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1.
Chin J Integr Med ; 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32144561

RESUMO

OBJECTIVE: To study the effect and mechanism of Huayu Wan (, HYW) in combination of chemotherapy of tumor treatment. METHODS: HYW serum was added in Lewis cells to assess its impact on fluorescent doxorubicin delivery in vitro. Then, Lewis tumor cells was implanted in C57BL/6 mice via xenograft transplantation. Tumor growth was measured and signal intensity corresponding to blood flow was assessed by laser doppler perfusion imaging (LDPI). Finally, the effect of HYW on the effificacy of doxorubicin was studied. RESULTS: HYW can improve the transfer of fluorescent doxorubicin into cells. The blood flow signal in the tumor tissues of the HYW group was higher than that of the control group (P<0.01). Furthermore, HYW improved drug delivery of doxorubicin to tumor tissues, and this activity was associated with HYW-induced microvascular proliferation (P<0.01). CONCLUSIONS: HYW can promote microangiogenesis and increase blood supply in tumor tissues, which in turn may increase the risk of metastasis. At the same time, HYW increases drug delivery and improves the effificacy of chemotherapy drugs through vascular proliferation. Therefore, rational judgment must be exercised when considering applying HYW to an antitumor regimen.

2.
Medicine (Baltimore) ; 99(3): e18828, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011495

RESUMO

BACKGROUND: Nausea and vomiting are the most common complications following chemotherapy and usually lead to decreased quality of life. Acupuncture therapy is an effective method for chemotherapy-induced nausea and vomiting (CINV), the effects and safety have been observed by many clinicians and demonstrated in a systematic review, which was included in the Cochrane Library in 2014. After several years, new studies have occurred and an updated systematic evaluation is needed. This protocol describes a method for performing a systematic review and meta-analysis to further evaluate the beneficial effects and safety of acupuncture for CINV. METHODS: A searching strategy will be carried out mainly in eight databases in English and Chinese, Cochrane Central Register of Controlled Trials, PubMed, Embase, China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang database, China Doctoral Dissertations Full-text Database, and China Master's Theses Full-text Database. Only randomized controlled trials related to acupuncture for CINV will be included to enhance the effectiveness. The effective percentage will be used as primary outcome. Changes in the symptoms of nausea and vomiting, like severity, duration, and frequency as well as quality of life will be assessed as secondary outcome. Side effects and adverse events will be used as safety evaluations. To ensure the quality of the systematic evaluation, study selection, data extraction, and quality assessment will be independently performed by 2 authors, and the third author will deal with any disagreement. The Review Manager V.5.3.3 s will be used to perform the data synthesis and subgroup analysis. RESULTS: There are additional studies, further explanations and more subgroup analyses compared with the previous systematic analysis to determine the effects and safety of acupuncture for CINV. CONCLUSION: The result of this systematic review may offer clinicians stronger evidence to assist patient in relieving CINV. ETHICS AND DISSEMINATION: There is no need to acquire ethical approval for individuals come from literatures instead of recruiting directly. The findings of this review will be reported in peer-reviewed publications and/or presented at relevant conferences TRIAL REGISTRATION NUMBER:: CRD42016045223.


Assuntos
Terapia por Acupuntura , Antineoplásicos/efeitos adversos , Náusea/induzido quimicamente , Náusea/prevenção & controle , Vômito/induzido quimicamente , Vômito/prevenção & controle , Humanos
3.
Artigo em Inglês | MEDLINE | ID: mdl-32109045

RESUMO

Sodium-ion batteries (SIBs) are recognized as attractive alternatives for grid-scale electrochemical energy storage applications. Transition metal oxide cathodes represent one of the most dynamic materials for industrialization among the various cathodes for SIBs. Here, a cation-doped cathode Na0.44Mn0.89Ti0.11O2 with a tunnel structure is introduced, which undergoes a lowered volume change of only 5.26% during the Na+ insertion/extraction process. Moreover, the average Na+ diffusion coefficients are enhanced by more than 3-fold upon the doping of the Ti cation. The obtained cathode delivers a practically usable capacity of 119 mAh g-1 at 0.1 C as well as an enhanced discharge capacity of 96 mAh g-1 at 5 C. Durability is demonstrated by the retained 71 mAh g-1 after 1000 cycles, corresponding to a capacity retention of 74%. This work demonstrates that the reticular Na0.44Mn0.89Ti0.11O2 is a promising ultrastable cathode material for the development of long-life sodium-ion batteries.

