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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(4): 1093-1100, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34362487

RESUMO

OBJECTIVE: To investigate the clinicopathologic characteristics, diagnosis and therapy of aggressive natural killer cell leukemia (ANKL) patients. METHODS: Clinical manifestations, cellular morphology, immunophenotypic analysis by flow cytometry (FCM), TCR gene rearrangement, pathology and Immunohistochemical analysis of bone marrow (BM) were combined to diagnose the six patients with ANKL. RESULTS: The median age of the patients were 35.5 years old. All the patients with fever, cytopenia and liver dysfunction. Imageological examination presented hepatosplenomegaly (6/6), and PET/CT presented diffusely increased metabolism in liver, spleen and BM (3/3). BM cytologic examination presented increased hematophagocyte at the early stage and 1%-42% leukemic cell were detected in BM with the progression of diseases. FCM showed the leukemic cells were positive for CD2(6/6), CD56(5/6), CD16(2/6), CD94(3/6), CD38(3/6), cCD3(1/5), CD8(1/6), CD7(2/6), CD57(1/6) and negative for CD3, CD4, TdT, cMPO, TCR α/ß, TCR γ/δ. The neoplastic cells were negative for TCR gene rearrangement. Five cases showed increased quantitation of whole blood Epstein-Barr virus (EBV) DNA. CONCLUSION: ANKL is a highly aggressive disease. Prompt and repeating BM examination is important to patient with fever, cytopenia and liver dysfunction. The diagnosis of ANKL relies mainly on the integration of clinical, morphologic, immunophenotypic finding and EBV-DNA increasement.


Assuntos
Infecções por Vírus Epstein-Barr , Leucemia Linfocítica Granular Grande , Adulto , Herpesvirus Humano 4 , Humanos , Imunofenotipagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada
2.
Pharmacol Res ; 170: 105697, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34062240

RESUMO

With the increase in human lifespan, population aging is one of the major problems worldwide. Aging is an irreversible progressive process that affects humans via multiple factors including genetic, immunity, cellular oxidation and inflammation. Progressive neuroinflammation contributes to aging, cognitive malfunction, and neurodegenerative diseases. However, precise mechanisms or drugs targeting age-related neuroinflammation and cognitive impairment remain un-elucidated. Traditional herbal plants have been prescribed in many Asian countries for anti-aging and the modulation of aging-related symptoms. In general, herbal plants' efficacy is attributed to their safety and polypharmacological potency via the systemic manipulation of the body system. Radix polygalae (RP) is a herbal plant prescribed for anti-aging and the relief of age-related symptoms; however, its active components and biological functions remained un-elucidated. In this study, an active methanol fraction of RP containing 17 RP saponins (RPS), was identified. RPS attenuates the elevated C3 complement protein in aged mice to a level comparable to the young control mice. The active RPS also restates the aging gut microbiota by enhancing beneficial bacteria and suppressing harmful bacteria. In addition, RPS treatment improve spatial reference memory in aged mice, with the attenuation of multiple molecular markers related to neuroinflammation and aging. Finally, the RPS improves the behavior and extends the lifespan of C. elegans, confirming the herbal plant's anti-aging ability. In conclusion, through the mouse and C. elegas models, we have identified the beneficial RPS that can modulate the aging process, gut microbiota diversity and rectify several aging-related phenotypes.

3.
Front Pharmacol ; 12: 683935, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122112

RESUMO

Neuroinflammation, an inflammatory response within the central nervous system (CNS), is a main hallmark of common neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), among others. The over-activated microglia release pro-inflammatory cytokines, which induces neuronal death and accelerates neurodegeneration. Therefore, inhibition of microglia over-activation and microglia-mediated neuroinflammation has been a promising strategy for the treatment of neurodegenerative diseases. Many drugs have shown promising therapeutic effects on microglia and inflammation. However, the blood-brain barrier (BBB)-a natural barrier preventing brain tissue from contact with harmful plasma components-seriously hinders drug delivery to the microglial cells in CNS. As an emerging useful therapeutic tool in CNS-related diseases, nanoparticles (NPs) have been widely applied in biomedical fields for use in diagnosis, biosensing and drug delivery. Recently, many NPs have been reported to be useful vehicles for anti-inflammatory drugs across the BBB to inhibit the over-activation of microglia and neuroinflammation. Therefore, NPs with good biodegradability and biocompatibility have the potential to be developed as an effective and minimally invasive carrier to help other drugs cross the BBB or as a therapeutic agent for the treatment of neuroinflammation-mediated neurodegenerative diseases. In this review, we summarized various nanoparticles applied in CNS, and their mechanisms and effects in the modulation of inflammation responses in neurodegenerative diseases, providing insights and suggestions for the use of NPs in the treatment of neuroinflammation-related neurodegenerative diseases.

