1.A multicenter clinical study on intramedullary vancomycin injection for preventing periprosthetic joint infection in total knee arthroplasty
Te LIU ; Jun FU ; Shiguang LAI ; Zhuo ZHANG ; Chi XU ; Lei GENG ; Yang LUO ; Peng REN ; Xin ZHI ; Quanbo JI ; Heng ZHANG ; Runkai ZHAO ; Haichao REN ; Ye TAO ; Qingyuan ZHENG ; Zeyu FENG ; Jianfeng YANG ; Yiming WANG ; Pengcheng LI ; Shuai LIU ; Wei CHAI ; Xiang LI ; Huiwu LI ; Xiaogang ZHANG ; Baochao JI ; Xianzhe LIU ; Xinzhan MAO ; Jianbing MA ; Xiangxiang SUN ; Jiying CHEN ; Yonggang ZHOU ; Jinliang WANG ; Weijun WANG ; Guoqiang ZHANG ; Ming NI
Chinese Journal of Orthopaedics 2025;45(12):803-811
Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.
2.Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells.
Yi WANG ; Xiao-Yu SUN ; Fang-Qi MA ; Ming-Ming REN ; Ruo-Han ZHAO ; Meng-Meng QIN ; Xiao-Hong ZHU ; Yan XU ; Ni-da CAO ; Yuan-Yuan CHEN ; Tian-Geng DONG ; Yong-Fu PAN ; Ai-Guang ZHAO
Journal of Integrative Medicine 2025;23(3):320-332
OBJECTIVE:
Gastric cancer (GC) is one of the most common malignancies seen in clinic and requires novel treatment options. Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L., which exhibits an anti-cancer effect in multiple types of tumors. However, the therapeutic effect and underlying mechanism of morin in treating GC remains elusive. The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC.
METHODS:
For in vitro experiments, the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45, human gastric adenocarcinoma cell line AGS, and human gastric epithelial cell line GES-1; for apoptosis analysis, microscopic photography, Western blotting, ubiquitination analysis, quantitative polymerase chain reaction analysis, flow cytometry, and RNA interference technology were employed. For in vivo studies, immunohistochemistry, biomedical analysis, and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC.
RESULTS:
Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose- and time-dependent manner, but did not inhibit human gastric epithelial cells GES-1. Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells, suggesting that apoptosis was the main type of cell death during the treatment. Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells, which mainly relied on B cell leukemia/lymphoma 2 (BCL-2) associated agonist of cell death (BAD) but not phorbol-12-myristate-13-acetate-induced protein 1. The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD, rather than the transcription regulation and the phosphorylation of BAD. Furthermore, the combination of morin and BCL-2 inhibitor navitoclax (also known as ABT-737) produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals. In addition, morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway.
CONCLUSION
Morin suppressed GC by inducing apoptosis, which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD. The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells, which may overcome the drug resistance of the BCL-2 inhibitor. These findings indicated that morin was a potent and promising agent for GC treatment. Please cite this article as: Wang Y, Sun XY, Ma FQ, Ren MM, Zhao RH, Qin MM, Zhu XH, Xu Y, Cao ND, Chen YY, Dong TG, Pan YF, Zhao AG. Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells. J Integr Med. 2025; 23(3): 320-332.
Humans
;
Flavonoids/therapeutic use*
;
Stomach Neoplasms/pathology*
;
Animals
;
Proto-Oncogene Proteins c-bcl-2/metabolism*
;
Cell Line, Tumor
;
Apoptosis/drug effects*
;
Cell Proliferation/drug effects*
;
Ubiquitination/drug effects*
;
Mice
;
Drug Synergism
;
Mice, Inbred BALB C
;
Mice, Nude
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Xenograft Model Antitumor Assays
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Flavones
3.Association between Organochlorine Exposures and Lung Functions Modified by Thyroid Hormones and Mediated by Inflammatory Factors among Healthy Older Adults.
