ABSTRACT
Capsular residual lens epithelial cells (CRLEC) undergo differentiation to fiber cells for lens regeneration or tansdifferentiation to myofibroblasts leading to posterior capsular opacification (PCO) after cataract surgery. The underlying regulatory mechanism remains unclear. Using human lens epithelial cell lines and the ex vivo cultured rat lens capsular bag model, we found that the lens epithelial cells secrete HSP90α extracellularly (eHSP90) through an autophagy-associated pathway. Administration of recombinant GST-HSP90α protein or its M-domain induces the elongation of rat CRLEC cells with concomitant upregulation of the crucial fiber cell transcriptional factor PROX1and its downstream targets, ß- and γ-crystallins and structure proteins. This regulation is abolished by PROX1 siRNA. GST-HSP90α upregulates PROX1 by binding to LRP1 and activating LRP1-AKT mediated YAP degradation. The upregulation of GST-HSP90α on PROX1 expression and CRLEC cell elongation is inhibited by LRP1 and AKT inhibitors, but activated by YAP-1 inhibitor (VP). These data demonstrated that the capsular residue epithelial cells upregulate and secrete eHSP90α, which in turn drive the differentiation of lens epithelial cell to fiber cells. The recombinant HSP90α protein is a potential novel differentiation regulator during lens regeneration.
Subject(s)
Lens, Crystalline , Proto-Oncogene Proteins c-akt , Rats , Animals , Humans , Proto-Oncogene Proteins c-akt/metabolism , Cell Differentiation , Lens, Crystalline/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Epithelial Cells/metabolism , Low Density Lipoprotein Receptor-Related Protein-1/geneticsABSTRACT
OBJECTIVE: This study aims to analyze the safety and effectiveness of a new model of surgery combined with Photodynamic therapy for treating Recurrent Respiratory Papillomatosis (RRP). METHODS: Review the case data of patients with RRP who opted for comprehensive surgery combined with Photodynamic therapy at the Nanjing BenQ Medical Center, from January 2021 to May 2023. The efficacy of this program was evaluated by comparing the annual number of surgeries and Derkay scores before and after the surgery. RESULTS: A total of 23 RRP patients were included in the study. After treatment, the recurrence rate was 65.2 % (15/23), with an average recurrence time of 94.3 ± 50.8 days. The average Derkay score at the time of recurrence was significantly lower than the average pre-treatment Derkay score (P < 0.001). The average annual recurrence rate before treatment was 2.2 ± 1.3, compared to 1.5 ± 1.5 after treatment, with no significant difference (P = 0.16). However, subgroup analysis revealed a significant decrease in the annual recurrence rate of adult-onset RRP after treatment (P = 0.01). The most common adverse reaction was mild pharyngeal pain (11/23). There were 3 cases of new-onset vocal cord adhesions. No patients experienced serious respiratory-related adverse reactions, anesthesia-related adverse reactions, or systemic phototoxic reactions. CONCLUSION: In conclusion, this study indicates that surgery combined with Photodynamic therapy (PDT) might be a safe and effective option for treating RRP, especially in patients with Adult-Onset Recurrent Respiratory Papillomatosis (AORRP).
