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1.
Pharmaceuticals (Basel) ; 17(10)2024 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-39458936

RESUMO

BACKGROUND: Gliomas, the most prevalent type of primary brain tumor, stand out as one of the most aggressive and lethal types of human cancer. METHODS & RESULTS: To uncover potential prognostic markers, we employed the weighted correlation network analysis (WGCNA) on the Chinese Glioma Genome Atlas (CGGA) 693 dataset to reveal four modules significantly associated with glioma clinical traits, primarily involved in immune function, cell cycle regulation, and ribosome biogenesis. Using the least absolute shrinkage and selection operator (LASSO) regression algorithm, we identified 11 key genes and developed a prognostic risk score model, which exhibits precise prognostic prediction in the CGGA 325 dataset. More importantly, we also validated the model in 12 glioma patients with overall survival (OS) ranging from 4 to 132 months using mRNA sequencing and immunohistochemical analysis. The analysis of immune infiltration revealed that patients with high-risk scores exhibit a heightened immune infiltration, particularly immune suppression cells, along with increased expression of immune checkpoints. Furthermore, we explored potentially effective drugs targeting 11 key genes for gliomas using the library of integrated network-based cellular signatures (LINCS) L1000 database, identifying that in vitro, both torin-1 and clofarabine exhibit promising anti-glioma activity and inhibitory effect on the cell cycle, a significant pathway enriched in the identified glioma modules. CONCLUSIONS: In conclusion, our study provides valuable insights into molecular mechanisms and identifying potential therapeutic targets for gliomas.

2.
Epigenetics ; 19(1): 2381849, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39109527

RESUMO

Gametogenetin binding protein 2 (GGNBP2) was indispensable in normal spermatids for transformation into mature spermatozoa in mice, and when Gametogenetin binding protein 2 is bound to BRCC36 and RAD51, the complex participates in repairing DNA double-strand breaks (DSB) during the meiotic progression of spermatocytes. Ggnbp2 knockout resulted in the up-regulation of H2AK119ubi and down-regulation of H2BK120ubi in GC-2 cells (mouse spermatogonia-derived cell line) and postnatal day 18 testis lysate. Our results also demonstrated that Gametogenetin binding protein 2 inducedASXL1 to activate the deubiquitinating enzyme BAP1 in deubiquitinating H2A, while Gametogenetin binding protein 2 knockout disrupted the interaction between ASXL1 and BAP1, resulting in BAP1 localization change. Furthermore, the Gametogenetin binding protein 2 deletion reduced H2B ubiquitination by affecting E2 enzymes and E3 ligase binding. Gametogenetin binding protein 2 regulated H2A and H2B ubiquitination levels and controlled H3K27 and H3K79 methylation by PRC2 subunits and histone H3K79 methyltransferase. Altogether, our results suggest that Ggnbp2 knockout increased DNA damage response by promoting H2A ubiquitination and H3K27trimethylation (H3K27me3) and reduced nucleosome stability by decreasing H2B ubiquitination and H3K79 dimethylation (H3K79me2), revealing new mechanisms of epigenetic phenomenon during spermatogenesis. Gametogenetin binding protein 2 seems critical in regulating histone modification and chromatin structure in spermatogenesis.


Assuntos
Histonas , Espermatogênese , Ubiquitinação , Animais , Masculino , Camundongos , Linhagem Celular , Histonas/metabolismo , Metilação , Camundongos Knockout , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Espermatogênese/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética
3.
Cell Biol Toxicol ; 40(1): 26, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38691186

RESUMO

Copper ionophore NSC319726 has attracted researchers' attention in treating diseases, particularly cancers. However, its potential effects on male reproduction during medication are unclear. This study aimed to determine whether NSC319726 exposure affected the male reproductive system. The reproductive toxicity of NSC319726 was evaluated in male mice following a continuous exposure period of 5 weeks. The result showed that NSC319726 exposure caused testis index reduction, spermatogenesis dysfunction, and architectural damage in the testis and epididymis. The exposure interfered with spermatogonia proliferation, meiosis initiation, sperm count, and sperm morphology. The exposure also disturbed androgen synthesis and blood testis barrier integrity. NSC319726 treatment could elevate the copper ions in the testis to induce cuproptosis in the testis. Copper chelator rescued the elevated copper ions in the testis and partly restored the spermatogenesis dysfunction caused by NSC319726. NSC319726 treatment also decreased the level of retinol dehydrogenase 10 (RDH10), thereby inhibiting the conversion of retinol to retinoic acid, causing the inability to initiate meiosis. Retinoic acid treatment could rescue the meiotic initiation and spermatogenesis while not affecting the intracellular copper ion levels. The study provided an insight into the bio-safety of NSC319726. Retinoic acid could be a potential therapy for spermatogenesis impairment in patients undergoing treatment with NSC319726.


