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OBJECTIVE: This study aims to compare the outcomes of robot-assisted drainage and conservative treatment in minor basal ganglia hemorrhage (10ml< hemorrhage volume ≤ 30 ml) patients with neurological dysfunction, and analyze patients treated with robot-assisted drainage in order to optimize this treatment strategy. METHODS: In a retrospective study conducted in December 2021 to December 2023, minor basal ganglia cerebral hemorrhage patients with neurological dysfunction were enrolled from the Department of Neurosurgery, Shanghai Ninth People's Hospital. The patients included both the surgical (robot-assisted drainage) and conservative groups. The efficacy of robot-assisted drainage compared with conservative treatment in patients with minor cerebral hemorrhage and neurological dysfunction was evaluated by modified Rankin Scale (mRS) score after 3 months, muscle strength (grade 1 to 5) and cost of hospitalization. RESULTS: Of the patients included, 23 received robot-assisted drainage and 20 received conservative treatment. There were no significant differences in gender, age, history of hypertension and diabetes, muscle strength and mRS score at admission. Female patients accounted for 32.6%, and male patients accounted for 67.4%. About 90% of the patients enrolled had a pre-existing hypertension history. The mRS score after 3 months indicated that prognosis of the patients was significantly better in the surgical treatment group than the conservative treatment group (favorable prognosis 69.57% VS. 35%, P = 0.034) while the patients underwent surgery paid higher hospital bills than patients treated conservatively. CONCLUSION: Compared with traditional conservative treatment, robot-assisted drainage surgery is more helpful to improve the prognosis of patients with minor basal ganglia hemorrhage (volume ≤ 30mL) accompanied by neurological dysfunction. Robot assisted surgery can safely and effectively remove the hematoma of minor basal ganglia hemorrhage, and there were 69.6% of surgery group patients had a good prognosis in this study.
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Hemorragia dos Gânglios da Base , Procedimentos Cirúrgicos Robóticos , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Hemorragia dos Gânglios da Base/cirurgia , Hemorragia dos Gânglios da Base/complicações , Procedimentos Cirúrgicos Robóticos/métodos , Estudos Retrospectivos , Idoso , Adulto , Resultado do Tratamento , Procedimentos Neurocirúrgicos/métodos , Doenças do Sistema Nervoso/cirurgia , Drenagem/métodos , Hemorragia Cerebral/cirurgia , Hemorragia Cerebral/complicaçõesRESUMO
BACKGROUND: Ulcerative colitis (UC) refers to an idiopathic chronic inflammatory bowel disease that starts with inflammation of the intestinal mucosa. Dietary fiber plays a crucial role in maintaining the normal architecture of the intestinal mucosa. In this study, the protective effect and potential mechanism of soluble dietary fiber from Rosa roxburghii Tratt residue (SDFR) on dextran sulfate sodium (DSS)-induced UC mice were explored. RESULTS: The results revealed that SDFR could ameliorate body weight loss and pathological injury, improve the structure and crypt destruction in colon in DSS-induced mice. Moreover, the levels of NO, IL-1ß, TNF-α, MPO and protein expression of iNOS and COX-2 were decreased after administration of SDFR. Notably, nontargeted metabolomics analysis indicated that there were significant differences in 51 potential metabolites in serum between the DSS and control groups. SDFR intervention could regulate aberrant alterations of these metabolites and mitigate UC via regulating metabolic pathways, including arachidonic acid and glycerophospholipid metabolism. CONCLUSION: This study provides novel evidence that SDFR could be used as a potential modulator to relieve UC. Also, the results provide a theoretical basis for the utilization of byproducts in Rosa roxburghii Tratt fruit processing. © 2024 Society of Chemical Industry.
