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Background: Alpha-1 antitrypsin deficiency (AATD) is an inherited disease, the common variant caused by a Pi*Z mutation in the SERPINA1 gene. Pi*Z AAT increases the risk of pulmonary emphysema and liver disease. Berberine (BBR) is a nature dietary supplement and herbal remedy. Emerging evidence revealed that BBR has remarkable liver-protective properties against various liver diseases. In the present study, we investigated the therapeutic effects and toxicities of BBR in Pi*Z hepatocytes and Pi*Z transgenic mice., Methods: Huh7.5 and Huh7.5Z (which carries the Pi*Z mutation) cells were treated with different concentrations of BBR for 48 hours. MTT was performed for cell viability assay. Intracellular AAT levels were evaluated by western blot. In vivo studies were carried out in wild type, native phenotype AAT (Pi*M), and Pi*Z AAT transgenic mice. Mice were treated with 50 mg/kg/day of BBR or solvent only by oral administration for 30 days. Western blot and liver histopathological examinations were performed to evaluate therapeutic benefits and liver toxicity of BBR., Results: BBR reduced intracellular AAT levels in Huh7.5Z cells, meanwhile, no Pi*Z-specific toxicity was observed. However, BBR did not reduce liver AAT load but significantly potentiated liver inflammation and fibrosis accompanying the activation of unfolded protein response and mTOR in Pi*Z mice, but not in wild type and Pi*M mice., Conclusions: BBR exacerbated liver inflammation and fibrosis specifically in Pi*Z mice. This adverse effect may be associated with the activation of unfolded protein response and mTOR. This study implicates that BBR should be avoided by AATD patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In forensic medicine, estimating the postmortem interval (PMI) is of great importance for the timeline and the reconstruction of the events surrounding death. Bone marrow (BM) is one of the largest organs in the body, with good resistance to autolysis and contamination. Therefore, the present study aims to correlate different postmortem intervals and bone marrow antioxidant enzyme levels using an Enzyme-linked immunosorbent assay (ELISA). In addition, detection of the changes in the histological structure of human bone marrow in relation to the time passed since death. BM samples from 20 forensic autopsy cadavers were obtained from cases referred to the Department of Forensic Medicine in the Ministry of Justice, Dakahlia Governorate, processed for histopathological examination as well as estimation of reduced glutathione (GSH), glutathione peroxidase (GPX), and glutathione reductase (GRX) using ELISA. Results of ELISA analysis showed a significant decrease in the level of antioxidant enzymes with increasing PMI; regarding histopathological examination, from 6 to > 18 h PMI, the changes in morphology after death were gradual, progressive, and regular, indicating great value in PMI determination. Also, 18 h of PMI showed loss of cellular details, absence of fat cells, and necrosis of BM with the nucleus dispersed as eosinophilic debris. Estimation of antioxidant enzymes level in human bone marrow using ELISA and detection of the changes in the histological structure of human bone marrow in relation to time passed since the death, either separately or in combination, can be used to estimate PMI accurately., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To investigate the response of nutritional supplement (LNS-PLW) on appetite score, energy intake, insulin and glucose levels in preeclamptic women., Design & Participants: Sixty under-weight preeclamptic primigravida were divided into two groups randomly and provided LNS-PLW/Placebo in the fasted state. Blood samples were collected at fasting state, after 30mins of supplementation, "ad libitum buffet" breakfast and lunch for glucose and insulin levels., Results: Total energy intake was higher significantly in the LNS-PLW group, although during breakfast it was significantly reduced. The insulin and glucose concentration was significantly increased after 30min of supplementation in the LNS-PLW group., Conclusion: Intake of the LNS-PLW by pre-eclamptic women had short-term suppression on subsequent meal but improved total energy intake during trial., (Copyright 2024 The Author(s).)

