Acute Hepatic Injury Model Research Articles

Pharmacokinetic-pharmacodynamic (PK/PD) modeling to study the hepatoprotective effect of Perilla Folium on the acute hepatic injury rats

Ethnopharmacological relevancePerilla Folium (PF), is a traditional medicinal material with the homology of medicine and food in China and has been widely used due to its rich nutritional content and medicinal value. The hepatoprotective effects of PF extract include their protection against acute hepatic injury, tert-butylhydroperoxide (t-BHP) induced oxidative damage, and Lipopolysaccharide (LPS) and D-galactosamine (D-GalN) induced hepatic injury have been well studied. However, there are few reports on the pharmacokinetics studies of PF extract in acute hepatic injury model rats, and the anti-hepatic injury activity of PF is still unclear. Aim of the studyThe differences in the plasma pharmacokinetic of 21 active compounds between the normal and model groups were compared， and established pharmacokinetics/pharmacodynamics (PK/PD) modeling was to analyze the hepatoprotective effects of PF. Materials and methodsThe acute hepatic injury model was induced with an intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-GalN), and the plasma pharmacokinetics of 21 active compounds of PF were analyzed in the normal and model groups using ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). The correlation between plasma components and hepatoprotective effects indicators (the alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactic dehydrogenase (LDH)) in the model group was also investigated and established a Pharmacokinetic/pharmacodynamic (PK/PD) correlation analysis of the hepatoprotective effects of PF. ResultsThe results revealed that organic acid compounds possessed the characteristics of faster absorption, shorter peak time and slower metabolism, while the flavonoid compounds had slower absorption and longer peak time, and the pharmacokinetics of various components were significantly affected after modeling. The results of PK/PD modeling analysis demonstrated that the plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long. ConclusionsThe plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long in vivo.

Canagliflozin attenuates thioacetamide-induced liver injury through modulation of HMGB1/RAGE/TLR4 signaling pathways

Thioacetamide (TAA), a classic liver toxic compound, is used to establish experimental models of liver injury via induction of inflammation and oxidative stress. The current study was employed to explore the effects of canagliflozin (CANA), a sodium glucose cotransporter 2 (SGLT-2) inhibitor and antidiabetic agent, on TAA-induced acute liver injury. MethodsA rat model of acute hepatic injury was established using single intraperitoneal injection of TAA (500 mg/kg) and rats received CANA (10 and 30 mg/kg, orally) once daily for 10 days prior to TAA challenge. Liver function, oxidative stress, and inflammatory parameters were measured in serum and hepatic tissues of rats. ResultsElevated levels of liver enzymes, hepatic malondialdehyde (MDA), and serum lactate dehydrogenase (LDH) were significantly attenuated by CANA. CANA also increased hepatic superoxide dismutase (SOD) and glutathione (GSH). Hepatic levels of high-mobility group box 1 (HMGB1), toll like receptor4 (TLR4), receptor for advanced glycation end products (RAGE), and pro-inflammatory cytokines (IL-6, and IL-1β) were normalized with CANA. Additionally, Hepatic expression of p-JNK/p-p38 MAPK was significantly attenuated by CANA compared to TAA-treated rats. CANA also decreased hepatic immunoexpression of NF-κB and TNF-α and attenuated hepatic histopathological alterations via reduction of inflammation and necrosis scores and collagen deposition. Moreover, mRNA expression levels of TNF-α and IL-6 were reduced upon CANA treatment. ConclusionCANA attenuates TAA-prompted acute liver damage, via suppressing HMGB1/RAGE/TLR4 signaling, regulation of oxidative stress and inflammation pathways.

Strategic application of liposomal system to R-α-lipoic acid for the improvement of nutraceutical properties

