Correlation of expression of silencing information regulator 2 related enzyme 1 and tumor necrosis factor-like weak inducer of apoptosis in articular effusion and knee osteoarthritis / 中国骨伤

OBJECTIVE@#To analyze the correlation between the expression of silencing information regulator 2 related enzyme 1 (SIRT1), tumor necrosis factor like weak inducer of apoptosis (TWEAK) and knee osteoarthritis.@*METHODS@#Total of 103 patients with knee joint (knee osteoarthritis group) from February 2019 to August 2021 were selected including 40 males and 63 females with an average age of (62.02±6.09) years;according to the modified Mankin score, 103 patients were divided into mild group (Mankin score 1-4 points, 31 cases) and moderate group (Mankin score 5-8 points, 40 cases) and severe group (Mankin score ≥9, 32 cases). Another 105 physical examination volunteers were selected as the control group including 46 males and 59 females with an average age of (62.11±6.34) years old. The levels of SIRT1 and TWEAK in articular effusion and serum were detected in the knee osteoarthritis group, while serum SIRT1 and TWEAK were detected in the control group only. The relationship between SIRT1, TWEAK and the occurrence and disease of knee osteoarthritis were analyzed.@*RESULTS@#Articular cavity fluid TWEAK, serum TWEAK, CRP, IL-6, IL-1β, white blood cell count and ESR were higher than those in the control group(P<0.05), articular cavity fluid SIRT1 and serum SIRT1 were lower than those in the control group(P<0.05). TWEAK level in the severe group was higher than that in the moderate and mild groups(P<0.05), SIRT1 was lower than that in the moderate and mild groups (P<0.05). The level of SIRT1 in articular cavity effusion was positively correlated with the serum level of SIRT1 (P<0.05), and negatively correlated with CRP, IL-6, IL-1β, white blood cell count, modified Mankin score and ESR (P<0.05). TWEAK level in articular cavity fluid was positively correlated with serum TWEAK level (P<0.05), C-reactive protein(CRP), interleukin(IL)-6, IL-1β, white blood cell count, modified Mankin score and erythrocyte sedimentation rate(ESR) (P<0.05). Body mass index, undertaking heavy physical work, and articular cavity fluid TWEAK were risk factors for the occurrence of knee osteoarthritis(P<0.05), and articular cavity fluid SIRT1 was a protective factor for the occurrence of knee arthritis (P<0.05). The area under curve(AUC) of SIRT1 and TWEAK for knee osteoarthritis was 0.641 and 0.653, and the AUC of SIRT1 and TWEAK for knee osteoarthritis was 0.879, which was higher than SIRT1 and TWEAK alone (z=6.105 and 6.225, P<0.05).@*CONCLUSION@#The level of SIRT1 in articular fluid in patients with knee arthritis is decreased and the level of TWEAK is increased. Low SIRT1 and high TWEAK are associated with the onset and exacerbation of knee osteoarthritis.

Serum tumor necrosis factor-like weak inducer of apoptosis levels are elevated in schizophrenia

Objective: The purpose of this study was to assess serum Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) concentrations to determine whether changes in patients with schizophrenia could have etiopathogenetic importance. Since very little research has addressed the connection between the inflammatory marker TWEAK and schizophrenia, we wanted to examine alterations of TWEAK and investigate the possible correlation between clinical symptomatology and serum concentrations. Methods: A total of 45 schizophrenia patients and 40 healthy controls were included in this study. The Positive Symptom Assessment scale and the Negative Symptom Assessment scale were administered to determine symptom severity. Venous blood samples were collected and serum TWEAK levels were measured. Results: Serum TWEAK levels were significantly higher in the schizophrenia group than the control group, independently of potential confounders, including sex, age, body mass index and smoking status. Conclusion: The results indicate that TWEAK is elevated in schizophrenia patients, which could deepen our understanding of the role of inflammation in the pathogenesis of schizophrenia.

