Boldine protects against carbon tetrachloride-induced chronic liver injury by regulating NF-κB signaling pathway.

Sustained liver injuries predominantly promote oxidative stress and inflammation that lead to the progression of chronic liver disease (CLD), including fibrosis, cirrhosis, and hepatocellular carcinoma. Boldine, an alkaloid isolated from Peumus boldus, has been shown to have antioxidant and anti-inflammatory effects. Currently, there is no definitive treatment option available for CLD. Therefore, we investigated the hepatoprotective effect of boldine against carbon tetrachloride (CCl4 )-induced chronic liver injury in rats. CCl4 (2 mL/kg., b.w., i.p.) was administered twice weekly for 5 weeks to induce chronic liver injury in rats. Separate groups of rats were given boldine (20 mg/kg b.w., and 40 mg/kg b.w.) and silymarin (100 mg/kg b.w.) orally, daily. Serum transaminases, lipid peroxidation, and antioxidant levels were measured, and nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (cox-2), interleukin-1 ß (IL-1ß), and α-smooth muscle actin (α-SMA) gene and protein expressions were evaluated. CCl4 administration increased liver marker enzymes of hepatotoxicity in serum and oxidative stress markers, inflammatory genes and α-smooth muscle actin expression in liver tissue. Boldine concurrent treatment suppressed CCl4 -induced elevation of transaminase levels in serum, restored enzymic and non-enzymic antioxidants, and downregulated NF-κB, TNF-α, Cox-2 and IL-1ß expressions, thereby suppressing hepatic inflammation. Boldine administration also repressed α-SMA expression. The results of this study demonstrate the antioxidant, anti-inflammatory, and antifibrotic properties of boldine, and it can be a potential therapeutic candidate in the treatment of CLD.

Thymoquinone protects thioacetamide-induced chronic liver injury by inhibiting TGF-ß1/Smad3 axis in rats.

Chronic liver injury due to various etiological factors results in excess secretion and accumulation of extracellular matrix proteins, leading to scarring of liver tissue and ultimately to hepatic fibrosis. If left untreated, fibrosis might progress to cirrhosis and even hepatocellular carcinoma. Thymoquinone (TQ), an active compound of Nigella sativa, has been reported to exhibit antioxidant, anti-inflammatory and anticancer activities. Therefore, the effect of TQ against thioacetamide (TAA)-induced liver fibrosis was assessed in rats. Fibrosis was induced with intraperitoneal administration of TAA (250 mg/kg b.w.) twice a week for 5 weeks. TQ (20 mg/kg b.w.) and silymarin (50 mg/kg b.w.) were orally administered daily for 5 weeks separately in TAA administered groups. Liver dysfunction was reported by elevated liver enzymes, increased oxidative stress, inflammation and fibrosis upon TAA administration. Our study demonstrated that TQ inhibited the elevation of liver marker enzymes in serum. TQ administration significantly increased antioxidant markers, such as superoxide dismutase, catalase, glutathione, glutathione peroxidase and glutathione reductase in the liver tissue of rats. Further, TQ significantly attenuated liver fibrosis, as illustrated by the downregulation of TAA-induced interleukin-ß, tumour necrosis factor-α, inducible nitric oxide synthase and fibrosis markers like transforming growth factor-ß (TGF-ß), α-smooth muscle actin, collagen-1, Smad3 and 7. Therefore, these findings suggest that TQ has a promising hepatoprotective property, as indicated by its potential to effectively suppress TAA-induced liver fibrosis in rats by inhibiting oxidative stress and inflammation via TGF-ß/Smad signaling.

Molecular insights on intracellular Wnt/ß-catenin signaling in alcoholic liver disease.

