Hepatic Histopathological Changes Research Articles

The effect of bariatric surgeries on nonalcoholic fatty liver disease.

Objective:A review of published data addressing hepatic histopathological, metabolical, and functional changes following gastric banding, sleeve gastrectomy, gastric bypass surgery, and biliopancreatic with duodenal switch surgeries on nonalcoholic fatty liver disease (NAFLD). NAFLD is currently the most common chronic liver disease. Owing to the strong relationship between obesity and NAFLD, the idea of weight reduction as a method to treat NAFLD has rapidly emerged. Bariatric surgery has proved to be the most efficient method for weight reduction; hence, their beneficial effects on NAFLD have been evaluated by several studies. A literature review of published data was performed during the years 2012-2014 using PubMed with the following key words: Bariatric, NAFLD, steatosis, sleeve gastrectomy, gastric bypass, gastric banding, biliopancreatic diversion with duodenal switch, obesity, and insulin resistance (IR). Exclusion criteria were non-English articles and inherited NAFLD, pregnancy-induced NAFLD, and children. The majority of published data are in favor of indicating that bariatric surgeries improve the histologic and metabolic changes associated with NAFLD. The suggested mechanisms are: The reversal of IR, reduction of inflammatory markers, and improved histological features of NAFLD. Accordingly, bariatric surgeries are potentially one of the future methods in treating patients with morbid obesity and NAFLD. However, some questions remain unanswered, such as whether timing of surgery, type of surgery most effective, and whether bariatric surgeries are capable of curing the disease. Long-term and well-designed prospective studies are needed to address these issues.

Parasitological evaluation of Ro 15-9268, a 9-acridanone-hydrazone derivative against Schistosoma mansoni in mice, and observations on changes in serum enzyme levels

Schistosoma mansoni is one of the major causes of schistosomiasis prevalent in tropical and subtropical areas, especially in poor communities. It is estimated that at least 90% of those requiring treatment for schistosomiasis live in Africa. The primary control strategy employed for schistosomiasis is mass drug administration (MDA).The aim is to reduce disease through treatments with a single lower dose of Ro 15-9268 as a new antischistosomal drug. In the present search, the efficacy of Ro 15-9268 was studied in mice using a dose of 12.5 mg/kg of body weight (b.wt.) against an Egyptian strain of S. mansoni. This was carried out at 2 days and 3, 4, and 6 weeks post-cercarial exposure of mice. The criteria used were the worm load, oogram pattern and number of ova in the liver and intestine, hepatic enzyme activity, and liver histopathology. The tested agent has led to a significant reduction in worm burden (89.80%) in liver and portomesenteric veins concurrent with a hepatic shift at the second week posttreatment followed by a complete disappearance of worms, 4 weeks postmedication. The oogram of infected animals treated revealed an increased number of dead ova 2 days posttreatment and complete absence of immature and mature ova 2 weeks later. The hepatic and intestinal egg counts significantly declined by about 96 and 98%, respectively, 6 weeks after treatment, and the fecal egg count completely disappeared from stool 4 weeks after medication. The hepatic histopathological changes were improved, ova were markedly degenerated, and worms showed fragmentation and degeneration after drug administration. In conclusion, when Ro 15-9268 was administered to mice infected with the Egyptian strain of S. mansoni, at a low dose level (12.5 mg/kg b.wt.), encouraging results were obtained. The drug showed high efficacy against schistosomal worms as well as histopathological inflammatory changes.

Preventive roles of swimming exercise and pioglitazone treatment on hepatic dysfunction in a rat model of metabolic syndrome

Pioglitazone (Pio) and swimming exercise (SE) are insulin sensitisers. This investigation was suggested because of the significant side effects associated with Pio treatment in metabolic syndrome (MetS). This study was, therefore, designed to investigate the preventive role of Pio treatment and SE in terms of efficiency and pathological changes in MetS in a rat model. Sixty male Sprague-Dawley rats were distributed equally among 6 groups: (i) control group (C), (ii) exercised control group (C+E), (iii) Pio-treated control group (C+Pio), (iv) group with MetS, (v) group with MetS treated with Pio (MetS+Pio), and (vi) exercised MetS group (MetS+E). Systolic blood pressure and heart rate were measured at the end of the experiments (16 weeks). Retro-orbital blood samples were used to determine the serum levels of glucose, insulin, lipids, gamma glutamyl transferase, alanine transaminase, aspartate transaminase, alkaline phosphatase, fetuin-A, and adiponectin. Semiquantitative reverse transcriptase - PCR insulin gene expression assays and hepatic histopathological examination were conducted. Swimming exercise significantly improved all of the aforementioned parameters, more so than the Pio treatment. In particular, the serum hepatic enzyme levels and hepatic histopathological changes were improved compared with the MetS group. These results suggested that swimming exercise might be an alternative physiological preventive tool against hepatic dysfunction to avoid the side effects associated with Pio treatment, and this could be demonstrated in a rat model of metabolic syndrome.

