OBJECTIVE To explore the effect and mechanism of berberine in ameliorating asthma in mice by regulating glycolysis via the hypoxia inducible factor-1α （HIF-1α）/pyruvate dehydrogenase kinase-1 （PDHK1） pathway.METHODS Mice were randomly divided into blank control group， model group， low- and high-dose berberine groups （100， 200 mg/kg， intragastric administration）， dimethyloxalylglycine （DMOG， HIF-1α agonist） group （2 mg， intranasal instillation）， and berberine+DMOG group （intragastric administration of 200 mg/kg berberine plus intranasal instillation of 2 mg DMOG）， with 12 mice in each group. Except for the blank control group， mice in the remaining groups were subjected to ovalbumin-induced sensitization and challenge to establish the asthma model. During the challenge period， mice were given corresponding drugs or normal saline once a day for 6 consecutive days. At 24 h after the last challenge， pulmonary function and airway reactivity of mice were determined； the content of ovalbumin-specific immunoglobulin E （OVA-sIgE） in serum was detected； inflammatory cells in bronchoalveolar lavage fluid （BALF） were counted； bronchial inflammation and goblet cell hyperplasia were histologically evaluated； the levels of inflammatory cytokines [interleukin-4 （IL-4）， IL-5， IL-13]， contents of glycolytic products [lactic acid， pyruvic acid， adenosine triphosphate （ATP）]， as well as mRNA and protein expressions related to the HIF-1α/PDHK1 pathway in lung tissue were measured.RESULTS Compared with the model group， the low- and high-dose berberine groups exhibited significantly elevated or increased dynamic lung compliance， peak expiratory flow， forced vital capacity （FVC）， forced expiratory volume in 0.1 second （FEV 0.1 ）， and FEV 0.1 /FVC （ P ＜0.05）， accompanied by significantly decreased airway resistance and enhanced pause value （ P ＜0.05）. Moreover， serum OVA-sIgE content， counts of white blood cell， neutrophil， lymphocyte， monocyte， eosinophil and basophil in BALF， scores for bronchial inflammation and goblet cell hyperplasia， levels of pulmonary inflammatory cytokines and contents of glycolytic products， as well as mRNA and protein expressions of HIF-1α， PDHK1， pyruvate kinase M2 and lactate dehydrogenase A were all significantly reduced （ P ＜0.05）. DMOG pretreatment obviously reversed the protective effects of high-dose berberine in asthmatic mice （ P ＜0.05）.CONCLUSIONS Berberine can inhibit the HIF-1α/PDHK1 pathway to decrease glycolytic level， so as to ameliorate airway inflammation and airway hyperresponsiveness in asthmatic mice.

Effective annotation of in vivo drug metabolites using liquid chromatography-mass spectrometry (LC-MS) remains a formidable challenge. Herein, a metabolic reaction-based molecular networking (MRMN) strategy is introduced, which enables the "one-pot" discovery of prototype drugs and their metabolites. MRMN constructs networks by matching metabolic reactions and evaluating MS² spectral similarity, incorporating innovations and improvements in feature degradation of MS² spectra, exclusion of endogenous interference, and recognition of redundant nodes. A minimum 75% correlation between structural similarity and MS² similarity of neighboring metabolites was ensured, mitigating false negatives due to spectral feature degradation. At least 79% of nodes, 49% of edges, and 97% of subnetworks were reduced by an exclusion strategy of endogenous ions compared to the Global Natural Products Social Molecular Networking (GNPS) platform. Furthermore, an approach of redundant ions identification was refined, achieving a 10%-40% recognition rate across different samples. The effectiveness of MRMN was validated through a single compound, plant extract, and mixtures of multiple plant extracts. Notably, MRMN is freely accessible online at https://yaolab.network, broadening its applications.

