susceptibility, the efficacy of glucocorticoids (GCs) treatment, and improvement of health-related quality of life., Methods: A total of 499 SLE patients and 499 controls were included in a case-control study, and 468 SLE patients treated with GCs for 12 weeks were involved in a follow-up study. Patients who completed the 12-week follow-up were divided into GCs-sensitive and GCs-insensitive group by using the SLE disease activity index. The SF-36 was used to evaluate the health-related quality of life of SLE patients, and genotyping was performed by improved multiplex ligation detection reaction., Results: rs2075800 was associated with SLE susceptibility (adjusted odds ratio [ORadj], 1.437; 95% confidence interval [CI], 1.113-1.855; Padj = 0.005; PBH = 0.020 by dominant model; ORadj, 1.602; 95% CI, 1.072-2.395; Padj = 0.022; PBH = 0.029 by TT vs CC model; ORadj = 1.396; 95% CI = 1.067-1.826; Padj = 0.015; PBH = 0.029 by TC vs CC model). In the follow-up study, rs2075799 was associated with the improvement in mental health (p = 0.004, PBH = 0.044), but we failed to find any association between the efficacy of GCs and Hsp70 gene polymorphisms., Conclusions: Hsp70 gene polymorphisms may be associated with susceptibility to SLE and improvement of mental health in Chinese Han population.

Objective: The important role of intestinal microbiota in systemic lupus erythematosus (SLE) has been recognized. Oral-gut microbiome axis is a crucial link in human health and disease, but few researches indicated the relationship between oral microorganisms and SLE. This study mainly explored the composition and changes of oral microorganisms in SLE patients with different stages, clinical manifestations and biomarkers., Design: Oral microbiota was detected by 16S ribosomal RNA gene sequencing from 20 SLE patients and 19 healthy controls (HCs). The evenness, diversity and composition of oral microbiota were analyzed. Moreover, receiver-operating characteristic analysis was conducted. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database was used to investigate microbiota functions., Results: The oral microbiota of SLE patients was imbalanced and the diversity was decreased, but no difference was found between new-onset and treated SLE patients. Families Lactobacillaceae, Veillonellaceae and Moraxellaceae were enriched in SLE patients. Families like Corynebacteriaceae, Micrococcaceae, Defluviitaleaceae, Caulobacteraceae, Phyllobacteriaceae, Methylobacteriaceae, Hyphomicrobiaceae, Sphingomonadaceae, Halomonadaceae, Pseudomonadaceae, Xanthomonadaceae, etc. were decreased in SLE patients. After multiple testing adjustment, families Sphingomonadaceae, Halomonadaceae, and Xanthomonadaceae were significantly decreased in SLE patients. And area under the curve was 0.953 (95% confidence intervals 0.890-1.000) to distinguish SLE patients from HCs. There were differences in metabolic pathways between SLE and HCs (P = 0.025)., Conclusions: These findings collectively support that oral microbiota dysbiosis and aberrant metabolic pathways were observed in patients with SLE. Our findings may provide suggestive evidences for the diagnosis and treatment of SLE., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

To investigate the effects of H 2 S on mitochondrial functions under low temperature stress, we analyzed the effects of 0.05 mmol·L -1 NaHS and 15 μmmol·L -1 HT (hypotaurine and H 2 S scavenger) on mitochondria antioxidant enzyme activities and mitochondrial permeability transition pore, mitochondrial membrane fluidity, mitochondrial membrane potential, Cyt c/a ratio and H + -ATPase activity in sweet cherry stigma and ovary with sweet cherry variety Zaodaguo under -2 ℃ low temperature stress. The results showed that low temperature stress increased the concentrations of mitochondrial H 2 O 2 and MDA, enhanced the mitochondrial membrane permeability, but decreased the mitochondrial membrane fluidity, membrane potential, Cyt c/a and H + -ATPase acti-vity. Application of NaHS at 0.05 mmol·L -1 could effectively reduce the concentrations of H 2 O 2 and MDA, and keep higher activities of SOD, POD and CAT of mitochondrial for longer time. Furthermore, application of 0.05 mmol·L -1 NaHS could decrease mitochondrial membrane permeability while increase mitochondrial membrane fluidity, membrane potential, Cyt c/a and H + -ATPase activity in stigma and ovary under low temperature stress. The effects of NaHS were completely offset by HT addition. The results suggested that exogenous H 2 S could alleviate the oxidative damage on stigma and ovary stress through decreasing H 2 O 2 accumulation, regulating mitochondria antioxidant system, increasing H + -ATPase activity, and mitigating mitochondria function under low temperature.