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1.
Artigo em Inglês | MEDLINE | ID: mdl-39052867

RESUMO

Magnesium (Mg) deficiency is associated with increased risk and malignancy in colorectal cancer (CRC), yet the underlying mechanisms remain elusive. Here, we used genomic, proteomic, and phosphoproteomic data to elucidate the impact of Mg deficiency on CRC. Genomic analysis identified 160 genes with higher mutation frequencies in Low-Mg tumors, including key driver genes such as KMT2C and ERBB3. Unexpectedly, initiation driver genes of CRC, such as TP53 and APC, displayed higher mutation frequencies in High-Mg tumors. Additionally, proteomic and phosphoproteomic data indicated that low Mg content in tumors may activate epithelial-mesenchymal transition (EMT) by modulating inflammation or remodeling the phosphoproteome of cancer cells. Notably, we observed a negative correlation between the phosphorylation of DBN1 at S142 (DBN1S142p) and Mg content. A mutation in S142 to D (DBN1S142D) mimicking DBN1S142p upregulated MMP2 and enhanced cell migration, while treatment with MgCl2 reduced DBN1S142p, thereby reversing this phenotype. Mechanistically, Mg2+ attenuated the DBN1-ACTN4 interaction by decreasing DBN1S142p, which in turn enhanced the binding of ACTN4 to F-actin and promoted F-actin polymerization, ultimately reducing MMP2 expression. These findings shed new light on the crucial role of Mg deficiency in CRC progression and suggest that Mg supplementation may be a promising preventive and therapeutic strategy for CRC.

2.
Front Genet ; 15: 1356105, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39081807

RESUMO

Background: Obstructive sleep apnea (OSA) syndrome and nonalcoholic fatty liver disease (NAFLD) have been shown to have a close association in previous studies, but their pathogeneses are unclear. This study explores the molecular mechanisms associated with the pathogenesis of OSA and NAFLD and identifies key predictive genes. Methods: Using the Gene Expression Omnibus (GEO) database, we obtained gene expression profiles GSE38792 for OSA and GSE89632 for NAFLD and related clinical characteristics. Mitochondrial unfolded protein response-related genes (UPRmtRGs) were acquired by collating and collecting UPRmtRGs from the GeneCards database and relevant literature from PubMed. The differentially expressed genes (DEGs) associated with OSA and NAFLD were identified using differential expression analysis. Gene Set Enrichment Analysis (GSEA) was conducted for signaling pathway enrichment analysis of related disease genes. Based on the STRING database, protein-protein interaction (PPI) analysis was performed on differentially co-expressed genes (Co-DEGs), and the Cytoscape software (version 3.9.1) was used to visualize the PPI network model. In addition, the GeneMANIA website was used to predict and construct the functional similar genes of the selected Co-DEGs. Key predictor genes were analyzed using the receiver operating characteristic (ROC) curve. Results: The intersection of differentially expressed genes shared between OSA and NAFLD-related gene expression profiles with UPRmtRGs yielded four Co-DEGs: ASS1, HDAC2, SIRT3, and VEGFA. GSEA obtained the relevant enrichment signaling pathways for OSA and NAFLD. PPI network results showed that all four Co-DEGs interacted (except for ASS1 and HDAC2). Ultimately, key predictor genes were selected in the ROC curve, including HDAC2 (OSA: AUC = 0.812; NAFLD: AUC = 0.729), SIRT3 (OSA: AUC = 0.775; NAFLD: AUC = 0.750), and VEGFA (OSA: AUC = 0.812; NAFLD: AUC = 0.861) (they have a high degree of accuracy in predicting whether a subject will develop two diseases). Conclusion: In this study, four co-expression differential genes for OSA and NAFLD were obtained, and they can predict the occurrence of both diseases. Transcriptional mechanisms involved in OSA and NAFLD interactions may be better understood by exploring these key genes. Simultaneously, this study provides potential diagnostic and therapeutic markers for patients with OSA and NAFLD.

