RESUMEN
BACKGROUND: Guizhi Shaoyao Zhimu decoction (GSZD) is a recognised herbal formula that has demonstrated efficacy in the treatment of rheumatoid arthritis (RA). Despite its recognised clinical benefits and widespread use, the precise mechanisms by which this decoction exerts its therapeutic effects are not fully understood. PURPOSE: To determine the impact of GSZD on collagen-induced arthritis (CIA) mice and MH7A cells and to explore the molecular mechanisms through which GSZD operates in RA. METHODS: The in vivo effects of GSZD were evaluated in a CIA model. Network pharmacology and bioinformatics approaches were employed to identify GSZD targets. Protein expression was measured by western blotting. Matrix metalloproteinases (MMPs) expression was detected using ELISA and quantitative RT-PCR. Cell migration and invasion were determined using the Boyden chamber assay. RESULTS: The arthritis score was significantly lowered by GSZD, which also alleviated joint swelling and bone damage, reduced the pathological score, and lowered the serum levels of MMPs in CIA mice. From a mechanistic perspective, we discovered that SLPI serves as a novel target gene of GSZD in MH7A cells. The findings indicated that GSZD treatment significantly suppressed the expression of SLPI, as well as the PI3K/AKT/NF-κB signalling pathway. Additionally, GSZD treatment decreased both the migration and invasion of MH7A cells, as well as MMPs expression. Further investigations of molecular mechanisms revealed that GSZD effectively inhibited SLPI expression and PI3K/AKT/NF-κB pathway activity in TNF-α-stimulated MH7A cells. CONCLUSION: The findings indicate that GSZD markedly reduced the severity of arthritis in CIA mice and restricted the migration, invasion, and expression of MMPs in MH7A cells by interfering with the SLPI and PI3K/AKT/NF-κB signalling pathways. Our research further elucidated the underlying mechanism by which GSZD exerts its therapeutic effects in the treatment of RA and showed for the first time that SLPI could serve as a novel therapeutic target for RA, offering potential avenues for more effective treatment strategies.
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Artritis Reumatoide , Medicamentos Herbarios Chinos , Regulación de la Expresión Génica , Inhibidor Secretorio de Peptidasas Leucocitarias , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Línea Celular , Animales , Ratones , Artritis Reumatoide/tratamiento farmacológico , Artritis Experimental/tratamiento farmacológico , Modelos Animales de Enfermedad , Inhibidor Secretorio de Peptidasas Leucocitarias/genética , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/tratamiento farmacológico , Masculino , Transducción de Señal/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ratones Endogámicos DBARESUMEN
Oxidative stress and neuroinflammation accompanied by microglial activation are increased in Alzheimer's disease (AD) and contribute to the pathogenesis of AD. Nuclear factor erythroid-derived 2-related factor 2 (Nrf2) is a master transcription factor that acts as an endogenous defense mechanism against oxidative stress and inflammation and is a potential target for preventing AD. Psoraleae Semen (PS) reportedly has antioxidant and anti-inflammatory effects. This study aimed to examine the effects of PS extract (PSE) on Nrf2 activation and prevention of cognitive dysfunction in AppNL-P-F AD model mice. The effects of PSE on antioxidant response element (ARE) activity and cytoprotection in PC12 cells and on microglial activation in BV-2 cells were evaluated. PSE showed high ARE activity and prevented 6-hydroxydopamine-induced cytotoxicity in PC12 cells. Moreover, PSE suppressed lipopolysaccharide-induced nitric oxide production in BV-2 cells. Oral administration of PSE prevented cognitive dysfunction in AppNL-P-F mice without affecting motor function. Our results support that PSE can contribute to the development of new preventive and therapeutic agents for AD focusing on Nrf2 activation.
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Enfermedad de Alzheimer , Modelos Animales de Enfermedad , Factor 2 Relacionado con NF-E2 , Extractos Vegetales , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/metabolismo , Células PC12 , Factor 2 Relacionado con NF-E2/metabolismo , Ratones , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas , Masculino , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/prevención & control , Óxido Nítrico/metabolismo , Elementos de Respuesta Antioxidante/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Ratones Transgénicos , Estrés Oxidativo/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismoRESUMEN
Plantago asiatica L., a perennial herb in the family Plantaginaceae, has been shown to impart several pharmacologic activities, including anti-oxidative, anti-inflammatory, and diuretic effects. In the study here, the anti-gout(y) arthritis (GA) effects of a crude extract from P. asiatica L. (PAE) were investigated in a rat GA model. For this, PAE was prepared by ethanol extraction and analyzed for phytochemicals by RP-HPLC and Q-TOF-MS. Thereafter, potential therapeutic effects of the PAE were investigated in rats; Wistar rats (male, 8 wk-of-age) were randomly allocated into four groups (n = 9/group) and intra-articularly injected with 3 mg monosodium urate (MSU) in saline solution to establish a GA model. For the study, rats received oral dosings of 0.3 mg colchicine/kg or 1 g PAE/kg (w/w) before and after gout was established. At fixed times after the treatments, assessment of joint swelling ratios and pathological changes in the joints, as well as of select cytokine expression in the blood, was done. RP-HPLC results showed the PAE contained at least 8 'active' ingredients, with plantamajoside, verbascoside, and cymaroside being the most abundant. In comparison to in control rats, MSU induced joint space narrowing, ankle joint swelling, and increased levels of pro-inflammatory interleukin (IL)-1ß, IL-17a, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, and reductions in anti-inflammatory IL-10 in the blood. PAE treatment significantly reversed patho- genic joint space narrowing and swelling, reversed the MSU-induced changes in inflammatory factors, and in general imparted effects very similar to those seen with colchicine (COL; known non-steroidal anti-inflammatory drug for clinical treatment of GA). Collectively, these findings provide experimental evidence supporting the potential applicability of PAE to treat gouty arthritis.
