The research progression of direct NLRP3 inhibitors to treat inflammatory disorders.

The NLRP3 inflammasome represents a cytoplasmic multiprotein complex with the capability to recognize a wide range of pathogen-derived, environmental, and endogenous stress-related factors. Dysregulated activation of the NLRP3 inflammasome has been implicated in the development of various inflammasome-associated disorders, highlighting its significance as a pivotal target for the treatment of inflammatory diseases. Nonetheless, despite its clinical importance, there is currently a lack of specific drugs available for directly targeting the NLRP3 inflammasome. Several strategies have been explored to target different facets of the NLRP3 inflammasome, with interventions aimed at directly inhibiting NLRP3 demonstrating the most promising efficacy and safety profiles. In this review, we provide a summary of direct inhibitors targeting NLRP3, elucidating their inhibitory mechanisms, clinical trial phases, and potential applications. Through this discussion, we aim to shed light on the implications of NLRP3 inhibition for the treatment of inflammatory diseases.

NLRP3 inflammasome activation mechanism and its role in autoimmune liver disease.

The NLRP3 inflammasome is a multiprotein binding compound comprising NLRP3, connector protein ASC, and effector protein pro-caspase-1. When the NLRP3 inflammasome senses a danger signal from the host or pathogen, activated caspase-1 cleaves the precursors of interleukin (IL)-1ß and IL-18 into mature proinflammatory cytokines, simultaneously causing lysis via the pore-forming protein gasdermin D. This induction of cell inflammatory pyroptosis suggests that it is a key process in the innate immune response to pathogens or cellular stress. Recent studies have shown that NLRP3 inflammasome also plays an important role in regulating autoimmune liver diseases, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosclerotic cholangitis. In this review, we summarize the structure, activation and modulation of the NLRP3 inflammasome, highlight the progress in research on the role of NLRP3 inflammasome in the occurrence and development of autoimmune liver diseases, and discuss potential strategies for targeting the NLRP3 inflammasome in the treatment of autoimmune liver diseases.

[Qualitative and quantitative analysis of major cholic acids in Suis Fellis Pulvis].

This study is to establish a qualitative method for rapid identification of bile acids in Suis Fellis Pulvis based on UHPLC-LTQ-Orbitrap-MS technology,and an HPLC-ELSD internal standard method for the quantitative determination of two glycine-conjugated BAs in Suis Fellis Pulvis.The chromatographic separation of the UHPLC-LTQ-Orbitrap-MS qualitative analysis was achieved on a Waters Acquity UPLC HSS T_3column(2.1 mm×100 mm,1.8µm),with 0.2%formic acid aqueous solution(A)-acetonitrile(B)as mobile phase ingradient elution.Electrospray ionization(ESI)source was applied and operated in negative ion mode.Quantitative analysis was performed at 30℃on a Diamonsil-C_(18)column(4.6 mm×250 mm,5µm).The mobile phase consisted of 0.2%formic acid solution and acetonitrile with gradient elution and the flow rate was 1.0 m L·min~(-1).An ELSD was used with a nitrogen flow-rate of1.4 L·min~(-1)at a drift tube temperature of 60℃and the gain was 1.A total of 14 bile acids in Suis Fellis Pulvis were characterized based on the accurate mass measurements,fragmentation patterns,chromatographic retention times,and reference materials.For the quantitative analysis method,the glycohyodeoxycholic acid and glycochenodeoxycholic acid had good linear relationship in the range of26.52-265.20 mg·L~(-1)(r=0.999 8)and 19.84-198.40 mg·L~(-1)(r=0.999 1),respectively.The average recoveries(n=6)were104.1%and 103.1%,and the RSD were 2.0%and 2.4%.The UHPLC-LTQ-Orbitrap-MS technology provides a fast and efficient qualitative analysis method for identification of bile acids in Suis Fellis Pulvis.The HPLC-ELSD internal standard method is accurate and reliable,which has reference value for the quality control of Suis Fellis Pulvis.

Effects of antimicrobial peptide and tributyrin on fecal microflora and blood indices of female calves.

This study evaluated the effects of antimicrobial peptide (AMP) and tributyrin (TB) on dairy calves in terms of growth performance, immunity, oxidative stress, and intestinal microflora. A total of 40 female calves were divided into four treatment groups (n = 10): basal diet +0.015% essential oil, basal diet +0.03% AMP, basal diet +0.15% TB, and basal diet +0.03% AMP + 0.15% TB. AMP and TB supplementation increased the average daily gain (ADG) and weaning weight, while reducing diarrhea occurrence. Additionally, AMP and TB supplementation reduced the levels of reactive oxygen species (ROS) and malonaldehyde (MDA), while increasing superoxide dismutase (SOD) levels and serum immunoglobulin M (IgM) levels. However, the combined use of AMP and TB did not significantly affect the average daily feed intake, ADG, weaning weight, or diarrhea incidence but decreased ROS levels, while increasing SOD levels as well as MDA and IgM levels. Moreover, AMP and TG supplementation increased the relative abundance of several beneficial fiber- and mucin-degrading bacteria in the gut, in contrast to combined AMP and TB supplementation. The 16S rRNA results showed that AMP supplementation significantly increased the relative abundance of Rikenellaceae_RC9_gut_group, Ruminococcaceae_UCG-014 and [Eubacterium]_coprostanoligenes group (p < .01), and significantly decreased the relative abundance of Ruminococcaceae_UCG-005 and Christensenellaceae_R-7_group (p < .01). The TB supplementation significantly increased the abundances of Rikenellaceae_RC9_gut_group and Ruminococcaceae_UCG-005 (p < .01), and significantly decreased the relative abundances of Ruminococcaceae_UCG-014, [Eubacterium]_coprostanoligenes group and Christensenellaceae_R-7_group (p < .01). The combined use of AMP and TB significantly increased the relative abundance of Rikenellaceae_RC9_gut_group and Bacteroides (p < .01), and significantly decreased the relative abundance of Ruminococcaceae_UCG-014, [Eubacterium]_coprostanoligenes group and Christensenellaceae_R-7_group (p < .01). In summary, diets supplemented with either AMP or TB improved the intestinal microflora, growth performance, and health of weaned calves, but combined use was detrimental to calf performance.

