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1.
Lancet Reg Health West Pac ; 31: 100646, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36419465

RESUMO

Background: Universal health coverage (UHC) is a core element of Sustainable Development Goals and has become a global healthcare priority. China has been committing to provide all citizens with affordable and equitable basic healthcare over past decades. However, progress towards UHC in China has not been comprehensively assessed. This study aims to comprehensively evaluate the progress towards UHC in China by examining trends in service coverage and financial protection from 1993 to 2018, and estimating the probability of achieving UHC targets by 2030. Methods: Following the framework proposed by World Health Organization and World Bank, we selected 12 prevention service indicators, 12 treatment service indicators, and two financial protection indicators to evaluate China's progress towards UHC. We used data from four nationally representative household surveys to assess the trends in service coverage and financial protection between 1993 and 2018, as well as their inequalities across subgroups. Meta-analysis was used to construct the composite prevention and treatment indices. The regression-based relative index of inequality was used to measure the income-related inequality of UHC indicators. Bayesian linear regression was conducted to predict progress towards UHC by 2030, and the probability of achieving UHC targets. Findings: Of the 24 service coverage indicators used in this study, most of them experienced improvements between 1993 and 2018. The composite prevention index increased from 65.6% (95% CI: 52.1%-77.9%) to 87.7% (95% CI: 81.8%-92.6%) and the composite treatment index increased from 57.1% (95% CI: 43.5%-70.1%) to 75.5% (95% CI: 66.6%-83.5%). The inequalities of service coverage experienced significant declines during this period. Based on our projections, most indicators except ones in the area of non-communicable diseases (NCD) will achieve the 80% coverage target by 2030, and the prevention and treatment indices will increase to 92.7% (95% CrI: 90.3%-94.7%) and 83.2% (95% CrI: 75.1%-88.8%) by then. However, we observed limited reductions in the incidences of catastrophic health expenditure and medical impoverishment. Inequalities in financial protection remained large in 2018. Interpretation: China had made significant progress in improving healthcare service coverage and reducing inequalities between 1993 and 2018. However, China faces great challenges in improving financial protection and controlling NCD on its path towards UHC. Establishment of a primary-healthcare-based integrated delivery system and provision of better financial protection for vulnerable population should be prioritized. Funding: None.

2.
Chemosphere ; 311(Pt 1): 137038, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36323385

RESUMO

Metal organic frameworks-Covalent organic frameworks (MOFs-COFs) nanocomposites could improve the catalytic performance. Herein, a novel nanocomposite catalyst (CC@Co3O4) derived from MOFs-COFs (COF@ZIF-67) was prepared on peroxymonosulfate (PMS) activation for bisphenol A (BPA) and rhodamine B (RhB) degradation. Owing to the Co species, oxygen vacancy (OV), surface hydroxyl (-OH), graphite N and ketone groups (C=O), the CC@Co3O4 exhibited higher catalytic degradation performance and total organic carbon (TOC) for BPA (93.8% and 22.3%) and RhB (98.2% and 82.5%) with a small quantity of catalyst (0.10 g/L) and low concentration of PMS (0.20 g/L) even without pH adjustment. Sulfate radicals (•SO4-), hydroxyl radicals (•OH), single oxygen (1O2), superoxide radicals (•O2-) and electron transfer process were all involved in the degradation of BPA and RhB. Among them, the degradation of BPA and RhB mainly depended on •O2- and 1O2, respectively. Meanwhile, the degradation pathways of BPA and RhB were proposed, and the biotoxicity of the degradation products was evaluated by freshwater chlorella. The results illustrated that the degradation products were environmentally friendly to organisms. In addition, the role of COF in the nanocomposites was also studied. The addition of COF remarkably improved the catalytic performance of CC@Co3O4 due to the faster electron transfer, more graphite N and C=O. Overall, this work may open the door to the development of COF-based catalysts in the field of water pollutant remediation.


