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The attribution of seizure freedom is yet to be achieved for patients suffering from refractory epilepsy, e.g. Dravet Syndrome (DS). The confined ability of mono-chemical entity-based antiseizure drugs (ASDs) to act directly at genomic level is one of the factors, combined with undetermined seizure triggers lead to recurrent seizure (RS) in DS, abominably affecting the sub-genomic architecture of neural cells. Thus, the RS and ASD appear to be responsible for the spectrum of exorbitant clinical pathology. The RS distresses the 5-HT-serotonin pathway, hypomethylates genes of CNS, and modulates the microRNA (miRNA)/long non-coding RNA (lncRNA), eventually leading to frozen molecular alterations. These changes shall be reverted by compatible epigenetic regulators (EGR) like, miRNA and lncRNA from Breast milk (BML) and Bacopa monnieri (BMI). The absence of studious seizure in SCN1A mutation-positive babies for the first 6 months raises the possibility that the consequences of mutation in SCN1A are subsidized by EGRs from BML. EGR-dependent-modifier gene effect is likely imposed by the other members of the SCN family. Therefore, we advocate that miRNA/lncRNA from BML and bacosides/miRNA from BMI buffer the effect of SCN1A mutation by sustainably maintaining modifier gene effect in the aberrant neurons. The presence of miRNA-155-5p, -30b-5p, and -30c-5p family in BML and miR857, miR168, miR156, and miR158 in BMI target at regulating SCN family and CLCN5 as visualized by Cystoscope. Thus, we envisage that the possible effects of EGR might include (a) upregulating the haploinsufficient SCN1A strand, (b) down-regulating seizure-elevated miRNA, (c) suppressing the seizure-induced methyltransferases, and (d) enhancing the GluN2A subunit of NMDA receptor to improve cognition. The potential of these EGRs from BML and BML is to further experimentally strengthen, long-haul step forward in molecular therapeutics.

Cardiovascular disease is the leading cause of morbidity and mortality all over the world. Emerging evidence emphasize the importance of extracellular vesicles (EVs) in the cell to cell communication in the cardiovascular system which is majorly mediated through non-coding RNA cargo. Advancement in sequencing technologies revealed a major proportion of human genome is composed of non-coding RNAs viz., miRNAs, lncRNAs, tRNAs, snoRNAs, piRNAs and rRNAs. However, our understanding of the role of ncRNAs-containing EVs in cardiovascular health and disease is still in its infancy. This book chapter provides a comprehensive update on our understanding on the role of EVs derived ncRNAs in the cardiovascular pathophysiology and their therapeutic potential.

Cardiovascular disease is the leading cause of morbidity and mortality all over the world. Emerging evidence emphasize the importance of extracellular vesicles (EVs) in the cell to cell communication in the cardiovascular system which is majorly mediated through non-coding RNA cargo. Advancement in sequencing technologies revealed a major proportion of human genome is composed of non-coding RNAs viz., miRNAs, lncRNAs, tRNAs, snoRNAs, piRNAs and rRNAs. However, our understanding of the role of ncRNAs-containing EVs in cardiovascular health and disease is still in its infancy. This book chapter provides a comprehensive update on our understanding on the role of EVs derived ncRNAs in the cardiovascular pathophysiology and their therapeutic potential.

Chronic alcohol consumption induces myocardial damage and a type of non-ischemic cardiomyopathy termed alcoholic cardiomyopathy, where mitochondrial ultrastructural damages and suppressed fusion activity promote cardiomyocyte apoptosis. The aim of the present study is to determine the role of mitochondrial fission proteins and/or other proteins that localise on cardiac mitochondria for apoptosis upon ethanol consumption. In vivo and in vitro chronic alcohol exposure increased mitochondrial Drp1 levels but knockdown of the same did not confer cardioprotection in H9c2 cells. These cells displayed downregulated expression of MFN2 and OPA1 for Bak-mediated cytochrome c release and apoptosis. Dysregulated PTEN/AKT cell survival signal in both ethanol treated and Drp1 knockdown cells augmented oxidative stress by promoting mitochondrial PTEN-L and MFN1 interaction. Inhibiting this interaction with VO–OHpic, a reversible PTEN inhibitor, prevented Bak insertion into the mitochondria and release of cytochrome c to cytoplasm. Thus, our study provides evidence that Drp1-mediated mitochondrial fission is dispensable for ethanol-induced cardiotoxicity and that stress signals induce mitochondrial PTEN-L accumulation for structural and functional dyshomeostasis. Our in vivo results also demonstrates the therapeutic potential of VO–OHpic for habitual alcoholics developing myocardial dysfunction.

