Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation. However, the shared mechanism is largely unknown. H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive. The present study demonstrated that levels of cartilage degradation, H2BK120ub1, and its regulator WW domain-containing adapter protein with coiled-coil (WAC) were increased in cartilage in human rheumatoid arthritis (RA) and osteoarthritis (OA) patients as well as in experimental RA and OA mice. By regulating H2BK120ub1 and H3K27me3, WAC regulated the secretion of inflammatory and cartilage-degrading factors. WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B, and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3. The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis (CIA) and collagenase-induced osteoarthritis (CIOA) mice. Through molecular docking and dynamic simulation, doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models. Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis, and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.

Hereditary gingival fibromatosis (HGF) is a rare inherited condition with fibromatoid hyperplasia of the gingival tissue that exhibits great genetic heterogeneity. Five distinct loci related to non-syndromic HGF have been identified; however, only two disease-causing genes, SOS1 and REST, inducing HGF have been identified at two loci, GINGF1 and GINGF5, respectively. Here, based on a family pedigree with 26 members, including nine patients with HGF, we identified double heterozygous pathogenic mutations in the ZNF513 (c.C748T, p.R250W) and KIF3C (c.G1229A, p.R410H) genes within the GINGF3 locus related to HGF. Functional studies demonstrated that the ZNF513 p.R250W and KIF3C p.R410H variants significantly increased the expression of ZNF513 and KIF3C in vitro and in vivo. ZNF513, a transcription factor, binds to KIF3C exon 1 and participates in the positive regulation of KIF3C expression in gingival fibroblasts. Furthermore, a knock-in mouse model confirmed that heterozygous or homozygous mutations within Zfp513 (p.R250W) or Kif3c (p.R412H) alone do not led to clear phenotypes with gingival fibromatosis, whereas the double mutations led to gingival hyperplasia phenotypes. In addition, we found that ZNF513 binds to the SOS1 promoter and plays an important positive role in regulating the expression of SOS1. Moreover, the KIF3C p.R410H mutation could activate the PI3K and KCNQ1 potassium channels. ZNF513 combined with KIF3C regulates gingival fibroblast proliferation, migration, and fibrosis response via the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK pathways. In summary, these results demonstrate ZNF513 + KIF3C as an important genetic combination in HGF manifestation and suggest that ZNF513 mutation may be a major risk factor for HGF.
Animals ; Humans ; Mice ; Fibromatosis, Gingival/pathology* ; Gingiva ; Kinesins/genetics* ; Mutation/genetics* ; Phosphatidylinositol 3-Kinases/genetics*

Objective:To identify the clinical characteristics and adverse events of patients with giant cell arteritis (GCA).Methods:Patients who were hospitalized and diagnosed with GCA in Zhongshan Hospital, Fudan University, from December 2009 to November 2020 were enrolled into a retrospective study analysis. Baseline data and follow-up data were collected. Adverse events were defined as one of the following events: relapses, ischemic complications and death. Patients with adverse events were analyzed in clinical features and risk factors by univariate and multivariate analysis. Associations with adverse events were assessed using ROC curve and survival curves.Results:A total of 69 patients with GCA were included in this study, with the male: female ratio of 1∶1.03. Fatigue and headache were common symptoms. Finally, 61 patients were followed up at the end of May in 2021. Over the mean follow-up time of (35±20) months, adverse events occurred in 16 cases (26.2%). Patients with adverse events had significantly lower levels of platelet and globulin at baseline than those without adverse events [(325±142)×10 9/L vs (238±112)×10 9/L, t=2.22, P=0.030]; [(31±6) g/L vs (26±6) g/L, t=2.74, P=0.008]. Red cell volume distribution width-coefficient of variation (RDW-CV) was considered an independent risk factor for adverse events [ OR (95% CI)=0.32 (0.14,0.74), P=0.008]. Further, patients especially with RDW-CV<14.75% were prone to have adverse events, which occurred in 2.6%, 20.5%, 25.6%, 33.3%, 41.00% in 1, 2, 3, 5, 10 years. Its risk increased significantly after 2 years ( P=0.042, P=0.021, P=0.002, P=0.001). The incidence of adverse events was much higher in patients with RDW-CV<14.75%(95% CI=0.002). Conclusion:Adverse events are common in patients with GCA. RDW-CV is an independent risk factor for having adverse events. Low level of RDW-CV predicts an increased risk of adverse events by the following years.

