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RATIONALE: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare but serious complication in patients with malignancy; its main manifestation includes acute pulmonary hypertension with severe respiratory distress. More than 200 cases have been reported since it was first identified in 1990. PTTM accounts for approximately 0.9% to 3.3% of deaths due to malignancy, but only a minority of patients are diagnosed ante-mortem, with most patients having a definitive diagnosis after autopsy. PATIENT CONCERNS: Two middle-aged women both died within a short period of time due to progressive dyspnea and severe pulmonary hypertension. DIAGNOSES: One patient was definitively confirmed as a gastrointestinal malignant tumor by liver puncture biopsy pathology. Ultimately, the clinical diagnosis was pulmonary tumor thrombotic microangiopathy. INTERVENTIONS: The patient was treated symptomatically with oxygen, diuresis, and anticoagulation, while a liver puncture was perfected to clarify the cause. OUTCOMES: Two cases of middle-aged female patients with rapidly progressive pulmonary hypertension and respiratory failure resulted in death with malignant neoplasm. LESSONS: PTTM has a rapid onset and a high morbidity and mortality rate. Our clinicians need to be more aware of the need for timely diagnosis through a targeted clinical approach, leading to more targeted treatment and a better prognosis.
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Microangiopatias Trombóticas , Humanos , Feminino , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/diagnóstico , Pessoa de Meia-Idade , Evolução Fatal , Hipertensão Pulmonar/etiologia , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/patologia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/diagnósticoRESUMO
Esophageal cancer (EC) is a common form of malignant tumor in the digestive system that is classified into two types: Esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinoma. ESCC is known for its early onset of symptoms, which can be difficult to identify, as well as its rapid progression and tendency to develop drug resistance to chemotherapy and radiotherapy. These factors contribute to the high incidence of disease and low cure rate. Therefore, a diagnostic biomarker and therapeutic target need to be identified for ESCC. Non-coding RNAs (ncRNAs) are a class of molecules that are transcribed from DNA but do not encode proteins. Initially, ncRNAs were considered to be non-functional segments generated during transcription. However, with advancements in high-throughput sequencing technologies in recent years, ncRNAs have been associated with poor prognosis, drug resistance and progression of ESCC. The present study provides a comprehensive overview of the biogenesis, characteristics and functions of ncRNAs, particularly focusing on microRNA, long ncRNAs and circular RNAs. Furthermore, the ncRNAs that could potentially be used as diagnostic biomarkers and therapeutic targets for ESCC are summarized to highlight their application value and prospects in ESCC.
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BACKGROUND: Chimeric antigen receptor natural killer (CAR-NK) cells represent a promising advancement in CAR cell therapy, addressing limitations observed in CAR-T cell therapy. However, our prior study revealed challenges in CAR-NK cells targeting CD19 antigens, as they failed to eliminate CD19+ Raji cells in NSG tumor-bearing mice, noting down-regulation or loss of CD19 antigen expression in some Raji cells. In response, this study aims to enhance CD19 CAR-NK cell efficacy and mitigate the risk of tumor recurrence due to target antigen escape by developing CD19 and CD20 (CD19/CD20) dual-targeted CAR-NK cells. METHODS: Initially, mRNA encoding anti-CD19 CARs (FMC63 scFv-CD8α-4-1BB-CD3ζ) and anti-CD20 CARs (LEU16 scFv-CD8α-4-1BB-CD3ζ) was constructed via in vitro transcription. Subsequently, CD19/CD20 dual-targeted CAR-NK cells were generated through simultaneous electrotransfection of CD19/CD20 CAR mRNA into umbilical cord blood-derived NK cells (UCB-NK). RESULTS: Following co-electroporation, the percentage of dual-CAR expression on NK cells was 86.4% ± 1.83%, as determined by flow cytometry. CAR expression was detectable at 8 h post-electric transfer, peaked at 24 h, and remained detectable at 96 h. CD19/CD20 dual-targeted CAR-NK cells exhibited increased specific cytotoxicity against acute lymphoblastic leukemia (ALL) cell lines (BALL-1: CD19+CD20+, REH: CD19+CD20-, Jurkat: CD19-CD20-) compared to UCB-NK, CD19 CAR-NK, and CD20 CAR-NK cells. Moreover, CD19/CD20 dual-targeted CAR-NK cells released elevated levels of perforin, IFN-γ, and IL-15. Multiple activation markers such as CD69 and cytotoxic substances were highly expressed. CONCLUSIONS: The creation of CD19/CD20 dual-targeted CAR-NK cells addressed the risk of tumor escape due to antigen heterogeneity in ALL, offering efficient and safe 'off-the-shelf' cell products. These cells demonstrate efficacy in targeting CD20 and/or CD19 antigens in ALL, laying an experimental foundation for their application in ALL treatment.