Altered Metabolic Signaling and Potential Therapies in Polyglutamine Diseases.

Polyglutamine diseases comprise a cluster of genetic disorders involving neurodegeneration and movement disabilities. In polyglutamine diseases, the target proteins become aberrated due to polyglutamine repeat formation. These aberrant proteins form the root cause of associated complications. The metabolic regulation during polyglutamine diseases is not well studied and needs more attention. We have brought to light the significance of regulating glutamine metabolism during polyglutamine diseases, which could help in decreasing the neuronal damage associated with excess glutamate and nucleotide generation. Most polyglutamine diseases are accompanied by symptoms that occur due to excess glutamate and nucleotide accumulation. Along with a dysregulated glutamine metabolism, the Nicotinamide adenine dinucleotide (NAD+) levels drop down, and, under these conditions, NAD+ supplementation is the only achievable strategy. NAD+ is a major co-factor in the glutamine metabolic pathway, and it helps in maintaining neuronal homeostasis. Thus, strategies to decrease excess glutamate and nucleotide generation, as well as channelizing glutamine toward the generation of ATP and the maintenance of NAD+ homeostasis, could aid in neuronal health. Along with understanding the metabolic dysregulation that occurs during polyglutamine diseases, we have also focused on potential therapeutic strategies that could provide direct benefits or could restore metabolic homeostasis. Our review will shed light into unique metabolic causes and into ideal therapeutic strategies for treating complications associated with polyglutamine diseases.

Untargeted Metabolomics Based Prediction of Therapeutic Potential for Apigenin and Chrysin.

The prominent flavonoids apigenin and chrysin have been demonstrated to have systemic benefits. Our previous work was first to establish the impact of apigenin and chrysin on cellular transcriptome. In the current study, we have revealed the ability of apigenin and chrysin to alter the cellular metabolome based on our untargeted metabolomics. Based on our metabolomics data, both these structurally related flavonoids demonstrate diverging and converging properties. Apigenin demonstrated the potential to possess anti-inflammatory and vasorelaxant properties through the upregulation of intermediate metabolites of alpha-linolenic acid and linoleic acid pathways. Chrysin, on the other hand, exhibited abilities to inhibit protein and pyrimidine synthesis along with downregulation of gluconeogenesis pathways based on the altered metabolites detected. Chrysin-mediated metabolite changes are mostly due to its ability to modulate L-alanine metabolism and the urea cycle. On the other hand, both the flavonoids also demonstrated converging properties. Apigenin and chrysin were able to downregulate metabolites involved in cholesterol biosynthesis and uric acid synthesis, namely 7-dehydrocholesterol and xanthosine, respectively. This work will provide understanding regarding the diverse therapeutic potential of these naturally occurring flavonoids and help us in curbing an array of metabolic complications.

Metabolic Activation of PARP as a SARS-CoV-2 Therapeutic Target-Is It a Bait for the Virus or the Best Deal We Could Ever Make with the Virus? Is AMBICA the Potential Cure?

The COVID-19 pandemic has had a great impact on global health and is an economic burden. Even with vaccines and anti-viral medications we are still scrambling to get a balance. In this perspective, we have shed light upon an extremely feasible approach by which we can control the SARS-CoV-2 infection and the associated complications, bringing some solace to this ongoing turmoil. We are providing some insights regarding an ideal agent which could prevent SARS-CoV-2 multiplication. If we could identify an agent which is an activator of metabolism and is also bioactive, we could prevent corona activation (AMBICA). Some naturally occurring lipid molecules best fit this identity as an agent which has the capacity to replenish our host cells, specifically immune cells, with ATP. It could also act as a source for providing a substrate for host cell PARP family members for MARylation and PARylation processes, leading to manipulation of the viral macro domain function, resulting in curbing the virulence and propagation of SARS-CoV-2. Identification of the right lipid molecule or combination of lipid molecules will fulfill the criteria. This perspective has focused on a unique angle of host-pathogen interaction and will open up a new dimension in treating COVID-19 infection.

Impact of Glucocorticoids on Cardiovascular System-The Yin Yang Effect.

