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The inflammatory response during alcoholic liver disease. Excessive consumption of alcohol causes lipopolysaccharide release from the gut activating toll-like receptor 4 on Kupffer cells (KCs). Pattern recognition receptors become activated by pathogen-associated molecular patterns/damage-associated molecular patterns which induces inflammation via release of proinflammatory cytokines and inflammasome activation. Interleukin (IL)-18 production from KCs causes activation of natural killer cells. Toll-like receptor stimulation in hepatic stellate cells results in the expression of IL-6, transforming growth factor-β1 and tumor necrosis factor-α. (Figure created with BioRender.com). DAMPs: Damage-associated molecular patterns; FFA: Free fatty acids; PAMPs: Pathogen-associated molecular patterns; IL: Interleukin; LPS: Lipopolysaccharide; NF-κB: Nuclear factor-κB; NK: Natural killer; NLRP3: NOD-, LRR-and pyrin domain-containing protein 3; PRR: Pattern recognition receptor; ROS: Reactive oxygen species; TGF-β: Transforming growth factor β; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α.
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Alcoholic liver disease (ALD) due to chronic alcohol consumption is a significant global disease burden and a leading cause of mortality. Alcohol abuse induces a myriad of aberrant changes in hepatocytes at both the cellular and molecular level. Although the disease spectrum of ALD is widely recognized, the precise triggers for disease progression...
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Context 1
... is one of the exogenous ligands for TLR4, a pattern recognition receptor found on KCs. LPS interaction with TLR4 initiates downstream signaling via TIR-domain-containing adapter-inducing IFN-β and IFN regulatory factor 3, leading to production of proinflammatory cytokines proinflammatory cytokines such as TNF-α and IL-1β (Figure 2), the former can activate the extrinsic pathway of apoptosis via the TNF receptor 1 and TNF receptor 2 signaling [42]. High levels of these death receptors, including Fas, are expressed in all liver cells, therefore, the extrinsic pathway is the main apoptotic pathway in hepatocytes, such that hepatocyte apoptosis has been correlated with severity of disease in AH [43]. ...
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Introduction: Previous research has shown the simultaneous presence of health diseases and alcohol abuse. This research emphasizes the importance of individual diseases, the simultaneous presence and association of different diseases, health and social consequences in patients with alcohol abuse.
Subjects and methods: A retrospective study on the s...
Alcoholic liver disease is one of the most prevalent chronic diseases that causes high morbidity and mortality worldwide. This study demonstrated the protective potential of Alcalase-black soybean-derived peptides (BSPs) against alcohol-induced liver injury in mice. BSPs were rich in oligopeptides (80%, w/w, <1,996 Da) and Lys. The median and high...
Citations
... Growing evidence indicates that mitochondrial dysfunction plays a major role in alcohol-induced hepatocyte regeneration and liver injury [7][8][9]. In AH, alcohol directly or indirectly causes cell damage and the release of reactive oxygen species (ROS), subsequently triggering oxidative stress, mitochondrial damage, and dysfunction [9,10]. ...
... Therefore, targeting GSDMD activation will be a promising therapeutic approach for AH. It has been demonstrated that mitochondrial dysfunction plays an essential role in alcohol-induced hepatocyte regeneration and liver injury [7][8][9]. During AH, liver cells release ROS as a direct result of alcohol intake. ...
Background
Mechanisms and consequences of Gasdermin D (GSDMD) activation in alcoholic hepatitis (AH) are unclear. In the present study, we investigated whether GSDMD induces hepatocyte pyroptosis by regulating mitochondrial dysfunction in AH.
Results
Liver damage in AH mice was assessed by HE staining, serum levels of AST, ALT, TC, and TG. The levels of IL-1β, IL-18, LDH, inflammasome-associated proteins and hepatocyte death were assessed to determine pyroptosis. Mitochondrial dysfunction was assessed through various parameters including mitochondrial DNA (mtDNA) levels, ROS generation, mitochondrial membrane potential, ATP contents, levels of mitochondrial function-related proteins and morphological changes of mitochondria. AH induced gasdermin D (GSDMD) activation, leading to increased protein expression of N-terminal GSDMD (GSDMD-N), NLRP3, and Caspase 11 in liver tissues. Downregulation of GSDMD alleviated alcohol-induced hepatocyte pyroptosis. Alcohol also causes mitochondrial dysfunction in hepatocytes in AH, which was improved by inhibiting GSDMD. Furthermore, enhancing mitochondrial function suppressed alcohol-induced hepatocyte pyroptosis. Further, knockdown of GSDMD or dynamin-related protein 1 (Drp1) improved AH-induced liver injury, accompanied by a decrease in hepatocyte pyroptosis.