ABSTRACT
BACKGROUND: Recent reports suggested combining ramucirumab with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) to overcome EGFR resistance in non-small cell lung cancer (NSCLC). Nonetheless, evidence supporting the activity of afatinib and ramucirumab is lacking. This study investigated the survival benefits and safety profile of afatinib plus ramucirumab in patients with treatment-naïve, EGFR-mutated, metastatic NSCLC. MATERIALS AND METHODS: The medical records of patients with EGFR-mutated NSCLC were retrospectively retrieved. Patients who received first-line sequential afatinib followed by ramucirumab and the first-line combination of afatinib plus ramucirumab were included. The Kaplan-Meier was used to estimate the progression-free survival (PFS) of all included patients, patients on sequential afatinib followed by ramucirumab (PFS1), and patients on the up-front combination of afatinib and ramucirumab (PFS2). RESULTS: Thirty-three patients were included (25 women; median age: 63 [45-82] years). The median follow-up of the included patients was 17 months (range 6-89 months). the median PFS for the whole cohort was 71 months (95% CI 67.2-74.8) with eight events during the follow-up. The median PFS1 and PFS2 were 71 months (95 CI not defined) and 26 months (95% CI 18.6-33.4), respectively. In terms of OS, the median OS for all patients and patients on sequential treatment was not defined, while the median OS for patients on upfront combination was 30 months (95% CI 20.9-39.1). There was no significant association between EGFR mutation type and PFS1 or PFS2. CONCLUSIONS: Afatinib plus ramucirumab could improve the PFS of patients with EGFR-positive NSCLC at a predictable safety profile. Our data also suggest a survival benefit of adding ramucirumab to afatinib in patients with uncommon mutations, which should be investigated further.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Female , Middle Aged , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Afatinib/therapeutic use , Retrospective Studies , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , ErbB Receptors/genetics , RamucirumabABSTRACT
An outbreak of COVID-19 in Shanghai, China, in March 2022 was caused by the Omicron variant. The epidemic lasted for more than 3 months, and the cumulative number of infected people reached 626,000. We investigated the impact of clinical factors on disease outcomes in patients with COVID-19. Using a case-control study design, we examined cases from fever clinics with confirmed Omicron variant infection, analyzed their population and laboratory diagnostic characteristics, and provided theoretical support for subsequent epidemic prevention and control. Logistic regression was used to identify factors associated with infection with the Omicron variant. The results of this study show that the COVID-19 vaccine can protect against infection with the Omicron variant, and more than 50% of infected people had not been vaccinated. Compared with the epidemic in Wuhan 2 years ago, most of the patients in the hospital in the Shanghai epidemic had underlying diseases (P = 0.006). A comparison of patients infected with the Omicron variant in Shanghai and patients with other respiratory tract infections showed no significant difference in the levels of neutrophils, lymphocytes, eosinophils, white blood cells, hemoglobin, or platelets (P > 0.05). People over 60 years old and those with underlying diseases were at risk for pneumonia (OR = 14.62 (5.49-38.92), P < 0.001; OR = 5.29 (2.58-10.85), P < 0.001, respectively), but vaccination was a protective factor (OR = 0.24 (0.12-0.49), P < 0.001). In summary, vaccination has a potential effect on infection with Omicron variant strains and provides protection against pneumonia. The severity of illness caused by the Omicron variant in 2022 was significantly lower than that of the original SARS-CoV-2 variant from two years previously.
Subject(s)
COVID-19 , Humans , Middle Aged , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2 , COVID-19 Vaccines , Case-Control Studies , China/epidemiologyABSTRACT
Obstructive sleep apnea is the most common type of sleep breathing disorder. Therefore, the purpose of our research is to construct and verify an objective and easy-to-use nomogram that can accurately predict a patient's risk of obstructive sleep apnea. In this study, we retrospectively collected the data of patients undergoing polysomnography at the Sleep Medicine Center of the First Affiliated Hospital of Guangzhou Medical University. Participants were randomly assigned to a training cohort (50%) and a validation cohort (50%). Logistic regression and Lasso regression models were used to reduce data dimensions, select factors and construct the nomogram. C-index, calibration curve, decision curve analysis and clinical impact curve analysis were used to evaluate the identification, calibration and clinical effectiveness of the nomogram. Nomograph validation was performed in the validation cohort. The study included 1035 people in the training cohort and 1078 people in the validation cohort. Logistic and Lasso regression analysis identified age, gender, diastolic blood pressure, body mass index, neck circumference and Epworth Sleepiness Scale as the predictive factors included in the nomogram. The training cohort (C-index = 0.741) and validation cohort (C-index = 0.745) had better identification and calibration effects. The areas under the curve of the nomogram and STOP-Bang were 0.741 (0.713-0.767) and 0.728 (0.700-0.755), respectively. Decision curve analysis and clinical impact curve analysis showed that the nomogram is clinically useful. We have established a concise and practical nomogram that will help doctors better determine the priority of patients referred to the sleep centre.