Wilson disease is a copper metabolism disorder caused by mutations in the ATP7B gene， which encodes a copper-transporting ATPase β， and can result in multisystem damage. The kidneys are the third most commonly affected organs after the liver and brain. In recent years， numerous diagnostic and treatment guidelines for Wilson disease have emerged. However， most of these focus primarily on hepatic and neurological manifestations and their management， with limited coverage of renal involvement. The high incidence， low awareness， and lack of clinical specificity of Wilson disease-related renal damage （WDRD） have made early detection and intervention particularly challenging in clinical practice. To further optimize the treatment of patients with WDRD， improve clinical diagnosis and management， and enhance patients' quality of life， the Neurology Committee of the Chinese Association of Integrative Medicine， in April 2024， initiated a revision of the first expert consensus on the integrated diagnosis， treatment， and management of WDRD. This effort brought together experts in hepatology， encephalopathy （neurology）， and nephrology from many tertiary-level grade A hospitals and research institutions across China. Through comprehensive literature review and integration of frontline clinical experience， the expert group jointly developed Chinese Expert Consensus on Integrated Chinese and Western Medicine Management of Wilson Disease-related Renal Damage （hereinafter referred to as the "Consensus"）. This article provides a detailed interpretation of the Consensus in terms of diagnostic criteria， traditional Chinese medicine （TCM） syndrome differentiation and treatment classification， and comprehensive disease management， aiming to better guide clinical application. Regarding diagnostic criteria， the Consensus integrates the latest standards in China and abroad， highlights the importance of biochemical diagnosis， and compensates for the limitations of genetic testing. In the area of TCM syndrome differentiation and treatment， the Consensus refines four major syndrome types， introduces a newly defined syndrome， i.e.， phlegm， blood stasis， and heat accumulation， and elaborates on treatment principles， prescriptions， and clinical modification rules for each syndrome. For comprehensive disease management， the Consensus emphasizes multi-dimensional intervention strategies， including diet， exercise， emotional regulation， medication， and medical care， with the goal of maximally controlling the progression of renal dysfunction and helping patients achieve a better quality of life.

Five novel nor-eremophilane-type sesquiterpenoids, peniroqueforins E-H and J (1-4 and 7), two new eremophilane-type sesquiterpenoids, peniroqueforins I and K (5 and 8), and a new eudesmane-type sesquiterpenoid, peniroqueforin L (9), along with four known compounds (6 and 10-12), were isolated and characterized from fungus Penicillium roqueforti (P. roqueforti). The structures and absolute configurations of these compounds were determined through comprehensive spectroscopic analyses, electronic circular dichroism (ECD) data analyses, and single-crystal X-ray diffraction methods. The anti-multi-drug resistance (MDR) cancer activity of these compounds was evaluated using SW620/Ad300 cells. Notably, the half maximal inhibitory concentration (IC₅₀) value of paclitaxel (PTX) combined with 1 in SW620/Ad300 cells was 50.36 nmol·L^-1, which was 65-fold more potent than PTX alone (IC₅₀ 3.26 μmol·L^-1). Subsequent molecular docking studies revealed an affinity between compound 1 and P-glycoprotein (P-gp), suggesting that this nor-eremophilane-type sesquiterpenoid (1) could serve as a potential lead for MDR reversal in cancer cells through P-gp inhibition.