4.
J Am Geriatr Soc ; 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32096884

RESUMO

OBJECTIVE: To test whether self-administered acupressure reduces stress and stress-related symptoms in caregivers of older family members. DESIGN: In this randomized, assessor-blind, controlled trial, 207 participants were randomized (1:1) to an acupressure intervention or a wait-list control group. SETTING: Community centers in Hong Kong, China. PARTICIPANTS: Primary caregivers of an older family member who screened positive for caregiver stress with symptoms of fatigue, insomnia, or depression. INTERVENTION: The 8-week intervention comprised four training sessions on self-administered acupressure, two follow-up sessions for learning reinforcement, and daily self-practice of self-administered acupressure. MEASUREMENTS: The primary outcome was caregiver stress (Caregiver Burden Inventory). Secondary outcomes included fatigue (Piper Fatigue Scale), insomnia (Pittsburgh Sleep Quality Index), depression (Patient Health Questionnaire), and health-related quality of life (QoL) (12-item Short-Form Health Survey version 2). An intention-to-treat analysis was adopted. RESULTS: Of 207 participants, 201 completed the study. Caregiver stress in the intervention group was significantly lower than that in the control group after 8 weeks (difference = -8.12; 95% confidence interval [CI] = -13.20 to -3.04; P = .002) and at 12-week follow-up (difference = -8.52; 95% CI = -13.91 to -3.12; P = .002). The intervention group, relative to the control group, also had significantly improved secondary outcomes of fatigue (difference = -0.84; 95% CI = -1.59 to -0.08; P = .031), insomnia (difference = -1.34; 95% CI = -2.40 to -0.27; P = .014), depression (difference = -1.76; 95% CI = -3.30 to -0.23; P = .025), and physical health-related QoL (difference = 3.08; 95% CI = 0.28-5.88; P = .032) after 8 weeks. CONCLUSION: Self-administered acupressure intervention significantly relieves self-reported caregiver stress and co-occurring symptoms in those caring for older family members. Further studies are needed to measure the symptoms objectively and to examine the clinical importance of the observed improvement in caregiver stress.

5.
Oncogene ; 39(11): 2408-2423, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31959898

RESUMO

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.

6.
J Neuroinflammation ; 17(1): 11, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31915018

RESUMO

BACKGROUND: Emerging evidence indicates that inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Several proteins including α-synuclein trigger the activation of NLRP3 inflammasome. However, few studies examined whether inflammasomes are activated in the periphery of PD patients and their possible value in the diagnosis or tracking of the progress of PD. The aim of this study was to determine the association between inflammasome-induced inflammation and clinical features in PD. METHODS: There were a total of 67 participants, including 43 patients with PD and 24 controls, in the study. Participants received a complete evaluation of motor and non-motor symptoms, including Hoehn and Yahr (H-Y) staging scale. Blood samples were collected from all participants. The protein and mRNA expression levels of inflammasomes subtypes and components in peripheral blood mononuclear cells (PBMCs) were determined using western blotting and RT-qPCR. We applied Meso Scale Discovery (MSD) immunoassay to measure the plasma levels of IL-1ß and α-synuclein. RESULTS: We observed increased gene expression of NLRP3, ASC, and caspase-1 in PBMCs, and increased protein levels of NLRP3, caspase-1, and IL-1ß in PD patients. Plasma levels of IL-1ß were significantly higher in patients with PD compared with controls and have a positive correlation with H-Y stage and UPDRS part III scores. Furthermore, plasma α-synuclein levels were also increased in PD patients and have a positive correlation with both UPDRS part III scores and plasma IL-1ß levels. CONCLUSIONS: Our data demonstrated that the NLRP3 inflammasome is activated in the PBMCs from PD patients. The related inflammatory cytokine IL-1ß and total α-synuclein in plasma were increased in PD patients than controls, and both of them presented a positive correlation with motor severity in patients with PD. Furthermore, plasma α-synuclein levels have a positive correlation with IL-1ß levels in PD patients. All these findings suggested that the NLRP3 inflammasome activation-related cytokine IL-1ß and α-synuclein could serve as non-invasive biomarkers to monitor the severity and progression of PD in regard to motor function.

