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Mitochondrial morphological dynamics affect the outcome of ischemic heart damage and pathogenesis. Recently, mitochondrial fission protein dynamin-related protein 1 (Drp1) has been identified as a mediator of mitochondrial morphological changes and cell death during cardiac ischemic injury. In this study, we report a unique relationship between Pim-1 activity and Drp1 regulation of mitochondrial morphology in cardiomyocytes challenged by ischemic stress. Transgenic hearts overexpressing cardiac Pim-1 display reduction of total Drp1 protein levels, increased phosphorylation of Drp1- S⁶³⁷, and inhibition of Drp1 localization to the mitochondria. Consistent with these findings, adenoviral-induced Pim-1 neonatal rat cardiomyocytes (NRCMs) retain a reticular mitochondrial phenotype after simulated ischemia (sI) and decreased Drp1 mitochondrial sequestration. Interestingly, adenovirus Pim-dominant negative NRCMs show increased expression of Bcl-2 homology 3 (BH3)-only protein p53 up-regulated modulator of apoptosis (PUMA), which has been previously shown to induce Drp1 accumulation at mitochondria and increase sensitivity to apoptotic stimuli. Overexpression of the p53 up-regulated modulator of apoptosis–dominant negative adenovirus attenuates localization of Drp1 to mitochondria in adenovirus Pim-dominant negative NRCMs promotes reticular mitochondrial morphology and inhibits cell death during sI. Therefore, Pim-1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology in response to sI.

Mechanistic target of rapamycin complex 1 (mTORC1), necessary for cellular growth, is regulated by intracellular signaling mediating inhibition of mTORC1 activation. Among mTORC1 regulatory binding partners, the role of Proline Rich AKT Substrate of 40 kDa (PRAS40) in controlling mTORC1 activity and cellular growth in response to pathological and physiological stress in the heart has never been addressed. This report shows PRAS40 is regulated by AKT in cardiomyocytes and that AKT-driven phosphorylation relieves the inhibitory function of PRAS40. PRAS40 overexpression in vitro blocks mTORC1 in cardiomyocytes and decreases pathological growth. Cardiomyocyte-specific overexpression in vivo blunts pathological remodeling after pressure overload and preserves cardiac function. Inhibition of mTORC1 by PRAS40 preferentially promotes protective mTORC2 signaling in chronic diseased myocardium. In contrast, strong PRAS40 phosphorylation by AKT allows for physiological hypertrophy both in vitro and in vivo, whereas cardiomyocyte-specific overexpression of a PRAS40 mutant lacking capacity for AKT-phosphorylation inhibits physiological growth in vivo, demonstrating that AKT-mediated PRAS40 phosphorylation is necessary for induction of physiological hypertrophy. Therefore, PRAS40 phosphorylation acts as a molecular switch allowing mTORC1 activation during physiological growth, opening up unique possibilities for therapeutic regulation of the mTORC1 complex to mitigate pathologic myocardial hypertrophy by PRAS40.

Diabetes is a multi‐organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. In the liver, insulin resistance contributes to hyperglycaemia and hyperlipidaemia, which further worsens the metabolic profile. Defects in mTOR signalling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. This study shows that specific mTORC1 inhibition by PRAS40 prevents the development of diabetic cardiomyopathy. This phenotype was associated with improved metabolic function, blunted hypertrophic growth and preserved cardiac function. In addition PRAS40 treatment improves hepatic insulin sensitivity and reduces systemic hyperglycaemia in obese mice. Thus, unlike rapamycin, mTORC1 inhibition with PRAS40 improves metabolic profile in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic‐related diseases. Synopsis Over‐expressing PRAS40 mice are protected against diabetic cardiomyopathy by reducing mTORC1 levels thereby preventing cellular remodeling and dysfunction. This data suggest a novel therapeutic approach against diabeticrelated diseases. Diabetic cardiomyopathy is prevented by mTORC1 inhibition with PRAS40 Insulin sensitivity is improved by PRAS40 in diabetic hearts Adverse metabolic remodeling in obese mice is prevented by mTORC1 inhibition Hepatic insulin signaling is improved by PRAS40 mediated inhibition of mTORC1 Graphical Abstract Over‐expressing PRAS40 mice are protected against diabetic cardiomyopathy by reducing mTORC1 levels thereby preventing cellular remodeling and dysfunction. This data suggest a novel therapeutic approach against diabeticrelated diseases.

