RESUMEN
Brown adipose tissue (BAT) is correlated to cardiovascular health in rodents and humans, but the physiological role of BAT in the initial cardiac remodeling at the onset of stress is unknown. Activation of BAT via 48 h cold (16°C) in mice following transverse aortic constriction (TAC) reduced cardiac gene expression for LCFA uptake and oxidation in male mice and accelerated the onset of cardiac metabolic remodeling, with an early isoform shift of carnitine palmitoyltransferase 1 (CPT1) toward increased CPT1a, reduced entry of long chain fatty acid (LCFA) into oxidative metabolism (0.59 ± 0.02 vs. 0.72 ± 0.02 in RT TAC hearts, p < .05) and increased carbohydrate oxidation with altered glucose transporter content. BAT activation with TAC reduced early hypertrophic expression of ß-MHC by 61% versus RT-TAC and reduced pro-fibrotic TGF-ß1 and COL3α1 expression. While cardiac natriuretic peptide expression was yet to increase at only 3 days TAC, Nppa and Nppb expression were elevated in Cold TAC versus RT TAC hearts 2.7- and 2.4-fold, respectively. Eliminating BAT thermogenic activation with UCP1 KO mice eliminated differences between Cold TAC and RT TAC hearts, confirming effects of BAT activation rather than autonomous cardiac responses to cold. Female responses to BAT activation were blunted, with limited UCP1 changes with cold, partly due to already activated BAT in females at RT compared to thermoneutrality. These data reveal a previously unknown physiological mechanism of UCP1-dependent BAT activation in attenuating early cardiac hypertrophic and profibrotic signaling and accelerating remodeled metabolic activity in the heart at the onset of cardiac stress.
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Tejido Adiposo Pardo , Fibrosis , Proteína Desacopladora 1 , Animales , Tejido Adiposo Pardo/metabolismo , Ratones , Masculino , Proteína Desacopladora 1/metabolismo , Fibrosis/metabolismo , Carnitina O-Palmitoiltransferasa/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Ratones Endogámicos C57BL , Cardiomegalia/metabolismo , Cardiomegalia/patología , Miocardio/metabolismo , Miocardio/patología , Estrés Fisiológico , Remodelación Ventricular/fisiología , Ratones Noqueados , FríoRESUMEN
Both genetic and epigenetic mechanisms intimately regulate cancer development and chemoresistance. Different genetic alterations are observed in multiple genes, and most are irreversible. Aside from genetic alterations, epigenetic alterations play a crucial role in cancer. The reversible nature of epigenetic modifications makes them an attractive target for cancer prevention and therapy. Specific epigenetic alteration is also being investigated as a potential biomarker in multiple cancers. c-MYC is one of the most important transcription factors that are centrally implicated in multiple types of cancer cells reprogramming, proliferation, and chemoresistance. c-MYC shows not only genetic alterations but epigenetic changes in multiple cancers. It has been observed that epigenome aberrations can reversibly alter the expression of c-MYC, both transcriptional and translational levels. Understanding the underlying mechanism of the epigenetic alterations of c-MYC, that has its role in multiple levels of cancer pathogenesis, can give a better understanding of various unresolved questions regarding cancer. Recently, some researchers reported that targeting the epigenetic modifiers of c-MYC can successfully inhibit cancer cell proliferation, sensitize the chemoresistant cells, and increase the patient survival rate. As c-MYC is an important transcription factor, epigenetic therapy might be one of the best alternatives for the conventional therapies that assumes the "one-size-fits-all" role. It can also increase the precision of targeting and enhance the effectiveness of treatments among various cancer subtypes. In this review, we highlighted the role of epigenetically modified c-MYC in cancer cell reprogramming, progression, and chemoresistance. We also summarize the potential therapeutic approaches to target these modifications for the prevention of cancer development and chemoresistant phenotypes.
