Taizhou First People's Hospital

Endometriomsis (EMs) is a complex and chronic gynecological disease characterized by distressing symptoms. Its pathogenesis remains unknown, and there is no effective treatment. Therefore, establishing patient-derived models is crucial for elucidating disease mechanisms and identifying potential therapeutic agents. We developed a coculture system combining epithelial organoids and stromal cells, enabling the study of their dynamic interactions. Using this model, we assessed the therapeutic efficacy of dienogest, a drug clinically used for treating endometriomas. The epithelial gland-like organoids and stromal cells derived from patients with endometriomas were isolated and cultured, respectively. Both of them were cocultured in matrix for partially mimicking invivo pathological features. Immunohistochemical (IHC) assay was used to identify their biomarkers. Cell viability was quantitatively assessed using the CellTiter-Glo® assay following drug treatment. We successfully cultured patient-derived epithelial gland-like organoids and stromal cells derived from patients with endometriomas, a form of endometriosis characterized by ovarian cysts. Morphological and immunohistochemical analyses confirmed high consistency with native endometriotic lesions. These models exhibited comparable expression profiles for key biological markers, including estrogen receptors (ERs), progesterone receptors (PRs), E-cadherin, CD44, Intercellular Adhesion Molecule-1 (ICAM1), Integrin Beta 3 (ITGB3), Cytokeratin 7 (CK7), Matrix Metalloproteinase 2/9 (MMP2/9), Tissue Inhibitor of Metalloproteinases 1 (TIMP1), and TIMP2. Notably, drug responsiveness varied among the patient-derived models by coculturing two types of cells, indicating potential interpatient heterogeneity in treatment outcomes. We propose that this patient-specific endometriomas model serves as a valuable platform for investigating disease mechanisms and screening drug in endometriomas. We established a novel coculture system integrating epithelial organoids and stromal cells to recapitulate the intricate cellular interactions within the endometriotic microenvironment, providing a more relevant invitro representation of the disease. Upon evaluation with dienogest, a clinically used therapeutic agent for endometriomas, the patient-derived models exhibited heterogeneous drug responses.

Loss of breast cancer susceptibility gene 2 (BRCA2) function was found to exacerbate doxorubicin-mediated cardiomyocyte apoptosis and promote heart failure progression. We hypothesized that upregulation of BRCA2 may alleviate hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy was established in mice via chronic angiotensin II (Ang II) administration (1.44 mg/kg/day) using osmotic minipumps. Cardiac BRCA2 expression was significantly downregulated in Ang II-treated mice. Cardiac hypertrophy triggered by Ang II in mice was significantly attenuated upon BRCA2 overexpression. Similarly, in cultured primary cardiomyocytes, Ang II-induced hypertrophic responses were suppressed by BRCA2 upregulation. The cardiac fibrosis was significantly attenuated after upregulation of BRCA2 in Ang II-induced hypertrophic cardiomyopathy. The myocardial inflammatory response to Ang II, characterized by elevated interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) levels, was markedly reduced with BRCA2 overexpression. The apoptotic biomarkers including Bax and cleaved caspase 3 (CC3) increased in the heart of hypertrophic cardiomyopathy, and attenuated after upregulation of BRCA2. These results indicated that upregulation of BRCA2 could improve hypertrophic cardiomyopathy. BRCA2 alleviated cardiac hypertrophy via attenuation of inflammation and apoptosis.

Central nervous system (CNS) injuries are a major cause of neurological impairment and long-term disability, driven by intertwined processes including neuroinflammation, oxidative stress, apoptosis, and disruption of the blood–brain barrier (BBB) or blood–spinal cord barrier (BSCB). This review summarizes the physicochemical features and neuroprotective mechanisms of tanshinone IIA (TanIIA), a lipophilic diterpene quinone from Salvia miltiorrhiza , and appraises preclinical evidence across CNS injury models. By synthesizing recent experimental findings from in vivo and in vitro models of cerebral ischemia and spinal cord injury, we focus on mechanistic pathways and functional outcomes. TanIIA shows BBB permeability and multi-target actions, including suppression of neuroinflammatory signaling, attenuation of oxidative damage, preservation of mitochondrial function, restoration of BBB/BSCB integrity, mitigation of aberrant glial activation, and promotion of neurological recovery. Emerging studies also suggest potential synergy with glucocorticoids, which may allow steroid dose reduction while maintaining efficacy in selected settings. While preclinical results are encouraging, key translational gaps remain, particularly regarding target specificity, pharmacokinetics, formulation, and clinically relevant dosing windows. Future work integrating multi-omics approaches with advanced disease-relevant models may accelerate the development of TanIIA-based therapeutics for CNS injuries.