Xiao Jie GUO ; Hui Min REN ; Ji Ran ZHANG ; Xiao MA ; Shi Lu TONG ; Song TANG ; Chen MAO ; Xiao Ming SHI
Biomedical and Environmental Sciences 2025;38(2):144-153
OBJECTIVE:
To examine the mechanistic of organochlorine-associated changes in lung function.
METHODS:
This study investigated 76 healthy older adults in Jinan, Shandong Province, over a five-month period. Personal exposure to organochlorines was quantified using wearable passive samplers, while inflammatory factors and thyroid hormones were analyzed from blood samples. Participants' lung function was evaluated. After stratifying participants according to their thyroid hormone levels, we analyzed the differential effects of organochlorine exposure on lung function and inflammatory factors across the low and high thyroid hormone groups. Mediation analysis was further conducted to elucidate the relationships among organochlorine exposures, inflammatory factors, and lung function.
RESULTS:
Bis (2-chloro-1-methylethyl) ether (BCIE), was negatively associated with forced vital capacity (FVC, -2.05%, 95% CI: -3.11% to -0.97%), and associated with changes in inflammatory factors such as interleukin (IL)-2, IL-7, IL-8, and IL-13 in the low thyroid hormone group. The mediation analysis indicated a mediating effect of IL-2 (15.63%, 95% CI: 0.91% to 44.64%) and IL-13 (13.94%, 95% CI: 0.52% to 41.07%) in the association between BCIE exposure and FVC.
CONCLUSION
Lung function and inflammatory factors exhibited an increased sensitivity to organochlorine exposure at lower thyroid hormone levels, with inflammatory factors potentially mediating the adverse effects of organochlorines on lung function.
Environmental Exposure
;
Hydrocarbons, Chlorinated/metabolism*
;
China
;
Ethyl Ethers/metabolism*
;
Environmental Monitoring
;
Thyroid Hormones/blood*
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Lung/physiology*
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Inhalation Exposure/statistics & numerical data*
;
Air Pollution/statistics & numerical data*
;
Air Pollutants/metabolism*
;
Humans
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Male
;
Female
;
Middle Aged
;
Aged
4.Mechanical thrombectomy using the retrograde semi-retrieval technique in the treatment of acute intracranial large vessel occlusion
Zhenjian MA ; Yongbo XU ; Wenjun WU ; Hecheng REN ; Hong LI ; Ming WEI
Journal of Xi'an Jiaotong University(Medical Sciences) 2025;46(6):930-936
Objective To investigate the short-term efficacy of the retrograde semi-retrieval technique(RESET)in the treatment of patients with acute intracranial large vessel occlusion.Methods This retrospective study involved 286 patients with acute intracranial large vessel occlusion who underwent mechanical thrombectomy using RESET at Tianjin Huanhu Hospital from November 2017 to March 2019.The patients were divided into two groups based on the presence or absence of intracranial atherosclerotic stenosis(ICAS):ICAS group(n=186,65%)and non-ICAS group(n=100,35%).Baseline characteristics,procedural outcomes,and 90-day modified Rankin Scale(mRS)scores were compared between the two groups.Results The two groups did not significantly differ in baseline characteristics,including age,gender,past medical history,on-admission National Institutes of Health Stroke Scale(NIHSS)score,and Alberta Stroke Program Early CT(ASPECT)score(all P>0.05).Successful vascular recanalization was achieved in 272 patients(95.1%),with 209 patients(73.1%)achieving complete recanalization with a single thrombectomy attempt.Rescue therapy was required in 33 patients(11.5%).Two patients in the ICAS group died due to postoperative symptomatic intracranial hemorrhage,and one patient in the non-ICAS group died due to postoperative multiple organ failure.Compared with the non-ICAS group,the ICAS group had a significantly longer puncture-to-recanalization time[141.36(124.11,156.53)min vs.65.17(53.92,83.25)min,P<0.001]but a significantly smaller number of thrombectomy attempts[1.00(1.00,1.00)vs.1.00(1.00,2.00),P=0.002].However,there were no significant differences between the two groups in terms of final recanalization rate,complete recanalization rate with a single thrombectomy attempt,distal embolism or embolization of new territory,symptomatic intracranial hemorrhage,perioperative death,or 90-day mRS score(all P>0.05).Conclusion RESET demonstrates satisfactory short-term efficacy in the treatment of acute intracranial large vessel occlusion.The number of thrombectomy attempts required for complete recanalization is significantly lower in the ICAS group than in the non-ICAS group,suggesting that RESET is particularly suitable for patients with ICAS.