5.
Phytother Res ; 35(2): 954-973, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32893437

RESUMO

Blood-brain barrier (BBB) dysfunction has been implicated in Alzheimer's disease (AD) and is closely linked to the release of proinflammatory cytokines in brain capillary endothelial cells. We have previously reported that lychee seed polyphenols (LSP) exerted anti-neuroinflammatory effect. In this study, we aimed to explore the protective effect of LSP on BBB integrity. The monolayer permeability of bEnd.3 cells, and the mRNA level and protein expression of tight junction proteins (TJs), including Claudin 5, Occludin, and ZO-1, were examined. In addition, the inhibition of Aß(25-35)-induced NLRP3 inflammasome activation, and the autophagy induced by LSP were investigated by detecting the expression of NLRP3, caspase-1, ASC, LC3, AMPK, mTOR, and ULK1. Furthermore, the cognitive function and the expression of TJs, NLRP3, caspase-1, IL-1ß, and p62 were determined in APP/PS1 mice. The results showed that LSP significantly decreased the monolayer permeability and inhibited the NLRP3 inflammasome in Aß(25-35)-induced bEnd3 cells. In addition, LSP induced autophagy via the AMPK/mTOR/ULK1 pathway in bEnd.3 cells, and improved the spatial learning and memory function, increased the TJs expression, and inhibited the expression of NLRP3, caspase-1, IL-1ß, and p62 in APP/PS1 mice. Therefore, LSP protects BBB integrity in AD through inhibiting Aß(25-35)-induced NLRP3 inflammasome activation via the AMPK/mTOR/ULK1-mediated autophagy.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Doença de Alzheimer/tratamento farmacológico , Autofagia/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Inflamassomos/efeitos dos fármacos , Litchi/química , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Polifenóis/uso terapêutico , Sementes/química , Animais , Masculino , Camundongos , Camundongos Transgênicos , Polifenóis/farmacologia , Transfecção
6.
Ageing Res Rev ; 65: 101202, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33161129

RESUMO

Neuroinflammation is considered as a detrimental factor in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), etc. Nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3), the most well-studied inflammasome, is abundantly expressed in microglia and has gained considerable attention. Misfolded proteins are characterized as the common hallmarks of neurodegenerative diseases due to not only their induced neuronal toxicity but also their effects in over-activating microglia and the NLRP3 inflammasome. The activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Emerging evidence indicates that microglial autophagy plays an important role in the maintenance of brain homeostasis and the negative regulation of NLRP3 inflammasome-mediated neuroinflammation. The excessive activation of NLRP3 inflammasome impairs microglial autophagy and further aggravates the pathogenesis of neurodegenerative diseases. In this review article, we summarize and discuss the NLRP3 inflammasome and its specific inhibitors in microglia. The crucial role of microglial autophagy and its inducers in the removal of misfolded proteins, the clearance of damaged mitochondria and reactive oxygen species (ROS), and the degradation of the NLRP3 inflammasome or its components in neurodegenerative diseases are summarized. Understanding the underlying mechanisms behind the sex differences in NLRP3 inflammasome-mediated neurodegenerative diseases will help researchers to develop more targeted therapies and increase our diagnostic and prognostic abilities. In addition, the superiority of the combined use of microglial autophagy inducers with the specific inhibitors of the NLRP3 inflammasome in the inhibition of NLRP3 inflammasome-mediated neuroinflammation requires further preclinical and clinical validations in the future.


