1.Danhong Injection Regulates Mitochondrial Dynamics in Rat Model of Chronic Heart Failure via AMPK/Drp1 Pathway
Jiahao YE ; Zizheng WU ; Yao ZHANG ; Lichong MENG ; Zhixi HU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(16):126-135
ObjectiveTo investigate the effects of Danhong injection on mitochondrial dynamics, morphology, and function in the rat model of chronic heart failure by mediating the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/dynamin-related protein 1 (Drp1) pathway. MethodsFrom 75 SD rats, 15 rats were randomly selected as the sham group, and the remaining 60 rats were used to prepare a rat model of chronic heart failure by abdominal aortic constriction (AAC). The modeled rats were randomly allocated into model, Danhong Injection (6 mL·kg-1), and captopril (8.8 mg·kg-1) groups and administrated with corresponding agents for 15 consecutive days. The levels of N-terminal pro-brain natriuretic peptide (NT-pro BNP), adenosine diphosphate (ADP), adenosine triphosphate (ATP), interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α and the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ were determined by enzyme-linked immunosorbent assay. The changes in cardiac function were detected by echocardiography. The ultrastructural changes of myocardial mitochondria were observed by transmission electron microscopy. Western blot was employed to assess the protein levels of AMPK, p-AMPK, Drp1, p-Drp1, optic atrophy 1 (Opa1), mitofusin (Mfn2), and fission l (Fis1) in the myocardial tissue. Real-time PCR was performed to determine the mRNA levels of Opa1, Mfn2, and Fis1, and immunohistochemistry to detect the expression of p-AMPK. ResultsCompared with the sham group, the model group showed elevated levels of NT-pro BNP, ADP, TNF-α, IL-6, and IL-1β (P<0.01), declined ATP level (P<0.01), weakened activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ (P<0.01), decreased left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) (P<0.01), and increased left ventricular internal diameter at end-diastole (LVDd) and leaf ventricular internal diameter at end-systole (LVIDs) (P<0.01). Electron microscopy results showed that the model group presented heavily abnormal myocardial structure, with large areas of myofilament structure destroyed and dissolved, significantly enlarged residual structural gaps, and fragmented mitochondria. Western blot results showed that the model group demonstrated down-regulated protein levels of p-AMPK, Mfn2, and Opa1 (P<0.01) and up-regulated protein levels of p-Drp1 and Fis1 (P<0.01) in the myocardial tissue. Real-time PCR results showed that the model group presented up-regulated mRNA level of Fis1 (P<0.01) and down-regulated mRNA levels of Mfn2 and Opa1 (P<0.01). Immunohistochemistry results showed reduced expression of p-AMPK in the model group compared with sham group (P<0.01). Compared with the model group, Danhong injection lowered the levels of NT-pro BNP, ADP, TNF-α, IL-6, and IL-1β (P<0.01), raised the level of ATP (P<0.01), increased the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ (P<0.05, P<0.01), increased the LVEF and LVFS (P<0.01), decreased the LVDd and LVIDs (P<0.05, P<0.01), alleviated mitochondrial damage, up-regulated the protein levels of p-AMPK, Mfn2, and Opa1 (P<0.05, P<0.01), down-regulated the protein levels of p-Drp1 and Fis1 (P<0.01), reduced the mRNA level of Fis1 (P<0.01), elevated the mRNA levels of Mfn2 and Opa1 (P<0.05, P<0.01), and promoted the expression of p-AMPK (P<0.05). ConclusionDanhong injection repairs the imbalance of mitochondrial dynamics, restores the mitochondrial function, improves the myocardial energy metabolism, and reduces the inflammatory response by regulating the AMPK/Drp1 pathway, thus improving the cardiac function.