Nucleolar stress, characterized by loss of nucleolar integrity, has not been described in the cardiac context. In addition to ribosome biogenesis, nucleoli are critical for control of cell proliferation and stress responses. Our group previously demonstrated induction of the nucleolar protein nucleostemin (NS) in response to cardiac pathological insult. NS interacts with nucleophosmin (NPM), a marker of nucleolar stress with cytoprotective properties. The dynamic behavior of NS and NPM reveal that nucleolar disruption is an early event associated with stress response in cardiac cells. Rapid translocation of NS and NPM to the nucleoplasm and suppression of new preribosomal RNA synthesis occurs in both neonatal rat cardiomyocytes (NRCM) and cardiac progenitor cells (CPC) upon exposure to doxorubicin or actinomycin D. Silencing of NS significantly increases cell death resulting from doxorubicin treatment in CPC, whereas NPM knockdown alone induces cell death. Overexpression of either NS or NPM significantly decreases caspase 8 activity in cultured cardiomyocytes challenged with doxorubicin. The presence of altered nucleolar structures resulting from myocardial infarction in mice supports the model of nucleolar stress as a general response to pathological injury. Collectively, these findings serve as the initial description of myocardial nucleolar stress and establish the postulate that nucleoli acts as sensors of stress, regulating the cellular response to pathological insults.

Pim-1 kinase exerts potent cardioprotective effects in the myocardium downstream of AKT, but the participation of Pim-1 in cardiac hypertrophy requires investigation. Cardiac-specific expression of Pim-1 (Pim-WT) or the dominant-negative mutant of Pim-1 (Pim-DN) in transgenic mice together with adenoviral-mediated overexpression of these Pim-1 constructs was used to delineate the role of Pim-1 in hypertrophy. Transgenic overexpression of Pim-1 protects mice from pressure-overload-induced hypertrophy relative to wild-type controls as evidenced by improved hemodynamic function, decreased apoptosis, increases in antihypertrophic proteins, smaller myocyte size, and inhibition of hypertrophic signaling after challenge. Similarly, Pim-1 overexpression in neonatal rat cardiomyocyte cultures inhibits hypertrophy induced by endothelin-1. On the cellular level, hearts of Pim-WT mice show enhanced incorporation of BrdU into myocytes and a hypercellular phenotype compared to wild-type controls after hypertrophic challenge. In comparison, transgenic overexpression of Pim-DN leads to dilated cardiomyopathy characterized by increased apoptosis, fibrosis, and severely depressed cardiac function. Furthermore, overexpression of Pim-DN leads to reduced contractility as evidenced by reduced Ca²⁺ transient amplitude and decreased percentage of cell shortening in isolated myocytes. These data support a pivotal role for Pim-1 in modulation of hypertrophy by impacting responses on molecular, cellular, and organ levels.

Ability of the heart to undergo pathological or physiological hypertrophy upon increased wall stress is critical for long-term compensatory function in response to increased workload demand. While substantial information has been published on the nature of the fundamental molecular signaling involved in hypertrophy, the role of extracellular matrix protein Fibronectin (Fn) in hypertrophic signaling is unclear. The objective of the study was to delineate the role of Fn during pressure overload-induced pathological cardiac hypertrophy and physiological growth prompted by exercise. Genetic conditional ablation of Fn in adulthood blunts cardiomyocyte hypertrophy upon pressure overload via attenuated activation of nuclear factor of activated T cells (NFAT). Loss of Fn delays development of heart failure and improves survival. In contrast, genetic deletion of Fn has no impact on physiological cardiac growth induced by voluntary wheel running. Down-regulation of the transcription factor c/EBPβ (Ccaat-enhanced binding protein β), which is essential for induction of the physiological growth program, is unaffected by Fn deletion. Nuclear NFAT translocation is triggered by Fn in conjunction with up-regulation of the fetal gene program and hypertrophy of cardiomyocytes in vitro. Furthermore, activation of the physiological gene program induced by insulin stimulation in vitro is attenuated by Fn, whereas insulin had no impact on Fn-induced pathological growth program. Fn contributes to pathological cardiomyocyte hypertrophy in vitro and in vivo via NFAT activation. Fn is dispensable for physiological growth in vivo, and Fn attenuates the activation of the physiological growth program in vitro.