Liver Disease After Intensive Care of Premature Baboons

Cholestasis affects 50% of extremely low-birth-weight infants. Its etiology remains poorly understood and the extent of liver injury in these infants is unclear. The premature baboon model provides an opportunity to study neonatal liver disease. We characterize hepatic histopathologic changes in this model. Archival tissue and data were obtained from the Southwest Foundation for Biomedical Research Primate Center, San Antonio, TX. Animals were selected based on history of antenatal steroid therapy and absence of sepsis or necrotizing enterocolitis with a protocol duration of at least 21 days and no early death (n = 45). Baboons had been treated per protocol in the neonatal intensive care unit (NICU). At necropsy, liver tissue was harvested and stored. Tissues from fetal gestational controls at similar ages were used for comparison (n = 28). Histologic changes were scored by consensus of 2 pathologists blinded to treatment group. Descriptive and comparative statistics were performed. Control fetal livers had extramedullary hematopoiesis (EMH) that decreased across the gestational range. There was evidence of hepatocyte iron storage and ongoing portal tract development. Livers of NICU-treated baboons had increased Kupffer cell hypertrophy and hemosiderosis. There was a shift away from erythroid EMH toward increased myeloid EMH. There was increased cholestasis, ductular proliferation, portal tract fibrosis, and steatosis in treated animals. We found pathologic changes in NICU-treated baboons comparable with findings reported in human infants. The baboon model of prematurity may be a useful tool to explore cholestasis and liver dysfunction in extremely low-birth-weight infants.

Toxicity and dose determination of quillaja saponin, aluminum hydroxide and squalene in olive flounder (Paralichthys olivaceus)

Adjuvants are substances added to vaccines to enhance the immune response of a given antigen. Most of the adjuvants are toxic at certain doses, and toxicity varies in different species. Moreover, there are no standard dosage limits set for adjuvant use in fish vaccines. We evaluated the acute toxicity, serum enzymes (AST/ALT) indicating hepatic injury and histopathological changes due to intra-peritoneal administration of different concentrations of a panel of adjuvants including quillaja saponin, aluminum hydroxide, squalene emulsion and Freund's incomplete adjuvant (FIA) with a dose ranging study of saponin (500, 160, 50, 16 and 5μgfish−1), aluminum hydroxide (5000, 1600, 500, 160 and 50μgfish−1), squalene emulsion (20, 10 and 5%), and FIA to determine the acceptable dosage for vaccination in olive flounder (Paralichthys olivaceus) fingerlings measuring 4.66±0.41g, 8.47±0.42cm. Saponin was highly toxic with a LD50 of approximately 105μgfish−1 (22.4mgkg−1) causing severe histological damage and AST level was high at dose above 16μgfish−1 and ALT, specific for liver damage was high only at 160μgfish−1 (11U/L) and was safe at 5μgfish−1. Aluminum hydroxide was toxic at 5000μgfish−1 and was acceptable at dose below 1600μgfish−1 with moderate histology and AST/ALT levels similar with control. Squalene emulsion showed increased inflammation at 20% and 10% emulsions and the inflammatory response was mild at a concentration of 5% oil emulsion and AST/ALT levels being similar to control in 10% and 5% emulsions and elevated in 20% on both sampling days. FIA was not lethal, but induced severe inflammation at injection site and around blood vessels. In comparison to FIA, saponin found to be safe at dose of 5μgfish−1, aluminum hydroxide below 1600μgfish−1, and squalene at 5% emulsion and could be accepted for vaccination studies. These results provide an insight for the selection of safer dose of adjuvants for intra-peritoneal vaccination of olive flounder.

