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Angiostrongylus cantonensis, a zoonotic parasite, can invade the human central nervous system (CNS) and cause acute eosinophilic meningitis or eosinophilic meningoencephalitis. Mice infected with A. cantonensis show elevated levels of pro-inflammatory cytokines, plasminogen activators, and matrix metalloproteinase-9, resulting in disruption of the blood-brain barrier (BBB) and immune cell infiltration into the CNS. Caveolin-1 (Cav-1) regulates the permeability of the BBB, which affects immune cells and cerebrospinal fluid. This intricate interaction ultimately fuels the progression of brain damage and edema. This study aims to investigate the regulatory role of Cav-1 in the pathogenesis of meningoencephalitis induced by A. cantonensis infection. We investigated pathological alterations by triphenyl-tetrazolium chloride, brain water content, BBB permeability, Western blot analysis, and gelatin zymography in BALB/c mice after A. cantonensis. The study evaluates the critical role of Cav-1 regulation through the TLR4/MyD88 signaling pathway, modulates tight junction proteins, influences BBB permeability, and contributes to brain damage in A. cantonensis-induced meningoencephalitis.
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Heat shock proteins (HSPs), which function as chaperones, are activated in response to various environmental stressors. In addition to their role in diverse aspects of protein production, HSPs protect against harmful protein-related stressors. Calycosin exhibits numerous beneficial properties. This study aims to explore the protective effects of calycosin in the heart under heat shock and determine its underlying mechanism. H9c2 cells, western blot, TUNEL staining, flow cytometry, and immunofluorescence staining were used. The time-dependent effects of heat shock analyzed using western blot revealed increased HSP expression for up to 2[Formula: see text]h, followed by protein degradation after 4[Formula: see text]h. Hence, a heat shock damage duration of 4[Formula: see text]h was chosen for subsequent investigations. Calycosin administered post-heat shock demonstrated dose-dependent recovery of cell viability. Under heat shock conditions, calycosin prevented the apoptosis of H9c2 cells by upregulating HSPs, suppressing p-JNK, enhancing Bcl-2 activation, and inhibiting cleaved caspase 3. Calycosin also inhibited Fas/FasL expression and activated cell survival markers (p-PI3K, p-ERK, p-Akt), indicating their cytoprotective properties through PI3K/Akt activation and JNK inhibition. TUNEL staining and flow cytometry confirmed that calycosin reduced apoptosis. Moreover, calycosin reversed the inhibitory effects of quercetin on HSF1 and Hsp70 expression, illustrating its role in enhancing Hsp70 expression through HSF1 activation during heat shock. Immunofluorescence staining demonstrated HSF1 translocation to the nucleus following calycosin treatment, emphasizing its cytoprotective effects. In conclusion, calycosin exhibits pronounced protective effects against heat shock-induced damages by modulating HSP expression and regulating key signaling pathways to promote cell survival in H9c2 cells.
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Apoptosis , Supervivencia Celular , Proteínas de Choque Térmico , Isoflavonas , Apoptosis/efectos de los fármacos , Isoflavonas/farmacología , Supervivencia Celular/efectos de los fármacos , Animales , Ratas , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/genética , Respuesta al Choque Térmico/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Línea Celular , Células Cultivadas , Caspasa 3/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Lung cancer is the most common malignant cancer worldwide. Combination therapies are urgently needed to increase patient survival. Calycosin is a phytoestrogen isoflavone that has been reported previously to inhibit tumor cell growth, although its effects on lung cancer remain unclear. The aim of this study was to investigate the effects of calycosin on cell proliferation and apoptosis of gemcitabine-resistant lung cancer cells. Using calycosin to treat human lung cancer cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0 GEMR) and examine the effects on the cells. Cultured human lung cancer cells (CL1-0) and gemcitabine-resistant lung cancer cells (CL1-0 GEMR) were treated with increasing concentrations of calycosin. Cell viability and apoptosis were studied by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide, flow cytometry, and TUNEL assays. Western blots were used to measure the expression levels of proliferation-related proteins and cancer stem cell proteins in CL1-0 GEMR cells. The results showed that calycosin treatment inhibited cell proliferation, decreased cell migration ability, and suppressed cancer stem cell properties in CL1-0 GEMR cells. Interestingly, in CL1-0 GEMR cells, calycosin treatment not only increased LDOC1 but also decreased GNL3L/NFκB protein levels and mRNA levels, in concentration-dependent manners. We speculate that calycosin inhibited cell proliferation of the gemcitabine-resistant cell line through regulating the LDOC1/GNL3L/NFκB pathway.