2.Cardiomyocyte Apoptosis in Chronic Heart Failure and Traditional Chinese Medicine Intervention
Kun LIAN ; Peiyao LI ; Zhiguang SONG ; Jianhang ZHANG ; Junxian LEI ; Lin LI ; Zhixi HU
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(16):165-172
Chronic heart failure is the terminal stage of various cardiovascular diseases, and cardiomyocyte apoptosis is the turning point of decompensation. Studies have shown that traditional Chinese medicine (TCM) could regulate apoptosis-related signaling pathways and factors and inhibit or up-regulate the expression of apoptosis-related proteins. Thus, TCM can reduce cardiomyocyte apoptosis, protect the myocardial tissue and improve the cardiac function, demonstrating remarkable clinical effects. In recent years, the research on the treatment of chronic heart failure based on the inhibition of cardiomyocyte apoptosis is increasing and becomes the current research hotspot. On the basis of literature review, this paper discovers that TCM regulates apoptosis factors and multiple signaling pathways to inhibit apoptosis and inflammation and delay the progression of chronic heart failure through classical pathways such as the death receptor pathway, the mitochondrial pathway, and the endoplasmic reticulum pathway. At the same time, the studies in this field have the following problems: Repeated studies with shallow, simple, and fragmented contents, treating animal models with TCM prescriptions without syndrome differentiation, treating diseases with drugs at only one concentration which is insufficient to indicate efficacy, and lacking comprehensive, holistic, and systematic studies on the relationships of apoptosis with inflammatory responses, pyroptosis, ferroptosis, and autophagy. In the future, more scientific, reasonable, comprehensive, and feasible experimental schemes should be designed on the basis of comprehensively mastering the research progress in this field, and the communication and cooperation between researchers in different disciplines should be strengthened. The specific pathological mechanism of cardiomyocyte apoptosis in chronic heart failure and the signaling pathways, active components, and action targets of TCM in inhibiting cardiomyocyte apoptosis in chronic heart failure should be elucidated. Such efforts are expected to provide sufficient reference for the clinical treatment of chronic heart failure.
3.Comparison of different regimens in isoprenaline-induced chronic heart failure models
Yuquan TAN ; Junyu ZHANG ; Meng YANG ; Fei WANG ; Senjie ZHONG ; Lin LI ; Zhixi HU
Acta Laboratorium Animalis Scientia Sinica 2024;32(2):161-167
Objective To compare animal models of chronic heart failure(CHF)prepared by three different protocols,to establish a stable,reliable,and reproducible mouse model of CHF.Methods Twenty-five male C57BL/6J mice were divided randomly into four groups:a blank group,model A group(MA group),model B group(MB group),and model C group(MC group).The model groups adopted different preparation protocols for continuous injection of isoprenaline.The MA group and MB group were dose-decreasing models:MA group:subcutaneous injection of 10 mg/kg on day 1,5 mg/kg on day 2,2.5 mg/(kg·d)on days 3~30,total 30 days;and MB group:subcutaneous injection of 20 mg/kg on day 1,10 mg/kg on day 2,5 mg/(kg·d)on days 3~14,total 14 days.The MC group used a constant dose of intraperitoneal injection of 7.5 mg/(kg·d)for 28 days.The day after the final injection,the survival and model-formation rates for each group of mice were calculated.Cardiac function was measured by cardiac ultrasound and serum levels of N-terminal pro B-type natriuretic peptide,interleukin-6,and tumor necrosis factor-α were measured.Results CHF was successfully induced in all the model groups after all injections at the end of the fourth week.However,comprehensive test result showed that the MC model was the most stable.Conclusions An isoprenaline-induced mouse model of CHF using constant intraperitoneal injection of 7.5 mg/(kg·d)for 28 days may be the most suitable model for subsequent research on traditional Chinese medicine.
