Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo

A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas. Analysis of single-cell RNA-Seq datasets revealed that FAS is highly expressed in epithelial cells and immune cells but down-regulated in colon-tumor cells in human colorectal-cancer patients. Codon usage-optimized mouse and human FAS cDNA was designed, synthesized, and encapsulated into cationic lipid to formulate nanoparticle DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Overexpression of codon usage-optimized FAS in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS+ tumor cells in vitro, suppressed colon tumor growth, and increased the survival of tumor-bearing mice in vivo. Overexpression of codon-optimized FAS-induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. DOTAP-Chol-mFAS therapy exhibited no significant liver toxicity. Our data determined that tumor-selective delivery of FAS DNA nanoparticles is sufficient for suppression of human colon tumor growth in vivo.

Comparing the effect of statins on hepatic fibrosis induced by carbon tetrachloride in Wistar rats

Background: The clinical studies have shown contrary results regarding hepatoprotective effect of statins. However, antifibrotic properties of statins in in vitro and in vivo experimental models have been demonstrated. The purpose of this study was to assess and compare the effect of statins on serum liver enzymes and their antifibrotic effects.Methods: Forty two rats were divided into 7 groups (I to VII) (n=6). Liver toxicity was induced by injecting carbon tetrachloride (1 ml/kg). Control groups received corn oil (0.1 ml/100 gm) and carboxy methyl cellulose (0.50%) respectively. Group III to VII received carbon tetrachloride (CCl4) for 6 weeks and then groups IV, V, VI and VII received simvastatin (10 mg/kg), atorvastatin (15 mg/kg), rosuvastatin (2 mg/kg) and silymarin (50 mg/kg) for another 8 weeks respectively. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels were estimated in all the groups at baseline, 6 weeks and 14 weeks. At 14 weeks, histopathology of liver was done in all groups.Results: At 14 weeks, all the test groups (IV, V and VI) showed a significant decrease in serum ALT, AST and ALP levels as compared to control (p<0.05) and group III (p<0.05). On intergroup comparison, liver enzymes in rats in group VI (rosuvastatin) and group V (atorvastatin) were decreased more in comparison to group IV (simvastatin) but the difference was not statistically significant except for AST levels where the difference was significant between the statins. There was decrease in hepatic fibrosis by statins with rosuvastatin being superior followed by atorvastatin and simvastatin.Conclusions: In the present study statins decreased the serum AST, ALT and ALP levels and histopathological changes were reversed by statins in CCl4 induced hepatotoxic models.

Dual mode of action of Talaromyces purpureogenus CFRM02 pigment to ameliorate alcohol induced liver toxicity in rats

Talaromyces purpureogenus CFRM02 pigment exhibited antioxidant activity by scavenging free radicals. The alcohol feeding lead to free radical generation causing pathophysiological processes of alcoholic liver disease (ALD) and alcoholic hepatitis. The T. purpureogenus CFRM02 pigment administered to rats ameliorated the ALD by scavenging ROS. The haematological analysis revealed the increased neutrophil circulation. The neutrophil infiltration was observed in the hepatocytes of the rats fed with pigment (600 mg/kg body weight). The increase in number of neutrophils help in the liver regeneration caused by alcoholic hepatitis. The dual mechanism of action of pigment, antioxidant and liver regeneration through neutrophil production is attributed to alleviate the ALD. These results suggested T. purpureogenus CFRM02 pigment represents a novel protective and therapeutic strategy against ALD.

Toxicodynamic aspects and new tools for assessing acetaminophen toxicity: a review

Acetaminophen (Tylenol®) or APAP is a widely used non-steroidal anti-inflammatory drug responsible for many cases of intoxication, suicide, and liver toxicity. Due to its toxicity mechanisms are not yet fully elucidated and this literature review aims to objectively bring some of the most recent and relevant scientific discoveries that can help in the understanding of the subject. After being ingested, paracetamol is absorbed and begins to be digested in the stomach, then being metabolized by the liver through phase I and phase II (glucuronyltransferases and sulfotransferases). When present in excess in the body, APAP forms an active metabolite known as N-acetyl-para-benzoquinone-imine (NAPQI). This metabolite is a reactive species capable of binding to living cells and proteins causing damages, which are largely responsible for injuries, especially in the liver. As a conclusion of this study, it can be inferred that the lesions caused by acetaminophen, in addition to protein adducts, also extend to mitochondria and proteins. New markers, in addition to enzymes already known from the CYP families, also include proteins and cytokines, in addition to molecular methods, messenger RNA and micro RNA have been used to study hepatotoxicity by APAP. This makes it easier to deeply understand the mechanisms of toxicity induced by acetaminophen and then to advance in studies with new therapies.