3.
Mol Nutr Food Res ; 68(12): e2300912, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38847553

RESUMO

Diabetic liver injury (DLI) is one of the complications of diabetes mellitus, which seriously jeopardizes human health. Punicalagin (PU), a polyphenolic compound mainly found in pomegranate peel, has been shown to ameliorate metabolic diseases such as DLI, and the mechanism needs to be further explored. In this study, a HFD/STZ-induced diabetic mouse model is established to investigate the effect and mechanism of PU on DLI. The results show that PU intervention significantly improves liver histology and serum biochemical abnormalities in diabetic mice, significantly inhibits the expression of pyroptosis-related proteins such as NLRP3, Caspase1, IL-1ß, and GSDMD in the liver of diabetic mice, and up-regulated the expression of autophagy-related proteins. Meanwhile, PU treatment significantly increases FoxO1 protein expression and inhibits TXNIP protein expression in the liver of diabetic mice. The above results are further verified in the HepG2 cell injury model induced by high glucose. AS1842856 is a FoxO1 specific inhibitor. The intervention of AS1842856 combined with PU reverses the regulatory effects of PU on pyroptosis and autophagy in HepG2 cells. In conclusion, this study demonstrates that PU may inhibit pyroptosis and upregulate autophagy by regulating FoxO1/TXNIP signaling, thereby alleviating DLI.


Assuntos
Autofagia , Proteínas de Transporte , Diabetes Mellitus Experimental , Proteína Forkhead Box O1 , Taninos Hidrolisáveis , Fígado , Camundongos Endogâmicos C57BL , Piroptose , Transdução de Sinais , Animais , Piroptose/efeitos dos fármacos , Taninos Hidrolisáveis/farmacologia , Autofagia/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Transdução de Sinais/efeitos dos fármacos , Humanos , Masculino , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Células Hep G2 , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Tiorredoxinas
4.
Int J Biol Sci ; 20(7): 2686-2697, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38725852

RESUMO

Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Breast cancer stem cells (BCSCs) are believed to play a crucial role in the carcinogenesis, therapy resistance, and metastasis of TNBC. It is well known that inflammation promotes stemness. Several studies have identified breast cancer-associated gene 2 (BCA2) as a potential risk factor for breast cancer incidence and prognosis. However, whether and how BCA2 promotes BCSCs has not been elucidated. Here, we demonstrated that BCA2 specifically promotes lipopolysaccharide (LPS)-induced BCSCs through LPS induced SOX9 expression. BCA2 enhances the interaction between myeloid differentiation primary response protein 88 (MyD88) and Toll-like receptor 4 (TLR4) and inhibits the interaction of MyD88 with deubiquitinase OTUD4 in the LPS-mediated NF-κB signaling pathway. And SOX9, an NF-κB target gene, mediates BCA2's pro-stemness function in TNBC. Our findings provide new insights into the molecular mechanisms by which BCA2 promotes breast cancer and potential therapeutic targets for the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Células-Tronco Neoplásicas , Fatores de Transcrição SOX9 , Ubiquitina-Proteína Ligases , Feminino , Humanos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Lipopolissacarídeos/farmacologia , Fator 88 de Diferenciação Mieloide/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Células-Tronco Neoplásicas/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fatores de Transcrição SOX9/metabolismo , Fatores de Transcrição SOX9/genética , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Regulação para Cima
5.
Sci Bull (Beijing) ; 69(8): 1071-1080, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38302332

RESUMO

The commercialization of lithium-sulfur (Li-S) batteries has been hindered by the shuttle effect and sluggish redox kinetics of lithium polysulfides (LiPSs). Herein, we reported a viologen-based ionic conjugated mesoporous polymer (TpV-Cl), which acts as the cathode host for modifying Li-S batteries. The viologen component serves as a reversible electron conveyer, leading to a comprehensive enhancement in the adsorption of polysulfides and improved conversion rate of polysulfides during the electrochemical process. As a result, the S@TpV-PS cathode exhibits outstanding cycling performance, achieving 300 cycles at 2.0 C (1 C = 1675 mA g-1) with low decay rate of 0.032% per cycle. Even at a high sulfur loading of 4.0 mg cm-2, S@TpV-PS shows excellent cycling stability with a Coulombic efficiency of up to 98%. These results highlight the significant potential of S@TpV-PS in developing high-performance Li-S batteries.

