MicroRNA-146a negatively regulates IL-33 in activated group 2 innate lymphoid cells by inhibiting IRAK1 and TRAF6.

Type II innate lymphoid cells (ILC2) play a very important role in the pathogenesis of allergic asthma. This study aims to investigate whether miR-146a inhibition of asthma is related with interleukin (IL)-33 signaling path way in ILC2 and the underlying mechanisms. Asthma mice model was induced by ovalbumin. miRNA146a mimics was administrated to asthma mice or transfected to activated ILC2 purified from asthma mice lung. RT-PCR was used to detect miRNA146a level in lung tissue and ILC2. IL-5 and IL-13 levels in culture supernatant were detected by flow cytometry. Interleukin-1 receptor-associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6), signal transducer and activator of transcription 1 (STAT1) protein expression levels were detected by western blot. miR-146a directly inhibited ILC2 function and suppressed ILC2 proliferation both in vivo and in vitro. During stimulation of ILC2, miR-146a expression gradually increased with a decrease of cell proliferation. Modulation of ILC2 function by miR-146a may depend on IL-33/interleukin 1 receptor-like 1 (IL1RL1 or ST2) signaling through inhibiting IRAK1 and TRAF6.miR-146a can inhibit IRAK1 and TRAF6, downstream molecules of ST2 signal pathway, thereby negatively regulate IL-33/ST2-activated ILC2 to inhibit asthma. Targeting miR-146 maybe a novel strategy for the treatment of allergic asthma.

Identification of differentially expressed genes in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease that affects exocrine glands. To study the molecular mechanism and identify crucial genes/pathways in pSS pathogenesis, the microarray-based whole-genome gene expression profiles from salivary glands of patients with pSS and non-sicca controls were retrieved. After normalization and subsequent batch effect adjustment, significance analysis of microarrays method was applied to five available datasets, and 379 differentially expressed genes (DEGs) were identified. The 300 upregulated DEGs were enriched in Gene Ontology terms of immune and inflammatory responses, including antigen processing and presentation, interferon-mediated signaling pathway, and chemotaxis. Previously reported pSS-associated genes, including HLA-DRA, TAP2, PRDM1, and IFI16, were found to be significantly upregulated. The downregulated DEGs were enriched in pathways of salivary secretion, carbohydrate digestion and absorption, and starch and sucrose metabolism, implying dysfunction of salivary glands during pathogenesis. Next, a protein-protein interaction network was constructed, and B2M, an upregulated DEG, was shown to be a hub, suggesting its potential involvement in pSS development. In summary, we found the activation of pSS-associated genes in pathogenesis, and provide clues for salivary glands dysfunction. Experimental investigation on the identified DEGs in this study will deepen our understanding on pSS.

Systemic treatment with resveratrol alleviates adjuvant arthritis-interstitial lung disease in rats via modulation of JAK/STAT/RANKL signaling pathway.

Interstitial lung disease (ILD) is the most common pulmonary manifestation of Rheumatoid arthritis (RA) lung disease. The mechanism of RA-ILD remains obscure and more effective treatments are still needed. Resveratrol (RSV) a phytoalexin found with anti-inflammation and antioxidant activity. RSV has been reported to protect against RA. In current study, we evaluated the effects of RSV on RA-ILD and further explored the underlying mechanisms. We established the RA-ILD rat model by injecting Freund's complete adjuvant (FCA). After administration of RSV into RA-ILD rats, the disease parameters were assessed, inflammatory cytokines productions were analyzed, and the effects of RSV on JAK/STAT/RANKL were evaluated. Injection of FCA caused RA-ILD in rats, which had clear lung damage, fibrosis, and elevated pro-inflammatory cytokines in both serum and lung. RSV treatment significantly ameliorated the lung disease and prevented pro-inflammatory cytokines production. In addition, RSV inhibited JAK/STAT/RANKL signaling pathway in RA-ILD rats. RSV treatment alleviates RA-ILD in rats by inhibiting JAK/STAT/RANKL signaling pathway.

