This study examined the effects of valproic acid (VPA), a histone deacetylase inhibitor, on carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Rats were divided into control, fibrotic, and VPA-treated groups. The fibrotic group received CCl4 injections to induce liver fibrosis, while the VPA-treated group also received VPA. After 6 weeks, liver tissue was analyzed. The fibrotic group showed disrupted liver architecture and hepatocyte damage. VPA treatment attenuated CCl4-induced fibrosis by preserving liver structure and reducing hepatocyte vacuolization. VPA also decreased expression of fibrosis markers α-SMA and Smad4, and lowered serum TGF
Iris Publishers - journals of biostatistics | Biomathematical Analysis of the...IrisPublishers
Liver fibrosis is the final common stage of the most chronic liver diseases, it is caused by several factors which lead to a major worldwide health care burden. Over the decades, the understanding of the liver fibrosis disease was growing rapidly, several studies reported that this progress could be regressed or reversed, which give us a bright prospect in developing anti-fibrotic therapies.In this experiment, liver fibrosis was fully developed after CCl4 induction for 7 weeks in eight animals. Clinical pathologic parameters, four indicators of hepatic fibrosis in monkey showed similarly changes in human. All animals had liver fibrosis after 1.5 months of CCl4 induction, and liver fibrosis still existed after 9 months recovery periods, the fibrosis stages in most animals had no obvious regression without treatment. Biomathematical analysis of the liver fibrosis would aid to utilize the anti-fibrotic therapies and their derivatives for various biomedical applications.
The role of curcumin in streptozotocin induced hepatic damage and the trans-d...Prof. Hesham N. Mustafa
Diabetic patients frequently suffer from non-alcoholic steatohepatitis. The current study aimed to investigate the role of curcumin and the response of hepatic stellate cells in streptozotocin (STZ)-induced hepatic damage. Sixty male rats were divided into three groups. The normal control injected with a citrate buffer vehicle and the diabetic control group which was injected intraperitoneally (IP) with a single-dose of streptozotocin (50mg/kg body weight) and a diabetic group was treated with an oral dose of curcumin at 80 mg/kg body weight daily for 60 days. Curcumin effectively counteracts oxidative stress-mediated hepatic damage and improves biochemical parameters. Alpha-smooth muscle actin (α-SMA) was significantly reduced, and insulin antibodies showed strong positive immunoreactivity with curcumin administration. These results optimistically demonstrate the potential use of curcumin, which is attributed to its antiradical/antioxidant activities and its potential β-cell regenerative properties. Also, it has the capability to encourage the trans-differentiation of hepatic stellate cells into insulin-producing cells for a period of time. In addition, as it is an anti-fibrotic mediator that inhibits hepatic stellate cell activation and the transition to myofibroblast-like cells, this suggests the possibility of considering curcumin's novel therapeutic effects in reducing hepatic dysfunction in diabetic patients.
Iris Publishers - journals of biostatistics | Biomathematical Analysis of the...IrisPublishers
Liver fibrosis is the final common stage of the most chronic liver diseases, it is caused by several factors which lead to a major worldwide health care burden. Over the decades, the understanding of the liver fibrosis disease was growing rapidly, several studies reported that this progress could be regressed or reversed, which give us a bright prospect in developing anti-fibrotic therapies.In this experiment, liver fibrosis was fully developed after CCl4 induction for 7 weeks in eight animals. Clinical pathologic parameters, four indicators of hepatic fibrosis in monkey showed similarly changes in human. All animals had liver fibrosis after 1.5 months of CCl4 induction, and liver fibrosis still existed after 9 months recovery periods, the fibrosis stages in most animals had no obvious regression without treatment. Biomathematical analysis of the liver fibrosis would aid to utilize the anti-fibrotic therapies and their derivatives for various biomedical applications.
The role of curcumin in streptozotocin induced hepatic damage and the trans-d...Prof. Hesham N. Mustafa
Diabetic patients frequently suffer from non-alcoholic steatohepatitis. The current study aimed to investigate the role of curcumin and the response of hepatic stellate cells in streptozotocin (STZ)-induced hepatic damage. Sixty male rats were divided into three groups. The normal control injected with a citrate buffer vehicle and the diabetic control group which was injected intraperitoneally (IP) with a single-dose of streptozotocin (50mg/kg body weight) and a diabetic group was treated with an oral dose of curcumin at 80 mg/kg body weight daily for 60 days. Curcumin effectively counteracts oxidative stress-mediated hepatic damage and improves biochemical parameters. Alpha-smooth muscle actin (α-SMA) was significantly reduced, and insulin antibodies showed strong positive immunoreactivity with curcumin administration. These results optimistically demonstrate the potential use of curcumin, which is attributed to its antiradical/antioxidant activities and its potential β-cell regenerative properties. Also, it has the capability to encourage the trans-differentiation of hepatic stellate cells into insulin-producing cells for a period of time. In addition, as it is an anti-fibrotic mediator that inhibits hepatic stellate cell activation and the transition to myofibroblast-like cells, this suggests the possibility of considering curcumin's novel therapeutic effects in reducing hepatic dysfunction in diabetic patients.
Biochemical Study on Endothelial Nitric Oxide Gene Polymorphism in Fatty Live...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Immunohistochemical Study of the Ameliorative Effect of Vitamin E on Liver Re...Prof. Hesham N. Mustafa
The liver is almost unique in its capacity for regeneration after hepatectomy but the exact mechanisms are not yet fully clarified. Antioxidants have been shown to promote liver regeneration after major hepatectomy. The present study evaluated the ameliorative effect of vitamin E administration on the liver regeneration after different periods of partial hepatectomy (PH) in rats. Fifty-six adult male albino rats were divided into three groups: Control sham operated group; partially hepatectomized group which were divided into three subgroups sacrificed at 1day, 3 days and 7days after the operation respectively; Partially Hepatectomized group with vitamin E pretreatment before PH where the rats were given a daily oral dose of vitamin E until the time of sacrifice of the rats. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA) and labeling index were demonstrated. After PH, the PCNA positive hepatocytes and the PCNA labeling indices were significantly high after the 1st day and then much decreased after the 3rd day, to be followed by a slight increase at the 7th day. Vitamin E pretreatment in PH rats resulted in a decrease in PCNA positive cells and its labeling indices in the 1st day with a gradual increase in the 3rd and 7th days. Vitamin E has an inhibitory effect in the first 24 hours on liver regeneration followed by stimulatory effect at the third and seventh days after PH. These data indicated that vitamin E pretreatment has an important role in regulation and enhancement of liver regeneration after PH.
Keywords:
Immunohistochemistry; Labeling Index; Vitamin E; Partial Hepatectomy; PCNA
Biochemical and Toxicological Investigations of 5-Fluorouracil, Nimesulide, a...BRNSS Publication Hub
The objective of this study was biochemical and toxicological investigations of 5-fluorouracil (5-FU), nimesulide, and ascorbic acid (Vitamin C) in Wistar rats with hepatocellular carcinoma in. Results showed that DENA increased the level of alpha fetoprotein (AFP), alkaline phosphatase (ALP), serum glutamic oxaloacetate transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), and total bilirubin which was decreased by the various combinations of 5-FU to normal. On the other hand, DENA resulted in decrease of blood glucose level, DFN decreased more than DF, and DFC showed results similar to DFN, while DFNC led to increased AFP, ALP, SGOT, SGPT, and total bilirubin levels to normal. Histopathological evaluations showed normal architecture of tissues of rat liver in normal group. Lesser damage of hepatocytes and low index of necrosis were in pre- and post-treated group of 5-FU+DF, DFN+DFC groups. DFNC treated group exhibited histological features resembling normal control animals.
Background- In homeopathy, Carcinosin 200C (Car200) and Natrum Sulphuricum 200C (Nat Sulph200), are generally used
individually in liver ailments depending on the totality of symptoms. This study was designed to examine if a combined treatment
of these two homeopathic remedies can provide better ameliorative effects in mammalian model mice (Mus musculus) with
reference to the generation of hepatotoxicity, free radicals and liver tumors induced by chronic feeding of two carcinogens,
p-dimethylaminoazobenzene (p-DAB) and phenobarbital (PB).
