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1.
Artigo em Inglês | MEDLINE | ID: mdl-35426038

RESUMO

Vascular calcification (VC) is a significant risk factor for cardiovascular mortality and morbidity in patients with atherosclerosis (AS), chronic kidney disease, and diabetes. Dickkopf1 (Dkk1) is a multifunctional secreted glycoprotein that has been explored as a novel potential antitumor target. Recently, Dkk1 was shown to be closely associated with AS development. However, the role of Dkk1 in VC remains elusive. In this study, we explored the role and molecular mechanisms of Dkk1 in VC based on a smooth muscle-specific Dkk1-knockout (Dkk1SMKO) mouse model. Our data indicated that Dkk1 expression was decreased under calcifying conditions and that Dkk1 overexpression alleviated high phosphate-induced vascular calcification. In vivo, smooth muscle Dkk1-specific knockout aggravated vascular calcification in mice. However, phospholipase D1 (PLD1) overexpression partially weakened the protective effect of Dkk1 against vascular calcification. Mechanistically, Dkk1 slowed vascular calcification by promoting the degradation of PLD1 via the regulating autophagosome formation and maturation. In conclusion, we found that Dkk1 could alleviate vascular calcification by regulating the degradation of PLD1.

2.
Inorg Chem ; 2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35477263

RESUMO

Recently, the development of porous absorbents for efficient CO2 and I2 capture has attracted considerable attention because of severe global climate change and environmental issues with the nuclear energy. Hence, a unique porous metal-organic framework (MOF), {[Co(L)]·DMF·2H2O}n (1, DMF = N,N-dimethylformamide) with uncoordinated N atoms was rationally constructed via using a heterofunctional 4,6-bis(4'-carboxyphenyl)pyrimidine (H2L) linker. Interestingly, 1 exhibits exceptional properties for I2 sorption, CO2 capture, and catalytic conversion. Particularly, I2 can be efficiently removed in both vapor and solution forms, and the adsorption amount can reach 676.25 and 345.28 mg g-1, respectively. Furthermore, complex 1 displays high adsorption capacity for CO2 (53.78 cm3 g-1, 273 K). Consequently, 1 is expected to be a promising and practical material for environmental purification due to its excellent adsorption properties.

3.
Research (Wash D C) ; 2022: 9802969, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35321260

RESUMO

Despite extensive efforts, COVID-19 pandemic caused by the SARS-CoV-2 virus is still at large. Vaccination is an effective approach to curb virus spread, but several variants (e.g., delta, delta plus, omicron, and IHU) appear to weaken or possibly escape immune protection. Thus, novel and quickly scalable approaches to restrain SARS-CoV-2 are urgently needed. Multiple evidences showed thermal sensitivity of SARS-CoV-2 and negative correlation between environmental temperature and COVID-19 transmission with unknown mechanism. Here, we reveal a potential mechanism by which mild heat treatment destabilizes the wild-type RNA-dependent RNA polymerase (also known as nonstructural protein 12 (NSP12)) of SARS-CoV-2 as well as the P323L mutant commonly found in SARS-CoV-2 variants, including omicron and IHU. Mechanistically, heat treatment promotes E3 ubiquitin ligase ZNF598-dependent NSP12 ubiquitination leading to proteasomal degradation and significantly decreases SARS-CoV-2 RNA copy number and viral titer. A mild daily heat treatment maintains low levels of both wild-type and P323L mutant of NSP12, suggesting clinical potential. Collectively, this novel mechanism, heat-induced NSP12 degradation, suggests a prospective heat-based intervention against SARS-CoV-2.