Assuntos
Inflamassomos , Doenças Neurodegenerativas , Autofagia , Feminino , Humanos , Masculino , Microglia , Proteína 3 que Contém Domínio de Pirina da Família NLR
7.
Oxid Med Cell Longev ; 2020: 6069354, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32832002

RESUMO

Naringin is a dihydroflavonoid, which is rich in several plant species used for herbal medicine. It has a wide range of biological activities, including antineoplastic, anti-inflammatory, antiphotoaging, and antioxidative activities. So it would be interesting to know if naringin has an effect on aging and aging-related diseases. We examined the effect of naringin on the aging of Caenorhabditis elegans (C. elegans). Our results showed that naringin could extend the lifespan of C. elegans. Moreover, naringin could also increase the thermal and oxidative stress tolerance, reduce the accumulation of lipofuscin, and delay the progress of aging-related diseases in C. elegans models of AD and PD. Naringin could not significantly extend the lifespan of long-lived mutants from genes in insulin/IGF-1 signaling (IIS) and nutrient-sensing pathways, such as daf-2, akt-2, akt-1, eat-2, sir-2.1, and rsks-1. Naringin treatment prolonged the lifespan of long-lived glp-1 mutants, which have decreased reproductive stem cells. Naringin could not extend the lifespan of a null mutant of the fox-head transcription factor DAF-16. Moreover, naringin could increase the mRNA expression of genes regulated by daf-16 and itself. In conclusion, we show that a natural product naringin could extend the lifespan of C. elegans and delay the progression of aging-related diseases in C. elegans models via DAF-16.


Assuntos
Envelhecimento/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/efeitos dos fármacos , Flavanonas/uso terapêutico , Fatores de Transcrição Forkhead/metabolismo , Longevidade/efeitos dos fármacos , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Flavanonas/farmacologia
8.
Biomed Pharmacother ; 130: 110575, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32768883

RESUMO

Emerging evidence indicates that the enhancement of microglial autophagy inhibits the NLRP3 inflammasome mediated neuroinflammation in Alzheimer's disease (AD). Meanwhile, low density lipoprotein receptor-related protein 1 (LRP1) highly expressed in microglia is able to negatively regulate neuroinflammation and positively regulate autophagy. In addition, we have previously reported that an active lychee seed fraction enriching polyphenol (LSP) exhibits anti-neuroinflammation in Aß-induced BV-2 cells. However, its molecular mechanism of action is still unclear. In this study, we aim to investigate whether LSP inhibits the NLRP3 inflammasome mediated neuroinflammation and clarify its molecular mechanism in Aß-induced BV-2 cells and APP/PS1 mice. The results showed that LSP dose- and time-dependently activated autophagy by increasing the expression of Beclin 1 and LC3II in BV-2 cells, which was regulated by the upregulation of LRP1 and its mediated AMPK signaling pathway. In addition, both the Western blotting and fluorescence microscopic results demonstrated that LSP could significantly suppress the activation of NLRP3 inflammasome by inhibiting the expression of NLRP3, ASC, the cleavage of caspase-1, and the release of IL-1ß in Aß(1-42)-induced BV-2 cells. In addition, the siRNA LRP1 successfully abolished the effect of LSP on the activation of AMPK and its mediated autophagy, as well as the inhibition of NLRP3 inflammasome. Furthermore, LSP rescued PC-12 cells which were induced by the conditioned medium from Aß(1-42)-treated BV-2 cells. Moreover, LSP improved the cognitive function and inhibited the NLRP3 inflammasome in APP/PS1 mice. Taken together, LSP inhibited the NLRP3 inflammasome-mediated neuroinflammation in the in vitro and in vivo models of AD, which was closely associated with the LRP1/AMPK-mediated autophagy. Thus, the findings from this study further provide evidences for LSP serving as a potential drug for the treatment of AD in the future.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Peptídeos beta-Amiloides , Inflamassomos/antagonistas & inibidores , Litchi , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos , Polifenóis/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Modelos Animais de Doenças , Inflamassomos/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RNA Interferente Pequeno , Ratos , Sementes
9.
Oxid Med Cell Longev ; 2020: 1293935, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32733632

