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H Shirin

Publications and source records attributed to H Shirin.

36 records · Page 2Linked to original sources
PubMed1999

Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac.

BACKGROUND & AIMS: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HRIs) were found incidentally to reduce new cases of colon cancer in 2 large clinical trials evaluating coronary events, although most patients in both treatment and control group were taking nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with reduced colon cancer incidence, predominantly by increasing apoptosis. We showed previously that lovastatin induces apoptosis in colon cancer cells. In the present study we evaluated the potential of combining lovastatin with sulindac for colon cancer chemoprevention. RESULTS: Lovastatin, 10-30 micromol/L, augmented sulindac-induced apoptosis up to 5-fold in 3 colon cancer cell lines. This was prevented by mevalonate (100 micromol/L) or geranylgeranylpyrophosphate (10 micromol/L) but not farnesylpyrophosphate (100 micromol/L), suggesting inhibition of geranylgeranylation of target protein(s) as the predominant mechanism. In an azoxymethane rat model of chemical-induced carcinogenesis, the total number of colonic aberrant crypt foci per animal (control, 161 +/- 11) and the number of foci with 4+ crypts (control, 40 +/- 4.5) decreased to 142 +/- 14 (NS) and 43 +/- 2.9 (NS), respectively, with 50 ppm lovastatin alone; to 137 +/- 5.4 (P = 0.053) and 36 +/- 2.1 (NS) with 80 ppm sulindac alone; and to 116 +/- 8.1 (P = 0.004) and 28 +/- 3.4 (P = 0.02) when 50 ppm lovastatin and 80 ppm sulindac were combined. CONCLUSIONS: Addition of an HRI such as lovastatin may augment chemopreventive effects of NSAIDs or/and may allow lower, less toxic doses of these drugs to be used.

Animals↗
PubMed1999

The hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea protect rats against thioacetamide-induced fulminant hepatic failure.

BACKGROUND/AIMS: Reactive oxygen species, proinflammatory cytokines, glutathione depletion and nitric oxide have all been implicated in the pathogenesis of fulminant hepatic failure. The aim of the present study was to examine the respective roles of these factors in the pathogenesis of thioacetamide-induced fulminant hepatic failure in rats. METHODS: Fulminant hepatic failure was induced by 3 consecutive intraperitoneal injections of thioacetamide (400 mg/kg) at 24-h intervals. Rats were pretreated with one of the following agents: the free radical scavengers dimethylsulfoxide (4 g/kg every 6 h) or dimethylthiourea (200 mg/kg every 12 h), the glutathione donor, N-acetylcysteine (130 or 200 mg/kg every 6 h), or the anti-tumor necrosis factor-alpha agents pentoxifylline (100 and 200 mg/kg) and soluble tumor necrosis factor receptor (100 or 1000 microg/rat). The nitric oxide synthase inhibitor N-mono-methyl arginine ester (L-NAME, 0.1 mg/ml) was administered in the drinking water, starting 7 days prior to thioacetamide administration. RESULTS: Serum levels of liver enzymes, blood ammonia and prothrombin time and the stage of hepatic encephalopathy were significantly improved in rats treated with dimethylsulfoxide or dimethylthiourea compared to the other treatment groups (p<0.001). Liver histology and the survival rate in these rats were not adversely affected by thioacetamide administration (p<0.001), while in all the other treatment groups those parameters were similar to control rats with fulminant hepatic failure. Furthermore, dimethylsulfoxide ameliorated liver damage and improved survival even when its administration was initiated 8 and 16 h after the first thioacetamide injection. The hepatic concentration of methanesulfinic acid, which is produced after direct interaction of dimethylsulfoxide with hydroxyl radicals, was increased five-fold in rats treated with thioacetamide+dimethylsulfoxide (p<0.001), suggesting a role for hydroxyl radical scavenging in the protection from fulminant hepatic failure in this model. In the group of thioacetamide-treated rats that were pretreated with L-NAME, liver enzymes, blood ammonia levels and the mortality rate were higher than in the control group, treated with thioacetamide only. CONCLUSIONS: In thioacetamide-induced fulminant hepatic failure, the hydroxyl radical scavengers dimethylsulfoxide and dimethylthiourea prevent liver injury. Neither N-acetylcysteine nor antagonists of tumor necrosis factor-alpha are protective in this rat model. Inhibition of nitric oxide formation aggravates liver damage and reduces the survival of rats with thioacetamide-induced liver damage.

