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1.
Stroke Vasc Neurol ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642253

RESUMO

INTRODUCTION: The safety outcomes of endovascular therapy for intracranial artery stenosis in a real-world stetting are largely unknown. The Clinical Registration Trial of Intracranial Stenting for Patients with Symptomatic Intracranial Artery Stenosis (CRTICAS) was a prospective, multicentre, real-world registry designed to assess these outcomes and the impact of centre experience. METHODS: 1140 severe, symptomatic intracranial arterial stenosis (ICAS) patients treated with endovascular therapy were included from 26 centres, further divided into three groups according to the annual centre volume of intracranial angioplasty and stent placement procedures over 2 years: (1) high volume for ≥25 cases/year; (2) moderate volume for 10-25 cases/year and (3) low volume for <10 cases/year. RESULTS: The rate of 30-day stroke, transient ischaemic attack or death was 9.7% (111), with 5.4%, 21.1% and 9.7% in high-volume, moderate-volume and low-volume centres, respectively (p<0.05). Multivariable logistic regression confirmed high-volume centres had a significantly lower primary endpoint compared with moderate-volume centres (OR=0.187, 95% CI: 0.056 to 0.627; p≤0.0001), while moderate-volume and low-volume centres showed no significant difference (p=0.8456). CONCLUSION: Compared with the preceding randomised controlled trials, this real-world, prospective, multicentre registry shows a lower complication rate of endovascular treatment for symptomatic ICAS. Non-uniform utilisation in endovascular technology, institutional experience and patient selection in different volumes of centres may have an impact on overall safety of this treatment.

2.
Oxid Med Cell Longev ; 2021: 9966223, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34567416

RESUMO

Palmatine is a naturally occurring isoquinoline alkaloid that has been reported to display neuroprotective effects against amyloid-ß- (Aß-) induced neurotoxicity. However, the mechanisms underlying the neuroprotective activities of palmatine remain poorly characterized in vivo. We employed transgenic Caenorhabditis elegans models containing human Aß 1-42 to investigate the effects and possible mechanisms of palmatine-mediated neuroprotection. Treatment with palmatine significantly delayed the paralytic process and reduced the elevated reactive oxygen species levels in Aß-transgenic C. elegans. In addition, it increased oxidative stress resistance without affecting the lifespan of wild-type C. elegans. Pathway analysis suggested that the differentially expressed genes were related mainly to aging, detoxification, and lipid metabolism. Real-time PCR indicated that resistance-related genes such as sod-3 and shsp were significantly upregulated, while the lipid metabolism-related gene fat-5 was downregulated. Further studies demonstrated that the inhibitory effects of palmatine on Aß toxicity were attributable to the free radical-scavenging capacity and that the upregulated expression of resistance-related genes, especially shsp, whose expression was regulated by HSF-1, played crucial roles in protecting cells from Aß-induced toxicity. The research showed that there were significantly fewer Aß deposits in transgenic CL2006 nematodes treated with palmatine than in control nematodes. In addition, our study found that Aß-induced toxicity was accompanied by dysregulation of lipid metabolism, leading to excessive fat accumulation in Aß-transgenic CL4176 nematodes. The alleviation of lipid disorder by palmatine should be attributed not only to the reduction in fat synthesis but also to the inhibition of Aß aggregation and toxicity, which jointly maintained metabolic homeostasis. This study provides new insights into the in vivo neuroprotective effects of palmatine against Aß aggregation and toxicity and provides valuable targets for the prevention and treatment of AD.

3.
Front Neurol ; 12: 700732, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512518

RESUMO

Objective: This work explores collateral circulation metrics, such as the anterior borderzone angle grading (ABZA-grading), as a predictor of the prognosis in patients with acute middle cerebral artery occlusion (MCAO) following endovascular treatment (EVT). Methods: Clinical data from 108 patients with acute MCAO, treated by EVT, were retrospectively analyzed. In patients with MCAO, ABZA is the angle between the median line of the sagittal sinus and the borderzone of the pial arterioles of ACA and MCA, and the ABZA/23.0° was rounded to obtain the corresponding collateral circulation score (ABZA-grading). In parallel, the primary outcome was defined as the 90-day clinical outcome by modified ranking scale score (mRS). Univariate analysis and logistic regression were used to analyze the independent predictors of the 90-day clinical outcome (mRS). Receiver operating characteristic curve (ROC) analysis was used to judge the predictive value of ABZA. Results: Univariate analysis and logistic regression analysis showed that ABZA-grading > 2 and age were independent predictors of the 90-day clinical outcome after EVT in patients with acute MCAO. The ROC analysis showed that ABZA alone could predict a favorable 90-day clinical outcome with an area under the curve (AUC) of 0.868. Using an ABZA of >57.8° (the corresponding ABZA-grading of >2) as the cut-off value, the predictive sensitivity and specificity were 75.7 and 88.7%, respectively. Contingency table analysis showed a statistical difference in mRS score between ABZA-grading subgroups, and ABZA-grading between stroke caused by large artery atherosclerosis (LAA) and cardiogenic embolism (CE). Conclusion: The ABZA-grading is an easy and objective assessment of collateral circulation that is independently associated with short-time clinical outcome after EVT in patients with acute MCAO. Therefore, it may guide selection of patients with acute ischemic stroke (AIS) suitable for EVT. The ABZA-grading of collateral circulation can be a supplemental metric to help differentiate stroke by LAA and CE.

