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Nanotechnology has seen exponential growth in last decade due to its unique physicochemical properties; however, the risk associated with this emerging technology has withdrawn ample attention in the past decade. Nanotoxicity is majorly contributed to the small size and large surface area of nanomaterials, which allow easy dispersion and invasion of anatomical barriers in human body. Unique physio-chemical properties of nanoparticles make the investigation of their toxic consequences intricate and challenging. This makes it important to have an in-depth knowledge of different mechanisms involved in nanomaterials's action and toxicity. Nano-toxicity has various effects on human health and diseases as they can easily enter into the humans via different routes, mainly respiratory, dermal, and gastrointestinal routes. This also limits the use of nanomaterials as therapeutic and diagnostic tools. This review focuses on the nanomaterial-cell interactions leading to toxicological responses. Different mechanisms involved in nanoparticle-mediated toxicity with the main focus on oxidative stress, genotoxic, and carcinogenic potential has also been discussed. Different methods and techniques used for the characterization of nanomaterials in food and other biological matrices have also been discussed in detail. Nano-toxicity on different organs-with the major focus on the cardiac and respiratory system-have been discussed. Conclusively, the risk management of nanotoxicity is also summarized. This review provides a better understanding of the current scenario of the nanotoxicology, disease progression due to nanomaterials, and their use in the food industry and medical therapeutics. Briefly, the required rules, regulations, and the need of policy makers has been discussed critically.

Heart failure is an aging-associated disease, which is the leading cause of death worldwide. Sirtuin family members have been largely studied in the context of aging and agingassociated diseases. Sirtuin 2 (SIRT2) is a cytoplasmic protein in the family of sirtuins that are NAD + -dependent class III histone deacetylases. In this work, we studied the role of SIRT2 in regulating NFAT transcription factor and the development of cardiac hypertrophy. Confocal microscopy analysis indicated that SIRT2 is localized in the cytoplasm of cardiomyocytes and SIRT2 levels are reduced during pathological hypertrophy of the heart. SIRT2 deficient mice develops spontaneous pathological cardiac hypertrophy, remodelling, fibrosis and dysfunction in an age-dependent manner. Moreover, young SIRT2 deficient mice develops exacerbated agonist-induced hypertrophy. On contrast, SIRT2 overexpression attenuated agonist-induced cardiac hypertrophy in cardiomyocytes in a cell autonomous manner. Mechanistically, SIRT2 binds to and deacetylates NFATc2 transcription factor. SIRT2 deficiency stabilizes NFATc2 and enhances nuclear localization of NFATc2, resulting in increased transcription activity. Our results suggest that inhibition of NFAT rescues the cardiac dysfunction in SIRT2 deficient mice. Thus, our study establishes SIRT2 as a novel endogenous negative regulator of NFAT transcription factor. _____________________________________

Global protein synthesis is emerging as an important player in the context of aging and age-related diseases. However, the intricate molecular networks that regulate protein synthesis are poorly understood. Here, we report that SIRT6, a nuclear-localized histone deacetylase represses global protein synthesis by transcriptionally regulating mTOR signalling via the transcription factor Sp1, independent of its deacetylase activity. Our results suggest that SIRT6 deficiency increases protein synthesis in mice. Further, multiple lines of in vitro evidence suggest that SIRT6 negatively regulates protein synthesis in a cell-autonomous fashion and independent of its catalytic activity. Mechanistically, SIRT6 binds to the zinc finger DNA binding domain of Sp1 and represses its activity. SIRT6 deficiency increased the occupancy of Sp1 at key mTOR signalling gene promoters resulting in enhanced expression of these genes and activation of the mTOR signalling pathway. Interestingly, inhibition of either mTOR or Sp1 abrogated the increased protein synthesis observed under SIRT6 deficient conditions. Moreover, pharmacological inhibition of mTOR restored cardiac function in muscle-specific SIRT6 knockout mice, which spontaneously develop cardiac hypertrophy. Overall, these findings have unravelled a new layer of regulation of global protein synthesis by SIRT6, which can be potentially targeted to combat aging-associated diseases like cardiac hypertrophy.

Doxorubicin (Dox) is an effective anti-cancer drug with severe reported cardiotoxicity. Cardiovascular risks associated with present cancer therapeutics demand urgent attention. There has been a growing interest in naturally occurring compounds to improve the therapeutic index as well as prevent non-tumour tissues from sustaining chemotherapy-induced damages. In the present study, the effects of curcumin, a polyphenol isolated from Curcuma longa and well known for its anti-oxidative, anti-cancerous and anti-inflammatory properties, was studied in relation to the Dox-induced cardiotoxicity. As literature suggests conflicting role of curcumin in Dox-induced cardiotoxicity, concentration- and time-dependent studies were conducted to study the different curcumin effects. H9C2 cardiomyoblasts were used in the study and cell viability assays were done to study Dox-induced cellular death. Drug uptake assay for Dox was performed followed by cellular growth inhibition analysis by FACS Calibur. Morphological alterations, intracellular ROS levels and mitochondrial integrity were observed by fluorescent-based microscopic studies. Catalases and superoxide dismutase-inbuilt anti-oxidant enzyme activities were studied, and it was observed that Dox-dependent cardiotoxicity occurs through ROS overproduction by exaggerating the inbuilt anti-oxidant mechanism. Expression analysis for cell death and ROS markers-BCl, Bax, SOD, catalase-was investigated by semi-quantitative RT-PCR, and the Dox-induced stress on cardiac cells was confirmed. Initiator and effector caspases activity analysis also confirmed these findings. Our study proposes that curcumin exerts time-dependent responses on Dox-induced cardiotoxicity, where parallel treatment potentiates and pre-treatment suppresses the Dox-induced toxicity in H9C2 cardiomyoblasts. In conclusion, pre-treatment of curcumin suppresses the Dox-induced cardiotoxicity and holds a great potential as future cardio-oncological therapeutics.

