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BACKGROUND: Persistent infection with high-risk human papillomavirus (HR-HPV) plays a key role in the onset of cervical cancer. This study was designed to examine the epidemiological trends and genotype distribution of HPV from 2014 to 2023 in the plateau region of Southwest China. METHODS: The findings could offer valuable insights for clinical screening of cervical cancer and the formulation of HPV vaccination policies. This retrospective study analyzed 66,000 women who received HPV-DNA testing at the First People's Hospital of Qujing, Yunnan, China, between 2014 and 2023. The cohort consisted of 33,512 outpatients, 3,816 inpatients, and 28,672 individuals undergoing health examinations. Cervical cells were collected for DNA extraction, and PCR amplification along with Luminex xMAP technology were used to detect 27 HPV genotypes. The data analysis was conducted using GraphPad Prism and IBM SPSS Statistics 27 software. RESULTS: The overall HPV infection rate at the First People's Hospital of Qujing declined from 24.92% in 2014 to 16.29% in 2023, averaging 16.02%. Specific infection rates were 18.50% among outpatients, 12.97% among inpatients, and 13.53% for health examination attendees. The predominant high-risk HPV genotypes identified were HPV52 (2.61%), HPV16 (2.06%), HPV58 (1.81%), HPV53 (1.55%), and HPV39 (1.09%). Meanwhile, the most frequent low-risk HPV genotypes were HPV6 (1.30%), HPV61 (1.21%), and HPV11 (0.85%). In HPV-positive cases, the distribution of single, double, triple, and quadruple or more infections were 79.90%, 15.17%, 3.59%, and 1.33%, respectively. The proportions of pure LR-HPV, pure HR-HPV, and mixed infections were 22.16%, 67.82%, and 10.02%, respectively. Age-specific analysis revealed a bimodal distribution of HPV infection, with the infection rate rapidly decreasing from 44.02% in the ≤ 19 age group to 19.55% in the 20-29 age group and 13.84% in the 30-39 age group, followed by a gradual increase to 14.64% in the 40-49 age group, 16.65% in the 50-59 age group, and 22.98% in the ≥ 60 age group. The coverage rates of the three available vaccines are all below 50%. The results of this study indicated a declining trend in HPV prevalence in the plateau region of Southwest China over the period from 2014 to 2023, especially in the reduction of genotypes targeted by vaccines. CONCLUSION: There were significant variations in the genotypes prevalent among different age groups, years, and patient sources within the same region. The underwhelming vaccination rates emphasize the critical need for developing either a multivalent vaccine or a personalized vaccine that targets the HPV genotypes common in the Chinese population. Furthermore, vaccinating adolescents to curb HPV infection and ensuring regular cervical cancer screenings for postmenopausal women are crucial steps.
Assuntos
Genótipo , Papillomaviridae , Infecções por Papillomavirus , Humanos , Feminino , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/virologia , China/epidemiologia , Adulto , Prevalência , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem , Papillomaviridae/genética , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Adolescente , Idoso , Neoplasias do Colo do Útero/virologia , Neoplasias do Colo do Útero/epidemiologia , DNA Viral/genética , Colo do Útero/virologiaRESUMO
Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.
Assuntos
Adenocarcinoma de Pulmão , Antineoplásicos , Neoplasias Pulmonares , Proteínas de Fusão Oncogênica , Compostos Organofosforados , Inibidores de Proteínas Quinases , Pirimidinas , Humanos , Compostos Organofosforados/uso terapêutico , Compostos Organofosforados/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Animais , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Prognóstico , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Lactamas/uso terapêutico , Carbazóis/uso terapêutico , Carbazóis/farmacologia , Sulfonas/uso terapêutico , Sulfonas/farmacologia , Crizotinibe/uso terapêutico , Crizotinibe/farmacologia , Linhagem Celular Tumoral , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Feminino , Camundongos , Inflamação/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Masculino , Quinase do Linfoma Anaplásico/genética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/metabolismo , Proliferação de Células/efeitos dos fármacos , Mutação , Aminopiridinas/uso terapêutico , Aminopiridinas/farmacologiaRESUMO
Polarity establishment is one of the key factors affecting early embryonic development. Polarity establishment begins with myosin phosphorylation in the 8-cell embryo, and phosphorylation activates actin leading to its initiation of contractility. Subsequently, actin undergoes reorganization to form an apical domain rich in microvilli on the non-contacting surface of each blastomere, and form the actomyosin ring that marks the maturation of the apical domain in conjunction with polar protein complexes and others. From the process of polarity establishment, it can be seen that the formation of the apical domain is influenced by actin-related proteins and polar protein complexes. Some zygote genome activation (ZGA) and lineage-specific genes also regulate polarity establishment. Polarity establishment underlies the first cell lineage differentiation during early embryonic development. It regulates lineage segregation and morphogenesis by affecting asymmetric cell division, asymmetric localization of lineage differentiation factors, and activity of the Hippo signaling pathway. In this review, we systematically summarize the mechanisms of early embryonic polarity establishment and its impact on lineage differentiation in mammals, and discuss the shortcomings of the currently available studies in terms of regulatory mechanisms and species, thereby providing clues and systematic perspectives for elucidating early embryonic polarity establishment.
