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Liver diseases constitute a major healthcare burden globally, including acute hepatic injury resulted from acetaminophen overdose, ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Attainable treatment strategies for most liver diseases remain inadequate, highlighting the importance of substantial pathogenesis. The transient receptor potential (TRP) channels represent a versatile signalling mechanism regulating fundamental physiological processes in the liver. It is not surprising that liver diseases become a newly explored field to enrich our knowledge of TRP channels. Here, we discuss recent findings revealing TRP functions across the fundamental pathological course from early hepatocellular injury caused by various insults, to inflammation, subsequent fibrosis and hepatoma. We also explore expression levels of TRPs in liver tissues of ALD, NAFLD and HCC patients from Gene Expression Omnibus (GEO) or The Cancer Genome Atlas (TCGA) database and survival analysis estimated by Kaplan-Meier Plotter. At last, we address the therapeutical potential and challenges by pharmacologically targeting TRPs to treat liver diseases. The aim is to provide a better understanding of the implications of TRP channels in liver diseases, contributing to the discovery of novel therapeutic targets and efficient drugs.
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Mytilus is a bivalve species with important economic and ecosystem value over worldwide. Mytilus antimicrobial peptides‚ with strong molecular diversity‚ has become a research focus. Two novel antimicrobial peptides were identified from Mytilus‚ with structural features that similar to arthropod defensins. However‚ the functional features and the immune mechanism of these two mussel defensins are unknown. For this reason‚ the two novel defensins‚ Arthropod like defensn-1 and -2 (ALD-1 and ALD-2‚ respectively)‚ were studied for the sequence features‚ expression profiles‚ and the dynamic expression pattern after different microbe induction. In addition‚ solid phase chemical synthesis technology was used for the synthesis of these two novel ALDs‚ and the function of synthesized peptides of ALD was verified. The results indicated that‚ two ALDs of M. coruscus have classical structure features similar to those of other arthropod defensins. These two ALDs are mainly presented in the tissues of mantle and digestive gland of mussel. The results also suggest that ALD-1 was expressed at higher levels in the gonads of males than in females (P<0. 05). The expression of two ALDs is developmentally regulated‚and both ALD-1 and ALD-2 were undetectable in larvae‚ but can be detected with high expression level at adult mussel with age of six months. The dynamic changes in the expression level of two ALDs after microbial induction were examined‚ and the results showed a marked increase in expression level observed in vivo for both ALDs. Interestingly‚ two ALDs showed different sensitivities to different microbes‚ indicating very complex responses during the mussel immune response. This observation strongly suggests the existence of different recognition mechanism or signal transduction pathway in mussels for the expression of ALD-1 and ALD-2. Moreover‚ both of two chemical synthesized ALDs showed significant antimicrobial activities against five tested microbes with an inhibition ratio of 20%-80%. These results provided basis for understanding the molecule mechanism of Mytilus immunology‚ and the function of novel Mytilus defensins‚ and thusly provided basis for the development of molecular resource for mussel antimicrobial peptides.
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Objective: This study assessed the distribution of "lethal dose/pharmaceutical product strength" in high-risk drugs.Methods: In 707 pharmaceutical products (312 ingredients) that had been defined as high-risk drugs in Japan, we collected acute toxicity information from these products on single dose toxicity studies conducted in mice, including median lethal dose (LD50) and approximate lethal dose (aLD). The LD50 and aLD were then divided by the strength (quantity of active ingredients) of the pharmaceutical product, after which the LD50or aLD values having an inequality sign was excluded.Results: We collected data on the acute lethal dose of 707 products (312 ingredients) from high-risk drugs. Data with an inequality sign, which was 143 of 495 products (28.9%) in tablets and capsules, then 43 of 212 items (20.3%) in injections, were excluded from the analysis. As observed, median (Q1, Q3) of "LD50/pharmaceutical product strength" and "aLD/pharmaceutical product strength" for tablets or capsules was 36.8 tablet/kg (11.5 tablet/kg, 144 tablet/kg) and 16.7 tablet/kg (6.9 tablet/kg, 65 tablet/kg), respectively. However, median (Q1, Q3) of "LD50/pharmaceutical product strength" and "aLD/pharmaceutical product strength" for injections were 1.3 bottle/kg (0.6 bottle/kg, 4.7 bottle/kg) and 0.8 bottle/kg (0.4 bottle/kg, 15 bottle/kg), respectively. In both cases, injections were distributed at a lower value than oral products.Conclusion: From this study, the distribution of "lethal dose/pharmaceutical product strength" in high-risk drugs was clarified. This information will therefore help pharmacists assess risks associated with individual pharmaceutical products.