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Antiinflamatorios , Artritis Gotosa , Modelos Animales de Enfermedad , Extractos Vegetales , Plantago , Ratas Wistar , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Ratas , Plantago/química , Masculino , Artritis Gotosa/tratamiento farmacológico , Artritis Gotosa/inducido químicamente , Artritis Gotosa/patología , Antiinflamatorios/farmacología , Citocinas/metabolismo , Humanos , Glucósidos/farmacología , Glucósidos/administración & dosificación , Ácido Úrico/sangreRESUMEN
INTRODUCTION: Studies have indicated a link between stress during pregnancy and stress reactivity in offspring. In this study, we investigated the effect of Cuscuta epithymum (CE) extract on seizure and body weight in offspring born to stressed parents (pre-pregnancy). METHODS: Male and female rats were randomly separated into four groups. Then, the animals were subjected to restraint stress once a day for 50 (male) and 15 (female) continuous days. At the same time, rats in the control and stress groups received normal saline while the other two groups received the CE extract. After the stress induction, the control and experimental rats were mated to create eight types of coupling combinations as follows: McFc, McFs, MsFc, MsFs, McFc + EX, McFs + EX, MsFc + EX and MsFs + EX (M, male; F, female; C, control; S, stress; EX, extract). Then, the pups were weighed on postnatal days (PND) 1, 15 and 25. They were also evaluated for pentylenetetrazol (PTZ)-induced seizure on PND 25. RESULTS: The results showed that prolonged parental exposure to stress led to a significant increase in the duration and number of tonic-clonic (TC) seizures, duration of standing on two legs, firmly clinging to the ground, number of head nodding, total score of seizure behaviours and duration of tail rigidity in offspring. Moreover, the onset of the first convulsive behaviour was accelerated. Furthermore, a significantly lower body weight was observed in pre-conceptionally stressed offspring. However, the CE extract significantly improved these symptoms. CONCLUSION: It can be concluded that CE administration possibly improves the consequences of pre-pregnancy stress, as well as seizure behaviours and weight loss in pups.
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Peso Corporal , Extractos Vegetales , Efectos Tardíos de la Exposición Prenatal , Estrés Psicológico , Animales , Femenino , Masculino , Ratas , Peso Corporal/efectos de los fármacos , Embarazo , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Cuscuta , Ratas Wistar , Pentilenotetrazol , Animales Recién Nacidos , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Restricción FísicaRESUMEN
PURPOSE: Obesity and metabolic syndrome are acknowledged as key factors contributing to the development of non-alcoholic fatty liver disease (NAFLD). Vitamin D (VitD) is a multifaceted secosteroid hormone known for its anti-fibrotic and anti-inflammatory properties, with its deficiency often linked to obesity. Our study aimed to investigate whether VitD supplementation could mitigate the liver pathology associated with NAFLD. MATERIALS AND METHODS: The NAFLD model was developed by subjecting male C57BL/6 mice to a high-fat diet (HFD) for 14 weeks. These mice were supplemented with VitD through intraperitoneal injection at a dosage of 7 µg/kg, administered three times per week for 7 weeks. RESULTS: HFD resulted in VitD deficiency, insulin resistance, and increased liver weight. It elevated serum levels of liver aminotransferases and triglyceride, ultimately leading to steatohepatitis with fibrosis. This model exhibited increased levels of transforming growth factor (TGF)-ß1, pro-inflammatory cytokines, HNF4α transcription factors, reactive oxygen species (ROS), renin-angiotensin system activity, and epithelial-mesenchymal transitions (EMT) within the liver. Supplementation with VitD resulted in the recovery of liver weight, improvement in histologic features associated with steatohepatitis, and reduction in alanine aminotransferases and triglyceride levels induced by the HFD. Additionally, it mitigated the HFD-induced over-expressions of TGF-ß1 and fibrosis-related genes, along with pro-inflammatory cytokines and ROS. Notably, no adverse effect was found due to VitD supplementation in this model. CONCLUSION: VitD ameliorates steatohepatitis within obesity-induced NAFLD through its multifaceted pathways. VitD supplementation emerges as a potentially safe, cost-effective, and direct treatment approach for NAFLD patients dealing with obesity or metabolic dysfunction.