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Reprogramación Celular , Neoplasias , Reprogramación Celular/genética , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Genes myc , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Transcripción/genéticaRESUMEN
Enzalutamide is an androgen receptor (AR) antagonist commonly used in the treatment of prostate cancer (CaP). However, due to the potential toxicity and development of resistance associated with Enzalutamide-based therapy, there is a need to explore additional compounds that can enhance its therapeutic effectiveness while minimizing toxicity. Lupeol is a pharmacologically active triterpene having anticancer effects. The objective of this study was to explore Lupeol's potential in enhancing the chemosensitivity of chemoresistant CaP cells to Enzalutamide in vitro and in a mouse model. To test our hypothesis, we performed cell viability and luciferase reporter gene assay, flow cytometry, animal studies, and histopathological analysis. Finally, we analyzed the change in selective metabolites in the prostate tissue by LCMS. Results demonstrated that a combination of Lupeol and Enzalutamide could better (i) suppress the Cancer Stem Cells (CSCs) and chemoresistant cells (PTEN-CaP8 and PC3) viability and migration, (ii) increase cell cycle arrest, (iii) inhibit the transcriptional activity of AR, c-MYC, c-FLIP, and TCF (iv) inhibit tumor growth in a mouse model (v) protect Enzalutamide-induced adverse effects in prostate glands and gut tissue (vi) decrease levels of testosterone and methionine metabolites. In conclusion, Lupeol enhances the pharmacological efficacy of Enzalutamide and reduces the adverse effects. Thus, Lupeol could be a promising adjuvant for improving Enzalutamide-based treatment outcomes and warrant further research.
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Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Humanos , Masculino , Animales , Ratones , Receptores Androgénicos/genética , Próstata/patología , Línea Celular Tumoral , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Nitrilos/farmacología , Triterpenos Pentacíclicos/farmacología , Resistencia a Antineoplásicos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológicoRESUMEN
BACKGROUND: The failing heart is energy starved with impaired oxidation of long-chain fatty acids (LCFAs) at the level of reduced CPT1 (carnitine palmitoyltransferase 1) activity at the outer mitochondrial membrane. Recent work shows elevated ketone oxidation in failing hearts as an alternate carbon source for oxidative ATP generation. We hypothesized that another short-chain carbon source, short-chain fatty acids (SCFAs) that bypass carnitine palmitoyltransferase 1, could similarly support energy production in failing hearts. METHODS: Cardiac hypertrophy and dysfunction were induced in rats by transverse-aortic constriction (TAC). Fourteen weeks after TAC or sham operation, isolated hearts were perfused with either the 4 carbon, 13C-labeled ketone (D3-hydroxybutyrate) or the 4 carbon, 13C-labeled SCFA butyrate in the presence of glucose and the LCFA palmitate. Oxidation of ketone and SCFA was compared by in vitro 13C nuclear magnetic resonance spectroscopy, as was the capacity for short-chain carbon sources to compensate for impaired LCFA oxidation in the hypertrophic heart. Adaptive changes in enzyme expression and content for the distinct pathways of ketone and SCFA oxidation were examined in both failing rat and human hearts. RESULTS: TAC produced pathological hypertrophy and increased the fractional contributions of ketone to acetyl coenzyme-A production in the tricarboxylic acid cycle (0.60±0.02 sham ketone versus 0.70±0.02 TAC ketone; P<0.05). However, butyrate oxidation in failing hearts was 15% greater (0.803±0.020 TAC SCFA) than ketone oxidation. SCFA was also more readily oxidized than ketone in sham hearts by 15% (0.693±0.020 sham SCFA). Despite greater SFCA oxidation, TAC did not change short-chain acyl coenzyme-A dehydrogenase content. However, failing hearts of humans and the rat model both contain significant increases in acyl coenzyme-A synthetase medium-chain 3 enzyme gene expression and protein content. The increased oxidation of SCFA and ketones occurred at the expense of LCFA oxidation, with LCFA contributing less to acetyl coenzyme-A production in failing hearts perfused with SCFA (0.190±0.012 TAC SCFA versus 0.3163±0.0360 TAC ketone). CONCLUSIONS: SCFAs are more readily oxidized than ketones in failing hearts, despite both bypassing reduced CPT1 activity and represent an unexplored carbon source for energy production in failing hearts.