4.
Dis Markers ; 2022: 4952812, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35251372

RESUMO

Colorectal cancer (CRC) remains an important malignancy worldwide with poor prognosis. It has been known that DNA repair genes are involved in the development and progression of various tumors. Therefore, the purpose of this study was to explore DNA repair gene-based prognostic biomarkers for CRC. In this study, the expressing pattern and prognostic values of DNA repair genes in CRC patients were analyzed using TCGA database. GO and KEGG enrichment analyses were conducted to clarify the functional roles of dysregulated genes. We observed 358 differentially expressed DNA repair genes in CRC specimens, including 84 downregulated genes and 275 upregulated genes. 36 survival-related DNA repair genes were correlated with CRC patients' five-year survival, including 6 low-risk genes and 30 high-risk genes. Among the 10 overlapping genes, we focused on SLC6A1 which was highly expressed in CRC, and multivariate analysis confirmed that SLC6A1 expression as well as age and clinical stage could be regarded as an independent predicting factor for CRC prognosis. KEGG assays revealed that SLC6A1 may influence the clinical progression via regulating TGF-beta and PI3K-Akt signaling pathways. In addition, we observed that SLC6A1 was negatively regulated by SLC6A1 methylation, leading to its low expression in CRC specimens. Overall, SLC6A1 is upexpressed in CRC and can be used as a marker of poor prognosis in CRC patients.


Assuntos
Neoplasias Colorretais/genética , Reparo do DNA/genética , Proteínas da Membrana Plasmática de Transporte de GABA , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Bases de Dados Genéticas/estatística & dados numéricos , Regulação para Baixo , Feminino , Humanos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Regulação para Cima
5.
Anal Sci ; 38(1): 175-182, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35287220

RESUMO

Misplaced or excessive hypochlorous acid in lysosomes has a close association with lots of diseases, so monitoring hypochlorous acid in lysosomes is particularly necessary. In the present work, a novel lysosome-targetable fluorescent probe (Lyso-R-HClO) for hypochlorous acid based on a HClO-mediated cyclization reaction was developed. In the fluorescent probe, the morpholine unit and the site of a HClO-mediated cyclization reaction were, respectively, used as the lysosome-targetable group and the response group. The probe has high selectivity and high sensitivity to hypochlorous acid, with a linear range from 5.0 × 10-8 to 3.0 × 10-6 M and a detection limit of 15 nM; it was successfully used to image endogenous and exogenous lysosomal HClO. Finally, Lyso-R-HClO was further applied to image lysosomal HClO produced in bacteria-infected macrophage with satisfactory results, which indicate that it is an useful tool for studies of lysosomal HClO and the role of lysosome.


Assuntos
Corantes Fluorescentes , Ácido Hipocloroso , Ciclização , Corantes Fluorescentes/metabolismo , Ácido Hipocloroso/metabolismo , Lisossomos/metabolismo
6.
Physiol Genomics ; 54(4): 141-152, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35285753

RESUMO

Sick sinus syndrome (SSS) is a term used for a variety of disorders defined by abnormal cardiac impulse formation and by abnormal propagation from the heart's sinoatrial node. In this study, we present a case from a Chinese family in which two closely related individuals had the symptoms and electrocardiographic evidence of SSS. We hypothesized that multiple individuals affected by the disease in the family was an indication of its genetic predisposition, and thus performed high-throughput sequencing for the participants from the family to detect potential disease-associated variants. One of the potential variants that was identified was a KCNG2 gene variant (NC_000018.9: g.77624068_77624079del). Further bioinformatic analysis showed that the observed variant may be a pathogenic mutation. The results of protein-protein docking and whole cell patch-clamp measurements implied that the deletion variant in KCNG2 could affect its binding the KV2.1 protein, and finally affect the function of Kv channel, which is an important determinant in regulation of heartbeat. Therefore, we inferred that the variable KCNG2 gene may affect the function of Kv channel by changing the binding conformation of KCNG2 and KV2.1 proteins and then adversely affect propagation from the sinoatrial node and cardiac impulse formation by changing the action potential repolarization of heart cells. In summary, our findings suggested that the dominant KCNG2 deletion variant in the examined Chinese family with SSS may be a potential disease-associated variant.