4.Research on optimization technology of ventilation system in an industrial X-ray inspection workshop
Yi GUAN ; Zhixi GUO ; Xiaojing ZHANG ; Chao WANG ; Xiuping LI ; Qingdong WU ; Song WANG ; Dongliang CHAI
Chinese Journal of Industrial Hygiene and Occupational Diseases 2024;42(11):862-868
Objective:To investigate the reasonable airflow organization and exhaust system facilities during the operation of the inspection workshop, and solve the problem of the accumulation of harmful gases such as ozone and nitrogen oxides in the workshop.Methods:In May 2023, computational fluid dynamics (CFD) technology was used to numerically simulate the diffusion of ozone and nitrogen oxides generated by industrial radiographic inspection operations, and the comparative detection method was used to analyze the ozone and nitrogen oxides concentrations before and after the renovation of the ventilation system of the inspection workshop.Results:After the renovation of ventilation system, the average concentration of ozone in the inspection workshop decreased from 0.81 mg/m 3 to 0.03 mg/m 3, and the average concentration of nitrogen oxides decreased from 0.42 mg/m 3 to 0.01 mg/m 3, and the differences were statistically significant ( t=20.51, 10.38, P<0.001) . Conclusion:The ventilation facilities of the inspection workshop are set up in the airflow organization mode of sending up and down the exhaust, and the ventilation pipes are scientifically designed through the calculation of ventilation hydraulic balance, which can effectively control the concentration of harmful gases in the inspection workshop.
5.Research on optimization technology of ventilation system in an industrial X-ray inspection workshop
Yi GUAN ; Zhixi GUO ; Xiaojing ZHANG ; Chao WANG ; Xiuping LI ; Qingdong WU ; Song WANG ; Dongliang CHAI
Chinese Journal of Industrial Hygiene and Occupational Diseases 2024;42(11):862-868
Objective:To investigate the reasonable airflow organization and exhaust system facilities during the operation of the inspection workshop, and solve the problem of the accumulation of harmful gases such as ozone and nitrogen oxides in the workshop.Methods:In May 2023, computational fluid dynamics (CFD) technology was used to numerically simulate the diffusion of ozone and nitrogen oxides generated by industrial radiographic inspection operations, and the comparative detection method was used to analyze the ozone and nitrogen oxides concentrations before and after the renovation of the ventilation system of the inspection workshop.Results:After the renovation of ventilation system, the average concentration of ozone in the inspection workshop decreased from 0.81 mg/m 3 to 0.03 mg/m 3, and the average concentration of nitrogen oxides decreased from 0.42 mg/m 3 to 0.01 mg/m 3, and the differences were statistically significant ( t=20.51, 10.38, P<0.001) . Conclusion:The ventilation facilities of the inspection workshop are set up in the airflow organization mode of sending up and down the exhaust, and the ventilation pipes are scientifically designed through the calculation of ventilation hydraulic balance, which can effectively control the concentration of harmful gases in the inspection workshop.
6.Application value of cystic plate approach for extrahepatic right hepatic pedicle dissection in minimally invasive anatomic liver resection
Kai WANG ; Shibo SUN ; Zhixi LI ; Shanhua TANG ; Xin WANG ; Yao LI ; Jie ZHOU ; Qifan ZHANG
Chinese Journal of Digestive Surgery 2023;22(4):E001-E001
