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Background: Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1G93A ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1G93A ALS mice could lead to differential and potentially improved benefits. Methods: We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1G93A ALS mice. To do so, Fn14 knockout mice (Fn14−/−) were crossed onto the SOD1G93A background to generate SOD1G93A;Fn14−/− mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14−/−, SOD1G93A and SOD1G93A;Fn14−/−). Results: Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1G93A mice. We then show that Fn14-depleted SOD1G93A mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function. Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size. Conclusions: Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and sirtuin1 (SIRT1) and the severity of condition and prognosis of patients with hyperlipidemic acute pancreatitis (HLAP), in order to provide reference basis for evaluating the condition and improving prognosis of HLAP patients. Methods: 167 HLAP patients admitted to the intensive care unit (ICU) of Ziyang First People's Hospital from November 2021 to May 2023 were selected as HLAP group, and 88 healthy volunteers during the same period were selected as control group. HLAP patients were divided into mild HLAP group (n = 66), moderate severe HLAP group (n = 58) and severe HLAP group (n = 43) according to the severity of the disease. According to the in-hospital outcome, HLAP patients were divided into death group (n = 36) and survival group (n = 131) Serum TWEAK and SIRT1 levels were detected by enzyme-linked immunosorbent assay. Factors affecting the prognosis of HLAP patients was analyzed by multivariate logistic regression analysis, and the value of serum TWEAK and SIRT1 levels in predicting the death of HLAP patients was analyzed by the receiver operating characteristic (ROC) curve. Results: Compared with control group, the serum TWEAK level was increased and the SIRT1 level was decreased in HLAP group (P < 0.05) The levels of serum TWEAK in mild HLAP group, moderate severe HLAP group and severe HLAP group increased in turn, and the levels of SIRTI decreased in turn (P < 0.05) Independent risk factors affecting the prognosis of patients with HLAP were severe HLAP, prolonged ICU stay and CRP, TWEAK were elevated, and the independent protective factor was the elevation of SIRT1(P<0.05). The area under the curve (AUC) of serum TWEAK and SIRT1 levels combined ( AUC = 0.9, 95% CI: 0.844 to 0.941) predicted death in patients with HLAP was greater than that predicted by serum TWEAK (AUC=0.786, 95% CI: 0.716 to 0.846) and SIRT1 (AUC=0.794, 95% CI: 0.724 to 0.852) levels alone predicted (P＜0.05). Conclusion: The level of serum TWEAK in HLAP patients is increase, and the level of SIRT1 is decrease, which is closely relate to the severity and prognosis of the disease. The combination of serum TWEAK and SIRT1 levels has a high value in predicting the prognosis of HLAP patients. [ABSTRACT FROM AUTHOR]

Objective: Osteoclast (OC) over-activation is an important cause of bone loss that is strongly correlated with inflammation. Although the CD163/TWEAK/Fn14 axis has been implicated in several inflammatory pathologies, its contributions to inflammatory bone loss remain poorly understood. This study aimed to evaluate the interaction of the CD163/TWEAK/Fn14 axis with OC in inflammatory bone loss. Methods: To assess the role of CD163 in bone homeostasis, we characterized the bone phenotypes of CD163-deficient mice and their wild-type littermates. CD163 and TWEAK levels were evaluated in the bone marrow of mice with LPS-induced bone loss and individuals with rheumatoid arthritis (RA). Bone mass changes were assessed using uCT and histology following supplementation with recombinant mouse CD163 protein (rCD163) or blockade of TWEAK/Fn14 signaling in CD163-deficient mice and mice with LPS-induced bone loss. The impact of CD163/TWEAK on OC differentiation and bone resorption capacity was analyzed in vitro. Results: CD163 deficiency caused decreased bone mass and increased OC abundance. Lower CD163 expression and higher TWEAK expression were observed in the bone marrow of mice with LPS-induced bone loss and individuals with RA. TWEAK, mainly derived from CD68+ macrophages, was responsible for bone loss, and supplementing rCD163 or blocking TWEAK/Fn14 signaling contributed to rescue bone loss. TWEAK/Fn14 synergistically promoted RANKL-dependent OC differentiation and bone resorption capability through downstream mitogen-activated protein kinases (MAPK) signaling, while the pro-osteoclastic effect of TWEAK was suppressed by CD163. Conclusion: Our findings suggest that the CD163/TWEAK/Fn14 axis is a potential therapeutic target for inflammatory bone loss by regulating osteoclastogenesis.

Background: Psoriasis is an autoimmune disease which has an effect on the joints and skin. Tumor Necrosis Factor‐Like Weak Inducer of Apoptosis (TWEAK) is a multi‐functional cytokine which regulates the cellular processes and has been related to a variation of conditions. Objectives: To measure the level of serum TWEAK in psoriatic diseased persons and its relationship to the PASI score pre‐ and post‐therapy with narrowband ultraviolet B phototherapy (NB‐UVB) and methotrexate (MTX). Methods: This randomized controlled trial was conducted on 40 patients and 20 healthy persons as controls. Patient Group was randomly subdivided to two groups. The 1st group consisted of 20 patients who received NB‐UVB treatment. The 2nd group included 20 MTX‐treated candidates. Blood samples were drawn from patients in order to detect serum TWEAK levels using ELISA. The research was registered on Clinical Trials Registration: RCT approval numbers: NCT0481191. Results: The mean PASI score percent improvement after 12 weeks of treatment was higher in the MTX group (90%) than NB‐UVB group (60%). The serum TWEAK level at baseline was 60.47 ± 12.6 pg/mL in NB‐UVB group and 54.69 ± 21.7 pg/mL in MTX group which reduced to 24.93 ± 17.6 pg/mL and 32.13 ± 23.6 pg/mL, respectively (p < 0.001), after 12 weeks of treatment. There was a positive correlation between the serum levels of TWEAK and severity of PASI score (r = 0.399, p = 0.014). Conclusion: TWEAK grades in psoriasis are substantially higher than in controls. TWEAK levels were dramatically reduced during NB‐UVB and MTX treatment. TWEAK may have a potential sign for psoriasis diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Copyright of Sanamed is the property of Sanamed and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim: Wound healing is a physiological process vital for survival because it restores skin integrity. Pathological scarring is an erroneous consequence of wound healing that occurs as a result of either excessive collagen deposition or degradation. Tumor necrosis factor like weak inducer of apoptosis (TWEAK) is believed to be a cytokine with major contributing effects in angiogenesis, inflammation, and cell division. This study aimed to explore the expression of TWEAK in different groups of scar tissue using immunohistochemistry and to compare the results with clinical and histological data. Materials and Methods: This study included 50 cases divided in 5 different wound healing groups. Detailed history taking and full physical examination were performed in addition to histopathological and immunohistochemical evaluation of TWEAK. Results: In the epidermis, mean H-scores of TWEAK were higher in hypertrophic scars and keloids than in normal and atrophic scars. In dermal blood vessels and fibroblasts, the granulation tissue, hypertrophic, and keloid cases mean H-scores of TWEAK was higher than those of normal and atrophic cases. Conclusion: Our findings highlighted the significance of TWEAK in angiogenesis, inflammation, and fibroblast proliferation pointing to helpful function in the normal healing process of wounds, but its higher level has been linked to the development of pathological scars. [ABSTRACT FROM AUTHOR]

The mitogen-activated protein kinase (MAPK) signaling pathway is involved in the epithelial–mesenchymal transition (EMT) and asthma; however, the role of mitogen-activated protein kinase kinase kinase 19 (MAP3K19) remains uncertain. Therefore, we investigated the involvement of MAP3K19 in in vitro EMT and ovalbumin (OVA)-induced asthma murine models. The involvement of MAP3K19 in the EMT and the production of cytokines and chemokines were analyzed using a cultured bronchial epithelial cell line, BEAS-2B, in which MAP3K19 was knocked down using small interfering RNA. We also evaluated the involvement of MAP3K19 in the OVA-induced asthma murine model using Map3k19-deficient (MAP3K19−/−) mice. Transforming growth factor beta 1 (TGF-β1) and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) induced the MAP3K19 messenger RNA (mRNA) expression in the BEAS-2B cells. The knockdown of MAP3K19 enhanced the reduction in E-cadherin mRNA and the production of regulated upon activation normal T cell express sequence (RANTES) via stimulation with TWEAK alone or with the combination of TGF-β1 and TWEAK. Furthermore, the expression of MAP3K19 mRNA was upregulated in both the lungs and tracheas of the mice in the OVA-induced asthma murine model. The MAP3K19−/− mice exhibited worsened eosinophilic inflammation and an increased production of RANTES in the airway epithelium compared with the wild-type mice. These findings indicate that MAP3K19 suppressed the TWEAK-stimulated airway epithelial response, including adhesion factor attenuation and RANTES production, and suppressed allergic airway inflammation in an asthma mouse model, suggesting that MAP3K19 regulates allergic airway inflammation in patients with asthma.

