Application of molecular dynamic simulations in modeling the excited state behavior of confined molecules.

Relative to isotropic organic solvent medium, the structure and conformation of a reactant molecule in an organized and confining medium are often different. In addition, because of the rigidity of the immediate environment, the reacting molecule have a little freedom to undergo large changes even upon gaining energy or modifications in the electronic structure. These alterations give rise to differences in the photochemistry of a molecular and supramolecular species. In this study, one such example is presented. α-Alkyl dibenzylketones upon excitation in isotropic solvents give products via Norrish type I and type II reactions that are independent of the chain length of the alkyl substituent. On the other hand, when these molecules are enclosed within an organic capsule of volume ~ 550 Å3, they give products that are strikingly dependent on the length of the α-alkyl substitution. These previously reported experimental observations are rationalized based on the structures generated by molecular modeling (docking and molecular dynamics (MD) simulations). It is shown that MD simulations that are utilized extensively in biologically important macromolecules can also be useful to understand the excited state behavior of reactive molecules that are part of supramolecular assemblies. These simulations can provide structural information of the reactant molecule and the surroundings complementing that with the one obtained from 1 and 2D NMR experiments. MD simulated structures of seven α-alkyl dibenzylketones encapsulated within the octa acid capsule provide a clear understanding of their unique behavior in this restricted medium. Because of the rigidity of the medium, these structures although generated in the ground state can rationalize the photochemical behavior of the molecules in the excited state.

Prevalence of exposure to needle stick and sharp-related injury and status of hepatitis B vaccination among healthcare workers: A cross-sectional study.

Background and Aims: Hepatitis B is a leading cause of chronic liver disease and subsequent liver transplantation. This is a vaccine-preventable illness. Health workers continue to be at risk for blood-borne pathogens due to occupational exposures. The overall goals of our study were to determine the prevalence of exposure to needle sticks and sharp-related injuries (NSSI) and hepatitis B vaccination status among healthcare workers (HCWs) of Nepalgunj Medical College Teaching Hospital (NGMCTH), Kohalpur, Banke, Nepal. Methods: A descriptive cross-sectional study was conducted among HCWs at the NGMCTH following ethics approval by the NGMCTH Ethics Review Committee. A pretested structured questionnaire was used to compile the data. Data was collected from September 15, 2021 to September 14, 2022. Collected data entered in Microsoft Excel and analyzed using statistical package for social sciences version 22. Analyzed data were presented using simple descriptive statistics with appropriate figures and tables. Results: A total of 304 among 506 HCWs (60.1%) participated in the survey were exposed to Needle sticks. Nine of whom (3.7%) were injured substantially (more than 10 times). Among nursing students, 21.3% had experience with NSSI. 71.7% of HCWs had received at least one dose of the hepatitis B vaccine, of whom 61.9% (44.5% of total HCWs) had received three doses. Conclusions: This study demonstrated that more than two-quarters of HCWs were exposed to NSSI. Despite being at risk, vaccination status was still low, and less than half only received three complete doses. Precaution should be taken when working with instrumentation and procedures. Hepatitis B immunization programs for HCWs should be delivered at no cost with 100% coverage and protection. Raising awareness about hepatitis B infection and immunization remains crucial to primary prevention.

Augmentation of NAD+ by Dunnione Ameliorates Imiquimod-Induced Psoriasis-Like Dermatitis in Mice.

Background: Dunnione has anti-inflammatory properties arising from its ability to alter the ratio of NAD+/NADH through NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action, followed by subsequent inhibition of NF-κB and inflammatory cytokines. Psoriasis is a chronic, inflammatory skin disorder in which the IL-23/Th17 axis plays an important role in inflammation. However, it is unclear whether modulation of NAD+ levels affects psoriasis, such as skin inflammation. Therefore, in this study, we investigated the effect of NAD+/NADH ratio modulation on imiquimod (IMQ)-induced, psoriasis-like skin inflammation in mice. Methods: Psoriasis-like skin inflammation was generated by daily topical application of IMQ cream. The severity of dermatitis was assessed using the Psoriasis Area Severity Index (PASI) and histochemistry. Expression of inflammatory cytokines was detected by enzyme-linked immunosorbent assay and quantitative PCR. Acetylation of NF-κB p65 and STAT3 was determined by Western blotting. Results: Dunnione improved IMQ-induced epidermal hyperplasia and inflammation, consistent with decreased levels of inflammatory cytokines (IL-17, IL-22, and IL-23) in skin lesions. Moreover, we found that an increase in the NAD+/NADH ratio by dunnione restored SIRT1 activity, thereby reduced imiquimod-induced STAT3 acetylation, which modulates the expression of psoriasis-promoting inflammatory cytokines, such as IL-17, IL-22, and IL-23. Conclusion: Pharmacological modulation of cellular NAD+ levels could be a promising therapeutic approach for psoriasis-like skin disease.