5.A multicenter clinical study on intramedullary vancomycin injection for preventing periprosthetic joint infection in total knee arthroplasty
Te LIU ; Jun FU ; Shiguang LAI ; Zhuo ZHANG ; Chi XU ; Lei GENG ; Yang LUO ; Peng REN ; Xin ZHI ; Quanbo JI ; Heng ZHANG ; Runkai ZHAO ; Haichao REN ; Ye TAO ; Qingyuan ZHENG ; Zeyu FENG ; Jianfeng YANG ; Yiming WANG ; Pengcheng LI ; Shuai LIU ; Wei CHAI ; Xiang LI ; Huiwu LI ; Xiaogang ZHANG ; Baochao JI ; Xianzhe LIU ; Xinzhan MAO ; Jianbing MA ; Xiangxiang SUN ; Jiying CHEN ; Yonggang ZHOU ; Jinliang WANG ; Weijun WANG ; Guoqiang ZHANG ; Ming NI
Chinese Journal of Orthopaedics 2025;45(12):803-811
Objective:To explore the safety and efficacy of intraosseous regional administration (IORA) of vancomycin for preventing infection in primary total knee arthroplasty (TKA).Methods:A total of 124 patients with knee osteoarthritis undergoing TKA between February 2024 and May 2024 at nine hospitals were enrolled. Preoperative infection prophylaxis involved either IORA (0.5 g vancomycin administered via intraosseous regional infusion before incision) or intravenous infusion (1 g vancomycin via peripheral vein). The IORA group included 15 males and 47 females with a median age of 66.5 years (range, 60.0-70.0 years), while the intravenous group included 14 males and 48 females with a median age of 66.0 years (range, 61.8-70.3 years) years. Intraoperative samples were collected including fat and synovium tissues after incision, before prosthesis placement, and after tourniquet release; distal femoral cancellous bone during femoral osteotomy; proximal tibial cancellous bone during tibial osteotomy; proximal intercondylar cancellous bone before prosthesis placement; and peripheral blood from non-infused arms at surgery initiation and after tourniquet release. Vancomycin concentrations were measured using liquid chromatography-tandem mass spectrometry. Vital sign changes were recorded from admission to 5~10 minutes post-IORA (IORA group) or post-incision (intravenous group). Follow-ups were conducted on postoperative day 1 and 3, and at 1 and 3 months, to document complications including IORA-related adverse events, periprosthetic joint infections, surgical site infections, red man syndrome, acute kidney injury, deep vein thrombosis and so on.Results:Vancomycin concentrations in bone, fat, and synovial tissue samples were significantly higher in the IORA group than in the intravenous group ( P<0.05), while vancomycin concentrations in blood samples were significantly lower in the IORA group than in the intravenous group ( P<0.05). Only 7.3%(41/558) of tissue samples in the IORA group had vancomycin concentrations below 2.0 μg/g (the minimum inhibitory concentration of vancomycin against coagulase-negative staphylococcus), compared to 59.3%(331/558) in the intravenous group (χ 2=11.285, P<0.001). In the intravenous group, 16.9%(21/124) of blood samples had vancomycin concentrations exceeding 15.0 mg/L (the threshold associated with a significantly increased risk of nephrotoxicity), while all concentrations in the IORA group were below this threshold, the difference was statistically significant (χ 2=22.943, P<0.001). There were no statistically significant difference ( P>0.05) in vital signs changes before and after vancomycin administration between the two groups. Two patients in the intravenous group experienced incision exudate, while no other related complications occurred in either group. Conclusions:Compared to the traditional intravenous infusion of 1 g vancomycin, intraosseous injection of a low dose (0.5 g) of vancomycin achieves higher local tissue concentrations in the knee joint with a lower incidence of adverse reactions and is safe for infection prophylaxis. Despite guidelines not recommending the routine use of vancomycin for preventing infection after primary TKA, intraosseous injection of 0.5 g vancomycin may be considered intraoperatively for primary TKA in the following scenarios: patients in medical institutions with a high prevalence of methicillin-resistant staphylococcus aureus (MRSA) infections, patients with potential preoperative MRSA colonization, or patients with cephalosporin allergy.