N ‐Heterocyclic compounds (NHCs) are widely encountered in natural products and pharmaceuticals with diverse biological activities, and constitute fundamental structural motifs in numerous organic compounds. Consequently, investigations into the synthesis and modification of these NHCs hold particular significance for chemists and pharmacologists. Of particularly note, multicomponents cascade cyclization reactions allow for creation of many bonds, even stereocenters, in a single step while maintaining predictable stereochemistry have drawn increasing interest, and its broader application has been reinforced by radical chemistry. Photocatalysis and electrocatalysis are two powerful strategies to promote the chemical reactions that have received tremendous attention in recent years. Moreover, photoelectrochemical, a fusion of electrochemical and photochemical, completes reactions that were once challenging, stands out as an effective tool. In these ways, a number of diversly NHCs are constructed. Herein, the most recent contributions on photocatalytic, electrocatalytic, and photoelectrocatalytic radical‐mediated three‐component cascade cyclization reactions to access NHCs are reviewed, providing more possible avenues for future work in this growing area.

To evaluate the efficacy and safety of mechanical thrombectomy performed beyond 24 hours from symptom onset in patients with acute ischemic stroke (AIS) and large vessel occlusion (LVO). In this retrospective cohort study, patients with LVO-related AIS who underwent mechanical thrombectomy within 72 hours of onset were enrolled from the Acute Stroke Patients for Stroke Management Quality Evaluation online database (CASE-Ⅱ, NCT04487340) between January 2017 and December 2024. Patients were stratified into beyond 24-hour thrombectomy group and within 24-hour thrombectomy group based on the time from onset to mechanical thrombectomy. Propensity score matching (PSM) was used to balance baseline characteristics between the two groups. Binary logistic regression and generalized linear models were employed to compare 3-month functional and safety outcomes between the groups. Sensitivity analyses were conducted separately in patients undergoing mechanical thrombectomy within the extended time window (6-24 hours) and in those receiving mechanical thrombectomy alone (without prior intravenous thrombolysis). Subgroup analyses were performed based on age, presence of atrial fibrillation, use of oral anticoagulants, pre-stroke modified Rankin Scale (mRS) score, baseline National Institutes of Health Stroke Scale (NIHSS) score, and occlusion site. Of the 9121 patients included, 277 underwent mechanical thrombectomy beyond 24 hours and 8844 within 24 hours. After PSM, 534 patients were analyzed (267 per group). No significant difference was found in the rate of 3-month functional independence (mRS score 0-2) between the beyond 24-hour and within 24-hour thrombectomy groups, both before and after matching (OR=0.977, 95%CI: 0.753-1.268, P=0.861; OR=1.151, 95%CI: 0.712-1.549, P=0.804, respectively). The rates of 24-hour symptomatic intracranial hemorrhage, 24-hour parenchymal hemorrhage, and 3-month all-cause mortality also showed no significant differences between the two groups (all P>0.05). Sensitivity analyses among patients in the extended time window (6-24 hours) and those receiving mechanical thrombectomy alone yielded similar results, with no significant differences in functional or safety outcomes (all P>0.05). Subgroup analyses revealed no significant heterogeneity in the 3-month functional independence across various baseline characteristics (all P>0.05). For AIS patients with LVO, the efficacy and safety of mechanical thrombectomy performed beyond 24 hours appear comparable to those of mechanical thrombectomy performed within 24 hours.

The HSK16149-201/301 trial demonstrated short-term efficacy of the GABA analog crisugabalin for diabetic neuropathic pain. In the current study, patients in both the crisugabalin and placebo control groups of the HSK16149-201/301 trial were invited to receive 80 mg/day crisugabalin for an additional 52 weeks. The primary end point was safety. The secondary end point was pain control as measured using the Short-Form McGill Pain Questionnaire (SF-MPQ). A total of 301 patients (mean age 59.7 years and males 58.1%) were enrolled. The rate of treatment-related adverse events (TRAEs) was 38.9% (117/301). The most frequent TRAEs were dizziness (27.2%), somnolence (8.3%), and peripheral edema (3.0%). The rate of Grade 3 or higher TRAEs was 1.7%. TRAEs led to dose reduction in 41 patients (13.6%), treatment interruption and discontinuation each in three patients (1.0%). At week 52, the mean difference in SF-MPQ pain rating index (PRI) and visual analog scale pain score from baseline was -2.5 (95% CI -2.9 to -2.0; paired t-test p < 0.0001) and -23.4 (95% CI -25.6 to -21.2; paired t-test p < 0.0001), respectively. The proportion of patients with SF-MPQ PPI score ≤ 1 increased by 19.0% over baseline (p < 0.0001). In summary, crisugabalin at 80 mg/day was well tolerated and demonstrated sustained analgesic activities. ClinicalTrials.gov identifier: NCT05890053.