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Actinas , Actomiosina , Animais , Actomiosina/metabolismo , Citocinese , Diferenciação Celular , Linhagem da Célula , Polaridade Celular/fisiologia , Mamíferos/metabolismoRESUMO
OBJECTIVE: To explore the potential action mechanism of Huotu Jiji Pellets (HJP) in the treatment of erectile dysfunction (ED) based on network pharmacology and molecular docking. METHODS: We identified the main effective compounds and active molecular targets of HJP from the database of Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Integrative Pharmacology-Based Research Platform of Traditional Chinese Medicine (TCMIP) and the therapeutic target genes of ED from the databases of Genecards. Then we obtained the common targets of HJP and ED using the Venny software, constructed a protein-protein interaction (PPI) network of HJP acting on ED, and screened out the core targets with the Cytoscape software. Lastly we performed GO functional enrichment and KEGG pathway enrichment analyses of the core targets followed by molecular docking of HJP and the core targets using Chem3D and AutoDock Tools and QuickVina-W software. RESULTS: A total of 64 effective compounds, 822 drug-related targets, 1 783 disease-related targets and 320 common targets were obtained in this study. PPI network analysis showed that the core targets of HJP for ED included ESR1, HSP90AA1, SRC, and STAT3. GO functional enrichment analysis indicated the involvement of the core targets in such biological processes as response to xenobiotic stimulus, positive regulation of kinase activity, and positive regulation of MAPK cascade. KEGG pathway enrichment analysis suggested that PI3K-Akt, apoptosis, MAPK, HIF-1, VEGF, autophagy and other signaling pathways may be related to the mechanism of HJP acting on ED. Molecular docking prediction exhibited a good docking activity of the key active molecules of HJP with the core targets. CONCLUSION: This study showed that HJP acted on ED through multi-components, multi-targets and multi-pathways, which has provided some evidence and reference for the clinical treatment and subsequent studies of the disease.
Assuntos
Medicamentos de Ervas Chinesas , Disfunção Erétil , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Farmacologia em Rede , Mapas de Interação de Proteínas , Masculino , Disfunção Erétil/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Transdução de SinaisRESUMO
PURPOSE: Most Hepatocellular carcinoma (HCC) patients are in advanced or metastatic stage at the time of diagnosis. Prognosis for advanced HCC patients is dismal. This study was based on our previous microarray results, and aimed to explore the promising diagnostic and prognostic markers for advanced HCC by focusing on the important function of KLF2. METHODS: The Cancer Genome Atlas (TCGA), Cancer Genome Consortium database (ICGC), and the Gene Expression Comprehensive Database (GEO) provided the raw data of this study research. The cBioPortal platform, CeDR Atlas platform, and the Human Protein Atlas (HPA) website were applied to analyze the mutational landscape and single-cell sequencing data of KLF2. Basing on the results of single-cell sequencing analyses, we further explored the molecular mechanism of KLF2 regulation in the fibrosis and immune infiltration of HCC. RESULTS: Decreased KLF2 expression was discovered to be mainly regulated by hypermethylation, and indicated a poor prognosis of HCC. Single-cell level expression analyses revealed KLF2 was highly expressed in immune cells and fibroblasts. The function enrichment analysis of KLF2 targets indicated the crucial association between KLF2 and tumor matrix. 33-genes related with cancer associated fibroblasts (CAFs) were collected to identify the significant association of KLF2 with fibrosis. And SPP1 was validated as a promising prognostic and diagnostic marker for advanced HCC patients. CXCR6 CD8+ T cells were noted as a predominant proportion in the immune microenvironment, and T cell receptor CD3D was discovered to be a potential therapeutic biomarker for HCC immunotherapy. CONCLUSION: This study identified that KLF2 is an important factor promoting HCC progression by affecting the fibrosis and immune infiltration, highlighting its great potential as a novel prognostic biomarker for advanced HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Linfócitos T CD8-Positivos , Prognóstico , Neoplasias Hepáticas/genética , Fibrose , Microambiente Tumoral/genética , Fatores de Transcrição Kruppel-Like/genéticaRESUMO
