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Here, we, for the first time, compared the cardioprotective effects of third-generation vasodilating beta-blocker nebivolol (Neb) and conventional beta-blocker metoprolol (Met) on LPS-induced injury in H9c2 cardiomyoblasts. Our findings denoted that Neb and Met pretreatment diminish LPS-mediated cytotoxicity and oxidative stress. Concomitantly, LPS-triggered inflammatory cytokines activation was significantly suppressed by Neb but not by Met. Pretreatment with either Neb or Met alleviated LPS-mediated mitochondrial impairment by enhancing the expression of genes related to its biogenesis such as PGC-1α, NRF1, and TFAM. On the contrary, Neb but not Met-upregulated mitochondrial fusion-related genes such as OPA, and MFN2. In summary, our findings suggest that Neb and Met treatment significantly ameliorated the LPS-induced cytotoxicity and oxidative stress. Additionally, these findings suggest that Neb but not Met significantly down-regulates LPS-induced proinflammatory factors, probably by enhancing mitochondrial biogenesis and fusion.
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We have recently illustrated that nebivolol can inhibit angiotensin II (Ang II)-mediated signaling in cardiomyoblasts; however, to date, the detailed mechanism for the beneficial effects of nebivolol has not been studied. Here, we investigated whether the inhibition of NO bioavailability by blocking eNOS (endothelial nitric oxide synthase) using L-NG-nitroarginine methyl ester (L-NAME) would attenuate nebivolol-mediated favorable effects on Ang II-evoked signaling in H9c2 cardiomyoblasts. Our data reveal that the nebivolol-mediated antagonistic effects on Ang II-induced oxidative stress were retreated by concurrent pretreatment with L-NAME and nebivolol. Similarly, the expressions of pro-inflammatory markers TNF-α and iNOS stimulated by Ang II were not decreased with the combination of nebivolol plus L-NAME. In contrast, the nebivolol-induced reduction in the Ang II-triggered mTORC1 pathway and the mRNA levels of hypertrophic markers ANP, BNP, and ß-MHC were not reversed with the addition of L-NAME to nebivolol. In compliance with these data, the inhibition of eNOS by L-N5-(1-Iminoethyl) ornithine (LNIO) and its upstream regulator AMP-activated kinase (AMPK) with compound C in the presence of nebivolol showed effects similar to those of the L-NAME plus nebivolol combination on Ang II-mediated signaling. Pretreatment with either compound C plus nebivolol or LNIO plus nebivolol showed similar effects to those of the L-NAME plus nebivolol combination on Ang II-mediated signaling. In conclusion, our data indicate that the rise in NO bioavailability caused by nebivolol via the stimulation of AMPK/eNOS signaling is key for its anti-inflammatory and antioxidant properties but not for its antihypertrophic response upon Ang II stimulation.
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In the current study, the possible outcome of gender difference and genotypic polymorphism of the ABCB1 gene encoding P-glycoprotein on the pharmacokinetics of azithromycin has been evaluated. An open-label, comparative pharmacokinetic study was done in healthy Pakistani volunteers (females (n = 8) and males (n = 8)). They were administered a single 500 mg oral dose of azithromycin. Blood samples (≈5 mL) were collected in heparinized tubes and the HPLC/MS/MS method was used to determine azithromycin plasma levels. ABCB1 polymorphism (single nucleotide polymorphisms) at C3435T, G26SST was performed using the RFLP-PCR method. The Student t test was applied to compare pharmacokinetic parameters of azithromycin between male and female human subjects (at 95% CI) using GraphPad Prism-8. A significant difference was observed in pharmacokinetic parameters between males and females, as Cmax in males (230 ± 80.2 ng/mL) was significantly higher than in females (224.9 ± 75.5 ng/mL), while [Formula: see text] was also significantly higher (p < 0.05) in males (2102 ± 200.3 ng·h-1·mL-1) compared to females (1825.7 ± 225.4 ng·h-1·mL-1). There was a significant variation in Cmax and AUC in three ABCB1 genotyping groups as well. Gender difference and ABCB1 gene polymorphisms have a significant impact on the pharmacokinetics of azithromycin, as they contribute to interindividual variability in therapeutic response.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Azitromicina/farmacocinética , Voluntários Saudáveis , Polimorfismo de Nucleotídeo Único , Caracteres Sexuais , Adulto , Feminino , Humanos , Masculino , Paquistão , Adulto JovemRESUMO
