On a deterministic mathematical model which efficiently predicts the protective effect of a plant extract mixture in cirrhotic rats.

In this work, we propose a mathematical model that describes liver evolution and concentrations of alanine aminotransferase and aspartate aminotransferase in a group of rats damaged with carbon tetrachloride. Carbon tetrachloride was employed to induce cirrhosis. A second groups damaged with carbon tetrachloride was exposed simultaneously a plant extract as hepatoprotective agent. The model reproduces the data obtained in the experiment reported in [Rev. Cub. Plant. Med. 22(1), 2017], and predicts that using the plants extract helps to get a better natural recovery after the treatment. Computer simulations show that the extract reduces the damage velocity but does not avoid it entirely. The present paper is the first report in the literature in which a mathematical model reliably predicts the protective effect of a plant extract mixture in rats with cirrhosis disease. The results reported in this manuscript could be used in the future to help in fighting cirrhotic conditions in humans, though more experimental and mathematical work is required in that case.

Saffron reduces the liver fibrosis in mice by inhibiting the JAK/STAT3 pathway.

PURPOSE: Chronic inflammation in the liver is a key trigger for liver injury and fibrosis in various liver diseases. Given the anti-inflammatory and antioxidant effects of Saffron, this study aimed to investigate the pharmacological effects of Saffron on hepatic inflammation and fibrosis. METHODS: The mice model of hepatic fibrosis was constructed using CCl4, and Saffron was administered at low (10 mg/kg) and high (20 mg/kg) doses by gavage. Then, the changes in liver function, liver inflammation and fibrosis markers were evaluated. The effects and mechanisms of Saffron on hepatic stellate cells were further investigated in in-vitro experiments. RESULTS: Saffron improved liver function, reduced liver inflammation and attenuated liver fibrosis in a dose-dependent manner in hepatic fibrosis mice. Furthermore, Western blotting showed that Saffron significantly inhibited JAK/STAT3 phosphorylation in fibrotic livers. CONCLUSIONS: Saffron can attenuate liver fibrosis by inhibiting the JAK/STAT3 pathway and the activation of hepatic stellate cell, providing a theoretical basis for the development of new anti-fibrotic drugs.

Liver fibrotic development is reduced through inflammation prevention by an adenosine derivative compound.

BACKGROUND: Liver fibrosis is a global health problem, and studying its development provides important information to address its treatment. Here, we characterized the effects of an adenosine compound (IFC-305) on preventing fibrosis and liver inflammation. METHODS: We studied the impact of IFC-305 on a carbon tetrachloride-induced liver fibrosis model in Wistar male rats at 4, 6, and 8 weeks. The effects were characterized by liver tissue histology, macrophages identification by flow cytometry with CD163+/CD11b/c+ antibodies, hepatic and plasmatic cytokine levels employing MILLIPLEX MAP and ELISA, Col1a1 and Il6 gene expression by RTqPCR, lipoperoxidation by TBARS reaction, and reactive oxygen species using 2'-7'dichlorofluorescin diacetate. RESULTS: CCl4-induced liver fibrosis and inflammation were significantly reduced in rats treated with IFC-305 at 6 and 8 weeks. In addition, we observed diminished expression of Col1a1; a decrease in the inflammatory cytokines IL-1ß, IL-6, MCP-1, TNF-α, and IL-4 a; reduction in inflammatory macrophages; inhibition of lipoperoxidation; and ROS production in Kupffer cells. CONCLUSION: This study showed that IFC-305 can inhibit liver fibrosis establishment by regulating the immune response during CCl4-induced damage. The immunomodulatory action of IFC-305 supports its use as a potential therapeutic strategy for preventing liver fibrosis.

Influence of omega- 3 fatty acids, soya isoflavones and their combination for abrogating carbon tetrachloride hazards in male rats.