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A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2 (ALDH2). The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported. Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types. Furthermore, the ALDH2∗2 polymorphism (rs671) is the most common single nucleotide polymorphism (SNP) in Asia. Epidemiological studies associate ALDH2∗2 with tumorigenesis and progression. This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence, progression, and treatment of tumors in various types of cancer. Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.
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Alcoholic liver disease (ALD) is a chronic liver disease in which the internal liver tissues are inflammation damaged caused by long-term excessive drinking. Direct or indirect induction of hepatic inflammatory response by ethanol and its derivatives in the metabolic process may be an important mechanism of ALD, but the underlying cellular and molecular mechanisms of this process are still unclear. Recent study found that interleukin-6 (IL-6) response to ethanol mediated inflammation of the liver cells with dual role. It is involved in an inflammatory process that drives alcohol damage, activate cell apoptosis signaling pathways to stimulate macrophage and lymphocyte acute reactive protein synthesis aggravate the inflammatory response, and can lead to liver cell regeneration, increase anti-inflammatory cytokine levels play anti-inflammatory function to improve the degree of liver injury, and exercise stress can cause muscle source sex IL-6 temporary increased significantly, change the liver oxidation-inflammatory state. Then the body is kept in the adaptive state of long-term anti-inflammation to prevent the inflammatory damage of liver cells. Based on deepening the understanding of ALD inflammation pathological mechanism at the same time, the review on alcoholic liver cell inflammation related factor change and the IL-6 regulation pathway, considering the clinical use of IL-6 joint inflammatory factor pathway of targeted therapy is expected to be a novel therapy, the feasibility for laboratory screening of inflammatory related ALD drug intervention, for the prevention of alcoholic liver disease and treatment to provide new targets and train of thought.
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Background: Chronic alcohol consumption gives rise to various health risks that include liver disease, heart disease, pancreatitis, central nervous system disorders and certain forms of cancer. Alcoholic liver disease (ALD) is a spectrum of clinicopathological abnormalities, reflecting an acute or chronic inflammation of the liver parenchyma induced by alcohol use. It is associated with changes in various biochemical parameters and also various clinical manifestations in the patients. The objective of the present study to evaluate clinical and biochemical profile of acute alcoholic liver disease.Methods: The prospective hospital-based case control study was done at MNR Medical College, in the department of General Medicine for duration of one year from March 2017 to April 2018. A total of 120 cases diagnosed clinically and biochemically as Acute alcoholic liver disease were included in the study.Results: The age group ranged from 20 to 60 years and the male to female ratio was 2.42. Majority of the patients were in the age group of 30-40 years (54.1%). Majority of the patients (66.6%) consumed >60 grams/24hours of alcohol. Jaundice, nausea and vomiting were seen in 83.3% cases followed by hepatomegaly in 66.6% cases. Majority of them had been consuming alcohol for more than 5 years.Conclusions: Chronic alcohol consumption is more common in adult males. Chronic alcoholics consume more amount of alcohol. Alcoholic liver disease has a varied clinical presentation and is associated with deranged biochemical parameters.
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Objective To study liver transplantation in the treatment of alcoholic liver disease (ALD).Methods A retrospective study was conducted on 40 patients with ALD who underwent liver transplantation in the Changzheng Hospital of the Second Military Medical University from April 2005 to June 2017.The data were expressed as mean ± standard deviation ((-x) ±s) in populations with a normal distribution,and as median (min～max) in populations with an abnormal distribution.The survival rate was analyzed by life tables,and the Cox regression analysis was used for multivariate analysis.Results All patients were followed up until August 31,2017.The follow-up time was 2 ～ 4518 days,with a median of 997 days.Among the 40 patients,8 had already died (3 died of multiple organ failure,2 of biliary complications,1 of liver failure,1 of sepsis and 1 of recurrence of hepatocellular carcinoma (HCC).The 1-year survival rate was 81.0％,and the 5-year survival rate was 77.0％.Four of 40 patients developed tumor recurrence.The initial recurrence time was 189 ～ 337 days (median 236.5).The recurrence sites included the liver,colon combined with lungs,lungs,and lumbar vertebrae.Six of 40 (15.0％) patients had relapse in alcoholism.Multivariate analysis showed that age was a prognostic factor (RR =1.109,P ＜0.05).Years of drinking,daily amount of alcohol intake,abstinence,a previous history of upper gastrointestinal bleeding,a previous history of splenectomy,co-existing hepatocellular carcinoma,preoperative MELD score,preoperative Child-Pugh score,total operation time,anhepatic period,cold ischemia time,amount of intraoperative bleeding,postoperative alcoholism relapse,tumor recurrence or new onset of tumor were not significantly correlated with the postoperative survival rate (P＞0.05).Conclusions ALD patients were mostly 40 ～ 60 years old.Age was an independent factor affecting survival.The younger the patient,the better the prognosis.Other factors were of no prognostic significance.
