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BACKGROUND AND OBJECTIVE: Clinical studies found high levels of hepatocyte growth factor (HGF) expression in patients with periodontitis. Studies suggest that HGF plays an important role in periodontitis, is involved in inflammation, and modulates alveolar bone integrity in periodontitis. This study aims to investigate the effects and mechanisms of HGF in the progression of experimental periodontitis. METHODS: We used silk thread ligation to induce periodontitis in HGF-overexpressing transgenic (HGF-Tg) and wild-type C57BL/6J mice. The effects of HGF overexpression on alveolar bone destruction were assessed by microcomputed tomography imaging at baseline and on days 7, 14, 21, and 28. We analyzed the cytokines (IL-6 and TNF-α) and lymphocytes in periodontitis tissues by enzyme-linked immunosorbent assay and flow cytometry. The effects of HGF on alveolar bone destruction were further tested by quantifying the systemic bone metabolism markers CTXI and PINP and by RNA sequencing for the signaling pathways involved in bone destruction. Western blotting and immunohistochemistry were performed to further elucidate the involved signaling pathways. RESULTS: We found that experimental periodontitis increased HGF production in periodontitis tissues; however, the effects of HGF overexpression were inconsistent with disease progression. In the early stage of periodontitis, periodontal inflammation and alveolar bone destruction were significantly lower in HGF-Tg mice than in wild-type mice. In the late stage, HGF-Tg mice showed higher inflammatory responses and progressively aggravated bone destruction with continued stimulation of inflammation. We identified the IL-17/RANKL/TRAF6 pathway as a signaling pathway involved in the HGF effects on the progression of periodontitis. CONCLUSION: HGF plays divergent effects in the progression of experimental periodontitis and accelerates osteoclastic activity and bone destruction in the late stage of inflammation.
Subject(s)
Alveolar Bone Loss , Hepatocyte Growth Factor , Mice, Inbred C57BL , Mice, Transgenic , Periodontitis , X-Ray Microtomography , Animals , Hepatocyte Growth Factor/metabolism , Periodontitis/metabolism , Periodontitis/pathology , Mice , Alveolar Bone Loss/metabolism , Alveolar Bone Loss/diagnostic imaging , Alveolar Bone Loss/pathology , Disease Models, Animal , Disease Progression , Tumor Necrosis Factor-alpha/metabolism , Interleukin-6/metabolism , Signal Transduction , Male , Enzyme-Linked Immunosorbent AssayABSTRACT
External interfaces, such as the air-water and solid-liquid interfaces, are ubiquitous in nature. Hydrophobic interactions are considered the fundamental driving force in many physical and chemical processes occurring in aqueous solutions. It is important to understand the effects of external interfaces on hydrophobic interactions. According to the structural studies on liquid water and the air-water interface, the external interface primarily affects the structure of the topmost water layer (interfacial water). Therefore, an external interface may affect hydrophobic interactions. The effects of interfaces on hydrophobicity are related not only to surface molecular polarity but also to the geometric characteristics of the external interface, such as shape and surface roughness. This study is devoted to understanding the effects of a smooth interface on hydrophobicity. Due to hydrophobic interactions, the solutes tend to accumulate at external interfaces to maximize the hydrogen bonding of water. Additionally, these can be demonstrated by the calculated potential mean forces (PMFs) using molecular dynamic (MD) simulations.
ABSTRACT
According to our recent studies on hydrophobicity, this work is aimed at understanding the dependence of hydrophobic interactions on the shape of a solute's surface. It has been observed that dissolved solutes primarily affect the structure of interfacial water, which refers to the top layer of water at the interface between the solute and water. As solutes aggregate in a solution, hydrophobic interactions become closely related to the transition of water molecules from the interfacial region to the bulk water. It is inferred that hydrophobic interactions may depend on the shape of the solute surface. To enhance the strength of hydrophobic interactions, the solutes tend to aggregate, thereby minimizing their surface area-to-volume ratio. This also suggests that hydrophobic interactions may exhibit directional characteristics. Moreover, this phenomenon can be supported by calculated potential mean forces (PMFs) using molecular dynamics (MD) simulations, where different surfaces, such as convex, flat, or concave, are associated with a sphere. Furthermore, this concept can be extended to comprehend the molecular packing parameter, commonly utilized in studying the self-assembly behavior of amphiphilic molecules in aqueous solutions.