Interplay between Solid Tumors and Tumor Microenvironment.

Over the past few decades, basic studies aimed at curing patients with cancer have been constantly evolving. A myriad of mechanistic studies on physiological changes and related factors in tumor growth and metastasis have been reported. Recently, several studies have been considerate to how tumors adapt to unfavorable environments, such as glucose deprivation, oxidative stress, hypoxic conditions, and immune responses. Tumors attempt to adapt to unfavorable environments with genetic or non-genetic changes, the alteration of metabolic signals, or the reconfiguration of their environment through migration to other organs. One of the distinct features in solid tumors is heterogeneity because their environments vary due to the characteristics of colony growth. For this reason, researchers are paying attention to the communication between growing tumors and neighboring environments, including stromal cells, immune cells, fibroblasts, and secreted molecules, such as proteins and RNAs. During cancer survival and progression, tumor cells undergo phenotype and molecular changes collectively referred to as cellular plasticity, which result from microenvironment signals, genetics and epigenetic alterations thereby contributing to tumor heterogeneity and therapy response. In this review, we herein discuss the adaptation process of tumors to adverse environments via communication with neighboring cells for overcoming unfavorable growth conditions. Understanding the physiology of these tumors and their communication with the tumor environment can help to develop promising tumor treatment strategies.

Modulation of Cellular NAD+ Attenuates Cancer-Associated Hypercoagulability and Thrombosis via the Inhibition of Tissue Factor and Formation of Neutrophil Extracellular Traps.

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD+) levels by accelerating the oxidation of NADH to NAD+, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD+ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD+ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD+ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis.

Augmentation of cellular NAD+ by NQO1 enzymatic action improves age-related hearing impairment.

Age-related hearing loss (ARHL) is a major neurodegenerative disorder and the leading cause of communication deficit in the elderly population, which remains largely untreated. The development of ARHL is a multifactorial event that includes both intrinsic and extrinsic factors. Recent studies suggest that NAD+ /NADH ratio may play a critical role in cellular senescence by regulating sirtuins, PARP-1, and PGC-1α. Nonetheless, the beneficial effect of direct modulation of cellular NAD+ levels on aging and age-related diseases has not been studied, and the underlying mechanisms remain obscure. Herein, we investigated the effect of ß-lapachone (ß-lap), a known plant-derived metabolite that modulates cellular NAD+ by conversion of NADH to NAD+ via the enzymatic action of NADH: quinone oxidoreductase 1 (NQO1) on ARHL in C57BL/6 mice. We elucidated that the reduction of cellular NAD+ during the aging process was an important contributor for ARHL; it facilitated oxidative stress and pro-inflammatory responses in the cochlear tissue through regulating sirtuins that alter various signaling pathways, such as NF-κB, p53, and IDH2. However, augmentation of NAD+ by ß-lap effectively prevented ARHL and accompanying deleterious effects through reducing inflammation and oxidative stress, sustaining mitochondrial function, and promoting mitochondrial biogenesis in rodents. These results suggest that direct regulation of cellular NAD+ levels by pharmacological agents may be a tangible therapeutic option for treating various age-related diseases, including ARHL.

Pharmacological stimulation of NQO1 decreases NADPH levels and ameliorates acute pancreatitis in mice.

Reactive oxygen species (ROS) regulates the activation of inflammatory cascades and tissue damage in acute pancreatitis. NADPH oxidase (NOX) is upregulated in pancreatitis and is one of the major enzymes involved in ROS production using NADPH as a general rate-limiting substrate. Dunnione, a well-known substrate of NAD(P)H:quinone oxidoreductase 1 (NQO1), reduces the ratio of cellular NADPH/NADP+ through the enzymatic action of NQO1. This study assessed whether a reduction in cellular NADPH/NADP+ ratio can be used to regulate caerulein-induced pancreatic damage associated with NOX-induced ROS production in animal models. Dunnione treatment significantly reduced the cellular NADPH/NADP+ ratio and NOX activity through the enzymatic action of NQO1 in the pancreas of the caerulein-injection group. Similar to these results, total ROS production and expressions of mRNA and protein for NOX subunits Nox1, p27phox, p47phox, and p67phox also decreased in the dunnione-treated group. In addition, caerulein-induced pancreatic inflammation and acinar cell injury were significantly reduced by dunnione treatment. This study is the first to demonstrate that modulation of the cellular NADPH:NADP+ ratio by enzymatic action of NQO1 protects acute pancreatitis through the regulation of NOX activity. Furthermore, these results suggest that modulation of the NADPH:NADP+ ratio in cells by NQO1 may be a novel therapeutic strategy for acute pancreatitis.