RESUMO

Secoisolariciresinol diglucoside (SDG) is a phytoestrogen and rich in food flaxseed, sunflower seeds, and sesame seeds. Among the beneficial pharmacological activities of SDG on health, many are age related, such as anticancer, antidiabetes, antioxidant, and neuroprotective effects. Thus, we investigated if SDG had an effect on antiaging in Caenorhabditis elegans (C. elegans). Our results showed that SDG could extend the lifespan of C. elegans by up to 22.0%, delay age-related decline of body movement, reduce the lethality of heat and oxidative stress, alleviate dopamine neurodegeneration induced by 6-hydroxydopamine (6-OHDA), and decrease the toxicity of Aß protein in C. elegans. SDG could increase the expression of the downstream genes of DAF-16, DAF-12, NHR-80, and HSF-1 at mRNA level. SDG could not extend the lifespan of mutants from genes daf-16, hsf-1, nhr-80, daf-12, glp-1, eat-2, and aak-2. The above results suggested that SDG might enhance the stress resistance, delay the progression of aging-related diseases, and extend the lifespan of C. elegans via DAF-16 and HSF-1.


Assuntos
Butileno Glicóis/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Glucosídeos/farmacologia , Longevidade/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Butileno Glicóis/envenenamento , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/metabolismo , Progressão da Doença , Glucosídeos/envenenamento , Longevidade/genética , Estresse Oxidativo/efeitos dos fármacos
10.
Mol Med Rep ; 22(3): 2115-2122, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32582988

RESUMO

Neuropathic pain (NP) is a refractory and long­lasting disease caused mostly by peripheral nerve injury. Currently, the mechanism of NP is yet to be elucidated. Intracellular calcium homeostasis is critical for some physiological functions, including the occurrence of NP. NCKX2, encoded by the solute carrier family 4 member 2 (SLC24A2) gene, is an important K+­dependent Na+­Ca2+ exchanger that mediates Ca2+ extrusion. The role of NCKX2 in the development of NP is unknown. For this purpose, a sciatic nerve chronic constriction injury (CCI) model was established and it was revealed that the expression levels of SLC24A2 and its encoded protein NCKX2 were both downregulated in the posterior horn of the spinal cord. Overexpression of SLC24A2 reduced both mechanical and thermal hyperalgesia and decreased the expression of inflammatory cytokines [interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α] in CCI rats. Using bioinformatics analyses, luciferase reporter assays, and a series of behavioral tests, it was demonstrated that the decrease in SLC24A2 after CCI treatment was directly regulated by increased microRNA (miR)­135a­5p in the spinal cord. Moreover, the effects of miR­135a­5p on NP were SLC24A2­dependent. In conclusion, the present results highlighted the suppressive role of NCKX2 in NP, which is mainly regulated by miR­135a­5p and mediates the release of inflammatory cytokines in the dorsal horn of the spinal cord. These findings deepen our understanding of the development of NP and provide novel candidates for NP treatment.


Assuntos
MicroRNAs/genética , Neuralgia/genética , Trocador de Sódio e Cálcio/genética , Animais , Biologia Computacional/métodos , Modelos Animais de Doenças , Regulação para Baixo , Masculino , Neuralgia/etiologia , Ratos , Regulação para Cima
11.
Biogerontology ; 21(5): 669-682, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32506187

RESUMO

Aging is related to the lowered overall functioning and increased risk for various age-related diseases in humans. Tectochrysin is a flavonoid compound and rich in a traditional Chinese Medicine Alpinia oxyphylla Miq., which has antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, anti-diarrhea, hepatoprotective, and neuro-protective effects. Therefore, we tested if tectochrysin had an effect on aging in Caenorhabditis elegans (C. elegans). Our results showed that tectochrysin could extend the lifespan of C. elegans by up to 21.0%, delay the age-related decline of body movement, improve high temperature-stress resistance and anti-infection capacity, and protected worms against Aß1-42-induced toxicity. Tectochrysin could not extend the lifespan of the mutants from genes daf-2, daf-16, eat-2, aak-2, skn-1, and hsf-1. Tectochrysin could increase the expression of DAF-16 regulated genes. The extension of lifespan by tectochrysin requires FOXO/DAF-16 and HSF-1. Overall, our findings suggest that tectochrysin may have a potential effect on extending lifespan and age-related diseases.

