Hepatic Marker Enzymes Research Articles

Evaluation of the Hypoglycemic and Hypolipidemic Potential of Extract Fraction of Quercus baloot Griff Seeds in Alloxan-induced Diabetic Mice.

The discovery and development of new phytomedicines can be greatly aided by plants because of their tremendous therapeutic benefits, efficiency, cost-effectiveness, lack of side effects, and cheaper therapies. In this regard, Quercus baloot, generally known as oak, is used in folkloric medicine for treating and preventing various human disorders, including diabetes. For this purpose, the present study aimed to evaluate crude methanolic extract and various fractions of Quercus baloot for antihyperlipidemic and antihyperglycemic potential followed by the analysis of active compounds. The hypoglycemic and hypolipidemic activity was evaluated in Swiss male Albino mice by administering an oral dose of 150-300 mg/kg of Q. baloot extracts in alloxan induced diabetic mice for 14 days. The results revealed that crude methanolic extract at a dose of 300 mg/kg exhibited a significant reduction in the blood glucose level (198.50 ± 1.99 mg/dl) at day 14 and the same treatment significantly increased the body weight (31.26 ± 0.27 g) at day 14 in comparison to the control group. Moreover, the biochemical parameters were investigated which presented an increase in high-density lipids (HDL) (30.33 ± 0.33 mg/dl), whereas low-density lipids (LDL) showed a significant decrease (105.66 ± 0.26 mg/dl). Additionally, triglyceride levels 104.83 ± 0.70 mg/dl, and total cholesterol 185.50 ± 0.76 mg/dl are significantly decreased. In serum biochemical analysis creatinine and hepatic enzyme markers, like serum glutamate pyruvate transaminase (32.00 ± 0.36 U/mg), serum glutamate oxaloacetate transaminase (34.33 ± 0.61 U/mg), and alkaline phosphatase (157.00 ± 0.73 U/mg), were significantly reduced by the crude methanolic extract at a dose of 300 mg/kg as compared to the control group. The antioxidant enzymes like Superoxide dismutase (4.57 ± 0.011), peroxidases dismutase (6.53 ± 0.014, and catalase (8.38 ± 0.014) at a dosage of 300 mg/kg of methanolic extract exhibited a significant increase. The histopathological study of the diabetic heart, liver, and pancreas showed substantial restoration of damaged tissues in the methanolic extract 150 and 300 mg/kg treated group, which supports the effectiveness of Q. baloot seeds. The gas chromatography-mass spectrometry analysis of methanolic extract identified 10 antidiabetic active compounds in the Q. baloot seeds, validating the antihyperglycemic activity. Thus, methanolic crude extract at the doses 150 and 300 mg/kg of Q. baloot showed significant antihyperlipidemic and antihyperglycemic activities, which validate the folkloric utilization of Q. baloot as a remedy in diabetes. In conclusion, the 300 mg/kg methanolic extract of Q. baloot has notable hypoglycemic and hypolipidemic potential, supporting the plant's traditional medicinal usage in the treatment of diabetes and its complications. Further studies are needed for the purification, characterization, and structural clarification of bioactive compounds.

Evaluation of Low-Dose Effects and Non-Monotonous Dose Response of Butyl p-hydroxybenzoate, or Butylparaben on Female Wistar Rats

Butylparaben (BP) is an extensively used synthetic preservative that has been testified as an endocrine disruptor and speculated to be toxic for the body all together. The present study evaluated the possible noxious impact of BP at minimum doses, i.e., 1, 5, and 10 mg/kg BW/day, on female Wistar rats following consecutive subcutaneous exposure for 7 and 21 days. The results of the genotoxic study exhibited that BP at a dose of 10 mg/kg BW/day significantly (p ˂ 0.05) induced micronucleated polychromatic erythrocytes (MNPCEs) formation in bone marrow of rats, both in short (7.3 ± 0.87 MNPCEs/1000 PCEs) and long-term exposures (6.6 ± 0.33 MNPCEs/1000 PCEs), which was in line with the results obtained for 17β-estradiol (E2)-treated reference control rats. Levels of hepatic toxicity marker enzymes, i.e., aspartate transaminase (AST) and alanine transaminase (ALT), were not altered substantially in any of the study durations, but the alkaline phosphatase (ALP) level increased significantly (p ˂ 0.05) at all BP doses, including E2. Variations in the serum HDL as well as cholesterol levels were found to be non-monotonous with respect to the applied BP doses. However, contrasting specifics were observed for triglycerides in terms of the study durations. Conclusively, the current study established that BP, even at low doses, could evidently disturb the circulating lipid content, hepatic enzyme levels, and even cause genotoxicity, and also pointed toward its non-monotonous dose response.