Assuntos
Cobre , Espermatogênese , Testículo , Tretinoína , Masculino , Animais , Espermatogênese/efeitos dos fármacos , Tretinoína/farmacologia , Cobre/toxicidade , Camundongos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/patologia , Espermatogônias/efeitos dos fármacos , Espermatogônias/metabolismo , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Meiose/efeitos dos fármacos , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Epididimo/patologia
4.
Acta Pharmacol Sin ; 45(9): 1848-1860, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38719954

RESUMO

Hypertensive cerebrovascular remodeling involves the enlargement of vascular smooth muscle cells (VSMCs), which activates volume-regulated Cl- channels (VRCCs). The leucine-rich repeat-containing family 8 A (LRRC8A) has been shown to be the molecular identity of VRCCs. However, its role in vascular remodeling during hypertension is unclear. In this study, we used vascular smooth muscle-specific LRRC8A knockout (CKO) mice and an angiotensin II (Ang II)-induced hypertension model. The results showed that cerebrovascular remodeling during hypertension was ameliorated in CKO mice, and extracellular matrix (ECM) deposition was reduced. Based on the RNA-sequencing analysis of aortic tissues, the level of matrix metalloproteinases (MMPs), such as MMP-9 and MMP-14, were reduced in CKO mice with hypertension, which was further verified in vivo by qPCR and immunofluorescence analysis. Knockdown of LRRC8A in VSMCs inhibited the Ang II-induced upregulation of collagen I, fibronectin, and matrix metalloproteinases (MMPs), and overexpression of LRRC8A had the opposite effect. Further experiments revealed an interaction between with-no-lysine (K)-1 (WNK1), which is a "Cl--sensitive kinase", and Forkhead transcription factor O3a (FOXO3a), which is a transcription factor that regulates MMP expression. Ang II induced the phosphorylation of WNK1 and downstream FOXO3a, which then increased the expression of MMP-2 and MMP-9. This process was inhibited or potentiated when LRRC8A was knocked down or overexpressed, respectively. Overall, these results demonstrate that LRRC8A knockout in vascular smooth muscle protects against cerebrovascular remodeling during hypertension by reducing ECM deposition and inhibiting the WNK1/FOXO3a/MMP signaling pathway, demonstrating that LRRC8A is a potential therapeutic target for vascular remodeling-associated diseases such as stroke.


Assuntos
Angiotensina II , Proteína Forkhead Box O3 , Hipertensão , Camundongos Knockout , Músculo Liso Vascular , Transdução de Sinais , Remodelação Vascular , Proteína Quinase 1 Deficiente de Lisina WNK , Animais , Músculo Liso Vascular/metabolismo , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genética , Camundongos , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/genética , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Células Cultivadas
5.
Phytomedicine ; 129: 155618, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38678949

RESUMO

BACKGROUND: Vascular calcification refers to the abnormal accumulation of calcium in the walls of blood vessels and is a risk factor often overlooked in cardiovascular disease. However, there is currently no specific drug for treating vascular calcification. Compound Danshen Dripping Pill (CDDP) is widely used to treat cardiovascular diseases, but its effect on vascular calcification has not been reported. PURPOSE: We investigated the effects of CDDP on vascular calcification in ApoE-/- mice and in vitro and elucidated its mechanism of action. STUDY DESIGN: Firstly, we found that CDDP has the potential to improve calcification based on network pharmacology analysis. Then, we performed the following experiments: in vivo, ApoE-/- mice were fed a high-fat diet randomly supplemented with CDDP for 16 weeks. Atherosclerosis and vascular calcification were determined. In vitro, human aortic smooth muscle cells (HASMCs), human umbilical vein endothelial cells (HUVECs), and human aortic endothelial cells (HAECs) were used to determine the mechanisms for CDDP-inhibited vascular calcification. RESULTS: In this study, we observed that CDDP reduced intimal calcification in atherosclerotic lesions of ApoE-deficient mice fed a high-fat diet, as well as the calcification in cultured SMCs and ECs. Mechanistically, CDDP inhibited the Wnt/ß-catenin pathway by up-regulating the expression of DKK1 and LRP6, which are upstream inhibitors of Wnt, leading to a reduction in the expression of osteoblastic transition markers (ALP, OPN, BMP2, and RUNX2). Furthermore, CDDP enhanced the secretion of DKK1, which plays a role in mediating EC-SMC crosstalk in calcification. Additionally, VC contributes to vascular aging by inhibiting Sirt1 and increasing senescence parameters (SA-ß-gal, p21, and p16). However, CDDP reversed these changes by activating Sirt1. CDDP also reduced the levels of pro-inflammatory cytokines and the senescence-associated secretory phenotype in vivo and in vitro. CONCLUSIONS: Our study suggests that CDDP reduces vascular calcification by regulating the DKK1/LRP6/ß-catenin signaling pathway in ECs/SMCs and interactions with the crosstalk of ECs and SMCs. It also reduces the senescence of ECs/SMCs, contributing to the Sirt1 activation, indicating CDDP's novel role in ameliorating vascular calcification.