Assuntos
Chlorella , Poluentes Ambientais , Grafite , Estruturas Metalorgânicas , Nanocompostos , Peróxidos/química , Nanocompostos/química , Oxigênio
3.
J Ethnopharmacol ; 301: 115836, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36252877

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Xingnaojing(XNJ)injection is a traditional Chinese medicine injection with neuroprotective effect, which has been widely used in the treatment of stroke for many years. AIM OF THE STUDY: This study aimed to explore the potential mechanism of XNJ in cerebral ischemia mediated by ferroptosis using proteomics and in vivo and in vitro experiments. MATERIALS AND METHODS: After the rat model of middle cerebral artery occlusion (MCAO) was successfully established, they were randomly divided into model, XNJ, and deferoxamine (DFO) group. Triphenyl tetrazolium chloride (TTC) staining, Hematoxylin and eosin (H&E), and Nissl staining were used to observe the infarct area, pathological changes and the degree of neuronal apoptosis of rat brain. Proteins extracted from rat brain tissues were analyzed by quantitative proteomics using tandem mass tags (TMT). Western blotting and immunohistochemical assessment were used to measure the expression of ferroptosis-related proteins. In vitro, the SH-SY5Y cells were subjected to hypoxia (37°C/5% CO2/1% O2) for 24 h to observe the survival rate, and detect the reactive oxygen species (ROS) content and ferroptosis-related proteins. RESULTS: In TTC and H&E experiments, we found that XNJ drug treatment reduced the infarct volume and brain tissue damage in MCAO rats. Nissl staining also showed that compared with MCAO group rats, the Nissl bodies of brain tissue after XNJ drug intervention were clear with a 3.54-fold increased times, suggesting that XNJ improved cerebral infraction, and neurological deficits in MCAO rats. Proteomics identified 101 intersected differentially expressed proteins (DEPs). According to the bioinformatics analysis, these DEPs were closely related to ferroptosis. Further research indicated that MCAO-induced cerebral ischemia was alleviated by upregulating recombinant glutathione peroxidase 4 (GPX4), ferroportin (FPN) expression, Heme oxygenase-1 (HO-1) expression, and downregulating cyclooxygenase-2 (COX-2), transferring receptor (TFR) and divalent metal transporter-1 (DMT1) expression after XNJ treatment. In addition, in vitro experiment indicated that XNJ improved the survival rate of hypoxia-damaged SH-SY5Y cells. XNJ increased the level of GPX4 and inhibited the protein expression of COX-2 and TFR after cell hypoxia. Moreover, different concentrations of XNJ (0.25%, 0.5%, 1%) reduced the ROS content of hypoxic cells, suggesting that XNJ could inhibit hypoxia-induced cell damage by regulating the expression of ferroptosis-related proteins and decreasing the production of ROS. CONCLUSIONS: XNJ could promote the recovery of neurological function in MCAO rats and hypoxia SH-SY5Y cells by regulating ferroptosis.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , Ferroptose , Neuroblastoma , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Ratos , Lesões Encefálicas/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Ciclo-Oxigenase 2 , Hipóxia/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Espécies Reativas de Oxigênio , Traumatismo por Reperfusão/tratamento farmacológico
4.
J Dermatol ; 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36412048

RESUMO

Vitiligo is a skin depigmentation disorder. GATA3 expression is downregulated in vitiligo patients, and its role and regulatory mechanism in vitiligo are unclear. GATA3 and HMGB1 levels were detected by qRT-PCR in peripheral blood cells of vitiligo patients and healthy controls, as well as H2 O2 -treated PIG1 cells. Their expression correlation was assessed by Pearson analysis. qRT-PCR, MTT assay, Ki67 immunostaining, flow cytometry, ELISA and Western blot were applied to determine GATA3 expression, cell survival, cell proliferation, cell apoptosis, melanin contents, and melanin-related protein expressions. The cellular distributions of HMGB1 and its deacetylation levels were detected by Western blot. The binding of GATA3 to SIRT3 promoter and effects on SIRT3 expression and HMGB1 deacetylation was determined by dual-luciferase assay, ChIP assay, and Western blot. GATA3 was decreased, and HMGB1 was increased in vitiligo. Pearson correlation assay showed that they were negatively correlated. H2 O2 significantly inhibited cell survival, proliferation, melanin secretion, and melanin-related protein expressions but remarkably increased cell apoptosis. GATA3 overexpression could distinctly reverse the effects of H2 O2 through decreasing HMGB1 expression and retained HMGB1 in nuclear due to the decreased HMGB1 acetylation. GATA3 bound to the SIRT3 and subsequently decreased H2 O2 -induced HMGB1 acetylation. Overexpressing HMGB1 or knockdown of SIRT3 could reverse the effects of GATA3 overexpression. GATA3 inhibited H2 O2 -induced injury in PIG1 cells and enhanced melanin secretion by SIRT3-regulated HMGB1 deacetylation, which might provide new evidence to treat vitiligo.