Alcoholic liver disease (ALD) is one of the most common health problems worldwide, especially in developing countries caused by chronic consumption of alcohol on a daily basis. The ALD spectrum is initiated with the early stages of alcoholic fatty liver (steatosis), progressing to alcoholic steatohepatitis, followed by the later stages of fibrosis and in some cases, cirrhosis and hepatocellular carcinoma (HCC). The Wnt/ß-catenin signaling required for healthy liver development, function, and regeneration is found to be aberrated in ALD, attributed to its progression. This review is to elucidate the association of Wnt/ß-catenin signaling with various stages of ALD progression. Alcohol causes downregulation of Wnt/ß-catenin signaling components and thereby suppressing the pathway. Reports have been published that aberrated Wnt/ß-catenin signaling, especially the absence of ß-catenin, results in decreased alcohol metabolism, causing steatosis followed by steatohepatitis via lipid accumulation, lipid peroxidation, liver injury, increased oxidative stress and apoptosis of hepatocytes, contributing to the advancement of ALD. Contrastingly, the progression of later stages of ALD like fibrosis and HCC depends on the increased activation of Wnt/ß-catenin signaling and its components. Existing studies reveal the varied expression of Wnt/ß-catenin signaling in ALD. However, the dual role of the Wnt/ß-catenin pathway in earlier and later stages of ALD is not clear. Therefore, studies on the Wnt/ß-catenin pathway and its components in various manifestations of ALD might provide insight in targeting the Wnt/ß-catenin pathway in ALD treatment.

Coleus vettiveroides ethanolic root extract induces cytotoxicity by intrinsic apoptosis in HepG2 cells.

Hepatocellular carcinoma (HCC) contributes to more than 80% of all primary cancers globally and ranks fourth in cancer-related deaths, due to the lack of an effective, definite therapeutic drug. Coleus vettiveroides (CV) has been used in Indian traditional medicine to treat diabetes, liver ailments, skin diseases, leukoderma, and leprosy. This study investigates the anticancer effect of CV ethanolic root extract in HepG2 cells. HepG2 cells were treated with CV extract, and its cytotoxicity was analyzed by MTT assay. AO/EB staining, propidium iodide staining, DCFH-DA assay, phalloidine staining, flow cytometry, and qPCR studies were performed for ROS expression, apoptosis and cell cycle analysis. The phytochemical analysis confirmed the presence of quercetin and galangin in CV root extract. The results showed that CV inhibited the proliferation of HepG2 cells, with altered cellular and nuclear morphology. CV was also found to increase intracellular ROS levels and oxidative stress markers in HepG2 cells. CV significantly altered the actin microfilament distribution in HepG2 cells and caused cell cycle arrest at the sub G0 -G1 phase. CV also induced mitochondria-mediated apoptosis, as evidenced by increased expression of p53, Bax, cytochrome C, Apaf-1, PARP, caspase-3 and caspase-9, and downregulated Bcl-2 expression. Therefore, CV exerts its anticancer effect by inducing mitochondrial dysfunction, oxidative stress, cytoskeletal disorganization, cell cycle arrest, and mitochondria-mediated apoptosis, and it could be a potent therapeutic option for HCC.

Unraveling the pathophysiologic role of galectin-3 in chronically injured liver.

Galectin-3 (Gal-3) previously referred to as S-type lectins, is a soluble protein that specifically binds to ß-galactoside carbohydrates with high specificity. Gal-3 plays a pivotal role in a variety of pathophysiological processes such as cell proliferation, inflammation, differentiation, angiogenesis, transformation and apoptosis, pre-mRNA splicing, metabolic syndromes, fibrosis, and host defense. The role of Gal-3 has also been implicated in liver diseases. Gal-3 is activated upon a hepatotoxic insult to the liver and its level has been shown to be upregulated in fatty liver diseases, inflammation, nonalcoholic steatohepatitis, fibrosis, cholangitis, cirrhosis, and hepatocellular carcinoma (HCC). Gal-3 directly interacts with the NOD-like receptor family, pyrin domain containing 3, and activates the inflammasome in macrophages of the liver. In the chronically injured liver, Gal-3 secreted by injured hepatocytes and immune cells, activates hepatic stellate cells (HSCs) in a paracrine fashion to acquire a myofibroblast like collagen-producing phenotype. Activated HSCs in the fibrotic liver secrete Gal-3 which acts via autocrine signaling to exacerbate extracellular matrix synthesis and fibrogenesis. In the stromal microenvironment, Gal-3 activates cancer cell proliferation, migration, invasiveness, and metastasis. Clinically, increased serum levels and Gal-3 expression were observed in the liver tissue of nonalcoholic steatohepatitis, fibrotic/cirrhotic, and HCC patients. The pathological role of Gal-3 has been experimentally and clinically reported in the progression of chronic liver disease. Therefore, this review discusses the pathological role of Gal-3 in the progression of chronic liver diseases.