Methods- 42 mice were divided into following groups comprising 6 mice each: normal untreated (control-1), normal+succussed
alcohol-fed (control-2; alcohol being “vehicle” of the drugs), p-DAB+PB fed (carcinogen-intoxicated), p-DAB+PB+succussed alcohol
fed (carcinogen-intoxicated control-3), p-DAB+PB+Nat Sulph200 fed (intoxicated drug-fed-1), p-DAB+PB+Car200 fed (intoxicated
drug-fed-2), and p-DAB+PB+Nat Sulph200+Car200 fed (intoxicated drug-fed-3). Cytogenetical endpoints like chromosome
aberrations, micronuclei, mitotic index and sperm head anomaly, biomarkers like aspartate and alanine aminotransferases, lipid
peroxidation, reduced glutathione content, gamma-glutamyl transferase, lactate dehydrogenase, glucose-6-phosphate
dehydrogenase, succinate dehydrogenase, superoxide dismutase, catalase and glutathione reductase were assayed at certain
intervals. Additionally, electron microscopical studies (scanning and transmission) and gelatin zymography for matrix
metalloproteinases were conducted in the liver at day 90 and 120.
Results- All toxicity parameters were favorably modulated by administration of either of the two homeopathic remedies, but the
protection level was greater in mice treated conjointly with both the drugs.
Conclusion- Conjoint use of Car200 and Nat Sulph200 in carcinogen-intoxicated mice ameliorated hepatotoxicity and oxidative
stress significantly more than when a single drug was administered and their clinical use in human liver ailments is validated.
La figura de Alberto Sols fue durante décadas una referencia para los bioquímicos españoles. Los días 20 y 21 de febrero de 2017, la Fundación Ramón Areces dedicó un simposio internacional a su memoria, rindiendo homenaje a sus principales logros: las levaduras como modelo experimental, la enzimología y regulación metabólica y la patología molecular. El encuentro científico, que estuvo coordinado por Carlos Gancedo y Joan Guinovart, reunió a expertos internacionales para debatir sobre el legado de este científico español.
Liver ischemia/reperfusion injury, a setting in which the functional mass is ...Prof. Hesham N. Mustafa
Liver ischemia reperfusion is induced during sur-gical procedures like liver transplantation and re-section. Multiple mechanisms have been postulat-ed to liver damage following liver ischemia reperfu-sion injury, such as oxidative stress and inflamma-tory reactions. The present study declares the pos-sible mechanism of tadalafil, toward modulating the inflammatory response. Forty-eight rats were divided into 4 groups as follows; Sham group sub-jected to midline laparotomy only. Tadalafil group administered Tadalafil 10 mg/kg intraperitoneal 45 min before sham operation. I/R (Ischemia-reperfusion) group, rats undergo 60 min of hepatic ischemia followed by 60 min of reperfusion. Tada-lafil + I/R group rats undergo a similar pattern of I/R after the treatment with Tadalafil 10 mg/kg, 45 min before ischemia. At the end of the reperfusion, the blood samples were collected for estimation of biochemical markers including liver enzymes using colorimetric assay method and serum: TNF-α (tumor necrosis factor-α), IL-6 (interleukin 6) le-vels, ICAM- 1 (Intercellular Adhesion Molecule-1) were measured. Tissues were evaluated by semi-quantitative and morphometrical approaches. Ta-dalafil succeeded in restoring normal levels of liverenzymes and ameliorating the oxidative stress as evidenced by decreasing MDA and restoring redu-ced glutathione levels in liver tissue homogenate. Also, Tadalafil exhibits anti-inflammatory effects, as it significantly decreased the levels of TNF-α, IL6 and ICAM-1. The findings are supported by BCL-2, TNF-α immunomarkers. It is concluded that modulation of the inflammatory response might be one of the mechanisms of Tadalafil-mediated he-patoprotection, so it is recommended as an adju-vant therapy in liver surgery.Keywords: Ischemia/reperfusion injury – Oxidative stress – Apoptosis – TNF-α – BCL-2
A Thesis Submitted to the College of Medicine and the Committee of Postgraduate Studies of the University of Al-Mustansiriya in Partial Fulfillment of the Requirements for the Degree of Master of Science in Pharmacology
The aim of the study was to investigate the damage created in tissue by using an in vivo isolated portal ischemia and reperfusion model in the rat liver and the effects of heparin administration on the complement system. A total of 25 male rats weighing 150-290 gr were used in the study. Following anesthesia with ketamine hydrochloride and xylazine hydrochloride, the incision area was shaved in all rats except the control group. The portal vein was isolated and clamped, and ischemia and reperfusion created. Two groups were sacrificed at the 24th hour and two at the 48th hour. Heparin was administered to one of the groups sacrificed at the 24th hour and not to the other group, and similarly one of the groups sacrificed at the 48th hour received heparin while the other did not. Biochemical and pathologic parameters were used to evaluate the damage using serum and liver tissue samples from the sacrificed rats. We used the liver GSH, MPO and C3 levels and the serum IL-6 level to evaluate the ischemia and reperfusion damage in the liver tissue. Heparin was shown to decrease the damage occurring after ischemia and reperfusion by decreasing complement activation and the MPO and IL-6 levels while increasing GSH levels as a result of the statistical analysis performed. Heparin was shown to prevent tissue damage after ischemia and reperfusion by decreasing complement activation and inflammation.
Flavin-Containing Dimethylaniline Monooxygenase 5 Drives Malignancies in Hepa...semualkaira
Hepatic microsomes play an important role in drug metabolism,
but the potential biological functions of hepatic microsome-containing proteins in Hepatocellular Carcinoma (HCC) remain unclear. Here, we used HCC and corresponding adjacent Non-Tumor
(NT) tissues to isolate hepatic microsomes and then performed
RNA high-throughput sequencing
Flavin-Containing Dimethylaniline Monooxygenase 5 Drives Malignancies in Hepa...semualkaira
Hepatic microsomes play an important role in drug metabolism, but the potential biological functions of hepatic microsome-con- taining proteins in Hepatocellular Carcinoma (HCC) remain un- clear. Here, we used HCC and corresponding adjacent Non-Tumor (NT) tissues to isolate hepatic microsomes and then performed RNA high-throughput sequencing. After screening, flavin-con- taining dimethylaniline monooxygenase (FMO5) showed a significantly high expression level and was associated with poor prognosis in patients with HCC.
Biochemical Study on Endothelial Nitric Oxide Gene Polymorphism in Fatty Live...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
Immunohistochemical Study of the Ameliorative Effect of Vitamin E on Liver Re...Prof. Hesham N. Mustafa
The liver is almost unique in its capacity for regeneration after hepatectomy but the exact mechanisms are not yet fully clarified. Antioxidants have been shown to promote liver regeneration after major hepatectomy. The present study evaluated the ameliorative effect of vitamin E administration on the liver regeneration after different periods of partial hepatectomy (PH) in rats. Fifty-six adult male albino rats were divided into three groups: Control sham operated group; partially hepatectomized group which were divided into three subgroups sacrificed at 1day, 3 days and 7days after the operation respectively; Partially Hepatectomized group with vitamin E pretreatment before PH where the rats were given a daily oral dose of vitamin E until the time of sacrifice of the rats. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA) and labeling index were demonstrated. After PH, the PCNA positive hepatocytes and the PCNA labeling indices were significantly high after the 1st day and then much decreased after the 3rd day, to be followed by a slight increase at the 7th day. Vitamin E pretreatment in PH rats resulted in a decrease in PCNA positive cells and its labeling indices in the 1st day with a gradual increase in the 3rd and 7th days. Vitamin E has an inhibitory effect in the first 24 hours on liver regeneration followed by stimulatory effect at the third and seventh days after PH. These data indicated that vitamin E pretreatment has an important role in regulation and enhancement of liver regeneration after PH.
Keywords:
Immunohistochemistry; Labeling Index; Vitamin E; Partial Hepatectomy; PCNA
Biochemical and Toxicological Investigations of 5-Fluorouracil, Nimesulide, a...BRNSS Publication Hub
The objective of this study was biochemical and toxicological investigations of 5-fluorouracil (5-FU), nimesulide, and ascorbic acid (Vitamin C) in Wistar rats with hepatocellular carcinoma in. Results showed that DENA increased the level of alpha fetoprotein (AFP), alkaline phosphatase (ALP), serum glutamic oxaloacetate transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT), and total bilirubin which was decreased by the various combinations of 5-FU to normal. On the other hand, DENA resulted in decrease of blood glucose level, DFN decreased more than DF, and DFC showed results similar to DFN, while DFNC led to increased AFP, ALP, SGOT, SGPT, and total bilirubin levels to normal. Histopathological evaluations showed normal architecture of tissues of rat liver in normal group. Lesser damage of hepatocytes and low index of necrosis were in pre- and post-treated group of 5-FU+DF, DFN+DFC groups. DFNC treated group exhibited histological features resembling normal control animals.