Studies have shown that carbon tetrachloride (CCl4) induces hepatic and renal damage arising from oxidative stress. The present study was undertaken to examine the effect of omega-3 fatty acids and/or soya isoflavones on CCl4 induced toxicity in male albino rat liver and kidney. For this purpose, 42 rats were divided as follows: group 1, rats serves as the control without any treatment; group 2, rats were administered a single dose of CCl4 intraperitoneally (1 mg/kg b. wt.); group 3, rats were supplemented daily with omega-300 orally (400 mg/kg b. wt.); group 4, rats were supplemented daily with pro-S orally (50 mg/kg b. wt.); group 5, rats were supplemented daily with omega-300 orally for four weeks, then after 24 hours treated with a single dose of CCl4 at the same tested doses. group 6, rats were supplemented daily with pro- S orally for four weeks, then after 24 hours treated with a single dose of CCl4 at the same tested doses; group 7, rats were supplemented daily with an oral combination of omega-300 and pro-S orally for four weeks, then after 24 hours treated with a single dose of CCl4 at the same tested doses. Results showed that CCl4 administration induces hepatic damage indicated by a significant increase in the activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST) and Aalanine aminotransferase (ALT) enzymes and glucose level, with a significant increase in malondialdehyde (MDA) and nitric oxide (NO) levels and a significant decrease of reduced glutathione (GSH) level in liver tissue. Also, CCl4 toxicity induce renal damage manifested in a significant increase in serum urea, creatinine, uric acid, and oxidative stress of kidney tissue reflected by increase of MDA, NO and the decrease of GSH levels. The pre-treatment with omega-3 fatty acids and/or soya isoflavones revealed ameliorative effect against deleterious effects of CCl4 toxicity on hepatic and renal tissues and all tested parameters. Results of the current study revealed also that the pre-treatment with omega-3 fatty acids and/or soya isoflavones to rats improved liver and kidney function and produced high antioxidant activity.

Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis.

BACKGROUND & AIMS: Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. METHODS: FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. RESULTS: FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. CONCLUSIONS: Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

microRNA-122 inhibits hepatic stellate cell proliferation and activation in vitro and represses carbon tetrachloride-induced liver cirrhosis in mice.

OBJECTIVE: This study aimed to determine the roles of microRNA (miR)-122 in the activation of hepatic stellate cells (HSCs) and liver cirrhosis. METHODS: Rat primary HSCs were incubated with transforming growth factor-beta (TGF-ß), during which miR-122 and EphB2 expression was measured. miR-122 mimic and/or pcDNA3.1 EphB2 was transfected into TGF-ß-induced HSCs. A mouse model of liver cirrhosis was established via an intraperitoneal injection of carbon tetrachloride (CCl4), followed by the injection of miR-122 agomir. Levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. Fibronectin (FN), alpha smooth muscle actin (α-SMA), Collagen I, miR-122, and EphB2 expression was evaluated in liver tissues and HSCs. Cell proliferation was measured using CCK-8 assay. Interactions between miR-122 and EphB2 were assessed using dual luciferase reporter assay. RESULTS: miR-122 (0.15-fold) was downregulated and EphB2 (mRNA: 5.06-fold; protein: 2.35-fold) was upregulated after TGF-ß induction of HSCs. Overexpressed miR-122 decreased proliferation and EphB2 (mRNA: 0.46-fold; protein: 0.62-fold), FN (mRNA: 0.45-fold; protein: 0.64-fold), α-SMA (mRNA: 0.48-fold; protein: 0.51-fold), and Collagen I (mRNA: 0.44-fold; protein: 0.51-fold) expression in HSCs, which was abrogated by EphB2 upregulation. miR-122 expression was reduced by 0.21-fold and serum ALT and AST levels were enhanced in mice following 8-week CCl4 induction along with increased expression of FN, α-SMA, and Collagen I in liver tissues, which was blocked by miR-122 overexpression. Moreover, EphB2 was a target gene of miR-122. CONCLUSION: miR-122 curtails HSC proliferation and activation by targeting EphB2 and suppresses liver cirrhosis in mice.

