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In vivo fluorescence indicated that acute AICAR treatment effectively promoted hepatic sinusoid microcirculation in BDL rats (n = 6, compared with the CTRL, *P < 0.05). a The gross evaluation of in vivo fluorescence when the cells were treated with AICAR. Normal: image of normal rat liver tissue; before: the BDL rat liver tissues before AICAR treatment; treated: BDL rat liver tissues after treatment with 40 mg AICAR for 15 min. b The hepatic sinus diameter changed after the cells were treated with 40 mg AICAR for 15 min. c The number of opened hepatic sinusoids after treatment with 40 mg AICAR for 15 min
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Recent studies have indicated that the Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) pathway is closely involved in liver fibrosis and other fibrotic diseases. However, whether targeting the AMPK pathway can rescue liver fibrosis and its complications, such as portal hypertension, is unknown. This study aimed to explore the thera...
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Background
Hereditary hemorrhagic telangiectasia (HHT) is marked by arteriovenous fusion comprising hepatic vascular malformations (HVaMs) with the chance of bleeding.
Aims
We investigated HVaMs in HHT patients by combination of contrast-enhanced ultrasound (CEUS) with perfusion imaging quantification to be able to sub-classify a high risk cohort...
Background
Circulating cirrhotic endothelial progenitor cells (EPC) interact with both liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC) and promote angiogenesis in vitro. This study evaluated the effect of cirrhotic and control EPCs on hepatic angiogenesis, microcirculation, and fibrosis in vivo in rat models of cirrhosis....
Citations
... Portal hypertension in cirrhosis refers to a series of problems caused by increased portal vein pressure due to the disturbance of blood circulation in the liver caused by cirrhosis, including ascites, establishment of collateral circulation, splenomegaly, and hypersplenism (Lunova et al. 2021). Fibrosis, regenerative nodule formation, and intrahepatic vasoconstriction lead to increased intrahepatic resistance, resulting in excessive blood retention in portal venous systems (Hu et al. 2019). In order to drain the stagnant blood from the portal system to the systemic circulation, collateral veins of the portal-system are gradually formed, in which bleeding from gastroesophageal varices can be fatal (Garbuzenko 2015). ...
Liver cirrhosis can cause disturbances in blood circulation in the liver, resulting in impaired portal blood flow and ultimately increasing portal venous pressure. Portal hypertension induces portal-systemic collateral formation and fatal complications. Extrahepatic angiogenesis plays a crucial role in the development of portal hypertension. Curcumol is a sesquiterpenoid derived from the rhizome of Curcumae Rhizoma and has been confirmed to alleviate liver fibrosis by inhibiting angiogenesis. Therefore, our study was designed to explore the effects of curcumol on extrahepatic angiogenesis and portal hypertension. To induce cirrhosis, Sprague Dawley rats underwent bile duct ligation (BDL) surgery. Rats received oral administration with curcumol (30 mg/kg/d) or vehicle (distilled water) starting on day 15 following surgery, when BDL-induced liver fibrosis had developed. The effect of curcumol was assessed on day 28, which is the typical time of BDL-induced cirrhosis. The results showed that curcumol markedly reduced portal pressure in cirrhotic rats. Curcumol inhibited abnormal splanchnic inflow, mitigated liver injury, improved liver fibrosis, and attenuated portal-systemic collateral shunting in cirrhotic rats. These protective effects were partially attributed to the inhibition on mesenteric angiogenesis by curcumol. Mechanically, curcumol partially reversed the BDL-induced activation of the JAK2/STAT3 signaling pathway in cirrhotic rats. Collectively, curcumol attenuates portal hypertension in liver cirrhosis by suppressing extrahepatic angiogenesis through inhibiting the JAK2/STAT3 signaling pathway.
... Viglino et al (65) reported that chronic treatment with AIcAR induces a metabolic shift in FFA-exposed cardiomyocytes, characterized by improved glucose transport and glycolysis and redirection of fatty acids towards neutral storage. Hu et al (66) found that AICAR treatment led to an improvement in liver fibrosis in rats with bile duct ligation by increasing the level of NO. Acute and chronic use of AIcAR have been demonstrated to relieve portal vein pressure without changing systemic hemodynamics (66). ...
... Hu et al (66) found that AICAR treatment led to an improvement in liver fibrosis in rats with bile duct ligation by increasing the level of NO. Acute and chronic use of AIcAR have been demonstrated to relieve portal vein pressure without changing systemic hemodynamics (66). AIcAR can also alleviate endothelial dysfunction and promote vasodilation by improving eNOS activity and increasing NO production (67,68). ...