Objective: This study sought to determine the mean prognostic usefulness of seleniumphosphate synthase (SEPHS1) by investigating its expression in 33 human malignancies and its relationship to tumor immunity.Methods: The expression of selenophosphate synthase 1 (SEPHS1) in 33 human malignant tumors was examined using the Genotype-Tissue Expression (GTEx), Cancer Genome Atlas (TCGA), and TIMER databases. Furthermore, the TCGA cohort was used to investigate relationships between SEPHS1 and immunological checkpoint genes (ICGs), tumor mutation burden (TMB), microsatellite instability (MSI), and DNA mismatch repair genes (MMRs). To establish independent risk factors and calculate survival probabilities for liver hepatocellular carcinoma (LIHC) and brain lower-grade glioma (LGG), Cox regression models and Kaplan-Meier curves were utilized. Eventually, the Genomics of Cancer Drug Sensitivity (GDSC) database was used to evaluate the drug sensitivity in LGG and LIHC patients with high SEPHS1 expression.Results: Overall, in numerous tumor tissues, SEPHS1 was highly expressed, and it significantly linked with the prognosis of LGG, ACC, and LIHC (P < .05). Furthermore, in numerous cancers, SEPHS1 expression was linked to tumor-infiltrating immune cells (TIICs), TMB, MSI, and MMRs. According to univariate and multivariate Cox analyses, SEPHS1 expression was significant for patients with LGG and LIHC.Conclusion: High SEPHS1 expression has a better prognosis for LGG, while low SEPHS1 expression has a better prognosis for LIHC. Chemotherapy was advised for LGG patients, particularly for those with high SEPHS1 expression because it can predict how responsive patients will be to 5-Fluorouracil and Temozolomide. This interaction between SEPHS1 and chemoradiotherapy has a positive clinical impact and may be used as evidence for chemotherapy for LGG and LIHC patients.
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Carcinoma Hepatocelular , Glioma , Neoplasias Hepáticas , Selênio , Humanos , FosfatosRESUMO
Voltage-gated sodium channel 1.7 (Nav1.7) remains one of the most promising drug targets for pain relief. In the current study, we conducted a high-throughput screening of natural products in our in-house compound library to discover novel Nav1.7 inhibitors, then characterized their pharmacological properties. We identified 25 naphthylisoquinoline alkaloids (NIQs) from Ancistrocladus tectorius to be a novel type of Nav1.7 channel inhibitors. Their stereostructures including the linkage modes of the naphthalene group at the isoquinoline core were revealed by a comprehensive analysis of HRESIMS, 1D, and 2D NMR spectra as well as ECD spectra and single-crystal X-ray diffraction analysis with Cu Kα radiation. All the NIQs showed inhibitory activities against the Nav1.7 channel stably expressed in HEK293 cells, and the naphthalene ring in the C-7 position displayed a more important role in the inhibitory activity than that in the C-5 site. Among the NIQs tested, compound 2 was the most potent with an IC50 of 0.73 ± 0.03 µM. We demonstrated that compound 2 (3 µM) caused dramatical shift of steady-state slow inactivation toward the hyperpolarizing direction (V1/2 values were changed from -39.54 ± 2.77 mV to -65.53 ± 4.39 mV, which might contribute to the inhibition of compound 2 against the Nav1.7 channel. In acutely isolated dorsal root ganglion (DRG) neurons, compound 2 (10 µM) dramatically suppressed native sodium currents and action potential firing. In the formalin-induced mouse inflammatory pain model, local intraplantar administration of compound 2 (2, 20, 200 nmol) dose-dependently attenuated the nociceptive behaviors. In summary, NIQs represent a new type of Nav1.7 channel inhibitors and may act as structural templates for the following analgesic drug development.
