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关键词： tendon stem cell   tumor necrosis factor-alpha   senescence   Achilles tendinitis   DNA damage  

摘要： Achilles tendinitis (AT) is a complex disorder that affects tendon tissue and often responds poorly to non-steroidal anti-inflammatory drugs. Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine involved in cell death and immune regulation, serves a central role in AT progression. The present study investigated the effects of TNF-alpha on tendon stem cells (TSCs) and evaluated potential therapeutic strategies for AT. TNF-alpha-induced changes in TSCs were determined by investigating markers of cellular senescence, reactive oxygen species (ROS) activity, DNA damage and the expression of key transcription factors, including NF-kappa B (phosphorylated-p65, p65), p53, p21, cyclin E and CDK2. To determine whether TNF-alpha-induced senescence could be reversed, TSCs were treated with etanercept, a TNF-alpha-specific inhibitor. TNF-alpha stimulation induced significant senescence in TSCs, as evidenced by increased ROS production, DNA damage and altered expression of senescence-associated transcription factors. TNF-alpha activated the NF-kappa B and p53/p21/cyclin E/CDK2 signaling pathways, promoting TSC senescence. Etanercept treatment effectively reversed these effects, decreasing TSC senescence, suppressing inflammatory cell infiltration, decreasing TNF-alpha protein expression and mitigating collagen fiber degradation. TNF-alpha promotes TSCs senescence through specific signaling pathways and etanercept can counteract these deleterious effects. These results provide insights into the pathogenesis of AT and highlight TNF-alpha inhibition as a promising therapeutic approach. Targeting TNF-alpha may offer a novel treatment strategy for individuals with AT.

关键词： Helicobacter pylori   IL-17   IL-23   Gastric ulcer and gastric cancer  

摘要： Background: Helicobacter pylori (H. pylori) infection is associated with various gastric diseases, including gastric ulcer (GU) and gastric cancer (GC). Objective: The research examines the levels of IL-17 and IL-23 in patients with H. pylori-induced gastric diseases and evaluates the correlation between these cytokines. Subjects and methods: This cross-sectional study was conducted from September 2020 to August 2022. A total of 96 patients were recruited and diagnosed with H. pylori. They were grouped into 56 with GU and 40 with GC. A health control (HC) group of 30 individuals without H. pylori was included. Serum levels of IL-17 and IL-23 were measured in all participants. Results: H. pylori-positive patients showed significantly higher IL-17 and IL-23 levels in GU and GC compared to negative groups (P < 0.001). Post-hoc analysis showed the highest level of both cytokines IL-17 and IL-23 difference between H. pylori-positive GC and control (-48.14, p < 0.001 and -36.75, p < 0.001, respectively). There was a positive correlation between IL-17 and IL-23 in both H. pylori-positive (r = 0.573, P < 0.05) and H. pylori-negative (r = 0.452, P < 0.05). High levels of IL-23 were found to increase the risk of GC significantly. Conclusion: The serum levels of IL-17 and IL-23 are significantly elevated in patients with GU and GC, regardless of H. pylori status, compared to healthy controls. This suggests their potential role as biomarkers for inflammation and disease progression in gastric conditions associated with H. pylori.

关键词： Allergic asthma   Airway inflammation response   IL-33   Ferroptosis   GPX4   Inflammation   Therapeutic targets  

摘要： In the context of asthma pathophysiology, especially during exacerbations and airway inflammation, interleukin33 (IL-33) holds a pivotal role. This study delves into elucidating the impact of IL-33 on ferroptosis during asthma exacerbations. Through comprehensive transcriptomic and proteomic analyses, IL-33 and GPX4 emerged as crucial regulators in this intricate process. In vitro experiments showcased the remarkable anti-inflammatory and ferroptosis-mitigating effects of an IL-33 antibody in IL-13-induced BEAS-2B cells. Subsequent in vivo validation in mice underscored the ability of the IL-33 antibody to diminish inflammatory responses, enhance GPX4 expression, and ameliorate asthma symptoms. These compelling findings suggest that the IL-33 antibody holds promise in suppressing ferroptosis, alleviating inflammation, and modulating GPX4 expression, thereby proposing novel therapeutic strategies for managing asthma exacerbations by targeting the IL-33 and ferroptosis pathways.