Background- In homeopathy, Carcinosin 200C (Car200) and Natrum Sulphuricum 200C (Nat Sulph200), are generally used
individually in liver ailments depending on the totality of symptoms. This study was designed to examine if a combined treatment
of these two homeopathic remedies can provide better ameliorative effects in mammalian model mice (Mus musculus) with
reference to the generation of hepatotoxicity, free radicals and liver tumors induced by chronic feeding of two carcinogens,
p-dimethylaminoazobenzene (p-DAB) and phenobarbital (PB).
Methods- 42 mice were divided into following groups comprising 6 mice each: normal untreated (control-1), normal+succussed
alcohol-fed (control-2; alcohol being “vehicle” of the drugs), p-DAB+PB fed (carcinogen-intoxicated), p-DAB+PB+succussed alcohol
fed (carcinogen-intoxicated control-3), p-DAB+PB+Nat Sulph200 fed (intoxicated drug-fed-1), p-DAB+PB+Car200 fed (intoxicated
drug-fed-2), and p-DAB+PB+Nat Sulph200+Car200 fed (intoxicated drug-fed-3). Cytogenetical endpoints like chromosome
aberrations, micronuclei, mitotic index and sperm head anomaly, biomarkers like aspartate and alanine aminotransferases, lipid
peroxidation, reduced glutathione content, gamma-glutamyl transferase, lactate dehydrogenase, glucose-6-phosphate
dehydrogenase, succinate dehydrogenase, superoxide dismutase, catalase and glutathione reductase were assayed at certain
intervals. Additionally, electron microscopical studies (scanning and transmission) and gelatin zymography for matrix
metalloproteinases were conducted in the liver at day 90 and 120.
Results- All toxicity parameters were favorably modulated by administration of either of the two homeopathic remedies, but the
protection level was greater in mice treated conjointly with both the drugs.
Conclusion- Conjoint use of Car200 and Nat Sulph200 in carcinogen-intoxicated mice ameliorated hepatotoxicity and oxidative
stress significantly more than when a single drug was administered and their clinical use in human liver ailments is validated.
La figura de Alberto Sols fue durante décadas una referencia para los bioquímicos españoles. Los días 20 y 21 de febrero de 2017, la Fundación Ramón Areces dedicó un simposio internacional a su memoria, rindiendo homenaje a sus principales logros: las levaduras como modelo experimental, la enzimología y regulación metabólica y la patología molecular. El encuentro científico, que estuvo coordinado por Carlos Gancedo y Joan Guinovart, reunió a expertos internacionales para debatir sobre el legado de este científico español.
Liver ischemia/reperfusion injury, a setting in which the functional mass is ...Prof. Hesham N. Mustafa
Liver ischemia reperfusion is induced during sur-gical procedures like liver transplantation and re-section. Multiple mechanisms have been postulat-ed to liver damage following liver ischemia reperfu-sion injury, such as oxidative stress and inflamma-tory reactions. The present study declares the pos-sible mechanism of tadalafil, toward modulating the inflammatory response. Forty-eight rats were divided into 4 groups as follows; Sham group sub-jected to midline laparotomy only. Tadalafil group administered Tadalafil 10 mg/kg intraperitoneal 45 min before sham operation. I/R (Ischemia-reperfusion) group, rats undergo 60 min of hepatic ischemia followed by 60 min of reperfusion. Tada-lafil + I/R group rats undergo a similar pattern of I/R after the treatment with Tadalafil 10 mg/kg, 45 min before ischemia. At the end of the reperfusion, the blood samples were collected for estimation of biochemical markers including liver enzymes using colorimetric assay method and serum: TNF-α (tumor necrosis factor-α), IL-6 (interleukin 6) le-vels, ICAM- 1 (Intercellular Adhesion Molecule-1) were measured. Tissues were evaluated by semi-quantitative and morphometrical approaches. Ta-dalafil succeeded in restoring normal levels of liverenzymes and ameliorating the oxidative stress as evidenced by decreasing MDA and restoring redu-ced glutathione levels in liver tissue homogenate. Also, Tadalafil exhibits anti-inflammatory effects, as it significantly decreased the levels of TNF-α, IL6 and ICAM-1. The findings are supported by BCL-2, TNF-α immunomarkers. It is concluded that modulation of the inflammatory response might be one of the mechanisms of Tadalafil-mediated he-patoprotection, so it is recommended as an adju-vant therapy in liver surgery.Keywords: Ischemia/reperfusion injury – Oxidative stress – Apoptosis – TNF-α – BCL-2
A Thesis Submitted to the College of Medicine and the Committee of Postgraduate Studies of the University of Al-Mustansiriya in Partial Fulfillment of the Requirements for the Degree of Master of Science in Pharmacology
The aim of the study was to investigate the damage created in tissue by using an in vivo isolated portal ischemia and reperfusion model in the rat liver and the effects of heparin administration on the complement system. A total of 25 male rats weighing 150-290 gr were used in the study. Following anesthesia with ketamine hydrochloride and xylazine hydrochloride, the incision area was shaved in all rats except the control group. The portal vein was isolated and clamped, and ischemia and reperfusion created. Two groups were sacrificed at the 24th hour and two at the 48th hour. Heparin was administered to one of the groups sacrificed at the 24th hour and not to the other group, and similarly one of the groups sacrificed at the 48th hour received heparin while the other did not. Biochemical and pathologic parameters were used to evaluate the damage using serum and liver tissue samples from the sacrificed rats. We used the liver GSH, MPO and C3 levels and the serum IL-6 level to evaluate the ischemia and reperfusion damage in the liver tissue. Heparin was shown to decrease the damage occurring after ischemia and reperfusion by decreasing complement activation and the MPO and IL-6 levels while increasing GSH levels as a result of the statistical analysis performed. Heparin was shown to prevent tissue damage after ischemia and reperfusion by decreasing complement activation and inflammation.
Flavin-Containing Dimethylaniline Monooxygenase 5 Drives Malignancies in Hepa...semualkaira
Hepatic microsomes play an important role in drug metabolism,
but the potential biological functions of hepatic microsome-containing proteins in Hepatocellular Carcinoma (HCC) remain unclear. Here, we used HCC and corresponding adjacent Non-Tumor
(NT) tissues to isolate hepatic microsomes and then performed
RNA high-throughput sequencing
Flavin-Containing Dimethylaniline Monooxygenase 5 Drives Malignancies in Hepa...semualkaira
Hepatic microsomes play an important role in drug metabolism, but the potential biological functions of hepatic microsome-con- taining proteins in Hepatocellular Carcinoma (HCC) remain un- clear. Here, we used HCC and corresponding adjacent Non-Tumor (NT) tissues to isolate hepatic microsomes and then performed RNA high-throughput sequencing. After screening, flavin-con- taining dimethylaniline monooxygenase (FMO5) showed a significantly high expression level and was associated with poor prognosis in patients with HCC.
Possible Protective Effect of Bone Marrow-Mesenchymal Stem Cells
(BM-MSCs) Against the Remote Liver Injury Induced by Renal Ischemia Reperfusion in Male Albino Rats
Background: Body of literature are becoming pronounced that pathological condition in one organ of the body might have an effect on other distal organs owing to the fact, that the entire body metabolism is orchestrated centrally.
Pathological events occurring in an organ are likely to be extended to other organs. Pretreatment that minimize these events are presumed to be beneficial to the extended organs.
Methods: Following 30 min of ischemia and 48 h of reperfusion in the kidney, rats under anesthesia were sacrificed and blood sample collected through cardiac puncture. Serum level of troponin I, and activities of total creatine kinase (CK), mass creatine kinase (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma –glutamyl transferase (GGT) were estimated spectrophotometrically.
Results: Serum troponin I increased to 0.031 ± 0.001 ng/ml in the ischemic group, and following pretreatment with Lmm (600mg/kg), serum level of troponin I decreased significantly to 0.021 ± 0.001 ng/ml (P<.05).><.05),><.05)><.05).