Herein we report the simultaneous detection of dopamine (DA) and uric acid (UA) using polydopamine (PDA) functionalized FeTiO3 nanohexagons. The nanohexagons were hydrothermally synthesized and subsequently functionalized with PDA in a Tris-buffer solution. The PDA functionalized nanostructure was characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared (FTIR), respectively. The SEM and TEM investigations revealed the presence of FeTiO3 nanohexagons along with a peripheral coating of PDA over the nanostructures. The XRD pattern confirmed the formation of the ilmenite structure, while the chemical structure was investigated through XPS and FTIR respectively. Using cyclic voltammetry (CV) the efficacy of FeTiO3-PDA electrode was evaluated toward DA oxidation. The enhanced activity of the functionalized electrode in DA oxidation, as compared to the untreated FeTiO3, may be attributed to the significant presence of hydroxyl, amine, and imine functional groups over the polymer layer. Differential pulse voltammetry (DPV) was utilized for the detection of DA and UA. With a linear range of 50 µM to 250 µM, the detection limits of 0.30 µM and 4.61 µM were determined for DA and UA, respectively. The peak separation of 263 mV between DA and UA demonstrates the sensor's remarkable selectivity. In addition, the study displayed the ability to detect both DA and UA simultaneously, and the validity of the sensor was evaluated in serum samples, respectively.
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In the title compound, [Fe(C5H5)(C25H17Cl3N3O)], the isolated cyclo-penta-dienyl (Cp) ring is disordered over two set of sites in a 0.577â (8):0.423â (8) ratio. The dihedral angle between the other Cp ring and its attached benzene ring is 13.6â (3)°, and that between the benzene ring and the guanidine group is 64.8â (2)°. One of the N-H groups forms both an intra- and an inter-molecular N-Hâ¯O hydrogen bond; the other N-H group does not form any hydrogen bonds. In the crystal, pairs of the inter-molecular N-Hâ¯O hydrogen bonds link the mol-ecules into inversion dimers.
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Mitochondrial dysfunction triggered by increased reactive oxygen species (ROS) generation is involved in the pathogenesis and development of cardiac hypertrophy. Nanoceria (cerium oxide nanoparticle) has powerful ROS-scavenging properties and is considered a potential therapeutic option for curbing ROS-related disorders. Here, we explored the signaling mechanism underlying the protective effects of nanoceria against angiotensin (Ang) II-stimulated pathological response in H9c2 cardiomyoblasts. Our data revealed that pretreatment of H9c2 cardiomyoblasts with nanoceria significantly prevented Ang II-stimulated generation of intracellular ROS, aberrant expression of pro-inflammatory cytokines, and hypertrophy markers. Nanoceria pretreatment increased the mRNA levels of genes regulating the cellular antioxidant defense system (SOD2, MnSOD, CAT) in Ang II-treated cells. Furthermore, nanoceria restored mitochondrial function by decreasing mitochondrial ROS, increasing mitochondrial membrane potential (MMP), and promoting the mRNA expression of genes associated with mitochondrial biogenesis (PGC-1α, TFAM, NRF1, and SIRT3) and mitochondrial fusion (MFN2, OPA1). Collectively, these findings demonstrate the protective effects of nanoceria against Ang II-mediated mitochondrial dysfunction and pathological hypertrophy in H9c2 cells.