7.
Acta Pharmacol Sin ; 41(2): 270-277, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31316177

RESUMO

KRAS is one of the most important proto-oncogenes. Its mutations occur in almost all tumor types, and KRAS mutant cancer is still lack of effective therapy. Prenyl-binding protein phosphodiesterase-δ (PDEδ) is required for the plasma membrane association and subsequent activation of KRAS oncogenic signaling. Recently, targeting PDEδ has provided new promise for KRAS mutant tumors. However, the therapeutic potential of PDEδ inhibition remains obscure. In this study, we explored how PDEδ inhibition was responded in KRAS mutant cancer cells, and identified KRAS mutant subset responsive to PDEδ inhibition. We first performed siRNA screen of KRAS growth dependency of a small panel of human cancer lines, and identified a subset of KRAS mutant cancer cells that were highly dependent on KRAS signaling. Among these cells, only a fraction of KRAS-dependent cells responded to PDEδ depletion, though KRAS plasma membrane association was effectively impaired. We revealed that the persistent RAF/MEK/ERK signaling seemed responsible for the lack of response to PDEδ depletion. A kinase array further identified that the feedback activation of EPH receptor A2 (EPHA2) accounted for the compensatory activation of RAF/MEK/ERK signaling in these cells. Simultaneous inhibition of EPHA2 and PDEδ led to the growth inhibition of KRAS mutant cancer cells. Together, this study gains a better understanding of PDEδ-targeted therapeutic strategy and suggests the combined inhibition of EPHA2 and PDEδ as a potential therapy for KRAS mutant cancer.

8.
Eur J Pharmacol ; 864: 172719, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586634

RESUMO

Gambogic acid (GA) is a potential anti-cancer compound that is extracted from the resin of Garciania hanburyi. The present study was designed to evaluate the anti-metastatic effect of GA on melanoma cell lines in vitro and to explore the underlying mechanism. The anti-proliferative activity of GA on melanoma cells was assessed by CCK-8 assay. The Wound-healing, transwell, adhesion, and tube formation assays were performed to examine the inhibition of GA on the cell's migration, invasion, adhesion, and angiogenesis capacities, respectively. Enzymatic activity of MMP-2 and MMP-9 were detected by gelatin zymography assay. Protein expressions regulated by GA treatment were tested by Western blot assay. The present results showed that GA significantly inhibited the proliferation of highly metastatic melanoma A375, B16-F10 cells and human umbilical vein endothelial cells (HUVECs) in time- and doses-dependent manners. Furthermore, GA significantly inhibited the migratory, invasive and adhesive properties of A375 and B16-F10 cells, and tube-forming potential of HUVECs at sub-IC50 concentrations, where no significant cytotoxicity was observed. Mechanistically, GA treatment suppressed the EMT and angiogenesis processes and reduced the enzymatic activity of MMP-2 and MMP-9. Moreover, abnormal PI3K/Akt and ERK signaling pathways in A375 and B16-F10 cells and HUVECs were notably suppressed by GA treatment. Collectively, our results suggest that GA exerts anti-metastasis activity in melanoma cells by suppressing the EMT and angiogenesis through the PI3K/Akt and ERK signaling pathways, and might be used as a phytomedicine against metastatic melanoma.