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Ion channels exhibit strong selectivity for specific ions over others under electrochemical potentials, such as KcsA for K+ over Na+. Based on the thermodynamic analysis, this study is focused on exploring the mechanism of ion selectivity in nanopores. It is well known that ions must lose part of their hydration layer to enter the channel. Therefore, the ion selectivity of a channel is due to the rearrangement of water molecules when entering the nanopore, which may be related to the hydrophobic interactions between ions and channels. In our recent works on hydrophobic interactions, with reference to the critical radius of solute (Rc), it was divided into initial and hydrophobic solvation processes. Additionally, the different dissolved behaviors of solutes in water are expected in various processes, such as dispersed and accumulated distributions in water. Correspondingly, as the ion approaches the nanopore, there seems to exist the "repulsive" or "attractive" forces between them. In the initial process (
ABSTRACT
In brief: Inflammation and abnormal immune response are the key processes in the development of endometriosis (EMs), and m6A modification can regulate the inflammatory response. This study reveals that METTL3-mediated N6-methyladenosine (m6A) modification plays an important role in EMs. Abstract: m6A modification is largely involved in the development of different diseases. This study intended to investigate the implication of m6A methylation transferase methyltransferase like 3 (METTL3) in EMs. EMs- and m6A-related mRNAs and long non-coding RNAs were identified through bioinformatics analysis. Next, EM mouse models established by endometrial autotransplantation and mouse endometrial stromal cell (mESC) were prepared and treated with oe-METTL3 or sh-MIR17HG for pinpointing the in vitro and in vivo effects of METTL3 on EMs in relation to MIR17HG through the determination of mESC biological processes as well as estradiol (E2) and related lipoprotein levels. We demonstrated that METTL3 and MIR17HG were downregulated in the EMs mouse model. Overexpression of METTL3 suppressed the proliferation, migration, and invasion of mESCs. In addition, METTL3 enhanced the expression of MIR17HG through m6A modification. Moreover, METTL3 could inhibit the E2 level and alter related lipoprotein levels in EMs mice through the upregulation of MIR17HG. The present study highlighted that the m6A methylation transferase METTL3 prevents EMs progression by upregulating MIR17HG expression.
Subject(s)
Endometriosis , Methyltransferases , Humans , Female , Mice , Animals , Methyltransferases/genetics , Methyltransferases/metabolism , Alternative Splicing , Endometriosis/genetics , Methylation , Up-RegulationABSTRACT
While monitoring expression of recombinant proteins is essential for obtaining high-quality biopharmaceutical and biotechnological products, existing assays for recombinant protein detection are laborious, time-consuming and expensive. This paper presents a microfluidic approach to rapid and cost-effective detection of tag-fused recombinant proteins via a dual-aptamer sandwich assay. Our approach addresses limitations in current methods for both dual-aptamer assays and generation of aptamers for such assays by first using microfluidic technology to isolate the aptamers rapidly and then employing these aptamers to implement a microfluidic dual-aptamer assay for tag-fused recombinant protein detection. The use of microfluidic technology enables the fast generation of aptamers and rapid detection of recombinant proteins with minimized consumption of reagents. In addition, compared with antibodies, aptamers as low-cost affinity reagents with an ability of reversible denaturation further decreases the cost of recombinant protein detection. For demonstration, an aptamer pair is isolated rapidly toward His-tagged IgE within two days, and then used in the microfluidic dual-aptamer assay for detecting His-tagged IgE in cell culture media within 10 min and with a limit of detection of 7.1 nM.
