Teratogenic effect of Carbamazepine use during pregnancy in the mice.

Carbamazepine use is the first choice of antiepileptic drugs among epileptic pregnant females. There are many inconclusive studies regard the safety of carbamazepine use during pregnancy. This study aims to investigate the morphological and histopathological teratogenic effects of carbamazepine use during pregnancy. The healthy pregnant females mice divided into equal five groups (each n=20). The first (control) group received distilled water/day. Second, third, fourth and fifth group received 8.75, 22.75, 52.5, 65 mg of carbamazepine/day respectively. Carbamazepine and water were given by gastric gavage throughout gestational period. Fetuses were delivered on the 18th day of gestation by hysterectomy. Fetal measurements and appearance were assessed with investigation the histopathological changes of brain and spinal cord. There was a significant decrease of weight, different organs weight, length, upper and lower limb length of mice in the first day of delivery in fifth group. There was a significant increase of weight, different organs weight, length, upper and lower limb length in the third group. Many congenital anomalies such as spina bifida, meromelia, microphalmia, oligodactyly, anencephaly, neurodegeneration of brain and spinal cord were noticedin fifth group. Teratogenic effect of carbamazepine represented as growth retardation and neurodevelopmental toxicity depending on its overdose degree.

Role of propolis (bee glue) in improving histopathological changes of the kidney of rat treated with aluminum chloride.

Humans are frequently exposed to aluminum from various food additives, therapeutic treatments and the environment, and it can be potentially toxic. This study is aimed to elucidate the protective effects of propolis against aluminum chloride (AlCl3 )-induced histopathological and immunohistochemical changes in kidney tissues of rats. Sixty Wistar Albino male rats (average weight 250-300 g) were divided into three equal groups. The first served as a negative control. The second received AlCl3 (34 mg/kg bw, 1/ 25 LD 50). The third were administered AlCl3 (34 mg/kg bw, 1/ 25 LD 50) plus propolis (50 mg/kg bw). Doses were given once daily via a gavage for 8 weeks every day. The results showed that shrunken glomeruli, intraglomerular congestion, loss of apical microvilli, degeneration of mitochondria and widened rough endoplasmic reticulum were also observed in the Proximal Convoluted Tubules of these animals. Treatment with propolis ameliorated the harmful effects of AlCl3 ; this was also proved histopathologically by the noticeable improvement in the renal tissues. There were also significant variations in the expressed of ki-67 and p53 proteins. It can be concluded that propolis may be promising as a natural therapeutic agent in AlCl3 -induced renal toxicity and oxidative stress in rat kidneys.

Potential anxiolytic and antidepressant-like effects of luteolin in a chronic constriction injury rat model of neuropathic pain: Role of oxidative stress, neurotrophins, and inflammatory factors.

This study aimed to examine the effects of luteolin (LUT) on chronic neuropathic pain (NP)-induced mood disorders (i.e., anxiety and depression) by regulating oxidative stress, neurotrophic factors (NFs), and neuroinflammation. Chronic constrictive injury (CCI) was used to induce NP in the animals. Animals in the treatment groups received LUT in three doses of 10, 25, and 50 mg/kg for 21 days. The severity of pain and mood disorders were examined. Finally, animals were sacrificed, and their brain tissue was used for molecular and histopathological studies. CCI led to cold allodynia and thermal hyperalgesia. Mood alterations were proven in the CCI group, according to the behavioral tests. Levels of glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), B-cell lymphoma-2 (Bcl2), superoxide dismutase (SOD), catalase (CAT), and nuclear factor erythroid-2-related factor 2 (Nrf2) were reduced in the hippocampus (HPC) and prefrontal cortex (PFC). Furthermore, the levels of MDA, Bcl-2-associated X protein (Bax), and inflammatory markers, including nuclear factor kappa B (NF-κB), NLR family pyrin domain containing 3 (NLRP3), interleukin-1ß (IL-1ß), IL-18, IL-6, and tumor necrosis factor-α (TNF-α) significantly increased in the HPC and PFC following CCI induction. LUT treatment reversed the behavioral alterations via regulation of oxidative stress, neurotrophines, and inflammatory mediators in the HPC and PFC. Findings confirmed the potency of LUT in the improvement of chronic pain-induced anxiety- and depressive-like symptoms, probably through antioxidant, anti-inflammatory, and neuroprotective properties in the HPC and PFC.

Implications of CEA and p53 overexpression in the poor prognosis of colorectal cancer.