9.
Neurosci Lett ; 709: 134379, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31323253

RESUMO

Deficiency of deleted in liver cancer 2 (DLC2), a novel domain to inhibit RhoA activity, plays an important role in inflammatory pain. However, the underlying mechanisms remain unclear. This study investigated the role of DLC2 and its downstream cascade of RhoA/ROCK in formalin-induced inflammatory pain using DLC2-knockout (DLC2-/-) mice and compared them with DLC2 wild-type (DLC2+/+) mice. Mechanical allodynia and thermal hyperalgesia were evaluated using von Frey filament aesthesiometer and Hargreaves test, respectively. The spinal cord dorsal horn (L3-L5) was selected for molecular and cellular identification by Western blot and immunofluorescence. DLC2-/- mice showed increased mechanical allodynia and thermal hyperalgesia. Expression of ROCK1, ROCK2 and IL-1ß was significantly higher in DLC2-/- mice. Intrathecal administration of RhoA inhibitor (C3 exoenzyme) or ROCK inhibitor (Y27632) significantly attenuated formalin-induced inflammatory hyperalgesia in DLC2-/- mice. ROCK2 and IL-1ß expression were reduced by C3 exoenzyme or Y27632. Spinal p38 activation was also inhibited by C3 exoenzyme or Y27632. Double-labelling immunofluorescence demonstrated co-localization of DLC2 with spinal dorsal microglia. The number of activated microglia in the spinal dorsal horn was significantly higher in DLC2-/- mice, but was reduced by Y27632. These findings indicate that DLC2 deficiency increased formalin-induced inflammatory hyperalgesia through regulating RhoA/ROCK2, and IL-1ß may be a downstream effector. Our results also suggest that RhoA/ROCK enhanced p38 activation plays an important role in formalin-induced inflammatory pain. The finding that DLC2 attenuated inflammatory pain through inhibiting RhoA/ROCK2 suggests that the DLC2/RhoA/ROCK2/p38/IL-ß pathway may be a potential therapeutic target to reduce inflammatory pain.

10.
Chin J Nat Med ; 17(3): 161-186, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30910054

RESUMO

Chimonanthus plants widely distributed in southern area of China, which have a long history of edibles and medicine. Phytochemical investigations have shown that Chimonanthus produced 143 non-volatile constituents, including alkaloids, flavonoids, terpenoids, coumarins and others, which exhibit significant anti-oxidant, anti-bacterial, anti-cancer, anti-inflammatory, antihyperglycemic, antihyperlipidemic and other biological activities. On the basis of systematic reviewing of literatures, this article overviews the non-volatile constituents and pharmacology of Chimonanthus from domestic and foreign over the last 30 years (until June 2018), and may provide a useful reference for the further development of Chimonanthus.


Assuntos
Calycanthaceae/química , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Animais , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/toxicidade , Humanos , Medicina Tradicional Chinesa , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/toxicidade , Fitoterapia
11.
J Vis Exp ; (143)2019 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-30735150

RESUMO

A proper animal model is crucial for a better understanding of diseases. Animal models established by different methods (subcutaneous injections, xenografts, genetic manipulation, chemical reagents induction, etc.) have various pathological characters and play important roles in investigating certain aspects of diseases. Although no single model can totally mimic the whole human disease progression, orthotopic organs disease models with a proper stromal environment play an irreplaceable role in understanding diseases and screening for potential drugs. In this article, we describe how to implant breast cancer cells into the mammary fat pad in a simple, less invasive, and easy-to-handle way, and follow the metastasis to distant organs. With the proper features of primary tumor growth, breast and nipple pathological changes, and a high occurrence of other organs' metastasis, this model maximumly mimics human breast cancer progression. Primary tumor growth in situ, long-distant metastasis, and the tumor microenvironment of breast cancer can be investigated by using this model.


