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1.
J. appl. oral sci ; 30: e20220076, 2022. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1386009

ABSTRACT

Abstract Objective The purpose of this study is to investigate the pathogenic role of PPARα in periodontal antigen treated gingival cells in vitro and in experimental periodontitis in vivo . Methodology Gingival fibroblasts, gingival epithelial cells and splenocytes were isolated from C57BL/6J wild type (WT) mice and treated with fixed P. gingivalis at for 48 hours. The mRNA levels of PPARs, TNFα, IL-1β and IL-10 were detected by Real-time quantitative PCR. Silk ligatures after being soaked in the P.gingivalis suspension were tied around both maxillary second molars of WT mice or PPARα knock-out (KO) mice for two weeks. PPARα agonist fenofibrate and vehicle control were injected into the different side of the palatal gingiva on days 3, 6, and 9. At day 14, bone resorption and gingival mRNA expression levels of PPARs, TNFα, IL-1β and IL-10 were measured by micro-computed tomography and RT-qPCR respectively. Results P. gingivalis treatment downregulated the expression of PPARα, but not PPARβ or PPARγ, and increased the expression of TNF-α and IL-1β in Gingival fibroblasts, gingival epithelial cells and splenocytes from WT mice. Gingival mRNA levels of PPARα were significantly decreased in experimental periodontitis in WT mice. The bone loss of PPARα KO mice in experimental periodontitis was significantly higher than WT mice and was not reduced by fenofibrate treatment. Gingival TNFα protein expressions were significantly increased by P. gingivalis associated ligation and decreased by fenofibrate treatment in WT mice but not in PPARα KO mice. Conclusion This study suggests that PPARα plays an essential role in periodontitis.

2.
Article in Chinese | WPRIM | ID: wpr-940799

ABSTRACT

ObjectiveTo observe the effects of five Huoxue Huayu prescriptions on blood lipid metabolism, liver tissue and adenosine triphosphate binding cassette transporter A1 (ABCA1) and peroxisome proliferator-activated receptor γ(PPARγ) expression in New Zealand rabbits with blood stasis syndrome, and to compare their differences in order to provide laboratory evidence for clinical selection of prescriptions and drugs. MethodSeventy New Zealand rabbits were randomly divided into normal group (n=10) and model group (n=60). The blood stasis syndrome was modeled by the method of starvation+high-fat feed+adrenaline. After the models were successfully established, they were randomly divided into Xuefu Zhuyutang(3.55 g·kg-1·d-1) group, Danshenyin(1.962 g·kg-1·d-1) group, Shixiaosan(0.56 g·kg-1·d-1) group, Huoluo Xiaolingdan(2.80 g·kg-1·d-1) group, and Taohong Siwutang(2.66 g·kg-1·d-1) group, and were given corresponding compound prescriptions by gavage. The normal group and model group were given the same dose of distilled water. After the treatment of 30 consecutive days, blood was taken from the abdominal aorta to detect the content of total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol(LDL-C) and apolipoprotein A1 (ApoA1). Hematoxylin-eosin(HE) staining was used to observe the changes in liver tissue. Real-time polymerase chain reaction (Real-time PCR) and Western blot were used to detect the mRNA and protein expression of ABCA1 and PPARγ in liver tissue, respectively. ResultCompared with the conditions in the normal group, increased mRNA and protein levels of HDL-C, LDL-C, TG, TC, and PPARγ (P<0.01), decreased ApoA1 level (P<0.05) and decreased mRNA and protein levels of ABCA1 (P<0.01) were found in the model group. Compared with the conditions in the model group, the HDL-C level in the five Huoxue Huayu prescriptions was lowered (P<0.05), and lowered TG level in Xuefu Zhuyutang group and Shixiaosan group (P<0.05), decreased LDL-C and TC levels in Shixiaosan group (P<0.05), and increased ApoA1 level in the Huoluo Xiaolingdan group (P<0.01) and Taohong Siwutang group (P<0.05) were observed. Furthermore, the mRNA and protein levels of ABCA1 in Xuefu Zhuyutang group, Shixiaosan group, Huoluo Xiaolingdan group and Taohong Siwutang group were elevated (P<0.05, P<0.01), and the elevated levels were higher than that of Danshenyin group (P<0.05). The mRNA level of PPARγ in the five Huoxue Huayu prescriptions was reduced (P<0.01), and its protein level was also decreased in Xuefu Zhuyutang group, Shixiaosan group, Huoluo Xiaolingdan group and Taohong Siwutang group (P<0.01). ConclusionThe five Huoxue Huayu prescriptions had a certain therapeutic effect on dyslipidemia,which might be achieved by up-regulating the expression of ApoA1 and ABCA1 to promote the production of HDL-C and strengthen the excretion of dysfunctional HDL-C. And Xuefu Zhuyutang had the optimal effect in lowering lipid.