Colorectal cancer (CRC) is one of the most frequent and aggressive types of cancer. Several clinicopathologic features have been studied to identify the prognostic factors that can provide information concerning the favorable or the poor outcome of colorectal cancer. In the present study, the relationship between serum CEA, p53 expression, and DNA index to the different clinicopathological characteristics of colorectal cancer patients was sought. Fifty patients with CRC were included in this study. p53 protein was detected immunohistochemically using specific monoclonal antibodies. Samples were investigated for DNA index using flow cytometry. In addition, the serum CEA was determined using ELISA. The results showed that 27/50 (54%) were positive for p53. Concerning CEA reactivity, it was found that 35/50 (70%) were reactive for CEA. These results indicate that CEA is more sensitive than p53 to detect colorectal cancer. There was a statistically significant difference between the recurrent and nonrecurrent groups in the CRC Duke's stages, survival time, serum CEA (p = 0.001, 0.016, < 0.001, respectively). Kaplan-Meier method and log-rank test showed that the mean survival time for cases positive for both p53 and CEA is significantly different from cases positive for CEA only, positive for p53 only, and negative for both p53 and CEA (p = 0.0002). Survival time was statistically significant with respect to sex, p53, CEA, and Duke's stages (p = 0.006, 0.024, 0.001, 0.017, respectively). Cox regression model showed that the prognosis of colorectal cancer is influenced by sex, p53, CEA reactivity, and CRC Duke's stages (p = 0.014, 0.006, 0.019, 0.014, respectively). In conclusion, the use of more than one tumor marker may successfully aid in the prediction of colorectal cancer prognosis.

Toxicological evaluation of subchronic use of pioglitazone in mice.

OBJECTIVES: Pioglitazone (Actos) is one of the most controversial recent oral antidiabetic drugs. It was originally authorized in the European Union in 2000, and approved as an oral monotherapy for overweight second type of diabetic patients in 2002. It belongs to the thiazolidinedione group which some of its members have been withdrawn from the market due to the hepatotoxicity or cardiotoxicity effects. This study investigates sub-chronic use of pioglitazone induced toxicity in mice by the assessment of renal and liver function tests, cardiac enzymes, and some hematological indices with histological changes of liver, kidney, heart, and bladder. MATERIALS AND METHODS: 120 albino mice were divided into four groups; 30 in each. The first group (control) received water, second (diabetic) group received alloxan only, while the third and the fourth groups received alloxan with 200 and 400 mg/kg/day of pioglitazone, respectively for 90 days. RESULTS: Prolonged use of pioglitazone induced significant abnormalities of hepatic, renal, and cardiac biomarkers and some hematological indices associated with histopathological changes in the liver, kidney, heart, and bladder that increased based on administered dose. CONCLUSION: Subchronic use of pioglitazone leads to hepatic, renal, cardiac, hematological, and bladder affection depending on the applied dose.

Histopathological Study of Cyclosporine Pulmonary Toxicity in Rats.

Cyclosporine is considered one of the common worldwide immunosuppressive drugs that are used for allograft rejection prevention. However, articles that address adverse effects of cyclosporine use on the vital organs such as lung are still few. This study aims to investigate pulmonary toxic effect of cyclosporine in rats by assessment of pulmonary histopathological changes using light and electron microscope examination. Sixty male adult albino rats were divided into three groups; each group consists of twenty rats. The first received physiological saline while the second and third groups received 25 and 40 mg/kg/day of cyclosporine, respectively, by gastric gavage for forty-five days. Cyclosporine reduced the lung and body weight with shrinkage or pyknotic nucleus of pneumocyte type II, degeneration of alveoli and interalveolar septum beside microvilli on the alveolar surface, emphysema, inflammatory cellular infiltration, pulmonary blood vessels congestion, and increase of fibrous tissues in the interstitial tissues and around alveoli with negative Periodic Acid-Schiff staining. Prolonged use of cyclosporine induced pulmonary ultrastructural and histopathological changes with the lung and body weight reduction depending on its dose.

Curcumin improves atorvastatin-induced myotoxicity in rats: Histopathological and biochemical evidence.

Atorvastatin is considered to be one of the most commonly used of all statins anti-hyperlipidemic drugs despite the fact that there is much controversy about its safety. Its therapeutic use becomes severely limited by the hazards of inducing myotoxicity. Curcumin is one of the safe spices that have chemoprotection and cytoprotection effects against endogenous and exogenous noxious stimuli. This study investigates the effect of curcumin on atorvastatin sub-chronic use-induced myotoxicity in rats by the assessment of serum creatinine phosphokinase, lactic acid dehydrogenase, myoglobin, troponin, potassium, creatinine, and histopathological changes of skeletal, smooth, and cardiac muscles by light and electron microscope examination. Eighty adult albino rats were divided into four groups; each group consists of 20 rats. The control group received water, the second group received atorvastatin, the third group received curcumin, and the fourth group received curcumin with atorvastatin for 90 days by gastric gavage. The prolonged use of atorvastatin induced significant abnormalities of all myotoxicity biomarkers associated with histopathological and ultrastructural changes in the different types of the muscles. Co-administration of curcumin with sub-chronic use of atorvastatin led to an improvement in myotoxicity manifestations.