IGFBP2 drives epithelial-mesenchymal transition in hepatocellular carcinoma via activating the Wnt/ß-catenin pathway.

Metastasis has emerged as a major impediment to achieve successful therapeutic outcomes in hepatocellular carcinoma (HCC). Nonetheless, the intricate molecular mechanisms governing the progression of HCC remain elusive. Herein, we present evidence highlighting the influence exerted by insulin-like growth factor-binding protein 2 (IGFBP2) as a potent oncogene driving the malignant phenotype. Our investigation reveals a marked elevation of IGFBP2 expression in primary tumors, concomitant with the presence of mesenchymal biomarkers in HCC. Through in vitro and in vivo experimentation, we demonstrate that the overexpression of IGFBP2 expedites the progression of epithelial-mesenchymal transition (EMT) and facilitates the metastatic potential of HCC cells, chiefly mediated by the Wnt/ß-catenin signaling pathway. Notably, knockdown of IGFBP2 significantly decreased the expression of total and nuclear ß-catenin, N-cadherin and vimentin in the treatment of the specific activator of Wnt/ß-catenin CHIR-99021. Collectively, our findings identify IGFBP2 as a pivotal regulator within the HCC EMT axis, whereby its overexpression confers the distinctly aggressive clinical features characteristic of the disease.

Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome.

NOD-like receptor protein 3 (NLRP3), an important intracellular pattern recognition receptor, is a component of the NLRP3 inflammasome along with apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and pro-caspase-1. Previous studies have shown that dysregulation of NLRP3 inflammasome may be associated with several human diseases, and therefore blocking NLRP3 inflammasome activation may represent a therapeutic strategy for various diseases. MCC950 is a specific small-molecule inhibitor that selectively blocks activation of the NLRP3 inflammasome. In recent years, research on MCC950 has expanded; its targets are gradually being elucidated, and its metabolism and toxicity have been a focus of study. Preclinical research of MCC950 has yielded promising findings, and MCC950 has shown good efficacy in the treatment of autoimmune diseases, cardiovascular diseases, metabolic diseases and other diseases. Furthermore, clinical trials of MCC950 and other inhibitors of NLRP3 inflammasome have also been conducted. In this review, we discuss the drug targets, metabolism, toxicity and preclinical and clinical research advances of MCC950. We further discuss the clinical therapeutic potential of MCC950 to provide insights for the further study and application of MCC950.

Dominant negative TGF-ß receptor type II in T lymphocytes promotes anti-tumor immunity by modulating T cell subsets and enhancing CTL responses.

Transforming growth factor-ß (TGF-ß) is a multifunctional regulatory cytokine that maintains tolerance in the immune system by regulating the proliferation, differentiation and survival of lymphocytes. TGF-ß blockade therapy for cancer has achieved some results but shows limited efficacy and side effects because these drugs are not selective and act on various types of cells throughout the body. We demonstrate here that dominant negative TGF-ß receptor type II specifically targeting T cells decreases tumor load in tumor-bearing mice. In addition, the dominant negative TGF-ß receptor type II promotes the proliferation and differentiation of T cells and increases the expression of T-bet, which in turn promotes the secretion of granzyme A, granzyme B, perforin and IFN-γ secreted by T cells, and enhances the cytotoxicity and anti-tumor effects of T cells. Moreover, we also found that dominant negative TGF-ß receptor type II reduces the proportion of regulatory T cells (Tregs) in tumor tissue and spleen of tumor-bearing mice. Co-culture experiments with T cells and tumor cells revealed that dominant negative TGF-ß receptor type II inhibited tumor cell proliferation and increased apoptosis. Our results indicate that specifically inhibiting TGF-ß receptor type II in T cells increases anti-tumor immunity and has a strong therapeutic potential.

The pathogenesis, models and therapeutic advances of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune disease characterized by the destruction of intrahepatic small bile ducts and the presence of antimitochondrial antibody (AMA), eventually progresses to liver fibrosis and cirrhosis. Genetic predisposition and environmental factors are involved in the occurrence of PBC, and the epitopes exposure and the imbalance of autoimmune tolerance are the last straw. The apoptosis of biliary epithelial cell (BEC) leads to the release of autoantigen epitopes, which activate the immune system, and the disorder of innate and adaptive immunity eventually leads to the start of disease. Animal models have unique advantages in investigating the pathogenesis and drug exploitation of PBC. Multiple models have been reported, and spontaneous model and induced model have been widely used in relevant research of PBC in recent years. Currently, the only drugs licensed for PBC are ursodesoxycholic acid (UDCA) and obeticholic acid (OCA). In the last few years, as the learned more about the pathogenesis of PBC, more and more targets have been discovered, and multiple targeted drugs are being in developed. In this review, the pathogenesis, murine models and treatment strategies of PBC were summarized, and the current research status was discussed to provide insights for the further study of PBC.