Beneficial effects of coconut oil (Cocos nucifera) on hematobiochemicl and histopathological markers in CCL4-intoxicated rabbits.

The study was designed to investigate the effect of Coconut Oil on the levels of some liver and hematological parameters in carbon tetrachloride intoxicated rabbits. Also the antioxidant capacity of Coconut Oil for various concentrations was assessed on the basis of percent scavenging of (DPPH) free radical. Experimental animals were divided into five groups, eight rabbits in each group. These were: group A (Normal control), group B (Toxic control), group C (Standard control), group D (Treated with Coconut Oil 50 mL/kg body weight after CCl4 intoxication), group E (Treated with Coconut Oil 200 mL/kg body weight after CCl4 intoxication). The effects observed were compared with a standard hepatoprotective drug silymarine (50 mL/kg body weight). The Coconut Oil (200 mL/kg body weight) significantly (P<0.05) reduced the elevated serum levels of alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) when compared to a toxic control rabbits. The results of extract treated rabbits were similar to silymarine administered rabbits group. Treatment with Coconut Oil root and silymarine caused no significant changes in RBC, Platelets, (Hb), (MCH) concentration and (HCT) values. However, significant (P<0.05) increase was observed in the total WBC count. The present study suggested that Coconut Oil can be used as an herbal alternative (need further exploration i.e to detect its bioactive compound and its efficacy) for hepatoprotective activity.

Therapeutic potential of stem cell and melatonin on the reduction of CCl4-induced liver fibrosis in experimental mice model.

Liver fibrosis is initial stage of any chronic liver disease and its end stage is develops into cirrhosis. Chronic liver diseases are a crucial global health issue and the cause of approximately 2 million deaths per year worldwide. Cirrhosis is currently the 11th most common cause of death globally. Mesenchymal stem cell (MSCs) treatment is the best way to treat acute and chronic liver disease. The aim of this study is to improve the therapeutic potential of MSCs combined with melatonin (MLT) to overcome CCl4-induced liver fibrosis and also investigate the individual impact of melatonin and MSCs against CCl4-induced liver impairment in animal model. Female BALB/c mice were used as CCL4-induced liver fibrotic animal model. Five groups of animal model were made; negative control, Positive control, CCl4+MSCs treated group, CCl4+MLT treated group and CCl4+MSCs+MLT treated group. Cultured MSCs from mice bone marrow were transplanted to CCl4-induced liver injured mice model, individually as well as together with melatonin. Two weeks after MSCs and MLT administration, all groups of mice were sacrificed for examination. Morphological and Histopathological results showed that combined therapy of MSCs+MLT showed substantial beneficial impact on CCl4-induced liver injured model, compared with MSCs and MLT individually. Biochemically, considerable reduction was observed in serum bilirubin and ALT levels of MLT+MSC treated mice, compared to other groups. PCR results shown down-regulation of Bax and up-regulation of Bcl-xl and Albumin, confirm a significant therapeutic effect of MSCs+MLT on CCI4-induced liver fibrosis. From the results, it is concluded that combined therapy of MSCs and MLT show strong therapeutic effect on CCL4-induced liver fibrosis, compared with MSCs and MLT individually.

A study on the antioxidant activity of rosmarinic acid against carbon tetrachloride-induced liver toxicity in adult male albino rats / Estudio sobre la actividad antioxidante del ácido rosmarínico contra la toxicidad hepática inducida por tetracloruro de carbono en ratas albinas macho adultas