Assuntos
Canais de Potássio Corretores do Fluxo de Internalização , Síndrome do Nó Sinusal , Nó Sinoatrial , Predisposição Genética para Doença , Humanos , Canais de Potássio Corretores do Fluxo de Internalização/genética , Deleção de Sequência , Síndrome do Nó Sinusal/diagnóstico , Síndrome do Nó Sinusal/genética , Nó Sinoatrial/patologia , Sequenciamento Completo do Genoma
7.
Water Sci Technol ; 85(3): 756-768, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35166698

RESUMO

Low Impact Development (LID) is an important approach for the construction of sponge airports. There are few researches on the application of LID facilities in airports. This study mainly analyzes the application of LID facilities in airports, and analyzes the reduction rate of LID facilities on the total runoff, peak present time and peaking volume by constructing EPA Storm Water Management Model (SWMM) in the eastern work area of an airport, which is located in a coastal city in northern China. This study selected three kinds of LID facilities: green roof, bio-detention facility and permeable pavement. Then three LID scenarios were formed according to different layout ratios of facilities (30%-90%), and the effects of different scenarios under different design rainstorms are simulated and analyzed. The results show that the control effect of LID scenario is enhanced with the increase of the proportion of LID facilities. The control effect of LID scenario gradually weakened with the increase of rainfall intensity. For high-frequency rainstorm, the maximum reduction rates of total runoff and peaking volume are 30.89% and 25.58% respectively, and the peak present time delay rate is up to 28.57%. For low-frequency rainstorm, the maximum reduction rates of total runoff and peaking volume are 17.96% and 14.95% respectively, and the peak present time delay rate is up to 6.12%. The flood control effect is more obvious when the LID facilities and pipe network are combined under the condition of low-frequency heavy rain. These conclusions present the effects under different combination ratio of LID facilities. It can provide the technical reference for the design and application of LID facilities for sponge airport construction in the future.


Assuntos
Chuva , Movimentos da Água , Aeroportos , China , Inundações
9.
Chin J Integr Med ; 28(3): 243-248, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35084700

RESUMO

OBJECTIVE: To determine whether salvianolic acid B (Sal B) exerts protective effects on diabetic peripheral neuropathy by attenuating apoptosis and pyroptosis. METHODS: RSC96 cells were primarily cultured with DMEM (5.6 mmol/L glucose), hyperglycemia (HG, 125 mmol/L glucose) and Sal B (0.1, 1, and 10 µ mol/L). Cells proliferation was measured by 3-(4, 5-cimethylthiazol-2-yl)-2, 5-dilphenyltetrazolium bromide assay. Reactive oxygen species (ROS) generation and apoptosis rate were detected by flow cytometry analysis. Western blot was performed to analyze the expressions of poly ADP-ribose polymerase (PARP), cleaved-caspase 3, cleaved-caspase 9, Bcl-2, Bax, NLRP3, ASC, and interleukin (IL)-1ß. RESULTS: Treatment with HG at a concentration of 125 mmol/L attenuated cellular proliferation, while Sal B alleviated this injury (P<0.05). In addition, Sal B inhibited HG-induced ROS production and apoptosis rate (P<0.05). Furthermore, treatment with Sal B down-regulated HG-induced PARP, cleaved-caspase 3, cleaved-caspase 9, Bax, NLRP3, ASC, and IL-1ß expression, but mitigated HG-mediated down-regulation of Bcl-2 expression (P<0.05). CONCLUSION: Sal B may protect RSC96 cells against HG-induced cellular injury via the inhibition of apoptosis and pyroptosis activated by ROS.