6.Mechanical thrombectomy using the retrograde semi-retrieval technique in the treatment of acute intracranial large vessel occlusion
Zhenjian MA ; Yongbo XU ; Wenjun WU ; Hecheng REN ; Hong LI ; Ming WEI
Journal of Xi'an Jiaotong University(Medical Sciences) 2025;46(6):930-936
Objective To investigate the short-term efficacy of the retrograde semi-retrieval technique(RESET)in the treatment of patients with acute intracranial large vessel occlusion.Methods This retrospective study involved 286 patients with acute intracranial large vessel occlusion who underwent mechanical thrombectomy using RESET at Tianjin Huanhu Hospital from November 2017 to March 2019.The patients were divided into two groups based on the presence or absence of intracranial atherosclerotic stenosis(ICAS):ICAS group(n=186,65%)and non-ICAS group(n=100,35%).Baseline characteristics,procedural outcomes,and 90-day modified Rankin Scale(mRS)scores were compared between the two groups.Results The two groups did not significantly differ in baseline characteristics,including age,gender,past medical history,on-admission National Institutes of Health Stroke Scale(NIHSS)score,and Alberta Stroke Program Early CT(ASPECT)score(all P>0.05).Successful vascular recanalization was achieved in 272 patients(95.1%),with 209 patients(73.1%)achieving complete recanalization with a single thrombectomy attempt.Rescue therapy was required in 33 patients(11.5%).Two patients in the ICAS group died due to postoperative symptomatic intracranial hemorrhage,and one patient in the non-ICAS group died due to postoperative multiple organ failure.Compared with the non-ICAS group,the ICAS group had a significantly longer puncture-to-recanalization time[141.36(124.11,156.53)min vs.65.17(53.92,83.25)min,P<0.001]but a significantly smaller number of thrombectomy attempts[1.00(1.00,1.00)vs.1.00(1.00,2.00),P=0.002].However,there were no significant differences between the two groups in terms of final recanalization rate,complete recanalization rate with a single thrombectomy attempt,distal embolism or embolization of new territory,symptomatic intracranial hemorrhage,perioperative death,or 90-day mRS score(all P>0.05).Conclusion RESET demonstrates satisfactory short-term efficacy in the treatment of acute intracranial large vessel occlusion.The number of thrombectomy attempts required for complete recanalization is significantly lower in the ICAS group than in the non-ICAS group,suggesting that RESET is particularly suitable for patients with ICAS.
