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2.
Comput Math Methods Med ; 2022: 2025756, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912142

RESUMO

Objective: Spinal cord injury (SCI) is one of the most devastating central injuries, resulting in serious locomotor deficits. Triad1 is known to play an important role in SCI, but its effects on the inflammatory response and physiological behavior have not been thoroughly studied. This study is aimed at examining the effects of Triad1 on the inflammatory response and neuronal injury in acute SCI in rats. Methods: Twenty-four male Sprague-Dawley (SD) rats were randomly divided into a control group, SCI group, sh-NC group, and Triad1 knockout group (sh-Triad1). The Basso Beattie Bresnahan locomotor rating scale was utilized for the assessment of the motor ability of rats. Hematoxylin and eosin (H&E), Luxol fast blue (LFB), and TUNEL staining were used to assess the pathological injury, demyelination, and neuronal apoptosis, respectively. ELISA was used to detect the levels of IL-1ß, IL-10, and TNF-α, and qRT-PCR was used to examine the expression level of Triad1. Furthermore, the protein levels of Triad1, Bax, Bcl-2, and cleaved caspase-3 were determined using western blotting. Results: The Triad1 expression level was upregulated in damaged spinal cord tissue. Knockdown of Triad1 improved motor function and reduced SCI as well as apoptosis of spinal cord neurons. In addition, the knockdown of Triad1 inhibited the inflammatory response caused by SCI. Conclusion: Knockdown of Triad1 can reduce SCI in rats with acute SCI by inhibiting the inflammatory response and apoptosis.


Assuntos
Traumatismos da Medula Espinal , Animais , Apoptose , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/genética
3.
Front Genet ; 13: 926511, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35923705

RESUMO

OCA (oculocutaneous albinism) refers to a group of heterogeneous congenital disorders of which the common manifestations are variable degrees of cutaneous hypopigmentation and significant visual impairment, including poor visual acuity, photophobia, and nystagmus. Molecular analysis may elucidate its pathogenesis and be in favor of accurate diagnosis. High-throughput sequencing and Sanger sequencing were performed to detect mutational alleles and in silico analysis was performed for prediction of variant pathogenicity. Ten TYR-related and two OCA2-related patients were identified with 16 different variants with potential pathogenicity. Two novel missense variants [TYR: c.623T > G, p(Leu208Arg) and OCA2: c.1325A > G, p(Asn442Ser)] are identified in this study, and three OCA cases are reported for the first time in Chinese population based on their associated variants. Analysis of crystal structures of TYR ortholog and its paralog TYRP1 suggests that the substitution of Leu208 may have an impact on protein stability. This study may facilitate OCA diagnosis by expanding the mutational spectrum of TYR and OCA2 as well as further basic studies about these two genes.

4.
Cell Biol Int ; 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35925004

RESUMO

Oleanolic acid (OA) and its derivatives show potent anticancer function. Pancreatic cancer (PC) is the fourth core motive of cancer-related deaths worldwide. Epidermal growth factor receptor (EGFR) has been implicated in PC and has been validated as a therapeutic target. Our study demonstrated that K73-03, an OA derivative, was identified as a potent inhibitor of EGFR by using reverse pharmacophore screening and molecular dynamics simulation assays. Moreover, Western blot analysis showed that K73-03 markedly suppressed the levels of phosphorylated-EGFR (p-EGFR) and phosphorylated-Akt (p-Akt). The inhibitory effect of K73-03 on PC cells was assessed in vitro and in vivo. Mechanistically, K73-03 effectively inhibited the cell proliferation of PC cells, and induced apoptosis and autophagy of ASPC-1 cells in a dose-dependent manner. Additionally, pretreatment with chloroquine, an autophagy inhibitor, significantly inhibited K73-03-induced autophagy and enhanced K73-03-induced apoptotic cell death. K73-03 also strongly repressed ASPC-1 cells xenograft growth in vivo. Thus, all these findings provided new clues about OA analog K73-03 as an effective anticancer agent targeted EGFR against ASPC-1 cells, it is worth further evaluation in the future.