SUMMARY: Carbon tetrachloride (CCl4) is a manufactured chemical and does not occur naturally in the environment. CCl4 is a clear liquid that evaporates very easily. It has a sweet odor. CCl4 is toxic to the mammalian liver and is hepatocarcinogenic in both rats and mice. Rosemary (Rosmarinus Officinalis) is commonly used as a spice and flavoring agent in food processing. It is known for its antioxidant properties. The present study aims to investigate the antioxidant activity of rosmarinic acid (RA) on CCl4-induced liver toxicity in adult male albino rats. Forty adult male albino rats were divided into 4 groups with 10 rats in each group. Group I (control group). Group II animals received RA at a dose of 50 mg/kg/day by oral gavage for 4 weeks. Group III animals received CCl4 intraperitoneally at a dose of 3ml/kg twice weekly for 4 weeks. Group IV animals received CCl4 Plus RA. At the end of the experiment, liver specimens are processed for histological, immunohistochemical, EM and biochemical studies. Administration of RA deceased the elevated serum liver enzymes (AST, ALT, and ALP), elevated MDA level and immunoexpression of the proapoptotic protein (Bax) induced by CCl4. It increased reduced glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and immunoexpression of the antiapoptotic protein (Bcl2). It also improved the histological and ultrastructural changes induced by CCl4. It appears that Rosmarinic acid has protective effects against CCl4-induced hepatotoxicity as indicated by biochemical, histological, immunohistochemical and ultrastructural results.

RESUMEN: El tetracloruro de carbono (CCl4) es un producto químico fabricado y no se encuentra de forma natural en el medio ambiente. CCl4 es un líquido transparente que se evapora fácilmente; tiene un olor dulce. CCl4 es tóxico para el hígado de los mamíferos y es hepatocarcinogénico tanto en ratas como en ratones. El romero (Rosmarinus officinalis) se usa comúnmente como condimento y agente aromatizante en el procesamiento de alimentos. Es conocido por sus propiedades antioxidantes. El presente estudio tuvo como objetivo investigar la actividad antioxidante del ácido rosmarínico (RA) sobre la toxicidad hepática inducida por CCl4 en ratas albinas macho adultas. Se dividieron cuarenta ratas albinas macho adultas en 4 grupos con 10 ratas en cada grupo. Grupo I (grupo control). Los animales del grupo II recibieron AR a una dosis de 50 mg / kg / día por sonda oral durante 4 semanas. Los animales del grupo III recibieron CCl4 por vía intraperitoneal a una dosis de 3 ml / kg dos veces por semana durante 4 semanas. Los animales del grupo IV recibieron CCl4 Plus RA. Al final del experimento, las muestras de hígado se procesaron para estudios histológicos, inmunohistoquímicos, EM y bioquímicos. La administración de AR eliminó las enzimas hepáticas séricas elevadas (AST, ALT y ALP), el nivel elevado de MDA y la inmunoexpresión de la proteína proapoptótica (Bax) inducida por CCl4. Aumentó el glutatión reducido (GSH), glutatión peroxidasa (GSH-Px), la superóxido dismutasa (SOD) y la inmunoexpresión de la proteína antiapoptótica (Bcl2). También mejoró los cambios histológicos y ultraestructurales inducidos por CCl4. El ácido rosmarínico puede tener efectos protectores contra la hepatotoxicidad inducida por CCl4, tal como lo indican los resultados bioquímicos, histológicos, inmunohistoquímicos y ultraestructurales.

In vivo protective effect of cinnamon aqueous extract in carbon tetrachloride-treated male albino rats

The liver as an organ is important for the metabolism of drugs and toxins. However, it is not immune from environmental insults. Exposure of liver cells to carbon tetrachloride (CCl4) results in the generation of tricholoromethyl radicals, which induce liver toxicity. This study aims at investigating the ameliorative effect of the cinnamon aqueous extract (CAE) against CCl4-induced hepatotoxicity in male albino rats. Hepatotoxicity was induced in rats through the intraperitoneal administration of 0.5 mL kg-1body weight of CCl4. The analyses of the results obtained showed significant reduction in the levels of serum biochemical markers for 400 and 600 mg kg-1bw of CAE protected rats as compared with CCl4group. In addition, CAE administration reversed liver tissue damaged via increased antioxidants markers. Histopathological examination of CAE treatment on rats showed improved changes to the liver damage caused by CCl4 with no evidence of steatosis and inflammation. This result hence suggests that CAE has marked hepatoprotective and healing activities against CCl4-induced liver damage and could serve as a suitable candidate in drug discovery for the treatment of liver toxicity.

