Higher Expression Levels of SSX1 and SSX2 in Patients with Colon Cancer: Regulated In Vitro by the Inhibition of Methylation and Histone Deacetylation.

Background and Objectives: Colon cancer (CC) has a high mortality rate and is often diagnosed at an advanced stage in Saudi Arabia. Thus, the identification and characterization of potential new cancer-specific biomarkers are imperative for improving the diagnosis of CC by detecting it at an early stage. Cancer-testis (CT) genes have been identified as potential biomarkers for the early diagnosis of various cancers. Among the CT genes are those belonging to the SSX family. In order to assess the usefulness of SSX family genes as cancer biomarkers for the detection of early-stage CC, the goal of this research was to validate the expressions of these genes in patients with CC and in matched patients with normal colons (NCs). Materials and Methods: RT-PCR assays were used to analyze the SSX1, SSX2, and SSX3 family gene expression levels in 30 neighboring NC and CC tissue samples from male Saudi patients. Epigenetic alterations were also tested in vitro using qRT-PCR analysis to determine whether reduced DNA methyltransferase or histone deacetylation could stimulate SSX gene expression via 5-aza-2'-deoxycytidine and trichostatin treatments, respectively. Results: The RT-PCR results showed SSX1 and SSX2 gene expression in 10% and 20% of the CC tissue specimens, respectively, but not in any of the NC tissue specimens. However, no SSX3 expression was detected in any of the examined CC or NC tissue samples. In addition, the qRT-PCR results showed significantly higher SSX1 and SSX2 expression levels in the CC tissue samples than in the NC tissue samples. The 5-aza-2'-deoxycytidine and trichostatin treatments significantly induced the mRNA expression levels of the SSX1, SSX2, and SSX3 genes in the CC cells in vitro. Conclusions: These findings suggest that SSX1 and SSX2 are potentially suitable candidate biomarkers for CC. Their expressions can be regulated via hypomethylating and histone deacetylase treatments, subsequently providing a potential therapeutic target for CC.

The Expression Patterns of Human Cancer-Testis Genes Are Induced through Epigenetic Drugs in Colon Cancer Cells.

BACKGROUND: The expression of human germline genes is restricted to the germ cells of the gonads, which produce sperm and eggs. The germline genes involved in testis development and potentially activated in cancer cells are known as cancer-testis (CT) genes. These genes are potential therapeutic targets and biomarkers, as well as drivers of the oncogenic process. CT genes can be reactivated by treatment with drugs that demethylate DNA. The majority of the existing literature on CT gene activation focuses on X-chromosome-produced CT genes. We tested the hypothesis that epigenetic landscape changes, such as DNA methylation, can alter several CT gene expression profiles in cancer and germ cells. METHODS: Colon cancer (CC) cell lines were treated with the DNA methyltransferase inhibitor (DNMTi) 5-aza-2'-deoxycytidine, or with the histone deacetylase inhibitor (HDACi) trichostatin A (TSA). The effects of these epigenetic treatments on the transcriptional activation of previously published CT genes (CTAG1A, SCP2D1, TKTL2, LYZL6, TEX33, and ACTRT1) and testis-specific genes (NUTM1, ASB17, ZSWIM2, ADAM2, and C10orf82) were investigated. RESULTS: We found that treatment of CC cell lines with 5-aza-2'-deoxycytidine or TSA correlated with activation of X-encoded CT genes and non-X-encoded CT genes in somatic (non-germline) cells. CONCLUSION: These findings confirm that a subset of CT genes can be regulated by hypomethylating drugs and subsequently provide a potential therapeutic target for cancer.

Cancer-Testis Gene Biomarkers Discovered in Colon Cancer Patients.