Background: Atherosclerosis is increased in patients with rheumatoid arthritis (RA) and early diagnosis of vascular disease leads to better outcome. Our aim was to evaluate whether aortic elasticity decreases in the subclinical stage of atherosclerosis in RA patients without any cardiovascular disease and to determine disease-related risk factors. Methods: One hundred fourteen patients with RA, 50 patients with spondyloarthritis, and 50 healthy control were included in this study. Aortic elasticity was evaluated by echocardiography (ECHO). The relationship between atherosclerosis and vascular risk factors, including age, disease activity, C-reactive protein, and serum tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) levels was investigated. Results: In ECHO evaluation, aortic stiffness was increased (P = .01), and aortic strain and elasticity were decreased (P < .01, P = .01) in RA patients compared to control groups. Serum tumor necrosis factor-like weak inducer of apoptosis levels were also significantly lower (P < .01) in RA, but no significant correlation was found with aortic strain measurement (P > .05). Aortic elasticity was shown to decrease significantly with age in all groups (P < .05). Conclusion: In this study, we observed deterioration of aortic parameters indicating early atherosclerosis in RA. Aging was found to be the single predictive factor for vascular disease. Although a decrease in sTWEAK level was detected in the RA group, no statistically significant relationship could be demonstrated between sTWEAK level and aortic elasticity parameters. However, the cross-sectional design of the study and possible fluctuations in serum markers depending on disease activity make it difficult to draw a clear conclusion on this subject. [ABSTRACT FROM AUTHOR]

Background: Targeting IL‐13 is highly efficacious in patients with Th2‐biased atopic dermatitis (AD), but inhibition of other inflammatory molecules might also limit disease. We investigated the importance of the TNF family cytokine TNF‐like weak inducer of apoptosis (TWEAK; TNFSF12) to keratinocyte dysregulation and the pathogenesis of AD in mice and also tested if blocking TWEAK has a similar therapeutic effect as targeting IL‐13. Methods: Conditional knockout mice lacking Fn14 (TNFRSF12A), the receptor for TWEAK, only in keratinocytes, were repetitively sensitized with house dust mite allergen and analyzed for AD‐like skin inflammation. To determine the translational potential, wild‐type mice with AD were therapeutically treated with anti‐TWEAK and/or anti‐IL‐13 antibodies, and skin inflammation was assessed. Results: Mice deficient in Fn14 in keratinocytes were resistant to developing maximal clinical features of AD, exhibiting reduced epidermal hyperplasia and dermal thickening, less skin infiltration of immune cells, and downregulated inflammatory gene expression. Moreover, therapeutic neutralization of TWEAK in wild‐type mice with AD reduced all of the pathological features to a comparable extent as blocking IL‐13. Conclusions: The activity of TWEAK in keratinocytes contributes to AD development, and neutralizing TWEAK represents a future potential therapeutic option in human AD similar to targeting IL‐13. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum neutrophil extracellular traps （NETs), tumor necrosis factor-like weak inducer of apoptosis （TWEAK), peripheral blood cluster of differentiation （CD)4+T/CD8+T ratio and disease activity and rena prognosis in patients with lupus nephritis （LN). Methods:137 LN patients （LN group） who were admitted to the Department of Nephrology, Affiliated Hospital of North Sichuan Medical College from August 2021 to August 2022 were selected, patients were divided into mild activity group （52 cases), moderate activity group （45 cases） and severe activity group （40 cases） according to the systemic lupus erythematosus disease activity index （SLEDAI）-2000 score. After 1 years of follow-up, patients were divided into poor prognosis group（43 cases） and good prognosis group （94 cases） according to the occurrence of kidney-related endpoint events, another 76 healthy volunteers （control group） were selected during the same period. The levels of serum NETs and TWEAK were detected by enzyme-linked immunosorbent assay, and the proportion of CD4+T/CD8+T in peripheral blood was detected by flow cytometry. The correlation between serum NETs, TWEAK, peripheral blood CD4+T/CD8+T and SLEDAI-2000 score in LN patients were analyzed by Spearman correlation analysis, the factors of poor prognosis in LN patients were analyzed by multivariate Logistic regression analysis, the predictive value of serum NETs, TWEAK and peripheral blood CD4+T/CD8+T for poor prognosis in LN patients were analyzed by receiver operating characteristic curve. Results: Compared with control group, the levels of serum NETs and TWEAK in LN group were increased, and the peripheral blood CD4+T/CD8+T was decreased （P＜0. 05). The serum NETs and TWEAK in mild activity group, moderate activity group and severe activity group increased in turn, and the peripheral blood CD4+T/CD8+T decreased in turn （P＜0. 05). SLEDAI-2000 score in LN patients was positively correlated with serum NETs and TWEAK, and negatively correlated with peripheral blood CD4+T/CD8+T （P＜0. 05）Chronic kidney disease stage 4, elevated SLEDAI-2000 score, elevated NETs and elevated TWEAK were independent risk factors for poor prognosis in LN patients, increased estimated glomerular filtration rate and elevated CD4+T/CD8+T were independent protective factors （P＜0. 05). The area under the curve of serum NETs, TWEAK and peripheral blood CD4+T/CD8+T combined to predict poor prognosis in LN patients was 0. 943, which was greater than 0. 790, 0. 788 and 0. 799 predicted by serum NETs, TWEAK and peripheral blood CD4+T/CD8+T alone （P＜0. 05). Conclusions: The levels of serum NETs and TWEAK in LN patients are increase, and the peripheral blood CD4+T/CD8+T is decrease, which are closely relate to disease activity and poor renal prognosis, serum NETs and TWEAK combine with peripheral blood CD4+T/CD8+ T has a high value in predicting renal prognosis in LN patients. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the role and mechanism of tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) in liver fibrosis. The liver Kupffer cells (KCs) and mononuclear macrophages (J774A.1) were used as the objects of study to induce M1 polarization with LPS/IFN‐γ. After TWEAK intervention, the M1 cell proportion and marker cytokine levels were detected. Thereafter, CD266 expression was silenced, and NLRP3 expression was inhibited by the NLRP3 inhibitor, so as to investigate the impact of TWEAK on M1 polarization of KCs. In addition, the mouse model of liver fibrosis was constructed to observe the influence of TWEAK on mouse liver fibrosis. According to our results, TWEAK promoted M1 polarization of liver KCs and J774A.1 cells, and silencing CD266 expression or treatment with the NLRP3 inhibitor suppressed the effect of TWEAK. In the mouse experiment, it was discovered that after knocking down NLRP3 expression or using NLRP3 inhibitor to antagonize the effect of TWEAK, the mouse liver function and M1 cell level in liver tissues were improved. [ABSTRACT FROM AUTHOR]