6.
Oral Oncol ; 133: 106064, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35952584
7.
Huan Jing Ke Xue ; 43(8): 3998-4007, 2022 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-35971698

RESUMO

To explore the periphytic algae community structure in the Yangtze River basin, samples were collected from 130 sampling sites, including the source to the estuary along the mainstream of the Yangtze River, eight primary tributaries, and the tributary of the Three Gorges area. The periphytic algae densities of different areas in the mainstream of the Yangtze River ranked from high to low were the upstream area, source area, middle and lower area, and the Jinsha River. The high periphytic algae density in the upstream area was associated with the shift in nutrition level, and the high periphytic algae density in the source area was associated with human activity. The spatial pattern of the periphytic algae community in the whole main stream from west to east presented the alternating dominance of Bacillariophyta and Cyanophyta; the Bacillariophyta (Navicula) had a competitive advantage in the main stream, and the distribution of the periphytic algae community was driven by total nitrogen, total phosphorus, and pH. For the tributary of the Yangtze River, the periphytic algae density in the Three Gorges tributary area was far higher than those in the eight primary tributaries; the periphytic algae community was dominated by Cyanophyta (Lyngbya), which had a competitive advantage in the tributaries of the Yangtze River. The distribution of the periphytic community was driven by dissolved oxygen and pH. According to the diversity analysis and assessment, the periphytic algae community in the source area showed lower species richness and higher evenness, thus leading to a high α-diversity and good assessment result (mesosaprobic zone). The middle and lower reaches of the Yangtze River also showed the same assessment result, the mesosaprobic zone. However, the community evenness of the middle and lower reaches was significantly lower than that of the source area, thus making the middle and lower reaches of the Yangtze River have a significantly lower α-diversity than that of the source area. All areas of the Yangtze River showed good water quality assessment; however, different areas had different WQI index numbers, and the assessment results of the WQI index were inconsistent with the results of the aquatic assessment. Therefore, a comprehensive assessment of aquatic ecosystem health should use both aquatic assessments and water quality assessments.

9.
Cancers (Basel) ; 14(15)2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35954358

RESUMO

BACKGROUND: The metastatic characteristics of hypopharyngeal squamous cell carcinoma (HSCC) lead to many diagnostic and therapeutic challenges, while functional long non-coding RNAs (lncRNAs) can provide effective strategies for its diagnosis and treatment. METHODS: RT-qPCR, Western blot, immunohistochemistry, and an immunofluorescence assay were used to detect the related gene expression. Flow cytometry was used to measure the percentage of CD8+ and CD4+ T cells. CCK-8 and transwell assays were performed to analyze the role of HOXA11-AS1. The targeted relationship of the FOSL1/PD-L1 promoter was measured by ChIP and dual-luciferase reporter assays. RNA pulldown and RIP assays were used to measure the interaction between HOXA11-AS1, FOSL1, and PTBP1. A tumor xenograft study was used to analyze HOXA11-AS1 function in vivo. RESULTS: HOXA11-AS1, PD-L1, and FOSL1 were upregulated in HSCC, and HOXA11-AS1 positively correlated with PD-L1. HOXA11-AS1 knockdown upregulated CD8+ T cells through an increase in IFN-γ concentration while decreasing the proliferation, migration, and invasion of HSCC cells. FOSL1 bound the PD-L1 promoter, increasing gene expression. HOXA11-AS1 enhanced the stability of FOSL1 mRNA by binding to PTBP1. HOXA11-AS1 or PTBP1 overexpression increased FOSL1 and PD-L1 expression. PD-L1 knockdown arrested the inhibiting function of HOXA11-AS1 overexpression on CD8+ T cell content. HOXA11-AS1 knockdown inhibited immune escape and metastasis through PD-L1 regulation by downregulating FOSL1 in vivo. CONCLUSION: HOXA11-AS1 promoted PD-L1 expression by upregulating FOSL1 levels through PTBP1, thereby facilitating immune escape, proliferation, and metastasis of HSCC cells.