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Colite Ulcerativa , Sulfato de Dextrana , Fibras na Dieta , NF-kappa B , Rosa , Animais , Rosa/química , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/prevenção & controle , Sulfato de Dextrana/efeitos adversos , Camundongos , Fibras na Dieta/farmacologia , Fibras na Dieta/análise , Masculino , NF-kappa B/metabolismo , NF-kappa B/genética , Humanos , Modelos Animais de Doenças , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/administração & dosagem , Colo/metabolismo , Colo/efeitos dos fármacos , Colo/patologia , Interleucina-1beta/metabolismo , Interleucina-1beta/sangue , Interleucina-1beta/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Resíduos/análise , Camundongos Endogâmicos C57BL , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genéticaRESUMO
BACKGROUND: Paclitaxel (PTX) is touted as an essential medicine due to its extensive use as a chemotherapeutic agent for various cancers and an antiproliferative agent for endovascular applications. Emerging studies in cardio-oncology implicate various vascular complications of chemotherapeutic agents. METHODS: We evaluated the inflammatory response induced by the systemic administration of PTX. The investigation included RNAseq analysis of primary human endothelial cells (ECs) treated with PTX to identify transcriptional changes in pro-inflammatory mediators. Additionally, we used dexamethasone (DEX), a well-known antiinflammatory compound, to assess its effectiveness in counteracting these PTX-induced changes. Further, we studied the effects of PTX on monocyte chemoattractant protein-1 (MCP-1) levels in the media of ECs. The study also extended to in vivo analysis, where a group of mice was injected with PTX and subsequently harvested at different times to assess the immediate and delayed effects of PTX on inflammatory mediators in blood and aortic ECs. RESULTS: Our RNAseq analysis revealed that PTX treatment led to significant transcriptional perturbations in pro-inflammatory mediators such as MCP-1 and CD137 within primary human ECs. These changes were effectively abrogated when DEX was administered. In vitro experiments showed a marked increase in MCP-1 levels in EC media following PTX treatment, which returned to baseline upon treatment with DEX. In vivo, we observed a threefold increase in MCP-1 levels in blood and aortic ECs 12 h post-PTX administration. Similar trends were noted for CD137 and other downstream mediators like tissue factor, vascular cell adhesion molecule 1, and E-selectin in aortic ECs. CONCLUSION: Our findings illustrate that PTX exposure induces an upregulation of atherothrombotic mediators, which can be alleviated with concurrent administration of DEX. Considering these observations, further long-term investigations should focus on understanding the systemic implications associated with PTX-based therapies and explore the clinical relevance of DEX in mitigating such risks.
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Anti-Inflamatórios , Quimiocina CCL2 , Dexametasona , Células Endoteliais , Mediadores da Inflamação , Camundongos Endogâmicos C57BL , Paclitaxel , Paclitaxel/efeitos adversos , Paclitaxel/administração & dosagem , Humanos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/efeitos adversos , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Dexametasona/efeitos adversos , Mediadores da Inflamação/metabolismo , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Masculino , Doença Iatrogênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , RNA-Seq , Fatores de Tempo , Regulação da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais , CamundongosRESUMO
This methodology paper highlights the surgical nuances of a rodent model of venous thrombosis, specifically in the context of cancer-associated thrombosis (CAT). Deep venous thrombosis is a common complication in cancer survivors and can be potentially fatal. The current murine venous thrombosis models typically involve a complete or partial mechanical occlusion of the inferior vena cava (IVC) using a suture. This procedure induces a total or partial stasis of blood and endothelial damage, triggering thrombogenesis. The current models have limitations such as higher variability in clot weights, significant mortality rate, and prolonged learning curve. This report introduces surgical refinements using vascular clips to address some of these limitations. Using a syngeneic colon cancer xenograft mouse model, we employed customized vascular clips to ligate the infrarenal vena cava. These clips allow residual lip space similar to a 5-0 polypropylene suture after IVC ligations. Mice with the suture method served as controls. The vascular clip method resulted in a consistent reproducible partial vascular occlusion and greater clot weights with less variability than the suture method. The larger clot weights, greater clot mass, and clot to the IVC luminal surface area were expected due to the higher pressure profile of the vascular clips compared to a 6-0 polypropylene suture. The approach was validated by gray scale ultrasonography, which revealed consistently greater clot mass in the infrarenal vena cava with vascular clips compared to the suture method. These observations were further substantiated with the immunofluorescence staining. This study offers an improved method to generate a venous thrombosis model in mice, which can be employed to deepen the mechanistic understanding of CAT and in translational research such as drug discovery.