Intercellular communication among liver cells in the perisinusoidal space of the injured liver: Pathophysiology and therapeutic directions.

Hepatic stellate cells (HSCs) in the perisinusoidal space are surrounded by hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and other resident immune cells. In the normal liver, HSCs communicate with these cells to maintain normal liver functions. However, after chronic liver injury, injured hepatocytes release several proinflammatory mediators, reactive oxygen species, and damage-associated molecular patterns into the perisinusoidal space. Consequently, such alteration activates quiescent HSCs to acquire a myofibroblast-like phenotype and express high amounts of transforming growth factor-ß1, angiopoietins, vascular endothelial growth factors, interleukins 6 and 8, fibril forming collagens, laminin, and E-cadherin. These phenotypic and functional transdifferentiation lead to hepatic fibrosis with a typical abnormal extracellular matrix synthesis and disorganization of the perisinusoidal space of the injured liver. Those changes provide a favorable environment that regulates tumor cell proliferation, migration, adhesion, and survival in the perisinusoidal space. Such tumor cells by releasing transforming growth factor-ß1 and other cytokines, will, in turn, activate and deeply interact with HSCs via a bidirectional loop. Furthermore, hepatocellular carcinoma-derived mediators convert HSCs and macrophages into protumorigenic cell populations. Thus, the perisinusoidal space serves as a critical hub for activating HSCs and their interactions with other cell types, which cause a variety of liver diseases such as hepatic inflammation, fibrosis, cirrhosis, and their complications, such as portal hypertension and hepatocellular carcinoma. Therefore, targeting the crosstalk between activated HSCs and tumor cells/immune cells in the tumor microenvironment may also support a promising therapeutic strategy.

Antitubercular drugs induced liver injury: an updated insight into molecular mechanisms.

Tuberculosis (TB) remains a major global health burden. Antitubercular drugs (ATDs) such as isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol are used as first-line therapy in TB patients. Drug-induced liver injury is one of the common side effects that leads to the discontinuation of ATDs in TB patients. Therefore, this review discusses the molecular pathogenesis of ATDs induced liver injury. The biotransformation of INH, RIF, and PZA in the liver liberates several reactive intermediates, leading to peroxidation of the hepatocellular membrane and oxidative stress. INH + RIF administration decreased the expression of bile acid transporters such as the bile salt export pump and multidrug resistance-associated protein 2 and induced liver injury by sirtuin 1 and farnesoid X receptor pathway. INH inhibits the nuclear translocation of Nrf2 by interfering with its nuclear importer, karyopherin ß1, thereby inducing apoptosis. INF + RIF treatments alter Bcl-2 and Bax homeostasis, mitochondrial membrane potential, and cytochrome c release, thereby triggering apoptosis. RIF administration enhances the expression of genes involved in fatty acid synthesis and hepatocyte fatty acid uptake (CD36). RIF induces the expression of peroxisome proliferator-activated receptor -γ and its downstream proteins and perilipin-2 by activating the pregnane X receptor in the liver to increase fatty infiltration into the liver. ATDs administration induces oxidative stress, inflammation, apoptosis, cholestasis, and lipid accumulation in the liver. However, ATDs toxic potentials are not elaborately studied at the molecular level in clinical samples. Therefore, future studies are warranted to explore ATDs induced liver injuries at the molecular level in clinical samples whenever possible.