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Ácidos Grasos Volátiles/metabolismo , Insuficiencia Cardíaca/fisiopatología , Cetonas/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Oxidación-Reducción , Ratas , Ratas Sprague-DawleyRESUMEN
Recently, a pathogen has been identified as a novel coronavirus (SARS-CoV-2) and found to trigger novel pneumonia (COVID-19) in human beings and some other mammals. The uncontrolled release of cytokines is seen from the primary stages of symptoms to last acute respiratory distress syndrome (ARDS). Thus, it is necessary to find out safe and effective drugs against this deadly coronavirus as soon as possible. Here, we downloaded the three-dimensional model of NSP10/NSP16 methyltransferase (PDB-ID: 6w6l) and main protease (PDB-ID: 6lu7) of COVID-19. Using these molecular models, we performed virtual screening with our anti-viral, inti-infectious, and anti-protease compounds, which are attractive therapeutics to prevent infection of the COVID-19. We found that top screened compound binds with protein molecules with good dock score with the help of hydrophobic interactions and hydrogen bonding. We observed that protease complexed with Cyclocytidine hydrochloride (anti-viral and anti-cancer), Trifluridine (anti-viral), Adonitol, and Meropenem (anti-bacterial), and Penciclovir (anti-viral) bound with a good docking score ranging from -6.8 to -5.1 (Kcal/mol). Further, NSP10/NSP16 methyltransferase complexed with Telbivudine, Oxytetracycline dihydrate (anti-viral), Methylgallate (anti-malarial), 2-deoxyglucose and Daphnetin (anti-cancer) from the docking score of -7.0 to -5.7 (Kcal/mol). In conclusion, the selected compounds may be used as a novel therapeutic agent to combat this deadly pandemic disease, SARS-CoV-2 infection, but needs further experimental research.HighlightsNSP10/NSP16 methyltransferase and main protease complex of SARS CoV-2 bind with selected drugs.NSP10/NSP16 methyltransferase and protease interacted with drugs by hydrophobic interactions.Compounds show good DG binging free energy with protein complexes.Ligands were found to follow the Lipinski rule of five.
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Antivirales/química , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Proteínas no Estructurales Virales/química , Proteínas Reguladoras y Accesorias Virales/química , Aciclovir/análogos & derivados , Aciclovir/química , Aciclovir/uso terapéutico , Ancitabina/química , Ancitabina/uso terapéutico , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/virología , Evaluación Preclínica de Medicamentos , Guanina , Humanos , Meropenem/química , Meropenem/uso terapéutico , Metiltransferasas , Modelos Moleculares , Simulación del Acoplamiento Molecular , Pandemias , Neumonía Viral/virología , Conformación Proteica/efectos de los fármacos , Ribitol/química , Ribitol/uso terapéutico , SARS-CoV-2 , Trifluridina/química , Trifluridina/uso terapéutico , Interfaz Usuario-Computador , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/ultraestructura , Proteínas Reguladoras y Accesorias Virales/antagonistas & inhibidores , Proteínas Reguladoras y Accesorias Virales/ultraestructuraRESUMEN
Thermogenesis is an important homeostatic mechanism essential for survival and normal physiological functions in mammals. Both brown adipose tissue (BAT) (i.e. uncoupling protein 1 (UCP1)-based) and skeletal muscle (i.e. sarcolipin (SLN)-based) thermogenesis processes play important roles in temperature homeostasis, but their relative contributions differ from small to large mammals. In this study, we investigated the functional interplay between skeletal muscle- and BAT-based thermogenesis under mild versus severe cold adaptation by employing UCP1-/- and SLN-/- mice. Interestingly, adaptation of SLN-/- mice to mild cold conditions (16 °C) significantly increased UCP1 expression, suggesting increased reliance on BAT-based thermogenesis. This was also evident from structural alterations in BAT morphology, including mitochondrial architecture, increased expression of electron transport chain proteins, and depletion of fat droplets. Similarly, UCP1-/- mice adapted to mild cold up-regulated muscle-based thermogenesis, indicated by increases in muscle succinate dehydrogenase activity, SLN expression, mitochondrial content, and neovascularization, compared with WT mice. These results further confirm that SLN-based thermogenesis is a key player in muscle non-shivering thermogenesis (NST) and can compensate for loss of BAT activity. We also present evidence that the increased reliance on BAT-based NST depends on increased autonomic input, as indicated by abundant levels of tyrosine hydroxylase and neuropeptide Y. Our findings demonstrate that both BAT and muscle-based NST are equally recruited during mild and severe cold adaptation and that loss of heat production from one thermogenic pathway leads to increased recruitment of the other, indicating a functional interplay between these two thermogenic processes.