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Neoplasias do Colo , Trombose Venosa , Humanos , Animais , Camundongos , Polipropilenos , Trombose Venosa/etiologia , Bioensaio , Modelos Animais de DoençasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Calcium oxalate (CaOx) kidney stones are widely acknowledged as the most prevalent type of urinary stones, with high incidence and recurrence rates. Incarvillea diffusa Royle (ID) is a traditionally used medicinal herb in the Miao Minzu of Guizhou province, China, for treating urolithiasis. However, the active components and the underlying mechanism of its pharmacodynamic effects remain unclear. AIM OF THE STUDY: This study aimed to investigate the potential inhibitory effect of the active component of ID on the formation of CaOx nephrolithiasis and elucidate the underlying mechanism. MATERIALS AND METHODS: In vivo, a CaOx kidney stone model was induced in Sprague-Dawley (SD) rats using an ethylene glycol and ammonium chloride protocol for four weeks. Forty-eight male SD rats were randomly assigned to 6 groups (n = 8): blank group, model group, apocynin group, and low, medium, and high dose of ID's active component (IDW) groups. After three weeks of administration, rat urine, serum, and kidney tissues were collected. Renal tissue damage and crystallization, Ox, BUN, Ca2+, CRE, GSH, MDA, SOD contents, and levels of IL-1ß, IL-18, MCP-1, caspase-1, IL-6, and TNF-α in urine, serum, and kidney tissue were assessed using HE staining and relevant assay kits, respectively. Protein expression of Nrf2, HO-1, p38, p65, and Toll-4 in kidney tissues was quantified via Western blot. The antioxidant capacities of major compounds were evaluated through DPPH, O2·-, and ·OH radical scavenging assays, along with their effects on intracellular ROS production in CaOx-induced HK-2 cells. RESULTS: We found that IDW could significantly reduce the levels of CRE, GSH, MDA, Ox, and BUN, and enhancing SOD activity. Moreover, it could inhibit the secretion of TNF-α, IL-1ß, IL-18, MCP-1, caspase-1, and decreased protein expression of Nrf2, HO-1, p38, p65, and Toll-4 in renal tissue. Three major compounds isolated from IDW exhibited promising antioxidant activities and inhibited intracellular ROS production in CaOx-induced HK-2 cells. CONCLUSIONS: IDW facilitated the excretion of supersaturated Ca2+ and decreased the production of Ox, BUN in SD rat urine, and mitigated renal tissue damage by regulating Nrf2/HO-1 signaling pathway. Importantly, the three major compounds identified as active components of IDW contributed to the inhibition of CaOx nephrolithiasis formation. Overall, IDW holds significant potential for treating CaOx nephrolithiasis.
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Oxalato de Cálcio , Nefrolitíase , Ratos , Masculino , Animais , Oxalato de Cálcio/urina , Espécies Reativas de Oxigênio/metabolismo , Interleucina-18/efeitos adversos , Interleucina-18/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/efeitos adversos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Nefrolitíase/induzido quimicamente , Nefrolitíase/tratamento farmacológico , Rim/metabolismo , Superóxido Dismutase/metabolismo , Caspases/metabolismoRESUMO
OBJECTIVE: To investigate the effect of modified alternate negative pressure drainage on postoperative outcomes after posterior lumbar interbody fusion (PLIF) surgery. METHODS: This was a prospective study involving 84 patients who underwent PLIF surgery between January 2019 and June 2020. Of these patients, 22 had single-segment surgery and 62 had two-segment surgery. Patients were grouped by surgical segment and admission sequence:the observation group included patients with a single-segment surgery, and the control group included patients with a two-segment surgery. Natural pressure drainage was given to 42 patients in the observation group (modified alternate negative pressure drainage group) after surgery, which was then changed to negative pressure drainage after 24 hours. In the control group, 42 patients were given negative pressure drainage after surgery, which was then changed to natural pressure drainage after 24 hours. The total drainage volume, drainage time, maximum body temperature at 24 hours and 1 week after surgery, and drainage-related complications were observed and compared between the two groups. RESULTS: There was no significant difference in operative time and intraoperative blood loss between the two groups. The postoperative total drainage volume was significantly lower in the observation group (456.69±124.50) ml than in control group (572.36±117.75) ml, and the drainage time was significantly shorter in the observation group (4.95±1.31) days than in the control group (4.00±1.17) days. Maximum body temperature at 24 hours after surgery was similar in both groups (37.09±0.31)°C in the observation group and (37.03±0.33)°C in the control group, while on the 1st week after surgery, it was slightly higher in the observation group (37.05±0.32)°C than in the control group (36.94±0.33)°C, but the difference was not significant. There were no significant differences in drainage-related complications, with one case(2.38%) of superficial wound infection in the observation group and two cases(4.76%) in control group. CONCLUSION: Modified alternate negative pressure drainage after posterior lumbar fusion can reduce the drainage volume and shorten the drainage time without increasing the risk of drainage-related complications.