The potential role of Alu Y in the development of resistance to SN38 (Irinotecan) or oxaliplatin in colorectal cancer.

BACKGROUND: Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown. RESULTS: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38 or oxaliplatin resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of 'DNA methylation entropy' to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples. CONCLUSION: Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy.

Association between human papillomavirus infection or immunization and risk for rheumatoid arthritis.

Background: Human papillomavirus (HPV) is a virus primarily transmitted through sexual contact. Little is known about the association between HPV infection or immunization and the risk for rheumatoid arthritis (RA). The purpose of this study was to evaluate whether HPV infection or immunization is related to the risk for RA in adults. Methods: Data were obtained from the 2007-2016 National Health and Nutrition Examination Survey (NHANES). We developed three independent multivariate logistic regression models to evaluate the association between HPV infection or immunization and the risk for RA in adults. Results: Finally, we analyzed 15,677 and 8,944 subjects, respectively. In all models, HPV infection was positively associated with an increased prevalence of RA in adults aged 18-59 years, with the highest value of the odds ratio (OR) in model 2 (after weighting: OR 1.095, 95% CI 1.092, 1.097), whereas HPV immunization significantly reduced the prevalence of RA in adults aged 18-59 years, with the lowest OR in model C (after weighting: OR 0.477, 95% CI 0.472, 0.481). These associations persisted after correction for confounders such as age, sex, race, education level, marital status, smoking, diabetes, hypertension, hyperlipidemia, and BMI. Conclusion: In summary, our study suggests that HPV infection is positively associated with the prevalence of RA in adults, and HPV immunization can reduce the prevalence of RA in adults. However, our findings need more powerful to prove these associations through rigorously designed prospective studies.

[Immune Thrombocytopenia Induced by Sintilimab in Lung Cancer: 
A Case Report and Literature Review].

Immune checkpoint inhibitors (ICIs) show unique advantages in the treatment of lung cancer, making the treatment of lung cancer enter the era of immunotherapy, but ICIs will also have adverse reactions, and the incidence of immune-induced hematological toxicity is not very high. Immunotherapy-induced thrombocytopenia is a rare adverse event.We report one case of thrombocytopenia induced by ICIs and review the literature on thrombocytopenia associated with ICIs and discuss the clinical features, possible mechanisms, and optimal treatment. 
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Brain glucose metabolism on [18F]-FDG PET/CT: a dynamic biomarker predicting depression and anxiety in cancer patients.

Objectives: To explore the correlation between the incidence rates of depression and anxiety and cerebral glucose metabolism in cancer patients. Methods: The experiment subjects consisted of patients with lung cancer, head and neck tumor, stomach cancer, intestinal cancer, breast cancer and healthy individuals. A total of 240 tumor patients and 39 healthy individuals were included. All subjects were evaluated by the Hamilton depression scale (HAMD) and Manifest anxiety scale (MAS), and were examined by whole body Positron Emission Tomography/Computed Tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG). Demographic, baseline clinical characteristics, brain glucose metabolic changes, emotional disorder scores and their relations were statistically analyzed. Results: The incidence rates of depression and anxiety in patients with lung cancer were higher than those in patients with other tumors, and Standard uptake values (SUVs) and metabolic volume in bilateral frontal lobe, bilateral temporal lobe, bilateral caudate nucleus, bilateral hippocampus, left cingulate gyrus were lower than those in patients with other tumors. We also found that poor pathological differentiation, and advanced TNM stage independently associated with depression and anxiety risk. SUVs in the bilateral frontal lobe, bilateral temporal lobe, bilateral caudate nucleus, bilateral hippocampus, left cingulate gyrus were negatively correlated with HAMD and MAS scores. Conclusion: This study revealed the correlation between brain glucose metabolism and emotional disorders in cancer patients. The changes in brain glucose metabolism were expected to play a major role in emotional disorders in cancer patients as psychobiological markers. These findings indicated that functional imaging can be applied for psychological assessment of cancer patients as an innovative method.