3.
Article in Chinese | WPRIM | ID: wpr-940726

ABSTRACT

ObjectiveTo reveal the effect of Wenxin prescription on mitochondrial energy metabolism and silent information regulator 1 (SIRT1)/peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)/recombinant estrogen-related receptor α (ERRα) signaling pathway in rats with myocardial ischemia-reperfusion injury. MethodTotally 90 male Wistar rats of SPF grade were randomly assigned into a sham operation group, a model group, and low-, medium-, and high-dose Wenxin prescription groups, with 18 rats in each group. The rats in low-, medium-, and high-dose Wenxin prescription groups were administrated with 0.99, 1.98, and 3.96 g·kg-1 granules by gavage, respectively, and those in the sham operation group and model group with the same amount of normal saline. Twenty-one days after pre-administration, the rat model of myocardial ischemia-reperfusion injury was established by ligation of the left anterior descending coronary artery for 30 min and reperfusion for 2 h, and the rats in the sham operation group were only threaded without ligation. Myocardial infarction area was observed through 2,3,5-triphenyl-2h-tetrazolium chloride (TTC) staining, and the myocardial histopathology through hematoxylin-eosin (HE) staining. The levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in serum, cytochrome C oxidase (CCO) and succinate dehydrogenase (SDH) in mitochondrion, and ATP in myocardial tissue were detected according to kit instructions. The mRNA and protein levels of SIRT1, PGC-1α, ERRα, and mitochondrial transcription factor A (TFAM) in myocardial tissue were determined by Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) and Western blot, respectively. ResultCompared with the sham operation group, the model group showed broken and disordered myocardial fibers, cytoplasmic edema, and pyknosis and deviation of nuclei. Moreover, the modeling increased the levels of CK-MB and LDH (P<0.05, P<0.01), lowered the levels of ATP, CCO, and SDH (P<0.05, P<0.01), and down-regulated the mRNA and protein levels of SIRT1, PGC-1α, ERRα, and TFAM in myocardial tissue (P<0.05, P<0.01). Compared with the model group, Wenxin prescription reduced the myocardial infarction area (especially in the high-dose group, P<0.01), restored the pathological changes, lowered the levels of CK-MB and LDH (P<0.05, P<0.01), increased the levels of ATP, CCO, and SDH (especially in the high-dose group, P<0.01), and up-regulated the mRNA and protein levels of SIRT1, PGC-1α, ERRα, and TFAM in myocardial tissue (P<0.05, P<0.01). ConclusionWenxin prescription can protect rats from myocardial ischemia-reperfusion injury by regulating myocardial mitochondrial energy metabolism via the SIRT1/PGC-1α/ERRα signaling pathway.