4.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360755

RESUMO

Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors; thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.


Assuntos
Achyranthes/química , Hipocampo/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores , Peptídeos , Proteínas de Plantas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/farmacologia , Proteínas de Plantas/química , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo
5.
Photodiagnosis Photodyn Ther ; 36: 102436, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34339844

RESUMO

Cutaneous blastomycosis is endemic to North America and is often caused by dimorphic fungi with spores that are inhaled, inoculated spores, or hyphae that infect immunosuppressed and healthy people. It is sporadic and described as a universal imitator with morphological manifestations as erythema, nodules, and ulcers. Our case demonstrated a 69-year-old female bitten by her pet dog who was then diagnosed with cutaneous blastomycosis through social history and detailed laboratory examinations. She experienced a prolonged failure with antibacterial treatment, negative stool and tissue culture, and chronic inflammatory cell infiltrates on tissue pathology. High-throughput sequencing was performed and showed evidence of Blastomyces dermatitidis aetiology. Photodynamic therapy combined with oral itraconazole was administered, and the patient recovered in a short time. Our case presents inoculated cutaneous blastomycosis and a treatment approach in which photodynamic therapy combined with oral itraconazole significantly reduced the duration of disease treatment and affords a promising choice for the treatment of cutaneous blastomycosis.

6.
Front Pharmacol ; 12: 716177, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456729

RESUMO

Neuroinflammation plays a crucial role in neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), and anti-inflammation has been considered as a potential therapeutic strategy. Achyranthes bidentate polypeptide fraction k (ABPPk) was shown to protect neurons from death and suppress microglia and astrocyte activation in PD model mice. However, how ABPPk regulates neuroinflammation to exert a neuroprotective role remains unclear. Toxic Aß oligomers (AßOs) can trigger inflammatory response and play an important role in the pathogenesis of AD. In the present study, for the first time, we investigated the effects and underlying mechanisms of ABPPk on neuroinflammation in AßOs-induced models of AD. In vitro, ABPPk pretreatment dose-dependently inhibited AßOs-induced pro-inflammatory cytokines mRNA levels in BV2 and primary microglia. ABPPk pretreatment also reduced the neurotoxicity of BV2 microglia-conditioned media on primary hippocampal neurons. Furthermore, ABPPk down-regulated the AßOs-induced phosphorylation of IκBα and NF-κB p65 as well as the expression of NLRP3 in BV2 microglia. In vivo, ABPPk pre-administration significantly improved locomotor activity, alleviated memory deficits, and rescued neuronal degeneration and loss in the hippocampus of AßOs-injected mice. ABPPk inhibited the activation of microglia in hippocampal CA3 region and suppressed the activation of NF-κB as well as the expression of NLRP3, cleaved caspase-1, and ASC in the brain after AßOs injection. ABPPk hindered the release of pro-inflammatory cytokines and promoted the release of anti-inflammatory cytokines in the brain. Notably, the polarization experiment on BV2 microglia demonstrated that ABPPk inhibited M1-phenotype polarization and promoted M2-phenotype polarization by activating the LPS- or AßOs-impaired autophagy in microglia. Taken together, our observations indicate that ABPPk can restore the autophagy of microglia damaged by AßOs, thereby promoting M2-phenotype polarization and inhibiting M1-phenotype polarization, thus playing a role in regulating neuroinflammation and alleviating neurotoxicity.