ABSTRACT
OBJECTIVE: This overview of systematic reviews aims to critically appraise and consolidate evidence from current systematic reviews (SRs)/meta-analyses on the effects of exercise interventions on cancer-related fatigue (CRF) in breast cancer patients. METHODS: SRs/meta-analyses that explored the effects of exercise interventions on CRF in breast cancer patients compared with the routine methods of treatment and care were retrieved from nine databases. The methodological quality of the included SRs was appraised using A MeaSurement Tool to Assess systematic Reviews II (AMSTAR II). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to calculate the grading of outcomes in the included SRs. The exercise type, frequency, duration, and inclusion/absence of supervision were further evaluated with subgroup analyses. The Stata 16.0 software was utilized for data analysis. RESULTS: Twenty-nine reviews were included. The overall methodological quality and level of evidence of the included reviews were unsatisfactory, with only three reviews rated as high methodological quality and no review identified as high-quality evidence. Moderate certainty evidence indicated that exercise could improve fatigue in breast cancer patients (SMD = - 0.40 [95%CI - 0.58, - 0.22]; P = 0.0001). Subgroup analysis based on the types of exercise showed that yoga (SMD = - 0.30 [95%CI - 0.56, - 0.05]; I2 = 28.7%) and aerobic exercise (SMD = - 0.29 [95%CI - 0.56, - 0.02]; I2 = 16%) had a significantly better effect on CRF in breast cancer patients; exercising for over 6 months (SMD = - 0.88 [95%CI - 1.59, - 0.17]; I2 = 42.7%; P = 0.0001), three times per week (SMD = - 0.77 [95%CI - 1.04, - 0.05]; I2 = 0%; P = 0.0001), and for 30 to 60 min per session (SMD = - 0.81 [95%CI - 1.15, - 0.47]; I2 = 42.3%; P = 0.0001) can contribute to a moderate improvement of CRF. Supervised exercise (SMD = - 0.48 [95%CI - 0.77, - 0.18]; I2 = 87%; P = 0.001) was shown to relieve CRF. CONCLUSION: Exercise played a favorable role in alleviating CRF in breast cancer. Yoga was recommended as a promising exercise modality for CRF management in the majority of the included studies. Exercising for at least three times per week with 30 to 60 min per session could be recommended as a suitable dosage for achieving improvement in CRF. Supervised exercise was found to be more effective in alleviating CRF than unsupervised exercise. More rigorously designed clinical studies are needed to specify the exact exercise type, duration, frequency, and intensity to have an optimal effect on CRF in breast cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: CRD42020219866.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/complications , Breast Neoplasms/therapy , Systematic Reviews as Topic , Fatigue/etiology , Fatigue/therapy , Exercise , Exercise Therapy/methods , Quality of LifeABSTRACT
PURPOSE: Impaired cardiorespiratory fitness (CRF) is a predictor of mortality in patients with type 2 diabetes mellitus (T2DM). It is still not known how the exercise hemodynamic response correlates with CRF. The purpose was to assess the correlation between hemodynamic changes and CRF in middle-aged patients with T2DM. METHODS: After 1:1 matching by age and sex, 139 T2DM patients and 139 non-T2DM controls who completed the exercise treadmill test were included. Maximal aerobic capacity (VO2max), exercise-induced changes in heart rate (ΔHR), systolic blood pressure (ΔSBP), diastolic blood pressure (ΔDBP), and rate-pressure product (ΔRPP) were measured. HRR1 was calculated as the maximum heart rate minus the heart rate after 1 min of rest. RESULTS: Compared to the control population, T2DM patients had decreased ΔHR (87 (77, 97) v 93 (84, 104) bpm, p < 0.05), ΔRPP (3833.64 ± 1670.34 v 4381.16 ± 1587.78 bpmâmmHg, p < 0.05), HRR1 (21 (14, 27) v 21 (17, 27) bpm, p < 0.05), and VO2max (32.76 ± 5.63 v 34.68 ± 5.70 ml/kg/min, p < 0.05). Multiple linear regression analysis showed that ΔHR and HRR1, yielded a positive correlation with VO2max in T2DM patients (ß = 0.325, P < 0.001; ß = 0.173, P = 0.01). CONCLUSION: The presence of impaired hemodynamic response and VO2max in middle-aged T2DM patients and the association of impaired ΔHR, HRR1, and VO2max may indicate a physiological pathway of impaired CRF, and our results support the need for cardiorespiratory screening and individualized treatment of middle-aged T2DM patients.