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Objective To investigate the role of tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 (TIPE2) for regulating the macrophage polarization in systemic lupus erythematosus and its curative effects on experimental SLE mice.Methods The mice were treated with activated lymphocytes derived DNA (ALD-DNA) for inducing mice model,randomly divided into AAV-scr control group and AAV-TIPE2 experimental group,and injected with AAV-TIPE2 or AAV-scr virus solution from the tail vein of mice.The expression of TIPE2 mRNA and protein in polarized macrophages,serum dsDNA antibody titer,urine protein and renal pathological index were detected.Results (1) The TIPE2 expression level of TIPE2 mRNA and protein in AAV-TIPE2-transfected cells was 13.5±1.6 times and 10.8±1.6 times of AAV-scr control group respectively.(2) M2 macrophage specific molecule MGL+ was 59.6% in AAV-TIPE2 group and MGL + cells in the AAV-scr group was 8.4%.M2/M1 odds ratio of AAV-TIPE2 experimental group to AAV-scr control group was 16.(3) The recombinant TIPE2 adenovirus related vector could stably expressed in transfected HEK-293.In vitro and in vivo experiments confirmed that AAV-TIPE2 was able to induce M2 polarization of macrophages in ALD-DNA-induced lupus mice.(4) The serum anti-dsDNA antibody,urinary protein and renal pathology in the AAV-TIPE2 group were significantly lower than those in the AAV-scr group(P<0.01).Conclusion TIPE2 alleviates the disease condition of ALD-DNA induced SLE mice through induction of macrophage polarization to M2 phenotype,which may be used as a promising therapeutic method for ALD-DNA induced SLE mice.
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Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available. Wuzhi Tablet (WZ), a preparation of extract fromthat is a traditional hepato-protective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ and the target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.
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BACKGROUND/AIMS: This study aimed to verify the reliability of the alcoholic liver disease (ALD)/nonalcoholic fatty liver disease (NAFLD) index (ANI) for distinguishing ALD in patients with hepatic steatosis from NAFLD, and to investigate whether ANI combined with γ-glutamyl transferase (GGT) would enhance the accuracy of diagnosis in China. METHODS: A hundred thirty-nine cases of fatty liver disease (FLD) were divided into two groups of ALD and NAFLD. The ANI was calculated with an online calculator. All indicators and ANI values were analyzed using statistical methods. RESULTS: ANI was significantly higher in patients with ALD than in those with NAFLD (7.11 ± 5.77 vs. -3.09 ± 3.89, p 0.05). CONCLUSIONS: ANI can help distinguish ALD from NAFLD with high accuracy; when ANI was combined with GGT, its effectiveness improved further.
