Exposure to Electromagnetic Fields from Mobile Phones and Fructose consumption Coalesce to Perturb Metabolic Regulators AMPK/SIRT1-UCP2/FOXO1 in Growing Rats.

Objective: In this study, the combined effect of two stressors, namely, electromagnetic fields (EMFs) from mobile phones and fructose consumption, on hypothalamic and hepatic master metabolic regulators of the AMPK/SIRT1-UCP2/FOXO1 pathway were elucidated to delineate the underlying molecular mechanisms of insulin resistance. Methods: Weaned Wistar rats (28 days old) were divided into 4 groups: Normal, Exposure Only (ExpO), Fructose Only (FruO), and Exposure and Fructose (EF). Each group was provided standard laboratory chow ad libitum for 8 weeks . Additionally, the control groups, namely, the Normal and FruO groups, had unrestricted access to drinking water and fructose solution (15%), respectively. Furthermore, the respective treatment groups, namely, the ExpO and EF groups, received EMF exposure (1,760 MHz, 2 h/day x 8 weeks). In early adulthood, mitochondrial function, insulin receptor signaling, and oxidative stress signals in hypothalamic and hepatic tissues were assessed using western blotting and biochemical analysis. Result: In the hypothalamic tissue of EF, SIRT1, FOXO 1, p-PI3K, p-AKT, Complex III, UCP2, MnSOD, and catalase expressions and OXPHOS and GSH activities were significantly decreased ( P < 0.05) compared to the Normal, ExpO, and FruO groups. In hepatic tissue of EF, the p-AMPKα, SIRT1, FOXO1, IRS1, p-PI3K, Complex I, II, III, IV, V, UCP2, and MnSOD expressions and the activity of OXPHOS, SOD, catalase, and GSH were significantly reduced compared to the Normal group ( P < 0.05). Conclusion: The findings suggest that the combination of EMF exposure and fructose consumption during childhood and adolescence in Wistar rats disrupts the closely interlinked and multi-regulated crosstalk of insulin receptor signals, mitochondrial OXPHOS, and the antioxidant defense system in the hypothalamus and liver.

Therapeutic Potential of HDAC Inhibitors in the Treatment of Cardiac Diseases: A Short Review.

Protein acetylation is a reversible central mechanism to control gene expression and cell signaling events. Current evidence suggests that pharmacological inhibitors for protein deacetylation have already been used in various disease conditions. Accumulating reports showed that several compounds that enhance histone acetylation in cells are in both the preclinical and clinical development stages targeting non-communicable diseases, which include cancerous and non-cancerous especially cardiovascular complications. These compounds are, in general, enzyme inhibitors and target a family of enzymes- called histone deacetylases (HDACs). Since HDAC inhibitors have shown to be helpful in preclinical models of cardiac complications, further research on developing novel compounds with high efficacy and low toxicity may be essential for treating cardiovascular diseases. In this review, we have highlighted the roles of HDAC and its inhibitors in cardiac complications.

Kaempferol 3-O-rutinoside from Antidesma acidum Retz. Stimulates glucose uptake through SIRT1 induction followed by GLUT4 translocation in skeletal muscle L6 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Antidesma acidum Retz, a perennial herb is known for its anti-diabetic potential among the traditional health care providers of the tribal communities of Manipur, India. Scientific validation of the ancient knowledge on traditional use of this plant with the help of modern tools and techniques can promote further research and its use in health care. AIM OF THE STUDY: Type 2 Diabetes (T2D) is a complex metabolic disorder and linked with hyperglycemia occurring from insufficiency in insulin secretion, action, or both. The aim of this study was to scientifically validate the traditional myth behind the uses of this plant material against diabetes. More specifically, it was aimed to determine the effect of methanolic extract of A. acidum leaves and/or any of its bioactive phytochemical(s), in enhancing insulin sensitization and subsequently stimulating the insulin signaling cascade of glucose metabolism. MATERIALS AND METHODS: Methanol was used for extraction from the leaf powder of A. acidum followed by bioactivity guided fractionation and isolation of most active component. Biological evaluation was performed to determine the glucose uptake ability against insulin resistance in skeletal muscle (L6) cells. To understand the detailed mechanism of actions of the purified compound, several molecular biology and structural biology experiments such as Western blot, siRNA transfection assay and molecular docking study were performed. RESULTS AND DISCUSSION: Bioactivity guided isolation of pure compound and spectral data analysis led us to identify the active component as Kaempferol 3-O-rutinoside (KOR) for the first time from the leaf of A. acidum. Over expression of NAD-dependent histone deacetylase, Sirtuin 1 (SIRT1) was observed following KOR treatment. SIRT1 plays an important role in the metabolic pathway and over expression of SIRT implies that it involves in insulin signaling directly or indirectly. Molecular docking and simulation study showed the strong involvement between KOR and SIRT1.Treatment with KOR resulted in significant over expression of SIRT1followed by upregulation of insulin-dependent p-IRS, AKT and AMPK signaling molecules, and stimulation of the GLUT4 translocation, which ultimately enhanced the glucose uptake in sodium palmitate-treated insulin resistant L6 myotubes. Further, the effect of KOR on IRS1, AKT and AMPK phosphorylation, GLUT4 translocation, and glucose uptake was attenuated in SIRT1-knockdown myotubes. CONCLUSION: Overall, the results of this study suggest that Kaempferol 3-O-rutinoside is the active component presents in the leaf of A. acidum which increases glucose consumption by inducing SIRT1 activation and consequently improves insulin sensitization. These results may find future applications in drug discovery research against T2DM.