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Cardiovascular diseases (CVDs) are the leading cause of death around the world, a trend that will progressively grow over the next decade. Recently, with the advancement of nanotechnology, innovative nanoparticles (NPs) have been efficiently utilized in disease diagnosis and theranostic applications. In this review, we highlighted the benchmark summary of the recently synthesized NPs that are handy for imaging, diagnosis, and treatment of CVDs. NPs are the carrier of drug-delivery payloads actively reaching more areas of the heart and arteries, allowing them novel therapeutic agents for CVDs. Herein, due to the limited availability of literature, we only focused on NPs mechanism in the cardiovascular system and various treatment-based approaches that opens a new window for future research and versatile approach in the field of medical and clinical applications. Moreover, current challenges and limitations for the detection of CVDs has also discussed.
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Doenças Cardiovasculares , Nanopartículas , Humanos , Nanomedicina/métodos , Medicina de Precisão , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/tratamento farmacológico , Nanopartículas/uso terapêutico , Diagnóstico por ImagemRESUMO
Objective: Non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes mellitus (T2DM) often coexist and drive detrimental effects in a synergistic manner. This study was designed to understand the changes in circulating lipid and lipoprotein metabolism in patients with T2DM with or without NAFLD. Methods: Four hundred thirty-four T2DM patients aged 18-60 years were included in this study. Fatty liver was assessed by FibroScan. The comprehensive metabolic lipid profiling of serum samples was assessed by using high-throughput proton NMR metabolomics. Results: Our data revealed a significant association between steatosis and serum total lipids in VLDL and LDL lipoprotein subclasses, while total lipids in HDL subclasses were negatively associated. A significant positive association was found between steatosis and concentration of lipids, phospholipids, cholesterol, and triglycerides in VLDL and LDL subclasses, while HDL subclasses were negatively associated. Furthermore, a significant, association was observed between fibrosis and concentrations of lipids, phospholipids, cholesterol, and triglycerides in very small VLDL, large, and very large HDL subclasses. Subgroup analysis revealed a decrease in the concentrations of lipids, phospholipids, cholesterol, and other lipid biomolecules in patients using antilipemic medications. Conclusion: The metabolomics results provide evidence that patients with T2DM with higher steatosis grades have altered lipid metabolomics compared to patients without steatosis. Increased lipid, phospholipids, cholesterol, and triglycerides concentration of VLDL and LDL subclasses are associated with steatosis in patients with T2DM.
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Ascorbic acid is a vital biomolecule for human beings. When the body's level of ascorbic acid is abnormal, it can lead to a number of illnesses. Its appropriate concentration is necessary for the oxidation of prostaglandins and cyclic adenosine monophosphate, the production of dopamine, norepinephrine, epinephrine, and carnitine, and the expansion and durability of the collagen triple helix in humans. In the present work, silver nanoparticle synthesis was performed through a paracetamol-mediated approach. Different characterization techniques, such as X-ray diffractometry (XRD), energy dispersive X-ray (EDX), Fourier transform infrared (FTIR), and scanning electron microscopy (SEM), were used to confirm the prepared nanoparticles. Subsequently, the prepared Ag NPs functionalized with an ionic liquid were used as a sensing platform for ascorbic acid in blood serum samples. To achieve the best possible results, the proposed biosensor was optimized with different parameters such as TMB concentration, time, amount of capped nanoparticles (NPs), and pH. The proposed biosensor offers a sensitive and straightforward method for ascorbic acid with a linear range from 2 × 10-9 to 3.22 × 10-7 M, an LOD of 1.3 × 10-8 M, an LOQ of 4.3 × 10-8 M, and an R2 of 0.9996, Moreover, applications of the proposed biosensor were successfully used for the detection of ascorbic acid in samples of human plasma, suggesting that Ag NPs with high peroxidase-like activity, high stability, and facile synthesis exhibited promising applications in biomedical fields.