Increased levels of serum free fatty acids (FFAs) are closely associated with microvascular dysfunction. In our previous study, a coronary microvascular dysfunction (CMD) model was successfully established via lipid infusion to increase the levels of serum FFAs in mice. However, the underlying mechanisms remained poorly understood. Therefore, the aim of the present study was to explore the mechanism underlying FFA‑induced CMD. A CMD mouse model was established via lipid combined with heparin infusion for 6 h to increase the concentration of serum FFAs. Following the establishment of the model, the coronary flow reserve (CFR), extent of leukocyte activation and cardiac microvascular structures were assessed in the mice. Cardiac microvascular endothelial cells (CMECs) were treated with different concentrations of palmitic acid and cell viability was evaluated. Changes in the expression levels of AMP‑activated protein kinase (AMPK), Krüppel‑like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS) were identified by immunohistochemical and western blot analyses. Experiments using AMPK activator, KLF2 overexpression plasmid, small interfering RNAs and nicorandil were subsequently designed to investigate the potential involvement of the AMPK/KLF2/eNOS signaling pathway. These experiments revealed that FFAs could induce CMD in mice, which was characterized by reduced CFR (1.89±0.37 vs. 2.74±0.30) and increased leukocyte adhesion (4,350±1,057.5 vs. 11.8±5.4 cells/mm2) compared with the control mice. CD11b expression and intracellular reactive oxygen species (ROS) levels were increased in CMD model mice compared with control mice. Serum TNF‑α and IL‑6 levels were higher in the model group than in the control group. Transmission electron microscopy revealed that CMECs in heart tissues of model mice were severely swollen. In addition, palmitic acid decreased CMEC viability and increased ROS production in a dose‑dependent manner. Notably, the AMPK/KLF2/eNOS signaling pathway was demonstrated to be suppressed by FFAs both in vivo and in vitro. Activation of this axis with AMPK activator, KLF2 overexpression plasmid or nicorandil restored the CFR in CMD model mice, inhibited oxidative stress and increased CMEC viability. Taken together, the results of the present study demonstrated that FFAs could induce CMD via inhibition of the AMPK/KLF2/eNOS signaling pathway, whereas activation of this pathway led to the alleviation of FFA‑induced CMD, which may be a therapeutic option for CMD.
... Microbiome-targeted therapies (MTTs) can be divided into four categories, namely antibiotics, prebiotics, probiotics and fecal microbiota transplantation (FMT). Antibiotics such as rifaximin and norfloxacin selectively decontaminate the intestines, which could lead to HVPG changes [17,18]. Probiotics could alter the make-up of the intestinal microbiome to decrease endotoxemia [19]. ...
Background
Modulation of the gut microbiome could favorably alter the hepatic venous pressure gradient (HVPG) in cirrhosis and portal hypertension (PH).
Aim
This meta-analysis was to evaluate the effects of microbiome-targeted therapies (MTTs) on HVPG in persons with cirrhosis and PH.
Methods
PubMed, The Cochrane Library, Embase, Web of Science and Scopus were searched for randomized clinical trials (RCTs) analyzing the effects on HVPG in people with cirrhosis who received MTTs. Clinical outcomes were pooled using RevMan5.3 software. A trial sequential analysis was applied to calculate the required information size and evaluate the credibility of the meta-analysis results.
Results
A total of six studies were included. MTTs were associated with a reduction of 1.22 mm Hg in HVPG (95% CI: -2.31, -0.14 mmHg, P = 0.03). Subgroup analysis showed a greater reduction with longer duration (-1.88 mmHg;95% CI: -3.23, -0.53; P = 0.006). In the trial sequential analysis of HVPG reduction, the cumulative Z curve crossed the traditional significance boundary without the achievement of required information size (330).
Conclusions
MTTs may be associated with a reduction in HVPG in patients with cirrhosis and PH. Microbiome-targeted therapies merit additional large-sample studies to define the efficacy of HVPG.
Systematic review registration
PROSPERO 2020: CRD4202021609 .
... Evidence for this strategy is supported by animal experiments where treatment with AMPK-activators, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin both lower HVPG. [17][18][19] Additional beneficial effects of metformin in rodents include reduced hepatic inflammation and improved liver fibrosis status. 17 Whether these findings translate into clinically relevant improvements in humans with cirrhosis and portal hypertension remains unresolved. ...
Background
Portal hypertension is the main determinant of clinical decompensation in patients with liver cirrhosis. In preclinical data metformin lowers portal pressure, but there are no clinical data for this beneficial effect.
Aims
To investigate the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion.