R-α-lipoic acid (RLA) and dihydrolipoic acid (DHLA), a reduced form of RLA, are potent endogenous antioxidants that can reduce oxidative damage. Despite their numerous nutraceutical potentials, clinical applications of RLA are still limited due to its poor solubility and stability problems. This study aimed to develop an RLA-loaded liposome (LIP/RLA) for the improvement of nutraceutical properties. LIP/RLA was developed by a typical solvent injection method. Uniform liposomes of LIP/RLA were observed by transmission electron microscopy, and the mean particle size was calculated to be ∼150 nm from the data of dynamic light scattering. LIP/RLA could prevent the degradation of RLA even under acidic conditions (pH 1.2) possibly due to the encapsulation of RLA into the liposomal structure. In the release test under pH6.8 with lipase, LIP/RLA showed relatively rapid release of RLA, possibly due to the lipolysis of phospholipids by lipase. After the oral administration of LIP/RLA (10 mg-RLA/kg, p.o.) in rats, the systemic exposures of RLA and DHLA increased by 2.8- and 5.8-fold, respectively. In a rat model of acute hepatic injury induced by carbon tetrachloride (CCl4) (0.7 mL-CCl4/kg, p.o.), orally dosed LIP/RLA (3 mg-RLA/kg, p.o.) resulted in 78.7% and 86.4% reductions of plasma alanine aminotransferase, and aspartate aminotransferase, respectively; however, RLA was found to be less effective possibly due to the poor oral absorption. The RLA-loaded liposomal system might be a promising carrier for poorly water-soluble materials with poor stability under acidic conditions, as well as RLA, to improve their oral absorption and nutraceutical properties.

SERP1 reduces inchoate acute hepatic injury through regulation of endoplasmic reticulum stress via the GSK3β/β‑catenin/TCF/LEF signaling pathway.

The liver is a crucial digestive organ of humans and in charge of detoxification. Acute hepatic injury is an aggressive type of hepatic disease and its harmful effect cannot be ignored. The present study examined the role and mechanism of stress-associated endoplasmic reticulum protein 1 (SERP1) in acute hepatic injury. Mice were injected intraperitoneally with D-galactosamine/lipopolysaccharide (LPS) and rat hepatocytes were induced by LPS to establish an acute hepatic injury model. Tissue lesions were observed by H&E staining, and biomarkers of hepatic injury in the serum were examined. Western blotting, immunohistochemistry and reverse transcription-quantitative PCR were performed to assess SERP1 expression in tissues and hepatocytes. A SERP1 overexpression plasmid was constructed to evaluate the role of SERP1 in inflammation, apoptosis, endoplasmic reticulum stress (ERS) and the GSK3β/β-catenin/T-cell factor (TCF)/lymphoid enhancing factor (LEF) signaling pathway. In addition, a GSK3β overexpression plasmid was constructed to investigate the role of GSK3β/β-catenin signal activation. Additionally, the present study investigated whether SERP1 regulated the endoplasmic reticulum via this pathway. In the present study, reliable animal and cellular hepatic injury models were established and verified. SERP1 overexpression reduced the expression of inflammatory factors, apoptosis-related proteins and ERS-related proteins, as well as the expression of proteins related to GSK3β/β-catenin/TCF/LEF signaling pathways. A GSK3β overexpression plasmid was constructed and it was revealed that GSK3β overexpression could reverse the effects of SERP1 overexpression in aforementioned aspects. This suggested that the activation of the GSK3β/β-catenin/TCF/LEF signaling pathway may be required for the regulation of SERP1. In conclusion, SERP1 regulated ERS via the GSK3β/β-catenin/TCF/LEF signaling pathway, thereby reducing inchoate acute hepatic injury.

Self-emulsifying drug delivery system of black seed oil with improved hypotriglyceridemic effect and enhanced hepatoprotective function

Abstract Black Seed Oil (BSO), obtained from the seeds of black cumin (Nigella sativa), has antioxidant, anti-inflammatory, and hepatoprotective effects. The present study was aimed to develop a self-emulsifying drug delivery system (SEDDS) of BSO, to improve hypotriglyceridemic and hepatoprotective function. SEDDS-BSO formed fine micelles with a mean droplet size of 183 nm and improved the dispersion behavior of BSO in water as evidenced by at least 2.6-fold higher dispersibility compared with BSO. In the CCl4-treated rat model of acute hepatic injury, SEDDS-BSO (10 mg-BSO/kg, p.o.) led to 91.7% and 86.8% reductions of alanine aminotransferase and aspartate aminotransferase, respectively, suggesting that SEDDS-BSO could attenuate hepatotoxicity compared to BSO. In addition, repeated oral administration of SEDDS-BSO (10 mg-BSO/kg, p.o.) for 7 days had a potent hypotriglyceridemic effect on rats with corn-oil-induced hypertriglyceridemia compared to BSO. Therefore, the SEDDS approach might be an efficacious dosage option to enhance the nutraceutical properties of BSO.