In Saudi Arabia, colon cancer (CC) is the most prevalent cancer in men and the third most common cancer in women. Rather than being detected through screening programs, most CC cases are diagnosed mainly during clinical exams. Because of the slow growth of CC and its ability to be treated at an early stage, screening for CC can reduce the incidence of death and mortality. Consequently, there is an urgent need to identify a potential new cancer-specific biomarker for detecting early illness. Much research has been conducted on distinct antigen classes as potential new cancer-specific biomarkers for the early identification of malignancy. The cancer-testis antigens (CTAs) are one such category of antigens, with protein presence largely normally confined to human germ line cells in the testis and aberrantly produced in some cancer cells. CTAs are potentially valuable for use as cancer biomarkers and in cancer therapeutics due to their distinctive expression pattern. The aim of this current study was to identify potential cancer-testis (CT) gene biomarkers in Saudi Arabian CC patients. In this study, a total of 20 matching CC and normal colon (NC) tissues were obtained from the Saudi population. Any genes that showed expression in CC tissues but not in matching NC tissues were subsequently verified for mRNA expression in eight breast and eight leukemia malignancies using RT-PCR to determine the specificity of any CC biomarkers. CTAG1A, SPZ1, LYZL6, SCP2D1, TEX33, and TKTL2 genes were expressed in varying numbers of CC tissues compared to no measurable expressions in all NC tissue specimens, making these genes suitable potential candidates for CC markers. The most frequently expressed CT genes in CC patients were CTAG1A (35%) and SCP2D1 (35%), followed by TKTL2 (25%), SPZ1 (20%), LYZL6 (15%), and TEX33 (5%). The LYZL6 gene shows a weak RT-PCR product in 25% of breast cancer (BC) patients but not in leukemia patients. The SCP2D1 gene appears to display expression in all leukemia patients but not in the BC patients. TKTL2 expression was also observed in 50% of leukemia samples but not in the BC samples. More experiments at the protein level and with a larger cohort of patients are required to evaluate this finding.

A promising antifibrotic drug, pyridoxamine attenuates thioacetamide-induced liver fibrosis by combating oxidative stress, advanced glycation end products, and balancing matrix metalloproteinases.

Liver fibrosis is a common chronic hepatic disease. This study was done to examine the effect of pyridoxamine against thioacetamide-induced hepatic fibrosis. Animals were divided into four groups (1) control group; (2) Thioacetamide group (200 mg/kg, i.p.) twice a week for eight weeks; (3) Pyridoxamine-treated group treated with pyridoxamine (100 mg/kg/day, i.p.) for eight weeks; (4) Thioacetamide and pyridoxamine group, in which pyridoxamine was given (100 mg/kg/day, i.p.) during thioacetamide injections. Thioacetamide treatment resulted in hepatic dysfunction manifested by increased serum levels of bilirubin, gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Oxidative stress was noted by increased hepatic lipid peroxidation and decreased glutathione (GSH). Increased concentrations of total nitrite/nitrate, advanced glycation end products (AGEs), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-ß (TGF-ß), matrix metalloproteinases (MMP-2&9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were noticed in hepatic tissues. Immunostaining sections also revealed overexpression of MMP-2, MMP-9 and collagen IV. Liver fibrosis was confirmed by severe histopathological changes. Pyridoxamine improved the assessed parameters. Moreover, histopathological and immunohistological studies supported the ability of pyridoxamine to reduce liver fibrosis. The findings of the present study provide evidence that pyridoxamine is a novel target for the treatment of liver fibrosis.

Chitosan nanoparticles as a promising candidate for liver injury induced by 2-nitropropane: Implications of P53, iNOS, VEGF, PCNA, and CD68 pathways.

The current article was designed to assess the role of chitosan nanoparticles (CNPs) in the management of hepatic injury induced by the hepatocarcinogen 2-nitropropane (2-NP). Rats were divided into three groups. The first group served as a control, the second group was injected with 2-NP, while the third group was treated with CNPs 1 h before 2-NP injection every other day for 4 weeks. The 2-NP injection upregulated serum AST and ALT activities, as well as hepatic TNF- α, IL-6, and MDA levels and the expression of vascular endothelial growth factor (VEGF) and caspase-3, whereas GSH contents and SOD activity were decreased. Immunohistochemistry investigations revealed that the hepatic protein expression of collagen I, inducible nitric oxide synthetase, proliferating cell nuclear antigen, cluster of differentiation, and p53 were upregulated. hematoxylin and eosin (H&E) and Masson's trichrome stains supported the previous parameters, and CNPs ameliorated most of the previous biochemical parameters. CNPs achieved promising results in the limitation of 2-NP hepatotoxicity.