4.
Article in Chinese | WPRIM | ID: wpr-940627

ABSTRACT

ObjectiveTo study the effect of isoflavones from Sojae Semen Praeparatum (ISSP) on lipid metabolism in atherosclerotic mice, and decipher the underlying mechanism via the peroxisome proliferator-activated receptor gamma/liver X receptor alpha/ATP-binding cassette transporter A1 (PPARγ/LXRα/ABCA1) signaling pathway. MethodFifty ApoE-/- mice were randomly assigned into the model group, western medicine (atorvastatin calcium, 3.03 mg·kg-1) group, and low-, medium-, and high-dose ISSP (2.5, 5, 10 mg·kg-1, respectively) groups, with 10 rats in each group. Atherosclerosis model mice were established by bilateral ovariectomy and feeding high-fat diet. Another 10 ApoE-/- mice receiving ovariectomy and high-fat diet were taken as the sham group. Some mice died of postoperative infection, and finally 6 mice were included in each group. One week after operation, each group was administrated with corresponding drugs or equivalent amount of normal saline. After 12 weeks, the levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified fatty acids (NEFAs) in serum and liver tissue were measured. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in serum were detected by enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining and oil red O staining were used for observation of aortic plaque formation and liver lipid deposition. The mRNA and protein levels of PPARγ, LXRα, ABCA1, and ATP-binding cassette transporter G1 (ABCG1) in liver were determined by real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) and Western blot. ResultCompared with the sham group, the modeling of atherosclerosis increased the aortic plaque area (P<0.01), elevated the serum TC, TG, LDL-C, TNF-α, and IL-6 levels (P<0.01), decreased the level of HDL-C (P<0.01), increased the liver index (P<0.05) and the levels of TC, TG, and NEFAs in liver (P<0.01), and caused obvious hepatic fat vacuoles and lipid deposition. In addition, the modeling down-regulated the mRNA levels of PPARγ, LXRα, ABCA1 in liver (P<0.05, P<0.01),and regulated the mRNA and protein levels of ABCG1(P<0.05, P<0.01). Compared with the model group, atorvastatin calcium and middle-, high-dose ISSP reduced the serum TC, TG, LDL-C, TNF-α, and IL-6 levels (P<0.01), decreased the liver index (P<0.01), alleviated the liver fat vacuoles and lipid deposition, and increased the levels of TC, TG, and NEFAs in the liver (P<0.05, P<0.01). Furthermore, they up-regulated the mRNA and protein levels of PPARγ, LXRα, ABCA1, and ABCG1 in the liver (P<0.05, P<0.01). ConclusionISSP may regulate lipid metabolism through PPARγ/LXRα/ABCA1 signaling pathway to down-regulate the expression of inflammatory cytokines in serum and alleviate liver lipid deposition, thereby suppressing the formation of atherosclerotic plaque.

5.
Article in Chinese | WPRIM | ID: wpr-940618

ABSTRACT

ObjectiveTo explore whether Hei Xiaoyaosan can inhibit the inflammatory response in the hippocampi of Alzheimer's disease (AD) rats by regulating and activating the Wnt/β-catenin signaling pathway to improve the cognitive and memory dysfunction. MethodAmong the 90 male Wistar rats, 12 were randomly selected as the blank group (normal saline) and 12 as the sham operation group (normal saline). For the remainder, amyloid β-protein42 (Aβ42) was injected in the left and right hippocampus to induce AD, and then the AD rats were randomized into model group, low-, medium-, and high-dose Hei Xiaoyaosan groups (corresponding doses of Hei Xiaoyaosan, ig), and donepezil group (donepezil hydrochloride,ig), with 12 in each group. The administration lasted 42 days. The pathological changes of hippocampal CA1 region was observed based on Nissl staining. The escape latency on the 1st to 5th day in Morris water maze was recorded and the spatial memory on the 6th day was tested. Enzyme-linked immunosorbent assay (ELISA) was employed to detect the expression of interleukin (IL)-6, IL-10, and tumor necrosis factor-α (TNF-α) in rat hippocampus and serum, Western blotting to examine the protein expression of glycogen synthase kinase-3β (GSK-3β), β-catenin, and peroxisome proliferator-activated receptor gamma (PPARγ), and real-time polymerase chain reaction (Real-time PCR) to determine the mRNA expression of rat GSK-3β, β-catenin, and PPARγ. ResultCompared with the blank group, the number of neurons in the hippocampal CA1 area of model group was significantly reduced, the arrangement was uneven, the cell body was damaged more obviously, and the Neisser body was unclear. The treatment group was significantly prolonged (P<0.01), and the number of crossing stations was significantly reduced (P<0.01), the levels of IL-10 in serum and hippocampus of rats in the model group were significantly decreased, while the levels of IL-6 and TNF-α were significantly increased (P<0.01), the GSK-3β protein and mRNA in the model group were significantly increased, and the protein expressions of β-catenin and PPARγ were significantly decreased (P<0.01), and the difference was more obvious. The number of neurons in the donepezil group was more distributed, neatly arranged, the structure was intact, and the Nissl bodies were clear and definite, the escape latency on the 3rd to 5th days in middle and high dose groups of Hei Xiaoyaosan and the donepezil group was significantly shortened (P<0.01), the number of crossing platforms increased significantly (P<0.01), the expression levels of IL-10 in the rat hippocampus and serum were significantly increased, while IL-6 and TNF-α were significantly decreased (P<0.01), GSK-3β in the rat hippocampus was significantly increased. The expressions of GSK-3β protein and mRNA were significantly decreased, while the expression levels of β-catenin and PPARγ protein and mRNA were significantly increased (P<0.01). There was no significant difference in each index between the donepezil hydrochloride group and the high-dose Hei Xiaoyaosan group. ConclusionHei Xiaoyaosan can inhibit the inflammatory response in the hippocampus of AD rats by regulating the Wnt/β-catenin signaling pathway, thereby alleviating the cognitive and memory impairment of AD rats.