Objectives TNF-like weak inducer of apoptosis (TWEAK) and its sole receptor fibroblast growth factor-inducible 14 (Fn14) are involved in various inflammatory conditions. This study was performed to investigate the potential role of TWEAK/Fn14 in immune-mediated necrotizing myopathy (IMNM). Methods Muscle biopsies from patients with IMNM (n  = 37) and controls (n  = 11) were collected. Human muscle cells were treated with TWEAK in vitro. Muscle biopsies and cultured muscle cells were analysed by immunostaining and quantitative PCR. Serum levels of TWEAK and Fn14 were detected by ELISA. Results TWEAK and Fn14 were overexpressed in IMNM muscle biopsies. The percentage of Fn14-positive myofibers correlated with disease severity, myonecrosis, regeneration and inflammation infiltrates. Fn14-positive myofibers tended to be surrounded or invaded by CD68 + macrophages. TWEAK treatment had a harmful effect on cultured muscle cells by inducing the production of multiple chemokines and pro-inflammatory cytokines. Serum Fn14 levels were increased in patients with IMNM and correlated with muscle weakness. Conclusions TWEAK/Fn14 signalling was activated in IMNM, most likely aggravating muscle damage via amplifying inflammatory response and macrophages chemotaxis. Fn14 seems to be a biomarker for assessing disease severity in IMNM. In addition, Fn14 may also contribute to muscle injury repair. [ABSTRACT FROM AUTHOR]

Rapidly progressive/crescentic glomerulonephritis (RPGN/CGN) involves the formation of glomerular crescents by maladaptive differentiation of parietal epithelial cells that leads to rapid loss of renal function. The molecular mechanisms of crescent formation are poorly understood. Therefore, new insights into molecular mechanisms could identify alternative therapeutic targets for RPGN/CGN. Analysis of kidney biopsies from patients with RPGN revealed increased interstitial, glomerular, and tubular expression of STING1, an accessory protein of the c‐GAS‐dependent DNA‐sensing pathway, which was also observed in murine nephrotoxic nephritis induced by an anti‐GBM antibody. STING1 was expressed by key cell types involved in RPGN and crescent formation such as glomerular parietal epithelial cells, and tubular cells as well as by inflammation accessory cells. In functional in vivo studies, Sting1−/− mice with nephrotoxic nephritis had lower kidney cytokine expression, milder kidney infiltration by innate and adaptive immune cells, and decreased disease severity. Pharmacological STING1 inhibition mirrored these findings. Direct STING1 agonism in parietal and tubular cells activated the NF‐κB‐dependent cytokine response and the interferon‐induced genes (ISGs) program. These responses were also triggered in a STING1‐dependent manner by the pro‐inflammatory cytokine TWEAK. These results identify STING1 activation as a pathological mechanism in RPGN/CGN and TWEAK as an activator of STING1. Pharmacological strategies targeting STING1, or upstream regulators may therefore be potential alternatives to treat RPGN. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Macrophages play a crucial role in regulating inflammation and innate immune responses, and their polarization into distinct phenotypes, such as M1 and M2, is involved in various diseases. However, the specific role of CD163, a scavenger receptor expressed by macrophages, in the transformation of M2 to M1 macrophages remains unclear. Here, dexamethasone-induced M2 macrophages were treated with lipopolysaccharide (LPS) to induce the transformation of M2 to M1 macrophages. We found that treatment with lipopolysaccharide (LPS) induced the transformation of M2-like macrophages to an M1-like phenotype, as evidenced by increased mRNA levels of Il1b and Tnf, decreased mRNA levels of Cd206 and Il10, and increased TNF-α secretion. Knockdown of CD163 enhanced the phenotypic features of M1 macrophages, while treatment with recombinant CD163 protein (rmCD163) inhibited the LPS-induced M2-to-M1 transformation. Furthermore, LPS stimulation resulted in the activation of P38, ERK, JNK, and NF-κB P65 signaling pathways, and this activation was increased after CD163 knockdown and suppressed after rmCD163 treatment during macrophage transformation. Additionally, we observed that LPS treatment reduced the expression of CD163 in dexamethasone-induced M2 macrophages, leading to a decrease in the CD163-TWEAK complex and an increase in the interaction between TWEAK and Fn14. Overall, our findings suggest that rmCD163 can inhibit the LPS-induced transformation of M2 macrophages to M1 by disrupting the TWEAK-Fn14 interaction and modulating the MAPK–NF–κB pathway.

Background: Rhabdomyolysis is a severe clinical syndrome associated to acute kidney injury (AKI) and chronic kidney disease (CKD). TWEAK/Fn14 signaling axis regulates renal inflammation and tubular cell death. However, the functional role of TWEAK/Fn14 in rhabdomyolysis remains unknown. Methods: Rhabdomyolysis was induced in wild-type, TWEAK- and Fn14-deficient mice or mice treated with TWEAK blocking antibody. Renal injury, inflammation, fibrosis and cell death were assessed. Additionally, we performed in vivo and in vitro studies to explore the possible signalling pathways involved in Fn14 regulation. Findings: Fn14 renal expression was increased in mice with rhabdomyolysis, correlating with decline of renal function. Mechanistically, myoglobin (Mb) induced Fn14 expression via ERK and p38 pathway, whereas Nrf2 activation diminished Mb-mediated Fn14 upregulation in cultured renal cells. TWEAK or Fn14 genetic depletion ameliorated rhabdomyolysis-associated loss of renal function, histological damage, tubular cell death, inflammation, and expression of both tubular and endothelial injury markers. Deficiency of TWEAK or Fn14 also decreased long-term renal inflammation and fibrosis in mice with rhabdomyolysis. Finally, pharmacological treatment with a blocking TWEAK antibody diminished the expression of acute renal injury markers and cell death and lessened residual kidney fibrosis and chronic inflammation in rhabdomyolysis. Interpretation: TWEAK/Fn14 axis participates in the pathogenesis of rhabdomyolysis-AKI and subsequent AKI-CKD transition. Blockade of this signaling pathway may represent a promising therapeutic strategy for reducing rhabdomyolysis-mediated renal injury. Funding: Spanish Ministry of Science and Innovation, ISCIII and Junta de Andalucía.

Fibroblast growth factor (FGF)-inducible 14 (Fn14) activates the classical and alternative NFkB (nuclear factor 'kappa-light-chain-enhancer' of activated Bcells) signaling pathway but also enhances tumor necrosis factor (TNF)-induced cell death. Fn14 expression is upregulated in non-hematopoietic cells during tissue injury and is also often highly expressed in solid cancers. In view of the latter, there were and are considerable preclinical efforts to target Fn14 for tumor therapy, either by exploiting Fn14 as a target for antibodies with cytotoxic activity (e.g. antibody-dependent cellular cytotoxicity (ADCC)-inducing IgG variants, antibody drug conjugates) or by blocking antibodies with the aim to interfere with protumoral Fn14 activities. Noteworthy, there are yet no attempts to target Fn14 with agonistic Fc effector function silenced antibodies to unleash the proinflammatory and cell death-enhancing activities of this receptor for tumor therapy. This is certainly not at least due to the fact that anti-Fn14 antibodies only act as effective agonists when they are presented bound to Fcg receptors (FcgR). Thus, there are so far no antibodies that robustly and selectively engage Fn14 signaling without triggering unwanted FcgR-mediated activities. In this study, we investigated a panel of variants of the anti-Fn14 antibody 18D1 of different valencies and domain architectures with respect to their inherent FcgRindependent ability to trigger Fn14-associated signaling pathways. In contrast to conventional 18D1, the majority of 18D1 antibody variants with four or more Fn14 binding sites displayed a strong ability to trigger the alternative NFkB pathway and to enhance TNF-induced cell death and therefore resemble in their activity soluble (TNF)-like weak inducer of apoptosis (TWEAK), one form of the natural occurring ligand of Fn14. Noteworthy, activation of the classical NFkB pathway, which naturally is predominately triggered by membrane-bound TWEAK but not soluble TWEAK, was preferentially observed with a subset of constructs containing Fn14 binding sites at opposing sites of the IgG scaffold, e.g. IgG1-scFv fusion proteins. A superior ability of IgG1-scFv fusion proteins to trigger classical NFkB signaling was also observed with the anti-Fn14 antibody PDL192 suggesting that we identified generic structures for Fn14 antibody variants mimicking soluble and membrane-bound TWEAK. [ABSTRACT FROM AUTHOR]

Periodontitis multifaktöriyel etiyolojisi olan kronik inflamatuar bir hastalıktır. Hastalık biofilm içerisindeki patojenler tarafından başlatılmaktadır. Hastalık ilerledikten sonra görülen doku yıkımı konağa ait koruyucu ve yıkıcı mekanizmalar arasındaki dengesizlikten kaynaklanır. Periodontal hastalığın teşhisinde kullanılan geleneksel yöntemler, hastalık aktivitesi ve prognozuna ilişkin bilgi vermemektedir. Bu konuda son yıllarda sklerostin ve tümör nekroz faktörü benzeri zayıf apoptoz indükleyicisinin (TWEAK) inflamasyon ve kemik metabolizması üzerindeki etkileri incelenmeye başlanmıştır. Bu derlemenin amacı, sklerostin ve TWEAK’in periodontal hastalık patogenezindeki rolünün değerlendirilmesi ve sklerostin ve TWEAK’in periodontal hastalık teşhisi için yararlı birer biyobelirteç olup olmadığının incelenmesidir.