Alanine Transaminase↗
PubMed1999

Treatment of concanavalin A-induced hepatitis in mice with low molecular weight heparin.

BACKGROUND/AIMS: Heparin has been noted to inhibit inflammation independent of its known anti-coagulant activity. In the present study, we examined the ability of heparin and low molecular weight heparin to prevent immune-mediated, concanavalin A-induced liver damage. METHODS: Mice were pretreated with either heparin or low molecular weight heparin (Fragmin) prior to their inoculation with concanavalin A (10 mg/kg). Liver enzymes, liver histology, and the serum levels of tumor necrosis factor-a, interleukin-6, and interleukin-10 were examined in the control and treated mice. RESULTS: The histopathologic damage in the liver, and the concanavalin A-induced release of aminotransferases, tumor necrosis factor-a, and interleukin-6 were significantly inhibited in mice pretreated with low molecular weight heparin, whereas the serum levels of the anti-inflammatory cytokine interleukin-10 were increased (p<0.01). Interestingly, maximal inhibition was obtained with low low molecular weight heparin doses (5 and 1 microg/mouse, p<0.001), while higher doses were less effective. Concanavalin A-induced liver injury was not prevented by pretreatment of the mice with heparan sulphate (p<0.001), which although it is structurally similar to heparin possesses neither anti-inflammatory nor anti-coagulant properties. CONCLUSIONS: This study demonstrates the efficacy of low molecular weight heparin in preventing immune-mediated liver damage in mice.

Alanine Transaminase↗
PubMed1999

Hypothyroidism protects rat liver from acetaminophen hepatotoxicity.

Recent data from animal studies suggest that induced hypothyroidism inhibits the development of liver injury in several animal models, including liver cirrhosis and fulminant hepatic failure in rats, and immune-mediated acute liver injury in mice. The aim of the present study was to determine whether hypothyroidism would likewise prevent acetaminophen-induced hepatic damage in rats. Liver damage was induced by acetaminophen (2 g/kg) administered by gavage to fasting rats as a single dose. Hypothyroidism was induced by methimazole, propylthiouracil, or surgical thyroidectomy and confirmed by elevated serum levels of TSH. Hypothyroidism significantly inhibited acetaminophen-induced liver damage as manifested by the decreased serum levels of liver enzymes, malondialdehyde and blood ammonia, as well as by the higher hepatic glutathione content, in all three groups of hypothyroid rats compared to euthyroid controls (P < 0.01). Histopathologic analysis showed significantly less liver necrosis and inflammation in the acetaminophen-treated hypothyroid rats. Oxygen extraction, measured in isolated perfused rat liver preparation, was also reduced in the hypothyroid livers to 42+/-8% compared to 81+/-14% of controls (P < 0.01). However, the expression of CYP2E1 in the livers of hypothyroid rats, as measured by western blot analysis, was not decreased compared to control rats. These results suggest that induced hypothyroidism, regardless of the mode of induction, protects rat liver from acetaminophen hepatotoxicity. This effect may be related to hypometabolism of liver cells, but the exact mechanism needs further clarification.

Acetaminophen↗
PubMed1999

Inhibition of concanavalin A-induced acute T cell dependent hepatic damage in mice by hypothyroidism.