Concurrent administration of farnesol protects acetaminophen-induced acute hepatic necrosis in mice.

Acetaminophen (APAP) is known to cause acute liver injury and acute liver failure in Western countries. This study investigates the protective role of farnesol (FAR) (C15 H26 O), a natural sesquiterpene alcohol in essential oils, against APAP-induced acute liver necrosis in mice. Mice were injected with a single dose of APAP (300 mg/kg) via an intraperitoneal route. Different groups of mice were concurrently treated with a single dose of FAR 25 mg/kg, FAR 50 mg/kg, and N-acetylcysteine. APAP administration caused a significant increase in transaminase activities and malondialdehyde (MDA) levels in the serum and liver tissue, respectively, with a concomitant decrease in intracellular antioxidants, including reduced glutathione (GSH) in the liver tissue. APAP intoxication upregulated proinflammatory cytokines such as tumor necrosis factor-α, interleukin-1ß (IL-1ß), IL-6, nuclear factor-κB (NF-κB), and IκB kinase ß in the liver tissue. FAR and N-acetylcysteine (NAC) administrations concurrently with APAP prevented serum transaminase increase in serum and MDA levels in the liver tissue. A high dose of FAR and NAC treatments significantly inhibited GSH and other antioxidant depletion. FAR and NAC treatments also downregulated the expression of proinflammatory markers. FAR treatments protects against APAP-induced acute liver injury and offers antioxidant and anti-inflammatory effects by inhibiting the NF-κB pathway involved in the transcription of genes responsible for inflammatory cytokine synthesis.

Coleus vettiveroides ethanolic root extract protects against thioacetamide-induced acute liver injury in rats.

Acute liver injury is caused by various factors, including oxidative stress and inflammation. Coleus vettiveroides, an ayurvedic medicinal plant, is known to possess antioxidant, antibacterial, and antidiabetic properties. In this current study, we investigated the protective effect of C. vettiveroides ethanolic root extract (CVERE) against thioacetamide (TAA)-induced acute liver injury in rats. A single dose of TAA (300 mg/kg, b.w., i.p.) was administered to induce acute liver injury. The treatment groups of rats were concurrently treated with CVERE (125 and 250 mg/kg, b.w., p.o.) and silymarin (100 mg/kg, b.w., p.o.), respectively. After 24 h of the experimental period, TAA-induced liver injury was confirmed by increased activity of serum transaminases and malondialdehyde levels in liver tissue, decreased levels of antioxidants, upregulated expression of the inflammatory marker gene, and altered liver morphology. Whereas CVERE simultaneous treatment inhibited hepatic injury and prevented the elevation of serum aspartate and alanine transaminases, alkaline phosphatase, and lactate dehydrogenase activities. CVERE attenuated TAA-induced oxidative stress by suppressing lipid peroxidation and restoring antioxidants such as superoxide dismutase, catalase, and reduced glutathione. Further, CVERE treatment was found to inhibit nuclear factor κB-mediated inflammatory signaling, as indicated by downregulated pro-inflammatory cytokines including tumor necrosis factor-α and interleukin-1ß. Our findings suggest that CVERE prevents TAA-induced acute liver injury by targeting oxidative stress and inflammation.