Glucocorticoids are not only endogenous hormones but are also administered exogenously as an anti-inflammatory and immunosuppressant for their long-term beneficial and lifesaving effects. Because of their potent anti-inflammatory property and ability to curb the cytokines, they are administered as lifesaving steroids. This property is not only made use of in the cardiovascular system but also in other major organ systems and networks. There is a fine line between their use as a protective anti-inflammatory and a steroid that could cause overuse-induced complications in major organ systems including the cardiovascular system. Studies conducted in the cardiovascular system demonstrate that glucocorticoids are required for growth and development and also for offering protection against inflammatory signals. Excess or long-term glucocorticoid administration could alter cardiac metabolism and health. The endogenous dysregulated state due to excess endogenous glucocorticoid release from the adrenals as seen with Cushing's syndrome or excess exogenous glucocorticoid administration leading to Cushing's-like condition show a similar impact on the cardiovascular system. This review highlights the importance of maintaining a glucocorticoid balance whether it is endogenous and exogenous in regulating cardiovascular health.

miR-133a-A Potential Target for Improving Cardiac Mitochondrial Health and Regeneration After Injury.

ABSTRACT: The various roles of muscle secretory factors and myokines have been well studied, but in recent decades, the role of myocyte-specific microRNAs (myomiRs) has gained momentum. These myomiRs are known to play regulatory roles in muscle health in general, both skeletal muscle and cardiac muscle. In this review, we have focused on the significance of a myomiR termed miR-133a in cardiovascular health. The available literature supports the claim that miR-133a could be helpful in the healing process of muscle tissue after injury. The protective function could be due to its regulatory effect on muscle or stem cell mitochondrial function. In this review, we have shed light on the protective mechanisms offered by miR-133a. Most of the beneficial effects are due to the presence of miR-133a in circulation or tissue-specific expression. We have also reviewed the potential mechanisms by which miR-133a could interact with cell surface receptors and also transcriptional mechanisms by which they offer cardioprotection and regeneration. Understanding these mechanisms will help in finding an ideal strategy to repair cardiac tissue after injury.

The Head-to-Toe Hormone: Leptin as an Extensive Modulator of Physiologic Systems.

Leptin is a well-known hunger-sensing peptide hormone. The role of leptin in weight gain and metabolic homeostasis has been explored for the past two decades. In this review, we have tried to shed light upon the impact of leptin signaling on health and diseases. At low or moderate levels, this peptide hormone supports physiological roles, but at chronically higher doses exhibits detrimental effects on various systems. The untoward effects we observe with chronically higher levels of leptin are due to their receptor-mediated effect or due to leptin resistance and are not well studied. This review will help us in understanding the non-anorexic roles of leptin, including their contribution to the metabolism of various systems and inflammation. We will be able to get an alternative perspective regarding the physiological and pathological roles of this mysterious peptide hormone.

Transcriptome analysis of two structurally related flavonoids; Apigenin and Chrysin revealed hypocholesterolemic and ketogenic effects in mouse embryonic fibroblasts.

There is no known single therapeutic drug for treating hypercholesterolemia that comes with negligible systemic side effects. In the current study, using next generation RNA sequencing approach in mouse embryonic fibroblasts we discovered that two structurally related flavonoid compounds. Apigenin and Chrysin exhibited moderate blocking ability of multiple transcripts that regulate rate limiting enzymes in the cholesterol biosynthesis pathway. The observed decrease in cholesterol biosynthesis pathway correlated well with an increase in transcripts involved in generation and trafficking of ketone bodies as evident by the upregulation of Bdh1 and Slc16a6 transcripts. The hypocholesterolemic potential of Apigenin and Chrysin at higher concentrations along with their ability to generate ketogenic substrate especially during embryonic stage is useful or detrimental for embryonic health is not clear and still debatable. Our study will serve as a steppingstone to further the investigation in whole animal studies and also in translating this knowledge to human studies.

MALAT1: a therapeutic candidate for a broad spectrum of vascular and cardiorenal complications.

Cardiovascular and renal complications cover a wide array of diseases. The most commonly known overlapping complications include cardiac and renal fibrosis, cardiomyopathy, cardiac hypertrophy, hypertension, and cardiorenal failure. The known or reported causes for the abovementioned complications include injury, ischemia, infection, and metabolic stress. To date, various targets have been reported and investigated in detail that are considered to be the cause of these complications. In the past 5 years, the role of noncoding RNAs has emerged in the area of cardiovascular and renal research, especially in relation to metabolic stress. The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) has shown immense promise among the long noncoding RNA targets for treating cardiorenal complications. In this review, we shed light on the role of MALAT1 as a primary and novel target in treating cardiovascular and renal diseases as a whole.

FoxO1-miRNA interacting networks as potential targets for mitochondrial diseases.