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Isoflavonas , Neoplasias Pulmonares , Humanos , Gemcitabina , Neoplasias Pulmonares/tratamiento farmacológico , Línea Celular Tumoral , FN-kappa B , Isoflavonas/farmacología , Proliferación Celular , Apoptosis , Proteínas Nucleares/farmacología , Proteínas Supresoras de Tumor/farmacología , Proteínas de Unión al GTP/farmacologíaRESUMEN
Fibroblast-like synoviocytes accumulation, proliferation and activation, and the subsequent inflammatory mediators production play a key role in the progression of rheumatoid arthritis (RA). It is well established that Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling triggers inflammation, and induces cytokine levels in RA. Ohwia caudata have long been used against many disorders. However, in RA, the effects of O. caudata have not been elucidated. In the current study, synoviocytes were used to evaluate the suppressive effects of O. caudate extract (OCE) on the pro-inflammatory cytokines production. In vitro, the underlying mechanisms by which OCE inhibits inflammatory response through regulation of suppressors of cytokine signaling 3 (SOCS3) and JAK2/STAT3 expression in IL-17A-treated HIG-82 synoviocytes were investigated. The results demonstrated that the proliferation of IL-17A-challenged cells were increased in comparison with non-stimulated control cells. The synoviocyte proliferation was decreased significantly of OCE concentrations in dose dependent manner. The p-JAK2, p-STAT3, interleukin (IL)-1ß, and IL-6 were reduced in IL-17A-challenged cells treated with OCE. Furthermore, AZD1480 (a JAK2-specific inhibitor) or WP1066 (a STAT3-specific inhibitor) affected the inflammatory mediators production in IL-17A-challenged synoviocytes, and OCE failed to mitigate the IL-17A-induced inflammatory mediators and SOCS3, acting as a feedback inhibitor of the JAK/STAT3 pathway, in the presence of SOCS3 siRNA, indicating that the beneficial effects of OCE on the regulation of inflammatory response homeostasis were dependent on SOCS3 and the JAK2/STAT3 signaling pathway. Our study also showed that SOCS3 was markedly activated by OCE in RA fibroblast-like synoviocytes, thereby decreasing the JAK/STAT3 pathway, and the IL-1ß, and IL-6 activation. Thus, O. caudate should be further investigated as a candidate anti-inflammatory and anti-arthritic agent.
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Artritis Reumatoide , Sinoviocitos , Humanos , Sinoviocitos/metabolismo , Janus Quinasa 2/metabolismo , Factor de Transcripción STAT3/metabolismo , Interleucina-6/metabolismo , Interleucina-17/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/metabolismoRESUMEN
Coronavirus disease 2019 (COVID-19) is a worldwide health threat that has long-term effects on the patients and there is currently no efficient cure prescribed for the treatment and the prolonging effects. Traditional Chinese medicines (TCMs) have been reported to exert therapeutic effect against COVID-19. In this study, the therapeutic effects of Jing Si herbal tea (JSHT) against COVID-19 infection and associated long-term effects were evaluated in different in vitro and in vivo models. The anti-inflammatory effects of JSHT were studied in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells and in Omicron pseudotyped virus-induced acute lung injury model. The effect of JSHT on cellular stress was determined in HK-2 proximal tubular cells and H9c2 cardiomyoblasts. The therapeutic benefits of JSHT on anhedonia and depression symptoms associated with long COVID were evaluated in mice models for unpredictable chronic mild stress (UCMS). JSHT inhibited the NF-ÆB activities, and significantly reduced LPS-induced expression of TNFα, COX-2, NLRP3 inflammasome, and HMGB1. JSHT was also found to significantly suppress the production of NO by reducing iNOS expression in LPS-stimulated RAW 264.7 cells. Further, the protective effects of JSHT on lung tissue were confirmed based on mitigation of lung injury, repression in TMRRSS2 and HMGB-1 expression and reduction of cytokine storm in the Omicron pseudotyped virus-induced acute lung injury model. JSHT treatment in UCMS models also relieved chronic stress and combated depression symptoms. The results therefore show that JSHT attenuates the cytokine storm by repressing NF-κB cascades and provides the protective functions against symptoms associated with long COVID-19 infection.