Subject(s)
Cardiorespiratory Fitness , Diabetes Mellitus, Type 2 , Blood Pressure , Cardiorespiratory Fitness/physiology , Case-Control Studies , Exercise/physiology , Exercise Test , Humans , Middle AgedABSTRACT
Several studies demonstrate that para-phenylenediamine (PPD) is often added to permanent oxidative hair dyes. Sub-chronic topical exposure to PPD in male rats damages their testicular function; however, little is known about the effects of PPD exposure on the female reproductive system, especially on oocyte quality. In this study, we found that PPD can affect the meiotic capacity of oocytes and their fertilization potential. In particular, PPD can damage the spindle/chromosome structure and prevent oocytes from developing and maturing normally. Furthermore, PPD exposure compromised the dynamics of cortical granules and their component, ovastacin. In addition to the protein level of Juno, the sperm receptors on the egg membrane, were substantially impaired in PPD-administered oocytes, thus leading to fertilization failure. Finally, we found that PPD exposure resulted in abnormal mitochondrial function, which led to oocyte degeneration, apoptosis, and increased ROS levels. Altogether, our study illustrates that mitochondrial dysfunction and redox perturbation are the major causes of the poor quality of oocytes exposed to PPD.
Subject(s)
Meiosis , Mitochondria , Oocytes , Phenylenediamines , Animals , Female , Hair Dyes/toxicity , Male , Mitochondria/drug effects , Oocytes/drug effects , Phenylenediamines/toxicity , Rats , Reactive Oxygen Species/metabolismABSTRACT
Ribosomal proteins (RPs) are important components of ribosomes and related to the occurrence and development of tumors. However, little is known about the effects of the RP network on cervical cancer (CC). In this study, we screened differentially expressed RPL34 in CC by high-throughput quantitative proteome assay. We found that RPL34 acted as a tumor suppressor and was downregulated in CC and inhibited the proliferation, migration, and invasion abilities of CC cells. Next, we verified that RPL34 regulated the CC through the MDM2-P53 pathway by using Act D medicine, MDM2 inhibitor, and a series of western blottingï¼WBï¼assays. Moreover, an antisense lncRNA, RPL34-AS1, regulated the expression of RPL34 and participated in the tumorigenesis of CC. RPL34 can reverse the effect of RPL34-AS1 in CC cells. Finally, by RNA-binding protein immunoprecipitation (RIP) assay we found that eukaryotic initiation factor 4A3 (EIF4A3), which binds to RPL34-AS1, regulated RPL34-AS1 expression in CC. Therefore, our findings indicate that RPL34-AS1-induced RPL34 inhibits CC cell proliferation, invasion, and metastasis through modulation of the MDM2-P53 signaling pathway, which provides a meaningful target for the early diagnosis and treatment of CC.
Subject(s)
Carcinoma in Situ/etiology , Neoplasm Proteins/metabolism , Proto-Oncogene Proteins c-mdm2/metabolism , Ribosomal Proteins/metabolism , Tumor Suppressor Protein p53/metabolism , Uterine Cervical Neoplasms/etiology , Adult , Animals , Carcinoma in Situ/metabolism , Carcinoma in Situ/pathology , Carcinoma in Situ/prevention & control , Cell Line, Tumor , Cell Movement , Cell Proliferation , DEAD-box RNA Helicases/metabolism , Down-Regulation , Eukaryotic Initiation Factor-4A/metabolism , Female , HeLa Cells , Humans , Immunoprecipitation/methods , Mice , Mice, Nude , Neoplasm Invasiveness , Neoplasm Proteins/analysis , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , RNA, Long Noncoding/metabolism , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/prevention & controlABSTRACT
The current provincial funding model in Ontario, Canada, does not offer dedicated funding to drive medication reconciliation (MedRec) programs during transitions into long-term care and retirement homes. This economic analysis aimed to estimate potential cost savings attributed to hospitalizations averted and decreases in polypharmacy by a MedRec program from a healthcare payer perspective. From a pool of 6,678 pharmacist recommendations, a limited sample of recommendations targeting specific medication-related adverse events showed potential savings of $622.35 per patient from hospital admissions avoided and of $1,414.52 per patient per year from medication discontinuations. Pharmacist-driven MedRec, conducted virtually, delivers substantial healthcare savings.