Penicillium/chemistry* ; Humans ; Sesquiterpenes/isolation & purification* ; Cell Line, Tumor ; Molecular Structure ; Drug Resistance, Neoplasm/drug effects* ; Antineoplastic Agents/pharmacology* ; Drug Resistance, Multiple/drug effects* ; Molecular Docking Simulation

Objective:To discuss the effect of sericin on the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/nuclear factor-κB(NF-κB)signaling pathway and apoptosis in the streptozotocin(STZ)-damaged INS-1 cells,and to clarify its mechanism.Methods:The INS-1 cells were cultured with complete medium containing 0,0.1,0.3,1.0,3.0,and 10.0 μmol·L-1 Akt1 inhibitor A-674563,10 mmol·L-1 STZ,and 600 mg·L-1 sericin,and divided into 0,0.1,0.3,1.0,3.0,and 10.0 μmol·L-1 A-674563 groups,and the control group(complete medium without drugs)was set up.Cell counting kit-8(CCK-8)method was used to detect the survival rates of the INS-1 cells,and the half-maximal inhibitory concentration(IC50)value was calculated to determine the optimal inhibitory concentration of A-674563,which was further verified by Western blotting method.The INS-1 cells were divided into normal control group(complete medium),model group(10 mmol·L-1 STZ+complete medium),and low,medium,and high doses of sericin groups(10 mmol·L-1 STZ+150 mg·L-1 sericin+complete medium,10 mmol·L-1 STZ+300 mg·L-1 sericin+complete medium,and 10 mmol·L-1 STZ+600 mg·L-1 sericin+complete medium).CCK-8 method was used to detect the survival rates of the INS-1 cells in various groups to determine the optimal concentration of sericin.Additionally,the INS-1 cells were divided into normal control group(complete medium),model group(10 mmol·L-1 STZ+complete medium),sericin group(10 mmol·L-1 STZ+600 mg·L-1 sericin+complete medium),and A-674563 group(10 mmol·L-1 STZ+600 mg·L-1 sericin+0.3 μmol·L-1 A-674563+complete medium).Flow cytometry was used to detect the apoptotic rates of the INS-1 cells in various groups;real-time fluorescence quantitative PCR(RT-qPCR)method was used to detect the expression levels of Akt1,NF-κB,tumor necrosis factor-α(TNF-α),and interleukin-6(IL-6)mRNA in the INS-1 cells in various groups;Western blotting method was used to detect the expression levels of phosphorylated Akt1(p-Akt1)and NF-κB proteins in the INS-1 cells in various groups;enzyme linked immunosorbent assay(ELISA)method was used to detect the levels of TNF-α and IL-6 in the INS-1 cells in various groups.Results:The survival rates of the INS-1 cells in control group was 100.00%±0.00%;in 0,0.1,0.3,1.0,3.0,and 10.0 μmol·L-1 A-674563+10 mmol·L-1 STZ+600 mg·L-1 sericin+complete medium groups,which were 82.50%±2.28%,69.47%±1.94%,51.51%±1.74%,38.94%±1.57%,24.79%±1.14%,and 19.85%±1.03%,respectively.The IC?? value of A-674563 for INS-1 cells was 0.3 μmol·L-1,and 0.3 μmol·L-1 A-674563 was selected for subsequent experiments.Compared with 0 μmol·L-1 A-674563,the expression level of p-Akt1 protein in the INS-1 cells after treated with 0.3 μmol·L-1 A-674563+10 mmol·L-1 STZ+600 mg·L-1 sericin+complete medium was significantly decreased(P<0.05).The CCK-8 results showed that compared with normal control group,the survival rate of the INS-1 cells in model group was significantly decreased(P<0.05);compared with model group,the survival rates of the INS-1 cells in low,medium,and high doses of sericin groups were significantly increased(P<0.05);compared with low and medium doses of sericin groups,the survival rate of the INS-1 cells in high dose of sericin group was significantly increased(P<0.05).Thus,600 mg·L-1 sericin was selected for subsequent experiments.The CCK-8 results showed that compared with normal control group,the survival rate of the INS-1 cells in model group was significantly decreased(P<0.05);compared with model group,the survival rate of the INS-1 cells in sericin group was significantly increased(P<0.05);compared with sericin group,the survival rate of the INS-1 cells in A-674563 group was significantly decreased(P<0.05).The flow cytometry results showed that compared with normal control group,the apoptotic rate of the INS-1 cells in model group was significantly increased(P<0.05);compared with model group,the apoptotic rate of the INS-1 cells in sericin group was significantly decreased(P<0.05);compared with sericin group,the apoptotic rate of the INS-1 cells in A-674563 group was significantly increased(P<0.05).The RT-qPCR results showed that compared with normal control group,the expression level of Akt1 mRNA in the INS-1 cells in model group was significantly decreased(P<0.05);compared with model group,the expression levels of Akt1 mRNA in the INS-1 cells in low,medium,and high doses of sericin groups were significantly increased(P<0.05);compared with low and medium doses of sericin groups,the expression level of Akt1 mRNA in the INS-1 cells in high dose of sericin group was significantly increased(P<0.05).Compared with normal control group,the