Cyanocobalamin and/or calcitriol mitigate renal damage-mediated by tamoxifen in rats: Implication of caspase-3/NF-κB signaling pathways.

AIM: Tamoxifen (TAMO) is a chemotherapeutic drug used for the treatment of breast cancer. Nevertheless, there is a lack of information available in regarding its nephrotoxicity. The purpose of this work was to investigate the impact of cyanocobalamin (COB) and/or calcitriol (CAL) injections on TAMO-induced nephrotoxicity. MAIN METHODS: Animals were allocated into five groups as follows: normal control group; TAMO (45 mg/kg) administered group; TAMO+COB (6mg/kg, i.p) treated group; TAMO+CAL (0.3 µg/kg, i.p) treated group; TAMO+COB+CAL combination groups. KEY FINDINGS: Renal injury induced by TAMO was confirmed by the alteration in renal function parameters in the serum (urea and creatinine), as well as in the urine (creatinine clearance, total protein and albumin). These results were supported by histopathological examination. Upregulation of renal inflammatory parameters; tumor necrosis factor (TNF)-α, interleukin (IL)-6, C-reactive protein (CRP); and transforming growth factor (TGF)-ß1 as well as in protein expression of nuclear factor-kappa B (NF-κB) and cleaved caspase-3 were observed to a greater extent in the TAMO-treated rats compared with the control. Renal fibrosis was also evidenced by a elevation in renal L-hydroxyproline level as well as by histomorphological collagen deposition in TAMO-treated groups compared to the control group. Administration of COB and/or CAL concurrently with TAMO significantly ameliorated the deviation in the above-studied parameters and improved the histopathological renal picture. SIGNIFICANCE: Inhibition of NF-κß-mediated inflammation and caspase-3-induced apoptosis are possible renoprotective mechanisms of COB and/or CAL against TAMO nephrotoxicity, which was more noticeable in the TAMO group treated with the combination of the two vitamins in question.

Effect of naked and PEG-coated gold nanoparticles on histopathology and cytokines expression in rat liver and kidneys.

Aim: To compare the effects of 5- and 50-nm naked and PEG-coated gold nanoparticles (AuNP) on proinflammatory cytokines (IL-1ß, IL-6, TNF-α) expression and histopathological changes in liver and kidneys of rats. Materials & methods: Rats were injected with different nanoparticles and sacrificed after 24 h. Results: Both 5- and 50-nm AuNPs, and 50-nm PEG-AuNPs caused granular clumping of cytoplasm, edema and hydropic dystrophy in hepatic cells. Naked AuNPs of both sizes caused mild shrinkage, whereas 50-nm PEG-AuNPs enlarged the Bowman's space and capsule. Larger nanoparticles produced more profound mRNA expression of cytokines in both the organs. Conclusion: These findings suggest the roles of particle size and coating on immunological response and histopathological changes.

Time-Course Evaluation of Iminodipropionitrile-Induced Liver and Kidney Toxicities in Rats: A Biochemical, Molecular and Histopathological Study.

Iminodipropionitrile (IDPN) is known to produce axonopathy and vestibular hair cell degeneration. Recent histopathological studies have shown IDPN-induced liver and kidney toxicities in rodents; however, the associated mechanisms are not clearly understood. We investigated the role of proinflammatory cytokines in IDPN-induced liver and kidney toxicities in rats. Rats were treated with saline (control) and IDPN (100 mg/kg, intraperitoneally) daily for 1, 5, and 10 days, respectively. Animals were killed 24 hours after the last dose and liver and kidneys were collected for histopathology and interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α messenger RNA expression analysis. Serum aspartate aminotransferase and alanine aminotransferase activities were significantly increased after 10 doses of IDPN. The level of serum creatinine was initially increased after the first dose of IDPN but subsided on days 5 and 10. Blood urea nitrogen levels were significantly increased on days 5 and 10 following IDPN exposure. Histopathology showed dose-dependent hepatotoxicity in IDPN-treated rats. Iminodipropionitrile-induced expression of proinflammatory cytokines peaked after day 1 in liver and after day 5 in kidneys. In conclusion, repeated exposure of IDPN for 10 days produced significant structural and functional damages in rat liver whereas kidneys showed gradual recovery with time. These findings point toward the role of inflammatory mediators in IDPN-induced toxicity in rats.