Assuntos
Tecido Adiposo , Glândulas Mamárias Animais/citologia , Neoplasias Mamárias Experimentais/patologia , Transplante de Neoplasias/métodos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Injeções , Camundongos , Camundongos Endogâmicos BALB C , Transplante Heterólogo , Microambiente Tumoral
12.
Neural Regen Res ; 14(6): 1037-1045, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30762016

RESUMO

Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer's disease remain unclear. In the present study, Alzheimer's disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer's disease-like diseases. APP/PS1 double transgenic (5XFAD; Jackson Laboratory) mice and their littermates (wild-type, controls) were used in this study. Additional 6-week-old and 10-week-old 5XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For 10-week-old 5XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer's disease. The use and care of animals were in strict accordance with the ethical standards of the Animal Ethics Committee of Capital Medical University, China on December 17, 2015 (approval No. AEEI-2015-182).

13.
Mol Neurobiol ; 56(8): 5626-5642, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30659419

RESUMO

Chemotherapy-induced cognitive impairment, also known as "chemobrain," is a common side effect. The purpose of this study was to examine whether ginsenoside Rg1, a ginseng-derived compound, could prevent chemobrain and its underlying mechanisms. A mouse model of chemobrain was developed with three injections of docetaxel, adriamycin, and cyclophosphamide (DAC) in combination at a 2-day interval. Rg1 (5 and 10 mg/kg daily) was given 1 week prior to DAC regimen for 3 weeks. An amount of 10 mg/kg Rg1 significantly improved chemobrain-like behavior in water maze test. In vivo neuroimaging revealed that Rg1 co-treatment reversed DAC-induced decreases in prefrontal and hippocampal neuronal activity and ameliorated cortical neuronal dendritic spine elimination. It normalized DAC-caused abnormalities in the expression of multiple neuroplasticity biomarkers in the two brain regions. Rg1 suppressed DAC-induced elevation of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), but increased levels of the anti-inflammatory cytokines IL-4 and IL-10 in multiple sera and brain tissues. Rg1 also modulated cytokine mediators and inhibited DAC-induced microglial polarization from M2 to M1 phenotypes. In in vitro experiments, while impaired viability of PC12 neuroblastic cells and hyperactivation of BV-2 microglial cells, a model of neuroinflammation, were observed in the presence of DAC, Rg1 co-treatment strikingly reduced DAC's neurotoxic effects and neuroinflammatory response. These results indicate that Rg1 exerts its anti-chemobrain effect in an association with the inhibition of neuroinflammation by modulating microglia-mediated cytokines and the related upstream mediators, protecting neuronal activity and promoting neuroplasticity in particular brain regions associated with cognition processing.


Assuntos
Antineoplásicos/efeitos adversos , Encéfalo/patologia , Disfunção Cognitiva/prevenção & controle , Citocinas/metabolismo , Ginsenosídeos/uso terapêutico , Inflamação/tratamento farmacológico , Microglia/patologia , Plasticidade Neuronal , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Comportamento Animal , Biomarcadores/sangue , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Citocinas/sangue , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Feminino , Ginsenosídeos/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Locomoção/efeitos dos fármacos , Imagem por Ressonância Magnética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Células PC12 , Ratos
14.
Transl Neurodegener ; 8: 3, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30675347