5.
Front Cardiovasc Med ; 9: 984087, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386298

RESUMO

Background and aims: Aortic dissection (AD) is a cardiovascular emergency with degeneration of the aortic media. Mounting evidence indicates obstructive sleep apnea (OSA) as an independent risk factor for AD development with unknown mechanisms. This study aims to establish a stable murine model of OSA-related AD (OSA-AD) and uncover the potential changes in gene transcripts in OSA-AD. Materials and methods: ApoE-/- mice were exposed to the chronic intermittent hypoxia (CIH) system combined with Ang II administration to establish the OSA-AD model. Pathological staining was performed to exhibit the physiological structure of the mouse aorta. The SBC mouse ceRNA microarray was used to identify significantly differentially expressed (DE) mRNAs, DE long-non-coding RNAs (DElncRNAs), and DE circular RNAs (DEcircRNAs) in OSA-AD tissues. Subsequently, bioinformatics analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG), and protein-protein interaction (PPI) analyses, were performed to evaluate the function of the significantly differentially expressed transcripts (DETs). The hub genes were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). Results: ApoE-/- mice exposed to CIH and Ang II showed a high ratio of aortic accident (73.33%) and significant aortic diameter dilatation (1.96 ± 0.175 mm). A total of 1,742 mRNAs, 2,625 lncRNAs, and 537 circRNAs were identified as DETs (LogFC ≥ 1.5 or ≤ -1.5, P < 0.05). GO and KEGG analyses demonstrated that the differentially expressed mRNAs (DEmRNAs) were most enriched in cell proliferation, migration, apoptosis, inflammation, and hypoxia-related terms, which are closely related to aortic structural homeostasis. The PPI network contained 609 nodes and 934 connections, the hub genes were highlighted with the CytoHubba plugin and confirmed by qRT-PCR in AD tissues. KEGG pathway analysis revealed that the cis-regulated genes of DElncRNAs and circRNAs-host genes were enriched in aortic structural homeostasis-related pathways. Conclusion: Our findings help establish a de novo OSA-AD animal model using ApoE-/- mice. Many DEmRNAs, DElncRNAs, and DEcircRNAs were screened for the first time in OSA-AD tissues. Our findings provide useful bioinformatics data for understanding the molecular mechanism of OSA-AD and developing potential therapeutic strategies for OSA-AD.

6.
Front Microbiol ; 13: 1032851, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386663

RESUMO

Biogenic and thermogenic gas are two major contributors to gas hydrate formation. Methane hydrates from both origins may have critical impacts on the ecological properties of marine sediments. However, research on microbial diversity in thermogenic hydrate-containing sediments is limited. This study examined the prokaryotic diversity and distributions along a sediment core with a vertical distribution of thermogenic gas hydrates with different occurrences obtained from the Qiongdongnan Basin by Illumina sequencing of 16S rRNA genes as well as molecular and geochemical techniques. Here, we show that gas hydrate occurrence has substantial impacts on both microbial diversity and community composition. Compared to the hydrate-free zone, distinct microbiomes with significantly higher abundance and lower diversity were observed within the gas hydrate-containing layers. Gammaproteobacteria and Actinobacterota dominated the bacterial taxa in all collected samples, while archaeal communities shifted sharply along the vertical profile of sediment layers. A notable stratified distribution of anaerobic methanotrophs shaped by both geophysical and geochemical parameters was also determined. In addition, the hydrate-free zone hosted a large number of rare taxa that might perform a fermentative breakdown of proteins in the deep biosphere and probably respond to the hydrate formation.