GLGZD improves cerebral ischemia-reperfusion injury in rats by inhibiting microglial activation / 中国药理学通报

Aim To study whether GLGZD exerts brain protection by affecting the activation of cortical microglia in cerebral ischemia-reperfusion rats. Methods The nylon thread plug was used to establish the MCAO model. After GLGZD treatment for seven days, mNSS was used to evaluate the neurological function of each group of rats, MRI to detect cerebral infarction volume in rats, TUNEL to detect the apoptotic rate of nerve cells, immunohistochemistry to detect TNF-α protein expression in ischemic cortical brain tissues, and RT-qPCR to detect mRNA expression of neuron-microglia interaction-related factors TWEAK, Fnl4, NIK, Rel B, CCL21, CXCR3 and microglial activation marker IBA-1 in ischemic cortical brain tissues. Results GL-GZD could significantly improve the neurological function of MCAO rats, and markedly reduce the infarct volume and apoptosis of ischemic cortical neurons in MCAO rats. It also could significantly down-regulate the expressions of TNF-a protein and TWEAK, Fnl4, NIK, Rel B, CCL21, CXCR3 and IBA-1 mRNA in ischemic cortex of MCAO rats. Conclusions GLGZD can significantly improve cerebral ischemia-reperfusion injury in rats, which may be related to inhibition of microglial cell activation by affecting TWEAK/Fn14/ CCL21/CXCR3 signaling pathway.

Effects of cryptotanshinone on airway inflammation models in asthmatic mice through tweak/fnl4 and tgf-pl/smads signaling pathways / 中国药理学通报

Aim To explore the therapeutic effect of cryptotanshinone(CTS) on airway remodeling model of asthmatic mice, and the relationship between its mechanism and the TWEAK/Fn14 and TGF-β1/Smads signaling pathway. Methods Forty female BALB/c mice were used for our study, eight mice as a group, and were assigned into five groups, namely, control group, OVA model group, CTS treatment group (20, 40 mg·kg-1), and Dex positive control group (1 mg·kg-1). HE and PAS staining were used to observe lung histopathological changes in mice; Diff-Quick staining was employed to count the types of cells; ELISA was used to detect the contents of proinflammatory cytokines in BALF; Western blot was applied to analyze the contents of TWEAK, Fn14, TGF-β1, Smad2/3, Smad4 in lung tissues; immunohistochemical method was used to detect the expression levels of TWEAK and TGF-β1 in lung tissues. Results CTS reduced the exudation of inflammatory cells and proliferation of goblet cells; CTS inhibited the generation of EOS, NEU, LYM and the total cells; CTS could reduce the level of proinflammatory cytokines of airway inflammation; the results of Western blot showed that CTS inhibited the protein expression of TWEAK, Fn14, TGF-β1, Smad2/3 and Smad4; immunohistochemical results indicated that CTS increased the expression of TWEAK and TGF-β1 in lung tissues. Conclusions CTS has therapeutic effect on the OVA-induced airway inflammation mouse model through TWEAK/Fn14 and TGF-β1/Smads signaling pathways.

Mechanism of TWEAK promoting macrophage-derived exosomal miR-7 to epithelial ovarian cancer cell through regulating Dicer / 上海交通大学学报（医学版）

Objective • To investigate the mechanism of tumor necrosis factor like weak inducer of apoptosis (TWEAK) promoting macrophagederived exosomal miR-7 to epithelial ovarian cancer (EOC). Methods • The expression of Dicer was detected by real-time PCR and Western blotting in TWEAK-stimulated macrophages. The expression of miR-7 was detected by real-time PCR in the macrophage and macrophage-derived exosome after silencing Dicer in macrophage. While in Dicer-overexpressing macrophage, real-time PCR was used to detect the expression of miR-7. Then TWEAK was used to stimulate the macrophage, and the expression of miR-7 in the macrophage and macrophage-derived exosome was detected by real-time PCR. The expression of key proteins in the nuclear factor-κB (NF-κB) pathway was detected by Western blotting in TWEAK-stimulated macrophage. After pretreatment of NF-κB inhibitor, Western blotting was used to detect the expression of Dicer and key proteins in the NF-κB pathway in TWEAKstimulated macrophage. Results • The expression of Dicer in macrophage was down-regulated after TWEAK stimulating. The expression of miR-7 was up-regulated in Dicer-silencing macrophage and macrophage-derived exosome. While the expression of miR-7 was down-regulated in the macrophage and the macrophage-derived exosome in Dicer-overexpressing macrophage after TWEAK stimulating. The expression of key proteins in the NF-κB pathway in macrophage was also up-regulated after TWEAK stimulating. After inhibition of NF-κB signaling pathway, the expression of Dicer was not significantly changed in TWEAK-stimulated macrophage compared to the control group. Conclusion • TWEAK can active NF-κB pathway and inhibit the expression of Dicer to promote macrophage-derived exosomal miR-7 to EOC cells.