Empagliflozin prohibits high-fructose diet-induced cardiac dysfunction in rats via attenuation of mitochondria-driven oxidative stress.

SGLT2 inhibitors show promising cardio-protection in the diabetic populace. However, the defending effect of SGLT2 inhibition in diabetes-associated cardiac complications and the molecular mechanism behind this effect are not thoroughly studied. Therefore, we aimed to investigate the effect of Empagliflozin, an SGLT2 inhibitor, in type-2 diabetic rat hearts. We induced type-2 diabetes in SD rats by giving a high-fructose diet for 20 weeks. We administered Empagliflozin (10 mg/kg p.o.) daily from the 12th week to the 20th week, along with high-fructose diet. We weighed the cardiac structure and function by echocardiography, electrocardiography, and blood pressure in diabetic rats. Other parameters like cardiac fibrosis, oxidative stress, and mitochondrial dynamics by protein expression were measured. To simulate a similar in-vivo condition, we persuaded insulin resistance in H9c2 cells by palmitic acid (PA) treatment. We then examined glucose uptake, cellular ROS, mitochondrial ROS and membrane potential in the presence and absence of Empagliflozin treatment. We saw a significant perturbation of the majority of the parameters associated with cardiac structure and function in high-fructose diet-induced diabetic rats. We found that administration of Empagliflozin improved all the perturbed parameters by attenuating insulin resistance, oxidative stress, and cardiac fibrosis and also by promoting cardiac mitochondrial fusion in high-fructose diet-induced type-2 diabetic rats. Empagliflozin also reduced palmitate-induced insulin resistance, total cellular ROS, and mitochondrial ROS in H9c2 cells. Our study concluded that SGLT2 inhibition with Empagliflozin prevented the high-fructose diet-insulted cardiac function by suppressing insulin resistance and oxidative stress and promoting mitochondrial fusion.

Pharmacologically active chemical composite of Musa balbisiana ameliorates oxidative stress, mitochondrial cellular respiration, and thereby metabolic dysfunction.

The ripe fruit pulp of different Musa species is known for its excellent source of nutrient contents. Musa balbisiana (MB) is one such variety of Musa species, mainly found in the southern part of Asia, especially in the North-eastern part of India, remains unexplored despite its continuous use by the local traditional healers. The present study focuses on identifying and quantifying the active chemicals present in the ripe fruit pulp of Musa balbisiana (RFPMB) to understand its combined efficacy and nutritional benefit to control human metabolic complications specially related to diabetes and cardiovascular disorder. Characterization and confirmation through targeted LC-MS and HPLC-PDA based assays followed by quantitative analysis led us to identify the major bioactive compounds in RFPMB as shikimic acid, p-hydroxybenzoic acid, vanillic acid, ferulic acid, sinapic acid, caffeic acid, syringic acid, chlorogenic acid, trans-cinnamic acid, and two essential fatty acids; linolenic acid and linoleic acid. The ripe fruit pulp is further analyzed to understand the nutritional and mineral content and found a substantial presence of calcium and potassium (15.74 ± 0.43 and 395.20 ± 9.5 mg/100 g of raw pulp, respectively) compared to other reported varieties. The active portion of RFPMB reduces the production of ROS, the expression of inflammatory marker genes TNF-α and TGF-ß, and accelerates the mitochondrial oxygen consumption rate (OCR) by enhancing the basal respiration, maximal respiration, and ATP production capacity of the targeted cells. The present study concluded that, a particular phytopharmaceutical composition of RFPMB with 11-biomarker compounds might be an efficacious formulation for developing a value-added nutraceutical product in managing metabolic complications and its related oxidative stress. PRACTICAL APPLICATIONS: This study has provided the prior information regarding the potential nutraceutical and phytochemical advantages of Musa balbisiana (MB) fruit pulp over other reported banana varieties. The HPLC-based quantification will give a clear understanding of the food values in comparison of bioactive compounds present in the active fraction of RFPMB, which can be an effective phytopharmaceutical in combating metabolic disorders and oxidative stress. Overall this study will help to commercialize a value-added product from this variety of banana with proper scientific validation.