Molecular subtypes of breast carcinoma in Saudi Arabia. A retrospective study.

OBJECTIVES: To determine the distribution of various molecular subtypes of breast cancer in Saudi Arabia and to assess the association between these subtypes and age at diagnosis, tumor size, histopathological type, grade, presence of carcinoma in-situ, and lymph node status.  METHODS: This observational retrospective study, between January 2010 and  December 2014, was conducted at King Khalid University Hospital, Riyadh, Saudi Arabia. We classified 359 breast cancers into 4 molecular subtypes, using immunohistochemistry: luminal A (estrogen receptor [ER], or progesterone receptor [PR] positive and human epidermal growth factor receptor 2 [HER2] negative), luminal B (ER and/or PR positive and HER2 positive), HER2-positive (ER and PR negative and HER2 positive), and triple negative (ER, PR, and HER2 negative). We evaluated the relationship between these subtypes and clinicopathological features using Chi square test.   RESULTS: The most prevalent subtype was luminal A (58.5%), followed in descending order of frequency by triple negative (14.8%), luminal B (14.5%), and HER2-positive (12.3%). The average age at diagnosis was 49.8 years, and average tumor size at diagnosis was 3.19 cm.   CONCLUSION: Luminal A tumor was the most common molecular subtype and HER2-positive was the least common. Most lobular carcinomas were luminal A tumors. Human epidermal growth factor receptor 2-positive and triple negative tumors had a higher histologic grade and a larger tumor size at diagnosis, and they were more common in women under 50 years. Carcinoma-in-situ was least common in triple negative tumors. We found no association between lymph node status and molecular subtypes.

Six Cases of Myofibroma--The Adult Counterpart of Infantile Myofibromatosis: Case Report.

The adult counterpart of infantile myofibromatosis is rare and is known as myofibroma. Cases are rare, and previous ones have been reported as isolated case reports; hence, there has been no consensus regarding the clinical presentation, surgical reconstruction, histological features, and recurrence of hand myofibromas. Over a 10-year period, the senior author treated 6 patients. We review our cases as well as 6 previously reported cases. The presentation is usually a single hand mass in a young adult. The tumor may arise from the lower dermis or from deeper fibrous structures of the hand including the palmar fascia. Tumors that arise from the dermis are best treated by skin excision to ensure complete excision. Histologically, the tumor is composed of highly cellular myofibroblast proliferation and is strongly positive to smooth muscle actin immune stain. The recurrence rate after excision is low.

A solitary fibrous tumor of the upper limb.

Solitary fibrous tumors (SFT) of the upper limb are extremely rare, and we report this tumor in the arm of a 30-year-old male. He is presented with a 22 cm painless mass. Complete surgical excision was performed. The histological diagnosis of SFT was based on the presence of ectatic blood vessels and positive staining for CD34 and vimentin. He remains disease-free at the 3-year follow-up interval. The report aims to increase the awareness of the criteria for the histological diagnosis of SFT, as well as the principles of their surgical excision and follow-up. 

Flexor tendon-to-volar plate repair: an experimental study and 3 case reports.

