RESUMEN
The metabolic network's primary sources of free fatty acids (FFAs) are long- and medium-chain fatty acids of triglyceride origin and short-chain fatty acids produced by intestinal microorganisms through dietary fibre fermentation. Recent studies have demonstrated that FFAs not only serve as an energy source for the body's metabolism but also participate in regulating arterial function. Excess FFAs have been shown to lead to endothelial dysfunction, vascular hypertrophy, and vessel wall stiffness, which are important triggers of arterial hypertension and atherosclerosis. Nevertheless, free fatty acid receptors (FFARs) are involved in the regulation of arterial functions, including the proliferation, differentiation, migration, apoptosis, inflammation, and angiogenesis of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). They actively regulate hypertension, endothelial dysfunction, and atherosclerosis. The objective of this review is to examine the roles and heterogeneity of FFAs and FFARs in the regulation of arterial function, with a view to identifying the points of intersection between their actions and providing new insights into the prevention and treatment of diseases associated with arterial dysfunction, as well as the development of targeted drugs.
Asunto(s)
Arterias , Ácidos Grasos no Esterificados , Humanos , Animales , Ácidos Grasos no Esterificados/metabolismo , Arterias/metabolismo , Aterosclerosis/metabolismo , Aterosclerosis/patología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Células Endoteliales/metabolismoRESUMEN
Focusing on multifunctional mesoporous carbonaceous materials (MCMs) is one of the hot research topics due to increasing demand in the high-energy-density devices of lithium-sulfur (Li-S) batteries (2600 Wh kg-1). On the premise of applying MCMs as a porous framework to load elemental sulfur, to improve the electronic conductivity of the cathode, and to trap the in situ-formed electrolyte-soluble intermediates of lithium polysulfides (LiPSs), the commercialization of MCMs-based energy storage devices still needs to solve solid/solid and solid/liquid interfacial issues such as the chemical anchoring of the electrically insulating active substances, the sluggish redox kinetics of intermediate LiPSs, and so on. Through the permutation of multifunctional MCMs serving as the primary sulfur-loading carrier of the cathode, as the secondary surface-coating layers of the separator, the cathode, and the anode separately, this Perspective highlights research challenges to clarify a comprehensive high-performance mechanism of MCM-based Li-S batteries and provides new chemical insight for potential application purposes.
RESUMEN
3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3 H)-one (3BDO) is a mTOR agonist that inhibits autophagy. The main purpose of this study is to investigate the effects of 3BDO on seizure and cognitive function by autophagy regulation in pentylenetetrazol (PTZ)-kindled epileptic mice model. The PTZ-kindled epileptic mice model was used in study. The behavioral changes and electroencephalogram (EEG) of the mice in each group were observed. The cognitive functions were tested by Morris water maze test. The loss of hippocampal neurons was detected by hematoxylin-eosin (HE) staining and immunofluorescence analysis. Immunohistochemistry, western blot and q-PCR were employed to detect the expression of autophagy-related proteins and mTOR in the hippocampus and cortex. Less seizures, increased hippocampal neurons and reduced astrocytes of hippocampus were observed in the 3BDO-treated epileptic mice than in the PTZ-kindled epileptic mice. Morris water maze test results showed that 3BDO significantly improved the cognitive function of the PTZ-kindled epileptic mice. Western blot analyses and q-PCR revealed that 3BDO inhibited the expression of LC3, Beclin-1, Atg5, Atg7 and p-ULK1/ULK1, but increased that of p-mTOR/mTOR, p-P70S6K/P70S6K in the hippocampus and temporal lobe cortex of epileptic mice. Immunohistochemistry and immunofluorescence also showed 3BDO inhibited the LC3 expression and increased the mTOR expression in the hippocampus of epileptic mice. In addition, the autophagy activator EN6 reversed the decrease in the 3BDO-induced autophagy and aggravated the seizures and cognitive dysfunction in the epileptic mice. 3BDO regulates autophagy by activating the mTOR signaling pathway in PTZ-kindled epileptic mice model, thereby alleviating hippocampus neuronal loss and astrocytes proliferation, reducing seizures and effectively improving cognitive function. Therefore, 3BDO may have potential value in the treatment of epilepsy.