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Reactive oxygen species (ROS) and Ca(2+) signals are closely associated with the pathogenesis of cardiac hypertrophy. However, the cause and effect of the two signals in cardiac hypertrophy remain to be clarified. We extend our recent report by investigating a potential interaction between ROS and Ca(2+) signals utilizing in vitro and in vivo angiotensin II (ANG II)-induced cardiac hypertrophy models. ANG II-induced initial Ca(2+) transients mediated by inositol trisphosphate (IP(3)) triggered initial ROS production in adult rat cardiomyocytes. The ROS generated by activation of the NAD(P)H oxidase complex via Rac1 in concert with Ca(2+) activates ADP-ribosyl cyclase to generate cyclic ADP-ribose (cADPR). This messenger-mediated Ca(2+) signal further augments ROS production, since 2,2'-dihydroxyazobenzene, an ADP-ribosyl cyclase inhibitor, or 8-Br-cADPR, an antagonistic analog of cADPR, abolished further ROS production. Data from short hairpin RNA (shRNA)-mediated knockdown of Akt1 and p47(phox) demonstrated that Akt1 is the upstream key molecule responsible for the initiation of Ca(2+) signal that activates p47(phox) to generate ROS in cardiomyocytes. Nuclear translocation of nuclear factor of activated T-cell in cardiomyocytes was significantly suppressed by treatment with NAD(P)H oxidase inhibitors as well as by shRNA against Akt1 and p47(phox). Our results suggest that in cardiomyocytes Ca(2+) and ROS messengers generated by ANG II amplify the initial signals in a cooperative manner, thereby leading to cardiac hypertrophy.
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Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Espécies Reativas de Oxigênio/metabolismo , Angiotensina II/efeitos adversos , Angiotensina II/farmacologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Hipertrofia/induzido quimicamente , Hipertrofia/patologia , Masculino , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismoRESUMO
Angiotensin II contributes to myocardial tissue remodeling and interstitial fibrosis through NADPH oxidase-mediated generation of oxidative stress in the progression of heart failure. Recent data have suggested that nebivolol, a third-generation ß-blocker, improves diastolic dysfunction by targeting nitric oxide (NO) and metabolic pathways that decrease interstitial fibrosis. We sought to determine if targeting NO would improve diastolic function in a model of tissue renin-angiotensin system overactivation. We used the transgenic (TG) (mRen2)27 rat, which overexpresses the murine renin transgene and manifests insulin resistance and left ventricular dysfunction. We treated 6- to 7-wk-old TG (mRen2)27 rats and age-matched Sprague-Dawley control rats with nebivolol (10 mg·kg(-1)·day(-1)) or placebo via osmotic minipumps for a period of 21 days. Compared with Sprague-Dawley control rats, TG (mRen2)27 rats displayed a prolonged diastolic relaxation time and reduced initial filling rate associated with increased interstitial fibrosis and left ventricular hypertrophy. These findings were temporally related to increased NADPH oxidase activity and subunits p47(phox) and Rac1 and increased total ROS and peroxynitrite formation in parallel with reductions in the antioxidant heme oxygenase as well as the phosphorylation/activation of endothelial NO synthase and PKB/Akt. Treatment with nebivolol restored diastolic function and interstitial fibrosis through increases in the phosphorylation of 5'-AMP-activated protein kinase, Akt, and endothelial NO synthase and reductions in oxidant stress. These results support that targeting NO with nebivolol treatment improves diastolic dysfunction through reducing myocardial oxidative stress by enhancing 5'-AMP-activated protein kinase and Akt activation of NO biosynthesis.