6.
J Proteome Res ; 23(3): 1014-1027, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38272855

RESUMO

Protein arginine methylations are important post-translational modifications (PTMs) in eukaryotes, regulating many biological processes. However, traditional collision-based mass spectrometry methods inevitably cause neutral losses of methylarginines, preventing the deep mining of biologically important sites. Herein we developed an optimized mass spectrometry workflow based on electron-transfer dissociation (ETD) with supplemental activation for proteomic profiling of arginine methylation in human cells. Using symmetric dimethylarginine (sDMA) as an example, we show that the ETD-based optimized workflow significantly improved the identification and site localization of sDMA. Quantitative proteomics identified 138 novel sDMA sites as potential PRMT5 substrates in HeLa cells. Further biochemical studies on SERBP1, a newly identified PRMT5 substrate, confirmed the coexistence of sDMA and asymmetric dimethylarginine in the central RGG/RG motif, and loss of either methylation caused increased the recruitment of SERBP1 to stress granules under oxidative stress. Overall, our optimized workflow not only enabled the identification and localization of extensive, nonoverlapping sDMA sites in human cells but also revealed novel PRMT5 substrates whose sDMA may play potentially important biological functions.


Assuntos
Arginina , Proteômica , Humanos , Células HeLa , Arginina/metabolismo , Processamento de Proteína Pós-Traducional , Metilação , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo
7.
Mol Cell Proteomics ; 22(5): 100545, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37031867

RESUMO

GSK3α and GSK3ß are two GSK3 isoforms with 84% overall identity and 98% identity in their catalytic domains. GSK3ß plays important roles in the pathogenesis of cancer, while GSK3α has long been considered a functionally redundant protein of GSK3ß. Few studies have specifically investigated the functions of GSK3α. In this study, unexpectedly, we found that the expression of GSK3α, but not GSK3ß, was significantly correlated with the overall survival of colon cancer patients in 4 independent cohorts. To decipher the roles of GSK3α in colon cancer, we profiled the phosphorylation substrates of GSK3α and uncovered 156 phosphosites from 130 proteins specifically regulated by GSK3α. A number of these GSK3α-mediated phosphosites have never been reported before or have been incorrectly identified as substrates of GSK3ß. Among them, the levels of HSF1S303p, CANXS583p, MCM2S41p, POGZS425p, SRRM2T983p, and PRPF4BS431p were significantly correlated with the overall survival of colon cancer patients. Further pull-down assays identified 23 proteins, such as THRAP3, BCLAF1, and STAU1, showing strong binding affinity to GSK3α. The interaction between THRAP3 and GSK3α was verified by biochemical experiments. Notably, among the 18 phosphosites of THRAP3, phosphorylation at S248, S253, and S682 is specifically mediated by GSK3α. Mutation of S248 to D (S248D), which mimics the effect of phosphorylation, obviously increased cancer cell migration and the binding affinity to proteins related to DNA damage repair. Collectively, this work not only discloses the specific function of GSK3α as a kinase but also suggests GSK3α as a promising therapeutic target for colon cancer.


Assuntos
Relevância Clínica , Neoplasias do Colo , Humanos , Proteínas do Citoesqueleto , Glicogênio Sintase Quinase 3 beta , Fosforilação , Isoformas de Proteínas , Proteínas Serina-Treonina Quinases , Proteômica , Proteínas de Ligação a RNA
8.
J Biol Chem ; 299(6): 104738, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37086786

