OBJECTIVE To investigate the effects and potential mechanism of Qiangxin decoction on mitochondrion of rats with chronic heart failure （CHF）. METHODS The CHF model was established by ligating the left anterior descending branch of the coronary artery. Modeled rats were divided into model group， Qiangxin decoction low-dose and high-dose groups （12.25， 24.50 g/kg， calculated by crude drug）， and chemical medicine group （Sacubitril valsartan sodium tablets， 10.42 mg/kg）， with 10 rats in each group； control group was set up without treatment. Each group of rats was orally administered with the corresponding medication or normal saline twice a day for 28 consecutive days. After the last medication， the contents of N-terminal pro-brain natriuretic peptide （NT-proBNP） and adenosine triphosphate （ATP） in serum and phosphatidic acid （PA） and cardiolipin （CL） in myocardial tissue were all detected； the pathological damage and collagen fibrosis of rat myocardial tissue were observed； the apoptosis of myocardial cells was determined； the ultrastructure of myocardial tissue was observed； the protein expressions of mitofusin 1 （Mfn1）， Mfn2， optic atrophy protein 1 （OPA1） and dynamin-related protein 1 （Drp1） were all detected in myocardial tissue. RESULTS Compared with control group，the serum content of NT-proBNP， apoptotic rate of myocardial cells， and relative expressions of S-OPA1 and Drp1 proteins were all increased significantly； serum content of ATP，contents of PA and CL， and relative expressions of Mfn1， Mfn2 and L-OPA1 proteins were all significantly reduced （P＜0.05）. There were abnormal membrane tissue structure in various layers of myocardial tissue， degeneration and necrosis of myocardial cells， and severe fibrosis； the mitochondria were swollen， with reduced or absent cristae， and uneven matrix density. After intervention with Qiangxin decoction， the levels of the aforementioned quantitative indicators in serum and myocardial tissue of rats （excluding CL content in the Qiangxin decoction low- dose group） were significantly reversed （P＜0.05）； the pathological damage of myocardial tissue had significantly improved， fibrosis had significantly reduced， mitochondrial morphology tended to be normal， cristae had increased， and matrix density was uniform. CONCLUSIONS Qiangxin decoction can regulate myocardial mitochondrial function and structural integrity of CHF rats， thereby improving myocardial energy metabolism and antagonizing myocardial fibrosis， the mechanism of which may be associated with activating PA/Mfn/CL signaling pathway.

OBJECTIVE To investigate the effects and potential mechanism of Qiangxin decoction on mitochondrion of rats with chronic heart failure （CHF）. METHODS The CHF model was established by ligating the left anterior descending branch of the coronary artery. Modeled rats were divided into model group， Qiangxin decoction low-dose and high-dose groups （12.25， 24.50 g/kg， calculated by crude drug）， and chemical medicine group （Sacubitril valsartan sodium tablets， 10.42 mg/kg）， with 10 rats in each group； control group was set up without treatment. Each group of rats was orally administered with the corresponding medication or normal saline twice a day for 28 consecutive days. After the last medication， the contents of N-terminal pro-brain natriuretic peptide （NT-proBNP） and adenosine triphosphate （ATP） in serum and phosphatidic acid （PA） and cardiolipin （CL） in myocardial tissue were all detected； the pathological damage and collagen fibrosis of rat myocardial tissue were observed； the apoptosis of myocardial cells was determined； the ultrastructure of myocardial tissue was observed； the protein expressions of mitofusin 1 （Mfn1）， Mfn2， optic atrophy protein 1 （OPA1） and dynamin-related protein 1 （Drp1） were all detected in myocardial tissue. RESULTS Compared with control group，the serum content of NT-proBNP， apoptotic rate of myocardial cells， and relative expressions of S-OPA1 and Drp1 proteins were all increased significantly； serum content of ATP，contents of PA and CL， and relative expressions of Mfn1， Mfn2 and L-OPA1 proteins were all significantly reduced （P＜0.05）. There were abnormal membrane tissue structure in various layers of myocardial tissue， degeneration and necrosis of myocardial cells， and severe fibrosis； the mitochondria were swollen， with reduced or absent cristae， and uneven matrix density. After intervention with Qiangxin decoction， the levels of the aforementioned quantitative indicators in serum and myocardial tissue of rats （excluding CL content in the Qiangxin decoction low- dose group） were significantly reversed （P＜0.05）； the pathological damage of myocardial tissue had significantly improved， fibrosis had significantly reduced， mitochondrial morphology tended to be normal， cristae had increased， and matrix density was uniform. CONCLUSIONS Qiangxin decoction can regulate myocardial mitochondrial function and structural integrity of CHF rats， thereby improving myocardial energy metabolism and antagonizing myocardial fibrosis， the mechanism of which may be associated with activating PA/Mfn/CL signaling pathway.