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Aclimatación/fisiología , Tejido Adiposo Pardo/metabolismo , Frío , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Termogénesis/fisiología , Animales , Ratones , Ratones Noqueados , Mitocondrias Musculares/genética , Proteínas Musculares/biosíntesis , Proteínas Musculares/genética , Proteolípidos/biosíntesis , Proteolípidos/genética , Proteína Desacopladora 1/biosíntesis , Proteína Desacopladora 1/genética , Regulación hacia Arriba/fisiologíaRESUMEN
Skeletal muscle has been suggested as a site of nonshivering thermogenesis (NST) besides brown adipose tissue (BAT). Studies in birds, which do not contain BAT, have demonstrated the importance of skeletal muscle-based NST. However, muscle-based NST in mammals remains poorly characterized. We recently reported that sarco/endoplasmic reticulum Ca(2+) cycling and that its regulation by SLN can be the basis for muscle NST. Because of the dominant role of BAT-mediated thermogenesis in rodents, the role of muscle-based NST is less obvious. In this study, we investigated whether muscle will become an important site of NST when BAT function is conditionally minimized in mice. We surgically removed interscapular BAT (iBAT, which constitutes â¼70% of total BAT) and exposed the mice to prolonged cold (4 °C) for 9 days. The iBAT-ablated mice were able to maintain optimal body temperature (â¼35-37 °C) during the entire period of cold exposure. After 4 days in the cold, both sham controls and iBAT-ablated mice stopped shivering and resumed routine physical activity, indicating that they are cold-adapted. The iBAT-ablated mice showed higher oxygen consumption and decreased body weight and fat mass, suggesting an increased energy cost of cold adaptation. The skeletal muscles in these mice underwent extensive remodeling of both the sarcoplasmic reticulum and mitochondria, including alteration in the expression of key components of Ca(2+) handling and mitochondrial metabolism. These changes, along with increased sarcolipin expression, provide evidence for the recruitment of NST in skeletal muscle. These studies collectively suggest that skeletal muscle becomes the major site of NST when BAT activity is minimized.
Asunto(s)
Tejido Adiposo Pardo/metabolismo , Señalización del Calcio/fisiología , Frío , Músculo Esquelético/metabolismo , Consumo de Oxígeno/fisiología , Termogénesis/fisiología , Animales , Masculino , RatonesRESUMEN
Sarcolipin (SLN) is a novel regulator of sarcoplasmic reticulum Ca(2+) ATPase (SERCA) in muscle. SLN binding to SERCA uncouples Ca(2+) transport from ATP hydrolysis. By this mechanism, SLN promotes the futile cycling of SERCA, contributing to muscle heat production. We recently showed that SLN plays an important role in cold- and diet-induced thermogenesis. However, the detailed mechanism of how SLN regulates muscle metabolism remains unclear. In this study, we used both SLN knockout (Sln(-/-)) and skeletal muscle-specific SLN overexpression (Sln(OE)) mice to explore energy metabolism by pair feeding (fixed calories) and high-fat diet feeding (ad libitum). Our results show that, upon pair feeding, Sln(OE) mice lost weight compared with the WT, but Sln(-/-) mice gained weight. Interestingly, when fed with a high-fat diet, Sln(OE) mice consumed more calories but gained less weight and maintained a normal metabolic profile in comparison with WT and Sln(-/-) mice. We found that oxygen consumption and fatty acid oxidation were increased markedly in Sln(OE) mice. There was also an increase in both mitochondrial number and size in Sln(OE) muscle, together with increased expression of peroxisome proliferator-activated receptor δ (PPARδ) and PPAR γ coactivator 1 α (PGC1α), key transcriptional activators of mitochondrial biogenesis and enzymes involved in oxidative metabolism. These results, taken together, establish an important role for SLN in muscle metabolism and energy expenditure. On the basis of these data we propose that SLN is a novel target for enhancing whole-body energy expenditure.