Aims: Chronic kidney disease (CKD) is a growing fatal health problem worldwide associated with vascular calcification. Therapeutic approaches are limited with higher costs and poor outcomes. Adenine supplementation is one of the most relevant CKD models to human. Insufficient Nitric Oxide (NO)/ cyclic Guanosine Monophosphate (cGMP) signaling plays a key role in rapid development of renal fibrosis. Natural products display proven protection against CKD. Current study therefore explored isoliquiritigenin, a bioflavonoid extracted from licorice roots, potential as a natural activator for soluble Guanylate Cyclase (sGC) in a CKD rat model., Materials and Methods: 60 male Wistar rats were grouped into Control group (n = 10) and the remaining rats received adenine (200 mg/kg, p.o) for 2 wk to induce CKD. They were equally sub-grouped into: Adenine untreated group and 4 groups orally treated by isoliquiritigenin low or high dose (20 or 40 mg/kg) with/without a selective sGC inhibitor, ODQ (1-H(1,2,4)oxadiazolo(4,3-a)-quinoxalin-1-one, 2 mg/kg, i.p) for 8 wk., Key Findings: Long-term treatment with isoliquiritigenin dose-dependently and effectively amended adenine-induced chronic renal and endothelial dysfunction. It not only alleviated renal fibrosis and apoptosis markers but also aortic calcification. Additionally, this chalcone neutralized renal inflammatory response and oxidative stress. Isoliquiritigenin beneficial effects were associated with up-regulation of serum NO, renal and aortic sGC, cGMP and its dependent protein kinase (PKG). However, co-treatment with ODQ antagonized isoliquiritigenin therapeutic impact., Significance: Isoliquiritigenin seems to exert protective effects against CKD and vascular calcification by activating sGC, increasing cGMP and its downstream PKG., Competing Interests: Declaration of competing interest The authors declare no known competing or financial interests or personal relations that might influence this work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Alpha-1 antitrypsin (AAT) deficiency (AATD) is an inherited disease caused by mutations in the serpin family A member 1 (SERPINA1, also known as AAT) gene. The most common variant, PI*Z (Glu342Lys), causes accumulation of aberrantly folded AAT in the endoplasmic reticulum (ER) of hepatocytes that is associated with a toxic gain of function, hepatocellular injury, liver fibrosis, and hepatocellular carcinoma. The unfolded protein response (UPR) is a cellular response to improperly folded proteins meant to alleviate ER stress. It has been unclear whether PI*Z AAT elicits liver cell UPR, due in part to limitations of current cellular and animal models. This study investigates whether UPR is activated in a novel human PI*Z AAT cell line and a new PI*Z human AAT (hAAT) mouse model. A PI*Z AAT hepatocyte cell line (Huh7.5Z) was established using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing of the normal ATT (PI*MM) gene in the Huh7.5 cell line. Additionally, novel full-length genomic DNA PI*Z hAAT and PI*M hAAT transgenic mouse models were established. Using these new models, UPR in Huh7.5Z cells and PI*Z mice were comprehensively determined. Robust activation of UPR was observed in Huh7.5Z cells compared to Huh7.5 cells. Activated caspase cascade and apoptosis markers, increased chaperones, and autophagy markers were also detected in Z hepatocytes. Selective attenuation of UPR signaling branches was observed in PI*Z hAAT mice in which the protein kinase R-like ER kinase and inositol-requiring enzyme1α branches were suppressed while the activating transcription factor 6α branch remained active. This study provides direct evidence that PI*Z AAT triggers canonical UPR and that hepatocytes survive pro-apoptotic UPR by selective suppression of UPR branches. Our data improve understanding of underlying pathological molecular mechanisms of PI*Z AATD liver disease., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Objective: Maternal under nutrition and low birth weight babies are among the common tragedies of developing countries like Pakistan. Preeclampsia and its significant association with fetal growth restriction due to spiral arteries remodeling and trophoblastic invasion decreases nutritional supply to growing fetus added by maternal under nutrition. This study was designed to see the effects of lipid based nutritional supplements for pregnant and lactating women LNS-PLW on maternal and fetal outcome of pre-eclampsia., Methods: Sixty underweight pre-eclamptic women were randomly assigned into two study Groups from April 2018 to December 2019 at the antenatal units of the tertiary Health care facilities of Lady Reading Hospital, Hayatabad Medical Complex Peshawar and Civil Hospital Matta Swat, KPK Pakistan in a randomized clinical trial. Participants were on routine drugs for pre-eclampsia and Iron and Folic Acid (60mg, 400 μg) daily, while participant of Group-2 (n=30) received one sachet of Lipid based nutritional supplement for pregnant and lactating women LNS-PLW in addition daily till delivery. The birth weight, gestational age, head-circumference, and birth length of babies were measured., Results: The significant improvement found in the birth weight (p-value 0.003), gestational age (p-value 0.006), head circumference (P-value of 0.0006) and birth length (P-value of 0.0017) of babies of Group-2 women. We observed that addition of Lipid based nutritional supplement for pregnant and lactating women LNS-LPW improved the birth outcome in underweight women of pre-eclampsia., Conclusion: The Prenatal supplementation of Lipid based nutritional supplement for pregnant and lactating women LNS-PLW can improve birth weight, gestational age, length and head circumference of babies of underweight preeclamptic women., Competing Interests: Conflicts of interest: None., (Copyright: © Pakistan Journal of Medical Sciences.)