Assuntos
Alcaloides , Canal de Sódio Disparado por Voltagem NAV1.7 , Camundongos , Animais , Humanos , Células HEK293 , Dor/tratamento farmacológico , Neurônios , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Gânglios Espinais , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
Objective To study the expression of selenoprotein genes in human immunodeficiency virus(HIV)infection and its mother-to-child transmission,so as to provide a theoretical basis for the prevention,diagnosis,and treatment of acquired immunodeficiency syndrome.Methods The dataset GSE4124 was downloaded from the Gene Expression Omnibus(GEO).Two groups of HIV-positive mothers(n=25)and HIV-negative mothers(n=20)were designed.HIV-positive mothers included a subset of transmitter(TR)mothers(n=11)and non-transmitter(NTR)mothers(n=14).Then,t-test was carried out to compare the expression levels of selenoprotein genes between the four groups(HIV-positive vs. HIV-negative,NTR vs. HIV-negative,TR vs. HIV-negative,TR vs. NTR).Univariate and multivariate Logistic regression were adopted to analyze the effects of differentially expressed genes on HIV infection and mother-to-child transmission.R software was used to establish a nomogram prediction model and evaluate the model performance.Results Compared with the HIV-negative group,HIV-positive,NTR,and TR groups had 8,5 and 8 down-regulated selenoprotein genes,respectively.Compared with the NTR group,the TR group had 4 down-regulated selenoprotein genes.Univariate Logistic regression analysis showed that abnormally high expression of GPX1,GPX3,GPX4,TXNRD1,TXNRD3,and SEPHS2 affected HIV infection and had no effect on mother-to-child transmission.The multivariate Logistic regression analysis showed that the abnormally high expression of TXNRD3(OR=0.032,95%CI=0.002-0.607,P=0.022)was positively correlated with HIV infection.As for the nomogram prediction model,the area under the receiver-operating characteristic curve for 1-year survival of HIV-infected patients was 0.840(95%CI=0.690-1.000),and that for 3-year survival of HIV-infected patients was 0.870(95%CI=0.730-1.000).Conclusions Multiple selenoprotein genes with down-regulated expression levels were involved in the regulation of HIV infection and mother-to-child transmission.The abnormal high expression of TXNRD3 was positively correlated with HIV infection.The findings provide new ideas for the prevention,diagnosis,and treatment of acquired immunodeficiency syndrome.
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Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Humanos , Feminino , Transmissão Vertical de Doenças Infecciosas , Nomogramas , Selenoproteínas/genéticaRESUMO
OBJECTIVE: To observe the clinical effect of Simiaotongzhuo Decoction (SMTZD) on the symptoms of type III prostatitis with damp-heat stagnation syndrome. METHODS: Using the randomized control method, we divided 140 cases of type III prostatitis with damp-heat stagnation syndrome into two groups and treated them orally with SMTZD at 200 ml per time bid (n = 65) and Tamsulosin Hydrochloride Sustained Release Capsules (THSRC) at 0.2 mg per time qd (n = 75), both for 6 weeks. Before and after medication, we recorded the counts of white blood cells (WBC) and lecithin bodies in the prostatic fluid, NIH-CPSI scores and traditional Chinese medicine syndrome (TCMS) scores, and compared them between the two groups of patients. RESULTS: Compared with the baseline, the WBC count and NIH-CPSI scores were decreased and the number of lecithin bodies increased in both the SMTZD (NIH-CPSI score: ï¼»18±6.47ï¼½ vs ï¼»9±5.02ï¼½) and THSRC groups after medication, with statistically significant difference only in the former group (P<0.05), the TCMS scores were significantly reduced in both the SMTZD (ï¼»21.97±5.12ï¼½ vs ï¼»6.4±4.88ï¼½, P<0.05) and the THSRC group (ï¼»20.73±4.97ï¼½ vs ï¼»11.33±5.93ï¼½, P<0.05), even more significantly in the former. No statistically significant difference was observed in the incidence of adverse reactions between the SMTZD and THSRC groups (9.2% vs 9.3%, P>0.05), and all the adverse reactions were mild. CONCLUSION: Simiaotongzhuo Decoction is safe and effective for the treatment of type III prostatitis with damp-heat stagnation syndrome, which can reduce the WBC count in the prostatic fluid, increase the number of lecithin bodies and improve the NIH-CPSI and TCMS scores of the patient.