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Dieta Alta en Grasa , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Obesidad , Vitamina D , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Dieta Alta en Grasa/efectos adversos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Masculino , Ratones , Vitamina D/uso terapéutico , Vitamina D/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Resistencia a la Insulina , Especies Reactivas de Oxígeno/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
OBJECTIVE: Cervical spondylotic radiculopathy (CSR) is characterized by neuropathic pain (NP). Although the analgesic effect of electroacupuncture (EA) has been widely recognized in clinical practice, the mechanism of EA in the treatment of CSR remains unknown. We previously reported that 7 days of EA improved behavioral markers of NP, attenuated increases in α-synuclein, synapsin 1 and 2, postsynaptic density (PSD)-95 and growth-associated protein (GAP)-43, and improved ultrastructural changes within synapses in a rat model of CSR. Herein, we present supplemental data from the same cohort of animals examining the timing of behavioral improvement within the first week (through additional measurements at 3 and 5 days into the EA treatment) and new data on the effects of EA on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-d-aspartic acid receptor (NMDAR) levels. METHODS: As previously reported, the rats were divided into four groups at random: normal, sham, CSR and CSR + EA. EA at bilateral LI4 and LR3 was administered once a day for 7 days (20 min each) in the CSR + EA group after the CSR model was established by inserting a fishing line under the laminae. Behavioral assessments were carried out prior to initiation of EA and at 3, 5 and 7 days into the 7-day treatment course. Concentrations ofγ-aminobutyric acid (GABA) and glutamate (Glu) were determined using enzyme-linked immunosorbent assay and ultraviolet colorimetry, respectively, and AMPAR (glutamate receptor (GluR)1 and GluR2 membrane protein) expression was determined using Western blotting. Immunohistochemistry was used to detect the protein expression and average optical density (AOD) of NMDAR1 (NR1), NMDAR2A (NR2A) and NMDAR2B (NR2B). Quantitative reverse transcription-polymerase chain reaction was used to detect the mRNA expression of NR1, NR2A and NR2B. Transmission electron microscopy was used to observe changes in synaptic ultrastructure. RESULTS: EA significantly improved the pressure pain threshold (PPT) and mechanical withdrawal threshold (MWT) 5 days into the intervention, although effects were less pronounced than at 7 days (at completion of treatment). However, significant effects on gait scores were not seen prior to 7 days. As previously reported, EA also improved markers of synaptic ultrastructure. In the spinal cord, GluR1 membrane protein expression was decreased, GluR2 membrane protein expression was increased, and the GluR1/GluR2 ratio was decreased. Protein and mRNA expression of NR1, NR2A and NR2B was significantly decreased. GABA concentration was markedly increased, while Glu concentration was markedly decreased. CONCLUSION: Evidence of EA analgesia (higher PPT and MWT scores) was seen after 5 days of EA, while positive effects on motor function required 7 days of treatment. The underlying mechanism may be related to inhibition of AMPAR and NMDAR expression, regulation of the concentration of related neurotransmitters and improvement of spinal cord synaptic plasticity. This study establishes a preliminary theoretical foundation for the use of EA in the clinical treatment of CSR.
Asunto(s)
Electroacupuntura , Plasticidad Neuronal , Radiculopatía , Ratas Sprague-Dawley , Receptores AMPA , Receptores de N-Metil-D-Aspartato , Espondilosis , Animales , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores AMPA/metabolismo , Receptores AMPA/genética , Masculino , Ratas , Radiculopatía/terapia , Radiculopatía/metabolismo , Radiculopatía/fisiopatología , Espondilosis/terapia , Espondilosis/metabolismo , Modelos Animales de Enfermedad , Humanos , Analgesia , Neuralgia/terapia , Neuralgia/metabolismoRESUMEN
Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and tightly regulated by macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in their niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophic muscle. Here we demonstrate intrinsic deletion of transcription factor Yin Yang 1 (YY1) in MuSCs exacerbates dystrophic pathologies by altering composition and heterogeneity of MPs and FAPs. Further analysis reveals YY1 loss induces expression of immune genes in MuSCs, including C-C motif chemokine ligand 5 (Ccl5). Augmented CCL5 secretion promotes MP recruitment via CCL5/C-C chemokine receptor 5 (CCR5) crosstalk, which subsequently hinders FAP clearance through elevated Transforming growth factor-ß1 (TGFß1). Maraviroc-mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we demonstrate YY1 represses Ccl5 transcription by binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study demonstrates the critical role of MuSCs in actively shaping their niche and provides novel insight into the therapeutic intervention of muscle dystrophy.