Asunto(s)
4-Butirolactona , Epilepsia , Excitación Neurológica , Animales , Ratones , Autofagia , Cognición , Modelos Animales de Enfermedad , Epilepsia/metabolismo , Hipocampo/metabolismo , Pentilenotetrazol , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , 4-Butirolactona/uso terapéuticoRESUMEN
Cardiolipin is a mitochondrial signature phospholipid that plays a pivotal role in maintaining cardiac health. A loss of tetralinoleoyl cardiolipin (TLCL), the predominant cardiolipin species in the healthy mammalian heart, is implicated in the pathogenesis of coronary heart disease (CHD) through poorly defined mechanisms. Here, we identified acyl-coenzyme A:lysocardiolipin acyltransferase-1 (ALCAT1) as the missing link between hypoxia and CHD in an animal model of myocardial infarction (MI). ALCAT1 is an acyltransferase that promotes mitochondrial dysfunction in aging-related diseases by catalyzing pathological remodeling of cardiolipin. In support of a causative role of ALCAT1 in CHD, we showed that ALCAT1 expression was potently upregulated by MI, linking myocardial hypoxia to oxidative stress, TLCL depletion, and mitochondrial dysfunction. Accordingly, ablation of the ALCAT1 gene or pharmacological inhibition of the ALCAT1 enzyme by Dafaglitapin (Dafa), a potent and highly specific ALCAT1 inhibitor, not only restored TLCL levels but also mitochondrial respiration by attenuating signal transduction pathways mediated by hypoxia-inducible factor 1α (HIF-1α). Consequently, ablation or pharmacological inhibition of ALCAT1 by Dafa effectively mitigated CHD and its underlying pathogenesis, including dilated cardiomyopathy, left ventricle dysfunction, myocardial inflammation, fibrosis, and apoptosis. Together, the findings have provided the first proof-of-concept studies for targeting ALCAT1 as an effective treatment for CHD.
Asunto(s)
Cardiolipinas , Enfermedad de la Arteria Coronaria , Animales , Cardiolipinas/metabolismo , Enfermedad de la Arteria Coronaria/metabolismo , Hipoxia/genética , Hipoxia/metabolismo , Mamíferos , Mitocondrias/genética , Mitocondrias/metabolismo , Estrés OxidativoRESUMEN
Brassinosteroids (BRs) play important roles in regulating plant reproductive processes. BR signaling or BR biosynthesis null mutants do not produce seeds under natural conditions, but the molecular mechanism underlying this infertility is poorly understood. In this study, we report that outer integument growth and embryo sac development were impaired in the ovules of the Arabidopsis thaliana BR receptor null mutant bri1-116. Gene expression and RNA-seq analyses showed that the expression of INNER NO OUTER (INO), an essential regulator of outer integument growth, was significantly reduced in the bri1-116 mutant. Increased INO expression due to overexpression or increased transcriptional activity of BRASSINAZOLE-RESISTANT 1 (BZR1) in the mutant alleviated the outer integument growth defect in bri1-116 ovules, suggesting that BRs regulate outer integument growth partially via BZR1-mediated transcriptional regulation of INO. Meanwhile, INO expression in bzr-h, a null mutant for all BZR1 family genes, was barely detectable; and the outer integument of bzr-h ovules had much more severe growth defects than those of the bri1-116 mutant. Together, our findings establish a new role for BRs in regulating ovule development and suggest that BZR1 family transcription factors might regulate outer integument growth through both BRI1-dependent and BRI1-independent pathways.
