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1.
J Tradit Chin Med ; 42(6): 940-947, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36378052

RESUMO

OBJECTIVE: To study the mechanism of Dangfei Liganning capsule in the treatment of rats with metabolic associated fatty liver disease (MAFLD). METHODS: Totally 48 specific pathogen free Sprague-Dawley male rats were randomly divided into normal Group, model group, Dangfei Liganning high, moderate, and low-dose groups and Essentiale group which were fed with high fat diet for 8 weeks, and gavage and molding were carried out simultaneously. Dangfei Liganning high, middle and low-dose group were given 0.27, 0.135 and 0.0675 g·kg·d respectively by gavage, Essentiale group was given 0.123 g·kg·d by gavage, the same amount of distilled water was given by gavage in the normal group and the model group. The rats were weighed at the 0th week, 2nd week, 4th week, 6th week and 8th weekend respectively. The rats were sacrificed at the end of the 8th week. Serum levels of alanine aminotransferase (ALT), alanine aminotransferase (AST), triglyceride (TG), total cholesterol (CHO), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein (LDL-C), total protein (TP), albumin (Alb), globulin (GLB), total bilirubin (TBIL), direct bilirubin (DBIL), tumor necrosis factor-α(TNF-α) and interleukin-6 (IL-6) were measured. The levels of liver tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and liver pathology [hematoxylin and eosin (HE) staining, oil red O staining] were detected. The expression levels of liver X receptor α (LXRα), steroid regulatory element binding protein-1 (SREBP-1) and fatty acid synthase (FAS) were detected by immunohistochemistry, Western blot and reverse transcription-polymerase chain reaction reverse transcription-polymerase chain reaction. RESULTS: From the beginning to the 8th week, the growth rate of body weight in the Dangfei Liganning high-dose group was slower than all other groups. There was no significant difference in ALB level in all groups ( 0.05). Compared with the model group, the levels of ALT, AST, LDL-C, TG, CHO, TP, GLB, TBIL, DBIL, IL-6, TNF-α were significantly decreased and HDL-C were significantly increased in Dangfei Liganning high-dose group (0.01, < 0.05). HE and oil red O staining showed that the fatty lesions in rat liver were alleviated, while the expressions of LXRα, SREBP-1, FAS mRNA and protein were significantly decreased (0.01). CONCLUSIONS: Dangfei Liganning capsule can slow down the increase of body weight of MAFLD rats, reduce the levels of transaminase, Lipid and inflammatory factors in MAFLD rats, promote the synthesis of liver protein and bile metabolism, and improve the liver fatty lesion of MAFLD rats, among which the Dangfei Liganning high-dose group is more effective. The mechanism of action may be through blocking LXR-SREBP-1-FAS signal pathway.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Ratos , Masculino , Animais , Receptores X do Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/farmacologia , Interleucina-6/genética , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ratos Sprague-Dawley , Alanina Transaminase/metabolismo , LDL-Colesterol , Fígado , Transdução de Sinais , Ácido Graxo Sintases/metabolismo , Ácido Graxo Sintases/farmacologia , Ácido Graxo Sintases/uso terapêutico , Bilirrubina , Peso Corporal
2.
Front Endocrinol (Lausanne) ; 13: 1041616, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387912

RESUMO

Objective: Recent evidence has revealed that the aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT ratio) may be closely associated with metabolic syndrome and insulin resistance. However, it is unclear whether the AST/ALT ratio correlates with prediabetes risk. The aim of our study was to examine the association between AST/ALT ratios and the risk of prediabetes among a large cohort of Chinese subjects. Methods: This retrospective cohort study recruited 75204 Chinese adults with normoglycemia at baseline who underwent physical examinations at the Rich Healthcare Group from 2010 to 2016. The AST/ALT ratio at baseline was the target independent variable, and the risk of developing prediabetes during follow-up was the dependent variable. Cox proportional-hazards regression was used to evaluate the independent association between the AST/ALT ratio and prediabetes. This study identified nonlinear relationships by applying a generalized additive model (GAM) and smooth curve fitting. In order to assess the robustness of this study, we performed a series of sensitivity analyses. Moreover, we performed a subgroup analysis to evaluate the consistency of the association in different subgroups. Data from this study have been updated on the DATADRYAD website. Results: The AST/ALT ratio was negatively and independently related to the prediabetes risk among Chinese adults (HR: 0.76, 95% CI: 0.75-0.84, P<0.0001) after adjusting demographic and biochemical covariates. Furthermore, a nonlinear relationship between the AST/ALT ratio and the risk of developing prediabetes was found at an inflection point of 1.50 for the AST/ALT ratio. When the AST/ALT ratio was to the left of the inflection point (AST/ALT ratio ≤ 1.50), the AST/ALT ratio was negatively related to the prediabetes risk (HR:0.70, 95%CI: 0.65-0.76, P<0.0001). In contrast, the relationship tended to be saturated when the AST/ALT ratio was more than 1.50 (HR: 1.01, 95%CI: 0.89-1.15, P=0.8976). Our findings remained robust across a range of sensitivity analyses. Subgroup analysis revealed that other variables did not alter the relationship between the AST/ALT ratio and prediabetes risk. Conclusion: This study revealed that AST/ALT ratio was negatively and independently associated with prediabetes risk among Chinese participants. The relationship between the AST/ALT ratio and prediabetes risk was nonlinear, and AST/ALT ratio ≤ 1.50 was strongly inversely correlated with prediabetes risk.


