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.

Oral hygiene practices and their socio-demographic correlates among Nepalese adult: evidence from non communicable diseases risk factors STEPS survey Nepal 2013.

BACKGROUND: Oral diseases remain a significant public health problem in Nepal, as do oral health behaviours. Socio-demographic factors play a crucial role in driving oral hygiene practices. This study aims to identify oral hygiene practices and associated socio-demographic factors in Nepalese population. METHODS: This descriptive, cross-sectional study recruited 4200 adults (15-69 years) through multistage cluster sampling. Data obtained from the WHO NCD STEPS instrument version 2.2 were analysed in STATA 13.0 using complex sample weighted analysis. RESULTS: Prevalence of cleaning teeth at least once a day was 94.9 % (95 % CI: 93.7-95.9), while that of cleaning teeth at least twice a day was 9.9 % (95 % CI: 8.2-11.9). Use of fluoridated toothpaste was seen among 71.4 % (95 % CI: 67.9-74.7) respondents. A 3.9 % (95 % CI: 3.1-5.0) made a dental visit in the last 6 months. The 45-69 years age group had lesser odds of cleaning teeth at least once a day (AOR: 0.4; 95 % CI: 0.2-0.8), in comparison to 15-29 years age group. Women had greater odds of cleaning teeth at least twice a day (AOR: 1.7; 95 % CI: 1.1-2.4) and having visited a dentist in the last 6 months (AOR: 2.2; 95 % CI: 1.2-3.8) compared to men. With reference to rural residents, urban population had higher odds of using fluoridated toothpaste (AOR: 2.3; 95 % CI: 1.4-3.4) and making a dental visit within the last 6 months (AOR: 1.9; 95 % CI:1.1-3.6). Inhabitants of the Terai had five-fold (AOR: 4.9; 95 % CI: 3.1-7.8) greater odds of cleaning teeth once per day than did hill residents. Those with higher education had greater odds than non-formal education holders of cleaning teeth at least once a day (AOR: 9.0; 95 % CI: 2.9-27.7), cleaning teeth at least twice a day (AOR: 5.6; 95 % CI: 2.9-10.6), using fluoridated toothpaste (AOR: 13.9; 95 % CI: 8.4-23.1), and having visited a dentist in the last 6 months (AOR: 2.8; 95 % CI: 1.4-5.4). CONCLUSIONS: Cleaning teeth at least once a day is widely prevalent in Nepal and a substantial number of population use fluoridated toothpaste. However, cleaning teeth twice a day and visiting a dentist is less common. Being women, Terai residents, urban residents, and educated were significantly associated with oral hygiene practices assessed in this study.

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.

How Does Reciprocal Exchange of Social Support Alleviate Individuals' Depression in an Earthquake-Damaged Community?

There is ample evidence to indicate the direct effects of receiving social support on mental health during and after a disaster. However, the importance of reciprocal exchanges of social support (i.e., balanced receipt and provision of social support) in maintaining the mental health status of individuals is not widely recognized. Using equity theory and reciprocity norms as a conceptual base, we distinguished two types of social support, namely, emotional support and instrumental support, and examined the effects of reciprocal exchanges of types of support on depression in survivors of an earthquake-damaged community. To collect data, in 2019, a questionnaire survey was conducted among 295 survivors of the 2015 Gorkha Earthquake in a rural village in Nepal. Our results showed that the relationship between reciprocal exchange of support and depression varied depending on the types of support. The amount of emotional support received by the individual alleviated his/her depression only when accompanied by giving emotional support. By contrast, the net amount of instrumental support given by the individual increased his/her depression. The practical implications of the study are discussed.

Quality of Drug in Health Facilities: A Cross-sectional Study.

BACKGROUND: Poor quality drugs result minor to detrimental effect on human health. The drug should be of standard quality and should be used appropriately in order to meet its therapeutic efficacy. This study aims to assess the quality of drug in Nepal. METHODS: A cross sectional study was conducted in randomly selected 88 health facilities in Nepal from 10th April to 30th June 2016. Selective medicines were collected from both private licensed pharmacies and selected public health facilities. Face to face interview with health facility in-charge of selected health facilities was carried out along with the direct observation of the medicine storage room. The collected medicine samples were dispatched to two laboratories for in-vitro analysis. The labels of the collected medicine were analyzed. The obtained data were entered in Epidata version 3.1, cleaned in Microsoft excel 2007 and analyzed in SPSS version 20. RESULTS: Out of 172 brands, nine brands of medicines were found substandard. Information regarding storage conditions, direction for use and category of the drug were lacking in the label of some brands of medicines. Some selected health facilities were found not meeting major requirements for drug storage: protection from sunlight, moisture, heat, well ventilation and proper sanitation. CONCLUSIONS: Few drugs were found to be substandard in Nepalese market from both public and private sectors. Adequate labeling and proper storage condition of medicines in health facilities were lacking.

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.

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.

Increased Cellular NAD+ Level through NQO1 Enzymatic Action Has Protective Effects on Bleomycin-Induced Lung Fibrosis in Mice.

BACKGROUND: Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to NAD+ by various quinones and thereby elevates the intracellular NAD+ levels. In this study, we examined the effect of increase in cellular NAD+ levels on bleomycin-induced lung fibrosis in mice. METHODS: C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with ß-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor ß1 (TGF-ß1) and ß-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT). RESULTS: ß-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-ß1, α-smooth muscle actin accumulation. In addition, ß-lapachone showed a protective role in TGF-ß1-induced ECM expression and EMT in A549 cells. CONCLUSION: Our results suggest that ß-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-ß1-induced EMT in vitro, by elevating the NAD+/NADH ratio through NQO1 activation.

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.

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.

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.