Assuntos
Líquidos Corporais , Prostatite , Humanos , Masculino , Estro , Temperatura Alta , Lecitinas , Prostatite/tratamento farmacológico , Síndrome , Tansulosina/uso terapêuticoRESUMO
OBJECTIVE: To explor the potential mechanisms of ferroptosis involvement in non-obstructive azoospermia based on bioinformatics and machine learning methods. METHODS: To obtain disease-related datasets and ferroptosis-related genes, we utilized the GEO database and FerrDb database, respectively. Using the R software, the disease dataset was subjected to normalization, differential analysis, and GO and KEGG enrichment analysis. The differentially expressed genes from the disease dataset were then intersected with the ferroptosis-related genes to identify common genes. Core genes were selected using three machine learning algorithms, namely LASSO, SVM-RFE, and random forest. Further analysis included exploring immune infiltration correlation, predicting target drugs, and conducting molecular docking simulations. RESULTS: The differential analysis of the GSE45885 dataset yielded 1751 differentially expressed genes, while the GSE145467 dataset yielded 4358 differentially expressed genes. The intersection of these two gene sets resulted in a disease-related gene set consisting of 508 genes. Taking the intersection of the disease-related gene set and the ferroptosis-related gene set, we obtained 17 disease-related ferroptosis genes. After machine learning-based screening, three core genes were identified: GPX4, HSF1, and KLHDC3. CONCLUSION: The mechanism underlying the involvement of ferroptosis in non-obstructive azoospermia may be linked to the downregulation of GPX4, HSF1, and KLHDC3 expression. This finding provides a basis for subsequent in-depth mechanistic and therapeutic studies.
Assuntos
Azoospermia , Ferroptose , Masculino , Humanos , Azoospermia/genética , Ferroptose/genética , Simulação de Acoplamento Molecular , Biologia Computacional , Aprendizado de MáquinaRESUMO
Natural polybrominated diphenyl ethers, often isolated from marine sponges, have been reported to possess various biological activities, such as antibacterial, antioxidant and antidiabetic effects. Via a high throughput screening of our marine natural product library, the polybrominated diphenyl ether 3 was found to display a KCNQ potassium channel activation effect. To obtain more compound 3 related natural products and their derivatives for further bioactivity study, a diversity-oriented synthesis was conducted, leading to the successful synthesis of five polybrominated diphenyl ether natural products (1-4, 6) and 30 new derivatives. Compound 3 was found to preferentially potentiate KCNQ1 potassium channel, whereas 17h relatively activated KCNQ2 potassium channel. The structure-activity relationship was analyzed assisted by molecular docking and 17h was further conducted for its agonistic mechanism study on KCNQ2 channel. This research work may give an insight for the discovery of marine polybrominated diphenyl ether derived new drug leads.
Assuntos
Produtos Biológicos , Poríferos , Animais , Produtos Biológicos/farmacologia , Éteres Difenil Halogenados/farmacologia , Canais de Potássio KCNQ , Simulação de Acoplamento MolecularRESUMO
Objective To investigate the expression regulation of autophagy-related genes(ATG)and the mechanism of autophagy in rheumatoid arthritis(RA).Methods The differentially expressed genes(DEG)of RA were identified from GSE55235 and GSE55457,on the basis of which the differentially expressed autophagy-related genes(DE-ATG)were selected from the Human Autophagy Database.STRING 11.0 and GeneMANIA were used to establish protein-protein interaction networks.Further,the transcription factor-gene-miRNA co-expression network was established via NetworkAnalyst and Cytoscape.Finally,receiver operating characteristic(ROC)curve and DrugBank were employed to evaluate the efficacy of the predicted biomarkers and the performance of drugs targeting DE-ATG.GraphPad Prism 8.2.1 and R 4.0.3 were used for statistical analysis and graphics.Results A total of 485 DEG were enriched in signaling pathways such as T cell activation,hormone regulation,osteoclast differentiation,RA,and chemokines.Eleven DE-ATG regulated the expression of RUNX1,TP53,SOX2,and hsa-mir-155-5p in synovial tissues of RA patients and were involved in the response to environmental factors such as 2,3,7,8-tetrachlorodibenzodioxin and silicon dioxide.The ROC curve analysis identified the DE-ATG with good sensitivity and specificity,such as MYC,MAPK8,CDKN1A,and TNFSF10,which can be used to distinguish certain phenotypes and serve as novel biomarkers for RA.Conclusions In RA,down-regulated DE-ATG expression may promote apoptosis and lysis of chondrocytes.The identified novel biomarkers provides new ideas and methods for diagnosing and treating RA.The establishment of transcription factor-miRNA-gene co-expression network provides direct evidence for dissecting synovial inflammation and articular cartilage destruction.