AIMS/BACKGROUND: Concanavalin A (Con A) activates T lymphocytes and causes acute T-cell-mediated hepatic injury in mice. Decreased thyroid hormonal production is associated with a variety of immunological manifestations, including inactivation of macrophages with reduced TNF production and reduced soluble IL-2 receptors in the serum. We have recently shown that hypothyroidism prevents the development of cirrhosis and also minimizes hepatic damage in rats with fulminant hepatic failure. In the present study we examined the effects of hypothyroidism on a mouse model of Con A induced T cell-mediated acute hepatitis. METHODS: Hypothyroidism was induced both medically (MMI, PTU) and surgically. Eight groups of 10 mice each were studied: euthyroid controls (2 groups: water, Con A) and hypothyroid (6 groups: MMI, PTU, Surgical, MMI-Con A, PTU-Con A, Surgical-Con A). RESULTS: Hepatic inflammation was significantly decreased in each of the Con A treated hypothyroid groups of mice. The serum transaminases, TNF-alpha and IL-6 levels were significantly elevated in the Con A treated group while near normal levels were found in the hypothyroid Con A treated groups (mean+/-SE AST: 1499+/-18 vs 78+/-10 IU/l, p<0.001; TNF: 2500+/-250 vs 135+/-15 pg/ml, p<0.001, IL-6: 12,200+/-300 vs 1260+/-140 pg/ml, p<0.001, respectively). CONCLUSIONS: Hypothyroidism, independent of the mode of induction, can effectively inhibit the development of acute T cell-mediated liver damage in mice. These results suggest that some decrease in thyroid function might have a role in the prevention of immune mediated liver diseases.

Alanine Transaminase↗
PubMed1999

Paradoxical increase in retinoblastoma protein in colorectal carcinomas may protect cells from apoptosis.

The retinoblastoma (Rb) gene is inactivated in a variety of human cancers, but in colorectal carcinomas there is frequently increased expression of this gene. This is paradoxical in view of the known role of Rb as a tumor suppressor gene. In the present study, we compared the levels of expression of the Rb protein (pRb) in normal human colorectal mucosa, adenomatous polyps, and carcinomas by immunohistochemistry. In vitro studies were also done to examine the phenotypic effects of an antisense oligodeoxynucleotide (AS-Rb) targeted to Rb mRNA in the HCT116 colon carcinoma cell line that expresses a relatively high level of pRb. The incidence of pRb-positive cells was increased during multistage colorectal carcinogenesis. In vitro treatment of HCT116 cells with AS-Rb decreased the level of pRb by about 70% and also decreased the levels of the cyclin D1 protein and cyclin D1-associated kinase activity. AS-Rb inhibited growth of HCT116 cells and induced apoptosis. Reporter assays indicated about a 17-fold increase in E2F activity. These findings suggest that the increased expression of pRb in colorectal carcinoma cells may provide a homeostatic mechanism that protects them from growth inhibition and apoptosis, perhaps by counterbalancing potentially toxic effects of excessive E2F activity.

Apoptosis↗
PubMed1998

Hypothyroidism minimizes liver damage and improves survival in rats with thioacetamide induced fulminant hepatic failure.

Recent data from animal studies suggest that induced hypothyroidism prevents the hyperdynamic circulation in portal vein ligated rats, liver cirrhosis in rats chronically treated with thioacetamide (TAA), and immune-mediated acute liver injury induced in mice by concanavalin A. Therefore, the aim of this present study is to determine whether hypothyroidism would likewise prevent fulminant hepatic failure (FHF) in rats. FHF was induced by 3 consecutive ip injections of TAA (400 mg/kg) at 24-hour intervals. Hypothyroidism was induced in rats by either methimazole (MMI) or propylthiouracil (PTU) and surgical thyroidectomy and was confirmed by elevated serum thyroid stimulating hormone levels. Serum levels of liver enzymes, blood ammonia, and prothrombin time were significantly lower in all 3 groups of hypothyroid rats. The stage of hepatic encephalopathy (HE) and the survival rates were significantly improved in the hypothyroid rats (P < .01); the histologic examination of their livers showed less necrosis and inflammation (P < .01). In the hypothyroid rats, the serum levels of malondialdehyde 48 hours after thioacetamide (TAA) administration were lower than in control rats (P < .01). Exogenous supplementation of hypothyroid rats with L-thyroxine started 48 hours before TAA administration abrogated the protective effects of hypothyroidism. The serum levels of tumor necrosis factor alfa (TNF-alpha), interleukin (IL) 2 and IL-6 after 24 hours were slightly lower in the hypothyroid rats, but the administration of soluble receptor of TNF (10-1,000 microg/rat) did not prevent the induction of fulminant liver failure by TAA. Oxygen extraction, studied in isolated perfused liver preparation, was significantly lower in livers of hypothyroid rats (P < .01). These results suggest that induced hypothyroidism decreases the development of liver injury in a rat model of FHF. The mechanism may involve diminished oxidative cell injury caused by decreased oxygen utilization and hypometabolism associated with hypothyroidism.

