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1.
Mol Cancer ; 21(1): 106, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477569

RESUMO

BACKGROUND: Lung cancer is a kind of malignancy with high morbidity and mortality worldwide. Paclitaxel (PTX) is the main treatment for non-small cell lung cancer (NSCLC), and resistance to PTX seriously affects the survival of patients. However, the underlying mechanism and potential reversing strategy need to be further explored. METHODS: We identified ALDH2 as a PTX resistance-related gene using gene microarray analysis. Subsequently, a series of functional analysis in cell lines, patient samples and xenograft models were performed to explore the functional role, clinical significance and the aberrant regulation mechanism of ALDH2 in PTX resistance of NSCLC. Furthermore, the pharmacological agents targeting ALDH2 and epigenetic enzyme were used to investigate the diverse reversing strategy against PTX resistance. RESULTS: Upregulation of ALDH2 expression is highly associated with resistance to PTX using in vitro and in vivo analyses of NSCLC cells along with clinicopathological analyses of NSCLC patients. ALDH2-overexpressing NSCLC cells exhibited significantly reduced PTX sensitivity and increased biological characteristics of malignancy in vitro and tumor growth and metastasis in vivo. EHMT2 (euchromatic histone lysine methyltransferase 2) inhibition and NFYA (nuclear transcription factor Y subunit alpha) overexpression had a cooperative effect on the regulation of ALDH2. Mechanistically, ALDH2 overexpression activated the RAS/RAF oncogenic pathway. NSCLC/PTX cells re-acquired sensitivity to PTX in vivo and in vitro when ALDH2 was inhibited by pharmacological agents, including the ALDH2 inhibitors Daidzin (DZN)/Disulfiram (DSF) and JIB04, which reverses the effect of EHMT2. CONCLUSION: Our findings suggest that ALDH2 status can help predict patient response to PTX therapy and ALDH2 inhibition may be a promising strategy to overcome PTX resistance in the clinic.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Aldeído-Desidrogenase Mitocondrial , Fator de Ligação a CCAAT/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Antígenos de Histocompatibilidade , Histona-Lisina N-Metiltransferase , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fatores de Transcrição
2.
Exp Gerontol ; 163: 111802, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35398474

RESUMO

BACKGROUND: Age-related chronic inflammatory process is often referred to as "inflammaging", which had been described in several human disorders, including sarcopenia. Recently, mitochondrial DNA (MtDNA) has moved into the spotlight as a "damage-associated molecular pattern" (DAMP) agent that can potentially elicit inflammation. Yet, the roles of this mitochondrial DAMP have never been investigated in sarcopenia. DESIGN: Cross-sectional study. PARTICIPANTS: From January 2021 to June 2021, elderly outpatients ≥65 years and able to finish a comprehensive geriatric assessment were recruited in our study. METHODS: Participants were divided into sarcopenia group and non-sarcopenia group according to the DXA scans and grip strength. Genomic DNA was extracted from plasma and peripheral blood mononuclear cells (PBMCs), and changes in MtDNA copies were quantified using qPCR. Plasma levels of inflammatory cytokines were measured using ELISA kits. Loss of mitochondrial membrane potential (Δψm) in PBMCs was analyzed using the fluorescent probe JC-1. RESULTS: Participants with sarcopenia were significantly older, more likely to be physically inactive, and had higher levels of circulating cell-free MtDNA (ccf-MtDNA) (all p < 0.05). After adjusting for potential confounders, ccf-MtDNA was independently associated with increased odds of sarcopenia (adjusted odds ratio (AOR), 1.576; p = 0.009). Furthermore, ROC curve analysis showed that ccf-MtDNA had an area under the curve (AUC) of 0.726 (95% CI: 0.607-0.844; p < 0.05) for distinguishing elderly subjects from sarcopenia. Compared with non-sarcopenia subjects, plasma interleukin (IL)-6 and IL-8 were significantly higher in sarcopenia subjects (both p < 0.05). By performing a correlation test, it was found that the level of IL-6 was positively correlated with ccf-MtDNA (r = 0.301; p < 0.05). Then, PBMCs were used as surrogates for mitochondria-rich cells, and the results showed that the relative amplification of MtDNA in PBMCs was significantly reduced (p < 0.05), whereas the depolarization of Δψm was significantly increased in sarcopenia subjects (p < 0.05). CONCLUSIONS: Taken together, our data suggested that circulating MtDNA might be a novel and important source of inflammatory stimuli potentially relevant for sarcopenia in elderly people, and this would provide an attractive therapeutic target to improve this disease.


