Alzheimer's disease (AD) is a neurodegenerative disease with clinical hallmarks of progressive cognitive impairment. Synergistic effects of the Aβ-Tau cascade reaction are tightly implicated in AD pathology, and microglial NLRP3 inflammasome activation drives neuronal tauopathy. However, the underlying mechanism of how Aβ mediates NLRP3 inflammasome remains unclear. Herein, we determined that oligomeric Aβ (o-Aβ) bound to microglial Kv2.1 and promoted Kv2.1-dependent potassium efflux to activate NLRP3 inflammasome resulting in neuronal tauopathy by using Kv2.1 inhibitor drofenine (Dfe) as a probe. The underlying mechanism has been intensively investigated by assays with Kv2.1 knockdown in vitro (si-Kv2.1) and in vivo (AAV-ePHP-si-Kv2.1). Dfe deprived o-Aβ of its capability to promote microglial NLRP3 inflammasome activation and neuronal Tau hyperphosphorylation by inhibiting the Kv2.1/JNK/NF-κB pathway while improving the cognitive impairment of 5×FAD-AD model mice. Our results have highly addressed that the Kv2.1 channel is required for o-Aβ-driven microglial NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Dfe as a Kv2.1 inhibitor shows potential in the treatment of AD.

Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

Triple-negative breast cancer (TNBC) remains a refractory subtype of breast cancer due to its resistance to various therapeutic strategies. In this study, we introduce a "brake-release and accelerator-pressing" approach to engineer a microneedle patch embedded with copper-doped Prussian blue nanoparticles (Cu-PB) and the ferroptosis inducer sorafenib (SRF) for raised chemodynamic (CDT)/photothermal (PTT) combination therapy against TNBC. Upon transdermal insertion, the dissolving microneedles swiftly disintegrate and facilitate the release of SRF. Under gentle external light exposure, copper ions (Cu²⁺) and iron ions (Fe³⁺) were liberated from Cu-PB. The direct chelation of Cu²⁺ and the indirect suppression by SRF, collectively attenuate glutathione peroxidase 4 (GPX4) enzymatic function, destabilizing the cellular redox equilibrium (referred to as the "brake-release" strategy). The release of Cu²⁺ and Fe³⁺ ions instigates a Fenton/Fenton-like reaction within tumor cells, further yielding hydroxyl radicals and elevating reactive oxygen species (ROS) concentrations (referred to as the "accelerator-pressing" strategy). This overwhelming ROS accumulation, coupled with the impaired clearance of resultant lipid peroxides (LPO), ultimately triggers a robust ferroptosis cell death response. In summary, this study presents an innovative combinatorial therapeutic strategy based on dual-ferroptosis induction for TNBC, implying a promising therapeutic platform for developing ferroptosis-centered treatments for this aggressive breast cancer subtype.