Mitochondrial homeostasis is important for the health and well-being of organ systems and organisms. Mitochondrial dysfunction is known to be the cause and consequence of metabolic diseases, including obesity, diabetes, cancer, neurodegeneration, cerebrovascular, and cardiovascular disease. For cardiovascular tissue, which relies mostly on oxidative phosphorylation, the role of mitochondria is inevitable. Rather than being biomarkers of mitochondrial health, miRNAs are now known as bioregulators of this important feature. Recent studies have shown a close interaction between Forkhead box other 1 (FoxO1) transcription factors and miRNAs in the cardiovascular system. These interactions have also been shown to regulate mitochondrial homeostasis. In this review, I highlight how understanding FoxO1 and miRNA interacting networks could enable us to limit mitochondrial dysfunction and associated pathologies.

A Population-Based Cross-Sectional Study of the Association between Liver Enzymes and Lipid Levels.

BACKGROUND: To examine the association between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels and liver enzyme functions. METHODS: The National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2012 was used to examine the association between liver enzymes and lipid levels amongst adults in the United States. RESULTS: Sixteen percent adults had ALT > 40 U/L, 11% had AST > 40 U/L, and 96% had ALP > 120 U/L. Age, gender, and race/ethnicity showed significant association with LDL, HDL, and triglycerides levels. LDL greater than borderline high was associated with little over two times higher odds of elevated ALT (OR: 2.33, 95% CI: 2.17, 2.53, p ≤ 0.001) and AST (OR: 2.79, 95% CI: 2.55, 3.06, p ≤ 0.001). High HDL was associated with 50% higher odds for elevated ALT (OR: 1.51, 95% CI: 1.39, 1.64, p ≤ 0.001) and over two-and-half fold elevated AST (OR: 2.77, 95% CI: 2.47, 3.11, p ≤ 0.001). LDL-C, HDL-C, and triglycerides were found to be good predictor of elevated ALT, AST, and ALP levels. Similarly, old age and female gender were significant predictor of elevated ALT and AST (p ≤ 0.001). CONCLUSIONS: Underlying hepatic pathophysiology from dyslipidemia deserves further exploration due to its potential effects on hepatic drug metabolism/detoxification.

Adipose tissue glycogen accumulation is associated with obesity-linked inflammation in humans.

OBJECTIVE: Glycogen metabolism has emerged as a mediator in the control of energy homeostasis and studies in murine models reveal that adipose tissue might contain glycogen stores. Here we investigated the physio(patho)logical role of glycogen in human adipose tissue in the context of obesity and insulin resistance. METHODS: We studied glucose metabolic flux of hypoxic human adipoctyes by nuclear magnetic resonance and mass spectrometry-based metabolic approaches. Glycogen synthesis and glycogen content in response to hypoxia was analyzed in human adipocytes and macrophages. To explore the metabolic effects of enforced glycogen deposition in adipocytes and macrophages, we overexpressed PTG, the only glycogen-associated regulatory subunit (PP1-GTS) reported in murine adipocytes. Adipose tissue gene expression analysis was performed on wild type and homozygous PTG KO male mice. Finally, glycogen metabolism gene expression and glycogen accumulation was analyzed in adipose tissue, mature adipocytes and resident macrophages from lean and obese subjects with different degrees of insulin resistance in 2 independent cohorts. RESULTS: We show that hypoxia modulates glucose metabolic flux in human adipocytes and macrophages and promotes glycogenesis. Enforced glycogen deposition by overexpression of PTG re-orients adipocyte secretion to a pro-inflammatory response linked to insulin resistance and monocyte/lymphocyte migration. Furthermore, glycogen accumulation is associated with inhibition of mTORC1 signaling and increased basal autophagy flux, correlating with greater leptin release in glycogen-loaded adipocytes. PTG-KO mice have reduced expression of key inflammatory genes in adipose tissue and PTG overexpression in M0 macrophages induces a pro-inflammatory and glycolytic M1 phenotype. Increased glycogen synthase expression correlates with glycogen deposition in subcutaneous adipose tissue of obese patients. Glycogen content in subcutaneous mature adipocytes is associated with BMI and leptin expression. CONCLUSION: Our data establish glycogen mishandling in adipose tissue as a potential key feature of inflammatory-related metabolic stress in human obesity.

Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration.

Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occurred through cell autonomous mechanisms that triggered Purkinje cell death. Moreover, our analyses demonstrated the mislocalization of lysosomal cathepsins within the cytosol of Npc1-deficient Purkinje cells. We provide evidence that this may be a consequence of damage to lysosomal membranes by reactive oxygen species (ROS), leading to the leakage of lysosomal contents that culminates in apoptotic cell death. Consistent with this notion, toxicity from ROS was attenuated in an NPC cell model by cystatin B over-expression or pharmacological inhibition of cathepsin B. The observation that Npc1 and Cstb deletion genetically interact to potently enhance the degenerative phenotype of the NPC cerebellum provides strong support for the notion that lysosomal membrane permeabilization contributes to cerebellar degeneration in NPC disease.

Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells.

To examine whether the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is altered in the endothelial cells in response to glucose and the significance of such alteration. We incubated human umbilical vein endothelial cells with media containing various glucose levels. We found an increase in MALAT1 expression peaking after 12 hrs of incubation in high glucose. This increase was associated with parallel increase in serum amyloid antigen 3 (SAA3), an inflammatory ligand and target of MALAT1 and was further accompanied by increase in mRNAs and proteins of inflammatory mediators, tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6). Renal tissue from the diabetic animals showed similar changes. Such cellular alterations were prevented following MALAT1 specific siRNA transfection. Results of this study indicate that LncRNA MALAT1 regulates glucose-induced up-regulation of inflammatory mediators IL-6 and TNF-α through activation of SAA3. Identification of such novel mechanism may lead to the development of RNA-based therapeutics targeting MALAT1 for diabetes-induced micro and macro vascular complications.

Lipoprotein lipase and angiopoietin-like 4 - Cardiomyocyte secretory proteins that regulate metabolism during diabetic heart disease.

Cardiac diseases have been extensively studied following diabetes and altered metabolism has been implicated in its initiation. In this context, there is a shift from glucose utilization to predominantly fatty acid metabolism. We have focused on the micro- and macro-environments that the heart uses to provide fatty acids to the cardiomyocyte. Specifically, we will discuss the cross talk between endothelial cells, smooth muscles and cardiomyocytes, and their respective secretory products that allows for this shift in metabolism. These changes will then be linked to alterations in the cardiovascular system and the augmented heart disease observed during diabetes. Traditionally, the heart was only thought of as an organ that supplies oxygen and nutrients to the body through its function as a pump. However, the heart as an endocrine organ has also been suggested. Secreted products from the cardiomyocytes include the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Both have been shown to have vasodilatory, diuretic and antihypertensive effects. These peptides have been extensively studied and their deficiency is considered to be a major cause for the initiation of cardiovascular and cardiometabolic disorders. Another secretory enzyme, lipoprotein lipase (LPL), has been implicated in diabetic heart disease. LPL is a triglyceride-hydrolyzing enzyme that is synthesized within the cardiomyocyte and secreted towards the lumen under various conditions. For example, moderate or short-term hyperglycemia stimulates the release of LPL from the cardiomyocytes towards the endothelial cells. This process allows LPL to contact lipoprotein triglycerides, initiating their break down, with the product of lipolysis (free fatty acids, FA) translocating towards the cardiomyocytes for energy consumption. This mechanism compensates for the lack of glucose availability following diabetes. Under prolonged, chronic conditions of hyperglycemia, there is a need to inhibit this mechanism to avoid the excess delivery of FA to the cardiomyocytes, an effect that is known to induce cardiac cell death. Thus, LPL inhibition is made possible by a FA-induced activation of PPAR ß/δ, which augments angiopoietin-like 4 (Angptl4), an inhibitor of LPL activity. In the current review, we will focus on the mediators and conditions that regulate LPL and Angptl4 secretion from the cardiomyocyte, which are critical for maintaining cardiac metabolic homeostasis.

Cardiac miR-133a overexpression prevents early cardiac fibrosis in diabetes.

Diabetic cardiomyopathy is a cascade of complex events leading to eventual failure of the heart and cardiac fibrosis being considered as one of its major causes. miR-133a is one of the most abundantly expressed microRNAs in the heart. We investigated the role of miR-133a during severe hyperglycaemia. And, our aim was to find out what role miR-133a plays during diabetes-induced cardiac fibrosis. We saw a drastic decrease in miR-133a expression in the hearts of streptozotocin-induced diabetic animals, as measured by RT-qPCR. This decrease was accompanied by an increase in the transcriptional co-activator EP300 mRNA and major markers of fibrosis [transforming growth factor-ß1, connective tissue growth factor, fibronectin (FN1) and COL4A1]; in addition, focal cardiac fibrosis assessed by Masson's trichome stain was increased. Interestingly, in diabetic mice with cardiac-specific miR-133aa overexpression, cardiac fibrosis was significantly decreased, as observed by RT-qPCR and immunoblotting of COL4A1, ELISA for FN1 and microscopic examination. Furthermore, Cardiac miR-133a overexpression prevented ERK1/2 and SMAD-2 phosphorylation. These findings show that miR-133a could be a potential therapeutic target for diabetes-induced cardiac fibrosis and related cardiac dysfunction.