Subject(s)
Cost Savings , Medication Reconciliation/economics , Drug-Related Side Effects and Adverse Reactions/prevention & control , Homes for the Aged , Hospitalization/economics , Humans , Long-Term Care , Ontario , Pharmaceutical Preparations/economics , Pharmacists , Polypharmacy , Retrospective StudiesABSTRACT
Ovarian cancer (OC) is a lethal gynecologic tumor, which brings its mortality to the head. CXCL12 and its receptor chemokine receptor 4 ( CXCR4) have been found to be highly expressed in OC and contribute to the disease progression by affecting tumor cell proliferation and invasion. Here, in this study, we aim to explore whether the blockade of CXCL12-CXCR4 axis with AMD3100 (a selective CXCR4 antagonist) has effects on the progression of OC. On the basis of the gene expression omnibus database of OC gene expression chips, the OC differentially expressed genes were screened by microarray analysis. OC (nonmetastatic and metastatic) and normal ovarian tissues were collected to determine the expressions of CXCL12 and CXCR4. A series of AMD3100, shRNA against CXCR4, and pCNS-CXCR4 were introduced to treat CAOV3 cells with the highest CXCR4 was assessed. Cell viability, apoptosis, migration, and invasion were all evaluated. The microarray analysis screened out the differential expression of CXCL12-CXCR4 in OC. CXCL12 and CXCR4 expressions were increased in OC tissues, particularly in the metastatic OC tissues. Downregulation of CXCR4 by AMD3100 or shRNA was observed to have a critical role in inhibiting cell proliferation, migration, and invasion of the CAOV3 OC cell line while promoting cell apoptosis. Overexpressed CXCR4 brought significantly promoting effects on the proliferation and invasiveness of OC cells. These results reinforce that the blockade of CXCL12-CXCR4 axis with AMD3100 inhibits the growth of OC cells. The antitumor role of the inhibition of CXCL12-CXCR4 axis offers a preclinical validation of CXCL12-CXCR4 axis as a therapeutic target in OC.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Movement/drug effects , Chemokine CXCL12/metabolism , Heterocyclic Compounds/pharmacology , Ovarian Neoplasms/drug therapy , Receptors, CXCR4/metabolism , Adult , Aged , Apoptosis/drug effects , Benzylamines , Cell Line, Tumor , Cell Proliferation/drug effects , Chemokine CXCL12/genetics , Cyclams , Female , Humans , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Ovarian Neoplasms/genetics , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Receptors, CXCR4/genetics , Signal TransductionABSTRACT
This study aims to evaluate the effects of PSMA7 silencing on cervical cancer (CC) cell proliferation and vascular endothelial growth factor (VEGF) expression through the ubiquitin-proteasome pathway. CC tissues (n = 43) and normal tissues (n = 27) were first collected from patients. Human CC cell line (SiHa) and human normal cervical epithelial cells (H8) were obtained and classified into the normal, blank, negative control (NC), PSMA7-shRNA1, and PSMA7-shRNA2 groups, respectively. In situ hybridization was used to detect the expressions of wild-type and mutant p53 proteins. Immunofluorescence assay was carried out to test the activity of 20S proteasomes. Reverse transcription quantitative polymerase chain reaction and Western blot analysis were both performed to determine the expressions of PSMA7, ubiquitin, P27, P53, and VEGF in sample tissues and cells. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to analyze cell proliferation rates, and flow cytometry was used to analyze the cell cycle and the apoptotic rate. Compared with normal tissues, CC tissues showed increased expression levels of PSMA7, ubiquitin, p53, VEGF as well as increased activity of 20S proteasomes but exhibited a decrease in p27 expression. Compared with the blank and NC groups, the PSMA7-shRNA1 and PSMA7-shRNA2 groups all had decreased expression levels of PSMA7, ubiquitin, p53, and VEGF as well as decreased cell proliferation, 20S proteasomes activity, and cell number in the S phase, increased p27 expression, cell apoptosis and cell number in the G0/G1 phase. Our study demonstrated that PSMA7 silencing can suppress CC cell proliferation and VEGF expression in addition to promoting cell apoptosis through inhibiting the UPP signaling pathway.