Asunto(s)
Metabolismo Basal/fisiología , Metabolismo Energético/fisiología , Proteínas Musculares/metabolismo , Obesidad/prevención & control , Proteolípidos/metabolismo , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/patología , Animales , Dieta Alta en Grasa/efectos adversos , Ingestión de Energía , Ácidos Grasos/metabolismo , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Modelos Biológicos , Proteínas Musculares/deficiencia , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Obesidad/etiología , Obesidad/metabolismo , Oxidación-Reducción , Consumo de Oxígeno , PPAR delta/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteolípidos/deficiencia , Proteolípidos/genética , Receptores Adrenérgicos beta 2/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Factores de Transcripción/metabolismo , Regulación hacia Arriba , Pérdida de PesoRESUMEN
CONTEXT: Potentilla fulgens Wall. ex Hook (Rosaceae) is a potent medicinal plant of the Western Himalayas, where its roots are traditionally used by the local people of Uttaranchal (India) to treat wounds and tiger bites. OBJECTIVE: The present study scientifically evaluates the wound healing activity of P. fulgens ethanol root extract (EPF) and its ethyl acetate fraction (PFEA) on experimental rats. MATERIALS AND METHODS: Wounds were inflicted on animals by using both excision and incision models. The wounded animals were treated for 16 days with EPF (oral: 200-400 mg/kg and topical: 5-10% w/w) and PFEA (oral: 75 mg/kg; topical: 1.75% w/w). Various physical (wound contraction, epithelialization rate, tensile strength) and biochemical parameters (hydroxyproline, hexosamine, proteins, DNA) were examined during the study. Oxidant product (lipidperoxidase), antioxidant enzymes (catalase, superoxide-dismutase) and reduced glutathione were determined. Morphological and histopathological studies of the skin tissues were monitored. RESULTS: A significant (p < 0.05) wound healing property was observed when the animals were treated topically with EPF (10% w/w) and PFEA (1.75% w/w). A significantly (p < 0.05) increased in the levels of hydroxyproline, hexosamine, protein and DNA up to 59.22, 70.42, 61.01 and 60.00% was observed, respectively. This effect was further demonstrated by the morphological and histopathological representation, thus showing significant (p < 0.05) re-epethelialization on the healing area. EPF and PFEA also showed significant (p < 0.05) antioxidant activity. CONCLUSIONS: The present study provided the scientific evidence, where P. fulgens rich in polyphenolic components possess remarkable wound healing activities, thereby supporting the traditional claims.
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Extractos Vegetales/farmacología , Polifenoles/farmacología , Potentilla/química , Cicatrización de Heridas/efectos de los fármacos , Animales , Antioxidantes/farmacología , Femenino , Masculino , Extractos Vegetales/toxicidad , Raíces de Plantas/química , Polifenoles/toxicidad , Ratas , Ratas Endogámicas , Piel/efectos de los fármacos , Piel/patologíaRESUMEN
Type 2 diabetes mellitus is associated with an accelerated muscle loss during aging, decreased muscle function, and increased disability. To better understand the mechanisms causing this muscle deterioration in type 2 diabetes, we assessed muscle weight, exercise capacity, and biochemistry in db/db and TallyHo mice at prediabetic and overtly diabetic ages. Maximum running speeds and muscle weights were already reduced in prediabetic db/db mice when compared with lean controls and more severely reduced in the overtly diabetic db/db mice. In contrast to db/db mice, TallyHo muscle size dramatically increased and maximum running speed was maintained during the progression from prediabetes to overt diabetes. Analysis of mechanisms that may contribute to decreased muscle weight in db/db mice demonstrated that insulin-dependent phosphorylation of enzymes that promote protein synthesis was severely blunted in db/db muscle. In addition, prediabetic (6-wk-old) and diabetic (12-wk-old) db/db muscle exhibited an increase in a marker of proteasomal protein degradation, the level of polyubiquitinated proteins. Chronic treadmill training of db/db mice improved glucose tolerance and exercise capacity, reduced markers of protein degradation, but only mildly increased muscle weight. The differences in muscle phenotype between these models of type 2 diabetes suggest that insulin resistance and chronic hyperglycemia alone are insufficient to rapidly decrease muscle size and function and that the effects of diabetes on muscle growth and function are animal model-dependent.