Asunto(s)
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Brasinoesteroides/farmacología , Proteínas de Unión al ADN/metabolismo , Óvulo Vegetal/crecimiento & desarrollo , Óvulo Vegetal/metabolismo , Factores de Transcripción/metabolismo , Arabidopsis/efectos de los fármacos , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Secuencia de Bases , Recuento de Células , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Modelos Biológicos , Mutación/genética , Especificidad de Órganos/efectos de los fármacos , Especificidad de Órganos/genética , Óvulo Vegetal/efectos de los fármacos , Tubo Polínico/efectos de los fármacos , Tubo Polínico/metabolismo , Polinización/efectos de los fármacos , Semillas/efectos de los fármacos , Semillas/metabolismoRESUMEN
Exercise training mitigates cardiac pathological remodeling and dysfunction caused by myocardial infarction (MI), but its underlying cellular and molecular mechanisms remain elusive. Our present study in an in vivo rat model of MI determined the impact of post-MI exercise training on myocardial fibrosis, mitochondrial biogenesis, antioxidant capacity, and ventricular function. Adult male rats were randomized into: (a) Sedentary control group; (b) 4-week treadmill exercise training group; (c) Sham surgery group; (d) MI group with permanent ligation of left anterior descending coronary artery and kept sedentary during post-MI period; and (e) post-MI 4-week exercise training group. Results indicated that exercise training significantly improved post-MI left ventricular function and reduced markers of cardiac fibrosis. Exercise training also significantly attenuated MI-induced mitochondrial damage and oxidative stress, which were associated with enhanced antioxidant enzyme expression and/or activity and total antioxidant capacity in the heart. Interestingly, the adaptive activation of the SIRT1/PGC-1α/PI3K/Akt signaling following MI was further enhanced by post-MI exercise training, which is likely responsible for exercise-induced cardioprotection and mitochondrial biogenesis. In conclusion, this study has provided novel evidence on the activation of SIRT1/PGC-1α/PI3K/Akt pathway, which may mediate exercise-induced cardioprotection through reduction of cardiac fibrosis and oxidative stress, as well as improvement of mitochondrial integrity and biogenesis in post-MI myocardium.
Asunto(s)
Infarto del Miocardio/patología , Infarto del Miocardio/rehabilitación , Condicionamiento Físico Animal/fisiología , Transducción de Señal/fisiología , Remodelación Ventricular/fisiología , Animales , Animales Modificados Genéticamente , Cardiotónicos , Corazón/fisiopatología , Masculino , Mitocondrias/metabolismo , Miocardio/metabolismo , Estrés Oxidativo/fisiología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Sirtuina 1/metabolismo , Función Ventricular Izquierda/fisiologíaRESUMEN
Nearly 1400 Bacillus strains growing in the plant rhizosphere were sampled from different sites on the Qinghai-Tibetan Plateau. Forty-five of the isolates, selected due to their biocontrol activity, were genome-sequenced and their taxonomic identification revealed that they were representatives of the Bacillus subtilis species complex (20) and the Bacillus cereus group (9). Majority of the remaining strains were found closely related to Bacillus pumilus, but their average nucleotide identity based on BLAST and electronic DNA/DNA hybridization values excluded closer taxonomic identification. A total of 45 different gene clusters involved in synthesis of secondary metabolites were detected by mining the genomes of the 45 selected strains. Except eight mesophilic strains, the 37 remaining strains were found either cold-adapted or psychrophilic, able to propagate at 10°C and below (Bacillus wiedmannii NMSL88 and Bacillus sp. RJGP41). Pot experiments performed at 10°C with winter wheat seedlings revealed that cold-adapted representatives of B. pumilus, B. safensis and B. atrophaeus promoted growth of the seedlings under cold conditions, suggesting that these bacilli isolated from a cold environment are promising candidates for developing of bioformulations useful for application in sustainable agriculture under environmental conditions unfavourable for the mesophilic bacteria presently in use.
RESUMEN
Novel 3D self-supported porous NiO@NiMoO4 core-shell nanosheets are grown on nickel foam through a facile stepwise hydrothermal method. Ultrathin NiO nanosheets on the nickel foam cross-linked to each other are used as the core, and tiny NiMoO4 nanosheets are further engineered to be immobilized uniformly on the NiO nanosheets to form the shell. This step-by-step construction of the architecture composed of ultrathin primary and secondary nanosheets efficiently avoids the agglomeration problems of individual ultrathin nanosheets. The ingenious architecture possesses the advantages of numerous diffusion channels for electrolyte ions, ideal pathways for electrons, and a large interfacial area for electrochemical reaction. The introduction of the NiMoO4 secondary nanosheets on the NiO primary nanosheets not only endows the heterostructure with high electrical conductivity and a large active area but also promotes an increase in oxygen vacancy content, which favors the improvement of electrocatalytic properties for the oxygen evolution reaction. The Tafel plot for the NiO@NiMoO4 core-shell architecture is as low as 32 mV dec-1, and the overpotential needed to reach 10 mA·cm-2 for NiO@NiMoO4 nanosheets is only 0.28 V.