Evaluation of Hepatoprotective Effect of <I>Nigella sativa</I> Oil in Cyclosporine Induced Hepatotoxicity in Albino Rats

Objective: The main objective of our study is to see the hepatoprotective effect of Nigella sativa in Cyclosporine induced hepatotoxicity in rats. Methods: the effect of Nigella sativa on cyclosporine induced hepatotoxicity was studied in albino rats. The animals were divided into 3 groups with 6 rats in each group. Group I served as vehicle control, Group II animals were given Cyclosporine 25mg/Kg body weight orally for 21 days and Group III were given Cyclosporine 25mg/Kg + Nigella sativa 1ml/Kg body weight orally for 21 days. The blood samples were collected for liver enzymes estimation before and after the experiment. The animals were sacrificed on 22 nd day and liver was subjected to histopathological examination. Results: Cyclosporine provoked hepatotoxicity was evident from increase of hepatic enzyme levels and histopathological changes. Addition of Nigella sativa has resulted in the decrease of elevated hepatic enzyme levels and improvement in histopathological changes in liver. Conclusion: The present study showed that Nigella sativa oil has protective effect on Cyclosporine induced hepatotoxicity in albino rats.

Exogenous bone morphogenetic protein-7 reduces hepatic fibrosis inSchistosoma japonicum-infected miceviatransforming growth factor-β/Smad signaling

To investigate the antifibrotic effects of bone morphogenetic protein-7 (BMP-7) on Schistosoma japonicum (S. japonicum)-induced hepatic fibrosis in BALB/C mice. Sixty BALB/C mice were randomly divided into three groups, including a control group (group A, n = 20), model group (group B, n = 20) and BMP-7 treated group (group C, n = 20). The mice in group B and group C were abdominally infected with S. japonicum cercariae to induce a schistosomal hepatic fibrosis model. The mice in group C were administered human recombinant BMP-7. Liver samples were extracted from mice sacrificed at 9 and 15 wk after modeling. Hepatic histopathological changes were assessed using Masson's staining. Transforming growth factor-beta 1 (TGF-β1), alpha-smooth muscle actin (α-SMA), phosphorylated Smad2/3 (pSmad2/3) and Smad7 protein levels and localization were measured by Western blotting and immunohistochemistry, respectively, and their mRNA expressions were detected by reverse transcription-polymerase chain reaction (RT-PCR). The schistosomal hepatic fibrosis mouse model was successfully established, as the livers of mice in group B and group C showed varying degrees of typical schistosomal hepatopathologic changes such as egg granuloma and collagen deposition. The degree of collagen deposition in group C was higher than that in group A (week 9: 22.95 ± 6.66 vs 2.02 ± 0.76; week 15: 12.84 ± 4.36 vs 1.74 ± 0.80; P < 0.05), but significantly lower than that in group B (week 9: 22.95 ± 6.66 vs 34.43 ± 6.96; week 15: 12.84 ± 4.36 vs 18.90 ± 5.07; P < 0.05) at both time points. According to immunohistochemistry data, the expressions of α-SMA, TGF-β1 and pSmad2/3 protein in group C were higher than those in group A (α-SMA: week 9: 21.24 ± 5.73 vs 0.33 ± 0.20; week 15: 12.42 ± 4.88 vs 0.34 ± 0.27; TGF-β1: week 9: 37.00 ± 13.74 vs 3.73 ± 2.14; week 15: 16.71 ± 9.80 vs 3.08 ± 2.35; pSmad2/3: week 9: 12.92 ± 4.81 vs 0.83 ± 0.48; week 15: 7.87 ± 4.09 vs 0.90 ± 0.45; P < 0.05), but significantly lower than those in group B (α-SMA: week 9: 21.24 ± 5.73 vs 34.39 ± 5.74; week 15: 12.42 ± 4.88 vs 25.90 ± 7.01; TGF-β1: week 9: 37.00 ± 13.74 vs 55.66 ± 14.88; week 15: 16.71 ± 9.80 vs 37.10 ± 12.51; pSmad2/3: week 9: 12.92 ± 4.81 vs 19.41 ± 6.87; week 15: 7.87 ± 4.09 vs 13.00 ± 4.98; P < 0.05) at both time points; the expression of Smad7 protein in group B was higher than that in group A and group C at week 9 (8.46 ± 3.95 vs 1.00 ± 0.40 and 8.46 ± 3.95 vs 0.77 ± 0.42; P < 0.05), while there were no differences in Smad7 expression between the three groups at week 15 (1.09 ± 0.38 vs 0.97 ± 0.42 vs 0.89 ± 0.39; P > 0.05). Although minor discrepancies were observed, the results of RT-PCR and Western blotting were mainly consistent with the immunohistochemical results. Exogenous BMP-7 significantly decreased the degree of hepatic fibrosis in both the acute and chronic stages of hepato-schistosomiasis, and the regulatory mechanism may involve the TGF-β/Smad signaling pathway.