Assuntos
Ácidos Nucleicos Livres , Sarcopenia , Idoso , Ácidos Nucleicos Livres/genética , Estudos Transversais , DNA Mitocondrial/genética , Humanos , Interleucina-6 , Leucócitos Mononucleares , Mitocôndrias/genética
3.
Phytomedicine ; 100: 154033, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35316727

RESUMO

BACKGROUND: Chronic excessive ethanol consumption damages the central nervous system and causes neurobehavioral changes, such as cognitive impairment, which is related to oxidative stress and inhibition of neurogenesis in the hippocampus. It is known that promoting neurogenesis improves learning memory, anxiety and depression. Lycium barbarum L. polyphenol (LBP) is the main active ingredient of Lycium barbarum L., which has excellent neuroprotective effects. However, the effects and mechanisms of LBP on ethanol-induced cognitive impairment are unclear. PURPOSE: To assess the effects and mechanisms of LBP on ethanol-induced cognitive impairment in mice. METHODS: Eight-weeks-old adult C57BL/6J mice were allowed to drink ethanol (10%) to establish a model of ethanol-induced cognitive impairment. From the 29th day of LBP (25, 50, 100, 200, 400 mg/kg, intragastric administration), the locomotor activity, novel object recognition (NOR), Y maze and Morris water maze (MWM) were sequentially performed to investigate the effect of LBP on ethanol-induced cognitive impairment in mice. Next, enzyme-linked immunosorbent assay, immunofluorescence, and western blotting were used to study the underlying mechanism of LBP on ethanol-induced cognitive impairment. RESULTS: LBP significantly decreased the escape latency and increased the number of crossings of the original platform in MWM, increased the spontaneous alteration behavior in the Y maze, and increased the preference index in the NOR in ethanol-induced mice. Notably, LBP significantly promoted the proliferation of neural stem cells, neural progenitor cells and neuroblasts, and increased the proportion of activated NSCs in mice with ethanol-induced cognitive impairment. Similarly, LBP significantly increased the number of newborn immature neurons and mature neurons. Moreover, LBP increased the levels of nuclear factor erythroid2-related factor 2 (Nrf2) and the downstream heme oxygenase-1(HO-1) protein expression, which led to a decrease of oxidative stress levels. CONCLUSION: LBP significantly improves cognitive impairment in ethanol-induced mice, which is attributed to the promotion of hippocampal neurogenesis and reduction of oxidative stress.


Assuntos
Disfunção Cognitiva , Medicamentos de Ervas Chinesas , Lycium , Animais , Apoptose , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Etanol/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Polifenóis/farmacologia
4.
Anal Chem ; 94(14): 5634-5641, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35357142

RESUMO

Supramolecular fluorescent probes for the detection of reactive oxygen species (ROSs) are designed based on a pro-guest strategy. Nine commercially available fluorescent dyes, six host molecules, and a pro-guest are used to rapidly generate a library of 54 potential supramolecular probes. These potential supramolecular probes are screened in a high-throughput fashion using a plate reader to discover seven "hits" or workable probes. The mechanism is confirmed to be ROS-induced conversion from a low-binding-affinity pro-guest to a high-binding-affinity guest and the competitive displacement of the encapsulated fluorescent dye. The response to H2O2 of four supramolecular probes is found to be concentration-dependent and may be used for quantitative analysis of H2O2. The supramolecular probe is selectively responsive toward other oxidative agents, such as NaClO and Na2SO3. The cell study shows that supramolecular probes are capable of detecting H2O2 in human cancer cells (MCF-7 or HeLa).