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Humans , Alcoholics , Aspartate Aminotransferases , China , Diagnosis , Diagnosis, Differential , Erythrocyte Indices , Fatty Liver , gamma-Glutamyltransferase , Liver Diseases, Alcoholic , ROC Curve , Sensitivity and Specificity , TransferasesABSTRACT
Objective: To study the effects of different extracts of Kansui Radix stir-baked with vinegar (KRV) on the function of expelling water retention with drastic purgative in cancerous ascites model rats. Methods: The cancerous ascites model rats were respectively ig administered with KRV powder, ethanol extract, aqueous extract, and ehanol and aqueous extract of KRV (340 mg/kg) for 7 d. The amounts of urine and ascites, the levels of urinary sodium, potassium, chloride ion, and pH value, and the contents of PRA, Ang II, and ALD in serum were investigated. UPLC-QTOF MS technology was used to explore the components differences in various extracts of KRV. Results: Compared with the control group, the amount of urine in model group was significantly reduced (P<0.05), the ascites generated, and the urinary sodium, potassium, chloride ion, pH value, and the contents of PRA, Ang II, and ALD in serum were all significantly increased (P<0.01). Compared with the model groups, the treatment groups showed decreasing trend in ascites; The amounts of urine in positive groups, powder groups, ethanol and aqueous extract groups showed a significant increase (P<0.05); The level of urinary sodium of water extraction groups showed significant decrease (P<0.05); The levels of urinary sodium, potassium, chloride ion, pH value, and the contents of PRA, Ang II, and ALD in serum of positive groups, powder groups, ethanol extract groups, and ethanol and aqueous extract groups all showed a significant decrease (P<0.05, 0.01). Diterpenes were inspected in the alcohol extract and alcohol and aqueous extract, fewer in the aqueous extract. Conclusion: Powder groups and ethanol and aqueous extract groups of KRV have remarkable effect on expelling water retention with drastic purgative, and there is no significant difference between the two groups, which could provide the basis for clinical medication of KRV that is made into the pill and powder. Diterpenes in KRV may be the active components on the function of expelling water retention with drastic purgative.
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Alcoholic liver disease (ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a) and PPARα (peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.
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En el hígado humano normal aproximadamente un 5% de su masa está compuesta por lípidos. Cuando tenemos aumento del depósito de grasa el término más utilizado es el de hígado graso o esteatosis e incluye el hígado graso no alcohólico (HGNA) y el hígado graso de etiología alcohólica (HGA), siendo aún la biopsia hepática considerada como el patrón de oro para determinar la severidad del daño hepático en cualquiera de estas entidades.
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Humans , Male , Female , Biopsy , Fatty Liver , Fatty Liver, AlcoholicABSTRACT
@#ObjectiveTo observe the effect of Yiqihuoxue recipe on left ventricular remodeling after acute myocardial infarction (AMI).Methods40 patients with AMI were randomly divided into treatment group and control group with 20 cases in each group and received Yiqihuoxue recipe or fasinopril respectively for 6 months. Changes of clinical symptoms, the level of plasma angiotensin Ⅱ(ATⅡ), aldosterone (ALD), endothelin (ET) and echocardiographical indexes: left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), ejection fraction (EF), left ventricular mass index (LvmassI), wall motion index (WMI), wall thick (WT), E/A were assessed before discharge, and in the end of 3rd and 6th month after AMI.ResultsClinical symptoms of patients of treatment group improved significantly (P<0.01). EF and E/A of all patients in two groups increased (P<0.01 or P<0.05), LvmassI and WT reduced (P<0.05), but there were no significantly differences between two groups in LVEDVI, LVESVI, EF, LvmassI, WMI, E/A and WT(P>0.05). The level of plasma ET decreased in treatment group (P<0.05), the level of plasma ATⅡ and ALD of control group decreased more than that of treatment group (P<0.05).ConclusionYiqihuoxue recipe can significantly improve clinical symptoms, cardic function, and left ventricular remodeling, showing a better clinical efficacy.
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Objective To study the relationship of lung and kidney in TCM by detecting the protein expression related to Na+ transportation in the kidney tissue of Lung-Qi deficiency model rats.Methods Lung-Qi deficiency model of rats were copied.Immunohistochemistry was applied to measure the expressions of ENaC and rBSCl in renal tubular epithelium.RIA was used to detect ALD and ANP levels in plasma and lung tissue.Results Compared with the control group,expressions of ENaC and rBSCl of renal tubule were upregulated markedly,ALD level increased and ANP level decreased obviously in the model group.Conclusion Lung can regulate the expressions of ENaC and rBSCl in the renal tubule by secreting ALD and ANP,which can regulate Na+ and water reabsorption in the renal tubule and then influence the water metabolism of the body.