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Artrite Reumatoide , MicroRNAs , Humanos , Artrite Reumatoide/genética , MicroRNAs/genética , Biomarcadores , Autofagia , Fatores de Transcrição/genética , Perfilação da Expressão Gênica/métodosRESUMO
BACKGROUND: Pneumonia caused by the 2019 novel Coronavirus (COVID-2019) shares overlapping signs and symptoms, laboratory findings, imaging features with influenza A pneumonia. We aimed to identify their clinical characteristics to help early diagnosis. METHODS: We retrospectively retrieved data for laboratory-confirmed patients admitted with COVID-19-induced or influenza A-induced pneumonia from electronic medical records in Ningbo First Hospital, China. We recorded patients' epidemiological and clinical features, as well as radiologic and laboratory findings. RESULTS: The median age of influenza A cohort was higher and it exhibited higher temperature and higher proportion of pleural effusion. COVID-19 cohort exhibited higher proportions of fatigue, diarrhea and ground-glass opacity and higher levels of lymphocyte percentage, absolute lymphocyte count, red-cell count, hemoglobin and albumin and presented lower levels of monocytes, c-reactive protein, aspartate aminotransferase, alkaline phosphatase, serum creatinine. Multivariate logistic regression analyses showed that fatigue, ground-glass opacity, and higher level of albumin were independent risk factors for COVID-19 pneumonia, while older age, higher temperature, and higher level of monocyte count were independent risk factors for influenza A pneumonia. CONCLUSIONS: In terms of COVID-19 pneumonia and influenza A pneumonia, fatigue, ground-glass opacity, and higher level of albumin tend to be helpful for diagnosis of COVID-19 pneumonia, while older age, higher temperature, and higher level of monocyte count tend to be helpful for the diagnosis of influenza A pneumonia.
Assuntos
COVID-19/diagnóstico , COVID-19/virologia , Técnicas de Laboratório Clínico , Vírus da Influenza A/fisiologia , Pneumonia/diagnóstico , Pneumonia/virologia , SARS-CoV-2/fisiologia , COVID-19/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pneumonia/diagnóstico por imagem , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
Chalcomoracin (CMR) is a kind of Diels-Alder adduct extracted from the mulberry leaves. Recent studies showed that CMR has a broad spectrum of anticancer activities and induces paraptosis in breast cancer and prostate cancer cells. In this study, we investigated the effects of CMR against human non-small cell lung cancer cells and the underlying mechanisms. We found that CMR dose-dependently inhibited the proliferation of human lung cancer H460, A549 and PC-9 cells. Furthermore, exposure to low and median doses of CMR induced paraptosis but not apoptosis, which was presented as the formation of extensive cytoplasmic vacuolation with increased expression of endoplasmic reticulum stress markers, Bip and Chop, as well as activation of MAPK pathway in the lung cancer cells. Knockdown of Bip with siRNA not only reduced the cell-killing effect of CMR, but also decreased the percentage of cytoplasmic vacuoles in H460 cells. Moreover, CMR also increased the sensitivity of lung cancer cells to radiotherapy through enhanced endoplasmic reticulum stress. In lung cancer H460 cell xenograft nude mice, combined treatment of CMR and radiation caused greatly enhanced tumor growth inhibition with upregulation of endoplasmic reticulum stress proteins and activation of pErk in xenograft tumor tissue. These data demonstrate that the anticancer activity and radiosensitization effect of CMR result from inducing paraptosis, suggesting that CMR could be considered as a potential anticancer agent and radiation sensitizer in the future cancer therapeutics.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Células Tumorais CultivadasRESUMO
