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1.
Nutrients ; 13(9)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34579143

RESUMO

Recent studies demonstrated that metabolic syndrome and cardiovascular diseases could be elicited by developmental programming, which is regulated by prenatal nutritional and environmental stress. In this study, we utilized a rat model to examine the effect of excessive maternal fructose intake during pregnancy and lactation on cardiac development and progression of pressure overload-induced cardiac hypertrophy in offspring. Transverse aortic constriction (TAC) was performed on 3-month-old male offspring to induce ventricular pressure overload. Four weeks post-TAC, echocardiographic assessment as well as histopathological and biochemical examinations were performed on the myocardium of the offspring. Echocardiographic and gross examinations showed that heart weight, interventricular septal thickness in diastole (IVD; d), and left ventricular posterior wall thickness in diastole (LVPW; d) were elevated in offspring with TAC and further increased by maternal fructose exposure (MFE). However, the left ventricular ejection function was not significantly affected. Myocardial histopathological examination revealed that the indices of fibrosis and oxidative stress were higher in offspring with MFE and TAC than those in animals receiving either treatment. Molecular examinations on the myocardium demonstrated an MFE-induced upregulation of p38-MAPK signaling. Next generation sequence (NGS) analysis indicated a modulation of the expression levels of several cardiac hypertrophy-associated genes, including GPR22, Myh7, Nppa, P2RX4, and Npy by MFE. Subsequent RT-PCR indicated that MFE regulated the expression levels of genes responsive to cardiac hypertrophy (i.e., Myh-7, ANP) and oxidative stress (i.e., GR, GPx, and NQO-1). In conclusion, MFE during pregnancy and lactation modulated myocardial gene expression, increased oxidative stress, and exacerbated ventricular pressure overload-induced cardiac remodeling in rat offspring.


Assuntos
Cardiomegalia/etiologia , Frutose/efeitos adversos , Coração/crescimento & desenvolvimento , Miocárdio/patologia , Efeitos Tardios da Exposição Pré-Natal , Pressão Ventricular/fisiologia , Animais , Aorta , Cardiomegalia/genética , Constrição , Feminino , Frutose/administração & dosagem , Expressão Gênica , Coração/efeitos dos fármacos , Coração/embriologia , Lactação , Masculino , Miocárdio/metabolismo , Estresse Oxidativo , Gravidez , Ratos
2.
Biomed J ; 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34229104

RESUMO

BACKGROUND: Aortic valve stenosis (AS) is a common, lethal cardiovascular disease. There is no cure except the valve replacement at last stage. Therefore, an understanding of the detail mechanism is imperative to prevent and intervene AS. Metabolic syndrome (MetS) is one of the major risk factors of AS whereas fructose overconsuming tops the list of MetS risk factors. However, whether the fructose under physiological level induces AS is currently unknown. MATERIAL AND METHODS: The human valve interstitial cells (hVICs), a crucial source to develop calcification, were co-incubated with fructose at 2 or 20 mM to mimic the serum fructose at fasting or post-fructose consumption, respectively, for 24 hours. The cell proliferation was evaluated by WST-1 assays. The expressions of osteogenic and fibrotic proteins, PI3K/AKT signaling, insulin receptor substrate 1 and mitochondrial dynamic proteins were detected by Western blot analyses. The mitochondrial oxidative phosphorylation (OXPHOS) was examined by Seahorse analyzer. RESULTS: hVICs proliferation was significantly suppressed by 20 mM fructose. The expressions of alkaline phosphatase (ALP) and osteocalcin were enhanced concurrent with the upregulated PI3K p85, AKT, phospho(p)S473-AKT, and pS636-insulin receptor substrate 1 (p-IRS-1) by high fructose. Moreover, ATP production capacity and maximal respiratory capacity were enhanced in the high fructose groups. Synchronically, the expressions of mitochondrial fission 1and optic atrophy type 1 were increased. CONCLUSION: These results suggested that high fructose stimulated the osteogenic differentiation of hVICs via the activation of PI3K/AKT/mitochondria signaling at the early stage. These results implied that high fructose at physiological level might have a direct, hazard effect on the progression of AS.