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Lesión Pulmonar Aguda , COVID-19 , Ratones , Humanos , Animales , Síndrome Post Agudo de COVID-19 , Lipopolisacáridos/efectos adversos , Síndrome de Liberación de Citoquinas , Citocinas/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lesión Pulmonar Aguda/metabolismo , FN-kappa B/metabolismoRESUMEN
Angiostrongylus cantonensis causes a form of parasitic meningitis in humans. Albendazole (ABZ) kills nematode larvae in the brain. However, dead larvae can trigger a severe inflammatory response, resulting in brain damage. Accumulating evidence suggests that calycosin represents a potential anti-inflammatory therapeutic candidate. In this study, we investigated the combined effects of ABZ and calycosin in angiostrongyliasis caused by A. cantonensis in BALB/c mice. Inflammatory mediators (such as phospho-nuclear factor-κB, cyclooxygenase-2, matrix metalloproteinase-9, tumour necrosis factor-α and interleukin-1ß) are associated with the development of meningitis and immune inflammatory reactions. We found that A. cantonensis significantly induces inflammatory mediator production and increases the bloodbrain barrier (BBB) permeability. However, co-administration of both ABZ and calycosin markedly suppressed meningitis and inflammatory mediator production and decreased the BBB permeability compared to treatment with a single drug. Furthermore, calycosin and ABZ plus calycosin treatment facilitated production of the antioxidant haem oxygenase-1 (HO-1). Moreover, co-therapy with ABZ and calycosin failed to mitigate angiostrongyliasis in the presence of tin-protoporphyrin IX, an HO-1-specific inhibitor. This finding suggests that the beneficial effects of ABZ plus calycosin treatment on the regulation of inflammation are mediated by the modulation of HO-1 activation. The present results provide new insights into the treatment of human angiostrongyliasis using co-therapy with ABZ and calycosin.
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Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease that results in joint destruction and disability in the adult population. RA is characterized by the accumulation and proliferation of fibroblast-like synoviocytes. Many pro-inflammatory mediators are associated with RA, such as interleukin (IL)-1ß, IL-6, IL-17, cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB). Furthermore, IL-17 upregulates the production of other pro-inflammatory mediators, including IL-1ß and IL-6, and promotes the recruitment of neutrophils in RA. Artemisia argyi, a traditional Chinese herbal medicine, is used for the treatment of diseases associated with inflammation and microbial infections. In this study, synoviocytes (HIG-82) were treated with varying doses of A. argyi extract (AAE) following IL-17A stimulation. Proliferation of the IL-17A-stimulated cells was increased compared to that of the non-stimulated control cells. However, cell proliferation decreased significantly in a dose-dependent manner following AAE treatment. Treatment of IL-17A-stimulated cells with AAE resulted in decreased levels of phosphorylated (p)-NF-κB, p-IκB-α, and COX-2. Enzyme-linked immunosorbent assay results showed that IL-1ß and IL-6 levels were increased in the IL-17A-stimulated group but decreased in the AAE treatment group. Additionally, we found that AAE facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and promoted its nuclear translocation, thereby inducing the expression of heme oxygenase-1. Moreover, AAE did not attenuate IL-17A-induced inflammatory mediator production in the presence of ML385, an Nrf2-specific inhibitor. These results suggest that the downregulation of expression of pro-inflammatory cytokines and the transcription factor NF-κB by AAE may be a potential therapeutic strategy for reducing inflammation associated with RA.