MicroRNA-199a-3p inhibits hepatic apoptosis and hepatocarcinogenesis by targeting PDCD4

Hepatic apoptosis and the initiated liver inflammation play the initial roles in inflammation-induced hepatocarcinogenesis. Molecular mechanisms underlying the regulation of hepatocyte apoptosis and their roles in hepatocarcinogenesis have attracted much attention. A set of microRNAs (miRNAs) have been determined to be dysregulated in hepatocellular carcinoma (HCC) and participated in cancer progression, however, the roles of these dysregulated miRNAs in carcinogenesis are still poorly understood. We previously analyzed the dysregulated miRNAs in HCC using high-throughput sequencing, and found that miR-199a/b-3p was abundantly expressed in human normal liver while markedly decreased in HCC, which promotes HCC progression. Whether miR-199a/b-3p participates in HCC carcinogenesis is still unknown up to now. Hence, we focused on the role and mechanism of miR-199a/b-3p in hepatocarcinogenesis in this study. Hepatic miR-199a/b-3p was determined to be expressed by miR-199a-2 gene in mice, and we constructed miR-199a-2 knockout and hepatocyte-specific miR-199a-2 knockout mice. Diethylnitrosamine (DEN)-induced hepatocarcinogenesis were markedly increased by hepatocyte-specific miR-199a-3p knockout, which is mediated by the enhanced hepatocyte apoptosis and hepatic injury by DEN administration. In acetaminophen (APAP)-induced acute hepatic injury model, hepatocyte-specific miR-199a-3p knockout also aggravated hepatic apoptosis. By proteomic screening and reporter gene validation, we identified and verified that hepatic programed cell death 4 (PDCD4), which promotes apoptosis, was directly targeted by miR-199a-3p. Furthermore, we confirmed that miR-199a-3p-suppressed hepatocyte apoptosis and hepatic injury by targeting and suppressing PDCD4. Thus, hepatic miR-199a-3p inhibits hepatocyte apoptosis and hepatocarcinogenesis, and decreased miR-199a-3p in hepatocytes may aggravate hepatic injury and HCC development.

Deficiency of apoptosis-stimulating protein 2 of p53 protects mice from acute hepatic injury induced by CCl4 via autophagy

BackgroundApoptosis-stimulating protein 2 of p53 (ASPP2) has a variety of biological functions, and is involved in cellular apoptosis, autophagy and inflammatory reaction. However, the role of ASPP2 in acute hepatic injury remains unclear. MethodsWe established an animal model of acute hepatic injury by intraperitoneal injection of CCl4. The expression profile of ASPP2 was measured in wild type (ASPP2+/+) mice with acute hepatic injury induced by CCl4. Hepatic pathological changes and liver function, apoptosis, inflammation and autophagic levels were measured in ASPP2+/+and ASPP2 haploid deletion (ASPP2+/−) mice with acute hepatic injury, respectively. After 3-methyladenine (3-MA) treatment, indicators of hepatic injury were observed in ASPP2+/+and ASPP2+/- mice with CCl4 injection. ResultsDuring the development of acute hepatic injury, ASPP2 expression significantly upregulated at 24 h and 48 h after CCl4 injection. ASPP2 haplotype deletion protected against acute hepatic injury, and this was mainly reflected in decreased ALT and AST levels, less hepatic tissue hemorrhage and necrosis, and reduced cellular inflammation and apoptosis in ASPP2+/− mice compared with ASPP2+/+ mice with acute hepatic injury. ASPP2 haploid deletion activates autophagy in mice with acute hepatic injury, and protects mice from acute hepatic injury via the autophagic signal pathway. ConclusionASPP2 haplotype deletion protected mice against acute hepatic injury through autophagy activation, which inhibited inflammation and apoptosis in acute hepatic injury.

Improved biopharmaceutical properties of carvedilol employing α-tocopheryl polyethylene glycol 1000 succinate-based self-emulsifying drug delivery system