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Camundongos , Animais , Receptores de Antígenos Quiméricos/metabolismo , Antígenos CD19/genética , Antígenos CD19/metabolismo , Citotoxicidade Imunológica/genética , Linhagem Celular Tumoral , Células Matadoras Naturais , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , RNA Mensageiro/metabolismoRESUMO
BACKGROUND AND PURPOSE: Blood-brain barrier (BBB) breakdown is one of the crucial pathological changes of cerebral ischaemia-reperfusion (I/R) injury. Trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effects against cerebral I/R injury as demonstrated in our previous study. This study was designed to investigate the effect of TLB on BBB disruption after cerebral I/R injury. EXPERIMENTAL APPROACH: Rats with focal cerebral ischaemia caused by transient middle cerebral artery occlusion were studied along with brain microvascular endothelial cells and human astrocytes to mimic BBB injury caused by oxygen and glucose deprivation/reoxygenation (OGD/R). KEY RESULTS: The results showed that TLB effectively maintained BBB integrity and inhibited neuronal loss following cerebral I/R challenge. Furthermore, TLB increased tight junction proteins including ZO-1, Occludin and Claudin 5, and decreased the levels of apolipoprotein E (APOE) 4, cyclophilin A (CypA) and phosphorylated nuclear factor kappa B (NF-κB), thereby reducing proinflammatory cytokines. TLB also decreased the Bax/Bcl-2 ratio and cleaved-caspase 3 levels along with a reduced number of apoptotic neurons. Molecular docking and transcriptomics predicted MMP9 as a prominent gene evoked by TLB treatment. The protective effects of TLB on cerebral I/R-induced BBB breakdown was largely abolished by overexpression of MMP9, and the beneficial effects of TLB on OGD/R-induced loss of BBB integrity in human brain microvascular endothelial cells and astrocyte co-cultures was markedly reinforced by knockdown of MMP9. CONCLUSIONS AND IMPLICATIONS: Our findings reveal a novel property of TLB: preventing BBB disruption following cerebral I/R via targeting MMP9 and inhibiting APOE4/CypA/NF-κB axis.
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Isquemia Encefálica , Flavonoides , Polifenóis , Traumatismo por Reperfusão , Ratos , Humanos , Animais , Barreira Hematoencefálica/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Aditivos Alimentares/metabolismo , Aditivos Alimentares/farmacologia , Células Endoteliais/metabolismo , NF-kappa B/metabolismo , Simulação de Acoplamento Molecular , Isquemia Encefálica/metabolismo , Reperfusão , Traumatismo por Reperfusão/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismoRESUMO
Brucine, a weak alkaline indole alkaloid, is one of the main bioactive and toxic constituents of Strychnos nux-vomica L., which exerts multiple pharmacological activities, such as anti-tumor, anti-inflammatory, and analgesic effect. However, its potential toxic effects limited its clinical application, especially central nervous system toxicity. The present study was designed to investigate the neurotoxicity and mechanism of brucine. Our results showed that brucine significantly induced Neuro-2a cells and primary astrocyte death, as evidenced by MTT assay and LDH release. Moreover, transcriptome analysis indicated that PPAR/NF-κB and apoptosis signaling pathways were involved in the brucine-induced cytotoxicity in Neuro-2a cells. Subsequently, in fact, brucine evidently inhibited PPARγ and promoted phosphorylation of NF-κB. Furthermore, PPARγ inhibitor aggravated the neurotoxicity, while NF-κB inhibitor substantially reversed brucine-induced neurotoxicity. Moreover, brucine also significantly induced neuronal apoptosis and triggered increase in ratio of Bax/Bcl-2 and level of cleaved caspase 3, as well as its activity as evidenced by TUNEL staining and Western blot. Furthermore, molecular docking analysis predicted that brucine directly bound to caspase 3. Intriguingly, a caspase 3 inhibitor (Z-DEVE-FMK) largely abolished the neurotoxicity of brucine. Our results reveal that brucine-induced neurotoxicity via activation of PPARγ/NF-κB/caspase 3-dependent apoptosis pathway. These findings will provide a novel strategy against brucine-induced neurotoxicity.