7.
Toxicol Ind Health ; : 7482337221138949, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36398892

RESUMO

Titanium dioxide nanoparticles (TiO2NPs) and cypermethrin (CPM) are widely used in various fields, and they can enter the environment in different ways. Combined exposure of TiO2NPs and CPM may increase the accumulation of pollutants in organisms and affect human health. This study was undertaken to evaluate the oxidative and inflammatory parameters associated with the combined exposure of TiO2NPs and CPM in rats. Twenty-four healthy male adult SD rats were randomly divided into four groups. The first group served as the control, while groups 2, 3, and 4 were treated with TiO2NPs (450 mg/m3); CPM (6.67 mg/m3) or combined exposure of TiO2NPs and CPM by inhalation for 90 days. We investigated the oxidative damage induced through combined exposure of TiO2NPs and CPM in rats by evaluating hematology of the rats and determining the blood biochemical index. Our results demonstrated that inhalation of TiO2NPs and CPM increased the levels of oxidative stress markers such as malondialdehyde and alkaline phosphatase in the serum of rats. These were accompanied by a decreased glutathione peroxidase and total superoxide dismutase levels. Furthermore, the level of glutathione peroxidase was further decreased while malondialdehyde was increased in the combined exposure of TiO2NPs and CPM. Interestingly, pathological sections showed that different degrees of tissue injury could be seen in the liver and lung tissues of each exposure group. In summary, the combined exposure of TiO2NPs and CPM can cause increased oxidative damage in rats and damage the tissue structure of the liver and lung.

8.
Front Psychiatry ; 13: 1013108, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36405920

RESUMO

Negative cognitive processing bias (NCPB) is a cognitive trait that makes individuals more inclined to prioritize negative external stimuli (cues) when processing information. Cognitive biases have long been observed in mood and anxiety disorders, improving validation of tools to measure this phenomenon will aid us to determine whether there is a robust relationship between NCPB and major depressive disorder, anxiety disorders and other clinical disorders. Despite the development of an initial measure of this trait, that is, the negative cognitive processing bias questionnaire (NCPBQ), the lack of psychometric examinations and applications in large-scale samples hinders the determination of its reliability and validity and further limits our understanding of how to measure the NCPB traits of individuals accurately. To address these issues, the current study evaluated the psychometric properties of the NCPBQ in a large-scale sample (n = 6,069), which was divided into two subsamples (Subsample 1, n = 3,035, serving as the exploratory subsample, and Subsample 2, n = 3,034, serving as the validation subsample), and further revised it into a standardized scale, that is the negative cognitive processing bias scale (NCPBS), based on psychometric constructs. The results show that NCPBS possesses good construct reliability, internally consistent reliability, and test-retest reliability. Furthermore, by removing two original items from NCPBQ, NCPBS was found to have good criterion-related validity. In conclusion, the present study provides a reliable and valid scale for assessing negative cognitive processing bias of individuals.

9.
Proc Natl Acad Sci U S A ; 119(45): e2205110119, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36396123

RESUMO

During coordinated development of two neighboring organs from the same germ layer, how precursors of one organ resist the inductive signals of the other to avoid being misinduced to wrong cell fate remains a general question in developmental biology. The liver and anterior intestinal precursors located in close proximity along the gut axis represent a typical example. Here we identify a zebrafish leberwurst (lbw) mutant with a unique hepatized intestine phenotype, exhibiting replacement of anterior intestinal cells by liver cells. lbw encodes the Cdx1b homeoprotein, which is specifically expressed in the intestine, and its precursor cells. Mechanistically, in the intestinal precursors, Cdx1b binds to genomic DNA at the regulatory region of secreted frizzled related protein 5 (sfrp5) to activate sfrp5 transcription. Sfrp5 blocks the mesoderm-derived, liver-inductive Wnt2bb signal, thus conferring intestinal precursor cells resistance to Wnt2bb. These results demonstrate that the intestinal precursors avoid being misinduced toward hepatic lineages through the activation of the Cdx1b-Sfrp5 cascade, implicating Cdx/Sfrp5 as a potential pharmacological target for the manipulation of intestinal-hepatic bifurcations, and shedding light on the general question of how precursor cells resist incorrect inductive signals during embryonic development.