7.Progress on effect of CypA/CD147 in diagnosis and treatment of cardiovascular system disease infected by SARS-CoV-2
Ming-Ren MA ; Fei WANG ; Xiao-Qing CAI ; Yan LIU ; Ling MA
Medical Journal of Chinese People's Liberation Army 2024;49(1):115-120
Corona virus disease 2019(COVID-19)epidemic has been effectively controlled,but its related complications still cannot be ignored,especially the cardiovascular circulatory system is the active site of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Angiotensin-converting enzyme 2(ACE2)is a type Ⅰ transmembrane glycoprotein that is highly expressed in heart,kidney and testis.Spike protein of SARS-CoV-2 invades host cells by binding to the cell surface receptor ACE2.However,there are still many deficiencies in the clinical application of vaccines and drugs developed based on this target.As a molecular chaperone,cyclophilin A(CypA)promotes protein folding and T cell activation.CD147 is one of the most widely studied CypA receptors,and the interaction of CypA/CD147 plays an important role in the entry of SARS-CoV-2 into host cells.However,there are few reports on the invasion of SARS-CoV-2 into the cardiovascular system through the CypA/CD147 signaling pathway.Based on this,this article summarizes the previous research evidence and the research basis of the research group,and reviews the structure and function of CypA/CD147,the role of CypA/CD147 in cardiovascular disease,and the cardiovascular disease caused by SARS-CoV-2 targeting CypA/CD147 signal pathway,in order to provide reference for the diagnosis and treatment of the COVID-19 complicated with cardiovascular system diseases.
8.Influence of Tongfu Xiefei Guanchang Solution on intestinal barrier and intestinal flora of rats with acute lung injury based on p38 MAPK/MLCK signaling pathway.
Ming MA ; Kun WANG ; Yan-Hua YANG ; Meng-Ru YUE ; Quan-Na REN ; Yu-Han CHEN ; Yong-Zhen SONG ; Zi-Fu XU ; Xu ZHAO
China Journal of Chinese Materia Medica 2024;49(21):5919-5931
The study is designed to observe the mechanism of Tongfu Xiefei Guanchang Solution(TFXF) in the treatment of acute lung injury(ALI) in rats by improving intestinal barrier and intestinal flora structure via p38 mitogen-activated protein kinase(p38 MAPK)/myosin light chain kinase(MLCK) signaling pathway. Sixty SPF-grade Wistar rats were randomly divided into the control(CON) group, lipopolysaccharide(LPS) group(7.5 mg·kg~(-1)), LPS + dexamethasone(DEX) group(3.5 mg·kg~(-1)), LPS + high-dose(HD)-TFXF group(14.74 g·kg~(-1)), LPS + middle-dose(MD)-TFXF group(7.37 g·kg~(-1)), and LPS + low-dose(LD)-TFXF group(3.69 g·kg~(-1)). ALI model of the rat was established by intraperitoneal injection of LPS. The lactate dehydrogenase(LDH) activity and total protein concentration in the bronchoalveolar lavage fluid(BALF) were measured; tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) levels in lung and colon tissue of rats were detected by enzyme linked immunosorbent assay(ELISA). Hematoxylin-eosin(HE) staining was used to observe the pathological expression in the lung and colon tissue of rats. The mRNA expression of p38 MAPK, TNF-α, and IL-1β in rat lung tissue was determined by real-time fluorescence quantitative polymerase chain reaction(real-time PCR). Western blot was used to detect the protein expression related to the p38 MAPK/MLCK signaling pathway in the colon tissue of rats. 16S rRNA sequencing was used to detect changes in the composition and content of intestinal flora in rats, and correlation analyses were performed to explore the regulatory role of intestinal flora in improving ALI in rats. The results showed that compared with those in the LPS group, the histopathological scores of lung and colon tissue, LDH activity, and total protein concentration in BALF were significantly reduced in rats in all groups after drug administration. Except for the LPS + LD-TFXF group, the remaining groups significantly reduced the levels of TNF-α and IL-1β in the lung and colon tissue of rats. The protein expressions of phosphorylated p38 mitogen-activated protein kinase(p-p38 MAPK)/p38, phosphorylated myosin light chain(p-MLC)/myosin light chain 2(MLC2), and MLCK in colon tissue of rats in each drug administration group were significantly decreased. The mRNA expression levels of p38 MAPK, TNF-α, and IL-1β were significantly reduced in the LPS + HD-TFXF group. 