Assuntos
Estado Pré-Diabético , Adulto , Humanos , Aspartato Aminotransferases/metabolismo , Alanina Transaminase/metabolismo , Estudos Retrospectivos , Estado Pré-Diabético/epidemiologia , China/epidemiologia
3.
Int J Mol Sci ; 23(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36292919

RESUMO

Jatrorrhizine (JAT) is one of the major bioactive protoberberine alkaloids found in rhizoma coptidis, which has hypoglycemic and hypolipidemic potential. This study aimed to evaluate the vasoprotective effects of JAT in diabetes and obesity and the underlying mechanism involved. Mouse aortas, carotid arteries and human umbilical cord vein endothelial cells (HUVECs) were treated with risk factors (high glucose or tunicamycin) with and without JAT ex vivo and in vitro. Furthermore, aortas were obtained from mice with chronic treatment: (1) control; (2) diet-induced obese (DIO) mice fed a high-fat diet (45% kcal% fat) for 15 weeks; and (3) DIO mice orally administered JAT at 50 mg/kg/day for the last 5 weeks. High glucose or endoplasmic reticulum (ER) stress inducer tunicamycin impaired acetylcholine-induced endothelium-dependent relaxations (EDRs) in mouse aortas, induced oxidative stress in carotid arteries and HUVECs, downregulated phosphorylations of Akt at Ser473 and eNOS at Ser1177 and enhanced ER stress in mouse aortas and HUVECs, and these impairments were reversed by cotreatment with JAT. JAT increased NO release in high-glucose-treated mouse aortas and HUVECs. In addition, chronic JAT treatment restored endothelial function with EDRs comparable to the control, increased Akt/eNOS phosphorylation, and attenuated ER stress and oxidative stress in aortas from DIO mice. Blood pressure, glucose sensitivity, fatty liver and its morphological change, as well as plasma levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and plasma lipid profile, were also normalized by JAT treatment. Collectively, our data may be the first to reveal the vasoprotective effect of JAT that ameliorates endothelial dysfunction in diabetes and obesity through enhancement of the Akt/eNOS pathway and NO bioavailability, as well as suppression of ER stress and oxidative stress.


Assuntos
Diabetes Mellitus , Medicamentos de Ervas Chinesas , Camundongos , Humanos , Animais , Estresse do Retículo Endoplasmático , Tunicamicina/farmacologia , Endotélio Vascular/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Acetilcolina/metabolismo , Alanina Transaminase/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Camundongos Endogâmicos C57BL , Diabetes Mellitus/metabolismo , Estresse Oxidativo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Obesidade/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Aspartato Aminotransferases/metabolismo , Lipídeos/farmacologia
4.
J Int Soc Sports Nutr ; 19(1): 623-637, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36250147

RESUMO

Background: The purpose of this study is to explore the effect of carbohydrate only or carbohydrate plus protein supplementation on endurance capacity and muscle damage. Methods: Ten recreationally active male runners (VO2max: 53.61 ± 3.86 ml/kg·min) completed run-to-exhaustion test three times with different intakes of intervention drinks. There was a 7-day wash-out period between tests. Each test started with 60 minutes of running at 70% VO2max (phase 1), followed by an endurance capacity test: time-to-exhaustion running at 80% VO2max (phase 2). Participants randomly ingested either 1) 0.4 g/kg BM carbohydrate before phase 1 and before phase 2 (CHO+CHO), 2) 0.4 g/kg BM protein before phase 1 and 0.4 g/kg BM carbohydrate before phase 2 (PRO+CHO), or 3) 0.4 g/kg BM carbohydrate before phase 1 and 0.4 g/kg BM protein before phase 2 (CHO+PRO). All subjects ingested carbohydrate (CHO) 1.2 g/kg BM during phase 1, and blood samples were obtained before, immediately, and 24 h after exercise for measurements of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK), and myoglobin (MB). Results: There was no significant difference in time to exhaustion between the three supplement strategies (CHO+CHO: 432 ± 225 s; PRO+CHO: 463 ± 227 s; CHO+PRO: 461 ± 248 s). However, ALT and AST were significantly lower in PRO+CHO than in CHO+CHO 24 h after exercise (ALT: 16.80 ± 6.31 vs. 24.39 ± 2.54 U/L; AST: 24.06 ± 4.77 vs. 31.51 ± 7.53 U/L, p < 0.05). MB was significantly lower in PRO+CHO and CHO+PRO than in CHO+CHO 24 h after exercise (40.7 ± 15.2; 38.1 ± 14.3; 64.3 ± 28.9 ng/mL, respectively, p < 0.05). CK increased less in PRO+CHO compared to CHO+CHO 24 h after exercise (404.22 ± 75.31 VS. 642.33 ± 68.57 U/L, p < 0.05). Conclusion: Carbohydrate and protein supplement strategies can reduce muscle damage caused by endurance exercise, but they do not improve endurance exercise capacity.


Assuntos
Carboidratos da Dieta , Resistência Física , Alanina Transaminase/metabolismo , Alanina Transaminase/farmacologia , Aspartato Aminotransferases/metabolismo , Aspartato Aminotransferases/farmacologia , Creatina Quinase , Estudos Cross-Over , Proteínas na Dieta , Método Duplo-Cego , Humanos , Masculino , Músculo Esquelético , Mioglobina
5.
Int J Mol Sci ; 23(19)2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36233086

RESUMO

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.


Assuntos
Antipiréticos , Doença Hepática Induzida por Substâncias e Drogas , Receptor Nuclear Órfão DAX-1 , Fator 2 Relacionado a NF-E2 , Acetaminofen/toxicidade , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Proteínas Correpressoras/metabolismo , Receptor Nuclear Órfão DAX-1/genética , Glutationa/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Receptores Nucleares Órfãos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
6.
Aquat Toxicol ; 252: 106322, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36240591

RESUMO

Cyhalofop­butyl is a highly effective aryloxyphenoxypropionate herbicide and widely used for weed control in paddy fields. With the increasing residue of cyhalofop­butyl, it poses a threat to the survival of aquatic organisms. Here, we investigated the effect of cyhalofop­butyl on zebrafish to explore its potential hepatotoxic mechanism. The results showed that cyhalofop­butyl induced hepatocyte degeneration, vacuolation and necrosis of larvae after embryonic exposure for 4 days and caused liver atrophy after 5 days. Meanwhile, the activities of enzymes related to liver function were significantly increased by 0.2 mg/L cyhalofop­butyl and higher, such as alanine transaminase (ALT) and aspartate transaminase (AST). And the contents of triglyceride (TG) involved in lipid metabolism were significantly decreased by 0.4 mg/L cyhalofop-buty. The expression of genes related to liver development was also significantly down-regulated. Furthermore, transcriptome results showed that the pathways involved in metabolism, immune system and endocrine system were significantly impacted, which may be related to hepatoxicity. To sum up, the present study demonstrated the hepatoxicity caused by cyhalofop-buty and its underlying mechanism. The results may provide new insights for the risk of cyhalofop­butyl to aquatic organisms and new horizons for the pathogenesis of hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Herbicidas , Poluentes Químicos da Água , Animais , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Alanina Transaminase/metabolismo , Poluentes Químicos da Água/toxicidade , Aspartato Aminotransferases/metabolismo , Herbicidas/toxicidade , Herbicidas/metabolismo , Triglicerídeos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Perfilação da Expressão Gênica , Fígado
7.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 57(10): 1048-1056, 2022 Oct 09.
Artigo em Chinês | MEDLINE | ID: mdl-36266079