3.
Int J Mol Sci ; 22(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34281226

RESUMO

Patients with Rett syndrome (RTT) show severe difficulties with communication, social withdrawl, and learning. Music-based interventions improve social interaction, communication skills, eye contact, and physical skills and reduce seizure frequency in patients with RTT. This study aimed to investigate the mechanism by which music-based interventions compromise sociability impairments in mecp2 null/y mice as an experimental RTT model. Male mecp2 null/y mice and wild-type mice (24 days old) were randomly divided into control, noise, and music-based intervention groups. Mice were exposed to music or noise for 6 h/day for 3 consecutive weeks. Behavioral patterns, including anxiety, spontaneous exploration, and sociability, were characterized using open-field and three-chamber tests. BDNF, TrkB receptor motif, and FNDC5 expression in the prefrontal cortex (PFC), hippocampus, basal ganglia, and amygdala were probed using RT-PCR or immunoblotting. mecp2 null/y mice showed less locomotion in an open field than wild-type mice. The social novelty rather than the sociability of these animals increased following a music-based intervention, suggesting that music influenced the mecp2-deletion-induced social interaction repression rather than motor deficit. Mechanically, the loss of BDNF signaling in the prefrontal cortex and hippocampal regions, but not in the basal ganglia and amygdala, was compromised following the music-based intervention in mecp2 null/y mice, whereas TrkB signaling was not significantly changed in either region. FNDC5 expression in the prefrontal cortex region in mecp2 null/y mice also increased following the music-based intervention. Collective evidence reveals that music-based interventions improve mecp2-loss-induced social dysfunction. BDNF and FNDC5 signaling in the prefrontal cortex region mediates the music-based-intervention promotion of social interactions. This study gives new insight into the mechanisms underlying the improvement of social behaviors in mice suffering from experimental Rett syndrome following a music-based intervention.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Musicoterapia , Córtex Pré-Frontal/metabolismo , Receptor trkB/metabolismo , Síndrome de Rett/terapia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Síndrome de Rett/metabolismo , Síndrome de Rett/psicologia , Comportamento Social
4.
Am J Physiol Endocrinol Metab ; 320(6): E1173-E1182, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33969706

RESUMO

Retinopathy is a leading cause of blindness, and there is currently no cure. Earlier identification of the progression of retinopathy could provide a better chance for intervention. Diet has profound effects on retinal function. A maternal high-fructose diet (HFD) triggers diseases in multiple organs. However, whether maternal HFD impairs retinal function in adult offspring is currently unknown. By using the rodent model of maternal HFD during pregnancy and lactation, our data indicated a reduced b-wave of electroretinography (ERG) in HFD female offspring at 3 mo of age compared with age-matched offspring of dams fed regular chow (ND). Immunofluorescence and Western blot analyses indicated that the distributions and expressions of synaptophysin, postsynaptic density protein 95 (PSD95), and phospho(p)-Ca2+/calmodulin-stimulated protein kinase IIα (CaMKIIα) were significantly suppressed in the HFD group. Furthermore, the ATP content and the mitochondrial respiratory protein, Mt CPX 4-2, were decreased. Moreover, the expressions of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and mitochondrial transcription factor A (TFAM) in the retina of the HFD group were downregulated. Treatment with coenzyme Q10 (Q10), a key mediator of the electron transport chain, effectively reversed these abovementioned dysfunctions. Together, these results suggested that maternal HFD impaired retinal function in adult female offspring. The mechanism underlying early-onset retinopathy may involve the reduction in the capacity of mitochondrial energy production and the suppression of synaptic plasticity. Most importantly, mitochondria could be a feasible target to reprogram maternal HFD-damaged retinal function.NEW & NOTEWORTHY In this study, we provide novel evidence that maternal high-fructose diet during gestation and lactation could induce early-onset retinopathy in adult female offspring. Of note, the insufficient energy content, downregulated mitochondrial respiratory complex 4-2, and impaired mitochondrial biogenesis might contribute to the decrease of synaptic plasticity resulting in retinal function suppression. Oral application with coenzyme Q10 for 4 wk could at least partially reverse the aforementioned molecular events and retinal function.


Assuntos
Frutose/efeitos adversos , Mitocôndrias/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Doenças Retinianas/induzido quimicamente , Fatores Etários , Animais , Dieta Hiperlipídica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Carboidratos da Dieta/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Frutose/farmacologia , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias/fisiologia , Biogênese de Organelas , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos , Ratos Sprague-Dawley , Doenças Retinianas/fisiopatologia
5.
Sci Rep ; 11(1): 8202, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33859259

RESUMO

The pathophysiologies of metabolic syndrome (MS) and overactive bladder (OAB) might overlap. Using fructose-fed rats (FFRs) as a rodent model of MS we investigated the effects of tadalafil (a phosphodiesterase type 5 inhibitor) on the dysregulated insulin signalling in the bladder mucosa and bladder overactivity. Micturition behaviour was evaluated. Concentration-response curves on detrusor relaxation to insulin stimulation were examined. Expression and phosphorylation of proteins in the insulin signalling pathway were evaluated by Western blotting. Levels of detrusor cGMP and urinary nitrite and nitrate (NOx) were measured. We observed FFRs exhibited metabolic traits of MS, bladder overactivity, and impaired insulin-activated detrusor relaxation in organ bath study. A high-fructose diet also impeded insulin signalling, reflected by overexpression of IRS1/pIRS1Ser307 and pIRS2Ser731 and downregulation of PI3K/pPI3KTyr508, AKT/pAKTSer473, and eNOS/peNOSSer1177 in the bladder mucosa, alongside decreased urinary NOx and detrusor cGMP levels. Tadalafil treatment restored the reduced level of mucosal peNOS, urinary NOx, and detrusor cGMP, improved the insulin-activated detrusor relaxation, and ameliorated bladder overactivity in FFRs. These results suggest tadalafil may ameliorate MS-associated bladder overactivity by restoring insulin-activated detrusor relaxation via molecular mechanisms that are associated with preservation of IR/IRS/PI3K/AKT/eNOS pathway in the bladder mucosa and cGMP production in the bladder detrusor.