Augmentation of NAD+ levels by enzymatic action of NAD(P)H quinone oxidoreductase 1 attenuates adriamycin-induced cardiac dysfunction in mice.

BACKGROUND: Adriamycin (ADR) is a powerful chemotherapeutic agent extensively used to treat various human neoplasms. However, its clinical utility is hampered due to severe adverse side effects i.e. cardiotoxicity and heart failure. ADR-induced cardiomyopathy (AIC) has been reported to be caused by myocardial damage and dysfunction through oxidative stress, DNA damage, and inflammatory responses. Nonetheless, the remedies for AIC are even not established. Therefore, we illustrate the role of NAD+/NADH modulation by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action on AIC. METHODS AND RESULTS: AIC was established by intraperitoneal injection of ADR in C57BL/6 wild-type (WT) and NQO1 knockout (NQO1-/-) mice. All Mice were orally administered dunnione (named NQO1 substrate) before and after exposure to ADR. Cardiac biomarker levels in the plasma, cardiac dysfunction, oxidative biomarkers, and mRNA and protein levels of pro-inflammatory mediators were determined compared the cardiac toxicity of each experimental group. All biomarkers of Cardiac damage and oxidative stress, and mRNA levels of pro-inflammatory cytokines including cardiac dysfunction were increased in ADR-treated both WT and NQO1-/- mice. However, this increase was significantly reduced by dunnione in WT, but not in NQO1-/- mice. In addition, a decrease in SIRT1 activity due to a reduction in the NAD+/NADH ratio by PARP-1 hyperactivation was associated with AIC through increased nuclear factor (NF)-κB p65 and p53 acetylation in both WT and NQO1-/- mice. While an elevation in NAD+/NADH ratio via NQO1 enzymatic action using dunnione recovered SIRT1 activity and subsequently deacetylated NF-κB p65 and p53, however not in NQO1-/- mice, thereby attenuating AIC. CONCLUSION: Thus, modulation of NAD+/NADH by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated heart failure, including AIC.

NAD+ augmentation ameliorates acute pancreatitis through regulation of inflammasome signalling.

Acute pancreatitis (AP) is a complicated disease without specific drug therapy. The cofactor nicotinamide adenine dinucleotide (NAD+) is an important regulator of cellular metabolism and homeostasis. However, it remains unclear whether modulation of NAD+ levels has an impact on caerulein-induced AP. Therefore, in this study, we investigated the effect of increased cellular NAD+ levels on caerulein-induced AP. We demonstrated for the first time that the activities and expression of SIRT1 were suppressed by reduction of intracellular NAD+ levels and the p53-microRNA-34a pathway in caerulein-induced AP. Moreover, we confirmed that the increase of cellular NAD+ by NQO1 enzymatic action using the substrate ß-Lapachone suppressed caerulein-induced AP with down-regulating TLR4-mediated inflammasome signalling, and thereby reducing the inflammatory responses and pancreatic cell death. These results suggest that pharmacological stimulation of NQO1 could be a promising therapeutic strategy to protect against pathological tissue damage in AP.

Association of serum magnesium level with poor glycemic control and renal functions in Nepalese patients with type 2 diabetes mellitus.