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Artemisia , Artritis Reumatoide , Medicamentos Herbarios Chinos , Sinoviocitos , Artemisia/metabolismo , Artritis Reumatoide/metabolismo , Células Cultivadas , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Medicamentos Herbarios Chinos/uso terapéutico , Fibroblastos/metabolismo , Hemo-Oxigenasa 1/metabolismo , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , FN-kappa B/metabolismo , Sinoviocitos/metabolismoRESUMEN
Diabetic neuropathy is a common complication of diabetes mellitus, posing a challenge in treatment. Previous studies have indicated the protective role of mesenchymal stem cells against several disorders. Although they can repair nerve injury, their key limitation is that they reduce viability under stress conditions. We recently observed that overactivation of the carboxyl terminus of heat shock protein 70 (Hsp70) interacting protein (CHIP) considerably rescued cell viability under hyperglycemic stress and played an essential role in promoting the beneficial effects of Wharton's jelly-derived mesenchymal stem cells (WJMSCs). Thus, the present study was designed to unveil the protective effects of CHIP-overexpressing WJMSCs against neurodegeneration using in vivo animal model based study. In this study, western blotting observed that CHIP-overexpressing WJMSCs could rescue nerve damage observed in streptozotocin-induced diabetic rats by activating the AMPKα/AKT and PGC1α/SIRT1 signaling pathway. In contrast, these signaling pathways were downregulated upon silencing CHIP. Furthermore, CHIP-overexpressing WJMSCs inhibited inflammation induced in the brains of diabetic rats by suppressing the NF-κB, its downstream iNOS and cytokines signaling nexus and enhancing the antioxidant enzyme system. Moreover, TUNEL assay demonstrated that CHIP carrying WJMSCs suppressed the apoptotic cell death induced in STZ-induced diabetic group. Collectively, our findings suggests that CHIP-overexpressing WJMSCs might exerts beneficial effects, which may be considered as a therapeutic strategy against diabetic neuropathy complications.
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Diabetes Mellitus Experimental , Neuropatías Diabéticas , Células Madre Mesenquimatosas , Gelatina de Wharton , Animales , Diferenciación Celular , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/prevención & control , Ratas , Estreptozocina/metabolismo , Estreptozocina/farmacologíaRESUMEN
Some clinical studies have indicated the patients with Alzheimer's disease (AD) display an increased risk of cardiovascular disease (CVD). Here, to examine the relationship between AD and CVDs, we investigated the changes in heart function in triple-transgenic late-stage AD model mice (3× Tg-AD; APPSwe, PS1M146V, and tauP301L). We fed the AD mice folic acid (FA) or folinic acid (FN) and analyzed the protective effects of the compounds on the heart; specifically, 20-month-old triple-transgenic AD mice, weighing 34-55 g, were randomly allocated into three groups-the AD, AD + FA, and AD + FN groups-and subject to gastric feeding with FA or FN once daily at 12 mg/kg body weight (BW) for 3 months. Mouse BWs were assessed throughout the trial, at the end of which the animals were sacrificed using carbon dioxide suffocation. We found that BW, whole-heart weight, and left-ventricle weight were reduced in the AD + FA and AD + FN groups as compared with the measurements in the AD group. Furthermore, western blotting of excised heart tissue revealed that the levels of the hypertrophy-related protein markers phospho(p)-p38 and p-c-Jun were markedly decreased in the AD + FA group, whereas p-GATA4, and ANP were strongly reduced in the AD + FN group. Moreover, the fibrosis-related proteins uPA, MMP-2, MEK1/2 and SP-1 were decreased in the heart in both AD + FN group. In summary, our results indicate that FA and FN can exert anti-cardiac hypertrophy and fibrosis effects to protect the heart in aged triple-transgenic AD model mice, particular in FN.
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Enfermedad de Alzheimer , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Cardiomegalia , Modelos Animales de Enfermedad , Fibrosis , Ácido Fólico/farmacología , Ácido Fólico/uso terapéutico , Humanos , Leucovorina , Ratones , Ratones TransgénicosRESUMEN
Oxidative stress-induced brain cell damage is a crucial factor in the pathogenesis of reactive oxygen species (ROS)-associated neurological diseases. Further, studies show that astrocytes are an important immunocompetent cell in the brain and play a potentially significant role in various neurological diseases. Therefore, elimination of ROS overproduction might be a potential strategy for preventing and treating neurological diseases. Accumulating evidence indicates that calycosin, a main active ingredient in the Chinese herbal medicine Huangqi (Radix Astragali Mongolici), is a potential therapeutic candidate with anti-inflammation and/or anticancer effects. Here, we investigated the protective effect of calycosin in brain astrocytes by mimicking in vitro oxidative stress using H2 O2 . The results revealed that H2 O2 significantly induced ROS and inflammatory factor (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß) production, whereas post-treatment with calycosin dramatically and concentration-dependently suppressed H2 O2 -induced damage by enhancing cell viability, repressing ROS and inflammatory factor production, and increasing superoxide dismutase (SOD) expression. Additionally, we found that calycosin facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and promoted its nuclear translocation, thereby inducing the expression of antioxidant molecules (heme oxygenase [HO]-1 and SOD) following H2 O2 treatment. Moreover, calycosin did not attenuated H2 O2 -induced astrocyte damage and ROS production in the presence of the ML385 (a Nrf2-specific inhibitor) and following Nrf2 silencing. Furthermore, calycosin failed to increase Akt phosphorylation and mitigate H2 O2 -induced astrocyte damage in the presence of the LY294002 (a selective phosphatidylinositol 3-kinase inhibitor), indicating that calycosin-mediated regulation of oxidative-stress homeostasis involved Akt/Nrf2/HO-1 signaling. These findings demonstrated that calycosin protects against oxidative injury in brain astrocytes by regulating oxidative stress through the AKT/Nrf2/HO-1 signaling pathway.
