COMPARATIVE TOXICITY STUDY OF CHLOROQUINE AND HYDROXYCHLOROQUINE ON ADULT ALBINO RATS

Expanded use of Chloroquine and hydroxychloroquine drugs for non-malarial disease entities has resulted in prolonged duration of therapy and higher daily dosages leading to cumulative doses greater than those used in antimalarial therapy. The aim of the study is to evaluate and compare the toxic effects of chloroquine and hydroxychloroquine on different organs of albino rats. The study was conducted on 60 normal albino rats divided into 3 groups, the 1st group is the control group that received only distilled water, the 2nd and the 3rd group were given a single daily oral doses equivalent to 1/10th of LD50 chloroquine and hydroxychloroquine respectively. Assessment of liver and kidney functions, and histopathological changes in liver, kidney, and heart in different groups was done. The chloroquine treated group showed significant elevation of serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin (TB), serum creatinine-urea (Cr-U), Creatine Kinase-MB, C-reactive protein and Malonic dialdehyde levels as compared to control and hydroxychloroquine treated group. The histopathological evaluation showed marked hydropic degeneragtion, vascular congestion, interstitial hemorrhage, and necrosis in the liver, kidney and heart of chloroquine treated group, while hydroxychloroquine treated group showed mild congestion and slight cellular degeneration. Thus, hydroxychloroquine is less toxic and physicians should prescribe it better than chloroquine. Chloroquine if prescribed for therapeutic uses should be taken for short periods

COMPARATIVE TOXICITY STUDY OF CHLOROQUINE AND HYDROXYCHLOROQUINE ON ADULT ALBINO RATS

Expanded use of Chloroquine and hydroxychloroquine drugs for non-malarial disease entities has resulted in prolonged duration of therapy and higher daily dosages leading to cumulative doses greater than those used in antimalarial therapy. The aim of the study is to evaluate and compare the toxic effects of chloroquine and hydroxychloroquine on different organs of albino rats. The study was conducted on 60 normal albino rats divided into 3 groups, the 1st group is the control group that received only distilled water, the 2nd and the 3rd group were given a single daily oral doses equivalent to 1/10th of LD50 chloroquine and hydroxychloroquine respectively. Assessment of liver and kidney functions, and histopathological changes in liver, kidney, and heart in different groups was done. The chloroquine treated group showed significant elevation of serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin (TB), serum creatinine-urea (Cr-U), Creatine Kinase-MB, C-reactive protein and Malonic dialdehyde levels as compared to control and hydroxychloroquine treated group. The histopathological evaluation showed marked hydropic degeneragtion, vascular congestion, interstitial hemorrhage, and necrosis in the liver, kidney and heart of chloroquine treated group, while hydroxychloroquine treated group showed mild congestion and slight cellular degeneration. Thus, hydroxychloroquine is less toxic and physicians should prescribe it better than chloroquine. Chloroquine if prescribed for therapeutic uses should be taken for short periods

GENE POLYMORPHISM FOR Α-RECEPTOR OF OESTROGENES AND ALTERATIONS IN BONE MINERAL DENSITY FOR ADULT CELIAC DISEASE PATIENTS

It is well known that osteopenia and osteoporosis are frequently found celiac disease patients presenting classical symptoms of malabsorption1. Osteomalacia cases have also been diagnosed in celiac patients who do not present clinical signs of malabsorption , in patients with latent celiac disease, as well as in first degree relatives of patients with celiac disease who do not suffer from celiac disease themselves. This suggests the presence of different pathogenic mechanisms2. The analysis of genetic polymorphism represents an effective approach for an in-depth screening of genes potentially implicated in the development of osteoporosis. Because of the central role that estrogen plays in bone metabolism, ER genes play an important role in the determination of bone mineral density and the risk of osteoporosis. The fact that osteoporotic phenotypes are observed in patients with a destructive mutation of the α receptor gene for estrogen together with the signs of reduced bone mineral density that are found in mice presenting a functional insufficiency of ER α, but not in mice showing reduced ER β function, demonstrates that ER α is one of the principal genes involved in the genesis of osteoporosis3. Previously , two intronic polymorphisms of the α ER gene, identified by restriction endonucleases PvuII and TA Xba and repetitive polymorphism sequences, have been linked to bone mass density in the Japanese population and in menopausal Italian women4

VALPROIC ACID INDUCES APOPTOSIS AND INCREASES CXCR7 EXPRESSION IN EPITHELIAL OVARIAN CANCER CELL LINE SKOV-3.