Increased Purinergic Responses Dependent on P2Y2 Receptors in Hepatocytes from CCl4-Treated Fibrotic Mice.

Inflammatory and wound healing responses take place during liver damage, primarily in the parenchymal tissue. It is known that cellular injury elicits an activation of the purinergic signaling, mainly by the P2X7 receptor; however, the role of P2Y receptors in the onset of liver pathology such as fibrosis has not been explored. Hence, we used mice treated with the hepatotoxin CCl4 to implement a reversible model of liver fibrosis to evaluate the expression and function of the P2Y2 receptor (P2Y2R). Fibrotic livers showed an enhanced expression of P2Y2R that eliminated its zonal distribution. Hepatocytes from CCl4-treated mice showed an exacerbated ERK-phosphorylated response to the P2Y2R-specific agonist, UTP. Cell proliferation was also enhanced in the fibrotic livers. Hepatic transcriptional analysis by microarrays, upon CCl4 administration, showed that P2Y2 activation regulated diverse pathways, revealing complex action mechanisms. In conclusion, our data indicate that P2Y2R activation is involved in the onset of the fibrotic damage associated with the reversible phase of the hepatic damage promoted by CCl4.

Hepatoprotective effect of a fucoidan extract from Sargassum fluitans Borgesen against CCl4-induced toxicity in rats.

The in vivo antifibrotic effect of a fucoidan extract (FE) from Sargassum fluitans Borgesen was evaluated in a carbon tetrachloride-induced liver damage model in rats over twelve weeks. Chemical analysis showed the FE to contain carbohydrates, sulfates, uronic acids, protein, phenols, and to have a molecular weight of ~60 kDa. Physiological, biochemical, histological and genetic assays were done. Daily oral administration of FE (50 mg/kg) reduced liver enzymatic activity, liver infiltration of inflammatory cells, collagen fiber deposition and gene expression cytokines such as interleukin beta 1 (IL-ß1), tumor necrosis factor alpha (TNF-α), transforming growth factor beta 1 (TGF-ß1), Smad-3, Smad-2, collagen 1 alpha 1 (col1α1) and tissue inhibitor of metalloproteinase 1 (TIMP-1). It also increased RNA expression of Smad-7 and metalloproteinase 2 and 9 (MMP2 and MMP9). The fucoidan extract exhibited an antifibrotic effect mediated by the inhibiting TGF-ß1/Smad pathway, as well as anti-inflammatory effects.

miR-125b acts as anti-fibrotic therapeutic target through regulating Gli3 in vivo and in vitro.

INTRODUCTION AND OBJECTIVES: Liver fibrosis is a major characteristic of most chronic liver diseases which leads to accumulation of extracellular matrix (ECM) proteins. Hedgehog (Hh) pathway activated by Gli genes participated in the pathogenesis of liver fibrosis. However, the regulatory role of miR-125b in liver fibrosis via targeting Gli genes remains unknown. MATERIALS AND METHODS: RT-qPCR and western blot were employed to the expression levels of mRNA and protein, respectively. The fibrosis level of liver tissue was determined by Masson's trichrome staining. The interaction between miR-125b and Gli3 was tested by luciferase reporter assay. In addition, LX2 cells were activated and CCl4-induced rat model was used in this study. RESULTS: miR-125b was significantly declined in serum samples of the clinical liver fibrosis patient, activated LX2 cells and the liver tissues of the CCl4-induced rat model. Furthermore, in cellular level, the alpha-smooth muscle actin (α-SMA) and Albumin expressions were ascending and descending in LX2 cells, respectively, with the decline of miR-125b. However, when transfecting with miR-125b mimic, the expressions of α-SMA and Albumin was reversed and Gli3 expression was notably repressed in LX2 cells. The target interaction between miR-125b and Gli3 was determined by dual-luciferase assays. It was further discovered that the changes of α-SMA, Albumin, and Gli3 were similar to the expression trend in LX2 cells with miR-125b mimic transfection. CONCLUSION: These results suggested that miR-125b might be protective against liver fibrosis via regulating Gli3 and it might be a promising target in the development of novel therapies to treat pathological fibrotic disorders.