6.
Article in Chinese | WPRIM | ID: wpr-940298

ABSTRACT

ObjectiveTo explore the mechanism of Shenxiong glucose injection (SGI) in inhibiting hydrogen peroxide (H2O2)-induced oxidative damage in H9c2 cells by tandem mass tags (TMT)-labeled quantitative proteomics. MethodH9c2 cells cultured in vitro were exposed to H2O2 for inducing oxidative damage. The cell viability was measured by cell proliferation and cytotoxicity assay (MTS), followed by peptide fractionation by high performance liquid chromatography (HPLC) and protein expression detection in H9c2 cells by ultrahigh performance liquid chromatography-mass spectrometry. MaxQuant (v1.5.2.8) was utilized for data retrieval, and the high-resolution mass spectrometry was conducted to screen out differentially expressed proteins, which were then subjected to gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis. The protein expression levels of perilipin 2 (Plin2) and tropomyosin 1 (Tpm1) in cells were measured by Western blot. ResultThe spectral analysis yielded 48 608 specific peptide fragments and 5 903 quantifiable proteins. Compared with the model group,the SGI group exhibited 82 differentially expressed proteins,of which 22 were up-regulated and 60 were down-regulated. GO analysis results showed that the differentially expressed proteins were mainly involved in biological processes such as programmed cell death regulation,regulation of cell proliferation,cardiovascular system development, and cell migration. As revealed by KEGG analysis, these proteins were mainly related to peroxisome proliferator-activated receptor (PPAR),focal adhesion,phosphatidylinositol 3-kinase/protein kinase B(PI3K/Akt),and Ras-related protein 1 (Rap1) pathways. Western blot results demonstrated that compared with the model group,SGI significantly increased the Plin2 protein expression and decreased the Tpm1 protein expression (P<0.01),consistent with the proteomics results. ConclusionSGI may inhibit cell apoptosis and antagonize H2O2-induced cell oxidative damage by regulating PPAR,focal adhesion,PI3K/Akt and Rap1 pathways,which should be further verified by subsequent experiments.