RESUMO

Background: Parkinson's disease (PD) is characterized by a chronic loss of dopaminergic neurons and the presence of proteinaceous inclusions (Lewy bodies) within some remaining neurons in the substantia nigra. Recently, astroglial inclusion body has also been found in some neurodegenerative diseases including PD. However, the underlying molecular mechanisms of how astroglial protein aggregation forms remain largely unknown. Here, we investigated the contribution of αB-crystallin (CRYAB), a small heat shock protein, in α-synuclein inclusion formation in astrocytes. Methods: Small interfering RNA (siRNA)-mediated CRYAB (siCRYAB) knockdown or CRYAB overexpression was performed to investigate the impact of CRYAB on the autophagy in human glioblastoma cell line U251 cells. Co-immunoprecipitation (co-IP) and immunoblotting were used to dissect the interaction among multiple proteins. The clearance of α-synuclein in vitro was evaluated by immunocytochemistry. CRYAB transgenic mice and transgenic mice overexpressing A30P mutant form of human α-synuclein were used to examine the influence of CRYAB to α-synuclein accumulation in vivo. Results: We found that knockdown of CRYAB in U251 cells or primary cultured astrocytes resulted in a marked augmentation of autophagy activity. In contrast, exogenous CRYAB disrupted the assembly of the BAG3-HSPB8-HSC70 complex via binding with BAG3, thereby suppressing the autophagy activity. Furthermore, CRYAB-regulated autophagy has relevance to PD pathogenesis. Knockdown of CRYAB remarkably promoted cytoplasmic clearance of α-synuclein preformed fibrils (PFFs). Conversely, selective overexpression of CRYAB in astrocytes markedly suppressed autophagy leading to the accumulation of α-synuclein aggregates in the brain of transgenic mice expressing human α-synuclein A30P mutant. Conclusions: This study reveals a novel function for CRYAB as a natural inhibitor of astrocytic autophagy and shows that knockdown of CYRAB may provide a therapeutic target against proteinopathies such as synucleinopathies.

15.
Neural Regen Res ; 14(5): 913-920, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30688278

RESUMO

Many studies have shown that (5R)-5-hydroxytriptolide is the optimal modified analogue of triptolide, possessing comparable immunosuppressive activity but much lower cytotoxicity than triptolide. Whether (5R)-5-hydroxytriptolide has preventive effects on neuroinflammation is unclear. This study was designed to pretreat primary astrocytes from the brains of neonatal Sprague-Dawley rats with 20, 100 and 500 nM (5R)-5-hydroxytriptolide for 1 hour before establishing an in vitro neuroinflammation model with 1.0 µg/mL lipopolysaccharide for 24 hours. The generation of nitric oxide was detected by Griess reagents. Astrocyte marker glial fibrillary acidic protein was measured by immunohistochemical staining. The levels of tumor necrosis factor-α and interleukin-1ß in the culture supernatant were assayed by enzyme linked immunosorbent assay. Nuclear factor-κB/p65 expression was examined by immunofluorescence staining. The phosphorylation of inhibitor of nuclear factor IκB-α and the location of nuclear factor-κB/P65 were determined using western blot assay. Our data revealed that (5R)-5-hydroxytriptolide inhibited the generation of nitric oxide, tumor necrosis factor-α and interleukin-1ß from primary astrocytes activated by lipopolysaccharide, decreased the positive reaction intensity of glial fibrillary acidic protein, reduced the expression of tumor necrosis factor alpha and interleukin-1ß in culture supernatant, inhibited the phosphorylation of IκB-α and the translocation of nuclear factor-κB/P65 to the nucleus. These results have confirmed that (5R)-5-hydroxytriptolide inhibits lipopolysaccharide-induced glial inflammatory response and provides cytological experimental data for (5R)-5-hydroxytriptolide in the treatment of neurodegenerative diseases.

16.
Neurosci Res ; 145: 22-29, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30125610

RESUMO

Electrical stimulation could enhance nerve regeneration and functional recovery. The objective of this study was to evaluate the regenerative effects of implanted electrodes with different contacts in resected sciatic nerve. Sciatic nerve resection and microsurgical repair models were established and randomly divided into four groups (point contact, 1/4 circle contact; whole-circle contact; no electrodes as control). Electrical stimulation was performed and electrophysiological, morphological and histological exams (of the sciatic nerve and muscle) were conducted at 4 and 10 weeks post-implantation. Point and 1/4 circle contact groups showed significantly higher scores in the sciatic functional index (SFI), increased amplitude of compound muscle action potential (AMP) and motor nerve conduction velocity (MNCV) compared to the control group at both 4 and 10 weeks post-implantation. Point and 1/4 circle contact morphologically promoted sciatic nerve regeneration and reduced muscular atrophy with less mechanical injury to the nerve trunk observed compared with the whole-circle contact group at both 4 and 10 weeks post-implantation. Electrodes with point and 1/4 circle contacts represented an alternatively portable and effective method of electrical stimulation to facilitate injured sciatic nerve regeneration and reduce subsequent muscular atrophy, which might offer a promising approach for treating peripheral nerve injuries.