The GLP-1 analog liraglutide attenuates acute liver injury in mice.

INTRODUCTION AND OBJECTIVES: Acute liver injury is a current health problem with few effective treatments. The present study investigated the hepatoprotective and curative potential of the glucagon-like peptide-1 analog liraglutide against carbon tetrachloride (CCl4)-induced hepatotoxicity. MATERIALS AND METHODS: Male Swiss mice were subjected to two protocols. The first protocol (Pretreatment) consisted of intraperitoneal (i.p.) treatment with liraglutide (0.057 and 0.118mgkg-1) or vehicle (distilled water) once daily for 7 days. On days 6 and 7, the animals were challenged with 2% CCl4 (5mgkg-1, i.p.). The second protocol (Late treatment) began with an injection of 5% CCl4 (5mgkg-1, i.p.) and subsequent treatment with liraglutide (0.057mgkg-1) or vehicle (distilled water) for 1 day. In both protocols, 24h after the last administration, blood and bile were collected from anesthetized animals, followed by euthanasia and liver collection. Plasma and bile underwent biochemical analyses, and histological, oxidative stress, and metabolic parameters were evaluated in the liver. RESULTS: Both liraglutide treatment protocols attenuated hepatotoxicity that was induced by CCl4, decreasing plasma levels of hepatic enzymes, stimulating the hepatic antioxidant system, and decreasing centrilobular necrosis, hepatic glycogen, and lipid accumulation. CCl4 tended to reduce bile lipid excretion, but liraglutide did not influence this parameter. CONCLUSIONS: The present results demonstrated the hepatoprotective and therapeutic effects of liraglutide, which may be attributable to a decrease in liver oxidative stress and the preservation of metabolism. Liraglutide may have potential as a complementary therapy for acute liver injury.

Advantages of adipose tissue stem cells over CD34+ mobilization to decrease hepatic fibrosis in Wistar rats.

INTRODUCTION AND OBJECTIVES: Chronic liver inflammation may lead to hepatic cirrhosis, limiting its regenerative capacity. The clinical standard of care is transplantation, although stem cell therapy may be an alternative option. The study aim was to induce endogenous hematopoietic stem cells (HSCs) with granulocyte colony stimulating factor (G-CSF) and/or intravenous administration of adipose tissue-derived mesenchymal stem cells (MSCs) to decrease hepatic fibrosis in an experimental model. MATERIAL AND METHODS: A liver fibrosis model was developed with female Wistar rats via multiple intraperitoneal doses of carbon tetrachloride. Three rats were selected to confirm cirrhosis, and the rest were set into experimental groups to evaluate single and combined therapies of G-CSF-stimulated HSC mobilization and intravenous MSC administration. RESULTS: Treatment with MSCs and G-CSF significantly improved alanine amino transferase levels, while treatment with G-CSF, MSCs, and G-CSF+MSCs decreased aspartate amino transferase levels. Hepatocyte growth factor (HGF) and interleukin 10 levels increased with MSC treatment. Transforming growth factor ß levels were lower with MSC treatment. Interleukin 1ß and tumor necrosis factor alpha levels decreased in all treated groups. Histopathology showed that MSCs and G-CSF reduced liver fibrosis from F4 to F2. CONCLUSIONS: MSC treatment improves liver function, decreases hepatic fibrosis, and plays an anti-inflammatory role; it promotes HGF levels and increased proliferating cell nuclear antigen when followed by MSC treatment mobilization using G-CSF. When these therapies were combined, however, fibrosis improvement was less evident.

Effects of the ingestion of different kinds of white grape juice (Vitis labrusca) during adolescence on body weight, biochemical parameters and oxidative stress in liver of adult Wistar rats.