Ammonia↗
PubMed1998

Pentoxifylline prevents concanavalin A-induced hepatitis by reducing tumor necrosis factor alpha levels and inhibiting adhesion of T lymphocytes to extracellular matrix.

BACKGROUND/AIMS: Concanavalin A activates T lymphocytes and causes T cell-mediated hepatic injury in mice. Tumor necrosis factor alpha is a critical mediator in this experimental model. T-cell-mediated liver injury involves the migration of immune cells, notably CD4+ T lymphocytes, into liver tissue. Pentoxifylline is a strong suppressor of tumor necrosis factor alpha release and prevents leukocyte adherence to vascular endothelium and down-regulates the expression of intercellular adhesion molecule-1 in monocytes. In this study, we examined the efficacy of pentoxifylline as a potential therapeutic compound for the treatment of concanavalin A hepatitis. METHODS: Balb/c mice were injected with 12 mg/kg concanavalin A with or without a single injection of pentoxifylline (5-300 mg/kg), 2 h prior to concanavalin A administration. Liver damage was evaluated by determining serum levels of liver enzymes and tumor necrosis factor alpha, and hepatic histopathology compared to mice treated with concanavalin A only. We also assessed the effects of pentoxifylline on the adhesive properties of T lymphocytes to fibronectin, as a paradigm for immune cell-extracellular matrix interactions required for migration. Pretreatment with pentoxifylline significantly reduced serum levels of liver enzymes (3800+/-650 vs 150+/-28 IU/l) and tumor necrosis factor alpha (710+/-105 vs 113+/-15 pg/ml) with no evidence of inflammation in histopathologic examination compared to control mice treated with concanavalin A. Pentoxifylline also inhibited the binding of murine T cells to fibronectin. All the effects of pentoxifylline were dose-dependent. CONCLUSIONS: These results indicate that high doses of pentoxifylline can prevent concanavalin A hepatitis by suppression of tumor necrosis factor alpha release and inhibition of T cells adhesion to extracellular matrix.

Animals↗
PubMed1997

Effects of intravenous immunoglobulins on T-cell mediated, concanavalin A-induced hepatitis in mice.

Concanavalin A (ConA) activates T lymphocytes and causes T-cell mediated hepatic injury in mice. The intravenous administration of human immunoglobulins has beneficial effects in T-cell mediated diseases such as experimental autoimmune encephalomyelitis and adjuvant arthritis. In the present study, we examined the effects of intravenous immunoglobulins in a mouse model of T-cell mediated, acute liver injury induced by concanavalin A. Balb/c mice were inoculated with 12 mg/kg concanavalin A with or without intravenous immunoglobulins at doses of 0.4, 0.6, 0.8 g/kg body wt. The serum levels of liver enzymes, tumor necrosis factor-alpha, interferon-gamma and interleukin-6 were assayed 2, 6 and 24 h after concanavalin A administration. Intravenous immunoglobulins did not prevent concanavalin A-induced hepatitis, as manifested by elevation of serum aminotransferases and histopathological evaluation. The serum levels of tumor necrosis factor-alpha in mice pretreated with immunoglobulins, measured 2 h after ConA treatment were reduced, while interferon-gamma levels measured 6 h after ConA inoculation were 5-fold higher than control levels. There was no effect of intravenous immunoglobulins on the release of interleukin 6. In conclusion, these results indicate that intravenous immunoglobulin is not effective in preventing T-cell mediated concanavalin A-induced hepatitis. The increased secretion of interferon-gamma and the incomplete suppression of tumor necrosis factor-alpha release may explain the lack of efficacy of intravenous immunoglobulin in this experimental model.