7.
Huan Jing Ke Xue ; 42(9): 4441-4451, 2021 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-34414744

RESUMO

Heavy metals in farmland soil are one of the most hazardous pollutants in the environment, owing to their universality and irreversibility. Modified biochar has been widely used in the adsorption and immobilization of heavy metals in soil, and its applicability is mainly determined by the types of heavy metals, pollution levels, and soil environmental conditions. Soil pollution is gradually becoming more complex and diversified, and heavy metal pollutants mostly occur in the form of compound pollution. However, most studies have focused on single heavy metal pollutant or the addition of heavy metal to soil. This study used rice straw as a raw material to prepare biochar, and modified it with K3PO4, KMnO4, and NaOH. The physicochemical and structural characteristics of the modified biochars were detected using a BET accelerated surface area and porosimetry system, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), and the biochars were then analyzed for the availability and forms of Cd and Cu in soils contaminated with heavy metals in the mining area. The results showed that the surface roughness of the modified biochar increased to different degrees with increases in specific surface area and pore volume, with the NaOH modified biochar showing the most significant increases from 4.96 m2·g-1 to 60.79 m2·g-1, and from 0.02 cm3·g-1 to 0.12 cm3·g-1, respectively. The pore diameter changed in the opposite direction. The absorption peaks of the functional groups of the modified biochar were all changed, with K3PO4 modified biochar exhibiting the greatest degree of change. The addition of biochar significantly improved the soil pH value (P<0.05), and the pH value of the soil treated with K3PO4 modified biochar exhibited the largest increase. With an application of 20.5% K3PO4 modified biochar, the availability of Cu and Cd in the soil was significantly reduced, by 75.44% and 67.70%, respectively. The immobilization efficiency of Cu was much higher than that of Cd. The best immobilization efficiency of Cu and Cd in soil was achieved with K3PO4 modified biochar. With an addition of 2% K3PO4 modified biochar, the immobilization efficiency of Cu and Cd was 61.06% and 4.12%, respectively. In summary, K3PO4 modified biochar had a better immobilization effect on both Cu and Cd in compound contaminated soil.


Assuntos
Recuperação e Remediação Ambiental , Poluentes do Solo , Cádmio , Carvão Vegetal , Poluição Ambiental/prevenção & controle , Fazendas , Solo , Poluentes do Solo/análise , Espectroscopia de Infravermelho com Transformada de Fourier
8.
Front Oncol ; 11: 649999, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34414103

RESUMO

Introduction: A modified and recombinant human endostatin (Rh-endostatin) is often used in the control of malignant pleural effusion (MPE) through intrapleural infusion. Objectives: To demonstrate the clinical response, survival, and safety of Rh-endostatin plus chemical irritants, their optimal combinations, treatment threshold, and optimal usage, we performed a new systematic review and meta-analysis. Methodology: All randomized controlled trials (RCTs) were collected from Chinese and English electronic databases (from inception until August 2020). We pooled the data using a series of meta-analyses and summarized the evidence quality following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results: We included 75 RCTs recruiting 4,678 patients, which reported six combinations for Rh-endostatin plus chemical irritants. Among the six combinations, only Rh-endostatin plus cisplatin (DDP) with enough trials might improve the complete response [2.29 (1.93, 2.71)] and quality of life [3.01 (2.49, 3.63)] and reduce treatment failure [0.29 (0.25, 0.33)] and progressive disease [0.27 (0.22, 0.34)]. It might not increase the risk of adverse drug reactions. For patients with lung cancer, moderate to massive effusion, initial treatment, Karnofsky Performance Status (KPS) score ≥60, or anticipated survival time ≥3 months, Rh-endostatin (30-45 mg each time, once or twice a week 3-4 times) plus DDP (30-60 mg/m2) obtained a significant improvement in clinical response and a reduction of failure and progressive disease. Most results had good robustness and moderate quality. Conclusions: Current evidence suggests that Rh-endostatin with DDP may be an optimal combination, which may improve clinical response and reduce failure and progressive disease with good safety. Rh-endostatin (30-40 mg each time, once or twice a week 3-4 times) with DDP (30-40 mg/m2) may be an optimal usage for achieving an ideal response.