Assuntos
Terapia por Estimulação Elétrica/métodos , Eletrodos Implantados , Traumatismos dos Nervos Periféricos/terapia , Recuperação de Função Fisiológica , Nervo Isquiático/lesões , Animais , Masculino , Músculo Esquelético/inervação , Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/patologia , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/patologia , Nervo Isquiático/ultraestrutura
17.
Res Vet Sci ; 122: 102-110, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30481676

RESUMO

Heat stress (HS) and its associated pathologies are major challenges facing the pig industry in southern China, and are responsible for large economic losses. However, the molecular mechanisms governing the abnormal secretion of HS-responsive hormones, such as glucocorticoids, are not fully understood. The goal of this study was to investigate differentially expressed proteins (DEPs) in the adrenal glands of pigs, and to elucidate changes in the immune neuroendocrine system in pigs following HS. Through a functional proteomics approach, we identified 1202 peptides, corresponding to 415 proteins. Of these, we found 226 DEPs between heat-stressed and control porcine adrenal gland tissue; 99 of these were up-regulated and 127 were down-regulated in response to HS. These DEPs included proteins involved in substrate transport, cytoskeletal changes, and stress responses. Ingenuity Pathway Analysis was used to identify the subcellular characterization, functional pathway involvement, regulatory networks, and upstream regulators of the identified proteins. Functional network and pathway analyses may provide insights into the complexity and dynamics of HS-host interactions, and may accelerate our understanding of the mechanisms of HS.


Assuntos
Glândulas Suprarrenais/metabolismo , Resposta ao Choque Térmico , Proteômica , Suínos , Animais , Regulação para Baixo , Regulação da Expressão Gênica , Regulação para Cima
18.
Eur J Pain ; 23(4): 812-822, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30570802

RESUMO

BACKGROUND: Total intravenous anesthesia with propofol has been shown to reduce postoperative pain in some clinical studies, but knowledge of its underlying analgesic mechanism remains limited. In this study, we compared the analgesic effects of propofol versus isoflurane in an animal model of postoperative pain and evaluated its underlying molecular mechanisms. METHODS: Plantar incision was made in the hind paws of rats under general anesthesia with 2.5% of inhalational isoflurane (isoflurane group) or intravenous infusion of propofol (1.5 mg kg-1  min-1 , propofol group). Mechanical allodynia was assessed by paw withdrawal threshold before and after incision. Spinal dorsal horns (L3-L5) were harvested 1 hr after incision to assess the level of phosphorylated GluN2B, p38MAPK, ERK, JNK, and EPAC using Western blot and immunofluorescence. RESULTS: Mechanical allodynia induced by plantar incision peaked at 1 hr and lasted for 3 days after incision. It was significantly less in the propofol group compared with the isoflurane group in the first 2 hr following incision. The incision-induced increases in phosphorylated GluN2B, p38MAPK, and EPAC1 were significantly reduced in the propofol group. The number of spinal dorsal neurons co-expressed with EPAC1 and c-Fos after the incision was significantly lower in the propofol group. CONCLUSION: Propofol reduced pain responses in an animal model of postoperative pain and suppressed the spinal GluN2B-p38MAPK/EPAC1 signaling pathway. Since the p38MAPK/EPAC pathway plays a critical role in the development of postoperative hyperalgesia, our results provide evidence-based behavioral, molecular, and cellular mechanisms for the analgesic effects of propofol when used for general anesthesia. SIGNIFICANCE: These findings may provide a new mechanism for the postsurgical analgesic effect of propofol, which is particularly interesting during the subacute period after surgery as it is the critical period for the development of persistent postsurgical pain.