Assuntos
Aterosclerose , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas , Células Endoteliais da Veia Umbilical Humana , Salvia miltiorrhiza , Calcificação Vascular , Animais , Calcificação Vascular/tratamento farmacológico , Humanos , Medicamentos de Ervas Chinesas/farmacologia , Salvia miltiorrhiza/química , Masculino , Dieta Hiperlipídica/efeitos adversos , Aterosclerose/tratamento farmacológico , Camundongos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Sirtuína 1/metabolismo , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Apolipoproteínas E/genética , Farmacologia em Rede , Via de Sinalização Wnt/efeitos dos fármacos , Aorta/efeitos dos fármacos , Canfanos , Peptídeos e Proteínas de Sinalização Intercelular , Panax notoginseng
6.
Discov Oncol ; 15(1): 73, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38478152

RESUMO

Polypeptide N-Acetylgalactosaminyltransferase (GALNTs) are critical enzymes that initiate mucin type-O glycosylation, and are closely associated with the occurrence and development of multiple cancers. However, the significance of GALNT2 in clear cell renal cell carcinoma (ccRCC) progression remains largely undetermined. Based on public multi-omics analysis, GALNT2 was strongly elevated in ccRCC versus adjoining nontumor tissues, and it displayed a relationship with poor overall survival (OS) of ccRCC patients. In addition, GALNT2 over-expression accelerated proliferation of renal cancer cell (RCC) lines. In contrast, GALNT2 knockdown using shRNAs suppressed cell proliferation, and this was rescued by LATS2 knockdown. Similarly, GALNT2 deficiency enhanced p-LATS2/LATS2 expression. LATS2 is activated by phosphorylation (p-LATS2) and, in turn, phosphorylate the downstream substrate protein YAP. Phosphorylated YAP (p-YAP) stimulated its degradation and cytoplasmic retention, as it was unable to translocate to the nucleus. This resulted in reduced cell proliferation. Subsequently, we explored the upstream miRNAs of GALNT2. Using dual luciferase reporter assay, we revealed that miR-139-5p interacted with the 3' UTR of GALNT2. Low miR-139-5p expression was associated with worse ccRCC patient outcome. Based on our experiments, miR-139-5p overexpression inhibited RCC proliferation, and this phenotype was rescued by GALNT2 overexpression. Given these evidences, the miR-139-5p-GALNT2-LATS2 axis is critical for RCC proliferation, and it is an excellent candidate for a new therapeutic target in ccRCC.

7.
Mol Hum Reprod ; 29(8)2023 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-37369038

RESUMO

The remodeling of uterine spiral arteries is a complex process requiring the dynamic action of various cell types. During early pregnancy, extravillous trophoblast (EVT) cells differentiate and invade the vascular wall, replacing the vascular smooth muscle cells (VSMCs). Several in vitro studies have shown that EVT cells play an important role in promoting VSMC apoptosis, however, the mechanism underlying this process is not fully understood. In this study, we demonstrated that EVT-conditioned media and EVT-derived exosomes could induce VSMC apoptosis. Through data mining and experimental verification, it was demonstrated that the EVT exosome miR-143-3p induced VSMC apoptosis in both VSMCs and a chorionic plate artery (CPA) model. Furthermore, FAS ligand was also expressed on the EVT exosomes and may play a co-ordinated role in apoptosis induction. These data clearly demonstrated that VSMC apoptosis is mediated by EVT-derived exosomes and their cargo of miR-143-3p as well as their cell surface presentation of FASL. This finding increases our understanding of the molecular mechanisms underlying the regulation of VSMC apoptosis during spiral artery remodeling.