Assuntos
Benzofuranos , Piroptose , Apoptose , Benzofuranos/farmacologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
10.
Front Plant Sci ; 12: 751853, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899778

RESUMO

Terpene synthases (TPSs) are essential for forming terpenes, which play numerous functional roles in attracting pollinators, defending plants, and moderating the interaction between plants. TPSs have been reported in some orchids, but genome-wide identification of terpenes in Cymbidium faberi is still lacking. In this study, 32 putative TPS genes were classified in C. faberi and divided into three subfamilies (TPS-a, TPS-b, and TPS-e/f). Motif and gene structure analysis revealed that most CfTPS genes had the conserved aspartate-rich DDxxD motif. TPS genes in the TPS-a and TPS-b subfamilies had variations in the RRX8W motif. Most cis-elements of CfTPS genes were found in the phytohormone responsiveness category, and MYC contained most of the numbers associated with MeJA responsiveness. The Ka/Ks ratios of 12/13 CfTPS gene pairs were less than one, indicated that most CfTPS genes have undergone negative selection. The tissue-specific expression patterns showed that 28 genes were expressed in at least one tissue in C. faberi, and TPS genes were most highly expressed in flowers, followed by leaves and pseudobulbs. In addition, four CfTPS genes were selected for the real-time reverse transcription quantitative PCR (RT-qPCR) experiment. The results revealed that CfTPS12, CfTPS18, CfTPS23, and CfTPS28 were mainly expressed in the full flowering stage. CfTPS18 could convert GPP to ß-myrcene, geraniol, and α-pinene in vitro. These findings of CfTPS genes of C. faberi may provide valuable information for further studies on TPSs in orchids.

11.
Microorganisms ; 9(11)2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34835430

RESUMO

Lipid metabolism plays an important role in the energy economy of ruminants. However, its interactions of fat, rumen fermentation, gas emission, and microorganisms are not yet clear. This study evaluated the effect of adding raw oilseeds to high-forage diets on in vitro ruminal fermentation, gas composition, and microbial profile. Three isoenergetic and isoproteic experimental diets were designed and used as fermentation substrate: control treatment (CON group) was the basal diet lacking oilseeds, the other two treatments were the basal diet supplemented by 100 g/kg dry matter (DM) raw whole soybean (S group) and 50 g/kg DM raw flaxseed (F group), respectively. Data showed that the acetate, butyrate, and total VFA concentration of culture fluids in the S group were lower (p < 0.05) than in the F group. There was a tendency to a higher level (p = 0.094) of propionate concentration in the F group compared with the other two groups. The gas production in the F group was higher (p < 0.05) than in the control group. There was a lower abundance of Sutterella (p < 0.05) and a greater abundance of Butyrivibrio (p < 0.05) in both of the two oilseed treatments. Methanobrevibacter (p = 0.078) in the F group was the lowest. Our results suggested that CH4 emission could be inhibited with flaxseed supplementation by propionate production metabolism, biohydrogenation of unsaturated fatty acid (FA), and toxicity to Methanobrevibacter, while regarding soybean seed supplementation, the emission of CH4 was more likely to be reduced through biohydrogenation of unsaturated FA modulated by Butyrivibrio.

12.
Blood Cancer Discov ; 2(4): 388-401, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34661159

RESUMO

The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RARα-targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes the PML/RARα protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RARα in complex with nuclear receptor corepressors leading to ubiquitin-mediated degradation via the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/RARα via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RARα, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein-associated cancers by hyperthermia. SIGNIFICANCE: Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.See related commentary by Wu et al., p. 300.


Assuntos
Hipertermia Induzida , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/genética , Tretinoína/uso terapêutico
14.
World J Clin Cases ; 9(18): 4520-4541, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34222420