Abstract Background Skeletal muscle atrophy is a common condition without a pharmacologic therapy. AGGF1 encodes an angiogenic factor that regulates cell differentiation, proliferation, migration, apoptosis, autophagy and endoplasmic reticulum stress, promotes vasculogenesis and angiogenesis and successfully treats cardiovascular diseases. Here, we report the important role of AGGF1 in the pathogenesis of skeletal muscle atrophy and attenuation of muscle atrophy by AGGF1. Methods In vivo studies were carried out in impaired leg muscles from patients with lumbar disc herniation, two mouse models for skeletal muscle atrophy (denervation and cancer cachexia) and heterozygous Aggf1+/− mice. Mouse muscle atrophy phenotypes were characterized by body weight and myotube cross‐sectional areas (CSA) using H&E staining and immunostaining for dystrophin. Molecular mechanistic studies include co‐immunoprecipitation (Co‐IP), western blotting, quantitative real‐time PCR analysis and immunostaining analysis. Results Heterozygous Aggf1+/− mice showed exacerbated phenotypes of reduced muscle mass, myotube CSA, MyHC (myosin heavy chain) and α‐actin, increased inflammation (macrophage infiltration), apoptosis and fibrosis after denervation and cachexia. Intramuscular and intraperitoneal injection of recombinant AGGF1 protein attenuates atrophy phenotypes in mice with denervation (gastrocnemius weight 81.3 ± 5.7 mg vs. 67.3 ± 5.1 mg for AGGF1 vs. buffer; P

Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily (TNFSF). It acts through its receptor fibroblast growth factor-inducible 14 (Fn14). Studies have indicated that TWEAK/Fn14 pathway activation controls multiple cellular responses, including proliferation, angiogenesis and induction of inflammatory cytokines. TWEAK/Fn14 is manifested in many tissues of our body and most importantly in the skin causing inflammation and many autoimmune and neoplastic cutaneous disorders. Evidence suggests that the TWEAK/Fn14 axis, the downstream signalling pathway and its inflammatory molecular expressions are involved in the pathogenesis of many cutaneous disorders such as psoriasis, atopic dermatitis (AD) vitiligo and melanoma. So, this literature review describes a brief introduction of TWEAK and TWEAK/Fn14 pathway and summarises the case-series and open-label studies performed in the field of dermatology and its potential therapeutic benefit. [ABSTRACT FROM AUTHOR]

Background: Endothelial cells (ECs) play a vital role in promoting the progression of malignant cells, and they exhibit heterogeneity in their phenotypic characteristics. We aimed to explore the initiating cells of ECs in osteosarcoma (OS) and investigate their potential interaction with malignant cells. Method: We obtained scRNA-seq data from 6 OS patients, and datasets were batch-corrected to minimize variations among samples. Pseudotime analysis was performed to investigate the origin of differentiation of ECs. CellChat was employed to examine the potential communication between endothelial cells and malignant cells, and gene regulatory network analysis was performed to identify transcription factor activity changes during the conversion process. Importantly, we generated TYROBP-positive ECs in vitro and investigated its role in OS cell lines. Finally, we explored the prognosis of specific ECs cluster and their impact on the tumor microenvironment (TME) at the bulk transcriptome level. Results: The results showed that TYROBP-positive ECs may play a crucial role in initiating the differentiation of ECs. TYROBOP-positive endothelial cells (ECs) exhibited the strongest crosstalk with malignant cells, likely mediated by TWEAK, a multifunctional cytokine. TYROBP-positive ECs exhibited significant expression of TME-related genes, unique metabolic and immunological profiles. Importantly, OS patients with low enrichment of TYROBP-positive ECs had better prognoses and a lower risk of metastasis. Finally, vitro assays confirmed that TWEAK was significantly increased in ECs-conditioned medium (ECs-CM) when TYROBP was over-expressed in EC cells, and could promote the proliferation and migration of OS cells. Conclusion: We concluded that TYROBP-positive ECs may be the initiating cells and play a crucial role in the promotion of malignant cell progression. TYROBPpositive ECs have a unique metabolic and immunological profile and may interact with malignant cells through the secretion of TWEAK. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily (TNFSF). It acts through its receptor fibroblast growth factor-inducible 14 (Fn14). Studies have indicated that TWEAK/Fn14 pathway activation controls multiple cellular responses, including proliferation, angiogenesis and induction of inflammatory cytokines. TWEAK/Fn14 is manifested in many tissues of our body and most importantly in the skin causing inflammation and many autoimmune and neoplastic cutaneous disorders. Evidence suggests that the TWEAK/Fn14 axis, the downstream signalling pathway and its inflammatory molecular expressions are involved in the pathogenesis of many cutaneous disorders such as psoriasis, atopic dermatitis (AD) vitiligo and melanoma. So, this literature review describes a brief introduction of TWEAK and TWEAK/Fn14 pathway and summarises the case-series and open-label studies performed in the field of dermatology and its potential therapeutic benefit.

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Abstract Background Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. Methods We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn −/−; SMN2 and the less severe Smn 2B/− SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations. Results Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak −/− , and Fn14 −/− mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models. Conclusions Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.

Abstract Background Uncontrolled inflammation is an important factor in the occurrence and development of acute lung injury (ALI). Fibroblast growth factor-inducible 14 (Fn14), a plasma membrane-anchored receptor, takes part in the pathological process of a variety of acute and chronic inflammatory diseases. However, the role of Fn14 in ALI has not yet been elucidated. This study aimed to investigate whether the activation of Fn14 exacerbated lipopolysaccharide (LPS)-induced ALI in mice. Methods In vivo, ALI was induced by intratracheal LPS-challenge combined with/without Fn14 receptor blocker aurintricarboxylic acid (ATA) treatment in C57BL/6J mice. Following LPS administration, the survival rate, lung tissue injury, inflammatory cell infiltration, inflammatory factor secretion, oxidative stress, and NLRP3 inflammasome activation were assessed. In vitro, primary murine macrophages were used to evaluate the underlying mechanism by which Fn14 activated the NLRP3 inflammasome. Lentivirus was used to silence Fn14 to observe its effect on the activation of NLRP3 inflammasome in macrophages. Results In this study, we found that Fn14 expression was significantly increased in the lungs of LPS-induced ALI mice. The inhibition of Fn14 with ATA downregulated the protein expression of Fn14 in the lungs and improved the survival rate of mice receiving a lethal dose of LPS. ATA also attenuated lung tissue damage by decreasing the infiltration of macrophages and neutrophils, reducing inflammation, and suppressing oxidative stress. Importantly, we found that ATA strongly inhibited the activation of NLRP3 inflammasome in the lungs of ALI mice. Furthermore, in vitro, TWEAK, a natural ligand of Fn14, amplified the activation of NLRP3 inflammasome in the primary murine macrophage. By contrast, inhibition of Fn14 with shRNA decreased the expression of Fn14, NLRP3, Caspase-1 p10, and Caspase-1 p20, and the production of IL-1β and IL-18. Furthermore, the activation of Fn14 promoted the production of reactive oxygen species and inhibited the activation of Nrf2-HO-1 in activated macrophages. Conclusions Our study first reports that the activation of Fn14 aggravates ALI by amplifying the activation of NLRP3 inflammasome. Therefore, blocking Fn14 may be a potential way to treat ALI.