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Fusão Vertebral , Humanos , Estudos Retrospectivos , Estudos Prospectivos , Vértebras Lombares/cirurgia , Drenagem , Resultado do TratamentoRESUMO
Hydrogen-bonding catalytic reactions have gained great interest. Herein, a hydrogen-bond-assisted three-component tandem reaction for the efficient synthesis of N-alkyl-4-quinolones is described. This novel strategy features the first proof of polyphosphate ester (PPE) as a dual hydrogen-bonding catalyst and the use of readily available starting materials for the preparation of N-alkyl-4-quinolones. The method provides a diversity of N-alkyl-4-quinolones in moderate to good yields. The compound 4h demonstrated good neuroprotective activity against N-methyl-á´ -aspartate (NMDA)-induced excitotoxicity in PC12 cells.
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Quinolonas , Ratos , Animais , Quinolonas/química , Ligação de Hidrogênio , Catálise , Hidrogênio , 4-QuinolonasRESUMO
Background: Paclitaxel is touted as an essential medicine due to its extensive use as a chemotherapeutic for various cancers and an antiproliferative agent for restenosis. Due to recent concerns related to long-term mortality, paclitaxel (PTX)-based endovascular therapy is now surrounded by controversies. Objective: Examine the inflammatory mediators driven by the systemic administration of PTX and explore the means to suppress these effects. Methods: RNAseq analysis, cell and mouse models. Results: RNAseq analysis of primary human endothelial cells (ECs) treated with PTX demonstrated transcriptional perturbations of a set of pro-inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1) and CD137, which were validated in EC lysates. These perturbations were abrogated with dexamethasone, a prototypic anti-inflammatory compound. The media of ECs pre-treated with PTX showed a significant increase in MCP-1 levels, which were reverted to baseline levels with DEX treatment. A group of mice harvested at different time points after PTX injection were analyzed for immediate and delayed effects of PTX. A 3-fold increase in MCP-1 was noted in blood and aortic ECs after 12 hours of PTX treatment. Similar changes in CD137 and downstream mediators such as tissue factor, VCAM-1 and E-selectin were noted in aortic ECs. Conclusions: Our study shows that systemic PTX exposure upregulates atherothrombotic markers, and co-delivery of DEX can subdue the untoward toxic effects. Long-term studies are needed to probe the mechanisms driving systemic complications of PTX-based therapies and evaluate the clinical potential of DEX to mitigate risk.
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Cerebral ischemia-reperfusion (I/R) injury as the consequence of revascularization after ischemic stroke is associated with mitochondrial dysfunction, oxidative stress, and neuron loss. In this study, we used a deprivation/reoxygenation (OGD/R) model to determine whether interactions between Netrin-1, AKT, and the mitochondrial AAA protease AFG3L2 could influence mitochondrial function in neurons after I/R. We found that Netrin-1 protects primary cortical neurons from OGD/R-induced cell death and regulates mitochondrial reactive oxygen species (ROS) and Ca2+ levels. The accumulation of mitochondrial calcium uniporter (MCU) subunits was monitored in cells by immunoblot analysis. Although the regulatory subunits MICU1 and MICU2 were relatively unaffected, the accumulation of the essential MCU regulator (EMRE) subunit was impaired. In OGD/R-induced cells, the 7 kDa form of EMRE was significantly reduced. Netrin-1 inhibited the accumulation of EMRE and mitochondrial Ca2+ levels by upregulating AFG3L2 and AKT activation. Loss of AFG3L2 or inhibition of AKT increased levels of 7 kDa EMRE. Moreover, overexpression of AKT increased the expression of AFG3L2 in Netrin-1-knockdown neurons after OGD/R. Our results demonstrate that Netrin-1 enhanced AFG3L2 protein expression via activation of AKT. We also observed that overexpression of Netrin-1 significantly reduced infarction size in an I/R-induced brain injury model in rats but not when AKT was inhibited. Our data suggest that AFG3L2 is a protein substrate of AKT and indicate that Netrin-1 attenuates cerebral I/R injury by limiting mitochondrial ROS and Ca2+ levels through activating AKT phosphorylation and AFG3L2.