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Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Benzopiranos/farmacologia , Diástole/efeitos dos fármacos , Etanolaminas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Renina/genética , Renina/fisiologia , Remodelação Ventricular/efeitos dos fármacos , Quinases Proteína-Quinases Ativadas por AMP , Animais , Diástole/fisiologia , Modelos Animais de Doenças , Fibrose , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , NADPH Oxidases/metabolismo , Nebivolol , Óxido Nítrico/metabolismo , Estresse Oxidativo/fisiologia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular/fisiologiaRESUMO
Several common degenerative mechanisms and mediators underlying the neuronal injury pathways characterize several neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's disease, as well as brain neurotrauma. Such common ground invites the emergence of new approaches and tools to study the altered pathways involved in neural injury alongside with neuritogenesis, an intricate process that commences with neuronal differentiation. Achieving a greater understanding of the impaired pathways of neuritogenesis would significantly help in uncovering detailed mechanisms of axonal regeneration. Among the several agents involved in neuritogenesis are the Rho and Rho kinases (ROCKs), which constitute key integral points in the Rho/ROCK pathway that is known to be disrupted in multiple neuropathologies such as spinal cord injury, traumatic brain injury, and Alzheimer's disease. This in turn renders ROCK inhibition as a promising candidate for therapeutic targets for treatment of neurodegenerative diseases. Among the novel tools to investigate the mechanisms involved in a specific disorder is the use of neuroproteomics/systems biology approach, a growing subfield of bioinformatics aiming to study and establishing a global assessment of the entire neuronal proteome, addressing the dynamic protein changes and interactions. This review aims to examine recent updates regarding how neuroproteomics aids in the understanding of molecular mechanisms of activation and inhibition in the area of neurogenesis and how Rho/ROCK pathway/ROCK inhibitors, primarily Y-27632 and Fasudil compounds, are applied in biological settings, promoting neuronal survival and neuroprotection that has direct future implications in neurotrauma.
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Lesões Encefálicas/metabolismo , Doenças Neurodegenerativas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteômica/métodos , Quinases Associadas a rho/antagonistas & inibidores , Animais , Humanos , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
The diagnosis of novel coronavirus (COVID-19) has gained the spotlight of the world's scientific community since December 2019 and it remains an important issue due to the emergence of novel variants around the globe. Early diagnosis of coronavirus is captious to prevent and hard to control. This pandemic can be eradicated by implementing suppressing strategies which can lead to better outcomes and more lives being saved. Therefore, the analysis showed that COVID-19 can only be managed by adopting public health measures, such as testing, isolation and social distancing. Much work has been done to diagnose coronavirus. Various testing technologies have been developed, opted and modified for rapid and accurate detection. The advanced molecular diagnosis relies on the detection of SARS-CoV-2 as it has been considered the main causative agent of this pandemic. Studies have shown that several molecular tests are considered essential for the confirmation of coronavirus infection. Various serology-based tests are also used in the detection and diagnosis of coronavirus including point-of-care assays and high-throughput enzyme immunoassays that aid in the diagnosis of COVID-19. Both these assays are time-consuming and have less diagnostic accuracy. Nanotechnology has the potential to develop new strategies to combat COVID-19 by developing diagnostics and therapeutics. In this review, we have focused on the nanotechnology-based detection techniques including nanoparticles and biosensors to obstruct the spread of SARS-CoV-2.
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Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the prevalence of NAFLD among Saudi patients with T2DM using transient elastography. Methods: A total of 490 patients with T2DM who attended diabetes and primary care clinics were recruited. Controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) were obtained via FibroScan to assess steatosis and fibrosis. Results: Of the examined 490 patients with T2DM, 396 (80.8%) had hepatic steatosis (CAP ≥248 dB/m): 326 (66.5%) had severe steatosis (CAP ≥280 dB/m), while 41 (8.4%) and 29 (5.9%) had mild (CAP ≥248 to <268 dB/m) and moderate steatosis (CAP ≥268 to <280 dB/m), respectively. Of the 396 patients with steatosis, only 35 (8.8%) had LSM ≥7.9 kPa, suggesting the presence of fibrosis, while 361 (91%) had LSM <7.9 kPa, indicating the absence of fibrosis. Increased body mass index (BMI), waist circumference, systolic blood pressure (SBP), and alanine aminotransferase (ALT) were positively associated with both steatosis and fibrosis. After adjusting for age and gender, data from logistic regression analysis demonstrated BMI, waist circumference, SBP, ALT, and high-density lipoprotein (HDL) as significant independent factors for steatosis, while SBP was the only significant predictor associated with fibrosis. Conclusions: Our results demonstrate an increase in prevalence of NAFLD in Saudi patients with T2DM, based on transient elastography and CAP score. The risk of NAFLD appears to be higher in T2DM patients with abdominal obesity, elevated SBP, and increased ALT levels, which supports the screening of these conditions in patients with T2DM.