Alcohol promotes liver fibrosis in high fat diet induced diabetic rats.

Type 2 diabetes (T2DM) and alcoholism are considered to be lifestyle-associated independent risk factors in fatty liver diseases (FLD) mediated cirrhosis and hepatocellular carcinoma (HCC). A combined effect of both these conditions may exacerbate the pathological changes and a pre-clinical exploration of this is expected to provide a mechanical detail of the pathophysiology. The present study aims to understand the effect of alcohol on pre- diabetic and type 2 diabetic female Wistar rats. In this experimental study, 12 Wistar rats (180-220 g) were randomly assigned into three groups: Normal (fed normal rat chow), alcohol (20 %) fed diabetic (HFD+STZ), and pre-diabetic rats (HFD alone). After, two months of the experimental period, blood and liver tissues were collected lipid metabolic alteration, liver injury, and fibrosis were determined following biochemical and histological methods. Data were analyzed using one-way ANOVA and Dunnett's Post Hoc test. Significant dyslipidemia was observed in the liver tissues of diabetic and pre-diabetic rats following alcohol ingestion. A significant (p<0.05) increase in lipid peroxidation status, and hepatic marker enzyme activities (p<0.0001) were observed in diabetic animals. In corroborating with these observations, hematoxylin and eosin staining of hepatic tissue revealed the presence of sinusoidal dilation along with heavily damaged hepatocytes and inflammatory cell infiltration. Further, significantly (p<0.001) increased hepatic hydroxyproline content and extended picrosirius red stained areas of collagen in liver tissue indicated initiation of fibrosis in alcohol-fed diabetic rats. Overall, the results indicate that alcohol consumption in T2DM conditions is more deleterious than pre diabetic conditions in progressing to hepatic fibrosis.

Fangchinoline protects hepatic ischemia/reperfusion liver injury in rats through anti-oxidative stress and anti-inflammation properties: an in silico study.

Liver ischemia-reperfusion (I/R) injury is a common cause of organ failure, developed by a sudden block in the blood and oxygen supply and subsequent restoration. I/R damage is responsible for acute and chronic rejection after organ transplantation, accounting for 10% of early graft failure. The study investigated the therapeutic properties of fangchinoline in liver injury-induced rats. The rats were divided into three groups: Sham, I/R without pretreatment, and I/R+10mg/kg fangchinoline pretreatment. Blood and liver samples were collected for assays, and an in silico docking analysis was conducted to determine fangchinoline's inhibitory effect. The pretreatment with 10mg/kg of fangchinoline effectively reduced hepatic marker enzymes such as AST, LDH, and ALT in the serum of rats with liver I/R damage. Fangchinoline treatment significantly reduced interleukin-8 (IL-8), IL-6, and tumor necrosis factor-α (TNF-α) in I/R-induced rats, boosting antioxidants and decreasing MDA. Histopathological studies showed liver injury protection, and fangchinoline inhibited TNF-α and IL-6 with improved binding affinity. Fangchinoline has hepatoprotective properties by reducing inflammation in rats with liver I/R damage, as demonstrated in the current study. Hence, it can be an effective salutary agent in preventing liver damage caused by I/R.

H-ras-targeted genetic therapy remarkably surpassed docetaxel treatment in inhibiting chemically induced hepatic tumors in rats

AimsHepatocellular carcinoma (HCC) is still a leading cause of cancer-related death worldwide. But its chemotherapeutic options are far from expectation. We here compared H-ras targeted genetic therapy to a commercial docetaxel formulation (DXT) in inhibiting HCC in rats. Main methodsAfter the physicochemical characterization of phosphorothioate-antisense oligomer (PS-ASO) against H-ras mutated gene, the PS-ASO-mediated in vitro hemolysis, in vivo hepatic uptake, its pharmacokinetic profile, tissue distribution in some highly perfused organs, its effect in normal rats, antineoplastic efficacy in carcinogen-induced HCC in rats were evaluated and compared against DXT treatment. Mutated H-ras expression by in situ hybridization, hep-par-I, CK-7, CD-15, p53 expression patterns by immunohistochemical methods, scanning electron microscopic evaluation of hepatic architecture, various hepatic marker enzyme levels and caspase-3/9 apoptotic enzyme activities were also carried out in the experimental rats. Key findingsPS-ASO showed low in vitro hemolysis (<3 %), and had a sustained PS-ASO blood residence time in vivo compared to DTX, with a time-dependent hepatic uptake. It showed no toxic manifestations in normal rats. PS-ASO distribution was although initially less in the lung than liver and kidney, but at 8 h it accumulated more in lung than kidney. Antineoplastic potential of PS-ASO (treated for 6 weeks) excelled in inhibiting chemically induced tumorigenesis compared to DTX in rats, by inhibiting H-ras gene expression, some immonohistochemical modulations, and inducing caspase-3/9–mediated apoptosis. It prevented HCC-mediated lung metastatic tumor in the experimental rats. SignificancePS-ASO genetic therapy showed potential to inhibit HCC far more effectively than DXT in rats.