Assuntos
Corantes Fluorescentes , Ensaios de Triagem em Larga Escala , Células HeLa , Humanos , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio/análise
5.
Front Cell Dev Biol ; 10: 842153, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35300424

RESUMO

Deficiency in T cell-mediated adaptive immunity, such as low CD8+ T cell infiltration, inhibits the immune surveillance, promotes malignant transformation, and facilitates tumor growth. Microbiota dysbiosis diminishes the immune system and contributes to the occurrence of cancer. However, the impact of oral dysbiosis on the occurrence and molecular mechanisms of oropharyngeal cancer (OPC) remains largely unknown. In the current study, we used 4-nitroquinoline-1-oxide (4NQO) to mimic tobacco-related carcinogenesis to generate a murine OPC model and determine the role of microbiota changes in OPC tumorigenesis. Our results showed that the oral flora composition of mice was deregulated during the tumorigenesis of OPC. The abundance of Streptococcus, Veillonella, Muribacter, Rodentibacter, and Gemella was increased, whereas the dominant genus Lactobacillus was gradually decreased with disease progression. We further demonstrated that infiltration of CD8+ T lymphocytes was markedly reduced due to the reduction of Lactobacillus. Supplementation of Lactobacillus increased the infiltration of CD8+ T cells, promoted the expression of IFN-γ and granzyme B, and lessened the OPC progression. Analyzing the metabolites of the Lactobacillus, we demonstrated that Lactobacillus enhanced the anti-tumor immune response by producing acetate in OPC development. Administration of acetate to mice could increase the expression of IFN-γ and IFN-γ-inducible chemokines in tumor tissues by activating GPR43 to promote the infiltration of CD8+ T lymphocytes and substantially delay the development of OPC. Together, our data suggest that dysbiosis of oral microbiota promotes the tumorigenesis of OPC through downregulation of cytotoxic T lymphocytes. Lactobacillus and its metabolite acetate improve the tumor microenvironment, which could be applied in the treatment of OPC.

6.
Zhongguo Zhen Jiu ; 42(2): 215-20, 2022 Feb 12.
Artigo em Chinês | MEDLINE | ID: mdl-35152590

RESUMO

Data mining technology was adopted to analyze the rules of acupoint selection in treatment of erectile dysfunction with acupuncture and moxibustion. All of the articles for acupuncture and moxibustion in treatment of erectile dysfunction were searched from the databases, i.e. Chinese national knowledge infrastructure (CNKI), Wanfang database, VIP, Chinese biomedical literature database (SinoMed) and PubMed, and the clinical trials on erectile dysfunction treated with acupuncture and moxibustion were screened. The database was set up by using Excel 2019 and input into R 4.0.3, and then, the therapeutic method, use frequency of acupoint, meridian tropism, collection visualization analysis, cluster analysis and association rule analysis were summarized. A total of 240 articles were included, with 516 prescriptions and 145 acupoints involved. The methods for treatment of erectile dysfunction included acupuncture and moxibustion therapy, acupuncture, acupoint injection, electroacupuncture, etc. The acupoints with high use frequency were Guanyuan (CV 4), Shenshu (BL 23), Sanyinjiao (SP 6), Mingmen (GV 4), Zusanli (ST 36), Zhongji (CV 3), Ciliao (BL 32), Qihai (CV 6), Taixi (KI 3) and Taichong (LR 3). The meridians involved with high frequency were the bladder meridian of foot-taiyang, the conception vessel, the spleen meridian of foot-taiyin, etc. The common acupoint combination was Shangliao (BL 31), Zhongliao (BL 33), Ciliao (BL 32), Xialiao (BL 34) and Sanyinjiao (SP 6), Shenshu (BL 23), Guanyuan (CV 4). In association rule analysis (confidence ≥ 90%, support ≥ 20%), there were 27 association rules in total. The acupoint combination with the highest support referred to "Shenshu (BL 23), Sanyinjiao (SP 6)→Guanyuan (CV 4)" (support 46.7%) and the acupoint combination with the highest confidence was "Sanyinjiao (SP 6), Qihai (CV 6)→Guanyuan (CV 4)" (confidence 98.0%). The acupoints could be divided into 5 effective clusters. Acupuncture and moxibustion therapy has a certain of rules of acupoint selection in treatment of erectile dysfunction, which provides the evidences for modern clinical trial and treatment.


