This review seeks to elucidate the therapeutic potential of tumor necrosis factor receptor 1 (TNFR1) and enhance our comprehension of its role in disease mechanisms. As a critical cell-surface receptor, TNFR1 regulates key signaling pathways, such as nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK), which are associated with pro-inflammatory responses and cell death. The intricate regulatory mechanisms of TNFR1 signaling and its involvement in various diseases, including inflammatory disorders, infectious diseases, cancer, and metabolic syndromes, have attracted increasing scholarly attention. Given the potential risks associated with targeting tumor necrosis factor-alpha (TNF-α), selective inhibition of the TNFR1 signaling pathway has been proposed as a promising strategy to reduce side effects and enhance therapeutic efficacy. This review emphasizes the emerging field of targeted therapies aimed at selectively modulating TNFR1 activity, identifying promising therapeutic strategies that exploit TNFR1 as a drug target through an evaluation of current clinical trials and preclinical studies. In conclusion, this study contributes novel insights into the biological functions of TNFR1 and presents potential therapeutic strategies for clinical application, thereby having substantial scientific and clinical significance.

The effects of ginger on gastrointestinal disorders such as ulcerative colitis have been widely investigated using experimental models; however, the mechanisms underlying its therapeutic actions are still unknown. In this study, we investigated the correlation between the therapeutic effects of ginger and the regulation of the gut microbiota. We used dextran sulfate sodium (DSS) to induce colitis and found that ginger alleviated colitis-associated pathological changes and decreased the mRNA expression levels of interleukin-6 and inducible nitric oxide synthase in mice. 16s rRNA sequencing analysis of the feces samples showed that mice with colitis had an intestinal flora imbalance with lower species diversity and richness. At the phylum level, a higher abundance of pathogenic bacteria, Proteobacteria and firmicutes, were observed; at the genus level, most samples in the model group showed an increase in Lachnospiraceae_NK4A136_group. The overall analysis illustrated an increase in the relative abundance of Lactobacillus_murinus, Lachnospiraceae_bacterium_615, and Ruminiclostridium_sp._KB18. These increased pathogenic bacteria in model mice were decreased when treated with ginger. DSS-treated mice showed a lower abundance of Muribaculaceae, and ginger corrected this disorder. The bacterial community structure of the ginger group analyzed with Alpha and Beta indices was similar to that of the control group. The results also illustrated that altered intestinal microbiomes affected physiological functions and adjusted key metabolic pathways in mice. In conclusion, this research presented that ginger reduced DSS-induced colitis severity and positively regulated the intestinal microbiome. Based on the series of data in this study, we hypothesize that ginger can improve diseases by restoring the diversity and functions of the gut microbiota.

The emergence of antibiotic-resistant bacteria has become a major challenge in current clinical treatment. As essential natural molecules involved in innate immunity, antimicrobial peptides (AMPs) have the potential to break the limits of antibiotic resistance. While AMPs are widely presented in various organisms on this planet, the marine environment is unique in generating a large number of AMPs that exhibit characteristic structures and functions. This review summarizes the structures and mechanisms of action of AMPs derived from invertebrates, fish, amphibians, reptiles, and mammals in the ocean. The comparison of AMPs from organisms in different habitats demonstrates the preference of Arg (arginine) and Leu (leucine) in marine AMPs, which might be associated with the adaptation to the unique features of bacterial membranes in marine environments. In addition, the potential and applications of marine AMPs for the development of novel antibiotics are also described. These summaries are expected to provide a reference for the development and utilization of marine resources in drug development or aquiculture.

True sea snakes (Hydrophiini) are among the last and most successful clades of vertebrates that show secondary marine adaptation, exhibiting diverse phenotypic traits and lethal venom systems. To better understand their evolution, we generated the first chromosome-level genomes of two representative Hydrophiini snakes, Hydrophis cyanocinctus and H. curtus. Through comparative genomics we identified a great expansion of the underwater olfaction-related V2R gene family, consisting of more than 1,000 copies in both snakes. A series of chromosome rearrangements and genomic structural variations were recognized, including large inversions longer than 30 megabase (Mb) on sex chromosomes which potentially affect key functional genes associated with differentiated phenotypes between the two species. By integrating multiomics we found a significant loss of the major weapon for elapid predation, three-finger toxin genes, which displayed a dosage effect in H. curtus. These genetic changes may imply mechanisms that drove the divergent evolution of adaptive traits including prey preferences between the two closely related snakes. Our reference-quality sea snake genomes also enrich the repositories for addressing important issues on the evolution of marine tetrapods, and provide a resource for discovering marine-derived biological products.

Tyrosine phosphatase SHP2, encoded by PTPN11, has been implicated in many physiologic and pathologic processes in neoplastic progression. However, controversies are emerging from many studies, indicating SHP2 has a dual role in different types of tumors. We aimed to explore the role of SHP2 in progression and prognosis of colorectal cancer (CRC). SHP2 inhibited CRC cell proliferation and migration, and the phosphorylation of STAT3 was negatively regulated by SHP2 in CRC. SHP2 and nuclear STAT3 were examined in 270 CRC tissues. SHP2 was significantly correlated with nuclear STAT3 (Spearman’s rho = −0.408, P ≤ 0.001). Based on Cox regression analysis, patients with high levels of SHP2 and low levels of nuclear STAT3 had longer disease-specific survival (DSS) (HR, 0.362; 95% CI, 0.165–0.794) and disease-free survival (DFS) (HR, 0.447; 95% CI, 0.227–0.877). Further, low levels of SHP2 and high levels of nuclear STAT3 were independently associated with adverse outcomes in the whole cohort (DFS; HR, 2.353; 95% CI, 1.199–4.619). These results suggest that combination of SHP2 and nuclear STAT3 is a strong prognostic predictor in CRC.

Snake has been used for centuries as a traditional Chinese medicine, especially for therapeutic treatment for inflammatory diseases; however, its mechanisms of action and active constituents remain controversial. In our study, a tumor necrosis factor receptor 1 (TNFR1) selective binding peptide, Hydrostatin-SN1 (H-SN1), which was screened from a Hydrophis cyanocinctus venom gland T7 phage display library, was shown to exhibit significant anti-inflammatory activity in vitro and in vivo. As a TNFR1 antagonist, it reduced cytotoxicity mediated by TNF-α in L929 fibroblasts and effectively inhibited the combination between TNF-α with TNFR1 in surface plasmon resonance analysis. H-SN1 was also shown to suppress TNFR1–associated signaling pathways as it minimized TNF-α-induced NF-кB and MAPK activation in HEK293 embryonic kidney and HT29 adenocarcinoma cell lines. We next determined the effect of H-SN1 in vivo using a murine model of acute colitis induced by dextran sodium sulfate, demonstrating that H-SN1 lowered the clinical parameters of acute colitis including the disease activity index and histologic scores. H-SN1 also inhibited TNF/TNFR1 downstream targets at both mRNA and protein levels. These results indicate that H-SN1 might represent a suitable candidate for use in the treatment of TNF-α-associated inflammatory diseases such as inflammatory bowel diseases.