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Diabetes Mellitus Tipo 2 , Técnicas de Imagem por Elasticidade , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Técnicas de Imagem por Elasticidade/métodos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Estudos de Coortes , Prevalência , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/epidemiologia , Cirrose Hepática/complicações , Fígado/patologiaRESUMO
Telmisartan, an angiotensin receptor blocker, may have unique benefits as it possesses partial peroxisome proliferator-activated receptor (PPAR)-γ agonist activity in addition to antihypertensive effects. In this study, we test whether treatment with telmisartan ameliorates cardiovascular abnormalities to a greater extent than olmesartan, which has little PPAR-γ activity. The hypertensive rodent model of tissue renin-angiotensin system activation, transgenic (mRen2)27 (Ren2) rats and their littermate Sprague-Dawley controls were used. Rats were treated with telmisartan (2 mg · kg(-1) · day(-1)), olmesartan (2.5 mg · kg(-1) · day(-1)), or vehicle via drinking water for 3 wk; these doses achieved similar blood pressure control, as measured by telemetry. Ren2 rats displayed impaired diastolic and systolic function using left ventricular (LV) pressure-volume (P-V) analysis. Load-independent diastolic indexes, including the time constant of isovolumic relaxation and the slope of the end-diastolic P-V relationship, as well as systolic indexes, including preload recruitable stroke work, the dP/dt(max)-end-diastolic volume (EDV) relationship, and the P-V area-EDV relationship, were elevated in Ren2 rats compared with Sprague-Dawley controls (P < 0.05). The Ren2 myocardium exhibited parallel increases in the oxidant markers NADPH oxidase and 3-nitrotyrosine. The increase in the prohypertrophic protein Jak2 in Ren2 rats was associated with cardiac structural abnormalities using light microscopic and ultrastructural analysis, which included interstitial fibrosis, cardiomyocyte and LV hypertrophy, and mitochondrial derangements. Both angiotensin receptor blockers attenuate these abnormalities to a similar extent. Our data suggest that the beneficial effect of telmisartan and olmesartan on cardiac structure and function may be predominantly pressor-related or angiotensin type 1 receptor dependent in this model of renin-angiotensin system activation.
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Benzimidazóis/farmacologia , Benzoatos/farmacologia , Coração/efeitos dos fármacos , Imidazóis/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Tetrazóis/farmacologia , Análise de Variância , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Testes de Função Cardíaca , Hipertrofia Ventricular Esquerda/metabolismo , Janus Quinase 2/metabolismo , Masculino , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Telemetria , TelmisartanRESUMO
In conditions of overnutrition, cardiac cells must cope with a multitude of extracellular signals generated by changes in nutrient load (glucose, amino acids, and lipids) and the hormonal milieu [increased insulin (INS), ANG II, and adverse cytokine/adipokine profile]. Herein, we review the diverse compensatory/adaptive mechanisms that counter the deleterious effects of excess nutrients and growth factors. We largely focus the discussion on evidence obtained from Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats, which are useful models to evaluate adaptive and maladaptive metabolic, structural, and functional cardiac remodeling. One adaptive mechanism present in the INS-resistant ZO, but absent in the diabetic ZDF heart, involves an interaction between the nutrient sensor kinase mammalian target of rapamycin complex 1 (mTORC1) and ANG II-type 2 receptor (AT2R). Recent evidence supports a cardioprotective role for the AT2R; for example, suppression of AT2R activation interferes with antihypertrophic/antifibrotic effects of AT1R blockade, and AT2R agonism improves cardiac structure and function. We propose a scenario, whereby mTORC1-signaling-mediated increase in AT2R expression in the INS-resistant ZO heart is a cardioprotective adaptation to overnutrition. In contrast to the ZO rat, heart tissues of ZDF rats do not show activation of mTORC1. We posit that such a lack of activation of the mTORâAT2R integrative pathway in cardiac tissue under conditions of obesity-induced diabetes may be a metabolic switch associated with INS deficiency and clinical diabetes.