Urinary Tumor Necrosis Factor-like Weak Inducer of Apoptosis as a Biomarker for Lupus Nephritis: A Meta-analysis

OBJECTIVE: This study evaluates serum or urinary tumor necrosis factor-like weak inducer of apoptosis (TWEAK) as a biomarker for lupus nephritis (LN). METHODS: We conducted a meta-analysis examining serum or urinary TWEAK levels in patients with systemic lupus erythematosus (SLE), patients with LN (active or inactive), and healthy controls. We tabulated correlation coefficients between urinary TWEAK level and total or renal SLE Disease Activity Index (tSLEDAI or rSLEDAI). RESULTS: Eight studies were included in this meta-analysis. The meta-analysis revealed that serum TWEAK levels tended to be higher in patients with SLE than in controls (standard mean difference [SMD]=0.850, 95% confidence interval [CI]=−0.067∼1.767, p=0.069). Urinary TWEAK was significantly higher in patients with active LN than in those with inactive LN (SMD=2.865, 95% CI= −0.831∼4.898, p=0.006). In addition, urinary TWEAK was positively associated with tSLEDAI and rSLEDAI (correlation coefficient= 0.436, 95% CI=0.204∼0.622, p=4.3×10⁻⁴; correlation coefficient=0.483, 95% CI=0.108∼0.738, p=0.014). Pooled sensitivity and specificity of urinary TWEAK for diagnosis of LN were 81.3% (95% CI, 73.3∼87.8) and 76.0% (95% CI, 66.3∼84.2), indicating good diagnostic accuracy. CONCLUSION: The meta-analysis demonstrated that urinary TWEAK was significantly higher in patients with active LN than in those with inactive LN, and that urinary TWEAK levels were positively correlated with renal disease activity.

Exosomal miRNA-7 from TWEAK-stimulated macrophages inhibiting the invasion and migration of ovarian cancer cells / 上海交通大学学报（医学版）

Objective · To determine the expression of miRNA-7 in TWEAK-stimulated macrophages and their secreted exosomes;to investigate the role of exosomal miRNA-7 from TWEAK-stimulated macrophages in modulating the metastasis of epithelial ovarian cancer (EOC) cells.Methods · Real-time PCR analysis was used to determine the miRNA-7 expression in TWEAK-stimulated macrophages,their exosomes and recipient HO8910-PM cells.The activity of EGFR signaling pathway in HO8910-PM cells was detected by Western blotting analysis.AntagomiR-7 was used to downregulate the miRNA-7expressions in macrophage exosomes and then their effect on metastasis of HO8910-PM cells was examined by transwell assay.Results ·TWEAK increased the levels of miRNA-7 in macrophages and their secreted exosomes and also resulted in an elevated level of miRNA-7 in recipient HO8910-PM cells,which eventually reduced the activity of EGFR/AKT/ERK1/2 pathway.Pre-transfection of antagomiR-7 remarkably decreased the levels of miRNA-7 in macrophages,their secreted exosomes and the recipient EOC cells,with the enhancement of HO8910-PM metastasis.Conclusion · Exosomal miRNA-7 from TWEAK-stimulated macrophages plays a critical role in suppressing the metastasis of EOC cells by attenuation of EGFR signaling pathway.

Plasma Levels of Tumor Necrosis Factor Superfamily Molecules Are Increased in Bipolar Disorder

OBJECTIVE: Patients with bipolar disorder (BD) exhibit peripheral low-grade inflammation. The aim of the current study was to investigate the involvement of hitherto unexplored components of the tumor necrosis factor (TNF) superfamily in BD. METHODS: Eighty patients with type I BD and 50 healthy controls matched for age and gender were enrolled in this study. All subjects were assessed with the Mini-Plus to evaluate psychiatric comorbidities; the Young Mania Rating Scale and the Hamilton Depression Rating Scale to evaluate manic and depressive symptoms severity, respectively. TNF superfamily molecules (TNF, TNF-related weak inducer of apoptosis [TWEAK], TNF-related apoptosis-inducing ligand [TRAIL], soluble TNF receptor type 1 [sTNFR1], and soluble TNF receptor type 2 [sTNFR2]) levels were measured by ELISA. RESULTS: Patients with BD, regardless of mood state, presented increased plasma levels of sTNFR1 and TWEAK in comparison with controls. CONCLUSION: These findings corroborate the view that TNF superfamily may play a role in BD pathophysiology.