The objective of this study was to evaluate the effects of the ingestion of different white grape juices: organic, conventional and conventional grape juice with 5% lemon juice during adolescence on biochemical serum profile and oxidative stress level in liver of adult Wistar rats. The phenolic and vitamin C composition of the juices were evaluated. During 32 days the rats were treated with the juices or oral water (gavage) for at a dose of 7 µL/g body weight. The animals were divided into 4 groups (n = 16/each). In the end, half of the animals received an intraperitoneal CCl4 injection of 3.0 mL/kg; the other ones received mineral oil. After euthanasia, biochemical parameters were evaluated in serum and oxidative stress in the liver. It is possible to emphasize that the juices have different phenolic and vitamin C contents. The juice consumption didn't alter the weight body and biochemical parameters in adult life.

The hydroethanolic Litchi chinensis leaf extract alleviate hepatic injury induced by carbon tetrachloride (CCl4) through inhibition of hepatic inflammation.

Various medicinal plants are traditionally used in a hepatoprotective manner, like, for example, the Litchi chinensis leaf infusion that is employed in Chinese medicine as liver tonics to strengthen hepatic functioning. In this context, the present study was designed to evaluate the hepatoprotective and acute toxicological effects of hydroethanolic L. chinensis leaf extract in HepG2 cells and mice. Specifically, the cytotoxicity and hepatoprotective activities of L. chinensis leaf extract were evaluated in HepG2 cells and in vivo against carbon tetrachloride (CCl4)-induced acute liver injury. The administration of CCl4 in mice provokes cell swelling, loss of sinusoid capillary spaces and structural disarrangement of the hepatic lobe, apoptosis and leukocyte infiltration. Further, CCl4 evokes an increase in serum alanine aminotransferase (ALT), tumor necrosis factor (TNF) and interleukin-6 (IL-6) levels in hepatic tissue. However, Silymarin, the positive control, and the L. chinensis extract were able to restore the viability of cells treated with CCl4 at all concentrations evaluated, reduced the inflammatory parameters, TNF and IL-6, reestablished hepatic tissue morphology and did not induce acute toxicological alterations. The data obtained underscore that the extract from L. chinensis leaves features hepatoprotective activity, corroborating with ethnopharmacological use, and does not lead to acute toxicological effects.

Stereological assessment of nephroprotective effects of Trachyspermum ammi essential oil against carbon tetrachloride-induced nephrotoxicity in mice / Evaluación estereológica de los efectos nefroprotectores del aceite esencial de Trachyspermum ammi contra la nefrotoxicidad inducida por tetracloruro de carbono en ratones

Trachyspermum ammi (T. ammi) has been used in folk medicine as anti-inflammatory, antipyretic, antibacterial, antifungal agent. The present study was conducted to investigate the protective effect of Trachyspermum ammi (T. ammi) essential oil against CC14- induced nephrotoxicity in mice. Thirty-five mice were divided into five groups as follows; positive control received olive oil 1 mL/ kg/ip, negative control received CC14 1 mg/kg/ip + 0.5 mL distilled water orally and tree treatment groups which received CC14 similar to the negative control and 200, 800 and 1600 µg/kg of T. ammi essential oil, respectively. All treatments were done twice a week (Saturday and Wednesday) for 45 days. On the last day, blood was sampled for urea and creatinine assessment and the left kidney was removed for stereological estimations. Essential oil of T. ammi at high dose significantly (p ≤ 0.05) decreased serum levels of creatinine and urea in comparison with CC14-treated group. Total volume of the kidney, cortex, proximal convoluted tubules (PC), glomerulus, vessels and interstitial tissue as well as total length of PC and vessel were significantly (p ≤ 0.05) increased following CC14 administration and were restored toward normal levels at high dose of T. ammi. Also, high dose of T. ammi improved glomerular loss significantly (p ≤ 0.05) as compared with CC14-treated group. Due to the chemical composition of T. ammi essential oil such as tymol, p-cymene, γ-terpinene which are antioxidant, it can be concluded that the essential oil of T. ammi can ameliorated renal injury induced following CC14 toxicity via its antioxidant components.