Subject(s)
Cell Proliferation , Proteasome Endopeptidase Complex/genetics , RNA Interference , RNA, Small Interfering/genetics , Ubiquitin/metabolism , Uterine Cervical Neoplasms/metabolism , Vascular Endothelial Growth Factor A/metabolism , Adult , Apoptosis , Cell Cycle Checkpoints , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p27/genetics , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Proteasome Endopeptidase Complex/metabolism , RNA, Small Interfering/metabolism , Signal Transduction , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/pathology , Vascular Endothelial Growth Factor A/genetics , Young AdultABSTRACT
Gastrodia elata Blume (G. elata) is a prominent traditional herb and its dry tuber is officially listed in the Chinese Pharmacopoeia. To ensure the quality of dried G. elata, the establishment of a nondestructive and convenient method to monitor the drying process is necessary. In this study, a nondestructive low-field nuclear magnetic resonance (LF-NMR) and magnetic resonance imaging (MRI) method was introduced to monitor the drying process of G. elata. Three water states (bound, immobilized, and free) in G. elata samples were investigated through multiexponential fitting and inversion of the NMR data. The variation and distribution of the three water states during drying were monitored by LF-NMR, and the spatial distribution of water and internal structural changes were analyzed by MRI. Linear analysis of the moisture content, L* (lightness), b* (yellowness), and NMR parameters showed good correlations among them. Furthermore, partial least squares regression (PLSR) model analysis, which takes into account all NMR parameters, also showed good correlations among these parameters. All results showed that LF-NMR was feasible and convenient for monitoring moisture content. Therefore, LF-NMR and MRI could be used to monitor the moisture content nondestructively in the drying process of Chinese traditional herbs.
Subject(s)
Desiccation/methods , Gastrodia/chemistry , Water/analysis , Least-Squares Analysis , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Plant Extracts/chemistryABSTRACT
The study aimed to investigate the mechanism by which the sonic Hedgehog (SHH) gene silencing acts upon epithelial-mesenchymal transition (EMT), proliferation, invasion, and migration of cervical cancer (CC) cells via the Hedgehog signaling pathway. RT-qPCR and Western blotting were all employed to detect the SHH mRNA and protein expressions. HeLa and CasKi cells were cultured and subsequently divided into the blank, negative control (NC), and SHH-RNAi groups. A cell counting kit-8 (CCK-8) assay was utilized for cell proliferation. Cell migration and invasion ability were evaluated through scratching test and Transwell assay. The mRNA and protein expressions of the Hedgehog signaling pathway-related factors were detected using RT-qPCR and Western blotting, respectively. After tumor xenograft in nude mice, tumor growth was subsequently observed. SHH mRNA and protein expressions were greater in the SHH-RNAi group than in the blank and NC groups. Compared with the blank group and NC groups, the SHH-RNAi group displayed inhibited levels of proliferation, migration, invasion abilities, as well as a decreased in the Hh signaling pathway-related factors, as well as a reduction in the mRNA and protein expressions of N-cadherin and Vimentin, however, on the contrary increased expressions of E-cadherin were observed. Following tumor xenograft in nude mice, tumor growth was exhibited vast levels of inhibition, particularly in the SHH-RNAi group in comparison to the blank and the NC groups. During the study it was well established that SHH gene silencing suppresses EMT, proliferation, invasion, and migration of CC cells through the repression of the Hedgehog signaling pathway.