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Factor 2 Relacionado con NF-E2 , Proteínas Proto-Oncogénicas c-akt , Astrocitos/metabolismo , Hemo-Oxigenasa 1/metabolismo , Isoflavonas , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
Common characteristics of aging include reduced somatic stem cell number, susceptibility to cardiac injuries, metabolic imbalances and increased risk for oncogenesis. In this study, Pleiotropic anti-aging effects of a decoction Jing Si herbal drink (JS) containing eight Traditional Chinese Medicine based herbs, with known effects against aging related disorders was evaluated. Adipose derived mesenchymal stem cells (ADMSCs) from 16 week old adult and 24 month old aging WKY rats were evaluated for the age-related changes in stem cell homeostasis. Effects of JS on self-renewal, klotho and Telomerase Reverse Transcriptase expression DNA damage response were determined by immunofluorescence staining. The effects were confirmed in senescence induced human ADMSCs and in addition, the potential of JS to maintain telomere length was evaluated by qPCR analysis in ADMSCs challenged for long term with doxorubicin. Further, the effects of JS on doxorubicin-induced hypertrophic effect and DNA damage in H9c2 cardiac cells; MPP+-induced damages in SH-SY5Y neuron cells were investigated. In addition, effects of JS in maintaining metabolic regulation, in terms of blood glucose regulation in type-II diabetes mice model, and their potential to suppress malignancy in different cancer cells were ascertained. The results show that JS maintains stem cell homeostasis and provides cytoprotection. In addition JS regulates blood glucose metabolism, enhances autophagic clearances in neurons and suppresses cancer growth and migration. The results show that JS acts on multiple targets and provides a cumulative protective effect against various age-associated disorders and therefore it is a candidate pleiotropic agent for healthy aging.
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Envejecimiento/efectos de los fármacos , Medicamentos Herbarios Chinos/administración & dosificación , Células Madre Mesenquimatosas/efectos de los fármacos , Medicina Regenerativa/métodos , Animales , Citoprotección/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Control Glucémico/métodos , Humanos , Ratones , Ratas , Ratas Endogámicas WKY , Homeostasis del Telómero/efectos de los fármacosRESUMEN
Stem cell therapy has been explored for the treatment of cerebral stroke. Several types of stem cells have been investigated to ensure the safety and efficacy in clinical trials.Cryopreserved umbilical cord blood (UCB) mononuclear cells (MNCs) obtained from healthy donors have a more stabilized quality, thereby ensuring a successful therapy. A phase I study was conducted on patients aged 45-80 years who sustained acute ischemic stroke. An UCB unit was obtained from a public cord blood bank based on ABO/Rh blood type, HLA matching score (6/6), and cell dose (total MNC count of 0.5-5 × 107 cells/kg). In addition, to facilitate blood brain barrier penetration of UCB, 4 doses of 100 mL mannitol was administered intravenously after 30 min after UCB transplantation and every 4 h thereafter. The primary outcomes were the number of disease (GVHD) within 100 days after transfusion. The secondary outcomes were changes in the National Institutes of Health Stroke Scale (NIHSS), Barthel index, and Berg Balance Scale scores. A 46-year-old male patient with identical ABO/Rh blood type, HLA matching score of 6/6, and MNC count of 2.63 × 108 cells/kg was enrolled. The patient did not present with serious AEs or GVHD during the 12-month study period. The patient's NIHSS score decreased from 9 to 1. Moreover, the Berg Balance Scale score increased from 0 to 48 and the Barthel index score from 0 to 90. This preliminary study showed that an adult patient with hemiplegia due to ischemic stroke completely recovered within 12 months after receiving allogeneic UCB therapy.