En la medicina popular se ha utilizado el aceite esencial de Trachyspermum ammi (T. ammi) como agente antiinflamatorio, antipirético, antibacteriano y anti fúngico. El presente estudio se realizó para investigar el efecto protector de Trachyspermum ammi (T. ammi) aceite esencial contra la nefrotoxicidad inducida en ratones. Treinta y cinco ratones fueron divididos en cinco grupos de la siguiente manera; el control positivo recibió 1 mL / kg / ip de aceite de oliva, el control negativo recibió 1 mg / kg / ip + 0,5 mL de agua destilada por vía oral y grupos de tratamiento arbóreo que recibieron un control similar al negativo y 200, 800 y 1600 mg / kg de T. aceite esencial de T. ammi, respectivamente. Todos los tratamientos se realizaron dos veces por semana (sábado y miércoles) durante 45 días. En el último día de tratamiento, se tomaron muestras de sangre para evaluar la urea y la creatinina, y se extrajo el riñón izquierdo para realizar estimaciones estereológicas. El aceite esencial de T. ammi a dosis altas significativamente (p ≤ 0,05) disminuyó los niveles séricos de creatinina y urea en comparación con el grupo tratado. El volumen total del riñón, la corteza, los túbulos contorneados proximales (PC), el glomérulo, los vasos y el tejido intersticial, así como la longitud total de la PC y el vaso aumentaron significativamente (p ≤ 0,05) después de la administración y se restablecieron a niveles normales con dosis altas de T. ammi. Además, una dosis alta de T. ammi mejoró significativamente la pérdida glomerular (p ≤ 0,05) en comparación con el grupo tratado. Debido a la composición química del aceite esencial de T. ammi como timol, p-cimeno, 𝛾-terpineno con propiedades antioxidantes, se puede concluir que el aceite esencial de T. ammi puede mejorar la lesión renal inducida después de la toxicidad a través de sus componentes antioxidantes.

Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin, TGF-ß1, IL-13 and oxidative stress.

AIM: To evaluate the therapeutic effects of bone marrow-derived CD11b+CD14+ monocytes in a murine model of chronic liver damage. METHODS: Chronic liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry, biochemical assessment, immunohistochemistry and enzyme-linked immunosorbent assay. RESULTS: CD11b+CD14+ monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6 and IL-1ß, in addition to pro-fibrotic factors, such as IL-13, transforming growth factor-ß1 and tissue inhibitor of metalloproteinase-1 also decreased, while IL-10 and matrix metalloproteinase-9 increased in the monocyte-treated group. CD11b+CD14+ monocyte transplantation caused significant changes in the hepatic expression of α-smooth muscle actin and osteopontin. CONCLUSION: Monocyte therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation, as well as increasing anti-fibrogenic factors.

Evaluation of liver fibrosis using Raman spectroscopy and infrared thermography: A pilot study.

Liver fibrosis is a pathological process that can escalate to cirrhosis and then liver failure, a major public health concern that affect hundreds of millions of people in both developed and developing countries. Detection of liver fibrosis during its earlier stages is a matter of great importance which may allow prevention of development of cirrhosis in patients with chronic liver disease. In this work, Raman spectroscopy and thermography were evaluated to detect early pathological signs of liver fibrosis in rats in which liver fibrosis was induced using carbon tetrachloride. Results show that Raman spectra of healthy and fibrotic livers significantly differ among each other and can be classified by principal component analysis and discriminant analysis. The PCA-LDA method has a sensitivity of 100%, specificity 85% and diagnostic accuracy of 93.5%. Thermography also revealed characteristic temperature patterns for fibrotic livers compared to healthy livers. Current data suggest that Raman spectroscopy and thermography could be used to detect fibrosis in ex vivo liver samples.