7.
Article in Chinese | WPRIM | ID: wpr-940219

ABSTRACT

ObjectiveTo investigate the effects of Asari Radix et Rhizoma-Zingiberis Rhizoma herb pair (XGHP) on lung and liver lipid metabolism in rats with chronic obstructive pulmonary disease (COPD). MethodForty SD male rats were divided into a normal group (10 rats) and a model group (30 rats). The method of cigarette smoke + tracheal injection of lipopolysaccharide(LPS) + cold stimulation was used to replicate COPD model with the syndrome of cold phlegm obstruction in lung. A COPD group, a XGHP group (5.4 g·kg-1·d-1), and an aminophylline group (0.5 g·kg-1·d-1) were established after successfully inducing the model, with 10 rats in each group. After treatment, the serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels of rats in each group were measured. Gas chromatography-mass spectrometer (GC-MS) was used to detect the differential metabolites in the lung and liver tissues of rats in each group, and the relevant targets of the differential metabolites were predicted by network pharmacology. Molecular docking was used to verify the binding ability of key components in XGHP to the relevant targets in network pharmacology. The mRNA and protein expression levels of peroxisome proliferator-activated receptor α (PPARα) and fatty acid binding protein 4 (FABP4) in lung and liver tissues of rats in each group were detected by real-time polymerase chain reaction (PCR) and Western blot. ResultXGHP significantly increased the levels of TG, TC, and LDL-C in serum (P<0.05), and decreased the level of HDL-C (P<0.05) in rats with COPD. GC-MS results showed that there were 8 lung differential metabolites and 17 liver differential metabolites in the COPD group and XGHP group. Network pharmacology predicted 59 common targets for the two differential metabolites, mainly enriched in the PPAR signaling pathway. Molecular docking results showed that the main components in XGHP were well combined with both PPARα and FABP4. Real-time PCR showed that XGHP effectively up-regulated the expression levels of PPARα and FABP4 mRNA (P<0.05), and Western blot showed that XGHP effectively up-regulated the expression levels of PPARα and FABP4 proteins (P<0.05) in lung and liver tissues of rats with COPD. ConclusionXGHP effectively improves the blood lipid levels of rats with COPD, which may be related to the increase of the expression levels of PPARα and FABP4 mRNA and proteins in the PPAR signaling pathway, thus regulating lung and liver lipid metabolism.

8.
Article in Chinese | WPRIM | ID: wpr-940122

ABSTRACT

ObjectiveTo investigate the effects of Asari Radix et Rhizoma-Zingiberis Rhizoma herb pair (XGHP) on lung and liver lipid metabolism in rats with chronic obstructive pulmonary disease (COPD). MethodForty SD male rats were divided into a normal group (10 rats) and a model group (30 rats). The method of cigarette smoke + tracheal injection of lipopolysaccharide(LPS) + cold stimulation was used to replicate COPD model with the syndrome of cold phlegm obstruction in lung. A COPD group, a XGHP group (5.4 g·kg-1·d-1), and an aminophylline group (0.5 g·kg-1·d-1) were established after successfully inducing the model, with 10 rats in each group. After treatment, the serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels of rats in each group were measured. Gas chromatography-mass spectrometer (GC-MS) was used to detect the differential metabolites in the lung and liver tissues of rats in each group, and the relevant targets of the differential metabolites were predicted by network pharmacology. Molecular docking was used to verify the binding ability of key components in XGHP to the relevant targets in network pharmacology. The mRNA and protein expression levels of peroxisome proliferator-activated receptor α (PPARα) and fatty acid binding protein 4 (FABP4) in lung and liver tissues of rats in each group were detected by real-time polymerase chain reaction (PCR) and Western blot. ResultXGHP significantly increased the levels of TG, TC, and LDL-C in serum (P<0.05), and decreased the level of HDL-C (P<0.05) in rats with COPD. GC-MS results showed that there were 8 lung differential metabolites and 17 liver differential metabolites in the COPD group and XGHP group. Network pharmacology predicted 59 common targets for the two differential metabolites, mainly enriched in the PPAR signaling pathway. Molecular docking results showed that the main components in XGHP were well combined with both PPARα and FABP4. Real-time PCR showed that XGHP effectively up-regulated the expression levels of PPARα and FABP4 mRNA (P<0.05), and Western blot showed that XGHP effectively up-regulated the expression levels of PPARα and FABP4 proteins (P<0.05) in lung and liver tissues of rats with COPD. ConclusionXGHP effectively improves the blood lipid levels of rats with COPD, which may be related to the increase of the expression levels of PPARα and FABP4 mRNA and proteins in the PPAR signaling pathway, thus regulating lung and liver lipid metabolism.

9.
Article in Chinese | WPRIM | ID: wpr-930460

ABSTRACT

Glucocorticoids have been applied to clinical treatment of autoimmune diseases and allergic diseases for over 60 years.In recent years, the clinical application of glucocorticoids is annually on the rise with the increased incidence of autoimmune and inflammatory diseases.Therefore, the adverse events of glucocorticoids have been well concerned.It is urgent to analyze the pharmacological mechanism of glucocorticoids, search for novel glucocorticoid receptor ligands with anti-inflammatory and immune inhibitory effects and less adverse events.This study aims to review the research progress of glucocorticoid receptor ligands.