In breast cancer, there has been evidence of atypical activation of signal transduction and activators of transcription 3 (STAT3). Thymoquinone (TQ) exerts its anti-neoplastic effect through diverse mechanisms, including STAT3 inhibition. The tumor suppressor, microRNA-125a-5p was reported to be downregulated in various breast cancer cells. Therefore, we investigated the influence of TQ and/or doxorubicin on microRNA-125a-5p and its correlation with STAT3 activation as well as tumor growth in mice bearing solid Ehrlich tumors. We found that TQ markedly suppressed inducible and constitutive phosphorylation of STAT3 in tumor tissue without affecting STAT5. Moreover, it attenuated tumor growth, downregulated STAT3 downstream target proteins, and increased the apoptotic activities of caspase-3 and -9. Interestingly, TQ-elicited synergism of doxorubicin anti-neoplastic activity was coupled with upregulation of tumoral microRNA-125a-5p. Taken together, the current findings raise the potential of TQ as a promising chemomodulatory adjuvant to augment mammary carcinoma sensitivity to doxorubicin., (© 2021 Wiley Periodicals LLC.)

Background: In patients with Acute Myeloid Leukemia (AML) the most frequent acquired molecular abnormalities and important prognostic indicators is nucleophosmin-1 (NPM1) mutations. Our study aims was molecular study of Nucleophosmin -1 gene in Acute Myeloid Leukemia in Kurdish population., Patients &methods: A total of 50 patients with AML, (36) of them attended Nanakaly Hospital and (14) attended Hiwa Hospital and 30 healthy subjects as control were selected randomly, all were matched of age and gender. Polymerase chain reaction (PCR) was used for detection of NPM1 gene mutation. Three samples of PCR product for NPM1 gene mutations were sequenced, and mutations were determined by comparison with the normal NPM1 sequence NCBI (GenBank accession number NM_002520)., Results: Out of 50 patients with AML, 5 (10%) of them were NPM1 gene mutation positive, and 45 (90%) were negative. The mutation were a base substitution (C to A), (G to C), (G to T), transversion mutation in addition of frame shift mutation and all mutated cases were heterozygous and retained a wild type allele., Conclusion: Identification of NPM1 mutations in AML are important for prognostication, treatment decision and optimization of patient care., (© 2021 Othman GO et al.)