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Adaptação Fisiológica/fisiologia , Doenças Cardiovasculares/fisiopatologia , Hipernutrição/fisiopatologia , Animais , Doenças Cardiovasculares/etiologia , Modelos Animais de Doenças , Síndrome Metabólica/fisiopatologia , Hipernutrição/complicações , Ratos , Ratos Zucker , Receptores de Angiotensina/fisiologia , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/fisiologiaRESUMO
Angiotensin-converting enzyme 2 (ACE2) has been recognized as a potential entry receptor for SARS-CoV-2 infection. Binding of SARS-CoV-2 to ACE2 allows engagement with pulmonary epithelial cells and pulmonary infection with the virus. ACE2 is an essential component of renin-angiotensin system (RAS), and involved in promoting protective effects to counter-regulate angiotensin (Ang) II-induced pathogenesis. The use of angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEIs) was implicitly negated during the early phase of COVID-19 pandemic, considering the role of these antihypertensive agents in enhancing ACE2 expression thereby promoting the susceptibility to SARS-CoV-2. However, no clinical data has supported this assumption, but indeed evidence demonstrates that ACEIs and ARBs, besides their cardioprotective effects in COVID-19 patients with cardiovascular diseases, might also be beneficial in acute lung injuries by preserving the ACE2 function and switching the balance from deleterious ACE/Ang II/AT1 receptor axis towards a protective ACE2/Ang (1-7)/Mas receptor axis.
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Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Tratamento Farmacológico da COVID-19 , Sistema Renina-Angiotensina , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , Humanos , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , SARS-CoV-2/fisiologia , Síndrome Respiratória Aguda GraveRESUMO
OBJECTIVES: Considering the complementary nature of signalling mechanisms and the therapeutic effects of nebivolol, a ß1-adrenoreceptor antagonist, and valsartan, an angiotensin receptor blocker (ARB), here we aimed to investigate whether nebivolol/valsartan combination would complement the cardioprotective effects of nebivolol on angiotensin II (ANG II)-induced pathology in H9c2 cardiomyoblasts. METHODS: H9c2 cardiomyoblasts were used to investigate the protective effects of nebivolol and nebivolol and valsartan combination against ANG II-induced pathology. Reactive oxygen species (ROS) generation was determined by 2',7'-dichlorofluorescein diacetate (DCFDA) and MitoSOX Red staining. Real-time PCR and immunoblotting were employed to quantify the changes in mRNA and protein expression levels, respectively. KEY FINDINGS: Our data revealed that pretreatment with nebivolol and nebivolol/valsartan combination significantly reduced ANG II-induced oxidative stress and mTORC1 signalling. Concurrently, ANG II-induced activation of inflammatory cytokines and fetal gene expressions were significantly suppressed by nebivolol and nebivolol/valsartan combination. Pretreatment with nebivolol and nebivolol/valsartan combination alleviated ANG II-induced impairment of mitochondrial biogenesis by restoring the gene expression levels of PGC-1α, TFAM, NRF-1 and SIRT3. Our data further show that nebivolol and nebivolol/valsartan combination mediated up-regulation in mitochondrial biogenesis is accompanied by decrease in ANG II-stimulated mitochondrial ROS generation as well as increase in expression of mitochondrial fusion genes MFN2 and OPA1, indicative of improved mitochondrial dynamics. SUMMARY: These findings suggest that both nebivolol and nebivolol/valsartan combination exert protective effects on ANG II-induced mitochondrial dysfunction by alleviating its biogenesis and dynamics. Moreover, addition of valsartan to nebivolol do not produce any additive effects compared with nebivolol alone on ANG II-induced cardiac pathology.