Assuntos
Terapia por Acupuntura , Disfunção Erétil , Meridianos , Moxibustão , Pontos de Acupuntura , Mineração de Dados , Disfunção Erétil/terapia , Humanos , Masculino , Tecnologia
7.
Anal Biochem ; 646: 114626, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35218735

RESUMO

Calcineurin is a Ca2+/calmodulin-dependent phosphatase. It is very important to study the affinity between calcineurin and its substrate or other interacting proteins. Two conserved motifs have been reported on the interactive proteins of calcineurin, namely, the PxIxIT motif and the LxVP motif. Here, we used 5(6)-carboxyfluorescein to fluorescently label the N-terminus of the short peptides derived from the two motifs and then determined the affinity between the protein and polypeptides. Microscale thermophoresis (MST) is very suitable for determining calcineurin with peptides containing the LxVP motif. The Kd values of the binding of calcineurin with NFATc1-YLAVP, NHE1-YLTVP, and A238L-FLCVK peptides were 6.72 ± 0.19 µM, 17.14 ± 0.35 µM, and 15.57 ± 0.10 µM, respectively. The GST pull-down results further confirmed the binding trend of the three peptides to calcineurin. However, fluorescently labeled PxIxIT polypeptides are not suitable for MST due to their own aggregation. We determined the binding affinity of the RCAN1-PSVVVH polypeptide to calcineurin by the fluorescence polarization (FP) method. MST and FP assays are fast and accurate in determining the affinity between protein-peptide interactions. Our research laid the foundation for screening the molecules that affect the binding between calcineurin and its substrates in the future.


Assuntos
Calcineurina , Calmodulina , Motivos de Aminoácidos , Calcineurina/química , Calmodulina/metabolismo , Polarização de Fluorescência , Ligação Proteica
8.
Int J Med Sci ; 19(2): 213-224, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35165507

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severely infects people and has rapidly spread worldwide. JingFangBaiDu San (JFBDS) has been used to treat prevalent epidemic pathogens, common cold, headache, cough due to lung-cold, and other symptoms; however, its treatment for COVID-19 is unknown. Molecular docking and network pharmacology were applied to obtain ingredient-protein structures and the herb-ingredient-disease target network model, respectively, to explore the potential mechanism of JFBDS in COVID-19 treatment. Network pharmacology analysis showed that acacetin, wogonin, and isorhamnetin were the main active ingredients of JFBDS, and EGFR, PIK3CA, LCK, MAPK1, MAPK3, MAPK8, STAT3, TNF, IL2, and RELA were speculated to be crucial therapeutic targets. Moreover, the Toll-like receptors, HIF-1, PIK3K/AKT, MAPK, NF-κB and NOD-like receptor signaling pathways were important for JFBDS in COVID-19 treatment. Molecular docking analysis indicated that ingredients of JFBDS could bind to angiotensin converting enzyme II, spike protein, and chymotrypsin like protease (3CLpro), which inhibits virus entry and replication in host cells. This study provides a new perspective for understanding potential therapeutic effects and mechanisms of JFBDS in COVID-19 and may facilitate its clinical application.


Assuntos
COVID-19/tratamento farmacológico , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Fitoterapia , Mapas de Interação de Proteínas
9.
Biomedicines ; 10(1)2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-35052801

RESUMO

The limited accuracy of cerebral infarct detection on CT images caused by the low contrast of CT hinders the desirable application of CT as a first-line diagnostic modality for screening of cerebral infarct. This research was aimed at utilizing convolutional neural network to enhance the accuracy of automated cerebral infarct detection on CT images. The CT images underwent a series of preprocessing steps mainly to enhance the contrast inside the parenchyma, adjust the orientation, spatially normalize the images to the CT template, and create a t-score map for each patient. The input format of the convolutional neural network was the t-score matrix of a 16 × 16-pixel patch. Non-infarcted and infarcted patches were selected from the t-score maps, on which data augmentation was conducted to generate more patches for training and testing the proposed convolutional neural network. The convolutional neural network attained a 93.9% patch-wise detection accuracy in the test set. The proposed method offers prompt and accurate cerebral infarct detection on CT images. It renders a frontline detection modality of ischemic stroke on an emergent or regular basis.