9.
Sci Rep ; 11(1): 14897, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290266

RESUMO

Collagen-type I alpha 1 chain (COL1A1) and COL1A2 are abnormally expressed in intracranial aneurysm (IA), but their mechanism of action remains unclear. This study was performed to investigate the mechanism of COL1A1 and COL1A2 affecting the occurrence and rupture of IA. Quantitative real-time polymerase chain reaction was used to measure the expression of hsa-miR-513b-5p, COL1A1, COL1A2, TNF-α, IL-6, MMP2, MMP3, MMP9 and TIMP4 in patients with ruptured IA (RA) (n = 100), patients with un-ruptured IA (UA) (n = 100), and controls (n = 100). Then, human vascular smooth muscle cells (HASMCs) were cultured, and dual luciferase reporter assay was performed to analyse the targeting relationship between miR-513b-5p and COL1A1 or COL1A2. The effects of the miR-513b-5p mimic and inhibitor on the proliferation, apoptosis, and death of HASMC and the RIP1-RIP3-MLKL and matrix metalloproteinase pathways were also explored. The effect of silencing and over-expression of COL1A1 and COL1A2 on the role of miR-513b-5p were also evaluated. Finally, the effects of TNF-α on miR-513b-5p targeting COL1A1 and COL1A2 were tested. Compared with those in the control group, the serum mRNA levels of miR-513b-5p, IL-6 and TIMP4 were significantly decreased in the RA and UA groups, but COL1A1, COL1A2, TNF-α, IL-1ß, MMP2, MMP3 and MMP9 were significantly increased (p < 0.05). Compared with those in the UA group, the expression of COL1A1, COL1A2, TNF-α, IL-1ß and MMP9 was significantly up-regulated in the RA group (p < 0.05). Results from the luciferase reporter assay showed that COL1A1 and COL1A were the direct targets of miR-513b-5p. Further studies demonstrated that miR-513b-5p targeted COL1A1/2 to regulate the RIP1-RIP3-MLKL and MMP pathways, thereby enhancing cell death and apoptosis. Over-expression of COL1A1 or COL1A2, rather than silencing COL1A1/2, could improve the inhibitory effect of miR-513b-5p on cell activity by regulating the RIP1-RIP3-MLKL and MMP pathways. Furthermore, over-expression of miR-513b-5p and/or silencing COL1A1/2 inhibited the TNF-α-induced cell proliferation and enhanced the TNF-α-induced cell death and apoptosis. The mechanism may be related to the inhibition of collagen I and TIMP4 expression and promotion of the expression of RIP1, p-RIP1, p-RIP3, p-MLKL, MMP2 and MMP9. MiR-513b-5p targeted the inhibition of COL1A1/2 expression and affected HASMC viability and extracellular mechanism remodelling by regulating the RIP1-RIP3-MLKL and MMP pathways. This process might be involved in the formation and rupture of IA.

10.
Front Pharmacol ; 12: 582447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34122057

RESUMO

Introduction: Aidi injection (Aidi) is composed of cantharidin, astragaloside, ginsenoside, and elentheroside E. As an important adjuvant therapy, Aidi in combination with gemcitabine and cisplatin (GP) is often used in the treatment of non-small cell lung cancer (NSCLC). Objectives: We performed a new evaluation to demonstrate the clinical efficacy and safety of the Aidi and GP combination and further explored an optimal strategy for achieving an ideal response and safety level in advanced NSCLC. Methodology: We collected all the related trials from Chinese and English-language databases, analyzed their methodological bias risk using the Cochrane evaluation Handbook for Systematic Reviews of Interventions Version 5.1.0, extracted all the data using a predefined data extraction form, pooled the data using a series of meta-analyses, and finally summarized the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: We included 70 trials with 5,509 patients. Compared with GP alone, the Aidi and GP combination showed a significant improvement in the objective response rate (ORR) [1.82 (1.62-2.04)], disease control rate (DCR) [2.29 (1.97-2.67)], and quality of life (QOL) [3.03 (2.55-3.60)] and a low incidence of hematotoxicity and gastrointestinal and hepatorenal toxicity. Aidi might be more suitable for patients who are first-treated, elderly, or patients with a Karnofsky Performance Status (KPS) score ≥ 60 or anticipated survival time (AST) ≥3 months. An Aidi (50 ml/day, 7-14 days/cycle for one to two cycles), gemcitabine (1000 mg/m2), and cisplatin (20-30 mg/m2, 40-50 mg/m2, or 60-80 mg/m2) might be an optimal regimen for realizing an ideal response and safety level. Most results were robust and of moderate quality. Conclusion: Current evidence indicates that Aidi's value in adjuvant chemotherapy may be broad-spectrum, not just for some regimens. The Aidi and GP combination may show a good short-term response, antitumor immunity, and safety level in patients with NSCLC. Aidi (50 ml/day, 7-14 days/cycle for one and two cycles) with GEM (1000 mg/m2) and DDP (20-30 mg/m2 or 40-50 mg/m2) may be an optimal regimen for realizing an ideal goal in patients who are first-treatment, elderly, or have a KPS score ≥ 60 or AST≥3 months.