关键词： Morin   Colitis   TLR4   ERK1/2   IL-17   HO-1  

摘要： Ulcerative colitis (UC) is an inflammatory bowel disease with indefinite etiology. Currently, immune alterations and their consequences are reported to exist beyond UC development. Herein, the potential coloprotective impact of 6 days-administration of two doses of morin (100, 200 mg/kg) was evaluated and compared to dexamethasone against acetic acid-induced ulcerative colitis with particular concern for the molecular immunomodulatory aspects of the underlying mechanisms. Results showed that morin improved the disease activity index, macroscopic ulcer score and survival rates and attenuated acetic acid-induced oxidative stress and inflammation, as indicated by the significant decrease in MDA, NO, TLR4, NF-kappa B, IL-6, IL-17, and IL-23 and a significant increase in the antioxidant defense markers TAC, SOD, GSH, NRF-2, and HO-1. In addition, morin exhibited a significant decrease in CD3, CD4, and ERK1/2 expression. UC-associated pathological changes were markedly normalized by morin. Thus, morin in a dose related manner, proved its coloprotective effect through alleviation of some adaptive immunity alterations beyond UC with molecular insights on its ability to initiate NRF-2/HO-1 signals, and inhibit CD3/CD4, and TLR4/NF-kappa B/IL-23/IL-17 signals in the context of ERK1/2/IL-6 repression.

关键词： Dysgeusia   Taste disorders   Tumor Necrosis Factor-alpha   Antineoplastic agents, Neoplasms  

摘要： Objectives: The aim of this study is to evaluate the role of TNF-alpha by investigating salivary levels and their influence on Dysgeusia in patients undergoing chemotherapy for breast tumors. Design: Clinicopathological and sociodemographic data, taste test results and subjective taste analysis, salivary flow, quality of life, ECOG performance status, body mass index (BMI), body surface area and other side effects were recorded. The saliva obtained was stored at-80 degrees C after addition of the protease inhibitor (Sigma;P2714-1BTLL), salivary TNF-alpha was measured using the TNF-alpha ELISA kit for human (ELH-TNFa-5, RayBio (R)) following the manufacturer's recommendation. The data was analyzed using Kolmogorov-Smirnov, Mann-Whitney, Spearman and Wilcoxon chi-square/Fisher's exact tests with all analyses adopted a 95 % confidence level in the SPSS for Windows software. Results: The group without dysgeusia (WD) had a longer chemotherapy time than the group with dysgeusia (D) (p <0.001) and a higher frequency of toxicity during CT than the D group (p = 0.012), the mean BMI increased slightly from 28.16 +/- 5.34-28.30 +/- 5.39 (p = 0.016), an increase which only occurred in the WD patients (p = 0.030) and not in the D patients (p = 0.106). There was a correlation with taste parameters, with an inversion between salivary TNF-alpha levels and the taste test (p = 0.033, r =-0.288). In the control group, salivary TNF-alpha concentration was directly correlated with VAS scale scores (p = 0.044, r = 0.266). Conclusions: The increase in salivary TNF alpha had a direct impact on gustatory tests, and the development of dysgeusia has a negative impact on the quality of life of patients undergoing antineoplastic treatment.

