RESUMEN
Parkinson's disease (PD) is intricately linked to abnormal gut microbiota, yet the specific microbiota influencing clinical outcomes remain poorly understood. Our study identified a deficiency in the microbiota genus Blautia and a reduction in fecal short-chain fatty acid (SCFA) butyrate level in PD patients compared to healthy controls. The abundance of Blautia correlated with the clinical severity of PD. Supplementation with butyrate-producing bacterium B. producta demonstrated neuroprotective effects, attenuating neuroinflammation and dopaminergic neuronal death in mice, consequently ameliorating motor dysfunction. A pivotal inflammatory signaling pathway, the RAS-related pathway, modulated by butyrate, emerged as a key mechanism inhibiting microglial activation in PD. The change of RAS-NF-κB pathway in PD patients was observed. Furthermore, B. producta-derived butyrate demonstrated the inhibition of microglial activation in PD through regulation of the RAS-NF-κB pathway. These findings elucidate the causal relationship between specific gut microbiota and PD, presenting a novel microbiota-based treatment perspective for PD.
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Clostridiales , Microbiota , Enfermedad de Parkinson , Humanos , Animales , Ratones , Microglía , Enfermedades Neuroinflamatorias , FN-kappa B , ButiratosRESUMEN
Canagliflozin is an antidiabetic medicine that inhibits sodium-glucose cotransporter 2 (SGLT2) in proximal tubules. Recently, it was reported to have several noncanonical effects other than SGLT2 inhibiting. However, the effects of canagliflozin on skeletal muscle regeneration remain largely unexplored. Thus, in vivo muscle contractile properties recovery in mice ischemic lower limbs following gliflozins treatment was evaluated. The C2C12 myoblast differentiation after gliflozins treatment was also assessed in vitro. As a result, both in vivo and in vitro data indicate that canagliflozin impairs intrinsic myogenic regeneration, thus hindering ischemic limb muscle contractile properties, fatigue resistance recovery, and tissue regeneration. Mitochondrial structure and activity are both disrupted by canagliflozin in myoblasts. Single-cell RNA sequencing of ischemic tibialis anterior reveals a decrease in leucyl-tRNA synthetase 2 (LARS2) in muscle stem cells attributable to canagliflozin. Further investigation explicates the noncanonical function of LARS2, which plays pivotal roles in regulating myoblast differentiation and muscle regeneration by affecting mitochondrial structure and activity. Enhanced expression of LARS2 restores the differentiation of canagliflozin-treated myoblasts, and accelerates ischemic skeletal muscle regeneration in canagliflozin-treated mice. Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration.
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Aminoacil-ARNt Sintetasas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Aminoacil-ARNt Sintetasas/metabolismo , Aminoacil-ARNt Sintetasas/farmacología , Animales , Canagliflozina/metabolismo , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Diferenciación Celular , Glucosa/metabolismo , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Isquemia/tratamiento farmacológico , Isquemia/metabolismo , Ratones , Músculo Esquelético/metabolismo , Sodio/metabolismo , Sodio/farmacología , Transportador 2 de Sodio-Glucosa/metabolismo , Transportador 2 de Sodio-Glucosa/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
Driven by the scarcity of effective treatment options in clinical settings, the present study aimed to identify a new potential target for Alzheimer's disease (AD) treatment. We focused on Lars2, an enzyme synthesizing mitochondrial leucyl-tRNA, and its role in maintaining mitochondrial function. Bioinformatics analysis of human brain transcriptome data revealed downregulation of Lars2 in AD patients compared to healthy controls. During in vitro experiments, the knockdown of Lars2 in mouse neuroblastoma cells (neuro-2a cells) and primary cortical neurons led to morphological changes and decreased density in mouse hippocampal neurons. To explore the underlying mechanisms, we investigated how downregulated Lars2 expression could impede the phosphatidylinositol 3-kinase/protein kinase B (PI3K-AKT) pathway, thereby mitigating AKT's inhibitory effect on glycogen synthase kinase 3 beta (GSK3ß). This led to the activation of GSK3ß, causing excessive phosphorylation of Tau protein and subsequent neuronal degeneration. During in vivo experiments, knockout of lars2 in hippocampal neurons confirmed cognitive impairment through the Barnes maze test, the novel object recognition test, and nest-building experiments. Additionally, immunofluorescence assays indicated an increase in p-tau, atrophy in the hippocampal region, and a decrease in neurons following Lars2 knockout. Taken together, our findings indicate that Lars2 represents a promising therapeutic target for AD.