Graviola Protects Against Hepatic Toxicity Associated with DMBA induced Breast Cancer via Restoration of Antioxidants and Attenuation of Inflammatory Pathways

Aims: This study documented hepatic tissue's protective activity against oxidative damage mediated experimental models of breast cancer. Background: Gaviola has a long history of improving the protection mechanism against many diseases as an antioxidant and anticancer dietary agent. Objective: The purpose of this study is to establish changes in hepatic profiling, antioxidants, inflammatory cytokine expression, and DMBA-induced hepatic histopathology of mammalian rats. Methods: 7,12-dimethylbenz[a] anthracene (DMBA), PAHs, used orally in female Sprague Dawley rats Fifty-seven days-old with breast cancer single-dose diluted in sesame oil of 20 mg/kg/body weight. The cancer-bearing animals had 45 days gastrogavagated at 200 mg/kg/body weight with Graviola. The serum samples were taken at the end of the experiment. The rats were sacrificed to establish the hepatic protective activity of the Graviola by testing hepatic and oxidative stress markers. Results: Graviola therapy shows that enzymatic and non-enzymatic antioxidants and lipid peroxide levels have increased efficiency and have restored the high activity of hepatic marker enzymes such as ALT, AST, ALP, and GGT. To date, hepatic expression of nuclear factor erythroid 2-like 2 (Nfe2l2) and nuclear factor kappa B subunit 1 (Nfkb1) mediated rats have normalized. In addition, histological observations have demonstrated that Graviola's treatment effectively protects the liver from the oxidative damage caused by DMBA, reinforcing its hepatic defensive nature. Conclusion: Graviola therapy improves the efficiency of both enzymatic and non-enzymatic antioxidants and lipid peroxide levels. It also helps in the restoration of other liver enzymes.

Preventive Effect of 6-shogaol on D-galactosamine Induced Hepatotoxicity Through NF-?B/MAPK Signaling Pathway in Rats.

This analysis aims to see whether 6-shogaol could protect rats against D-galactosamine (D-GalN)-induced Hepatotoxicity. The Wistar rats were divided into four groups (n=6). Group 1 received a standard diet, Group 2 received an oral administration of 6-shogaol (20 mg/kg b.wt), Group 3 received an intraperitoneal injection of D-GalN (400 mg/kg b.wt) on 21st day, and Group 4 received an oral administration of 6-shogaol (20mg/kg b.wt) for 21 days and D-GalN (400 mg/kg b.wt) injection only on 21st day. The hepatic marker enzymes activity, lipid peroxidative markers level increased significantly and antioxidant activity/level significantly reduced in D-GalN-induced rats. 6-shogaol Pretreatment effectively improves the above changes in D-GalN-induced rats. Further, inflammatory marker expression and MAPK signaling molecules were downregulated by 6-shogaol. These findings showed that 6-shogaol exerts hepatoprotective effects via the enhanced antioxidant system and attenuated the inflammation and MAPK signaling pathway in D-GalN-induced rats.

Hibiscus-cisplatin combination treatment decreases liver toxicity in rats while increasing toxicity in lung cancer cells via oxidative stress- apoptosis pathway

Cisplatin (CIS) is a broad-spectrum anti-carcinogen that causes cytotoxic effects both in normal and cancer cells. The purpose of this study was to test whether Hibiscus sabdariffa (HS) extract can reduce CIS-induced hepatotoxicity in rodents and to assess its anticancer activity in vitro. Treatment with HS extract at daily doses of 500 mg/kg before and after a single dose of CIS (10 mg/kg) reduced hepatotoxicity in Wistar male albino rats. HS extract reduced activity of hepatic damage marker enzymes ( i.e. alanine and aspartate aminotransferases), necrosis, and apoptosis in liver tissues of CIS-treated rats. This hepatic protection was associated with reduced oxidative stress in liver tissues. The antioxidant effects of HS were manifested as a normalization of malondialdehyde levels and glutathione levels which were all raised after CIS-induction. In addition, HS treatment resulted in a decrease of catalase, and superoxide dismutase activity. The combined effects of CIS and HS were also studied in two human lung cancer cell lines (A549 and H460). Treatment with HS (20 μg /mL) enhanced the cytotoxic activity of CIS both in A549 and H460 cell lines. Interestingly, HS increased CIS-induced apoptosis and oxidative stress more clearly in A549 cells indicating that HS extract in combination with CIS could increase the efficacy of CIS in the treatment of cancer.

