As the core hub of energy metabolism in eukaryotes, mitochondria participate in a variety of cellular activities, including metabolic regulation of the cell matrix, apoptosis, and the activation of signal transduction pathways. Their functional status is closely linked to the initiation and progression of various diseases. Neurodegenerative diseases are primarily characterized by the progressive loss and dysfunction of neurons, and mitochondrial dysfunction is considered one of the key triggers in this process. The specific mechanisms by which mitochondrial dysfunction contributes to neurodegenerative diseases have attracted widespread attention. When misfolded or unfolded proteins are detected, a process known as the mitochondrial unfolded protein response (mtUPR) is activated to promote proper protein folding or degradation, thereby restoring mitochondrial function. As a mitochondrial stress defense mechanism, mtUPR primarily regulates the expression of nuclear-encoded genes, such as chaperones and proteases, to alleviate mitochondrial stress. Studies have shown that, in addition to misfolded and unfolded proteins, other mitochondrial stresses—such as mitochondrial DNA abnormalities and reactive oxygen species (ROS)—can also induce mtUPR. The biological functions of mtUPR extend beyond mitochondria and are crucial for the health of the entire cell and even the whole organism. The mtUPR process involves communication between mitochondria and the nucleus, a phenomenon that is highly conserved and has been observed across different species. Abnormal activation or inhibition of mtUPR is closely associated with the development of various neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. An in-depth exploration of the dynamic regulatory role and molecular mechanisms of mtUPR is therefore of great significance for understanding the pathogenesis of these disorders. In addition to neuron loss, neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain, including insoluble fibrils of amyloid beta, phosphorylated tau, or α-synuclein. While the molecular pathways of mtUPR are largely conserved across different diseases, the possibility of differential regulatory factors cannot be excluded. Although mtUPR activation is predominantly recognized for its cytoprotective role, it may exert deleterious effects when overstimulated or sustained. Chronic mtUPR activity has been linked to mitochondrial dysfunction and increased neuronal vulnerability, contributing to the pathogenesis of various neurodegenerative diseases. This review summarizes the fundamental concepts, major inducers, and signaling pathways of the mtUPR. We focus on the intrinsic relationship and regulatory patterns between mtUPR and neurodegenerative diseases, providing insights that may aid the development of targeted therapies. Finally, we discuss the challenges and future directions of mtUPR research in this field, aiming to pave the way for new therapeutic breakthroughs. A major limitation arises from the experimental models currently used; most findings rely on model organisms or cultured cells, which cannot fully replicate the complexity of human neurons. Future research should therefore focus on three main directions: (1) defining the molecular switches that determine whether mtUPR acts in a protective or detrimental manner; (2) elucidating differences in mtUPR molecular pathways across various models of neurodegenerative diseases; and (3) establishing robust biomarkers for mtUPR activity.

Hepatocellular carcinoma(HCC)expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming.Aldolase A(ALDOA)plays a prominent role in glycolysis;however,little is known about its role in HCC development.In the present study,we aim to explore how ALDOA is involved in HCC proliferation.HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout,which is consistent with ALDOA overexpression encouraging HCC prolifera-tion.Mechanistically,ALDOA knockout partially limits the glycolytic flux in HCC cells.Meanwhile,ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase;ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function.A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun,and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells.In HCC patients,the expression level of ALDOA was correlated with the phosphorylation level of c-Jun(Thr93)and poor prognosis.Remarkably,hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models,and the knockdown of Aldoa strikingly decreased HCC development in vivo.Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription,opening additional avenues for anti-cancer therapies.