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ETHNOPHARMACOLOGICAL RELEVANCE: Increasing evidence suggests that ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, may play a substantial role in the traumatic brain injury (TBI) pathophysiology. 3-n-butylphthalide (NBP), a compound extracted from the seeds of Apium graveolens Linn (Chinese celery) and used in China to treat ischemic stroke, has demonstrated encouraging anti-reactive oxygen species (ROS) effects. Ascertaining whether NBP can inhibit ferroptosis and its mechanism could potentially expand its use in models of neurological injury and neurodegenerative diseases. METHODS AND RESULTS: In this study, we used erastin-induced in vitro ferroptosis models (HT22 cells, hippocampal slices, and primary neurons) and an in vivo controlled cortical impact mouse model. Our study revealed that NBP administration mitigated erastin-induced death in HT-22 cells and decreased ROS levels, lipid peroxidation, and mitochondrial superoxide indicators, resulting in mitochondrial protection. Moreover, the ability of NBP to inhibit ferroptosis was confirmed in organotypic hippocampal slice cultures and a TBI mouse model. NBP rescued neurons, inhibited microglial activation, and reduced iron levels in the brain tissue. The protective effect of NBP can be partly attributed to the inhibition of the AHR-CYP1B1 axis, as evidenced by RNA-seq and CYP1B1 overexpression/inhibition experiments in HT22 cells and primary neurons. CONCLUSIONS: Our study underscores that NBP inhibition of the AHR-CYP1B1 axis reduces ferroptosis in neuronal damage and ameliorates brain injury.
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Thrombus is an extremely dangerous factor in the human body that can block the blood vessel. Once thrombosis happens in venous of lower limbs, local blood flow is impeded. This leads to venous thromboembolism (VTE) and even pulmonary embolism. In recent years, venous thromboembolism has frequently occurred in a variety of people, and there is no effective treatment for patients with different venous structures. For the patients with venous isomer with single valve structure, we establish a coupled computational model to simulate the process of thrombolysis with multi-dose treatment schemes by considering the blood as non-Newtonian fluid. Then, the corresponding in vitro experimental platform is built to verify the performance of the developed mathematical model. At last, the effects of different fluid models, valve structures and drug doses on thrombolysis are comprehensively studied through numerical and experimental observations. Comparing with the experimental results, the relative error of blood boosting index (BBI) obtained from non-Newtonian fluid model is 11% smaller than Newtonian fluid. In addition, the BBI from venous isomer is 1300% times stronger than patient with normal venous valve while the valve displacement is 500% times smaller. As consequence, low eddy current and strong molecular diffusion near the thrombus in case of isomer promote thrombolysis rate up to 18%. Furthermore, the 80 µM dosage of thrombolytic drugs gets the maximum thrombus dissolution rate 18% while the scheme of 50 µM doses obtains a thrombolysis rate of 14% in case of venous isomer. Under the two administration schemes for isomer patients, the rates from experiments are around 19.1% and 14.9%, respectively. It suggests that the proposed computational model and the designed experiment platform can potentially help different patients with venous thromboembolism to carry out clinical medication prediction.
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Trombosis , Tromboembolia Venosa , Válvulas Venosas , Humanos , Tromboembolia Venosa/tratamiento farmacológico , Terapia Trombolítica/métodos , Simulación por ComputadorRESUMEN
Abstract Pyroptosis is considered one of a critical factor in the recovery of neurological function following traumatic brain injury. Brain injury activates a molecular signaling cascade associated with pyroptosis and inflammation, including NLRP3, inflammatory cytokines, caspase-1, gasdermin D (GSDMD), and other pyroptosis-related proteins. In this study, we explored the neuroprotective effects of LDC7559, a GSDMD inhibitor. Briefly, LDC7559, siRNA-GSDMD (si-GSDMD), or equal solvent was administrated to mice with a lipopolysaccharide + nigericin (LPS + Nig) model in vitro or with controlled cortical impact brain injury. The findings revealed that inflammation and pyroptosis levels were decreased by LDC7559 or si-GSDMD treatment both in vitro and in vivo. Immunofluorescence staining, brain water content, hematoxylin and eosin staining, and behavioral investigations suggested that LDC7559 or si-GSDMD inhibited microglial proliferation, ameliorated cerebral edema, reduced brain tissue loss, and promoted brain function recovery. Taken together, LDC7559 may inhibit pyroptosis and reduce inflammation by inhibiting GSDMD, thereby promoting the recovery of neurological function.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Fármacos Neuroprotectores , Ratones , Animales , Microglía/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/farmacología , Fármacos Neuroprotectores/farmacología , Piroptosis , Inflamación/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Encefálicas/metabolismoRESUMEN
Type 2 diabetes mellitus (T2DM) is a prevalent risk factor for cognitive impairment. Aerobic exercise can improve T2DM-related cognitive impairment; however, the possible mechanisms remain elusive. Thus, we assessed db/m mice and leptin receptor-deficient (db/db) mice that did or did not perform aerobic exercise (8 m/min, 60 min/day, and 5 days/week for 12 weeks). In this study, cognitive function was significantly impaired in the T2DM mice; aerobic exercise improved cognitive impairment through activating the AMPK/SIRT1 signalling pathway and inhibiting the JAK2/STAT3 signalling pathway in T2DM mice. However, after the application of RO8191 (JAK2 activator) or Compound C (AMPK inhibitor), the positive improvement of the exercise was evidently suppressed. Taken together, our data indicated that long-term aerobic exercise improves type 2 diabetes mellitus-related cognitive impairment by inhibiting JAK2/STAT3 and enhancing AMPK/SIRT1 pathways in mice.