OBJECTIVE: To explore the improvement effect of electroacupuncture (EA) based on Xingnao Kaiqiao acupuncture (acupuncture for regaining consciousness and opening orifices) on cognitive impairment in mice with Parkinson's disease (PD), and to explore its regulatory mechanisms on the kinesin family member 5A (KIF5A)/mitochondrial Rho GTPase 1 (Miro1) pathway and mitophagy in prefrontal cortical neurons. METHODS: A total of 70 male C57BL/6J mice of clean grade were randomly divided into a normal group (12 mice), a sham operation group (12 mice), and a model pre-screening group (46 mice). Unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle was adopted to establish the PD model in the model pre-screening group. Twenty-four mice after successful modeling were randomly selected and divided into a model group and an EA group, 12 mice in each one. In the EA group, acupuncture was applied at "Shuigou" (GV26) and bilateral "Sanyinjiao" (SP6) and "Neiguan" (PC6), ipsilateral "Sanyinjiao" (SP6) and "Neiguan" (PC6) were connected to EA respectively, with disperse-dense wave, 5 Hz/20 Hz in frequency, 0.5 mA in current intensity, 20 min a time, 6 times a week for 30 days. Cognitive function was assessed by Y-maze and Morris water maze tests; morphology of prefrontal cortex was observed by H.E. staining; reactive oxygen species (ROS) level in prefrontal cortex was detected by fluorescence probe method; mitochondrial morphology and autophagosome ultrastructure were observed by transmission electron microscopy; the mRNA expression of tyrosine hydroxylase (TH) was detected by quantitative real-time PCR; the protein expression of TH, KIF5A, Miro1, p62, Parkin and PTEN induced kinase 1 (PINK1) was detected by Western blot. RESULTS: Compared with the sham operation group, both the model group and the EA group exhibited increased rotation number of per minute (P<0.001). Compared with the sham operation group, in the model group, the novel arm exploration time of Y-maze test was shortened (P<0.001), the escape latency of Morris water maze test was prolonged (P<0.05) and the platform crossing number of Morris water maze test was reduced (P<0.01); in the prefrontal cortex, the number of cellular vacuole and neurons with karyopyknosis was increased (P<0.001), and mitochondrial autophagosomes could be observed; in the prefrontal cortex, the relative expression of ROS was increased (P<0.001), the protein and mRNA expression of TH was decreased (P<0.001), the protein expression of Miro1, PINK1, Parkin was increased (P<0.001, P<0.01), the protein expression of KIF5A and p62 was decreased (P<0.001). Compared with the model group, in the EA group, the novel arm exploration time of Y-maze test was prolonged (P<0.01), the escape latency of Morris water maze test was shortened (P<0.05) and the platform crossing number of Morris water maze test was increased (P<0.05); in the prefrontal cortex, the number of cellular vacuole and neurons with karyopyknosis was decreased (P<0.001), and the number of mitochondrial autophagosomes reduced and the mitochondrial morphology was improved; in the prefrontal cortex, the relative expression of ROS was decreased (P<0.01), the protein and mRNA expression of TH was increased (P<0.001, P<0.01), the protein expression of Miro1, PINK1, Parkin was decreased (P<0.001, P<0.01, P<0.05), the protein expression of KIF5A and p62 was increased (P<0.01, P<0.05). CONCLUSION Xingnao Kaiqiao electroacupuncture effectively alleviates cognitive impairment and damage of neuronal function in PD mice, its mechanism may be related to the regulation of KIF5A/Miro1 pathway, hence reducing the mitophagy in prefrontal cortical neurons.