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Diabetes Mellitus Tipo 2/complicaciones , Modelos Animales de Enfermedad , Resistencia a la Insulina , Desarrollo de Músculos , Músculo Esquelético/metabolismo , Estado Prediabético/complicaciones , Sarcopenia/complicaciones , Animales , Animales no Consanguíneos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Actividad Motora , Desarrollo de Músculos/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/patología , Fosforilación/efectos de los fármacos , Resistencia Física/efectos de los fármacos , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/metabolismo , Estado Prediabético/patología , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Sarcopenia/prevención & controlRESUMEN
BACKGROUND: Prior experimental and epidemiologic data support a link between exposure to fine ambient particulate matter (<2.5 µm in aerodynamic diameter, PM2.5) and development of insulin resistance/Type II diabetes mellitus. This study was designed to investigate whether inhalational exposure of concentrated PM2.5 in a genetically susceptible animal model would result in abnormalities in energy metabolism and exacerbation of peripheral glycemic control. METHODS: KKay mice, which are susceptible to Type II DM, were assigned to either concentrated ambient PM2.5 or filtered air (FA) for 5-8 weeks via a whole body exposure system. Glucose tolerance, insulin sensitivity, oxygen consumption and heat production were evaluated. At euthanasia, blood, spleen and visceral adipose tissue were collected to measure inflammatory cells using flow cytometry. Standard immnunohistochemical methods, western blotting and quantitative PCR were used to assess targets of interest. RESULTS: PM2.5 exposure influenced energy metabolism including O2 consumption, CO2 production, respiratory exchange ratio and thermogenesis. These changes were accompanied by worsened insulin resistance, visceral adiposity and inflammation in spleen and visceral adipose depots. Plasma adiponectin were decreased in response to PM2.5 exposure while leptin levels increased. PM2.5 exposure resulted in a significant increase in expression of inflammatory genes and decreased UCP1 expression in brown adipose tissue and activated p38 and ERK pathways in the liver of the KKay mice. CONCLUSIONS: Concentrated ambient PM2.5 exposure impairs energy metabolism, concomitant with abnormalities in glucose homeostasis, increased inflammation in insulin responsive organs, brown adipose inflammation and results in imbalance in circulating leptin/adiponectin levels in a genetically susceptible diabetic model. These results provide additional insights into the mechanisms surrounding air pollution mediated susceptibility to Type II DM.
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Contaminantes Atmosféricos/toxicidad , Contaminación del Aire/efectos adversos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Material Particulado/toxicidad , Adipocitos Marrones/efectos de los fármacos , Animales , Cámaras de Exposición Atmosférica , Glucemia/metabolismo , Western Blotting , Peso Corporal/efectos de los fármacos , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/patología , Citometría de Flujo , Homeostasis/efectos de los fármacos , Insulina/fisiología , Ratones , Miografía , Tamaño de los Órganos/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Tamaño de la Partícula , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacos , Termogénesis/efectos de los fármacosRESUMEN
The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.
Asunto(s)
Glucosa , Homeostasis , Músculo Esquelético , NAD , Receptores Acoplados a Proteínas G , Animales , Músculo Esquelético/metabolismo , NAD/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Masculino , Glucosa/metabolismo , Ratones , Ratones Noqueados , Humanos , Mitocondrias/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , FosforilaciónRESUMEN
Curare, a selective skeletal muscle relaxant, has been used clinically to reduce shivering and as an anesthetic auxiliary in abdominal surgery. It is also widely used in animal experiments to block neuromuscular junction activity. Effective doses of curare diminish muscle contraction without affecting brain function, but at higher doses it is known to be lethal. However, the exact dose of curare initiating muscle relaxation vs. lethal effect has not been fully characterized in mice. In this study we carefully examined the dose-response for achieving muscle inactivity over lethality in both male and female mice (C57BL6/J). The most striking finding of this study is that female mice were highly susceptible to curare; both the ED50 and LD50 were at least 3-fold lower than male littermates. This study shows that gender-specific differences can be an important factor when administering skeletal muscle relaxants, particularly curare or other analogous agents targeted to the neuromuscular junction.
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Curare/administración & dosificación , Fármacos Neuromusculares no Despolarizantes/administración & dosificación , Consumo de Oxígeno/efectos de los fármacos , Factores Sexuales , Animales , Metabolismo Basal/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Curare/toxicidad , Relación Dosis-Respuesta a Droga , Conducta Alimentaria/efectos de los fármacos , Femenino , Inmovilización , Estimación de Kaplan-Meier , Masculino , Ratones , Ratones Endogámicos C57BL , Fármacos Neuromusculares no Despolarizantes/toxicidadRESUMEN
Western diet (WD) impairs glucose tolerance and cardiac lipid dynamics, preceding heart failure with reduced ejection fraction (HFrEF) in mice. Unlike diabetic db/db mice with high cardiac triglyceride (TG) and rapid TG turnover, WD mice had high TG but slowed turnover, reducing lipolytic PPAR⺠activation. WD deranged cardiac TG dynamics by imbalancing synthesis and lipolysis, with low cardiac TG lipase (ATGL), low ATGL co-activator, and high ATGL inhibitory peptide. By 24 weeks of WD, hearts shifted from diastolic dysfunction to diastolic dysfunction with HFrEF with decreases in GLUT4 and exogenous glucose oxidation and elevated ß-hydroxybutyrate dehydrogenase 1 without increasing ketone oxidation.