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Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Monocitos/metabolismo , Accidente Cerebrovascular/terapia , Trasplante Homólogo/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is the standard treatment for acute ischemic stroke. Standard-dose rt-PA (0.9 mg/kg) is known to achieve good recanalization but carries a high bleeding risk. Lower dose of rt-PA has less bleeding risk but carries a high re-occlusion rate. We investigate if induced pluripotent stem cells (iPSCs) can improve the thrombolytic effect of low-dose rt-PA (0.45 mg/kg). METHODS: Single irradiation with 6 mW/cm2 light-emitting diode (LED) for 4 h at rat common carotid artery was used as thrombosis model according to our previous report. Endothelin-1 (ET-1), intercellular adhesion molecule-1 (ICAM-1), and interleukin 1 beta (IL-1 beta) were used as the inflammatory markers for artery endothelial injury. Angiopoietin-2 (AP-2), brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were examined in artery wall and iPSCs culture. Animal ultrasound was used to evaluate the stenosis degree of common carotid artery before and at 2 h, 24 h, 4 days and 7 days after LED irradiation. RESULTS: After LED irradiation alone, there was a persistent occlusion from 2 h to 7 days. Standard-dose rt-PA alone could recanalize the occluded artery from 24 h to 7 days to stenotic degree ≤ 50%. Low-dose rt-PA or 1 × 106 mouse iPSCs alone could not recanalize the occluded arteries from 2 h to 7 days. Combination use of low-dose rt-PA plus 1 × 106 mouse iPSCs caused better recanalization from 24 h to 7 days. ET-1, ICAM-1 and IL-1 beta were strongly expressed after LED irradiation but reduced after iPSCs treatment. AP-2, BDNF and VEGF were rarely induced after LED irradiation but strongly expressed after iPSCs treatment. In vitro study showed iPSCs could express AP-2, BDNF and VEGF. CONCLUSION: The adjuvant use of iPSCs may help improving the thrombolytic effect of low-dose rt-PA by suppressing inflammatory factors and inducing angiogenic trophic factors. Stem cells could be a potential regimen in acute thrombolytic therapy to improve recanalization and reduce complications.
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Isquemia Encefálica , Trombosis de las Arterias Carótidas , Células Madre Pluripotentes Inducidas , Accidente Cerebrovascular , Animales , Ratones , Ratas , Accidente Cerebrovascular/terapia , Activador de Tejido Plasminógeno , Factor A de Crecimiento Endotelial VascularRESUMEN
Background: Rheumatoid arthritis is an autoimmune disease that may lead to severe complications. The fruit of Psoralea corylifolia L. (PCL) is widely used in traditional Chinese medicine as a well-known herbal treatment for orthopedic diseases. However, there is a lack of studies of its effects on rheumatoid arthritis. The purpose of the study was to investigate the effects and mechanisms of concentrated herbal granules of PCL on rheumatoid arthritis to provide some insights for future development of new drug for the treatment of rheumatoid arthritis. Methods: We used collagen-induced arthritis (CIA) DBA/1J mice as an experimental model to mimic human rheumatoid arthritis. The mice were immunized with collagen on days 0 and 21 and then orally administered 200 mg/kg/day PCL on days 22-49. Starch was used as a control. The mice were sacrificed on day 50. Clinical phenotypes, joint histopathology, and immunological profiles were measured. Results: Compared to the CIA or CIA + Starch group, the CIA + PCL group had significantly ameliorated clinical severity and decreased paw swelling. Histopathological analysis of the hind paws showed that PCL mitigated the erosion of cartilage and the proliferation of synovial tissues. There were significant differences in the levels of TNF-α, IL-6 and IL-17A, as measured by ELISA, and the percentages of CD4 + IL-17A+, CD4 + TNF-α+, CD4 + IFN-γ+ T cells. Furthermore, we also found that in mice treated with CIA + PCL, the percentage and number of bone marrow-derived suppressor cells (MDSCs; Gr1+ CD11b+) increased significantly. Conclusions: We provided evidence for the potential antiarthritic effects of PCL through the inhibition of inflammation and increase of MDSCs. These findings indicate that PCL may be a promising therapeutic herb for the treatment of rheumatoid arthritis.