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NF-kappa B , PPAR gama , Caspase 3 , Simulação de Acoplamento Molecular , Apoptose , Anti-Inflamatórios/farmacologia , Transdução de SinaisRESUMO
Myocardial infarction (MI) refers to the death of cardiomyocytes triggered by a lack of energy due to myocardial ischemia and hypoxia, and silent mating type information regulation 2 homolog 3 (SIRT3) plays an essential role in protecting against myocardial oxidative stress and apoptosis, which are deemed to be the principal causes of MI. Icariside II (ICS II), one of the main active ingredients of Herbal Epimedii, possesses extensive pharmacological activities. However, whether ICS II can protect against MI is still unknown. Therefore, this study was designed to investigate the effect and possible underlying mechanism of ICS II on MI both in vivo and in vitro. The results showed that pretreatment with ICS II not only dramatically mitigated MI-induced myocardial damage in mice but also alleviated H9c2 cardiomyocyte injury elicited by oxygen and glucose deprivation (OGD), which were achieved by suppressing mitochondrial oxidative stress and apoptosis. Furthermore, ICS II elevated the phosphorylation level of adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) expression, thereby activating SIRT3. However, these protective effects of ICS II on MI injury were largely abolished in SIRT3-deficient mice, manifesting that ICS II-mediated cardioprotective effects are, at least partly, due to the presence of SIRT3. Most interestingly, ICS II directly bound with SIRT3, as reflected by molecular docking, which indicated that SIRT3 might be a promising therapeutic target for ICS II-elicited cardioprotection in MI. In conclusion, our findings illustrate that ICS II protects against MI-induced oxidative injury and apoptosis by targeting SIRT3 through regulating the AMPK/PGC-1α pathway.
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Angiogenesis plays a pivotal role in the recovery of neurological function after ischemia stroke. Herein, we investigated the effect of trilobatin (TLB) on angiogenesis after cerebral ischemia-reperfusion injury (CIRI). The effect of TLB on angiogenesis after CIRI were investigated in mouse brain microvascular endothelium bEnd.3 cells and middle cerebral artery occlusion (MCAO)-induced CIRI rat model. The cell proliferation and angiogenesis were observed using immunofluorescence staining. The cell cycle, expressions of cell cycle-related proteins and SIRT 1-7 were determined by flow cytometry and western blot, respectively. The binding affinity of TLB with SIRT7 was predicted by molecular docking. The results showed that TLB concentration-dependently promoted bEnd.3 cell proportion in the S-phase. TLB significantly increased the protein expressions of SIRT6, SIRT7, and VEGFA, but not affected SIRT1-SIRT5 protein expressions. Moreover, TLB not only dramatically alleviated neurological impairment after CIRI, but also enhanced post-stroke neovascularization and newly formed functional vessels in cerebral ischemic penumbra. Furthermore, TLB up-regulated the protein expressions of CDK4, cyclin D1, VEGFA and its receptor VEGFR-2. Intriguingly, TLB not only directly bound to SIRT7, but also increased SIRT7 expression at day 28. Our findings reveal that TLB promotes cerebral microvascular endothelial cells proliferation, and facilitates angiogenesis after CIRI via mediating SIRT7/VEGFA signaling pathway in rats. Therefore, TLB might be a novel restorative agent to rescue ischemia stroke.
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Flavonoides , Polifenóis , Traumatismo por Reperfusão , Sirtuínas , Animais , Células Endoteliais/metabolismo , Flavonoides/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Neovascularização Patológica , Polifenóis/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais , Sirtuínas/metabolismo , Fator A de Crescimento do Endotélio VascularRESUMO
Based on the structural skeleton of natural products boeravinones, two types of 6H-chromeno[3,4-b]quinoline derivatives were designed and synthesized by nitrogen atom substitution strategy. Then, their cytotoxic activities were evaluated against six human tumor cell lines including HepG2 (hepatocellular carcinoma), A2780 (ovarian cancer), Hela (cervical cancer), HCT116 (colorectal cancer), SW1990 (pancreatic cancer), and MCF7 (breast cancer). The results showed that compounds ZML-8 and ZML-14 exhibited robust inhibitory activities against HepG2 cells with IC50 values of 0.58 and 1.94 µM, respectively. In addition, ZML-8 and ZML-14 showed higher selectivity against HepG2 and L-02 cells than Topotecan. Mechanistically, ZML-8 and ZML-14 not only induced cell cycle arrest in the G2/M phase and cell apoptosis, but also dose-dependently inhibited topoisomerase I activity and induced DNA damage in HepG2 cells. Molecular docking showed that ZML-8 and ZML-14 could interact with topoisomerase I-DNA complex with a similar binding mode to Topotecan. Inhibitory activities of these two compounds on topoisomerase I were then confirmed in both cell-free systems and in whole-cell lysates. Taken together, compounds ZML-8 and ZML-14 merit further development as a new generation of non-camptothecin topoisomerase I inhibitors for the treatment of cancer.
