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51.
Rebecca M. Peter Md. Shahid Sarwar Sarah Z. Mostafa Yujue Wang Xiaoyang Su Ah-Ng Kong 《Molecular carcinogenesis》2023,62(8):1136-1146
Kirsten rat sarcoma virus (KRAS) oncogene, found in 20%–25% of lung cancer patients, potentially regulates metabolic reprogramming and redox status during tumorigenesis. Histone deacetylase (HDAC) inhibitors have been investigated for treating KRAS-mutant lung cancer. In the current study, we investigate the effect of HDAC inhibitor (HDACi) belinostat at clinically relevant concentration on nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial metabolism for the treatment of KRAS-mutant human lung cancer. LC-MS metabolomic study of belinostat on mitochondrial metabolism was performed in G12C KRAS-mutant H358 non-small cell lung cancer cells. Furthermore, l -methionine (methyl-13C) isotope tracer was used to explore the effect of belinostat on one-carbon metabolism. Bioinformatic analyses of metabolomic data were performed to identify the pattern of significantly regulated metabolites. To study the effect of belinostat on redox signaling ARE-NRF2 pathway, luciferase reporter activity assay was done in stably transfected HepG2-C8 cells (containing pARE-TI-luciferase construct), followed by qPCR analysis of NRF2 and its target gene in H358 cells, which was further confirmed in G12S KRAS-mutant A549 cells. Metabolomic study reveals significantly altered metabolites related to redox homeostasis, including tricarboxylic acid (TCA) cycle metabolites (citrate, aconitate, fumarate, malate, and α-ketoglutarate); urea cycle metabolites (Arginine, ornithine, argino-succinate, aspartate, and fumarate); and antioxidative glutathione metabolism pathway (GSH/GSSG and NAD/NADH ratio) after belinostat treatment. 13C stable isotope labeling data indicates potential role of belinostat in creatine biosynthesis via methylation of guanidinoacetate. Moreover, belinostat downregulated the expression of NRF2 and its target gene NAD(P)H:quinone oxidoreductase 1 (NQO1), indicating anticancer effect of belinostat is mediated, potentially via Nrf2-regulated glutathione pathway. Another HDACi panobinostat also showed potential anticancer effect in both H358 and A549 cells via Nrf2 pathway. In summary, belinostat is effective in killing KRAS-mutant human lung cancer cells by regulating mitochondrial metabolism which could be used as biomarkers for preclinical and clinical studies. 相似文献
52.
Md Ahshanul Haque Nuzhat Choudhury S. M. Tanvir Ahmed Fahmida Dil Farzana Mohammad Ali Farina Naz Mohammad Jyoti Raihan Sheikh Shahed Rahman Towfida Jahan Siddiqua Abu Syed Golam Faruque Tahmeed Ahmed 《Maternal & child nutrition》2022,18(4)
Child wasting is defined as a weight‐for‐height/length z‐score (WLZ/WHZ) < −2, and this indicator of nutritional status is used worldwide. However, a precise measurement is required for the assessment of a child''s nutritional status, which may not always be possible due to expensive instruments, especially in poor resource settings. In some instances, mid‐upper arm circumference‐for‐age z‐score (MUACZ) is also being used for screening purposes, which is a simple and useful nutritional indicator. The objective of this paper is to identify the optimal cut‐off point for the MUACZ to identify wasted children, and also to determine if the same factors are associated with MUACZ and wasting. Data were derived from the Suchana evaluation data. The optimal cut‐off value was estimated via receiver operating characteristic (ROC) curve analysis using acute malnutrition as a gold standard with maximum sensitivity and specificity. Multiple logistic regression was used to assess the associated factors with the MUACZ. Using the gold standard indicator of nonwasting (WLZ ≥ −2), a positive outcome, the optimal cut‐off point for the MUACZ was −1.27. The area under the ROC curve was 0.88, indicating that the model had a power of 88% to differentiate between the positive and negative classes. It implies that a child''s MUACZ was correlated with WLZ, and a MUACZ below −1.27 appeared to accurately identify wasting among children aged 3–23 months. MUACZ < −1.27 might be another useful indicator of childhood wasting than a WLZ < −2. 相似文献
53.