Wnt/beta-catenin signaling and its modulators in nonalcoholic fatty liver diseases.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern associated with significant morbidity and mortality. NAFLD is a spectrum of diseases originating from simple steatosis, progressing through nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis that may lead to hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflammatory cytokines expression leading to inflammation, oxidative stress, and mitochondrial dysfunction denoted as "two-hit hypothesis", advancing with a "third hit" of insufficient hepatocyte proliferation, leading to the increase in hepatic progenitor cells contributing to fibrosis and HCC. Wnt/ß-catenin signaling is responsible for normal liver development, regeneration, hepatic metabolic zonation, ammonia and drug detoxification, hepatobiliary development, etc., maintaining the overall liver homeostasis. The key regulators of canonical Wnt signaling such as LRP6, Wnt1, Wnt3a, ß-catenin, GSK-3ß, and APC are abnormally regulated in NAFLD. Many experimental studies have shown the aberrated Wnt/ß-catenin signaling during the NAFLD progression and NASH to hepatic fibrosis and HCC. Therefore, in this review, we have emphasized the role of Wnt/ß-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.

Hepatic stellate cells in the injured liver: Perspectives beyond hepatic fibrosis.

Over the last two decades, our understanding of the pathological role of hepatic stellate cells (HSCs) in fibrotic liver disease has increased dramatically. As HSCs are identified as the principal collagen-producing cells in the injured liver, several experimental and clinical studies have targeted HSCs to treat liver fibrosis. However, HSCs also play a critical role in developing nonfibrotic liver diseases such as cholestasis, portal hypertension, and hepatocellular carcinoma (HCC). Therefore, this review exclusively focuses on the role of activated HSCs beyond hepatic fibrosis. In cholestasis conditions, elevated bile salts and bile acids activate HSCs to secrete collagen and other extracellular matrix products, which cause biliary fibrosis and cholangitis. In the chronically injured liver, autocrine and paracrine signaling from liver sinusoidal endothelial cells activates HSCs to induce portal hypertension via endothelin-1 release. In the tumor microenvironment (TME), activated HSCs are the major source of cancer-associated fibroblasts (CAF). The crosstalk between activated HSC/CAF and tumor cells is associated with tumor cell proliferation, migration, metastasis, and chemoresistance. In TME, activated HSCs convert macrophages to tumor-associated macrophages and induce the differentiation of dendritic cells (DCs) and monocytes to regulatory DCs and myeloid-derived suppressor cells, respectively. This differentiation, in turn, increases T cells proliferation and induces their apoptosis leading to reduced immune surveillance in TME. Thus, HSCs activation in chronically injured liver is a critical process involved in the progression of cholestasis, portal hypertension, and liver cancer.

Porphyromonas gingivalis and dental stem cells crosstalk amplify inflammation and bone loss in the periodontitis niche.

Periodontitis is the sixth most prevalent disease, and almost 3.5 billion people are affected globally by dental caries and periodontal diseases. The microbial shift from a symbiotic microbiota to a dysbiotic microbiota in the oral cavity generally initiates periodontal disease. Pathogens in the periodontal microenvironment interact with stem cells to modulate their regenerative potential. Therefore, this review focuses on the interaction between microbes and stem cells in periodontitis conditions. Microbes direct dental stem cells to secrete a variety of pro-inflammatory cytokines and chemokines, which increase the inflammatory burden in the damaged periodontal tissue, which further aggravates periodontitis. Microbial interaction also decreases the osteogenic differentiation potential of dental stem cells by downregulating alkaline phosphatase, runt-related transcription factor 2, type 1 collagen, osteocalcin, osteopontin, and so on. Microbe and stem cell interaction amplifies pro-inflammatory cytokine signaling in the periodontitis niche, decreasing the osteogenic commitment of dental stem cells. A clear understanding of microbial stem cell interactions is crucial in designing regenerative therapies using stem cells in the management of periodontitis.

Quercetin Inhibits the Epithelial to Mesenchymal Transition through Suppressing Akt Mediated Nuclear Translocation of ß-Catenin in Lung Cancer Cell Line.