RESUMO

Objective: Brain and muscle ARNT-like protein 1 (BMAL1) is a core component of hepatocyte molecular clock and plays an important role in the regulation of other related rhythmic genes in the body through a transcriptional-translational feedback loop in molecular circadian oscillations. Therefore, the aim of this study was to investigate the role of BMAL1 in the rat periodontitis-induced liver injury. Methods: Twelve male Wistar rats were divided into the control group and the periodontitis group according to the random number table method. The rats in the control group were untreated. The periodontitis models were established by ligating the necks of the bilateral maxillary first molars in the periodontitis group rats. After 8 weeks, periodontal clinical indexes of rats in both groups were examined and executed. Micro-CT scans of the maxilla were performed and levels of the alveolar bone resorption were analyzed. Pathological changes in periodontal and liver tissue of rats in two groups were detected by HE and oil red O staining. Biochemical kits were used to detect glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), total cholesterol (TC) and triglycerides (TG) in serum. The gene and protein expression levels of BMAL1, nuclear factor kappa-B (NF-κB) and tumor necrosis factor-α (TNF-α) in liver tissue were measured by real time fluorescent quantitative-PCR (qRT-PCR), immunohistochemistry (IHC) and Western blotting (WB) assays. Apoptosis was detected in liver tissues by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) kit staining. Results: The results of HE staining of maxillary first molars and micro-CT results of maxillary bones showed that alveolar bone resorption was significant in the periodontitis group of rats. The liver histopathology results showed infiltrated inflammatory cells in the liver tissue, disorganized liver cords and a large number of lipid droplets formed in the hepatocytes of the periodontitis group compared with the control group. The results of serum biochemical assay showed that the levels of GOT [(62.77±2.59) U/L], GPT [(47.54±1.04) U/L], TC [(3.19±0.23) mmol/L] and TG [(1.11±0.09) mmol/L] in the serum of rats with periodontitis were significantly higher than that in the control group respectively [GOT: (38.66±2.47) U/L, GPT: (31.48±1.57) U/L, TC: (1.60±0.05) mmol/L and TG: (0.61±0.09) mmol/L](P=0.003, P=0.001, P=0.002, P=0.038). qRT-PCR results showed that the mRNA expression level of BMAL1 was significantly decreased in liver tissue of the periodontitis group [(0.60±0.04)%] compared to the control group [(1.01±0.07)%] (t=4.80, P=0.009), while the mRNA expression levels of NF-κB and TNF-α [(1.62±0.12)%, (2.69±0.16)%] were significantly increased compared to the control group [(1.00±0.03)%, (1.03±0.16)%] (P=0.008, P=0.002); IHC results showed that the protein expression level of BMAL1 in liver tissue of the periodontitis group (averaged optical density, AOD) (11.58±2.15) was down-regulated compared to the control group (AOD) (22.66±1.67) (P=0.015), while NF-κB and TNF-α (AOD) (31.77±2.69, 24.31±2.32) were up-regulated compared to the control group (AOD) (19.40±1.82, 11.92±0.94) (P=0.019, P=0.008). WB results showed that the protein expression level of BMAL1 in liver tissue was down-regulated in the periodontitis group [(0.63±0.10)%] compared to the control group [(1.00±0.06)%] (t=3.19, P=0.033), while NF-κB and TNF-α [(1.61±0.12)%, (2.82±0.23)%] were up-regulated compared to the control group [(1.00±0.12)%, (1.00±0.11)%] (P=0.022, P=0.002). TUNEL staining showed increased apoptotic cells in the liver tissue of the periodontitis group of rats compared to the control group. Conclusions: Periodontitis may induce liver injury by down-regulating the BMAL1 expression levels in liver tissue, which in turn activates NF-κB signaling molecules, leading to the elevated levels of inflammation and apoptosis in rat liver.


Assuntos
Reabsorção Óssea , Doença Hepática Crônica Induzida por Substâncias e Drogas , Periodontite , Animais , Masculino , Ratos , Alanina Transaminase/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Aspartato Aminotransferases/metabolismo , Biotina/metabolismo , Encéfalo , Colesterol , DNA Nucleotidilexotransferase/metabolismo , Músculos/metabolismo , NF-kappa B/metabolismo , Ratos Wistar , RNA Mensageiro/metabolismo , Triglicerídeos , Fator de Necrose Tumoral alfa/metabolismo
8.
Front Immunol ; 13: 988668, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36268033