Mesenchymal stem cell transplantation alleviates Sjögren's syndrome symptoms by modulating Tim-3 expression.

Mesenchymal stem cell (MSC) transplantation has been proven to be an effective treatment for Sjögren's syndrome (SS) to improve salivary gland pathology and exocrine function, but the mechanism remains unclear. A recently reported inhibitory receptor, Tim-3, also appears to be closely related to autoimmune diseases. Here, we aimed to explore the roles of Tim-3 in the pathogenesis of SS and MSC treatment. The results showed that Tim-3 was downregulated in T cells of SS patients and nonobese diabetic (NOD) mice, which is correlated with SS pathogenesis. MSC transplantation ameliorated SS-like symptoms and pathological changes in the submandibular glands with modulated Tim-3 expression, resulting in attenuation of localized inflammation, fibrosis, and epithelial-mesenchymal transition. Furthermore, Tim-3 is crucial for the inhibitory effect of MSCs on PBMC proliferation in vitro. Therefore, our work has demonstrated that MSC transplantation effectively mitigates the pathological changes of SS by regulating Tim-3 expression, which provides a novel mechanism of MSC treatment and indicates a brand-new perspective of the combination of inhibitory-receptor-targeted treatment and MSC therapy in SS.

Celastrol ameliorates osteoarthritis via regulating TLR2/NF-κB signaling pathway.

Objectives: Osteoarthritis (OA) is a joint disease characterized by degeneration of joint cartilage and is a significant cause of severe joint pain, physical disability, and impaired quality of life in the aging population. Celastrol, a Chinese herbal medicine, has attracted wide interests because of its anti-inflammatory effects on a variety of diseases. This study aimed to investigate the effect of celastrol on OA as well as the mechanisms in vivo and in vitro. Methods: A rat knee OA model was established using "medial collateral ligament transection (MCLT) + partial meniscectomy (pMMT)". Eight weeks after surgery, the OA rats started to receive intra-articular injection of celastrol (1 mg/kg) once a week. Safranin O-fast green (S&F) and hematoxylin and eosin (H&E) staining were used to estimate histopathological changes. Micro-CT was used to evaluate bone volume of the subchondral bone of the knee joint. Chondrocytes were isolated from the knee cartilage of rats and OA patients. Enzyme linked immunosorbent assay (ELISA), Western Blot (WB), Polymerase Chain Reaction (PCR), and Immunohistochemistry (IHC) were used to detect the expression of inflammatory factors and stromal proteins, respectively. Results: We found that celastrol treatment significantly delayed the progression of cartilage damage with a significant reduction in osteophyte formation and bone resorption in OA rat model. In IL-1ß-stimulated rat chondrocytes, celastrol significantly suppressed the production of inflammatory factors such as cyclooxygenase-2 (COX2), interleukin-6 (IL-6), and prostaglandin E2 (PEG2), and reduced IL-1ß-induced matrix degradation by down-regulating the expression of matrix metalloproteinase 13 (MMP13). In addition, we found that toll-like receptor 2 (TLR2) was up-regulated in OA patients and rat knee OA models, while celastrol inhibited TLR2 signal and its downstream nuclear factor-kappa B (NF-κB) phosphorylation. Conclusion: In summary, celastrol may improve OA by inhibiting the TLR2/NF-κB signaling pathway, which provides innovative strategies for the treatment of OA.

Elevated soluble CD163 predicts renal function deterioration in lupus nephritis: a cohort study in Eastern China.