11.
Int Urol Nephrol ; 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34191230

RESUMO

BACKGROUND: Piperazine ferulate, a derivative of ferulic acid has been widely used in clinical practice for cardiovascular and kidney diseases in China. The objective of this meta-analysis was to investigate the benefits by adding piperazine ferulate to angiotensin receptor blockers (ARBs) in diabetic nephropathy patients. METHODS: PubMed, Embase, Cochrane Library, Wangfang, VIP, and CNKI database (until March 17, 2021) were comprehensively searched for randomized controlled trials investigating the effects of adding piperazine ferulate to ARBs in diabetic nephropathy patients. RESULTS: Data were retrieved from 14 RCTs involving 1374 patients. When compared with ARBs alone, co-administration of piperazine ferulate and ARBs significantly reduced urinary albumin excretion rate (weighted mean differences [WMD] - 20.32 µg/min; 95% confidence interval [CI] - 28.45 to - 12.19), 24-h proteinuria (WMD - 91.08 mg; 95% CI - 107.24 to - 74.91), ß2-microglobulin (standard mean difference [SMD] - 2.07; 95% CI - 2.51 to - 1.63), serum level of creatinine (WMD - 8.39 µmol/L; 95% CI - 11.87 to - 4.92), fibrinogen (WMD - 0.40 g/L; 95% CI - 0.46 to - 0.33), and plasma viscosity (WMD - 0.56 mPa s; 95% CI - 0.91 to - 0.21). Subgroup analysis showed that the effects of piperazine ferulate on UAER and serum creatinine were stronger in early diabetic nephropathy. However, piperazine ferulate had no significant effects on the serum blood urea nitrogen and fasting blood glucose. CONCLUSION: Adding piperazine ferulate to ARBs may achieve additional renal protective benefits, particular in early diabetic nephropathy patients.

12.
Neuroreport ; 32(6): 518-524, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33788819

RESUMO

Achyranthes bidentata polypeptide k (ABPPk), a powerful active component from a traditional Chinese medicinal herb-Achyranthes bidentata Bl., has exhibited promising neuroprotective activity due to its multiple-targeting capability. However, the effect of ABPPk on the survival, growth and axonal regeneration of spinal cord motor neurons remains unclear. Here, a modified method, which is more optimized for embryonic cells in ambient carbon dioxide levels, was used for acquisition of rat embryonic spinal cord motor neurons with high survival and purity. ABPPk concentration-dependently enhanced the neuronal viability and promoted the neurite outgrowth. Co-culture of motor neurons and skeletal myocytes model indicated that ABPPk enhanced the neuromuscular junction development and maturation. A microfluidic axotomy model was further established for the axonal disconnection, and ABPPk significantly accelerated the axonal regeneration of motor neurons. Furthermore, we demonstrated that the upregulation of three neurofilament protein subunits in motor neurons might be relevant to the mechanisms of the growth-promoting effect of ABPPk. Our findings provide an experimental and theoretical basis for the development of ABPPk as a potential application in the development of treatment strategy for nerve injury diseases.

13.
Am J Physiol Cell Physiol ; 320(5): C880-C891, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33502949

RESUMO

Renal cell carcinoma (RCC) has the highest mortality rate among urological cancers and tumor angiogenesis that plays a critical role in RCC progress. Epidermal growth factor-like domain multiple 7 (EGFL7) has been recently identified as a regulator in RCC tumor angiogenesis and progression. Long noncoding RNA (LncRNA) HOTAIR has been considered as a pro-oncogene in multiple cancers, but its precise mechanism of tumor angiogenesis has rarely been reported. MicroRNA-126 (miR-126) functions as a tumor suppressor in RCC. However, the underlying tumor angiogenesis mechanism of HOTAIR/miR-126 axis in RCC has not been studied. The proliferation, migration, angiogenesis, and expression of EGFL7 and related proteins in extracellular signal-regulated kinase (ERK)/activators of transcription 3 (STAT3) signal pathway were determined to examine the effect and mechanism of HOTAIR and miR-126 on RCC progress. The regulatory relationship of HOTAIR and miR-126, as well as miR-126 and EGFL7 were tested using dual-luciferase reporter assay. Aenograft RCC mice model was used to examine the effect of HOTAIR on RCC tumor growth and metastasis in vivo. HOTAIR knockdown and miR-126 overexpression suppressed the proliferation, migration, and angiogenesis of RCC cells. HOTAIR regulated EGFL7 expression by competitively binding to miR-126. Knockdown of HOTAIR significantly suppressed the RCC tumor progression and lung metastasis in vivo. These findings suggest that lncRNA HOTAIR regulate RCC angiogenesis through miR-126/EGFL7 axis and provide a new perspective on the molecular pathways of angiogenesis in RCC development, which might be potential therapeutic targets for RCC treatment.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Carcinoma de Células Renais/metabolismo , Família de Proteínas EGF/metabolismo , Neoplasias Renais/metabolismo , MicroRNAs/metabolismo , Neovascularização Patológica , RNA Longo não Codificante/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Família de Proteínas EGF/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Densidade Microvascular , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/genética , Transdução de Sinais , Carga Tumoral
14.
Acta Pharmacol Sin ; 42(5): 665-678, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32860006

