Jessica Hernandez

Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria.

AMP‐kinase (AMPK) activation reduces cardiac hypertrophy, although underlying molecular mechanisms remain unclear. In this study, we elucidated the anti‐hypertrophic action of metformin, specifically, the role of the AMPK/eNOS/p53 pathway. H9c2 rat cardiomyocytes were treated with angiotensin II (AngII) for 24 hrs in the presence or absence of metformin (AMPK agonist), losartan [AngII type 1 receptor (AT1R) blocker], Nω‐nitro‐L‐arginine methyl ester (L‐NAME, pan‐NOS inhibitor), splitomicin (SIRT1 inhibitor) or pifithrin‐α (p53 inhibitor). Results showed that treatment with metformin significantly attenuated AngII‐induced cell hypertrophy and death. Metformin attenuated AngII‐induced activation (cleavage) of caspase 3, Bcl‐2 down‐regulation and p53 up‐regulation. It also reduced AngII‐induced AT1R up‐regulation by 30% (P < 0.05) and enhanced AMPK phosphorylation by 99% (P < 0.01) and P‐eNOS levels by 3.3‐fold (P < 0.01). Likewise, losartan reduced AT1R up‐regulation and enhanced AMPK phosphorylation by 54% (P < 0.05). The AMPK inhibitor, compound C, prevented AT1R down‐regulation, indicating that metformin mediated its effects via AMPK activation. Beneficial effects of metformin and losartan converged on mitochondria that demonstrated high membrane potential (Δψm) and low permeability transition pore opening. Thus, this study demonstrates that the anti‐hypertrophic effects of metformin are associated with AMPK‐induced AT1R down‐regulation and prevention of mitochondrial dysfunction through the SIRT1/eNOS/p53 pathway.

The beneficial effects of AMP kinase activation against oxidative stress are associated with prevention of PPARα-cyclophilin D interaction in cardiomyocytes

AMP kinase (AMPK) plays an important role in the regulation of energy metabolism in cardiac cells. Furthermore, activation of AMPK protects the heart from myocardial infarction and heart failure. The present study examines whether or not AMPK affects the peroxisome proliferator-activated receptor-α (PPARα)/mitochondria pathway in response to acute oxidative stress in cultured cardiomyocytes. Cultured H9c2 rat embryonic cardioblasts were exposed to H2O2-induced acute oxidative stress in the presence or absence of metformin, compound C (AMPK inhibitor), GW6471 (PPARα inhibitor), or A-769662 (AMPK activator). Results showed that AMPK activation by metformin reverted oxidative stress-induced inactivation of AMPK and prevented oxidative stress-induced cell death. In addition, metformin attenuated reactive oxygen species generation and depolarization of the inner mitochondrial membrane. The antioxidative effects of metformin were associated with the prevention of mitochondrial DNA damage in cardiomyocytes. Coimmunoprecipitation studies revealed that metformin abolished oxidative stress-induced physical interactions between PPARα and cyclophilin D (CypD), and the abolishment of these interactions was associated with inhibition of permeability transition pore formation. The beneficial effects of metformin were not due to acetylation or phosphorylation of PPARα in response to oxidative stress. In conclusion, this study demonstrates that the protective effects of metformin-induced AMPK activation against oxidative stress converge on mitochondria and are mediated, at least in part, through the dissociation of PPARα-CypD interactions, independent of phosphorylation and acetylation of PPARα and CypD.

Mitochondria-targeted antioxidant preserves contractile properties and mitochondrial function of skeletal muscle in aged rats

Mitochondrial dysfunction plays a central role in the pathogenesis of sarcopenia associated with a loss of mass and activity of skeletal muscle. In addition to energy deprivation, increased mitochondrial ROS damage proteins and lipids in aged skeletal muscle. Therefore, prevention of mitochondrial ROS is important for potential therapeutic strategies to delay sarcopenia. This study elucidates the pharmacological efficiency of the new developed mitochondria-targeted ROS and electron scavenger, XJB-5-131 (XJB) to restore muscle contractility and mitochondrial function in aged skeletal muscle. Male adult (5-month old) and aged (29-month old) Fischer Brown Norway (F344/BN) rats were treated with XJB for four weeks and contractile properties of single skeletal muscle fibres and activity of mitochondrial ETC complexes were determined at the end of the treatment period. XJB-treated old rats showed higher muscle contractility associated with prevention of protein oxidation in both muscle homogenate and mitochondria compared with untreated counterparts. XJB-treated animals demonstrated a high activity of the respiratory complexes I, III, and IV with no changes in citrate synthase activity. These data demonstrate that mitochondrial ROS play a causal role in muscle weakness, and that a ROS scavenger specifically targeted to mitochondria can reverse age-related alterations of mitochondrial function and improve contractile properties in skeletal muscle.

Type 2 diabetes mellitus and colorectal neoplasia risk in Hispanics: a case-control study.

AIMS There is inconclusive evidence regarding the potential link between diabetes mellitus (DM) and colorectal cancer (CRC). Associations between type 2 DM and colorectal neoplasia (CRN; colorectal cancer and/or adenomas) have not been well studied in Hispanics, an ethnic minority at high risk for type 2 DM. This study aims to assess the association between type 2 DM and CRN in Hispanics. METHODS Hispanics with incident CRN and colonoscopy-negative controls from 2005 to 2009 were evaluated. Diagnosis of type 2 DM was established by previous medical diagnosis and/or use of DM treatments. Unconditional logistic regression was performed to estimate odds ratios for the association between type 2 DM and CRN. RESULTS A total of 451 participants (mean age 61.1±11.9years, 59.6 % men) were evaluated (218 with incident CRC, 77 with colorectal adenomas, and 156 colonoscopy-negative controls). The prevalence of type 2 DM in this study was 25.1%. After adjusting for potential confounding variables, women with type 2 DM were 2.74 (95% CI: 0.94-7.99) times more likely to have CRN and 4.83 times more likely to present with proximal colonic CRN (95% CI: 1.25-18.58) than women without type 2 DM. No statistically significant associations were found between type 2 DM and CRN among men. CONCLUSIONS An increased odds for CRN and proximal location of CRN was observed among Hispanic women with type 2 DM. Since DM is a highly prevalent disease in this population, adherence to routine CRC screening is of outmost importance.