RESUMO

Background: Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are the two most common subtypes of liver failure. They are both life-threatening clinical problems with high short-term mortality. Although liver transplantation is an effective therapeutic, its application is limited due to the shortage of donor organs. Given that both ACLF and ALF are driven by excessive inflammation in the initial stage, molecules targeting inflammation may benefit the two conditions. MicroRNAs (miRNAs) are a group of small endogenous noncoding interfering RNA molecules. Regulation of miRNAs related to inflammation may serve as promising interventions for the treatment of liver failure. Aims: To explore the role and mechanism of miR-125b-5p in the development of liver failure. Methods: Six human liver tissues were categorized into HBV-non-ACLF and HBV-ACLF groups. Differentially expressed miRNAs (DE-miRNAs) were screened and identified through high-throughput sequencing analysis. Among these DE-miRNAs, miR-125b-5p was selected for further study of its role and mechanism in lipopolysaccharide (LPS)/D-galactosamine (D-GalN) -challenged Huh7 cells and mice in vitro and in vivo. Results: A total of 75 DE-miRNAs were obtained. Of these DE-miRNAs, miR-125b-5p was the focus of further investigation based on our previous findings and preliminary results. We preliminarily observed that the levels of miR-125b-5p were lower in the HBV-ACLF group than in the HBV-non-ACLF group. Meanwhile, LPS/D-GalN-challenged mice and Huh7 cells both showed decreased miR-125b-5p levels when compared to their untreated control group, suggesting that miR-125b-5p may have a protective role against liver injury, regardless of ACLF or ALF. Subsequent results revealed that miR-125b-5p not only inhibited Huh7 cell apoptosis in vitro but also relieved mouse ALF in vivo with evidence of improved liver histology, decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduced tumor necrosis factor-α (TNF-α) and IL-1ß levels. Based on the results of a biological prediction website, microRNA.org, Kelch-like ECH-associated protein 1 (Keap1) was predicted to be one of the target genes of miR-125b-5p, which was verified by a dual-luciferase reporter gene assay. Western blot results in vitro and in vivo showed that miR-125b-5p could decrease the expression of Keap1 and cleaved caspase-3 while upregulating the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1(HO-1). Conclusion: Upregulation of miR-125b-5p can alleviate acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway, and regulation of miR-125b-5p may serve as an alternative intervention for liver failure.


Assuntos
Insuficiência Hepática Crônica Agudizada , MicroRNAs , Animais , Humanos , Camundongos , Insuficiência Hepática Crônica Agudizada/genética , Insuficiência Hepática Crônica Agudizada/terapia , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Caspase 3/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Galactosamina , Heme Oxigenase-1/metabolismo , Inflamação , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Lipopolissacarídeos , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
9.
J Transl Med ; 20(1): 479, 2022 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-36266691

RESUMO

BACKGROUND: Explanted livers from patients with inherited metabolic liver diseases possess the potential to be a cell source of good-quality hepatocytes for hepatocyte transplantation (HT). This study evaluated the therapeutic effects of domino HT using hepatocytes isolated from explanted human livers for acute liver failure (ALF). METHODS: Isolated hepatocytes were evaluated for viability and function and then transplanted into D-galactosamine/lipopolysaccharide-induced ALF mice via splenic injection. The survival rate was analyzed by the Kaplan-Meier method and log-rank test. Liver function was evaluated by serum biochemical parameters, and inflammatory cytokine levels were measured by ELISA. The pathological changes in the liver tissues were assessed by hematoxylin-eosin staining. Hepatocyte apoptosis was investigated by TUNEL, and hepatocyte apoptosis-related proteins were detected by western blot. The localization of human hepatocytes in the injured mouse livers was detected by immunohistochemical analyses. RESULTS: Hepatocytes were successfully isolated from explanted livers of 10 pediatric patients with various liver-based metabolic disorders, with an average viability of 85.3% ± 13.0% and average yield of 9.2 × 106 ± 3.4 × 106 cells/g. Isolated hepatocytes had an excellent ability to secret albumin, produce urea, uptake indocyanine green, storage glycogen, and express alpha 1 antitrypsin, albumin, cytokeratin 18, and CYP3A4. Domino HT significantly reduced mortality, decreased serum levels of alanine aminotransferase and aspartate aminotransferase, and improved the pathological damage. Moreover, transplanted hepatocytes inhibited interleukin-6 and tumor necrosis factor-α levels. Domino HT also ameliorates hepatocyte apoptosis, as evidenced by decreased TUNEL positive cells. Positive staining for human albumin suggested the localization of human hepatocytes in ALF mice livers. CONCLUSION: Explanted livers from patients with inheritable metabolic disorders can serve as a viable cell source for cell-based therapies. Domino HT using hepatocytes with certain metabolic defects has the potential to be a novel therapeutic strategy for ALF.


Assuntos
Hepatócitos , Falência Hepática Aguda , Doenças Metabólicas , Animais , Criança , Humanos , Camundongos , Alanina Transaminase/metabolismo , Albuminas/metabolismo , alfa 1-Antitripsina/metabolismo , Aspartato Aminotransferases/metabolismo , Citocromo P-450 CYP3A/metabolismo , Galactosamina/efeitos adversos , Glicogênio/metabolismo , Interleucina-6/metabolismo , Queratina-18/metabolismo , Lipopolissacarídeos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/cirurgia , Doenças Metabólicas/induzido quimicamente , Doenças Metabólicas/cirurgia , Albumina Sérica Humana/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ureia/metabolismo , Hepatócitos/transplante
10.
Pharm Biol ; 60(1): 1960-1968, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36205548

RESUMO

CONTEXT: Swertia mussotii Franch. (Gentianaceae) is a source of the traditional Tibetan medicine, ZangYinChen, and is used to treat chronic hepatitis and many types of jaundice. OBJECTIVE: This study explored the therapeutic effects and mechanism of S. mussotii on non-alcoholic fatty liver disease in diet-induced hypercholesterolaemia. MATERIALS AND METHODS: After a week of adaptive feeding, 32 Sprague-Dawley rats were divided into four groups: (1) Control, (2) Control-S, (3) Model, and (4) Model-S. During the 12 experimental weeks, we established the Model using a high-fat diet. Control-S and Model-S were given 1.0 g/kg S. mussotii water extract via gavage starting in the fifth week until the end of experiment. RESULTS: When compared with Model rats, the S. mussotii water extract led to a reduction in high-density lipoproteins (43.9%) and albumin (13.9%) and a decrease in total cholesterol (54.0%), triglyceride (45.6%), low-density lipoproteins (8.6%), aspartate aminotransferase (11.0%), alanine aminotransferase (15.5%), alkaline phosphatase (19.1%), total protein (6.4%), and glucose (20.8%) in serum. A reduction in three cytokines (IL-1ß, IL-6, and TNFα) was detected. Histopathological examination showed that liver steatosis was significantly relieved in S. mussotii-treated high-fat diet rats. S. mussotii also caused a downregulation in the expression of TLR4 (43.2%), MyD88 (33.3%), and a decrease in phosphorylation of NF-κB. DISCUSSION AND CONCLUSIONS: Our findings indicate that S. mussotii may act as a potential anti-inflammation drug via inhibition of the TLR4/MyD88/NF-κB pathway. Further in vivo and in vitro studies are needed to validate its potential in clinical medicine.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Swertia , Alanina Transaminase/metabolismo , Albuminas/metabolismo , Albuminas/farmacologia , Fosfatase Alcalina , Animais , Aspartato Aminotransferases , Colesterol/metabolismo , Dieta Hiperlipídica , Glucose/metabolismo , Interleucina-6/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/farmacologia , Lipoproteínas LDL/metabolismo , Fígado , Fator 88 de Diferenciação Mieloide , NF-kappa B/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fosforilação , Ratos , Ratos Sprague-Dawley , Swertia/metabolismo , Receptor 4 Toll-Like/metabolismo , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Água/farmacologia
11.
Drug Des Devel Ther ; 16: 3327-3342, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36199629