Immunomodulatory effect of schisandrae oil in mouse model of autoimmune hepat...LucyPi1
Abstract Objective: To study the immunomodulatory effect of schisandra oil (SCO) in mouse model of autoimmune hepatitis induced by concanavalin A (ConA). Methods: C57BL/6 mice were divided into control group, model group and SCO group. Mice in SCO group were given SCO at 5 mg/kg by intragastric administration every day for 7 days, followed by intravenous injection of ConA at 10 mg/kg. 10 hours after ConA injection, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured by the kits, the expression of inflammatory cytokines like interferon-γ (IFN-γ), interleukin-4 (IL-4), interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in liver was detected by real-time quantitative PCR, and the T cell activation and IFN-γ expression in spleen and MLN were examined by flow cytometry. Results: Compared with control group, each indicator in model group were significantly higher. In SCO preventive treatment group, the levels of serum ALT, AST and LDH were significantly reduced (all P < 0.001), the expression levels of inflammatory cytokines in liver were downregulated, the T cell activation in spleen and MLN was inhibited (P = 0.006 and P = 0.008), the percentages of IFN-γ+ CD8+ and IFN-γ+ CD4+ T cells were decreased, and the frequencies of Th2 and Th17 cells in spleen and MLN were also decreased at the same time. Conclusion: SCO has a protective effect on immune liver injury by inhibiting the activation of T cells and reducing the expression of inflammatory cytokines, which reflects that SCO plays a role in the immunomodulation of autoimmune hepatitis, indicating that SCO is of great significance for the maintenance of autoimmune homeostasis.
Objective: Ischemia-reperfusion (I/R) leads to reactive oxygen species formation and cell death in kidney tissue with injury and organ transplantation. Simvastatin (SIM) is an antioxidant, anti-inflammatory, and anticoagulant agent. Alterations in I/R-induced acute kidney injury model with SIM treatment were analyzed.
Study Design: Wistar rats (n=28) were grouped into Sham, Ischemia, I/R, and I/R+SIM treated. Left rat kidney renal vessels were clamped for 60 minutes for ischemia, and the I/R group had 6 hours of reperfusion. 10 mg/kg SIM was given orally for 28 days. MDA, GSH, and MPO were analyzed. Kidney tissues were paraffin embedded, and primary antibodies TNF-α and caspase-3 were applied for immunohistochemistry.
Results: In the I/R group, intense inflammatory cell infiltration around the vessels and necrosis in the glomerular structures were observed. In the treated group, proximal and distal tubular cells were found to be close to normal. Immunoexpression of caspase-3 in the ischemia group was positive in degenerative glomeruli. In the treated group, TNF-α expression was negative in the glomerular structures. MDA and MPO levels were significantly increased in ischemia and I/R.
Conclusion: We suggest that SIM treatment improved kidney tissue structure and function in a model of I/R injury.
Keywords: caspase-3; immunohistochemistry; ischemia/reperfusion; kidney; MPO; simvastatin
Liver Fibrosis: Difficulties in Diagnostic and Treatment: A Review-Crimson Pu...CrimsonGastroenterology
Early discovery of liver fibrosis and cirrhosis is becoming more relevant because of enhanced incidence of hepatocellular carcinoma. There a many underlying factors in developing liver fibrosis (i.e. viral hepatitis, steatohepatitis). Diagnosis of liver fibrosis is difficult; chronic liver failure and less distinct fibrosis stages can be underestimated, when laboratory routine parameters and native ultrasound of the liver are unsuspicious. Liver biopsy is a common element of diagnostic workup in hepatic cirrhosis, alongside clinical examination and abdominal ultrasound, and is the accepted diagnostic gold standard. But there is no unitary system of histological classification used to evaluate the degree of fibrosis, and individual systems are often validated only for individual disease entities. On the other hand liver biopsy is of less tolerance for patients. In the last years serological markers for detecting liver fibrosis were developed with different validity. Various imaging modalities have been proposed as methods for assessing liver fibrosis
by liver stiffness measurement. They are sufficient to approve the suspicious of liver fibrosis and/or to uncover unknown chronic liver failure. Studies showed the clinical usefulness of acoustic radiation force impulse shear wave elasticity imaging (ARFI-SWEI) is efficient as a preventive screening method to uncover fibrosis. The ARFI-SWEI system is integrated in an ultrasound device has a good accuracy and high reproducibility. Therapy of liver fibrosis depends on underlying disease and degree of liver failure. When liver failure can be cured liver fibrosis can regress. Direct antifibrotic drugs are
actually not available but in progress.
Evaluation of the Hepa Wash treatment in pigs with acute liver failureEnrique Moreno Gonzalez
Mortality of patients with acute liver failure (ALF) is still unacceptably high. Available liver
support systems are still of limited success at improving survival. A new type of albumin
dialysis, the Hepa Wash® system, was newly introduced. We evaluated the new liver support
system as well as the Molecular Adsorbent Recycling System (MARS) in an ischemic
porcine model of ALF.
Effect of Platelet Rich Plasma (PRP) Injection on the Endocrine
Pancreas of the Experimentally Induced Diabetes in Male Albino Rats: A
Histological and Immunohistochemical Study
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
Contact us if you are interested:
Email / Skype : kefaya1771@gmail.com
Threema: PXHY5PDH
New BATCH Ku !!! MUCH IN DEMAND FAST SALE EVERY BATCH HAPPY GOOD EFFECT BIG BATCH !
Contact me on Threema or skype to start big business!!
Hot-sale products:
NEW HOT EUTYLONE WHITE CRYSTAL!!
5cl-adba precursor (semi finished )
5cl-adba raw materials
ADBB precursor (semi finished )
ADBB raw materials
APVP powder
5fadb/4f-adb
Jwh018 / Jwh210
Eutylone crystal
Protonitazene (hydrochloride) CAS: 119276-01-6
Flubrotizolam CAS: 57801-95-3
Metonitazene CAS: 14680-51-4
Payment terms: Western Union,MoneyGram,Bitcoin or USDT.
Deliver Time: Usually 7-15days
Shipping method: FedEx, TNT, DHL,UPS etc.Our deliveries are 100% safe, fast, reliable and discreet.
Samples will be sent for your evaluation!If you are interested in, please contact me, let's talk details.
We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
1. Research Communication
Effect of Histone Deacetylase Inhibitor on
Epithelial-mesenchymal Transition of Liver
Fibrosis
Maggie M. Ramzy 1
*
Hend M Abdelghany1
Nagwa M. Zenhom1
Nashwa F. El-Tahawy2
1
Department of Biochemistry, Faculty of Medicine, Minia University, Egypt
2
Department of Histology and Cell Biology, Faculty of Medicine, Minia
University, Egypt
Abstract
Liver fibrosis is an excessively reversible wound healing pro-
cess and the fibrotic disorder is the activation of hepatic stel-
late cell that requires extensive alterations in gene expression.
As reversible deacetylation of histone proteins modulate gene
expression, we examined the effect of valproic acid (VPA) as
selective histone deacetylase inhibitor on CCl-4 induced liver
fibrosis. Thirty rats were divided into three equal groups; con-
trol group, fibrotic group and VPA-treated group. The rats
were sacrificed after 6 weeks of liver fibrosis induction. The
histopathological effect on liver tissue was examined. The
expression of a-SMA and Smad-4 mRNA and serum levels of
TGF-b1, alanine aminotransferase, and aspartate aminotrans-
ferase were determined. Treatment of rats with VPA attenu-
ated carbon tetrachloride-induced liver fibrosis. Moreover, a-
SMA and Smad-4 expression was repressed under VPA treat-
ment and both serum TGF-b1 and liver enzymes were signifi-
cantly decreased. The histone deacetylase inhibitor-1 VPA
inhibits the epithelial–mesenchymal transition and affects
hepatic stellate cell activation during liver fibrosis through
downregulation of Smad4 and a-SMA expression which may
serve as a promising agent in liver fibrosis treatment. VC 2018
IUBMB Life, 70(6):511–518, 2018
Keywords: liver fibrosis; histone deacetylase inhibitor; valproic acid;
TGF-b; a-SMA; and Smad-4
INTRODUCTION
Liver fibrosis is an important pathological wound healing pro-
cess in reaction to liver injury characterized by progressive
accumulation of extracellular matrix (ECM) components (1).