RESUMEN
During the development of heart failure (HF), the capacity for cardiomyocyte (CM) fatty acid oxidation (FAO) and ATP production is progressively diminished, contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor-interacting protein 140 (RIP140, encoded by Nrip1) has been shown to function as a transcriptional corepressor of oxidative metabolism. We found that mice with striated muscle deficiency of RIP140 (strNrip1-/-) exhibited increased expression of a broad array of genes involved in mitochondrial energy metabolism and contractile function in heart and skeletal muscle. strNrip1-/- mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and CM-specific RIP140-deficient (csNrip1-/-) mice were protected against the development of HF caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in CMs were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fatty acid oxidation, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and fatty acid utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for the treatment of HF.
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Insuficiencia Cardíaca , Proteína de Interacción con Receptores Nucleares 1 , Animales , Ratones , Cardiomegalia/metabolismo , Metabolismo Energético/genética , Ácidos Grasos/metabolismo , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Miocitos Cardíacos/metabolismo , Proteína de Interacción con Receptores Nucleares 1/genética , Proteína de Interacción con Receptores Nucleares 1/metabolismoRESUMEN
Muscle fitness and mass deteriorate under the conditions of obesity and aging for reasons yet to be fully elucidated. Herein, we describe a novel pathway linking peripheral nutrient sensing and skeletal muscle function through the sweet taste receptor TAS1R2 and the involvement of ERK2-PARP1-NAD signaling axis. Muscle-specific deletion of TAS1R2 (mKO) in mice produced elevated NAD levels due to suppressed PARP1 activity, improved mitochondrial function, increased muscle mass and strength, and prolonged running endurance. Deletion of TAS1R2 in obese or aged mice also ameliorated the decline in muscle mass and fitness arising from these conditions. Remarkably, partial loss-of-function of TAS1R2 (rs35874116) in older, obese humans recapitulated the healthier muscle phenotype displayed by mKO mice in response to exercise training. Our findings show that inhibition of the TAS1R2 signaling in skeletal muscle is a promising therapeutic approach to preserve muscle mass and function.
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The transcription factor NANOG regulates self-renewal and pluripotency in embryonic cells, and its downregulation leads to cell differentiation. Recent studies have linked upregulation of NANOG in various cancers and the regulation of expression of different molecules, and vice versa, to induce proliferation, metastasis, invasion and chemoresistance. Thus NANOG is an oncogene that functions by inducing stem cells' circuitries and heterogeneity in cancers. Understanding NANOG's role in various cancers may lead to it becoming a therapeutic target to halt cancer progression. The NANOG network can also be targeted to resensitize resistant cancer cells to conventional therapies. The current review focuses on NANOG regulation in the various signaling networks leading to cancer progression and chemoresistance, and highlights the therapeutic aspect of targeting NANOG in various cancers.
Lay abstract NANOG is a gene that is mainly expressed during development of the embryo. In adult tissues, NANOG is hardly expressed. In embryonal cells, NANOG is responsible for generating stem cells. Once the cells are differentiated into their specific function, they no longer need this renewing property. So expression of NANOG in differentiated 'adult' cells is harmful as it helps tumor cells to grow. NANOG expression also enables the tumor cells to keep on evolving their microenvironment, thus making it difficult for conventional therapy to destroy them. This review highlights the factors that influence NANOG's expression in cancer progression and chemoresistance and how it can be targeted for therapy.