PURPOSE: To investigate the histology and tensile strength of flexor tendon-to-volar plate repair in a sheep model and to evaluate outcomes in 3 clinical cases. METHODS: The flexor digitorum profundus (FDP) tendon of the hind limb of the sheep was cut at the ankle. The proximal end of the FDP tendon was then repaired to a distally based flap of the underlying volar plate after 2 cm of the distal FDP tendon were excised such that the distal FDP tendon was not directly in contact with the repair site. The repair was studied histologically and tested biomechanically at 8 intervals (0, 1, 2, 3, 4, 5, 6, 8, and 12 wk) following repair. Three clinical cases with flexor tendon-to-volar plate repair are presented. In all cases, the circumstances of the injury precluded the usual tendon-to-tendon repair. The first patient had a laceration of FDP in zone 1A and the other 2 patients had delayed 2-stage flexor tendon reconstruction. RESULTS: The mean breaking strength of the tendon-to-volar plate repair was 26 N at 0 week, 62 N at 1 week, 52 N at 2 weeks, and then progressively increased to reach 312 N at 12 weeks. Histologically, thin randomly arranged collagen fibers were seen at the repair site at 3 weeks; and healing with thick parallel collagen bundles were seen at 6 weeks. Clinically, the flexor tendon-to-volar plate repairs healed without rupture. All patients obtained full active range of motion at the metacarpophalangeal and proximal interphalangeal joints. The active range of motion at the distal interphalangeal joint was 0° to 50° in 2 patients and 0° to 40° in the third patient. CONCLUSIONS: The flexor tendon can heal to the volar plate in the sheep model. CLINICAL RELEVANCE: Suture of tendon to volar plate is an option in distal zone 1 FDP repair and FDP tendon reconstruction.

Mimicry of Minute Pulmonary Meningothelial-like Nodules to Metastatic Deposits in a Patient with Infiltrating Lobular Carcinoma: A Case Report and Review of the Literature.

Minute pulmonary meningothelial-like nodules (MPMNs) are incidentally found lesions in lung resection specimens and autopsies. MPMNs have been associated with neoplastic and non-neoplastic pulmonary conditions and occasionally with extrapulmonary diseases. We report a case of a female patient presenting with invasive lobular carcinoma of the breast and MPMNs, masquerading as metastatic deposits. We describe the morphological, immunohistochemical and ultrastructural features of MPMNs and emphasize the importance of their recognition for proper staging and treatment of patients. To our knowledge, this is the first case in the English literature describing this coexistence.

Profile of mycosis fungoides in 43 Saudi patients.

BACKGROUND AND OBJECTIVES: Mycosis fungoides (MF) is a rare disease; and to our knowledge, there are no reports on its profile in Arabs. The objective of this study was to preliminarily analyze the clinical characteristics of MF patients seen in our institution. DESIGN AND SETTING: Retrospective review of 140 patients with pathologic or clinical diagnosis or differential diagnosis of MF for the period 2000-2006. PATIENTS AND METHODS: Pathology reports with diagnosis or differential diagnosis of MF were retrieved and suspected cases were identified and reviewed. For pathologically confirmed cases, sociodemographic, clinical, laboratory, and radiological details were collected. Details of staging, treatment modalities, and disease status at the last follow-up were retrieved. RESULTS: A total of 43 pathologically confirmed MF patients (skin phototypes IV and V) with a mean age at diagnosis of 33.5 years were reviewed. This comprised 29 males (M:F ratio, 2:1), and the majority (86%) of patients had early-stage (I and II) MF. Twenty-one (48.8%) patients had classic MF; 18 (41.8%), hypopigmented MF; and 4 (9.3%), other variants. The male-to-female ratio was higher in the hypopigmented (3.5:1) than in the classic variant (1.6:1). The mean age at diagnosis was lower in the hypopigmented compared to the classic variant (25 versus 38.8 years, P=.019). The mean duration of follow-up was 27.6 months (range, 1-98 months). At the final assessment, 4 (9.5%) patients recovered; whereas 35 (83.3%) had MF skin disease; 1 had (2.4%) extracutaneous disease; and 2 (4.8%) died of MF. CONCLUSIONS: MF tends to affect younger Saudi patients. The hypopigmented variant constitutes a significant proportion of MF cases, especially in younger patients.

Treatment with dipyridamole improves cardiac function and prevent injury in a rat model of hemorrhage.