Although the etiologies of liver diseases may vary, fibrosis and
cirrhosis develop through common signaling pathways. Cas-
cades of reactions occurs leading to the accumulation of colla-
gen and other ECM components. Sustained stimulation and
accumulation of these materials lead to the liver cirrhosis,
destruction of liver structures, and decreased liver function
(2). ECM is deposited by a prominent population of myofibro-
blasts (3) which are absent from the normal liver and are
derived from hepatic stellate cells (HSCs) in the injured liver
(4). Consecutive rounds of epithelial–mesenchymal transition
(EMT) and mesenchymal–epithelial transition (MET) suggest
that EMT could be reversible and associated with epigenetic
modifications (5). Epigenetic modifications include DNA meth-
ylation, post-translational histone modifications, and RNA-
based mechanisms mediated by small non-coding microRNAs
(6). Histone modifications are regulated by histone acetyltrans-
ferases and histone deacetylases (HDACs) (7) through which
they have an effect on chromatin remodeling and have essen-
tial roles in regulating gene transcription (8).
HDACs are divided into four classes according to their
sequence: class I including HDAC1, 2, 3, and 8, class II includ-
ing HDAC4, 5, 6, 7, 9, and 10, class III including SIRT1
to SIRT7, and finally class IV of HDACs which consists of
HDAC11-related enzymes (9,10). Recently, much attention has
been focused on the ability of HDAC inhibitors to regulate
EMT (11). Valproic acid (VPA), a branched short-chain fatty
acid and a known treatment for several conditions including
VC 2018 International Union of Biochemistry and Molecular Biology
Volume 70, Number 6, June 2018, Pages 511–518
*Address correspondence to: Maggie M. Ramzy, Department of Biochem-
istry, Faculty of Medicine, Minia University, Egypt.
E-mail: maggiemaher24@gmail.com
Received 6 February 2018; Accepted 5 March 2018
DOI 10.1002/iub.1742
Published online 30 March 2018 in Wiley Online Library
(wileyonlinelibrary.com)
IUBMB Life 511
2. epilepsy and bipolar disorder (12,13), is a selective class I- his-
tone deacetylase inhibitor which can prevent death in experi-
mental models following hemorrhagic shock (14). Recently, a
great number of the studies linking VPA with liver disease
have suggested an essential role for VPA and its sodium salt in
remodeling fibrosis (1) as inhibition of HDACs may suppress
EMT through their effects on TGF-b1 signaling (11). Previ-
ously, it has been reported that inhibition of HDAC activity
suppresses EMT induced by transforming growth factor-b
(TGF-b) in human renal epithelial cells (15).
TGF-b, mediates its action through binding to its serine/
threonine kinases-mediated receptors and subsequently acti-
vates signal transduction pathways via the downstream tran-
scription factors, SMADs (16).
Smad2 and/or Smad3 are two mediators of the Smad pro-
tein family. They are activated and associated with Smad4
then Smad protein complexes are translocated to the nucleus
to participate in transcriptional activation of target genes (17).
TGF-b/SMAD signaling plays a critical role in the EMT (18) so
this pathway could be the potential target for prevention and
treatment of fibrosis (19) and SMAD4 as a common mediator
can be a target for controlling HSCs activation during liver
fibrosis (16).
Resolution of liver fibrosis is associated with concomitant
reduction of HSCs activation and global cellular proliferation
(20) therefore, studying the underlying mechanisms of HSC
activation is an important step toward identification of molecu-
lar targets and the development of more effective therapies
(21). HSCs proliferate and differentiate into myofibroblast-like
cells with remarkable upregulation of a-smooth muscle actin
(a-SMA) which is referred to the activation of HSCs (22). Anti-
fibrotic drug research focuses on either the prevention/inhibi-
tion of the HSC activation and/or the stimulation of apoptosis
of the activated HSC (23).
The present study was designed to examine the effect of
VPA, a selective HDAC1 inhibitor on liver fibrosis and stellate
cell activation as this could have potential applications for new
therapeutic strategies against liver fibrosis.
MATERIAL AND METHODS
Animals
This study was carried out on 30 male Wistar albino rats. Rats
were kept in animal house under standard conditions of
boarding and feeding with free access to water.
The animals were divided into three groups: (i) control
group (10 rats) received vehicle by intraperitoneal injection
twice weekly for 6 weeks, (ii) fibrotic group (10 rats) was
received 0.5 lL/g body weight carbon tetrachloride (CCl4)
(Sigma–Aldrich, St. Louis, MO, USA) diluted 93 in corn oil
(Sigma–Aldrich, St. Louis, MO, USA) by intraperitoneal injec-
tion twice weekly for 6 weeks, (iii)treated group (10 rats); as
fibrotic group but rat received drinking water containing 0.4%
VPA twice a week, starting 2 days before the first CCl4
injection (24) which is considered clinically relevant dose in
vivo without significant toxicity (25). During the injection
period, animals were kept in their cages well ventilated, in
12 h day/night cycle. Ethical approval was obtained for the
study from Research Ethics Committee, Faculty of Medicine,
Minia University.
Experimental Procedures
Animals were sacrificed at the end of week six and the blood
was collected and centrifuged at 3,000 rpm for 15 min to
obtain serum which kept frozen at 2808C for determination of
serum TGF-b1, alanine aminotransferase (ALT), and amino-
transferase (AST). The liver tissue was removed and weighed.
Some specimens were immediately frozen in liquid nitrogen,
stored at 2808C for real-time polymerase chain reaction (RT-
PCR) and other parts were fixed in 10% buffered formalin for
histopathological studies.
Histological Procedures
Fixed liver specimens were processed for paraffin block prepa-
ration. Some sections of 5–7 lm thickness were cut, mounted
on glass slides and stained with hematoxylin and eosin (H&E)
and other sections were stained with Masson’s Trichrome (26)
Liver sections were examined and images were digitally cap-
tured using a high-resolution color digital camera mounted on
the microscope (Olympus, Japan), connected to a computer.
Morphometric Study
1. Morphological changes were evaluated in H&E sections
according to Ishak-modified HAI system (27). In brief, the
necroinflammation scores were calculated as the sum of the
four categories: periportal or periseptal interface hepatitis
(0–4); confluent necrosis (0–6); focal (spotty) lytic necrosis,
apoptosis, and focal inflammation (0–4); portal inflammation
(0–4). The final numerical score was the result of summa-
tion of three separate fields per rat for six rats in each
group.
2. For scoring of hepatic fibrosis; the following were applied
according to Ishak-modified HAI system (27): 0, no fibrosis;
1, fibrous expansion of some portal areas with or without
short fibrous septa; 2, fibrous expansion of most portal
areas with or without short fibrous septa; 3, fibrous expan-
sion of most portal areas with occasional portal-to-portal
(P–P) bridging; 4, fibrous expansion of portal areas with
marked portal bridging [P–P as well as portal-to-central (P–
C)]; 5, marked bridging (P–P and/or P–C) with occasional
nodules (incomplete cirrhosis); 6, cirrhosis, probable, or
definite.
Biochemical Analysis
The levels of serum ALT, AST were estimated using Randox
Kits (UK) according to the method of Reitman and Frankel
(28). Determination of serum TGF-b1 was done by a commer-
cial ELISA kit according to the manufacturer’s instructions
(Abcam, UK).
IUBMB LIFE
512 EFFECT OF HDAC INHIBITOR ON EMT
3. Real-time Reverse Transcription Polymerase Chain
Reaction for the Relative Quantification of a-SMA and
Smad4
Total RNA was extracted from homogenized liver specimen
using ribozol RNA extraction reagent (Amresco, Solon, OH,
USA) following the manufacturer’s instructions.
cDNAs were synthesized using Revert Aid First Strand
cDNA Synthesis kit (Fermentas, Life Sciences, ON, Canada).
cDNA was reversely transcribed from 5 lg of mRNA in tran-
scription buffer, 200 U M-MuLV Reverse Transcriptase, 20 U
RNase inhibitor at 428C for 60 min followed by immediate
cooling on ice. RT-PCR was performed with 50 ng cDNA per
reaction using 25 lL of SYBR Green QPCR Mix (Solis BioDyne)
containing 20 lM of specific primers in the RT-PCR Detection
System. The SYBR green data were analyzed with a relative
quantification to GAPDH (Glyceraldehyde-3-phosphate dehy-
drogenase) as reference gene. The sets of primers used were
as follows: Smad4 sense primers, 50
-
GTTCAGGTAGGAGAGACGTTTAAGGT-30
, and Smad4 antisense,
50
-CCTTTACATTCCAACTGCACTCCT-3, a-SMA sense primers; 50
-
ACTGGGACGACATGGAAAAG-30
and antisense 50
-
CATCTCCAGAGTCCAGCACA-30
and GAPDH sense primers: 50
-
GTCGGTGTGAACGGATTTG-30
and antisense 50
-
CTTGCCGTGGGTAGAGTCAT-30
. The relative expression level
of each gene was calculated using the formula 2(–DDCt)
method
(29). They were scaled relative to controls where control sam-
ples were set at a value of 1. Thus, results for all experimental
samples were graphed as relative expression compared with
the control.