关键词： Resveratrol   Acute lung injury   Excessive autophagy/mitophagy   TNF/NF-kappa B/JNK pathway   DNMT2/TRDMT1  

摘要： Acute lung injury (ALI) is a hypoxic respiratory insufficiency disease characterized by oxidative damage, inflammatory response, and autophagic cell death. Resveratrol (Res) modulates the autophagy activation and excessive autophagy inhibition to counteract oxidative stress, yet the latter mechanism has been vague. Herein, effects and regulatory mechanisms of Res on lung injury, inflammation, and autophagy/mitophagy were explored in lipopolysaccharide (LPS)-stimulated rats and RAW264.7 cells. Transcriptome data exhibited that, Res influenced oxidative stress, inflammation, apoptosis, necroptosis, proliferation, and migration probably through TNF/NF-kB-mediated phagosome and lysosome formations in ALI rats. In subsequent assays, Res significantly reversed the LPS-induced lung injury and mitochondrial dysfunction via activating the SIRT1/PGC-1 alpha pathway. Also, Res reduced LPS-triggered inflammatory cytokines through restraining the TNF/NF-kappa B/JNK pathway. Importantly, Res attenuated excessive LC3/ATG5/p62-mediated autophagy and PINK1/Parkin-adjusted mitophagy, decreasing the autophagic flux by inactivating the NF-kappa B pathway. Thus, Res augmented antioxidative and anti-inflammatory effects most likely through ameliorating the excessive autophagy/mitophagy via two converging pathways (SIRT1/PGC-1 alpha and TNF/NF-kappa B/JNK). Notably, Res down-regulated the DNMT2/ TRDMT1 expression and probably adopted a similar binding pattern with plant flavonoids to block this enzyme. Altogether, these findings will provide a novel mechanism and therapeutic strategy for ALI or related lung diseases by Res-modulated autophagy/mitophagy inactivation and DNMT2/TRDMT1 inhibition.

关键词： aa   amino acid   ADC   antibody-drug conjugate   AMPK   AMP-activated protein kinase   BBB   blood–brain barrier   BiTE   bispecific T-cell engager   CAF   cancer-associated fibroblast   CAR   chimeric antigen receptor   CDK   cyclin-dependent kinase   CDX   cell line–derived xenograft   CIE   clathrin-independent endocytosis   CME   clathrin-mediated endocytosis   CNS   central nervous system   CRC   colorectal cancer   CSC   cancer stem cell   ctDNA   circulating tumor DNA   CTGF   connective tissue growth factor   CTX   cetuximab   DUB   deubiquitinase   ECD   extracellular ligand-binding domain   ecDNA   extrachromosomal DNA   ECM   extracellular matrix   EGF   epidermal growth factor   EGFR   epidermal growth factor receptor   EGFRvIII   EGFR variant III   EMT   epithelial-mesenchymal transition   ERRα   estrogen-related receptor alpha   ESCC   esophageal squamous cell carcinoma   ESCRT   endosomal sorting complex required for transport   Ex20in   exon 20 insertion   FDA   US Food and Drug Administration   GBM   glioblastoma multiforme   GC   gastric cancer   GRB2   growth factor receptor-bound protein 2   GTP   guanosine triphosphate   HB   heparin-binding   HDAC6   histone deacetylase 6   HGF   hepatocyte growth factor   HOX   homeobox   HNSCC   head and neck squamous cell carcinoma   HPV   human papillomavirus   mAb   monoclonal antibody   NRG1   neuregulin 1   NSCLC   non–small cell lung cancer   ICI   immune checkpoint inhibitor   IL   interleukin   ILV   intraluminal vesicle   KDD   kinase domain duplication   MAPK   mitogen-activated protein kinase   ORR   objective response rate   OS   overall survival   PARP   poly(ADP-ribose) polymerase   PBC   platinum-based chemotherapy   PDX   patient-derived xenograft   PDK1   phosphoinositide-dependent kinase 1   PIP2   phosphatidylinositol-4,5-biphosphate   PIP3   phosphatidylinositol (3,4,5)-trisphosphate   PFS   progression-free survival   PR   partial response   PROTAC   proteolysis-targeting chimera   PTEN   phosphatase and tensin homolog   RTK   receptor tyrosine kinase   Sac-TMT   sacituzumab tirumotecan   SCC   squamous cell carcinoma   SCLC   small cell lung cancer   sEGFR   soluble epidermal growth factor receptor   SFK   Src family kinase   SH2   Src homology 2   STYK1   serine/threonine/tyrosine kinase 1   TEAD   tr  