Sirt3 ameliorates mitochondrial dysfunction and oxidative stress through regulating mitochondrial biogenesis and dynamics in cardiomyoblast.

Sirtuins are the endogenously present anti-aging protein deacetylases that regulate the mitochondrial biogenesis and function. Especially Sirt3, a mitochondrial sirtuin, is well known for maintaining mitochondrial function and health. In the present study, we have explored the novel role of Sirt3 in mitochondrial biogenesis and shown the role of Sirt3 in mito-nuclear communication through AMPK-α in Sirt3 knockdown and Sirt3 overexpressed H9c2 cells. The study found that impaired mitochondrial function in Sirt3-knockdown H9c2 cells was associated with decreased expression of mitochondrial DNA encoded genes, reduced SOD2 expression and activity. The study also revealed that Sirt3 knockdown affects mitochondrial biogenesis and dynamics. To further confirm the role of Sirt3 on mitochondrial biogenesis and health, we did Sirt3 overexpression in H9c2 cells. Sirt3 overexpression enhanced the expression of mitochondrial DNA encoded genes, increased SOD2 activity and altered mitochondrial dynamics. Sirt3 overexpression also caused an increase in mitochondrial biogenesis gene and protein (PGC-1α and TFAM) expression. All these changes were confirmed with mitochondrial functional parameters like basal respiration, maximal respiratory capacity, spare respiratory capacity and ATP production. We found decreased mitochondrial function in Sirt3-knockdown H9c2 cells when compared to control H9c2 cells. Together our data conclude that Sirt3 regulates cardiac mitochondrial health and function through the Sirt3-AMPKα-PGC-1α axis.

Simultaneous exposure to electromagnetic field from mobile phone and unimpeded fructose drinking during pre-, peri-, and post-pubertal stages perturbs the hypothalamic and hepatic regulation of energy homeostasis by early adulthood: experimental evidence.

The present-day children-adolescents ubiquitously use the mobile phones and unrestrictedly consume fructose-laden diet. Unfortunately, a rise in the incidence of insulin resistance and fatty liver syndrome in young adults has also been recorded. To delineate a possible correlate, the effect of exposure to electromagnetic field (EMF) from the mobile phone and unrestricted fructose intake during pre-, peri-, and post-pubertal stages of development on orexigenic and anorexigenic signals arising from the hypothalamus and liver of rats is investigated here. The study design included four arms, i.e., "Normal", "Exposure Only (ExpO)", "Fructose Only (FruO)", and "Exposure with Fructose (EF)", wherein weaned rats received either "normal chow and drinking water" or "normal chow and fructose (15%) drinking solution" in presence and absence of EMF exposure (2 h/day) for 8 weeks. The results indicate that the total calories consumed by the EF were higher by early adulthood than normal, possibly under the influence of the raised levels of the orexigenic hormone, i.e., ghrelin, and it reflected as raised rate of weight gain. At early adulthood, the EF recorded mitigated response and sensitivity of insulin. Despite EF being a "fed-state", both centrally and peripherally, the glycolysis was restrained, but the gluconeogenesis was raised. Additionally, the altered lipid profile and the glycogen levels indicate that the EF developed fatty liver. The energy homeostasis of the EF was compromised as evidenced by (a) reduced expression of the glucosensors-GLUT2 and glucokinase in the hypothalamus and liver and (b) reduced expression of the cellular energy regulator-AMPK, orexigenic peptide-NPY, and anorexigenic peptide-POMC in the hypothalamus. Taken together, the present study evidences that the exposure to EMFfrom the mobile phone and unrestricted fructose intake during childhood-adolescence impairs the central and peripheral pathways that mediate the glucosensing, glucoregulation, feeding, and satiety behavior by early adulthood.