In-vivo Ameliorative Potential Effect of N-Acetylcysteine and Gallic Acid against Hepatotoxicity Induced by Mercuric Chloride in Wistar Rats

Mercury is a highly toxic metal induces oxidative stress in the body and results in a variety of adverse health effects including liver damage. In the present experimental study was to investigate the hepatoprotective effect of some phytochemical on Mercury intoxicated rats. During treatment periods, a sub-lethal dose of mercuric chloride (1.29 mg/kg body weight) treated rat liver tissue shows hepatic injury is mainly associated with distortion of the metabolic function of the liver in rats, it is Hepatic damage can be evaluated by biochemical analysis of the serum tests, includes levels of serum Alanine and Aspartate aminotransferases, alkaline phosphatase, lactic dehydrogenase of liver marker enzymes. In the present experimental study, drastically altered in the level of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), Lactic dehyrogenase (LDH) and Bilirubin levels were observed in the blood serum of mercuric chloride intoxicated Wistar rats. The activity of liver marker enzymes such as ALT AST, ALP and LDH were significantly increased. In addition, lipid peroxidation (LPO) were significantly increased while the activities of the levels of non enzymatic antioxidants (reduced glutathione (GSH)) and enzymatic antioxidants (glutathione peroxidase (GPx) superoxide dismutase (SOD) and catalase (CAT)) were significantly decreased in liver tissues and the toxicity with mercury is associated with oxidative stress in which mercury induces the formation of free radicals including ROS. It alters the antioxidant capacity of the cells to promote cellular damages. During the recovery period, the hepatic marker enzymes, enzymatic antioxidant and non-enzymatic antioxidant are restored to near normal level in liver tissues. Our experimental studies indicate that treatment for N-Acetylcysteine and Gallic acid exhibited the strong hepatoprotective activity against mercuric chloride induced liver damage in Wistar rat.

Andrographis paniculata (Burm.f.) Nees Alleviates Methotrexate-Induced Hepatotoxicity in Wistar Albino Rats.

Andrographis paniculata is a herbal plant used in traditional medicinal approaches to treat various ailments and diseases. Methotrexate (MTX) is a clinically used immunosuppressant and anticancer drug. One of the increasing concerns with MTX use is liver toxicity. The aim of this study is to investigate the potential effect of aqueous leaf extract of Andrographis paniculata against methotrexate-induced hepatotoxicity. Wistar albino rats were grouped into five groups, and the drugs were administered. MTX (20 mg/kg b.w.) was intraperitoneally injected into rats on the ninth day alone. Aqueous leaf extract of Andrographis paniculata (500 mg/kg b.w./day) was orally administered for 10 days. We confirmed the beneficial effect of aqueous extracts of Andrographis paniculata on restoring the hepatic enzyme markers, lipid profile, antioxidant level, anti-inflammatory marker (IL-10), anti-apoptosis (bcl-2), significant suppression of inflammatory cytokines (TNF-α, and IL-6), apoptosis marker (caspase 3) and cellular tissue damage caused by MTX. Overall, we revealed that Andrographis paniculata reduces critical aspects of oxidative stress, inflammatory processes, and apoptosis, thus protecting against methotrexate-induced hepatotoxicity.

Potential Ameliorative Effects of Graviola (Annona muricata L.) Fruits on Carbon-tetrachloride Induced Hepatic Injury in Rats: Antioxidant, Apoptotic, Anti-inflammatory Markers, and Histopathological Studies