expression levels of NF-κB,TNF-α,and IL-6 mRNA in the INS-1 cells in model group were significantly increased(P<0.05);compared with model group,the expression levels of NF-κB,TNF-α,and IL-6 mRNA in the INS-1 cells in sericin group were significantly decreased(P<0.05);compared with sericin group,the expression level of NF-κB mRNA in the INS-1 cells in A-674563 group was significantly increased(P<0.05).The Western blotting results showed that compared with normal control group,the expression level of p-Akt1 protein in the INS-1 cells in model group was significantly decreased(P<0.05);compared with model group,the expression levels of p-Akt1 protein in the INS-1 cells in low,medium,and high doses of sericin groups were significantly increased(P<0.05);compared with low and medium doses of sericin groups,the expression level of p-Akt1 protein in the INS-1 cells in high dose of sericin group was significantly increased(P<0.05).Compared with normal control group,the expression level of NF-κB protein in the INS-1 cells in model group was significantly increased(P<0.05);compared with model group,the expression level of NF-κB protein in the INS-1 cells in sericin group was significantly decreased(P<0.05);compared with sericin group,the expression level of NF-κB protein in the INS-1 cells in A-674563 group was significantly increased(P<0.05).The ELISA results showed that compared with normal control group,the levels of TNF-α and IL-6 in the INS-1 cells in model group were significantly increased(P<0.05);compared with model group,the levels of TNF-α and IL-6 in the INS-1 cells in sericin group were significantly decreased(P<0.05);compared with sericin group,the levels of TNF-α and IL-6 in the INS-1 cells in A-674563 group were significantly increased(P<0.05).Conclusion:Sericin alleviates the PI3K/Akt/NF-κB signaling pathway-mediated inflammatory response and apoptosis by targeting Akt1,exerting a protective effect against STZ-induced damage in INS-1 cells.

Background Injury poses a serious threat to human health. As global warming continues to intensify, there is an urgent need to explore the impact of temperature changes on injury deaths. However limited research has focused on this issue. Objective To investigate the relationship between daily mean temperature change (Tm) and injury death, as well as to estimate the associated future death burden in Hunan Province. Methods We employed an individual-level, time-stratified case-crossing design to establish a conditional logistic regression model to analyze the exposure-response relationship between daily mean temperature change and injury death in Hunan Province from 2013 to 2018. Consequently, we conducted subgroup analysis of gender, age group, and injury type. Finally, we estimated the excess burden of injury death attributable to temperature changes under a sustainable development path [low emission scenario (SSP1-2.6)], regional competition path [high emission scenario (SSP3-7.0)], or fossil fuel development path [very high emission scenario (SSP5-8.5)]. Results The study collected 155577 injury deaths in Hunan Province. The results indicated that for each 1 ℃ increment in daily mean temperature, the cumulative excess risk (CER) of injury mortality among Hunan residents increased by 0.71% (95%CI: 0.53%, 0.90%). Notably, the CER for intentional injuries (1.06%, 95%CI: 0.51%, 1.61%) was higher than that for unintentional injuries (0.66%, 95%CI: 0.46%, 0.87%). Warmer temperatures were positively associated with CER of mortality due to drowning, falls, transport injuries, assaults, and suicides, while they were negatively associated with mortality due to poisoning. Compared with 2010–2019, for 2090–2099, the excess mortality rate (EMR) due to ambient temperature increase in Hunan Province under the SSP5-8.5 scenario (14.62/100000, 95%CI: 10.81/100000, 18.40/100000) would be higher than that of the SSP3-7.0 scenario (10.28/100000, 95%CI: 7.58/100000, 12.97/100000) and the SSP1-2.6 scenario (3.35/100000, 95%CI: 2.46/100000, 4.23/100000); the EMR would be around 2.5 times among men (20.64/100000, 95%CI: 14.44/100000, 26.8/100000) than that among women (8.33/100000, 95%CI: 3.98/100000, 12.6/100000). Among unintentional injuries, the leading contributors to EMR would be drowning (4.46/100000), falls (3.96/100000), and transport injuries (2.96/100000). And among intentional injuries, the EMR for suicide (2.08/100000) would be higher than that for assault (0.47/100000). Conclusion Climate warming will increase the total burden of injury-related deaths among residents in Hunan Province, especially in the absence of effective mitigation strategies and measures. It is necessary to strengthen the prevention and control of severe injuries closely related to temperature changes, such as drowning, falls, traffic, and suicides injuries, in order to reduce injury deaths associated with climate change.