Conclusion
GSDMD induces hepatocyte pyroptosis by modulating mitochondrial dysfunction during AH-induced inflammation and liver injury. These findings may pave the way to develop new therapeutic treatments for AH.
... Alcohol-associated liver disease (ALD) is characterized by notable intracellular changes, encompassing endoplasmic reticulum (ER) stress, Golgi disorganization, mitochondrial dysfunction, activation of inflammatory pathways, and perturbed autophagy [1][2][3]. Over several years, our research groups have delved into the effects of ethanol Golgi, we co-stained MYH10 with TGOLN2/TGN46, a marker of the trans-Golgi and TGN. ...
The development of alcohol-associated liver disease (ALD) is associated with disorganized Golgi apparatus and accelerated phagophore formation. While Golgi membranes may contribute to phagophores, association between Golgi alterations and macroautophagy/autophagy remains unclear. GOLGA4/p230 (golgin A4), a dimeric Golgi matrix protein, participates in phagophore formation, but the underlying mechanism is elusive. Our prior research identified ethanol (EtOH)-induced Golgi scattering, disrupting intra-Golgi trafficking and depleting RAB3D GTPase from the trans-Golgi. Employing various techniques, we analyzed diverse cellular and animal models representing chronic and chronic/binge alcohol consumption. In trans-Golgi of non-treated hepatocytes, we found a triple complex formed between RAB3D, GOLGA4, and MYH10/NMIIB (myosin, heavy polypeptide 10, non-muscle). However, EtOH-induced RAB3D downregulation led to MYH10 segregation from the Golgi, accompanied by Golgi fragmentation and tethering of the MYH10 isoform, MYH9/NMIIA, to dispersed Golgi membranes. EtOH-activated autophagic flux is evident through increased WIPI2 recruitment to the Golgi, phagophore formation, enhanced LC3B lipidation, and reduced SQSTM1/p62. Although GOLGA4 dimerization and intra-Golgi localization are unaffected, loss of RAB3D leads to an extension of the cytoplasmic N-terminal domain of GOLGA4, forming GOLGA4-positive phagophores. Autophagy inhibition by hydroxychloroquine (HCQ) prevents alcohol-mediated Golgi disorganization, restores distribution of ASGR (asialoglycoprotein receptor), and mitigates COL (collagen) deposition and steatosis. In contrast to short-term exposure to HCQ, extended co-treatment with both EtOH and HCQ results in the depletion of LC3B protein via proteasomal degradation. Thus, (a) RAB3D deficiency and GOLGA4 conformational changes are pivotal in MYH9-driven, EtOH-mediated Golgiphagy, and (b) HCQ treatment holds promise as a therapeutic approach for alcohol-induced liver injury.
... A lcohol abuse is a global public health concern because it is responsible for the high prevalence of alcoholic cardiac and hepatic diseases [1,2]. It is reported that heavy alcohol consumption caused disorders in organs through impairing mitochondrial functions [3]. ...
Our previous study examined the phytochemical composition and bio-activities of raw daylily flower (Hemerocallis fulva L.). However, this plant food is usually served via heat process such as cooking in a soup. This study aimed to investigate the phytochemical profile and biofunctions of steamed daylily flower (SDF). The content of total phenolic acids, total flavonoids, total carotenoids, total anthocyanins and total triterpenoids in SDF aqueous extract was assessed. Normal cardiac and hepatic cells, H9c2 and L-02 cells, were used to evaluate the protective effects of SDF against ethanol. SDF concentrations of 0.25%, 0.5%, and 1% were applied to treat H9c2 or L-02 cells for 48 h at 37 °C initially, followed by exposure to ethanol at 150 mM for 24 h at 37 °C. Results showed that the content of assessed phytochemicals was in the range of 1019–2045 mg/100 g dry weight. Flavonoids and triterpenoids were two major detected phytochemicals in SDF. SDF treatments at 0.5% and 1% increased the viability of H9c2 cells, but at three concentrations enhanced the survival of L-02 cells. SDF at 0.5% and 1% up-regulated Bcl-2 messenger RNA (mRNA) expression and down-regulated Bax mRNA expression. Ethanol increased reactive oxygen species production, decreased glutathione content, as well as lowered glutathione peroxidase and catalase activities. SDF treatments reversed these changes. SDF at 0.5% and 1% reduced the activity of cytochrome P450 2E1 and nicotinamide adenine dinucleotide phosphate oxidase, limited p47phox mRNA expression, as well as enhanced factor E2-related factor 2 and heme oxygenase-1 mRNA expression. SDF at three concentrations decreased gp91phox mRNA expression. In conclusion, these novel findings indicated that SDF aqueous extract was rich in phytochemicals and provided anti-apoptotic and anti-oxidative actions to protect cardiac and hepatic cells against ethanol. Thus, SDF might be considered as a functional food with multiple bio-activities.