Assuntos
Anestésicos Inalatórios/farmacologia , Anestésicos Intravenosos/farmacologia , Fatores de Troca do Nucleotídeo Guanina/efeitos dos fármacos , Isoflurano/farmacologia , Dor Pós-Operatória/metabolismo , Propofol/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Corno Dorsal da Medula Espinal/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Hiperalgesia/metabolismo , Masculino , Período Pós-Operatório , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Mol Neurobiol ; 56(3): 2234-2243, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30008071

RESUMO

Chemotherapy-induced cognitive impairment, often referred to as "chemobrain," is a common side effect. In this study, mice received three intraperitoneal injections of a combination of docetaxel, adriamycin, and cyclophosphamide (DAC) at 2-day intervals. A water maze test was used to examine cognitive performance, and manganese-enhanced magnetic resonance imaging (MEMRI) was used to examine hippocampal neuronal activity. The whole brain, prefrontal cortex, hippocampus, and blood samples were then collected for cytokine measurement. The DAC-treated mice displayed a significantly shorter duration spent in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In a separate experiment using in vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines without changing the rate of spine formation, leading to a striking loss of spines in the medial prefrontal cortex. DAC treatment resulted in significant elevations in the levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) and in significant decreases in the levels of the anti-inflammatory cytokines IL-4 and IL-10 in most of the sera and brain tissues examined. The IL-6 and TNF-α levels of several sera and brain tissues showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain.


Assuntos
Antineoplásicos/farmacologia , Transtornos Cognitivos/induzido quimicamente , Cognição/efeitos dos fármacos , Citocinas/metabolismo , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Antineoplásicos/efeitos adversos , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/metabolismo , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Docetaxel/efeitos adversos , Docetaxel/farmacologia , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacologia , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Imagem por Ressonância Magnética , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos
20.
Neuropsychiatry (London) ; 8(4): 1249-1262, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364895

RESUMO

Fatigue, the most common side effect of cancer treatments, is observed to intensify during external-beam radiation therapy (EBRT). The underlying molecular mechanisms remain unclear. This study investigated the differentially expressed genes/proteins and their association with fatigue intensification during EBRT. Fatigue scores measured by FACT-F and peripheral blood were collected prior to treatment (baseline D0), at midpoint (days 19-21, D21) and endpoint (days 38-42, D42) from men (n=30) with non-metastatic prostate cancer undergoing EBRT. RNA extracted from peripheral blood was used for gene expression analysis. Plasma arginase I and arginine were examined using ELISA and liquid chromatography-tandem mass spectrometry. Differences in fatigue scores, gene and protein expression between times points following EBRT were analyzed by one way ANOVA followed by Post Hoc t-test. Fatigue scores decreased significantly from baseline (44.6 ± 8.1) to midpoint (37.3 ± 10.6, p=0.000, low scores indicating high fatigue) and to endpoint (37.4 ± 10.1, p=0.001) during EBRT. ARG1 (encoding arginase type 1) was significantly up regulated from baseline to midpoint of EBRT (fold change =2.41, p<0.05) whereas genes associated with the adaptive immune functional pathway (CD28, CD27, CCR7, CD3D, CD8A and HLA-DOB) were significantly downregulated >2-fold between the study time points. The changes in gene expression were associated with patient reported fatigue intensity. Moreover, the upregulation of ARG1 was negatively correlated with the absolute lymphocyte count (R2=0.561, p=0.01) only in the high level of fatigue group (n=17) during EBRT. Increased ARG1 expression is known to result in arginine deficiency, which leads to immunosuppression by impairing lymphocyte proliferation and activation. EBRT-induced ARG1 upregulation may play an essential role in fatigue intensification via the arginine deficiency and suppression of T-cell proliferation pathways. These findings may provide novel insights into the molecular-genetic mechanisms underlying the development and intensification of cancer treatment-related fatigue.

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