Protective Effects of Lactobacillus plantarum CCFM8610 against Acute Cadmium Toxicity in Mice

This study evaluated the protective effects of Lactobacillus plantarum CCFM8610, a selected probiotic with good cadmium binding capacity, against acute cadmium toxicity in mice. Ninety mice were divided into prevention and therapy groups. In the prevention groups, CCFM8610 was administered at 10(9) CFU once daily for 7 days, followed by a single oral dose of cadmium chloride at 1.8 mg cadmium for each mouse. In the therapy groups, the same dose of CCFM8610 was administered for 2 days after an identical single dose of cadmium exposure. Mice that received neither cadmium nor culture or that received cadmium alone served as negative and positive controls, respectively. The effects of both living and dead CCFM8610 on cadmium ion concentrations in feces, liver, and kidney were determined. Moreover, the alterations in reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and histopathology in the liver and kidney were investigated. The results showed that compared to the mice that received cadmium only, CCFM8610 treatment can effectively decrease intestinal cadmium absorption, reduce tissue cadmium accumulation, alleviate renal and hepatic oxidative stress, and ameliorate hepatic histopathological changes. Living CCFM8610 administered after cadmium exposure offered the most significant protection. Our results suggested that CCFM8610 is more effective against acute cadmium toxicity than a simple antioxidant treatment due to its special physiological functions and that it can be considered a new dietary therapeutic strategy against acute cadmium toxicity.

The protective effects of dexmedetomidine on the liver and remote organs against hepatic ischemia reperfusion injury in rats

AimTo investigate the protective effects of dexmedetomidine against hepatic ischemia/reperfusion (IR) injury and hepatic IR induced remote organ injury. MethodsForty Wistar albino rats were divided into the following four groups: sham, dexmedetomidine, IR, and IR + dexmedetomidine. Hepatic ischemia was created by the Pringle maneuver for 30 min followed by a 30 min reperfusion period in the IR and IR + dexmedetomidine groups. The dexmedetomidine and IR + dexmedetomidine groups were administered dexmedetomidine (100 μg/kg, single dose) intraperitoneally after the anesthesia insult. Blood samples and hepatic, renal, and lung tissue specimens were obtained to measure serum and tissue total oxidative activity (TOA), total antioxidant capacity (TAC), paraoxonase (PON-1), and oxidative stress index (OSI) after 60 min in all groups. ResultsAccording to the biochemical analyses of the samples taken from the serum and the liver, lung, and kidney tissues, when comparing the sham group and the IR group, TOA and OSI values were higher in the IR group, while TAC and PON-1 values were lower (p < 0.05). It was observed that TOA and OSI values were significantly lower, while TAC and PON-1 values increased with dexmedetomidine treatment (p < 0.05). In addition, dexmedetomidine ameliorated hepatic histopathological changes inducing IR, but there were no significant histopathological changes in the remote organs. ConclusionThis study demonstrated that dexmedetomidine markedly reduced the oxidative stress in serum, liver, and remote organs induced by hepatic IR injury, and ameliorated the histopathological damage in the liver.

Neonatal intrahepatic cholestasis caused by citrin deficiency: a histopathologic study of 10 cases

To investigate the diagnostic value of histopathological changes in the liver of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Liver specimens from 10 cases of NICCD were evaluated by hematoxylin-eosin stain, histochemistry and immunohistochemistry (EnVision method). SLC25A13 mutation analysis was performed to correlate with histopathology. Most specimens showed varying degrees of fat deposition in hepatocytes, necrotic inflammation, cholestasis and fibrosis (so-called tetralogy). The combination of the above four histological changes was highly characteristic for NICCD. With the progression of the disease, hepatic fibrosis deteriorated and ultimately led to cirrhosis. NICCD should be suspected in the presence of cholestasis during infancy. A liver biopsy must be performed to rule out other liver diseases. The tetralogy of the hepatic histopathological changes has a highly diagnostic value for NICCD, which is also practical for accurately assessing the degree of inflammation and fibrosis, and similarly the progression of hepatic cirrhosis.