Assuntos
Exossomos , MicroRNAs , Gravidez , Feminino , Humanos , Trofoblastos/metabolismo , Músculo Liso Vascular/metabolismo , Exossomos/genética , Artéria Uterina/metabolismo , Apoptose/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Miócitos de Músculo Liso/metabolismo
8.
J Ethnopharmacol ; 315: 116673, 2023 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-37268257

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine theory believes that qi deficiency and blood stasis are the key pathogenesis of heart failure with preserved ejection fraction (HFpEF). As a representative prescription for replenishing qi and activating blood, QiShenYiQi dripping pills (QSYQ) has been used for treating heart diseases. However, the pharmacological mechanism of QSYQ in improving HFpEF is not well understood. AIM OF THE STUDY: The objective of the study is to investigate the cardioprotective effect and mechanism of QSYQ in HFpEF using the phenotypic dataset of HFpEF. MATERIALS AND METHODS: HFpEF mouse models established by feeding mice combined high-fat diet and Nω-nitro-L-arginine methyl ester drinking water were treated with QSYQ. To reveal causal genes, we performed a multi-omics study, including integrative analysis of transcriptomics, proteomics, and metabolomics data. Moreover, adeno-associated virus (AAV)-based PKG inhibition confirmed that QSYQ mediated myocardial remodeling through PKG. RESULTS: Computational systems pharmacological analysis based on human transcriptome data for HFpEF showed that QSYQ could potentially treat HFpEF through multiple signaling pathways. Subsequently, integrative analysis of transcriptome and proteome showed alterations in gene expression in HFpEF. QSYQ regulated genes involved in inflammation, energy metabolism, myocardial hypertrophy, myocardial fibrosis, and cGMP-PKG signaling pathway, confirming its function in the pathogenesis of HFpEF. Metabolomics analysis revealed fatty acid metabolism as the main mechanism by which QSYQ regulates HFpEF myocardial energy metabolism. Importantly, we found that the myocardial protective effect of QSYQ on HFpEF mice was attenuated after RNA interference-mediated knock-down of myocardial PKG. CONCLUSION: This study provides mechanistic insights into the pathogenesis of HFpEF and molecular mechanisms of QSYQ in HFpEF. We also identified the regulatory role of PKG in myocardial stiffness, making it an ideal therapeutic target for myocardial remodeling.


Assuntos
Insuficiência Cardíaca , Humanos , Camundongos , Animais , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/metabolismo , Volume Sistólico , Multiômica , Miocárdio/patologia
9.
Urol Case Rep ; 47: 102335, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37066105

RESUMO

[This corrects the article DOI: 10.1016/j.eucr.2020.101496.].

10.
Acta Pharm Sin B ; 13(3): 1036-1052, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36970211

RESUMO

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE-/-LDLR-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

11.
Urol Case Rep ; 47: 102336, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36793383

RESUMO

[This corrects the article DOI: 10.1016/j.eucr.2020.101332.].

12.
Front Genet ; 13: 993731, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36523765

RESUMO

Background: Low educational attainment has been reported as a risk factor for many diseases. However, conclusion on the association between educational attainment and endometrial cancer (EC) are inconsistent in previous observational studies. This study aims to explore the potential causal association between educational attainment and EC. Methods: A Mendelian Randomization analysis was performed using publicly summary-level data sets of genome-wide association studies (GWAS). A total of 306 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of educational attainment from the Social Science Genetic Association Consortium GWAS summary data of 1,131,881 participants of European ancestry. SNPs of EC were obtained from the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium and the UK Biobank involving 121,885 people. We conducted inverse variance weighted (IVW) to estimate the causal effect as our primary outcome. And we perform several sensitivity analyses, including MR-Egger regression, weighted median method, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier) global test, and leave-one-out sensitivity analysis, to evaluate the effect of pleiotropism on the causal estimates. Results: Genetic predisposition towards 4.2 years of additional educational attainment was associated with 38% lower risk of EC. (odds ratio 0.72, 95% confidence interval 0.62 to 0.83; p = 1.65*10-5). The consistent results of sensitivity analyses indicated our causal estimates were reliable. Genetic predisposition towards longer educational attainment was associated with lower risk of obesity, high waist-to-hip ratio (WHR), and diabetes. Conclusion: This study indicated that low educational attainment was a causal risk factor for EC, especially for EC with endometrioid histology. Low educational attainment might lead to EC through the mediator of obesity, high WHR, and diabetes.

