ObjectiveTo observe the pharmacodynamic efficacy of phlorizin in improving hepatic glycolipid metabolism disorders in type 2 diabetic mellitus （T2DM） rats and to explore its mechanism of action based on the insulin receptor substrate-1 （IRS-1）/phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsA high-fat diet and streptozotocin （STZ） were used to establish T2DM rat models. The rats were randomly assigned into six groups： the blank control group， model group， metformin group （300 mg·kg^-1）， and phlorizin high-dose （100 mg·kg^-1） and low-dose groups （25 mg·kg^-1）. The rats were given intragastric administration for 6 weeks. The changes in body weight and fasting blood glucose （FBG） were observed， and the oral glucose tolerance test （OGTT） was carried out. The levels of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， glycated serum protein （GSP）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT） in serum were detected by an automatic biochemical analyzer. The levels of fasting insulin （FINS）， interleukin （IL）-1β， IL-6， and tumour necrosis factor （TNF）-α were detected by enzyme-linked immunosorbent assay （ELISA）. The levels of superoxide dismutase （SOD） and malondialdehyde （MDA） were detected by the biochemical assays. The pancreas index， liver index， and insulin resistance index were calculated. Hematoxylin-eosin （HE） staining was used to evaluate the pathological changes in liver and pancreatic tissues. The immunofluorescence method was used to detect the changes in insulin and glucagon in pancreatic tissue. Western blot was used to detect the expression of related proteins in the IRS-1/PI3K/Akt pathway of liver tissue and its downstream glycogen synthase kinase-3β （GSK-3β） and forkhead box transcription factor O1 （FoxO1） proteins. ResultsCompared with the blank control group， the body weight of rats in the model group continued to decrease， while the FBG level increased significantly. The area under the OGTT blood glucose curve （AUC）， GSP， TC， TG， LDL-C， IL-1β， IL-6， TNF-α， MDA， pancreatic index and liver index increased significantly， while the levels of HDL-C， SOD， and FINS decreased significantly （P0.05， P0.01）. Histological results showed that the pancreatic islets of rats in the model group exhibited atrophy and severe structural abnormalities. The insulin-positive β-cells decreased significantly （P0.01）， while the glucagon-positive α-cells increased significantly （P0.01）. Inflammatory cell infiltration and partial necrosis were observed in the liver tissues of the model group rats. The expressions of p-IRS-1/IRS-1， p-GSK-3β/GSK-3β， and p-FoxO1/FoxO1 proteins in the liver of the model group increased significantly （P0.01）， while the expressions of p-PI3K/PI3K and p-Akt/Akt proteins decreased significantly （P0.01）. Compared with the model group， the diabetic symptoms of rats in all administration groups were improved. The changes in body weight and FBG were close to those of the blank control group. The levels of OGTT-AUC， GSP， TC， TG， LDL-C， MDA， IL-1β， IL-6， TNF-α and the pancreatic index， liver index were obviously reduced （P0.05， P0.01）， while the levels of HDL-C， SOD， and FINS obviously increased （P0.05， P0.01）. The pathological changes of the pancreas and liver in rats in all treatment groups were effectively improved. The insulin-positive β-cells in the pancreas increased significantly （P0.01）， while the glucagon-positive α-cells decreased significantly （P0.01）. The protein expressions of p-IRS-1/IRS-1， p-GSK-3β/GSK-3β， and p-FoxO1/FoxO1 in the liver were significantly reduced （P0.01）， while the protein expressions of p-PI3K/PI3K and p-Akt/Akt significantly increased （P0.01）. ConclusionPhlorizin reversed the weight loss and abnormal increase of FBG in T2DM rats， improved blood lipid profiles， oxidative stress， and inflammatory levels， alleviated insulin resistance， and had certain protective effects on the liver and pancreas. The hypoglycemic mechanism may involve regulating the IRS-1/PI3K/Akt signaling pathway to inhibit the activities of GSK-3β and FoxO1， thereby promoting liver glycogen synthesis and suppressing hepatic gluconeogenesis， ultimately improving glycolipid metabolism disorders.