Comparison between the protective effects of vitamin K and vitamin A on the modulation of hypervitaminosis D3 short-term toxicity in adult albino rats.

BACKGROUND/AIM: Vitamin D3 has increased risk of toxicity due to its common use in multivitamin preparations. Vitamin K and vitamin A play an important role in vitamin D action. The goal of the current study was to compare the protective effects of vitamin K and vitamin A on the modulation of hypervitaminosis D3 toxicity in rats by assessing serum calcium, renal function tests, cardiac enzymes, and related histopathological changes. MATERIALS AND METHODS: Eighty adult albino rats were divided into four groups; each group consisted of 20 rats. The first group received water; the second received a toxic dose of vitamin D3; the third received a toxic dose of vitamin D3 with vitamin A; and the fourth received a toxic dose of vitamin D3 with vitamin K. RESULTS: Vitamin D3 toxicity led to significant abnormalities of cardiac enzymes, renal function tests, and serum calcium associated with histopathological changes in the kidney, heart, lung, adrenal gland, and aorta. Individual administration of vitamin A or vitamin K with a toxic dose of vitamin D improved the biochemical and histopathological abnormalities of hypervitaminosis D3. CONCLUSION: Vitamins A and K showed the same protective effects in the modulation of hypervitaminosis D3 short-term toxicity.

Relationship of Helicobacter pylori to Bcl-2 family expression, DNA content, and pathological characteristics of gastric cancer.

BACKGROUND: Despite the fact that the association of Helicobacter pylori with an increased risk of gastric cancer has been well documented, the exact mechanisms of this association have not been fully elucidated. Scarce data on H. pylori infection and its relationship with the different pathological characteristics are available in Egypt. AIM OF THE STUDY: The rationale of the present study was to determine the prevalence of H. pylori in a group of gastric cancer patients and to analyze the relationship between H. pylori infection with the different pathological characteristics including the types of gastric cancer and tumor location within the stomach, in addition, to investigate the Bcl-2 and Bax expressions along with DNA flow cytometric analysis in the gastric cancer patients with and without H. pylori infection. METHODS: Samples were obtained from 66 consecutive patients with gastric cancer (46 males and 20 females). The youngest patient was 20 yr old, the oldest 76 yr with mean age of 52.8 yr. The samples were subjected for histopathological characterization, H. pylori detection, DNA flow cytometric analysis, and Bcl-2 and Bax expressions detection, in addition to apoptosis analysis. RESULTS: The obtained results showed that the H. pylori infection was found in 38/66 (57.6%) [Odds ratio=1.357 with 95% confidence interval (CI) 0.84-2.2]. There was a statistical significance for Bcl-2, Bax, and apoptosis with H. pylori status (p = 0.009, 0.008, 0.032, respectively). On the other hand, There was a statistical significance for H. pylori infection with the disease grade (p = 0.015) and lymph node metastasis (p = 0.05). No statistical significance was found between H. pylori status with the patients' age, gender, tumor site, tumor type, depth of invasion, and stromal reaction. CONCLUSIONS: These data may indicate that the H. pylori infection not only contributes in the disease formation through the apoptosis dysregulation but also takes a part in the disease dissemination and progression. In addition, it may reflect a biologic, pathogenic, and ethnic background affecting the relationship of H. pylori infection to gastric cancer in the Egyptian patients. A high rate of smoking in Egypt and the diet are important factors that may affect such background. Further studies are warranted.

Effects of Physalis peruviana L on Toxicity and Lung Cancer Induction by Nicotine Derived Nitrosamine Ketone in Rats.