Geissoschizine methyl ether (GM) is an indole alkaloid isolated from Uncaria rhynchophyll (UR) that has been used for the treatment of epilepsy in traditional Chinese medicine. An early study in a glutamate-induced mouse seizure model demonstrated that GM was one of the active ingredients of UR. In this study, electrophysiological technique was used to explore the mechanism underlying the antiepileptic activity of GM. We first showed that GM (1-30 µmol/L) dose-dependently suppressed the spontaneous firing and prolonged the action potential duration in cultured mouse and rat hippocampal neurons. Given the pivotal roles of ion channels in regulating neuronal excitability, we then examined the effects of GM on both voltage-gated and ligand-gated channels in rat hippocampal neurons. We found that GM is an inhibitor of multiple neuronal channels: GM potently inhibited the voltage-gated sodium (NaV), calcium (CaV), and delayed rectifier potassium (IK) currents, and the ligand-gated nicotinic acetylcholine (nACh) currents with IC50 values in the range of 1.3-13.3 µmol/L. In contrast, GM had little effect on the voltage-gated transient outward potassium currents (IA) and four types of ligand-gated channels (γ-amino butyric acid (GABA), N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainite (AMPA/KA receptors)). The in vivo antiepileptic activity of GM was validated in two electricity-induced seizure models. In the maximal electroshock (MES)-induced mouse seizure model, oral administration of GM (50-100 mg/kg) dose-dependently suppressed generalized tonic-clonic seizures. In 6-Hz-induced mouse seizure model, oral administration of GM (100 mg/kg) reduced treatment-resistant seizures. Thus, we conclude that GM is a promising antiepileptic candidate that inhibits multiple neuronal channels.
Assuntos
Anticonvulsivantes/farmacologia , Hipocampo/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Ativação do Canal Iônico/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Convulsões/tratamento farmacológico , Animais , Canais de Cálcio , Modelos Animais de Doenças , Eletrochoque , Ativação do Canal Iônico/genética , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: To investigate gene rearrangement and protein expression of ETS related gene (ERG ) in prostate cancer of Chinese patients and its correlation with clinicopathological characteristics and prognosis. METHODS: This study collected 482 cases of prostatic adenocarcinomas diagnosed by prostate biopsy in West China Hospital of Sichuan University from 2009 to 2014. Fluorescencein situ hybridization (FISH) and immuno-histochemical staining (IHC) were performed to access the ERG rearrangement and protein expression respectively. Relationship between ERG rearrangement and protein expression was assessed by Spearman rank order correlation. The correlations of ERG rearrangement and protein expression with clinicopathological variables and prognosis were further analyzed. RESULTS: ERG rearrangement was detected in 87 (18.0 %) cases, of which 45 (51.7%) was translocation and 42 (48.3%) was deletion. ERG protein expression was detected in 74 (15.4%) cases. Follow-up data was obtained in 368 cases. ERG rearrangement and protein expression had no correlations to age, Gleason score and pre-operation PSA level ( P>0.05), but ERG protein level was decreased in metastatic cases or castration resistant prostate cancer (CRPC) cases ( P<0.05) . Kaplan-Meier curve showed both gene rearrangement and protein expression of ERG had no prognostic significance. CONCLUSIONS: ERG rearrangement, as well as ERG protein expression, could not serve as an independent prognostic biomarker.