RESUMO

O-linked GlcNAc (O-GlcNAc) is an emerging post-translation modification that couples metabolism with cellular signal transduction by crosstalk with phosphorylation and ubiquitination to orchestrate various biological processes. The mechanisms underlying the involvement of O-GlcNAc modifications in N6-methyladenosine (m6A) regulation are not fully characterized. Herein, we show that O-GlcNAc modifies the m6A mRNA reader YTH domain family 1 (YTHDF1) and fine-tunes its nuclear translocation by the exportin protein Crm1. First, we present evidence that YTHDF1 interacts with the sole O-GlcNAc transferase (OGT). Second, we verified Ser196/Ser197/Ser198 as the YTHDF1 O-GlcNAcylation sites, as described in numerous chemoproteomic studies. Then we constructed the O-GlcNAc-deficient YTHDF1-S196A/S197F/S198A (AFA) mutant, which significantly attenuated O-GlcNAc signals. Moreover, we revealed that YTHDF1 is a nucleocytoplasmic protein, whose nuclear export is mediated by Crm1. Furthermore, O-GlcNAcylation increases the cytosolic portion of YTHDF1 by enhancing binding with Crm1, thus upregulating downstream target (e.g. c-Myc) expression. Molecular dynamics simulations suggest that O-GlcNAcylation at S197 promotes the binding between the nuclear export signal motif and Crm1 through increasing hydrogen bonding. Mouse xenograft assays further demonstrate that YTHDF1-AFA mutants decreased the colon cancer mass and size via decreasing c-Myc expression. In sum, we found that YTHDF1 is a nucleocytoplasmic protein, whose cytosolic localization is dependent on O-GlcNAc modification. We propose that the OGT-YTHDF1-c-Myc axis underlies colorectal cancer tumorigenesis.


Assuntos
Neoplasias Colorretais , Processamento de Proteína Pós-Traducional , Camundongos , Animais , Humanos , Fosforilação , Ubiquitinação , Carcinogênese/genética , Neoplasias Colorretais/genética , N-Acetilglucosaminiltransferases/metabolismo , Acetilglucosamina/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
9.
Mol Cell Proteomics ; 22(5): 100532, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36934880

RESUMO

Adenomatous polyposis coli (APC) is an important tumor suppressor and is mostly linked to the regulation of the Wnt/ß-catenin signaling pathway. APC mutation has been identified as an early event in more than 80% of sporadic colorectal cancers (CRCs). Moreover, prognostic differences are observed in CRC patients with APC mutations. Although previous genomics studies have investigated the roles of concomitant gene mutations in determining the phenotypic heterogeneity of APC-mutant tumors, valuable prognostic determinants for APC-mutant CRC patients are still lacking. Based on the proteome and phosphoproteome data, we classified APC-mutant colon cancer patients and revealed genomic, proteomic, and phosphoproteomic heterogeneity in APC-mutant tumors. More importantly, we identified RAI14 as a key prognostic determinant for APC-mutant but not APC-wildtype colon cancer patients. The heterogeneity and the significance of prognostic biomarkers in APC-mutant tumors were further validated in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) colon cancer cohort. In addition, we found that colon cancer patients with high expression of RAI14 were less responsive to chemotherapy. Knockdown of RAI14 in cell lines led to reduced cell migration and changes in epithelial-mesenchymal transition (EMT)-related markers. Mechanistically, knockdown of RAI14 remodeled the phosphoproteome associated with cell adhesion, which might affect EMT marker expression and promote F-actin degradation. Collectively, this work describes the phenotypic heterogeneity of APC-mutant tumors and identifies RAI14 as an important prognostic determinant for APC-mutant colon cancer patients. The prognostic utility of RAI14 in APC-mutant colon cancer will provide early warning and increase the chance of successful treatment.


Assuntos
Neoplasias do Colo , Proteínas do Citoesqueleto , Fatores de Transcrição , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias do Colo/genética , Proteínas do Citoesqueleto/genética , População do Leste Asiático , Prognóstico , Proteômica , Fatores de Transcrição/genética
10.
Adv Sci (Weinh) ; 10(5): e2203884, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36563124