Indazole and its Derivatives in Cardiovascular Diseases: Overview, Current Scenario, and Future Perspectives.

Indazoles are a class of heterocyclic compounds with a bicyclic ring structure composed of a pyrazole ring and a benzene ring. Indazole-containing compounds with various functional groups have important pharmacological activities and can be used as structural motifs in designing novel drug molecules. Some of the indazole-containing molecules are approved by FDA and are already in the market. However, very few drugs with indazole rings have been developed against cardiovascular diseases. This review aims to summarize the structural and pharmacological functions of indazole derivatives which have shown efficacy against cardiovascular pathologies in experimental settings.

Evaluation of therapeutic effect of Premna herbacea in diabetic rat and isoverbascoside against insulin resistance in L6 muscle cells through bioenergetics and stimulation of JNK and AKT/mTOR signaling cascade.

BACKGROUND: Premna herbacea Roxb., a perennial herb is well documented for its therapeutic uses among the traditional health care-givers of Assam, India. Scientific validation on the traditional use of the medicinal plant using modern technology may promote further research in health care. PURPOSE: This study evaluates the therapeutic potential of methanolic extract of P. herbacea (MEPH) against type 2 diabetes mellitus (T2DM) and its phytochemical(s) in ameliorating insulin resistance (IR), thereby endorsing the plant bioactives as effective anti-hyperglycemic agents. METHODS: The anti-diabetic potential of the plant extract was explored both in L6 muscle cells and high fructose high fat diet (HF-HFD) fed male Sprague Dawley (SD) rats. Bioactivity guided fractionation and isolation procedure yielded Verbascoside and Isoverbascoside (ISOVER) as bioactive and major phytochemicals in P. herbacea. The bioenergetics profile of bioactive ISOVER and its anti-hyperglycemic potential was validated in vitro by XFe24 analyzer, glucose uptake assay and intracellular ROS generation by flourometer, FACS and confocal microscopy. The potential of ISOVER was also checked by screening various protein markers via immunoblotting. RESULTS: MEPH enhanced glucose uptake in FFA-induced insulin resistant (IR) L6 muscle cells and decreased elevated blood glucose levels in HF-HFD fed rats. Isoverbascoside (ISOVER) was identified as most bioactive phytochemical for the first time from the plant in the Premna genus. ISOVER activated the protein kinase B/AMP-activated protein kinase signaling cascades and enhanced glucose uptake in IR-L6 muscle cells. ISOVER decreased the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) and increased that of mammalian target of rapamycin (mTOR), thereby attenuating IR. However, molecular docking revealed that ISOVER increases insulin sensitivity by targeting the JNK1 kinase as a competitive inhibitor rather than mTOR. These findings were further supported by the bioenergetics profile of ISOVER. CONCLUSION: This study for the first time depicts the functional properties of ISOVER, derived from Premna herbacea, in ameliorating IR. The phytochemical significantly altered IR with enhanced glucose uptake and inhibition of ROS through JNK-AKT/mTOR signaling which may pave the way for further research in T2DM therapeutics.

Allyl Methyl Sulfide Preserved Pressure Overload-Induced Heart Failure Via Modulation of Mitochondrial Function.

BACKGROUND: Cardiovascular diseases are the leading cause of death globally, and they are causing enormous socio-economic burden to the developed and developing countries. Allyl Methyl Sulfide (AMS) is a novel cardioprotective metabolite identified in the serum of rats after raw garlic administration. The present study explored the cardioprotective effect of AMS on thoracic aortic constriction (TAC)-induced cardiac hypertrophy and heart failure model in rats. METHODS: Thoracic aortic constriction (TAC) by titanium ligating clips resulted in the development of pressure overload-induced cardiac hypertrophy and heart failure model. Four weeks prior to TAC and for 8 weeks after TAC, Sprague Dawley (SD) rats were administered with AMS (25 and 50 mg/kg/day) or Enalapril (10 mg/kg/day). RESULTS: We have observed AMS (25 and 50 mg/kg/day) intervention significantly improved structural and functional parameters of the heart. mRNA expression of fetal genes i.e., atrial natriuretic peptide (ANP), alpha skeletal actin (α-SA) and beta myosin heavy chain (ß-MHC) were reduced in AMS treated TAC hearts along with decrease in perivascular and interstitial fibrosis. AMS attenuated lipid peroxidation and improved protein expression of endogenous antioxidant enzymes i.e., catalase and manganese superoxide dismutase (MnSOD) along with electron transport chain (ETC) complex activity. AMS increased mitochondrial fusion proteins i.e., mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy protein (OPA1), and reduced fission protein i.e., dynamin-related protein 1 (DRP1). Preliminary study suggests that AMS intervention upregulated genes involved in mitochondrial bioenergetics in normal rats. Further, in-vitro studies suggest that AMS reduced mitochondrial reactive oxygen species (ROS), preserved mitochondrial membrane potential and oxygen consumption rate (OCR) in isoproterenol-treated cardiomyoblast. CONCLUSION: This study demonstrated that AMS protected cardiac remodelling, LV dysfunction and fibrosis in pressure overload-induced cardiac hypertrophy and heart failure model by improving endogenous antioxidants and mitochondrial function.