... The molecular and biochemical mechanisms of alcoholic liver injury pathogenesis and the exact triggers of disease progression are not completely understood. Many mechanisms have been postulated to be involved in the pathology of alcoholic liver injury, such as mitochondrial damage, oxidative stress, endoplasmic reticulum stress, inflammatory pathway activation and dysfunctional lipid metabolism [4,17,18]. A better understanding of these mechanisms and the role of different cell types in this process is essential for the prevention and treatment of alcoholic liver injury. ...
... mechanisms have been postulated to be involved in the pathology of alcoholic live such as mitochondrial damage, oxidative stress, endoplasmic reticulum stress, in tory pathway activation and dysfunctional lipid metabolism [4,17,18]. A bette standing of these mechanisms and the role of different cell types in this process is for the prevention and treatment of alcoholic liver injury. ...
Alcoholic liver disease (ALD) is currently considered a global healthcare problem with limited pharmacological treatment options. There are abundant cell types in the liver, such as hepatocytes, endothelial cells, Kupffer cells and so on, but little is known about which kind of liver cells play the most important role in the process of ALD. To obtain a cellular resolution of alcoholic liver injury pathogenesis, 51,619 liver single-cell transcriptomes (scRNA-seq) with different alcohol consumption durations were investigated, 12 liver cell types were identified, and the cellular and molecular mechanisms of the alcoholic liver injury were revealed. We found that more aberrantly differential expressed genes (DEGs) were present in hepatocytes, endothelial cells, and Kupffer cells than in other cell types in alcoholic treatment mice. Alcohol promoted the pathological processes of liver injury; the specific mechanisms involved: lipid metabolism, oxidative stress, hypoxia, complementation and anticoagulation, and hepatocyte energy metabolism on hepatocytes; NO production, immune regulation, epithelial and cell migration on endothelial cells; antigen presentation and energy metabolism on Kupffer cells, based on the GO analysis. In addition, our results showed that some transcription factors (TFs) are activated in alcohol-treated mice. In conclusion, our study improves the understanding of liver cell heterogeneity in alcohol-fed mice at the single-cell level. It has potential value for understanding key molecular mechanisms and improving current prevention and treatment strategies for short-term alcoholic liver injury.
... Oxidative stress is essential for the assembly and activation of NLRP3 inflammasome [38]. In reaction to toxic compounds, KCs in the liver release a large amount of ROS [39], and damaged hepatocytes may also release ROS and DAMPs [40]. DAMPs cause the activation of the tumor necrosis factor receptor (TNFR), Toll-like receptors (TLR), and IL receptor 1, which in turn causes the signaling of the NLRP3 inflammasome [41][42][43]. ...
The nicotinamide adenine dinucleotide phosphate hydrogen oxidase (NADPH oxidase or NOX) plays a critical role in the inflammatory response and fibrosis in several organs such as the lungs, pancreas, kidney, liver, and heart. In the liver, NOXs contribute, through the generation of reactive oxygen species (ROS), to hepatic fibrosis by acting through multiple pathways, including hepatic stellate cell activation, proliferation, survival, and migration of hepatic stellate cells; hepatocyte apoptosis, enhancement of fibrogenic mediators, and mediation of an inflammatory cascade in both Kupffer cells and hepatic stellate cells. ROS are overwhelmingly produced during malignant transformation and hepatic carcinogenesis (HCC), creating an oxidative microenvironment that can cause different and various types of cellular stress, including DNA damage, ER stress, cell death of damaged hepatocytes, and oxidative stress. NOX1, NOX2, and NOX4, members of the NADPH oxidase family, have been linked to the production of ROS in the liver. This review will analyze some diseases related to an increase in oxidative stress and its relationship with the NOX family, as well as discuss some therapies proposed to slow down or control the disease’s progression.
... There is a significant rise in the incidence of patients diagnosed with fatty liver, otherwise known as hepatic steatosis, defined as a fat content greater than than 5% of liver weight [1]. Steatosis is characteristic of both alcoholic liver disease (ALD), associated with a high risk of developing alcohol-related hepatitis [2], and non-alcoholic fatty liver disease (NAFLD) [3], associated with the risk of long-term extrahepatic cardiometabolic diseases including heart attack, stroke, type 2 diabetes (T2D) and insulin resistance [4,5]. The pathophysiological characteristics underlying NAFLD are clinical features of metabolic syndrome and are associated with insulin resistance, which exacerbates NAFLD by increasing hepatic lipogenesis and inhibiting adipose tissue lipolysis [6][7][8]. ...