13.
Nat Commun ; 13(1): 6578, 2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36323669

RESUMO

Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.


Assuntos
Histona-Lisina N-Metiltransferase , Neoplasias , Humanos , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Elementos Facilitadores Genéticos , Histonas/metabolismo , RNA de Cadeia Dupla , Piroptose , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Interferons/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
14.
Front Genet ; 13: 1010657, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36263435

RESUMO

Background: The etiology of preeclampsia (PE) remains unclear. With the utilization of metabolomics, dysregulated production of several metabolic components in human plasma, such as lipids, amino acids, androgens and estrogens, was found to be important in the pathogenesis of PE. Transcriptomics adds more in-depth information, and the integration of transcriptomics and metabolomics may yield further insight into PE pathogenesis than either one alone. Objectives: We investigated the placental metabolomics and transcriptomics of PE patients to identify affected metabolic pathways and potential biological targets for exploring the disease pathogenesis. Methods: Integrated transcriptomics and metabolomics were used to analyze five paired human placentas from patients with severe PE and normal pregnancies. This was followed by further validation of our findings in a publicly available dataset of 173 PE vs. 157 control placentas. In addition, weighted gene coexpression network construction was performed to assess the correlation between genetic alterations and diseases. Results: We identified 66 and 41 differentially altered metabolites in negative and positive ion modes, respectively, in the PE group compared to the control group, and found 2,560 differentially expressed genes. Several pathways were aberrantly altered in the PE placenta at both the metabolic and transcriptional levels, including steroid hormone biosynthesis, the cAMP signaling pathway, neuroactive ligand-receptor interactions, taste transduction and prion diseases. Additionally, we found 11 differential metabolites and 11 differentially expressed genes involved in the steroid hormone biosynthesis pathway, indicating impaired metabolism of steroid hormones in the PE placenta. Furthermore, we found that CYP11A1, HSD3B2, and HSD17B6 are highly correlated with diseases. Conclusion: Our findings provide a profile of the dysregulated steroid hormone biosynthesis in PE placenta, we observed a dysregulated cortisol-to-cortisone ratio, testosterone accumulation, decreased testosterone downstream metabolites, impaired production of estrone and estriol, and aberrant hydroxylation and methylation of estradiol. Disorders of placental steroid hormone metabolism might be a consequence or a compensatory change in pathological placentation in PE, which underscores the need to investigate the physiology of steroid hormone metabolites in the etiology of PE.

15.
Front Pharmacol ; 13: 1014991, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36278163

RESUMO

Diabetic retinopathy (DR) is increasingly becoming a main complication of diabetes, and is difficult to cure. In our research, network pharmacology analysis suggested that both compound Danshen dripping pills (CDDP) and bezafibrate (BZF) have potential protective effects against DR and the two drugs may act synergistically. The pharmacological effects of the coadministration of CDDP and BZF were elucidated in db/db mice, which simulate DR. Fluorescein fundus angiography showed that coadministration attenuated vascular leakage. Optical coherence tomography and hematoxylin and eosin staining showed that coadministration improved retinal thickness better than CDDP monotherapy. In addition, cell fluorescence images of reactive oxygen species revealed that coadministration of CDDP and BZF had more potent effects against oxidative stress than CDDP monotherapy. Metabolomics analysis showed that coadministration reduced the ratio of oxidized glutathione to reduced glutathione further than CDDP monotherapy. Coadministration of CDDP and BZF may provide additional protective effects by resisting vascular leakage, increasing retinal thickness, and inhibiting inflammation and oxidative stress in DR.