Objective To explore the mechanism of Shenqi Buzhong(SQBZ)Formula for alleviating mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease(COPD)in light of the AMPK/SIRT1/PGC-1α pathway.Methods Fifty male SD rat models of COPD,established by intratracheal lipopolysaccharide(LPS)instillation,exposure to cigarette smoke,and gavage of Senna leaf infusion,were randomized into 5 groups(n=10)for treatment with saline(model group),SQBZ Formula at low,moderate and high doses(3.08,6.16 and 12.32 g/kg,respectively),or aminophylline(0.024 g/kg)by gavage for 4 weeks,with another 10 untreated rats as the control group.Pulmonary function of the rats were tested,and pathologies and ultrastructural changes of the lung tissues were examined using HE staining and transmission electron microscopy.The levels of SOD,ATP,MDA,and mitochondrial membrane potential in the lungs were detected using WST-1,colorimetric assay,TBA,and JC-1 methods.Flow cytometry was used to analyze ROS level in the lung tissues,and the protein expression levels of P-AMPKα,AMPKα,SIRTI,and PGC-1α were detected using Western blotting.Results The rat models of COPD showed significantly decreased lung function,severe histopathological injuries of the lungs,decreased pulmonary levels of SOD activity,ATP and mitochondrial membrane potential,increased levels of MDA and ROS,and decreased pulmonary expressions of P-AMPKα,SIRTI,and PGC-1α proteins.All these changes were significantly alleviated by treatment with SQBZ Formula and aminophylline,and the efficacy was comparable between high-dose SQBZ Formula group and aminophylline group.Conclusion SQBZ Formula ameliorates mitochondrial dysfunction in COPD rats possibly by activating the AMPK/SIRT1/PGC-1α pathway.

Objective To investigate the effect of esketamine on postoperative depression in frail elderly patients undergoing thoracoscopic radical resection of lung cancer.Methods A total of 88 frail elderly patients undergoing elective thoracoscopic radical resection of lung cancer were assigned randomly(using a randomization table)and in a double-blind way(blinding applies to both researchers and patients)to an esketamine group(Esk group,n=44)and a normal saline group(NS group,n=44).In the Esk group,0.25 mg/kg esketamine was injected intravenously during anesthesia induction,followed by continuous infusion of esketamine at 0.125 mg/kg per hour until 20 min before the end of surgery.In the NS group,equivalent volumes of normal saline were administered using the same method.The primary outcome was the score for the 17-item Hamilton Rating Scale for Depression(HAMD-17)on days 7 and 30 after surgery.The secondary outcomes included sleep quality and cognitive function.Sleep quality was assessed using the numerical rating scale(NRS)on days 1,3,and 7 after surgery and the Pittsburgh Sleep Quality Index(PSQI)on day 30 after surgery.Cognitive function was assessed using the Mini-Mental State Examination(MMSE)on days 1,3,7,and 30 after surgery.The other indicators included the levels of serum brain-derived neurotrophic factor(BDNF),5-hydroxytryptamine(5-HT),S100β protein,and neuron specific enolase(NSE)at 24 hours(T1),48 hours(T2),and 72 hours(T3)after surgery,as well as perioperative data and postoperative safety outcomes.Results Three patients were excluded from the Esk group and the NS group,respectively,and eventually,41 patients in each group were included in the statistical analysis.There were no statistically significant differences between the two groups in terms of age,sex,body mass index,American Society of Anesthesiologists(ASA)classification,comorbidities,educational attainment,and the scores for HAMD-17,PSQI,and MMSE 1 day before surgery(P＞0.05).Concerning the primary outcome,compared with those of the NS group,the HAMD-17 scores of patients in the Esk group were significantly lower at 7 days(median[P25,P75])(7[6,8]vs.7[6,12],P=0.045)and 30 days(6[6,7]vs.7[6,9],P=0.020)after surgery.Concerning the secondary outcomes,compared with those of the NS group,the sleep NRS scores of patients in the Esk group were significantly lower at 1,3,and 7 days after surgery(P＜0.01),and the MMSE scores were significantly higher(P＜0.05).Concerning the other indicators,compared with those of the NS group,the concentrations of serum BDNF and 5-HT in the Esk group were significantly higher(P＜0.05 or 0.01)at T1-T3,while the content of S100β was significantly lower(P＜0.01)at T1-T3;the levels of serum NSE were significantly lower at T1 and T2(P＜0.01);the consumption of propofol,sufentanil,remifentanil,and sevoflurane during surgery in the Esk group was significantly reduced(P＜0.05 or 0.01);the incidence of postoperative nausea/vomiting and hyperalgesia was significantly lower(P＜0.01);the duration of postoperative mechanical ventilation,length-of-stay in postanesthesia care unit(PACU),and postoperative length-of-stay in the hospital were significantly shorter(P＜0.01).Conclusion Esketamine can improve the postoperative depressive state,sleep quality,and cognitive function in frail elderly patients undergoing thoracoscopic radical resection of lung cancer.

