Paracetamol-Mediated Synthesis of Silver Nanoparticles and Their Functionalization with Ionic Liquid for the Colorimetric Biosensing of Ascorbic Acid.

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.

Comparison of the Protective Effects of Nebivolol and Metoprolol against LPS-Induced Injury in H9c2 Cardiomyoblasts.

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.

Protective Effects of Nanoceria against Mitochondrial Dysfunction and Angiotensin II-Induced Hypertrophy in H9c2 Cardiomyoblasts.

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.

Alterations in circulating lipidomic profile in patients with type 2 diabetes with or without non-alcoholic fatty liver disease.

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.

Nanoparticle: A Promising Player in Nanomedicine and its Theranostic Applications for the Treatment of Cardiovascular Diseases.

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.

Transient elastography for the prevalence of non-alcoholic fatty liver disease in patients with type 2 diabetes: Evidence from the CORDIAL cohort study.

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.

Inhibition of eNOS Partially Blunts the Beneficial Effects of Nebivolol on Angiotensin II-Induced Signaling in H9c2 Cardiomyoblasts.

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.

Therapeutic significance of nano- and biosensor technology in combating SARS-CoV-2: a review.

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.

Comparative beneficial effects of nebivolol and nebivolol/valsartan combination against mitochondrial dysfunction in angiotensin II-induced pathology in H9c2 cardiomyoblasts.

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.

Renin-angiotensin system at the interface of COVID-19 infection.

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.

Retention of anions in cobalt hydroxide with Ni substitution to emphasize the role of anions and cations for high current density in oxygen evolution reactions.

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.

Recent Progress and Perspectives on Electrochemical Regeneration of Reduced Nicotinamide Adenine Dinucleotide (NADH).

NAD is a cofactor that maintains cellular redox homeostasis and has immense industrial and biological significance. It acts as an enzymatic mediator in several biocatalytic electrochemical reactions and undergoes oxidation/reduction to form NAD+ or NADH, respectively. The NAD redox couple (NAD+ /NADH) mostly exists in enzyme-assisted metabolic reactions as a coenzyme during which electrons and protons are transferred. NADH shuttles these charges between the enzyme and the substrate. In order to understand such complex metabolic reactions, it is vital to study the bio-electrochemistry of NADH. In addition, the regeneration of NADH in industries has attracted significant attention due to its vast usage and high cost. To make biocatalysis economically viable, primary methods of NADH regeneration including enzymatic, chemical, photochemical and electrochemical methods are widely used. This review is mainly focused on the electrochemical reduction of NAD+ to NADH with specific details on the mechanism and kinetics of the reaction. It provides emphasis on the different routes (direct and mediated) to electrochemically regenerate NADH from NAD+ highlighting the NAD dimer formation. Also, it describes the electrocatalysts developed until now and the scope for development in this area of research.

The effect of gender and ABCB1 gene polymorphism on the pharmacokinetics of azithromycin in healthy male and female Pakistani subjects.

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.

Synthesis and functionalization of chitosan built hydrogel with induced hydrophilicity for extended release of sparingly soluble drugs.

Addressing the functional biomaterials as next-generation therapeutics, chitosan and alginic acid were copolymerized in the form of chemically crosslinked interpenetrating networks (IPNs). The native hydrogel was functionalized via carbodiimide (EDC), catalyzed coupling of soft ligand (1,2-Ethylenediamine) and hard ligand (4-aminophenol) to replace -OH groups in alginic acid units for extended hydrogel- interfaces with the aqueous and sparingly soluble drug solutions. The chemical structure, Lower solution critical temperature (LCST ≈ 37.88 °C), particle size (Zh,app ≈ 150-200 nm), grain size (160-360 nm), surface roughness (85-250 nm), conductivity (37-74 mv) and zeta potential (16-32 mv) of native and functionalized hydrogel were investigated by using FT-IR, solid state-13C-NMR, TGA, DSC, FESEM, AFM and dynamic light scattering (DLS) measurements. The effective swelling, drug loading (47-78%) and drug release (53-86%) profiles were adjusted based on selective functionalization of hydrophobic IPNs due to electrostatic complexation and extended interactions of hydrophilic ligands with the aqueous and drug solutions. Drug release from the hydrogel matrices with diffusion coefficient n ≈ 0.7 was established by Non- Fickian diffusion mechanism. In vitro degradation trials of the hydrogel with a 20% loss of wet mass in simulated gastric fluid (SGF) and 38% loss of wet mass in simulated intestinal fluid (SIF), were investigated for 400 h through bulk erosion. Consequently, a slower rate of drug loading and release was observed for native hydrogel, due to stronger H-bonding, interlocking and entanglement within the IPNs, which was finely tuned and extended by the induced hydrophilic and functional ligands. In the light of induced hydrophilicity, such functional hydrogel could be highly attractive for extended release of sparingly soluble drugs.