OBJECTIVE: This study investigated the association between soluble scavenger receptor differentiation antigen 163 (sCD163) and the severity and prognosis of renal injury in lupus nephritis (LN). METHODS: Serum sCD163 levels in 121 Eastern Chinese patients with LN who underwent renal biopsy were determined by enzyme-linked immunosorbent assays. Clinical data were collected, and the glomerular filtration rate and disease activity score of lupus were calculated. Pathological classification was performed, and renal pathological scores were assessed by the activity index (AI) and chronic index (CI). Kaplan-Meier survival curves were drawn to evaluate prognosis. RESULTS: The pathological classification, AI and CI scores in the high sCD163 group were increased. The sCD163 levels were positively correlated with serum creatinine, blood urea nitrogen, AI scores and CI scores and negatively correlated with the estimated glomerular filtration rate. Kaplan-Meier survival analysis showed that the incidence of renal endpoint events was increased in the high sCD163 group compared with the normal sCD163 group. CONCLUSION: The serum sCD163 level correlates with the severity of LN and is an important indicator of poor renal prognosis in patients with LN.

Activation of COL11A1 by PRRX1 promotes tumor progression and radioresistance in ovarian cancer.

PURPOSE: Although radiotherapy is a common treatment option for all kinds of cancer patients, including ovarian cancer, a major obstacle limiting its application in the development of resistance. Therefore, it is urgently needed to clarify the mechanism of radiosensitivity modulation. MATERIALS AND METHODS: We obtained open datasets and analyzed the expression of collagen type XI alpha 1 (COL11A1) in ovarian cancer patients with different stages. Meanwhile, the correlation of COL11A1 and survival outcomes is determined by Kaplan-Meier analysis. The role of COL11A1 in cell proliferation was observed in an in vitro knockdown system. SKOV3 radioresistant cells were established to determine the role of COL11A1 on radioresistant in ovarian cancer. RESULTS AND DISCUSSION: COL11A1 were highly enriched in late-stage ovarian cancer tumor tissues and negatively correlated with survival outcomes in ovarian cancer. The functional analysis found that COL11A1 promoted ovarian cancer cell proliferation in vitro. Importantly, COL11A1 decreased radiosensitivity in ovarian cancer by AKT activation. Paired related homeobox 1 (PRRX1) acted as an upstream transcription factor to regulate COL11A1 expression in ovarian cancer. Increased COL11A1 expression is related to low survival outcomes and radiosensitivity in ovarian cancer. CONCLUSIONS: Targeting COL11A1 is a promising strategy for improving radiotherapy efficiency.

Bufotalin ameliorates experimental Sjögren's syndrome development by inhibiting Th17 generation.

Chronic inflammatory autoimmune disease Sjögren's syndrome (SS) is characterized by the reduced secretion of exocrine glands, suggesting strategies targeting inflammation to be a potential option for SS therapy. Bufotalin, an active constituent of Bufadienolides, exerts potent antitumor effects with unknown effects on autoimmune diseases including SS. This study aims to investigate whether bufotalin possesses therapeutic potentials to SS and the underlying mechanisms. The experimental Sjögren's syndrome (ESS) murine model was constructed by SG-immunization and murine naïve CD4+ T cells were cultured under Th17 polarization conditions with or without low doses of bufotalin treatment. Saliva flow rate was measured, and flow cytometry was applied to analyze T cell subpopulations. ELISA was conducted to determine the levels of targeted inflammatory cytokines. Bufotalin-treated ESS mice showed higher saliva flow rates, lower serum levels of autoantibodies (anti-M3R and anti-SSA IgG), lower serum levels of pro-inflammatory cytokines, as well as lower Th17 cell population from spleens and cervical lymph nodes. Additionally, in vitro study showed that bufotalin inhibits Th17 polarization and secretion of cytokines IL-17 and IFN-γ. Bufotalin at a low dose significantly ameliorates ESS development, possibly via inhibiting pro-inflammatory Th17 population and secretion of inflammatory cytokines during ESS pathogenesis.

Mir-23a inhibition attenuates ischemic/reperfusion-induced myocardial apoptosis by targeting XIAP.