RESUMO

Triple-negative breast cancer (TNBC) has higher molecular heterogeneity and metastatic potential and the poorest prognosis. Because of limited therapeutics against TNBC, irradiation (IR) therapy is still a common treatment option for patients with lymph nodes or brain metastasis. Thus, it is urgent to develop strategies to enhance the sensitivity of TNBC tumors to low-dose IR. Here, the authors report that E3 ubiquitin ligase Ring finger protein 126 (RNF126) is important for IR-induced ATR-CHK1 pathway activation to enhance DNA damage repair (DDR). Mechanistically, RNF126 physically associates with the MRE11-RAD50-NBS1 (MRN) complex and ubiquitinates MRE11 at K339 and K480 to increase its DNA exonuclease activity, subsequent RPA binding, and ATR phosphorylation, promoting sustained DDR in a homologous recombination repair-prone manner. Accordingly, depletion of RNF126 leads to increased genomic instability and radiation sensitivity in both TNBC cells and mice. Furthermore, it is found that RNF126 expression is induced by IR activating the HER2-AKT-NF-κB pathway and targeting RNF126 expression with dihydroartemisinin significantly improves the sensitivity of TNBC tumors in the brain to IR treatment in vivo. Together, these results reveal that RNF126-mediated MRE11 ubiquitination is a critical regulator of the DDR, which provides a promising target for improving the sensitivity of TNBC to radiotherapy.


Assuntos
Dano ao DNA , Reparo do DNA , Neoplasias de Mama Triplo Negativas , Ubiquitina-Proteína Ligases , Animais , Humanos , Camundongos , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Reparo do DNA/genética , Reparo do DNA/efeitos da radiação , Proteína Homóloga a MRE11/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/radioterapia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
11.
Nutrients ; 14(22)2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36432428

RESUMO

High free sugar intake can lead to increased dental caries, obesity, and other health risks among adolescents. Studies have shown that family factors, especially parents, are one of the primary factors influencing adolescents' sugar intake. This study aims to investigate the influence of adolescent parents' free sugar intake, knowledge, attitude, and practice (KAP) on adolescents' free sugar intake. A total of 1090 pairs of adolescents and their parents from 10 secondary schools in Changsha were enrolled in a cross-sectional study. Free sugar intakes of parents and adolescents were measured using the food frequency questionnaire (FFQ). The current status of parents' knowledge, attitude, and practice in consuming free sugar was investigated using online and offline questionnaires. Parental free sugar intake was 11.55 (5.08, 21.95) g/d, and that of adolescents was 41.13 (19.06, 80.58) g/d. Parental free sugar intake, free sugar knowledge level, intake behavior, and guidance behavior were associated with adolescent free sugar intake. A superior level of parental free sugar knowledge (adjusted OR = 0.726, 95% CI: 0.557~0.946) was a protective factor for adolescent free sugar intake. Moderate and high levels of parental free sugar intake (adjusted OR = 1.706, 95% CI: 1.212~2.401; adjusted OR = 2.372, 95% CI: 1.492~3.773, respectively) were risk factors for free sugar intake in adolescents. Given the importance of parental influence on the adolescent free sugar intake, further limiting parental intake and increasing awareness of free sugars could play an active role in future interventions for adolescents' free sugar intake.


Assuntos
Cárie Dentária , Humanos , Adolescente , Estudos Transversais , Cárie Dentária/epidemiologia , Cárie Dentária/etiologia , Cárie Dentária/prevenção & controle , Pais , Relações Pais-Filho , Açúcares
12.
Am J Physiol Gastrointest Liver Physiol ; 322(3): G360-G367, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35018817

RESUMO

In the past, hepatic stellate cells (HSCs) were considered to be noninflammatory cells and to contribute to liver fibrosis by producing extracellular matrix. Recently, it was found that HSCs can also secrete cytokines and chemokines and therefore participate in hepatic inflammation. Autophagy participates in many immune response processes in immune cells. It is unclear whether autophagy is involved in inflammatory cytokine induction in HSCs. MAPK p38, Ulk1 phosphorylation, and the Ulk1-Atg13 complex were analyzed in HSC-T6 cells after LPS treatment. The relationship between autophagy inhibition and inflammation was investigated in primary rat HSCs. We discovered that LPS inhibited autophagy through MAPK p38. The activation of MAPK p38 induced Ulk1 phosphorylation, which disrupted the Ulk1-Atg13 complex and therefore inhibited autophagy. Furthermore, in primary rat HSCs, we demonstrated that autophagy inhibition regulated IL-1ß induction, which depended on the MAPK p38/Ulk1 pathway. Our results reveal a continuous signaling pathway, MAPK p38-Ulk1 phosphorylation-Ulk1-Atg13 disruption, which inhibits autophagy and induces IL-1ß expression in HSCs.NEW & NOTEWORTHY LPS inhibits autophagy in a concentration- and dose-dependent manner in HSC-T6 cells. MAPK p38 induces phosphorylation of Ulk1, which disrupts the Ulk1-Atg13 complex and is therefore required for the inhibition of autophagy by LPS. LPS induces IL-1ß expression via the MAPK p38/Ulk1 pathway in HSCs.