Myocardial aging is an independent risk factor for cardiovascular disease. Cardiac aging promotes adverse myocardial remodeling and the accumulation of poorly functioning senescent cells, leading to a decline in cardiac performance. Pathological remodeling is associated, in part, with changes occurring at the mitochondrial level exacerbating heart disease. Mitochondrial alteration during heart failure includes cellular changes in fuel utilization and alterations in mitochondrial dynamics, implicating mitochondrial biology as an important facet of cardiac aging biology. Pim kinases are protective in a cardiac context, in part by maintaining mitochondrial integrity. However, Pim protein expression diminishes during cardiac aging. Therefore, cardiac mitochondrial dynamics and metabolism were investigated in relationship to Pim kinases. The relationship between Pim1 and Dynamin Related Protein 1 (Drp1) was assessed as a novel mechanism to prevent Drp1 mediated fission. Drp1 mediates fission by mitochondrial localization during pathological challenge, sensitizing cardiomyocytes to apoptosis. Overexpressing Pim1 decreased total Drp1 levels, increased phosphorylation of Drp1 at serine 637, and inhibited Drp1 localization to mitochondria while preserving reticular morphology after simulated ischemia. Overexpression of Pim1 dominant negative (PDN) increased total mitochondrial Drp1, reduced phospho Drp1, and increased mitochondrial fragmentation. PDN hearts exhibit upregulation of BH3 only protein p53 upregulated modulator of apoptosis (PUMA) that mediates mitochondrial Drp1 accumulation and increased sensitivity to apoptotic stimuli. Therefore, Pim1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology. Cellular pathological hypertrophic remodeling and fetal gene program activation was evident in Pim Triple KnockOut (PTKO) mice phenotypic of cardiac aging. Cardiomyocyte senescence manifested by increased expression of cell cycle inhibitors and decreased telomere lengths. Changes in expression of PPARγ coactivator-1 (PGC- 1) α and β led to alterations in mitochondrial ultrastructure and metabolism. An energystarved phenotype was determined with decreased ATP and increased pAMPK:AMPK ratio, confirming changes in the PPAR signaling circuit. Overexpression of PGC-1α and c-Myc rescued changes in metabolism and restored energy homeostasis. These studies confirm the significant impact of Pim kinases on mitochondrial biology and support the notion to utilize Pim as a tool to prevent cardiac aging by preserving mitochondrial dynamics and metabolism.

Myocardial aging is an independent risk factor for cardiovascular disease. Cardiac aging promotes adverse myocardial remodeling and the accumulation of poorly functioning senescent cells, leading to a decline in cardiac performance. Pathological remodeling is associated, in part, with changes occurring at the mitochondrial level exacerbating heart disease. Mitochondrial alteration during heart failure includes cellular changes in fuel utilization and alterations in mitochondrial dynamics, implicating mitochondrial biology as an important facet of cardiac aging biology. Pim kinases are protective in a cardiac context, in part by maintaining mitochondrial integrity. However, Pim protein expression diminishes during cardiac aging. Therefore, cardiac mitochondrial dynamics and metabolism were investigated in relationship to Pim kinases. The relationship between Pim1 and Dynamin Related Protein 1 (Drp1) was assessed as a novel mechanism to prevent Drp1 mediated fission. Drp1 mediates fission by mitochondrial localization during pathological challenge, sensitizing cardiomyocytes to apoptosis. Overexpressing Pim1 decreased total Drp1 levels, increased phosphorylation of Drp1 at serine 637, and inhibited Drp1 localization to mitochondria while preserving reticular morphology after simulated ischemia. Overexpression of Pim1 dominant negative (PDN) increased total mitochondrial Drp1, reduced phospho Drp1, and increased mitochondrial fragmentation. PDN hearts exhibit upregulation of BH3 only protein p53 upregulated modulator of apoptosis (PUMA) that mediates mitochondrial Drp1 accumulation and increased sensitivity to apoptotic stimuli. Therefore, Pim1 activity prevents Drp1 compartmentalization to the mitochondria and preserves reticular mitochondrial morphology. Cellular pathological hypertrophic remodeling and fetal gene program activation was evident in Pim Triple KnockOut (PTKO) mice phenotypic of cardiac aging. Cardiomyocyte senescence manifested by increased expression of cell cycle inhibitors and decreased telomere lengths. Changes in expression of PPARγ coactivator-1 (PGC-1) and β led to alterations in mitochondrial ultrastructure and metabolism. An energy-starved phenotype was determined with decreased ATP and increased pAMPK:AMPK ratio, confirming changes in the PPAR signaling circuit. Overexpression of PGC-1 and c-Myc rescued changes in metabolism and restored energy homeostasis. These studies confirm the significant impact of Pim kinases on mitochondrial biology and support the notion to utilize Pim as a tool to prevent cardiac aging by preserving mitochondrial dynamics and metabolism.