Aims: Although chloroquine and diclofenac are not cardiovascular drugs, their chronic administration may trigger cardiotoxicity. We, therefore, evaluated the cardiotoxic impact of diclofenac in chloroquine-treated adjuvant arthritic rats and the protective role of Rho-kinase inhibitors., Methods: 90 male rats were equally distributed into 9 groups including control. Arthritis was induced by S.C injection of Complete Freund's adjuvant in hind paw plantar surface. Arthritic rats were subdivided into 8 groups, orally treated with: no drug, chloroquine (50 mg/kg), diclofenac sodium (1 mg/kg) and chloroquine + diclofenac. To study the role of Rho-kinase in chloroquine/diclofenac-triggered cardiotoxicity, four arthritic groups were also co-treated with Rho-kinase inhibitors (fasudil or atorvastatin) along with diclofenac and chloroquine + diclofenac., Key Findings: All treatments significantly elevated serum cardiac injury and dysfunction markers as well as left ventricular malondialdehyde but depleted antioxidants with the greatest effect in the combination group. Chloroquine and/or diclofenac; in particular, their combination shifted the balance between left ventricular pro- and anti-apoptotic proteins towards myocardial apoptosis. Surprisingly, treatment with diclofenac or chloroquine/diclofenac markedly up-regulated cardiac RhoA and Rho-kinase1. Such up-regulation was coupled with a greater increase in cardiac oxidative damage biomarkers in the combination group than in individually-treated ones. However, Rho-kinase inhibition protected against diclofenac-induced increase in myocardial oxidative damage markers., Significance: Diclofenac greatly amplified cardiac oxidative damage in chloroquine-treated arthritic rats via up-regulation of Rho-kinase1. However, Rho-kinase inhibitors provided cardioprotection against diclofenac toxicity. Overall, they could be used as safer adjuvants to diclofenac during the treatment of rheumatoid arthritis with chloroquine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. There was no fund or grant received to conduct this research., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Oxygen is transported in the blood through red blood cells and a protein called hemoglobin. The protein consists of two alpha and two beta chains. The lack of any of these chains is caused by the malfunction of the genes that produce them, and can lead to a genetic disease called thalassemia. In β-thalassemia, hemoglobin does not produce enough beta protein. According to mild to severe effects on the body, β-thalassemia is divided into three types minor, interstitial and major thalassemia. There are increasing risks for thrombosis complications in thalassemia major. The purpose of this study was to evaluate protein C and protein S levels in β-thalassemia major and their association to the hypercoagulable state. Seventy patients with β-thalassemia major and 35 apparently healthy subjects as a control group were investigated for protein C and protein S. The mean of protein C (71.31%) and protein S (34.3%) levels were significantly reduced in β- thalassemia major patients in comparison with control subjects (p-value <0.001). Mean of fibrinogen level (2.42) g/l was significantly decreased in β-thalassemia major patients while the mean of D dimer level (0.43) μg/ml was significantly increased in comparison to control subjects (p-value 0.001). This study demonstrates a chronic hypercoagulable state in B- thalassemia major patients.

Introduction: Patients with acute-on-chronic liver failure (ACLF) have low survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) improves survival in ACLF and erythropoietin (EPO) promotes hepatic regeneration in animal studies. The aim of this study is to determine whether coadministration of G-CSF and EPO improves the outcome in ACLF., Methods: The study was conducted in the Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka. Consecutive patients with ACLF were randomly assigned into group A and group B. Group A patients received subcutaneous G-CSF (5 mcg/kg/d) for 6 days and subcutaneous EPO (40 mcg/wk) for 4 weeks and group B patients received only standard medical care (control group). All patients were followed up for 3 months. The primary end point was to see survival at 3 months., Results: Patients had comparable baseline characteristics; hepatitis B virus infection was the commonest etiology of ACLF as both acute and chronic events. A higher proportion of patients were male in both groups. The survival was higher in group A than in group B at the end of 3 months (36.4% vs 29.4%; p = 0.457), but this was not statistically significant. Regarding complications, hepatorenal syndrome was higher in group B than in group A (36.7% vs 41.7%). In both the groups, Child-Turcotte-Pugh score and model for end-stage liver disease scores were similar before treatment and improved during follow-up., Conclusion: This is one of the early human studies that demonstrate potential hepatic regeneration using EPO in ACLF patients. Further study with a larger cohort will be needed to reproduce the results of the present work., How to Cite This Article: Haque Md N, Al-Mahtab M, Das DC, et al . Effect of Granulocyte Colony-stimulating Factor and Erythropoietin on Patients with Acute-on-chronic Liver Failure. Euroasian J Hepato-Gastroenterol 2020;10(2):64-67., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2020; Jaypee Brothers Medical Publishers (P) Ltd.)