Caloric restriction has been associated with increased life span and reduced aging-related disorders and reduces fibrosis in several diseases. Fibrosis is characterized by deposition of excess fibrous material in tissues and organs and is caused by aging, chronic stress, injury, or disease. Myofibroblasts are fibroblast-like cells that secrete high levels of extracellular matrix proteins, resulting in fibrosis. Histological studies have identified many-fold increases of myofibroblasts in aged organs where myofibroblasts are constantly generated from resident tissue fibroblasts and other cell types. However, it remains unclear how aging increases the generation of myofibroblasts. Here, using mouse models and biochemical assays, we show that sirtuin 6 (SIRT6) deficiency plays a major role in aging-associated transformation of fibroblasts to myofibroblasts, resulting in tissue fibrosis. Our findings suggest that SIRT6-deficient fibroblasts transform spontaneously to myofibroblasts through hyperactivation of transforming growth factor β (TGF-β) signaling in a cell-autonomous manner. Importantly, we noted that SIRT6 haploinsufficiency is sufficient for enhancing myofibroblast generation, leading to multiorgan fibrosis and cardiac dysfunction in mice during aging. Mechanistically, SIRT6 bound to and repressed the expression of key TGF-β signaling genes by deacetylating SMAD family member 3 (SMAD3) and Lys-9 and Lys-56 in histone 3. SIRT6 binding to the promoters of genes in the TGF-β signaling pathway decreased significantly with age and was accompanied by increased binding of SMAD3 to these promoters. Our findings reveal that SIRT6 may be a potential candidate for modulating TGF-β signaling to reduce multiorgan fibrosis during aging and fibrosis-associated diseases.

Heart is a dynamic organ that undergoes remodeling in response to both physiological and pathological stimuli. One of the fundamental cellular processes that facilitates changes in the size and shape of this muscular organ is the protein synthesis. Traditionally changes in cardiac protein synthesis levels were measured by radiolabeled tracers. However, these methods are often cumbersome and suffer from radioactive risk. Recently a nonradioactive method for detecting protein synthesis under in vitro conditions called the Surface Sensing of Translation (SUnSET) was described in cell lines of mouse dendrites and T cells. In this work, we provide multiple lines of evidence that the SUnSET assay can be applied to reliably detect changes in protein synthesis both in isolated neonatal primary cardiomyocytes and heart. We successfully tracked the changes in protein synthesis by western blotting as well as immunohistochemical variants of the SUnSET assay. Applying the SUnSET assay, we measured the cardiac protein synthesis during the different ages of mice. Further, we successfully tracked the increase in cardiac protein synthesis during different stages of a well-established model for pathological hypertrophy. Overall, we propose SUnSET assay as a simple, reliable and robust method to measure protein synthesis in the cardiac milieu.

Objective:The objective of the following study is to determine the use of ultrasound as an important adjunct to clinical and laboratory profile in diagnosing dengue fever and in predicting the severity of the disease by correlating imaging features with platelet count. The variation in sonographic features seen in patients from different age groups was also studied.Materials and Methods:This is a retrospective study. 96 patients who were serologically diagnosed as having dengue fever between April and August 2012 were referred for ultrasound scanning of the abdomen and thorax and the imaging findings were analyzed.Results:Out of 96 sero-positive dengue cases, 64 (66.7%) patients showed edematous gallbladder (GB) wall thickening, 62 (64.5%) patients showed ascites, 48 (50%) patients had pleural effusion, 17 (17.7%) patients had hepatomegaly, 16 (16.7%) patients had splenomegaly and in 17 (17.7%) patients ultrasound findings were normal. Edematous GB wall thickening, ascites and pleural effusion were the most common combination of findings in all age groups. Edematous GB wall thickening was seen in 97.8% of patients with platelet count of less than 40,000 along with ascites (86.9%) and pleural effusion (58.6%). In patients with platelet count between 40,000 and 80,000 ascites was more common than edematous GB wall thickening. Significantly no abnormal sonographic finding was detected in patient with platelet count more than 150,000.Conclusion:Sonographic features of thickened GB wall, pleural effusion (bilateral or right side), ascites, hepatomegaly and splenomegaly should strongly favor the diagnosis of dengue fever in patients presenting with fever and associated symptoms, particularly during an epidemic. The degree of thrombocytopenia showed a significant direct relationship to abnormal ultrasound features.