Glucocorticoid excess induces accumulation of cardiac glycogen and triglyceride: suggested role for AMPK.

Glucocorticoids include steroid hormones released from the adrenal cortex or synthetic analogues developed for various inflammatory and immune disorders. GCs are known to play an important role in maintaining the body's metabolic balance, but their irregular activity has been associated with complications like Cushing's syndrome, insulin resistance, and heart disease. Conventional GC action is through their nuclear receptor activation, but specific and non-specific membrane bound receptor mediated non-genomic actions have also been reported. GCs increase AMPK phosphorylation at Thr172, in addition to augmenting AMPK protein and gene expressions. AMPK is insulin mimetic in many of its actions like glucose uptake and inhibition of lipolysis, and these properties of AMPK are made used in conditions like insulin resistance and diabetes. Nevertheless, if AMPK is activated by GC in the absence of diabetes or decreased insulin signaling, accumulation of substrates in the form of glycogen and triglycerides could precipitate cardiac abnormalities. Glycogen storage can lead to many disorders like hypertrophy, conduction system disease and Wolff Parkinson White syndrome. TG accumulation is associated with generation of free radicals, ceramide formation, mitochondrial dysfunction and cardiac cell death. In this review, we outline the cardiometabolic changes associated with GC, especially related to augmentation in AMPK, and link these changes to cardiac dysfunction.

FoxO1 is crucial for sustaining cardiomyocyte metabolism and cell survival.

Diabetic cardiomyopathy is a term used to describe cardiac muscle damage-induced heart failure. Multiple structural and biochemical reasons have been suggested to induce this disorder. The most prominent feature of the diabetic myocardium is attenuated insulin signalling that reduces survival kinases (Akt), potentially switching on protein targets like FoxOs, initiators of cell death. FoxO1, a prominent member of the forkhead box family and subfamily O of transcription factors and produced from the FKHR gene, is involved in regulating metabolism, cell proliferation, oxidative stress response, immune homeostasis, pluripotency in embryonic stem cells, and cell death. In this review we describe distinctive functions of FoxOs, specifically FoxO1 under conditions of nutrient excess, insulin resistance and diabetes, and its manipulation to restore metabolic equilibrium to limit cardiac damage due to cell death. Because FoxO1 helps cardiac tissue to combat a variety of stress stimuli, it could be a major determinant in regulating diabetic cardiomyopathy. In this regard, we highlight studies from our group and others who illustrate how cardiac tissue-specific FoxO1 deletion protects the heart against cardiomyopathy and how its down-regulation in endothelial tissue could prevent against atherosclerotic plaques. In addition, we also describe studies that show FoxO1's beneficial qualities by highlighting their role in inducing anti-oxidant, autophagic, and anti-apoptotic genes under stress conditions of ischaemia-reperfusion and myocardial infarction. Thus, the aforementioned FoxO1 traits could be useful in curbing cardiac tissue-specific impairment of function following diabetes.

Diabetes triggers a PARP1 mediated death pathway in the heart through participation of FoxO1.

Cardiomyocyte cell death is a major contributing factor for diabetic cardiomyopathy, and multiple mechanisms have been proposed for its development. We hypothesized that following diabetes, an increased nuclear presence of the Forkhead transcription factor, FoxO1, could turn on cardiac cell death through mediation of nitrosative stress. Streptozotocin (100 mg/kg) was used to induce irreversible hyperglycemia in Wistar rats, and heart tissues and blood samples extracted starting from 1 to 4 days. Diazoxide (100 mg/kg), which produced acute reversible hyperglycemia, were followed for up to 12 h. In both animal models of hyperglycemia, attenuation of survival signals was accompanied by increased nuclear FoxO1. This was accompanied by a simultaneous increase in iNOS expression and iNOS induced protein nitrosylation of GAPDH, increased GAPDH binding to Siah1 and facilitated nuclear translocation of the complex. Even though caspase-3 was cleaved during diabetes, its nitrosylation modification affected its ability to inactivate PARP. As a result, there was PARP activation followed by nuclear compartmentalization of AIF, and increased phosphatidyl serine externalization. Our data suggests a role for FoxO1 mediated iNOS induced S-nitrosylation of target proteins like GAPDH and caspase-3 in initiating cardiac cell death following hyperglycemia, and could explain the impact of glycemic control in preventing cardiovascular disease in patients with diabetes.