Asunto(s)
Quimiocina CCL5 , Macrófagos , Músculo Esquelético , Distrofia Muscular de Duchenne , Factor de Transcripción YY1 , Animales , Factor de Transcripción YY1/metabolismo , Factor de Transcripción YY1/genética , Quimiocina CCL5/metabolismo , Quimiocina CCL5/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Ratones , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Macrófagos/metabolismo , Receptores CCR5/metabolismo , Receptores CCR5/genética , Ratones Endogámicos mdx , Nicho de Células Madre , Ratones Noqueados , Maraviroc/farmacología , Ratones Endogámicos C57BL , Masculino , Factor de Crecimiento Transformador beta1/metabolismo , Células Madre/metabolismo , Modelos Animales de EnfermedadRESUMEN
Alzheimer's disease (AD) is characterized by oxidative stress-mediated memory dysfunction and neuronal cell death. This study investigated the effects of an ethanol extract from Bauhinia coccinea (EEBC) on memory impairment and neuronal damage in a memory deficit mouse model. EEBC was administered to ICR mice at doses of 50, 100, or 200 mg/kg daily for 3 weeks. Cognitive impairment was induced via scopolamine (SCO) injection. Brain tissues were analyzed for acetylcholine (ACh) levels, acetylcholinesterase (AChE) activity, neuronal apoptosis, and antioxidant markers. Behavioral tests showed that SCO injection induced memory loss, whereas EEBC significantly ameliorated SCO-mediated memory impairment. EEBC regulated the cholinergic system by decreasing ACh levels and enhancing AChE activity. Nissl staining and immunohistochemistry for NeuN showed that EEBC exerted neuroprotective effects in SCO-injected mice brains. Moreover, EEBC significantly reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells increased by SCO treatment. EEBC also reversed the SCO-induced changes in apoptosis-related protein expression in brain tissues. Furthermore, EEBC significantly reduced malondialdehyde levels and activated catalase in SCO-administered brains. Quantitative RNA sequencing showed involvement of lipid metabolism in EEBC memory function regulation. Thus, EEBC is a promising candidate for attenuating AD progression as it targets the cholinergic system and neuronal apoptosis.
Asunto(s)
Antioxidantes , Apoptosis , Bauhinia , Trastornos de la Memoria , Ratones Endogámicos ICR , Extractos Vegetales , Escopolamina , Animales , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Extractos Vegetales/farmacología , Extractos Vegetales/química , Apoptosis/efectos de los fármacos , Ratones , Antioxidantes/farmacología , Masculino , Bauhinia/química , Estrés Oxidativo/efectos de los fármacos , Acetilcolinesterasa/metabolismo , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Acetilcolina/metabolismoRESUMEN
Improving gut dysbiosis and impaired gut-brain axis has been a potent therapeutic strategy for treating myocardial infarction (MI). Geniposide (GEN), a traditional Chinese medicine extract, has demonstrated substantial cardioprotective properties post-MI. Nevertheless, the effect of GEN on gut microbial, gut-brain communication, and its potential mechanism remains unclear. In this study, we initially found that GEN significantly alleviated MI-induced cardiac dysfunction from echocardiographic data and decreased myocardial fibrosis, inflammation, apoptosis and hypertrophy post-MI. Additionally, we investigated the effects of GEN on gut pathology, and observed that GEN led to a remarkable change in gut microbiota as evidenced by altering ß-diversity and short-chain fatty acids (SCFAs) levels, and alleviated intestinal damage indicated by reduced inflammation and barrier permeability post-MI. Finally, our investigation into brain pathology revealed that GEN induced a remarkable inhibition in PVN inflammation and sympathetic activity following MI. Collectively, these findings imply that the cardioprotective effects of GEN against MI were mediated possibly via an improvement in the impaired gut-brain axis. Mechanically, GEN-induced increase of microbiota-derived SCFAs might be the critical factor linking gut microbiota and reduced neuroinflammation with PVN, which leads to the suppression of sympathetic activation, therefore protecting the myocardium against MI-induced damage.
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Eje Cerebro-Intestino , Microbioma Gastrointestinal , Iridoides , Infarto del Miocardio , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Iridoides/farmacología , Masculino , Eje Cerebro-Intestino/efectos de los fármacos , Miocardio/metabolismo , Miocardio/patología , Ácidos Grasos Volátiles/metabolismo , Ratones , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Inflamación , Apoptosis/efectos de los fármacos , Disbiosis , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patologíaRESUMEN
Previous research has identified a variety of factors that contribute to the development and maintenance of wounds. Concurrently, electroacupuncture has been demonstrated to facilitate wound healing. However, the effects of transcutaneous electrical acustimulation (TEA) on wound healing, as well as its relationship with key factors such as Wnt3a, TGF-ß, Akt, c-Myc, VEGF-A, SP1, nitric oxide (NO), and mitochondrial function, remain largely unexplored. We hypothesize that TEA will activate the signaling factors and enhance mitochondrial functions to promote the repair of skin wounds in mice. An in vivo experimental study was conducted utilizing mouse models with skin wounds. The study comprised three groups: a TEA treatment with wound group, a skin wound model group, and a control group. Wound areas were measured by calculating the product of the length and width of each wound using calipers. Single-cell suspensions were prepared by excising the wound and the immediately surrounding tissue. These suspensions were stained with Trypan blue to assess cell viability, with specific probes to measure the rate of reactive oxygen species (ROS) positivity, and with reagents to quantify NO content. Western blotting (WB) was employed to evaluate protein levels associated with tissue changes, while quantitative polymerase chain reaction (qPCR) was used to assess RNA expression levels. Immunofluorescence staining was performed to visualize protein content and other relevant cellular structures within tissue sections. TEA exhibited anti-inflammatory properties and promoted wound healing in mice. Western blot analysis revealed that TEA enhanced the expression of proteins associated with Wnt3a, TGF-ß, Akt, c-Myc, VEGF-A, and SP1 during the wound healing process. Immunofluorescence staining of tissue sections indicated that TEA upregulated the expression of COL1A1, MFN1, GRP75, GRP78, GRP75/ROS, GRP78/ROS, ISCU, and UCP1 while downregulating FIS1. Additionally, qPCR results demonstrated that TEA promoted the expression of IL-10 and miRNA205-5p while inhibiting MMP9 levels. TEA modulates various signaling molecules, influences chaperone proteins related to stress recovery responses, along with mitochondrial dynamics and metabolism.