Lung cancer is a first leading cause of cancer related death worldwide. Quercetin (QUE) has chemo-preventive effect against a variety of cancers. However, the molecular mechanism of QUE mediated inhibition of cancer cell migration and epithelial to mesenchymal transition (EMT) is not clear in lung cancer. Therefore, this study investigates the effect of QUE on EMT and metastasis of lung cancer cell line (A549). The MTT assay, scratch wound healing assay, Transwell migration and invasion assay performed to assess the cell viability and migration potential of lung cancer cells after treatment with different concentration of QUE. Further, chemokines gene expression was analyzed by qPCR and EMT markers were analyzed by immunocytochemistry and Western blot. QUE inhibits cell viability in a dose-dependent (10-80 µM) manner both at 24 and 48 h treatment. The Akt/MAPK/ß-catenin and EMT marker protein expressions were decreased significantly, whereas TIMP-2 expression was increased upon QUE treatment. QUE inhibits cell migration and invasion of A-549 cells. In addition, Immunocytochemistry result showed that QUE can reduce nuclear translocalisation of ß-catenin in A549 cells. Our results suggest that QUE can inhibit the metastatic potential in lung cancer by altering the Akt/MAPK/ß-catenin signaling pathway and inhibiting the nuclear translocation of ß-catenin.

The ambiguous role of sirtuins in head and neck squamous cell carcinoma.

Oral cancer is one of the most leading cancer responsible for significant morbidity and mortality. The sirtuins (SIRTs) are a family of class III histone deacetylases and are known to regulate a variety of molecular signaling associated with different cancer types including oral malignancies. SIRT1 acts as bifunctional in a variety of cancer. In oral cancer, SIRT1 seems to work as a tumor suppressor. The carcinogenic potential of SIRT1 is also reported in oral cancer, and hence, its role is still ambiguous. SIRT2 is also said to play a dual-faced role in different types of cancers. However, in oral cancer, SIRT2 is not studied and its role remains obscure. SIRT3 expression was positively correlated with oral malignancies. However, studies also showed the anti-cancer role of SIRT3 in oral cancer. SIRT7 loss was observed in oral cancer cells, while its overexpression caused the suppression of oral cancer cells proliferation, migration, and invasiveness. The role of other SIRTs in oral cancer was studied meagerly or reports not available. To date, only the roles of SIRT1, SIRT3, and SIRT7 have been reported in oral malignancies. Therefore, understanding the regulatory mechanisms employed by sirtuins to modulate oral cancer is important for developing potential anti-cancer therapeutic strategies.

Lagerstroemia speciosa (L.) Pers., ethanolic leaves extract attenuates dapsone-induced liver inflammation in rats.

Drug-induced liver injury is a common cause of acute liver failure. Dapsone is increasingly used in combination with rifampicin for the treatment of leprosy and also for several dermatological disorders. Clinically, abnormal liver function and focal bile duct destruction were reported after dapsone therapy. Lagerstroemia speciosa Pers., commonly known as Banaba has been traditionally used to treat various ailments including diabetes and obesity due to its antioxidant and anti-inflammatory efficacies. This study investigated the hepatoprotective effect of ethanolic banaba leaves extract (EBLE) against dapsone-induced hepatotoxicity in rats. Dapsone (30 mg/kg, i.p.) was administered twice daily for 30 days. In separate groups, rats were post-treated orally with EBLE (250 and 500 mg/kg) and silymarin (100 mg/kg) once daily for 30 days after dapsone administration. The marker enzymes of hepatotoxicity, oxidative stress markers, inflammatory markers and histopathology of liver were done. HPTLC analysis confirmed the presence of 12.87 µg of corosolic acid per mg of EBLE. Dapsone administration-induced significant (p < 0.001) elevation of marker enzymes of hepatotoxicity in serum. This treatment also increased lipid peroxidation (p < 0.001) and pro-inflammatory markers (tumor necrosis factor-alpha, transforming growth factor-beta, and nuclear factor kappa-B) expressions (p < 0.001) and decreased antioxidants (p < 0.001) such superoxide dismutase, catalase and glutathione in the liver tissue. All these abnormalities were significantly (p < 0.001) mitigated after EBLE (500 mg/kg) and silymarin post-treatments. The results of this study suggest that silymarin and EBLE can be used for dapsone-induced hepatotoxicity.