Glycogen storage disease type Ⅱ,also known as Pompe disease,is an autosomal recessive metabolic myopathy with pulmonary hypertension as a rare complication.We reported a case of pulmonary hypertension in adult with late-onset glycogen storage disease type Ⅱ.Her arterial blood gas results indicated type Ⅱ respiratory failure,lung function indicated severe restricted ventilation dysfunction,sleep monitoring indicated severe sleep apnea hypopnea,severe nocturnal hypoxemia,echocardiography-derived systolic pulmonary pressure was 62 mmHg(1 mmHg=0.133 kPa),electromyography indicated myogenic lesion,and whole exon sequencing indicated GAA gene mutation.Supportive therapy and enzyme replacement therapy are applied in this patient.

Objectives:To observe the effectiveness and safety of recombinant human brain natriuretic peptide(rhBNP)for the treatment of patients with right heart failure caused by pulmonary arterial hypertension(PAH).Methods:A total of 421 patients with right heart failure caused by PAH who were hospitalized in Fuwai Hospital from January 2019 to June 2024 were retrospectively included in this study.All patients were treated with rhBNP on top of conventional therapy.24 h urine volume,body weight,liver and renal function index,electrolyte,uric acid,red blood cell distribution width(RBCDW),cardiac function,blood pressure and heart rate before and after the treatment of rhBNP were compared.Clinical symptoms,signs and the occurrence of adverse events during treatment were also observed.Results:Compared with baseline,after treatment with rhBNP,the 24 h urine volume increased.The levels of body weight,transaminase,total bilirubin,direct bilirubin,uric acid,RBCDW,systolic blood pressure,heart rate,and N-terminal pro-B-type natriuretic peptide significantly decreased(all P<0.05).There were no statistically significant differences in the levels of serum creatinine,and tricuspid annular plane systolic excursion to pulmonary artery systolic pressure ratio(both P>0.05).Dyspnea and lower limbs edema were improved in 75.2%cases(227/302)and 66.9%cases(281/420)respectively.The incidence of adverse events and severe adverse events during rhBNP treatment were 1.2%(5/421)and 0.5%(2/421)respectively.Conclusions:Adding rhBNP on top of standard medication can effectively increase 24 h urine volume,reduce body weight,improve some prognostic indicators,improve the clinical symptoms and signs of heart failure without negatively affecting the renal function in right heart failure patients caused by PAH.Blood pressure should be closely monitored during the treatment process.