6.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800916

RESUMO

Gut microbiota-derived metabolites, in particular short chain fatty acids (SCFAs) and their receptors, are linked to hypertension. Fructose and antibiotics are commonly used worldwide, and they have a negative impact on the gut microbiota. Our previous study revealed that maternal high-fructose (HF) diet-induced hypertension in adult offspring is relevant to altered gut microbiome and its metabolites. We, therefore, intended to examine whether minocycline administration during pregnancy and lactation may further affect blood pressure (BP) programmed by maternal HF intake via mediating gut microbiota and SCFAs. Pregnant Sprague-Dawley rats received a normal diet or diet containing 60% fructose throughout pregnancy and lactation periods. Additionally, pregnant dams received minocycline (50 mg/kg/day) via oral gavage or a vehicle during pregnancy and lactation periods. Four groups of male offspring were studied (n = 8 per group): normal diet (ND), high-fructose diet (HF), normal diet + minocycline (NDM), and HF + minocycline (HFM). Male offspring were killed at 12 weeks of age. We observed that the HF diet and minocycline administration, both individually and together, causes the elevation of BP in adult male offspring, while there is no synergistic effect between them. Four groups displayed distinct enterotypes. Minocycline treatment leads to an increase in the F/B ratio, but decreased abundance of genera Lactobacillus, Ruminococcus, and Odoribacter. Additionally, minocycline treatment decreases plasma acetic acid and butyric acid levels. Hypertension programmed by maternal HF diet plus minocycline exposure is related to the increased expression of several SCFA receptors. Moreover, minocycline- and HF-induced hypertension, individually or together, is associated with the aberrant activation of the renin-angiotensin system (RAS). Conclusively, our results provide a new insight into the support of gut microbiota and its metabolite SCAFs in the developmental programming of hypertension and cast new light on the role of RAS in this process, which will help prevent hypertension programmed by maternal high-fructose and antibiotic exposure.


Assuntos
Antibacterianos/toxicidade , Frutose/toxicidade , Microbioma Gastrointestinal/fisiologia , Hipertensão/microbiologia , Minociclina/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Animais , Antibacterianos/administração & dosagem , Ácidos Graxos Voláteis/metabolismo , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/isolamento & purificação , Bactérias Gram-Positivas/metabolismo , Hipertensão/etiologia , Rim/efeitos dos fármacos , Rim/metabolismo , Lactação , Masculino , Minociclina/administração & dosagem , Óxido Nítrico/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/biossíntese , Receptores de Superfície Celular/genética , Sistema Renina-Angiotensina/fisiologia
7.
Int J Mol Sci ; 21(15)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32752013

RESUMO

Gut microbiota-dependent metabolites, in particular trimethylamine (TMA), are linked to hypertension. Maternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or consumption of food high in fructose (HFR) can induce hypertension in adult offspring. We examined whether 3,3-maternal dimethyl-1-butanol (DMB, an inhibitor of TMA formation) therapy can protect adult offspring against hypertension arising from combined HFR and TCDD exposure. Pregnant Sprague-Dawley rats received regular chow or chow supplemented with fructose (60% diet by weight) throughout pregnancy and lactation. Additionally, the pregnant dams received TCDD (200 ng/kg BW orally) or a corn oil vehicle on days 14 and 21 of gestation, and days 7 and 14 after birth. Some mother rats received 1% DMB in their drinking water throughout pregnancy and lactation. Six groups of male offspring were studied (n = 8 for each group): regular chow (CV), high-fructose diet (HFR), regular diet+TCDD exposure (CT), HFR+TCDD exposure (HRT), high-fructose diet+DMB treatment (HRD), and HFR+TCDD+DMB treatment (HRTD). Our data showed that TCDD exacerbates HFR-induced elevation of blood pressure in male adult offspring, which was prevented by maternal DMB administration. We observed that different maternal insults induced distinct enterotypes in adult offspring. The beneficial effects of DMB are related to alterations of gut microbiota, the increase in nitric oxide (NO) bioavailability, the balance of the renin-angiotensin system, and antagonization of aryl hydrocarbon receptor (AHR) signaling. Our findings cast new light on the role of early intervention targeting of the gut microbiota-dependent metabolite TMA, which may allow us to prevent the development of hypertension programmed by maternal excessive fructose intake and environmental dioxin exposure.