Endophilin A2: A Potential Link to Adiposity and Beyond.

Adipose tissue plays a central role in regulating dynamic crosstalk between tissues and organs. A detailed description of molecules that are differentially expressed upon changes in adipose tissue mass is expected to increase our understanding of the molecular mechanisms that underlie obesity and related metabolic co-morbidities. Our previous studies suggest a possible link between endophilins (SH3Grb2 proteins) and changes in body weight. To explore this further, we sought to assess the distribution of endophilin A2 (EA2) in human adipose tissue and experimental animals. Human paired adipose tissue samples (subcutaneous and visceral) were collected from subjects undergoing elective abdominal surgery and abdominal liposuction. We observed elevated EA2 gene expression in the subcutaneous compared to that in the visceral human adipose tissue. EA2 gene expression negatively correlated with adiponectin and chemerin in visceral adipose tissue, and positively correlated with TNF-α in subcutaneous adipose tissue. EA2 gene expression was significantly downregulated during differentiation of preadipocytes in vitro. In conclusion, this study provides a description of EA2 distribution and emphasizes a need to study the roles of this protein during the progression of obesity.

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by ß-Adrenergic Stimulation.

Ca2+ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca2+-mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by ß-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated signal, indicating that the Ca2+ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenol-mediated Ca2+ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that ß-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively.

Biologically Active New N, N', N''-Tri-Substituted Ferrocenyl Phenylguanidines and their Characterization.

BACKGROUND: Introducing new candidates for various biological targets is a prime characteristic of the present day medicinal research and development. Guanidines are the important bioactive compounds and are well recognized for their diverse biological activities, especially as anticancer, antimicrobial and antioxidant agents. Due to the favorable electronic properties of ferrocene like lipophilicity, redox activity, stability in solution state and its easy derivatization, have made ferrocenyl compounds very popular molecules for biological uses. OBJECTIVES: Keeping in sight, it is valuable to synthesize ferrocenyl guanidines to increase the binding potency with DNA, make them redox active and more lipophilic compounds. METHODS: Six new ferrocenyl phenylguanidines (F1 - F6) have been synthesized via multi step protocol. The structures of F1 - F6 were established by using elemental analysis, UV-visible, multinuclear (1H and 13C) NMR and FTIR spectroscopy. Solution phase redox behavior, of the synthesized compounds, has been characterized by cyclic voltammetry. Two compounds (F2 & F4) were characterized by single crystal XRD. RESULTS: Due to the biological importance of guanidines; these ferrocenyl guanidiens were screened for different biological activities like antibacterial, antifungal, antioxidant and DNA binding. DNA interaction study was done by using UV-visible spectrometry and cyclic voltammetry revealed good binding capacity of the test compounds. CONCLUSION: The results revealed that the ferrocene incorporation to guanidines enhances their DNA binding ability. A similar trend was found in antioxidant and antimicrobial studies. Being the bioactive molecules these compounds are potential drug candidates.

Regulation of cardiac miR-208a, an inducer of obesity, by rapamycin and nebivolol.