10.
J Inorg Biochem ; 229: 111728, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35066349

RESUMO

Bacteria maintain copper balance by various copper response mechanisms. A plasmid gene encoding a methionine rich protein targeted to periplasm is adjacent to the sil operon that confers heavy metal resistance. However, the gene product Orf91 has not been characterized before. Using X-ray crystallography, we solved the structures of Orf91 in apo, cuprous ion-bound, and cupric ion-bound forms. An Orf91 protomer consists of three helices of which the C-terminal two helices belong to domain of unknown function 305 (DUF305), and two Orf91s dimerize into a six-helical bundle. The MxxHH motif specific for DUF305 is critical for cuprous ion binding, and the MxxMxxMHxxMM motif in the N-terminal helix contributes to cupric ion binding. The first histidine of MxxHH shows alternative conformations related to the redox state of copper ion. We suggest that Orf91 is an adaptable copper sponge in the periplasmic space.


Assuntos
Cobre/metabolismo , Proteínas de Escherichia coli/metabolismo , Proteínas Periplásmicas/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Cobre/química , Cristalografia por Raios X , Escherichia coli/química , Proteínas de Escherichia coli/química , Histidina/química , Histidina/metabolismo , Metionina/química , Metionina/metabolismo , Proteínas Periplásmicas/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Multimerização Proteica
11.
Phytomedicine ; 96: 153847, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34836744

RESUMO

BACKGROUND: N-methyl-d-aspartate receptors (NMDARs) have been demonstrated to play central roles in stroke pathology and recovery, including dual roles in promoting either neuronal survival or death with their different subtypes and locations. PURPOSE: We have previously demonstrated that pseudoginsenoside-F11 (PF11) can provide long-term neuroprotective effects on transient and permanent ischemic stroke-induced neuronal damage. However, it is still needed to clarify whether NMDAR-2A (NR2A)-mediated pro-survival signaling pathway is involved in the beneficial effect of PF11 on permanent ischemic stroke. MATERIAL AND METHODS: PF11 was administrated in permanent middle cerebral artery occlusion (pMCAO)-operated rats. The effect of PF11 on oxygen-glucose deprivation (OGD)-exposed primary cultured neurons were further evaluated. The regulatory effect of PF11 on NR2A expression and the activation of its downstream AKT-CREB pathway were detected by Western blotting and immunofluorescence in the presence or absence of a specific NR2A antagonist NVP-AAM077 (NVP) both in vivo and in vitro. RESULTS: PF11 dose- and time-dependently decreased calpain1 (CAPN1) activity and its specific breakdown product α-Fodrin expression, while the expression of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII-α) was significantly upregulated in the cortex and striatum of rats at 24 h after the onset of pMCAO operation. Moreover, PF11 prevented the downregulation of NR2A, p-AKT/AKT, and p-CREB/CREB in both in vivo and in vitro stroke models. Finally, the results indicated treatment with NVP can abolish the effects of PF11 on alleviating the ischemic injury and activating NR2A-mediated AKT-CREB signaling pathway. CONCLUSIONS: Our results demonstrate that PF11 can exert neuroprotective effects on ischemic stroke by inhibiting the activation of CAPN1 and subsequently enhancing the NR2A-medicated activation of AKT-CREB pathway, which provides a mechanistic link between the neuroprotective effect of PF11 against cerebral ischemia and NR2A-associated pro-survival signaling pathway.


Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Animais , Isquemia Encefálica/tratamento farmacológico , Calpaína , Ginsenosídeos , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais
12.
Exp Neurol ; 347: 113907, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34715133

RESUMO

Propensity to relapse, even after long-term abstinence, is a crucial feature of methamphetamine (METH) abuse. We and other laboratories have reported that acute treatment of oxytocin (OXT), a hormone and neuropeptide, could inhibit reinstatement of METH seeking in animal studies. However, the effects of repeated OXT treatment on METH reinstatement as well as underlying mechanisms are still unclear. In the present study, the effects of repeated OXT treatment during abstinence on context- or restraint stress-induced reinstatement were investigated using the mice conditioned place preference (CPP) paradigm. After three intermittent injections of METH (2 mg/kg, i.p.) to induce CPP, mice received a daily bilateral intra-hippocampus injection of OXT (0.625, 1.25 or 2.5 µg) for 8 consecutive days before the context- or restraint stress-induced reinstatement test. Meanwhile, adult hippocampal neurogenesis (AHN) level was detected using immunostaining. To further clarify the role of AHN underlying OXT's effects on METH-CPP reinstatement, temozolomide (TMZ, 25 mg/kg, i.p.) was employed to deplete AHN prior to OXT treatment. The data showed that repeated OXT treatment (1.25 and 2.5 µg, intra-hippocampus) significantly inhibited both context- and restraint stress-induced METH-CPP reinstatement and concomitantly promoted AHN in a dose-dependent manner. Notably, TMZ pre-treatment markedly abolished all the above-mentioned effects of OXT, suggesting that AHN was closely involved in OXT's inhibition on reinstatement induced by both triggers. Taken together, the present study indicated that repeated OXT treatment during abstinence could inhibit both context- and restraint stress-induced METH-CPP reinstatement possibly by promoting AHN in mice, which provided a better understanding for OXT's beneficial effects on METH addiction.