Our recent findings have demonstrated that rodent models of closed head traumatic brain injury exhibit comprehensive evidence of progressive and enduring orofacial allodynias, a hypersensitive pain response induced by non-painful stimulation. These allodynias, tested using thermal hyperalgesia, correlated with changes in several known pain signaling receptors and molecules along the trigeminal pain pathway, especially in the trigeminal nucleus caudalis. This study focused to extend our previous work to investigate the changes in monoamine neurotransmitter immunoreactivity changes in spinal trigeminal nucleus oralis, pars interpolaris and nucleus tractus solitaries following mild to moderate closed head traumatic brain injury, which are related to tactile allodynia, touch-pressure sensitivity, and visceral pain. Our results exhibited significant alterations in the excitatory monoamine, serotonin, in spinal trigeminal nucleus oralis and pars interpolaris which usually modulate tactile and mechanical sensitivity in addition to the thermal sensitivity. Moreover, we also detected a robust alteration in the expression of serotonin, and inhibitory molecule norepinephrine in the nucleus tractus solitaries, which might indicate the possibility of an alteration in visceral pain, and existence of other morbidities related to solitary nucleus dysfunction in this rodent model of mild to moderate closed head traumatic brain injury. Collectively, widespread changes in monoamine neurotransmitter may be related to orofacial allodynhias and headache after traumatic brain injury., Competing Interests: Conflicts of interest: There is no financial, personal, or other form of conflict of interest among all the authors or the organizations they are affiliated with.

Background: The prevalence of diabetes Mellitus in Saudi Arabia is 24%, ranking it among the top ten Worldwide. Diabetes education focuses on self-management and relies on numeracy skills. Poor numeracy may go unrecognized and it is important to have an assessment tool in Arabic to measure such a skill in diabetes care., Objectives: To validate a 15-item Diabetes Numeracy Test (DNT-15) in the Arabic Language as a tool to assess the numeracy skills of patients with diabetes and to test its properties among Saudi patients with diabetes., Methods: A 15-question Arabic-language test to assess diabetes numeracy among patients with diabetes on the basis of the diabetes numeracy test (DNT-15) was validated among a sample Arabic speaking Saudi patients with diabetes. Data collection included patients' demographics, long-term glycemic control, diabetes type, duration, co-morbidities, and diabetes related knowledge questions. Internal reliability was assessed using Kuder-Richardson Formula 20 (KR-20)., Results: The average score of Arabic DNT-15 was 53.3% and took an average of 30 minutes to complete. The scores significantly correlated with education, income, HbA1c, and diabetes knowledge (p<0.05). Content Validity Ratio (CVR) of 0.75 and Content Validity Index (CVI) of 0.89 supported good content validity. The Arabic DNT-15 also had good internal reliability (KR20 = 0.90)., Conclusion: Patients with diabetes need numeracy skills to manage their disease. Level of education does not reflect level of numeracy, and low numeracy skills might be unnoticed by health care providers. The Arabic DNT-15 is a valid and reliable scale to identify Arabic speaking patients with difficulties in certain diabetes-related numeracy skills.

Introduction: Although surgery is the preferred treatment for grade III&IV pancreatic trauma, there is a growing movement for non-operative management. in blunt pancreatic trauma. Very few studies compare operative versus non-operative management in adult patients., Methods: Retrospective analysis of a prospectively maintained database was performed from 2004 to 2013 in the department of gastrointestinal surgery, NIMS, Hyderabad. Comparative analysis was performed between patients who failed versus those who were successfully managed with non-operative management., Results: 34 patients had grade III/IV trauma out of which 8 were operated early with the remaining 26 initially under a NOM strategy, 10 of them could be successfully managed without any operation. Post-traumatic pancreatitis, Necrotizing pancreatitis, Ileus, contusion on CT, surrounding organ injuries are independently associated with failure of NOM on a univariate analysis. On multivariate logistic regression presence of necrosis& associated organ injury are factors that predict failure of NOM independently. Development of a pseudocyst is the only significant factor that is associated with a success of NOM., Conclusions: Non-operative measures should be attempted in a select group of grade III&IV blunt pancreatic trauma. In hemodynamically stable patients with a controlled leak walled off as a pseudocyst without associated organ injuries and pancreatic necrosis, NOM has a higher success rate.