Hemorrhagic shock is a leading cause of death despite the improvement in emergency services. One reason is that the resuscitation policies are designed to reestablish tissue perfusion, but not to prevent the inflammatory response to shock that cause myocardial dysfunction and injury. Dipyridamole is a platelet inhibitor that promotes anti-inflammatory effects. The present study investigated the therapeutic value of treatment with dipyridamole before resuscitation from hemorrhagic shock on myocardial injury and protection. Male Sprague-Dawley rats were assigned to 3 experimental groups (n=6 per group): 1) hemorrhage, 2) hemorrhage treated with dipyridamole, and 3) sham hemorrhage. Rats were hemorrhaged over 60min to reach a mean arterial blood pressure of 40mmHg. After 60min hemorrhagic shock, rats were treated or not by injection of 1mL of (20µg/L) dipyridamole intra-arterially. Resuscitation was made in vivo by reinfusion of the shed blood to restore norm tension for 30min. Arterial blood samples were collected for measurements of TNF-α. Left ventricular generated pressure and +dP/dtmax was significantly higher in dipyridamole treated rats compared to the untreated group. Myocardial biopsy samples were taken for light and electron microscopy. Dipyridamole decreased the number of inflammatory cells and mitochondrial swollen. Dipyridamole also decreased the plasma levels of TNF-α. Our results demonstrate that treatment with dipyridamole before in vivo resuscitation of hemorrhagic shock protect the myocardium against post-resuscitation myocardial dysfunction by decreasing the inflammatory response to shock.

Clinicopathological pattern of malignant parotid gland tumors in Saudi Arabia.

OBJECTIVE: To report our experience of varied presentations and diverse histopathological spectrum of parotid gland malignancies. METHODS: This retrospective analysis incorporated patients with histological evidence of malignant parotid tumors at King Khalid University Hospital, Riyadh, Saudi Arabia over a 20-year period from 1984 through 2004. The medical records of these patients were analyzed for their demographic characteristics, clinical features, operations performed, and pathological diversity. RESULTS: Thirty-two patients comprised this study group. There is a male preponderance over females with a ratio of 2.2:1 (22 men and 10 women) and mean age of 51.8 (range 28-81 years). A painless lump was the most frequent clinical manifestation observed in 23 (71.8%) patients followed by facial nerve dysfunction in 14 (43.7%) patients. Parotidectomy was performed in 22 (68.7%) patients: 16 superficial and 6 total. A partial facial nerve sacrifice was undertaken in 14 (43.7%), and total nerve sacrifice in 9 (28.1%) patients. Four (12.5%) patients presented with cervical lymph node metastases necessitating radical neck dissection. Nine (28.1%) patients had mucoepidermoid carcinoma, 8 (25%) adenoid cystic carcinoma, 6 (18.7%) adenocarcinoma, not otherwise specified, and 2 (6.2%) were reported to have carcinoma in pleomorphic adenoma. Twenty (62.5%) specimens revealed high-grade aggressive lesions, and out of these, 19 (59.3%) patients presented with stage III/IV disease. CONCLUSION: Malignant parotid tumors are exceedingly rare, occurring at a relatively earlier age group with male preponderance, and invariably declare at a late clinical stage in our community. Histopathological features hallmark a locally advanced disease with an aggressive behavior.

The potential anti-inflammatory effect of tetrahydrobiopterin administration in renal mass reduction-induced chronic renal failure in rats.

OBJECTIVE: To investigate the impact of tetrahydrobiopterin (BH4) supplementation on the markers of inflammation, and on the histological picture of the kidney in chronic renal failure C-reactive protein (CRF) induced in rats by subtotal nephrectomy (SNx). METHODS: This study was performed at the Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia during the period from December 2005 to January 2007. Chronic renal failure was induced by 5/6 SNx in 20 male Wister rats, and another 10 rats were sham operated by flank incision and served as controls. Ten SNx rats received 10mg kg-1 BH4 intraperitoneally daily for 4 weeks. Plasma C-reactive protein (CRP), interlukin-6 (IL-6), malondialdehyde (MDA), and kidney functions were measured in all rats. Histopathological examination of the kidney tissues was also performed. RESULTS: Untreated CRF rats showed significant elevation of plasma CRP, IL-6, and MDA levels, and significant decrease in plasma albumin and total protein levels, tubuloglomerular fibrosis and, interstitial tubular infiltration with inflammatory cells in comparison with the sham-operated rats. Tetrahydrobiopterin treatment decreased CRP, IL-6, and MDA levels, and decreased tubuloglomerular fibrosis and interstitial inflammation in treated CRF rats. CONCLUSION: Supplementation with exogenous BH4 decreased markers of inflammation and protected the kidney against post-renal mass reduction histologic damage. Restoration of intracellular BH4 balance could normalize nitrous oxide production. Therefore, BH4 might be a promising strategy in attenuating inflammation in CRF. This may decrease endothelial dysfunction and limit the associated cardiovascular morbidity and mortality of this disease.