Background
The fatty liver index (FLI) is frequently used as a non-invasive clinical marker for research,
prognostic and diagnostic purposes. It is also used to stratify individuals with hepatic steatosis such as non-alcoholic fatty liver disease (NAFLD), and to detect the presence of type 2 diabetes or cardiovascular disease. The FLI is calculated using a combination of anthropometric and blood biochemical variables; however, it reportedly excludes 8.5-16.7% of individuals with NAFLD. Moreover, the FLI cannot quantitatively predict liver fat, which might otherwise render an improved diagnosis and assessment of fatty liver, particularly in longitudinal studies. We propose FLI+ using predictive regression modelling, an improved index reflecting liver fat content that integrates 12 routinely-measured variables, including the original FLI.
Methods and findings
We evaluated FLI+ on a dataset from the UK Biobank containing 28,796 individual estimates of proton density fat fraction derived from magnetic resonance imaging across normal to severe levels and interpolated to align with the original FLI range. The results obtained for FLI+ outperform the original FLI by delivering a lower mean absolute error by approximately 47%, a lower standard deviation by approximately 20%, and an increased adjusted R2 statistic by approximately 49%, reflecting a more accurate representation of liver fat content.
Conclusions
Our proposed model predicting FLI+ has the potential to improve diagnosis and provide a
more accurate stratification than FLI between absent, mild, moderate and severe levels of
hepatic steatosis.
... Acute alcohol binge drinking is a major health issue (1,17). Alcohol has been shown to cause oxidative damage, increase ROS production as well as alter mitochondrial function and induce apoptosis (17). ...
... Acute alcohol binge drinking is a major health issue (1,17). Alcohol has been shown to cause oxidative damage, increase ROS production as well as alter mitochondrial function and induce apoptosis (17). To date, limited studies have assessed the effects of both acute ethanol and acetaldehyde on oxidative damage and apoptosis in the liver over a 24-h period. ...
Binge drinking is a major public health issue and ethanol-related liver insult may play a major role in the pathology of alcoholic liver disease. However, the degree of oxidative stress, cell death and contribution of acetaldehyde to liver damage over a 24-h period has yet to be determined. Herein, we aimed to investigate the effect of acute alcohol and elevated acetaldehyde levels on hepatic oxidative damage, apoptosis, and antioxidant enzyme activity over a 24-h period. Male Wistar rats were divided into four groups and animals were pre-injected (intraperitonially [i.p.]) with either saline (0.15 mol/L) or cyanamide (5-mmol/kg body weight), followed by either saline (0.15 mol/L) or ethanol (75-mmol/kg bodyweight). After 2.5, 6 and 24 h, hepatic cytosolic and mitochondrial fractions were analysed for indices of oxidative stress. At 2.5 h, cytosolic glutathione and malondialdehyde levels were significantly reduced and increased, respectively, with alcohol treatment. Caspase-3 activity and cytochrome c levels were increased with alcohol treatment at 24 h. The combination of cyanamide and alcohol treatment at 24 h led to a significant increase in serum alanine aminotransferase levels, and reduced albumin and total protein levels. Furthermore, glutathione peroxidase activity and glutathione reductase activity were significantly decreased and increased, respectively. Finally, superoxide dismutase activity was decreased in cytosol and increased in the mitochondria after cyanamide and ethanol treatment, respectively. This study indicates a complex differential effect of alcohol and acetaldehyde, whereby alcohol toxicity in the mitochondria takes place throughout the 24-h period, but raised acetaldehyde has a further detrimental effect on liver function.
... Накопление ацетальдегида инициирует снижение скорости β-окисления жирных кислот в митохондриях с их последующим отложением в печени (стеатоз). Помимо этого, ацетальдегид обладает способностью связываться с другими белками в интрацитозольном пространстве гепатоцита, образуя комплексы или гибридные молекулы (аддукты), -это приводит к повреждению и гибели клеток печени [23,26]. В свою очередь, повышение активности CYP2E1 у лиц, злоупотребляющих алкоголем, сопряжено с увеличением генерации реактивных форм Рисунок 2. Звенья патогенеза различных форм стеатогепатита Figure 2. Links in the pathogenesis of different forms of steatohepatitis [23,26]. ...