Aluminum (Al) is an environmental xenobiotic that stimulates free radical generation and hence reproductive toxicity. Coenzyme Q10 (CoQ10) effectively counteracts free radical-induced tissue damage. Omega-3 polyunsaturated fatty acids present in fish oil (FO) exert beneficial effects on reproduction in male animals. This study therefore investigated the effects of both agents on testicular dysfunction induced by aluminum chloride (AlCl3). Fifty male rats were gavaged with either 1% gum acacia (control group) or AlCl3 (34 mg/kg/day) for ten weeks. Concurrently, AlCl3-treated rats received no treatment, CoQ10 (10 mg/kg/day, p.o.), and/or FO (400 mg/kg/day, p.o.) for ten weeks. AlCl3 caused a significant decrease in serum testosterone, luteinizing hormone (LH), and follicular stimulating hormone (FSH), as well as testicular weight, antioxidant enzyme gene expression and activities, reduced glutathione, zinc, adenosine 3',5'-cyclic monophosphate (cAMP) contents, and number of Leydig cells, along with down-regulation of 3beta-hydroxysteroid dehydrogenase (3β-HSD), 17β-HSD, steroidogenic acute regulatory protein (STAR), and cholesterol side-chain cleavage enzyme (P450scc) gene expression. However, testicular Al, malondialdehyde (MDA), and nitric oxide (NO) levels were markedly increased. Treatment with CoQ10 and FO, alone or in combined form led to an improvement in the aforementioned biomarkers. Overall, individual or combined treatment with CoQ10 and FO could ameliorate the toxic effects of AlCl3 on testicular tissues by mechanisms related to their potent antioxidant potential and stimulatory effects on steroidogenic enzymes transcription. CoQ10 seems to be better than FO regarding oxidative and nitrosative stress, Zn deficiency, and Al overload. However, FO showed more pronounced effect than CoQ10 on hormones, steroidogenic markers, and cAMP. A cocktail of both demonstrated greater protective effects on testicular tissues than monotherapy.

Cadmium is a potential environmental and industrial pollutant affecting human tissues and organs including liver and testes. The protective role of fenugreek seed powder (FSP) was investigated in male rats subjected to cadmium-induced testicular injury and hepatic dysfunction. Testicular damage and hepatotoxicity were induced by oral administration of cadmium chloride (5 mg/kg body weight, once a day) for 7 weeks. FSP was given at 5% w/w in chow diet for 8 weeks, starting 1 week before cadmium administration. FSP intake significantly increased serum testosterone level and testis weight that were reduced by cadmium. FSP also compensated deficits in hepatic and testicular antioxidant defense system, interleukin-4 and nitric oxide levels, reduced serum liver function enzyme activities and suppressed lipid peroxidation in hepatic and testicular tissues resulted from cadmium administration. Additionally, FSP attenuated the cadmium-induced elevations in hepatic and testicular tumor necrosis factor-α and transforming growth factor-beta1 levels as well as cadmium deposition and hydroxyproline content. The protective effect afforded by FSP was mainly due its antioxidant, antifibrotic and anti-inflammatory effects. In conclusion, the results of the present work indicated that FSP may represent a promising medicinal herb to protect hepatic and testicular tissues from the detrimental effects of cadmium., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

The possible effectiveness of resveratrol, a polyphenol present in different plants comprising berries, grapes and peanuts, on the prevention of doxorubicin-induced cardiac toxicity and fibrosis was investigated. Forty adult male Wistar albino rats were divided into four groups. Group I received normal saline, group II gavaged with resveratrol (20 mg/kg, daily for 4 weeks), group III received doxorubicin (2.5 mg/kg i.p. in six injections for 2 weeks; accumulative dose of 15 mg/kg), and group IV received doxorubicin + resveratrol (starting resveratrol intake 2 weeks before doxorubicin administration). Resveratrol significantly alleviated the increase in left ventricular lipid peroxidation, hydroxyproline, and tumor necrosis factor alpha levels as well as serum creatine kinase-myocardial band (CK-MB) activity and prevented the decrease in body and heart weights in doxorubicin-treated group. However, a marked protection against reduced glutathione content depletion and superoxide dismutase activity reduction was observed in the left ventricles of rats pretreated with resveratrol in combination with doxorubicin. Resveratrol also ameliorated the up-regulation of left ventricular caspase-3 and transforming growth factor-beta1 gene expression as well as left ventricular histopathological changes including necrosis and fibrosis induced by doxorubicin. Collectively, our results suggest that resveratrol provides a significant protection against doxorubicin-induced cardiotoxicity and fibrosis in rats. Therefore, it may be used as a promising cardioprotective agent in patients treated with doxorubicin due to malignant diseases. So, further clinical trials are required to confirm these findings.