Plant parts play a crucial function to protect organisms from the toxic/carcinogenic effects of some compounds. The present study was carried out to investigate the protective effects of Graviola aqueous extract (GAE) against carbon tetrachloride (CCl4) which induced hepatic injury in rats. Thirty male albino Wistar rats were divided into five groups: group I was used as controls, group II received daily GAE (300 mg/kg bw) alone orally for six weeks, group III received by IP injection CCl4 in olive oil (50% V/V, 2 ml/kg bw), twice a week for two weeks, group IV, CCl4+GAE (curative group) injected CCl4 twice a week for two weeks then concomitant with GAE (300 mg/kg BW) daily for next four weeks, and group V, GAE+CCl4 (prophylactic group), received GAE, 300 mg/kg/day once daily orally four weeks, then concomitant with CCl4 twice a week for next two weeks. The obtained results showed that the administration of CCl4 caused hepatotoxicity as monitored by the significant (p≤0.05) increase in the levels of hepatic markers enzymes (alanine aminotransferase, ALT, aspartate aminotransferase, AST and alkaline phosphatase, ALP), total bilirubin (TB) and a decrease in hematological parameters such as white blood cell (WBC), red blood cell count (RBC), and blood platelet count (PLT). Also, our results showed that CCl4 caused a significant (p≤0.05) increase in oxidative stress markers (malondialdehyde, MDA, reactive oxygen species, ROS, nitric oxide, NO), pro-inflammatory tumor necrosis factor-alpha (TNF-α,) level, and proapoptotic markers caspase-3, and B-cell lymphoma 2 (BCL-2)-like protein 4 (Bax). Furthermore, a significant (p≤0.05) decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), reduced glutathione (GSH), and an antiapoptotic agent B-cell lymphoma 2 (Bcl-2) was observed in liver tissue. The detected CCl4 effects were normalized by GAE administration, either a prophylactic or curative dose. Besides, GAE reduced the histopathological changes induced by CCl4.In conclusion, GAE was effective in both protecting and enhancing the liver deficits induced by CCl4 through many potential mechanisms including antioxidant, anti-inflammatory, antiapoptotic properties. Therefore, Graviola extracts up to 300 (mg/kg bw) could be considered a promising hepatoprotective supplement but more human clinical trials are also needed to validate the findings of the current research.

Evaluation of Liver and Kidney Function Markers of Mature Albino Male Rats Fed with Maize-Plantain Pudding Delicacy Cooked in Metallic Plates and Edible Plant Leaves

Traditional maize-plantain puddings are usually cooked in diverse containers such as aluminium plates, cast iron plates and all types of edible plant leaves. This paper therefore, evaluates biochemical markers of liver and kidney function of mature albino male rats fed with maize-plantain pudding delicacy cooked in aluminium and cast iron plates and edible Zingiber officinale (ginger) and Musa paradisiaca (plantain) leaves using appropriate standard methods. Data obtained reveal that the activities of hepatic marker enzymes; alanine transaminase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the serum and liver were significantly lower in rats given the pudding extracts when compared with the control. No significant differences were observed in urea and creatinine levels in the serum and kidney of rats given pudding extracts as compared to control. In conclusion, this study has proved that maize-plantain pudding organized using ginger leaves, plantain leaves and cast iron plate are beneficial in the maintenance and improvement of liver and kidney function when compared with aluminium plate. However, in this efficacy maize-plantain pudding cooked using ginger leaves was found to be more effective than the pudding cooked using plantain leaves and cast iron plate.&#x0D;

Heavy metal–induced genotoxic, physiological, and biochemical responses in Schizothorax esocinus (Heckel 1838) inhabiting the Dal Lake, India, and phytoremediation by indwelling plants

Heavy metals have animmense impact on aquatic ecosystems, and their toxic effects are transferred to the inhabiting organisms. Experiments were conducted to investigate the health of snow trout Schizothorax esocinus inhabiting Dal Lake. Heavy metals (Cd > Ni > Cu > Cr) were found to accumulate in the major immune organs of the fish (head kidney, liver, spleen, thymus) which led to change in the overall physiology. The head kidney, liver, and spleen of a fish contain high amount of these metals. The least accumulation of these metals was found in the blood, whereas Cd and Ni were completely absent in the integument. Hepatic marker enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)) were normal, while the renal marker enzyme creatine kinase showed marked difference in its value. The cortisol level was normal, while immunoglobulin M showed elevated level representing active immunity. At a cellular level, the histopathology of immune organs showed marked damage. Metallothionein (MT) and glutathione peroxidase (GPX) genes showed variable expression pattern in the immune organs with the head kidney showing the highest expression of both the genes, and blood showed the least. We observed that the aquatic plants (Nelumbo nucifera and Trapa natans) inhabiting the lake played an important role in phytoremediation. An integrated approach involving biochemical, hematological, genotoxic, and histopathological studies can provide a valuable information to understand fish adaptive patterns and monitor water quality.

HEPATOPROTECTIVE ACTIVITY OF HOMALOMENA AROMATICA AGAINST CCL4 INDUCED LIVER INJURY IN SWISS ALBINO MICE

The in vivo hepatoprotective activity of Homalomena aromatica was evaluated in carbon tetrachloride-induced hepatic injury model in Swiss albino mice. Effects of the methanolic rhizome extracts of Homalomena aromatica (HAME) at a dose of 200 mg/kg body weight and 500 mg/kg body weight was tested for its efficacy on CCl4 (1ml/kg body weight) induced liver injury. Hepatic toxicity enzyme markers and histological parameters were studied. Daily oral administration of HAME (500 mg/kg) reduced liver toxicity marker enzyme activity significantly as compared to the control. The results were also supported by the histopathological studies. Recovery of the liver tissue was observed in the highest dose (500 mg/kg) of HAME. The progression of liver damage could be inhibited by the protective effect of HAME and the normal architecture of the liver could be preserved. The plant can therefore be a potential therapeutic candidate to treat liver injury.