ObjectiveTo observe the pharmacodynamic efficacy of phlorizin in improving hepatic glycolipid metabolism disorders in type 2 diabetic mellitus （T2DM） rats and to explore its mechanism of action based on the insulin receptor substrate-1 （IRS-1）/phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsA high-fat diet and streptozotocin （STZ） were used to establish T2DM rat models. The rats were randomly assigned into six groups： the blank control group， model group， metformin group （300 mg·kg^-1）， and phlorizin high-dose （100 mg·kg^-1） and low-dose groups （25 mg·kg^-1）. The rats were given intragastric administration for 6 weeks. The changes in body weight and fasting blood glucose （FBG） were observed， and the oral glucose tolerance test （OGTT） was carried out. The levels of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， glycated serum protein （GSP）， aspartate aminotransferase （AST）， and alanine aminotransferase （ALT） in serum were detected by an automatic biochemical analyzer. The levels of fasting insulin （FINS）， interleukin （IL）-1β， IL-6， and tumour necrosis factor （TNF）-α were detected by enzyme-linked immunosorbent assay （ELISA）. The levels of superoxide dismutase （SOD） and malondialdehyde （MDA） were detected by the biochemical assays. The pancreas index， liver index， and insulin resistance index were calculated. Hematoxylin-eosin （HE） staining was used to evaluate the pathological changes in liver and pancreatic tissues. The immunofluorescence method was used to detect the changes in insulin and glucagon in pancreatic tissue. Western blot was used to detect the expression of related proteins in the IRS-1/PI3K/Akt pathway of liver tissue and its downstream glycogen synthase kinase-3β （GSK-3β） and forkhead box transcription factor O1 （FoxO1） proteins. ResultsCompared with the blank control group， the body weight of rats in the model group continued to decrease， while the FBG level increased significantly. The area under the OGTT blood glucose curve （AUC）， GSP， TC， TG， LDL-C， IL-1β， IL-6， TNF-α， MDA， pancreatic index and liver index increased significantly， while the levels of HDL-C， SOD， and FINS decreased significantly （P0.05， P0.01）. Histological results showed that the pancreatic islets of rats in the model group exhibited atrophy and severe structural abnormalities. The insulin-positive β-cells decreased significantly （P0.01）， while the glucagon-positive α-cells increased significantly （P0.01）. Inflammatory cell infiltration and partial necrosis were observed in the liver tissues of the model group rats. The expressions of p-IRS-1/IRS-1， p-GSK-3β/GSK-3β， and p-FoxO1/FoxO1 proteins in the liver of the model group increased significantly （P0.01）， while the expressions of p-PI3K/PI3K and p-Akt/Akt proteins decreased significantly （P0.01）. Compared with the model group， the diabetic symptoms of rats in all administration groups were improved. The changes in body weight and FBG were close to those of the blank control group. The levels of OGTT-AUC， GSP， TC， TG， LDL-C， MDA， IL-1β， IL-6， TNF-α and the pancreatic index， liver index were obviously reduced （P0.05， P0.01）， while the levels of HDL-C， SOD， and FINS obviously increased （P0.05， P0.01）. The pathological changes of the pancreas and liver in rats in all treatment groups were effectively improved. The insulin-positive β-cells in the pancreas increased significantly （P0.01）， while the glucagon-positive α-cells decreased significantly （P0.01）. The protein expressions of p-IRS-1/IRS-1， p-GSK-3β/GSK-3β， and p-FoxO1/FoxO1 in the liver were significantly reduced （P0.01）， while the protein expressions of p-PI3K/PI3K and p-Akt/Akt significantly increased （P0.01）. ConclusionPhlorizin reversed the weight loss and abnormal increase of FBG in T2DM rats， improved blood lipid profiles， oxidative stress， and inflammatory levels， alleviated insulin resistance， and had certain protective effects on the liver and pancreas. The hypoglycemic mechanism may involve regulating the IRS-1/PI3K/Akt signaling pathway to inhibit the activities of GSK-3β and FoxO1， thereby promoting liver glycogen synthesis and suppressing hepatic gluconeogenesis， ultimately improving glycolipid metabolism disorders.