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Proteína Homeótica Nanog/metabolismo , Neoplasias/metabolismo , Animales , Carcinogénesis/metabolismo , Resistencia a Antineoplásicos , Epigénesis Genética , Humanos , Proteína Homeótica Nanog/genética , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & controlRESUMEN
New organometallic drug candidates [Ph2Sn(HL)], 1, and [Ru(η6--p-cymene)(HL)Cl], 2, were designed and synthesized by in situ reaction of a Schiff base ligand (HL) and diphenyltin dichloride and [RuCl2(p-cymene)]2, respectively. The drug candidates 1 and 2 have been characterized by spectroscopic methods (Fourier-transform infrared spectroscopy, UV-vis, and 1H/13C NMR), elemental analysis, and single X-ray crystallographic studies (in case of 1). The ground-state geometry optimization of 1 and 2 was performed by density functional theory calculations. The interaction of 1 and 2 with tRNA was assessed by absorption spectroscopy, cyclic voltammetry, circular dichroism, and ethidium bromide displacement assay using fluorescence emission spectroscopy to determine their potential to act as antitumor agents. The cytotoxicity of 1 and 2 was screened against human liver carcinoma (Huh7), prostate cancer (Du145), and the normal prostate cell line (PNT 2). The results implicated a dose-dependent growth inhibition of the two cancer cells at concentrations (2.5-15 µM) of 1 and 2 with the treatment after 48 h. Interestingly, 1 revealed good selective activity toward the liver cancer cell line (Huh7). Furthermore, both the drug candidates 1 and 2 were found to be nontoxic toward the PNT 2 normal cell line. These studies lay a paradigm for rational efficacious drug design for chemotherapeutic intervention in cancers using new tailored organometallic drug entities; organotin(IV) and organoruthenium(II) have been demonstrated to be viable for the safe administration and specific targeted drug uptake by the resistant cancerous cell lines at low intracellular concentrations.
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BACKGROUND: The resistance of cancer cells to different therapies is one of the major stumbling blocks for successful cancer treatment. Various natural and pharmaceuticals drugs are unable to control drug-resistance cancer cell's growth. Also, chemotherapy and radiotherapy have several side effects and cannot apply to the patient in excess. In this context, chemosensitization to the therapy-resistant cells by non-toxic phytochemicals could be an excellent alternative to combat therapy-resistant cancers. OBJECTIVE: To review the currently available literature on chemosensitization of therapy resistance cancers by Lupeol for clinically approved drugs through targeting different cell signaling pathways. METHODS: We reviewed relevant published articles in PubMed and other search engines from 1999 to 2019 to write this manuscript. The key words used for the search were "Lupeol and Cancer", "Lupeol and Chemosensitization", "Lupeol and Cell Signaling Pathways", "Cancer Stem Cells and Lupeol" etc. The published results on the chemosensitization of Lupeol were compared and discussed. RESULTS: Lupeol chemosensitizes drug-resistant cancer cells for clinically approved drugs. Lupeol alone or in combination with approved drugs inhibits inflammation in different cancer cells through modulation of expression of IL-6, TNF-α, and IFN-γ. Lupeol, through altering the expression levels of BCL-2, BAX, Survivin, FAS, Caspases, and PI3K-AKT-mTOR signaling pathway, significantly induce cell deaths among therapy-resistant cells. Lupeol also modulates the molecules involved in cell cycle regulation such as Cyclins, CDKs, P53, P21, and PCNA in different cancer types. CONCLUSION: Lupeol chemosensitizes the therapy-resistant cancer cells for the treatment of various clinically approved drugs via modulating different signaling pathways responsible for chemoresistance cancer. Thus, Lupeol might be used as an adjuvant molecule along with clinically approved drugs to reduce the toxicity and increase the effectiveness.
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Neoplasias/tratamiento farmacológico , Triterpenos Pentacíclicos/farmacología , Transducción de Señal/efectos de los fármacos , Apoptosis , Línea Celular Tumoral , Resistencia a Antineoplásicos , HumanosRESUMEN
Metamaterials are engineered materials that offer the flexibility to manipulate the incident waves leading to exotic applications such as cloaking, extraordinary transmission, sub-wavelength imaging and negative refraction. These concepts have largely been explored in the context of electromagnetic waves. Acoustic metamaterials, similar to their optical counterparts, demonstrate anomalous effective elastic properties. Recent developments have shown that coiling up the propagation path of acoustic wave results in effective elastic response of the metamaterial beyond the natural response of its constituent materials. The effective response of metamaterials is generally evaluated using the 'S' parameter retrieval method based on amplitude of the waves. The phase of acoustic waves contains information of wave pressure and particle velocity. Here, we show using finite-element methods that phase reversal of transmitted waves may be used to predict extreme acoustic properties in space coiling metamaterials. This change is the difference in the phase of the transmitted wave with respect to the incident wave. This method is simpler when compared with the more rigorous 'S' parameter retrieval method. The inferences drawn using this method have been verified experimentally for labyrinthine metamaterials by showing negative refraction for the predicted band of frequencies.