Assuntos
Adenocarcinoma/genética , Rearranjo Gênico , Neoplasias da Próstata/genética , Biomarcadores Tumorais , China , Humanos , Masculino , Prognóstico , Regulador Transcricional ERG/genéticaRESUMO
OBJECTIVE: To investigate the expressions of sphingosine-1-phosphate receptors 1-3 (S1P1- 3) in the corpus cavernosum of castrated male rats and its relationship with the NOS/NO/cGMP and RhoA/Rho kinase signaling pathways. METHODS: We equally randomized 18 eight-week-old healthy male SD rats into a sham-operation control, a castration, and a testosterone replacement (TR) group and harvested the bilateral testes and epididymides from the rats in the latter two groups, followed by 4 weeks of subcutaneous injection of testosterone propionate at 3 mg per kilogram of the body weight per day for those in the TR group and that of plant oil for those in the control and castration groups. At the age of 12 weeks, we measured the serum testosterone (T) level and maximum intracavernous pressure/mean arterial pressure (ICPmax/MAP) of the animals and determined the expressions of SlP1-3, eNOS, P-eNOS, ROCK1, and ROCK2 in the corpus cavernosum by Western blot and immunohistochemistry. RESULTS: The serum T level was significantly decreased in the rats of the castration group as compared with those of the control and TR groups ([0.41 ± 0.04] vs [16.01 ± 1.02] and [15.84 ± 1.32] nmol/L, P < 0.01), with no statistically significant difference between the latter two groups. The ICPmax/MAP at 0 V, 3 V, and 5 V electric stimulation was remarkably lower in the rats of the castration group (0.088 ± 0.014, 0.323 ± 0.014, and 0.432 ± 0.012) than in those of the control group (0.155 ± 0.011, 0.711 ± 0. 010, and 0.819 ± 0.024) and TR group (0.153 ± 0.012, 0.696 ± 0.017, and 0.763 ± 0.027) (P < 0.01), with no significant difference between the latter two groups. With GAPDH as internal control, the animals of the castration group showed markedly reduced expressions of S1P1 ([49.99 ± 3.39]%), eNOS ([46.82 ± 3.81]%) , and P-eNOS ([45.42 ± 4.35]%) in comparison with those in the control group ([72.57 ± 3.06], [89.76 ± 3.98], and [82.53 ± 8.92] and TR group ([71.77 ± 4.43], [87.19 ± 4.23], and [79.82 ± 7.38]%) (P < 0.01) , while the expressions of S1P2, S1P3, ROCK1, and ROCK2 were significantly upregulated in the castration group ([82.35 ± 4.13], [61.03 ± 5.14], [74.50 ± 4.02], and [69.83 ± 5.75]%) as compared with those in the control group ([41.67 ± 1.68], [31.66 ± 2.67], [35.69 ± 5.56], and [39.85 ± 7.17]%) and TR group ([42.80 ± 3.87], [32.25 ± 4.22], 38.06 ± 5.21], and [42.36 ± 4.44]%) (P < 0.01). CONCLUSION: Androgen deficiency induces significant reduction of ICPmax/ MAP in male rats, which is possibly associated with the decline of S1P1 in the corpus cavernosum, inhibition of the eNOS/NO/cGMP signaling pathway, increased expressions of S1P2 and S1P3, and activation of the RhoA/Rho kinase signaling pathway.
Assuntos
Orquiectomia , Pênis/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Testosterona/farmacologia , Animais , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Testosterona/sangue , Quinases Associadas a rho/metabolismoRESUMO
BACKGROUND: Although SDF-1/CXCR4 pathway is a potential mechanism of tumor proliferation and progression, the mechanism of controlling CXCR4 expression is not fully understood. This study was to confirm that miR-494-3p might be a potentially post-transcriptional regulator of CXCR4 and over-expression of miR-494 might suppress prostate cancer progression and metastasis. MATERIALS AND METHODS: We firstly postulated the post-transcriptional regulation of CXCR4 by miR-494-3p through bioinformatics analysis, and then it was demonstrated that miR-494-3p could regulate the CXCR4 mRNA post-transcriptionally by binding to the predicted site by dual reporter gene assays. The biological effect of miR-494-3p on prostate cancer cells proliferation, apoptosis, migration, and invasion was measured by MTT, TUNEL, flow cytometry, migration, and invasion assays. RESULTS: It was shown that the mRNA and protein expression levels of CXCR4 were significantly up-regulated in PC-3 and DU145, whereas barely detected in LNCaP and RWPE-1. However, the CXCR4 protein levels were inversely related to the mature miR-494-3p expression levels in RWPE-1 and prostate cancer cells. The constitutive over-expression of miR-494-3p could down-regulate the protein level of CXCR4 in PC-3 and DU145. MiR-494-3p also could bind to the seed sequences in the 3'-UTR of the CXCR4 gene. Artificial over-expression of miR-494-3p could inhibit the growth, promote the apoptosis, and inhibit the migration and invasion of PC-3 and DU145 cells in vivo. CONCLUSIONS: Our results suggested that miR-494-3p might play crucial role in prostate cancer by post-transcriptional regulation to CXCR4 mRNA. MiR-494-3p/CXCR4 pathway may be a potential therapeutic target to prevent prostate cancer progression and metastasis.