RESUMO

Aim: Liver regulates metabolism of biomolecules and injury of liver causes distortion of metabolic functions. This injury may be oxidative or inflammatory induced by numerous factors including alcohol, pathogens and xenobiotics. This scientific study was planned to investigate the anti-inflammatory and anti-oxidant potential of p-coumaric acid (p-CA) on Lipopolysaccharide/D-Galactosamine (LPS/D-GalN) induced liver injury. Methods: DPPH analysis, reducing power assay and HPLC analysis were performed during in-vitro studies of p-CA. Similarly, in-vivo experiments were performed using Wistar Albino rats. Normal control and intoxicated group received (5mL/kg normal saline p.o), standard treatment groups received ascorbic acid (100mg/kg p.o) and silymarin (25mg/kg p.o), while p-CA treatment groups received (100mg/kg p.o) for 28-days. After completion of 28-days, LPS/D-GalN injection (300 mg D-GalN/kg and 10 µg LPS/kg i.p.) was given at 6th, 12th and 24-hours to all groups except normal control group. Animals were sacrificed; serum and liver samples were harvested and subjected to biochemical and histological examinations, respectively. Results: The results revealed that p-CA possess strong antioxidant activity. Increased levels of leukocyte infiltration (TLC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), lipid panel (eg TG, TC, LDL-C, VLDL-C), whereas decreased HDL-C levels noticed in LPS/D-GalN groups as compared to normal control groups. Pro-Inflammatory markers (eg TNF-α, IL-6, IL-1ß) and lipid peroxidation marker, eg malondialdehyde (MDA) increased while superoxide dismutase (SOD) and reduced glutathione (GSH) levels were decreased significantly in groups treated with LPS/D-GalN. ANOVA with Bonferroni post hoc analysis was used for statistical analysis of. H&E staining was done to assess architectural abnormalities among liver cells. Conclusion: In conclusion, p-CA could ameliorate LPS/D-GalN induced hepatic injury via regulation of immune responses, liver function enzymes, lipid profile, oxidative stress and pro-inflammatory markers.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Silimarina , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Aspartato Aminotransferases/metabolismo , Bilirrubina , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , LDL-Colesterol , Ácidos Cumáricos , Galactosamina/farmacologia , Glutationa/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Fígado , Malondialdeído/metabolismo , Ratos , Ratos Wistar , Solução Salina/farmacologia , Silimarina/farmacologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Phytomedicine ; 107: 154484, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36215787

RESUMO

BACKGROUND: Translocator protein (TSPO) is an 18-kDa transmembrane protein found primarily in the mitochondrial outer membrane, and it is implicated in inflammatory responses, such as cytokine release. Koumine (KM) is an indole alkaloid extracted from Gelsemium elegans Benth. It has been reported to be a high-affinity ligand of TSPO and to exert anti-inflammatory and immunomodulatory effects in our recent studies. However, the protective effect of KM on sepsis-associated liver injury (SALI) and its mechanisms are unknown. PURPOSE: To explore the role of TSPO in SALI and then further explore the protective effect and mechanism of KM on SALI. METHODS: The effect of KM on the survival rate of septic mice was confirmed in mouse models of caecal ligation and puncture (CLP)-induced and lipopolysaccharide (LPS)-induced sepsis. The protective effect of KM on CLP-induced SALI was comprehensively evaluated by observing the morphology of the mouse liver and measuring liver injury markers. The serum cytokine content was detected in mice by flow cytometry. Macrophage polarization in the liver was examined using western blotting. TSPO knockout mice were used to explore the role of TSPO in sepsis liver injury and verify the protective effect of KM on sepsis liver injury through TSPO. RESULTS: KM significantly improved the survival rate of both LPS- and CLP-induced sepsis in mice. KM has a significant liver protective effect on CLP-induced sepsis in mice. KM treatment ameliorated liver ischaemia, improved liver pathological injuries, and decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and proinflammatory cytokines in serum. Western blotting results showed that KM inhibited M1 polarization of macrophages and promoted M2 polarization. In TSPO knockout mice, we found that TSPO knockout can improve the survival rate of septic mice, ameliorate liver ischaemia, improve liver pathological injuries, and decrease the levels of ALT, AST, and LDH. In addition, TSPO knockout inhibits the M1 polarization of macrophages in the liver of septic mice and promotes M2 polarization and the serum levels of proinflammatory cytokines. Interestingly, in TSPO knockout septic mice, these protective effects of KM were no longer effective. CONCLUSIONS: We report for the first time that TSPO plays a critical role in sepsis-associated liver injury by regulating the polarization of liver macrophages and reducing the inflammatory response. KM, a TSPO ligand, is a potentially desirable candidate for the treatment of SALI that may regulate macrophage M1/M2 polarization through TSPO in the liver.