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Mitocondrias , Especies Reactivas de Oxígeno , Transducción de Señal , Piel , Proteína Wnt3A , Cicatrización de Heridas , Animales , Ratones , Mitocondrias/metabolismo , Piel/patología , Piel/metabolismo , Piel/lesiones , Especies Reactivas de Oxígeno/metabolismo , Proteína Wnt3A/metabolismo , Proteína Wnt3A/genética , Modelos Animales de Enfermedad , Óxido Nítrico/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Factor de Crecimiento Transformador beta/metabolismo , Estimulación Eléctrica Transcutánea del Nervio/métodos , Proteínas Proto-Oncogénicas c-mycRESUMEN
The purpose of this research was to evaluate the therapeutics effects of photobiomodulation and high intensity laser therapy after a sciatic nerve crush injury. Following the crush injuries of sciatic nerve, 33 rats were randomly divided into three groups. The injured sciatic nerves of the rats in the control group were left to heal spontaneously, whereas HILT (120 J/session and 1064 nm) and photobiomodulation therapy (PBM) (2.4 J/session and 650 nm) were started immediately after surgery and performed once every 3 days (10 session in total) during the postoperative period. Electrophysiological evaluations were conducted before surgery and at the end of the healing period. The Sciatic Functional Index (SFI) was assessed before surgery and at the end of the healing period. The ratio of the inner axonal diameter to the total outer axonal diameter (g-ratio) and schwann cells per square micrometer were histomorphometrically evaluated. At the end of the 30-day healing period, significantly better SFI scores were noted in the HILT group compared with PBM (p=0.002) and control (p < 0.001) groups. HILT exhibited positive effects on latency and duration values when compared PBM (p=0.002, p=0.014) and control (p=0.003, p < 0.001) groups. The number of nerves with an optimum g-ratio was higher in the HILT group which indicates a better rate of myelination. Functional, histomorphometric, and electrophysiological investigations of the present study revealed that HILT seems to be a superior treatment modality for peripheral nerve regeneration.
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Lesiones por Aplastamiento , Terapia por Luz de Baja Intensidad , Regeneración Nerviosa , Nervio Ciático , Animales , Terapia por Luz de Baja Intensidad/métodos , Regeneración Nerviosa/efectos de la radiación , Nervio Ciático/lesiones , Nervio Ciático/efectos de la radiación , Ratas , Lesiones por Aplastamiento/radioterapia , Lesiones por Aplastamiento/terapia , Masculino , Ratas Wistar , Axones/efectos de la radiación , Axones/fisiología , Modelos Animales de Enfermedad , Compresión NerviosaRESUMEN
Spinal cord injury (SCI), characterized by the disruption of neural pathways and an increase in inflammatory cell infiltration, leads to profound and lasting neurological deficits, with a high risk of resulting in permanent disability. Currently, the therapeutic landscape for SCI is notably sparse, with limited effective treatment options available. Methylprednisolone (MP), a widely used clinical anti-inflammatory agent for SCI, requires administration in high doses that are associated with significant adverse effects. In this study, we introduce an innovative approach by substituting cholesterol with MP to engineer a novel Lipid Nanoparticle (MP-LNP). This strategy aims to enhance the localization and concentration of MP at the injury site, thereby amplifying its therapeutic efficacy while mitigating systemic side effects. Furthermore, we explore the integration of C3 transferase mRNA into MP-LNPs. C3 transferase, a potent inhibitor of the RhoA pathway, has shown promise in facilitating neurological recovery in animal models of SCI and is currently being evaluated in clinical trials. The novel formulation, MP-LNP-C3, is designed for direct administration to the injury site during decompression surgery, offering a targeted therapeutic modality for SCI. Our findings reveal several significant advantages of this approach: Firstly, the incorporation of C3 transferase mRNA into MP-LNPs does not compromise the structural integrity of the nanoparticles, ensuring efficient mRNA expression within the spinal cord. Secondly, the MP-LNP formulation effectively attenuates inflammation and reduces the adverse effects associated with high-dose MP treatment in the acute phase of SCI. Lastly, MP-LNP-C3 demonstrates notable neuroprotective properties and promotes enhanced recovery of motor function in SCI mouse models. Together, these results underscore the potential of this innovative LNP-based therapy as a promising avenue for advancing the treatment of clinical SCI.