Objective:To investigate the application value of cystic plate approach (CPA) for extrahepatic right hepatic pedicle dissection in minimally invasive anatomical hepatectomy (MIALR).Methods:The retrospective cohort study was conducted. The clinicopathological data of 42 patients with primary liver cancer who underwent laparoscopic right hemi-hepatectomy in Nanfang Hospital of Southern Medical University from August 2020 to August 2022 were collected. There were 36 males and 6 females, aged (55±13)years. Of the 42 patients, 25 cases undergoing CPA for extrahepatic right hepatic pedicle dissection were divided into the CPA group, and 17 cases undergoing traditional approach for extrahepatic right hepatic pedicle dissection were divided into the traditional approach group. Observation indicators: (1) surgical situations; (2) postoperative situations. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M( IQR), and comparison between groups was conducted using the Mann?Whitney U test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi?square test or Fisher exact probability. Comparison of ordinal data was conducted using the non‐parameter rank sum test. Results:(1) Surgical situations. All patients in the two groups underwent laparoscopic right hemi-hepatectomy successfully, with the surgical margin as negative. The operative time, volume of intraoperative blood loss, time of dissection of the targeted hepatic pedicle, cases undergoing dissection of the trunk of right anterior hepatic pedicle and its operation time, cases undergoing dissection of the trunk of right posterior hepatic pedicle and its operation time, cases with hepatic pedicle injury, cases with hepatic tissue injury, cases with dissection space as large and small were 150.00(130.00)minutes, 100.00(100.00)mL, 472.00(201.00)seconds, 10 and 366.00(94.75)seconds, 9 and 564.00(138.50)seconds, 2, 2, 25, 0 in patients of the CPA group, versus 140.00(113.00)minutes, 100.00(125.00)mL, 670.00(107.00)seconds, 8 and 663.00(136.00)seconds, 7 and 783.00(189.00)seconds, 8, 5, 2, 19 in patients of the traditional approach group. There were significant differences in the time of dissection of the targeted hepatic pedicle, time of dissection of the trunk of right anterior hepatic pedicle, time of dissection of the trunk of right posterior hepatic pedicle, hepatic tissue injury, dissection space between the two groups ( Z=-4.809, -3.254, -3.188, χ2=6.493, 34.314, P<0.05) and there was no significant difference in the operation time, volume of intraoperative blood loss, dissection of the trunk of right anterior hepatic pedicle, dissection of the trunk of right posterior hepatic pedicle, hepatic tissue injury between the two groups ( Z=-0.282, -0.412, χ2=0.095, 0.002, 1.976, P>0.05). (2) Postoperative situations. There was no patient undergoing postoperative hemorrhage in both of the two groups. The alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBil) and prothrombin time (PT) at postoperative day 3, cases with postoperative biliary fistula, pathological type of tumor (hepatocellular carcinoma, intrahepatic cholangiocarcinoma) were 68.00(48.50)U/L, 52.00(35.50)U/L, 28.30(12.35)mmol/L, 12.40(2.40)seconds, 2, 21, 4 in patients of the CPA group. The above indicators were 58.00(25.00)U/L, 41.00(19.50)U/L, 26.80(14.25)mmol/L, 12.50(2.95)seconds, 5, 15, 2 in patients of the traditional approach group. There was no significant difference in the ALT, AST, TBil, PT at postoperative day 3, cases with postoperative biliary fistula between the two groups ( Z=-1.218, -1.488, -0.205, -0.320, χ2=1.976, P>0.05), and there was no significant difference in the pathological type of tumor between the two groups ( P>0.05). Conclusion:Application of CPA for extrahepatic right hepatic pedicle dissection in MIALR is safe and feasible.