RESUMO

BACKGROUND: The high morbidity and mortality of colorectal cancer (CRC) have posed great threats to human health. Circular RNA (CircRNA) and microRNA (miRNA), acting as competing endogenous RNAs (ceRNAs), have been found to play vital roles in carcinogenesis. However, the biological function of ceRNAs in CRC pathogenesis and prognosis remains largely unexplored. AIM: To identify the CRC-specific circRNA-miRNA-mRNA regulatory network and uncover the subnetwork associated with its prognosis. METHODS: CircRNAs, miRNAs and mRNAs differentially expressed (DE) in CRC tissues were selected by expression file analysis in the Gene Expression Omnibus (GEO) database, and the downstream target molecules of circRNAs and miRNAs were predicted. Then, the intersection of differentially expressed RNA molecules with the predicted targets was determined to obtain a ceRNA network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the possible mechanism of pathogenesis. A survival analysis using the gene profiles and clinical information in The Cancer Genome Atlas (TCGA) database was performed to identify the mRNAs associated with the clinical outcome of CRC patients and construct a prognostic subnetwork. RESULTS: We downloaded three datasets (GSE126095, GSE41655 and GSE41657) of large-scale CRC samples from the GEO database. There were 55 DEcircRNAs, 114 DEmiRNAs and 267 DEmRNAs in CRC tissues compared with normal tissues. After intersecting these molecules with predicted targets, 19 circRNAs, 13 miRNAs and 28 mRNAs were chosen to develop a circRNA-miRNA-mRNA network. GO and KEGG functional enrichment analyses indicated that the retinol metabolic process, leukocyte chemotaxis, extracellular matrix remodeling, endoplasmic reticulum stress, alcohol dehydrogenase activity, gastric acid secretion, nitrogen metabolism and NOD-like receptor signaling pathway might participate in the tumorigenesis of CRC. After verifying the identified mRNA effect in the TCGA database, we finally recognized 3 mRNAs (CA2, ITLN1 and LRRC19) that were significantly associated with the overall survival of CRC patients and constructed a ceRNA subnetwork including 5 circRNAs (hsa_circ_0080210, hsa_circ_0007158, hsa_circ_0000375, hsa_circ_0018909 and hsa_circ_0011536) and 3 miRNAs (hsa-miR-601, hsa-miR-671-5p and hsa-miR-765), which could contain innovative and noninvasive indicators for the early screening and prognostic prediction of CRC. CONCLUSION: We proposed a circRNA-miRNA-mRNA regulatory network closely associated with the progression and clinical outcome of CRC that might include promising biomarkers for carcinogenesis and therapeutic targets.

15.
Front Cell Infect Microbiol ; 11: 648175, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34141627

RESUMO

Background: Evidence suggests that circadian rhythm disorder is associated with a variety of gastrointestinal diseases, and the circadian rhythm plays a key role in maintaining the homeostasis of intestinal flora. The underlying mechanisms are still not completely identified. This study was aimed to explore whether jet lag-caused circadian disruption influences gut microbiome and its metabolites. Methods: Mice were synchronized with 12-h light/dark cycles (control group) or subjected to daily 8-h advance of the light/dark cycle for every 3 days (jet-lagged group). Four months later, fecal samples and jejunal contents were collected and analyzed by 16S rRNA gene sequencing. In addition, fecal samples were subjected to metabolome analysis with ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Results: The results of 16s rRNA sequencing showed that chronic jet lag led to decreased microbial abundance, richness, and diversity in both feces and jejunal contents. ANOSIM analysis revealed significant difference between control and jet-lagged groups. As the colonic microbiome, the abundance of Bacteroidetes phylum was significantly decreased and that of Actinobacteria phylum was increased in jet-lagged mice. Jet lag increased the ratio of Firmicutes to Bacteroidetes, an indicator for the imbalance of gut microbiota. Metabolome analysis of fecal samples showed that the levels of tryptophan and its derivatives were decreased in jet-lagged mice. In addition, fecal levels of secondary bile acids changed under jet lag conditions. Correlation analysis identified associations between tryptophan (and its derivatives) levels and colonic microbiota. Conclusions: This study presents a comprehensive landscape of gut microbiota and its metabolites in mice subjected to chronic jet lag. The results suggest that circadian disruption may lead to changes in fecal and jejunal microbiota and fecal metabolites. Moreover, our results demonstrate a novel interplay between the gut microbiome and metabolome.