Background: Uncontrolled inflammation is an important factor in the occurrence and development of acute lung injury (ALI). Fibroblast growth factor-inducible 14 (Fn14), a plasma membrane-anchored receptor, takes part in the pathological process of a variety of acute and chronic inflammatory diseases. However, the role of Fn14 in ALI has not yet been elucidated. This study aimed to investigate whether the activation of Fn14 exacerbated lipopolysaccharide (LPS)-induced ALI in mice. Methods: In vivo, ALI was induced by intratracheal LPS-challenge combined with/without Fn14 receptor blocker aurintricarboxylic acid (ATA) treatment in C57BL/6J mice. Following LPS administration, the survival rate, lung tissue injury, inflammatory cell infiltration, inflammatory factor secretion, oxidative stress, and NLRP3 inflammasome activation were assessed. In vitro, primary murine macrophages were used to evaluate the underlying mechanism by which Fn14 activated the NLRP3 inflammasome. Lentivirus was used to silence Fn14 to observe its effect on the activation of NLRP3 inflammasome in macrophages. Results: In this study, we found that Fn14 expression was significantly increased in the lungs of LPS-induced ALI mice. The inhibition of Fn14 with ATA downregulated the protein expression of Fn14 in the lungs and improved the survival rate of mice receiving a lethal dose of LPS. ATA also attenuated lung tissue damage by decreasing the infiltration of macrophages and neutrophils, reducing inflammation, and suppressing oxidative stress. Importantly, we found that ATA strongly inhibited the activation of NLRP3 inflammasome in the lungs of ALI mice. Furthermore, in vitro, TWEAK, a natural ligand of Fn14, amplified the activation of NLRP3 inflammasome in the primary murine macrophage. By contrast, inhibition of Fn14 with shRNA decreased the expression of Fn14, NLRP3, Caspase-1 p10, and Caspase-1 p20, and the production of IL-1β and IL-18. Furthermore, the activation of Fn14 promoted the production of reactive oxygen species and inhibited the activation of Nrf2-HO-1 in activated macrophages. Conclusions: Our study first reports that the activation of Fn14 aggravates ALI by amplifying the activation of NLRP3 inflammasome. Therefore, blocking Fn14 may be a potential way to treat ALI. [ABSTRACT FROM AUTHOR]

Background: Rosacea is a chronic inflammatory skin disease of unknown pathogenesis. TWEAK and TRAIL are two cytokines thought to have a role in the pathogenesis of some inflammatory and autoimmune diseases. Aims: The purpose of this study was to examine TWEAK and TRAIL serum levels and oxidative stress markers in patients with rosacea. Material and Method: Forty rosacea patients and 40 sex‐ and age‐matched healthy controls were involved in the study. Serum TWEAK and TRAIL levels were evaluated with ELISA kits. Serum total antioxidant status, total oxidant status, total thiol, native thiol, disulfide levels were evaluated, and oxidative stress index was computed. Results: Serum levels of TWEAK, TRAIL, and oxidative stress markers did not differ statistically in the patients and controls. Both TWEAK and TRAIL levels in the patients were detected to be statistically higher in male than in female. Conclusion: TWEAK and TRAIL may not have a systemic effect in rosacea, unlike other inflammatory diseases. More studies are needed to investigate the role of TWEAK and TRAIL in rosacea. [ABSTRACT FROM AUTHOR]

The type I interferon (TI-IFN) pathway regulates innate immunity, inflammation, and apoptosis during infection. However, the contribution of the TI-IFN pathway or upstream signaling pathways to tubular injury in kidney disease is poorly understood. Upon observing evidence of activation of upstream regulators of the TI-IFN pathway in a transcriptomics analysis of murine kidney tubulointerstitial injury, we have now addressed the impact of the TI-IFN and upstream signaling pathways on kidney tubulointerstitial injury. In cultured tubular cells and kidney tissue, IFNa/ß binding to IFNAR activated the TI-IFN pathway and recruited antiviral interferon-stimulated genes (ISG) and NF-κB-associated proinflammatory responses. TWEAK and lipopolysaccharide (LPS) signaled through TBK1/IKKe and IRF3 to activate both ISGs and NF-κB. In addition, TWEAK recruited TLR4 to stimulate TBK1/IKKe-dependent ISG and inflammatory responses. Dual pharmacological inhibition of TBK1/IKKe with amlexanox decreased TWEAK- or LPS-induced ISG and cytokine responses, as well as cell death induced by a complex inflammatory milieu that included TWEAK. TBK1 or IRF3 siRNA prevented the TWEAK-induced ISG and inflammatory gene expression while IKKe siRNA did not. In vivo, kidney IFNAR and IFNß were increased in murine LPS and folic acid nephrotoxicity while IFNAR was increased in human kidney biopsies with tubulointerstitial damage. Inhibition of TBK1/IKKe with amlexanox or IFNAR neutralization decreased TI-IFN pathway activation and protected from kidney injury induced by folic acid or LPS. In conclusion, TI-IFNs, TWEAK, and LPS engage interrelated proinflammatory and antiviral responses in tubular cells. Moreover, inhibition of TBK1/IKKe with amlexanox, and IFNAR targeting, may protect from tubulointerstitial kidney injury. [ABSTRACT FROM AUTHOR]

مقدمه: فعالیت‌های ورزشی، روشی پیشنهادی جهت کاهش التهاب و آتروفی و کنترل بیماری دیابت می‌باشد. اسپیرولینا نیز دارای اثرات ضد التهابی است. هدف از انجام پژوهش حاضر، بررسی تأثیر هشت هفته تمرینات تناوبی با شدت بالا (High-intensity interval training یا HIIT) همراه با مصرف اسپیرولینا، بر تغییرات بیان ژن‌های مسیر التهاب و آتروفی در عضله‌ی نعلی رت‌های مسن چاق مبتلابه دیابت بود.روش‌ها: در این مطالعه‌ی تجربی، 40 سر رت نر مسن نژاد ویستار 20 ماهه با میانگین وزنی 325-280 گرم، پس از خریداری، هشت هفته تحت رژیم پرچرب چاق و پس از آن، با تزریق درون صفاقی 40 میلی‌گرم بر کیلوگرم استرپتوزوسین (Streptozotocin یا STZ) دیابتی شدند. سپس در پنج گروه مساوی (HIIT، HIIT + مکمل، مکمل، شم و شاهد) به مدت هشت هفته و 5 جلسه در هفته، به اجرای HIIT روی تردمیل (با شدت 90 درصد حداکثر اکسیژن مصرفی) در گروه‌های تمرینی و مصرف اسپیرولینا در روزهای تمرین برای گروه‌های HIIT + مکمل و مکمل (50 میلی‌گرم به ازای هر کیلوگرم وزن بدن) پرداختند. بیان ژن‌ها به روش Real-time polymerase chain reaction (Real time-PCR) اندازه‌گیری شد. داده‌ها با استفاده از آزمون‌ One-way ANOVA و آزمون تعقیبی Tukey مورد تجزیه و تحلیل قرار گرفت.یافته‌ها: القای دیابت در رت‌های چاق و مسن، موجب افزایش معنی‌داری در بیان ژن‌های Tweak، Fn14 و Atrogin-1 بین گروه‌های مورد بررسی نسبت به گروه شاهد گردید، اما تمرین و مصرف مکمل این متغیرها را در گروه‌های تمرینی و مکمل نسبت به سایر گروه‌ها به طور معنی‌داری کاهش داد. پس از تمرین، توده‌ی بدنی در گروه‌های HIIT، مکمل و HIIT + مکمل نسبت به گروه‌های شم و شاهد به طور معنی‌داری کاهش یافت و توده‌ی عضله‌ی نعلی نسبت به گروه شاهد تنها در گروه‌های HIIT و HIIT + مکمل، به طور معنی‌داری افزایش داشت.نتیجه‌گیری: با توجه به نتایج تحقیق حاضر، ترکیب HIIT + مکمل به عنوان یک روش مؤثر جهت کاهش آتروفی و افزایش سلامت عضلانی در سالمندان مبتلا به دیابت پیشنهاد می‌شود.

Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and is activated by its ligand TNF-like weak inducer of apoptosis (TWEAK). The latter occurs as a homotrimeric molecule in a soluble and a membrane-bound form. Soluble TWEAK (sTWEAK) activates the weakly inflammatory alternative NF-KB pathway and sensitizes for TNF-induced cell death while membrane TWEAK (memTWEAK) triggers additionally robust activation of the classical NF-KB pathway and various MAP kinase cascades. Fn14 expression is limited in adult organisms but becomes strongly induced in non-hematopoietic cells by a variety of growth factors, cytokines and physical stressors (e.g., hypoxia, irradiation). Since all these Fn14-inducing factors are frequently also present in the tumor microenvironment, Fn14 is regularly found to be expressed by non-hematopoietic cells of the tumor microenvironment and most solid tumor cells. In general, there are three possibilities how the tumor-Fn14 linkage could be taken into consideration for tumor therapy. First, by exploitation of the cancer associated expression of Fn14 to direct cytotoxic activities (antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxic payloads, CART-cells) to the tumor, second by blockade of potential protumoral activities of the TWEAK/Fn14 system, and third, by stimulation of Fn14 which not only triggers proinflammtory activities but also sensitizes cells for apoptotic and necroptotic cell death. Based on a brief description of the biology of the TWEAK/Fn14 system and Fn14 signaling, we discuss the features of the most relevant Fn14-targeting biologicals and review the preclinical data obtained with these reagents. In particular, we address problems and limitations which became evident in the preclinical studies with Fn14-targeting biologicals and debate possibilities how they could be overcome. [ABSTRACT FROM AUTHOR]

Depuis la fin des IUFM, se sont succédé la masterisation (2010), les ESPE (2014) et les INSPE (2019). Ces réformes de la formation initiale des enseignants ont grandement transformé le travail des professionnels au sein de ces structures. En deçà des changements structurels, cet article s'intéresse au travail des formateurs à partir du grain fin de leur activité au sein de dispositifs prescrits par les réformes. Plus précisément, c'est à partir d'un épisode improvisé où une formatrice expérimentée, affectée par un échange entre pairs débutants, a tenté d'interrompre une situation de formation que nous mettons en évidence des conflits dans son activité d'ajustement provoqués par l'introduction non accompagnée de nouveaux dispositifs. Nous montrerons également comment un dispositif d'intervention-recherche a permis à un collectif de formateurs de revenir sur cette situation, d'en faire l'analyse et de s'engager dans un développement potentiel de leur activité d'ajustement d'en tirer des pistes potentielles de transformation de leur activité. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family involved in various diseases including brain inflammatory pathologies such as multiple sclerosis. It has been demonstrated that TWEAK can induce cerebrovascular permeability in an in vitro model of the blood–brain barrier. The molecular mechanisms playing a role in TWEAK versus TNFα signaling on cerebral microvascular endothelial cells are not well defined. Therefore, we aimed to identify gene expression changes in cultures of human brain microvascular endothelial cells (hCMEC/D3) to address changes initiated by TWEAK exposure. Taken together, our studies highlighted that gene involved in leukocyte extravasation, notably claudin-5, were differentially modulated by TWEAK and TNFα. We identified differential gene expression of hCMEC/D3 cells at three timepoints following TWEAK versus TNFα stimulation and also found distinct modulations of several canonical pathways including the actin cytoskeleton, vascular endothelial growth factor (VEGF), Rho family GTPases, and phosphatase and tensin homolog (PTEN) pathways. To our knowledge, this is the first study to interrogate and compare the effects of TWEAK versus TNFα on gene expression in brain microvascular endothelial cells. [ABSTRACT FROM AUTHOR]

Background: Despite the era of biologic therapy in the management of psoriasis, methotrexate, the traditional backbone of psoriasis treatment, does not stop surprising us with what it can offer.Objective: In this study, we aimed to evaluate the peripheral expression and the serum levels of TWEAK in patients with psoriasis vulgaris before and after receiving methotrexate treatment.Methods: The study included 58 patients with moderate to severe psoriasis vulgaris, and 90 apparently healthy individuals as a control group. Before starting the treatment course, all patients were evaluated clinically using Psoriasis Area Severity Index (PASI) score and were subjected to TWEAK serum levels and peripheral expression measurement using ELISA and qRT-PCR techniques, respectively. After 12 weeks of treatment with methotrexate (intramuscular methotrexate; up to 30mg per week) the patients were re-evaluated both clinically and in the laboratory.Results: The baseline serum TWEAK levels and its peripheral mRNA expression in the patients group were significantly lower than those in the control group. After 12 weeks of treatment with methotrexate, the PASI scores were reduced significantly while the serum TWEAK levels and its peripheral expression were significantly elevated.Conclusion: Enhancing TWEAK expression and elevating its serum levels in psoriasis patients seems to be a newly observed mechanism of action of methotrexate. [ABSTRACT FROM AUTHOR]

Pemphigus is a severe autoimmune blistering disease characterized by acantholysis triggered by autoantibodies against desmoglein 1 and 3 (DSG1/3). Apoptosis plays a pivotal role in facilitating acantholysis, yet the precise underlying mechanism remains obscure. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to promote apoptosis and disrupt cell junctions, although its involvement in pemphigus pathogenesis remains ambiguous. Our study observed decreased DSG1/3 expression alongside increased TWEAK/fibroblast growth factor-inducible 14 (Fn14) expression and keratinocyte apoptosis in both lesional and perilesional skin. In vitro experiments revealed that TWEAK-stimulated keratinocytes exhibited enhanced apoptosis, STAT1 phosphorylation, and reduced intercellular DSG1/3 expression. Notably, bulk-RNA sequencing unveiled that CASPASE-3 was responsible for mediating the DSG1/3 depletion, as confirmed by direct interaction with DSG1/3 in a co-immunoprecipitation assay. Naloxone, known for preserving cellular adhesion and preventing cell death, effectively reduced apoptosis and restored DSG1/3 levels in TWEAK-stimulated keratinocytes. The anti-apoptotic properties of naloxone were further validated in a murine pemphigus model. Our findings elucidate that TWEAK facilitates keratinocyte apoptosis by augmenting caspase-3 activity, leading to DSG1/3 depletion and apoptosis in pemphigus. Importantly, naloxone can counter TWEAK-induced apoptosis in pemphigus pathogenesis, offering a potential therapeutic intervention., Competing Interests: Declaration of Competing interest The authors have declared that no conflict of interest exists., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) and is activated by its ligand TNF-like weak inducer of apoptosis (TWEAK). The latter occurs as a homotrimeric molecule in a soluble and a membrane-bound form. Soluble TWEAK (sTWEAK) activates the weakly inflammatory alternative NF-κB pathway and sensitizes for TNF-induced cell death while membrane TWEAK (memTWEAK) triggers additionally robust activation of the classical NF-κB pathway and various MAP kinase cascades. Fn14 expression is limited in adult organisms but becomes strongly induced in non-hematopoietic cells by a variety of growth factors, cytokines and physical stressors (e.g., hypoxia, irradiation). Since all these Fn14-inducing factors are frequently also present in the tumor microenvironment, Fn14 is regularly found to be expressed by non-hematopoietic cells of the tumor microenvironment and most solid tumor cells. In general, there are three possibilities how the tumor-Fn14 linkage could be taken into consideration for tumor therapy. First, by exploitation of the cancer associated expression of Fn14 to direct cytotoxic activities (antibody-dependent cell-mediated cytotoxicity (ADCC), cytotoxic payloads, CAR T-cells) to the tumor, second by blockade of potential protumoral activities of the TWEAK/Fn14 system, and third, by stimulation of Fn14 which not only triggers proinflammtory activities but also sensitizes cells for apoptotic and necroptotic cell death. Based on a brief description of the biology of the TWEAK/Fn14 system and Fn14 signaling, we discuss the features of the most relevant Fn14-targeting biologicals and review the preclinical data obtained with these reagents. In particular, we address problems and limitations which became evident in the preclinical studies with Fn14-targeting biologicals and debate possibilities how they could be overcome.