Subject(s)
Nomograms , Sleep Apnea, Obstructive , Body Mass Index , Humans , Polysomnography/methods , Retrospective Studies , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/epidemiologyABSTRACT
Rapid and highly sensitive determination of clozapine (CLZ), a psychotropic drug for the treatment of refractory schizophrenia, in patients is of great significance to reduce the risk of disease recurrence. However, direct electroanalysis of CLZ in human whole blood remains a great challenge owing to the remarkable fouling that occurs in a complex matrix. In this work, a miniaturized, integrated, disposable electrochemical sensing platform based on the integration of nanochannel arrays on the surface of screen-printed carbon electrodes (SPCE) is demonstrated. The device achieves high determination sensitivity while also offering the electrode anti-fouling and anti-interference capabilities. To enhance the electrochemical performance of SPCE, simple electrochemical polarization including anodic oxidation and cathodic reduction is applied to pretreat SPCE. The electrochemically polarized SPCE (p-SPCE) exhibits an enhanced electrochemical peak signal toward CLZ compared with bare SPCE. An electrochemically assisted self-assembly method (EASA) is utilized to conveniently electrodeposit a vertically ordered mesoporous silica nanomembrane film (VMSF) on the p-SPCE, which could further enrich CLZ through electrostatic interactions. Owing to the dual signal amplification based on the p-SPCE and VMSF nanochannels, the developed VMSF/SPCE sensor enables determination of CLZ in the range from 50 nM to 20 µM with a low limit of detection (LOD) of 28 nM (S/N = 3). Combined with the excellent anti-fouling and anti-interference abilities of VMSF, direct and sensitive determination of CLZ in human blood is also achieved.
Subject(s)
Clozapine , Carbon , Electrochemical Techniques/methods , Electrodes , Humans , Limit of Detection , Silicon DioxideABSTRACT
BACKGROUND: HSPB5 is an ATP-independent molecular chaperone that is induced by heat shock or other proteotoxic stresses. HSPB5 is cytoprotective against stress both intracellularly and extracellularly. It acts as a potential therapeutic candidate in ischemia-reperfusion and neurodegenerative diseases. RESULTS: In this paper, we constructed a recombinant plasmid that expresses and extracellularly secrets a HSPB5-Fc fusion protein (sHSPB5-Fc) at 0.42 µg/ml in CHO-K1 cells. This sHSPB5-Fc protein contains a Fc-tag at the C-terminal extension of HSPB5, facilitating protein-affinity purification. Our study shows that sHSPB5-Fc inhibits heat-induced aggregation of citrate synthase in a time and dose dependent manner in vitro. Administration of sHSPB5-Fc protects lens epithelial cells against cisplatin- or UVB-induced cell apoptosis. It also decreases GFP-Httex1-Q74 insolubility, and reduces the size and cytotoxicity of GFP-Httex1-Q74 aggregates in PC-12 cells. CONCLUSION: This recombinant sHSPB5-Fc exhibits chaperone activity to protect cells against proteotoxicity.