10.
J Agric Food Chem ; 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35944096

RESUMO

Unsaturated fatty acids are easily affected by metal ions, leading to the changes of their flavor, nutrition, and safety through lipid oxidation. Nevertheless, there is a lack of comprehensive evaluation of the pro-oxidative ability of different metal ions, which have different effects on different lipids. Thus, in this work, crude lipids extracted from abalone were incubated with different metal ions, and the comprehensive lipid oxidation products were analyzed by nontargeted lipidomics approaches using an ultra-high-performance liquid chromatography-Q-Exactive HF-X Orbitrap Mass Spectrometer (UPLC-Q-Exactive HF-X). Results showed that the overall pro-oxidative ability from strong to weak was Fe3+, Fe2+, Cu2+, Zn2+, Mn2+, Mg2+, Na+, and K+. Among them, Fe3+ and Fe2+ could promote the accumulation of oxidation intermediates and branched fatty acid esters of hydroxy fatty acids. Na+, K+, Cu2+, and Mg2+ could accelerate the oxidation of N-acyl ethanolamines and ceramides. K+ and Na+ had more influences on the free fatty acids than Zn2+ and Mn2+. Slow oxidation of triglyceride may be attributed to its long distance from the oil-water interface and the restriction of the polar headgroups of phospholipids on free radicals.

11.
Water Res ; 221: 118807, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35810634

RESUMO

Harmful algal blooms (HABs) worldwide are experiencing obvious changes under the combined impacts of global warming, eutrophication, and other driving forces. In the East China Sea (ECS), large-scale blooms caused by dinoflagellates occurred since 2000 and there has been an apparent shift of bloom-causative microalgae from diatoms to dinoflagellates. To predict the future evolution of HABs in this region, a model was developed based on the competition between diatoms and dinoflagellates, which would serve to reproduce the seasonal succession of microalgal blooms driven by multiple environmental factors. The evolution features of HABs were then projected under different scenarios of eutrophication and global warming. Under the 'business as usual' scenario, dinoflagellate blooms are expected to become more frequent with higher peak biomass concentrations over the next 30 years. Changes in nutrient composition of the Changjiang riverine discharge may largely give rise to this phenomenon, and accelerated warming associated with climate change may result in earlier occurrence of dinoflagellate blooms. To prevent further intensification of dinoflagellate blooms, efforts could be made to reduce nitrogen inputs and maintain or even increase silicate inputs from the Changjiang river.


Assuntos
Diatomáceas , Dinoflagelados , Microalgas , China , Mudança Climática , Eutrofização , Proliferação Nociva de Algas , Rios
12.
Org Lett ; 24(27): 4886-4891, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35775741

RESUMO

The highly regioselective C6-H hydroxylalkylation of purines and purine nucleosides within 10 min via the α-C(sp3)-H functionalization of alcohols at room temperature is reported here for the first time. The reaction tolerated various functional groups, which have the potential for further modification to afford other valuable molecules. The reported method avoids metal catalysts, light, and protecting groups, giving a direct strategy to access 6-substitued alkylated purines and nucleosides with pharmaceutical bioactivities.


Assuntos
Álcoois , Nucleosídeos de Purina , Catálise , Nucleosídeos , Temperatura
13.
Biomaterials ; 287: 121599, 2022 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-35777332

RESUMO

The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) is the major physical barrier that hinders the delivery of anti-tumor drugs, leading to strong inherent chemotherapy resistance as well as establishing an immunosuppressive tumor microenvironment (TME). However, forcibly destroying the stroma barrier would break the balance of delicate signal transduction and dependence between tumor cells and matrix components. Uncontrollable growth and metastasis would occur, making PDAC more difficult to control. Hence, we design and construct an aptamer-decorated hypoxia-responsive nanoparticle s(DGL)n@Apt co-loading gemcitabine monophosphate and STAT3 inhibitor HJC0152. This nanoparticle can reverse its surficial charge in the TME, and reduce the size triggered by hypoxia. The released ultra-small DGL particles loading gemcitabine monophosphate exhibit excellent deep-tumor penetration, chemotherapy drugs endocytosis promotion, and autophagy induction ability. Meanwhile, HJC0152 inhibits overactivated STAT3 in both tumor cells and tumor stroma, softens the stroma barrier, and reeducates the TME into an immune-activated state. This smart codelivery strategy provides an inspiring opportunity in PDAC treatment.