Hepatoprotective effects of dieckol-rich phlorotannins from Ecklonia cava, a brown seaweed, against ethanol induced liver damage in BALB/c mice

Alcoholic liver disease, which is one of the most serious liver disorders, has been known to cause by ethanol intake. In the present study, in vivo hepatoprotective effects of dieckol-rich phlorotannins (DRP) from Ecklonia cava, a brown seaweed, on ethanol induced hepatic damage in BALB/c mice liver were investigated. After administration of 5 and 25mg/kg mouse of DRP and 4g/kg mice ethanol, the body weights and survival rates were increased as compared to the control, which is ethanol-treated group without DRP. The glutamic oxaloacetic transaminase and glutamic pyruvic transaminase levels in the serum were lower than those of the control. DRP exhibited a reduction of the total cholesterol. The lower levels of SOD enzyme and a reduction of the formation of malondialdehyde were occurred in mice fed with 5 and 25mg/kg mouse of DRP. Finally the effect on improvement of fatty liver induced by ethanol was observed by taking out the liver immediately after dissecting the mouse. However, no significant difference was observed on hepatic histopathological changes. In conclusion, this study indicated that DRP could protect liver injury induced by ethanol in vivo. It suggested that DRP possesses the beneficial effect to human against ethanol-induced liver injury.

Extrahepatic biliary atresia: Correlation of histopathology and liver function tests with surgical outcomes

Aims:To correlate the age at surgery, liver function tests, and hepatic and portal tract histo-pathological changes with surgical outcome in the form of disappearance of jaundice in extrahepatic biliary atresia (EHBA).Materials and Methods:This is a retrospective study of 39 cases of EHBA. There were 19 males and 10 females. Kasai's portoenterostomy (KPE) along with liver biopsy was performed in these patients; for purpose of correlation this biopsy was considered to be the preoperative biopsy. These patients were divided into three groups based upon surgical outcome: (A) disappearance of jaundice; (B) initial disappearance of jaundice with recurrence after 3 months; and (C) persistence of jaundice. Postoperatively, liver function tests and liver biopsies were repeated at 3 months after the KPE.Results:There were 11 patients in group A (28%), 21 patients in group B (54%), and seven patients in group C (18%). The age at surgery was comparable in all the three groups. The postoperative levels of serum bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGTP) showed statistically significant improvement as compared with the preoperative levels in group A and B patients. Patients belonging to group C showed no improvement in the liver functions following surgery. The preoperative hepatic histopathological changes (hepatocellular alteration, cholestasis, bile ductular proliferation, and bile duct inflammation) showed a significant difference among the three groups; patients with lesser degrees of pre-existing histopathological changes had better outcome following surgery. Fibrosis was seen in all the three groups preoperatively but the difference was not statistically significant. Group C had significant fibrosis in more than 50% patients. Additional findings, viz. ductal plate malformation (9 patients, 23%) and giant cell transformation (19 patients, 49%) did not show any correlation with surgical outcomes.Conclusions:The liver function tests and the histopathological features appeared to affect the final surgical outcome of these patients. Higher degree of cholestasis, hepatocellular alteration, bile ductule proliferation, bile duct inflammation showed definite correlation with poor surgical outcome. High grade hepatic fibrosis and portal edema showed a trend towards poor outcome but did not achieve statistical significance.

Nanotitanium dioxide toxicity in mouse lung is reduced in sanding dust from paint.

BackgroundLittle is known of how the toxicity of nanoparticles is affected by the incorporation in complex matrices. We compared the toxic effects of the titanium dioxide nanoparticle UV-Titan L181 (NanoTiO2), pure or embedded in a paint matrix. We also compared the effects of the same paint with and without NanoTiO2.MethodsMice received a single intratracheal instillation of 18, 54 and 162 μg of NanoTiO2 or 54, 162 and 486 μg of the sanding dust from paint with and without NanoTiO2. DNA damage in broncheoalveolar lavage cells and liver, lung inflammation and liver histology were evaluated 1, 3 and 28 days after intratracheal instillation. Printex 90 was included as positive control.ResultsThere was no additive effect of adding NanoTiO2 to paints: Therefore the toxicity of NanoTiO2 was reduced by inclusion into a paint matrix. NanoTiO2 induced inflammation in mice with severity similar to Printex 90. The inflammatory response of NanoTiO2 and Printex 90 correlated with the instilled surface area. None of the materials, except of Printex 90, induced DNA damage in lung lining fluid cells. The highest dose of NanoTiO2 caused DNA damage in hepatic tissue 1 day after intratracheal instillation. Exposure of mice to the dust from paints with and without TiO2 was not associated with hepatic histopathological changes. Exposure to NanoTiO2 or to Printex 90 caused slight histopathological changes in the liver in some of the mice at different time points.ConclusionsPulmonary inflammation and DNA damage and hepatic histopathology were not changed in mice instilled with sanding dust from NanoTiO2 paint compared to paint without NanoTiO2. However, pure NanoTiO2 caused greater inflammation than NanoTiO2 embedded in the paint matrix.