Objective:To explore the risk factors for in-hospital death after complete recanalization by mechanical thrombectomy and establish a risk prediction model in patients with acute large vessel occlusion stroke of the anterior circulation.Methods:A total of 468 patients with anterior circulation acute large vessel occlusion stroke who underwent mechanical thrombectomy in Stroke Center (Second Affiliated Hospital of Dalian Medical University), Department of Interventional Therapy (First Affiliated Hospital of Dalian Medical University), and Department of Neurointervention and Neurocritical Care (Central Hospital Affiliated to Dalian University of Technology) from January 2016 to November 2023 were selected. All patients achieved complete recanalization (modified thrombolysis in cerebral infarction: grading 3) immediately after thrombectomy. The clinical data, laboratory and imaging results of the patients were collected, and these patients were divided into in-hospital death group ( n=52) and in-hospital survival group ( n=416) according to occurrence of in-hospital death (all-cause death). Univariate analysis and multivariate Logistic regression analysis were used to screen the risk factors for in-hospital death, and a risk prediction model was constructed. Receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of the model, calibration curve and Hosmer-Lemeshow test were used to evaluate the accuracy of the model, and decision curve was used to evaluate the clinical utility of the model. Results:Univariate analysis showed that the in-hospital death group had significantly higher proportions of female patients, patients with atrial fibrillation, and patients with symptomatic intracranial hemorrhage compared with the in-hospital survival group (50.0% vs. 31.3%; 57.7% vs. 41.6%; 38.5% vs.11.8%), and significantly higher baseline blood glucose, and National Institutes of Health Stroke Scale score, neutrophil count, and neutrophil/lymphocyte ratio within 24 hours of thrombectomy (8.10 [7.05, 11.79] vs. 7.31[6.46, 9.25], 20 [16, 32] vs. 15 [10, 22], 10.09 [7.87, 13.19] vs. 8.47 [6.73, 10.32], 10.63 [5.87, 15.69] vs. 7.13 [5.16, 10.91], P<0.05). Multivariate Logistic regression analysis showed that female ( OR=2.533, 95% CI: 1.306-4.910, P=0.006), atrial fibrillation history ( OR=1.999, 95% CI: 1.044-3.827, P=0.037), neutrophil count within 24 hours of thrombectomy ( OR=1.162, 95% CI: 1.055-1.279, P=0.002), and symptomatic intracranial hemorrhage ( OR=4.066, 95% CI: 1.897-8.718, P<0.001) were independent risk factors for in-hospital death after complete recanalization; risk prediction model, accordingly, was 0.929×female+0.692×atrial fibrillation history+0.150×neutrophil count+1.403×symptomatic intracranial hemorrhage-5.349 ( P: probability of event occurrence). Area under ROC curve of the model was 0.765 (95% CI: 0.689-0.842, P<0.001); calibration curve and Hosmer-Lemeshow test of the model showed good accuracy ( χ2=7.656, P=0.468); decision curve of the model showed good clinical utility at threshold probability of 0.05-0.90. Conclusion:For patients with acute large vessel occlusion stroke at the anterior circulation complicated with atrial fibrillation, symptomatic intracranial hemorrhage or elevated neutrophil count within 24 hours of thrombectomy, or female patients with acute large vessel occlusion stroke at the anterior circulation, in-hospital death still needs to be highly alert after complete recanalization by mechanical thrombectomy.