RESUMEN
There is a notable correlation between mitochondrial homeostasis and metabolic disruption. In this review, we report that obesity-induced disruption of mitochondrial homeostasis adversely affects lipid metabolism, adipocyte differentiation, oxidative capacity, inflammation, insulin sensitivity, and thermogenesis in thermogenic fat. Elevating mitochondrial homeostasis in thermogenic fat emerges as a promising avenue for developing treatments for metabolic diseases, including enhanced mitochondrial function, mitophagy, mitochondrial uncoupling, and mitochondrial biogenesis. The exerkines (e.g., myokines, adipokines, batokines) released during exercise have the potential to ameliorate mitochondrial homeostasis, improve glucose and lipid metabolism, and stimulate fat browning and thermogenesis as a defense against obesity-associated metabolic diseases. This comprehensive review focuses on the manifold benefits of exercise-induced exerkines, particularly emphasizing their influence on mitochondrial homeostasis and fat thermogenesis in the context of metabolic disorders associated with obesity.
RESUMEN
Adipose tissue undergoes changes with aging, leading to increased adiposity, inflammatory cell infiltration, reduced angiogenesis, heightened oxidative stress, and alterations in its metabolic function. Regular exercise has been recognized as a powerful intervention that can positively influence adipose tissue health and mitigate the effects of aging. However, the molecular mechanisms underlying the benefits of regular exercise on aging adipose tissue function remain poorly understood. Adipokines released through regular exercise play a potential role in mitigating adipose tissue aging, enhancing the metabolism of glucose and lipids, reducing inflammation and fibrosis, and promoting fat browning and thermogenesis. This review comprehensively summarizes the benefits of regular exercise in addressing the age-related decline in adipose tissue function. Utilizing relevant examples of this approach, we address the possibility of designing therapeutic interventions based on these molecular mechanisms.
RESUMEN
Engaging in regular exercise and physical activity contributes to delaying the onset of cardiovascular diseases (CVDs). However, the physiological mechanisms underlying the benefits of regular exercise or physical activity in CVDs remain unclear. The disruption of mitochondrial homeostasis is implicated in the pathological process of CVDs. Exercise training effectively delays the onset and progression of CVDs by significantly ameliorating the disruption of mitochondrial homeostasis. This includes improving mitochondrial biogenesis, increasing mitochondrial fusion, decreasing mitochondrial fission, promoting mitophagy, and mitigating mitochondrial morphology and function. This review provides a comprehensive overview of the benefits of physical exercise in the context of CVDs, establishing a connection between the disruption of mitochondrial homeostasis and the onset of these conditions. Through a detailed examination of the underlying molecular mechanisms within mitochondria, the study illuminates how exercise can provide innovative perspectives for future therapies for CVDs.
Asunto(s)
Enfermedades Cardiovasculares , Ejercicio Físico , Homeostasis , Humanos , Homeostasis/fisiología , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/terapia , Ejercicio Físico/fisiología , Mitocondrias/metabolismo , Animales , Mitofagia , Dinámicas Mitocondriales , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Terapia por Ejercicio/métodos , Biogénesis de OrganelosRESUMEN
The underlying pathogenesis of chronic inflammatory pain is greatly complex, but the relevant therapies are still unavailable. Development of effective candidates for chronic inflammatory pain is highly urgent. We previously identified that trifluoro-icaritin (ICTF) exhibited a significant therapeutic activity against complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, however, the precise mechanisms remain elusive. Here, the paw withdrawal threshold (PWT), paw withdrawal latency (PWL), and CatWalk gait analysis were used to determine the pain-related behaviors. The expression and co-localization of pain-related signaling molecules were detected by Western blot and immunofluorescence staining. Our results demonstrated that ICTF (3.0 mg/kg, i.p.) effectively attenuated mechanical allodynia, thermal hyperalgesia and improved motor dysfunction induced by CFA, and the molecular docking displayed that CB2 receptor may be the therapeutic target of ICTF. Furthermore, ICTF not only up-regulated the levels of CB2 receptor, IL-10, ß-endorphin and CD206, but also reduced the expression of P2Y12 receptor, NLRP3, ASC, Caspase-1, IL-1ß, CD11b, and iNOS in the spinal cord of CFA rats. Additionally, the immunofluorescence staining from the spinal cord showed that ICTF significantly increased the co-expression between the microglial marker Iba-1 and CB2 receptor, IL-10, ß-endorphin, respectively, but markedly decreased the co-localization between Iba-1 and P2Y12 receptor. Conversely, intrathecal administration of CB2 receptor antagonist AM630 dramatically reversed the inhibitory effects of ICTF on CFA-induced chronic inflammatory pain, leading to a promotion of pain hypersensitivity, abnormal gait parameters, microglial activation, and up-regulation of P2Y12 receptor and NLRP3 inflammasome, as well as the inhibition of CB2 receptor and IL-10/ß-endorphin cascade. Taken together, these findings highlighted that ICTF alleviated CFA-induced neuroinflammation by enhancing CB2 receptor-mediated IL-10/ß-endorphin signaling and suppressing microglial activation in the spinal cord, and uncovered that CB2 receptor may be exploited as a novel and promising target for ICTF treatment of chronic inflammatory pain.