12.
Cancers (Basel) ; 12(1)2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31941010

RESUMO

Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1ß, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1ß and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-κB signaling pathway via increasing reactive oxygen species (ROS) levels in A549 and H1299 cells, and N-acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-κB and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-κB/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future.

13.
Transl Lung Cancer Res ; 9(6): 2411-2427, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33489803

RESUMO

Background: Circular RNAs (circRNAs) are known to participate in lung cancer. However, their role in spinal metastasis (SM) of lung adenocarcinoma remains elusive. In this study, we determined that hsa_circ_0006571 serves as a sponge for miR-138, which targets sirtuin 1 (Sirt1) in the development of SM. Methods: A human circRNA microarray was performed to compare SM and lung adenocarcinoma samples. The expression of hsa_circ_0006571 and miR-138 was determined using quantitative polymerase chain reaction (qPCR) in vitro and in vivo. Cell proliferation was performed by Cell Counting Kit-8 (CCK-8) and apoptosis was analyzed by Annexin V/PI staining. RNA-pulldown and RNA immunoprecipitation (RIP) were used to analyze the interaction between hsa_circ_0006571. Tumor metastasis was determined through a xenograft experiment in vivo. Results: Hsa_circ_0006571 was observed to be significantly upregulated in SM tissues through circRNA microarray and qPCR. We detected a lower expression of miR-138 in SM tissues compared with lung adenocarcinoma. Hsa_circ_0006571 silencing suppressed lung cancer cell proliferation and migration while promoting apoptosis. Hsa_circ_0006571 interacted with miR-138 to promote expression of Sirt1, leading to activation of epithelial-mesenchymal transition (EMT). Xenograft experiments showed that downregulation of hsa_circ_0006571 delayed the SM of lung adenocarcinoma cells via the miR-138-Sirt1 axis. Conclusions: Hsa_circ_0006571 promoted tumor cell migration and invasion via the miR-138/Sirt1 pathway. Our observations indicate that circRNAs are possible novel therapeutic targets for SM of lung adenocarcinoma.

14.
Phytomedicine ; 65: 153088, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31627105

RESUMO

BACKGROUND: Emerging evidences indicate the important roles of autophagy in anti-oxidative stress, which is closely associated with cancer, aging and neurodegeneration. OBJECTIVE: In the current study, we aimed to identify autophagy inducers with potent anti-oxidative effect from traditional Chinese medicines (TCMs) in PC-12 cells and C. elegans. METHODS: The autophagy inducers were extensively screened in our herbal extracts library by using the stable RFP-GFP-LC3 U87 cells. The components with autophagic induction effect in Trillium tschonoskii Maxim. (TTM) was isolated and identified by using the autophagic activity-guided column chromatography and Pre-HPLC technologies, and MS and NMR spectroscopic analysis, respectively. The anti-oxidative effect of the isolated autophagy inducers was evaluated in H2O2-induced PC-12 cells and C. elegans models by measuring the viability of PC-12 cells and C. elegans, with quantitation on the ROS level in vitro and in vivo using H2DCFDA probe. RESULTS: The total ethanol extract of TTM was found to significantly increase the formation of GFP-LC3 puncta in stable RFP-GFP-LC3 U87 cells. One novel steroidal saponin 1-O-[2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl-(1→2)-4-O-acetyl-α-L-arabinopyranosyl]-21-Deoxytrillenogenin, (Deoxytrillenoside CA, DTCA) and one known steroidal saponin 1-O-[2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl-(1→2)-4-O-acetyl-α-L-arabinopyranosyl]-21-O-acetyl-epitrillenogenin (Epitrillenoside CA, ETCA) were isolated, identified and found to have novel autophagic effect. Both DTCA and ETCA could activate autophagy in PC-12 cells via the AMPK/mTOR/p70S6K signaling pathway in an Atg7-dependent. In addition, DTCA and ETCA could increase the cell viability and decrease the intracellular ROS level in H2O2-treated PC-12 cells and C. elegans, and the further study demonstrated that the induced autophagy contributes to their anti-oxidative effect. CONCLUSION: Our current findings not only provide information on the discovery of novel autophagy activators from TTM, but also confirmed the anti-oxidative effect of the components from TTM both in vitro and in vivo.