BACKGROUND: Hypomagnesaemia has been shown to be associated with type 2 diabetes mellitus (T2DM) and its complications. The present study investigated the association of hypomagnesaemia with T2DM and its complications in patients hailed mostly from the western hilly region of Nepal. METHODS: This study was conducted among 150 type 2 diabetic patients and 150 of non-diabetic controls between May to September 2016. Relevant demographic, anthropometric, physiological and biochemical variables were measured using standard protocols. Statistical analyses were performed by SPSS version 17.0. RESULTS: Hypomagnesaemia (1.7±0.2mg/dl) was present in 50% of diabetic patients and none in the healthy controls (2.0±0.2mg/dl). It was inversely correlated with levels of glycated hemoglobin (HbA1c) (r=-0.299), total cholesterol (r=-0.219), low density lipoprotein-cholesterol (r=-0.168) and creatinine (r=-0.215) and directly correlated with serum creatinine based glomerular filtration rate (eGFRcr) (r=0.196). Subjects with hypomagnesaemia were significantly older (57.4±11.5years) and had higher levels of HbA1c (8.4±1.2%) and serum total cholesterol (248.3±72.0mg/dl). The methods of diabetes control did not have a significant influence on serum magnesium level. Patient's age (OR: 1.05 (95% CI-1.01-1.09)), poor glycemic control (OR: 6.78 (95% CI-2.56-17.95)) and low eGFRcr (OR: 4.89 (95% CI-1.78-13.40)) were the significant predictors of hypomagnesaemia. CONCLUSION: Half of type 2 diabetic population under study had hypomagnesaemia without regard to the method of diabetes control. Old age, poor glycemic control, and low eGFRcr were the significant predictors of low serum magnesium in these patients. Besides their regular anti-diabetic treatment, clinicians should also consider dietary supplementation of magnesium to prevent further complications of diabetes in these patients.

Prevalence and pattern of dyslipidemia in Nepalese individuals with type 2 diabetes.

BACKGROUND: Atherogenic dyslipidemia is an important modifiable risk factor for cardiovascular disease among patients of type 2 diabetes mellitus. Timely detection and characterization of this condition help clinicians estimate future risk of cardiovascular disease and take appropriate preventive measures. The aim of this study was to determine the prevalence, pattern and predictors of dyslipidemia in a cohort of Nepalese patients with type 2 diabetes. RESULTS: We found mixed dyslipidemia as the most prevalent (88.1%) and isolated dyslipidemia (10.1%) as the least prevalent forms of dyslipidemia in our patients. The most prevalent form of single dyslipidemia was high LDL-C (73.8%) and combined dyslipidemia was high TG, high LDL-C and low HDL-C (44.7%). Prevalence of all single and mixed dyslipidemia was higher in patients with poor glycemic control and hypertension. The glycemic status of patients correlated with their fasting serum lipid profile. Dyslipidemia was associated mainly with male gender, poor glycemic control and hypertension. CONCLUSIONS: Atherogenic dyslipidemia is associated mainly with male gender, poor glycemic control and hypertension. It is highly prevalent in Nepalese patients with type 2 diabetes. Urgent lifestyle modification, sustained glycemic control and aggressive lipid lowering treatment plans are necessary to minimize the future risk of cardiovascular disease in this population.

Prevalence of Hepatitis D Among Patients with Hepatitis B Viral Infection Attending a Tertiary Care Centre of Nepal.

INTRODUCTION: Worldwide there is variation in prevalence of Hepatitis D viral infection. Superinfection and co infection with hepatitis B viral infection is known to occur in 15-20 million people. METHODS: This was a descriptive cross-sectional hospital based study carried out in NAMS, Bir hospital, Kathmandu, Nepal from period of January 2017 to June 2017. Consecutive patients of chronic hepatitis B viral infection of HBsAg positive with more than two-time upper normal limit of ALT were enrolled and tested for HDV IgG. RESULTS: Forty patients were enrolled during study period. Mean age was 30.9±12.2 years. Males were 28 (70%) and females 12 (30%). Most of the patients were asymptomatic for HBV infection 32 (80%). HBeAg negative chronic hepatitis was most commonly present in 31 (77.5%). Family history of Hepatitis B viral infection was seen in 7 (17.5%) and sexual promiscuity in 5 (12.5%) as the mode of acquisition of hepatitis B viral infection. HBcIgM was positive in three patients with mean HBV DNA of 4.97x10(5)±4.5x10(5) IU/ml in HBeAg positive group. HDV IgG was negative in all patients. CONCLUSIONS: Coinfection and superinfection of hepatitis D virus were found to be uncommon at Bir hospital, Nepal.

Significance of Non-Invasive Markers as Predictor of Esophageal Varices in Liver Cirrhosis.