Assuntos
Hepatócitos , Peixe-Zebra , Animais , Peixe-Zebra/genética , Hepatócitos/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Fígado/metabolismo
10.
FASEB J ; 36(12): e22617, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36412513

RESUMO

Early-onset preeclampsia (ePE) originates from abnormal implantation and placentation that involves trophoblast invasion, but its pathophysiology is not entirely understood. N6-methyladenosine (m6A) regulators mediate the progression of various cancers. The invasiveness of trophoblast cells is similar to that of tumor cells. However, little is known regarding the potential role of m6A modification in ePE and the underlying mechanism. This study aimed to explore the m6A level in placental tissue samples collected from ePE patients and to investigate whether m6A modification was an essential part of PE pathogenesis. The m6A level in placental tissue samples of 80 PE participants was examined. MeRIP-microarray, RNA-Seq, luciferase reporter assay, and RNA immunoprecipitation chip (RIP) assay were performed. The m6A level in the ePE group was significantly reduced compared with the control group. Wilms' tumor 1-associating protein (WTAP) regulated trophoblast cell migration and invasion. Mechanistically, the high mobility group nucleosomal binding domain 3 (HMGN3) gene was a target gene of WTAP in trophoblast (p < .05). WTAP enhanced the stability of HMGN3 mRNA through binding with its 3'-UTR m6A site(+485A, +522A). HMGN3 was recognized by m6A recognition protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which was inhibited when knocking down WTAP. Both m6A and WTAP levels were downregulated in ePE. The m6A modification mediated by WTAP/IGF2BP1/HMGN3 axis might contribute to abnormal trophoblast invasion. Our work provided a foundation for further exploration of RNA epigenetic regulatory patterns in ePE, and indicated a new treatment strategy for ePE.


Assuntos
Pré-Eclâmpsia , Trofoblastos , Humanos , Feminino , Gravidez , Trofoblastos/metabolismo , Pré-Eclâmpsia/genética , Placenta/metabolismo , RNA Mensageiro/genética , RNA/metabolismo , Fatores de Processamento de RNA , Proteínas de Ciclo Celular/metabolismo
11.
Aging (Albany NY) ; 14(21): 8818-8838, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36347025

RESUMO

BACKGROUND: N6-methyladenosine (m6A) is the most abundant epigenetic modification. Although the dysregulation of m6A regulators has been associated with cancer progression in several studies, its relationship with cancer prognosis and clinicopathology is still controversial. Therefore, we evaluated the prognostic and clinicopathological value of m6A regulators in cancers by performing a comprehensive meta-analysis. METHODS: The PubMed, Cochrane Library, Web of Science, and Embase databases were searched up to April 2022. Hazard ratios were used to analyze the association between m6A with prognosis. We also analyze the relationship between m6A and clinicopathology using odds ratios. RESULTS: METTL3 overexpression predicted poor overall survival and disease-free survival in cancer patients (p < 0.001) such as gastric cancer (p < 0.001), esophageal squamous cell carcinoma (p < 0.001), oral squamous cell carcinoma (p = 0.002) and so on. Additionally, METTL3 overexpression was associated with poor pT stage (p < 0.001), pN stage (p < 0.001), TNM stage (p < 0.001), tumor size >5 cm (p < 0.001) and vascular invasion (p = 0.024). Conversely, METTL14 overexpression was positively associated with better OS (p < 0.001), negatively with poor pT stage (p = 0.001), pM stage (p = 0.002), pN stage (p = 0.011) and TNM stage (p < 0.001). Moreover, KIAA1429 overexpression was associated with poor OS (p = 0.001). YTHDF1 overexpression was also associated with advanced pM stage (p < 0.001) and tumor size >5 cm (p < 0.001). However, ALKBH5 overexpression was negatively associated with vascular invasion (p = 0.032). CONCLUSIONS: High expression of METTL3 predicted poor outcome. In contrast, high expression of METTL14 was associated with better outcome. Thus, we suggest that among all the m6A regulators, METTL3 and METTL14 could be potential prognostic markers in cancers.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias Bucais , Humanos , Prognóstico , Metiltransferases/genética
12.
Anal Chem ; 94(46): 16196-16203, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36358017