Assuntos
Microbioma Gastrointestinal , Síndrome do Jet Lag , Animais , Cromatografia Líquida , Fezes , Camundongos , RNA Ribossômico 16S , Espectrometria de Massas em Tandem
16.
Oncol Lett ; 22(1): 517, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33986877

RESUMO

SRY-related high-mobility group box 9 (SOX9) is an important transcriptional factor that regulates diverse genes involved in development and stemness. Dysregulation of SOX9 encourages carcinogenesis in various types of cancer, including breast cancer. The present study aimed to explore the role of SOX9 in triple-negative breast cancer (TNBC). SOX9 expression was significantly upregulated in the TNBC MDA-MB-231, MDA-MB-436 and MDA-MB-468 cell lines compared with that in BT-549 cells. Based on a lentivirus assay, SOX9 inhibition in MDA-MB-231 and MDA-MB-436 cells suppressed cell proliferation and colony formation. Apoptosis was increased and the cell cycle was arrested at the G0/G1 phase in SOX9-knockdown cells. Transwell and wound-healing assays demonstrated that SOX9 inhibition decreased the migration and invasion of MDA-MB-231 and MDA-MB-436 cells. RNA sequencing identified that numerous genes were regulated by SOX9, including nucleophosmin, thioredoxin reductase 1, succinate dehydrogenase complex subunit D, nuclear receptor binding SET domain protein 2, eukaryotic translation initiation factor 4γ1 and glycogen phosphorylase L. Overall, the current study suggested that SOX9 acted as an oncogene in TNBC.

17.
Pharmacol Res ; 169: 105656, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964470

RESUMO

Non-small cell lung cancer (NSCLC) is one of the most frequently diagnosed cancers and the leading causes of cancer death worldwide. Therefore, new therapeutic agents are urgently needed to improve patient outcomes. Plumbagin (PLB), a natural sesquiterpene present in many Chinese herbal medicines, has been reported for its anti-cancer activity in various cancer cells. In this study, the effects and underlying mechanisms of PLB on the tumorigenesis of NSCLC were investigated. PLB dose-dependently inhibited the growth of NSCLC cell lines. PLB promoted ROS production, activated the endoplasmic reticulum (ER) stress pathway, and induced cell apoptosis, accompanied by the decreased expression level of ADP-ribosylation factor 1 (ARF1) in NSCLC cancer cells, and those effects of PLB could be reversed by the pretreatment with N-acetyl-L-cysteine (NAC). More importantly, the calcium chelator (BM) significantly reversed PLB-induced cell apoptosis. Furthermore, PLB significantly inhibited the growth of both H1975 xenograft and LLC1 tumors and exhibited antitumor activity by enhancing the number and the effector function of CD8+ T cells in KRASLA2 mice model and the LLC1 xenograft. Our findings suggest that PLB exerts potent antitumor activity against NSCLC in vitro and in vivo through ARF1 downregulation and induction of antitumor immune response, indicating that PLB is a new novel therapeutic candidate for the treatment of patients with NSCLC.


Assuntos
Fator 1 de Ribosilação do ADP/metabolismo , Antineoplásicos Fitogênicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Naftoquinonas/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos Nus , Naftoquinonas/farmacologia , Transplante de Neoplasias
18.
Ann Transl Med ; 9(6): 452, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33850849

RESUMO

BACKGROUND: Due to varying degrees of difficulty in obtaining different mesenchymal stem cells (MSCs), the distinct pain levels and treatment costs, and for providing concrete evidence for future clinical practice, a thorough comparison of all relevant MSCs remained critical. Hence, this study aimed to achieve this objective to compare the efficacy of MSCs obtained from different sources in clinical outcomes and cartilage repair of knee osteoarthritis (KOA). METHODS: The EmBase, PubMed and Cochrane Library databases were searched for eligible studies. Randomized controlled trials (RCTs) that compared MSCs from different sources with placebo or each other in KOA patients. Conventional meta-analysis and frequentist network meta-analysis (NMA) were conducted. The primary clinical outcome was pain relief. The frequentist NMA was conducted using Stata with the "network" command. RESULTS: Eight studies (seven trials) involving 203 KOA patients were included in this meta-analysis. The MSCs were considered superior over placebo for pain relief and improved function in KOA, but showed no statistically significant differences for cartilage regeneration. Among all the MSCs, the adipose tissue-derived MSCs (AD-MSCs) most effectively relieved pain. CONCLUSION: These findings suggested that MSCs are effective in the treating of KOA. AD-MSCs might be the most effective for relieving pain, and Umbilical cord-derived mesenchymal stem cells (UC-MSCs) might be the most effective for improving function. However, the current evidence does not support the use of MSCs for improving cartilage repair in KOA patients.