Summary: Mitochondria shape cytosolic calcium ([Ca2+]c) transients and utilize the mitochondrial Ca2+ ([Ca2+]m) in exchange for bioenergetics output. Conversely, dysregulated [Ca2+]c causes [Ca2+]m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ uptake exhibited elevated [Ca2+]c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca2+-induced shape change that is distinct from mitochondrial fission and swelling. [Ca2+]c elevation, but not MCU-mediated Ca2+ uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca2+-dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca2+ sensor that decodes metazoan Ca2+ signals as MiST. : Metazoan Ca2+ signal determines mitochondrial shape transition (MiST) and cellular quality control. Nemani et al. find that mitochondria undergo shape changes upon Ca2+ stress. MiST is distinct from matrix Ca2+-induced swelling and mitochondrial dynamics. The conserved Ca2+ sensor Miro1 enables MiST and promotes autophagy/mitophagy. Keywords: mitochondrial shape, MiST, calcium, Miro, EF hand, PTP, MCU, mitophagy, autophagy, mitochondrial dynamics

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly contagious strain of coronavirus that causes Coronavirus Disease 2019 (COVID-19) infection, which has distressed the world's health and wealth. This Global Pandemic outbreak has affected public health enormously at various customs. The investigation of SARS-CoV-2 is still at infancy; however, based on the available reports, this review gives an overview of the epidemiology, genomic landscape, diversity of SARS-CoV-2, viral genome pathogenic interactions, associating factors for COVID-19 infections, post-COVID-19, disease manifestations with their comorbidities, the major obstacles and the preventive measures along with current vaccine strategies of SARS-CoV-2. This review also summarizes all the relevant evidence of COVID-19 illness, which can provide valuable information on the SARS-CoV-2 genome and its mode of action strategies, thus delivering additional knowledge about COVID-19.

Mitochondrial integrity is indispensable for cardiac health. With the advent of modern imaging technologies, mitochondrial motility and dynamics within the cell are extensively studied. Terminally differentiated and well-structured cardiomyocytes depict little mitochondrial division and fusion, questioning the contribution of mitochondrial fusion proteins (Mitofusin 1/2 and Optic Atrophy 1 protein) and fission factors (Dynamin-like protein 1 and mitochondrial fission 1 protein) in cardiomyocyte homeostasis. Emerging evidences suggest that alterations in mitochondrial morphology from globular, elongated network to punctate fragmented disconnected structures are a pathological response to ensuing cardiac stress and cardiomyocyte cell death, bringing forth the following question, "what maintains this balance between fusion and fission?" The answer hinges upon the classical "junk" DNA: microRNAs, the endogenous non-coding RNAs. Because of their essential role in numerous signaling pathways, microRNAs are considered to play major roles in the pathogenesis of various diseases. Mitochondria are not exempted from microRNA-mediated regulation. This review defines the importance of mitochondrial structural integrity and the microRNA-mitochondrial dynamics tandem, an imminent dimension of the cardiac homeostasis network. Elucidating their coordinated interaction could spur RNA-based therapeutics for resuscitating functional mitochondrial population during cardiovascular disorders.

Ca2+ dynamics and oxidative signaling are fundamental mechanisms for mitochondrial bioenergetics and cell function. The MCU complex is the major pathway by which these signals are integrated in mitochondria. Whether and how these coactive elements interact with MCU has not been established. As an approach towards understanding the regulation of MCU channel by oxidative milieu, we adapted inflammatory and hypoxia models. We identified the conserved cysteine 97 to be the only reactive thiol in human MCU that undergoes S-glutathionylation. Furthermore, biochemical, structural and superresolution imaging analysis revealed that MCU oxidation promotes MCU higher-order oligomer formation. Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher [Ca2+]m uptake rate, elevated mROS and enhanced [Ca2+]m overload-induced cell death. In contrast, these effects were largely independent of MCU interaction with its regulators. These findings reveal a distinct functional role for Cys-97 in ROS sensing and regulation of MCU activity.