Asunto(s)
Metilprednisolona , Nanopartículas , ARN Mensajero , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/terapia , Animales , Metilprednisolona/farmacología , Metilprednisolona/uso terapéutico , Nanopartículas/química , ARN Mensajero/metabolismo , ARN Mensajero/genética , Ratones , Liposomas/química , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Femenino , Médula Espinal/metabolismo , Médula Espinal/efectos de los fármacos , Lípidos/química , Toxinas Botulínicas , ADP Ribosa TransferasasRESUMEN
OBJECTIVE: Our previous study found that astrocytes are involved in cumulative analgesia; however, the underlying mechanism remains unclear. The aim of this study was to further explore the potential role of astrocytes in the effects of electroacupuncture (EA) on neuropathic pain by focusing on the glutamate-glutamine cycle. METHODS: 69 male Sprague-Dawley (SD) rats were randomly divided into a normal control group, untreated chronic constriction injury (CCI) model group and EA-treated model (CCI + EA) group. EA was applied bilaterally at ST36 and GB34. Pain thresholds were assessed using behavioral tests and thermal stimuli. We examined the co-expression of glutamate/aspartate transporter (GLAST) via immunofluorescence and measured the expression levels of GLAST, glutamate transporter (GLT)-1 and glutamine synthetase (GS) using Western blotting and polymerase chain reaction (PCR). Glutamate (Glu) and gamma-aminobutyric acid (GABA) levels were detected by high-performance liquid chromatography (HPLC). To validate the impact of GLAST/GLT-1 in the analgesic effect of EA, an additional 30 SD male rats were divided into groups receiving intrathecal saline, GLAST antagonist or GLT-1 antagonist alongside EA. RESULTS: Post-CCI, pain thresholds were decreased, GLAST expression was diminished, and spinal Glu levels were increased. EA treatment reversed these effects, improved pain thresholds and GLAST/GLT-1 expression in astrocytes, and reduced Glu levels. Antagonist administration negated the analgesic effects of EA. CONCLUSION: Repeated EA administration inhibited CCI-induced chronic neuropathic pain in rats, corresponding to a reversal of decreased expression of GLAST and GLT-1, which may have accelerated the clearance of Glu and thereby reduced its concentration. Regulation of the astroglial glutamate-glutamine cycle is a potential target of EA.
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Astrocitos , Electroacupuntura , Ácido Glutámico , Glutamina , Neuralgia , Ratas Sprague-Dawley , Animales , Masculino , Neuralgia/terapia , Neuralgia/metabolismo , Neuralgia/genética , Astrocitos/metabolismo , Ácido Glutámico/metabolismo , Ratas , Glutamina/metabolismo , Modelos Animales de Enfermedad , Humanos , Analgesia por Acupuntura , Transportador 2 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Umbral del Dolor , Puntos de AcupunturaRESUMEN
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that gradually destroys cognitive, memory, and thinking skills. Although increasing evidence has demonstrated that Ganoderma lucidum triterpenoids (GLT) can ameliorate the motor and spatial learning disorders of AD, the underlying mechanism remains unclear. Hence, in this study, GLT were obtained by using a traditional Chinese medicine processing method, and then the effects of GLT on motor and spatial learning disorders in 5xFAD mice were investigated by using various techniques such as behavioral analysis, micro-dialysis, and neurophysiological recording. Compared with the 5xFAD group, 0.5 g/kg GLT could decrease escape latency, the total number of limb errors, and the duration of errors. This dose could also increase the number of crossing the original platform, the total movement time, and the distance in the central region of the open-field box, as well as the maximum movement speed and continuous movement time on the rotating rod. After GLT treatment, the glutamate (Glu) content and variation coefficient of a simple spike of Purkinje cells decreased compared with the 5xFAD group, thereby improving the spatial learning and memory ability. Overall, this study shows that GLT may be a potential therapeutic method for patients with AD.
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Enfermedad de Alzheimer , Reishi , Triterpenos , Animales , Triterpenos/farmacología , Ratones , Reishi/química , Enfermedad de Alzheimer/tratamiento farmacológico , Aprendizaje Espacial/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Memoria/efectos de los fármacosRESUMEN
Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson's disease (PD), α-synuclein (α-syn), as an example of protein aggregates, we find that aspirin is able to reduce α-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the α-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.