The main objective of this study was to develop a self-emulsifying drug delivery system (SEDDS) of carvedilol (CAR) with improved oral absorption and hepatoprotective properties. SEDDS-CAR was prepared based on d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and physicochemically characterized. Pharmacokinetic behaviors after the oral administration of CAR samples in rats were evaluated to clarify the possible enhancement of the oral absorption of CAR. The hepatoprotective effects of orally dosed CAR samples were assessed in a rat model of acute hepatic injury induced by carbon tetrachloride (CCl4). SEDDS-CAR showed the immediate formation of fine micelles with a mean droplet size of 84 nm when introduced in aqueous media. SEDDS-CAR improved the dissolution behavior of CAR in distilled water as evidenced by at least five-fold higher solubility than the equilibrium solubility of CAR. After the single oral administration of SEDDS-CAR (10 mg-CAR/kg) in rats, enhanced CAR exposure was observed with an increase of AUC0–∞ showing a 2.5-fold increase compared with crystalline CAR. In CCl4-treated rats, orally dosed SEDDS-CAR (10 mg-CAR/kg, p.o.) led to 91.8 and 91.2% reductions of ALT and AST, respectively; however, crystalline CAR was found to be less effective. From these findings, SEDDS-CAR might be an efficacious oral dosage option for enhancing the hepatoprotective potential of CAR.

Cilostazol attenuates indices of liver damage induced by thioacetamide in albino rats through regulating inflammatory cytokines and apoptotic biomarkers

Even though cilostazol was assessed before in several models of atherosclerosis, so far its full systematic effect as a natural anti-inflammatory and anti-apoptotic mediator in the protection of liver damage and complication has not been fully clarified, which is the target of this study. For that purpose, we examined the protective effect of cilostazol (10 and 5mg/kg, p.o. b.wt.) in an acute hepatic injury model by orally injecting it for 3 weeks prior to a single dose of TAA (300mg/kg, i.p) injection. Ursodeoxycholic acid was used as a standard drug (50mg/kg, p.o. b.wt.). After injection of thioacetamide by 48hr, rats were sacrificed. On the serum biochemical level, cilostazol ameliorated the thioacetamide consequence, where it presented a significant enhancement in the liver enzymes activities [Aspartate aminotransferase (AST) & Alanine aminotransferase (ALT)]. On the other hand, at the tissue level (Liver), it revealed a significant improvement in pro-inflammatory cytokines [Tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), Nuclear factor kappa B (NF-κB), NF-κB (P65/P50 nucleus translocation), caspase-3, cleaved caspase-3 & C-reactive protein (CRP)], redox level [Reduced glutathione (GSH) & Malondialdehyde (MDA)], histopathological findings, Reverse transcription polymerase chain reaction (RT-PCR) analysis (expression of TNF-α and NF-κB mRNA levels), and immunohistochemical reaction (caspase-3 & TNF-α). Obviously, the high dose of cilostazol (10mg/kg, p.o. b.wt.) displayed a more pronounced effect than its lower one and nearly equal to ursodeoxycholic acid in the most of the parameters. These results give a new awareness into the hopeful molecular mechanisms by which cilostazol attenuates several factors participated in the progression of liver damage.

Effects of mannose density on in vitro and in vivo cellular uptake and RNAi efficiency of polymeric nanoparticles

To evaluate the effects of mannose density on in vitro and in vivo cellular uptake and RNA interference (RNAi) efficiency of polymeric nanoparticles (NPs) in macrophages, mannose-modified trimethyl chitosan-cysteine (MTC) conjugates with mannose densities of 4%, 13%, and 21% (MTC-4, MTC-13, and MTC-21) were synthesized. Tumor necrosis factor-alpha (TNF-α) siRNA loaded MTC NPs with particle sizes of ∼150 nm exhibited desired structural stability and effectively protected siRNA from enzymatic degradation. Generally, cellular uptake and RNAi efficiency were affected by mannose density. As expected, MTC-21 NPs presented the maximum in vitro uptake and RNAi efficacy in Raw 264.7 cells among all NPs tested. However, MTC-4 NPs exhibited the optimal in vivo uptake by peritoneal exudate cell macrophages (PECs). In the inflammation model of acute hepatic injury, orally delivered MTC-4 and MTC-13 NPs worked better in silencing TNF-α expression and alleviating liver damage than MTC-21 NPs. As for the ulcerative colitis model, MTC-4 NPs outperformed MTC-13 and MTC-21 NPs with respect to TNF-α knockdown and therapeutic efficacy following oral administration. These results highlighted the importance of ligand density in cellular uptake and RNAi efficiency, which could serve as a guideline in the rational design of targeted nanocarriers for anti-inflammation therapy.

Hepatoprotective and urease inhibitory activities of garlic conjugated gold nanoparticles

Garlic conjugated gold nanoparticles were successfully synthesized and their hepatoprotective potential was determined in a CCl4-induced acute hepatic injury model.

Protective effects of hesperidin on concanavalin A-induced hepatic injury in mice.