Assuntos
Condicionamento Operante/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Metanfetamina/administração & dosagem , Neurogênese/efeitos dos fármacos , Ocitocina/administração & dosagem , Restrição Física/psicologia , Animais , Condicionamento Operante/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Hipocampo/citologia , Hipocampo/fisiologia , Bombas de Infusão Implantáveis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologia , Restrição Física/efeitos adversos
13.
J Cancer Res Ther ; 17(5): 1225-1233, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34850771

RESUMO

BACKGROUND: The aim of this meta-analysis was to investigate the rs1799794 and rs1799796 polymorphisms of X-ray repair cross-complementing group 3 (XRCC3) in relation to breast cancer susceptibility. MATERIALS AND METHODS: PubMed, Embase, the Cochrane Library, Web of Science, and Scopus were searched for eligible studies published until June 24, 2019. All analyses were carried out using Stata 14.0 software. Subgroup analyses were performed according to cancer types, ethnicity, source of controls, and method. RESULTS: Our meta-analysis included articles reporting 13 studies of SNP rs1799794 and seven articles reporting 10 studies of SNP rs1799796. Overall, significant associations were observed between the XRCC3 rs1799794 polymorphism and breast cancer risk in the dominant model and heterozygote model (GG + AG vs. AA: odds ratio [OR] =1.06, 95% confidence interval [CI]: 1.00-1.11, P = 0.037, I2 = 47%; AG vs. AA: OR = 1.08, 95% CI: 1.02-1.13, P = 0.006, I2 = 42.3%) and between the XRCC3 rs1799796 polymorphism and breast cancer risk in the homozygote model (GG vs. AA: OR = 0.91, 95% CI: 0.84-0.99, P = 0.021, I2 = 33.3%). CONCLUSIONS: The results of this meta-analysis suggest that the variant G allele of the XRCC3 rs1799794 polymorphism is a low-penetrant risk factor for developing breast cancer, whereas the variant G allele of the XRCC3 rs1799796 polymorphism has a protective effect against breast cancer development.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Humanos , Prognóstico , Fatores de Risco
14.
Water Res ; 209: 117937, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34922104

RESUMO

Increased grazing and agricultural production, industrialization, population growth, and consequent land use land cover (LULC) changes considerably increase water consumption. Global climate change exaggerates the uncertainty of water sources and supplies. Unfortunately, most current examinations are either confined within disciplinary silos or not integrated for considering wide-ranging socioenvironmental, management, and policy factors. The paper develops an integrated regional water environment modeling framework, examining how climate, LULC, socioenvironmental, and policy factors interact with the water environment. It also adopts a block-based econometric panel data analysis to quantify this framework. The paper extracts seasonal water area and LULC data through image processing from 2000 to 2014 in the Hulun-Buir watershed, Inner Mongolia of China. The paper quantitatively analyzed the interactions between seasonal water changes and major driving factors, such as climatic, land-use, socioeconomic, policy, space, and time. Many of these driving factors were interacting with the seasonal water environment and showing long-term causal relationships. The socioeconomic variables explained 71% of the variance of seasonal water change, the environmental and climatic factors about 9%, the regional disparities around 13%, and the yearly differences about 4%. The findings confirm that it is critical to carry out a time-series examination of causal relationships between seasonal water change and its manifold driving factors at the scale of regional watershed studies. This integrated watershed modeling framework is suitable for adaptation in other geographic areas or for integrated studies of other socio-environmental systems.