Animals ; Electroacupuncture ; Male ; Mice ; Parkinson Disease/physiopathology* ; Cognitive Dysfunction/psychology* ; Kinesins/genetics* ; Humans ; Mitophagy ; Mice, Inbred C57BL ; rho GTP-Binding Proteins/genetics* ; Mitochondria/genetics* ; Prefrontal Cortex/metabolism*

Pulpitis is a common infective oral disease in clinical situations. The regulatory mechanisms of immune defense in pulpitis are still being investigated. Osteomodulin (OMD) is a small leucine-rich proteoglycan family member distributed in bones and teeth. It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells (hDPSCs). In this study, the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated. The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining. Intriguingly, the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens. The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide (LPS)-induced inflammation. A conditional Omd knockout mouse model with pulpal inflammation was established. LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice, whereas OMD administration exhibited a protective effect against pulpitis. Mechanistically, the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB (NF-κB) signaling pathway. Interleukin-1 receptor 1 (IL1R1), a vital membrane receptor activating the NF-κB pathway, was significantly downregulated in OMD-overexpressing hDPSCs. Additionally, the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking. In vivo, excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist. Overall, OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway. OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.
Pulpitis/metabolism* ; NF-kappa B/metabolism* ; Animals ; Signal Transduction ; Humans ; Mice ; Mice, Knockout ; Dental Pulp/metabolism* ; Disease Models, Animal ; Lipopolysaccharides

Polycystic ovary syndrome (PCOS) is the predominant cause of subfertility in reproductive-aged women; however, its pathophysiology remains unknown. Neurotensin (NTS) is a member of the gut-brain peptide family and is involved in ovulation; its relationship with PCOS is unclear. Here, we found that NTS expression in ovarian granulosa cells and follicular fluids was markedly decreased in patients with PCOS. In the in vitro culture of cumulus-oocyte complexes, the neurotensin receptor 1 (NTSR1) antagonist SR48692 blocked cumulus expansion and oocyte meiotic maturation by inhibiting metabolic cooperation and damaging the mitochondrial structure in oocytes and surrounding cumulus cells. Furthermore, the ERK1/2-early growth response 1 pathway was found to be a key downstream mediator of NTS/NTSR1 in the ovulatory process. Animal studies showed that in vivo injection of SR48692 in mice reduced ovulation efficiency and contributed to irregular estrus cycles and polycystic ovary morphology. By contrast, NTS partially ameliorated the ovarian abnormalities in mice with dehydroepiandrosterone-induced PCOS. Our findings highlighted the critical role of NTS reduction and consequent abnormal NTSR1 signaling in the ovulatory dysfunction of PCOS, suggesting a potential strategy for PCOS treatment.