Allylmethylsulfide, a Sulfur Compound Derived from Garlic, Attenuates Isoproterenol-Induced Cardiac Hypertrophy in Rats.

Allylmethylsulfide (AMS) is a novel sulfur metabolite found in the garlic-fed serum of humans and animals. In the present study, we have observed that AMS is safe on chronic administration and has a potential antihypertrophic effect. Chronic administration of AMS for 30 days did not cause any significant differences in the body weight, electrocardiogram, food intake, serum biochemical parameters, and histopathology of vital organs. Single-dose pharmacokinetics of AMS suggests that AMS is rapidly metabolized into Allylmethylsulfoxide (AMSO) and Allylmethylsulfone (AMSO2). To evaluate the efficacy of AMS, cardiac hypertrophy was induced by subcutaneous implantation of ALZET® osmotic minipump containing isoproterenol (~5 mg/kg/day), cotreated with AMS (25 and 50 mg/kg/day) and enalapril (10 mg/kg/day) for 2 weeks. AMS and enalapril significantly reduced cardiac hypertrophy as studied by the heart weight to body weight ratio and mRNA expression of fetal genes (ANP and ß-MHC). We have observed that TBARS, a parameter of lipid peroxidation, was reduced and the antioxidant enzymes (glutathione, catalase, and superoxide dismutase) were improved in the AMS and enalapril-cotreated hypertrophic hearts. The extracellular matrix (ECM) components such as matrix metalloproteinases (MMP2 and MMP9) were significantly upregulated in the diseased hearts; however, with the AMS and enalapril, it was preserved. Similarly, caspases 3, 7, and 9 were upregulated in hypertrophic hearts, and with the AMS and enalapril treatment, they were reduced. Further to corroborate this finding with in vitro data, we have checked the nuclear expression of caspase 3/7 in the H9c2 cells treated with isoproterenol and observed that AMS cotreatment reduced it significantly. Histopathological investigation of myocardium suggests AMS and enalapril treatment reduced fibrosis in hypertrophied hearts. Based on our experimental results, we conclude that AMS, an active metabolite of garlic, could reduce isoproterenol-induced cardiac hypertrophy by reducing oxidative stress, apoptosis, and stabilizing ECM components.

NLRP3 inflammasome drives inflammation in high fructose fed diabetic rat liver: Effect of resveratrol and metformin.

AIMS: To unravel the underlying mechanism of hepatic inflammation during type 2 diabetes (T2DM), we established the diabetic rat model by feeding with high fructose diet for twenty weeks and studied the involvement of inflammasome in the liver of these rats. MATERIALS AND METHODS: Male SD rats weighing 180-200 g were divided in four groups: 1) Control (Con group) rats were fed with corn starch diet, 2) diabetic (Dia group) rats were fed with 65% of fructose, 3) diabetic along with resveratrol (10 mg/kg/day); p.o. (Dia + Resv group) and 4) diabetic along with metformin (300 mg/kg/day); p.o. (Dia + Met group), for twenty weeks. We evaluated the establishment of T2DM in fructose fed rats and the effect of resveratrol and metformin treatment on different diabetic parameters in these rats. Further we investigated the role of NLRP3 inflammasome on T2DM induced liver inflammation and effect of resveratrol and metformin treatment on NLRP3 inflammasome driven inflammatory response. KEY FINDINGS: Rats from Dia group; manifested insulin resistance, hyperinsulinemia, hyperglycemia, elevated uric acid along with hypertriglyceridemia after fructose feeding for twenty weeks. Mostly, above parameters were attenuated in resveratrol and metformin treated groups. Expression of NLRP3 inflammasome components in liver were increased in Dia group rats with elevated transcript levels of pro-inflammatory cytokines. Histopathological examination revealed increase in glycogen content and fibrosis in Dia group rats; which was considerably reduced with resveratrol and metformin treatment. SIGNIFICANCE: Our study suggests that management of inflammation may be considered as an alternative approach to prevent liver tissue injury during chronic diabetic condition.