摘要： Epidermal growth factor receptor (EGFR) plays a crucial role in tumorigenesis across multiple cancer types. EGFR mutations, overexpression, amplifications, dysregulated signaling, and impaired receptor downregulation drive cancer progression, particularly in non-small cell lung cancer, glioblastoma, colorectal cancer, gastric cancer, and head and neck cancers. Over the past decades, EGFR-targeted therapies, including tyrosine kinase inhibitors and monoclonal antibodies, have significantly improved patient outcomes. However, drug resistance inevitably arises through on-target mutations, activation of bypass signaling pathways, and disruptions in receptor trafficking and degradation. To overcome resistance, novel therapeutic strategies such as new generation of tyrosine kinase inhibitors, antibody-drug conjugates, and targeted protein degradation approaches like proteolysis-targeting chimeras are being actively explored. Additionally, combination therapies targeting parallel or compensatory pathways are being explored in mitigating drug resistance. Advances in genomic profiling and liquid biopsy technologies further enable personalized treatment strategies tailored to individual genetic backgrounds. In this review, we provide an overview of EGFR signaling and examine the landscape of EGFR mutations and currently available targeted therapies, while highlighting key resistance mechanisms. Furthermore, emerging strategies designed to overcome resistance are discussed, offering insights into future directions for EGFR-targeted cancer treatment. Significance Statement: Epidermal growth factor receptor (EGFR) is a key driver of tumorigenesis across multiple cancers, with overexpression, mutations, and amplifications promoting disease progression and therapeutic resistance. Despite the success of EGFR-targeted therapies, resistance remains a significant barrier to sustainable efficacy. This review provides an overview of EGFR biology and therapy, resistance mechanisms, and e

关键词： Alzheimer's disease (AD   IL‐1 family of cytokines   neuroinflammation  

摘要： Alzheimer's disease (AD) is a long-term, progressive, degenerative disorder. One of the most important pathological characteristics of AD is the deposition of β-amyliod (Aβ) peptide, which initiates a spectrum of cerebral neuroinflammation. Vascular changes also play an important role in the pathophysiology of the disease. Cytokines, secreted by immune cells, can facilitate cell-to-cell signaling and influence the functions of the central nervous system (CNS). These important mediators of the immune system, which are known to orchestrate various molecular and cellular mechanisms in both physiological and pathological situations, can be upregulated or downregulated, leading to a complex crosstalk with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. In particular, the interleukin (IL)-1 family of cytokines has been implicated to significantly correlate with AD pathogenesis among other cytokines in the CNS. The IL-1 family of cytokines is essential in both the innate and adaptive immune responses. This pleiotropic family of cytokines includes IL-1α, IL-1β, IL-1 receptor antagonist (RA), IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36RA, IL-37, and IL-38. Recent studies have demonstrated that the upregulation of pro-inflammatory cytokines, such as IL-1α and IL-1β, or the downregulation of anti-inflammatory mediators, exerts multifaceted influences on both neurodegeneration and neuroprotection. The lack of effective treatment for AD necessitates the search for new drugs that target several processes in the disease's pathology. This review aims to give a comprehensive overview of the emerging roles of the IL-1 family of cytokines in AD pathology and to explain their perspectives on introducing novel strategies for effective therapeutic/neuropsychiatric management of AD in clinical settings by discussing both the pathogenic and protective roles of these cytokines.