The authors investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating oxidative stress in sporadic breast cancer. PCR-restriction fragment length polymorphism (RFLP) and PCR-amplified fragment length polymorphism (AFLP) methods were used for genetic analysis in 222 sporadic breast cancer cases and 235 controls. Standardized food frequency questionnaire was used for dietary micronutrient assessment. 8-oxo-2'-deoxyguanosine (8-oxodG), folate, and estradiol were estimated using commercial ELISA kits. Reverse-phase HPLC coupled with fluorescence detector was used for plasma homocysteine analysis. Total glutathione was estimated using Ellman's method. Reduced folate carrier 1 (RFC1) G80A and methylenetetrahydrofolate reductase (MTHFR) C677T were associated with risks of 1.34 (95% CI 1.01-1.79)- and 1.84 (95% CI 1.14-3.00)-folds, respectively, for sporadic breast cancer while cytosolic serine hydroxymethyl transferase (cSHMT) C1420T was associated with reduced risk (OR 0.71, 95% CI 0.53-0.94). Significant increase in plasma 8-oxo-2'-deoxyguanosine (P < 0.004) and homocysteine (P < 0.0001); and significant decrease in total glutathione (P < 0.01) and dietary folate (P = 0.006) was observed in cases than in controls. Oxidative DNA damage showed direct association with menopause (P = 0.02), RFC1 G80A (P < 0.05) and homocysteine (P < 0.0001); and inverse association with dietary folate (P < 0.0001), plasma folate (P < 0.0001), cSHMT C1420T (P < 0.05) and glutathione (P < 0.001). To conclude, the aberrations in one-carbon metabolism induce oxidative stress in sporadic breast cancer either by affecting the folate pool or by impairing remethylation.

Objective: To investigate whether genetic polymorphisms are the underlying causes for aberrations in folate pathway that was reported in autistic children., Basic Methods: A total of 138 children diagnosed as autistic based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria and Autism Behavior Checklist scoring and 138 age and sex matched children who are nonautistic were tested for five genetic polymorphisms, that is, cytosolic serine hydroxyl methyl transferase (SHMT1 C1420T), methylene tetrahydrofolate reductase (MTHFR C677T and MTHFR A1298C), methionine synthase reductase (MTRR A66G), methionine synthase (MS A2756G) using PCR-restriction fragment length polymorphism methods. Fisher's exact test and logistic regression analysis were used for statistical analyses., Results: MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (16.3 vs. 6.5%) with 2.79-fold increased risk for autism [95% confidence interval (CI): 1.58-4.93]. The frequencies of MTRR 66A allele (12.7 vs. 21.0%) and SHMT 1420T allele (27.9 vs. 45.3%) were lower in autistic group compared with nonautistic group with odds ratios 0.55 (95% CI: 0.35-0.86) and 0.44 (95% CI: 0.31-0.62), respectively, indicating reduced risk. MTHFR 1298C-allele frequency was similar in both the groups (53.3 vs. 53.6%) and hence individually not associated with any risk. However, this allele was found to act additively in the presence of MTHFR 677T allele as evidenced by 8.11-fold (95% CI: 2.84-22.92) risk associated with MTHFR 677CT+TT/1298AC+CC genotypes cumulatively., Conclusion: MTHFR C677T is a risk factor, whereas MTRR A66G and SHMT C1420T polymorphisms reduce risk for autism. MTHFR A1298C acts additively in increasing the risk for autism.