RESUMO
Background: Sepsis mortality and morbidity are aggravated by acute lung injury (ALI) or acute respiratory distress syndrome. Published studies have discovered that hyperoside (HYP) has an anti-inflammatory and therapeutic effect in many diseases. However, whether HYP treatment can attenuate sepsis-induced ALI is still obscure. Methods: In this study, a cecal ligation and puncture (CLP)-induced sepsis mouse model was constructed. The mouse lungs were harvested and assessed using proteomics, immunohistochemistry, immunofluorescence, and enzyme-linked immunosorbent assay for pro-inflammatory cytokines. Human lung microvascular endothelial cells (HLMVECs) were induced with lipopolysaccharide (LPS) for the in vitro model. Results: The results showed that HYP treatment attenuated sepsis-induced ALI through an increased survival rate, decreased inflammatory factor expression, and lung tissue apoptosis. At the same time, HYP pretreatment restored angiogenesis in CLP-induced mouse lung tissues. Proteomics detection showed that Atg13 played a vital role in HYP-mediated protection against sepsis-induced ALI. The in vitro experiment showed HYP treatment attenuated LPS-induced HLMVEC damage by regulating Atg13-mediated autophagy. Inhibiting autophagy or silencing Atg13 reversed the protective effect of HYP against sepsis-induced ALI. Conclusion: Taken together, we conclude that HYP attenuated sepsis-induced ALI by regulating autophagy and inhibiting inflammation.
Assuntos
Lesão Pulmonar Aguda , Sepse , Camundongos , Humanos , Animais , Lipopolissacarídeos/metabolismo , Células Endoteliais/metabolismo , Lesão Pulmonar Aguda/metabolismo , Pulmão/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , AutofagiaRESUMO
BACKGROUND AND AIM: Mitochondrial dysfunction plays a major role in critical initiating or propagating events in nonalcoholic fatty liver disease (NAFLD), but its pathogenesis remains obscure. Recently, microRNAs have been found to affect oxidant stress and lipid metabolism. In this study, we elucidated the functions of microRNA-421 in the development of NAFLD and identified its potential targets. METHODS: An experimental model for the study of NAFLD was constructed by feeding a high fat diet to C57BL/6J mice. Differentially expressed miRNA in livers of NAFLD mice compared with controls were identified by high-throughput sequencing. Relative repression of luciferase expression standardized to a transfection control was analyzed by luciferase reporter assays. RESULTS: The microRNA profiling presented that microRNA-421 expression was significantly upregulated in hepatic tissues of NAFLD model mouse. The sirtuin 3 was identified as a functionally relevant target of microRNA-421. The microRNA-421 acts upstream of SIRT3/FOXO3 pathway in modulation the oxidant stress and lipid metabolism. Overexpression of microRNA-421 decreased SIRT3 and FOXO3 protein levels, and then led to MnSOD and CAT decrease, the downstream targets of SIRT3/FOXO3 pathway. On the contrary, suppression of microRNA-421 had adverse effects on performance of celluar oxidative damage. CONCLUSIONS: Regulating or inhibiting hepatic microRNA-421 could decrease celluar oxidative damage and contribute to therapeutic potential in NAFLD.
Assuntos
MicroRNAs/metabolismo , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Sirtuína 3/metabolismo , Animais , Proteína Forkhead Box O3/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sirtuína 3/antagonistas & inibidoresRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Erzhu Jiedu Recipe (EZJDR) is a formula of traditional Chinese medicine (TCM) for treating hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). However, its effective components and the mechanism of action remain unclear. AIM OF THE STUDY: To explain how the active compounds of EZJDR suppress the growth of hepatoma cells. METHODS: UHPLC-Q-Exactive Orbitrap HRMS was used to identify the chemical constituents of EZJDR and their distribution in the serum and liver of mice. Together with experimental investigations, network pharmacology unraveled the molecular mechanism of components of EZJDR underlying the inhibited Hep3B cells. RESULTS: A total of 138 compounds which can be divided into 18 kinds of components (such as sesquiterpenoids, diterpenoids, anthraquinones, flavonoids and so on) were found in the aqueous extract of EZJDR. Of these components, the tricyclic-diterpenoids exhibited a highest exposure in the serum (74.5%) and liver (94.7%) of mice. The network pharmacology revealed that multiple components of EZJDR interacted with key node genes involved in apoptosis, proliferation, migration and metabolism through various signaling pathways, including ligand binding and protein phosphorylation. In vitro experiments demonstrated that 6 tricyclic-diterpenoids, 2 anthraquinones and 1 flavonoid inhibited the viability of Hep3B cells, with IC50 values ranging from 3.81 µM to 37.72 µM. Dihydrotanshinone I had the most potent bioactivity, arresting the S phase of cell cycle and inducing apoptosis. This compound changed the expression of proteins, including Bad, Bax, Bcl-2, Bal-x, caspase3 and catalase, which were associated with mitochondria-mediated apoptotic pathways. Moreover, dihydrotanshinone I increased the levels of p21 proteins, but decreased the phosphorylated p53, suggesting accumulation of p53 protein prevented cell cycle progression of Hep3B cells with damaged DNA. CONCLUSIONS: These results suggested that multiple components of EZJDR-diterpenoid, anthraquinone and flavonoid-could be the effective material for the treatment of HBV-HCC. This research provided valuable insights into the molecular mechanism of action underlying the therapeutic effects of EZJDR.