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Isquemia Encefálica , Traumatismo por Reperfusão , Animais , Ratos , Isquemia Encefálica/metabolismo , Glucose/metabolismo , Mitocôndrias/metabolismo , Netrina-1/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Cálcio/metabolismoRESUMO
Polysaccharides have received extensive attention due to their multiple physiological functions, especially their remarkable antioxidant capacity. In this study, a novel acidic polysaccharide (PSMP-2) with a molecular weight (Mw) of 1.28 × 106 Da from Salvia miltiorrhiza Bunge was extracted and purified via DEAE-52 cellulose column and Sephadex G-100 column chromatography. The structure of PSMP-2 was characterised by high-performance gel permeation chromatography (HPGPC), high-performance liquid chromatography (HPLC), Fourier transforms infrared spectroscopy (FT-IR) and methylation analysis. The results showed that PSMP-2 was an acidic heteropolysaccharide composed of rhamnose (Rha) (6.15%), galacturonic acid (GalA) (55.98%), and galactose (Gal) (21.27%) and arabinose (Ara) (16.69%). PSMP-2 contained five major glycosidic linkages, (1â)-linked-Ara, (1â2, 4)-linked-Rha, (1â4)-linked-Gal, (1â6)-linked-Gal, (1â3, 6)-linked-Gal, in a molar ratio of 5.98: 1.45: 72.23: 16.40: 3.94. The IC50 of PSMP-2 on 2, 2-Diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl free radical scavenging ability were 0.991 mg/mL and 4.007 mg/mL, respectively. It could regulate the activity of antioxidant enzymes in vivo and had good antioxidant activity. To sum up, a novel acidic polysaccharide (Mw of 1.28 × 106 Da) with antioxidant activity was isolated from S. miltiorrhiza, and its application prospect in the field of medicine and food was preliminarily revealed.
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Antioxidantes , Salvia miltiorrhiza , Antioxidantes/química , Salvia miltiorrhiza/química , Espectroscopia de Infravermelho com Transformada de Fourier , Polissacarídeos/química , Galactose/químicaRESUMO
Sorghum (Sorghum bicolor L.) is the fifth largest crop in the world and has potential health benefits, but vast quantities of sorghum roots are discarded after harvest. Based on the previous antiplatelet aggregation for this species, two new multi-substituted 3H-indole alkaloids sorghumine A (1) and sorghumine B (2), together with 14 known compounds (3-16), were found from the water extract of sorghum roots. Compounds 1-2 were identified by analyzing their spectroscopic data and physic and chemical properties, and the absolute configuration was further determined by electronic circular dichroism (ECD) analysis and calculations. 1-2, 4, 6-8 and 13-15 showed significant inhibition of platelet aggregation induced by adenosine diphosphate. 2-4, 6-9 and 11 showed significant inhibition of platelet aggregation induced by collagen. 4-6, 8, 10-11 and 16 showed significant inhibition on platelet aggregation induced by thrombin. Furthermore, molecular docking showed that active compounds can bind to P2Y12 and COX-1 receptors in platelet.
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Sorghum , Simulação de Acoplamento Molecular , Plaquetas , Agregação Plaquetária , Inibidores da Agregação Plaquetária/farmacologiaRESUMO
Kaji-ichigoside F1 (KF1), a natural oleanane-type triterpenoid saponin, is the main active constituent from Rosa roxburghii. In the southwest regions of China, particularly in Guizhou Province, this plant was used as a Miao ethnic medicine to prevent and treat dyspepsia, dysentery, hypoimmunity, and neurasthenia. In the present study, the neuroprotective effect of KF1 was evaluated against N-methyl-D-aspartate (NMDA)-induced neurotoxicity in vivo and in vitro. An NMDA-induced PC12 cell neurotoxicity assay showed that KF1 effectively improved cellular viability, inhibited the release of lactate dehydrogenase (LDH), and reduced cell apoptosis. Furthermore, KF1-treated NMDA-induced excitotoxicity mice displayed a remarkable capacity for improving spatial learning memory in the Y-maze and Morris water maze tests. In addition, KF1 increased the levels of the neurotransmitters 5-hydroxytryptamine, dopamine, and monoamine oxidase and reduced the calcium ion concentration in the hippocampus of mice. Hematoxylin and eosin and Nissl staining indicated that KF1 effectively reduced the impairment of neurons. Furthermore, Western blot assays showed that KF1 decreased NMDAR1 expression. In contrast, the NMDAR2B (NR2B), glutamate receptor (AMPA), TrkB, protein kinase B (AKT), mammalian target of rapamycin (mTOR), PSD95, and synapsin 1 were upregulated in NMDA-induced PC12 cells and an animal model. These results suggest that KF1 has a remarkable protective effect against NMDA-induced neurotoxicity, which is directly related to the regulation of the NMDA receptor and the activation of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and BDNF/AKT/mTOR signaling pathways.