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Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/química , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Simulação de Acoplamento Molecular , Inibidores da Topoisomerase I , Inibidores da Topoisomerase II/farmacologiaRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive impairment that currently is uncurable. Previous study shows that trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect in experimental models of AD. In the present study we investigated the molecular mechanisms underlying the beneficial effect of TLB on experimental models of AD in vivo and in vitro. APP/PS1 transgenic mice were administered TLB (4, 8 mg· kg-1 ·d-1, i.g.) for 3 months; rats were subjected to ICV injection of Aß25-35, followed by administration of TLB (2.5, 5, 10 mg· kg-1 ·d-1, i.g.) for 14 days. We showed that TLB administration significantly and dose-dependently ameliorated the cognitive deficits in the two AD animal models, assessed in open field test, novel object recognition test, Y-maze test and Morris water maze test. Furthermore, TLB administration dose-dependently inhibited microglia and astrocyte activation in the hippocampus of APP/PS1 transgenic mice accompanied by decreased expression of high-mobility group box 1 (HMGB1), TLR4 and NF-κB. In Aß25-25-treated BV2 cells, TLB (12.5-50 µM) concentration-dependently increased the cell viability through inhibiting HMGB1/TLR4/NF-κB signaling pathway. HMGB1 overexpression abrogated the beneficial effects of TLB on BV2 cells after Aß25-35 insults. Molecular docking and surface plasmon resonance assay revealed that TLB directly bound to HMGB1 with a KD value of 8.541×10-4 M. Furthermore, we demonstrated that TLB inhibited Aß25-35-induced acetylation of HMGB1 through activating SIRT3/SOD2 signaling pathway, thereby restoring redox homeostasis and suppressing neuroinflammation. These results, for the first time, unravel a new property of TLB: rescuing cognitive impairment of AD via targeting HMGB1 and activating SIRT3/SOD2 signaling pathway.
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Doença de Alzheimer , Disfunção Cognitiva , Proteína HMGB1 , Fármacos Neuroprotetores , Sirtuína 3 , Superóxido Dismutase , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Animais , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Flavonoides , Aditivos Alimentares/farmacologia , Aditivos Alimentares/uso terapêutico , Proteína HMGB1/metabolismo , Camundongos , Camundongos Transgênicos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Polifenóis , Ratos , Transdução de Sinais , Sirtuína 3/efeitos dos fármacos , Sirtuína 3/metabolismo , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
29 novel 20(S)-aminophosphonate derivatives of camptothecin were synthesized via a FeCl3 - catalyzed one-pot reaction. All of these compounds displayed similar or superior cytotoxic activity in comparison with that of Irinotecan against Hep3B, MCF-7, A-549, MDA-MB-231, KB, and multidrug-resistant (MDR) KB-vin cell lines. Out of them, compound B07 exhibited significant cytotoxicity and 10-fold improvement in activity compared to Irinotecan. Mechanistically, B07 not only induced cell apoptosis and cell cycle arrest in Hep3B and MCF-7 cells, but also inhibited Topoisomerase I activity in the cell and cell-free system in a manner similar to that of Irinotecan. In both xenograft and primary HCC mouse models, B07 showed significant anti-tumor activity and was more potent than Irinotecan. Additionally, the acute toxicity assay showed that B07 had no apparent toxicity to the mouse liver, kidney, and hemopoietic system of the FVB/N mice. Therefore, these findings indicate that compound B07 could be a potential Topoisomerase I poison drug candidate for further clinical trial.