10.
Article in Chinese | WPRIM | ID: wpr-930290

ABSTRACT

Objective:To explore the correlation between serum adipocyte fatty acid binding protein 4 (FABP4) and peroxisome proliferator activated receptor gamma (PPAR gamma) levels and metabolism related fatty liver disease (MAFLD) and type 2 diabetes mellitus (T2DM) .Methods:230 patients with T2DM and MAFLD in Zhangjiakou First Hospital from Feb. 2019 to Feb. 2021 were selected. According to their disease conditions, 80 patients with T2DM and without MAFLD were set as simple T2DM group, 78 patients with MAFLD and normal glucose tolerance were set as simple MAFLD group, 72 patients with T2DM and MAFLD were set as T2DM and MAFLD group, and 100 healthy volunteers in the same period were selected as the control group.Results:The levels of HOMA-IR and FABP4 in T2DM patients were significantly higher than those in the control group ( P<0.05) , while the levels of HDL-C, crea and PPAR γ in T2DM grou were significantly lower than those in the control group ( P<0.05) . The levels of BMI, AST, alt, GGT, TG, HOMA-IR and FABP4 in MAFLD group were significantly higher than those in control group ( P<0.05) , while the level of PPAR γ in MAFLD group was significantly lower than that in control group ( P<0.05) . BMI, AST, alt, GGT, TG, HOMA-IR and FABP4 of T2DM patients with MAFLD were significantly higher than those of T2DM patients without MAFLD and control group ( P<0.05) , while HDL-C and PPAR γ were significantly lower than those of T2DM patients without MAFLD and control group ( P<0.05) . HOMA-IR and FABP4 in T2DM patients with MAFLD were significantly higher than those in MAFLD group ( P<0.05) , while HDL-C, crea and PPAR γ were significantly lower than those in MAFLD group ( P<0.05) . FABP4 was positively correlated with HOMA-IR and CREA (all P<0.05) , and negatively correlated with HDL-Cand PPAR γ (all P<0.05) . PPAR γ was positively correlated with TG and ALT (all P<0.05) , and negatively correlated with HOMA-IR ( P<0.05) . Alt, TG, HOMA-IR, FABP4 and PPAR γ were independent risk factors for MAFLD in T2DM patients ( P<0.05) . Conclusion:FABP4 is positively correlated with the occurrence of T2DM and MAFLD, PPAR γ is negatively correlated with the occurrence of T2DM and MAFLD, the negative feedback loop regulation of FABP4 and PPAR γ can cause the occurrence of insulin resistance, so as to improve the risk of T2DM combined with MAFLD, and provide clinical basis for clinical disease prevention and treatment.

11.
Acta Pharmaceutica Sinica B ; (6): 2129-2149, 2022.
Article in English | WPRIM | ID: wpr-929399

ABSTRACT

Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.

12.
Acta Pharmaceutica Sinica B ; (6): 558-580, 2022.
Article in English | WPRIM | ID: wpr-929314

ABSTRACT

Hepatocellular carcinoma (HCC) is an aggressive human cancer with increasing incidence worldwide. Multiple efforts have been made to explore pharmaceutical therapies to treat HCC, such as targeted tyrosine kinase inhibitors, immune based therapies and combination of chemotherapy. However, limitations exist in current strategies including chemoresistance for instance. Tumor initiation and progression is driven by reprogramming of metabolism, in particular during HCC development. Recently, metabolic associated fatty liver disease (MAFLD), a reappraisal of new nomenclature for non-alcoholic fatty liver disease (NAFLD), indicates growing appreciation of metabolism in the pathogenesis of liver disease, including HCC, thereby suggesting new strategies by targeting abnormal metabolism for HCC treatment. In this review, we introduce directions by highlighting the metabolic targets in glucose, fatty acid, amino acid and glutamine metabolism, which are suitable for HCC pharmaceutical intervention. We also summarize and discuss current pharmaceutical agents and studies targeting deregulated metabolism during HCC treatment. Furthermore, opportunities and challenges in the discovery and development of HCC therapy targeting metabolism are discussed.