BACKGROUNDTumor necrosis factor-α (TNF-α) has been implicated in the development of diabetes following chronic pancreatitis. However, its role in abnormal glucose metabolism (AGM) after acute pancreatitis (AP) and post-pancreatitis diabetes mellitus remains unclear.AIMTo investigate the role of TNF-α in AP-associated AGM and its effects on islet β-cell apoptosis, focusing on the underlying molecular mechanisms.METHODSClinical data were collected to assess AGM’s incidence and identify the characteristics in 369 AP patients. In vitro, AP models were established using lipopolysaccharide in 266-6 acinar cells and MIN-6 β-cells. Cell proliferation, apoptosis, and protein expression were analyzed using the Cell Counting Kit-8 assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and western blotting. The TNF-α and insulin concentration in co-culture medium was measured by enzyme-linked immunosorbent assay. In vivo, an AP mouse model was induced using sodium taurocholate, and pancreatic tissues were analyzed through hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and western blotting. TNF-α levels were assessed by enzyme-linked immunosorbent assay. A TNF-α inhibitor was applied to the AP cell model to reassess apoptosis and protein expression.RESULTSAGM occurred in 40.38% of AP patients. Body mass index, severity grade, recurrence frequency, and lung injury were significantly associated with AGM. AP models in 266-6 and MIN-6 cells showed reduced β-cell proliferation, insulin secretion, and increased apoptosis, which correlated with inflammation severity. Similar findings of β-cell apoptosis were confirmed in the mouse model. TNF-α levels were significantly elevated in AP models, with higher levels in severe inflammation. Increased Bax and caspase-3 expression and decreased Bcl-2 expression were observed in both in vitro and in vivo models. These changes intensified with increasing inflammation. TNF-α inhibition reduced apoptosis and altered protein expression patterns, decreasing Bax and caspase-3, while increasing Bcl-2 in MIN-6 cells.CONCLUSIONTNF-α contributes to β-cell apoptosis and AGM in AP through the Bax/Bcl-2/caspase-3 signaling pathway, suggesting TNF-α as a potential therapeutic target for preventing AP-associated AGM.

BackgroundInterferon gamma (IFNγ) priming is a prominent approach to enhance the immune-regulatory capacity of mesenchymal stromal cells (MSCs). Despite its potential, the concentration of IFNγ vary between studies, and how MSCs response to different concentrations of IFNγ is unclear.MethodsMSCs were treated with various concentrations of IFNγ (0, 1, 5, 10, 50, and 100 ng/mL) for 48 h. Followed by RNA sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to profile gene expression and chromatin accessibility, respectively. Integrative analysis was conducted to elucidate the epigenetic regulation of MSCs response to different doses of IFNγ.ResultsWe found that low dose IFNγ (1 ng/mL) treatment was sufficient to induced significant changes in gene expression and chromatin accessibility. RNA-seq revealed that IFNγ activated genes involved in immune response and inactivated genes related to cell-cycle regulation. ATAC-seq showed that IFNγ reduced global enhancer accessibility of MSCs, possibly by downregulation of the SWI/SNF complex. Moreover, IFNγ selectively opened enhancer regions associated with immune response genes while closing regions linked to proliferation-related genes. Motif enrichment analysis identified binding sites for transcription factors such as IRF and AP-1 family members in open and closed regions, respectively, highlighting selective regulatory mechanisms.ConclusionsThis study demonstrates that low dose IFNγ is sufficient to modulate the transcriptional and epigenetic landscape of MSCs by selectively altering enhancer landscape. Our results provide insights into the regulatory mechanisms underlying IFNγ priming and offer a resource for the rational design of strategies to optimize MSC licensing for therapeutic applications.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13287-025-04801-9.