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Antineoplásicos/farmacologia , Camptotecina/farmacologia , Desenho de Fármacos , Organofosfonatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Camptotecina/síntese química , Camptotecina/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Organofosfonatos/síntese química , Organofosfonatos/química , Relação Estrutura-AtividadeRESUMO
The rapid development of a NH3 sensor puts forward a great challenge for active materials and integrated sensing systems. In this work, an ultrasensitive NH3 sensor based on two-dimensional (2D) wormlike mesoporous polypyrrole/reduced graphene oxide (w-mPPy@rGO) heterostructures, synthesized by a universal soft template method is reported, revealing the structure-property coupling effect of the w-mPPy/rGO heterostructure for sensing performance improvement, and demonstrates great potential in the integration of a self-powered sensor system. Remarkably, the 2D w-mPPy@rGO heterostructrure exhibits preferable response toward NH3 (ΔR/R0 = 45% for 10 ppm NH3 with a detection limit of 41 ppb) than those of the spherical mesoporous hybrid (s-mPPy@rGO) and the nonporous hybrid (n-PPy@rGO) due to its large specific surface area (193 m2/g), which guarantees fast gas diffusion and transport of carriers. Moreover, the w-mPPy@rGO heterostructures display outstanding selectivity to common volatile organic compounds (VOCs), H2S, and CO, prominent antihumidity inteference superior to most existing chemosensors, superior reversibility and favorable repeatability, providing high potential for practicability. Thus, a self-powered sensor system composed of a nanogenerator, a lithium-ion battery, and a w-mPPy@rGO-based sensor was fabricated to realize wireless, portable, cost-effective, and light-weight NH3 monitoring. Impressively, our self-powered sensor system exhibits high response toward 5-40 mg NH4NO3, which is a common explosive to generate NH3 via alkaline hydrolysis, rendering it a highly prospective technique in a NH3-based sensing field.
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Quinazoline derivatives display multiple pharmacological activities and target various biological receptors. Based on the skeleton of quinazoline core, we designed and synthesized three new quinazoline-phenyl chlormethine conjugates (I-III) bearing a Schiff base (C = N) linker, and investigated their anti-tumor effects on HepG2-xenografted tumor and human cancer cell line HepG2. Among these compounds, compound II showed better inhibitory effect against HepG2 cells. In the present study, TUNEL staining, western blot, molecular docking, and siRNA were used to investigate the inhibitory mechanism of compound II towards hepatoma. Compound II inhibited HepG2-xenografted tumor growth in nude mice. Moreover, Compound II not only up-regulated Bax/Bcl-2 ratio and active-caspase 3 level, but also down-regulated Sirt1 expression and its activity, as well as PGC-1α expression. Furthermore, compound II also significantly suppressed the promotion of HepG2 cell proliferation, as evidenced by MTT assay and lactate dehydrogenase (LDH) release assay. Of note, the cytotoxicity of Compound II on HepG2 cells mainly via regulating Sirt1/caspase 3 signaling pathway, consisting with the results in vivo. Intriguingly, z-DEVD-FMK, a caspase 3 inhibitor, almost abolished the inhibitory effects of compound II. Of note, knockdown of caspase 3 by siRNA significantly reversed the inhibitory effect of compound II on HepG2. Interestingly, compound II directly bonded to Sirt1, indicating that Sirt1 might be a promising therapeutic target of compound II. In summary, our findings reveal that compound II, a new synthetical phenyl chlormethine-quinazoline derivative, contributes to the apoptosis of HepG2 cells both in vivo and in vitro through mediating Sirt1/caspase 3 singling pathway. These findings demonstrate that compound II may be a new potent agent against hepatocellular carcinoma.
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Aims: Neuroinflammation and oxidative stress are deemed the prime causes of brain injury after cerebral ischemia/reperfusion (I/R). Since the silent mating-type information regulation 2 homologue 3 (Sirt3) pathway plays an imperative role in protecting against neuroinflammation and oxidative stress, it has been verified as a target to treat ischemia stroke. Therefore, we attempted to seek novel Sirt3 agonist and explore its underlying mechanism for stroke treatment both in vivo and in vitro. Results: Trilobatin (TLB) not only dramatically suppressed neuroinflammation and oxidative stress injury after middle cerebral artery occlusion in rats, but also effectively mitigated oxygen and glucose deprivation/reoxygenation injury in primary cultured astrocytes. These beneficial effects, along with the reduced proinflammatory cytokines via suppressing Toll-like receptor 4 (TLR4) signaling pathway, lessened oxidative injury via activating nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways, in keeping with the findings in vivo. Intriguingly, the TLB-mediated neuroprotection on cerebral I/R injury was modulated by reciprocity between TLR4-mediated neuroinflammatory responses and Nrf2 antioxidant responses as evidenced by molecular docking and silencing TLR4 and Nrf2, respectively. Most importantly, TLB not only directly bonded to Sirt3 but also increased Sirt3 expression and activity, indicating that Sirt3 might be a promising therapeutic target of TLB. Innovation: TLB is a naturally occurring Sirt3 agonist with potent neuroprotective effects via regulation of TLR4/nuclear factor-kappa B and Nrf2/Kelch-like ECH-associated protein 1 (Keap-1) signaling pathways both in vivo and in vitro. Conclusion: Our findings indicate that TLB protects against cerebral I/R-induced neuroinflammation and oxidative injury through the regulation of neuroinflammatory and oxidative responses via TLR4, Nrf2, and Sirt3, suggesting that TLB might be a promising Sirt3 agonist against ischemic stroke.