Assuntos
Lipopolissacarídeos , Sepse , Alanina Transaminase/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Aspartato Aminotransferases/metabolismo , Proteínas de Transporte/metabolismo , Citocinas/metabolismo , Alcaloides Indólicos/farmacologia , Lactato Desidrogenases/metabolismo , Ligantes , Lipopolissacarídeos/farmacologia , Fígado/metabolismo , Macrófagos , Camundongos , Camundongos Knockout , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo
13.
Aging (Albany NY) ; 14(17): 7137-7155, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36107005

RESUMO

OBJECTIVE: To investigate the mechanism of alanine aminotransferase 1 (ALT1) in the progression of HCC, the differentially expressed proteins (DEPs) in the ALT1 interaction network were identified by targeted proteomic analysis. METHODS: Wound healing and transwell assays were conducted to assess the effect of ALT1 on cellular migration and invasion. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were performed to identify alterations in proliferation and apoptosis. After coimmunoprecipitation processing, mass spectrometry with iso-baric tags for relative and absolute quantitation was utilized to explore the protein interactions in ALT1 knockdown HepG2 cells. RESULTS: The results showed that ALT1 knockdown inhibits the migration, invasion, proliferation of HepG2 cells, and promotes apoptosis. A total of 116 DEPs were identified and the bioinformatics analysis suggested that the ALT1-interacting proteins were primarily associated with cellular and metabolic processes. Knockdown of ALT1 in HepG2 cells reduced the expression of Ki67 and epithelial cell adhesion molecule (EP-CAM), while the expression of apoptosis-stimulating protein 2 of p53 (ASPP2) was increased significantly. Suppression of the ALT1 and EP-CAM expression contributed to alterations in epithelial-mesenchymal transition (EMT) -associated markers and matrix metalloproteinases (MMPs). Additionally, inhibition of ALT1 and Ki67 also decreased the expression of apoptosis and proliferation factors. Furthermore, inhibition of ALT1 and ASPP2 also changed the expression of P53, which may be the signaling pathway by which ALT regulates these biological behaviors. CONCLUSIONS: This study indicated that the ALT1 protein interaction network is associated with the biological behaviors of HepG2 cells via the p53 signaling pathway.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante/metabolismo , Alanina Transaminase/metabolismo , Apoptose , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Molécula de Adesão da Célula Epitelial/metabolismo , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Antígeno Ki-67/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Metaloproteinases da Matriz/metabolismo , Proteômica , Sincalida/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
14.
Life Sci ; 309: 120964, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36115584

RESUMO

INTRODUCTION AND AIM: Purpurin, a naturally occurring anthraquinone isolated from the roots of Rubia cordifolia, exhibits anti-cancer, anti-genotoxic, anti-microbial, neuromodulatory and photodynamic activity. However, purpurin's in vivo and in vitro antioxidant mechanism remains unexplored. The present study explores the anti-oxidative mechanism of purpurin under the influence of alcohol using in vivo and in vitro test systems. METHODS: Mice hepatocytes and alcohol-induced liver toxicity model were used to evaluate the effect of purpurin. The non-enzymatic and enzymatic oxidative stress markers were estimated by the colorimetric method. The reactive oxygen species (ROS) were quantified in mitochondria and cells using flow cytometer. Real-time PCR and western blotting were used to quantify cytochrome 450 subtype 2E1 (CYP2E1) and Nrf2 expression in the liver tissue of mice. In silico studies were performed through receptor-ligand binding interaction. KEY FINDINGS: Purpurin effectively reduced total cellular and mitochondrial ROS in primary hepatocytes and WRL-68 cells. It prevented alcohol-induced ROS-dependent biochemical and cellular insults observed by analysing the serum glutamic pyruvic transaminase (SGPT), glutamic-oxaloacetic transaminase (SGOT) levels and CYP2E1 expression in liver tissue of alcohol-administered mice. Moreover, it also restored the activity of antioxidant enzymes. Its antioxidant effect was established by glutathione and ROS-dependent mechanisms using buthionine sulfoximine and N-acetyl cysteine. Along with alcohol, purpurin up-regulated Nrf2 expression in hepatocytes. SIGNIFICANCE: This work confirmed the ameliorative effect of purpurin for alcohol-induced hepatotoxicity by drabbing free radicals and curbing oxidative stress via activation of antioxidant signalling pathways.


Assuntos
Antraquinonas , Doença Hepática Induzida por Substâncias e Drogas , Etanol , Fator 2 Relacionado a NF-E2 , Animais , Camundongos , Alanina Transaminase/metabolismo , Antraquinonas/farmacologia , Antioxidantes/farmacologia , Aspartato Aminotransferases/metabolismo , Butionina Sulfoximina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cisteína/farmacologia , Citocromo P-450 CYP2E1/metabolismo , Etanol/toxicidade , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Glutationa/metabolismo , Ligantes , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
15.
Immun Inflamm Dis ; 10(10): e700, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36169257

RESUMO

INTRODUCTION: Ischemia-reperfusion (IR) injury is induced by an interrupted blood flow and succeeding blood restoration, which is common in the operation of liver transplantation. Serious IR injury is a major reason leading to transplant failure. Hepatic IR is featured by excessive inflammatory response, oxidative stress, and apoptosis. Sinomenine (SIN) is derived from the herb Sinomeniumacutum and shows properties of anti-inflammation and antiapoptosis in multiple IR-induced organ injuries. However, the effect of SIN in hepatic IR has not been investigated. METHODS: This study aims to investigate impacts of SIN on hepatic IR and the involved signaling pathway. An in vivo rat model of syngeneic orthotopic liver transplantation was constructed to induce the hepatic IR injury. RESULTS: Results showed that SIN pretreatment provided a significant prevention against IR-induced hepatic injury as manifested by the downregulated activities of serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, the alleviatedoxidative stress as shown by increased activities of serum superoxide dismutase and glutathione peroxidase, and decreased serum level of malondialdehyde, the suppressed inflammatory responses as shown by downregulated serum tumor necrosis factor-α, interleukin (IL)-6, IL-8 levels, and upregulated IL-10 level, as well as attenuated apoptosis as shown by decreased protein expression of cleaved caspase-3 and -9. In line with these results, SIN pretreatment also alleviatedthe hepatic histopathological changes in IR rats and induced Nrf-2/HO-1 activation. The use of brusatol, a selective inhibitor for Nrf-2, effectively reversed SIN-induced above effects. CONCLUSIONS: Altogether, our results demonstrate that SIN might be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.