RESUMO

Quantification of exosomal multi-miRNA can reveal the initiation, progression, and metastasis of tumors, which is conducive to the noninvasive early diagnosis of cancer. However, low-sensitivity and single-plex detection characteristics of traditional methods seriously hinder the accuracy and specificity of exosomal miRNAs in cancer diagnosis. Herein, we design an ultramultiplexing strategy that enables simultaneous and sensitive detection of multiple exosomal miRNAs by nanosatellites (magnetic beads (MBs) @ NaLnF4) and catalytic hairpin assembly (CHA) amplification in combination with inductively coupled plasma-mass spectrometry (ICP-MS) to diagnose cancer accurately. The competitive binding of target exosomal miRNAs with the recognition sequences on nanosatellites triggers the drop of NaLnF4 from MBs, followed by a CHA reaction that releases more NaLnF4 labels for ICP-MS detection. This method is used to detect ten types of miRNAs simultaneously with a detection limit of 0.01 fM, which is one order of magnitude lower than the quantitative reverse transcription polymerase chain reaction (qRT-PCR) method. Linear discriminant analysis as a machine learning algorithm is subsequently applied to analyze the signals of exosomal multi-miRNA, and the discrimination accuracy of ten cell exosomes reaches 98.6%. In a clinical cohort of 42 patients, including five cancer types and healthy controls, exosomal multi-miRNA analysis achieves accurate cancer diagnosis and classification with 100% accuracy. Our results show that the combination of nanosatellites, CHA, and ICP-MS provides a universal biosensing platform for simultaneous and ultrasensitive detection of multiple targets.


Assuntos
Técnicas Biossensoriais , Exossomos , MicroRNAs , Neoplasias , Humanos , MicroRNAs/análise , Exossomos/química , Neoplasias/diagnóstico , Técnicas Biossensoriais/métodos
13.
Am J Cancer Res ; 12(10): 4602-4621, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36381312

RESUMO

HOXC10 has been reported to be upregulated in ovarian cancer (OC) tissues, attributing to the metastasis of OC. However, the specific functions of HOXC10 in OC, especially its role in chemoresistance, remain to be determined. Therefore, in this study, we explored the function and the underlying mechanisms of HOXC10 in carboplatin resistance of OC. A variety of approaches were utilized to analyze the expression of HOXC10 and its related genes. The effect of HOXC10 in cell growth and chemoresistance was investigated in carboplatin-resistant OC subline TOV21G-R and the parental TOV21G-P cells. ROC curve and survival analysis were conducted to determine the predictive value of HOXC10 and ABCC3 combination in carboplatin resistance and the prognosis of OC. Luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay were used to explore the direct regulation of ß-catenin by HOXC10. Our results demonstrated that the expression of HOXC10 was upregulated both in the carboplatin-resistant OC tissues and TOV21G-R cells. Furthermore, the upregulation of HOXC10 could promote the expression of ABCC3 by transcriptionally upregulating ß-catenin. Moreover, overexpression of HOXC10 could decrease the sensitivity of cells to carboplatin, while knocking down HOXC10 had the opposite effect both in vitro and in vivo. Therefore, the expression of HOXC10/ABCC3 could be a novel biomarker for predicting the carboplatin resistance and the prognosis of OC patients.