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Flavonoides/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/farmacologia , Polifenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 3/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Biomarcadores , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Suscetibilidade a Doenças , Flavonoides/química , Modelos Moleculares , Fator 2 Relacionado a NF-E2/química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/química , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Relação Estrutura-Atividade , Receptor 4 Toll-Like/químicaRESUMO
In this study, an innovative gas sensing mechanism, self-responsive sensing mechanism, has been detected in the supramolecular hydrogel-based sensors. The self-responsive ability of as-fabricated hydrogel-based sensors to the target gas (e.g., NO2, NH3, etc.) is determined by three synergetic supramolecular interactions, namely, hydrogen bonding, molecule crystallization, and electrostatic interactions existing in hydroxyls, poly(vinyl alcohol) (PVA) crystallization, and poly(ionic liquids) of the intrinsic hydrogel networks, respectively. On account of unique synergetic supramolecular interactions, the sensors not only exhibit a rapid, reversible, and reproducible response but also show good tensile and compressive properties and excellent recovery property. The results demonstrate the potential of the self-responsive sensing mechanism as a pathway to realize a new generation of highly responsive hydrogel-based gas sensors.
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Amônia/análise , Hidrogéis/química , Dióxido de Nitrogênio/análise , Amônia/química , Carragenina/química , Cristalização , Ligação de Hidrogênio , Dióxido de Nitrogênio/química , Álcool de Polivinil/química , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Resistência à Tração , Água/químicaRESUMO
For the purpose of advancing our research on diverse C-20 decorated derivatives of camptothecin (CPT), 46 new CPT acylthiourea derivatives were synthesized and evaluated in vitro for their cytotoxicity. All the compounds showed promising in vitro cytotoxicity against six tumor cell lines (Hep3B, MCF7, A549, MDA-MB-231, KB and KB-vin). Out of them, compound c20 possesses remarkable in vitro cytotoxic activity and is more potent than topotecan. Mechanistically, c20 not only induces cell cycle arrest and cell apoptosis in A549 cells, but also inhibits Topo I activity in the cell and cell-free system in a manner similar to that of topotecan. In both xenograft and primary HCC mouse models, c20 displays significant in vivo anti-cancer activity and is more potent than topotecan. In addition, the acute toxicity assay showed that c20 has no apparent toxicity to mouse liver, kidney and hemopoietic system of the FVB/N mice. Take together, these results indicated that compound c20 could be a potential anti-cancer candidate for further clinical trial.
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Antineoplásicos/farmacologia , Camptotecina/farmacologia , Desenho de Fármacos , Ureia/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Camptotecina/síntese química , Camptotecina/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/químicaRESUMO
ß-amyloid (Aß) is one of the inducing factors of astrocytes activation and neuroinflammation, and it is also a crucial factor for the development of Alzheimer's disease (AD). Icariside II (ICS II) is an active component isolated from a traditional Chinese herb Epimedium, which has shown to attnuate lipopolysaccharide (LPS)-induced neuroinflammation through regulation of NF-κB signaling pathway. In this study we investigated the effects of ICS II on LPS-induced astrocytes activation and Aß accumulation. Primary rat astrocytes were pretreated with ICS II (5, 10, and 20 µM) or dexamethasone (DXMS, 1 µM) for 1 h, thereafter, treated with LPS for another 24 h. We found that ICS II pretreatment dose dependently mitigated the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) in the astrocytes. Moreover, ICS II not only exerted the inhibitory effect on LPS-induced IκB-α degradation and NF-κB activation, but also decreased the levels of Aß1-40, Aß1-42, amyloid precursor protein (APP) and beta secretase 1 (BACE1) in the astrocytes. Interestingly, molecular docking revealed that ICS II might directly bind to BACE1. It is concluded that ICS II has potential value as a new therapeutic agent to treat neuroinflammation-related diseases, such as AD.