Statistical Analysis
Statistics were done using statistical package for the social sci-
ences (SPSS) program (SPSS Inc., version 20). All data were
expressed as mean 6 standard deviation (SD). One-way ANOVA
followed by Tukey’s post-hoc were used for assessment of the
statistical significance of differences between sample mean
values between more than two groups and between two
groups respectively. A P value of 0.05 was considered statisti-
cally significant.
RESULTS
Histopathological Studies
Liver sections from control group showed normal hepatic
structure. Hepatocytes were polygonal cells arranged in
A representative photomicrograph of rat liver from
the control group shows normal lobular architecture.
Hepatocytes (arrows) with acidophilic cytoplasm and
rounded vesicular nuclei arranged in plates (lines)
radiating from the central veins (CV) and separated
by blood sinusoids (S). Note that some hepatocytes
are binucleated (circle). Inset: portal tract containing
branches of the portal vein (PV), hepatic artery (HA),
and bile duct (D). H&E 3400.
Representative photomicrographs of rat liver from the fibrotic group showing: (a) disrupted lobular architecture with dilated
blood sinusoids (s), areas of degenerations (circles), and numerous inflammatory cell infiltrations (arrows). Inset shows a con-
fluent area of degeneration showing apoptotic hepatocytes with densely stained cytoplasm and pyknotic (arrows) or frag-
mented nuclei (arrowheads). Some degenerated hepatocytes with ill-defined cell boundaries and ghosts of nuclei (rectangle).
(b) & inset show hepatocytes around central vein (CV) with vacuolated cytoplasm and malformed nuclei (arrows). Notice the
scattered apoptotic cells (circles). H&E: (a) 340, (b) 3100, insets 3400.
FIG 1
FIG 2
RAMZY ET AL. 513
4. anastomosing plates and cords. The plates radiated from the
central vein (CV) and separated by blood sinusoids (Fig. 1).
The CCl4 group showed disturbed morphology characterized
by variable and patchy areas of degenerations with inflamma-
tory cells infiltration. Hepatocytes showed various degenera-
tive features, for example, numerous apoptotic hepatocytes
with densely stained cytoplasm and pyknotic or fragmented
nuclei; others were degenerated with ill-defined cell bound-
aries and ghosts of nuclei, and others with vacuolated cyto-
plasm and malformed nuclei (Fig. 2a, b). The VPA-treated
group showed preserved hepatocytes and lobular architecture
(Fig. 3a). However, few areas surrounding the CV showed
some hepatocytes with vacuolated cytoplasm (Fig. 3b). The
morphometric study confirmed these results as shown in Table 1.
Masson’s Trichrome Staining
Masson’s trichrome stained liver sections showed no signs of
collagen deposition in the control group; minimal amount sur-
rounding the CV and portal tract (Fig. 4a). Liver sections from
fibrotic group revealed increased deposition of collagen fibers
around CVs, portal tract, and extended between them with
both portal to portal (P–P) and portal to central (P–C) bridging
characterized by formation of nodules (Fig. 4b). Liver tissues
from VPA-treated group showed decreased collagen deposition
with more extension of normal hepatic parenchyma and
reduction of fibrous septa (Fig. 4c). Fibrosis scores (Table 2)
were significantly increased in CCL4 group compared to con-
trol group (P 5 0.0001), while it were significantly decreased in
VPA-treated group compared to fibrotic group (P 5 0.0001).
Regenerating hepatocytes were obviously present in rats of
VPA-treated group, which evidenced by appearance of paren-
chyma nodules (pseudonodules) that did not take the fibrosis
stain (Fig. 4c).
Liver Enzymes Assay and Serum TGF-b
Live enzymes assay showed that ALT and AST were highly sig-
nificantly increased in fibrotic group (P < 0.001) compared to
control group and markedly suppressed in VPA-treated group
(P < 0.001) as compared to fibrotic group but still significantly
higher than control group. Also Serum TGF-b1 was increased
significantly (P < 0.001) in the fibrotic group in comparison with
control group. Serum TGF-b was significantly reduced in VPA-
treated group compared with that in fibrotic group (Table 3).
Relative Expression of a-SMA and Smad-4 by RT-PCR
Liver a-SMA relative mRNA expression was highly significantly
elevated in the fibrotic livers compared to healthy livers
(P 5 0.0001) suggesting increase in HSC activation. VPA treat-
ment significantly suppresses the strong up-regulation of a-
SMA as its expression was highly significantly decreased in
VPA-treated group compared to fibrotic group (P 5 0.0001)
and was non-significant compared to control group (P 5 0.058)
(Fig. 5).
On assessment of Smad-4 mRNA expression, it was found
that VPA significantly reduced Smad-4 mRNA level in treated
group compared to fibrotic group (P 5 0.0001) but still signifi-
cantly higher than control group (P 5 0.008) (Fig. 5).
DISCUSSION
Hepatic fibrosis is a severe consequence of needless accumula-
tion of excessive connective tissues in the liver (30). HSCs are
implicated in chronic liver disease, as they are the most
important source of matrix and the main origin of myofibro-
blasts in the liver, which renders them an important target for
Representative photomicrographs of rat liver from VPA-treated group showing: (a) preserved hepatocytes and lobular architec-
ture with apparent normal hepatocytes (arrows) with acidophilic cytoplasm and rounded vesicular nuclei arranged in plates
(lines) radiating from the central veins (CV) and separated by blood sinusoids (S). (b) Few areas surrounding the central vein
(CV) show some hepatocytes with vacuolated cytoplasm (arrows). H&E: a &b 3400
Histopathological scoring of rat livers (H&E
sections) in the studied groups (n 5 10)
Groups
Histopathological score
P valueMean 6 SEM
Control group 0.2 6 0.1
Fibrotic group 8.9 6 0.6 0.0001c
*
VPA-treated group 3.1 6 0.9 0.0001c
*
0.0001cl
*
c: vs. the control group; cl: vs. fibrotic group.
*P 0.05 is significant.
FIG 3
TABLE 1
IUBMB LIFE
514 EFFECT OF HDAC INHIBITOR ON EMT
5. the treatment of liver fibrosis (31). HSC activation is an initial
event in liver fibrosis (24) and recent studies in animal models
have convincingly shown that liver fibrosis regression is in
part driven by the reversion of activated HSCs to quiescence-
like HSCs (32,33). The involvement of epigenetic regulation
during HSC activation was reported in a previous study by
Mann et al. (34). Lately, VPA was shown to have antifibrotic
effects in both experimental liver fibrosis and adriamycin-
induced nephropathy model (24,35). In the current study, VPA;
as HDAC inhibitor, reserved the histopathological changes in
the livers induced by CCl4. HE sections of the CCl4 group
showed disturbed lobular architecture with areas of focal
necrosis, which was in agreement with Mir et al. (36). While
administration of VPA, reduced the morphological changes
observed in the CCl4 group. This was in agreement with Aher
et al. (23) who described the beneficial effects of VPA in rats
with TAA-induced hepatic fibrosis in which the drug prevented
the infiltration of inflammatory cells and further induced-DNA
damage and apoptosis in activated HSC.
Indeed, Masson’s Trichrome-stained sections showed that
VPA-treated animals had less collagen deposition and decreased
fibrosis score as demonstrated by a decreased septal formation
and deposition of lower amounts of interstitial collagens than in
the CCl4-treated animals. This could be explained by Mannaerts
et al. (24) who mentioned that VPA hindered the process of fibro-
genesis induced by CCl4 through inhibition of HSCs activation.
Also our results showed that VPA has an effect on serolog-
ical marker for liver fibrosis (TGF-b1) and liver enzymes (ALT
and AST) suggesting that inhibition of HDACs may suppress
EMT through effects on TGF-b1 signaling as the level of TGF-
b1 started to decline in VPA-treated animals compared to
fibrotic animals. This confirms the fundamental role of histone
deacetylation in liver fibrosis and the contribution of the com-
plexity of gene regulation by the acetylation state of histone
molecules in HSCs (1).