14.
J Med Chem ; 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36384290

RESUMO

KRAS mutations (G12C, G12D, etc.) are implicated in the oncogenesis and progression of many refractory cancers. Son of sevenless homolog 1 (SOS1) is a key regulator of KRAS to modulate KRAS from inactive to active states. Herein, we disclosed efficacy-improving tetra-cyclic quinazoline derivatives as an enhanced scaffold for inhibiting the SOS1-KRAS interaction. Compound 37, which conjugated 1-carbonitrile-cyclopropane to tetra-cyclic quinazoline, showed a twofold higher oral drug exposure and 2.5-fold longer half-life than BI-3406 in CD-1 mouse plasma. In a Mia-paca-2 xenograft model, 37 administrated alone inhibited tumor growth by 71%. Preclinical investigations demonstrated that 37 had a limited inhibition of CYP and hERG. Overall, our studies showed that 37 was a promising drug candidate for treatment of KRAS-driven cancer.

15.
Adv Sci (Weinh) ; : e2205461, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36385484

RESUMO

Rabies is a fatal neurological zoonotic disease caused by the rabies virus (RABV), and the approved post-exposure prophylaxis (PEP) procedure remains unavailable in areas with inadequate medical systems. Although strategies have been proposed for PEP and postinfection treatment (PIT), because of the complexity of the treatment procedures and the limited curative outcome, developing an effective treatment strategy remains a holy grail in rabies research. Herein, a facile approach is proposed involving photothermal therapy (PTT) and photothermally triggered immunological effects to realize effective PEP and PIT simultaneously. The designed photothermal agent (N+ TT-mCB nanoparticles) featured positively charged functional groups and high photo-to-heat efficiency, which are favorable for virus targeting and inactivation. The level of the virus at the site of infection in mice is significantly decreased upon treatment with orthotopic PTT, and the transfer of the virus to the brain is significantly inhibited. Furthermore, the survival ratio of the mice three days postinfection is increased by intracranial injection of N+ TT-mCB and laser irradiation. Overall, this work provides a platform for the effective treatment of RABV and opens a new avenue for future antiviral studies.

16.
Biomaterials ; 291: 121898, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36379162

RESUMO

Although face masks as personal protective equipment (PPE) are recommended to control respiratory diseases with the on-going COVID-19 pandemic, improper handling and disinfection increase the risk of cross-contamination and compromise the effectiveness of PPE. Here, we prepared a self-cleaning mask based on a highly efficient aggregation-induced emission photosensitizer (TTCP-PF6) that can destroy pathogens by generating Type I and Type II reactive oxygen species (ROS). The respiratory pathogens, including influenza A virus H1N1 strain and Streptococcus pneumoniae (S. pneumoniae) can be inactivated within 10 min of ultra-low power (20 W/m2) white light or simulated sunlight irradiation. This TTCP-PF6-based self-cleaning strategy can also be used against other airborne pathogens, providing a strategy for dealing with different microbes.

17.
Brain Res ; 1798: 148155, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36343723

RESUMO

Interferon-regulatory factor 5 (IRF5) participates in the regulation of apoptosis, affects the phenotype of inflammatory macrophages and plays an essential role in the inflammatory response. However, the role of IRF5 in the progression of amyotrophic lateral sclerosis (ALS) remains largely unknown. Here, we show that IRF5 mainly accumulated in the nucleus in cells expressing the truncated 25 kD C-terminal fragments of TDP-43 (TDP-25, named TDP-25 cells hereafter). IRF5 knockdown using a lentivirus carrying an shRNA in TDP-25 cells exerted a protective effect and reduced the level of the apoptosis-related protein cleaved caspase-9 and the cell cycle arrest protein p21, while increasing the expression of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its target molecule glutamate-cysteine ligase modulatory subunit (GCLM). Furthermore, IRF5-knockdown cells showed improved mitochondrial swelling and cristae dilation. In addition, we found that IRF5 mediated neuronal injury partly through the negative regulation of TANK-binding kinase 1 (TBK1). These data indicate that the loss of IRF5 in TDP-25 cells exerts a protective effect mainly by inhibiting apoptosis, regulating cell cycle arrest and alleviating oxidative stress.