Subject(s)
Protective Agents/pharmacology , alpha-Crystallin B Chain/genetics , alpha-Crystallin B Chain/pharmacology , Animals , Apoptosis/drug effects , CHO Cells , Cricetinae , Cricetulus , Cytoprotection , Epithelial Cells/chemistry , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Humans , Protective Agents/chemistry , Protective Agents/metabolism , Protein Aggregates , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Recombinant Fusion Proteins/pharmacology , alpha-Crystallin B Chain/chemistry , alpha-Crystallin B Chain/metabolismABSTRACT
NEW FINDINGS: What is the central question of this study? The therapeutic effect of ivabradine on patients with chronic heart failure and chronic stable angina pectoris is mediated through a reduction in heart rate: what are the haemodynamic characteristics and the mechanism of the inotropic effect? What is the main finding and its importance? Ivabradine has a positive inotropic effect and lowers the heart rate both in vivo and in vitro. These effects are likely mediated by ivabradine's significant increase of the fast component rate constant mediated by sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and decrease of the slow component rate constant that is mediated by the Na+ /Ca2+ exchanger and sarcolemmal Ca2+ -ATPase during the Ca2+ transient decay phase. ABSTRACT: Ivabradine's therapeutic effect is mediated by a reduction of the heart rate; however, its haemodynamic characteristics and the mechanism of its inotropic effect are poorly understood. We aimed to investigate the positive inotropic effect of ivabradine and its underlying mechanism. The results demonstrated that ivabradine increased the positive inotropy of the rat heart in vivo by increasing the stroke work, cardiac output, stroke volume, end-diastolic volume, end-systolic pressure, ejection fraction, ±dP/dtmax , left ventricular end-systolic elastance and systolic blood pressure without altering the diastolic blood pressure and arterial elastance. This inotropic effect was observed in both non-paced and paced rat isolated heart. Ivabradine increased the Ca2+ transient amplitude and the reuptake rates of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), lowered the diastolic Ca2+ level and suppressed the combined extrusion rate of the Na+ /Ca2+ exchanger and the sarcolemmal Ca2+ -ATPase. In addition, ivabradine widened the action potential duration, hyperpolarized the resting membrane potential, increased sarcoplasmic reticulum Ca2+ content and reduced Ca2+ leak. Overall, ivabradine had a positive inotropic effect brought about by enhanced SERCA2a activity, which might be mediated by increased phospholamban phosphorylation. The positive inotropic effect along with the lowered heart rate underlies ivabradine's therapeutic effect in heart failure.
Subject(s)
Calcium/metabolism , Ivabradine/pharmacology , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Animals , Calcium-Binding Proteins/metabolism , Heart Failure/metabolism , Heart Rate/drug effects , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Rats , Rats, Sprague-Dawley , Sarcoplasmic Reticulum/drug effects , Sarcoplasmic Reticulum/metabolism , Sodium-Calcium Exchanger/metabolism , Stroke Volume/drug effectsABSTRACT
It has been demonstrated that liguzinediol (2,5-dihydroxymethyl-3,6-dimethylpyrazine, LZDO), a derivative of ligustrazine from Ligusticum wallichii Franch, exerts positive inotropy in isolated rat heart mediated by the sarcoplasmic reticulum Ca-ATPase (SERCA2a). Here, we further explore the underlying mechanism of the positive inotropic effect of LZDO in rat hearts. In vivo and ex vivo rat heart experiments, biochemistry, and Western blot techniques were used to analyze the rat heart contractility, and SERCA2a activity, phospholamban (PLB) phosphorylation, and protein phosphatase (PP1 and PP2A) activities in rat left ventricular myocytes, respectively. LZDO (20 mg/kg) significantly increased the inotropy of rat heart in vivo. In isolated rat heart experiments, LZDO (100 µM) restored the decreased inotropy induced by caffeine (0.5 mM); however, calyculin A (4 nM), an inhibitor of PP1 and PP2A, eliminated the inotropic effect of LZDO (100 µM). Moreover, LZDO (1, 10, and 100 µM) significantly enhanced SERCA2a activity and increased the levels of phosphorylated PLB on both serine-16 (Ser-16) and threonine-17 (Thr-17). In addition, LZDO (100 µM) significantly inhibited the activities of PP1 and PP2A. The positive inotropic effects of LZDO on in vivo and ex vivo rat hearts seem to be mediated through inhibition of PP1/PP2A, which may suppress dephosphorylated PLB and enhance SERCA2a activity. LZDO may prove effective in treating heart failure in clinical settings based on its unique biological mechanism.