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Astrócitos/efeitos dos fármacos , Flavonoides/farmacologia , Inflamação/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/metabolismo , Astrócitos/metabolismo , Relação Dose-Resposta a Droga , Flavonoides/administração & dosagem , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Inflamação/patologia , Lipopolissacarídeos , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Cuzhi2haofang (CZ2HF), a traditional Chinese medicine, has been used clinically for the treatment of amnesia. However, whether CZ2HF is capable of alleviating learning and memory impairment in Alzheimer's disease (AD) remains to be elucidated. The present study was designed to explore the effect and mechanism of CZ2HF on ßamyloid 2535 (Aß2535)induced impairment in the learning and memory of rats. Morris water maze test was used to determine spatial learning and memory ability in Aß2535induced AD rats and hippocampal neuronal damage and apoptosis were observed using hematoxylin and eosin staining, Nissl staining and terminal deoxynucleotidyltransferasemediated dUTP nickend labeling (TUNEL) assays, respectively. The levels of ßamyloid 142 (Aß142), proinflammatory factors, such as cyclooxygenase2 (COX2), tumor necrosis factorα (TNFα) and interleukin1ß (IL1ß) and apoptosisassociated genes including B cell leukemia/lymphoma 2 (Bcl2), Bcl-2associated X, apoptosis regulator (Bax), procaspase3, inhibitor of κB (IκBα) degradation and phosphorylatednuclear factorκB p65 (pNFκB p65) activation were analyzed using western blotting. The findings of the present study revealed that CZ2HF treatment significantly attenuated Aß2535induced cognitive impairments in rats. Subsequently, CZ2HF treatment markedly inhibited neuronal damage and deletions. Furthermore, CZ2HF reduced TNFα, IL1ß, COX2 protein expression levels, Bax/Bcl2 ratio, and reduced Aß142 and activecaspase3 levels. In addition, IκBα degradation and pNFκB p65 activation were reduced by CZ2HF. These findings suggested that CZ2HF treatment improved Aß2535induced learning and memory impairment and hippocampal neuronal injury, and its underlying mechanism may be due to the inhibition of neuroinflammation and neuronal apoptosis. CZ2HF may be a potential agent for the treatment of AD.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Apoptose , Medicamentos de Ervas Chinesas/uso terapêutico , Inflamação/patologia , Aprendizagem , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/patologia , Neurônios/patologia , Fragmentos de Peptídeos/toxicidade , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Hipocampo/patologia , Masculino , Transtornos da Memória/fisiopatologia , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/metabolismoRESUMO
Lithocarpus polystachyus Rehd. (sweet tea; ST) leaves is a type of Chinese folkloric medicine from southern China. The purpose of the present study was to explore the neuroprotective effect of ST, and to explore its underlying mechanisms in hydrogen peroxide (H2O2)induced neuronal cell injury in cultured human neuroblastoma. H2O2 was used as oxidant inducer and human SHSY5Y neuroblastoma cells were treated with various concentrations of ST. Cell viability and cell death were detected using MTT and LDH assays, respectively. Additionally, the production of intracellular and mitochondrial reactive oxygen species (ROS) were determined by 2',7'dichlorodihydrofluorescein diacetate (DCFHDA) and MitoSOX Red, respectively. The production of malondialdehyde (MDA), reduced glutathione (GSH) level, glutathione peroxidase (GSHPx), superoxide dismutase (SOD) activities, and NAD+/NADH ratio were confirmed using relevant kits. The expression of adenosine monophosphateactivated protein kinase (AMPK), peroxisome proliferatoractivated receptor coactivator (PGC)1α, Sirt3, isocitrate dehydrogenase (IDH)2, forkhead boxO3a (Foxo3a), and SOD2 were analyzed by western blot analysis. It was demonstrated that pretreatment with ST enhanced cell viability and repressed cell death, and it also reduced intracellular and mitochondrial ROS accumulation. Additionally, ST attenuated MDA production and enhanced GSH level, GSHPx and SOD activities. Furthermore, ST not only increased NAD+/NADH ratio, but also inhibited the decrease of AMPK, PGC1α, Sirt3, IDH2, Foxo3a, and SOD2. The present study revealed that ST exerts protective effects against oxidative stressinduced SHSY5Y cells injury, and the underlying mechanisms are, at least partly, associated with its antioxidant capacity and function through mitochondrial Sirt3 signaling pathway.