Assuntos
Dieta da Carga de Carboidratos/efeitos adversos , Microbioma Gastrointestinal , Hipertensão , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Animais , Dioxinas/efeitos adversos , Feminino , Frutose/efeitos adversos , Masculino , Metilaminas/farmacologia , Gravidez , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley
8.
Artigo em Inglês | MEDLINE | ID: mdl-32492926

RESUMO

Maternal high-fructose diets (HFD) impair the learning and memory capacity of adult female offspring via histone deacetylase 4 (HDAC4). Hippocampal adult neurogenesis is important for supporting the function of existing neural circuits. In this study, we investigated the effects of maternal HFD on hippocampal neural stem cell (NSC) proliferation and neuronal differentiation in adult offspring. Increased nuclear HDAC4 enzyme activity was detected in the hippocampus of HFD female offspring. The Western blot analyses indicated that the expressions of sex-determining region Y box2 (SOX2) and the transcription factor Paired Box 6 (PAX6), which are critical for the progression of NSC proliferation and differentiation, were downregulated. Concurrently, the expression of Ki67 (a cellular marker for proliferation) and doublecortin (DCX), which are related to NSC division and neuronal differentiation, was suppressed. Intracerebroventricular infusion with class II HDAC inhibitor (Mc1568, 4 weeks) led to the upregulation of these proteins. Environmental stimulation reversed the expression of Ki67 and DCX and the counts of Ki67- and DCX-positive cells in the hippocampi of HFD offspring as a result of providing the enriched housing for 4 weeks. Together, these results demonstrate that the suppressive effects of maternal HFD on hippocampal NSC proliferation and neuronal differentiation are reversibly mediated through HDAC4 and can be effectively reversed by environmental stimulation. The advantageous effects of environmental enrichment were possibly mediated by HDAC4 suppression.


Assuntos
Giro Denteado , Dieta , Frutose , Histona Desacetilases , Adulto , Diferenciação Celular , Proliferação de Células , Feminino , Hipocampo , Humanos , Neurogênese
9.
Mov Disord ; 35(9): 1662-1667, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32374915

RESUMO

BACKGROUND: Alexander disease (AxD) is an autosomal-dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acidic protein (GFAP) gene. OBJECTIVES: The objective of this report is to characterize the clinical phenotype and identify the genetic mutation associated with adult-onset AxD. METHODS: A man presented with progressive unsteadiness since age 16. Magnetic resonance imaging findings revealed characteristic features of AxD. The GFAP gene was screened, and a candidate variant was functionally tested to evaluate causality. RESULTS: A homozygous c.197G > A (p.Arg66Gln) mutation was found in the proband, and his asymptomatic parents were heterozygous for the same mutation. This mutation affected GFAP solubility and promoted filament aggregation. The presence of the wild-type protein rescued mutational effects, consistent with the recessive nature of this mutation. CONCLUSIONS: This study is the first report of AxD caused by a homozygous mutation in GFAP. The clinical implication is while examining patients with characteristic features on suspicion of AxD, GFAP screening is recommended even without a supportive family history. © 2020 International Parkinson and Movement Disorder Society.


Assuntos
Doença de Alexander , Adolescente , Adulto , Doença de Alexander/diagnóstico por imagem , Doença de Alexander/genética , Proteína Glial Fibrilar Ácida/genética , Homozigoto , Humanos , Masculino , Mutação/genética , Fenótipo
10.
J Biomed Sci ; 27(1): 68, 2020 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-32446297

RESUMO

BACKGROUND: Tissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT1R) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring. METHODS: Pregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, AT1R, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction. RESULTS: Increased systolic BP, plasma norepinephrine level and sympathetic vasomotor activity were exhibited by young HFD offspring. Reactive oxygen species (ROS) level was also elevated in RVLM where sympathetic premotor neurons reside, alongside augmented protein expressions of AT1R and pg91phox subunit of NADPH oxidase, decrease in superoxide dismutase 2; and suppression of transcription factors for mitochondrial biogenesis, peroxisome proliferator-activated receptor γ co-activator α (PGC-1α) and mitochondrial transcription factor A (TFAM). Maternal HFD also attenuated AMPK phosphorylation and protein expression of SIRT1 in RVLM of young offspring. Oral administration of a HMG-CoA reductase inhibitor, simvastatin, or an AMPK activator, metformin, to young HFD offspring reversed maternal HFD-programmed increase in AT1R and decreases in SIRT1, PGC-1α and TFAM; alleviated ROS production in RVLM, and attenuated sympathoexcitation and hypertension. CONCLUSION: Dysfunction of AMPK-regulated AT1R expression and SIRT1-mediated mitochondrial biogenesis may contribute to tissue oxidative stress in RVLM, which in turn primes increases of sympathetic vasomotor activity and BP in young offspring programmed by excessive maternal fructose consumption.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Frutose/administração & dosagem , Regulação da Expressão Gênica , Mitocôndrias/fisiologia , Receptor Tipo 1 de Angiotensina/genética , Sirtuína 1/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Feminino , Hipertensão/genética , Exposição Materna , Biogênese de Organelas , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Sirtuína 1/metabolismo
11.
J Nutr Biochem ; 81: 108378, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32330843