Subject(s)
Cardiotonic Agents/pharmacology , Heart/drug effects , Protein Phosphatase 1/antagonists & inhibitors , Protein Phosphatase 2/antagonists & inhibitors , Pyrazines/pharmacology , Animals , Calcium Channel Agonists/pharmacology , Enzyme Inhibitors/pharmacology , Heart/physiology , Male , Marine Toxins , Organ Culture Techniques , Oxazoles/pharmacology , Protein Phosphatase 1/metabolism , Protein Phosphatase 2/metabolism , Rats , Rats, Sprague-Dawley , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolismABSTRACT
[This corrects the article DOI: 10.3389/fmicb.2023.1291030.].
ABSTRACT
Objectives: Recurrent respiratory papillomatosis (RRP) is the most common benign laryngeal tumor in children. It can cause serious psychological and mental burden on patients since RRP requires repeated surgical treatment. This study aims to delineate the global trends and identify hotspots related to RRP over the past two decades. Methods: We systematically gathered research findings on RRP from 2004 to 2023, utilizing the Web of Science as our data source. Subsequently, we performed a comprehensive bibliometric analysis of the literature using Vosviewer, CiteSpace, and Bibliometrics online analysis platform. Results: A total of 839 publications were finally identified on RRP from 2004 to 2023. The United States has the largest number of publications (392), accounting for 46.7%. The Capital Medical University is the most productive organization (24), followed by the Centers for Disease Control and Prevention (18). The most productive journal was the Laryngoscope, with 86 publicatios. Comparatively, Vaccine is the most cited journal (2297). Craig S. Derkay ranked highest among all authors in publication (16). Burst detection shows onset, adjuvant therapy, management, juvenile-onset RRP, systemic bevacizumab, avastin, human papillomavirus vaccine are recent keywords of great interest to researchers. Conclusion: Research on RRP has progressed significantly over the past two decades, especially in terms of therapeutic strategies. We strongly believe that this article will provide new research directions for other researchers and may contribute to future breakthroughs in the field.
ABSTRACT
The prevalence of non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers, with the Wnt/ß-catenin signaling pathway exhibiting robust activation in this particular subtype. The expression of FAM83A (family with sequence similarity 83, member A) has been found to be significantly upregulated in lung cancer, leading to the stabilization of ß-catenin and activation of the Wnt signaling pathway. In this study, we conducted a screening of down-regulated miRNAs in lung cancer with FAM83A as the target. Ultimately, we identified miR-1 as a negative regulator of FAM83A and confirmed that FAM83A is a direct target gene of miR-1 through dual luciferase reporter assays. The overexpression of miR-1 significantly attenuated the expression level of FAM83A and suppressed the Wnt signaling pathway, leading to a reduction in the expression levels of downstream target genes AXIN2, CyclinD1, and C-MYC. Additionally, it decreased the nuclear translocation of ß-catenin. In addition, overexpression of miR-1 accelerated the degradation of ß-catenin by inhibiting FAM83A, promoted the assembly of ß-catenin degradation complex, and inhibited the proliferation, migration and invasion of NSCLC cells. In summary, miR-1 may be a potential candidate miRNA for the treatment of NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Gene Expression Regulation, Neoplastic , Lung Neoplasms , MicroRNAs , Neoplasm Proteins , Wnt Signaling Pathway , beta Catenin , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/metabolism , Wnt Signaling Pathway/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , beta Catenin/metabolism , beta Catenin/genetics , Cell Line, Tumor , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Cell Proliferation/genetics , Cell Movement/genetics , A549 CellsABSTRACT
The present study describes a novel method for green synthesis of silver nanoparticles using Cnidium monnieri (CM-AgNPs). Cnidium monnieri fruit is an excellent anti tinea drug that can be used externally to treat superficial fungal infections in the human body. The aqueous ethanolic extract of Cnidium monnieri fruit was prepared and employed in the synthesis of stable silver nanoparticles via biological reduction method. The synthesis conditions of CM-AgNPs was systematically optimized using Box-Behnken design. CM-AgNPs were well characterized by UV-spectroscopy and X-ray powder diffraction (XRD), and it was confirmed that the synthesized particles were AgNPs. The possible functional groups required for the reduction and stabilization of CM-AgNPs in the extract were identified through FTIR spectrum. The size of CM-AgNPs structure was confirmed to be approximately 44.6 nm in polydisperse spherical shape through scanning electron microscopy (SEM), transmission electron microscopy (TEM), and laser dynamic light scattering (DLS). Further, the minimum inhibitory concentration 90% (MIC90) ratios values of Cm-AgNPs against Trichophyton rubrum (7 d), T. mentagrophytes (7 d) and Candida albicans (24 h) were 3.125, 3.125, and 0.78125 µg/mL, respectively, determined by the broth micro dilution method. Finally, the result was concluded that the synthesized AgNPs could be further evaluated in large scale as a potential human topical antifungal agent.