MicroRNAs are a group of single-strand, non-coding RNAs that inhibit the translation of protein-coding genes. Recent studies indicated that miRNAs are broadly involved in the development of cardiovascular diseases, including arrhythmia, hypertrophy, heart failure and cardiac injury. In this study, we report that miR-23a, a tumor suppressor, acts as an apoptotic promoter in rats undergoing ischemic/reperfusion. In rats subjected to ischemic/reperfusion injury, the expression of miR-23a in heart tissue was upregulated significantly. The infarct area and the apoptosis rate also increased. In contrast, knockdown of miR-23a by tail injection of antagomir-23a attenuated the ischemic/reperfusion injury. Moreover, we used Western blots to determine that miR-23a targeted XIAP to influence the expression of caspase and the NFkB pathway. In summary, miR-23a was shown to be part of a novel regulatory pathway that contributed to ischemic/reperfusion injury.

MiR-98 inhibits cell proliferation and invasion of non-small cell carcinoma lung cancer by targeting PAK1.

A family of small non-coding RNAs, ~22 nt in length, known as microRNAs (miRNAs), regulating ~30% of all human gene expression, have been reported to be involved in the pathogenesis of a number of types of cancers, including non-small cell carcinoma lung cancer (NSCLC). P21-activated protein kinase 1 (PAK1) is a clinical biomarker of Non-small carcinoma lung cancer. Here, we found that miR-98 is down-regulated, whereas PAK1 is highly expressed in NSCLC tissues and cells. We demonstrated that miR-98 directly targets the 3'UTR of PAK1 and down-regulates its expression at the mRNA and protein level. Also, miR-98 inhibited and PAK1 stimulated proliferation, migration, invasion and apoptosis of NSCLC cells. In agreement, PAK1 over-expression counteracted the inhibitory effect of miR-98. This current study suggests that exogenous miR-98 may serve as novel potential maker for NSCLC therapy.

A maladaptive role for EP4 receptors in mouse mesangial cells.

Roles of the prostaglandin E2 E-prostanoid 4 receptor (EP4) on extracellular matrix (ECM) accumulation induced by TGF-ß1 in mouse glomerular mesangial cells (GMCs) remain unknown. Previously, we have identified that TGF-ß1 stimulates the expression of FN and Col I in mouse GMCs. Here we asked whether stimulation of EP4 receptors would exacerbate renal fibrosis associated with enhanced glomerular ECM accumulation. We generated EP4(Flox/Flox) and EP4(+/-) mice, cultured primary WT, EP4(Flox/Flox) and EP4(+/-) GMCs, AD-EP4 transfected WT GMCs (EP4 overexpression) and AD-Cre transfected EP4(Flox/Flox) GMCs (EP4 deleted). We found that TGF-ß1-induced cAMP and PGE2 synthesis decreased in EP4 deleted GMCs and increased in EP4 overexpressed GMCs. Elevated EP4 expression in GMCs augmented the coupling of TGF-ß1 to FN, Col I expression and COX2/PGE2 signaling, while TGF-ß1 induced FN, Col I expression and COX2/PGE2 signaling were down-regulated in EP4 deficiency GMCs. 8 weeks after 5/6 nephrectomy (Nx), WT and EP4(+/-) mice exhibited markedly increased accumulation of ECM compared with sham-operated controls. Albuminuria, blood urea nitrogen and creatinine (BUN and Cr) concentrations were significantly increased in WT mice as compared to those of EP4(+/-) mice. Urine osmotic pressure was dramatically decreased after 5/6 Nx surgery in WT mice as compared to EP4(+/-) mice. The pathological changes in kidney of EP4(+/-) mice was markedly alleviated compared with WT mice. Immunohistochemical analysis showed significant reductions of Col I and FN in the kidney of EP4(+/-) mice compared with WT mice. Collectively, this investigation established EP4 as a potent mediator of the pro-TGF-ß1 activities elicited by COX2/PGE2 in mice GMCs. Our findings suggested that prostaglandin E2, acting via EP4 receptors contributed to accumulation of ECM in GMCs and promoted renal fibrosis.