Oxidant stress induces constitutive calcium entry by tacking glutathiones onto the Orai CRAC channel activator STIM1., Oxidant stress influences many cellular processes, including cell growth, differentiation, and cell death. A well-recognized link between these processes and oxidant stress is via alterations in Ca2+ signaling. However, precisely how oxidants influence Ca2+ signaling remains unclear. Oxidant stress led to a phenotypic shift in Ca2+ mobilization from an oscillatory to a sustained elevated pattern via calcium release–activated calcium (CRAC)–mediated capacitive Ca2+ entry, and stromal interaction molecule 1 (STIM1)– and Orai1-deficient cells are resistant to oxidant stress. Functionally, oxidant-induced Ca2+ entry alters mitochondrial Ca2+ handling and bioenergetics and triggers cell death. STIM1 is S-glutathionylated at cysteine 56 in response to oxidant stress and evokes constitutive Ca2+ entry independent of intracellular Ca2+ stores. These experiments reveal that cysteine 56 is a sensor for oxidant-dependent activation of STIM1 and demonstrate a molecular link between oxidant stress and Ca2+ signaling via the CRAC channel.

Ca2+ dynamics and oxidative signaling are fundamental mechanisms for mitochondrial bioenergetics and cell function. The MCU complex is the major pathway by which these signals are integrated in mitochondria. Whether and how these coactive elements interact with MCU have not been established. As an approach toward understanding the regulation of MCU channel by oxidative milieu, we adapted inflammatory and hypoxia models. We identified the conserved cysteine 97 (Cys-97) to be the only reactive thiol in human MCU that undergoes S-glutathionylation. Furthermore, biochemical, structural, and superresolution imaging analysis revealed that MCU oxidation promotes MCU higher order oligomer formation. Both oxidation and mutation of MCU Cys-97 exhibited persistent MCU channel activity with higher [Ca2+]m uptake rate, elevated mROS, and enhanced [Ca2+]m overload-induced cell death. In contrast, these effects were largely independent of MCU interaction with its regulators. These findings reveal a distinct functional role for Cys-97 in ROS sensing and regulation of MCU activity.

Background Cardiac isoform of alpha 2 macroglobulin (CA2M), a serum protein (182000Mr) has been used as a diagnostic molecular marker for cardiac manifestations in HIV and diabetic patients. This study investigates the reliability of CA2M as an early diagnostic marker for cardiac manifestations in HIV patients and factors that could possibly influence their levels. Methods A total of 206 serum samples were analysed from HIV patients with cardiac diseases (68), with non-cardiac ailments (48), opportunistic infections (34) and without other co-morbidities (56). The immuno-cross-reactivity between human serum CA2M and anti-rat CA2M antibody was tested and quantified by sandwich enzyme linked immunosorbent assay (ELISA). Results The CA2M levels were high in HIV patients with cardiac diseases irrespective of the manifestations. The CA2M levels were not influenced by opportunistic infections, non-cardiac ailments and patient parameters like age, sex, duration of illness, past history of other co-morbidities. Conclusion CA2M can be used as a reliable early diagnostic marker in HIV patients with cardiac manifestations. CA2M levels were not influenced by other patient parameters.

Rationale: Peroxisome proliferator-activated receptors (PPARs) (α, γ, and δ/β) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPARδ deficiency in mice leads to depressed myocardial fatty acid oxidation, bioenergetics, and premature death with lipotoxic cardiomyopathy. Objective: To explore the essential role of PPARδ in the adult heart. Methods and Results: We investigated the consequences of inducible short-term PPARδ knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPARδ knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase and manganese superoxide dismutase, leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPARγ coactivator-1 were substantially decreased in the short-term PPARδ deficient heart, concomitant with a decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPARδ knockout hearts. Consequently, PPARδ deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy. Conclusions: PPARδ is an essential regulator of cardiac mitochondrial protection and biogenesis and PPARδ activation can be a potential therapeutic target for cardiac disorders.