Animals↗
PubMed1997

Analysis of Arg-Gly-Asp mimetics and soluble receptor of tumour necrosis factor as therapeutic modalities for concanavalin A induced hepatitis in mice.

BACKGROUND/AIMS: It has been shown that synthetic non-peptidic analogues of Arg-Gly-Asp, a major cell adhesive ligand of extracellular matrix, prevented an increase in serum aminotransferase activity, as a manifestation of concanavalin A induced liver damage in mice. This study examined the effects of an Arg-Gly-Asp mimetic on liver histology and cytokine release in response to concanavalin A administration, and the efficacy of soluble receptor of tumour necrosis factor (TNF) alpha in preventing hepatitis in this model of liver injury. METHODS: Mice were pretreated with either the Arg-Gly-Asp mimetic SF-6,5 or recombinant soluble receptor of TNF alpha before their inoculation with 10 mg/kg concanavalin A. Liver enzymes, histology, and the serum values of TNF alpha and interleukin (IL)6 were examined. RESULTS: The histopathological damage in the liver, and the concanavalin A induced release of TNF alpha and IL6 were significantly inhibited by the synthetic Arg-Gly-Asp mimetic (p < 0.001). Liver injury, manifested by the increase in serum aminotransferase and cytokines, as well as by histological manifestations of hepatic damage, was effectively prevented by pretreatment of the mice with the soluble TNF receptor (p < 0.001). CONCLUSIONS: This study confirms the efficacy of a synthetic Arg-Gly-Asp mimetic and soluble TNF receptor in the prevention of immune mediated liver damage in mice.

Alanine Transaminase↗
PubMed1997

Methotrexate in chronic active Crohn's disease: a double-blind, randomized, Israeli multicenter trial.

BACKGROUND: At present only one large controlled study has indicated that parenteral methotrexate may be effective in chronic active Crohn's disease (CD). AIM: To evaluate the effectiveness of oral methotrexate in chronic steroid-dependent CD. PATIENTS: Patients with active CD, who have received steroids and/or immunosuppressives for at least 4 months during the preceding 12 months and with a current Harvey-Bradshaw index of > or = 7 were studied. METHODS: Methotrexate (12.5 mg weekly) or 6-mercaptopurine (50 mg daily), or placebo were given during the 9 months of the trial in addition to steroids and 5-aminosalicylic acid as clinically indicated. RESULTS: Eighty-four patients were included (methotrexate, 26 patients; 6-mercaptopurine, 32 patients; placebo, 26 patients). The proportion of patients entering first remission as well as the proportions of patients relapsing after first remission were not significantly different between the groups. The mean Harvey-Bradshaw index and the mean monthly steroid dose were also similar. However, when each patient was evaluated as his or her own control, the reduction in steroid dose, the general well being, and the reduction in abdominal pain were significantly better in the methotrexate treated patients. CONCLUSIONS: Methotrexate at a weekly oral dose of 12.5 mg was found to be moderately better than 6-mercaptopurine and placebo in patients with chronic active CD.

Abdominal Pain↗
PubMed1994

Differentiation between major and milder acute mental stress by means of the leukocyte adhesiveness/aggregation test.