To determine if resolution of liver fibrosis is associated
with concomitant reduction of HSCs activation, expression of
a-SMA was examined. Our results showed remarkable upregu-
lation of a-SMA mRNA which indicates the activation of
HSCs (22) and its expression was significantly declined by VPA
Representative Photomicrographs of rat liver from the studied groups showing: (a) normal liver structure from control group
with minimal amounts of collagen (arrows) surrounding central vein (CV) and portal tract (PT). (b) Extensive collagen deposi-
tion with portal to portal (P–P) bridging (arrows) forming nodules (n). Inset shows extensive collagen deposition around central
vein (CV) in the fibrotic group. (c) VPA-treated group shows decreased collagen deposition (arrow). Notice the pseudonodules
(pn) that not surrounded by collagen fibers (thick arrows). Masson’s Trichrome 3100
Fibrosis scoring of rat livers (Masson’s Trichrome
sections) in the studied groups (n 5 10)
Groups
Fibrosis score
P valueMean 6 SEM
Control group 0.0 6 0.1
Fibrotic group 4.7 6 0.2 0.0001c
*
VPA-treated group 1.9 6 0.1 0.0001c
*
0.0001cl
*
c: vs. the control group; cl: vs. fibrotic group.
*P 0.05 is significant.
FIG 4
TABLE 2
RAMZY ET AL. 515
6. treatment, this in agree with Mannaerts et al. (24) which sug-
gested that a-SMA is one of the strongest VPA-dependent gene
expression changes during HSC activation as VPA treatment in
vitro resulted in decreased a-SMA protein. On the other hand,
Trichostatin A (TSA), the broad spectrum inhibitor has been
shown to inhibit HSC activation (37) but because of TSA’s lim-
ited use in vivo (38), it was important to test the effect of the
more selective class I HDI as VPA on HSC activation.
Previous studies have revealed that therapeutic interven-
tions of hepatocyte growth factor (HGF) as remarkable anti-
fibrotic effects in induced-liver fibrosis by CCl4 is associated
with decreased a-SMA expression, attenuated deposition of
collagen and reduced serum level of ALT and AST (39,40) con-
firming that inhibition of HSC activation are pivotal goals for
intervention in the hepatic fibrogenesis cascade (1).
Since Smads are involved in the regulation of collagen
expression (41), the effect of VPA on Smad4, which is involved
in the fibrogenic pathway, was examined. Our results showed
that expression of Smad4 in fibrotic liver tissue is significantly
increased while VPA was able to exert significant decrease in
its expression. SMAD4 could potentially be used as a target for
the EMT so previously Lan et al. (42) suggested that VPA
inhibits Smad4 expression in prostatic carcinoma cells and it
was very important as disruption of the of Smad4 pathway
leads to the inhibition of TGF-b signals (42). Also recently it
was demonstrated that VPA is an effective inhibitor of type I
collagen expression in conjunctival fibroblasts via the selective
regulation of Smads (41).
On the other hand, previous study has shown that TSA
(broad spectrum HDAC inhibitor) exerted anti-EMT effects and
these effects rely on epigenetic modulation of type I collagen
by deactivating the homolog 3 (Smad3)/Smad4 transcription
complex (43). As VPA is known to have higher efficiency with
lower toxicity than TSA (44), it might be a suitable alternative to
TSA in epigenetic reprogramming of liver fibrosis remodeling.
To our knowledge, this is the first study to demonstrate
that VPA downregulates Smad4 expression in CCl4-induecd
fibrosis model and this may be considered as one of the critical
therapeutic strategy for the treatment of liver fibrosis as it has
prominent role in TGF-b signaling in chronic liver disease.
Previously it was shown that the early TGF-b responders
Smad6 and Smad7 were not affected by VPA treatment (24)
but our study showed that some late responses to TGF-b1
stimulation through smad4 are affected, this may suggest that
class I HDACs are not the only VPA-targets in HSCs involved in
the fibrotic process.
The promising findings of HDAC inhibition in liver fibrosis
are recently highlighted and a growing body of evidence now
supports the safety and efficacy of HDAC inhibitors in experi-
mental models of liver disease (45). Hence, it may be helpful to
show that the VPA as histone deacetylase inhibitor-1 has an
effect on EMT and HSC activation of liver fibrosis and further
evaluation of VPA cellular effects and mechanisms, coupled
Level of liver enzymes and serum TGF-b in different
groups of the study
Control
group
(mean 6 SD)
Fibrotic
group
(mean 6 SD)
VPA-treated
group
(mean 6 SD)
ALT (U/mL) 29.1 6 3.8 161.9 6 15.9a
68.6 6 8.1a,b
AST (U/mL) 59.6 6 6.8 127.8 6 19.2a
90.8 6 4.4a,b
TGF-b (pg/mL) 173.3 6 10.89 286.2 6 28.29a
214.2 6 24.66a,b
a
Statistically significant compared to control group.
b
Statistically significant compared to fibrotic group.
(a) Relative expression of a-SMA mRNA in liver tissues in control, fibrotic group, and VPA-treated group. (b) Relative expres-
sion of Smad4 mRNA in liver tissues in control, fibrotic group and VPA-treated group. (**, P 0.001): highly significant, NS:
non-significant.
TABLE 3
FIG 5
IUBMB LIFE
516 EFFECT OF HDAC INHIBITOR ON EMT
7. with regulated drug uptake, may help towards optimizing the
clinical benefits of VPA while minimizing possible side effects.
REFERENCES
[1] Chen, P. J., Huang, C., Meng, X. M., and Li, J. (2015) Epigenetic modifica-
tions by histone deacetylases: biological implications and therapeutic poten-
tial in liver fibrosis. Biochimie 116, 61–69.
[2] Baik, S. J., Kim, T. H., Yoo, K., Moon, I. H., Choi, J. Y., et al. (2017)
Decreased S100B expression in chronic liver diseases. Korean J. Intern.
Med. 32, 269.
[3] Hinz, B., Phan, S. H., Thannickal, V. J., Prunotto, M., Desmoulie`re, A., et al.
(2012) Recent developments in myofibroblast biology: paradigms for con-
nective tissue remodeling. Am. J. Pathol. 180, 1340–1355.
[4] Lemoinne, S., Cadoret, A., El Mourabit, H., Thabut, D., and Housset, C.
(2013) Origins and functions of liver myofibroblasts. Biochim. Biophys. Acta
1832, 948–954.
[5] Lamouille, S., Xu, J., and Derynck, R. (2014) Molecular mechanisms of
epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196.
DOI: 10.1038/nrm3758(PMID: 24556840).
[6] Wilson, A. G. (2008) Epigenetic regulation of gene expression in the inflam-
matory response and relevance to common diseases. J. Periodontol. 79,
1514–1519.
[7] Khan, N. M., Jeffers, S., Kumar, C., Hackett, F., Boldog, N., et al. (2008)
Determination of the class and isoform selectivity of small molecule histone
deacetylase inhibitors. Biochem. J. 409, 581–589.
[8] Pang, M. and Zhuang, S. (2010) Histone deacetylase: a potential therapeutic
target for fibrotic disorders. J. Pharmacol. Exp. Ther. 335, 266–272.
[9] regoretti, I. V., Lee, Y. M., and Goodson, H. V. (2004) Molecular evolution of
the histone deacetylase family: functional implications of phylogenetic anal-
ysis. J. Mol. Biol. 338, 17–31.
[10] Grozinger, C. M. and Schreiber, S. L. (2002) Deacetylase enzymes: biological
functions and the use of small-molecule inhibitors. Chem. Biol. 9, 3–16.
[11] Sakamoto, T., Kobayashi, S., Yamada, D., Nagano, H., Tomokuni, A., et al.
(2016) A histone deacetylase inhibitor suppresses epithelial-mesenchymal
transition and attenuates chemo-resistance in biliary tract cancer. PLoS One
11, e0145985. DOI:10.1371/journal.pone.0145985.
[12] Isoherranen, N., Yagen, B., and Bialer, M. (2003) New CNS-active drugs
which are second-generation valproic acid: can they lead to the develop-
ment of a magic bullet? Curr. Opin. Neurol. 16, 203–211.