... Помимо этого, ацетальдегид обладает способностью связываться с другими белками в интрацитозольном пространстве гепатоцита, образуя комплексы или гибридные молекулы (аддукты), -это приводит к повреждению и гибели клеток печени [23,26]. В свою очередь, повышение активности CYP2E1 у лиц, злоупотребляющих алкоголем, сопряжено с увеличением генерации реактивных форм Рисунок 2. Звенья патогенеза различных форм стеатогепатита Figure 2. Links in the pathogenesis of different forms of steatohepatitis [23,26]. Свободные радикалы инициируют перекисное окисление липидов, повреждая гепатоциты и опосредованно индуцируя локальный иммунный ответ [26]. ...
... В свою очередь, повышение активности CYP2E1 у лиц, злоупотребляющих алкоголем, сопряжено с увеличением генерации реактивных форм Рисунок 2. Звенья патогенеза различных форм стеатогепатита Figure 2. Links in the pathogenesis of different forms of steatohepatitis [23,26]. Свободные радикалы инициируют перекисное окисление липидов, повреждая гепатоциты и опосредованно индуцируя локальный иммунный ответ [26]. Все вышеперечисленные патогенетические механизмы способствуют формированию алкогольного стеатогепатита [22]. ...
Steatohepatitises is an etiologically heterogeneous group of pathological changes in the liver, which are characterized by the inflammatory infiltration of the hepatic parenchyma with underlying fatty degeneration of hepatocytes. Whatever is the etiological cause, the clinical significance of steatohepatitis involves the formation of liver fibrosis and, as a result, an increased risk of developing liver cirrhosis and hepatocellular carcinoma, which are life-threatening conditions. It is common practice to identify the following etiological variants of steatohepatitis: metabolic (55–65% of cases), alcoholic (45–55% of cases) and drug-induced (approximately 5% of cases). The pathogenetic basis of metabolic steatohepatitis lies in the mechanisms of increased lipolysis, excess free fatty acid pool and reduced β-oxidation stemming from obesity and insulin resistance. Pathogenetic factors mediating the development of alcoholic steatohepatitis are the toxic activity of acetaldehyde and increased CYP2E1 activity. Intake of some hepatotoxic drugs increases lipogenesis in hepatocytes and disrupts the electron transport chain, which leads to the formation of liver steatosis followed by transformation into steatohepatitis. Whatever is the etiological varient, steatohepatitis is asymptomatic in the prevailing majority of cases. However, some patients may present complaints of weakness, discomfort, or indolent pain in the right hypochondrium. A detailed history taking is essential for the establishment of the etiological cause of liver damage. Laboratory tests allow to diagnose steatohepatitis in increased levels of hepatic transaminases, usually not exceeding 2–3 times the normal values. In addition to liver enzymes, increased levels of alkaline phosphatase and GGTP can also be observed in steatohepatitis. Ultrasound imaging is the most accessible instrumental tool in clinical practice to establish the primary diagnosis of hepatic steatosis. Indirect elastometry is an equally informative non-invasive method for diagnosing steatohepatitis, which allows to measure both the degree of steatosis (the function of determining the ultrasonic controlled attenuation parameter (CAP) and liver fibrosis.
... A similar consideration can be made for alcohol, which is a common susceptibility factor for PCT development [77]. Alcohol is a hepatotoxin that generates toxic metabolites able to induce liver damage via different mechanisms such as oxidative stress, endotoxin production, impaired immunity, hypoxia, and endoplasmic-reticulum malfunction [78]. Interestingly, alcohol has been associated with hepcidin down-regulation via oxidative stress both in hepatoma cell lines and rodents [79], indicating another way for alcohol to trigger or enhance the clinical expression of PCT. ...
Iron is a trace element that is important for many vital processes, including oxygen transport, oxidative metabolism, cellular proliferation, and catalytic reactions. Iron supports these functions mainly as part of the heme molecule. Heme synthesis is an eight-step process which, when defective at the level of one of the eight enzymes involved, can cause the development of a group of diseases, either inherited or acquired, called porphyrias. Despite the strict link between iron and heme, the role of iron in the different types of porphyrias, particularly as a risk factor for disease development/progression or as a potential therapeutic target or molecule, is still being debated, since contrasting results have emerged from clinical observations, in vitro studies and animal models. In this review we aim to deepen such aspects by drawing attention to the current evidence on the role of iron in porphyrias and its potential implication. Testing for iron status and its metabolic pathways through blood tests, imaging techniques or genetic studies on patients affected by porphyrias can provide additional diagnostic and prognostic value to the clinical care, leading to a more tailored and effective management.
