irAE-colitis induced by CTLA-4 and PD-1 blocking were ameliorated by TNF blocking and modulation of gut microbial.

Immune-related adverse events, particularly colitis (irAE-colitis), are significant impediments to the advancement of immune checkpoint therapy. To address this, blocking TNF-α and modulating gut microbiota are effective strategies. However, their precise roles in irAE-colitis pathogenesis and potential reciprocal relationship remain unclear. An irAE-colitis model was established to evaluate the toxicity of DICB and the efficacy of Infliximab, validated through a tumor irAE-colitis mice model. Co-administration of Infliximab with DICB mitigates colitis and enhances efficacy. Analysis of fecal samples from mice reveals altered gut microbiota composition and function induced by irAE-colitis, restored by Infliximab. Notably, Bacteriodes abundance is significantly higher in irAE-colitis. Disruption of arachidonic acid and tyrosine metabolism, and steroid hormone biosynthesis is evident. Mechanistically, a regenerative feedback loop involving DICB, TNF-α and gut microbiota underlies irAE-colitis pathogenesis. In conclusion, Infliximab shows therapeutic effects against DICB toxicity, highlighting the unforeseen roles of gut microbiota and TNF-α in irAE-colitis.

A TNF-α blocking peptide that reduces NF-κB and MAPK activity for attenuating inflammation.

Overexpression of tumor necrosis factor-α (TNF-α) is implicated in many inflammatory diseases, including septic shock, hepatitis, asthma, insulin resistance and autoimmune diseases, such as rheumatoid arthritis and Crohn's disease. The TNF-α signaling pathway is a valuable target, and anti-TNF-α drugs are successfully used to treat autoimmune and inflammatory diseases. Here, we study anti-inflammatory activity of an anti-TNF-α peptide (SN1-13, DEFHLELHLYQSW). In the cellular level assessment, SN1-13 inhibited TNF-α-induced cytotoxicity and blocks TNF-α-triggered signaling activities (IC50 = 15.40 µM). Moreover, the potential binding model between SN1-13 and TNF-α/TNFRs conducted through molecular docking revealed that SN1-13 could stunt TNF-α mediated signaling thought blocking TNF-α and its receptor TNFR1 and TNFR2. These results suggest that SN1-13 would be a potential lead peptide to treat TNF-α-mediated inflammatory diseases.

Comparative Venom Multiomics Reveal the Molecular Mechanisms Driving Adaptation to Diverse Predator-Prey Ecosystems in Closely Related Sea Snakes.

Predator-prey arms races are ideal models for studying the natural selection and adaptive evolution that drive the formation of biological diversity. For venomous snakes, venom is a key bridge linking snakes with their prey, but whether and how venom evolves under the selection of diet remains unclear. Here, we focused on two closely related sea snakes, Hydrophis cyanocinctus and Hydrophis curtus, which show significant differences in prey preferences. Data-independent acquisition (DIA)-based proteomic analysis revealed different degrees of homogeneity in the venom composition of the two snakes, which was consistent with the differential phylogenetic diversity of their prey. By investigating the sequences and structures of three-finger toxins (3FTx), a predominant toxin family in elapid venom, we identified significant differences between the two sea snakes in the binding activity of 3FTx to receptors from different prey populations, which could explain the trophic specialization of H. cyanocinctus. Furthermore, we performed integrated multiomic profiling of the transcriptomes, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and proteomes of the venom glands; constructed venom-related mRNA-miRNA-lncRNA networks; and identified a series of noncoding RNAs involved in the regulation of toxin gene expression in the two species. These findings are highly informative for elucidating the molecular basis and regulatory mechanisms that account for discrepant venom evolution in response to divergent diets in closely related snakes, providing valuable evidence for the study of coselection and coevolution in predator-prey ecosystems.

Discovery of an Anti-TNF-α 9-mer Peptide from a T7 Phage Display Library for the Treatment of Inflammatory Bowel Disease.

Inhibiting TNF-α-mediated acute inflammation is an effective treatment against inflammatory bowel disease. In this study, TNF-α-based T7 phage display library screening combined with in vitro and in vivo assays was applied. A lead peptide, pep2 (ACHAWAPTR, KD = 5.14 µM), could directly bind to TNF-α and block TNF-α-triggered signaling activation. Peptide pep2 inhibits TNF-α-induced cytotoxicity and attenuates the inflammation by decreasing NF-κB and MAPK signaling activities in a variety of cells. Furthermore, pep2 attenuated colitis induced by dextran sodium sulfate in mice in both prophylactic and therapeutic settings. Moreover, pep2 reduced the phosphorylation of p38, ERK1/2, JNK1/2, p65, and IκBα in colonic tissues as well as downregulated inflammatory genes. And HIS3, TRP5, and ARG9 may be the key amino acids in pep2 to bind TNF-α by molecular docking. Collectively, targeting TNF-α with pep2 can attenuate the inflammation in vivo and vitro by inhibiting NF-κB and MAPK signaling pathways.

[Lung Adenocarcinomas with Pulmonary Miliary Metastases: A Case Report and Literature Review].

BACKGROUND: Lung adenocarcinoma with miliary metastasis in both lungs is easily misdiagnosed. The aim of this study is to investigate the clinical features of lung adenocarcinoma with miliary metastases in both lungs and to improve the clinician's understanding of the disease. METHODS: The clinical manifestation, radiology and pathology were analyzed in one patient with miliary intrapulmonary carcinomatosis in Affiliated Hospital of Zunyi Medical University. A review of literature was performed with "miliary intrapulmonary carcinomatosis", "lung cancer miliary", "pulmonary nodule, lung cancer" and "EGFR miliary" as key words in PubMed, Wangfang datebase and CNKI. RESULTS: The patient was a 52 year-old woman with a history of productive cough for 2 months, which aggraveted with shortness of breath for 1 month. Her computed tomography of chest showed diffuse military nodules distributed at bilateral lungs. Computed tomography (CT)-guided needle biopsy of the left lung revealed lung adenocarcinoma and epidermal growth factor receptor (EGFR) exon 21 L858R mutation. The patient was treated with gefitinib 250 mg per day. The chest CT was reviewed several times during this period, which shows the double lung nodules were reduced. The patient is generally in good condition and her symptoms have improved. By literature review, we found relevant 7 Chinese articles and 56 English articles, a total of 16 cases have been reported. 17 patients were lung adenocarcinoma, 2 patients did not describe whether to detect EGFR gene mutations, 1 patient did not have EGFR gene mutation; 10 patients were EGFR exon 19 deletion, 1 patient was ALK positive, 1 patient was EGFR exon 21L858R mutation, 2 patients were EGFR exon 20 insertion. CONCLUSIONS: Lung adenocarcinoma with miliary metastasis in both lungs is a rare phenomenon. We should pay attention to the performance to avoid misdiagnosis. Most of the adenocarcinoma subtypes have EGFR mutations, and EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment choice for this type of patients.