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Fármacos Neuroprotetores , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , N-Metilaspartato/metabolismo , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismoRESUMO
We report herein an efficient polyphosphoric acid (PPA) promoted one-pot protocol for the synthesis of flavanone derivatives from 2-hydroxyacetophenones and benzaldehydes. A variety of flavanones were produced in moderate to excellent yields and evaluated for their neuroprotective effects against N-methyl-d-aspartate (NMDA)-induced excitotoxicity in PC12 cells. Derivatives bearing electron-donating groups exhibited better neuroprotective activity. Compound 3m demonstrated the best protective potency and reversed the intracellular calcium (Ca2+) influx caused by NMDA, suggesting that flavanones protected the PC12 cells against NMDA-induced neurotoxicity via inhibition of Ca2+ overload.
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This work reported a simple and practical protocol for the preparation of methylthiomethyl (MTM) esters/ethers directly from carboxylic acid/phenol and dimethylsulfoxide (DMSO) as solvent and methylthiomethyl source. With different types of carboxylic acids/phenols the reactions underwent smooth transformation to afford the corresponding MTM esters/ethers in moderate to excellent yields. This method features catalyst-free, easy to operate, broad substrate scope, good functional group tolerance and involvement of the formation of DMSO enolate.
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Nerve injury-induced neuropathic pain is a type of chronic pain associated with neuroinflammatory response and neuronal death; however the underlying molecular mechanisms are still unclear. Dual-specificity phosphatase 8 (DUSP8) can mediate numerous cellular events, but whether it's involved in neuropathic pain is unknown. In the study, we found that spinal nerve ligation (SNL) operation on rats significantly decreased DUSP8 expression levels in ipsilateral spinal cord (ISC) tissues. Consistently, lipopolysaccharide (LPS) exposure also reduced DUSP8 in murine microglial cells. Adeno-associated virus (AAV)-mediated DUSP8 over-expression was found to considerably ameliorate SNL-induced neuropathic pain in rats. Additionally, neuronal death in the ISC tissues was also attenuated by AAV-DUSP8 following SNL surgery. Moreover, SNL-triggered neuroinflammation and microglial activation were also mitigated upon DUSP8 over-expression by suppressing nuclear factor κB (NF-κB) signaling, which were validated in LPS-exposed microglial cells. Importantly, our in vitro experiments indicated that inflammatory response in microglial cells contributed to neuron death, and such effect could also be ameliorated by DUSP8 over-expression. Notably, we found that DUSP8 directly interacted with transforming growth factor ß activated kinase-1 (TAK1) in microglial cells. Both SNL and LPS led to the activation of TAK1/p38/JNK1/2 signaling, whereas being strongly abolished by DUSP8. Intriguingly, TAK1 blockage significantly diminished LPS-induced inflammation and neuron death, whereas being accelerated by DUSP8 knockdown, further indicating that DUSP8-ameliorated neuropathic pain was largely TAK1-dependent. Together, all our findings revealed that DUSP8/TAK1 signaling may be a potential target for neuropathic pain alleviation.