18.
J Med Chem ; 65(22): 15123-15139, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36351049

RESUMO

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptides P1GCGT1 and P1GCGCGT1 were designed using an in silico approach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain, P1GCGT1 and P1GCGCGT1 could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among which I-1 and I-4 were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated that I-1 and I-4 induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed that I-1 and I-4 were effective at targeting HER2. Moreover, I-1 and I-4 showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.


Assuntos
Neoplasias da Mama , Animais , Humanos , Camundongos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Camundongos Nus , Peptídeos/farmacologia , Peptídeos/uso terapêutico
19.
Phytomedicine ; 108: 154530, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36356328

RESUMO

BACKGROUND: Intracerebral hemorrhage (ICH) is a life-threatening stroke subtype with high rates of disability and mortality. Naoxueshu oral liquid is a proprietary Chinese medicine that absorbs hematoma and exhibits neuroprotective effects in patients with ICH. However, the underlying mechanisms remain obscure. PURPOSE: Exploring and elucidating the pharmacological mechanism of Naoxueshu oral liquid in the treatment of ICH. STUDY DESIGN AND METHODS: The Gene Expression Omnibus (GEO) database was used to download the gene expression data on ICH. ICH-related hub modules were obtained by weighted gene co-expression network analysis (WGCNA) of differentially co-expressed genes (DEGs). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the obtained key modules to identify the ICH-related signaling pathways. Network pharmacology technology was applied to forecast the targets of Naoxueshu oral liquid and to establish a protein-protein interaction (PPI) network of overlapping targets between Naoxueshu oral liquid and ICH. Functional annotation and enrichment pathway analyses of the intersectional targets were performed using the omicsbean database. Finally, we verified the therapeutic role and mechanism of Naoxueshu oral liquid in ICH through molecular docking and experiments. RESULTS: Through the WGCNA analysis, combined with network pharmacology, it was found that immune inflammation was closely related to the early pathological mechanism of ICH. Naoxueshu oral liquid suppressed the inflammatory response; hence, it could be a potential drug for ICH treatment. Molecular docking further confirmed that the effective components of Naoxueshu oral liquid docked well with CD163. Finally, the experimental results showed that Naoxueshu oral liquid treatment in the ICH rat model attenuated neurological deficits and neuronal injury, decreased hematoma volume, and promoted hematoma absorption. In addition, Naoxueshu oral liquid treatment also significantly increased the levels of Arg-1, CD163, Nrf2, and HO-1 around hematoma after ICH. CONCLUSION: This study demonstrated that Naoxueshu oral liquid attenuated neurological deficits and accelerated hematoma absorption, possibly by suppressing inflammatory responses, which might be related to the regulation of Nrf2/CD163/HO-1 that interfered with the activation of M2 microglia, thus accelerating the clearance and decomposition of hemoglobin in the hematoma.

20.
Front Public Health ; 10: 1034907, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36419995

RESUMO

Limited health literacy is a serious public health problem. It is strongly associated with increased hospital admissions and readmission, poorer self-management, and health outcomes. It can lead to poor management of chronic disease, lower health care quality, increased mortality, and higher healthcare expenditures. Understanding China's current situation and the progress of health literacy levels are critical to achieving practical solutions for improving population health. This paper intended to provide a concise overview of the key milestones and specific practices in health literacy in China. We summarized the characteristics and changing profile of health literacy from 2008 to 2020 in China. We developed an intervention framework based on social ecosystem theory for improving health literacy in China. Meanwhile, some multi-level actionable recommendations were proposed. The study revealed that China has made progress in improving health literacy in the last decades. Health literacy levels increased from 6.48% of the population in 2008 to 23.15% in 2020. Geographic disparities were substantial. The East performed better health literacy than the Central and West, and cities had higher adequate health literacy than rural areas. Social development index, age, and education level were highly associated with health literacy. A global joint effort to improve health literacy will be required. And we advocate a whole-of-society approach that involves the participation of the entire ecosystem around the targeted population.


Assuntos
Letramento em Saúde , Humanos , Ecossistema , China/epidemiologia , Saúde Pública , Doença Crônica
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