16.
Front Genet ; 13: 942203, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36105078

RESUMO

It is clinical reported that YangXue QingNao Wan (YXQNW) combined with donepezil can significantly improve the cognitive function of AD patients. However, the mechanism is not clear. A network pharmacology approach was employed to predict the protein targets and affected pathways of YXQNW in the treatment of AD. Based on random walk evaluation, the correlation between YXQNW and AD was calculated; while a variety of AD clinical approved Western drugs were compared. The targets of YXQNW were enriched and analyzed by using the TSEA platform and MetaCore. We proved that the overall correlation between YXQNW and AD is equivalent to clinical Western drugs, but the mechanism of action is very different. Firstly, YXQNW may promote cerebral blood flow velocity by regulating platelet aggregation and the vasoconstriction/relaxation signal pathway, which has been verified by clinical meta-analysis. Secondly, YXQNW may promote Aß degradation in the liver by modulating the abnormal glucose and lipid metabolisms via the adiponectin-dependent pathway, RXR/PPAR-dependent lipid metabolism signal pathway, and fatty acid synthase activity signal pathway. We also verified whether YXQNW indeed promoted Aß degradation in hepatic stellate cells. This work provides a novel scientific basis for the mechanism of YXQNW in the treatment of AD.

17.
Front Physiol ; 13: 991719, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36060690

RESUMO

KRAS plays critical roles in regulating a range of normal cellular events as well as pathological processes in many tissues mediated through a variety of signaling pathways, including ERK1/2 and AKT signaling, in a cell-, context- and development-dependent manner. The in vivo function of KRAS and its downstream targets in gonadal steroidogenic cells for the development and homeostasis of reproductive functions remain to be determined. To understand the functions of KRAS signaling in gonadal theca and interstitial cells, we generated a Kras mutant (tKrasMT) mouse line that selectively expressed a constitutively active Kras G12D in these cells. Kras G12D expression in ovarian theca cells did not block follicle development to the preovulatory stage. However, tKrasMT females failed to ovulate and thus were infertile. The phosphorylated ERK1/2 and forkhead box O1 (FOXO1) and total FOXO1 protein levels were markedly reduced in tKrasMT theca cells. Kras G12D expression in theca cells also curtailed the phosphorylation of ERK1/2 and altered the expression of several ovulation-related genes in gonadotropin-primed granulosa cells. To uncover downstream targets of KRAS/FOXO1 signaling in theca cells, we found that the expression of bone morphogenic protein 7 (Bmp7), a theca-specific factor involved in ovulation, was significantly elevated in tKrasMT theca cells. Chromosome immunoprecipitation assays demonstrated that FOXO1 interacted with the Bmp7 promoter containing forkhead response elements and that the binding activity was attenuated in tKrasMT theca cells. Moreover, Foxo1 knockdown caused an elevation, whereas Foxo1 overexpression resulted in an inhibition of Bmp7 expression, suggesting that KRAS signaling regulates FOXO1 protein levels to control Bmp7 expression in theca cells. Thus, the anovulation phenotype observed in tKrasMT mice may be attributed to aberrant KRAS/FOXO1/BMP7 signaling in theca cells. Our work provides the first in vivo evidence that maintaining normal KRAS activity in ovarian theca cells is crucial for ovulation and female fertility.

18.
Oxid Med Cell Longev ; 2022: 1718353, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35910835

RESUMO

Diabetic retinopathy (DR), a diabetic microangiopathy caused by diabetes, affects approximately 93 million people, worldwide. However, the drugs used to treat DR have limited efficacy and the variety of side effects. This is possibly because the complicated pathogenesis of DR is associated with multiple proteins. In this work, we attempted to identify potential drugs against DR-associated proteins and predict potential targets for drugs using in silico prediction of chemical-protein interactions (CPI) based on multitarget quantitative structure-activity relationship (mt-QSAR) method. Therefore, we developed 128 binary classifiers to predict the CPI for 15 DR targets using random forest (RF), k-nearest neighbours (KNN), support vector machine (SVM), and neural network (NN) algorithms with MACCS, extended connectivity fingerprints (ECFP6) fingerprints, and protein descriptors. In order to facilitate discovery of the novel drugs and target identification using the 128 binary classifiers, a free web server (DRDB) was developed. Compound Danshen Dripping Pills (CDDP), composed of Salvia miltiorrhiza, Panax notoginseng, and borneol, is commonly used in the treatment of cardiovascular diseases. To explore the applicability of DRDB, the potential CPIs of CDDP in treatment of DR were investigated based on DRDB. In vitro experimental validation demonstrated that cryptotanshinone and protocatechuic acid, two key components of CDDP, are capable of targeting ICAM-1 which is one of the key target of DR. We hope that this work can facilitate development of more effective clinical strategies for the treatment of DR.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Algoritmos , Retinopatia Diabética/tratamento farmacológico , Humanos , Aprendizado de Máquina , Proteínas , Relação Quantitativa Estrutura-Atividade
19.
Cell Cycle ; 21(21): 2223-2238, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35792905