[13] Bialer, M. and Yagen, B. (2007) Valproic acid: second generation. Neurother-
apeutics 4, 130–137.
[14] Alam, H. B., Shuja, F., Butt, M. U., Duggan, M., Li, Y., Zacharias, N., et al.
(2009) Surviving blood loss without blood transfusion in a swine poly-
trauma model. Surgery 146, 325–333.
[15] Yoshikawa, M., Hishikawa, K., Marumo, T., et al. (2007) Inhibition of histone
deacetylase activity suppresses epithelial-to-mesenchymal transition
induced by TGF-b1 in human renal epithelial cells. J. Am. Soc. Nephrol. 18,
58–65.
[16] Khanizadeh, S., Ravanshad, M., Hosseini, S., Davoodian, P., Nejati Zadeh,
A., et al. (2015) Blocking of SMAD4 expression by shRNA effectively inhibits
fibrogenesis of human hepatic stellate cells. Gastroenterol. Hepatol. Bed
Bench 8, 262–269.
[17] Nakao, A., Afrakhte, M., Moren, A., Nakayama, T., Christian, J. L., et al.
(1997) Identification of Smad7, a TGF beta-inducible antagonist of TGF –
beta signaling. Nature 389, 631–635.
[18] Drabsch, Y. and ten Dijke, P. (2012) TGF-beta signalling and its role in can-
cer progression and metastasis. Cancer Metastasis Rev. 31, 553–568.
[19] Leask, A. and Abraham, D. J. (2004) TGF-b signaling and the fibrotic
response. FASEB J. 18, 816–827.
[20] Atta, H., El-Rehany, M., Hammam, O., Abdel-Ghany, H., Ramzy, M., et al.
(2014) Mutant mmp-9 and HGF gene transfer enhance resolution of CCL4-
induced liver fibrosis in rats: role of ASH1 and EZH2 methyltransferases
repression. PLoS ONE 9, e112384. DOI:10.1371/journal.pone.0112384.
[21] Wallace, K., Burt, A. D., and Wright, M. C. (2008) Liver fibrosis. Biochem. J.
411, 1–18.
[22] Mallat, A. and Lotersztajn, S. (2013) Cellular mechanisms of tissue fibrosis.
5. Novel insights into liver fibrosis. Am. J. Physiol. Cell Physiol. 305, C789–
C799.
[23] Aher, J. S., Khan, S., Jain, S., Tikoo, K., and Jena, G. (2015) Valproate ameli-
orates thioacetamide-induced fibrosis by hepatic stellate cell inactivation.
Hum. Exp. Toxicol. 34, 44–55.
[24] Mannaerts, I., Nuytten, N. R., Rogiers, V., Vanderkerken, K., van Grunsven,
L. A., et al. (2010) Chronic administration of valproic acid inhibits activation
of mouse hepatic stellate cells in vitro and in vivo. Hepatology 51, 603e 614.
[25] Xia, Q., Sung, J., Chowdhury, W., Chen, C. L., H€oti, N., et al. (2006) Chronic
administration of valproic acid inhibits prostate cancer cell growth in vitro
and in vivo. Cancer Res. 66, 7237–7244.
[26] Bancroft, J. D., Suvarna, S., Kim Layton, C. (2013) Bancroft’s Theory and
Practice of Histological Techniques. vol. 5, pp. 6–10, Churchill Livingstone,
China.
[27] Ishak, K., Baptista, A., Bianchi, L., Callea, F., De Groote, J., et al. (1995) His-
tological grading and staging of chronic hepatitis. J. Hepatol. 22, 696–699.
[28] Reitman, S. and Frankel, S. (1957) A colourimetric method for the determi-
nation of glutmate-oxaloacetate and glutmate-pyruvate transaminase. J.
Clin. Pathol. 28, 56.
[29] Van Guilder, H. D., Vrana, K. E., and Freeman, W. M. (2008) Twenty-five
years of quantitative PCR for gene expression analysis. BioTechniques 44,
619–626.
[30] Ahmad, A. and Ahmad, R. (2012) Understanding the mechanism of hepatic
fibrosis and potential therapeutic approaches. Saudi J. Gastroenterol. 18,
155.
[31] Geerts, A. (2004) On the origin of stellate cells: mesodermal, endodermal or
neuro-ectodermal? J. Hepatol. 40, 331–334.
[32] Kisseleva, T., Cong, M., Paik, Y., Scholten, D., Jiang, C., et al. (2012) Myofi-
broblasts revert to an inactive phenotype during regression of liver fibrosis.
Proc. Natl. Acad. Sci. 109, 9448–9453. DOI:10.1073/pnas.1201840109.
[33] Troeger, J. S., Mederacke, I., Gwak, G. Y., Dapito, D. H., Mu, X., et al.
(2012) Deactivation of hepatic stellate cells during liver fibrosis resolu-
tion in mice. Gastroenterology 143, 1073–1083.e22. https://doi.org/10.
1053/ j.gastro.2012.06.036.
[34] Mann, J., Oakley, F., Akiboye, F., Elsharkawy, A., Thorne, A. W., et al. (2006)
Regulation of myofibroblast transdifferentiation byDNAmethylation and
MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ.
14, 275–285.
[35] Van Beneden, K., Geers, C., Pauwels, M., Mannaerts, I., Verbeelen, D., et al.
(2011) Valproic acid attenuates proteinuria and kidney injury. J. Am. Soc.
Nephrol. 22, 1863–1875.
[36] Mir, A., Anjum, F., Riaz, N., Iqbal, H., Wahedi, H. M., et al. (2010) Carbon tet-
rachloride (CCl4)-induced hepatotoxicity in rats: curative role of Solanum
nigrum. J. Med. Plants Res. 4, 2525–2532.
[37] Rombouts, K., Knittel, T., Machesky, L., Braet, F., Wielant, A., et al. (2002)
Actin filament formation, reorganization and migration are impaired in
hepatic stellate cells under influence of trichostatin A, a histone deacetylase
inhibitor. J. Hepatol. 37, 788–796.
[38] Elaut, G., Torok, G., Vinken, M., Laus, G., Papeleu, P., et al. (2002) Major
phase I biotransformation pathways of Trichostatin a in rat hepatocytes
and in rat and human liver microsomes. Drug Metab. Dispos. 30, 1320–
1328.
[39] Kanemura, H., Iimuro, Y., Takeuchi, M., Ueki, T., Hirano, T., et al. (2008)
Hepatocyte growth factor gene transfer with naked plasmid DNA amelio-
rates dimethylnitrosamine-induced liver fibrosis in rats. Hepatol. Res. 38,
930–939.
[40] Jiang, Z. Z., Xia, G. Y., Zhang, Y., Dong, L., He, B. Z., et al. (2013) Attenua-
tion of hepatic fibrosis through ultrasound-microbubble-mediated HGF gene
transfer in rats. Clin. Imaging 37, 104–110.
[41] Seet, L. F., Toh, L. Z., Finger, S. N., Chu, S. W., Stefanovic, B., et al. (2016)
Valproic acid suppresses collagen by selective regulation of Smads in con-
junctival fibrosis. J. Mol. Med. 94, 321–334.
RAMZY ET AL. 517
8. [42] Lan, X., Lu, G., Yuan, C., Mao, S., Jiang, W., et al. (2016) Valproic acid (VPA)
inhibits the epithelial–mesenchymal transition in prostate carcinoma via the
dual suppression of SMAD4. J. Cancer Res. Clin. Oncol. 142, 177–185.
[43] Kaimori, A., Potter, J. J., Choti, M., Ding, Z., Mezey, E., et al. (2010) Histone
deacetylase inhibition suppresses the transforming growth factor beta1-
induced epithelial-to-mesenchymal transition in hepatocytes. Hepatology
52, 1033–1045.
[44] Hu, S., Ni, W., Chen, C., Sai, W., Hazi, W., et al. (2012) Comparison
between the effects of valproic acid and trichostatin A on in vitro develop-
ment of sheep somatic cell nuclear transfer embryos. J. Anim. Vet. Adv.
1868–1872.
[45] Van Beneden, K., Mannaerts, I., Pauwels, M., Van den Branden, C., and Van
Grunsven, L. A. (2013) HDAC inhibitors in experimental liver and kidney
fibrosis. Fibrogenesis tissue Repair 6, 1.
IUBMB LIFE
518 EFFECT OF HDAC INHIBITOR ON EMT