Impending Chemotherapeutic Impact of Arthrospira platensis Nanoparticles and/or Sorafenib against Hepatocellular Carcinoma through Modulation of Antioxidant Status, Tumor Marker Genes, and Anti-Inflammatory Signaling Pathways.

This study investigated Arthrospira platensis nanoparticles (NSP) to overcome sorafenib resistance in diethyl nitrosamine-induced hepatocellular carcinoma (HCC) in rats. This study used sixty Wistar male rats randomly grouped into two main groups, the normal control group, and the HCC model. For the normal control group (n = 12), animals were injected i.p. with PBS two times/week for 16 weeks. The remaining 48 rats were injected i.p. with using a single dose of diethyl nitrosamine (DENA) (200 mg/kg, ip), followed by phenobarbital sodium (0.05%) in drinking water for 16 weeks. At the end of the 16th week, rats were allocated into four groups (11 rats/each), one group was left without treatment (DENA group), and the other three groups were treated with either sorafenib (30 mg/kg; p.o.) or Arthrospira platensis Nanoparticles (NSP) (0.5 mg/kg body weight) once daily orally with the aid of gastric gavage or their combination for another four weeks. Blood and tissue samples were collected for further biochemical, histological, immunohistochemical, and gene expression analysis. Our result revealed that DENA-treated rats showed a marked elevation of hepatic enzyme markers with an increase in the total protein and globulin and decreases in the hepatic SOD. Catalase and GSH, with significantly increased MDA levels, subsequently increased the tumor biomarkers (AFP and CEA). On the molecular level, the DENA-treated rats showed significant up-regulation of Cyp19 mRNA and the inflammatory cytokines (TNF-α, iNOS, and TGF-1β) as well as the Ki-67 gene expression (p < 0.05) with down-regulation of the PPAR-γ and FOXO-1. In addition, the HCC group showed a loss of hepatic architecture, as well as atypia, swelling, macrosteatosis of hepatocytes, and fibrosis, besides increased vascularization. The immunohistochemical findings show increased expression of both GPC-3 and Hep Par 1 in the HCC group. SOR, NSP, or a combination of NSP and SOR.NSP treatment significantly overturned the DENA's harmful effect near the normal levels and restored all cancer biomarkers and antioxidant activities, indicating the chemotherapeutic impact of NSP. The present study provides evidence that NSP exerts a major anticancer effect on DENA-induced HCC. SOR/NSP is a promising combination for tumor suppression and overcoming sorafenib resistance in HCC by modulating antioxidants, anti-inflammatory signals, and tumor markers.

Molecular mechanism for the involvement of CYP2E1/NF-κB axis in bedaquiline-induced hepatotoxicity

Bedaquiline (BDQ) is a new class of anti-tubercular (anti-TB) drugs and is currently reserved for multiple drug resistance (MDR-TB). However, after receiving fast-track approval, its clinical studies demonstrate that its treatment is associated with hepatotoxicity and labeled as ‘boxed warning’ by the USFDA. No data is available on BDQ to understand the mechanism for drug-induced liver injury (DILI), a severe concern for therapeutic failure/unbearable tolerated toxicities leading to drug resistance. Therefore, we performed mechanistic studies to decipher the potential of BDQ at three dose levels (80 to 320 mg/kg) upon the repeated dose administration orally using a widely used mice model for TB. Results of BDQ treatment at the highest dose level showed that substantial increase of hepatic marker enzymes (SGPT and SGOT) in serum, oxidative stress marker levels (MDA and GSH) in hepatic tissue, and pro-inflammatory cytokine levels (TNF-α, IL-6, and IL-1β) in serum compared to control animals. Induction of liver injury situation was further evaluated by Western blotting for various protein expressions linked to oxidative stress (SOD, Nrf2, and Keap1), inflammation (NF-ĸB and IKKβ), apoptosis (BAX, Bcl-2, and Caspase-3) and drug metabolism enzymes (CYP3A4 and CYP2E1). The elevated plasma level of BDQ and its metabolite (N-desmethyl BDQ) were observed, corresponding to BDQ doses. Histopathological examination and SEM analysis of the liver tissue corroborate the above-mentioned findings. Overall results suggest that BDQ treatment-associated generation of its cytotoxic metabolite could act on CYP2E1/NF-kB pathway to aggravate the condition of oxidative stress, inflammation, and apoptosis in the liver and precipitating hepatotoxicity.