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Heart failure (HF) and cardiac hypertrophy is an unfavorable outcome of pathological cardiac remodeling and represents the most important contributing factor for HF and cardiac hypertrophy. Amygdalin (AMG) is a cyanogenic glycoside derived from bitter almonds. Accumulating evidences have highlighted their pharmacological potentials against various diseases. However, there is no report delineating the potential of AMG against angiotensin (Ang II) induced cardiac injuries. Thus, the present study was performed to explore whether AMG could ameliorate Ang II induced cardiomyopathies and thereby ascertain the underlying mechanisms thereof. To this end, H9c2 cells were treated with Ang II and thereafter treated with various concentration of AMG and finally the cardio-protective effects of AMG were analyzed through Western blotting, immunofluorescence, and insilico analysis. Our results showed that the cardiomyocyte cell size, inflammatory markers and cytokines(pNF-κB, TNF-α, iNOS and COX-2) were markedly increased following Ang II treatment; nevertheless, treatment with AMG led to considerable decrement in the Ang II induced enlargement of the cardiomyocytes, and attenuate the expression of hypertrophic markers(ANP, BNP and MHC-7), inflammatory markers and cytokines. Additionally, oxidative stress related proteins (Nrf2, catalase, SOD-2, and GPX-4) were markedly increased following AMG treatment. Molecular docking reveals the interaction of AMG with Nrf2 possessing good binding affinity. Cumulatively, our study highlights the cardio-protective role of AMG against Ang II induced cardiomyopathies, including oxidative stress and inflammation effects. The intriguing in vitro results warrants the need of further animal studies to truly ascertain their potentialities.
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Amigdalina , Angiotensina II , Amigdalina/farmacología , Angiotensina II/metabolismo , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/prevención & control , Simulación del Acoplamiento Molecular , Miocitos Cardíacos/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Estrés OxidativoRESUMEN
BACKGROUND: Toxocara canis, a source of visceral larva migrans, causes toxocariasis and induces respiratory symptoms. The reasons by which the pulmonary pathological alteration in the lungs infected with T. canis remain unclear. METHODS: The involvement of the pulmonary pathological alteration by histology, enzyme activity, and Western blot analysis in the lungs of BALB/c mice after the infection of 2000 embryonated eggs. RESULTS: The pathological effects gradually increased after the infection culminated in severe leukocyte infiltration and hemorrhage from days 4-14 post-inoculation. Gelatin zymography using substrate showed that the relative activity of matrix metalloproteinase (MMP) -9 and MMP-2 significantly increased in T. canis-infected mice. Western blot analysis indicated that the MMPs protein level of fibronectin monomer significantly increased in T. canis-infected mice compared with that in uninfected control. T. canis larvae mainly initiated leukocyte infiltration and hemorrhage in the lungs. CONCLUSION: These phenomena subsequently induced the activities of MMPs in parallel with the pathological changes in early stage pulmonary inflammation. In conclusion, T. canis larval migration activated the MMPs and caused pulmonary pathogenesis.
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Pulmón/patología , Metaloproteinasas de la Matriz/metabolismo , Toxocara canis/patogenicidad , Toxocariasis/patología , Animales , Fibronectinas/metabolismo , Hemorragia/patología , Larva/patogenicidad , Leucocitos/patología , Pulmón/metabolismo , Pulmón/parasitología , Masculino , Ratones , Ratones Endogámicos BALB C , Toxocariasis/metabolismo , Toxocariasis/parasitologíaRESUMEN
Peroxisome proliferator-activated receptor gamma (PPARγ) regulates neuroinflammation, and its agonists act as neuroprotective agents. This study aims to investigate the correlation between PPARγ and proinflammatory enzyme expression in astroglia infected with Toxoplasma gondii tachyzoite in vitro. Our results showed that matrix metalloprotease (MMP)-2, MMP-9, cyclooxygenase-2 (COX-2), prostaglandin (PGE)-2, inducible nitric-oxide synthase (iNOS), and nitric oxide (NO) were significantly increased in T. gondii-infected astroglia. Furthermore, the expression levels of MMP-2, MMP-9, COX-2, PGE-2, iNOS, and NO were significantly decreased by rosiglitazone-a PPARγ agonist. By contrast, the treatment with GW9662, a PPARγ antagonist, efficiently increased the expression levels of MMP-2, MMP-9, COX-2, PGE-2, iNOS, and NO. These results suggested that the treatment with rosiglitazone offers a potential strategy for controlling the inflammatory factors in T. gondii infection.