Hesperidin (HDN) is a citrus bioflavonoid, which widely exists in many plants. Previous researches have proved that HDN has several functions such as anti-oxidant, anti-tumor, anti-inflammatory, immune regulation and so on. In the present study, we explored the protective effects of HDN on concanavalin A (Con A)-induced hepatic injury. Acute hepatic injury model was established successfully by intravenous administration of Con A (15 mg/kg) in male C57BL/6 mice, and HDN was pretreated for 10 days before Con A challenge. It was found that the hepatic injury was notably improved in HDN pretreated mice. Furthermore, hepatic oxidative stress and the production of proinflammatory cytokines including TNF-α and IFN-γ were decreased by HDN pretreatment. More importantly, compared with Con A-treated mice, the expression and releasing of HMGB1 and T-cell activation were markedly reduced in HDN pretreated mice. Thus, these results suggest that HDN protects mice from Con A-induced hepatic injury by suppressing hepatocyte oxidative stress, producing cytokines, expressing and releasing HMGB1 and activating T cells.

Effects of fish oil on cell proliferation and liver injury in an experimental model of acute hepatic injury induced by carbon tetrachloride.

We aimed to investigate the effect of fish oil on the hepatic injury and cell cycle phases as well as cellular proliferation- regeneration in a rat model of acute hepatic injury induced by carbon tetrachloride. Compensatory cell proliferation and tissue regeneration occurs as an endogenous response following chemical damage to the liver and enable animals to over come the injury. Data related to effect of fish oil on liver injury induced by chemical hepatotoxicants are controversial. 60 male Wistar-albino rats were fed either with a diet supplemented with 20% fish oil or standard rat feed for 2 weeks. After an overnight fast, rats in each group were administered either 1 ml/kg carbon tetrachloride or saline intraperitoneally. Fish oil enriched diet significantly enhanced the carbon tetrachloride - associated necroinflammatory damage, ballooning degeneration and the elevation of serum transaminases induced by carbon tetrachloride. Furthermore fish oil diet prevented cell proliferation, increased the proportion of cells in the G0/G1phase concomitant with a decrease in the proportion of cells in the S phase cells. Fish oil diet exacerbates the hepatic injury and prevents cell proliferation-regeneration in normal and injured liver cells. Suppression of tissue regeneration by fish oil may lead to progression of the hepatic injury (Tab. 3, Fig. 4, Ref. 31).

Evaluation of hepatoprotective activity of alcoholic and aqueous extracts of Selaginella lepidophylla

ObjectiveTo screen Selaginella lepidophylla (S. lepidophylla) that are used in traditional medicine for their claimed hepatoprotective properties. MethodsAlcoholic and aqueous extracts of S. lepidophylla were evaluated for their hepatoprotective activity using CCl4 and paracetamol induced acute hepatic injury model. ResultsTreatment with CCl4 and paracetamol significantly increased liver weight and volume compared to the normal group. Pretreatment with silymarin alcoholic and aqueous extracts significantly prevent increase in liver weight and volume. ConclusionsFrom the present experimental study it can be concluded that alcoholic and aqueous extract of S. lepidophylla exhibited significant hepatoprotective activity against CCl4 and paracetamol induced hepatotoxicity in rats, as result showed in physical, biochemical and histopathological parameters.

Hepatoprotective effects of eburicoic acid and dehydroeburicoic acid from Antrodia camphorata in a mouse model of acute hepatic injury

The hepatoprotective effects of eburicoic acid (TR1) and dehydroeburicoic acid (TR2) from Antrodia camphorata (AC) against carbon tetrachloride (CCl4)-induced liver damage were investigated in mice. TR1 and TR2 was administered intraperitoneally (i.p.) for 7days prior to the administration of CCl4. Pretreatment with TR1 and TR2 prevented the elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and liver lipid peroxides in CCl4-treated mice. The activities of antioxidant enzymes [catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)], nitric oxide (NO) production, and tumour necrosis factor-alpha (TNF-α) were decreased after the treatment with TR1 and TR2 in CCl4-treated mice. Western blotting revealed that TR1 and TR2 significantly decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions and increased the expression of cytochrome P4502E1 (CYP2E1) in CCl4-treated mice. Therefore, we speculate that TR1 and TR2 protect the liver from CCl4-induced hepatic damage via antioxidant and anti-inflammatory mechanisms.