16S rRNA sequencing results showed that the abundance of intestinal flora was significantly higher in the LPS + HD-TFXF group, and intestinal floras including Sobs, Shannon, and Npshannon were significantly higher. The β-diversity distribution of intestinal flora tends toward the CON group, and the abundance of Firmicutes was significantly higher. The abundance of Proteobacteria was significantly reduced; the abundance of Bacteroides was significantly reduced, and the abundance of Ruminococcus was significantly higher. The main species differences were Blautia, Roseburia_sp_499, and Butyricicoccus. TNF-α and IL-1β of lung tissue were negatively correlated with Muribaculaceae, unclassified norank_f_Eubacterium_coprostanoligenes, and Ruminococcus and positively correlated with Bacteroides. Meanwhile, TNF-α and IL-1β of colon tissue were negatively correlated with unclassified norank_f_Eubacterium_coprostanoligenes and Ruminococcus and positively correlated with Bacteroides. The predicted biological function of the flora was related to the biosynthesis of secondary metabolites, amino acid biosynthesis, sugar metabolism, and oxidative phosphorylation. The above studies show that TFXF can repair lung and colon tissue structure and regulate inflammatory factor levels by modulating the abundance and diversity of intestinal flora species in ALI rats. Its mechanism of action in ameliorating ALI in rats may be related to the inhibition of inflammation, improvement of intestinal mucosal permeability, and maintenance of intestinal flora homeostasis and barrier through the p38 MAPK/MLCK signaling pathway.
Animals
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Acute Lung Injury/genetics*
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Rats
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p38 Mitogen-Activated Protein Kinases/genetics*
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Drugs, Chinese Herbal/pharmacology*
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Myosin-Light-Chain Kinase/genetics*
;
Male
;
Gastrointestinal Microbiome/drug effects*
;
Rats, Wistar
;
Signal Transduction/drug effects*
;
Interleukin-1beta/metabolism*
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Tumor Necrosis Factor-alpha/metabolism*
;
Lung/metabolism*
;
Intestinal Mucosa/metabolism*
;
Humans
9.Effects of Yiqi tongmai formula on atherosclerosis in ApoE-/- mice and its mechanism
Quanna REN ; Yuhan CHEN ; Kun WANG ; Ming MA ; Yanhua YANG ; Yu ZHANG ; Xu ZHAO
China Pharmacy 2024;35(18):2232-2237
OBJECTIVE To investigate the effects of Yiqi tongmai formula on atherosclerosis (AS) in ApoE-/- mice and its mechanism. METHODS Forty ApoE-/- mice were randomly divided into model group, positive control group [atorvastatin calcium, 2.6 mg/(kg·d)], and low-dose, medium-dose and high-dose groups of Yiqi tongmai formula [0.46, 0.91, 1.82 g/(kg·d), by raw material], with 8 mice in each group. Eight C57BL/6J mice were selected as the normal group. Except for the normal group, the other groups were given a high-lipid diet and relevant drug or normal saline intragastrically, once a day, for 12 consecutive weeks. After the last medication, the serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) as well as the contents of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) were measured in mice. The proportion of aortic plaque area in each group of mice was detected and calculated, and the pathological morphological changes of the aortic sinus were observed; the protein phosphorylation levels of aortic phosphoinositide 3-kinase (PI3K), protein kinase B (aka Akt) and mammalian target of rapamycin (mTOR) were examined. RESULTS Compared with the model group, the serum levels of TC, TG and LDL-C and the contents of TNF-α, IL-1β and MCP-1 (including low-dose group) were decreased significantly in medium-dose and high-dose groups of Yiqi tongmai formula, while the content of HDL-C in high-dose group was increased significantly (P<0.05 or P<0.01); aortic plaques of the mice were reduced in Yiqi tongmai formula groups to different extents, and pathological changes such as lipid deposition and inflammatory cell infiltration were relieved to different extents; the proportion of aortic plaque area, the protein phosphorylation levels of PI3K, Akt and mTOR in aortic tissue were significantly reduced in medium-dose and high-dose groups of Yiqi tongmai formula (P<0.05 or P<0.01). CONCLUSIONS Yiqi tongmai formula can improve lipid metabolism, reduce inflammatory response, and delay plaque development in AS mice. Its effect may be related to the inhibition of PI3K/Akt/mTOR signaling pathway activation.