Asunto(s)
Adyuvante de Freund , Interleucina-10 , Microglía , Enfermedades Neuroinflamatorias , Receptor Cannabinoide CB2 , Transducción de Señal , Médula Espinal , betaendorfina , Animales , Masculino , Ratas , betaendorfina/metabolismo , Flavonoides/farmacología , Flavonoides/uso terapéutico , Adyuvante de Freund/toxicidad , Hiperalgesia/metabolismo , Hiperalgesia/tratamiento farmacológico , Interleucina-10/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Ratas Sprague-Dawley , Receptor Cannabinoide CB2/metabolismo , Receptor Cannabinoide CB2/agonistas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoRESUMEN
BACKGROUND: The method for compressing hemorrhagic sites after transradial access has been a topic of interest, yet definitive guidelines remain elusive. This study aims to address this gap by optimizing the mechanical compression hemostasis protocol after transradial access. METHODS: This retrospective analysis included 300 patients from the Department of Cerebrovascular Diseases, Shanghai Fourth People's Hospital affiliated to Tongji University, who underwent transradial access for cerebrovascular angiography. Following the procedure, patients received radial artery compression hemostasis using a balloon compressor. They were divided into group A (n=100, continuous deflation) and group B (n=200, intermittent deflation) according to different hemostasis methods. The incidence of bleeding at the puncture site and complications were compared between the two groups. RESULTS: The rate of bleeding at the puncture site was significantly lower in group B (20 out of 200 patients) compared to group A (20 out of 100 patients) (P=0.032). Similarly, the incidence of puncture site complications, such as edema, congestion, and wound infection was lower in group B (5 out of 200 patients) compared to group A (10 out of 100 patients) (P=0.006). CONCLUSION: Four hours of compression with intermittent deflation (group B) emerged as the optimal compression method after transradial access, demonstrating fewer complications at the patient's puncture site.
RESUMEN
We report the synthesis of xNi-yFe/γ-Al2O3 catalysts which were applied to the reductive amination of polypropylene glycol (PPG) for the preparation of polyether amine (PEA). The catalysts were characterized by N2-sorption, X-ray diffraction, H2-temperature programmed reduction, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy to reveal the synergistic effect of the bimetallic Ni-Fe-loaded catalysts. It was found that in the reductive amination of PPG to PEA, the conversion and product selectivity of the reaction were closely related to the types of active centers of the catalyst. In particular, the surface Ni0 content increased by adding Fe as a promoter, with a maximum Ni0 content on the 15Ni-7.5Fe/Al2O3 catalyst, which also led to the highest conversion rate (>99%). In addition, no deactivation was observed after three cycles of reaction carried out by the catalyst.