Phytochemical Analysis and Hepatoprotective Activity of Elytraria acaulis

Introduction: The emerging of new diseases, resistance to contemporary using drugs and inadequate usage of commonly available drugs leading to different side effects and sometimes to mortality. So, there is need to identify efficient drugs from easily available sources. Traditional medicines from medicinal plants have been using since ancient times to treat different diseases, are easily available herbal formulations and there were still many medicinal plants were unexplored about their therapeutic potentiality. So, the current research is aimed to explore phytochemical constituent and hepatoprotective potentiality of Elytraria acaulis on paracetamol-induced liver toxicity. Methodology: The root parts Elytraria acaulis were used for extraction through maceration procedure using hexane, ethyl acetate and hydro-alcoholic (70% ethanol). The dried extracts used for further for phytochemical analysis using standard procedures and evaluated liver protection on paracetamol-induced liver toxicity by estimating liver bio markable enzymes such as AST (SGOT), ALT (SGPT), ALP and total bilirubin levels. Results: Qualitative phytochemical screening of E. acaulis extracts revealed the presence of different phytochemical constituents like steroids, terpenoids, flavonoids, alkaloids, glycosides, phenols, tannins, saponins and carbohydrates in them. The hydroalcoholic extract has more flavonoid content i.e., 23.84±0.28 (mg/gm) than other two extracts. The tested three extracts of E. acaulis had showed concentration dependent hepatoprotective activity. Among three extracts hydro-alcoholic extract had more potentially compared to other two extracts. The percentage protection produced by the hydro-alcoholic extract on the enhancement of AST(SGOT), ALT (SGPT), ALP and total bilirubin levels were 21.54%, 21.94%, 21.20%, and 20.52%, 36.27%, 38.26%, 37.55% and 36.14%, 67.76%, 70.04%, 69.83% and 68.61% respectively. Conclusion: The Elytraria acaulis root extracts had showed significant biological activities and own different phytochemical constituents. The hydroalcoholic extract possess more phenolic, flavonoid contents and the same had showed more potentiality against liver toxicity. The current results offer vital information about the traditional medicinal value of it. The further research is valuable and is under progress in evaluation of different biological activities and isolation of individual bioactive molecules from E. acaulis.

MTHFR Polymorphism Is Associated With Severe Methotrexate-Induced Toxicity in Osteosarcoma Treatment

BackgroundPrevious studies have revealed the critical role of methylene tetrahydrofolate reductase (MTHFR) polymorphisms in response to high-dose methotrexate (MTX)-induced toxicity in osteosarcoma patients. However, the conclusions remain controversial. In this setting, we performed a meta-analysis to determine their association more precisely.MethodEligible studies were searched and screened in PubMed, Web of Science, Cochrane Library, Clinical-Trials.gov, Embase, and China National Knowledge Infrastructure (CNKI) following specific inclusion and exclusion criteria. The required information was retrieved and collected for subsequent meta-analysis. Association between MTHFR polymorphism and MTX toxicity was evaluated by odds ratios (ORs).ResultsSeven studies containing 585 patients were enrolled and analyzed in this meta-analysis. Overall, the MTX related grade 3-4 liver toxicity was significantly associated with MTHFR rs1801133 allele (T vs. C: OR=1.61, 95%CI=1.07-2.42, P=0.024), homozygote (TT vs. CC: OR=2.11, 95%CI=1.06-4.21, P=0.011), and dominant genetic model (TT/TC vs. CC: OR=3.15, 95%CI=1.30-7.60, P=0.035) in Asian population. Meanwhile, close associations between MTX mediated grade 3-4 mucositis and MTHFR rs1801133 polymorphism were identified in allele contrast (T vs. C: OR=2.28, 95%CI=1.49-3.50, P&lt;0.001), homozygote comparison (TT vs. CC: OR=4.07, 95%CI=1.76-9.38, P=0.001), heterozygote comparison (TC vs. CC: OR=2.55, 95%CI=1.20-5.42, P=0.015), recessive genetic model (TT vs. TC/CC: OR=2.09, 95%CI=1.19-3.67, P=0.010), and dominant genetic model (TT/TC vs. CC: OR=2.97, 95%CI=1.48-5.96, P=0.002). Additionally, kidney toxicity was corelated with the heterozygote comparison (TC vs. CC: OR=2.63, 95%CI=1.31-5.29, P=0.007) of rs1801133 polymorphism.ConclusionThe MTHFR rs1801133 polymorphism was significantly associated with severer liver toxicity induced by high-dose MTX treatment in the Asian population. In the meantime, patients with MTHFR rs1801133 polymorphism were predisposed to MTX- related mucositis.