Marrow-Derived Mesenchymal Stem Cells Restore Biochemical Markers of Acute Liver Injury in Experimental Model

Bone marrow–derived mesenchymal stem cells were investigated as prompters of liver regeneration in an experimental model of acute hepatic injury. A model was created in Wistar rats through intraperitoneal injection of carbon tetrachloride (CCl4). Bone marrow–derived mesenchymal stem cells collected from the long bones of 10 Wistar rats were intravenously infused 24 hours after induction of acute liver failure in 16 rats, group A. In group B, the control group, 16 rats received a peritoneal injection of CCl4, and an intravenous infusion of normal saline solution. All rats were sacrificed at 2, 3, 4, and 7 days post-CCl4 injection to examined biochemical markers and pathological appearances. The platelet counts were higher in group A versus group B on post-CCl4 infusion days 2 (P = .02) and 3 (P = .001), as were the transaminase trends in glutamic oxaloacetic (P = .002), and glutamic-pyruvic transaminases (P < .0001). Pathological examination showed a greater grade of hepatocellular necrosis with neutrophilic infiltration in group B (P = .02). In conclusion, infusion of bone marrow–derived mesenchymal stem cell resulted in a less aggressive picture of hepatic damage.

Experimental study of active ingredients group in liver protection from Erzhi Wan on acute hepatic injury induced by CCl4 in mice

To study the active ingredients in liver protection from Erzhi Wan (AIEP) on acute hepatic injury induced by carbon tetrachloride (CCl4) in mice. Sixty Kunming mice were randomly divided into six groups: the normal group, the model group, bifendate group (150 mg x kg(-1)), high AIEP group (19.8 g x kg(-1)), middle AIEP group (13.2 g x kg(-1)) and low AIEP group (6.6 g x kg(-1)). The treatment groups were orally administered once per day for 7 d separately, whereas the normal and model groups were orally administered with saline. Except normal rats, all the other rats were injected intraperitoneally CCl4 20 mL x kg(-1) once. The rats were sacrificed 16 h after CCl4 administration. Serum and liver samples were collected for analysis. The acute hepatic injury model was prepared by CCl4 injected intraperitoneally. Then, the therapeutic effects of AIEP on the model were evaluated by the activity determination of serum alanine aminotransferase and aspirate aminotransferase (ALT and AST), superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in liver,and the hepatic pathohistological changes following the treatment. The activities of ALT and AST and the MDA content in liver was significantly increased and the activity of SOD was largely inhibited in the animals of modeling group. Following the treatment with AIEP, ALT and AST activities and MDA content were significantly reduced and SOD activity was obviously increased in the mice of treatment group. Furthermore, AIEP could ameliorate the hepatic pathological changes. AIEP have protective effects on acute hepatic injury induced by CCL4 in mice, and are the effect of the liver protecting active sites.

Ex vivo-expanded bone marrow stem cells home to the liver and ameliorate functional recovery in a mouse model of acute hepatic injury

Stem cell transplantation provides a theoretical approach for liver regeneration medicine; it may promote liver regeneration and self-repair. However, the transplantation of bone marrow-mesenchymal stem cells expanded ex vivo as a therapy for liver disease has rarely been investigated. This study aimed to explore whether bone marrow stem cells expanded ex vivo home to the liver and foster hepatic recovery after CCl4 injury. Bone marrow cells from BALB/c mice were expanded ex vivo by multiple-passage cultivation, characterized by cytoflow immunofluorescence, and pre-labeled with PKH26 before intravenous infusion into animals treated with CCl4. The integration of bone marrow cells into the liver was examined microscopically, and plasma hepatic enzymes were determined biochemically. Cultured bone marrow cells exhibited antigenic profiles comparable to those of primary medullary stem cells. Double immunofluorescence showed colocalization of these cells with proliferative activity and albumin expression in the liver of CCl4-treated mice. Densitometry showed increased in situ cell proliferation (50+/-14 vs 20+/-3 cells/high-power field, P<0.05) and albumin expression (149+/-25 vs 20+/-5 cells/high-power field, P<0.05) in the liver, as well as reduced serum aminotransferase levels (P<0.05) and better survival rates (P<0.05) in animals receiving cultured bone marrow cells relative to controls. Ex vivo-expanded bone marrow cells are capable of relocating to and proliferating in the chemically-injured liver. Transplantation of these pluripotent stem cells appears to improve serum indices of liver function and survival rate in mice after CCl4-induced hepatic damage.