INTRODUCTION: Upper gastro-intestinal endoscopy remains the gold standard for screening for esophageal varices but it has its own limitations. It is an invasive, expensive and uncomfortable procedure and needs clinical expertise. Accordingly, this study was conducted to establish the role of non-invasive markers for prediction of esophageal varices in liver cirrhosis. METHODS: A hospital based descriptive cross-sectional study was carried out in Liver unit of National Academy of Medical Sciences, Bir Hospital, from October 2016 to September 2017. Complete blood count, liver function test, liver ultrasound and upper gastro-intestinal endoscopy were done for all patients to detect esophageal varices and to correlate with different non-invasive markers. RESULTS: Total 191 patients of liver cirrhosis were studied after exclusion. Platelet count of 92082.00±43435.83/mm3 and spleen size of 144.21±10.71 mm was found to be good predictors of presence of EV (P≤0.001). Significant association between Child-Turcotte-Pugh class and presence of varices was observed (P≤0.001). AST/ALT ratio with cutoff value of 1.415 showed sensitivity of 82.4% and specificity of 36.4%. APRI at a cutoff value of 1.3 showed a sensitivity of 83.2% and specificity of 50%. CONCLUSIONS: Platelet count, spleen size and Child-Turcotte-Pugh class are good predictors of presence of esophageal varices in patients with liver cirrhosis. AST/ALT ratio and APRI score are not good substitutes for upper gastro-intestinal endoscopy.

Dunnione ameliorates cisplatin ototoxicity through modulation of NAD(+) metabolism.

Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

Dunnione ameliorates cisplatin-induced small intestinal damage by modulating NAD(+) metabolism.

Although cisplatin is a widely used anticancer drug for the treatment of a variety of tumors, its use is critically limited because of adverse effects such as ototoxicity, nephrotoxicity, neuropathy, and gastrointestinal damage. Cisplatin treatment increases oxidative stress biomarkers in the small intestine, which may induce apoptosis of epithelial cells and thereby elicit damage to the small intestine. Nicotinamide adenine dinucleotide (NAD(+)) is a cofactor for various enzymes associated with cellular homeostasis. In the present study, we demonstrated that the hyper-activation of poly(ADP-ribose) polymerase-1 (PARP-1) is closely associated with the depletion of NAD(+) in the small intestine after cisplatin treatment, which results in downregulation of sirtuin1 (SIRT1) activity. Furthermore, a decrease in SIRT1 activity was found to play an important role in cisplatin-mediated small intestinal damage through nuclear factor (NF)-κB p65 activation, facilitated by its acetylation increase. However, use of dunnione as a strong substrate for the NADH:quinone oxidoreductase 1 (NQO1) enzyme led to an increase in intracellular NAD(+) levels and prevented the cisplatin-induced small intestinal damage correlating with the modulation of PARP-1, SIRT1, and NF-κB. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological NQO1 substrates could be a promising therapeutic approach for protecting against cisplatin-induced small intestinal damage.

Estimation of 10-Year Risk of Coronary Heart Disease in Nepalese Patients with Type 2 Diabetes: Framingham Versus United Kingdom Prospective Diabetes Study.

BACKGROUND: Predicting future coronary heart disease (CHD) risk with the help of a validated risk prediction function helps clinicians identify diabetic patients at high risk and provide them with appropriate preventive medicine. AIM: The aim of this study is to estimate and compare 10-year CHD risks of Nepalese diabetic patients using two most common risk prediction functions: The Framingham risk equation and United Kingdom Prospective Diabetes Study (UKPDS) risk engine that are yet to be validated for Nepalese population. PATIENTS AND METHODS: We conducted a hospital-based, cross-sectional study on 524 patients with type 2 diabetes. Baseline and biochemical variables of individual patients were recorded and CHD risks were estimated by the Framingham and UKPDS risk prediction functions. Estimated risks were categorized as low, medium, and high. The estimated CHD risks were compared using kappa statistics, Pearson's bivariate correlation, Bland-Altman plots, and multiple regression analysis. RESULTS: The mean 10-year CHD risks estimated by the Framingham and UKPDS risk functions were 17.7 ± 12.1 and 16.8 ± 15 (bias: 0.88, P > 0.05), respectively, and were always higher in males and older age groups (P < 0.001). The two risk functions showed moderate convergent validity in predicting CHD risks, but differed in stratifying them and explaining the patients' risk profile. The Framingham equation predicted higher risk for patients usually below 70 years and showed better association with their current risk profile than the UKPDS risk engine. CONCLUSIONS: Based on the predicted risk, Nepalese diabetic patients, particularly those associated with increased numbers of risk factors, bear higher risk of future CHDs. Since this study is a cross-sectional one and uses externally validated risk functions, Nepalese clinicians should use them with caution, and preferably in combination with other guidelines, while making important medical decisions in preventive therapy of CHD.