BackgroundThe violent aggressive behaviors of patients with schizophrenia usually have the characteristics of suddenness， unpredictability， high severity， and great difficulty in prevention. Early identification and accurate assessment of their risk of violent aggression have significant clinical significance. ObjectiveTo construct a predictive model for the violence risk in hospitalized patients with schizophrenia， to identify the key factors influencing the occurrence of violent behavior in these patients， so as to provide references for clinical precise quantitative assessment and early intervention. MethodsA total of 200 patients with schizophrenia who were hospitalized at Taiyuan Psychiatric Hospital from March 2022 to September 2024 and met the diagnostic criteria of the International Classification of Diseases， eleventh edition （ICD-11） were collected to form the modeling cohort. They were randomly divided into a training set （n=140） and a test set （n=60） at a ratio of 7∶3. Based on the least absolute shrinkage and selection operator （LASSO） regression algorithm， the feature variables were screened and dimension-reduced. The support vector machine （SVM） from machine learning was selected for model training and prediction. The discrimination efficacy of the model was evaluated by the area under the receiver operating characteristic （ROC） curve （AUC）， accuracy， precision， sensitivity， specificity， F1 value， and Brier value. ResultsLASSO regression screening identified 16 feature variables. Pearson correlation analysis revealed a positive correlation between prior violent behavior frequency and clinical psychiatric symptom scores （r=0.580， P<0.01）， a positive correlation between hospitalization compliance and current disease status （r=0.550， P=0.003）， and a positive correlation between educational level and family per capita monthly income （r=0.367， P<0.01）. The SVM model achieved an AUC of 0.853， accuracy of 0.800， precision of 0.810， sensitivity of 0.895， specificity of 0.636， F1 value of 0.850， and Brier value of 0.168. ConclusionThe SVM model has a relatively high level of applicability and overall predictive performance in the assessment of violent risk in schizophrenia patients， which is helpful for the early identification of violent risks in such patients. ［Funded by Specialized Research Project for Enhancing the Competence of Health Professionals in Taiyuan City （number， Y2023006）］

From the theoretical perspective of "body fluids and blood stasis mixing"， environmental microplastics （MPs） are conceptualized as a "novel turbid-toxin". This study aims to elucidate the complete pathogenic pathway through which MPs act as a key driving force （the "crucible" of pathogenesis） in the initiation and progression of atherosclerosis （AS）. By tracing the classical theories in the Chapter The Occurrence of All Diseases of Miraculous Pivot （Ling Shu）， this paper clarifies the core connotations of "body fluids"-it not only refers to endogenous pathological fluids and lipid turbidity but also provides a theoretical basis for incorporating "exogenous turbid fluids"， thereby laying a logical foundation for conceptualizing MPs as a "novel turbid-toxin". Meanwhile， the implications of "blood" （encompassing both blood quality abnormalities and blood stasis） and the dynamic process of "mixing" are elucidated. Drawing upon modern toxicological evidence， this paper demonstrates the high homology between MPs and "exogenous turbid-fluids" from three aspects： Morphology， toxicity， and invasion routes. The micro/nano-scale particle morphology of MPs enables mobility within the bloodstream. The multiple exposure pathways of MPs correspond to the traditional Chinese medicine understanding of pathogens invading through the mouth， nose， and skin. The characteristics of accumulating in vivo while inducing oxidative stress and inflammatory responses of MPs fully embody the pathogenic features-adhesion， binding， and vessel damage-of "turbid-toxin". On this basis， the dynamic pathogenesis of MP-induced AS is systematically interpreted. Initially， MPs with the "turbid-toxin" nature impair nutrient-defense harmony and cause endothelial dysfunction. Subsequently， as the core of "mixing"， they interact with blood lipids and immune cells， generating heat and phlegm to form a major pathological hub of chronic inflammation. Ultimately， this process drives the coalescence of phlegm， stasis， and turbid-toxin into tangible plaques， evolving from stable lesions to vulnerable masses and accumulations. By integrating classical pathogenic model with contemporary environmental medicine， this study establishes an analytical framework that bridges macro-theory and micro-mechanisms for understanding the cardiovascular risks of MPs through an integrative Chinese-Western medicine lens.

BACKGROUND:Epidemiological studies indicate that individuals with neurodegenerative diseases exhibit a comparatively lower risk of developing the majority of cancers.Although the precise mechanisms underlying this inverse correlation remain unclear,it is noteworthy that aberrant glucose metabolism,a pathological factor common to both conditions,may significantly contribute to this association.OBJECTIVE:To review the potential relationship between cancers and neurodegenerative diseases in glucose metabolism.METHODS:PubMed was searched for relevant literature using the search terms of"cancer,neurodegenerative diseases,Alzheimer's disease,Parkinson's disease,metabolic reprogramming,glucose metabolism,aerobic glycolysis,neuroprotection,aging,"and 136 articles were finally included for analysis.RESULTS AND CONCLUSION:Cancer and neurodegenerative diseases exhibit a profound pathological correlation at the level of glucose metabolism imbalance associated with aging.Cancer cells promote uncontrolled proliferation,invasion,and metastasis through the persistent activation of aerobic glycolysis,whereas neurodegenerative diseases are characterized by a reduction in aerobic glycolysis.Restoring aerobic glycolysis may confer neuroprotective effects and delay disease progression.The key nodes of glucose metabolism demonstrate a bidirectional regulatory pattern:metabolic regulators,which are significantly upregulated or aberrantly activated in cancer,are inhibited or functionally inactivated in neurodegenerative diseases.Mitochondria play a crucial role in mediating the aging process through the regulation of reactive oxygen species homeostasis and mitochondrial autophagy.They establish regulatory networks that connect cancer and neurodegenerative diseases,and maintaining their functional homeostasis is of paramount importance for disease prevention and treatment.