Background: The chemokine receptor, CXCR7 is described to play a biologically relevant role in tumor growth and spread. Recently, it was reported that CXCR7 overexpression is associated with an unfavorable prognosis and metastatis of epithelial ovarian cancer (EOC). Aware that, several reports indicated that Histone deacetylases (HDACs) regulate the expression and activity of many proteins involved in both cancer initiation and progression, the aim of this work, was to study the effect of the HDAC inhibitor valproic acid (VPA) on the expression of CXCR7 as well as its impact on survival function in the epithelial ovarian cell line (SKOV-3). Methods: cells were cultured with varying concentrations of VPA (1, 2, 3, 4, 5 and 10 mM) for different durations (0, 12 h, 24 h and 48 h). Cell survival was assessed by Neutral red assay and by colony counting which being stained with crystal violet. CXCR7 expression was determined at mRNA level using quantitative real-time PCR (qRT-PCR) or at the protein level using western blotting. Results: VPA reduces cell survival of SKOV-3 cancer cells. The inhibition effect of VPA was dose and time-dependent. Exposure to VPA at concentrations above 2 mM at 24 h resulted in an increase expression of CXCR7 at both the mRNA and protein levels . Conclusion: These observations provide, for the first time, a better insight into the epigenetic mechanisms involved in regulating CXCR7 expression in EOC and will open new avenues for evaluating drugs that specifically stimulate the apoptosis of EOC with minimal unwanted side effect

VALPROIC ACID INDUCES APOPTOSIS AND INCREASES CXCR7 EXPRESSION IN EPITHELIAL OVARIAN CANCER CELL LINE SKOV-3.

Background: The chemokine receptor, CXCR7 is described to play a biologically relevant role in tumor growth and spread. Recently, it was reported that CXCR7 overexpression is associated with an unfavorable prognosis and metastatis of epithelial ovarian cancer (EOC). Aware that, several reports indicated that Histone deacetylases (HDACs) regulate the expression and activity of many proteins involved in both cancer initiation and progression, the aim of this work, was to study the effect of the HDAC inhibitor valproic acid (VPA) on the expression of CXCR7 as well as its impact on survival function in the epithelial ovarian cell line (SKOV-3). Methods: cells were cultured with varying concentrations of VPA (1, 2, 3, 4, 5 and 10 mM) for different durations (0, 12 h, 24 h and 48 h). Cell survival was assessed by Neutral red assay and by colony counting which being stained with crystal violet. CXCR7 expression was determined at mRNA level using quantitative real-time PCR (qRT-PCR) or at the protein level using western blotting. Results: VPA reduces cell survival of SKOV-3 cancer cells. The inhibition effect of VPA was dose and time-dependent. Exposure to VPA at concentrations above 2 mM at 24 h resulted in an increase expression of CXCR7 at both the mRNA and protein levels . Conclusion: These observations provide, for the first time, a better insight into the epigenetic mechanisms involved in regulating CXCR7 expression in EOC and will open new avenues for evaluating drugs that specifically stimulate the apoptosis of EOC with minimal unwanted side effect