Assuntos
Hepatopatias , Traumatismo por Reperfusão , Alanina/uso terapêutico , Alanina Transaminase/metabolismo , Alanina Transaminase/uso terapêutico , Animais , Aspartato Aminotransferases/metabolismo , Aspartato Aminotransferases/uso terapêutico , Caspase 3/metabolismo , Glutationa Peroxidase/uso terapêutico , Interleucina-10 , Interleucina-8 , Lactato Desidrogenases , Hepatopatias/patologia , Malondialdeído , Morfinanos , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Superóxido Dismutase/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo
16.
Oxid Med Cell Longev ; 2022: 5721167, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36120593

RESUMO

Methods: Sixty patients with a mean age of 68.60 ± 2.10 comprising 29 females (48.33%), who were admitted to an academic tertiary care facility within the first 12 hours poststroke symptoms onset or last known well (LKW), in case symptom onset time is not clear, were included in this study. AIS was confirmed based on a noncontrast head CT scan and also neurological symptoms. Patients were randomly and blindly assigned to OEA of 300 mg/day (n = 20) or 600 mg/day (n = 20) or placebo (n = 20) in addition to the standard AIS treatment for three days. A blood sample was drawn at 12 hours from symptoms onset or LKW as the baseline followed by the second blood sample at 72 hours post symptoms onset or LKW. Blood samples were assessed for inflammatory and biochemical parameters, oxidative stress (OS) biomarkers, and lipid profile. Results: Compared to the baseline, there is a significant reduction in the urea, creatinine, triglyceride, high-density lipoprotein, cholesterol, alanine transaminase, total antioxidant capacity, malondialdehyde (MDA), total thiol groups (TTG), interleukin-6 (IL-6), and C-reactive protein levels on the follow-up blood testing in the OEA (300 mg/day) group. In patients receiving OEA (600 mg/day) treatment, there was only a significant reduction in the MDA level comparing baseline with follow-up blood testing. Also, the between-group analysis revealed a statistically significant difference between patients receiving OEA (300 mg/day) and placebo in terms of IL-6 and TTG level reduction when comparing them between baseline and follow-up blood testing. Conclusion: OEA in moderate dosage, 300 mg/day, add-on to the standard stroke treatment improves short-term inflammatory, OS, lipid, and biochemical parameters in patients with AIS. This effect might lead to a better long-term neurological prognosis.


Assuntos
Antioxidantes , AVC Isquêmico , Idoso , Alanina Transaminase/metabolismo , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Creatinina , Endocanabinoides , Etanolamina , Feminino , Humanos , Interleucina-6/metabolismo , Lipoproteínas HDL/metabolismo , Malondialdeído , Ácidos Oleicos/farmacologia , Estresse Oxidativo , Compostos de Sulfidrila , Triglicerídeos , Ureia
17.
PLoS One ; 17(9): e0275273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36166461

RESUMO

BACKGROUND: Comorbidity of Opisthorchis viverrini (OV) infection and nonalcoholic fatty-liver disease (NAFLD) enhances NAFLD progression to nonalcoholic steatohepatitis (NASH) by promoting severe liver inflammation and fibrosis. Here, we investigated the effect of supplementation with curcumin-loaded nanocomplexes (CNCs) on the severity of NASH in hamsters. METHODOLOGY: Hamsters were placed in experimental groups as follows: fed standard chow diet (normal control, NC); fed only high-fat and high-fructose (HFF) diet; O. viverrini-infected and fed HFF diet (HFFOV); group fed with blank nanocomplexes (HFFOV+BNCs); groups fed different doses of CNCs (25, 50 and 100 mg/kg body weight: HFFOV+CNCs25; HFFOV+CNCs50; HFFOV+CNCs100, respectively) and a group given native curcumin (HFFOV+CUR). All treatment were for three months. RESULTS: The HFF group revealed NAFLD as evidenced by hepatic fat accumulation, ballooning, mild inflammation and little or no fibrosis. These changes were more obvious in the HFFOV group, indicating development of NASH. In contrast, in the HFFOV+CNCs50 group, histopathological features indicated that hepatic fat accumulation, cell ballooning, cell inflammation and fibrosis were lower than in other treatment groups. Relevantly, the expression of lipid-uptake genes, including fatty-acid uptake (cluster of differentiation 36), was reduced, which was associated with the lowering of alanine aminotransferase, total cholesterol and triglyceride (TG) levels. Reduced expression of an inflammation marker (high-mobility group box protein 1) and a fibrosis marker (alpha smooth-muscle actin) were also observed in the HFFOV+CNCs50 group. CONCLUSION: CNCs treatment attenuates the severity of NASH by decreasing hepatic steatosis, inflammation, and fibrosis as well as TG synthesis. CNCs mitigate the severity of NASH in this preclinical study, which indicates promise for future use in patients.


Assuntos
Curcumina , Hepatopatia Gordurosa não Alcoólica , Opistorquíase , Opisthorchis , Actinas/metabolismo , Alanina Transaminase/metabolismo , Animais , Colesterol/metabolismo , Cricetinae , Curcumina/metabolismo , Curcumina/farmacologia , Curcumina/uso terapêutico , Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose/metabolismo , Humanos , Inflamação/patologia , Lipídeos/farmacologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Opistorquíase/complicações , Opistorquíase/tratamento farmacológico , Triglicerídeos/metabolismo
18.
Fish Shellfish Immunol ; 130: 261-272, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36122639