RESUMEN
The recent reports of resistance in Plasmodium falciparum to artemisinin derivatives and their partner drugs demand intensive studies toward understanding the molecular mechanisms of resistance. In this study, we examined the in vitro susceptibility of 63 P. falciparum field isolates collected from the China-Myanmar border area to chloroquine (CQ) and piperaquine (PPQ). Parasite isolates remained highly resistant to CQ, with the geometric mean 50% inhibitory concentration (IC50) of 252.7 nM and a range of 51.9 to 1,052.0 nM. In comparison, these parasites had a geometric mean IC50 of 28.4 nM for PPQ, with a fairly wide range of 5.3 to 132.0 nM, suggesting that certain parasite isolates displayed relatively high levels of resistance to PPQ. Interestingly, within the 4 years of study, the parasites exhibited a continuous decline in susceptibilities to both CQ and PPQ, and there was a significant correlation between responses to CQ and PPQ (Pearson correlation coefficient = 0.79, P < 0.0001). Consistent with the CQ-resistant phenotype, all parasites carried the pfcrt K76T mutation, and most parasites had the CVIET type that is prevalent in Southeast Asia. In contrast, pfmdr1 mutations were relatively rare, and no gene amplification was detected. Only the pfmdr1 N1042D mutation was associated with resistance to CQ. For the pfmrp1 gene, four substitutions reached relatively high prevalence of >22%, and the I876V mutation was associated with reduced sensitivity to CQ. However, we could not establish a link between PPQ responses and the polymorphisms in the three genes associated with quinoline drug resistance.
Asunto(s)
Cloroquina/farmacología , Plasmodium falciparum/efectos de los fármacos , Polimorfismo Genético/genética , Proteínas Protozoarias/genética , Quinolinas/farmacología , Antimaláricos/farmacología , Resistencia a Medicamentos/genética , Humanos , Concentración 50 Inhibidora , Mutación , Plasmodium falciparum/genética , Plasmodium falciparum/patogenicidadRESUMEN
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucelotide repeat that encodes an abnormal polyglutamine (PolyQ) tract in the disease protein, ataxin-3. The formation of neuronal intranuclear inclusions in the specific brain regions is one of the pathological hallmarks of SCA3. Acceleration of the degradation of the mutant protein aggregates is proven to produce beneficial effects in SCA3 and other PolyQ diseases. Lithium is known to be neuroprotective in various models of neurodegenerative disease and can reduce the mutant protein aggregates by inducing autophagy. In this study, we explored the therapeutic potential of lithium in a SCA3 Drosophila model. We showed that chronic treatment with lithium chloride at specific doses notably prevented eye depigmentation, alleviated locomotor disability, and extended the median life spans of SCA3 transgenic Drosophila. By means of genetic approaches, we showed that co-expressing the mutant S9E, which mimicked the phosphorylated S9 state of Shaggy as done by lithium, also partly decreased toxicity of gmr-SCA3tr-Q78. Taken together, our findings suggest that lithium is a promising therapeutic agent for the treatment of SCA3 and other PolyQ diseases.
Asunto(s)
Glucógeno Sintasa Quinasa 3/metabolismo , Cloruro de Litio/farmacología , Trastornos del Movimiento/prevención & control , Proteínas del Tejido Nervioso/metabolismo , Fármacos Neuroprotectores/farmacología , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Factores de Edad , Animales , Animales Modificados Genéticamente , Ataxina-3 , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Drosophila , Activación Enzimática/efectos de los fármacos , Ojo/efectos de los fármacos , Ojo/patología , Ojo/ultraestructura , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Humanos , Microscopía Electrónica de Rastreo , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Trastornos del Movimiento/etiología , Trastornos del Movimiento/genética , Proteínas del Tejido Nervioso/genética , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/prevención & control , Proteínas Nucleares/genética , Péptidos/genética , Proteínas Represoras/genéticaRESUMEN
The benefits of regular physical activity are related to delaying and reversing the onset of ageing and age-related disorders, including cardiomyopathy, neurodegenerative diseases, cancer, obesity, diabetes, and fatty liver diseases. However, the molecular mechanisms of the benefits of exercise or physical activity on ageing and age-related disorders remain poorly understood. Mitochondrial dysfunction is implicated in the pathogenesis of ageing and age-related metabolic diseases. Mitochondrial health is an important mediator of cellular function. Therefore, exercise alleviates metabolic diseases in individuals with advancing ageing and age-related diseases by the remarkable promotion of mitochondrial biogenesis and function. Exerkines are identified as signaling moieties released in response to exercise. Exerkines released by exercise have potential roles in improving mitochondrial dysfunction in response to age-related disorders. This review comprehensive summarizes the benefits of exercise in metabolic diseases, linking mitochondrial dysfunction to the onset of age-related diseases. Using relevant examples utilizing this approach, the possibility of designing therapeutic interventions based on these molecular mechanisms is addressed.