Assuntos
Células Estreladas do Fígado , Lipopolissacarídeos , Animais , Autofagia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Citocinas/metabolismo , Células Estreladas do Fígado/metabolismo , Inflamação/metabolismo , Interleucina-1beta , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Fosforilação , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Front Chem ; 9: 717210, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660527

RESUMO

Cadmium is one of the most toxic heavy metal contaminants in soils and water bodies and poses a serious threat to ecosystems and humans. However, cadmium is also an important resource widely used in many industries. The recovery of cadmium in the form of high-value products is considered as an ideal disposal strategy for Cd-contaminated environments. In this work, Pistia stratiotes was used to recycle cadmium from wastewaters through phytoaccumulation and then transformed into carbon-supported cadmium sulfide photocatalyst (CdS@C) through carbonization and hydrothermal reaction. The CdS@C photocatalyst contained a mixture of cubic and hexagonal CdS with lower band gap energy (2.14 eV) and high electron-hole separation efficiency, suggesting an excellent photoresponse ability and photocatalytic efficiency. The impressive stability and photocatalytic performance of CdS@C were demonstrated in efficient photodegradation of organic pollutants. •OH and O2•- were confirmed as the major active species for organic pollutants degradation during CdS@C photocatalysis. This work provides new insights into addressing Cd contaminated water bodies and upcycling in the form of photocatalyst.

14.
BMC Infect Dis ; 21(1): 567, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34126939

RESUMO

BACKGROUND & AIMS: There is limited evidence on the efficacy and safety of nucleos(t) ide analogues (NAs) in the treatment of HBV-ACLF. Our objective was to evaluate the outcomes among TAF, TDF and ETV, three first-line antivirals against chronic hepatitis B, in patients with HBV-ACLF. METHODS: Patients with HBV-related ACLF were recruited and received daily TAF (25 mg/d), TDF (300 mg/d) and ETV (0.5 mg/d). They were prospectively followed-up. The primary endpoint was overall survival at week 12 and week 48, the secondary endpoints were virological response and biochemical response. RESULTS: Forty gender and age matched eligible subjects were recruited and divided into three groups: TAF group, TDF group and ETV group. By week 48, 8 (80%) patients in TAF group, 6 (60%) patients in TDF group and 17 (85%) patients in ETV group survived without liver transplantation (P = 0.251). After 4 weeks of NAs treatment, all three groups showed paralleling reduction of HBV DNA levels. All three groups presented similar biochemical responses at week 4, patients treated with TAF showed a priority in total bilirubin reduction, albumin and cholesterol maintenance. Additionally, although there was no significant difference in changes of serum urea, serum creatinine, serum cystatin C and estimated GFR among the three groups by treatment week 4, TDF showed unfavorable renal safety even in short -term treatment. The treatment using NAs was well-tolerated and there was no serious drug-related adverse event reported. CONCLUSIONS: TAF, TDF and ETV are of similar efficacy and safety in short-term and long-term treatment of HBV-ACLF. TRIAL REGISTRATION: This study is ongoing and is registered with ClinicalTrials.gov , NCT03640728 (05/02/2019).