Objective:To investigate the alterations of individual metabolic brain network properties in patients with mild cognitive impairment (MCI) and their correlations with cognitive function.Methods:One hundred and five participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) database enrolled from March 2012 to February 2016 were chosen, including 61 MCI patients and 44 normal controls (NC). Cognitive assessments, including mini-mental state examination (MMSE), auditory verbal learning test (AVLT), trail making test (TMT), and semantic verbal fluency (SVF) score, were performed in both groups; differences of above scores and clinical data between the participants from the two groups were compared. T1-weighted imaging and fluorodeoxyglucose positron emission tomography (FDG-PET) images were collected in both groups; individual metabolic brain networks were constructed based on differences in effect sizes between brain regions and network properties were calculated. Spatial correlation analysis was used to compare the correlations of metabolic brain networks at the individual and group levels. General linear model was employed to compare the differences in network properties between the two groups. Partial correlation analysis was used to examine the correlations of differential network properties with cognitive function in MCI patients. A support vector machine (SVM) classification model was constructed based on individual metabolic brain network properties, and receiver operating characteristic (ROC) curve was used to explore the diagnostic value of this SVM classification model in MCI.Results:(1) Compared with the NC group, the MCI group had significantly lower MMSE and AVLT-immediate recall scores, and longer TMT-A completion time ( P<0.05). (2) Spatial correlation analysis revealed a positive correlation between individual metabolic brain networks and group-level metabolic brain networks in patients of the MCI group ( r=0.825, P<0.001). No significant differences in global network properties were noted between the two groups ( P>0.05). Compared with the NC group, the MCI group significantly decreased degree centrality in the left A8vl, right A39c, and right V5/MT+ regions, increased degree centrality in the left anterior cuneus, decreased nodal efficiency in the left A8vl, right V5/MT+, and right caudal hippocampus regions, increased nodal shortest path length and nodal clustering coefficient in the left A8vl region ( P<0.05). (3) The degree centrality at the A8vl of ventral part of the left middle frontal gyrus and nodal efficiency in right caudal hippocampus region were positively correlated with AVLT-immediate recall scores ( r=0.331, P=0.010; r=0.282, P=0.030), nodal efficiency in the left A8vl region was negatively correlated with TMT-A completion time ( r=-0.470, P<0.001), and nodal efficiency in the left A8vl region was positively correlated with SVF score ( r=0.263, P=0.044). (4) Area under the curve of SVM classification model in diagnosing MCI was 0.880 (95% CI: 0.813-0.945, P<0.001), with an accuracy rate of 0.790. Conclusions:Patients with MCI have alterations in individual metabolic brain network properties, among which the degree centrality and nodal efficiency of some nodes are closely related to cognitive function changes. Models constructed based on individual metabolic brain network properties can help to effectively diagnose MCI.

Objective:To share our experience of single-port transoral Da Vinci robotic surgery for laryngeal and pharyngeal benign tumors.Methods:Three patients aged over 18 years and diagnosed respectively with epiglottic cyst, aryepiglottic fold cyst and thyroglossal duct cyst at tongue base were included who received operations in Hainan Hospital of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine (Boao Research Hospital of Hainan) between August 1, 2023 and April 10, 2024. There were 1 male and 2 females, with an average age of 59 years old. The clinical diagnosis of these 3 patients was respectively epiglottic cyst, aryepiglottic fold cyst and thyroglossal duct cyst at tongue base. Intraoperative conversion rate, blood loss, operation time, hospital stay, pain score and swallowing function score were analyzed.Results:All three patients successfully underwent the operations with the single-port Da Vinci robotic system. The clean-contaminated resection rate of the tumors was 100%. The conversion rate was nil. The blood loss was 0-7 ml. The operation time was 5-30 minutes. There were no adverse events such as loosening of teeth and soft tissue abrasions of pharyngeal side wall. The rate of oral feeding within 24 hours after surgery was 100%. No postoperative coughing, bleeding, or dyspnea occurred. The average length of hospital stay was 3.7 days. The VAS score decreased 3 days after surgery compared to 1 day after surgery. The swallowing function recovered 1 month after surgery.Conclusion:The single-port transoral robotic surgery for laryngeal and pharyngeal benign lesions is safe and efficient, with fewer complications.