Assuntos
Fagaceae/química , Peróxido de Hidrogênio/toxicidade , Neuroblastoma/patologia , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Transdução de Sinais , Sirtuína 3/metabolismo , Adenilato Quinase/metabolismo , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Proteína Forkhead Box O3/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Isocitrato Desidrogenase/metabolismo , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , NAD/metabolismo , Neuroblastoma/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND/AIMS: Icariside II (ICS II) is an active component from Epimedium brevicornum, a Chinese medicine extensively used in China. Our previous study has proved that ICS II protects against learning and memory impairments and neuronal apoptosis in the hippocampus induced by beta-amyloid25-35 (Aß25-35) in rats. However, its in-depth underlying mechanisms remain still unclear. Hence this study was designed to explore the potential underlying mechanisms of ICS II by experiments with an in vivo model of Aß25-35-induced cognitive deficits in rats combined with a neuronal-like PC12 cells injury in vitro model. METHODS: The cognitive deficits was measured using Morris water maze test, and apoptosis, intracellular reactive oxygen species (ROS) and mitochondrial ROS levels were detected by TUNEL, DCFH-DA and Mito-SOX staining, respectively. Expression of Bcl-2, Bax, brain derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB), and cAMP response element binding (p-CREB) and active-Caspase 3 levels were evaluated by Western blot. RESULTS: It was found that ICS II, a phosphodiesterase-5 inhibitor, significantly attenuated cognitive deficits caused by Aß25-35 injection in rats, and ICS II not only significantly enhanced the expression of BDNF and TrkB, but also activated CREB. Furthermore, ICS II also significantly abrogated Aß25-35-induced PC12 cell injury, and inhibited Aß25-35-induced intracellular reactive oxygen species (ROS) overproduction, as well as mitochondrial ROS levels. In addition, ICS II up-regulated the expressions of BDNF and TrkB consistent with the findings in vivo. ANA-12, a TrkB inhibitor, blocked the neuroprotective effect of ICS II on Aß25-35-induced neuronal injury. CONCLUSION: ICS II mitigates Aß25-35-induced cognitive deficits and neuronal cell injury by upregulating the BDNF/TrkB/CREB signaling, suggesting that ICS II can be used as a potential therapeutic agent for dementia, such as Alzheimer's disease.
Assuntos
Doença de Alzheimer/prevenção & controle , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Flavonoides/farmacologia , Transdução de Sinais/efeitos dos fármacos , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , Animais , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Células PC12 , Fragmentos de Peptídeos/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor trkB/metabolismoRESUMO
Oxidative stress-induced neuronal cell damage is a crucial factor in the pathogenesis of mitochondria-associated neurological diseases. Therefore, elimination of overproduction of mitochondrial reactive oxygen species (mtROS) may be a potential strategy for prevention and treatment of neurological diseases. In the present study, the neuroprotective effects of trilobatin (TLB), a novel small molecule monomer derived from Lithocarpus polystachyus Rehd, and its underlying mechanisms were investigated in vitro using hydrogen peroxide (H2O2)-induced oxidative stress model in a neuron-like PC12 cell. The findings revealed that pre-treatment with TLB dramatically concentration-dependently suppressed H2O2-induced PC12 cells damage by enhancing cell viability, repressed reduction of mitochondrial membrane potential (MMP) and decreased mtROS overgeneration, thereby deferring cell apoptosis. Further study demonstrated that TLB not only increased the enzymatic activities of glutathione peroxidase (GPx), isocitrate dehydrogenase 2 (IDH2),superoxide dismutase 2 (SOD2) and deacetylation of SOD2, but also activated silent mating-type information regulation 2 homolog 3 (Sirt3) within the mitochondria and thereby upregulating forkheadboxO3a (FoxO3a), which regulated mitochondrial DNA genes, then led to improving complex I activity and adenosine triphosphate (ATP) synthesis. What's more, TLB up-regulated p-adenosine monophosphate-activated protein kinase (AMPK) level, the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), and ERRα. Intriguingly, TLB failed to mitigate H2O2-induced PC12 injury in the presence of the AMPK inhibitor (Compound C), indicating that the beneficial effects of TLB on the regulation of mtROS homeostasis were reliance on AMPK -Sirt3 signaling pathway. Moreover, TLB also facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) and promoted antioxidant gene expression in turn, and knockdown of Nrf2 by siRNA dramatically reduced the neuroprotective effects of TLB. Notably, AMPK inhibitor abolished the activation of Nrf2 and Sirt3, whereas, knockdown of Nrf2 blocked the upregulation of Sirt3, but it did not affect p-AMPK level. In conclusion, our findings demonstrate that TLB protects against oxidative injury in neuronal PC12 cells through regulating mtROS homeostasis in the first time, which is, at least partly, mediated through the AMPK/Nrf2/Sirt3 signaling pathway.