7.Application value of cystic plate approach for extrahepatic right hepatic pedicle dissection in minimally invasive anatomic liver resection
Kai WANG ; Shibo SUN ; Zhixi LI ; Shanhua TANG ; Xin WANG ; Yao LI ; Jie ZHOU ; Qifan ZHANG
Chinese Journal of Digestive Surgery 2023;22(4):489-496
Objective:To investigate the application value of cystic plate approach (CPA) for extrahepatic right hepatic pedicle dissection in minimally invasive anatomical hepatectomy (MIALR).Methods:The retrospective cohort study was conducted. The clinicopathological data of 42 patients with primary liver cancer who underwent laparoscopic right hemi-hepatectomy in Nanfang Hospital of Southern Medical University from August 2020 to August 2022 were collected. There were 36 males and 6 females, aged (55±13)years. Of the 42 patients, 25 cases undergoing CPA for extrahepatic right hepatic pedicle dissection were divided into the CPA group, and 17 cases undergoing traditional approach for extrahepatic right hepatic pedicle dissection were divided into the traditional approach group. Observation indicators: (1) surgical situations; (2) postoperative situations. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distribution were represented as M( IQR), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test or Fisher exact probability. Comparison of ordinal data was conducted using the non‐parameter rank sum test. Results:(1) Surgical situations. All patients in the two groups underwent laparos-copic right hemi-hepatectomy successfully, with the surgical margin as negative. The operation time, volume of intraoperative blood loss, time of dissection of the targeted hepatic pedicle, cases under-going dissection of the trunk of right anterior hepatic pedicle and its operation time, cases under-going dissection of the trunk of right posterior hepatic pedicle and its operation time, cases with hepatic pedicle injury, cases with hepatic tissue injury, cases with dissection space as large and small were 150.00(130.00)minutes, 100.00(100.00)mL, 472.00(201.00)seconds, 10 and 366.00(94.75)seconds, 9 and 564.00(138.50)seconds, 2, 2, 25, 0 in patients of the CPA group, versus 140.00(113.00)minutes, 100.00(125.00)mL, 670.00(107.00)seconds, 8 and 663.00(136.00)seconds, 7 and 783.00(189.00)seconds, 8, 5, 2, 19 in patients of the traditional approach group. There were significant differences in the time of dissection of the targeted hepatic pedicle, time of dissection of the trunk of right anterior hepatic pedicle, time of dissection of the trunk of right posterior hepatic pedicle, hepatic pedicle injury, dissection space between the two groups ( Z=-4.809, -3.254, -3.188, χ2=6.493, 34.314, P<0.05) and there was no significant difference in the operation time, volume of intraoperative blood loss, dissection of the trunk of right anterior hepatic pedicle, dissection of the trunk of right posterior hepatic pedicle, hepatic tissue injury between the two groups ( Z=-0.282, -0.412, χ2=0.095, 0.002, 1.976, P>0.05). (2) Postoperative situations. There was no patient under-going postoperative hemorrhage in both of the two groups. The alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBil) and prothrombin time (PT) at postoperative day 3, cases with postoperative biliary fistula, pathological type of tumor (hepatocellular carcinoma, intrahepatic cholangiocarcinoma) were 68.00(48.50)U/L, 52.00(35.50)U/L, 28.30(12.35)mmol/L, 12.40(2.40)seconds, 2, 21, 4 in patients of the CPA group. The above indicators were 58.00(25.00)U/L, 41.00(19.50)U/L, 26.80(14.25)mmol/L, 12.50(2.95)seconds, 5, 15, 2 in patients of the traditional approach group. There was no significant difference in the ALT, AST, TBil, PT at postoperative day 3, postoperative biliary fistula between the two groups ( Z=-1.218, -1.488, -0.205, -0.320, χ2=1.976, P>0.05), and there was no significant difference in the pathological type of tumor between the two groups ( P>0.05). Conclusion:Application of CPA for extrahepatic right hepatic pedicle dissection in MIALR is safe and feasible.
8.Development of a nomogram prediction model based on 3D quantitative parameters for mediastinal lymph node metastases in clinical stage ⅠA lung adenocarcinoma
Zhixi LI ; Yongjun PAN ; Zhikang YE ; Yingjun ZHOU ; Guoneng CHEN ; Zhichao ZUO ; Wei ZHANG
Journal of Practical Radiology 2023;39(12):1936-1940
Objective To develop a nomogram based on pulmonary nodules preoperative CT signs and 3D quantitative parameters for predicting mediastinal lymph node metastases in patients with clinical stage ⅠA lung adenocarcinoma.Methods The imaging data of 164 patients who underwent preoperative CT scan and systematic lymph node dissection were analyzed retrospectively.Commercially available AI software was used to extract 3D quantitative parameters of pulmonary nodules automatically,and CT signs of pulmonary nodules were analyzed.Logistic regression was used to explore the role of these parameters in predicting pathological nodal involvement.A nomogram prediction model was established,then discrimination and calibration of the model were evaluated.Results Among 164 enrolled patients,19(11.6%)were tested positive for mediastinal lymph node metastases at pathology review.The nomogram incorporated spiculation,lobulation,the largest cross-sectional area,and carcinoembryonic antigen(CEA).The model showed great discrimination and calibration,with a C-index of 0.942[95%confidence interval(CI)0.923-0.961].The predicted value of the model fitted well with the actual observed value on the calibration curve.Conclusion The nomogram prediction model based on preoperative CT signs,3D quantitative parameters,and CEA can estimate the probability of mediastinal lymph node metastases in clinical stage ⅠA lung adenocarcinoma.This model may help with clinical decision-making and individualized evaluation.