RESUMO

Excessive apoptosis of placental trophoblast cells is considered a major cause of pre-eclampsia (PE) pathogenesis. Phosphorylation of the widely expressed cAMP response element binding protein (CREB) regulates apoptosis and may be involved in PE incidence. Low-dose aspirin (LDA) is an effective approach for preventing PE with unclear mechanisms. Thus we examined whether LDA protects against PE by inhibiting trophoblast cell apoptosis through CREB. The effects of LDA on human PE placenta, PE model rat placenta, and hydrogen peroxide (H2O2)-induced HTR-8/SVneo cell apoptosis were analyzed. TUNEL assay, immunohistochemistry, Cell Counting Assay Kit-8 (CCK-8) assay, western blot, and flow cytometry assay were performed. In the placenta of human PE and rat PE models, the TUNEL index increased and was partially corrected with LDA pre-treatment. Meanwhile, decreased Bcl-2 and increased Bax expression were significantly reversed by LDA pre-treatment. In HTR-8/SVneo cells, H2O2 decreased cell viability, promoted apoptosis, reduced the Bcl-2/Bax ratio, aggravated loss of mitochondrial membrane potential (MMP), increased cytoplasmic cytochrome c release, and simultaneously activated caspase-9 and caspase-3. These effects were effectively restored by LDA pre-treatment in the cells. Moreover, LDA promoted CREB phosphorylation in trophoblast cells. CREB interference further promoted apoptosis, reduced the Bcl-2/Bax ratio, and increased MMP loss. CREB interference also reversed the inhibitory effect of LDA on H2O2-induced apoptosis in HTR-8/SVneo cells. Thus, LDA was shown to inhibit trophoblast cell mitochondrial apoptosis by activating the CREB/Bcl-2 pathway, providing novel evidence for the protective mechanism of LDA in PE.Abbreviations; PE: Pre-eclampsia; LDA: low-dose aspirin; CREB: cAMP response element binding protein; ROS: reactive oxygen species; H2O2: hydrogen peroxide; PBS: Phosphate-buffered saline; Bcl-2: B-cell lymphoma-2; MMP: Mitochondrial membrane potential; Cyt-c: CytochromeC.


Assuntos
Pré-Eclâmpsia , Trofoblastos , Animais , Apoptose , Aspirina/metabolismo , Aspirina/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Movimento Celular/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Citocromos c/metabolismo , Feminino , Humanos , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/toxicidade , Fosfatos/metabolismo , Fosfatos/farmacologia , Placenta/metabolismo , Pré-Eclâmpsia/patologia , Gravidez , Ratos , Espécies Reativas de Oxigênio/metabolismo , Trofoblastos/metabolismo , Proteína X Associada a bcl-2/metabolismo
20.
Sensors (Basel) ; 22(12)2022 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-35746383

RESUMO

Missing tag incidents are common in RFID-enabled supply-chain and warehousing scenarios due to cargo theft and employee error operations, which may lead to serious economic losses or potential safety hazards. On the premise of ensuring the accuracy of missing tag detection, this paper aims to improve the time efficiency in an integrated RFID system. Unlike prior work focusing on detecting missing items from a large number of homogeneous tags that are monitored by a single reader, one integrated RFID system possesses multiple readers to communicate with the heterogeneous tags, which have different categorical attributes. In addition, the prior work required repeating the execution several times to capture the missing tags in assorted categories, which is of low time efficiency. Thus, a protocol called Multi-reader Missing Tag Detection (MMTD) is proposed to capture the missing tag quickly and reliably, which can detect missing tags from different categories in a parallel manner and is much more time-efficient than previous work. MMTD has two major advantages compared to prior work: (i) It leverages the knowledge of the spatial distribution of tags to divide up a difficult detection task into several lightweight tasks, which are shared by multiple readers. (ii) It personalizes the time frame of the reader based on the tag population to optimize the utilization of the communication channel. The final simulation results reveal that MMTD is the best in time-efficiency among the comparison protocols, and MMTD outperforms the other missing tag detection protocols by at least 1.5× in the Integrated RFID scenarios.


Assuntos
Dispositivo de Identificação por Radiofrequência , Simulação por Computador , Monitorização Fisiológica , Dispositivo de Identificação por Radiofrequência/métodos
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