13.
Acta Pharmaceutica Sinica B ; (6): 483-495, 2022.
Article in English | WPRIM | ID: wpr-929310

ABSTRACT

Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.

14.
Acta Pharmaceutica Sinica B ; (6): 680-693, 2021.
Article in English | WPRIM | ID: wpr-881162

ABSTRACT

As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced

15.
Article in English | WPRIM | ID: wpr-880995

ABSTRACT

OBJECTIVE@#This research is to investigate the antihyperglycaemic activity and the underlying mechanisms of action of the ethylacetate extract of Chlorophytum alismifolium (EACA) tubers in a type 2 diabetes model.@*METHODS@#The tubers were processed and sequentially extracted in hexane followed by ethylacetate, using a Soxhlet apparatus, and subjected to gas chromatography-mass spectrometry (GC-MS). The acute toxicity of EACA was investigated in albino Wistar rats. An antihyperglycaemic study was carried out using high-fat diet (pelletized diet and margarine in the ratio of 10:1 and 20% fructose solution) and streptozotocin-induced hyperglycaemic Wistar rats. The effects of the extract (150, 300 and 600 mg/kg) on blood glucose level, insulin, peroxisome proliferator-activated receptor-γ (PPAR-γ) and dipeptidyl peptidase-4 (DPP-4) were evaluated using enzyme-linked immunosorbent assay.@*RESULTS@#The oral median lethal dose in Wistar rats was estimated to be > 5000 mg/kg. Treatment with EACA at all doses significantly reduced the fasting blood glucose levels, compared to the hyperglycaemic control, and over time. Administration of EACA increased the serum insulin and PPAR-γ levels while decreasing DPP-4 levels. GC-MS analysis revealed the presence of 13 compounds, with isothiazole and isoxazolidine covering total area of 24.6% and 22.69%, respectively.@*CONCLUSION@#The findings from this study showed that EACA has important compounds with beneficial effect in type 2 diabetes and acts by increasing insulin secretion and PPAR-γ level and decreasing DPP-4 activity.

16.
Acta Pharmaceutica Sinica B ; (6): 1493-1512, 2021.
Article in English | WPRIM | ID: wpr-888816

ABSTRACT

Macrophages are typically identified as classically activated (M1) macrophages and alternatively activated (M2) macrophages, which respectively exhibit pro- and anti-inflammatory phenotypes, and the balance between these two subtypes plays a critical role in the regulation of tissue inflammation, injury, and repair processes. Recent studies indicate that tissue cells and macrophages interact

17.
Article in English | WPRIM | ID: wpr-888651

ABSTRACT

OBJECTIVE@#To investigate the cardioprotective effect of Danqi Tablet (DQT, ) on ischemic heart model rats and the regulative effect on energy metabolism through peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α).@*METHODS@#Rat ischemic heart model was induced by ligation of left anterior descending coronary artery. Totally 40 Sprague-Dawley rats were randomly divided into sham group, model group, DQT group (1.5 mg/kg daily) and trimetazidine (TMZ) group (6.3 mg/kg daily) according to a random number table, 10 rats in each group. Twenty-eight days after continuous administration, cardiac function was assessed by echocardiography and the structures of myocardial cells were observed by hematoxylin-eosin staining. The level of adenosine triphosphate (ATP) in myocardial cells was measured by ATP assay kit. Expressions level of key transcriptional regulators, including PGC-1α, Sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK), and downstream targets of PGC-1α, such as mitofusin 1 (MFN1), mitofusin 2 (MFN2) and superoxide dismutase 2 (SOD2) were measured by Western blot. Expression level of PGC-1α was examined by immunohistochemical staining.@*RESULTS@#The rat ischemic heart model was successfully induced and the heart function in model group was compromised. Compared with the model group, DQT exerted cardioprotective effects, up-regulated the ATP production in myocardial cells and inhibited the infiltration of inflammatory cells in the margin area of infarction of the myocardial tissues (P<0.01). The expressions of PGC-1α, SIRT1 and AMPK were increased in the DQT group (all P<0.05). Furthermore, the downstream targets, including MFN1, MFN2 and SOD2 were up-regulated (P<0.05 or P<0.01). Compared with the TMZ group, the expression levels of PGC-1α, MFN1 and SOD2 were increased by DQT treatment (P<0.05 or P<0.01).@*CONCLUSION@#DQT regulated energy metabolism in rats with ischemic heart model through AMPK/SIRT1 -PGC-1α pathway. PGC-1α might serve as a promising target in the treatment of ischemic heart disease.