15.
Biology (Basel) ; 10(11)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34827097

RESUMO

TEOSINTE-BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors play an essential role in regulating various physiological and biochemical functions during plant growth. However, the function of TCP transcription factors in G. hirsutum has not yet been studied. In this study, we performed genome-wide identification and correlation analysis of the TCP transcription factor family in G. hirsutum. We identified 72 non-redundant GhTCP genes and divided them into seven subfamilies, based on phylogenetic analysis. Most GhTCP genes in the same subfamily displayed similar exon and intron structures and featured highly conserved motif structures in their subfamily. Additionally, the pattern of chromosomal distribution demonstrated that GhTCP genes were unevenly distributed on 24 out of 26 chromosomes, and that fragment replication was the main replication event of GhTCP genes. In TB1 sub-family genes, GhTCP62 was highly expressed in the axillary buds, suggesting that GhTCP62 significantly affected cotton branching. Additionally, subcellular localization results indicated that GhTCP62 is located in the nucleus and possesses typical transcription factor characteristics. The overexpression of GhTCP62 in Arabidopsis resulted in fewer rosette-leaf branches and cauline-leaf branches. Furthermore, the increased expression of HB21 and HB40 genes in Arabidopsis plants overexpressing GhTCP62 suggests that GhTCP62 may regulate branching by positively regulating HB21 and HB40.

16.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34782465

RESUMO

Ischemic stroke can induce neurogenesis. However, most stroke-generated newborn neurons cannot survive. It has been shown that MR-409, a potent synthetic agonistic analog of growth hormone-releasing hormone (GHRH), can protect against some life-threatening pathological conditions by promoting cell proliferation and survival. The present study shows that long-term treatment with MR-409 (5 or 10 µg/mouse/d) by subcutaneous (s.c.) injection significantly reduces the mortality, ischemic insult, and hippocampal atrophy, and improves neurological functional recovery in mice operated on for transient middle cerebral artery occlusion (tMCAO). Besides, MR-409 can stimulate endogenous neurogenesis and improve the tMCAO-induced loss of neuroplasticity. MR-409 also enhances the proliferation and inhibits apoptosis of neural stem cells treated with oxygen and glucose deprivation-reperfusion. The neuroprotective effects of MR-409 are closely related to the activation of AKT/CREB and BDNF/TrkB pathways. In conclusion, the present study demonstrates that GHRH agonist MR-409 has remarkable neuroprotective effects through enhancing endogenous neurogenesis in cerebral ischemic mice.


Assuntos
Hormônio Liberador de Hormônio do Crescimento/agonistas , Hormônio Liberador de Hormônio do Crescimento/metabolismo , AVC Isquêmico/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hormônio Liberador de Hormônio do Crescimento/genética , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/metabolismo , Plasticidade Neuronal , Fármacos Neuroprotetores , Proteínas Tirosina Quinases/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos
17.
Transl Psychiatry ; 11(1): 495, 2021 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-34580274

RESUMO

Schizophrenia (SZ) is a neurodevelopmental disorder. There remain significant gaps in understanding the neural trajectory across development in SZ. A major research focus is to clarify the developmental functional changes of SZ and to identify the specific timing, the specific brain regions, and the underlying mechanisms of brain alterations during SZ development. Regional homogeneity (ReHo) characterizing brain function was collected and analyzed on humans with SZ (hSZ) and healthy controls (HC) cross-sectionally, and methylazoxymethanol acetate (MAM) rats, a neurodevelopmental model of SZ, and vehicle rats longitudinally from adolescence to adulthood. Metabolomic and proteomic profiling in adult MAM rats and vehicle rats was examined and bioanalyzed. Compared to HC or adult vehicle rats, similar ReHo alterations were observed in hSZ and adult MAM rats, characterized by increased frontal (medial prefrontal and orbitofrontal cortices) and decreased posterior (visual and associated cortices) ReHo. Longitudinal analysis of MAM rats showed aberrant ReHo patterns as decreased posterior ReHo in adolescence and increased frontal and decreased posterior ReHo in adulthood. Accordingly, it was suggested that the visual cortex was a critical locus and adolescence was a sensitive window in SZ development. In addition, metabolic and proteomic alterations in adult MAM rats suggested that central carbon metabolism disturbance and mitochondrial dysfunction were the potential mechanisms underlying the ReHo alterations. This study proposed frontal-posterior functional imbalance and aberrant function developmental patterns in SZ, suggesting that the adolescent visual cortex was a critical locus and a sensitive window in SZ development. These findings from linking data between hSZ and MAM rats may have a significant translational contribution to the development of effective therapies in SZ.