The type I interferon (TI-IFN) pathway regulates innate immunity, inflammation, and apoptosis during infection. However, the contribution of the TI-IFN pathway or upstream signaling pathways to tubular injury in kidney disease is poorly understood. Upon observing evidence of activation of upstream regulators of the TI-IFN pathway in a transcriptomics analysis of murine kidney tubulointerstitial injury, we have now addressed the impact of the TI-IFN and upstream signaling pathways on kidney tubulointerstitial injury. In cultured tubular cells and kidney tissue, IFNα/β binding to IFNAR activated the TI-IFN pathway and recruited antiviral interferon-stimulated genes (ISG) and NF-κB-associated proinflammatory responses. TWEAK and lipopolysaccharide (LPS) signaled through TBK1/IKKε and IRF3 to activate both ISGs and NF-κB. In addition, TWEAK recruited TLR4 to stimulate TBK1/IKKε-dependent ISG and inflammatory responses. Dual pharmacological inhibition of TBK1/IKKε with amlexanox decreased TWEAK- or LPS-induced ISG and cytokine responses, as well as cell death induced by a complex inflammatory milieu that included TWEAK. TBK1 or IRF3 siRNA prevented the TWEAK-induced ISG and inflammatory gene expression while IKKε siRNA did not. In vivo, kidney IFNAR and IFNβ were increased in murine LPS and folic acid nephrotoxicity while IFNAR was increased in human kidney biopsies with tubulointerstitial damage. Inhibition of TBK1/IKKε with amlexanox or IFNAR neutralization decreased TI-IFN pathway activation and protected from kidney injury induced by folic acid or LPS. In conclusion, TI-IFNs, TWEAK, and LPS engage interrelated proinflammatory and antiviral responses in tubular cells. Moreover, inhibition of TBK1/IKKε with amlexanox, and IFNAR targeting, may protect from tubulointerstitial kidney injury.

Background: Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. Methods: We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn−/−; SMN2 and the less severe Smn2B/− SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations. Results: Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak−/−, and Fn14−/− mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models. Conclusions: Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle. [ABSTRACT FROM AUTHOR]

Objective: Obesity is characterized by a low-grade inflammatory state in adipose tissue. Tumor Necrosis Factor Weak Inducer of Apoptosis (TWEAK) and Cluster of Differentiation 163 (CD163) are cytokines potentially involved in the pathogenesis of obesity. Little is known about them in children. The aim of this study was to observe serum levels of TWEAK and CD163 in prepubertal children with obesity compared to lean, and to evaluate its changes after a 2-year intervention program in children with obesity. Methods: Case-control study with a prospective follow-up of cases for 2 years in a referral pediatric endocrine outpatient centre. Seventy-three prepubertal children with obesity, and forty-seven age- and gender-matched lean controls were studied. Sixty-two cases finished the program. Anthropometric parameters, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), lipid profile, and concentrations of TWEAK and CD163 were determined. Children with obesity were re-evaluated after a 2-year intervention program consisting of diet and exercise.Weight loss was considered if z-score Body Mass Index (BMI) decreased at least 0.5 Standard Deviations (SD). Results:We observed higher CD163 levels in children with obesity compared to controls. No significant differences were observed in TWEAK and CD163/TWEAK ratio at baseline. After the 2-year intervention program, TWEAK levels were higher and CD163/TWEAK ratio was lower in children with weight loss than those without weight loss. CD163 decreased in both groups. Conclusion: TWEAK and CD163 seem to have a role in the pathogenesis of obesity in prepubertal children. [ABSTRACT FROM AUTHOR]

Although the number of cases and mortality of COVID-19 are seemingly declining, clinicians endeavor to establish indicators and predictors of such responses in order to optimize treatment regimens for future outbreaks of SARS-CoV-2 or similar viruses. Considering the importance of aberrant immune response in severe COVID-19, in the present study, we aimed to explore the dynamic of serum TNF-like weak inducer of apoptosis (TWEAK) levels in critically-ill COVID-19 patients and establish whether these levels may predict in-hospital mortality and if TWEAK is associated with impairment of testosterone levels observed in this population. The present single-center cohort study involved 66 men between the ages of 18 and 65 who were suffering from a severe type of COVID-19. Serum TWEAK was rising during the first week after admission to intensive care unit (ICU), whereas decline to baseline values was observed in the second week post-ICU admission (p = 0.032) but not in patients who died in hospital. Receiver-operator characteristics analysis demonstrated that serum TWEAK at admission to ICU is a significant predictor of in-hospital mortality (AUC = 0.689, p = 0.019). Finally, a negative correlation was found between serum TWEAK at admission and testosterone levels (r = −0.310, p = 0.036). In summary, serum TWEAK predicts in-hospital mortality in severe COVID-19. In addition, inflammatory pathways including TWEAK seem to be implicated in pathophysiology of reproductive hormone axis disturbance in severe form of COVID-19. [ABSTRACT FROM AUTHOR]

The present COVID pandemic has transformed a physical world to a digital world. Electronic communication has become a major part of the human life that leads to a threat to digital network. so, hiding and protecting the information against unintended persons is highly essential nowadays. This can be done by encryption process. Encryption techniques are derived from mathematical concepts like number theory, graph theory, and algebra. The present paper explains a tweakable block cipher using Catalan numbers of applied number theory. Here the Catalan number acts as a public key. A cyclic permutation is secret key between the legitimate users that acts as a tweak in encryption process. [ABSTRACT FROM AUTHOR]

TWEAK (tumor necrosis factor-like weak inducer of apoptosis) is a member of the TNF superfamily that controls a multitude of cellular events including proliferation, migration, differentiation, apoptosis, angiogenesis, and inflammation. TWEAK control of these events is via an expanding list of intracellular signalling pathways which include NF-κB, ERK/MAPK, Notch, EGFR and AP-1. Two receptors have been identified for TWEAK – Fn14, which targets the membrane bound form of TWEAK, and CD163, which scavenges the soluble form of TWEAK. TWEAK appears to elicit specific events based on the receptor to which it binds, tissue type in which it is expressed, specific extrinsic conditions, and the presence of other cytokines. TWEAK signalling is protective in healthy tissues, but in chronic inflammatory states become detrimental to the tissue. Consistent data show a role for the TWEAK/FN14/CD163 axis in metabolic disease, chronic autoimmune diseases, and acute ischaemic stroke. Low circulating concentrations of soluble TWEAK are predictive of poor cardiovascular outcomes in those with and without diabetes. This review details the current understanding of the TWEAK/Fn14/CD163 axis as one of the chief regulators of immune signalling and its cell-specific role in metabolic disease development and progression. [ABSTRACT FROM AUTHOR]