Polycystic Ovary Syndrome/physiopathology* ; Female ; Animals ; Neurotensin/metabolism* ; Receptors, Neurotensin/antagonists & inhibitors* ; Mice ; Ovulation/drug effects* ; Humans ; Granulosa Cells/metabolism* ; Adult ; Oocytes/metabolism* ; MAP Kinase Signaling System ; Signal Transduction ; Follicular Fluid/metabolism* ; Disease Models, Animal ; Gonadotropin-Releasing Hormone/analogs & derivatives*

ObjectiveTo investigate the association between neutrophil-to-lymphocyte and platelet ratio （NLPR） and recompensation in patients with hepatitis B cirrhotic ascites， and to establish an individualized risk prediction model. MethodsThe patients with hepatitis B cirrhotic ascites who were hospitalized in Department of Gastroenterology， The General Hospital of Western Theater Command of Chinese PLA， from January 2015 to December 2022 were enrolled. General information and laboratory markers were collected， and NLPR was calculated. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups， and the chi-square test or the chi-square test with correction was used for comparison of categorical data between two groups. The subjects were randomly divided into a training set and a validation set at a ratio of 7∶3. In the training set， univariate and multivariate binary Logistic regression analyses were used to investigate the independent influencing factors for recompensation in patients with hepatitis B cirrhotic ascites， and a nomogram was established； the receiver operating characteristic （ROC） curve was used to assess the value of the new model in predicting recompensation in patients with hepatitis B cirrhotic ascites， and the Delong test was used for comparison of the area under the ROC curve （AUC）. The calibration curve and the decision curve were plotted for the model， and the model was assessed in terms of degree of fitting and predictive benefits. ResultsA total of 360 patients were enrolled， among whom134 achieved recompensation. There were 252 patients in the training set and 108 patients in the validation set， and there were no significant differences in baseline characteristics between the two groups （all P>0.05）. The Logistic regression analysis showed that the onset of hepatic encephalopathy （odds ratio ［OR］=0.066， 95% confidence interval ［CI］： 0.008 — 0.545， P=0.012）， NLPR （OR=0.950， 95%CI： 0.912 — 0.989， P=0.012）， alpha-fetoprotein （OR=1.012， 95%CI： 1.005 — 1.020， P<0.001）， and albumin （OR=1.096， 95%CI： 1.031 — 1.166， P=0.003） were independent influencing factors for recompensation in patients with hepatitis B cirrhotic ascites. The above four factors were included in a nomogram predictive model， which had an AUC of 0.776， a sensitivity of 66.5%， and a specificity of 76.3% in the training set and an AUC of 0.746， a sensitivity of 63.4%， and a specificity of 75.7% in the validation set， while Model for End-Stage Liver Disease score， Child-Pugh score， and albumin-bilirubin score had an AUC of 0.574， 0.628， and 0.621， respectively. The nomogram model had a better performance than the other three scores in predicting recompensation in patients with hepatitis B cirrhotic ascites （Z=4.191， 3.369， and 3.527， P<0.001， P=0.001， and P<0.001）. The calibration curve and the decision curve showed that the model had a good degree of fitting， and the decision made using this model could bring net benefits. ConclusionNLPR has a good value in predicting recompensation in patients with hepatitis B cirrhotic ascites， and the nomogram model established can help to predict recompensation in such patients in clinical practice.

OBJECTIVE To observe the changes of cardiac function,local inflammation level and macrophage M2 polarization in mice with acute myocardial infarction(AMI after electroacupuncture preconditioning at the Neiguan point,and to explore the possible mechanisms from the perspective of regulating the DNA-PK/Rictor/Myc signaling pathway.METHODS Male C57BL/6J mice were randomly divided into sham group,model group and electroacupuncture group,with 10 mice in each group.The electroacupuncture group received bilateral electroacupuncture interventions at the Neiguan points,sparse-dense wave,2/15 Hz,1 mA,20 min/time,once a day for 3 consecutive days,and AMI models were performed 0.5 h after the electroacupuncture interventions.The myocardial ischemia model was prepared by ligating the left anterior descending branch.Echocardiography was used to detect cardiac ejection frac-tion(EF and fractional shortening(FS to evaluate cardiac function;HE and TUNEL staining were used to observe the pathological morphology of myocardium and apoptosis of cardiomyocytes,and immunohistochemistry and ELISA were used to detect IL-1β,TNF-α and NLRP3 in infarcted myocardium and peripheral blood to evaluate the level of inflammation;flow cytometry was used to detect cardiac macrophage polarization status,and Western blot method to detect the protein expression levels of DNA-PK,p-DNA-PK,Rictor and Myc in infarcted myocardium.RESULTS Compared with the sham group,the model group showed significantly lower EF and FS(P<0.000 1,significant inflammatory cell infiltration,significantly higher cardiomyocyte apoptotic index(P<0.001,up-regulated expression of IL-1β,NLRP3 and TNF-α in the myocardium and serum(P<0.01,P<0.001,a significant increase in the percentage of macrophages(P<0.001,a decrease in the percentage of cardiac M2-type macrophages(P<0.000 1,and a significant decrease in the expression levels of p-DNA-PK,Rictor and Myc proteins in myocardium(P<0.05,P<0.000 1.Compared with the model group,EF and FS were significantly higher in the electroacupuncture group(P<0.000 1,inflammatory cell infiltration was re-duced,cardiomyocyte apoptotic index was decreased(P<0.01,and the expression of IL-1β,NLRP3 and TNF-α was down-regula-ted in myocardium and serum(P<0.05,P<0.01,P<0.001;the macrophage percentage was decreased(P<0.05,cardiac M2-type macrophage percentage was increased(P<0.01,and p-DNA-PK,Rictor and Myc protein expression was enhanced in myocardium(P<0.05,P<0.01,P<0.000 1.CONCLUSION Electroacupuncture preconditioning may promote macrophage M2 polarization,attenuate local inflammation,and reduce cardiomyocyte apoptosis by modulating the DNA-PK/Rictor/Myc signaling pathway,thus im-proving cardiac function and achieving myocardial protective effects.