OBJECTIVE: Resistance to obesity is observed in rodents and humans treated with rapamycin (Rap) or nebivolol (Neb). Because cardiac miR-208a promotes obesity, this study tested whether the modes of actions of Rap and Neb involve inhibition of miR-208a. METHODS: Mouse cardiomyocyte HL-1 cells and Zucker obese (ZO) rats were used to investigate regulation of cardiac miR-208a. RESULTS: Angiotensin II (Ang II) increased miR-208a expression in HL-1 cells. Pretreatment with an AT1 receptor (AT1R) antagonist, losartan (1 µM), antagonized this effect, whereas a phospholipase C inhibitor, U73122 (10 µM), and an NADPH oxidase inhibitor, apocynin (0.5 mM), did not. Ang II-induced increase in miR-208a was suppressed by Rap (10 nM), an inhibitor of nutrient sensor kinase mTORC1, and Neb (1 µM), a 3rd generation ß-blocker that suppressed bioavailable AT1R binding of (125) I-Ang II. Thus, suppression of AT1R expression by Neb, inhibition of AT1R activation by losartan, and inhibition of AT1R-induced activation of mTORC1 by Rap attenuated the Ang II-induced increase in miR-208a. In ZO rats, Rap treatment (750 µg kg(-1)  day(-1) ; 12 weeks) reduced obesity despite similar food intake, suppressed cardiac miR-208a, and increased cardiac MED13, a suppresser of obesity. CONCLUSIONS: Rap and Neb suppressed cardiac miR-208a. Suppression of miR-208a and increase in MED13 correlated with attenuated weight gain despite leptin resistance.

Synthesis, characterization, DNA binding and in vitro antimicrobial studies of a novel tetra-substituted N-isopropyl-N-(4-ferrocenylphenyl)-N'-(2,6-diethylphenyl)-N″-benzoylguanidine: crystallographic structure and quantum chemical computations.

A novel tetra-substituted guanidine, N-isopropyl-N-(4-ferrocenylphenyl)-N'-(2,6-diethylphenyl)-N″-benzoylguanidine (1), [(CH3)2CH)(C5H5FeC5H4C6H4)NC(NHCOC6H5)(NHC6H3(CH2CH3)2] has been synthesized and characterized by elemental analysis, FT-IR, multinuclear ((1)H, (13)C) NMR spectroscopy, single crystal X-rays diffraction analysis and density functional theory based quantum chemical calculations. The torsion angles indicating that the guanidine moiety and carbonyl group are almost co-planar, due to the pseudo hexagonal ring formed by intramolecular N-H⋯O hydrogen bonds. The DNA interaction studies performed by cyclic voltammetry and UV-visible spectroscopy are in close agreement with the binding constants (K) 1.4×10(4) and 1.2×10(4) respectively. The shift in peak potential, current and absorption maxima of the studied ferrocenyl guanidine in the presence of DNA discovered that CV coupled with UV-vis spectroscopy could provide an opportunity to elaborate DNA interaction mechanism, a prerequisite for the design of new drug like agents and understanding the molecular basis of their action. The synthesized compound (1) has also been screened for their antibacterial and antifungal.

Ferrocene-based guanidine derivatives: in vitro antimicrobial, DNA binding and docking supported urease inhibition studies.

Some novel ferrocenyl guanidines 1-8 were synthesized and characterized by different spectroscopic methods, elemental analysis and single crystal X-rays diffraction techniques. The crystallographic studies revealed that the existence of the strong non-bonding interactions facilitate these molecules to interact with biological macro-molecules like DNA that described to inherit good biological activities. The DNA interaction studies carried out by cyclic voltammetry (CV) and UV-visible spectroscopy are in close agreement with the binding constants (K) (0.79-5.4) × 10(5) (CV) and (0.72-5.1) × 10(5) (UV-vis). The shift in peak potential, current and absorption maxima of the studied ferrocenyl guanidines in the presence of DNA revealed that CV coupled with UV-vis spectroscopy could provide an opportune to characterize metal-based compounds-DNA interaction mechanism, a prerequisite for the design of new anticancer agents and understanding the molecular basis of their action. The compounds 1-8 have been screened for their antibacterial, antifungal and urease inhibition potency. A concurrent in silico study has also been applied on ferrocene moiety impregnated guanidines 1-8 to identify most active compounds having for inhibiting the activity of urease (pdb id 3LA4). Most of the compounds were found as potent inhibitors of urease and the compound 1 was found to be the most active with an IC50 of 16.83 ± 0.03 µM. The docking scores are in close agreement with the in vitro obtained IC50 values of inhibitors 1-8.