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Aspirina , Lisina , Enfermedad de Parkinson , Complejo de la Endopetidasa Proteasomal , Proteolisis , Ubiquitinación , alfa-Sinucleína , Aspirina/farmacología , alfa-Sinucleína/metabolismo , Animales , Ubiquitinación/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Ratones , Humanos , Lisina/metabolismo , Proteolisis/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Modelos Animales de Enfermedad , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Ratones Endogámicos C57BL , Masculino , Agregado de Proteínas/efectos de los fármacos , Lisosomas/metabolismo , Lisosomas/efectos de los fármacosRESUMEN
Jiawei Chaihu Shugan decoction (JWCHSGD) is a traditional Chinese medicine well-known for its beneficial effects in treating epilepsy (Xianzheng in ancient Chinese), but the molecular mechanism of its action remains unclear. To investigate the molecular mechanism of JWCHSGD's prevention of epilepsy-mediated neuron from necroptosis and inflammation via the circRNA-Csnk1g3/Csnk1g3-85aa/ CK1γ3/TNF-α signal pathway. In vitro, murine neuronal HT22 cells were treated in six groups: control, model, carbamazepine, and three JWCHSGD doses (high, medium, low). Viability and apoptosis were assessed via CCK-8 and flow cytometry. In vivo, 60 C57BL/6J mice were divided into six groups: control, model, carbamazepine, JWCHSGD, JWCHSGD + Sh Circ_Csnk1g3, and JWCHSGD + Sh NC. An epilepsy model was induced, and treatments were administered for two weeks. Outcomes included EEG, hippocampal histopathology, apoptosis (TUNEL), and mRNA/protein expression of key pathway markers. In HT22 cells, the model group showed reduced viability, increased apoptosis, and elevated mRNA/protein levels of Csnk1g3-85aa, RIP1, RIP3, MLKL, TNF-α, IL-6, and IL-1ß (P < 0.05). JWCHSGD and carbamazepine increased viability and decreased apoptosis, reversing these molecular changes (P < 0.05). In mice, the model group had heightened epileptic discharges, neuronal damage, and apoptosis, along with increased expression of the same markers (P < 0.05). JWCHSGD and carbamazepine mitigated these effects (P < 0.05). JWCHSGD reduces epileptic events by regulating the circRNA-Csnk1g3/Csnk1g3-85aa/CK1γ3/TNF-α signaling pathway, impacting necroptosis and inflammation in hippocampal neurons and HT22 cells.
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Medicamentos Herbarios Chinos , Epilepsia , Hipocampo , Necroptosis , Neuronas , Animales , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Epilepsia/tratamiento farmacológico , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Medicamentos Herbarios Chinos/farmacología , Necroptosis/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/patología , Ratones Endogámicos C57BL , Masculino , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Línea Celular , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
CONTEXT: Modified Xiao-Qing-Long-decoction (MXQLD) is believed to have the potential to alleviate lung diseases. OBJECTIVE: We explored the effects and mechanisms of MXQLD in acute respiratory distress syndrome (ARDS). MATERIALS AND METHODS: Thirty male C57BL/6 mice were randomized into sham (distilled water), model (distilled water), MXQLD (1 g/kg MXQLD), DEX (distilled water + 0.7 mg/kg dexamethasone), MXQLD + oe-HDAC7 (HDAC7 over-expression + 1 g/kg MXQLD) groups. Except for HDAC7 over-expression on day 0 and dexamethasone injection on day 12, all treatments were administered every two days from day 0 to day 10. On day 12, except for the sham group, all mice underwent cecal ligation and puncture surgery to establish ARDS models. After surgery, pulmonary functions, protein concentration of bronchoalveolar lavage fluid (BALF) and lung tissue morphology in mice were detected. Furthermore, pro-inflammatory cytokine concentrations (IL-6, IL-1ß, and TNF-α) in BALF supernatant and serum were quantified. Additionally, HDAC7, Nur77, ZO-1, occludin, and claudin protein expressions were detected. RESULTS: MXQLD treatment improved pulmonary functions and alleviated lung injury for ARDS mice. Furthermore, MXQLD treatment decreased protein concentration in BALF, and inhibited pro-inflammatory cytokine release in BALF supernatant and serum for ARDS mice. Additionally, MXQLD treatment down-regulated HDAC7 expression, but up-regulated Nur77, ZO-1, occludin, and claudin expressions for ARDS mice. Importantly, the preventive effects of MXQLD in ARDS mice were reversed by HDAC7 over-expression. DISCUSSION AND CONCLUSION: MXQLD may prevent inflammation and promote Nur77 expression in ARDS by inhibiting HDAC7 expression, indicating that MXQLD may be a promising drug for preventing ARDS.
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Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Histona Desacetilasas , Inflamación , Ratones Endogámicos C57BL , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Síndrome de Dificultad Respiratoria , Animales , Masculino , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Ratones , Histona Desacetilasas/metabolismo , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Líquido del Lavado Bronquioalveolar , Citocinas/metabolismo , Antiinflamatorios/farmacología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismoRESUMEN
Aspiration pneumonia is a serious respiratory condition, which is particularly prevalent in patients with dysphagia, neurological disorders, or those undergoing surgical interventions. The formation of multispecies biofilms in the oral cavity, involving the bacterial periodontopathogen Porphyromonas gingivalis and the opportunistic pathogenic fungus Candida albicans, may also be related to the development of this serious disease, contributing also to the resistance to standard antimicrobial treatment. Therefore, this research aimed to evaluate the efficacy of selected antibioticsâlevofloxacin, metronidazole, meropenem, vancomycinâand antifungal agentsâamphotericin B, caspofungin, and fluconazoleâon these mixed biofilms in the aspiration pneumonia model. While metronidazole and levofloxacin effectively inhibited bacterial viability in the mixed biofilms, lower doses increased release of bacterial proteases. In the conditions of mixed biofilms meropenem and vancomycin showed reduced efficacy, requiring significantly higher doses to achieve similar effect in mixed biofilms as in single bacterial cultures. Treatment with antifungals revealed that amphotericin B significantly impacted fungal cell viability within mixed biofilms, and this effect was enhanced when the antifungal drug was applied in the presence of P. gingivalis. Caspofungin and fluconazole showed variable efficacy, with caspofungin being more effective against C. albicans cells within biofilm.These findings indicated that due to the mutual microbial protection in the mixed-species biofilm, P. gingivalis retained its virulence despite increasing antibiotic doses. However, no excessive benefit of mixed biofilms was observed for C. albicans in the presence of antifungals, indicating the minor importance of yeasts in aspiration pneumonia development and their protective role for other pathogens in mixed-species infection.