Assuntos
Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Caenorhabditis elegans/efeitos dos fármacos , Dissacaridases/farmacologia , Saponinas/farmacologia , Trillium/química , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Proteína 7 Relacionada à Autofagia/metabolismo , Caenorhabditis elegans/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Dissacaridases/química , Humanos , Peróxido de Hidrogênio/farmacologia , Células PC12 , Extratos Vegetais/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Saponinas/química , Saponinas/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
15.
J Cancer Res Clin Oncol ; 145(9): 2343-2355, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280348

RESUMO

PURPOSE: Combinations of bortezomib (Velcade), cyclophosphamide and dexamethasone have shown significant efficacy and safety for patients of newly diagnosed multiple myeloma (NDMM). In this study, we compared the efficacy and safety of modified VCD regimens with novel changes in bortezomib dose and schedule for NDMM. METHODS: Eighty-five NDMM patients from multiple centers were randomly assigned to a high-dose (1.6 mg/m2) (group A) or a low-dose (1.3 mg/m2) (group B) bortezomib, administrated on days 1, 6, 11, and 16 subcutaneously in a 4-week cycle for nine cycles, combined with 40 mg dexamethasone on bortezomib days and cyclophosphamide 300 mg/m2 on days 1-3 intravenously. RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During induction, for patients with R-ISS stage III, the CR or better rate in group A was superior to that in group B (P = 0.01). Of patients < 65, the CR or better rate of group A was superior to that of group B (P = 0.004). Rapid onset of CR occurred in group A (P < 0.01). Meanwhile, rate of 3-4 diarrhea was higher in group A (P = 0.03), which caused higher rate of dose reduction for patients ≥ 65 (P = 0.041). No significant difference between the two groups in PFS and OS. CONCLUSIONS: The studied high-dose VCD as induction regimen had an improved CR rate, especially in patients < 65 or with R-ISS stage III, and is feasible for young and high-risk patients. Trial registration ClinicalTrials.gov: NCT02086942.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Teniposídeo/administração & dosagem , Resultado do Tratamento
16.
Oxid Med Cell Longev ; 2019: 5768953, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249646

RESUMO

Aging is a complex life process, and a unified view is that metabolism plays key roles in all biological processes. Here, we determined the lipidomic profile of Caenorhabditis elegans (C. elegans) using ultraperformance liquid chromatography high-resolution mass spectrometry (UPLC-HRMS). Using a nontargeted approach, we detected approximately 3000 species. Analysis of the lipid metabolic profiles at young adult and ten-day-old ages among wild-type N2, glp-1 defective mutant, and double mutant daf-16;glp-1 uncovered significant age-related differences in the total amount of phosphatidylcholines (PC), sphingomyelins (SM), ceramides (Cer), diglycerides (DG), and triglycerides (TG). In addition, the age-associated lipid profiles were characterized by ratio of polyunsaturated (PUFA) over monounsaturated (MUFA) lipid species. Lipid metabolism modulation plays an important role in reproduction-regulated aging; to identify the variations of lipid metabolites during germ line loss-induced longevity, we investigated the lipidomic profiles of long-lived glp-1/notch receptor mutants, which have reproductive deficiency when grown at nonpermissive temperature. The results showed that there was some age-related lipid variation, including TG 40:2, TG 40:1, and TG 41:1, which contributed to the long-life phenotype. The longevity of glp-1 mutant was daf-16-dependent; the lipidome analysis of daf-16;glp-1 double mutant revealed that the changes of some metabolites in the glp-1 mutant were daf-16-dependent, while other metabolites displayed more complex epistatic patterns. We first conducted a comprehensive lipidome analysis to provide novel insights into the relationships between longevity and lipid metabolism regulated by germ line signals in C. elegans.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Lipídeos/análise , Longevidade , Reprodução , Transdução de Sinais , Animais , Caenorhabditis elegans/crescimento & desenvolvimento
17.
Orthop Surg ; 11(1): 60-65, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30767427