Protective effect of aescin from the seeds of Aesculus hippocastanum on liver injury induced by endotoxin in mice

To investigate the effect and underlying mechanism of aescin on acute liver injury induced by endotoxin, liver injury was established by injecting lipopolysaccharide (LPS) in mice. Animals were assigned to seven groups: the control group and groups treated with LPS (40 mg/kg), aescin (3.6 mg/kg), LPS plus dexamethasone (4 mg/kg) and LPS plus aescin (0.9, 1.8 or 3.6 mg/kg). Hepatic histopathological changes were examined under a light microscope. Activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were determined. Levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO) and antioxidative parameters in liver homogenate were measured. Glucocorticoid receptor (GR), 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11 beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expressions in liver were determined by western blotting. Treatment with escin could inhibit immigration of inflammatory cells, alleviate the degree of necrosis, and decrease serum ALT and AST activities. Aescin also down-regulated levels of inflammation mediators (TNF-α, IL-1β and NO) and 11β-HSD2 expression in liver, up-regulated GR expression, enhanced endogenous antioxidative capacity, but have no obvious effect on 11β-HSD1 expression in liver. The findings suggest aescin has protective effects on endotoxin-induced liver injury, and the underlying mechanisms were associated with its anti-inflammatory effects, up-regulating GR expression, down-regulating 11β-HSD2 experssion, and antixoidation.

Assessing the toxicity of ingested Taihu Lake water on mice via hepatic histopathology and matrix metalloproteinase expression

Water from Taihu Lake (China) is used as a drinking source. The frequency of contamination in Taihu Lake has increased over the past decade and the bloom-forming cyanobacteria are the dominant species during eutrophication. Cyanobacteria can produce various harmful secondary substances including microcystins capable of endangering human health and ecological safety. This study investigated toxicity of ingested Taihu Lake water on mice via hepatic histopathology and matrix metalloproteinase (MMP) expression. Water was sampled from four Taihu Lake locations, Meiliang Bay 2 group (M2), Meiliang Bay 1 group (M1), Lake Center (H) and Xukou Bay (X), along a gradient of decreasing degree of eutrophication. The experimental design consists of five groups of male mice (Mus musculus, ICR): one control and four groups ingesting water from the four sampling sites for 90 days. Compared to control, M1 and M2 mice showed hepatic histopathological changes including swollen, vacuolar degeneration or inflammatory. Immunohistochemical staining demonstrated a higher expression of MMP-2 proteins in M2 group and a lower expression of MMP-9 in M1. Enzyme-linked immunosorbent assay indicated that MMP-9 concentration was significantly reduced from 0.55 to 0.28 ng/g liver weight in M2 (p < 0.05). Real time PCR revealed a down-regulation of MMP-9 mRNA by 2.2 fold in M1 and an up-regulation of MMP-2 mRNA by 1.73 fold in H. Using this mouse model as a gauge of water toxicity, our results revealed that potential health risks induced by Taihu Lake water might arise from the use of this source water by local resident.

English

In the present study Spirulina platensis has been investigated as a possible modifier of mercury induced hepatic damages and alteration of lipid profile in albino rats. The results revealed that the rats treated with mercuric chloride (HgCl2) showed a significant increase in levels of blood hydroperoxide, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol (TC), triglycerides and low density lipoprotein-cholesterol (LDL-C). Moreover, hepatic malondialdehyde (MDA) concentration of HgCl2 group elevated significantly. On the other hand, plasma protein, high density lipoprotein-cholesterol (HDL-C) and hepatic glutathione (GSH) of HgCl2 treated following administration of HgCl2 shows necrosis and cytoplasmic vacuolization by Mercury intoxication induces some pathological alterations in the liver as necrosis and cytoplasmic vacuolization. The rise in plasma hepatic enzymes, cholesterol, triglycerides, LDL-C, hydroperoxide, and histopathological changes were significantly attenuated by Spirulina. Moreover, the levels of plasma HDL-C and protein and hepatic glutathione in Spirulina+HgCl2 group showed a significant increase as compared with HgCl2 group. Spirulina significantly alleviated the hepatotoxicity induced by HgCl2 and modified the lipid profile through its antioxidant properties. Key words: Spirulina platensis, mercuric chloride, hydroperoxide, liver enzymes, glutathione, cholesterol, triglycerides, HDL, LDL.