18.
Article in Chinese | WPRIM | ID: wpr-877630

ABSTRACT

OBJECTIVE@#To investigate the protective effect of electroacupuncture (EA) at "Zusanli" (ST 36) in pregnant rats on lung dysplasia of newborn rats with intrauterine growth restriction (IUGR) induced by maternal food restriction.@*METHODS@#Twenty-four female SD rats were randomly divided into a control group, a control+EA group, a model group and a model+EA group, 6 rats in each group. From the 10th day into pregnancy to the time of delivery, the rats in the model group and the model+EA group were given with 50% dietary restriction to prepare IUGR model. From the 10th day into pregnancy to the time of delivery, the rats in the control+EA group and the model+EA group were treated with EA at bilateral "Zusanli" (ST 36), once a day. The body weight of offspring rats was measured at birth, and the body weight and lung weight of offspring rats were measured on the 21st day after birth. The lung function was measured by small animal lung function detection system; the lung tissue morphology was observed by HE staining; the content of peroxisome proliferator activated receptor γ (PPARγ) in lung tissue was detected by ELISA.@*RESULTS@#Compared with the control group, the body weight at birth as well as the body weight, lung weight, lung dynamic compliance (Cdyn) and PPARγ at 21 days after birth in the model group were significantly decreased (@*CONCLUSION@#EA at "Zusanli" (ST 36) may protect the lung function and lung histomorphology changes by regulating the level of PPARγ of lung in IUGR rats induced by maternal food restriction.


Subject(s)
Acupuncture Points , Animals , Electroacupuncture , Female , Fetal Growth Retardation/therapy , Lung , Pregnancy , Rats , Rats, Sprague-Dawley
19.
Article in Chinese | WPRIM | ID: wpr-906451

ABSTRACT

Objective:To observe the effects of Da Chaihutang on Cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB)/peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1<italic>α</italic>) pathway in nutritionally obese rats and the protective mechanism on liver mitochondria. Method:A total of 120 8-week-old male SD rats were randomly divided into a control group (<italic>n</italic>=20) and an experimental group (<italic>n</italic>=100). The rats in the control group were fed on a normal diet, while those in the experimental group were administered with a high-fat feed. Successfully modeled rats were randomly divided into a model group, a positive drug (metformin) group, and low-, medium- and high-dose Da Chaihutang groups (4.25, 8.5, and 17 g∙kg<sup>-1</sup>, respectively), with 20 rats in each group. After treatment with Da Chaihutang, the body weight, Lee's index, liver mitochondrial membrane potential and mitochondrial ultrastructure, PGC-1<italic>α </italic>expression and CREB phosphorylation of each group were measured and compared. Result:Compared with the control group, the model group showed increased body weight and Lee's index (<italic>P</italic><0.01), whereas decreased mitochondrial membrane potential, PGC-1<italic>α</italic> expression, and CREB phosphorylation level (<italic>P</italic><0.01). As compared with the model group, Da Chaihutang significantly reduced the body weight and Lee's index of obese rats (<italic>P</italic><0.05, <italic>P</italic><0.01), enhanced liver mitochondrial membrane potential (<italic>P</italic><0.05, <italic>P</italic><0.01) to protect the integrity of mitochondrial structure, up-regulated PGC-1<italic>α</italic> expression and promoted CREB phosphorylation (<italic>P</italic><0.05, <italic>P</italic><0.01). Conclusion:Da Chaihutang protects the structure and function of mitochondria and inhibits weight gain in obese rats by activating the CREB/PGC-1<italic>α</italic> pathway.

20.
Acta Pharmaceutica Sinica B ; (6): 3806-3819, 2021.
Article in English | WPRIM | ID: wpr-922442

ABSTRACT

Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and

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