HEPATOPROTECTIVE POTENTIALS OF ACTIVE FRACTIONS OF Lawsonia inermis (Lythraceae) AGAINST ACETAMINOPHEN-INDUCED LIVER DAMAGE IN RATS

Lawsonia inermis (henna) is widely distributed across African countries. It has been used by herbal doctors in treating oxidative stress-related diseases in humans. Its leaves contain valuable antioxidants and protective molecules, which can protect humans against hepatic damage from toxic effects. This study analyzed the hepatoprotective ability of L. inermis leaf fractions againstacetaminophen-induced liver damage in rats. Fifty-four (54) rats were divided into nine (9) groups, and each group allocated six (6) rats. Group 1, 2, 3, 4, 5, 6, 7, 8 and 9 were given 2 mL/kg/day of normal saline, normal control (NCN), 600 mg/kg/day of acetaminophen alone, negative control (NCA), 600mg/kg/day of acetaminophen and 200 mg of n-hexane fraction (AH200), 600mg/kg/day of acetaminophen and 400 mg of n-hexane fraction (AH400), 600 mg/kg/day of acetaminophen and 200 mg of ethyl acetate fraction (AE200), 600 mg/kg/day of acetaminophen and 400 mg of ethyl acetate fraction (AE400), 600mg/kg/day of acetaminophen and 200 mg of methanol fraction (AM200), 600mg/kg/day of acetaminophen and 400 mg of methanol fraction (AM400), 600mg/kg/day of acetaminophen and 25 mg/kg/day of silymarin (AS25), respectively. The serum chemistry, lipid profiles, hepatic enzyme markers and oxidative stress markers were analyzed using standard methods. Histopathological examination ofhepatocytes of the treated rats was determined. The results revealed lower significant values of total protein, albumin, globulin, HDL, SOD, CAT, and GPx, and higher significant values of serum bilirubin, glucose, creatinine and urea, triglyceride, cholesterol, LDL, ALT, AST, ALP, LDH and MDA in NCA-treated rats than in the others. Interestingly, higher insignificantly levels of total protein, albumin, globulin, HDL, SOD, CAT, and GPx, and lowered insignificantly values of bilirubin, glucose, creatinine, urea, triglyceride, cholesterol, LDL, asnd ALT, AST, ALP, LDH, and MDA were noted among L. inermis fractions treated rats. Abnormal hepatic cellarchitectures were observed in the livers of NCA-treated rats than in other groups, however, reduced hepatic dysfunction/normal liver cell architectures were restored among the rats treated with L. inermis leave fractions. These results have suggested that all levels of L. inermis leave fractions in this study possessed hepatoprotective potential against acetaminophen-inducedhepatic cell damage,

Protective effect of Euphorbia thymifolia and Euphorbia hirta against carbon tetrachloride-induced hepatotoxicity in Wistar rats

Objectives The present study aims to investigate the protective effect of Euphorbia thymifolia and Euphorbia hirta extracts on in vitro antioxidant activity and in vivo analysis on hepatic marker enzyme levels and histopathological changes in the liver of carbon tetrachloride (CCl4) induced hepatotoxicity rats. Materials and methods This study includes 42 adult male Albino Wistar rats randomly divided into seven treatment groups, including control (basal diet, G1), CCl4-induced single dose (1.5 ml/kg, i.p.) as the negative control (G2), G1 supplemented with 300 mg/kg of ethanol extract of E. thymifolia (G3) and E. hirta (G4), G2 supplemented with 300 mg/kg of ethanol extract of E. thymifolia (G5), E. hirta (G6), and silymarin (25 mg/kg b.w.) used as a standard drug (G7) for 21-days experimental period. Results The ethanolic extracts of E. thymifolia and E. hirta exhibited potential in vitro antioxidant activity in a dose-dependent manner (25 μg/ml, 50 μg/ml, 100 μg/ml, 200 μg/ml and 250 μg/ml). Oxidative stress caused by CCl4-induced the liver damage, including changes in liver marker enzymes (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase), enzymatic (superoxide dismutase and catalase), non-enzymatic antioxidants (lipid peroxides and glutathione) and hepatocellular alterations such as hydropic degeneration, irregular hepatocytes, and distention of the vein. Administration of E. thymifolia and E. hirta significantly (p < 0.05) restored the enzyme activity along with the histology of the liver. Conclusion The results from the current study demonstrate that E. thymifolia and E. hirta have the property of restoring hepatic redox capacity and antioxidant activities against CCl4-induced acute liver damage.