Following previous observations that the adhesive state of white blood cells in the peripheral blood increases during stress, we examined 645 volunteers in various conditions of anticipatory anxiety. The volunteer subjects included 465 controls in whom stress was related solely to impending venipuncture, 149 persons under moderate stress (students before delivering a graded lecture, patients before dental treatment, etc), as well as 31 individuals under major stress (eg, before induction of anesthesia in the operating room). The respective values of aggregated leukocytes in the peripheral blood were 5.2 +/- 3.8, 6 +/- 4.2, and 19.3 +/- 9.3% of aggregated cells, with a significant difference (p < .0001) between the third and the other two groups. In both discriminant analysis and multiple regression, the leukocyte adhesiveness/aggregation test (LAAT) was shown to be superior to the white blood cell count for the detection of major stress. The LAAT had a sensitivity of 0.8, compared with only 0.35 for leukocyte count for that purpose. We concluded that the LAAT could be a powerful tool for the diagnosis of major acute mental stress and for discrimination between conditions causing major stress and those conditions that are less stressful.

Adolescent↗
PubMed1992

Erythromycin base-induced rash and liver function disturbances.

OBJECTIVE: To report a case of erythromycin base-induced rash and liver function disturbances. CASE SUMMARY: A patient with erythema nodosum and high antistreptolysin-O titers was treated with erythromycin on the assumption that occult streptococcal infection was the cause of the erythema nodosum. Forty-eight hours after the initiation of therapy the patient developed fever, severe generalized rash, pruritus, and cholestatic and hepatocellular liver function disturbances. Extensive evaluation to determine the cause of liver function disturbances was unrevealing. Marked improvement was noticed within days after cessation of erythromycin. DISCUSSION: Case reports in the literature on the adverse effects of erythromycin and its derivatives were reviewed. The possible immunologic mechanism involved is postulated. CONCLUSIONS: Erythromycin base must be added to the list of erythromycin derivatives that can cause rash and liver function disturbances. The concomitant appearance of fever, rash, jaundice, and liver function disturbances raises the possibility of hypersensitivity as the mechanism for the liver disturbances.

Adult↗
PubMed1989

[Infection with Mycobacterium avium complex in the nonimmunocompromised host].

Pulmonary infection due to mycobacterium avium complex has been considered exceedingly rare, with only 50 case reports in the literature until 1982. However, during the past decade the dissemination of the acquired immune deficiency syndrome has been accompanied by a marked increase in the frequency of reported infections due to this agent, although infection in the noncompromised host remains rare. We describe an 80-year-old man who was not immunocompromised but who was infected with mycobacterium avium complex.

Aged↗
PubMedDate not supplied

The use of synthetic analogues of Arg-Gly-Asp (RGD) and soluble receptor of tumor necrosis factor to prevent acute and chronic experimental liver injury.

In chronic viral hepatitis, autoimmune hepatitis, and some chronic cholestatic liver diseases, T-lymphocytes serve as effector cells of the immunostimulatory processes. Cellular interactions of immune cells with extracellular matrix (ECM) components are regulated primarily via the beta 1 subfamily of integrin receptors. The target epitope of several such integrin receptors is the Arg-Gly-Asp (RGD) sequence, a cell adhesion motif shared by several matrix-associated adhesive glycoproteins. We review the use of synthetic nonpeptidic analogues of RGD and of soluble receptor of tumor necrosis factor (TNF)-alpha in the prevention of immune-mediated, concanavalin A-induced liver damage in mice and of RGD analogues in inhibiting the development of liver cirrhosis in rats. The concanavalin A-induced elevation of serum transaminases and TNF-alpha, and the infiltration of liver tissue by inflammatory cells, were inhibited by pretreatment of the mice with the synthetic RGD mimetics and soluble TNF receptor. In rats, the progression of thioacetamide-induced liver cirrhosis was markedly inhibited by the coadministration of the RGD mimetic SF-6,5. The compounds described here may be examined therapeutically for pathological conditions in the liver, manifested as necroinflammation, cholestasis and fibrosis.

Animals↗