T-type Ca2+ channels are often aberrantly expressed in different human cancers and participate in the regulation of cell cycle progression, proliferation and death. Methods: RT-PCR, Q-PCR, western blotting and whole-cell patch-clamp recording were employed to assess the expression of T-type Ca2+ channels in leukemia cell lines. The function of T-type Ca2+ channels in leukemia cell growth and the possible mechanism of the effect of T-type Ca2+ channel antagonists on cell proliferation and apoptosis were examined in T-lymphoma cell lines. We show that leukemia cell lines exhibited reduced cell growth when treated with T-type Ca2+ channel inhibitors, mibefradil and NNC-55-0396 in a concentration-dependent manner. Mechanistically, these inhibitors played a dual role on cell viability: (i) blunting proliferation, through a halt in the progression to the G1-S phase; and (ii) promoting cell apoptosis, partially dependent on the endoplasmic reticulum Ca2+ release. In addition, we observed a reduced phosphorylation of ERK1/2 in MOLT-4 cells in response to mibefradil and NNC-55-0396 treatment. These results indicate that mibefradil and NNC-55-0396 regulate proliferation and apoptosis in T-type Ca2+ channel expressing leukemia cell lines and suggest a potential therapeutic target for leukemia.

Inflammatory bowel disease (IBD) is a chronic, life-threatening inflammatory disease of gastrointestinal tissue characterized by inflammation of the gut. Recent studies have shown that gut microbiota is involved in the pathophysiology of IBD. However, it is unknown whether direct inhibition of NLR family pyrin domain containing 3 (NLRP3) inflammasome regulates IBD and alters gut microbiota. Here, the NLRP3 expression was evaluated in the colon of IBD subjects. Then, we investigated the effects of NLRP3 inhibition by MCC950 on the gut microbiota and IBD-like symptoms induced by dextran sulfate sodium (DSS). Firstly, NLRP3 and IL-1β levels were increased in patients with IBD as compared with healthy individuals. Then, the animal experiment showed that NLRP3 inhibition by MCC950 significantly attenuated IBD-like symptoms such as diarrhea and colonic inflammation in DSS-induced mice. In addition, NLRP3 inhibition inhibited NLRP3/ASC/caspase-1/IL-1β signaling pathway in the colon, which was over-activated by DSS. Furthermore, MCC950 increased the abundance of phylum Firmicutes, decreased the abundance of phylum Bacteroidetes, and increased the Firmicutes/Bacteroidetes ratio, indicating that the inhibition of NLRP3 inflammasome could regulate the abundance of intestinal flora. According to correlation analysis, NLRP3 might produce its functional role in the regulation of oxidation indicators by changing the gut microbiota composition, especially the phylum Bacteroidota, genus Lactobacillus and species Lactobacillus reuteri. This study suggests that NLRP3 inflammasome inhibition attenuates IBD-like symptoms by regulating gut microbiota, and provides a basis for the clinical application of NLRP3 as a target for the treatment of IBD.

Purpose: Ferroptosis, characterized by iron-dependent lipid reactive oxygen species accumulation, plays a critical role in the pathophysiology of depression. Our research aims to elucidate the potential antidepressant mechanisms of asiaticoside, a bioactive compound known for its neuroprotective and immunomodulatory properties. Methods: The antidepressant-like properties of asiaticoside in a model of chronic restraint stress (CRS)-induced depression in mice, with a particular focus on its interaction with ferroptosis-related pathways. Results: The behavioral results revealed that asiaticoside significantly ameliorated CRS-induced depressive symptoms, as evidenced by increased sucrose preference and reduced immobility time. At the molecular level, asiaticoside enhanced the expression of brain-derived neurotrophic factor (BDNF), phosphorylated tropomyosin receptor kinase B (pTrkB), phosphorylated nuclear factor erythroid 2-related factor 2 (pNrf2), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11), indicating its neuroprotective and antioxidative effects. In addition, asiaticoside suppressed the expression of ferroptosis markers, including ferritin light chain (FLC) and transferrin receptor only in CA1 region. Transmission electron microscopy (TEM) further confirmed that asiaticoside preserved mitochondrial integrity in CA1 neuronal cells. Conclusion: In conclusion, our findings suggest that asiaticoside exerts its antidepressant-like effects through the modulation of BDNF/Nrf2/GPX4 signaling pathway against neuronal ferroptosis in the hippocampal CA1 region.