This study was aimed at understanding the relationships among the drug resistance and genome characteristics of group A Streptococcus in Jiangsu Province.A total of 149 group A Streptococcus strains were collected from hospitals between 2016 and 2023.Thirteen antimicrobial minimal inhibitory concentrations were detected with the micro-dilution broth method.The GAS strains were typed with emm genotyping analysis and whole genome sequencing,to determine the carriage rates of drug resistance genes and the evolutionary relationships among strains.The resistance rates of 149 GAS strains to erythromy-cin,tetracycline,and clindamycin exceeded 90％,whereas the strains showed sensitivity to 8 different antibiotics,including penicillin.Notably,the resistance rates to erythromycin,tetracycline,and clindamycin consistently increased over time.All strains were classified into 9 emm types,among which emm12 accounted for the highest proportion(77/149;51.68％).Signifi-cant statistical differences were observed among emm types,in terms of the drug resistance rate,number of resistant species,and prevalence of drug resistance genes.Furthermore,SNP evolutionary tree analysis revealed 3 distinct clusters within the GAS strains:emm12,emm1,and other emm types.emm 12 and emm1 were the dominant GAS strains in Jiangsu Province.Most isolates were resistant to erythromycin,tetracycline,and clindamycin.Differences in phenotypes and genomic characteris-tics were observed among emm types.

Time rhythm and the immune system play crucial roles in the pathogenesis of allergic rhinitis.Traditional Chinese medicine(TCM)believes that the circulation of qi and blood in lung meridian follows the principle of"yang during the day,yin at night",which has a defensive function to protect the body from external pathogens.Qi stagnation in lung meridian and impaired qi and blood circulation can lead to the invasion of external pathogens,exacerbating allergic reactions,especially during the active period of the lung meridian,when the immune system is most sensitive to allergens.Based on this,this paper proposes the concept of"bidirectional regulation among meridian,time rhythm,and immune system",and in combination with TCM theory of midnight-noon and ebb-flow doctrine,analyzes the fluctuations of allergic rhinitis symptoms and the temporal changes of meridian qi and blood,and reveals the rhythmic relationship between meridian activity and immune response.This paper combines existing clinical and experimental studies to support this hypothesis,integrating the time dimension into traditional TCM syndrome differentiation and treatment,offering a more individualized treatment approach.This concept not only provides novel scientific evidence for TCM treatment of allergic rhinitis,but also offers theoretical support for optimizing treatment timing and intervention strategies.

OBJECTIVES: To explore the mechanism of Shenqi Buzhong (SQBZ) Formula for alleviating mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease (COPD) in light of the AMPK/SIRT1/PGC-1α pathway. METHODS: Fifty male SD rat models of COPD, established by intratracheal lipopolysaccharide (LPS) instillation, exposure to cigarette smoke, and gavage of Senna leaf infusion, were randomized into 5 groups (n=10) for treatment with saline (model group), SQBZ Formula at low, moderate and high doses (3.08, 6.16 and 12.32 g/kg, respectively), or aminophylline (0.024 g/kg) by gavage for 4 weeks, with another 10 untreated rats as the control group. Pulmonary function of the rats were tested, and pathologies and ultrastructural changes of the lung tissues were examined using HE staining and transmission electron microscopy. The levels of SOD, ATP, MDA, and mitochondrial membrane potential in the lungs were detected using WST-1, colorimetric assay, TBA, and JC-1 methods. Flow cytometry was used to analyze ROS level in the lung tissues, and the protein expression levels of P-AMPKα, AMPKα, SIRTI, and PGC-1α were detected using Western blotting. RESULTS: The rat models of COPD showed significantly decreased lung function, severe histopathological injuries of the lungs, decreased pulmonary levels of SOD activity, ATP and mitochondrial membrane potential, increased levels of MDA and ROS, and decreased pulmonary expressions of P-AMPKα, SIRTI, and PGC-1α proteins. All these changes were significantly alleviated by treatment with SQBZ Formula and aminophylline, and the efficacy was comparable between high-dose SQBZ Formula group and aminophylline group. CONCLUSIONS SQBZ Formula ameliorates mitochondrial dysfunction in COPD rats possibly by activating the AMPK/SIRT1/PGC-1α pathway.
Animals ; Pulmonary Disease, Chronic Obstructive/drug therapy* ; Drugs, Chinese Herbal/therapeutic use* ; Sirtuin 1/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Rats, Sprague-Dawley ; Male ; Rats ; AMP-Activated Protein Kinases/metabolism* ; Mitochondria/metabolism* ; Disease Models, Animal ; Signal Transduction/drug effects*