Background and Objectives: Mesenchymal stem cells (MSCs) have the multipotent capacity to differentiate into multiple tissue lineages as well as to self-renew, which is the main origin of adipocytes. IL6/IL6R pathway exerts a significant role in tissue regeneration and cell differentiation. Whereas, the underlying mechanism between IL6/IL6R pathway and MSCs adipogenesis differentiation remains elusive. Methods: MSCs from healthy donors were cultured in adipogenesis differentiation medium for 0∼14 days, during which their adipogenesis differentiation degree was evaluated by Oil Red O staining. The expression of IL6R was detected in MSCs during adipogenesis differentiation. Knockdown and overexpression of IL6R were respectively performed using siRNA and lentivirus to investigate its effect on MSCs adipogenesis differentiation. The adipogenesis marker genes expression and MAPK pathway activation were detected by Western blotting. The role of P38 pathway in the adipogenesis differentiation of MSCs was determined using the specific inhibitor SB203580. Results: The expression of IL6 and IL6R increased during adipogenesis differentiation in MSCs, which were positively correlated with Oil Red O quantification result. Knockdown and overexpression experiments demonstrated a positive correlation between the expressions of IL6R and MSCs adipogenesis differentiation, accompanied by same trend of P38 phosphorylation. Besides, the specific P38 inhibitor SB203580 markedly inhibited the adipogenesis differentiation potential of MSCs. Conclusions This study reveals IL6R facilitates the adiogenesis differentiation of MSCs via activating P38 pathway.

Objective: To study the constitutional features of diseases spectrum of inpatients with liver disease in infectious diseases department of three comprehensive hospitals to provide resource allocation proposition for the construction of Department of Infectious Diseases. Methods: Inpatients data were extracted from the department of infectious diseases of three comprehensive hospitals (Kunming General Hospital of the People's Liberation Army, Yuxi People's Hospital and Dali People's Hospital) between January 2010 to December 2015, and were retrospectively analyzed. The distribution of patients with viral hepatitis (A, B, C, E) and severe liver disease (Severe hepatitis, cirrhosis, liver cancer) was further analyzed in hospitalized patients. Data were analyzed by one-way analysis of variance. A chi-squared test was used for comparison between groups. The change trends of disease constituent ratio in different years were checked by 2 test. Results: Liver disease, tuberculosis and AIDS were the three common diseases of three comprehensive hospitals in Yunnan, accounting for 58.61% of all admissions. However, an inpatients with liver diseases (17.25%, 3555/20606, 95% CI 16.73%-17.77%) were significantly lower than tuberculosis inpatients (33.98%, 7002/20606, 95% CI 33.34%-34.62%). An observations from different hospitals and at different time points showed that the proportion of patients with liver disease was lower than that of tuberculosis patients. The proportion of inpatients with HBV infection showed a downward trend (P < 0.001), whereas the proportions of inpatients with HCV and severe liver diseases showed an increased trend over time (P < 0.001). Conclusion The proportion of inpatients with liver diseases was lower than tuberculosis inpatients in the Department of Infectious Diseases of three comprehensive hospitals. Hence, the paucity of the disease spectrum should be considered for resource allocation in the construction of infectious disease department.

Ankylosing spondylitis (AS) is a type of autoimmune disease that predominantly affects the spine and sacroiliac joints. However, the pathogenesis of AS remains unclear. Some evidence indicates that infection with bacteria, especially Gram-negative bacteria, may have an important role in the onset and progression of AS. Recently, many studies have demonstrated that mesenchymal stem cells (MSCs) dysfunction may contribute to the pathogenesis of many rheumatic diseases. We previously demonstrated that MSCs from AS patients exhibited markedly enhanced osteogenic differentiation capacity in vitro under non-inflammatory conditions. However, the properties of MSCs from AS patients in an inflammatory environment have never been explored. Lipopolysaccharide (LPS), a proinflammatory substance derived from the outer membrane of Gram-negative bacteria, can alter the status and function of MSCs. However, whether MSCs from AS patients exhibit abnormal responses to LPS stimulation has not been reported. Autophagy is a lysosome-mediated catabolic process that participates in many physiological and pathological processes. The link between autophagy and AS remains largely unknown. The level of autophagy in ASMSCs after LPS stimulation remains to be addressed. In this study, we demonstrated that although the basal level of autophagy did not differ between MSCs from healthy donors (HDMSCs) and ASMSCs, LPS-induced autophagy was weaker in ASMSCs than in HDMSCs. Specifically, increased TRAF4 expression in ASMSCs impaired LPS-induced autophagy, potentially by inhibiting the phosphorylation of Beclin-1. These data may provide further insight into ASMSC dysfunction and the precise mechanism underlying the pathogenesis of AS.
Autoimmune Diseases ; Autophagy* ; Bacteria ; Gram-Negative Bacteria ; Humans ; In Vitro Techniques ; Membranes ; Mesenchymal Stromal Cells* ; Pathologic Processes ; Phosphorylation ; Rheumatic Diseases ; Sacroiliac Joint ; Spine ; Spondylitis, Ankylosing* ; Tissue Donors ; TNF Receptor-Associated Factor 4*