Relationship of Traditional Chinese Medical Syndromes of Type 2 Diabetic Nephropathy with Inflammatory Factors / 广州中医药大学学报

Objective To explore the relationship between traditional Chinese medicine(TCM) syndrome types of diabetic nephropathy(DN) patients and inflammatory factors, thus to supply evidence for syndrome differentiation, clinical treatment, illness evaluation and prognosis of DN patients. Methods The study was carried out in 120 cases of DN patients, and the patients were differentiated into TCM syndromes according to the clinical manifestations. Blood and urine samples were detected with enzyme-linked immunosorbent assay (ELISA). The correlation of syndrome types with blood and urine tumour necrosis factor-like weak inducer of apoptosis (TWEAK), interleukin-1β(IL-1β) and IL-10 was analyzed, and the detection results were compared to 30 healthy volunteers. Results (1) Compared with the healthy control, abnormal blood and urine TWEAK content and abnormal blood IL-1β were shown in DN patients at the stages of non-albuminuria, small-amount albuminuria, large-amount albuminuria, and renal insufficiency(P<0.05); blood IL-10 content was increased in DN patients without albuminuria(P<0.05).(2) DN patients with yin-deficiency and dryness-heat had higher blood and urine TWEAK contents than DN patients with other syndrome types (P<0.05). The blood TWEAK content was in decreasing sequence in the syndrome types of yin-deficiency and dryness-heat, Qi-yin deficiency, spleen-kidney Qi deficiency, yin-yang deficiency; the urine TWEAK content was in decreasing sequence in the syndrome types of yin-deficiency and dryness-heat, Qi-yin deficiency, spleen-kidney Qi deficiency, yin-yang deficiency(P<0.05). DN patients with damp-heat syndrome had the highest blood IL-1βcontent (P < 0.05), and yin-deficiency and dryness-heat had the lowest IL-1β content (P < 0.05). DN patients with yin-deficiency and dryness-heat had higher blood IL-10 content (P<0.05), and the blood IL-10 content was in decreasing sequence in the syndrome types of yin-deficiency and dryness-heat, Qi-yin deficiency, spleen-kidney Qi deficiency, yin-yang deficiency. Conclusion TCM syndrome types of DN patients are correlated with TWEAK, IL-1β and IL-10, and the results will supply evidence for syndrome differentiation, clinical treatment, illness evaluation and prognosis of DN patients .

Research progress in TWEAK and its receptor functions in cardiovascular diseases / 军事医学

Tumor necrosis factor-like weak inducer of apoptosis ( TWEAK ) is a member of the superfamily .TWEAK binds to its receptor [ fibroblast growth factor-inducible 14 ( Fnl4 ) and the serum level of soluble CD 163 ( sCD163 ) ] and regulates many cellular activities via associated signal pathways ,including proliferation,migration,differentiation,apoptosis, angiogenesis and inflammation ,which play a significant role in the formation and development of cardiovascular diseases , such as atherosclerosis , heart failure , cardiomyopathy , and peripheral vascular disease .This review summarizes functions of TWEAK and its receptor in cardiovascular diseases .

Association of serum and urine TWEAK with lupus nephritis activity and its underlying mechanism / 安徽医科大学学报

Objective To discuss the expression of tumor necrosis factor-like weak inducer of apoptosis ( TWEAK) in serum, urine and renal tissue in lupus nephritis( LN) . Methods The serum and urine levels of TWEAK were assessed by ELISA in LN patients and normal controls. Immunohistochemistry was used to detect the expressions of TWEAK in the kidney of patients and healthy controls. Results The serum and urine concentrations of TWEAK and MCP-1 were significantly higher in LN patients than those in healthy controls(P<0. 01). In addition,the level of serum TWEAK showed positive correlation with SLEDAI and negative correlation with serum C3 level ( P <0. 01),the expression of urine TWEAK showed positive correlation with SLEDAI (P<0. 05). In healthy renal tis-sues TWEAK was distributed mainly in renal tubules and rarely seen in glomerular while the expressions of TWEAK increased in renal tubular and glomeruli stainings were found in LN paitients. TWEAK could induce increased mac-rophage migration, may be involved in the pathological progression of lupus nephritis. Conclusion TWEAK may play key roles in the pathogenesis of LN. Meanwhile, TWEAK in serum and urine may be useful as markers of dis-ease activity. The change of TWEAK maybe associated with the pathology category of LN.