Hepatic Pharmacokinetics of Cationic Drugs in a High-Fat Emulsion-Induced Rat Model of Nonalcoholic Steatohepatitis

The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine, and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced nonalcoholic steatohepatitis (NASH). Studies were undertaken using an in situ-perfused rat liver and multiple indicator dilution, and outflow data were analyzed with a physiologically based organ pharmacokinetic model. Hepatic extraction (E) was significantly lower in the NASH model, and lipophilicity was the main solute structural determinant of the observed differences in intrinsic elimination clearance (CL(int)) and permeability-surface area product (PS) with pK(a) defining the extent of sequestration in the liver [apparent distribution ratio (K(v))]. The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in K(v), and an increase in both total liver cytochrome P450 (P450) concentration and P450 isoform expression for Cyp3a2 and Cyp2d2, causing an increase CL(int) in NASH rat livers compared with control livers. Changes in hepatic pharmacokinetics (PS, K(v), CL(int), and E ratio) as a result of NASH were related to the physicochemical properties of drugs (lipophilicity or pK(a)) and hepatic histopathological changes (fibrosis index, steatosis index, and P450 concentration) by stepwise regression analysis. Thus, it appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in NASH-induced P450 expression, whereas NASH-induced fibrosis and steatohepatitis inhibit E by decreasing hepatocyte permeability through fibrosis and hepatic sequestration.

Effect of airborne particulate matter exposure on pregnancy and fetal development in female mice

To investigate subacute exposure of airborne particulate matter (PM) on pregnancy and fetal development in female mice. Forty female and forty male ICR adult mice were caged separately by 1:1 to get access to pregnancy. The pregnant mice were randomized into control group (A), small (B), middle (C), large (D) or overdose (E) PM challenge groups (n = 8-11), and were administered with 30 µl of phosphate buffered solution (A) or resuspended standard PM SRM 1649a at 0.09 (B), 0.52 (C), 1.85 (D) or 69.2 (E) µg/µl, once per trid from d 0 till d 19 of pregnancy via instillation onto the base of the tongue. Fetal mice were harvested by cesarean section at the time when spontaneous delivery occurred. Body weight of the pregnant mice, gestational days, intrauterine survival and growth, hepatic and pneumonic histopathological changes of the fetal mice were investigated. Lung/body and liver/body weight ratios were calculated. Expressions of mRNA and protein of CYP1A1 in the fetal lung and CYP1A2 in the fetal liver were assayed. (1) All of the pregnant mice survived pregnancy throughout the entire experiment. Body weight of the pregnant mice was not significantly different among all the groups at gestational d 1 and 7 (P > 0.05), but significantly lower in group E [(41.8 ± 5.8) and (48.9 ± 8.9) g] than in group A [(45.9 ± 1.8) and (56.2 ± 4.9) g] at gestational d 14 and 18 (P < 0.05). The gestational days were significantly decreased in group E [(19.3 ± 1.3) d] when compared with group A [(20.5 ± 0.7) d; P < 0.05] and were not significantly different among groups A, B, C and D (P > 0.05). Lung/body and liver/body weight ratios of the fetal mice were significantly increased in group E [(1.21 ± 0.18) and (4.68 ± 0.21)%] as compared with groups A, B, C and D (P < 0.05). (2) Mortality rates of the fetuses were significantly higher in group E (23.0%) than in groups A (0.8%), B (0.9%), C (1.7%) and D (3.7%) (P < 0.05), but were not significantly different among groups A, B, C and D (P > 0.05) despite of an increasing tendency. (3) Pathological changes in the liver and lung of the fetuses were conspicuous in group E. The fetal liver injury was histopathologically evidenced by deranged tissue structure, degenerated parenchyma of hepatic cells, and mildly stained cytoplasm. Adipose degeneration was represented by clear-boundary intracytoplasmic vacuoles in most of the liver cells, and cell pyknosis with heavily stained cytoplasm was observed in some of the liver cells. Inflammatory cell infiltration and focal necrosis were occasionally found in the hepatic tissue. The fetal lung exhibited bronchiole with narrow lumina, vascular engorgement in the submucosal layer, interstitial and alveolar edema, thickened alveolar septum, granulocyte and lymphocyte infiltrations within the pulmonary alveoli and around the bronchioles. The above pathological changes were lesser in groups C and D, and were not or least found in groups A and B. (4) Protein expressions of CYP1A1 in the fetal lung and CYP1A2 in the fetal liver were significantly increased in group E (1.20 ± 0.40 and 2.55 ± 0.89) when compared with group A (0.77 ± 0.36 and 2.08 ± 0.31) (P < 0.05). mRNA expressions of CYP1A1 in the fetal lung were significantly increased in groups C (0.36 ± 0.12), D (0.41 ± 0.08) and E (0.43 ± 0.11) compared with group A (0.21 ± 0.10), and significantly increased in groups D and E compared with group B (0.28 ± 0.10, P < 0.05). mRNA expressions of CYP1A2 in the fetal liver were significantly increased in groups C (0.37 ± 0.13), D (0.36 ± 0.14) and E (0.43 ± 0.16) compared with group A (0.21 ± 0.03), and significantly increased in group E compared with group B (0.24 ± 0.11, P < 0.05). PM elicited embryotoxigenicity and resulted in adverse pregnancy outcomes in mice by intrauterine exposure of overdose PM. The expressions of cancer-related genes CYP1A1 and CYP1A2 were up-regulated in organs after the middle- and large-dose subacute exposure of PM, which may have a potential role on the future development.