BACKGROUND:Ankylosing spondylitis is an autoimmune disease at high inflammatory state, and its pathogenesis is stil unclear. Besides, there is a lack of entirely satisfactory curative strategies. OBJECTIVE: To explore the immunoregulation capability of bone marrow mesenchymal stem cels from ankylosing spondylitis patients on macrophages and the potential therapeutic use of bone marrow mesenchymal stem cels from healthy donors on ankylosing spondylitis. METHODS: Bone marrow mesenchymal stem cels were extracted from 21 healthy donors and 25 ankylosing spondylitis patients respectively, and passage 4 cels were used in subsequent experiments. A human monocytic cel line was induced to differentiate into macrophages. The phenotypic markers of bone marrow mesenchymal stem cels and macrophages were detected by flow cytometry. Expressions of tumor necrosis factor-α and tumor necrosis factor-α-stimulated gene 6 (TSG-6) proteins in the supernatant of co-culture system were detected by ELISA. Quantitative real-time PCR was applied to detect the mRNA level of cytokines secreted by bone marrow mesenchymal stem cels and macrophages. RESULTS AND CONCLUSION:The typical mesenchymal stem cel surface markers were expressed in both bone marrow mesenchymal stem cels from healthy donors and patients with ankylosing spondylitis, and CD68 was detected positively in induced macrophages. The protein and mRNA levels of tumor necrosis factor-α secreted by macrophages co-cultured with bone marrow mesenchymal stem cels from patients with ankylosing spondylitis were obviously higher than those from healthy donors (P < 0.05). TSG-6 secreted by bone marrow mesenchymal stem cels from patients with ankylosing spondylitis was lower than that by bone marrow mesenchymal stem cels from healthy donors in both RNA transcriptional and protein levels (P < 0.05). Our study demonstrates that bone marrow mesenchymal stem cels from patients with ankylosing spondylitis shows abnormal immunoregulatory function on inhibiting the tumor necrosis factor-α secretion from macrophages, which reveals a mechanism of immune disorder in ankylosing spondylitis. The therapeutic mechanism of bone marrow mesenchymal stem cels from healthy donors may work by secreting enough TSG-6 to inhibit the activation of macrophages in patients with ankylosing spondylitis, and thereby to decrease the secretion of tumor necrosis factor-α. Cite this article:Sun SH, Wang P, Su CY, Xie ZY, Li YX, Li D, Wang S, Su HJ, Wu XH, Deng W, Wu YF, Shen HY. Bone marrow mesenchymal stem cels derived from patients with ankylosing spondylitis show abnormal immunoregulation capability on macrophages. Zhongguo Zuzhi Gongcheng Yanjiu. 2016;20(1):13-19.

Objective To explore the epidemic characteristics,clinical features and treatment outcome of brucellosis in the Dali area of Yunnan province.Methods The clinical data of 43 cases with brucellosis from Janurany 2012 to September 2015 were retrospectively analyzed.Results Among 43 cases,there were 35 males,8 females, 37 farmers,5 veterinary,and 1 teacher.42 patients had a clear history of contact with cattle and sheep,1 case of no clear history of exposure to cattle and sheep,mainly fever,accompanied by chills,headache,joint pain,low back pain, weight loss,hepatosplenomegaly etc.Laboratory routine examination showed no specificity,SAT was detected in 30 cases,positive rate was 100.0%,blood culture in 28 cases,23 cases were positive,the positive rate was 82.1%. 41 cases of adult patients with rifampicin and tetracycline or doxycycline + levofloxacin and cefotaxime drugs combined therapy,treatment for 6 weeks,2 cases of children took rifampicin and SMZ -TMP treatment for 6 weeks, improvement rate was 100%,there was no recurrence and death cases.Conclusion Dali area is popular in brucellosis, the clinical manifestations and the infection way diversification,need the attention of the clinicians.