Asunto(s)
Ejercicio Físico , Enfermedades Metabólicas , Humanos , Ejercicio Físico/fisiología , Enfermedades Metabólicas/terapia , Enfermedades Metabólicas/metabolismo , Mitocondrias/metabolismo , Envejecimiento , Transducción de SeñalRESUMEN
Neuropathic pain is still a serious and unsolved health problem. Activation of α7 nicotinic acetylcholine receptor (α7nAChR) is known to modulate neuropathic pain by inhibiting microglial activation and BDNF/TrkB/KCC2 signaling. We previously identified that trifluoro-icaritin (ICTF) has an attenuated effect on spared nerve injury (SNI)-induced neuropathic pain, but its potential mechanisms remain unknown. Here, the pain-related behaviors were determined by paw withdrawal threshold (PWT), CatWalk gait analysis, rotarod test, open field test and elevated plus maze test. The expression of pain-related signal molecules was evaluated by Western blot and immunoï¬uorescence staining. The results showed that ICTF (5.0 mg/kg, i.p.) successfully relieved SNI-induced mechanical allodynia and anxiety-like behavior, we subsequently found there existed either positive or negative correlation between mechanical allodynia and gait parameters or rotating speed following ICTF treatment. Moreover, ICTF not only enhanced the expression of spinal α7nAChR, KCC2, CD206 and IL-10, but also decreased the levels of spinal BDNF, TrkB, CD11b, Iba-1, CD40 and IL-1ß in SNI rats. Conversely, α7nAChR antagonist α-Bgtx (I.T.) effectively reversed the inhibitory effects of ICTF on SNI rats, resulting in a remarkable improvement of mechanical allodynia, activation of microglia. and suppression of α7nAChR-mediated BDNF/TrkB/KCC2 signaling. Additionally, exogenous BDNF (I.T.) dramatically abrogated both blockade of BDNF/TrkB/KCC2 cascade and alleviation of mechanical allodynia by ICTF treatment. Altogether, the study highlighted that ICTF could relieve SNI-induced neuropathic pain by suppressing microglial activation via α7nAChR-mediated inhibition of BDNF/TrkB/KCC2 signaling in the spinal cord, suggesting that ICTF may be served as a possible painkiller against neuropathic pain.
Asunto(s)
Neuralgia , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Ratas , Receptor Nicotínico de Acetilcolina alfa 7/genética , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Ratas Sprague-Dawley , Médula Espinal/metabolismoRESUMEN
Developing high-performance and low-cost electrocatalysts toward methanol oxidation reaction (MOR) is essential for fuel cell applications. Herein, we report a defect engineering strategy integrating amorphization and phosphorization to construct directly interconnected networks of amorphous NiCo-based metal-organic framework nanowires (a-NiCo-MOFNWs) with phosphorus (P) doping. The resulting P-doped a-NiCo-MOFNWs (a-NiCo-MOFNWs-P) network displays superior MOR efficiency and long-term durability over 1000 cyclic voltammetry (CV) measurements. The special structure of directly interconnected networks and the synergistic effect between the amorphous MOFs and dispersed phosphorus species give rise to abundant exposed active sites, accelerated electron transport, and increased porosity for mass transfer, thus boosting the reaction kinetics of MOR. This work provides additional insights into the network assembly and structural evolution of one-dimensional (1D) MOFs, and also opens up new avenues for the design of highly reactive and robust non-precious metal-based electrocatalysts.
RESUMEN
Autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders primarily affecting the cerebellum. Nearly 33 genetically distinct subtypes have been defined, and 19 seemingly unrelated disease genes have been identified so far. Recently, mutations in the ATPase family gene 3-like 2 (AFG3L2) gene were presented to cause SCA28 subtype. In order to define the frequency of SCA28 mutation in Chinese mainland, we performed molecular genetic analysis in 67 unrelated affected individuals with ADCA. At last, we did not find AFG3L2 gene mutation, except for three known single nucleotide polymorphisms (SNP)s. It suggests that SCA28 subtype is very rare in Chinese mainland.