EVALUATION OF SECONDARY OSTEOPOROSIS WITH BONE MINERAL DENSITOMETRY AND BONE TURNOVER MARKERS

Osteoporosis is as a very complex multi-factorial pathogenesis; thereby any doctor facing a case of osteoporosis must be very careful. Diagnostic procedures are complex and include careful monitoring of the history of patient, physical examination and some laboratory analysis. In this study, 201 patients aged between 50 and 95 years were selected from 4872 patients consulting orthopedic clinics. This group (201 patients: 168 women, 33 men) showed evidence of osteoporosis: BMD DXA with reduced bone mineral density,T-score: greater than -2.5 SD, or X-ray signs of non traumatic fractures. Patients also underwent biochemical and instrumental investigations for an assessment of bone metabolism. Age, gender, medical history as well as tests of rheumatic metabolism, calcium-phosphorus and some indices of bone turnover were determined for each patient. Interestingly, our data showed that 104 patients had a vertebral fracture without trauma, 22 hypothyroid patients were undergoing treatment with levothyroxine, 3 patients were suffering from autoimmune thyroiditis, 3 patients were suffering from secondary hyperparathyroidism with vitamin D deficiency, 2 patients were suffering from adenoma with primary hyperparathyroidism, 20 were diabetic patients, 7 patients had monoclonal gammopathy, 7 women had hystero- ovario salpingectomy, 7 patients were HCV positive, 4 patients with rheumatoid arthritis had been treated with corticosteroids, 2 patients were suffering from multiple myeloma, and 1 patient had Crohn's disease. There was also 1 suspected case of ulcerative colitis, 5 patients were suffering from celiac disease and other cases described in the paper. As a result of this diverse association, the approach to treating osteoporotic patients should be then accurate and multidisciplinary. It is then important to perform laboratory tests and investigations for correct diagnosis and adequate treatment

EVALUATION OF SECONDARY OSTEOPOROSIS WITH BONE MINERAL DENSITOMETRY AND BONE TURNOVER MARKERS

Osteoporosis is as a very complex multi-factorial pathogenesis; thereby any doctor facing a case of osteoporosis must be very careful. Diagnostic procedures are complex and include careful monitoring of the history of patient, physical examination and some laboratory analysis. In this study, 201 patients aged between 50 and 95 years were selected from 4872 patients consulting orthopedic clinics. This group (201 patients: 168 women, 33 men) showed evidence of osteoporosis: BMD DXA with reduced bone mineral density,T-score: greater than -2.5 SD, or X-ray signs of non traumatic fractures. Patients also underwent biochemical and instrumental investigations for an assessment of bone metabolism. Age, gender, medical history as well as tests of rheumatic metabolism, calcium-phosphorus and some indices of bone turnover were determined for each patient. Interestingly, our data showed that 104 patients had a vertebral fracture without trauma, 22 hypothyroid patients were undergoing treatment with levothyroxine, 3 patients were suffering from autoimmune thyroiditis, 3 patients were suffering from secondary hyperparathyroidism with vitamin D deficiency, 2 patients were suffering from adenoma with primary hyperparathyroidism, 20 were diabetic patients, 7 patients had monoclonal gammopathy, 7 women had hystero- ovario salpingectomy, 7 patients were HCV positive, 4 patients with rheumatoid arthritis had been treated with corticosteroids, 2 patients were suffering from multiple myeloma, and 1 patient had Crohn's disease. There was also 1 suspected case of ulcerative colitis, 5 patients were suffering from celiac disease and other cases described in the paper. As a result of this diverse association, the approach to treating osteoporotic patients should be then accurate and multidisciplinary. It is then important to perform laboratory tests and investigations for correct diagnosis and adequate treatment

Medicago orbicularis Has Antioxidant, Antihemolytic, and Anti-cancerous Activities and Augments Cisplatin-Induced Cytotoxicity in A549 Lung Cancer Cells

Cancer is the second leading cause of death, worldwide. Lung cancer is the leading cause of cancer-related mortality. Plant-based therapeutics and herbal medicine have played a vital role in the development of several anti-cancerous agents, and has been used to reduce the severe side effects of chemotherapy as well. Since the anti-lung cancer properties of the plant Medicago. orbicularis are not explored yet, we identified its phytochemical composition and investigated the anti-oxidant, anti-hemolytic, and anti-cancerous properties of extracts of this plant in A549 human lung adenocarcinoma cells. Results show that all parts of M. orbicularis (stems, leaves, and fruits) exhibit remarkable anti-oxidant and hemolytic activities. In addition, all extracts showed a dose-dependent anti-cancerous cytotoxic activity against A549 cells; with fruit extracts being the most potent. This cytotoxic effect could be related, at least partly, to the induction of apoptosis, where M. orbicularis fruit extracts activated Caspase-3 and PARPP-1, and reduced the ratio of anti-apoptotic BCL-2/ pro-apoptotic BAX, thereby promoting cellular death. Furthermore, the use of M. orbicularis, in combination with a conventional chemotherapeutic agent, cisplatin, was assessed. Indeed, combination of cisplatin and M. orbicularis fruit extracts was more cytotoxic and induced more aggregation of A549 cells than either treatment alone. GC-MS analysis and total polyphenol and flavonoid content determination indicated that M. orbicularis is rich in compounds that have anti-cancerous effects. M. orbicularis may be a potential source of anti-cancerous agents to manage progression of lung cancer and its resistance to therapy.This work was supported by the a grant from the Lebanese University to SN and student grants number QUST-1-BRC-2022-315; QUST-1-BRC-2022-316, QUST-1-BRC-2023-836; and QUST-1-BRC-2023-846 to AS. Publication fees APC were covered by Qatar National Library (QNL)