BACKGROUND:Ursolic acid can promote the directed differentiation of bone marrow mesenchymal stem cells into osteoblasts.However,there are few reports on whether ursolic acid has osteogenic effect on human periodontal ligament stem cells. OBJECTIVE:To investigate the effect of ursolic acid on proliferation and osteogenic differentiation of human periodontal ligament stem cells. METHODS:The human periodontal ligament stem cells were isolated and cultured.Passage 3 cells were selected and treated with ordinary medium containing different concentrations(0,1,2,4,6,8 μmol/L)of ursolic acid.After intervention for 1,3,5,7 days,the cell proliferation was detected by CCK-8 assay and the appropriate intervention concentration was screened.Passage 3 human periodontal ligament stem cells were treated with osteogenic induction solution containing 0,1,2,4 μmol/L ursolic acid,respectively.After 7 days of intervention,the mRNA expressions of alkaline phosphatase,Runx2,and osteocalcin were detected by qRT-PCR.After 14 days of intervention,the formation of mineralized nodules was observed by alizarin red staining.Passage 3 human periodontal ligament stem cells were taken and the control group was added with osteogenic induction solution;the ursolic acid group and the antagonist group were added with osteogenic induction solution containing ursolic acid(2 μmol/L)and the bone morphogenetic protein signaling pathway antagonist Noggin,respectively.The ursolic acid+antagonist group was added with osteogenic induction solution containing ursolic acid(2 μmol/L)and Noggin,the inhibitor of bone morphogenetic protein signaling pathway,and cultured for 7 days.qRT-PCR and western blot assay were used to detect the mRNA and protein expressions of bone morphogenetic protein 2,Smad1,osteopontin,and Runx2. RESULTS AND CONCLUSION:(1)1,2,4 μmol/L ursolic acid could promote the proliferation of human periodontal ligament stem cells.6,8 μmol/L ursolic acid could inhibit the proliferation of human periodontal ligament stem cells,and 1,2,4 μmol/L ursolic acid was selected to intervene in subsequent experiments.(2)Compared with 0 μmol/L,1,2,4 μmol/L ursolic acid could promote the expression of alkaline phosphatase,Runx2,and osteocalcin mRNA and the formation of mineralized nodules(P<0.05),and the effect of 2 μmol/L ursolic acid was the most significant.(3)Compared with the control group,the mRNA and protein expressions of bone morphogenetic protein 2,Smad1,osteopontin,and Runx2 in the ursolic acid group were increased(P<0.05),while mRNA and protein expressions of the above indexes were decreased in the antagonist group(P<0.05).Compared with the ursolic acid group,mRNA and protein expressions of above indexes were decreased in ursolic acid+antagonist group(P<0.05).(4)The results indicate that ursolic acid promotes osteogenic differentiation of human periodontal ligament stem cells through bone morphogenetic protein signaling pathway.

Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2 (Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation.

Objective:To investigate the current prevalence and control status of coal-burning-borne endemic fluorosis in key areas of the disease in Zhenxiong County of Yunnan Province, thereby providing scientific basis for formulating subsequent prevention strategies and measures.Methods:From October to November 2023, a simple random sampling method was used to conduct a survey in three key townships (towns) in Zhenxiong County, Chishuiyuan Town, Yanyuan Town, and Linkou Yi and Miao Ethnic Township. Three administrative villages were selected from each township (town) as survey sites, and dental fluorosis examination on children aged 8 - 12 years who were born and lived in the local area was conducted. Thirty households were selected from each survey site, the use of household stoves and the formation of related healthy living behaviors were investigated. At the same time, a survey was conducted among primary school students and housewives to investigate their knowledge of coal-burning-borne endemic fluorosis prevention and control. The control and elimination of endemic areas were evaluated according to the "Assessment Protocol for Control and Elimination of Key Endemic Diseases (2019 Edition)".Results:A total of 1 172 children were examined, and the detection rate of dental fluorosis was 7.76% (91/1 172), with a dental fluorosis index of 0.11. A total of 295 households were investigated, and the qualified improved stoves rate and the correct use rate of qualified improved stoves were 95.59% (282/295) and 100% (282/282), respectively. The correct drying rate of edible corn and chili peppers was 79.66% (235/295). The awareness rates of coal-burning-borne endemic fluorosis prevention and control knowledge among housewives and primary school students were 46.69% (409/876) and 82.49% (440.5/534), respectively. Among the 9 villages investigated, two villages had met the criteria for eliminating endemic disease areas, two villages had met the criteria for controlling endemic disease areas, and the remaining 5 villages were uncontrolled.Conclusions:After implementing the comprehensive prevention and control measures mainly based on changing stoves, coal-burning-borne endemic fluorosis condition in Zhenxiong County has been effectively controlled, but there is still a significant gap between the elimination goals of some endemic fluorosis areas. Therefore, it is necessary to continue to strengthen prevention and control measures and promote health education.