Objective To investigate the correlation between opportunistic infections in patients with HIV /AIDS in Dali of Yunnan Province and CD +4 lymphocyte count,discover the incidence trend of opportunistic infections in patients with HIV /AIDS in Dali and instruct early diagnosis and treatment.Methods Choosing 454 cases of opportunistic infections in patients with HIV /AIDS in Infectious Disease Dali Prefectural Hospital were chosen,ana-lyze various opportunistic infections,examining CD +4 lymphocyte count and analyze the differences of opportunistic infections on CD +4 lymphocyte count.Results 454 cases opportunistic infections with HIV /AIDS,48.24% were HCV infections,38.72% of various tuberculosis consumption phthisis,28.41% of bacterial pneumonia and 25.77%of oral condida monilia infections,high rate of opportunistic infections when CD +4 lymphocyte count <200 /μL;when CD +4 <50 /μL,53.33% of the patients with more than three pathogen infections,thus higher than those CD +4 >350 /μL of 5.56%(χ2 =34.88,P <0.01);The high rate of opportunistic infections found on patients without the treatment of HAART(40.83%,U =9.05,P <0.01),comparing to 18.79% of those with the treatment.Conclusion The com-mon opportunistic infections in our area are HCV,various tuberculosis consumption phthisis,bacterial pneumonia and oral condida monilia infections;high rate of opportunistic infections happens when CD +4 lymphocyte count are low and lower rate on those with the treatment of HAART,offering an effective method on controlling opportunistic infections.

Objective Glioblastoma,being one of the most malignant forms of adult brain tumors,is usually associated with a dismal prognosis.Given that the protein expression of O (6)-methylguanine-DNA methyltransferase (MGMT) is the most important determinant of temozolomide (TMZ) resistance,great efforts have been made to suppress it by regulating MGMT-related transcription factors.Resveratrol is a terpenoid that exhibits broad pro-apoptotic activity in various types of cancers,including glioblastoma.However,the effects of resveratrol on nuclear factor-κB (NF-κB) -MGMT signaling in glioblastomas have not yet been fully elucidated.In this article,we want to find that the molecular mechanisms of resveratrol reverses temozolomide resistance in glioblastoma cells.Methods Human malignant glioblastomas cell line T98G glioma cells was conventionally cultured in vitro; MTT assay was employed to detect the cell viability after being treated with dimethylsulfoxide (control group),or 100,200,400 and 800 μmol/L resveratrol,or 50,100,200 and 400 μmol/L TMZ or TMZ (100 μmol/L) combined with resveratrol (100 μmol/L); Hoechst33342 staining was employed to observe the effects of 100 μmol/L resveratrol,100 μmol/L TMZ or TMZ (100 μmol/L) combined with resveratrol (100 μmol/L) on T98G nuclear morphology changes; Flow cytometry and Western blotting were used to detect the T98G cell apoptosis and expressions ofMGMT,NF-κB signaling pathway related proteins.Results T98G cells after being treated with different concentrations of resveratrol for 24 and 72 h,the cell vitality decreased with 50％ inhibiting concentration (IC50) reaching 127.5 and 86.2 μmol/L,respectively; T98G cells after being treated with different concentrations of TMZ for 24 and 72 h,the cell vitality decreased with IC50 reaching 2.5 and 3.2 mmol/L,respectively; significant decreased cell vitality in the combination treatment with TMZ and resveratrol group was noted as compared with that in the TMZ or resveratrol treatment groups (P＜0.05).Hoechst 33258 staining and Western blotting revealed apoptotic morphological changes of T98G cell nuclei and increased apoptosis in the TMZ or resveratrol treatment groups,and more obvious changes were noted in the combination treatment with TMZ and resveratrol group.As compared with that in the control group,significantly increased MGMT protein expression in the 100 μmol/LTMZ treatment group was noted (P＜0.05),while no obvious MGMT protein expression was noted in the resveratrol treatment group and combination treatment with TMZ and resveratrol group; as compared with those in the control group,significantly increased IkB-α expression and decreased NF-κB p65 expression in the resveratrol treatment group (P＜0.05),significantly decreased IkB-α expression and increased NF-κB p65 expression in the TMZ treatment group (P＜0.05),and decreased NF-κB p65 expression in the combination treatment with TMZ and resveratrol group (P＜0.05).Conclusion Down-regulation of MGMT in T98G glioblastoma cells by NF-κB-dependent pathway is one of the important molecular mechanism of resveratrol reversing temozolomide resistance.