RESUMO

The mechanisms beneath the initiation of neuroinflammation are still inconclusive. Growing evidence proposes the maternal effect on the development of neuroinflammation. In this study, we evaluated the upstream regulators and the indices of neuroinflammation in the hippocampi of female offspring at 3 months old. The accumulation of nuclear factor-κB (NF-κB, 65 kDa), a cytokine-encoding transcription factor, was increased in microglia. The enhanced microglial activation was detected in CA1, CA3 and dentate gyrus (DG) HFD group with upregulation of CD11b and ionized calcium binding adaptor molecule 1 (Iba-1). Moreover, proinflammatory cytokines (including TNFα, IL-1ß and IL-6) were significantly increased in HFD group. Peroxisome proliferator-activated receptors γ (PPARγ) is a transcription factor involved in the suppression of NF-κB expression and in encoding endogenous antioxidants (such as catalase and glutathione peroxidases). On the contrary, the expression of nuclear PPARγ was suppressed in hippocampal neurons of the HFD group. In addition, the expressions of glutathione peroxidase 1 (GPx1) was suppressed in HFD group. Oral application with pioglitazone, a PPARγ agonist, effectively ceased the neuroinflammation and reversed the expression of antioxidants in HFD group. Together, these results for the first time demonstrated that maternal HFD triggered the waxing and waning of NF-κB and PPARγ may initiate neuroinflammation in the hippocampus of adult female offspring. Our findings further suggest that PPARγ could be the feasible targets to reprogram the hippocampal impairment induced by maternal HFD.


Assuntos
Frutose/farmacologia , Hipocampo/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , PPAR gama/metabolismo , Animais , Citocinas/metabolismo , Dieta/métodos , Feminino , Frutose/efeitos adversos , Hipocampo/efeitos dos fármacos , Inflamação/etiologia , Mediadores da Inflamação/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Inflamação Neurogênica , Neurônios/metabolismo , Pioglitazona/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
12.
J Neuroinflammation ; 16(1): 224, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729994

RESUMO

BACKGROUND: Decreased heart rate variability (HRV) leads to cardiovascular diseases and increased mortality in clinical studies. However, the underlying mechanisms are still inconclusive. Systemic inflammation-induced neuroinflammation is known to impair the autonomic center of cardiovascular regulation. The dynamic stability of blood pressure and heart rate (HR) is regulated by modulation of the reciprocal responses of sympathetic and parasympathetic tone by the baroreflex, which is controlled by the nucleus of the solitary tract (NTS). METHODS: Systemic inflammation was induced by E. coli lipopolysaccharide (LPS, 1.2 mg/kg/day, 7 days) peritoneal infusion via an osmotic minipump in normotensive Sprague-Dawley rats. Systolic blood pressure (SBP) and HR were measured by femoral artery cannulation and recorded on a polygraph under anesthesia. The low-frequency (LF; 0.25-0.8 Hz) and high-frequency (HF; 0.8-2.4 Hz) components of SBP were adopted as the indices for sympathetic vasomotor tone and parasympathetic vasomotor tone, while the baroreflex effectiveness index (BEI) was adopted from the analysis of SBP and pulse interval (PI). The plasma levels of proinflammatory cytokines and mitochondrial DNA (mtDNA) oxidative damage were analyzed by ELISA. Protein expression was evaluated by Western blot. The distribution of oxidative mtDNA was probed by immunofluorescence. Pharmacological agents were delivered via infusion into the cisterna magna with an osmotic minipump. RESULTS: The suppression of baroreflex sensitivity was concurrent with increased SBP and decreased HR. Neuroinflammatory factors, including TNF-α, CD11b, and Iba-1, were detected in the NTS of the LPS group. Moreover, indices of mtDNA damage, including 8-OHdG and γ-H2AX, were significantly increased in neuronal mitochondria. Pentoxifylline or minocycline intracisternal (IC) infusion effectively prevented mtDNA damage, suggesting that cytokine and microglial activation contributed to mtDNA damage. Synchronically, baroreflex sensitivity was effectively protected, and the elevated blood pressure was significantly relieved. In addition, the mtDNA repair mechanism was significantly enhanced by pentoxifylline or minocycline. CONCLUSION: These results suggest that neuronal mtDNA damage in the NTS induced by neuroinflammation could be the core factor in deteriorating baroreflex desensitization and subsequent cardiovascular dysfunction. Therefore, the enhancement of base excision repair (BER) signaling in mitochondria could be a potential therapeutic strategy for cardiovascular reflex dysregulation.