Assuntos
Insuficiência Hepática Crônica Agudizada/tratamento farmacológico , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Alanina , Guanina/análogos & derivados , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Tenofovir/uso terapêutico , Resultado do Tratamento
15.
Am J Transl Res ; 13(3): 952-966, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841632

RESUMO

Local application of lithium or aspirin with biological scaffold has been identified as a potent means to improve bone formation. In this study, lithium and aspirin modified calcium phosphate cement (Asp-Li/CPC) was prepared, and the feasibility of this biological scaffold in the treatment of osteoporotic bone defect was observed in vivo and in vitro. In vitro experiments confirmed that Asp-Li/CPC had better ability to promote MC3T3-E1 cells differentiation into osteoblasts, osteoblast mineralization and viability, and promote cell expression of ALP, OP, RUNX-2, OC and COL-1 protein than simple CPC or lithium modified CPC by MTT, Alizarin red staining and Western blot evaluation. In vivo experiments confirmed that Asp-Li/CPC presented the strongest effect on bone regeneration and bone mineralization through the comparison with CPC group and Li/CPC group with X-ray images, Micro-CT and Histological evaluation. RT-qPCR analysis showed that Asp-Li/CPC, Li/CPC group and CPC group demonstrated increased BMP2, Smad1, OPG than the OVX group (P<0.05), while Asp-Li/CPC exhibited decreased TNF-α, IFN-γ and RANKL than the OVX group (P<0.05). Experiments in vivo and in vitro show that Asp-Li/CPC is a scheme for rapid repair of femoral condylar defects, and these effects may be achieved by inhibiting local inflammation and through BMP-2/Smad1 and OPG/RANKL signaling pathway.

16.
World J Clin Cases ; 9(2): 308-320, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33521099

RESUMO

Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.

17.
BMC Gastroenterol ; 21(1): 43, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509116

RESUMO

BACKGROUND: A series of evidence revealed that body mass index was an important confounding factor in the research of uric acid and ischemic heart disease/hypertension. The objective of this study was to investigate whether obesity status can modify the association between serum uric acid and the severity of liver damage in NAFLD, and the possible interactive effect of hyperuricemia and obesity. METHODS: We conducted a cross-sectional study in a total of 557 ultrasound diagnosed-NAFLD. The hepatic steatosis and liver fibrosis were quantitatively evaluated by transient elastography. Hyperuricemia was defined as serum uric acid > 420 µmol/L in men, > 360 µmol/L in women and obesity was defined as body mass index ≥ 25 kg/m2. The adjusted OR values of hyperuricemia and obesity were analyzed by multivariate logistic regression analysis, and the additive model was used to investigate the possible interactive effect. RESULTS: Multivariate regression analysis showed that hyperuricemia was associated with serious hepatic steatosis (1.74[1.09-2.79]) and elevated ALT (2.17[1.38-3.41]), but not with advanced fibrosis (1.61[0.91-2.85]). The association was further investigated in different BMI group. Hyperuricemia was associated with higher odds of serious hepatic steatosis (2.02[1.14-3.57]) and elevated ALT (2.27[1.37-3.76]) only in obese NAFLD, not in non-obese subjects. Similarly, patients with hyperuricemia had higher odds of advanced fibrosis in obese subjects (2.17[1.13-4.18]), not in non-obese subjects (0.60[0.14-2.70]). Furthermore, there was an additive interaction between hyperuricemia and obesity on the odds of serious hepatic steatosis (AP: 0.39[0.01-0.77]) and advanced fibrosis. (AP: 0.60[0.26-0.95]). CONCLUSIONS: Hyperuricemia and obesity had a significantly synergistic effect on the hepatic steatosis and fibrosis. Thus, management of uric acid may need to be targeted in obese NAFLD.


Assuntos
Hiperuricemia , Hepatopatia Gordurosa não Alcoólica , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Hiperuricemia/complicações , Hiperuricemia/epidemiologia , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Ácido Úrico
18.
Mol Med Rep ; 22(3): 2573-2582, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32705254