Most of the newly developed drugs fails to achieve sufficient bioavailability in to brain due to low water solubility and low permeability. Drug delivery systems are one method for achieving entry of molecules to their desired site of action within the body. Dendrimers are the customizable nanopolymers with uniform and well-defined particle size and shape. Dendrimers are of eminent interest for biomedical applications because of their ability to cross cell membranes. This potential pharmaceutical delivery system crosses the blood brain barrier (BBB) and other important target points. The high level of control over the dendritic architecture (size, branching density, surface functionality) make dendrimers ideal carriers in the field of brain drug delivery of anticancer, antiinflammatory, and antimicrobial agents. Examples of dendrimers such as poly(amidoamine) (PAMAM), poly(propylene imine) (PPI) and polyether-copolyester (PEPE), Glyco, PEGylated, peptide and pH dendrimers are of outmost significance. These dendrimers carry the drug molecules by physical interactions (encapsulation) or through chemical bonding (prodrug approach), while pH sensitive dendrimers are able to deliver drug molecules by alteration of ionic exchange in the brain microenvironment at the tumor site. Techniques employing dendrimers could be especially useful for drugs targeting to Alzheimer's and Prion's diseases. The present review should be of value to scientists who wish to work on the dendrimers for the delivery of molecules into the brain by systemic dosing. 相似文献
54.
Ventilator-associated pneumonia is associated with significant patient morbidity, mortality, and increased health care costs. In the current economic climate, it is crucial to implement cost-effective prevention strategies that have proven efficacy. Multiple prevention measures have been proposed by various expert panels. Global strategies have focused on infection control, and reduction of lower airway colonization with bacterial pathogens, intubation, duration of mechanical ventilation, and length of stay in the intensive care unit. Routine use of the Institute for Healthcare Improvement ventilator care bundle is widespread, and has been clearly demonstrated to be an effective method for reducing the incidence of ventilator-associated pneumonia. In this article, we examine specific aspects of the Institute for Healthcare Improvement bundle, better-designed endotracheal tubes, use of antibiotics and probiotics, and treatment of ventilator-associated tracheobronchitis to prevent ventilator-associated pneumonia. 相似文献
55.
56.
Effect of birth weight on adulthood renal function: A bias‐adjusted meta‐analytic approach 下载免费PDF全文
Sumon Kumar Das Munim Mannan Abu Syed Golam Faruque Tahmeed Ahmed Harold David McIntyre Abdullah Al Mamun 《Nephrology (Carlton, Vic.)》2016,21(7):547-565
While the association between low birth weight (LBW; <2500 g) and development of adult chronic renal disease (CKD) is inconsistently reported, less information is available regarding association of high birth weight (HBW; ≥4000 g) with CKD. We undertook a systematic review and meta‐analysis on studies published before 30 September 2015 and report associations between birth weight and renal function. Blood (glomerular filtration rate (GFR)) and urine (microalbuminuria/albumin excreation rate (AER)/urinary albumin creatinine ratio (ACR)) parameters were used to define CKD. Three different effect size estimates were used (odds ratio, regression coefficient and mean difference). The odds of developing CKD in the life course among those born LBW was 1.77 (95% CI: 1.42, 2.20) times and 1.68 (1.27, 2.33) times, assessed by blood and urine parameters respectively. Higher risk was also observed among Asian and Australian populations (blood: OR 2.68; urine: OR 2.28), individuals aged ≤30 years (blood: OR 2.30; urine: OR 1.26), and ≥50 years (blood: OR 3.66; urine: OR 3.10), people with diabetes (blood: OR 2.51), and aborigines (urine: OR 2.32). There was no significant association between HBW and CKD. For every 1 kg increase in BW, the estimated GFR increased by 2.09 mL/min per 1.73 m2 (1.33–2.85), and it was negatively associated with LogACR (ß ?0.07, 95% CI: ?0.14, 0.00). LBW inborn had lower mean GFR ?4.62 (?7.10, ?2.14) compared with normal BW. Findings of this study suggest that LBW increased the risk of developing CKD, and HBW did not show any significant impact. 相似文献
57.
58.