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Biopelículas , Candida albicans , Neumonía por Aspiración , Porphyromonas gingivalis , Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candida albicans/fisiología , Porphyromonas gingivalis/efectos de los fármacos , Neumonía por Aspiración/tratamiento farmacológico , Neumonía por Aspiración/microbiología , Células Epiteliales/microbiología , Animales , Humanos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Modelos Animales de Enfermedad , Viabilidad Microbiana/efectos de los fármacos , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Pruebas de Sensibilidad Microbiana , Candidiasis/tratamiento farmacológico , Candidiasis/microbiologíaRESUMEN
Chronic kidney disease (CKD) is a major health concern, with renal interstitial fibrosis (RIF) as a key feature. Effective management of RIF is crucial for treating CKD. Yiqi Juanshen decoction (YQJSD), as traditional Chinese medicine, has shown promising results in CKD treatment. This study evaluates YQJSD's effectiveness in ameliorating RIF and explores the underlying molecular mechanisms using the unilateral ureteral obstruction (UUO) model. YQJSD has been shown to effectively reduce serum creatinine and blood urea nitrogen levels, decrease extracellular matrix deposition, and down-regulate the expression of α-SMA, COL4α1, Fibronectin (FN). Mechanistically, YQJSD exerts its effects by modulating multiple pathways: it inhibits the NF-κB signaling pathway, inhibiting the expression of pro-inflammatory cytokines like NF-κB1, IL-1ß, TNF-α, and CCR1. Simultaneously, YQJSD suppresses the epithelial-mesenchymal transition (EMT) by downregulating the expression of Snail1, Vimentin, Twist1, and FSP1, while increasing E-cadherin expression. Moreover, YQJSD can regulate the PI3K/AKT signaling pathway by decreasing the expression of LOXL2 and PIK3R1, along with p-AKT1/2/3. This modulation of the LOXL2/PI3K/AKT pathway contributes to the inhibition of both EMT and inflammation, highlighting a critical role in the therapeutic intervention against RIF. These findings suggest that YQJSD may serve as a promising therapeutic management of RIF in CKD patients.
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Medicamentos Herbarios Chinos , Transición Epitelial-Mesenquimal , Fibrosis , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Transición Epitelial-Mesenquimal/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Masculino , Aminoácido Oxidorreductasas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Riñón/metabolismo , Riñón/patología , Riñón/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Ratones , Modelos Animales de Enfermedad , Obstrucción Ureteral/tratamiento farmacológico , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patología , Obstrucción Ureteral/complicacionesRESUMEN
OBJECTIVE: The primary objective of this study was to elucidate the underlying pharmacological mechanisms by which Jingui Shenqi Wan (JGSQW) alleviates postmenopausal osteoporosis (PMOP). Through a systematic investigation, we sought to identify the specific molecular pathways through which JGSQW modulates the progression of PMOP, thereby providing a scientific basis for its clinical application. METHODS: We established an ovariectomized (OVX) mouse model to simulate estrogen deficiency-induced PMOP. Initially, micro-CT imaging and Alcian blue hematoxylin/orange G (ABH/OG) staining were employed to assess the effects of JGSQW on bone microarchitecture and bone mass preservation. Immunohistochemistry (IHC) was then utilized to evaluate the expression of osteogenic markers, including Osterix (OSX), Runx2, and Osteopontin (OPN). Additionally, Tartrate - Resistant Acid Phosphatase (TRAP) staining was performed to visualize and quantify osteoclasts. We further investigated the potential role of JGSQW in modulating the pyroptosis pathway. RESULTS: JGSQW effectively alleviates the destruction of bone microstructure and the loss of bone mass caused by estrogen deficiency, an effect that appears to be mediated by promoting osteogenesis. Additionally, JGSQW significantly downregulates the expression of GSDMD in osteoblasts and mitigates the abnormal release of inflammatory factors, thereby maintaining the normal functional activities of osteoblasts. CONCLUSION: JGSQW may effectively mitigate the progression of estrogen deficiency-induced PMOP by inhibiting the dysregulated activation of osteoblast pyroptosis.