RESUMO

Mitochondrial dysfunction is considered to be one of the important pathogenesis in Parkinson's disease (PD). We previously showed that pyrroloquinoline quinone (PQQ) could protect SH-SY5Y cells and dopaminergic neurons from cytotoxicity and prevent mitochondrial dysfunction in rotenone-induced PD models. In the present study we investigated the mechanisms underlying the protective effects of PQQ in a mouse PD model, which was established by intraperitoneal injection of rotenone (3 mg·kg-1·d-1, ip) for 3 weeks. Meanwhile the mice were treated with PQQ (0.8, 4, 20 mg·kg-1·d-1, ip) right after rotenone injection for 3 weeks. We showed that PQQ treatment dose-dependently alleviated the locomotor deficits and nigral dopaminergic neuron loss in PD mice. Furthermore, PQQ treatment significantly diminished the reduction of mitochondria number and their pathological change in the midbrain. PQQ dose-dependently blocked rotenone-caused reduction in the expression of PGC-1α and TFAM, two key activators of mitochondrial gene transcription, in the midbrain. In rotenone-injured human neuroblastoma SH-SY5Y cells, PTMScan Direct analysis revealed that treatment with PQQ (100 µM) differentially regulated protein phosphorylation; the differentially expressed phosphorylated proteins included the signaling pathways related with adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway. We conducted Western blot analysis and confirmed that AMPK was activated by PQQ both in PD mice and in rotenone-injured SH-SY5Y cells. Pretreatment with AMPK inhibitor dorsomorphin (4 µM) significantly attenuated the protective effect and mitochondrial biogenesis by PQQ treatment in rotenone-injured SH-SY5Y cells. Taken together, PQQ promotes mitochondrial biogenesis in rotenone-injured mice and SH-SY5Y cells via activation of AMPK signaling pathway.

15.
Clin Chim Acta ; 512: 1-6, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33159948

RESUMO

PURPOSE: To evaluate the efficacy of diagnosis systems based upon instance segmentation with convolutional neural networks (CNNs) for diagnosing acute promyelocytic leukemia (APL) in bone marrow smear images. MATERIALS AND METHODS: A self-established dataset was used in this study that was exempted from review by the institution review board, which consisted of 13,504 bone marrow smear images. One subset of the dataset with 12,215 labeled images was split into training (80%) and validation (20%), another with 1289 labeled images was used to test, in which each test entry consists of about 130 images. An instance segmentation method named Mask R-CNN was used to detect and classify the nucleated cells. Here, we train a trained neural network from scratch; for comparison, we also use a network pre-trained on MS COCO (common objects in context, a data set provided by Microsoft which can be used for image recognition, the images in MS coco dataset are divided into training, validation and test sets) and fine-tuned with our dataset and both were trained with same data augmentation scheme. Diagnosis systems based on trained models and "FAB Classification" (French-American-British classification systems, a series of diagnostic criteria for acute leukemia, which was first proposed in 1976) were developed for diagnosing the test entry as APL or as not. Average precision (AP) and average recall (AR) were used to evaluate model performance. RESULTS: The best-performing model had an average precision of 62.5%, which was the augmented pre-trained Mask R-CNN with average recall 84.1%. The average precision of the pre-trained model was greater than that of the model trained from scratch (P < 0.05). Augmenting the dataset further increased accuracy (P < 0 0.03). CONCLUSION: Deep learning technology such as instance segmentation with Mask R-CNN may accurately diagnose APL in bone marrow smear images with an average precision of 62.5% when 0.5 as IoU thresholds. A data augmentation and pre-trained approach further improved accuracy.


Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/diagnóstico por imagem , Redes Neurais de Computação
16.
Chemosphere ; 264(Pt 2): 128600, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33059292

RESUMO

Priming effect (PE) is increasingly recognized as an important mechanism in the microbial degradation of dissolved organic matter (DOM) from freshwater to the ocean. However, potential PE during the mixing of DOM from different sources and the effects on different DOM constituents are still largely unknown. This study examined the PE after adding DOM from typical natural and anthropogenic sources (rainwater, fresh plant, leaf litter, and wastewater) into pre-aged river DOM, using dissolved organic carbon (DOC) measurement, absorption spectroscopy, and fluorescence excitation-emission matrices-parallel factor analysis (EEMs-PARAFAC). The plant-derived DOM had a low humic content and was dominated by benzoic acid-like and tyrosine-like fluorescent components (C4 and C5), which showed a high DOC bioavailability of 80%. DOC in rainwater and wastewater also had high bioavailabilities (45%-50%), while DOM in the leaf litter leachate showed high aromaticity, average molecular weight, and humic content but low DOC bioavailability (12%). There was generally limited PE (<5% of the initial values) on the degradation of DOC and chromophoric DOM (CDOM) for most samples. Two humic-like components (C2 and C3) showed little PE, while the humic-like C1 and C6, tyrosine-like C5, and tryptophan-like C7 showed variable PE after adding rainwater, wastewater, and plant leachate. Overall, the results revealed that the DOM from typical natural and anthropogenic sources had different composition and bioavailability, and their inputs to aquatic environments would result in variable PE on the bulk DOC and different DOM components.


Assuntos
Água Doce , Rios , Análise Fatorial , Água Doce/análise , Substâncias Húmicas/análise , Espectrometria de Fluorescência , Águas Residuárias
17.
Biochim Biophys Acta Mol Cell Res ; 1868(1): 118877, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33007330

RESUMO

Metformin has been suggested as an anti-cancer agent. However, increasing reports show that some tumors are resistant to metformin. Identification of factors affecting metformin mediated cancer therapy is of great significance. FGFR1 is a receptor-tyrosine-kinase that is frequently overexpressed in breast cancer, which is associated with poor-prognosis. To investigate the effect of FGFR1 overexpression on metformin-induced inhibition of breast cancer cells, we demonstrated that FGFR1 overexpression rendered MCF-7 and T47D cells resistant to metformin. In particular, we found that, in addition to AKT and ERK1/2 activation, FGFR1-induced activation of IRS1 and IGF1R, key regulators connecting metabolism and cancer, was associated with metformin resistance. Targeting IRS with IRS1 KO or IRS inhibitor NT157 significantly sensitized FGFR1 overexpressing cells to metformin. Combination of NT157 with metformin induced enhanced inhibition of p-IGF1R, p-ERK1/2 and p-mTOR. Moreover, we demonstrated that IRS1 functions as a critical mediator of the crosstalk between FGFR1 and IGF1R pathways, which involves a feedback loop between IRS1 and MAPK/ERK. Our study highlights the significance of FGFR1 status and IRS1 activation in metformin-resistance, which will facilitate the development of strategies targeting FGFR overexpression-associated metformin resistance.


Assuntos
Neoplasias da Mama/genética , Proteínas Substratos do Receptor de Insulina/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor IGF Tipo 1/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Metformina/farmacologia , Pirogalol/análogos & derivados , Pirogalol/farmacologia , Sulfonamidas/farmacologia , Serina-Treonina Quinases TOR/genética
18.
Molecules ; 25(19)2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32977419

RESUMO

Neuroinflammation is a feature common to neurodegenerative diseases, such as Parkinson's disease (PD), which might be responsive to therapeutic intervention. Rotenone has been widely used to establish PD models by inducing mitochondrial dysfunction and inflammation. Our previous studies have reported that pyrroloquinoline quinone (PQQ), a naturally occurring redox cofactor, could prevent mitochondrial dysfunction in rotenone induced PD models by regulating mitochondrial functions. In the present study, we aimed to investigate the effect of PQQ on neuroinflammation and the mechanism involved. BV2 microglia cells were pre-treated with PQQ followed by rotenone incubation. The data showed that PQQ did not affect the cell viability of BV2 cells treated with rotenone, while the conditioned medium (CM) of BV2 cells pre-treated with PQQ significantly increased cell viability of SH-SY5Y cells. In rotenone-treated BV2 cells, PQQ dose-dependently decreased lactate dehydrogenase (LDH) release and suppressed the up-regulation of pro-inflammation factors, such as interleukin-1ß (IL-1ß), IL-6 and tumor necrosis factor-α (TNF-α) in the cultured media, as well as nitric oxide (NO) release induced by rotenone. PQQ pretreatment also increased the ratio of LC3-II/LC3-I and expression of Atg5 in BV2 cells stimulated with rotenone. Additionally, the autophagosome observed by transmission electron microscopy (TEM) and co-localization of mitochondria with lysosomes indicated that mitophagy was induced by PQQ in rotenone-injured BV2 cells, and the PINK1/parkin mediated mitophagy pathway was regulated by PQQ. Further, autophagy inhibitor, 3-methyladenine (3-MA), partially abolished the neuroprotective effect of PQQ and attenuated the inhibition of inflammation with PQQ pretreatment. Taken together, our data extend our understanding of the neuroprotective effect of PQQ against rotenone-induced injury and provide evidence that autophagy enhancement might be a novel therapeutic strategy for PD treatment.