THE CORRELATION BETWEEN THE METABOLIC DISORDERS IN OBESE MEN AND THE BODY MASS INDEX (BMI)

Background: The influence of body weight on serum lipids and uric acid is often overlooked in clinical practice. Objective: To study the magnitude of metabolic disorders (dyslipidemia and hyper-urecaemia) in asymptomatic obese men and its relation to body mass index (BMI). Methods: The study was conducted between September 2013 and July of 2014 at the medical analyses center in the Faculty of Public Health, Lebanese University. The weight, height, BMI, waist circumference (WC) uric acid, and lipid profile of 148 obese males, apparently healthy, compared with 80 males in a control group (BMI < 25 kg / m²), were investigated. Subjects were grouped by BMI and WC in accordance with the National Institutes of Health cutoff points. Within the normal-weight (18.5-24.9), overweight (25.0-29.9), and obese (≥ 30.0) BMI categories, we distributed the results of all the blood tests and we computed the prevalence of dyslipidemia and hyperurecaemia. Results: The present work revealed that with increasing body weight, the mean total cholesterol, LDL-C, triglycerides(TG), and uric acid increased; while the mean HDL-C decreased. These changes were as follows: the means difference between the first and second group and between the second and the third group were 29 and 31 mg/dl respectively regarding total cholesterol; for TG, these were 47.5 and 53.4 mg/dl; for LDL-C, these were 12 and 29 mg/dl; for HDL-C, these were 3.6 and 3.5 mg/dl; for uric acid, these were 0.3 mg/dl as a common difference, P=0.0245). Conclusion: Excess body weight is associated with deleterious changes in the lipoprotein profile and uric acid

CXCL12 expression by healthy and malignant ovarian epithelial cells

<p>Abstract</p> <p>Background</p> <p>CXCL12 has been widely reported to play a biologically relevant role in tumor growth and spread. In epithelial ovarian cancer (EOC), CXCL12 enhances tumor angiogenesis and contributes to the immunosuppressive network. However, its prognostic significance remains unclear. We thus compared CXCL12 status in healthy and malignant ovaries, to assess its prognostic value.</p> <p>Methods</p> <p>Immunohistochemistry was used to analyze CXCL12 expression in the reproductive tracts, including the ovaries and fallopian tubes, of healthy women, in benign and borderline epithelial tumors, and in a series of 183 tumor specimens from patients with advanced primary EOC enrolled in a multicenter prospective clinical trial of paclitaxel/carboplatin/gemcitabine-based chemotherapy (GINECO study). Univariate COX model analysis was performed to assess the prognostic value of clinical and biological variables. Kaplan-Meier methods were used to generate progression-free and overall survival curves.</p> <p>Results</p> <p>Epithelial cells from the surface of the ovary and the fallopian tubes stained positive for CXCL12, whereas the follicles within the ovary did not. Epithelial cells in benign, borderline and malignant tumors also expressed CXCL12. In EOC specimens, CXCL12 immunoreactivity was observed mostly in epithelial tumor cells. The intensity of the signal obtained ranged from strong in 86 cases (47%) to absent in 18 cases (<10%). This uneven distribution of CXCL12 did not reflect the morphological heterogeneity of EOC. CXCL12 expression levels were not correlated with any of the clinical parameters currently used to determine EOC prognosis or with HER2 status. They also had no impact on progression-free or overall survival.</p> <p>Conclusion</p> <p>Our findings highlight the previously unappreciated constitutive expression of CXCL12 on healthy epithelia of the ovary surface and fallopian tubes, indicating that EOC may originate from either of these epithelia. We reveal that CXCL12 production by malignant epithelial cells precedes tumorigenesis and we confirm in a large cohort of patients with advanced EOC that CXCL12 expression level in EOC is not a valuable prognostic factor in itself.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00052468">NCT00052468</a></p