RESUMO

Microplastic particles (MPs) are environmental pollutants that can cause varying levels of aquatic toxicity. Probiotics have been shown to reduce the negative effects of toxic substances. However, the protective effect of probiotics against the adverse effects of MPs has yet to be reported. The current study sought to determine the effects of the commercial probiotic AquaStar® Growout on polystyrene (PS)-MPs-mediated hepatic oxidative stress in Nile tilapia (Oreochromis niloticus). Fishes were assigned into four groups: the first group was the control, the second group was exposed to 1 mg/L of 0.5 µm PS-MPs, and the third and fourth groups were exposed to 1 mg/L of 0.5 µm PS-MPs and pre-fed with probiotics at levels of 3 g/kg and 6 g/kg diet, respectively. At the end of the experiment, probiotics administration reversed liver damage caused by the PS-MPs, reducing serum levels of malondialdehyde, aspartate aminotransferase, and alanine aminotransferase, and increasing the total antioxidant capacity. Furthermore, probiotics alleviated PS-MPs-induced oxidative stress by restoring antioxidant enzyme activities (superoxide dismutase, catalase, glutathione S-transferase, and glutathione peroxidase) and reducing oxidized glutathione and enhancing the redox state. Besides, probiotics supplementation decreased the transcriptional level of C-reactive protein and tumor necrosis factor-α following PS-MPs exposure. Furthermore, probiotics counteracted PS-MPs-associated reactive oxygen species production and mitogen-activated protein kinases (MAPKs) phosphorylation status. These findings suggested that probiotics could decrease liver damage caused by PS-MPs through their antioxidant properties and modulation of MAPK signaling pathways.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Ciclídeos , Poluentes Ambientais , Probióticos , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Proteína C-Reativa/metabolismo , Catalase/metabolismo , Dissulfeto de Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Malondialdeído/metabolismo , Microplásticos/toxicidade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo , Plásticos , Polietileno , Poliestirenos , Probióticos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Chemosphere ; 308(Pt 2): 136327, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36087723

RESUMO

The S-triazine herbicide ametryn (AMT) is relatively low adsorbed in soils and has high solubility in water, thus believed to affect non-target aquatic organisms such as amphibians. Temperature increases can intensify the effects of herbicides, possibly increasing the susceptibility of amphibians to these compounds. The aim of this study was to evaluate the influence of temperature (25 and 32 °C) on the responses of biochemical biomarkers in bullfrog tadpoles (Lithobates catesbeianus) exposed to different concentrations of AMT (0, 10, 50 and 200 ng.L-1) for a period of 16 days. The antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) and the biotransformation enzyme glutathione S-transferase (GST) had their activity decreased at the highest temperature (32 °C). SOD activity was reduced at 200 ng.L-1 and 32 °C compared to the control at the same temperature. AMT exposure also decreased the activities of alanine aminotransferase and gamma glutamyl transferase. On the other hand, the activities of acetylcholinesterase, carboxylesterase, alkaline phosphatase, levels of lipid peroxidation and protein carbonyl, as well genotoxic markers (micronucleus and nuclear abnormalities frequencies) were unchanged. The evaluation of integrated biomarker response index (IBR) indicated highest variations at the concentration of 200 ng.L-1 at 32 °C, suggesting that the combination of high AMT concentrations and temperatures generate more pronounced negative effects to tadpoles.


Assuntos
Herbicidas , Poluentes Químicos da Água , Acetilcolinesterase/metabolismo , Alanina Transaminase/metabolismo , Fosfatase Alcalina/metabolismo , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Catalase/metabolismo , Glutationa Transferase/metabolismo , Herbicidas/metabolismo , Larva , Rana catesbeiana/metabolismo , Solo , Superóxido Dismutase/metabolismo , Temperatura , Triazinas/metabolismo , Água/metabolismo , Poluentes Químicos da Água/metabolismo
20.
Zhongguo Zhong Yao Za Zhi ; 47(17): 4634-4642, 2022 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-36164869

RESUMO

Salvianolic acid B(Sal B), tanshinone Ⅱ_A(TSN Ⅱ_A), and glycyrrhetinic acid(GA) lipid emulsion(GTS-LE) was prepared by the high-speed dispersion method combined with ultrasonic emulsification.The preparation process of the emulsion was optimized by single-factor method and D-optimal method with appearance, centrifugal stability, and particle size of the emulsion as evalua-tion indexes, followed by verification.In vitro release of Sal B, TSN Ⅱ_A, and GA in GTS-LE was performed by reverse dialysis.In vivo pharmacokinetic evaluation was carried out in mice.The acute liver injury model was induced by acetaminophen.The effect of oral GTS-LE on the acute liver injury was investigated by serum liver function indexes and pathological changes in liver tissues of mice.The results showed that under the optimal preparation process, the average particle size of GTS-LE was(145.4±9.25) nm and the Zeta potential was(-33.6±1.45) mV.The drug-loading efficiencies of Sal B, TSN Ⅱ_A, and GA in GTS-LE were above 95%, and the drug release in vitro conformed to the Higuchi equation.The pharmacokinetic results showed that the C_(max) of Sal B, TSN Ⅱ_A, and GA in GTS-LE was 3.128, 2.7, and 2.85 times that of the GTS-S group, and AUC_(0-t) of Sal B, TSN Ⅱ_A, and GA in GTS-LE was 3.09, 2.23, and 1.9 times that of the GTS-S group.After intragastric administration of GTS-LE, the activities of alanine aminotransferase and aspartate aminotransferase were significantly inhibited, the content of malondialdehyde was reduced, and the structure of hepatocytes recovered to normal.In conclusion, GTS-LE can delay the release of Sal B and promote the release of TSN Ⅱ_A and GA.The encapsulation of three drug components in the emulsion can improve the oral bioavailability to varying degrees and can effectively prevent the acute liver injury caused by acetaminophen.


Assuntos
Abietanos , Acetaminofen , Antipiréticos , Benzofuranos , Doença Hepática Induzida por Substâncias e Drogas , Depsídeos , Ácido Glicirretínico , Abietanos/uso terapêutico , Acetaminofen/efeitos adversos , Acetaminofen/uso terapêutico , Alanina Transaminase/metabolismo , Animais , Antipiréticos/efeitos adversos , Antipiréticos/uso terapêutico , Aspartato Aminotransferases/metabolismo , Benzofuranos/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Depsídeos/uso terapêutico , Emulsões , Ácido Glicirretínico/uso terapêutico , Fígado/efeitos dos fármacos , Malondialdeído , Camundongos
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