ABSTRACT
Hyperuricemia nephropathy, also known as gouty nephropathy, refers to renal damage induced by hyperuricemia caused by excessive production of serum uric acid or low excretion of uric acid. the persistence of symptoms will lead to changes in renal tubular phenotype and accelerate the progress of renal fibrosis. The existence and progressive aggravation of symptoms will bring a heavy burden to patients, their families and society, affect their quality of life and reduce their well-being. With the increase of reports on hyperuricemia nephropathy, the importance of related signal pathways in the pathogenesis of hyperuricemia nephropathy is becoming more and more obvious, but most studies are limited to the upper and lower mediating relationship between 1 or 2 signal pathways. The research on the comprehensiveness of signal pathways and the breadth of crosstalk between signal pathways is limited. By synthesizing the research results of signal pathways related to hyperuricemia nephropathy in recent years, this paper will explore the specific mechanism of hyperuricemia nephropathy, and provide new ideas and methods for the treatment of hyperuricemia nephropathy based on a variety of signal pathway crosstalk and personal prospects.
Subject(s)
Hyperuricemia , Kidney Calculi , Humans , Uric Acid , Hyperuricemia/complications , Quality of Life , Signal Transduction , Kidney Calculi/complicationsABSTRACT
The Wnt/ß-catenin signaling is usually abnormally activated in hepatocellular carcinoma (HCC), and pituitary tumor-transforming gene 1 (PTTG1) has been found to be highly expressed in HCC. However, the specific mechanism of PTTG1 pathogenesis remains poorly understood. Here, we found that PTTG1 is a bona fide ß-catenin binding protein. PTTG1 positively regulates Wnt/ß-catenin signaling by inhibiting the destruction complex assembly, promoting ß-catenin stabilization and subsequent nuclear localization. Moreover, the subcellular distribution of PTTG1 was regulated by its phosphorylation status. Among them, PP2A induced PTTG1 dephosphorylation at Ser165/171 residues and prevented PTTG1 translocation into the nucleus, but these effects were effectively reversed by PP2A inhibitor okadaic acid (OA). Interestingly, we found that PTTG1 decreased Ser9 phosphorylation-inactivation of GSK3ß by competitively binding to PP2A with GSK3ß, indirectly leading to cytoplasmic ß-catenin stabilization. Finally, PTTG1 was highly expressed in HCC and associated with poor patient prognosis. PTTG1 could promote the proliferative and metastasis of HCC cells. Overall, our results indicated that PTTG1 plays a crucial role in stabilizing ß-catenin and facilitating its nuclear accumulation, leading to aberrant activation of Wnt/ß-catenin signaling and providing a feasible therapeutic target for human HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , beta Catenin/genetics , beta Catenin/metabolism , Cell Line , Wnt Signaling Pathway/genetics , Cell Line, TumorABSTRACT