Vitamin D Deficiency in Rats Causes Cardiac Dysfunction by Inducing Myocardial Insulin Resistance.

SCOPE: Cause-effect relationship between vitamin D deficiency and cardiometabolic abnormalities remains undefined. The aim is to investigate the role of vitamin D deficiency in cardiac failure, through possible involvement in myocardial insulin signaling. METHODS AND RESULTS: Male SD rats (n = 6) are fed a normal diet (Con), vitamin D-deficient diet [Con(-)], or high-fat, high fructose diet (HFHFrD) for 20 weeks. Cardiac hypertrophy and fetal gene program are confirmed in Con(-) group. Cardiac dysfunction is assessed by echocardiography. Elevated renin, TGF-ß and collagen-1α mRNAs, p-ERK1/2, and perivascular fibrosis indicate cardiac remodeling in Con(-) group. Increased serum insulin, triglycerides, and blood pressure, and decreased glucose tolerance and HDL cholesterol are observed in Con(-) rats. Decreased p-Akt/Akt, GLUT4, SOD2, and catalase, and increased NF-κB, TNF-α, and IL-6 are observed in Con(-) hearts. In H9c2 cells, calcitriol attenuates palmitate-induced insulin resistance. VDR-silenced H9c2 cells show reduced Akt phosphorylation, GLUT4 translocation, and 2-NBDG uptake. Findings in Con(-) and HFHFrD groups are comparable. CONCLUSION: Vitamin D deficiency in rats mimic high-fat-, high-fructose-induced metabolic syndrome and cardiac dysfunction. This study demonstrates that vitamin D deficiency is an independent risk factor for heart failure, at least in part, through induction of myocardial insulin resistance.

Beneficial effects of fenofibrate in pulmonary hypertension in rats.

Pulmonary hypertension (PH) is a morbid complication of cardiopulmonary as well as several systemic diseases in humans. It is rapidly progressive and fatal if left untreated. In the present study, we investigated the effect of PPARα agonist fenofibrate (FF) on monocrotaline (MCT)-induced PH in rats. FF, because of its pleiotropic property, could be helpful in reducing inflammation, oxidative stress, and reactive oxygen species. On day 1, MCT (50 mg/kg, s.c.) was given to all the rats in MCT, sildenafil, and FF group except normal control rats. After 3 days of giving MCT, sildenafil (175 µg/kg, orally) and FF (120 mg/kg, orally) were given for 25 days. Echocardiography, hemodynamic parameters, fulton's index, histopathology, oxidative stress parameters, inflammatory markers, Bcl2/Bax gene expression ratio in the right ventricle, and protein expression for NOX-1 in lungs were studied in all the groups. FF has shown to prevent decrease in ratio of pulmonary artery acceleration time to ejection time, increase in ratio of right ventricular outflow tract dimension to aortic outflow dimension, rise in right ventricular systolic pressure, right ventricular hypertrophy, increase in the percentage medial wall thickness (%MWT), increase in oxidative stress and inflammation, increase in NADPH oxidase-1 (NOX-1) expression, and decrease in mRNA expression of Bcl2/Bax ratio caused by MCT. To conclude, FF prevented MCT-induced PH in rats by various mechanisms. It might be helpful in preventing PH in patients who are likely to develop PH.

Ultra-small silver nanoparticles induced ROS activated Toll-pathway against Staphylococcus aureus disease in silkworm model.