McCarty KM Chen YC Quamruzzaman Q Rahman M Mahiuddin G Hsueh YM Su L Smith T Ryan L Christiani DC 《Environmental health perspectives》2007,115(3):341-345
OBJECTIVE: We investigated whether primary and secondary arsenic methylation ratios were associated with skin lesions and whether GSTT1, GSTP1, and GSTM1 polymorphisms modify these relationships. METHODS: A case-control study of 600 cases and 600 controls that were frequency matched on age and sex was conducted in Pabna, Bangladesh, in 2001-2002. Individual well water, urine, and blood samples were collected. Water arsenic concentration was determined using inductively coupled plasma mass spectrometry (ICP-MS). Urinary arsenic speciation was determined using high performance liquid chromatography hydride with generator atomic absorption spectrometry and ICP-MS. Genotyping was conducted using multiplex polymerase chain reaction and TaqMan. RESULTS: A 10-fold increase in primary methylation ratio [monomethylarsonic acid (MMA)/(arsenite + arsenate] was associated with a 1.50-fold increased risk of skin lesions (multivariate odds ratio = 1.50; 95% confidence interval, 1.00-2.26). We observed significant interaction on the multiplicative scale between GSTT1 wildtype and secondary methylation ratio [dimethylarsinic acid/MMA; likelihood ratio test (LRT), p = 0.01]. No significant interactions were observed for GSTM1 or GSTP1 or for primary methylation ratios. CONCLUSION: Our findings suggest that increasing primary methylation ratios are associated with an increase in risk of arsenic-related skin lesions. The interaction between GSTT1 wildtype and secondary methylation ratio modifies risk of skin lesions among arsenic-exposed individuals. 相似文献
59.
A distinct and replicable variant of the squamous cell carcinoma gene inositol polyphosphate‐5‐phosphatase modifies the susceptibility of arsenic‐associated skin lesions in Bangladesh 下载免费PDF全文
Wei Jie Seow MS ScD Wen‐Chi Pan MS ScD Molly L. Kile ScD Lin Tong MS Andrea A. Baccarelli MD MPH PhD Quazi Quamruzzaman MD Mahmuder Rahman MD Golam Mostofa MCom Muhammad Rakibuz‐Zaman MD Muhammad Kibriya MD PhD Habibul Ahsan MD Xihong Lin PhD David C. Christiani MD MS MPH 《Cancer》2015,121(13):2222-2229
60.
Darren A. Yuen Bailey E. Stead Yanling Zhang Kathryn E. White M. Golam Kabir Kerri Thai Suzanne L. Advani Kim A. Connelly Tomoko Takano Lei Zhu Alison J. Cox Darren J. Kelly Ian W. Gibson Takamune Takahashi Raymond C. Harris Andrew Advani 《Journal of the American Society of Nephrology : JASN》2012,23(11):1810-1823
Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS−/− mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS−/− mice, even though it inhibited glomerular capillary enlargement in both. In eNOS−/− mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS−/− mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS−/− glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.One of the earliest features of kidney disease in diabetes is an alteration in the size- and/or charge-selective properties of the glomerular filtration barrier, a trilaminar structure that normally prevents the free passage of macromolecules into the urinary space. Manifested clinically as albuminuria, this disruption in the filtration barrier may result from structural or molecular changes in the fenestrated glomerular endothelial cells, podocytes, and/or the interpositioned glomerular basement membrane (GBM). High glucose-mediated molecular events1 and flow-mediated stress forces induce endothelial dysfunction in diabetes2 and diabetic nephropathy in particular.3 However, the mechanism by which such injury may translate to loss of glomerular permselectivity remains incompletely understood.Endothelial dysfunction in diabetic nephropathy is perhaps most readily observed as “neoangiogenesis” of the glomerular capillaries.4,5 A number of experimental studies exploiting antiangiogenic therapies would appear, at first glance, to endorse a role for abnormal angiogenesis in the development of diabetic nephropathy.6 The proangiogenic growth factor, vascular endothelial growth factor (VEGF), for example, is abundantly expressed by podocytes within the diabetic glomerulus7 and strategies to block the activity of VEGF have been reported to attenuate albuminuria,8–10 despite evidence to the contrary in the nondiabetic setting.11,12 Podocytes act as the final barrier to macromolecular flow and, over recent years, injury to this specialized epithelial cell type has been acknowledged as playing a pivotal role in the pathogenesis of albuminuria in diabetes. Bidirectional crosstalk between glomerular endothelial cells and neighboring podocytes, accordingly, represents an alternative route via which endothelial injury may translate to urinary leakage of albumin.13,14One of the major obstacles to the study of pathogenetic mechanisms in diabetic nephropathy has been the lack of an animal model that develops disease analogous to that seen in humans.15 However, augmented renal injury has recently been described in diabetic mice genetically deficient in endothelial nitric oxide synthase (eNOS), the major NOS isoform responsible for NO generation within the micro- and macrovasculature.16–20 In this study, we sought to establish the role that eNOS plays in glomerular capillary growth in diabetes and in the paradoxical response to anti-VEGF therapy, as well as the effects of eNOS deficiency on communication with neighboring podocytes and its response to “standard of care” with renin-angiotensin-aldosterone system (RAAS) blockade. 相似文献