Acute respiratory distress syndrome(ARDS)is a common respiratory emergency,but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures.Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS,but the application of hydrogen has flammable and explosive safety concerns.Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance,thus improving ARDS in patients and animal models.Coral calcium hydrogenation(CCH)is a new solid molecular hydrogen carrier prepared from coral calcium(CC).Whether and how CCH affects acute lung injury in ARDS re-mains unstudied.In this study,we observed the therapeutic effect of CCH on lipopolysaccharide(LPS)induced acute lung injury in ARDS mice.The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable,demonstrating a significant improvement compared to the untreated ARDS model group.CCH treatment significantly reduced pulmonary hemorrhage and edema,and improved pulmonary function and local microcirculation in ARDS mice.CCH promoted mitochon-drial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2(Trx2),improved lung mitochondrial dysfunction induced by LPS,and reduced oxidative stress damage.The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation.

Objective:To clarify the content on exercise training in patients with connective tissue disease-associated pulmonary arterial hypertension through a scoping review.Methods:Using the scoping review methodological framework proposed by Arksey and O'Malley as a guide, Chinese and English databases such as PubMed, Embase, Wanfang Data, and China National Knowledge Infrastructure were searched to screen the literature on exercise training for patients with connective tissue disease-associated pulmonary arterial hypertension. The search period was from database establishment to April 30, 2024. Two researchers extracted basic information of the included literature, content of the pre-exercise training assessment, exercise training program, and outcome indicators.Results:A total of 13 articles were included. The content of the pre-exercise training assessment in patients with connective tissue disease-associated pulmonary arterial hypertension was not standardized. The type of exercise training was based on aerobic, resistance and respiratory training, with a focus on home exercise. The main outcome indicators included the 6-minute walk distance, cardiopulmonary function, quality of life, and muscle strength.Conclusions:There are various types of exercise training for patients with connective tissue disease-associated pulmonary arterial hypertension, which are safe and feasible. Future research should focus on conducting home-based exercise training programs and constructing core outcome indicators to assess the effectiveness of exercise training.

After ostomy surgery, patients lose the ability to control their anal sphincter, relying on ostomy pouches for excretion. Convex baseplates offer several advantages, including preventing leakage, reducing the risk of stoma and peripheral skin complications, and adapting to the dynamic stoma shapes caused by peristaltic expansion and contraction of the stoma. This article reviews the structure and features of convex baseplates, usage considerations, existing challenges, and future prospects, aiming to provide a reference for the standardized clinical use of convex baseplates and to improve patient health outcomes.

Objective:To systematically summarize, describe, and evaluate the evidence related to convex baseplates use in adult ostomy patients through an evidence map, in order to identify research gaps and future directions.Methods:A systematic search was conducted in Chinese and English databases, including China National Knowledge Infrastructure, Wanfang Data, VIP, and PubMed, and others, from database inception to September 2024. Randomized controlled trials and quasi-experimental studies on convex baseplates use in adult ostomy patients were included. Literature quality was assessed using the Cochrane Handbook 5.1.0 bias risk assessment tool and the critical appraisal tool for quasi-experimental studies from the Joanna Briggs Institute Centre for Evidence-Based Healthcare. Based on the PICO principle [participant (P) , intervention (I) , comparison (C) , outcome (O) ] , an evidence mapping coding system was extracted and developed by integrating relevant guidelines and consensus. Data extraction and coding were performed using EPPI-Reviewer software, and key evidence characteristics and literature quality were presented using bubble charts.Results:A total of eight randomized controlled trials and six quasi-experimental studies were included. Most of the 14 studies had a high risk of bias. The target populations for interventions were divided into two categories: prevention and treatment. The main complications involved stoma skin-mucosal separation, stoma peristomal dermatitis, and stoma height issues. The main outcome measures included baseplate seal integrity, wound healing, complication rates, clinical symptoms, adverse events, patient acceptance, and quality of life.Conclusions:Most of the studies on convex baseplates has focused on enterostomy patients. The majority of studies have a high risk of bias, and the number of studies is limited. Further clarification is needed on the selection criteria for convex baseplates with different characteristics, and the clinical application effects of convex baseplates urgently need further evaluation.