Nicotine-derived nitrosamine ketone (NNK) is considered a key tobacco smoke carcinogen inducing lung tumors. Physalis peruviana L (harankash) is considered one plant with marked health benefits. This study aimed to evaluate Physalis peruviana L effect on the toxic effect of NNK induced lung cancer in the rats by using pulmonary histopathological, immunohistochemical and DNA flow cytometric analyses. Sixty adult male rats were divided into four groups, each consisting of fifteen animals. The first group received saline, the second received two successive toxic doses of NNK only while the third received two successive toxic doses of NNK with a single daily dose of Physalis peruviana L. The fourth group received a single daily dose of Physalis peruviana L only. Toxic doses of NNK induced hyperplasia and adenocarcinoma in the lung and positive immunoreactivity for Ki-67 and p53 staining with disturbance of the lung DNA content. Administration of Physalis peruviana L with NNK led to a mild pulmonary hyperplasia and weak expression of Ki-67 and p53 with an improvement in the lung DNA content. Physalis peruviana L may protect against NNK induced lung carcinogenesis due to its antioxidant and anti-proliferative effects.

Immunohistochemical expressions of uPA and its receptor uPAR and their prognostic significant in urinary bladder carcinoma.

BACKGROUND: The authors found previously that plasma levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR) were elevated in patients with bladder carcinoma and were associated with features of biologically aggressive disease. The present study has been performed to analyze the expressions of two antigens by immunohistochemical staining in bladder transitional cell carcinoma. PATIENTS AND METHODS: The tumors from 72 men and 28 women with a mean age 46.15 years (range 30-67 years) were examined. Paraffin sections of 5 microm thickness were prepared for immunohistochemical staining of uPA and uPAR antigens. Age, sex, tumor grade and stage, DNA ploidy, lymph node status, and metastases were evaluated in relation to outcome. Univariate and multivariate analysis of survival were performed. RESULTS: The overall 5-year survival was 66%. Thirty six and 46 cases were positive for uPA and uPAR expressions, respectively. In univariate analysis, tumor stage, lymph node status, metastases, uPA and uPAR have a significant impact on the survival for these patients. In a Cox proportional hazard model, uPAR sustained its significant impact on survival. CONCLUSIONS: These findings suggest that uPAR is an independent additional prognostic factor in patients with transitional cell carcinoma of the bladder.

Elevated renin levels in patients with liver cirrhosis and hepatocellular carcinoma.

Liver fibrosis is the common consequence of chronic liver injury of any etiology, disrupting the normal architecture,and causing hepatocellular dysfunction and portal hypertension. Since the renin-angiotensin system (RAS) may be involved in chronic liver diseases, in the present study we assayed renin levels using ELISA in groups of Egyptian patients with liver cirrhosis (N=32) and hepatocellular carcinoma (HCC) (N=67), for comparison with twenty five healthy controls. The results showed significant differences between the control and liver cirrhosis patients (P<0.001) and also the controls and HCC patients (P<0.001), without significant variation between the patient groups. Furthermore, in HCC patients, it was found that the renin levels negatively correlated with serum albumin and prothrombin time (P=0.003 for each) and positively with α-fetoprotein (P=0.04). Thus, it is concluded that renin levels are elevated in patients with liver cirrhosis and HCC and suitable medical intervention should be placed for management of such alteration. Moreover, further studies are warranted to explore its prognostic significance.

Significance of matrix metalloproteinase 9 and CD34 expressions in esophageal carcinoma: correlation with DNA content.

BACKGROUND: Esophageal carcinoma is common in many countries, and it is characterized by poor prognosis and rapid clinical progression with a high frequency of lymph node metastasis and recurrence. The present study was carried out to evaluate the correlation between vascular endothelial cell marker (CD34), matrix metalloproteinase type 9 (MMP9), and DNA content in esophageal carcinoma. METHODS: A total of 38 patients were classified with histopathologic examination as 8 cases with adenocarcinoma, 24 cases with squamous cell carcinoma, and the last 6 cases with undifferentiated carcinoma. The obtained results of the patient group were compared with the results of 6 cases with proven normal esophageal mucosa as a control group. The samples of patients and controls were subjected to immunohistochemical evaluation of CD34 and MMP9 expression along with DNA index determination using flow cytometry. RESULTS: There was a significant difference between patients and normal cases in DNA index, CD34, and MMP9 pattern (P = 0.003, <0.001, and 0.002, respectively). DNA index was positively correlated with MMP9 (r = 0.574, P < 0.001) and with CD34 (r = 0.562, P < 0.001). MMP9 was correlated with CD34 (r = 0.55, P < 0.001). A significant difference was found in both microvessel density and MMP9 expression with respect to tumor grade and stage. The microvessel density in patients with highly positive staining for MMP9 was higher than in those with negative and weak staining for MMP9 (P = 0.002). CONCLUSION: The analysis of DNA content along with detection of CD34 and MMP9 in esophageal cancer can successfully differentiate the different pathologic lesions and hence can be used powerfully in disease prognosis reflecting valuable information about the aggressiveness and activity of those lesions.