RESUMO

The aims of the present study were to investigate the role of sphingosine kinase 2 (Sphk2) in hypertrophic scar (HS) formation and its underlying mechanisms. The expression levels of Sphk2 and Smad7 in HS tissues and healthy skin tissues of patients undergoing plastic surgery were determined using immunohistochemical staining. Subsequently, the expression levels of Sphk2 and collagen I in human embryonic skin fibroblasts (control) and human HS fibroblasts (HSF) were detected using western blot analysis and immunofluorescence assay, respectively. Following Sphk2 silencing, Smad7 overexpression or both Sphk2 and Smad7 silencing, HSF proliferative ability was assessed using Cell Counting Kit­8 assay and proliferation­associated proteins were evaluated using western blot analysis. In addition, the level of apoptosis in HSF was assessed using flow cytometry and expression levels of apoptotic­associated proteins were determined using western blotting. Furthermore, the expression levels of collagen I and proteins in the TGF­ß1/Smad signaling pathway were detected using western blot analysis. The results indicated that the expression of Sphk2 was significantly increased, while Smad7 expression was decreased in HS tissue. Moreover, the upregulation of Sphk2 and collagen I expression levels was identified in HSF. The present results also indicated that Sphk2 silencing or Smad7 overexpression inhibited proliferation, but promoted apoptosis of HSF, coupled with changes in the expression levels of proliferation­associated proteins, with an increase in p21 and a decrease in cyclin D1 expression levels, and apoptosis­associated proteins, with an increase in Bax and cleaved caspase­3, and a decrease in Bcl­2, which were reversed following transfection with both Sphk2 and Smad7 using small interfering RNA in HSF. In addition, the expression levels of transforming growth factor­ß1, phosphorylated (p)­Smad2, p­Smad3 and collagen I were reduced following Sphk2 silencing or Smad7 overexpression, which were abolished by silencing both Sphk2 and Smad7. Collectively, the present results indicated that inhibition of Sphk2 attenuated HS formation via upregulation of Smad7 expression, thus Sphk2 may serve as a potential therapeutic target for the treatment of HS.


Assuntos
Cicatriz Hipertrófica/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteína Smad7/metabolismo , Regulação para Cima , Adulto , Linhagem Celular , Proliferação de Células , Colágeno Tipo I/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Inativação Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Transdução de Sinais , Adulto Jovem
19.
Pharmacol Res ; 155: 104748, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32147403

RESUMO

The dysfunction of E3 ubiquitin ligases is important in the pathogenesis of many human diseases, as they play important roles in multiple cellular processes. In this review, we evaluated the structures, functions and clinical significance of two RING-type E3 ubiquitin ligases from the same subfamily, ring-finger protein 126 (RNF126) and breast cancer associated gene 2 (BCA2). Interestingly, the expression of RNF126 and BCA2 are regulated by multiple signaling pathways, including EGFR, ERK, AKT, and NF-κB. RNF126 and BCA2 appear to be functional mediators for not only DNA damage repair but also cancer development. Due to their significant functions in cell proliferation and DNA damage repair, RNF126 and BCA2 may be two potential diagnostic biomarkers and therapeutic targets for cancers.


Assuntos
Neoplasias/enzimologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Dano ao DNA , Reparo do DNA , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Transdução de Sinais
20.
Z Gerontol Geriatr ; 53(7): 671-678, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31781847

RESUMO

Previous studies have demonstrated the beneficial effect of melatonin (MEL) on bone tissue and bone metabolism. Rapamycin (RAP) promotes osteoblast proliferation and inhibits osteoclast proliferation, and positively affects bone regeneration; however, reports about effects of RAP on bone loss for aged female rats with MEL administration are limited. This study investigated the impact of treatment with RAP on bone loss for aged female rats with MEL administration. Female Sprague-Dawley rats weighing approximately 520 g were randomly divided into 3 groups of 10: group CON, group MEL and group MEL + RAP and received saline, MEL, RAP plus MEL treatment until death at 12 weeks, respectively. The results of maintaining bone mass and bone strength with RAP plus MEL administration were evaluated by histology, microcomputerized tomography (Micro-CT), gene expression analysis and biomechanical testing. Results from this study indicated that MEL + RAP had stronger effects on the prevention and treatment of osteoporosis than MEL administration. Administration of MEL + RAP produced the strongest effects on bone parameters and strength for distal femurs and regulation of OPG/RANKL signalling pathway-related gene expression. These results seemed to indicate that RAP could increase the effects of MEL on age-dependent bone loss.


Assuntos
Melatonina/metabolismo , Animais , Densidade Óssea , Osso e Ossos , Feminino , Ratos , Ratos Sprague-Dawley , Sirolimo
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