Assuntos
Anti-Inflamatórios/farmacologia , Autofagia/efeitos dos fármacos , Microglia/citologia , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Cofator PQQ/farmacologia , Rotenona/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/patologia , Fármacos Neuroprotetores/uso terapêutico , Cofator PQQ/uso terapêutico
19.
Phytomedicine ; 76: 153260, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32535483

RESUMO

BACKGROUND: Aderivative of Shiitake mushrooms, Lentinan is used to control malignant pleural effusion (MPE) through intrathoracic infusion. PURPOSE: To determine the clinical response, survival and safety of Lentinan plus chemical irritants, and the optimal combinations with chemical irritants, indication, threshold and optimal regimen for achieving the desired responses. STUDY DESIGN: We performed a new systematic review and meta-analysis following the PRISMA guidelines. METHODS: We collected all randomized controlled trials (RCTs) regarding Lentinan plus chemical irritants from Chinese and English electronic databases (from inception until March 2019). We evaluated their bias risk, synthesized data using meta-analysis, and summarized evidence quality following the Grades of Recommendation Assessment, Development and Evaluation approach. RESULTS: We included 65 RCTs involving 4,080 patients and nine chemical irritants. Most trials had unclear bias risk. Lentinan with cisplatin significantly improved complete response [Risk ratio (RR) = 1.68, 95% confidence intervals (CI) (1.51 to 1.87), p < 0.00001, Fig.3a] and quality of life [RR = 1.51 95% CI (1.41 to 1.62), p < 0.00001, Fig.4], and decreased the risk of treatment failure, myelosuppression, gastrointestinal reaction, and chest pain. For patients with moderate to large volume of the pleural effusion, primary treatment, KPS score ≥ 50-60, or anticipated survival time ≥ 3months, Lentinan (3-4 mg/time, once a week for three to four times) withcisplatin (30-40 mg/m2 or 50-60 mg/m2) significantly improved complete response and decreased failure. Most results were robust and moderate quality. CONCLUSION: The results suggest that Lentinan with chemical irritants, especially cisplatin is beneficial to the patient with MPE, and provide evidence for the indication, threshold, and optimal regimen that may achieve success and decrease failure.

20.
Acta Biomater ; 112: 1-13, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32470527

RESUMO

Biomimetic nanotechnology through camouflaging synthetic nanoparticles (NPs) with natural cell membranes, which bestows with immune evasion and superior targeting capacity, has been extensively used in drug delivery systems (DDS) over the last decades. These biomimetic NPs not only retain the physicochemical features of the synthetic vehicles but also inherit the cell membranes' intrinsic functionalities. Combined with these benefits, optimized nano-biomimetic DDS allow maximum delivery efficacy. Compared to erythrocyte/cancer single cell membrane, the hybrid cell membrane expressing CD47 membrane protein and self-recognition molecules, from erythrocytes and cancer cells, provides remarkable features to the synthetic vehicles, such as immune evasion, long-term circulation, and homotypic targeting. In this review, we describe the preparation strategies, the camouflaging mechanism, and the antitumor applications of hybrid cell membrane-camouflaged NPs. Moreover, we discuss further modification of the hybrid cell membrane and the surface properties of fusion cellular membranes. Finally, we summarize the primary challenges and opportunities associated with these NPs. STATEMENT OF SIGNIFICANCE: Camouflaging synthetic nanoparticles with hybrid cell membrane has been extensively highlighted in recent years. The resultant biomimetic nanoparticles not only reserve the physicochemical properties of the synthetic nanoparticles but also inherit the biological functions of source cells. Compared with single cell membrane, hybrid cell membrane can endow synthetic nanoparticles with multiple biofunctions derived from the original source cells. To provide a timely review of this rapidly developing subject of research, this paper summarized recent progress on the hybrid cell membrane-camouflaged nanoparticles as drug delivery systems for cancer diagnosis and treatment. In this review, we focused primarily on five different types of hybrid cell membrane-camouflaged nanoparticles with the preparation strategies, the camouflaging mechanism, and the antitumor applications. Moreover, further modification of the hybrid cell membrane was also discussed for isolating effectively circulating tumor cells.


Assuntos
Materiais Biomiméticos , Nanopartículas , Neoplasias , Biomimética , Membrana Celular , Sistemas de Liberação de Medicamentos , Membrana Eritrocítica , Nanotecnologia , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico
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