RESUMO

OBJECTIVE: A retrospective study was designed to evaluate the effectiveness of CT-guided core needle biopsy in diagnosing spinal lesions through comparison with C-arm guidance. METHODS: From April 2013 to July 2017, a total of 188 patients, who suffered from spinal lesions or had malignant tumor history with a new spinal fracture, were included in this study. There were 96 men and 92 women, with an average of 57.1 years. A total of 238 core needle biopsies were performed. A total of 140 core needle biopsies were carried out under C-arm guidance in 102 patients (group 1); 98 core needle biopsies were carried out under CT guidance in 86 patients (group 2); 108 core needle biopsies were performed in thoracic vertebrae, 116 were in lumbar vertebrae, and 14 were in sacral vertebrae. Seventy-eight patients accepted surgical treatment after biopsies. For these patients, the histological pathologies of the biopsy and surgery were compared to evaluate the accuracy of the biopsy. For the other 110 patients who did not receive surgical treatment, the treatment response and the clinical course were used to evaluate the accuracy of the biopsy. The success rate, the diagnostic accuracy rate, the true positive/negative rate, and complications of the two groups were calculated and compared. RESULTS: There were no significant differences in sex, age, and lesion sites between the C-arm guidance group (group 1) and the CT guidance group (group 2). There were no complications in the two groups. Pathological diagnoses were established in 232 of 238 biopsies. They revealed that 52 were primary malignant tumors, 12 were benign tumors, 70 were metastatic tumors, 4 were tuberculosis, and 94 were classified as "other." The success rate of group 2 was higher than that of group 1, but it was not statistically significant (95.7% vs 100%; P = 0.098). According to the final diagnosis, the diagnostic accuracy rates were calculated and compared. There was no significant difference between the two groups (95.5% vs 96.9%; P = 0.835). The kappa coefficient was used to analyze the concordance between the histological pathologies of the biopsy and the final diagnosis in the two groups. The kappa values of the two group were 0.909 and 0.939, respectively. The results showed good consistency in both groups, but seemed better for group 2. CONCLUSION: CT-guided core needle biopsy is a relatively safe and effective procedure for diagnosing spinal lesions with a high diagnostic accuracy rate and few complications.


Assuntos
Biópsia com Agulha de Grande Calibre/métodos , Doenças da Coluna Vertebral/diagnóstico por imagem , Doenças da Coluna Vertebral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia com Agulha de Grande Calibre/efeitos adversos , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Radiografia Intervencionista/métodos , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/patologia , Neoplasias da Coluna Vertebral/secundário , Tomografia Computadorizada por Raios X/métodos , Adulto Jovem
18.
Molecules ; 23(6)2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29874836

RESUMO

Aging is a major risk factor for many prevalent diseases. Pharmacological intervention to improve the health span and extend the lifespan could be a preventive elixir for aging and age-related diseases. The non-steroid anti-inflammation medicine aspirin was reported to delay aging in Caenorhabditis elegans (C. elegans) and mice. We are wondering if the analogues of aspirin could also present antiaging activity. Here, we synthesized several aspirin derivatives and investigated their thermotolerance and antiaging effect in C. elegans. One of the compounds, 5-(bis(3-methylbut-2-en-1-yl)amino)-2-hydroxybenzoic acid, moderately increased the survival of C. elegans under heat stress, but could not extend the lifespan under optimum conditions. This compound could increase the mRNA level of stress response gene gst-4, and the mRNA and protein expression level of heat shock protein hsp-16.2 under heat stress. The failure of activating the transcription factor DAF-16 might explain why this compound could not act as aspirin to extend the lifespan of C. elegans. Our results would help further the investigation of the pharmacological activity of aspirin analogues and the relationship between structures and activity.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Aspirina/análogos & derivados , Caenorhabditis elegans/efeitos dos fármacos , Resposta ao Choque Térmico , Proteínas de Helminto/metabolismo , Temperatura Alta , Animais , Aspirina/química , Aspirina/farmacologia , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Helminto/genética , Longevidade , RNA Mensageiro/genética
19.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(3): 824-828, 2018 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-29950227