Objective To explore the efficacy and safety of omalizumab in the treatment of allergic bronchopulmonary aspergillosis(ABPA).Methods The clinical data of 26 ABPA patients treated with omalizumab in Zhongshan Hospital,Fudan University from November 2018 to December 2023 and 24 ABPA patients treated with prednisone combined with itraconazole in the same period were analyzed retrospectively.The primary outcomes were exacerbation times and oral corticosteroid-sparing effect.The secondary outcomes were respiratory symptoms,circulating eosinophil count,total immunoglobin E(IgE)level,specific IgE for aspergillus,pulmonary function(the percentage value of forced expiratory volume in one second predicted[FEV1%pred]),fraction of exhaled nitric oxide(FeNO),thoracic computed tomography(CT)manifestation and adverse reactions.Results In omalizumab group,the exacerbation times of ABPA after 6 and 12 months of treatment were 0(0,0)times/6 months and 0(0,1)times/6 months,there was no significant difference(P=0.157),which were significantly lower than those of the baseline(1[1,2]times/6 months,P＜0.001).The oral dose of prednisone decreased from 10(5,15)mg/d(before treatment)to 3.125(0,5)mg/d(6 months after treatment,P＜0.001).After 12 months of treatment,the oral dose of prednisone was 0(0,3.125)mg/d,which was significantly lower than that of the baseline dose(P=0.003).After treatment with omalizumab for 12 months,the FeNO level decreased significantly(26[13,36]×10﹣9 vs 30[18,56]×10﹣9,P=0.049).There was no significant difference in blood eosinophil count,total IgE level,specific IgE for aspergillus and FEV1%pred before and after omalizumab treatment.After 6 months of treatment with omalizumab,respiratory symptoms were relieved in 23 patients(88.5%)and radiographic improvement was achieved in eight out of sixteen patients(50%)with mucus plugs.More patients successfully discontinued oral prednisone when treated with omalizumab for 12 months than those in control group(P=0.035).During the treatment of omalizumab,4(15.4%)patients had a slight increase in alanine aminotransferase(ALT),and 1 patient was complicated with hepatocellular carcinoma during follow-up.Conclusions Omazumab treatment can effectively reduce the number of acute episodes of ABPA,reduce the dosage of oral glucocorticoids,improve FeNO,facilitate the absorption of mucus plugs,and has high safety.

A 29-year-old man visited Zhongshan Hospital, Fudan University in December 2021. The patient presented with recurrent coughing, sputum, and wheezing, high level of serum total IgE, positive aspergillus fumigatus-specific IgE and extremely severe mixed ventilatory dysfunction. These features and thoracic CT results scan showed bronchiectasis and allergic bronchopulmonary aspergillosis. In consideration of his clinical characteristics, including low levels of fractional exhaled nitric oxide (FeNO), and nasal nitric oxide (nNO), persistent cough after birth, consanguineous marriage of his parents, etc. we ratiocinated a possibility of hereditary diseases, especially primary ciliary dyskinesia (PCD). From this perspective, whole exome sequencing (WES) was performed and the diagnosis of PCD was ultimately confirmed.