Bioavailability, anti-inflammatory and anti-arthritic effect of Acetyl Keto Boswellic acid and its combination with methotrexate in an arthritic animal model

Ethnopharmacological relevanceRheumatoid arthritis is one of the most common disabling chronic progressive autoimmune diseases affecting the adult world population. Boswellia serrata has been a known anti-inflammatory agent since ancient times. Therefore, research on Boswellia extract based on Acetyl Keto Boswellic Acid (AKBA) content evaluating its efficacy and safety is necessary.The study aimed to find a suitable Boswellia extract rich in AKBA to evaluate its bioavailability, anti-inflammatory, and anti-arthritic effect. In addition, the synergistic action of AKBA extract with methotrexate (MTX) was also assessed on an animal model. Materials and methodsOral bioavailability of AKBA and the anti-inflammatory activity of 10% AKBA (5, 10, 20, 40 mg/kg b.w) was assessed and compared with 2% AKBA (40 mg/kg) and diclofenac (10 mg/kg). The effect of 10% AKBA at 20 mg/kg and 40 mg/kg was evaluated in the FCA induced arthritis animal model alone and combined with methotrexate (MTX) at 2 mg/kg b.w. Subplantar injection of FCA produced edema within a few hours with progressive arthritis by the 9th day after injection. All the treatments were initiated from the 10th day until the 45th day. Oral administration of 10% AKBA was done daily and MTX by intraperitoneal route once a week from day 10 to day 45. Paw volume, erythrocyte sedimentation rate (ESR), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, oxidative markers (superoxide dismutase (SOD) levels, malondialdehyde (MDA), total proteins and liver histopathology were examined. Results10% AKBA provided 8.48-fold, 24.22-fold, 47.36-fold, and 110.53-fold higher AUC (0-α) of AKBA at 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg, respectively compared to 2% AKBA at 40 mg/kg. Percentage paw edema inhibition of 10% AKBA at 20 mg/kg and 40 mg/kg were significantly higher than 2% regular AKBA (40 mg/kg) and diclofenac (10 mg/kg). 10% AKBA at a dose of 20 and 40 mg/kg significantly reduced ESR compared with FCA treated group. A combination of methotrexate with 10% AKBA showed the highest reduction in ESR. 10% AKBA at both dose levels significantly reduced hepatic marker enzymes and total bilirubin levels. Treatment with 10% AKBA showed a significant increase in total proteins, antioxidant enzymes and a decrease in malondialdehyde levels. Similarly, 10% AKBA protected the hepatocytes compared with the FCA and FCA + MTX treated group. 10% AKBA was capable of significantly minimizing FCA and FCA + MTX induced changes. ConclusionAnti-inflammatory activity of AKBA due to inhibition of lipoxygenase (LOX) enzymes supports the use of AKBA in inflammatory disorders. Combination therapy of 10% AKBA with MTX is effective in inhibiting arthritis and circumventing hepatotoxicity produced by MTX in arthritic animals.

Evaluation of Hepatoprotective Activity of Whole Fruit Extracts of Luffa Acutangula. Var. Amara and Rhizome Extracts of Rheum Emodi in CCl4 - Induced Chronic Hepatotoxicity

To investigate the hepatoprotective activity of whole fruit extracts of Luffa acutangula.var. amara and rhizome extracts of Rheum emodi in CCl4 treated rats. The dried powders of L. amara and R. emodi were extracted successively with petroleum ether, ethanol and distilled water. The hepatoprotective capacity of the extract of the whole fruits of L. amara and the rhizomes of R. emodi was analyzed in liver injured CCl4- treated male rats. The present study explored the possibilities of using low doses of both plant extracts (150mg/kg, and 300mg/kg bw, po route) to treat CCL4 intoxicated albino rats in both acute and chronic models of hepatic damage, evident by increased serum levels of glutamate pyruvate transaminase (SGPT), glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), direct bilirubin, total bilirubin, cholesterol and triglycerides, all being implicated in considerable hepatic damage.&#x0D; Histopathological examination in CCl4 treated rats revealed collapse of liver parenchyma with early fibrosis and chronic inflammatory cell infiltration in patchy areas around central vein (Pic.group-2) when compared to the control group. Histopathological and physical examinations also indicated their effectiveness with their dose tolerability and liver protection.&#x0D; Ethanolic and aqueous extracts of the whole fruits of L. amara and rhizomes of R. emodi were indicative of more hepatoprotective properties when compared to the petroleum ether extracts of both plants against CCl4 induced liver damage as confirmed from hepatic serum marker enzyme activities and histopathological studies.