Safranal Effect against Cyclophosphamide-Induced Liver Injury

The liver is the primary organ for drug metabolism, elimination, Cyclophosphamid is the classical alkylating agent nitrogen mustard, its metabolism into two cytotoxic metabolites, and increase reactive oxygen species that is make liver toxicity. Safranal as the most abundant chemical in saffron essential oil, it have anti-oxidant, anti-inflammatory, antiapoptic and free radical scavenger activity. The aim of study is to assess the protective effects of safranal on the cyclophosphamide-induce liver toxicity in rat model. This occur by using five different groups of rats; control group, treatment group, cyclophosamide group (intraperitoneal i.p), cyclophosamide and (50mg and 100mg) oral safranal treatment groups. This study showed this protective by decreasing liver parameter enzyme (aminotransferase enzyme) and MDA level, increases glutathione and NRF2

Hepatoprotective Role of Virgin Coconut Oil and Neem Extract in Acetaminophen Induced Liver Toxicity

Aim: To study the comparative hepatoprotective effect of Virgin Coconut Oil (VCO) and Neem (Azadirachta indica) leaf extract in acetaminophen (Paracetamol) induced liver toxicity. Methods: About 60 mixed population of rats (male/female) of Wistar and Sprague-Dawley species were randomly selected for the proposed study and are segregated into four equal groups. Every group contains 15 animal subjects. Group A was the control group given normal diet. In Group B, the rats were treated with a single dose of 2gm / kg body weight paracetamol, orally. Simultaneously, Group C were given an oral Neem extract of 500mg/kg body weight for 2 weeks days in combination with single dose of Paracetamol, while Group D were provided with 6.7ml/Kg/body weight Virgin Coconut Oil (VCO) for 15 days. Data was analyzed using SPSS Version 20.0 with level of significance being kept at p-value ≤0.05. Results: The mean values of ALT were 23.1, 100.5, 29.85, and 31.09 U/L in Group A, B, C, and D respectively. While, the mean values of AST were 25.6 U/L (Group A), 41 U/L (Group B), 19.3 U/L (Group C), and 15.2 U/L (Group D). The ALP showed maximum response indicated by the mean values of 221 U/L, 444 U/L, 241 U/L, and 243 U/L in Group A, B, C, and D respectively. Group B suggested the paracetamol induced liver toxicity indicated by the increase in hepatic DMEs right after the acetaminophen induction. Conclusion: Azadirachta Indica and Virgin Coconut Oil displayed hepatoprotective effects on the Wistar and Sprague-Dawley rats that were subjected to Paracetamol. Keywords: hepatic, Drug Metabolizing enzymes, Acetaminophen, Virgin coconut oil, Neem extract, Paracetamol, Wistar

Hepatoprotective Screening of Seriphidium kurramense (Qazilb.) Y.R. Ling

Investigation on medicinal plants’ therapeutic potential has gained substantial importance in the discovery of novel effective and safe therapeutic agents. The present study is aimed at investigating the hepatoprotective potential of Seriphidium kurramense methanolic extract (SKM) against carbon tetrachloride- (CCl4-) induced hepatotoxicity in rats. S. kurramense is one of the most imperative plants for its various pharmacological activities. Therefore, this study was aimed at evaluating the hepatoprotective potential against CCl4-induced liver toxicity. The serum samples were analyzed for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) together with the oxidative stress mediator levels as nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), reduced glutathione (GSH), and superoxide dismutase (SOD) as well as peroxidation and H2O2 activity. CCl4 administration resulted in an elevated free radical generation, altered liver marker (AST and ALT) enzymes, reduced antioxidant enzyme, and increased DNA damage. Methanolic extract of S. kurramense decreased CCl4-induced hepatotoxicity by increasing the antioxidant status and reducing H2O2 and nitrate content generation as well as reducing DNA damage. Additionally, SKM reversed the morphological alterations induced by CCl4 in the SKM-treated groups. These results demonstrated that SKM displayed hepatoprotective activity against CCl4-induced hepatic damage in experimental rats.