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Objective To approach the clinical effect and safety of glutathione in patients with alcoholic liver disease(ALD).Method The patients were divided into two groups, including the control group and treatment group.Two groups are all treated with routine therapy such as Ganlixin,potassium magnesium aspartate,mulivitamins and so on,the treatment group add glutathione,to inspect clinical menifetation and liver function changes of two groups before and after treatments.Result Among the treatment group,43.6%showed notable effective result,51.3%effective,the total dffective rate is 94.9%. Among the control group, 19.4%showed notable effective result, 58.3%effective,the total dffective rate is 78.7%.There is a significant different between the two groups (P
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Objective To study investigate the influence of large volume slow speed paracentesis on kidney blood flow in patients with cirrhosis.Methods Plasma rennin(PRA),angiotensin-Ⅱ,aldosterone(ALD)and blood pressure,pulse were detected before and 1 hour after large volume slow speed paracentesis in 15 paients.Results After paracentesis,patients had significant reductions in diastolic pressure[(76.0?7.9)mm Hg vs(70.7?8.0)mm Hg,P
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Object To probe into the antihypertension activity mechanism of extracts from Compound Jueming (CJ). Methods The method of radioimmunoassay was used to assay the concentration of the related substances on spontaneously hypertensive rats (SHR) such as angiotensin Ⅱ (ANGⅡ), renin activity (RA), endothelin (ET), atrial natriuretic polypeptide (ANP), aldosterone (ALD), and urine. Results All of the three doses (9.5, 7.2, and 4.8 g/kg) of extracts from CJ reduced ANG Ⅱ and RA, but had no influence on ALD, ET, ANP, and urine in SHR. Conclusion The antihypertension effect of extracts from CJ is related to decreasing of renin angiotensin, but not to ALD, ET, ANP, and urine.
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AIM: To compare the effects of Yuxingcao(Herba houttuyniae),Paojiang(Radix aconiti lateralis praeparata) and Fuzi(Rhizoma Zingiberis recens(blastfried)) on ventricular remodeling induced by high pressure in rats. METHODS: Ventricular remodeling model was induced by constriction of abdominal aorta in rats.After 1 week,the model rats were divided randomly into 5 groups,such as model control,captopril,Yuxingcao,Paojiang and Fuzi.In addition,a sham-operated group was designed.The rats were given per oral captopril,Yuxingcao,Paojiang and Fuzi respectively for consecutive 3 weeks.Rats in sham-operated group and model control group were treated with distilled water.The blood pressure was measured.The ratio of LVW/BW,HW/BW was calculated as an index indicating the grade of ventricular hypertrophy.The contents of AngⅡ,ET in heart tissue and blood level of aldosterone(ALD) were determined by radio-immunoassay.The myocardium collagen volume fraction(CVF),perivascular circumferential area(PVCA) and the content of type Ⅰ and Ⅲ collagen were determined by histological assay using the picric acid/sirius red stain.The expression of protein kinase C(PKC) was determined by immunohistochemical analysis. RESULTS: Yuxingcao could lower the blood pressure and the ratio of LVW/BW,HW/BW;reduce the level of AngⅡ,ET in myocardium and ALD in blood serum,decrease myocardium CVF,PVCA and the content of type Ⅰ,Ⅲ collagen,and inhibit the expression of PKC.Paojiang did not show obvious effects mentioned above,neither did Fuzi,except that it decreased the level of AngⅡ in myocardium. CONCLUSION: Yuxingcao,the herb with cool nature,can attenuate the ventricular remodeling,and inhibit the over-activity of neuroendocrine factor release.Paojiang and Fuzi,the herbs with hot nature,fail to show that.
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The purpose of this investigation is to improve ethanol production and decrease acetate formation in Saccharomyces cerevisiae strain YS2-?adh2.The strain YS2-?adh2 with deleted alcohol dehydrogenase Ⅱ(adh2) gene was isolated in our lab with higher ethanol production than that of the strain YS2.The ace-taldehyde dehydrogenase Ⅵ(ald6) gene encoded a cytosolic acetaldehyde dehydrogenase,a key enzyme of the pyruvate dehydrogenase(PDH) bypass,transfers acetaldehyde to acetate.To disrupt ald6 gene of the strain YS2-?adh2,ald6 gene targeting cassettes were synthesized by long flanking homology PCR(LFH-PCR) and then were transformed into YS2-?adh2 mutants by LiAc/SS Carrier DNA/PEG method.Positive transformants were selected with G418 and further confirmed by PCR.Once correctly integrated into the genome,the selective marker was rescued by transforming the plasmid pSH65 into the positive transformants and inducing the Cre expression with a Cre/loxP-mediated marker removal procedure.We named the ald6 gene knocked-out strain as YS2-?adh2-?ald6 which has a 12.5% higher ethanol production and a 18% lower acetate formation compared to the strain YS2.