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Fosfatases de Especificidade Dupla , MAP Quinase Quinase Quinases , Neuralgia , Animais , Camundongos , Ratos , Fosfatases de Especificidade Dupla/metabolismo , Hiperalgesia/metabolismo , Inflamação/metabolismo , Ligadura , Lipopolissacarídeos , Neuralgia/metabolismo , Doenças Neuroinflamatórias , Neurônios/metabolismo , Ratos Sprague-Dawley , Medula Espinal , Nervos Espinhais/cirurgia , MAP Quinase Quinase Quinases/metabolismoRESUMO
Background: The etiology of primary trigeminal neuralgia remains unclear and is worthy of further study; In this study, the morphometric characteristics of ovale foramina between various groups were compared and analyzed to explore the novel cause of primary trigeminal neuralgia. Methods: High-resolution three-dimensional reconstruction images from head computed tomography of 109 patients with primary trigeminal neuralgia affecting the third branch of the trigeminal nerve and 46 healthy controls were retrospectively reviewed. Among the 109 primary trigeminal neuralgia patients, 79 patients with apparent neurovascular compression (not simply contact) demonstrated on MRI or during surgery were divided into the classical trigeminal neuralgia group and 30 patients with MRI showing no significant abnormalities were divided into idiopathic trigeminal neuralgia group. The morphometric parameters including the area, width and length of ovale foramina were examined through the use of radiologic methods. Results: In this study, the average minimum area, width and length of 79 ovale foramina on the affected and unaffected sides in the classical trigeminal neuralgia group were 21.83 ± 8.45, 21.94 ± 7.93 mm2, 2.32 ± 0.91, 2.58 ± 0.81, 5.32 ± 1.29, and 5.26 ± 1.21 mm, respectively. No significant difference in these parameters was observed (p > 0.05). However, in the idiopathic trigeminal neuralgia group, the average minimum area, width and length of 30 ovale foramina were 21.33 ± 8.21, 22.85 ± 8.36 mm2, 2.25 ± 0.90, 2.79 ± 0.96, 5.20 ± 1.27, and 5.28 ± 1.19 mm, respectively. The width on the symptomatic side was significantly smaller (p = 0.03) than that on the asymptomatic side. No significant difference in area (p = 0.48) or length (p = 0.79) was observed. In addition, when compared with the healthy control group, the area and width of ovale foramina on the symptomatic side in both groups were significantly smaller. No significant difference in length was observed. Conclusions: By comparing and analyzing the statistical data, it can be inferred that a narrow foramen ovale is associated with primary trigeminal neuralgia, as well as its recurrence after microvascular decompression.
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Aberrant hyperactivation of Wnt signaling, driven by nuclear ß-catenin in the colonic epithelium, represents the seminal event in the initiation and progression of colorectal cancer (CRC). Despite its established role in CRC tumorigenesis, clinical translation of Wnt inhibitors remains unsuccessful. Late SV40 factor (LSF; encoded by TFCP2) is a transcription factor and a potent oncogene. The current study identified a chemotype, named factor quinolinone inhibitors (FQIs), that specifically inhibits LSF DNA-binding, partner protein-binding, and transactivation activities. The role of LSF and FQIs in CRC tumor growth was examined. Herein, the study showed that LSF and ß-catenin interacted in several CRC cell lines irrespective of their mutational profile, which was disrupted by FQI2-34. FQI2-34 suppressed Wnt activity in CRC cells in a dose-dependent manner. Leveraging both allogeneic and syngeneic xenograft models showed that FQI2-34 suppressed CRC tumor growth, significantly reduced nuclear ß-catenin, and down-regulated Wnt targets such as axis inhibition protein 2 (AXIN-2) and SRY-box transcription factor 9, in the xenograft cells. FQI2-34 suppressed the proliferation of xenograft cells. Adenocarcinomas from a series of stage IV CRC patients revealed a positive correlation between LSF expression and Wnt targets (AXIN-2 and SRY-box transcription factor 9) within the CRC cells. Collectively, this study uncovers the Wnt inhibitory and CRC growth-suppressive effects of these LSF inhibitors in CRC cells, revealing a novel target in CRC therapeutics.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Transplante de Células-Tronco Hematopoéticas , Proteína Axina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