Assuntos
Esquizofrenia , Animais , Encéfalo , Mapeamento Encefálico , Imageamento por Ressonância Magnética , Acetato de Metilazoximetanol , Proteômica , Ratos
18.
Nanomaterials (Basel) ; 11(9)2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34578632

RESUMO

Pancreatic cancer is an aggressive malignancy associated with poor prognosis and a high tendency in developing infiltration and metastasis. K-ras mutation is a major genetic disorder in pancreatic cancer patient. RNAi-based therapies can be employed for combating pancreatic cancer by silencing K-ras gene expression. However, the clinical application of RNAi technology is appreciably limited by the lack of a proper siRNA delivery system. To tackle this hurdle, cationic poly (cyclohexene carbonate) s (CPCHCs) using widely sourced CO2 as the monomer are subtly synthesized via ring-opening copolymerization (ROCOP) and thiol-ene functionalization. The developed CPCHCs could effectively encapsulate therapeutic siRNA to form CPCHC/siRNA nanoplexes (NPs). Serving as a siRNA carrier, CPCHC possesses biodegradability, negligible cytotoxicity, and high transfection efficiency. In vitro study shows that CPCHCs are capable of effectively protecting siRNA from being degraded by RNase and promoting a sustained endosomal escape of siRNA. After treatment with CPCHC/siRNA NPs, the K-ras gene expression in both pancreatic cancer cell line (PANC-1 and MiaPaCa-2) are significantly down-regulated. Subsequently, the cell growth and migration are considerably inhibited, and the treated cells are induced into cell apoptotic program. These results demonstrate the promising potential of CPCHC-mediated siRNA therapies in pancreatic cancer treatment.

19.
Artigo em Inglês | MEDLINE | ID: mdl-34449390

RESUMO

Realistic speech-driven 3D facial animation is a challenging problem due to the complex relationship between speech and face. In this paper, we propose a deep architecture, called Geometry-guided Dense Perspective Network (GDPnet), to achieve speaker-independent realistic 3D facial animation. The encoder is designed with dense connections to strengthen feature propagation and encourage the re-use of audio features, and the decoder is integrated with an attention mechanism to adaptively recalibrate point-wise feature responses by explicitly modeling interdependencies between different neuron units. We also introduce a non-linear face reconstruction representation as a guidance of latent space to obtain more accurate deformation, which helps solve the geometry-related deformation and is good for generalization across subjects. Huber and HSIC (Hilbert-Schmidt Independence Criterion) constraints are adopted to promote the robustness of our model and to better exploit the non-linear and high-order correlations. Experimental results on the public dataset and real scanned dataset validate the superiority of our proposed GDPnet compared with state-of-the-art model. We will make the code available for research purposes.

20.
Chin J Nat Med ; 19(8): 608-620, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34419260

RESUMO

Brucea javanica oil emulsion (BJOE) has been used to treat tumor in China for more than 40 years. However, its components and effectiveness in the treatment of acute lymphocytic leukemia (ALL) and its mechanism of anti-cancer activity remain unknown. In the current study, high-performance liquid chromatography-evaporative light scattering detector (HPLC-ELSD) was used to analyze the components of BJOE. Then, the anti-leukemia effects of BJOE were examined both in vitro and in vivo using ALL Jurkat cells and the p388 mouse leukemia transplant model, respectively. The primary ALL leukemia cells were also used to confirm the anti-leukemia effects of BJOE. The apoptotic-related results indicated that BJOE induced apoptosis in Jurkat cells and were suggestive of intrinsic apoptotic induction. Moreover, BJOE inhibited Akt (protein kinase B) activation and upregulated its downstream targets p53 and FoxO1 (forkhead box gene, group O-1) to initiate apoptosis. The activation of GSK3ß was also involved. Our findings demonstrate that BJOE has anti-leukemia effects on ALL cells and can induce apoptosis in Jurkat cells through the phosphoinositide3-kinase (PI3K) /Akt signaling pathway.


Assuntos
Apoptose , Brucea , Óleos Vegetais/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Brucea/química , Quinase 3 da Glicogênio Sintase , Humanos , Células Jurkat , Camundongos , Fosfatidilinositol 3-Quinases/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Sementes/química , Transdução de Sinais
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