Assuntos
Barorreflexo/fisiologia , DNA Mitocondrial , Inflamação/fisiopatologia , Núcleo Solitário/fisiopatologia , Animais , Barorreflexo/efeitos dos fármacos , Pressão Sanguínea/fisiologia , DNA Mitocondrial/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Sprague-Dawley
13.
Int J Mol Sci ; 20(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100865

RESUMO

Adult metabolic syndrome is considered to be elicited by the developmental programming which is regulated by the prenatal environment. The maternal excess intake of fructose, a wildly used food additive, is found to be associated with developmental programing-associated cardiovascular diseases. To investigate the effect of maternal fructose exposure (MFE) on endothelial function and repair, which participate in the initiation and progress of cardiovascular disease, we applied a rat model with maternal fructose excess intake during gestational and lactational stage and examined the number and function of endothelial progenitor cells (EPCs) in 3-month-old male offspring with induction of critical limb ischemia (CLI). Results showed that the circulating levels of c-Kit+/CD31+ and Sca-1+/KDR+ EPC were reduced by MFE. In vitro angiogenesis analysis indicated the angiogenic activity of bone marrow-derived EPC, including tube formation and cellular migration, was reduced by MFE. Western blots further indicated the phosphorylated levels of ERK1/2, p38-MAPK, and JNK in circulating peripheral blood mononuclear cells were up-regulated by MFE. Fourteen days after CLI, the reduced blood flow recovery, lowered capillary density, and increased fibrotic area in quadriceps were observed in offspring with MFE. Moreover, the aortic endothelium-mediated vasorelaxant response in offspring was impaired by MFE. In conclusion, maternal fructose intake during gestational and lactational stage modulates the number and angiogenic activity of EPCs and results in poor blood flow recovery after ischemic injury.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Frutose/metabolismo , Frutose/farmacologia , Isquemia/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Fluxo Sanguíneo Regional , Animais , Ataxina-1 , Medula Óssea/metabolismo , Doenças Cardiovasculares , Movimento Celular , Modelos Animais de Doenças , Extremidades/patologia , Isquemia/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas , Proteínas Proto-Oncogênicas c-kit , Ratos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
14.
J Nutr Biochem ; 69: 87-97, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063919

RESUMO

High fructose ingestion enhances mortality which has been linked to autonomic dysregulation. However, the underlying mechanisms are still largely unknown. In the present study, we demonstrated that 3 months of high fructose diet (HFD) ingestion induced mortality in 18-week-old Wistar Kyoto rats (WKY) during anesthesia. Concurrently, the low frequency (LF) and the high frequency (HF) elements of the power spectral analyses of SBP were increased. Of note, the decreased ratio of LF and HF (LF/HF), an index of sympathetic and parasympathetic balance, suggested an autonomic imbalance. In the rostral ventrolateral medulla (RVLM), a center of sympathetic outflow, the levels of presynaptic (synaptophysin) and postsynaptic (postsynaptic density protein 95 and phospho-Ca2+/calmodulin-dependent protein kinase II) proteins were increased. The down-regulation of insulin receptor ß and insulin receptor substrate 1 suggested the status of insulin desensitization. Moreover, the up-regulation of AMP-activated protein kinase and sirtuin 1 suggested the enhancement of energy sensing to activate autophagy. Simultaneously, the accumulations of Beclin-1, ATG12 and LC3B were increased in RVLM. Pioglitazone (PIO), an insulin sensitizer, effectively relieved the accumulation of Beclin-1 and ATG12 as well as the synaptic proteins synchronized with the reverses of insulin and energy sensing signals. Moreover, the autonomic dysregulation and anesthesia-associated mortality were intervened. Together, these results suggested that the HFD-induced, anesthesia-associated mortality rate was related to the autonomic abnormality derived from the RVLM synaptic alteration, which is strongly related to insulin desensitization-associated autophagy. PIO intervened the HFD-induced mortality via reversal of the above-mentioned molecules.


Assuntos
Autofagia/efeitos dos fármacos , Frutose/efeitos adversos , Bulbo/efeitos dos fármacos , Pioglitazona/farmacologia , Animais , Autofagia/fisiologia , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Dieta/efeitos adversos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Masculino , Bulbo/metabolismo , Bulbo/patologia , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/etiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Mortalidade , Proteínas/metabolismo , Ratos Wistar
15.
Neurochem Res ; 44(7): 1567-1581, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30888577

RESUMO

Dexamethasone is an approved steroid for clinical use to activate or suppress cytokines, chemokines, inflammatory enzymes and adhesion molecules. It enters the brain, by-passing the blood brain barrier, and acts through genomic mechanisms. High levels of dexamethasone are able to induce neuronal cell loss, reduce neurogenesis and cause neuronal dysfunction. The exact mechanisms of steroid, especially the dexamethasone contribute to neuronal damage remain unclear. Therefore, the present study explored the mitochondrial dynamics underlying dexamethasone-induced toxicity of human neuroblastoma SH-SY5Y cells. Neuronal cells treatment with the dexamethasone resulted in a marked decrease in cell proliferation. Dexamethasone-induced neurotoxicity also caused upregulation of mitochondrial fusion and cleaved caspase-3 proteins expression. Mitochondria fusion was found in large proportions of dexamethasone-treated cells. These results suggest that dexamethasone-induced hyperfused mitochondrial structures are associated with a caspase-dependent death process in dexamethasone-induced neurotoxicity. These findings point to the high dosage of dexamethasone as being neurotoxic through impairment of mitochondrial dynamics.