Oxysterols are a family of 27-carbon cholesterol oxidation derivatives found in low-density lipoproteins (LDLs) and atherosclerotic plaques where they trigger several biological responses involved in the initiation and progression of atherosclerosis. Several pieces of evidence suggest that oxysterols contribute to endothelial dysfunction (ED) due to their ability to alter membrane fluidity and cell permeability leading to inflammation, oxidative stress and apoptosis. The present study aimed to investigate the molecular events occurring in human microvascular endothelial cells (HMEC-1) in response to autoxidation-generated 3β-hydroxy-5β-hydroxy-B-norcholestane-6β-carboxaldehyde (SEC-B) exposure. Our results highlight that SEC-B rapidly activates HMEC-1 by inducing oxidative stress, nitric oxide (NO) production and pro-inflammatory cytokine release. Exposure to SEC-B up to 24 h results in persistent accumulation of the vasodilator NO paralleled by an upregulation of the endothelial nitric oxide synthase (eNOS) enzyme and downregulation of Caveolin-1 (Cav-1) protein levels. Moreover, reduced expression and extracellular release of the vasoconstrictor factor endothelin-1 (ET-1) are observed. Furthermore, SEC-B stimulates the expression of the cytokines interleukin-6 (IL-6) and tumor necrosis factor-like weak inducer of apoptosis (TWEAK). This proinflammatory state leads to increased monocyte recruitment on activated HMEC-1 cells. Our findings add new knowledge on the role of SEC-B in ED and further support its potential implication in atherosclerosis. [ABSTRACT FROM AUTHOR]

Among recent technological advances, microfluidic biochips have been leading a prominent solution for healthcare and miniaturized bio-laboratories with the assurance of high sensitivity and reconfigurability. On increasing more unreliable communication networks day-by-day, technological shifts in the fields of communication and security are now converging. In today's cyber threat landscape, these microfluidic biochips are ripe targets of powerful cyber-attacks from different hackers or cyber-criminals. Hence, securing such systems is of paramount importance. This paper presents the security aspects of digital microfluidic biochip layout to protect the confidentiality of layout data from unscrupulous people and man-in-the-middle attacks. We propose an authentication mechanism with an error control mechanism that provides reliability, authentication, trustworthy and safety for both storage and communication of GDS, i.e., Graphical Design System, file generally used for digital microfluidic biochip layouts. Simulation results articulate the efficacy of the proposed security model without the overhead of the bioprotocol completion time. The proposed scheme, which used AES as an encryption algorithm with a 256-bit encryption key, has also shown a speedup of 6.0 (with 85% efficiency) faster than the prior efficient scheme. We hope to develop a secure layout design flow for biochips to achieve better resistance to any attack. [ABSTRACT FROM AUTHOR]

Liver injury and inflammation are the most commonly observed adverse outcomes following exposure to penta-brominated flame retardants (penta-BFRs). However, the role of inflammation in the development of liver injury in their alternatives has not yet been explored. Our study aimed to investigate the effects and the underlying mechanism of perinatal exposure to pentabromoethylbenzene (PBEB), a penta-BDE alternative, on liver injury in adult offspring mice under both chow and western diet in later life. Results showed that perinatal exposure to PBEB at 0.2 mg/kg or above led to liver injury in male offspring upon challenge with a western diet, but not in females. Utilizing the Olink immunology panel, our study specifically revealed an upregulation of tumor necrosis factor-related weak inducer of apoptosis (TWEAK) within the livers of male mice. This cytokine was further demonstrated to derive from the secretion by infiltrating macrophages in livers both in vivo and in vitro, which facilitated a shift towards M1 macrophage polarization. TWEAK further activated the hepatic NF-κB and NLRP3 inflammasome pathways, subsequently leading to hepatic pyroptosis in male mice of maternal PBEB exposure. Inhibition of TWEAK signaling mitigated macrophage polarization and inflammasome induction in a co-culture system of macrophages and liver cells. Our findings revealed that perinatal exposure to PBEB precipitated liver injury, partially through an inflammatory pathway mediated by macrophage-derived TWEAK, in male mice offspring under western diet. [Display omitted] • Perinatal PBEB exposure leads to hepatic inflammation in male offspring. • Perinatal PBEB exposure induces TWEAK from macrophage in male offspring livers. • TWEAK elevates M1 macrophage biomarkers in male offspring livers. • TWEAK activates NLRP3 inflammasome, causing a pyroptosis in male offspring livers. [ABSTRACT FROM AUTHOR]

ObjectiveObesity is characterized by a low-grade inflammatory state in adipose tissue. Tumor Necrosis Factor Weak Inducer of Apoptosis (TWEAK) and Cluster of Differentiation 163 (CD163) are cytokines potentially involved in the pathogenesis of obesity. Little is known about them in children. The aim of this study was to observe serum levels of TWEAK and CD163 in prepubertal children with obesity compared to lean, and to evaluate its changes after a 2-year intervention program in children with obesity.MethodsCase-control study with a prospective follow-up of cases for 2 years in a referral pediatric endocrine outpatient centre. Seventy-three prepubertal children with obesity, and forty-seven age- and gender-matched lean controls were studied. Sixty-two cases finished the program. Anthropometric parameters, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), lipid profile, and concentrations of TWEAK and CD163 were determined. Children with obesity were re-evaluated after a 2-year intervention program consisting of diet and exercise. Weight loss was considered if z-score Body Mass Index (BMI) decreased at least 0.5 Standard Deviations (SD).ResultsWe observed higher CD163 levels in children with obesity compared to controls. No significant differences were observed in TWEAK and CD163/TWEAK ratio at baseline. After the 2-year intervention program, TWEAK levels were higher and CD163/TWEAK ratio was lower in children with weight loss than those without weight loss. CD163 decreased in both groups.ConclusionTWEAK and CD163 seem to have a role in the pathogenesis of obesity in prepubertal children.

Leixi Xue,1,* Yi Zhang,1,* Jiajun Xu,1 Wentian Lu,1 Qing Wang,1 Jinxiang Fu,2 Zhichun Liu1 1Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 2Department of Hematology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhichun LiuDepartment of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Sanxiang Road No. 1055, Suzhou, Jiangsu, 215004, People’s Republic of ChinaTel +86 13771994276Email liuzhichun5190@163.comJinxiang FuDepartment of Hematology, The Second Affiliated Hospital of Soochow University, Sanxiang Road No. 1055, Suzhou, Jiangsu, 215004, People’s Republic of ChinaTel +86 13962525217Email fjx3000@126.comPurpose: Current studies on the mechanism of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in lupus nephritis (LN) mainly focus on the inflammatory pathway. Herein, we aimed to determine whether TWEAK could promote the progression of renal interstitial fibrosis by regulating peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) expression and intervening in lipid metabolism in LN.Materials and Methods: MRL/lpr mice, an animal model of lupus, were treated with the anti-TWEAK antibody or co-treated with adeno-associated virus-mediated PGC-1α short hairpin RNA (shRNA). In addition, human proximal tubular epithelial cells (HK2 cells) were treated with recombinant human TWEAK (rhTWEAK) or ammonium pyrrolidine dithiocarbamate (PDTC) in vitro.Results: The renal contents of free fatty acids and triglycerides were higher in MRL/lpr mice than in MRL/MpJ mice; however, these contents were decreased by treatment with the anti-TWEAK antibody. Based on immunofluorescence staining, the expression of PGC-1α was markedly more in the renal tubules of MRL/MpJ mice than in the glomeruli. However, treatment with anti-TWEAK antibody increased the levels of PGC-1α and its downstream target genes, which were remarkably lower in MRL/lpr mice than in MRL/MpJ mice. Anti-TWEAK antibody effectively eased renal interstitial fibrosis, which manifested as a decrease in the deposition of collagen fibers and the inhibition of type I collagen and fibronectin expression. However, the therapeutic effects of the anti-TWEAK antibody were abolished by PGC-1α shRNA. Treatment with rhTWEAK decreased PGC-1α expression in both dose- and time-dependent manners in HK2 cells in vitro. PDTC, an inhibitor of IκBα phosphorylation, suppressed the decrease in the PGC-1α protein level induced by rhTWEAK treatment.Conclusion: Our results suggest that TWEAK prevents renal tubular PGC-1α expression by promoting NF-κB activation, resulting in a deficiency in lipid metabolism and the progress of renal interstitial fibrosis. The upregulation of renal tubular PGC-1α expression to improve lipid metabolism is one of the mechanisms employed by the anti-TWEAK antibody to treat renal interstitial fibrosis.Keywords: TWEAK, lupus nephritis, renal interstitial fibrosis, PGC-1α, lipid metabolism