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Disfunción Cognitiva , Diabetes Mellitus Tipo 2 , Condicionamiento Físico Animal , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Disfunción Cognitiva/etiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Janus Quinasa 2/metabolismo , Ratones , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Sirtuina 1/genética , Sirtuina 1/metabolismoRESUMEN
OBJECTIVE: To investigate the etiology, clinical as well as neuroimaging characteristics, and outcomes after proper treatment in a series of 18 patients with osmotic demyelination syndrome. METHODS: Medical records, including video records, of 18 patients with osmotic demyelination syndrome were retrospectively examined. Demographic and clinical information, imaging results, plans of management, and outcomes during the follow-up period were collected and analyzed. RESULTS: Eighteen patients, including 10 males and 8 females, were included in the present study. The mean age at diagnosis of CNS insult was 47.4 ± 13.3 years (ranged from 30 to 78 years). Etiologies included rapidly corrected hyponatremia (50%), alcoholism (27.8%), and others. Neurological manifestations included encephalopathy (61.1%), dysphonia (50%), extrapyramidal symptoms (38.9%), and seizures (22.2%). Neuroimaging results showed that 6 patients (33.3%) had central pontine myelinolysis, 5 (27.8%) had extrapontine myelinolysis, and 7 (38.9%) had both. After treatment, 12 patients showed improvement and the other 6 did not. Among these patients, those who showed symptoms of encephalopathy had a favorable outcome. The majority of those who presented with mental retardation, seizures, and no other symptoms recovered better than their counterparts who had other symptoms. Nine out of 11 patients with pseudobulbar paralysis and/or extrapyramidal symptoms showed improvement, but the other 2 did not show improvement. Five patients who did not improve after treatment during admission were followed up for 1-3 months with rehabilitation training recommended, and it was found that 3 showed significant improvement after training, and the other 2 did not respond to this training. CONCLUSIONS: Osmotic demyelination syndrome is a complex disease entity due to a variety of etiologies, manifesting with symptoms involving diverse systems of the brain. Early identification and removal/correction of conditions leading to osmotic demyelination syndrome are the key to prevent and/or manage this disease.
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Mielinólisis Pontino Central/diagnóstico por imagen , Mielinólisis Pontino Central/terapia , Neuroimagen/métodos , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Ósmosis , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Osteoarthritis (OA), a degenerative disorder, is considered to be one of the most common forms of arthritis. Limonin (Lim) is extracted from lemons and other citrus fruits. Limonin has been reported to have anti-inflammatory effects, while inflammation is a major cause of OA; thus, we propose that limonin may have a therapeutic effect on OA. In this study, the therapeutic effect of limonin on OA was assessed in chondrocytes in vitro in IL-1ß induced OA and in the destabilization of the medial meniscus (DMM) mice in vivo. The Nrf2/HO-1/NF-κB signaling pathway was evaluated to illustrate the working mechanism of limonin on OA in chondrocytes. In this study, it was found that limonin can reduce the level of IL-1ß induced proinflammatory cytokines such as INOS, COX-2, PGE2, NO, TNF-α, and IL-6. Limonin can also diminish the biosynthesis of IL-1ß-stimulated chondrogenic catabolic enzymes such as MMP13 and ADAMTS5 in chondrocytes. The research on the mechanism study demonstrated that limonin exerts its protective effect on OA through the Nrf2/HO-1/NF-κB signaling pathway. Taken together, the present study shows that limonin may activate the Nrf2/HO-1/NF-κB pathway to alleviate OA, making it a candidate therapeutic agent for OA.