Assuntos
Dexametasona/toxicidade , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dinaminas , GTP Fosfo-Hidrolases/metabolismo , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Regulação para Cima
16.
Am J Physiol Endocrinol Metab ; 316(4): E622-E634, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668149

RESUMO

Excessive maternal high-fructose diet (HFD) during pregnancy and lactation has been reported to cause metabolic disorders in the offspring. Whether the infant's brain metabolism is disturbed by maternal HFD is largely unknown. Brain energy metabolism is elevated dramatically during fetal and postnatal development, whereby maternal nutrition is a key factor that determines cellular metabolism. Astrocytes, a nonneuronal cell type in the brain, are considered to support the high-energy demands of neurons by supplying lactate. In this study, the effects of maternal HFD on astrocytic glucose metabolism were investigated using hippocampal primary cultures of female infants. We found that glycolytic capacity and mitochondrial respiration and electron transport chain were suppressed by maternal HFD. Mitochondrial DNA copy number and mitochondrial transcription factor A expression were suppressed by maternal HFD. Western blots and immunofluorescent images further indicated that the glucose transporter 1 was downregulated whereas the insulin receptor-α, phospho-insulin receptor substrate-1 (Y612) and the p85 subunit of phosphatidylinositide 3-kinase were upregulated in the HFD group. Pioglitazone, which is known to increase astrocytic glucose metabolism, effectively reversed the suppressed glycolysis, and lactate release was restored. Moreover, pioglitazone also normalized oxidative phosphorylation with an increase of cytosolic ATP. Together, these results suggest that maternal HFD impairs astrocytic energy metabolic pathways that were reversed by pioglitazone.


Assuntos
Astrócitos/efeitos dos fármacos , Açúcares da Dieta/farmacologia , Frutose/farmacologia , Glicólise/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Pioglitazona/farmacologia , Animais , Astrócitos/metabolismo , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/metabolismo , Feminino , Desenvolvimento Fetal , Transportador de Glucose Tipo 1/efeitos dos fármacos , Transportador de Glucose Tipo 1/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Cultura Primária de Células , Ratos , Receptor de Insulina/efeitos dos fármacos , Receptor de Insulina/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo
17.
Int J Mol Sci ; 19(9)2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30158497

RESUMO

BACKGROUND: Periventricular white-matter (WM) injury is a prominent feature of brain injury in preterm infants. Thyroxin (T4) treatment reduces the severity of hypoxic-ischemic (HI)-mediated WM injury in the immature brain. This study aimed to delineate molecular events underlying T4 protection following periventricular WM injury in HI rats. METHODS: Right common-carotid-artery ligation, followed by hypoxia, was performed on seven-day-old rat pups. The HI pups were injected with saline, or 0.2 or 1 mg/kg of T4 at 48⁻96 h postoperatively. Cortex and periventricular WM were dissected for real-time (RT)-quantitative polymerase chain reactions (PCRs), immunoblotting, and for immunofluorescence analysis of neurotrophins, myelin, oligodendrocyte precursors, and neointimal. RESULTS: T4 significantly mitigated hypomyelination and oligodendrocyte death in HI pups, whereas angiogenesis of periventricular WM, observed using antiendothelium cell antibody (RECA-1) immunofluorescence and vascular endothelium growth factor (VEGF) immunoblotting, was not affected. T4 also increased the brain-derived neurotrophic factors (BDNFs), but not the nerve growth factor (NGF) expression of injured periventricular WM. However, phosphorylated extracellular signal regulated kinase (p-ERK) and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) concentrations, but not the BDNF downstream pathway kinases, p38, c-Jun amino-terminal kinase (c-JNK), or Akt, were reduced in periventricular WM with T4 treatment. Notably, T4 administration significantly increased BDNF and phosphorylated CREB in the overlying cortex of the HI-induced injured cortex. CONCLUSION: Our findings reveal that T4 reversed BNDF signaling to attenuate HI-induced WM injury by activating ERK and CREB pathways in the cortex, but not directly in periventricular WM. This study offers molecular insight into the neuroprotective actions of T4 in HI-mediated WM injury in the immature brain.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Tiroxina/farmacologia , Substância Branca/efeitos dos fármacos , Substância Branca/metabolismo , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
18.
Biomed J ; 41(3): 169-183, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-30080657