RESUMO

OBJECTIVE: To compare the pharmaco-economic effect of 3 chemotherapeutic regimens in the treatment of patients with multiple myeloma(MM). METHODS: One hundred and thirty-eight newly diagnosed cases of MM in our hospital were analyzed retrospectively, and then MM patients were divided into group A, B and C group according to therapeutic regimen. Group A was treated with VCD therapeutic regimen (bortezomib + cyclophosphamide + dexamethasone, 63 cases), The patients in group B was treated with BiCTD therapeutic regimen (clarithromycin+cyclophosphamide+thalidomide+dexamethasone, 44 cases), The patients in group C was treated with CTD therapeutic regimen (cyclophosphamide+ thalidomide+dexamethasone, 33 cases). The clinical efficacy, adverse reaction, cost-effectiveness were observed and analysed after 4 courses of treatment among 3 groups. RESULTS: The overall response rates of group A, B and C were 96.83%, 81.82% and 64.52% with statistical significant difference (P<0.01). The high efficiency response rates of 3 groups were 82.5%, 59.09%, 32.26% with very significant statistical difference (P<0.01). The infection rate of group A was statistically and significantly higher than other 2 groups (P=0.048), and the constipation rate in group A was statistically and significantly higer than that in group B and C (P<0.05). The cost-effectiveness ratios of 3 groups were 69567.44, 20765.12 and 21475.48, respectively. The incremental cost-effectiveness ratio of group A and B were 183933.21 and 22259.09, as compared with group C. The result was in accordance with sensitivity test. CONCLUSION: Clinicial efficacy of group A is the best,but group B has advantages on cost-effectiveness ratio as compared with other groups, otherwise, group B has low incidence of adverse reaction. In the view of safety, therapeutic efficacy and pharmacoeconomics for treatment of patients with MM, the BiCTD regimen has been confirmed to be superior to the other 2 groups.


Assuntos
Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Análise Custo-Benefício , Ciclofosfamida , Dexametasona , Humanos , Estudos Retrospectivos , Talidomida , Resultado do Tratamento
20.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(2): 477-483, 2018 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-29665919

RESUMO

OBJECTIVE: To investigate the effects of bortezomib(BTZ) and thalidomide(TM) on peripheral blood memory T-cells (Tm) and regulatory T cells(Tregs) in patients with multiple myeloma(MM). METHODS: Eighty-six MM patients received 2 courses of chemotherapy were divided into effective (partial response at least) group (63 cases) and ineffective (no partial response) group (17 cases) according to therapeutic efficacy; these 80 patients were divided into BTZ group (38 cases) and TM group (42 cases) yet according to therapeutic regimens, 20 newly diagnosed MM patients were used as baseline group, 30 healthy volunteers were used as healthy control group. The Tm subsets and Treg in peripheral blood of each groups were detected by flow cytometry. RESULTS: The CD4+ central memory T cells (CD4+ TCM) percentage of CD4+ Tm, the CD18+ TCM percentage of CD18+Tm and ratio of CD8+ TCM and CD8+ effector memory T cells (TEM) (CD8+ TCM/TEM) in baseline group were all significantly lower than those in healthy control group (P<0.05). After treatment with BTZ regimen or TM regimen, the CD8+TCM percentage of CD8+ Tm in effective group significantly increased to level of healthy control group (P<0.05); the Treg cell level in effective and in effective groups was not significantly different from that in baseline group(P>0.05), but the Treg percentage of CD4+ cells ineffective group was significantly higher than that in baseline group and ineffective group (P<0.05). According to ROC curve, the critical value of CD8+TCM/TEM for predicting chemotherapeutic response was 0.27 with sensitivity of 57.1% and specificity of 94.1%. CONCLUSION: When MM patients are in an immuno-exhanstive status, the treatment with BTZ or TM both can reverse the immuno-inhibitory status of MM patients, moreover, does not affect the Treg cell count; the Treg percentage in BTZ and TM effective groups both are significantly higher than that in baseline group and ineffective group. The ratio of CD8+TCM/TEM contributes to evaluating the chemotherapeutic efficacy.


Assuntos
Mieloma Múltiplo , Bortezomib , Citometria de Fluxo , Humanos , Subpopulações de Linfócitos T , Linfócitos T Reguladores , Talidomida
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