BACKGROUND:Epidemiological studies indicate that individuals with neurodegenerative diseases exhibit a comparatively lower risk of developing the majority of cancers.Although the precise mechanisms underlying this inverse correlation remain unclear,it is noteworthy that aberrant glucose metabolism,a pathological factor common to both conditions,may significantly contribute to this association.OBJECTIVE:To review the potential relationship between cancers and neurodegenerative diseases in glucose metabolism.METHODS:PubMed was searched for relevant literature using the search terms of"cancer,neurodegenerative diseases,Alzheimer's disease,Parkinson's disease,metabolic reprogramming,glucose metabolism,aerobic glycolysis,neuroprotection,aging,"and 136 articles were finally included for analysis.RESULTS AND CONCLUSION:Cancer and neurodegenerative diseases exhibit a profound pathological correlation at the level of glucose metabolism imbalance associated with aging.Cancer cells promote uncontrolled proliferation,invasion,and metastasis through the persistent activation of aerobic glycolysis,whereas neurodegenerative diseases are characterized by a reduction in aerobic glycolysis.Restoring aerobic glycolysis may confer neuroprotective effects and delay disease progression.The key nodes of glucose metabolism demonstrate a bidirectional regulatory pattern:metabolic regulators,which are significantly upregulated or aberrantly activated in cancer,are inhibited or functionally inactivated in neurodegenerative diseases.Mitochondria play a crucial role in mediating the aging process through the regulation of reactive oxygen species homeostasis and mitochondrial autophagy.They establish regulatory networks that connect cancer and neurodegenerative diseases,and maintaining their functional homeostasis is of paramount importance for disease prevention and treatment.

Background: Advances in intensive care have markedly improved survival after severe brain injury, leading to a growing population of patients with prolonged disorders of consciousness (pDOC). Current management of pDOC remains largely supportive, and evidence-based neuromodulatory interventions are limited; moreover, existing guidelines provide insufficiently explicit recommendations regarding mechanisms of action and objective biomarkers of treatment response. Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a potential noninvasive intervention; however, its modulatory effects on brain function in pDOC are not yet well characterized, and the paucity of integrative mechanistic evidence has constrained its translation into routine clinical practice. Objectives: Within a multimodal assessment framework, this study aims to systematically elucidate the neurobiological mechanisms by which taVNS modulates brain function and autonomic activity in patients with pDOC, and to evaluate its clinical potential to enhance levels of consciousness. Methods: In this randomized controlled trial, 60 patients with vegetative state/minimally conscious state will be enrolled and randomly allocated to a taVNS group, a transcutaneous nonauricular vagus nerve stimulation group (sham), or a control group (n = 20 per group) for a 4-week intervention. The primary outcome will be changes in the Coma Recovery Scale-Revised scores from baseline to weeks 1, 2, and 4 of treatment. Secondary outcomes will include functional brain activity assessed by electroencephalography and functional near-infrared spectroscopy, as well as autonomic modulation indexed by heart rate variability. Functional prognosis will be evaluated using the Glasgow Outcome Scale-Extended at the end of treatment and at a 6-month follow-up. Safety will be assessed by continuous monitoring and documentation of adverse events throughout the study period. Results and discussion: By integrating electroencephalography–functional near-infrared spectroscopy with heart rate variability, this study will characterize the effects of taVNS on functional brain networks and consciousness recovery in pDOC across complementary behavioral, electrophysiological, hemodynamic, and autonomic domains, while interrogating potential sources of clinical and neurobiological heterogeneity. The findings are expected to provide a mechanistic and evidence-based foundation for the mechanism-driven clinical implementation of taVNS and the optimization of stimulation protocols in pDOC. Clinical trial registration: International Traditional Medicine Clinical Trial Registry, ITMCTR20250021041, https://itmctr.ccebtcm.org.cn.

Mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern to activate the stimulator of interferon genes (STING) signaling in macrophages, promoting tissue inflammation. However, its role in acute myocardial infarction (AMI) remains unclear. Macrophage-specific Sting1 knockout mice were used to validate STING's pathological role in AMI. Cardiac and liver mtDNA were used to activate macrophages in co-culture systems with cardiomyocytes to assess fibrosis and hypertrophy. Panaxatriol saponin (PTS) was tested for its ability to block mtDNA-driven macrophage activation and subsequent cardiomyocyte damage. STING-PTS binding ability was analyzed. AMI rats received PTS to evaluate its effects on myocardial inflammation and ventricular remodeling. In vivo, macrophage-specific Sting1 knockout reduced myocardial inflammation and injury after AMI. In vitro, mtDNA-activated macrophages induced cardiomyocyte fibrosis and hypertrophy through STING signaling. PTS suppressed mtDNA-driven macrophage activation by directly binding STING, thereby blocking inflammatory cascades. In AMI rats, PTS treatment attenuated acute inflammation and reversed ventricular remodeling. These findings establish the mtDNA-STING axis in macrophages as a critical driver of post-AMI inflammation and identify pharmacological STING inhibition with PTS as a promising therapeutic strategy. The study bridges genetic validation with translational applications, highlighting macrophage STING as a novel target for ischemic heart disease management.

Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be elucidated. Serum creatinine (SCr) and blood urea nitrogen (BUN) were detected through pathological evaluation after CTD (1.5 mg/kg) oral gavage in mice in 3 days. Kidney lipidomics based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate lipids disorder after CTD exposure in mice. Then, spatial metabolomics based on matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to detect the kidney spatial distribution of lipids. Integrative analysis was performed to reveal the spatial lipid disorder mechanism and verify key lipids in vitro. The results showed that the levels of SCr and BUN were increased, and tubular necrosis was observed in mouse kidneys, resulting in acute tubular necrosis (ATN) in CTD-induced AKI. Then, lipidomics results revealed that after CTD exposure, 232 differential lipid metabolites and 11 pathways including glycerophospholipid (GP) and sphingolipid (SL) metabolism were disrupted. Spatial metabolomics revealed that 55 spatial differential lipid metabolites and nine metabolic pathways were disturbed. Subsequently, integrative analysis found that GP metabolism was stimulated in the renal cortex and medulla, whereas SL metabolism was inhibited in the renal cortex. Up-regulated lysophosphatidylcholine (LysoPC) (18:2(9Z,12Z)), LysoPC (16:0/0:0), glycerophosphocholine, and down-regulated sphingomyelin (SM) (d18:0/16:0), SM (d18:1/24:0), and SM (d42:1) were key differential lipids. Among them, LysoPC (16:0/0:0) was increased in the CTD group at 1.1196 μg/mL, which aggravated CTD-induced ATN in human kidney-2 (HK-2) cells. LysoPC acyltransferase was inhibited and choline phosphotransferase 1 (CEPT1) was activated after CTD intervention in mice and in HK-2 cells. CTD induces ATN, resulting in AKI, by activating GP metabolism and inhibiting SL metabolism in the renal cortex and medulla, LysoPC (16:0/0:0), LysoPC acyltransferase, and CEPT1 may be the therapeutic targets.

This study was conducted retrospectively on a cohort of 68 patients with steroid 5 α-reductase 2 (SRD5A2) deficiency and 46,XY disorders of sex development (DSD). Whole-exon sequencing revealed 28 variants of SRD5A2 , and further analysis identified seven novel mutants. The preponderance of variants was observed in exon 1 and exon 4, specifically within the nicotinamide adenine dinucleotide phosphate (NADPH)-binding region. Among the entire cohort, 53 patients underwent initial surgery at Sichuan Provincial People's Hospital (Chengdu, China). The external genitalia scores (EGS) of these participants varied from 2.0 to 11.0, with a mean of 6.8 (standard deviation [s.d.]: 2.5). Thirty patients consented to hormone testing. Their average testosterone-to-dihydrotestosterone (T/DHT) ratio was 49.3 (s.d.: 23.4). Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome; and their T/DHT ratios were below the diagnostic threshold. Furthermore, assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants. These mechanisms include interference with NADPH binding (c.356G>C, c.365A>G, c.492C>G, and c.662T>G) and destabilization of the protein structure (c.727C>T). The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts. Seven novel variations were identified, and the variant database for the SRD5A2 gene was expanded. These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.
Humans ; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/genetics* ; Disorder of Sex Development, 46,XY/blood* ; Male ; Membrane Proteins/genetics* ; Child, Preschool ; Child ; Retrospective Studies ; Adolescent ; Female ; Mutation ; Testosterone/blood* ; Infant ; Dihydrotestosterone/blood*