Assuntos
Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Mitocôndrias/efeitos dos fármacos , Mioblastos Cardíacos/efeitos dos fármacos , Miocárdio/patologia , Nebivolol/farmacologia , Valsartana/farmacologia , Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Cardiomegalia/metabolismo , Cardiomegalia/prevenção & controle , Técnicas de Cultura de Células , Combinação de Medicamentos , Coração/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Inflamação/metabolismo , Inflamação/prevenção & controle , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mioblastos Cardíacos/patologia , Miocárdio/citologia , Miocárdio/metabolismo , Nebivolol/uso terapêutico , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Valsartana/uso terapêuticoRESUMO
Angiotensin-(1-7) [ANG-(1-7)], one of the bioactive peptides produced in the renin-angiotensin system, plays a pivotal role in cardiovascular physiology by providing a counterbalance to the function of ANG II. Recently, it has been considered as a potential candidate for therapeutic use in the treatment of various types of cardiovascular diseases. The aim of the present study is to explain the modulatory role of ANG-(1-7) in atrial natriuretic peptide (ANP) secretion and investigate the functional relationship between two peptides to induce cardiovascular effects using isolated perfused beating rat atria and a cardiac hypertrophied rat model. ANG-(1-7) (0.01, 0.1, and 1 muM) increased ANP secretion and ANP concentration in a dose-dependent manner at high atrial pacing (6.0 Hz) with increased cGMP production. However, at low atrial pacing (1.2 Hz), ANG-(1-7) did not cause changes in atrial parameters. Pretreatment with an antagonist of the Mas receptor or with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), or nitric oxide synthase blocked the augmentation of high atrial pacing-induced ANP secretion by ANG-(1-7). A similar result was observed with the inhibition of the Na(+)/H(+) exchanger-1 and Ca(2+)/calmodulin-dependent kinase II (CaMKII). ANG-(1-7) did not show basal intracellular Ca(2+) signaling in quiescent atrial myocytes. In an in vivo study using an isoproterenol-induced cardiac hypertrophy animal model, an acute infusion of ANG-(1-7) increased the plasma concentration of ANP by twofold without changes in blood pressure and heart rate. A chronic administration of ANG-(1-7) increased the plasma ANP level and attenuated isoproterenol-induced cardiac hypertrophy. The antihypertrophic effect was abrogated by a cotreatment with the natriuretic peptide receptor-A antagonist. These results suggest that 1) ANG-(1-7) increased ANP secretion at high atrial pacing via the Mas/PI3K/Akt pathway and the activation of Na(+)/H(+) exchanger-1 and CaMKII and 2) ANG-(1-7) decreased cardiac hypertrophy which might be mediated by ANP.
Assuntos
Angiotensina I/farmacologia , Fator Natriurético Atrial/metabolismo , Estimulação Cardíaca Artificial , Fragmentos de Peptídeos/farmacologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/efeitos dos fármacos , Trocadores de Sódio-Hidrogênio/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotônicos/farmacologia , GMP Cíclico/metabolismo , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proto-Oncogene Mas , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Receptores do Fator Natriurético Atrial/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trocadores de Sódio-Hidrogênio/efeitos dos fármacosRESUMO
Herein, we report the fabrication of remarkably fine nickel-substituted α-Co(OH)2 sheets using an ingenious co-precipitation method at a lower pH value. An α-CoNiOOH sheet retains the parent α-Co(OH)2 structure consisting of both tetrahedral (Td) and octahedral (Oh) sites with the retention of interlayer chloride ions, which is in contrast to the previous reports. The as-synthesized α-CoNiOOH sheet exhibits excellent oxygen evolution reactions (OERs) and produces a current of 10 mA cm-2 at an overpotential of merely 190 mV in an alkaline environment. Moreover, the α-CoNiOOH sheet attains an exceptionally high current density of 100 mA cm-2 at a low overpotential of only 270 mV. Additionally, this electrocatalyst possesses a 33 mV dec-1 Tafel slope with higher values of TOF (11 s-1) and double-layer capacitance (7.76 mF cm-2). This enhancement is attributed partially to the substitution of Ni during the conversion of α-Co(OH)2 to α-CoNiOOH and partially to the exceptionally thin sheets allowing potential octahedral sites for improved oxygen evolution reactions.