RESUMO

BACKGROUND: α-synuclein (SNCA) accumulation in the substantia nigra is one of the characteristic pathologies of Parkinson's disease (PD). A53T missense mutations in the SNCA gene has been proved to enhance the expression of SNCA and accelerate the onset of PD. Mitochondrial dysfunction in SNCA aggregation has been under debate for decades but the causal relationship remains uncertain. At a later stage of PD, the cellular dysfunctions are complicated and multiple factors are tangled. Our aim here is to investigate the mitochondrial functional changes and clarify the main causal mechanism at earlier-stage of PD. METHODS: We used the mutant A53T SNCA-expressed neuro 2a (N2a) cells without detectable cell death to investigate: 1) whether SNCA overexpression impairs the mitochondrial respiration and biogenesis. 2) The role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signal in SNCA-induced mitochondria dysfunction. RESULTS: Accompanying with the increment of SNCA, reactive oxygen species (ROS) accumulation was increased. The maximal respiratory capacity was suppressed. Meanwhile, mitochondrial complex 1 activity and the activity of nicotinamide adenine dinucleotide (NADH) cytochrome C reductase (NCCR) were decreased. Moreover, the mitochondrial DNA (mtDNA) copy number was decreased. On the other hand, the nuclear peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), Nrf2, and the cytosolic mitochondrial transcription factor A (TFAM) were increased at an early stage and declined thereafter. Above factors triggered by SNCA were reversed by tBHQ, a Nrf2 activator. CONCLUSION: These results suggested that at an early stage, SNCA-overexpressed increase mtROS accumulation, mitochondrial dysfunction and mtDNA decrement. Nrf2, PGC-1α and TFAM were upregulated to compromise mitochondrial dysfunction. tBHQ effectively reversed the SNCA-induced mitochondrial dysfunction.


Assuntos
Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/fisiologia , Consumo de Oxigênio , alfa-Sinucleína/fisiologia , Animais , Linhagem Celular Tumoral , Hidroquinonas/farmacologia , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/fisiologia
19.
Biomed J ; 41(2): 96-101, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29866605

RESUMO

Metabolic syndrome (MetS) is a highly prevalent complex trait despite recent advances in pathophysiology and pharmacological treatment. MetS can begin in early life by so-called the developmental origins of health and disease (DOHaD). The DOHaD concept offers a novel approach to prevent MetS through reprogramming. High fructose (HF) intake has been associated with increased risk of MetS. HF diet becomes one of the most commonly used animal model to induce MetS. This review discusses the maternal HF diet induced programming process and reprogramming strategy to prevent MetS of developmental origin, with an emphasis on: (1) an overview of metabolic effects of fructose consumption on MetS; (2) insight from maternal HF animal models on MetS-related phenotypes; (3) impact of HF consumption induces organ-specific transcriptome changes; and (4) application of reprogramming strategy to prevent maternal HF consumption-induced MetS. Research into the preventions and treatments of MetS that begin early in life will have a lifelong impact and profound savings in disease burden and financial costs.


Assuntos
Frutose/efeitos adversos , Síndrome Metabólica/etiologia , Animais , Carboidratos da Dieta/efeitos adversos , Modelos Animais de Doenças , Feminino , Frutose/metabolismo , Humanos , Síndrome Metabólica/prevenção & controle , Síndrome Metabólica/terapia , Gravidez , Transcriptoma
20.
Mol Nutr Food Res ; : e1800066, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29710384

RESUMO

SCOPE: High-fructose (HF) intake, oxidative stress, nutrient-sensing signals, and gut microbiota dysbiosis are closely related to the development of hypertension. It was investigated whether resveratrol can prevent hypertension induced by maternal plus post-weaning HF diets in adult offspring via the above-mentioned mechanisms. METHODS AND RESULTS: Female Sprague-Dawley rats received either a normal (ND) or 60% high-fructose (HF) diet during gestation and lactation. Male offspring were assigned to five groups (maternal diet/post-weaning diet; n = 8 per group): ND/ND, ND/HF, HF/ND, HF/HF, and HF/HF+ Resveratrol. Resveratrol (50 mg L-1 ) was administered in drinking water from weaning to 3 months of age. It was found that HF/HF induced hypertension in adult offspring. Maternal HF diet altered gut microbiota composition in adult offspring, including decreasing the abundance of genera Bacteroides, Dysgonomonas, and Turicibacter, while increasing phylum Verrucomicrobia and Akkermansia muciniphila. Additionally, HF/HF diets increased oxidative stress and decreased renal mRNA expression of Prkaa2, Prkag2, Ppara, Pparb, Ppargc1a, and Sirt4. Resveratrol reduced renal oxidative stress, activated nutrient-sensing signals, modulated gut microbiota, and prevented associated HF/HF-induced programmed hypertension. CONCLUSION: Targeting oxidative stress, nutrient-sensing signals, and gut microbiota by resveratrol might be a useful therapeutic strategy for the treatment of hypertension induced by excessive consumption of fructose in the adult rat offspring.

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