ABSTRACT
BACKGROUND: Homeobox C6 (HOXC6) plays a part in malignant progression of some tumors. However, the expression of HOXC6 and its clinical significance remains unclear in cervical carcinoma (CC). The purpose of this study is to verify the effects of HOXC6 gene silencing on CC through the TGF-ß/smad signaling pathway. METHODS: CC tissues and corresponding paracancerous tissues were collected from CC patients with involvement of a series of HOXC6-siRNA, HA-HOXC6 and the TGF-ß/smad pathway antagonist. HOXC6 expression was analyzed in six CC cell lines (C-33A, HeLa, CaSki, SiHa, ME-180, and HCC-94) by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The mRNA and protein expression of HOXC6, TGF-ß1, TGF-ß RII, smad4, smad7, E-cadherin, N-cadherin, Vimentin, ki-67, proliferating cell nuclear antigen (PCNA), p27, and Cyclin D1 were determined by RT-qPCR and western blot analysis. Cell proliferation, apoptosis and cell cycle were detected by MTT assay and flow cytometry, respectively. RESULTS: Higher positive expression rate of HOXC6 protein was observed in CC tissues and HOXC6 was related to TNM stage, lymphatic metastasis, cancer types, primary lesion diameter, and histological grade of CC. Silencing HOXC6 inhibited epithelial-mesenchymal transition (EMT) (shown as decreased N-cadherin and Vimentin, and increased E-cadherin) through the inactivation of the TGF-ß/smad signaling pathway. HOXC6 gene silencing hindered cell proliferation and accelerated cell apoptosis of CC cells. Furthermore, the effect of HOXC6 silencing was enhanced when the TGF-ß/smad signaling pathway was suppressed. CONCLUSION: The results reveal that HOXC6 gene silencing may inhibit EMT event and cell viability in CC through the inhibition of the activation of TGF-ß/smad signaling pathway.
ABSTRACT
As a crucial member of the small ubiquitin-like modifier system, SUMO-specific protease 3, was identified to be essential for cell proliferation and ribosomal RNA processing. Recent studies showed that SUMO-specific protease 3 was elevated in ovarian cancer compared to normal tissue samples. However, the connection between SUMO-specific protease 3-specific expression and clinicopathological parameters of epithelial ovarian cancer, as well as the physiologically potential role of SUMO-specific protease 3 in epithelial ovarian cancer remained unclear. In this study, an analysis of 124 paraffin-embedded slices by immunohistochemistry indicated that SUMO-specific protease 3 expression was positively correlated with the International Federation of Gynecology and Obstetrics stages (p = 0.025), tumor grade (p = 0.004), and lymph node metastasis (p = 0.001) and was also a critical prognostic factor for the overall survival of epithelial ovarian cancer patients, as revealed by Kaplan-Meier curve analysis. Knockdown of SUMO-specific protease 3 weakened the proliferation, migration, and invasion capability of ovarian cancer cells, down-regulated the expression of Proliferating Cell Nuclear Antigen, Forkhead Box C2, and N-cadherin, and resulted in upregulation of p21 and E-cadherin. Consistent with our results, SUMO-specific protease 3 had been verified to promote cell proliferation, metastasis, and tumorigenesis in multiple malignant cancers, which was a redox-sensitive molecule mediating the epithelial-mesenchymal transition. Collectively, our findings for the first time specifically supported that SUMO-specific protease 3 might play an important role in the regulation of epithelial ovarian cancer progression and could serve as a potential biomarker for prognosis as well as provide a promising therapeutic target against epithelial ovarian cancer.