Hepatocellular carcinoma (HCC) expresses abundant glycolytic enzymes and displays comprehensive glucose metabolism reprogramming. Aldolase A (ALDOA) plays a prominent role in glycolysis; however, little is known about its role in HCC development. In the present study, we aim to explore how ALDOA is involved in HCC proliferation. HCC proliferation was markedly suppressed both in vitro and in vivo following ALDOA knockout, which is consistent with ALDOA overexpression encouraging HCC proliferation. Mechanistically, ALDOA knockout partially limits the glycolytic flux in HCC cells. Meanwhile, ALDOA translocated to nuclei and directly interacted with c-Jun to facilitate its Thr93 phosphorylation by P21-activated protein kinase; ALDOA knockout markedly diminished c-Jun Thr93 phosphorylation and then dampened c-Jun transcription function. A crucial site Y364 mutation in ALDOA disrupted its interaction with c-Jun, and Y364S ALDOA expression failed to rescue cell proliferation in ALDOA deletion cells. In HCC patients, the expression level of ALDOA was correlated with the phosphorylation level of c-Jun (Thr93) and poor prognosis. Remarkably, hepatic ALDOA was significantly upregulated in the promotion and progression stages of diethylnitrosamine-induced HCC models, and the knockdown of A ldoa strikingly decreased HCC development in vivo. Our study demonstrated that ALDOA is a vital driver for HCC development by activating c-Jun-mediated oncogene transcription, opening additional avenues for anti-cancer therapies.

Processing for deodorization is widely used in the production of animal-derived Chinese medicinal materials. In this study, Heracles Neo ultra-fast gas-phase electronic nose combined with chemometrics was employed to analyze the overall odor difference of Cervi Cornu Pantotrichum(focusing on that derived from Cervus nippon Temminck in this study) before and after processing. The results showed that the electronic nose effectively distinguished between the medicinal materials and decoction pieces of Cervi Cornu Pantotrichum. HS-GC-MS was used to identify and quantify the volatile components in the medicinal materials and decoction pieces of Cervi Cornu Pantotrichum, and 35 and 37 volatile components were detected in the medicinal materials and decoction pieces, respectively. The medicinal materials and decoction pieces contained 28 common volatile components contributing to the odor of Cervi Cornu Pantotrichum. The odor activity value(OAV) of each volatile component was calculated based on the olfactory threshold and relative content. The results showed that there were 17 key odor substances such as isovaleraldehyde, 2-methylbutanal, isobutyraldehyde, hexanal, and methanethiol in the medicinal materials and decoction pieces of Cervi Cornu Pantotrichum. All of them had bad odor and were the main source of the odor of Cervi Cornu Pantotrichum. The results of principal component analysis(PCA) and orthogonal partial least squares-discriminant analysis(OPLS-DA) showed that there were significant differences in volatile components between the medicinal materials and decoction pieces of Cervi Cornu Pantotrichum. Based on the thresholds of P<0.05 and Variable Importance in Projection(VIP)>1, 21 differential volatile odor components were screened out. Among them, isopentanol, isovaleraldehyde, 2-methylbutanal, n-nonanal, and dimethylamine were the key differential odor compounds between the medicinal materials and decoction pieces of Cervi Cornu Pantotrichum. The odor compounds and their relative content reduced, and some flavor substances such as esters were produced after processing with wine, which was the main reason for the reduction of the odor after processing of Cervi Cornu Pantotrichum.
Odorants/analysis* ; Electronic Nose ; Gas Chromatography-Mass Spectrometry/methods* ; Animals ; Volatile Organic Compounds/analysis* ; Deer ; Drugs, Chinese Herbal/chemistry*