Syringic acid and silymarin concurrent administration inhibits sodium valproate-induced liver injury in rats.

Sodium valproate (SV) is a well-known anti-epileptic drug, also used to control convulsions, bipolar disorders and migraines. SV has been shown to induce liver toxicity in clinical subjects. Syringic acid (SA), a natural polyphenolic compound has potential antioxidant, anti-inflammatory and several beneficial effects. Therefore, in this study, we evaluated hepatoprotective effect of SA against SV-induced liver injury in rats. Wistar rats were treated with SV orally at a dose of 500 mg/kg, once daily, for 14 days. Another three groups of rats were administered with SV and concurrently treated with SA (40 and 80 mg/kg) and silymarin (SIL) (100 mg/kg) for 14 days. SV administration for 14 days caused significant (p < .001) elevation of liver transaminases and ALP in serum. Liver MDA level was significantly (p < .001) increased with a concomitant decrease (p < .001) in enzymic antioxidants activities in SV administered rats. SV administration also caused the upregulation of proinflammatory markers such as tumor necrosis factor α, c-Jun N-terminal kinase, nuclear factor kappa B, cyclooxygenase-2 and Interleukin 6 expressions in liver tissue. Histopathological studies also revealed the presence of inflammatory cell infiltration and hepatocellular necrosis upon SV administration. At both doses, concurrent administration of SA and SIL significantly (p < .001) inhibited the liver transaminase activities in serum, oxidative stress, and proinflammatory markers expression in liver tissue. Our current results suggest that SA can be a promising herbal drug that can inhibit SV-induced hepatotoxicity when administered together due its potential anti-inflammatory effects.

Boldine treatment protects acetaminophen-induced liver inflammation and acute hepatic necrosis in mice.

Drug-induced liver injury (DILI) is a frequent cause responsible for acute liver failure (ALF). Acetaminophen (APAP) is a known hepatotoxin predictably causing intrinsic DILI. At high doses, APAP causes acute liver necrosis and responsible for ALF and liver transplant cases in 50% and 20% of patients, respectively, in the United States alone. Oxidative stress and glutathione depletion are implicated in APAP-induced liver necrosis. Boldine, a plant-derived compound is shown to have promising antioxidant potential. Therefore, this study investigates the protective effect of boldine against APAP-induced acute hepatic necrosis in mice. A single toxic dose of APAP (300 mg/kg b.w. p.o.) was administered in overnight-fasted mice to induce acute liver necrosis. Separately, APAP + boldine and APAP + N-acetylcysteine (NAC) simultaneous treatments were also given. Serum transaminases and reduced glutathione, enzymic antioxidants, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and, IL-6 were evaluated in liver tissue. Acute APAP intoxication significantly elevated serum marker enzymes of hepatotoxicity. APAP administration increased lipid peroxidation, TNF-α, IL-1ß, and IL-6 protein expressions. The enzymic antioxidants and reduced glutathione levels were decreased in liver tissue of APAP intoxicated mice. Boldine and NAC simultaneous treatments prevented APAP-induced oxidative stress, inflammation, and necrosis. The results of this study suggest the crucial role of boldine to protect against APAP induced hepatotoxicity by virtue of its antioxidant and anti-inflammatory properties.

Dapsone-induced hepatic complications: it's time to think beyond methemoglobinemia.

Drug-induced liver injury is an important cause of hepatotoxicity and poses a challenging clinical problem with respect to both diagnosis and management. Patients susceptible to hepatotoxicity on exposure to dapsone is constantly on the rise. Dapsone (4,4'-diaminodiphenylsulfone) is clinically used alone or in combination with rifampicin for the treatment of a variety of dermatological disorders such as acne, dermatitis herpetiformis, psoriasis, Toxoplasma gondii infections, leprosy and pneumocystis carinii pneumonia in AIDS patients. However, the clinical use of dapsone is limited because of dose-dependent adverse hematological reactions. The cholestatic injury caused by dapsone and its N- hydroxylated metabolites hinders bile flow and causes oxidative stress and hepatic necrosis, further, leading to hemolysis responsible for hepatitis due to iron overload in the liver. Hence, clinicians' awareness of the hepatotoxic potential of dapsone is highly warranted.