Abnormal activation of Wnt/ß-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer. Family with sequence similarity 83 member A (FAM83A) was shown recently to have oncogenic effects in a variety of cancer types, but the biological roles and molecular mechanisms of FAM83A in pancreatic cancer need further investigation. Here, we newly discovered that FAM83A binds directly to ß-catenin and inhibits the assembly of the cytoplasmic destruction complex thus inhibiting the subsequent phosphorylation and degradation. FAM83A is mainly phosphorylated by the SRC non-receptor kinase family member BLK (B-lymphoid tyrosine kinase) at tyrosine 138 residue within the DUF1669 domain that mediates the FAM83A-ß-catenin interaction. Moreover, FAM83A tyrosine 138 phosphorylation enhances oncogenic Wnt/ß-catenin-mediated transcription through promoting ß-catenin-TCF4 interaction and showed an elevated nucleus translocation, which inhibits the recruitment of histone deacetylases by TCF4. We also showed that FAM83A is a direct downstream target of Wnt/ß-catenin signaling and correlates with the levels of Wnt target genes in human clinical pancreatic cancer tissues. Notably, the inhibitory peptides that target the FAM83A-ß-catenin interaction significantly suppressed pancreatic cancer growth and metastasis in vitro and in vivo. Our results revealed that blocking the FAM83A cascade signaling defines a therapeutic target in human pancreatic cancer.
Subject(s)
Neoplasm Proteins , Pancreatic Neoplasms , beta Catenin , src-Family Kinases , Humans , beta Catenin/genetics , beta Catenin/metabolism , Carcinogenesis/genetics , Cell Transformation, Neoplastic/genetics , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Pancreatic Neoplasms/genetics , Phosphorylation/genetics , Tyrosine/metabolism , Wnt Signaling Pathway/genetics , src-Family Kinases/genetics , src-Family Kinases/metabolism , Pancreatic NeoplasmsABSTRACT
OBJECTIVES: Obstructive Sleep Apnea (OSA) is a kind of respiratory disease that occurs apnea repeatedly during sleep. The purpose of this study was to investigate the influence of sex on anthropometric methods and four scales for screening OSA. METHODS: The basic data and PSG data of 2108 patients who underwent PSG examination at the Sleep Medicine Center of the First Affiliated Hospital of Guangzhou Medical University from July 2017 to December 2020 were continuously included. Then the sensitivity, specificity, positive predictive value, negative predictive value, AUC and DOR of the anthropometric method and the four scales were calculated. RESULTS: 2108 OSA patients were enrolled from the Sleep Medicine Center, including 1644 males (78.0%). The average neck circumference and waist circumference of male and female patients were respectively (39.4±3.4) cm and (96.7±13.8) cm,(34.6±3.5) cm and (90.1±11.6) cm. In female patients. the AUC of NoSAS was the largest. When AHI was 5, 15, and 30 evens/h as the cut-off point, in male patients, the sensitivity of NHR was the highest,in female patients, the sensitivity of WHR was the highest. CONCLUSIONS: NHR and WHR are good tools for screening OSA in male and female patients respectively. They are worthy of promotion.