Methods
In a randomised, double-blinded study design, we investigated 32 patients with cirrhosis before and 90 minutes after ingestion of 1000-mg metformin (n = 16) or placebo (n = 16). Liver vein catherisation was performed to evaluate HVPG and indocyanine green (ICG) infusion for investigation of hepatic blood flow.
Results
The mean relative change in HVPG was −16% (95% CI: −28% to −4%) in the metformin group compared with 4% (95% CI: −6% to 14%) in the placebo group (time × group interaction, P = 0.008). In patients with baseline HVPG ≥12 mm Hg clinically significant improvements in HVPG (HVPG <12 mm Hg or a >20% reduction in HVPG) were observed in 46% (6/13) of metformin-treated and in 8% (1/13) of placebo-treated patients (P = 0.07). There were no changes or differences in systemic blood pressure, heart rate, hepatic plasma and blood flow, hepatic ICG clearance, hepatic O2 uptake or inflammation markers between groups.
Conclusions
A single oral metformin dose acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This offers a promising perspective of a safe and inexpensive treatment option that should be investigated in larger-scale clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension.
... By activating the AMPK/ eNOS pathway in LSECs, AICAR enhances NO synthesis in the liver without changing systemic hemodynamics, thereby ameliorating cell functions as well as reducing portal pressure. AICAR has also been shown to directly alleviate HSCs contraction in vitro [92]. Consistently, metformin improves the age-related pseudocapillarization of LSECs by activating the AMPK/eNOS pathway [93]. ...
Chronic liver diseases are attributed to liver injury. Development of fibrosis from chronic liver diseases is a dynamic process that involves multiple molecular and cellular processes. As the first to be impacted by injury, liver sinusoidal endothelial cells (LSECs) are involved in the pathogenesis of liver diseases caused by a variety of etiologies. Moreover, capillarization of LSECs has been recognized as an important event in the development of chronic liver diseases and fibrosis. Studies have reported that various cytokines (such as vascular endothelial growth factor, transforming growth factor-β), and pathways (such as hedgehog, and Notch), as well as epigenetic and metabolic factors are involved in the development of LSEC-mediated liver fibrosis. This review describes the complexity and plasticity of LSECs in fibrotic liver diseases from several perspectives, including the cross-talk between LSECs and other intra-hepatic cells. Moreover, it summarizes the mechanisms of several kinds of LSECs-targeting anti-fibrosis chemicals, and provides a theoretical basis for future studies.
... The 5-Aminoimidazole-4-Carboxamide Ribonucleoside (AICAR) is a potent AMP-mimetic that may regulate a wide range of metabolic network, although the downstream mechanisms by which AICAR exerts hepatoprotective effects need to be further elucidated. Nonetheless, it has been demonstrated that chronic AICAR administration improved hemodynamic alterations related to liver fibrosis and portal hypertension in rats [207]. ...
Nonalcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver dysfunctions and it is predicted to become the primary cause of liver failure and hepatocellular carcinoma. Mitochondria are highly dynamic organelles involved in multiple metabolic/bioenergetic pathways in the liver. Emerging evidence outlined that hepatic mitochondria adapt in number and functionality in response to external cues, as high caloric intake and obesity, by modulating mitochondrial biogenesis, and maladaptive mitochondrial response has been described from the early stages of NAFLD. Indeed, mitochondrial plasticity is lost in progressive NAFLD and these organelles may assume an aberrant phenotype to drive or contribute to hepatocarcinogenesis. Severe alimentary regimen and physical exercise represent the cornerstone for NAFLD care, although the low patients' compliance is urging towards the discovery of novel pharmacological treatments. Mitochondrial-targeted drugs aimed to recover mitochondrial lifecycle and to modulate oxidative stress are becoming attractive molecules to be potentially introduced for NAFLD management. Although the path guiding the switch from bench to bedside remains tortuous, the study of mitochondrial dynamics is providing intriguing perspectives for future NAFLD healthcare.
... The anti-diabetic effects of the black ginseng extract in type 2 diabetes were investigated by activating AMPK in the liver, 47) AICAR, an agonist of AMPK, can alleviate liver cirrhosis in bile duct ligation (BDL) model rats. 48) CC can reserve the inhibitory effect of metformin on the NLRP3 inflammasome by activating AMPK signaling in diabetic cardiomyopathy. 49) We, in the current research, observed that CC restrained the protective effect of RA on the liver of mice that received Con A by inhibiting AMPK signaling. ...