Effects of mycophenolate mofetil on cisplatin-induced renal dysfunction in rats.

PURPOSE: Inflammation and oxidative stress are important events among the plethora of mechanisms involved in cisplatin (CDDP)-induced nephrotoxicity. The aim of this study was to evaluate the effect of mycophenolate mofetil (MMF), an immunosuppressive, in the protection against CDDP-induced renal dysfunction. METHODS: Rats were divided into four groups; untreated-control group, CDDP-treated group (7 mg/kg, single intraperitoneal dose), MMF-treated group (40 mg/kg/day orally for 5 successive days) and the fourth group was treated with both drugs and MMF treatment was started 1 day prior to CDDP administration. Nephrotoxicity was assessed 7 days after the CDDP treatment by measuring serum indices of nephrotoxicity, kidney weight as a percentage of total body weight, kidney's tissue peroxidative alterations and total nitrate/nitrite concentration (NOx) and the results were confirmed histopathologically. RESULTS: Rats treated with CDDP showed marked nephrotoxicity as evidenced from the significant increase in serum creatinine and urea levels and decrease in serum calcium and albumin levels. Kidneys of CDDP-treated rats showed significant increases in kidney weight and malondialdehyde (MDA) production level and decreases in total NOx concentration, glutathione peroxidase (GPx) activity and reduced glutathione (GSH) content levels. Histopathological assessment of kidneys of CDDP-treated rats revealed extensive tubular necrosis with "sloughing off" of the renal tubular lining cells, intratubular hyaline casts and mononuclear cell infiltration. Treatment with MMF significantly protected the rats against CDDP-induced nephrotoxicity. The rise in serum creatinine and urea levels, kidney weight and kidney tissue MDA production, depletion of "endogenous antioxidant reserve" including GPx activity and reduced GSH content levels and the deleterious histopathological changes induced by CDDP treatment were significantly mitigated by MMF treatment. CONCLUSIONS: MMF treatment dramatically ameliorates CDDP-induced renal dysfunction.

Cardioprotective effects of subcutaneous ebselen against daunorubicin-induced cardiomyopathy in rats.

Daunorubicin is an anthracycline antitumour agent that can cause severe cardiomyopathy leading to a frequently fatal congestive heart failure. Although the exact molecular mechanisms of cardiotoxicity are not well established, oxidative mechanisms involving daunorubicin-induced superoxide anion production have been proposed. In the present study, we showed that ebselen a seleno-organic compound exhibiting glutathione peroxidase-like and antioxidant activities, significantly ameliorated daunorubicin-induced cardiomyopathy. Subcutaneous administration of ebselen to daunorubicin-treated rats showed significant improvement in serum cardiac indices including creatine kinase isoenzyme and lactate dehydrogenase as well as serum glutathione (GSH) peroxidase. Moreover, myocardium of daunorubicin/ebselen-treated rats showed significant improvement in daunorubicin-induced depletion of GSH peroxidase activity and reduced glutathione content, in addition to attenuation of daunorubicin-induced increase in cardiac malondialdehyde production and total nitrate/nitrite concentration levels. These results were confirmed by histopathological examination of ventricles of daunorubicin/ebselen-treated rats that revealed significant improvement of the characteristic cardiomyopathic changes induced by daunorubicin treatment. Interestingly, control rats treated with ebselen showed significant elevation in serum lactate dehydrogenase activity, cardiac malondialdehyde production and total nitrate/nitrite concentration levels compared with the untreated control animals. In conclusion, ebselen treatment significantly alleviates daunorubicin-induced cardiomyopathy.

Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats.

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg(-1) intraperitoneally and 30 mg kg(-1) orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.