BACKGROUND: Spiropachysine A is the extracted compound of traditional Chinese ethnic medicine Pachysandra axillaries Franch. var. styiosa (Dunn) M. Cheng. Spiropachysine A is the primary active steroidal alkaloids (SAs) widely used to facilitate blood circulation and relieve pain and inflammation. Few previous studies have investigated the anti-cancer activity of Spiropachysine A to treat hepatocellular carcinoma (HCC), and its molecular mechanism remains unknown. PURPOSE: This study aims to investigate the anti-cancer activity of Spiropachysine A and the underlying mechanisms by inducing methuosis in vitro and in vivo. METHODS: Here, the activity of Spiropachysine A against cancer was evaluated by the experiments with MHCC-97H cells and the xenografted mice model. The cell proliferation was examined using MTT assay, and cell morphological characteristics were observed by microscope cellular imaging. The effects of autophagy, paraptosis, and oncosis on cytoplasmic vacuolisation were detected using immunofluorescence staining, transmission electron microscopy (TEM) and western blotting (WB). The cell cycle distribution and apoptosis were analysed by flow cytometry. Hematoxylin eosin (H & E) staining was used to observe the pathological changes of the tissues. RESULTS: The in vitro and in vivo results indicated that Spiropachysine A could inhibit HCC cells proliferation (IC50 = 2.39 ± 0.21 µM against MHCC-97H cells) and tumor growth (TGI = 32.81 ± 0.23% at 25 mg/kg and 50.32 ± 0.26% at 50 mg/kg). The morphological changes of the treated cells showed that cell proliferation inhibition caused by Spiropachysine A was associated with numerous cytoplasmic vacuolization. Mechanistically, Spiropachysine A-induced methuosis rather than autophagy or arapaptic because the autophagy flux was blocked, leading to the increased LC3-II/I value and an accumulation of selective autophagy substrate p62. And, there was no activation of the regulatory parapaptic MAPK pathway. Additionally, the TEM and Lucifer yellow (LY) accumulation data confirmed that Spiropachysine A significantly triggered methuosis instead of oncosis. Further, the study indicated that the anti-proliferative activity of Spiropachysine A was independent of PCD since no alterations in apoptosis and cell cycle arrest-related proteins were observed after Spiropachysine A treatment. Impressively, the increased expression of Rac1 was observed in Spiropachysine A-treated MHCC-97H cells and its xenograft tumours, confirming that Spiropachysine A inhibited cell proliferation and induced methuosis through Ras/Rac1 signal pathways. CONCLUSIONS: Spiropachysine A was collectively identified as a novel methuosis inducer that suppresses HCC in vitro and in vivo. The underlying mechanisms might be involved in the Ras/Rac1 pathway. Such data predict that Spiropachysine A is a promising candidate for developing novel chemotherapeutic agents as a methuosis inducer for cancer therapy.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Apoptose , Autofagia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/patologia , Camundongos , NecroseRESUMO
Mitochondria can supply adenosine triphosphate (ATP) to the tissue, which can regulate metabolism during the pathologic process and is also involved in the pathophysiology of neuronal injury after stroke. Recent studies have suggested that selective autophagy could play important roles in the pathophysiological process of stroke, especially mitophagy. It is usually mediated by the PINK1/Parkin-independent pathway or PINK1/Parkin-dependent pathway. Moreover, mitophagy may be a potential target in the therapy of stroke because the control of mitophagy is neuroprotective in stroke in vitro and in vivo. In this review, we briefly summarize recent researches in mitophagy, introduce the role of mitophagy in the pathogenesis of stroke, then highlight the strategies targeting mitophagy in the treatment of stroke, and finally propose several issues in the treatment of stroke by targeting mitophagy.
Assuntos
Mitofagia/genética , Acidente Vascular Cerebral/patologia , HumanosRESUMO
A range of novel 1-phenyl-benzopyrrolizidin-3-one derivatives were synthesized and evaluated for neuroprotective effects against N-methyl-á´ -aspartate (NMDA)-induced injury in PC12 cells. Interestingly, derivatives that 1-phenyl moiety bearing electron-donating group, especially benzyloxy, and the trans-forms exhibited better protective activity against NMDA-induced neurotoxicity. Compound 11 m demonstrated the best neuroprotective potency and shown a dose-dependent prevention. The increased intracellular calcium (Ca2+) influx caused by NMDA in PC12 cells was reversed in the case of compound 11 m pretreatment at 15 µM. These results suggested that the synthesized 1-phenyl-benzopyrrolizidin-3-one derivatives exerted neuroprotective effect on NMDA-induced excitotoxicity in PC12 cells associated with inhibition of Ca2+ overload and can be further optimized for the development of neuroprotective agents.