Differential toxicity of Mn2+ and Mn3+ to rat liver tissues: Oxidative damage, membrane fluidity and histopathological changes

Toxicity due to overexposure to manganese (Mn) is becoming increasingly prevalent. Mn-induced neurodegenerative toxicity has been demonstrated, but little is known concerning the adverse effects of the element on the liver. Under physiological conditions, manganese primarily exists as divalent manganese (Mn(2+)) and trivalent manganese (Mn(3+)). The present study was designed to evaluate and compare the effects of Mn(2+) and Mn(3+) on oxidative hepatic damage, membrane fluidity and histopathological changes in rats. Rats exposed to Mn(2+) or Mn(3+) (2.0mg Mn/kg body weight) showed significant inhibition of superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity, as well as decreased levels of glutathione (GSH) and increased levels of malondialdehyde (MDA) in liver tissues. We also showed a significant inhibition of SOD activity and increased MDA levels in hepatocyte nuclei. We also observed reduced Na(+),K(+)-ATPase activity, increased MDA levels and decreased plasma membrane fluidity, which was accompanied by an increase of fluorescence anisotropy (r) values, in hepatic plasma membranes. In addition, Mn(2+) and Mn(3+) both caused histopathological changes, such as mononuclear cell infiltration, congestion, enlargement of the veins and sinusoids, hepatocellular damage, necrotic changes, mitochondrial hyperplasia, swelling and vacuolization, as determined by light and electron microscopy. Taken together, these data suggest that both Mn(2+) and Mn(3+) inhibit the normal physiological functioning of the liver. Under the experimental conditions used, the adverse effects of Mn(2+) were more severe than those of Mn(3+).

Non-alcoholic fatty liver disease in subjects with type 2 diabetes mellitus and non-diabetics with special reference to insulin resistance and hepatic histopathological changes

Aims Non alcoholic fatty liver disease (NAFLD) includes simple steatosis and non alcoholic steatohepatitis (NASH). The present study was intended to evaluate insulin resistance (IR) in patients with NAFLD and correlate Insulin resistance [IR] with histopathological grades of liver involvement. Material and Methods It constituted of forty two consecutive patients (ultrasonographically established) with fatty liver admitted to our hospital. Ninteen were patients with Type 2 diabetes mellitus, 23 were normoglycemic and 12 age-matched healthy persons served as controls. IR was assessed by using HOMA-IR. Histopathological grading and staging of NAFLD was done as per Brunt system. Results Diabetics had significantly higher IR than both the other groups while non diabetics with NAFLD also had higher IR (p < 001) than controls. There was no difference in the HDLc values between the three groups, whereas all other lipid parameters were higher in the patients. The IR was significantly higher 6.83(±2.51) in patients with grade 3 NASH as compared to patients with grade I changes 3.04(±1.58) (p < 0.05) irrespective of glycemic status. Similarly, the level of total cholesterol was significantly higher in patients with grade-3 NASH as compared to grade-1. Serum billirubin and liver enzymes (AST, ALT, ALP) were significantly higher in subjects with Grade 3 NASH when compared with Grade-1. Conclusion Insulin resistance and dyslipidemia rather than the glycemic status.were the determinant factors that had positive correlation with higher histopathological grades of NAFLD.