Vulnerability assessment of an urban area to earthquake hazards is the requirement to attaining sustainable urban resilience. Quetta city is the capital of the province of Balochistan surrounded by mountains with the existence of many active faults. The main objective of the current study was to assess the earthquake vulnerability in Quetta valley. A total of 400 households were selected for the primary household survey. A simple random sampling technique is employed using proportionate allocation method because of the heterogeneity of the area in terms of population. Secondary data was taken from the Geological Survey of Pakistan (GSP), the Pakistan Bureau of Statistics (PBS), and the United States Geological Survey (USGS). Analytical Hierarchal Process (AHP) & Weighted Linear Combination (WLC) methods are used to identify earthquake vulnerability. The results of the study reveal that the Northwestern and Southeastern parts of Quetta are seismically vulnerable to earthquake hazard; its geology coupled with the human dimension indicates a more disastrous future events. Results of the composite earthquake vulnerability show that seven out of thirteen Zones of Quetta city are highly vulnerable to all four components of vulnerability. Four Zones have a medium level of vulnerability and only two Zones are considered low earthquake vulnerable Zones in the study area. The topmost influential factors that make Quetta city highly earthquake-vulnerable are the soil type (0.45), peak ground acceleration (0.34), proximity to the hospitals and fire service stations (0.22, 0.21), elderly population (0.22) and fault lines (0.21) as shown in Fig. 12. This research study has significant implications for urban planners and provides a risk reduction platform in order to reduce future earthquake losses and make Quetta city more resilient and sustainable.

Background The popularity of fermented foods such as kefir, kuniss, and tofu has been greatly increasing over the past several decades, and the ability of probiotic bacteria to exert anticancer effects has recently become the focus of research. While we have recently demonstrated the ability of the novel kefir product PFT (Probiotics Fermentation Technology) to exert anticancer effects in vitro, here we demonstrate its ability to inhibit Ehrlich ascites carcinoma (EAC) in mice. Methods Mice were inoculated intramuscularly with EAC cells to develop solid tumors. PFT was administered orally (2 g/kg/day) to mice 6 days/week, either 2 days before tumor cell inoculation or 9 days after inoculation to mice bearing solid tumors. Tumor growth, blood lymphocyte levels, cell cycle progression, apoptosis, apoptotic regulator expression, TNF-α expression, changes in mitochondrial membrane potential (MMP), PCNA, and CD4+ and CD8+ T cells in tumor cells were quantitatively evaluated by flow cytometry or RT-PCR. Further studies in vitro were carried out where EAC cells along with several other human cancer cell lines were cultured in the presence of PFT (0–5 mg/mL). Percent cell viability and IC 50 was estimated by MTT assay. Results Our data shows that PFT exerts the following: 1) inhibition of tumor incidence and tumor growth; 2) inhibition of cellular proliferation via a marked decrease in the expression of tumor marker PCNA; 3) arrest of the tumor cell cycle in the sub-G0/G1 phase, signifying apoptosis; 4) induction of apoptosis in cancer cells via a mitochondrial-dependent pathway as indicated by the up-regulation of p53 expression, increased Bax/Bcl-2 ratio, decrease in the polarization of MMP, and caspase-3 activation; and 5) immunomodulation with an increase in the number of infiltrating CD4 + and CD8 + T cells and an enhancement of TNF-α expression within the tumor. Conclusions PFT reduces tumor incidence and tumor growth in mice with EAC by inducing apoptosis in EAC cells via the mitochondrial-dependent pathway, suppressing cancer cell proliferation, and stimulating the immune system. PFT may be a useful agent for cancer prevention.