The hepatoprotective effects of dihydromyrcenol and geranyl formate in an experimental model of acute hepatic injury induced by the use of carbon tetrachloride

We aimed to investigate the hepatoprotective effects of dihydromyrcenol and geranyl formate extracted from the Vitis vinifera L. plant in a rat model of acute hepatic injury induced by carbon tetrachloride. The study was performed on 54 Sprague-Dawley male rats. The animals were divided into 9 study groups with 6 rats in each. At the end of the 7-day study period, the animals were sacrificed. The effects of dihydromyrcenol and geranyl formate on hepatic injury were evaluated based on the comparisons of the changes in the weight, serum levels of alanine aminotransferase and aspartate aminotransferase, and histopathological changes in the liver. Dihydromyrcenol significantly reduced the carbon tetrachloride-associated ballooning degeneration and apoptotic cell counts; this reduction was moderate with low doses of geranyl formate, while no reductions were observed with high doses of geranyl formate. The changes in the alanine aminotransferase and aspartate aminotransferase levels were in accordance with these findings. It can be concluded that in an experimental model of acute hepatic injury induced by carbon tetrachloride, dihydromyrcenol presents a hepatoprotective effect, while geranyl formate presents partial hepatoprotective effects at low doses and no hepatoprotective effects at high doses.

Pathological and MR-DWI study of the acute hepatic injury model after stem cell transplantation.

To investigate apparent diffusion coefficient (ADC) values as an indication of reconditioning of acute hepatic injury (AHI) after allogeneic mononuclear bone marrow cell (MBMC) transplantation. Three groups were used in our study: a cell transplantation group (n = 21), transplantation control group (n = 21) and normal control group (n = 10). AHI model rabbits in the cell transplantation group were injected with 5 mL of MBMC suspension at multiple sites in the liver and the transplantation controls were injected with 5 mL D-Hanks solution. At the end of the 1st, 2nd and 4th wk, 7 rabbits were randomly selected from the cell transplantation group and transplantation control group for magnetic resonance diffusion-weighted imaging (MR-DWI) and measurement of the mean ADC values of injured livers. After MR-DWI examination, the rabbits were sacrificed and the livers subjected to pathological examination. Ten healthy rabbits from the normal control group were used for MR-DWI examination and measurement of the mean ADC value of normal liver. At all time points, the liver pathological scores from the cell transplantation group were significantly lower than those in the transplantation control group (27.14 ± 1.46 vs 69.29 ± 6.16, 22.29 ± 2.29 vs 57.00 ± 1.53, 19.00 ± 2.31 vs 51.86 ± 6.04, P = 0.000). The mean ADC values of the cell transplantation group were significantly higher than the transplantation control group ((1.07 ± 0.07) × 10⁻³ mm²/s vs (0.69 ± 0.05) × 10⁻³ mm²/s, (1.41 ± 0.04) × 10⁻³ mm²/s vs (0.84 ± 0.06) × 10⁻³ mm²/s, (1.68 ± 0.04) × 10⁻³ mm²/s vs (0.86 ± 0.04) × 10⁻³ mm²/s, P = 0.000). The pathological scores of the cell transplantation group and transplantation control group gradually decreased. However, their mean ADC values gradually increased to near that of the normal control. At the end of the 1st wk, the mean ADC values of the cell transplantation group and transplantation control group were significantly lower than those of the normal control group [(1.07 ± 0.07) × 10⁻³ mm²/s vs (1.76 ± 0.03) × 10⁻³ mm²/s, (0.69 ± 0.05) × 10⁻³ mm²/s vs (1.76 ± 0.03) × 10⁻³ mm²/s, P = 0.000]. At any 2 time points, the pathological scores and the mean ADC values of the cell transplantation group were significantly different (P = 0.000). At the end of the 1st wk, the pathological scores and the mean ADC values of the transplantation control group were significantly different from those at the end of the 2nd and 4th wk (P = 0.000). However, there was no significant difference between the 2nd and 4th wk (P = 0.073 and 0.473, respectively). The coefficient of correlation between the pathological score and the mean ADC value in the cell transplantation group was -0.883 (P = 0.000) and -0.762 (P = 0.000) in the transplantation control group. Tracking the longitudinally dynamic change in the mean ADC value of the AHI liver may reflect hepatic injury reconditioning after allogeneic MBMC transplantation.