Assuntos
Carcinoma Hepatocelular , Diterpenos , Medicamentos de Ervas Chinesas , Furanos , Neoplasias Hepáticas , Fenantrenos , Quinonas , Humanos , Camundongos , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Proteína Supressora de Tumor p53 , Cromatografia Líquida de Alta Pressão , Farmacologia em Rede , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Antraquinonas/uso terapêutico , Diterpenos/uso terapêuticoRESUMO
BACKGROUND: Hepatitis B cirrhosis with hyperalphafetoproteinemia is the intermediate stage of liver cirrhosis progressing to hepatocellular carcinoma (HCC), there is no effective way to treat precancerous lesions of liver in modern medicine. In recent decades, clinical and experimental evidence shows that Chinese medicine (CM) has a certain beneficial effect on Hepatitis B Cirrhosis. Therefore, this trial aims to evaluate the efficacy and safety of a CM erzhu jiedu recipe (EZJDR) for the treatment of Hepatitis B Cirrhosis with Hyperalphafetoproteinemia. METHODS: We designed a randomized, double blind, placebo-controlled clinical trial. A total of 72 patients of Hepatitis B Cirrhosis with hyperalphafetoproteinemia were randomized in 2 parallel groups. Patients in the control group received placebo granules similar to the EZJDR. In the EZJDR group, patients received EZJDR twice a day, after meals, for 48âweeks. The primary efficacy measures were changes in serum alpha-fetoprotein (AFP) and alpha-fetoprotein alloplasm (AFP-L3); The secondary indicators of efficacy are changes in liver function indicators, HBV-DNA level; Liver stiffness measurement (LSM); Hepatic portal vein diameter; T lymphocyte subgroup indexes during treatment. All data will be recorded in case report forms and analyzed by Statistical Analysis System software. Adverse events will also be evaluated. RESULTS: The results showed that EZJDR can significantly inhibit the levels of AFP and AFP-L3 in patients with hepatitis B cirrhosis and hyperalphafetoproteinemia and have good security. ETHICS AND DISSEMINATION: The study protocol was approved by the Medical Ethics Committee of Shuguang Hospital, affiliated with University of Traditional Chinese Medicine, Shanghai (NO.2018-579-08-01). TRIAL REGISTRATION: This trial was registered on Chinese Clinical Trial Center (NO.ChiCTR1800017165).