An ecofriendly synthesized gold nanoparticles induces cytotoxicity via apoptosis in HepG2 cells.

Microbes have long been used for the synthesis of a variety of nanoparticles. Hepatocellular carcinoma (HCC) is the primary liver cancer and it is the second leading cause of cancer-related mortality worldwide. In this study, we have synthesized Enterococcus mediated gold nanoparticles (AuNPs) and investigated their cytotoxic potential against human hepatocellular cancer cell line (HepG2). AuNPs were synthesized using Enterococcus sp. RMAA. HepG2 cells were treated with different concentrations of AuNPs for 24 hours and cytotoxicity was analyzed by MTT ((4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. AuNPs induced reactive oxygen species expression was analyzed by 2',7'-dichlorodihydrofluorescein diacetate staining. Morphological changes related to apoptosis was analyzed by annexin V/propidium iodide staining. Protein expression of proliferating cell nuclear antigen (PCNA) was done by western blotting analysis. Bacterial-mediated AuNPs caused significant cytotoxicity in HepG2 cells. AuNPs treatment also caused the significant expression of ROS and morphological damage related to apoptosis. AuNPs treatments were responsible for the dislocation of cytochrome c from mitochondria to cytosol. The protein expression of PCNA was significantly decreased upon AuNPs treatment. These findings suggest that Enterococcus-mediated AuNPs can inhibit the proliferation of HepG2 cells via intracellular ROS mediated apoptosis, decreased PCNA expressions, and it may have the potential to treat HCC.

Mitochondria: A critical hub for hepatic stellate cells activation during chronic liver diseases.

BACKGROUND: Upon liver injury, quiescent hepatic stellate cells (qHSCs), reside in the perisinusoidal space, phenotypically transdifferentiate into myofibroblast-like cells (MFBs). The qHSCs in the normal liver are less fibrogenic, migratory, and also have less proliferative potential. However, activated HSCs (aHSCs) are more fibrogenic and have a high migratory and proliferative MFBs phenotype. HSCs activation is a highly energetic process that needs abundant intracellular energy in the form of adenosine triphosphate (ATP) for the synthesis of extracellular matrix (ECM) in the injured liver to substantiate the injury. DATA SOURCES: The articles were collected through PubMed and EMBASE using search terms "mitochondria and hepatic stellate cells", "mitochondria and HSCs", "mitochondria and hepatic fibrosis", "mitochondria and liver diseases", and "mitochondria and chronic liver disease", and relevant publications published before September 31, 2020 were included in this review. RESULTS: Mitochondria homeostasis is affected during HSCs activation. Mitochondria in aHSCs are highly energetic and are in a high metabolically active state exhibiting increased activity such as glycolysis and respiration. aHSCs have high glycolytic enzymes expression and glycolytic activity induced by Hedgehog (Hh) signaling from injured hepatocytes. Increased glycolysis and aerobic glycolysis (Warburg effect) end-products in aHSCs consequently activate the ECM-related gene expressions. Increased Hh signaling from injured hepatocytes downregulates peroxisome proliferator-activated receptor-γ expression and decreases lipogenesis in aHSCs. Glutaminolysis and tricarboxylic acid cycle liberate ATPs that fuel HSCs to proliferate and produce ECM during their activation. CONCLUSIONS: Available studies suggest that mitochondria functions can increase in parallel with HSCs activation. Therefore, mitochondrial modulators should be tested in an elaborate manner to control or prevent the HSCs activation during liver injury to subsequently regress hepatic fibrosis.