14.
Cell Biol Toxicol ; 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35844005

RESUMO

OBJECTIVE: To explore the effects of exosomes loaded with circular RNA PARD3 on EBV-miR-BART4-induced stemness and resistance of cisplatin in nasopharyngeal carcinoma side population (NPC-SP) cells through the miR-579-3p/SIRT1/SSRP1 axis. METHODS: Sixty-five cancer tissues and 65 noncancerous tissues were collected from NPC patients or patients with rhinitis. The expressions of circPARD3, miR-579-3p, SIRT1, and SSRP1 were detected by qRT-PCR, western blot, or immunohistochemistry. In vivo tumor formation assay was performed in nude mice. Immunofluorescence and qRT-PCR were conducted for the determination of CD44 and CD133 expressions, and flow cytometry combined with Hoechst 33,342 dye efflux for identifying SP cells, CCK-8 and EdU assays for cell proliferation, and Transwell assay for migration and invasion. RESULTS: CircPARD3, SIRT1, and SSRP1 were upregulated while miR-579-3p was downregulated in NPC tissues and cells. CircPARD3 was positively correlated with the expressions of SIRT1 and SSRP1, and miR-579-3p was negatively correlated with circPARD3, SIRT1, and SSRP1. Exosomes loaded with circPARD3 promoted EBV-miR-BART4-induced stemness and cisplatin resistance in NPC-SP cells, while miR-579-3p reversed the effect of exosomal circPARD3 on EBV-miR-BART4-induced stemness and cisplatin resistance in NPC-SP cells. Additionally, miR-579-3p suppressed EBV-miR-BART4-induced stemness and cisplatin resistance in NPC-SP cells by regulating SIRT1. SIRT1 upregulated SSRP1 expression by catalyzing H3K4 methylation and down-regulation of SSRP1 reversed the effect of SIRT1 on EBV-miR-BART4-induced stemness and cisplatin resistance in NPC-SP cells. CONCLUSION: Exosomes loaded with circPARD3 promoted EBV-miR-BART4-induced stemness and cisplatin resistance in NPC-SP cells through the miR-579-3p/SIRT1/SSRP1 axis. Graphical Headlights • EBV-miR-BART4 induces the stemness and resistance of NPC-SP cells. • CircPARD3 regulates SIRT1 by miR-579-3p. • SIRT1 regulates SSRP1 expression by histone methylation. • Exosomes loaded with circPARD3 promotes EBV-miR-BART4-induced NPC-SP cell stemness and resistance by the miR-579-3p/SIRT1/SSRP1 axis.

15.
J Tradit Chin Med ; 42(4): 556-564, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35848972

RESUMO

OBJECTIVE: To investigate the influence of Qihuang decoction on enteric nervous system after gastrectomy in rats. METHODS: The morphology, distribution and number of intestinal neurons in enteric nervous system (ENS) were observed by immunofluorescence labeling and confocal laser scanning microscopy. Reverse transcription-polymerase chain reaction and Western blot were used to detect the mRNA and protein expression of intestinal neurotransmitters and corresponding receptors in ENS. RESULTS: The morphology and distribution of enteric neurons in ENS were changed after gastrectomy, and these neurons in Qihuang decoction group were similar with that of sham operation group. The number of ACh and SP positive neurons, mRNA and protein expression of excitatory neurotransmitters (AChE, SP) and receptors (M3R, NK1R) were decreased after gastrectomy. And the intervention of Qihuang decoction could increase the number of ACh and SP positive neurons and promote the expression of their mRNA and protein. For vasoactive intestinal peptide (VIP) and nitric oxide synthase (NOS), the number of neurons and mRNA and protein expression of inhibitory neurotransmitters (VIP and NOS) and receptors (VIP2R) were increased after gastrectomy. And these rising indexes fall back after the intervention of Qihuang decoction. Besides, the intestinal propulsion rate in QH group was significantly increased than that in SEN and IEN group. CONCLUSIONS: These experimental results showed that after gastrectomy, early intervention with Qihuang decoction in small intestine will contribute to the postoperative recovery of enteric nervous system and intestinal propulsion rate, and consequently enhance gastrointestinal motility.