9.Recent advances in research on chelators as metallo-β-lactamase inhibitors
Zhixi ZHU ; Jielin ZHANG ; Yijun CHEN
Journal of China Pharmaceutical University 2022;53(4):410-422
The major reason for the resistance of Gram-negative bacteria to β-lactam antibiotics is the expression of β-lactamases.Metallo-β-lactamases (MBL) hydrolyze almost all types of β-lactam antibiotics including carbapenems, posing a challenge to global public health. Developing MBL inhibitors is an important method to treat the infections caused by resistant bacteria. As an important type of MBL inhibitors, chelating agents can inhibit MBL by chelating, stripping, and binding Zn2+ in the active center of MBL.This review summarizes recent publications on chelators as MBL inhibitors, discussing their chemical structures, inhibitory potency, synergistic effects with antibiotics, selectivity and mechanism of action, including EDTA and related compounds, aspergillomarasmine A (AMA) and its derivatives, NOTA and related compounds, pyridine carboxylic acid and pyridine methylamine compounds, aiming to provide reference for future development of potent, selective and safe clinical MBL inhibitors.
10.Role of Inflammation in Development of Chronic Heart Failure: Based on "Toxic Pathogen Theory"
Shumin HUANG ; Ziyi WANG ; Qian ZHANG ; Xiaoqian LIAO ; Siyuan HU ; Zhixi HU
Chinese Journal of Experimental Traditional Medical Formulae 2022;28(18):198-204
Chronic heart failure is a serious heart disease with dyspnea and limited activity tolerance as the main clinical manifestations. Activation of the inflammatory system can significantly stimulate cardiac fibrosis and remodeling and promote the progression of heart failure, playing a key role in the development of the disease. Studies have confirmed that inflammation is involved in the development of different types of heart failure. "Toxic pathogen theory" is an important basic theory of traditional Chinese medicine (TCM) to explain the occurrence of diseases. We concluded the similarities between TCM toxic pathogens and inflammation in concept, disease location, etiology, syndrome differentiation, and clinical characteristics. Chronic heart failure is manifested by the toxic pathogens of turbid phlegm, stagnated blood, and accumulated fluid. Heart vessel obstruction is the main pathological factor, and the inflammatory factors produced by necrotic cardiomyocytes are the microscopic manifestations of the obstruction. Therefore, based on the "toxic pathogen theory", this study aimed to clarify the role of inflammation in the development of chronic heart failure from both macroscopic and microscopic perspectives. Moreover, this paper proposed that the stagnated blood has not been transformed into toxin in the early stage of the disease and thus the products of clearing heat and detoxification should not be used. At the development stage of the disease when the transformation tends to begin, treatment should be based on syndrome differentiation, and detoxifying Chinese medicine should be used in order to achieve the goal of "removing toxin without harming the healthy Qi". At the late stage of heart failure, toxins have been accumulated and detoxifying medicines and therapies should be applied to eliminate the toxic pathogens. This study is expected to lay a foundation for the modern research on the role of inflammation in the development of chronic heart failure with TCM theory and guide the diagnosis and treatment of this disease.

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