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Astrocitos/enzimología , Astrocitos/parasitología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , PPAR gamma/fisiología , Toxoplasma/fisiología , Animales , Encéfalo/citología , Línea Celular , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Fibroblastos/parasitología , Prepucio/citología , Humanos , Masculino , Óxido Nítrico/análisis , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Conejos , Rosiglitazona/farmacologíaRESUMEN
Angiostrongylus cantonensis causes a human central nervous system (CNS) infection characterized by eosinophilic meningitis or meningoencephalitis. Individuals infected with A. cantonensis exhibit unbalanced walking. The mechanism of extensive neurological impairments of hosts caused by A. cantonensis larvae remains unclear. Tight junction proteins (e.g., claudin-5 and zonula occludens-1) are the most important regulators of paracellular permeability and cellular adhesion. In a previous study, we found that increased matrix metalloproteinase-9 (MMP-9) activity may be associated with blood-CNS barrier disruption and/or the degeneration of Purkinje cells in eosinophilic meningitis caused by A. cantonensis. In the present study, the co-localization of MMP-9 and tight junction proteins on the degeneration of Purkinje cells was measured via confocal laser scanning immunofluorescence microscopy. The statistical evidence indicated that MMP-9 correlated between tight junction protein disruption and Purkinje cell degeneration at 20 days post-infection with A. cantonensis. In conclusion, Purkinje cell degeneration is highly correlated with tight junction protein disruption via the MMP-9 activation pathway.
Asunto(s)
Angiostrongylus cantonensis/fisiología , Metaloproteinasa 9 de la Matriz/metabolismo , Células de Purkinje/patología , Infecciones por Strongylida/parasitología , Proteínas de Uniones Estrechas/metabolismo , Animales , Modelos Animales de Enfermedad , Larva/fisiología , Ratones , Células de Purkinje/metabolismo , Células de Purkinje/parasitología , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/patologíaRESUMEN
Parkinson's disease (PD) is a disease of the human nervous system with an onset, in the sixth and seventh decades of the human life. Chiefly perceived as progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) with the ensued loss of dopamine in the striatum and the presence of Lewy bodies, consisting of α-synuclein agglomeration. In which the neuronal bridge between substantia nigra and striatum plays an advent role in the motor system. Dilapidation of these neurons results in dopamine depletion which in-turn makes hay to PD. Eventually, the etiology and pathogenesis of PD were still on a hike of dilemma. Traditional Chinese medicine (TCM), including Chinese herbal remedies, acupuncture, and manipulative therapies, is commonly used as an adjunctive therapy in different diseases, particularly neurological diseases, in Asian countries. Additionally, TCM might improve the prognoses and the quality of life of patients with PD because it induces less adverse drug reactions. The present review describes research on the various neuroprotective components and herbal extracts from herbal medicines in the context of addressing the effects of PD.
Asunto(s)
Medicina Tradicional China/métodos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/terapia , Animales , Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina , Neuronas Dopaminérgicas/efectos de los fármacos , Humanos , Ratones , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Porción Compacta de la Sustancia Negra/metabolismo , Sustancia Negra/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
Eating of excessive raw or undercooked environmental snails produces angiostrongyliasis demyelination caused by Angiostrongylus cantonensis (A. cantonensis). The aim of this study was to investigate the association between extracellular signal-regulated kinase (Erk)1/2-nuclear factor (NF)-κB pathway and myelin basic protein (MBP) expression in RSC96 Schwann cells treated with A. cantonensis-conditioned culture medium, which was prepared by culturing the third-stage (L3) nematode larvae in DMEM for 72 h. The supernatants were collected and filtered before use. Our results showed that MBP was produced in the RSC96 cells at 16 h to 48 h post-stimulation (PS). Phosphorylated (p)-NF-κB levels were significantly increased from 8 h to 48 h PS, as were the p-Erk1/2 levels at the same time points. Additionally, expression of p-NF-κB and MBP was significantly decreased by treatment with QNZ, an NF-κB inhibitor. Treatment with PD98059, an Erk kinase inhibitor, efficiently reduced p-Erk1/2, p-NF-κB and MBP expression in the Schwann cells. These results suggest that A. cantonensis-conditioned culture medium induced suppression of the Erk1/2-NF-κB signaling pathway leading to reduced MBP production in RSC96 Schwann cells. Thus, inhibiting this signaling intermediate involved in MBP expression may be a potential method for controlling inflammatory development of A. cantonensis-induced MBP changes in preceded demyelination.