Mechanism Study on Nano-Realgar Intervention of TWEAK-NF-κB Signal Pathway through Downregulation of Chemokines in Kidney Expression among MRL/lpr Mice / 世界科学技术-中医药现代化

This study was aimed to explore the molecular mechanism of nano-realgar in treatment of systematic lupus erythematosus (SLE) lupus nephritis (LN). Intragastric administration of equal volume of high-, middle-, low-dose nano-realgar suspension, and normal saline (NS) were given to MRL/lpr mice, respectively. The observations were made on levels of ANA, ds-DNA antibody, IgG and IgM in blood serum, as well as TWEAK, NF-κB, MCP-1 mRNA and protein expression levels in renal tissues. The results showed that compared with the NS group, levels of ANA, ds-DNA antibody, IgG and IgM were obviously reduced (P < 0.05); the levels of TWEAK, NF-κB and MCP-1 mRNA were obviously reduced (P < 0.05); the protein expression levels of TWEAK, NF-κB and MCP-1 mRNA were obviously reduced (P < 0.05) in the high-, middle-, low-dose nano-realgar group. It was concluded that nano-realgar intervened the TWEAK-NF-κB signal pathway through downregulating MCP-1 expression among MRL/lpr mice, in order to reduce the levels of ANA, ds-DNA antibody, IgG and IgM for relieving autoimmune damages in the treatment of SLE (LN).

The Effects of TWEAK, Fn14, and TGF-beta1 on Degeneration of Human Intervertebral Disc

OBJECTIVE: The purpose of this study is to explain the effect and reciprocal action among tumor necrosis factor (TNF) like weak inducer of apoptosis (TWEAK), fibroblast growth factor-inducible 14 (Fn14), and transforming growth factor-beta1 (TGF-beta1) on degeneration of human intervertebral disc (IVD). METHODS: Human intervertebral disc tissues and cells were cultured with Dulbecco's Modified Eagle's Medium/Nutrient F-12 Ham (DMEM/F-12) media in 37degrees C, 5% CO2 incubator. When IVD tissues were cultured with TWEAK, Fn14 that is an antagonistic receptor for TWEAK and TGF-beta1, the level of sulfated glycosaminoglycan (sGAG) was estimated by dimethyl methyleneblue (DMMB) assay and sex determining region Y (SRY)-box 9 (Sox9) and versican messenger ribonucleic acid (mRNA) levels were estimated by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: When human IVD tissue was cultured for nine days, the sGAG content was elevated in proportion to culture duration. The sGAG was decreased significantly by TWEAK 100 ng/mL, however, Fn14 500 ng/mL did not change the sGAG production of IVD tissue. The Fn14 increased versican and Sox9 mRNA levels decreased with TWEAK in IVD tissue TGF-beta1 20 ng/mL elevated the sGAG concentration 40% more than control. The sGAG amount decreased with TWEAK was increased with Fn14 or TGF-beta1 but the result was insignificant statistically. TGF-beta1 increased the Sox9 mRNA expression to 180% compared to control group in IVD tissue. Sox9 and versican mRNA levels decreased by TWEAK were increased with TGF-beta1 in primary cultured IVD cells, however, Fn14 did not show increasing effect on Sox9 and versican. CONCLUSION: This study suggests that TWEAK would act a role in intervertebral disc degeneration through decreasing sGAG and the mRNA level of versican and Sox9.

Mechanism of TWEAK on the synthesis of MMP-9 in fibroblast-like synoviocytes of rheumatoid arthritis / 中华微生物学和免疫学杂志

Objective To discuss the role of p38MAPK signal pathway in the process of TWEAK inducing rheumatoid arthritis(RA) fibroblast-like synoviocyte(FLS) to synthesize MMP-9 and look for a new target for RA treatment. Methods RA FLS were primarily cultured and stimulated with TWEAK. Western blot was used to detect the expression of p-p38MAPK and p65 in RA FLS. FLS were pretreated by SB203580 or not. ELISA was used to detect the concentration of MMP-9 in cell-cultured fluid. The mRNA expression of MMP-9 was measured by RT-PCR. Results TWEAK( 100 ng/ml) can make p38MAPK phosphorylated and increased the expression of p65 protein in the cell nucleus. SB203580 can partially inhibit the expression of MMP-9 and MMP-9 mRNA produced by RA FLS which is induced by TWEAK. Conclusion TWEAK induced RA FLS to synthesize MMP-9, in that process, the p38MAPK signal trausduction pathway was in active state, and induced the expression of NF-κB.

TNEAK-Fn14 Pathway and Central Nervous System / 国际脑血管病杂志

Tumor necrosis factor-like weak inducer of apoptosis(TWEAK)is a new member of the tumor necrosis factor family.After TWEAK binding to its receptor Fn14.it induces extensive biological activities.TWEAK-Fn14 pathway participates in pathophysiological mechanisms of cell apoptosis,regulation of the blood-brain barrier permeability and inflammation in central nervous system,and it is closely correlated with the diseases such as ischernic stroke.multiple sclerosis and gliocytoma.