Subject(s)
Sleep Apnea, Obstructive , Anthropometry , Female , Humans , Male , Mass Screening/methods , Sleep , Sleep Apnea, Obstructive/diagnosis , Surveys and QuestionnairesABSTRACT
Background: To use network pharmacology and gut microbiota sequencing to investigate the probable mechanism of Bining decoction (BN) in the treatment of gouty nephropathy (GN). Methods: Firstly, the mechanism of therapeutic effects of BN on GN were collected by integrating network pharmacology. Secondly, the treatment effects of BN against GN in 30 Institute of Cancer Research (ICR) mice were evaluated by performing biochemical tests [uric acid, blood urea nitrogen, and creatinine (UA, BUN, and Cr)] and evaluating the renal weight index. Finally, 16S rRNA sequencing was utilized for elucidating the therapeutical effect of BN in GN. Results: The results of gut microbiota sequencing analysis showed the abundance of Faecalibaculum, Romboutsia, Bifidobacterium, Bacteroides, Odoribacter, Lachnospiraceae NK4A136 group, unclassified_f__Lachnospiraceae, Roseburia, norank_f__Lachnospiraceae, Lactobacillus, Dubosiella, norank_f__Muribaculaceae, and Turicibacter in the BN group had a significant changed between-group comparisons. Using a network pharmacology-related database, 413 active components of BN were identified, as well as 1,085 GN-associated targets. The 118 targets of disease targets and component targets were mapped, of which the top 10 genes were selected. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that 157 pathways were enriched, which was partially consistent with the metabolic pathways of gut microbiota sequencing analysis. Conclusions: Combining 16S rRNA gene sequencing and network pharmacology analysis, similar signaling pathways were followed: "Pathways in cancer" and "Adipocytokine signaling pathway". The results reveal that BN increases the abundance of Turicibacter, regulates the expression of JAK2 in the JAK/STAT pathway, increases the beneficial bacteria Turicibacter associated with intestinal butyric acid, which could enhance the intestinal barrier, and exert anti-inflammatory effects.
ABSTRACT
Chronic hepatitis E virus (HEV) infection is frequently reported in immunocompromised patients, but has also been increasingly reported in non-immunocompromised individuals. We characterized the course of chronic HEV infection in immunocompetent rabbits. In two independent experiments, 40 specific-pathogen-free rabbits were infected with a rabbit HEV genotype 3 strain in serial diluted titers (108 to 104 copies/mL). Serum and fecal samples were collected weekly and were tested for HEV RNA, antigen, anti-HEV and liver enzymes. Rabbits that spontaneously cleared the infection before 10 weeks post-inoculation (wpi) were kept to the end of the study as recovery control. Liver tissues were collected from HEV-infected rabbits at 5, 10 and 26 wpi for histopathological analysis. Nineteen rabbits (47.5%) developed chronic HEV infection with persistent viraemia and fecal HEV shedding for >6 months. Seroconversion to anti-HEV was observed in 84.2% (16/19) of the chronically infected rabbits. Serum levels of aminotransferase were persistently elevated in most of the rabbits. Characterizations of chronic HEV infection in immunocompetent settings could be recapitulated in rabbits, which can serve as a valuable tool for future studies on pathogenesis.
Subject(s)
Hepatitis E virus , Hepatitis E , Animals , Hepatitis E virus/genetics , Humans , RNA, Viral/genetics , Rabbits , Specific Pathogen-Free Organisms , Virus SheddingABSTRACT
Purpose: The purpose of this study was to explore the therapeutic role of heat shock protein 90 (Hsp90) in wound healing of injury cornea epithelium. Methods: The right eye of C57BL/6N male mice were performed the debridement wounds in the center of the cornea using an algerbrush II blade. The injured area was determined by staining the cornea with fluorescein sodium and measured with image-J. Immunoblotting, ELISA and immunochemistry were used for determining protein expression. The quantitation PCR was performed to measure mRNA expression. Results: Hsp90α is upregulated at both the mRNA and protein levels, and is secreted extracellularly into the corneal stroma and tear film during the healing process after corneal injury in mice. This upregulation is associated with activation of HSF1. Administration of recombinant exogenous Hsp90α (eHsp90α) speeds up wound healing of injured corneal epithelium. The eHsp90α binds to low-density lipoprotein (LDL)-related protein-1 (LRP-1) on the corneal epithelial cells and increases phosphorylation of AKT at S473, which is associated with proliferation and migration corneal epithelial cells in vitro or vivo. Inhibition of AKT by its inhibitor LY294002 abolishes eHsp90α-induced migration and proliferation of corneal epithelial cells. Conclusion: Hsp90α is upregulated and secreted after corneal injury and acts to promote the healing process. Recombinant Hsp90α may be a promising therapeutic drug candidate for corneal injury.