Subject(s)
Biomarkers, Tumor/genetics , Cysteine Endopeptidases/biosynthesis , Neoplasm Proteins/biosynthesis , Neoplasms, Glandular and Epithelial/genetics , Ovarian Neoplasms/genetics , Adult , Aged , Biomarkers, Tumor/biosynthesis , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Cell Proliferation/genetics , Cysteine Endopeptidases/genetics , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Proteins/genetics , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/pathology , PrognosisABSTRACT
Overexpression of c-Yes has been noted to correlation with several human cancers. However, the effects of c-Yes on epithelial ovarian cancer (EOC) development remain unclear. The aim of this study is going to prove the effects of c-Yes and related mechanisms in proliferation, metastasis and invasion of EOC. Immunohistochemical analysis was performed in 119 human EOC samples, and the data was correlated with clinic pathologic features. Furthermore, western blot analysis is performed for c-Yes in EOC samples and cell lines to evaluate their protein levels and molecular interaction. Kaplan-Meier survival analysis shows that the strong expression of c-Yes exhibited a significant correlation with poor prognosis in human EOC (P<0.01(â)). Meanwhile, we found that knockdown of c-Yes by shRNA inhibited the ability of migration and invasion in EOC cells via the PI3K/AKT pathway. In a word, these results suggested that c-Yes plays an important role in migration and invasion of EOC.
Subject(s)
Cell Movement , Neoplasms, Glandular and Epithelial/enzymology , Neoplasms, Glandular and Epithelial/pathology , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-yes/metabolism , Carcinoma, Ovarian Epithelial , Cell Line, Tumor , Cell Proliferation , Female , Gene Knockdown Techniques , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Ki-67 Antigen/metabolism , Middle Aged , Neoplasm Invasiveness , Signal TransductionABSTRACT
BACKGROUND: Insomnia is one of the most frequent complaints encountered in primary care practice, one that results in significant clinical consequences and cost burden to the public health system. It is more common in elderly adults (≥65 years of age), with frequent complaints regarding sleep maintenance and early morning wakening. Current treatment options have limitations. This review was conducted to evaluate the evidence behind ultra-low-dose doxepin in insomnia and to discuss its potential advantages, its place in therapy and its implications in practice in the treatment of older patients. METHODS: A systematic literature search was conducted of MEDLINE via Ovid, PubMed and EMBASE using the MeSH and key terms "doxepin," "sleep initiation and maintenance disorders," "insomnia," and "low dose." Only randomized controlled trials comparing 3 mg and/or 6 mg of doxepin to placebo and involving participants diagnosed with primary insomnia were included. Primary outcomes for this review were objective sleep study parameters. RESULTS: Five studies were identified, 3 of which (n = 571) were conducted in older adults. Doxepin 3 mg and 6 mg significantly reduced waking after sleep onset and increased total sleep time. There was no significant difference between the 2 doses of doxepin. Latency to persistent sleep did not differ significantly compared with placebo for any doses of doxepin. The most frequent adverse events reported were somnolence and headache. Adverse events did not appear to be dose-related, and studies reported the incidence of adverse effects to be comparable to placebo. CONCLUSION: Doxepin 3 mg and 6 mg significantly improved and sustained sleep maintenance and sleep duration into the last third of the night but did not significantly affect sleep onset. Sleep benefits were achieved without next-day residual or discontinuation effects. Doxepin appears to be well suited for managing insomnia in older people.
ABSTRACT
The controlled release of antioxidant substances at the intestinal oxidative damage site is crucial for alleviating intestine-related diseases. Herein, the novel ROS-responsive carrier was synthesized through simple amidation reaction between carboxymethyl chitosan (CMC) and methionine (Met), a natural organic compound containing ROS-responsive linkages (thioether). Initially, astaxanthin (AXT) nanoparticles (AXT2@CMT) with excellent stability and drug loading capacity (39.68 ± 0.23⯵g/mL) were prepared by optimizing various reaction conditions. In the simulated high-concentration ROS environment of the intestine, CMT achieved a transition from hydrophobic groups (thioether) into hydrophilic groups (sulfone), which was conducive to the controlled release of AXT. In vitro cell experiments revealed that AXT2@CMT could effectively alleviate the oxidative damage in intestinal epithelioid cell line No. 6 (IEC-6 cell) caused by H2O2. This study achieved a straightforward preparation of ROS-responsive nanocarrier through food ingredients, offering a theoretical foundation for the controlled release of AXT at the intestinal oxidative damage site.