Nicotinamide adenine dinucleotide: An essential factor in preserving hearing in cisplatin-induced ototoxicity.

Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced ototoxicity. Although much attention has been directed at identifying ways to protect the inner ear from cisplatin-induced damage, the precise underlying mechanisms have not yet been elucidated. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of cellular energy metabolism and homeostasis. NAD(+) acts as a cofactor for various enzymes including sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), and therefore, maintaining adequate NAD(+) levels has therapeutic benefits because of its effect on NAD(+)-dependent enzymes. Recent studies demonstrated that disturbance in intracellular NAD(+) levels is critically involved in cisplatin-induced cochlear damage associated with oxidative stress, DNA damage, and inflammatory responses. In this review, we describe the importance of NAD(+) in cisplatin-induced ototoxicity and discuss potential strategies for the prevention or treatment of cisplatin-induced ototoxicity with a particular focus on NAD(+)-dependent cellular pathways.

Prevalence of metabolic syndrome in Nepalese type 2 diabetic patients according to WHO, NCEP ATP III, IDF and Harmonized criteria.

BACKGROUND: Metabolic syndrome (MetS) present in type 2 diabetic patients greatly increases the risk of strokes and cardiovascular diseases. Timely detection and mapping of MetS facilitates appropriate preventive and therapeutic approaches to minimize these risks. Our study aimed to determine the prevalence of MetS among Nepalese type 2 diabetic patients using WHO (1999), NCEP ATP III (2001), IDF (2005) and Harmonized (2009) definitions and identify the diagnostic concordance and disparity resulting from these four definitions. METHODS: Clinical and biochemical data were collected for 1061 type 2 diabetic patients at Manipal Teaching Hospital, Pokhara, Nepal. The data was analyzed in order to identify prevalence of MetS in these patients. Statistical analysis included usage of Student's t- and Chi-square tests, kappa statistics and 95% confidence intervals. RESULTS: The total age adjusted prevalence rates of MetS were 80.3%, 73.9%, 69.9% and 66.8% according to Harmonized, NCEP ATP III, WHO and IDF definitions, respectively. Prevalence increased with the age and was higher in females (p <0.001) according to WHO, NCEP ATP III and Harmonized definitions. Patients of Dalit community had the highest prevalence (p<0.05) according to NCEP ATP III and Harmonized definitions while Mongoloid and Newar patients had the highest prevalence (p <0.05) according to WHO and IDF definitions, respectively. Prevalence was also highest among patient engaged in agriculture occupation. Central obesity and hypertension were respectively the most and the least prevalent components of MetS. The highest overall agreement was between Harmonized and NCEP ATP III definitions (κ =0.62, substantial) and the lowest between WHO & IDF definitions (κ=0.26, slight). The Harmonized definition had the highest sensitivity (99.9%) and negative predictive value (98.9%) while NCEP ATP III definition had the highest specificity (98.9%) and positive predictive values (99.9%) in identifying the cases of MetS. CONCLUSIONS: The prevalence of MetS among Nepalese type 2 diabetic patients was very high suggesting that these patients were at increased risk of strokes, cardiovascular diseases and premature death. The Harmonized definition was the most sensitive while NCEP ATP III and IDF definitions were the most specific in detecting the presence of MetS in Nepalese type 2 diabetic patients.

Cisplatin-induced Kidney Dysfunction and Perspectives on Improving Treatment Strategies.

Cisplatin is one of the most widely used and highly effective drug for the treatment of various solid tumors; however, it has dose-dependent side effects on the kidney, cochlear, and nerves. Nephrotoxicity is the most well-known and clinically important toxicity. Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely associated with cisplatin-induced nephrotoxicity. Even though the establishment of cisplatin-induced nephrotoxicity can be alleviated by diuretics and pre-hydration of patients, the prevalence of cisplatin nephrotoxicity is still high, occurring in approximately one-third of patients who have undergone cisplatin therapy. Therefore it is imperative to develop treatments that will ameliorate cisplatin-nephrotoxicity. In this review, we discuss the mechanisms of cisplatin-induced renal toxicity and the new strategies for protecting the kidneys from the toxic effects without lowering the tumoricidal activity.