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/deficiência , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/etiologia , Medicina Tradicional Chinesa/normas , Distribuição de Qui-Quadrado , Método Duplo-Cego , Fibrose/complicações , Fibrose/tratamento farmacológico , Hepatite B/complicações , Hepatite B/tratamento farmacológico , Humanos , Medicina Tradicional Chinesa/métodos , Medicina Tradicional Chinesa/estatística & dados numéricos , PlacebosRESUMO
OBJECTIVE: To evaluate the clinical effect of Xuefu Zhuyu Decoction (XFZYD) on the incidence of complications of rib fracture in patients with blunt chest injury. METHODS: One hundred and twenty patients with rib fracture stratified according to the AIS scale in three layers (1-3) were equally assigned to two groups, the treated group and the control group, all received conventional treatment, but XFZYD was administered to patients in the treated group additionally. The incidence of complications in patients, including atelectasis, pleural effusion, pulmonary contusion, pleurocentesis and closed thoracic drainage, were observed. RESULTS: The incidence of pleural effusion in patients of AIS-1 and -2 in the treated group was 20% and 45% respectively, which was remarkable lower than that in the control group (55% and 85%) respectively (P < 0.05); in the treated group, 10% patients of AIS-3, for whom close thoracic drainage was applied, while in the control group, the percentage reached 60%, showing significant difference between groups (P < 0.05). CONCLUSION: XFZYD could reduce the incidence of pleural effusion in patients with blunt chest injured rib fracture of AIS-1 or -2, and reduce the utilization of close thoracic drainage in those of AIS-3, so it is good for clinical practice.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Fitoterapia , Derrame Pleural/prevenção & controle , Fraturas das Costelas/complicações , Fraturas das Costelas/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/etiologia , Traumatismos Torácicos/complicações , Ferimentos não Penetrantes/complicaçõesRESUMO
OBJECTIVE: To study the effect of total flavonoids of Astmgali Radix (TFA) on liver cirrhosis induced with dimethylnitrosamine (DMN) in rats, and the effect on peroxisome proliferator-activated receptor γ (PPARγ), uncoupling protein 2 (UCP2) and farnesoid X receptor (FXR). METHODS: Fifty-three Sprague-Dawley rats were randomly divided into a control group (10 rats) and a DMN group (43 rats). Rats in the DMN group were given DMN for 4 weeks and divided randomly into a model group (14 rats), a low-dosage TFA group (14 rats) and a high-dosage TFA group (15 rats) in the 3rd week. Rats were given TFA for 4 weeks at the dosage of 15 and 30 mg/kg in the low- and high-TFA groups, respectively. At the end of the experiment blood and liver samples were collected. Serum liver function and liver tissue hydroxyproline content were determined. hematoxylin-eosin (HE), Sirus red and immunohistochemical stainings of collagen I, smooth muscle actin (α-SMA) was conducted in paraffinembedded liver tissue slices. Real time polymerase chain reaction (PCR) was adopted to determine PPARγ, UCP2 and FXR mRNA levels. Western blot was adopted to determine protein levels of collagen I, α-SMA, PPARγ, UCP2 and FXR. RESULTS: Compared with the model group, TFA increased the ratio of liver/body weight (low-TFA group P<0.05, high-TFA group P<0.01), improved liver biochemical indices (P<0.01 for ALT, AST, GGT in both groups, P<0.05 for albumin and TBil in the high-TFA group) and reduced liver tissue hydroxproline content (P<0.01 in both groups) in treatment groups significantly. HE staining showed that TFA alleviated liver pathological changes markedly and Sirus red staining showed that TFA reduced collagen deposition, alleviated formation and extent of liver pseudolobule. Collagen I and α-SMA immunohistochemical staining showed that staining area and extent markedly decreased in TFA groups compared with the model group. TFA could increase PPARγ, it regulated target UCP2, and FXR levels significantly compared with the model group (in the low-TFA group all P<0.05, in the high group all P<0.01). CONCLUSION: TFA could improve liver function, alleviate liver pathological changes, and reduce collagen deposition and formation of liver pseudolobule in rats with liver cirrhosis. The antifibrotic effect of TFA was through regulating PPARγ signal pathway and the interaction with FXR.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Flavonoides/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Actinas/metabolismo , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Dimetilnitrosamina , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/farmacologia , Hidroxiprolina/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , PPAR gama/genética , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteína Desacopladora 2/genética , Proteína Desacopladora 2/metabolismoRESUMO
Atractylodis Rhizoma is a traditional medicinal herb, which has antibacterial, antiviral, antiinflammatory and antiallergic, anticancer, gastroprotective and neuroprotective activities. It is widely used for treating fever, cold, phlegm, edema and arthralgia syndrome in SouthEast Asian nations. In this study, 6 chemical compositions of Atractylodis Rhizoma were characterized by spectral analysis and their antiviral activities were evaluated in vitro and in vivo. Among them, atractylon showed most significant antiviral activities. Atractylon treatment at doses of 1040 mg/kg for 5 days attenuated influenza A virus (IAV)induced pulmonary injury and decreased the serum levels of interleukin (IL)6, tumor necrosis factorα and IL1ß, but increased interferonß (IFNß) levels. Atractylon treatment upregulated the expression of Τolllike receptor 7 (TLR7), MyD88, tumor necrosis factor receptorassociated factor 6 and IFNß mRNA but downregulated nuclear factorκB p65 protein expression in the lung tissues of IAVinfected mice. These results demonstrated that atractylon significantly alleviated IAVinduced lung injury via regulating the TLR7 signaling pathway, and may warrant further evaluation as a possible agent for IAV treatment.