Abstract 1918: Type 2 diabetes mellitus and colorectal neoplasia risk in Puerto Rican Hispanics: A case-control study

Background: Epidemiological studies have provided inconclusive evidence regarding the potential link between type 2 diabetes mellitus (DM) and colorectal cancer (CRC).The association between type 2 DM and colorectal neoplasia (colorectal cancer and/or adenomas) has not been well studied in Hispanics, an ethnic minority at high risk for type 2 DM. Objective: To evaluate the association between type 2 DM and colorectal neoplasia (CRN) in Puerto Rican Hispanic adults enrolled in the studies Epidemiology of Loss of Imprinting in Colorectal Cancer, Familial Colorectal Cancer Registry and the Type 2 diabetes mellitus and colorectal neoplasia risk in Hispanics: A case-control study at the VA Caribbean Healthcare System. Methods: The case-control study included patients with incident CRN and controls with negative colonoscopy and without previous history of CRC or adenomas evaluated from January 1, 2005 to December 31, 2009. Diagnosis of type 2 DM was established by previous medical diagnosis and/or anti-diabetic medications use. Unconditional logistic regression was employed to estimate the odds ratio (OR) between type 2 DM and CRN using STATA 10.0. Results: A total of 422 participants (mean age 60.8 ± 12.1 yrs., 61.1% males), prevalence of type 2 DM was 26.3%. 276 patients with CRN and 146 controls were evaluated. In the cases, the prevalence of colorectal adenomas was 25.4% (70/276) and the prevalence of colorectal cancer was 74.6% (206/276). Colorectal neoplasia were mostly adenocarcinomas (60.4%), located in the distal colon (37.3%), and with TNM stage III (21.4%). Cases were mostly men (p=0.01), had lower education (p Conclusion: We did not observe a statistical significant association between type 2 DM and CRN. Nonetheless, a tendency towards an increase risk of colorectal neoplasia was observed among type 2 DM patients on adjusted analysis. Possible explanation for our lack of association may be related to high prevalence of type 2 DM in cases and controls and/or the high prevalence of obesity in the study sample. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1918. doi:10.1158/1538-7445.AM2011-1918

Pion scattering to 6 sup minus stretched states in sup 24 Mg and sup 26 Mg

Inelastic {pi}{sup {plus minus}} cross-section measurements at pion incident energies of 150 and 180 MeV were made on 6{sup {minus}} states in {sup 24,26}Mg. In particular, we have determined the ({ital f}{sub 7/2}{ital d5/2}{sup {minus}1}){sub 6}{sup {minus}} isoscalar {ital Z}{sub 0}=0.21{plus minus}0.02 strength for the strongest {ital T}=0, {ital J} {sup {pi}}=6{sup {minus}} state located at 12.11{plus minus}0.05 MeV in {sup 24}Mg, and the isoscalar {ital Z}{sub 0}=0.17{plus minus}0.04 and isovector {ital Z}{sub 1}=0.21{plus minus}0.02 strength for the strongest {ital T}=1, {ital J} {sup {pi}}=6{sup {minus}} state located at 9.18 MeV in {sup 26}Mg. The distorted-wave impulse-approximation pion cross-section calculations required a multiplicative normalization factor of 1.2{plus minus}0.1 in order to reproduce the pure isovector strength deduced from electron scattering for the well-known {ital T}=1, {sup {pi}}=6{sup {minus}} state at 15.15 MeV in {sup 24}Mg and the {ital T}=2, {ital J} {sup {pi}}=6{sup {minus}} state at 18.05 MeV in {sup 26}Mg.

Pion scattering to6−stretched states inMg24andMg26

Inelastic {pi}{sup {plus minus}} cross-section measurements at pion incident energies of 150 and 180 MeV were made on 6{sup {minus}} states in {sup 24,26}Mg. In particular, we have determined the ({ital f}{sub 7/2}{ital d5/2}{sup {minus}1}){sub 6}{sup {minus}} isoscalar {ital Z}{sub 0}=0.21{plus minus}0.02 strength for the strongest {ital T}=0, {ital J} {sup {pi}}=6{sup {minus}} state located at 12.11{plus minus}0.05 MeV in {sup 24}Mg, and the isoscalar {ital Z}{sub 0}=0.17{plus minus}0.04 and isovector {ital Z}{sub 1}=0.21{plus minus}0.02 strength for the strongest {ital T}=1, {ital J} {sup {pi}}=6{sup {minus}} state located at 9.18 MeV in {sup 26}Mg. The distorted-wave impulse-approximation pion cross-section calculations required a multiplicative normalization factor of 1.2{plus minus}0.1 in order to reproduce the pure isovector strength deduced from electron scattering for the well-known {ital T}=1, {sup {pi}}=6{sup {minus}} state at 15.15 MeV in {sup 24}Mg and the {ital T}=2, {ital J} {sup {pi}}=6{sup {minus}} state at 18.05 MeV in {sup 26}Mg.