关键词： Sarcopenia   Ursolic acid   Skeletal atrophy   Gut microbiota   IL-17a pathway  

摘要： Sarcopenia significantly impairs quality of life, especially in diabetic patients, where effective treatment options remain limited. The IL-17a-related gutmuscle axis suggests a potential role of the gut microbiota in the development of sarcopenia. Ursolic acid (UA) has shown promise as an anti-sarcopenic agent. Nevertheless, the relationship between UA and the IL-17a-related gut-muscle axis remains unclear. In this research, sarcopenia model was established using streptozotocin in vivo and in vitro with TNF- alpha-managed C2C12 myotubes. UA significantly altered the gut microbiota, notably increasing observed OTUs and the Shannon index of sarcopenic mice. Specifically, UA effectively mitigated the decrease of Bacteroides thetaiotaomicron and restored the total level of short-chain fatty acids, particularly reducing propionic acid and increasing isovaleric acid. Additionally, UA markedly improved muscle quality and function, as evidenced by increased body weight, grip strength, and muscle weight, as well as significantly decreased expression of Atrogin-1 and MuRF-1. Moreover, RNA sequencing results clearly indicated that UA suppressed the IL-17 signaling pathway in sarcopenic mice. Furthermore, UA alleviated oxidative stress and apoptosis in sarcopenic mice. Notably, UA inhibited the IL-17a pathway in sarcopenic mice by suppressing the heightened expression of the proteins. In vitro experiments further confirmed that UA inhibited TNF- alpha-induced myotube atrophy, reduced Atrogin-1 and MuRF-1 expression, and strongly suggested that IL-17a may be a key target of UA in combating myotube atrophy. The study emphasizes the importance of UA in alleviating

关键词： group 3 innate lymphoid cells   interleukin-17A   interleukin-1 beta   neutrophilic asthma  

摘要： IL-17A-producing group 3 innate lymphoid cells (ILC3s) have been found to participate in the development of various phenotypes of asthma, however, little is known about how ILC3s mediate neutrophilic airway inflammation. Elevated IL-1 beta has been reported in neutrophilic asthma (NA) and IL-1 beta receptor is highly expressed on lung ILC3s. Therefore, we hypothesize that IL-1 beta aggravates neutrophilic airway inflammation via provoking IL-17A-producing ILC3s. We sought to determine the pathological roles of the IL-1 beta-ILC3-IL-17A axis in neutrophilic airway inflammation. Lung ILC subsets were measured in eosinophilic asthma (ovalbumin [OVA]/Alum) and NA (OVA/lipopolysaccharides [LPS]) murine models. Rag2(-/-) (lacking adaptive immunity), RORc(-/-) (lacking transcription factor ROR gamma t), Rag2(-/-)RORc(-/-) (lacking adaptive immunity and ILC3s), and ILCs depletion mice were used to verify the roles of ILC3s in neutrophilic airway inflammation by measurement of CXCL-1, IL-17A, IL-22 and neutrophil counts in bronchoalveolar lavage fluid (BALF), detection of Muc5ac in lung tissues, and quantification of IL-17A-producing ILC3s after treatment of anti-IL-17A or recombinant IL-1 beta (rIL-1 beta) and its monoclonal antibody. NLRP3, Caspase 1 and their induction of IL-1 beta were detected in lung tissues of OVA/LPS-induced mice. The OVA/LPS model was characterized by an enrichment of airway neutrophilia, lung ROR gamma t(+) ILC3s and Th17 cytokines (IL-17A and IL-22) and neutrophilic chemokine C-X-C motif (chemokine) ligand 1 (CXCL-1), compared to the phenotypic features of airway eosinophilia, GATA3(+) ILC2s and type-2 cytokines in OVA/Alum model. The concentration of CXCL-1 and neutrophil counts in BALF were decreased by anti-IL-17A. ROR gamma t deficiency led to a decrease in IL-17A and CXCL-1 levels and neutrophil counts in BALF. ILC depletion in Rag2(-/-) mice ameliorated OVA/LPS-induced IL-17A, IL-22, CXCL-1 and airway neutrophil counts. IL-17A-producing ILCs