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Artritis Experimental/tratamiento farmacológico , Condrocitos/efectos de los fármacos , Inflamación/tratamiento farmacológico , Interleucina-1beta/toxicidad , Limoninas/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Osteoartritis/tratamiento farmacológico , Animales , Artritis Experimental/etiología , Artritis Experimental/metabolismo , Artritis Experimental/patología , Condrocitos/metabolismo , Condrocitos/patología , Regulación de la Expresión Génica , Hemo Oxigenasa (Desciclizante)/genética , Hemo Oxigenasa (Desciclizante)/metabolismo , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Masculino , Meniscos Tibiales/cirugía , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Osteoartritis/etiología , Osteoartritis/metabolismo , Osteoartritis/patologíaRESUMEN
BACKGROUND: Canagliflozin (CANA) administration increases the risk of lower limb amputation in the clinic. The present study aimed to investigate whether and how CANA interferes with the intracellular physiological processes of bone marrow derived mesenchymal stem cells (BM-MSCs) and its contribution to ischaemic lower limb. METHODS: The in vivo blood flow recovery in ischaemic lower limbs following CANA treatment was evaluated. The cellular function of BM-MSCs after CANA treatment were also assessed in vitro. In silico docking analysis and mutant substitution assay were conducted to confirm the interaction of CANA with glutamate dehydrogenase 1 (GDH1). FINDINGS: Following CANA treatment, attenuated angiogenesis and hampered blood flow recovery in the ischaemic region were detected in diabetic and non-diabetic mice, and inhibition of the proliferation and migration of BM-MSCs were also observed. CANA was involved in mitochondrial respiratory malfunction in BM-MSCs and the inhibition of ATP production, cytochrome c release and vessel endothelial growth factor A (VEGFA) secretion, which may contribute to reductions in the tissue repair capacity of BM-MSCs. The detrimental effects of CANA on MSCs result from the inhibition of GDH1 by CANA (evidenced by in silico docking analysis and H199A-GDH1/N392A-GDH1 mutant substitution). INTERPRETATION: Our work highlights that the inhibition of GDH1 activity by CANA interferes with the metabolic activity of the mitochondria, and this interference deteriorates the retention of and VEGFA secretion by MSCs. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province and Wenzhou Science and Technology Bureau Foundation.
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Canagliflozina/farmacología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Comunicación Paracrina/efectos de los fármacos , Daño por Reperfusión/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Animales , Apoptosis/efectos de los fármacos , Sitios de Unión , Canagliflozina/química , Ciclo Celular/efectos de los fármacos , Movimiento Celular , Proliferación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Glutamato Deshidrogenasa/química , Glutamato Deshidrogenasa/metabolismo , Humanos , Extremidad Inferior/irrigación sanguínea , Trasplante de Células Madre Mesenquimatosas , Ratones , Mitocondrias Musculares/efectos de los fármacos , Mitocondrias Musculares/metabolismo , Mitocondrias Musculares/ultraestructura , Modelos Moleculares , Neovascularización Fisiológica/efectos de los fármacos , Unión Proteica , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/etiología , Daño por Reperfusión/patología , Relación Estructura-ActividadRESUMEN
Post-stroke cognitive impairment (PSCI) is a severe complication of stroke. Predicting PSCI is difficult because some risk factors for stroke, such as blood glucose level and blood pressure, are affected by many other elements. Although recent studies have shown that high serum uric acid (UA) levels are associated with cognitive dysfunction and may be a risk factor for PSCI, its impact remains unclear. Accordingly, the present study aimed to explore the association between serum UA level and PSCI. In total, 274 patients who experienced acute cerebral infarction, confirmed between January 2016 and December 2018, were enrolled. Baseline data and biological indicators were recorded. According to the Montreal Cognitive Assessment (MoCA) scores, patients were divided into two groups: PSCI and non-PSCI. Logistic regression analysis was used to determine possible risk factors for PSCI. Results demonstrated that serum UA levels were significantly higher in the PSCI group than in the non-PSCI group. Multivariable logistic analysis revealed that age, years of education, and UA level were independent risk factors for PSCI. PSCI patients were subdivided according to serum UA level: high and low. Hypertension history and homocysteine (Hcy) levels differed significantly between the high and low UA level groups. Further analysis revealed that a history of hypertension and Hcy demonstrated a certain correlation (râ¯=â¯0.163, 0.162; Pâ¯<â¯0.05), suggesting that serum UA level was an independent risk factor for PSCI. These findings indicate that serum UA level was correlated with PSCI in post-stroke patients and is anticipated to be used in clinical practice to reduce the incidence of PSCI.