Assuntos
Sistema Nervoso Entérico , Animais , Sistema Nervoso Entérico/metabolismo , Gastrectomia , Neurotransmissores/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Peptídeo Intestinal Vasoativo/genética , Peptídeo Intestinal Vasoativo/metabolismo
16.
Immunotherapy ; 14(13): 1027-1041, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35796042

RESUMO

Objective: This study evaluated the cost-effectiveness of pembrolizumab/chemotherapy combinations for previously untreated metastatic triple-negative breast cancer patients in the USA with PD-L1 combined positive score ≥10. Methods: A partitioned-survival model was developed to project health outcomes and direct medical costs over a 20-year time horizon. Efficacy and safety data were from randomized clinical trials. Comparative effectiveness of indirect comparators was assessed using network meta-analyses. A series of sensitivity analyses were performed to test the robustness of the results. Results: Pembrolizumab/chemotherapy resulted in total quality-adjusted life-year (QALY) gains of 0.70 years and incremental cost-effectiveness ratio of US$182,732/QALY compared with chemotherapy alone. The incremental cost-effectiveness ratio for pembrolizumab/nab-paclitaxel versus atezolizumab/nab-paclitaxel was US$44,157/QALY. Sensitivity analyses showed the results were robust over plausible values of model inputs. Conclusion: Pembrolizumab/chemotherapy is cost effective compared with chemotherapy as well as atezolizumab/nab-paclitaxel as first-line treatment for PD-L1-positive metastatic triple-negative breast cancer from a US payer perspective.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Análise Custo-Benefício , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
17.
J Agric Food Chem ; 70(28): 8569-8581, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35816090

RESUMO

Diabetes mellitus (DM) is a serious metabolic disease characterized by persistent hyperglycemia, with a continuously increasing morbidity and mortality. Although traditional treatments including insulin and oral hypoglycemic drugs maintain blood glucose levels within the normal range to a certain extent, there is an urgent need to develop new drugs that can effectively improve glucose metabolism and diabetes-related complications. Notably, accumulated evidence implicates that the gut microbiota is unbalanced in DM individuals and is involved in the physiological and pathological processes of this metabolic disease. In this review, we introduce the molecular mechanisms by which the gut microbiota contributes to the development of DM. Furthermore, we summarize the preclinical studies of bioactive natural products that exert antidiabetic effects by modulating the gut microbiota, aiming to expand the novel therapeutic strategies for DM prevention and management.


Assuntos
Produtos Biológicos , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/farmacologia
18.
Mol Psychiatry ; 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35879403

RESUMO

Hyperphosphorylation of the microtubule associated protein tau is associated with several neurodegenerative diseases including Alzheimer's Disease (AD), collectively referred to as tauopathies. However, the mechanisms by which tau is linked to synaptic dysfunction and memory impairment remain unclear. To address this question, we constructed a mouse model with brain-specific deficiency of SIRT1 (SIRT1 flox/Cre + ). Here, we show that increase of site-specific phosphorylation of tau is coupled with the strengthened O-GlcNAcylation of tau triggered by reduced O-GlcNAcase (OGA) and increased O-GlcNAc transferase (OGT) protein level in the brain of SIRT1 flox/Cre+ mice. SIRT1 deletion in mice brain changes the synaptosomal distribution of site-specific phospho-tau. Learning and memory deficiency induced by dendritic spine deficits and synaptic dysfunction are revealed via SIRT1 flox/Cre+ mice. Our results provide evidence for SIRT1 as a potential therapeutic target in clinical tauopathies.

19.
Br J Nutr ; : 1-11, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35876046

RESUMO

The aim of this study was to explore the status of thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) in three areas with differing water iodine concentrations; and to discuss the relationships between these two thyroid antibodies and thyroid diseases in the three areas. We investigated 2503 adults from three areas. Urinary iodine concentrations, thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), TPOAb, TGAb and thyroid volume (TV) were measured, and thyroid ultrasonography was performed. The positivity rates of TGAb(+), TPOAb(+) and TGAb(+) and TPOAb(+) or TGAb(+) were significantly higher in iodine fortification (IF) areas than iodine adequate (IA) areas (all P < 0·05). In IF and iodine excess areas, the positivity rates of TPOAb(+), TGAb(+) and TPOAb(+) or TGAb(+) significantly increased with age (all P for trend < 0·05). The levels of TSH, TV and the prevalence of overt hypothyroidism, subclinical hypothyroidism and goitre were significantly elevated in the thyroid antibody-positive groups in the three areas, but the FT3 was diminished (all P < 0·010). Positivity for TPOAb and TGAb was associated with an increased risk of subclinical hypothyroidism in the three areas. In areas with different median water iodine, positivity for both TPOAb and TGAb was associated with elevated TSH values. Notably, with the increased levels of TPOAb, the frequency of abnormally elevated TSH increased dramatically in the three areas.

20.
Oral Oncol ; 133: 106046, 2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35908361
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