19.
Int J Biol Sci ; 17(5): 1234-1249, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33867842

RESUMO

Dickkopf-1 (DKK1) was recently shown to play an important role in cardiovascular disease. The aim of this work was to assess the role of DKK1 in the regulation of smooth muscle cell function by mechanical stretch and the mechanisms underlying this process. Methods: Wild-type C57BL/6J mice were subjected to sham or abdominal aortic constriction (AAC) surgery. The expression level of DKK1 was examined by immunohistochemical staining and Western blotting. Analyses of DKK1 function in vascular smooth muscle cell (VSMC) proliferation and migration were performed. Transcriptome sequencing analysis was performed to identify the differentially expressed genes and pathways regulated by DKK1. Smooth muscle-specific Dkk1 knockout mice were used to confirm the function of DKK1 in vivo. Chromatin immunoprecipitation (ChIP) was used to confirm DNA-protein interactions. Promoter luciferase analysis was used to detect transcription factor activity. Results: We found that AAC significantly increased DKK1 protein levels in the thoracic aorta and coronary artery in vivo. In vitro, high-level stretch (18%) induced the expression of DKK1 in VSMCs. Knocking down DKK1 inhibited VSMC proliferation and migration under high-level stretch (18%). We identified ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as a target gene of DKK1. Knockdown of UHRF1 with small interfering RNAs partially reversed the regulatory effect of recombinant DKK1 on VSMCs. Specific deletion of DKK1 in VSMCs was sufficient to attenuate the AAC-induced upregulation of UHRF1, thickening of arterial media and increase in VSMC proliferation. Furthermore, we found that DKK1 regulated UHRF1 expression through the YAP-TEAD pathway. TEAD1 and TEAD4 bound directly to the promoter of UHRF1, and blocking the YAP-TEAD interaction inhibited UHRF1 upregulation due to DKK1. Conclusions: This study reveals that DKK1 mediates the mechanical stretch regulation of smooth muscle cell function by modulating UHRF1 expression through the YAP-TEAD pathway.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Músculo Liso Vascular/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , /metabolismo , Animais , Doenças Cardiovasculares/metabolismo , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Regulação para Cima
20.
Brain Res ; 1757: 147299, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33516816

RESUMO

Autism spectrum disorder (ASD) patients are often reported altered patterns of functional connectivity (FC) on resting-state functional magnetic resonance imaging (rsfMRI) scans. However, the results in similar brain regions were inconsistent. In this study, we first investigated statistical differences in large-scale resting-state networks (RSNs) on 192 healthy controls (HCs) and 103 ASD patients by using independent component analysis (ICA). Second, an image-based meta-analysis (IBMA) was applied to discover the consistency of spatial patterns from different sites. Last, utilizing these patterns as features, we used Support Vector Machine (SVM) classifier to identify whether a subject was suffering from ASD or not. As a result, six RSNs were obtained with ICA. In each RSN, we identified altered functional connectivity between ASD and HC across the multi-site data. We calculated the area under the receiver operating characteristic curve plots (AUC) to determine the classification performance. The AUC value of classification reaches 0.988. In conclusion, the present study indicates that intrinsic connectivity patterns produced from rsfMRI data could yield a possible biomarker of ASD and contributed to the neurobiology of ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Mapeamento Encefálico , Encéfalo/fisiopatologia , Aprendizado de Máquina , Imageamento por Ressonância Magnética , Transtorno do Espectro Autista/diagnóstico , Mapeamento Encefálico/métodos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Vias Neurais/fisiopatologia
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