10.Effect of Yiqi Tongmai Formula in Intervening in Liver Inflammation and Lipidosis in ApoE-∕- Mice Based on NF-κB/NLRP3 Signaling Pathway
Yuhan CHEN ; Quanna REN ; Kun WANG ; Tingting SU ; Yanhua YANG ; Ming MA ; Yu ZHANG ; Xu ZHAO
Chinese Journal of Experimental Traditional Medical Formulae 2024;30(15):64-72
ObjectiveTo investigate the effect of Yiqi Tongxin formula (YQTM) on liver inflammation in apolipoprotein E-∕- (ApoE-∕-) mice by regulating the nuclear transcription factor-κB (NF-κB)/NOD-like receptor protein 3 (NLRP3) signaling pathway. MethodForty ApoE-∕- mice were randomly divided into a model group, an atorvastatin group (positive drug group), and low-, medium-, and high-dose YQTM groups (0.39, 0.78, 1.56 g·kg-1). Each drug administration group was given the corresponding concentration of the drug by gavage on the basis of high-fat feeding for 12 consecutive weeks. Eight C57BL/6J mice were used as a blank group and fed with normal chow. After 12 weeks, oil red O staining and Masson staining were used to observe the aortic lesions in mice and to determine whether the modeling was successful. Oil red O staining was used to observe the lipidosis in the livers of mice. Hematoxylin-eosin (HE) staining was used to observe the tissue lesions in the livers of mice. Masson staining was used to observe the distribution of collagen fibers in the livers of mice. Enzyme markers were used to detect the total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) in mouse serum, as well as total cholesterol (TC) and triglyceride (TG) in the liver. Interleukin-1β (IL-1β) and IL-18 were detected in mouse liver by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry (IHC) was utilized to observe the expression regions of NF-κB and NLRP3 in the livers of mice. Western blot was employed to detect the protein expression levels of NF-κB, NF-κB inhibitory protein (IκB), IκB kinase β (IKKβ), phosphorylated NF-κB (p-NF-κB), phosphorylated IκB (p-IκB), phosphorylated IKK β (p-IKKβ), NLRP3, and Caspase-1 in the livers of mice. ResultCompared with the blank group, the model group showed severe aortic lipidosis, and the intracellular fat droplets in the livers aggregated in large quantities. The cytoplasm was filled with fat vacuoles(P<0.01). The serum levels of TG, TC, LDL-C, AST, and ALT were significantly elevated in the mice(P<0.01). TG and TC levels were elevated in the liver(P<0.01). The levels of IL-1β and IL-18 in liver tissue, as well as the protein expression levels of NF-κB, IκB, IKKβ, p-NF-κB, p-IκB, p-IKKβ, NLRP3, and Caspase-1 in the liver were significantly elevated(P<0.01). Compared with the model group, the aortic arch plaques of mice in each YQTM group were attenuated, and the fat aggregation in the liver was reduced. The inflammatory cell infiltration was alleviated(P<0.05,P<0.01). The serum levels of TG, TC, LDL-C, AST, and ALT were significantly reduced(P<0.05,P<0.01). TG and TC levels in the liver were reduced. The IL-1β and IL-18 levels in liver tissue, as well as protein expression levels of NF-κB, IκB, IKKβ, p-NF-κB, p-IκB, p-IKKβ, NLRP3, and Caspase-1 in the liver were significantly reduced(P<0.05,P<0.01). ConclusionThe intervention mechanism of YQTM on liver inflammation in ApoE-∕- mice may be related to the down-regulation of the NF-κB/NLRP3 signaling pathway.

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