The present study investigated the therapeutic action of flavonoids loaded silver nanoparticles (FLV-Ag NPs) on a silkworm, Bombyx mori L., larvae infected by the S. aureus, where an in vivo model system was used. FLV-Ag NPs were synthesized using a Ricinus communis L. leaf extracted flavonoid mixture in various concentrations. The reduction reaction was performed under a simple sunlight exposure condition. In the reduction process, quercetin and kaempferol loadings were also found. They were confirmed by UV-visible, TEM, XRD, XPS, DLS and FTIR spectroscopic techniques. TEM confirmed that the synthesized NPs were monodispersed and with an average size of 5.8nm±0.04. Initially, those synthesized FLV-Ag NPs were tested against S. aureus in in vitro by comparing their potential inhibitory activity with only flavonoids mixture (FLVs) and pure silver nanoparticles (Ag NPs). Furthermore, these FLV-Ag NPs were used to treat S. aureus infected B. mori larvae and the therapeutic efficacy was measured. Our results demonstrate that the FLV-Ag NPs are effective in curing the S. aureus infection through the induced expression of antimicrobial peptide genes, the enhanced oxidative enzyme levels, and the promoted phagocytosis of S. aureus by the haemocytes in silkworm larvae. On the basis of these results, it is proposed that the mechanism of the antimicrobial activity of FLV-Ag NPs involves the NPs-insect fat body cell association and a reactive oxygen species-mediated Toll-pathway.

Large-Area Monolayer MoS2 for Flexible Low-Power RF Nanoelectronics in the GHz Regime.

Flexible synthesized MoS2 transistors are advanced to perform at GHz speeds. An intrinsic cutoff frequency of 5.6 GHz is achieved and analog circuits are realized. Devices are mechanically robust for 10,000 bending cycles.

Mitochondrial modulators in experimental Huntington's disease: reversal of mitochondrial dysfunctions and cognitive deficits.

Huntington's disease (HD) is a chronic neurodegenerative condition involving impaired mitochondrial functions. The present study evaluates the therapeutic potential of combined administration of mitochondrial modulators: alpha-lipoic acid and acetyl-l-carnitine on mitochondrial dysfunctions in 3-NP-induced HD. Our results reveal 3-NP administration resulted in compromise of mitochondrial functions in terms of: (1) impaired activity of mitochondrial respiratory chain enzymes, altered cytochrome levels, reduced histochemical staining of complex-II and IV, reduced in-gel activity of complex-I to V, and reduced mRNA expression of respiratory chain complexes; (2) enhanced mitochondrial oxidative stress indicated by increased malondialdehyde, protein carbonyls, reactive oxygen species and nitrite levels, along with decreased Mn-superoxide dismutase and catalase activity; (3) mitochondrial structural changes measured by mitochondrial swelling, reduced mitochondrial membrane potential and ultra-structure changes; (4) increased cytosolic cytochrome c levels, caspase-3 and -9 activity along with altered expression of apoptotic proteins (AIF, Bim, Bad, and Bax); and (5) impaired cognitive functions assessed using Morris water maze and Y-maze. Combination of mitochondrial modulators (alpha-lipoic acid + acetyl-l-carnitine) on the other hand ameliorated 3-NP-induced mitochondrial dysfunctions, oxidative stress, histologic alterations, and behavioral deficits, suggesting their therapeutic efficacy in the management of HD.

Synthesis and evaluation of novel triazoles and mannich bases functionalized 1,4-dihydropyridine as angiotensin converting enzyme (ACE) inhibitors.

A series of novel diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate embedded triazole and mannich bases were synthesized, and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. Screening of above synthesized compounds for ACE inhibition showed that triazoles functionalized compounds have better ACE inhibitory activity compared to that of mannich bases analogues. Among all triazoles we found 6 h, 6 i and 6 j to have good ACE inhibition activity with IC50 values 0.713 µM, 0.409 µM and 0.653 µM, respectively. Among mannich bases series compounds, only 7c resulted as most active ACE inhibitor with IC50 value of 0.928 µM.

Synthesis of thio-heterocyclic analogues from Baylis-Hillman bromides as potent cyclooxygenase-2 inhibitors.

A series of thio-substituted pyrimidine, benzoxazole, benzothiazole and triazole analogues were synthesized from Baylis-Hillman bromides in a clean and efficient way. The synthesized twenty new compounds were subjected to in vitro COX-1 and COX-2 inhibitory activity. Majority of compounds found to be highly selective COX-2 inhibitor. Seven compounds (16e, 16f, 16k, 16l, 16m, 16r and 16s) displayed anti-inflammatory activity at micromolar concentrations with IC50 values for COX-2 inhibition ranging from 2.93 to 5.34 µM compared to reference drug whose IC50 is 2.66 µM. All these seven compounds had very little COX-1 inhibition property and thus are suitable candidates for anti-inflammatory drugs with less gastrointestinal side effect.