Rosmarinic acid (RA) is extensively utilized in herbal medicine in China. The AMP-activated protein kinase (AMPK) signaling can be activated by RA and inhibited by the synthetic, reversible AMP-competitive inhibitor, Compound C (CC). The objective of this study was to investigate the role of AMPK signaling involving the protective effects of RA on concanavalin A (Con A)-induced autoimmune hepatitis (AIH) in mice. BALB/c mice were treated with RA, with or without CC, followed by the pretreatment with Con A. Analysis of serum aminotransferases and cytokines were conducted and liver tissue histology was performed to evaluate hepatic injury. Cytokine levels in serum and hepatic tissue were respectively measured by enzyme-linked immunoassay (ELISA) and used quantitative (q)PCR. Levels of phosphorylated acetyl CoA carboxylase in the liver, representing AMPK activation, were detected by Western blotting. Compared with the Con A group, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in RA group (100 and 150 mg/kg/d) were significantly reduced. RA also reduced hepatocyte swelling, cell death, and infiltration of leukocytes in the liver of Con A-treated mice. Serum levels of cytokines, such as interferon-γ (IFN-γ), interleukin-2 (IL-2) and interleukin-1β (IL-1β), were reduced by RA pretreatment, while the levels of serum interleukin-10 (IL-10), an anti-inflammatory cytokine, was elevated. These protective effects were reversed by treatment with CC. RA treatment reduced the hepatic damage via the activation of AMPK in the mice of Con A-induced. So RA acts as a potential part in the therapy of autoimmune hepatitis.
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... Since L-arginine-to-ADMA ratios represent NO bioavailability [22], both ADMA and SDMA are inhibitors of NO synthase [33], signals formed by NO pathway are supposed to cause vasodilatation. Therefore, our data are in accordance with the previous findings reported that AICAR ameliorates portal hypertension via preserving NO pathway [34]. We conducted the AICRA/P group to evaluate the programming effect of AICAR in control offspring. ...
High consumption of saturated fats links to the development of hypertension. AMP-activated protein kinase (AMPK), a nutrient-sensing signal, is involved in the pathogenesis of hypertension. We examined whether early intervention with a direct AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) during pregnancy or lactation can protect adult male offspring against hypertension programmed by high saturated fat consumption via regulation of nutrient sensing signals, nitric oxide (NO) pathway, and oxidative stress. Pregnant Sprague–Dawley rats received regular chow or high saturated fat diet (HFD) throughout pregnancy and lactation. AICAR treatment was introduced by intraperitoneal injection at 50 mg/kg twice a day for 3 weeks throughout the pregnancy period (AICAR/P) or lactation period (AICAR/L). Male offspring (n = 7–8/group) were assigned to five groups: control, HFD, AICAR/P, HFD + AICAR/L, and HFD + AICAR/P. Male offspring were killed at 16 weeks of age. HFD caused hypertension and obesity in male adult offspring, which could be prevented by AICAR therapy used either during pregnancy or lactation. As a result, we demonstrated that HFD downregulated AMPK/SIRT1/PGC-1α pathway in offspring kidneys. In contrast, AICAR therapy in pregnancy and, to a greater extent, in lactation activated AMPK signaling pathway. The beneficial effects of AICAR therapy in pregnancy is related to restoration of NO pathway. While AICAR uses in pregnancy and lactation both diminished oxidative stress induced by HFD. Our results highlighted that pharmacological AMPK activation might be a promising strategy to prevent hypertension programmed by excessive consumption of high-fat food.
5’AMP-activated protein kinase (AMPK) activators show potential for treating Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) due to their inhibiting effects on fatty acid and cholesterol synthesis. The absence of treatments for NASH, and its propensity for progression to severe disease, lead us to identify and characterize BI9774, a small molecule AMPK activator, which we used to evaluate this potential, including its ability to reduce the NASH specific qualities of fibrosis and inflammation in a preclinical study.
Male Lep ob /Lep ob mice on a control or NASH inducing (AMLN) diet, with liver fibrosis were given BI9774 or vehicle for 6 weeks while metabolic and NASH endpoints were evaluated.
BI9774 treatment decreased plasma ALT, terminal liver weight, and liver lipids. RNA expression of collagen-related genes decreased, although collagen protein and inflammation remained unaltered. We also observed increased heart weight and glycogen levels, and increased expression of genes associated with cardiac hypertrophy.
AMPK activation improved many metabolic endpoints, but lack of significant improvement in liver fibrosis and negative cardiac effects suggest systemic AMPK activation is not an ideal NASH therapy. Reductions in steatosis and fibrosis-related genes indicate that, with extended treatment, a liver specific AMPK activator has potential to resolve hepatic fibrosis.
Summary Statement
Fatty liver disease affects up to 30 percent of adults worldwide with 30% of patients progressing to more sever liver disease. AMPK activation can help reduce liver fat.