Gastrointestinal cancers account for 39.0% of global cancer-related deaths. The rising incidence of early-onset gastrointestinal cancers poses a substantial public health challenge due to their aggressive nature and poor prognosis. Using the Global Burden of Disease (GBD) 2021 database, we analyzed temporal trends (1990-2021) in age-standardized incidence (ASIR), mortality (ASMR), and disability-adjusted life years (ASDR) rates for early-onset gastrointestinal cancers among individuals aged 15-49 years. Analyses included burden by age, sex, region, and socio-demographic index (SDI). Joinpoint regression estimated average annual percentage changes (AAPC), and future trends (2022-2036) were projected using the Bayesian Age-Period-Cohort model. In 2021, there were 499,800 new cases of early-onset gastrointestinal cancers globally. Colorectal and stomach cancers were most prevalent. From 1990-2021, ASIR increased only for colorectal cancer (AAPC: 0.37, 95%CI: 0.24-0.50), while declines occurred in esophageal, stomach, liver, pancreatic, and gallbladder/biliary tract cancers. Males bore a higher burden except for gallbladder/biliary tract cancer. Significant disparities existed across regions, genders, and SDI levels. Smoking and high body-mass index were leading risk factors. Projections indicate rising ASIRs for early-onset colorectal and esophageal cancers, stable liver cancer incidence, and diminishing incidence, mortality, and DALYs rates for stomach, pancreatic, and gallbladder and biliary tract cancers. Early-onset gastrointestinal cancers represent a substantial and evolving global burden, with notable variations by cancer type, age, sex, region, and SDI. Targeted prevention and healthcare strategies are urgently needed to address modifiable risk factors and reduce disparities.

IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is an IgA-mediated systemic small vessel vasculitis that tends to be more severe in adults than in children. Early diagnosis of IgAV involving the gastrointestinal tract remains difficult, especially in patients who present with gastrointestinal symptoms before purpura. This study aims to systematically analyze the abdominal imaging and endoscopic features of adult patients with abdominal IgAV, providing assistance to clinicians in the early recognition of this condition. This multicenter retrospective study was conducted in three large tertiary hospitals in China from January 2017 to January 2024. A total of 108 adult patients with abdominal IgAV, who had complete abdominal imaging and/or endoscopy results, were enrolled. The clinical manifestations, abdominal imaging findings, endoscopic characteristics, and serological indicators of the patients were analyzed. The median age of the patients was 40 years (IQR: 26-55), with a male-to-female ratio of 2:1. Acute abdominal pain was the most common presenting symptom (100 patients, 92.59%). Bowel wall thickening was the most frequent finding on abdominal imaging (50/86 patients, 58.14%). Gastrointestinal endoscopy showed findings of congestion and erosion (32/67 patients, 47.76%), and erosion with ulcers (21/67 patients, 31.34%). Among patients with both imaging and endoscopic results, the duodenum (28/51 patients, 54.90%) and ileum (28/51 patients, 54.90%) were the most commonly affected sites. Laboratory findings revealed elevated white blood cell count (WBC), neutrophil-to-lymphocyte ratio (NLR), C-reactive protein (CRP), D-dimer and fibrinogen levels, along with decreased albumin level. Comparing patients with gastrointestinal symptoms versus purpura as the initial symptom, those with gastrointestinal symptoms had higher levels of WBC (p < 0.05) and NLR (p < 0.01). The most common symptom in adult abdominal IgAV patients is acute abdominal pain. In the early stage of the disease, most patients exhibit elevated levels of WBC, NLR, CRP, D-dimer, and fibrinogen, along with decreased albumin level. The duodenum and ileum are the most commonly affected sites. By integrating these findings, clinicians can identify abdominal IgAV patients earlier and more accurately.