ABSTRACT
Langerhans cells (LCs) play a critical role in skin immune responses and the development of psoriasis. Yinxieling (YXL) is a representative Chinese herbal medicine for the treatment of psoriasis in South China. It was found to improve psoriasis without obvious side effects in the clinic. Here we attempted to clarify whether and how YXL regulates the differentiation and functions of LCs in Imiquimod (IMQ)-induced psoriasis in vivo and induced LCs in vitro. The Psoriasis Area Severity Index (PASI) score was used to evaluate the efficacy of YXL for IMQ-induced psoriasis-like mice. Flow cytometry was utilized to analyze the effects of YXL, to regulate the differentiation, migration, maturation, and antigen presentation of LCs. The results show that YXL significantly alleviated skin inflammation, as reduced in PASI score and classic psoriasis characteristics in pathological sections. Although there was no effect on the proportion of total DCs in the skin-draining lymph nodes, the expression of epidermal LCs and its transcription factor PU.1 were both markedly inhibited. LCs were also prevented from migrating from epidermal to skin-draining lymph nodes and mature. In addition, the number of LCs carrying antigens in the epidermis increased, which suggested that YXL could effectively prevent LCs from presenting antigens. In vitro, YXL had a significant impact on inhibiting the differentiation of LCs. Further data showed that YXL decreased the relative expression of transforming growth factor-ß (TGFß) messenger RNA (mRNA) and interleukin-23 (IL-23) mRNAs. Thus, YXL alleviates psoriasis by regulating differentiation, migration, maturation, and antigen presentation via the TGFß/PU.1/IL-23 signal axis.
Subject(s)
Langerhans Cells , Psoriasis , Animals , Mice , Interleukin-23 , Transforming Growth Factor beta1 , Psoriasis/chemically induced , Psoriasis/drug therapy , Transforming Growth Factor beta , RNA, MessengerABSTRACT
Isoflurane, a commonly used inhaled anesthetic, has been found to have a cardioprotective effect. However, the precise mechanisms have not been fully elucidated. Here, we found that isoflurane preconditioning enhanced OGD/R-induced upregulation of miR-210, a hypoxia-responsive miRNA, in AC16 human myocardial cells. To further test the roles of miR-210 in regulating the effects of isoflurane preconditioning on OGD/R-induced cardiomyocyte injury, AC16 cells were transfected with anti-miR-210 or control anti-miRNA. Results showed that isoflurane preconditioning attenuated OGD/R-induced cardiomyocyte cytotoxicity (as assessed by cell viability, LDH and CK-MB levels), which could be reversed by anti-miR-210. Isoflurane preconditioning also prevented OGD/R-induced increase in apoptotic rate, caspase-3 and caspase-9 activities, and Bax level and decrease in Bcl-2 expression level, while anti-miR-210 blocked these effects. We also found that anti-miR-210 prevented the inhibitory effects of isoflurane preconditioning on OGD/R-induced decrease in adenosine triphosphate content; mitochondrial volume; citrate synthase activity; complex I, II, and IV activities; and p-DRP1 and MFN2 expression. Besides, the expression of BNIP3, a reported direct target of miR-210, was significantly decreased under hypoxia condition and could be regulated by isoflurane preconditioning. In addition, BNIP3 knockdown attenuated the effects of miR-210 silencing on the cytoprotection of isoflurane preconditioning. These findings suggested that isoflurane preconditioning exerted protective effects against OGD/R-induced cardiac cytotoxicity by regulating the miR-210/BNIP3 axis.
ABSTRACT
Since chemotherapy's therapeutic impact is diminished by drug resistance, treating ovarian cancer is notably challenging. Thereafter, it is critical to develop cutting-edge approaches to treating ovarian cancer. Baohuoside I (derived from Herba Epimedii) is reported to have antitumor properties in various malignancies. It is unknown, however, what role Baohuoside I plays in cisplatin (DDP)-resistant ovarian cancer cells. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT), colony formation, and flow cytometry assay were used to investigate the impact of Baohuoside I on ovarian cancer A2780 cells and DDP-resistant A2780 (A2780/DDP) cells. The level of microtubule associated protein 1 light chain 3 (LC3) was determined using immunofluorescence staining. Utilizing the mRFP-GFP-LC3B tandem fluorescent probe allowed us to analyse the autophagy flux. Analysis of mRNA and protein level was performed using RT-qPCR and Western blot analysis, respectively. The interaction between hypoxia inducible factor 1 subunit alpha (HIF-1α) and autophagy related 5 (ATG5) promoter was investigated by dual luciferase and ChIP assay. Additionally, evaluation of Baohuoside I's role in ovarian cancer was performed using a nude mouse xenograft model. Baohuoside I decreased the viability and proliferation and triggered the apoptosis of both A2780 and A2780/DDP cells in a concentration-dependent manner. Baohuoside I also increased the sensitivity of A2780/DDP cells to DDP. Concurrently, HIF-1α could promote A2780/DDP cells resistance to DDP. In addition, HIF-1α could induce the autophagy of A2780/DDP cells through transcriptionally activating ATG5, and Baohuoside I imporved the chemosensitivity of A2780/DDP cells to DDP by downregulating HIF-1α. Moreover, Baohuoside I could inhibit the chemoresistance to DDP in ovarian cancer in vivo. Baohuoside I sensitizes ovarian cancer cells to DDP by suppressing autophagy via downregulating the HIF-1α/ATG5 axis. Consequently, Baohuoside I might be evaluated as a new agent for enhancing the chemotherapeutic efficacy of drug treatment for ovarian cancer.
Subject(s)
Antineoplastic Agents , Ovarian Neoplasms , Animals , Mice , Humans , Female , Cisplatin/pharmacology , Cisplatin/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Autophagy , Apoptosis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Proliferation , Autophagy-Related Protein 5ABSTRACT
Among gynecological malignancies, ovarian cancer has the highest mortality rate and has sparked widespread interest in studying the mechanisms underlying ovarian cancer development. Based on TCGA and GEO databases, we investigated the highly expressed autophagy-related genes that determine patient prognosis using limma differential expression and Kaplan-Meier survival analyses. The biological processes associated with these genes were also predicted using GO/KEGG functional enrichment analysis. CCK-8, cell scratch, and transwell assays were used to investigate the effects of PXN on the proliferation, migration, and invasion abilities of ovarian cancer cells. Transmission electron microscopy was used to observe the autophagosomes. The expression of autophagy proteins and the PI3K/Akt/mTOR and p110ß/Vps34/Beclin1 pathway proteins in ovarian cancer cells was detected using western blot; autophagy protein expression was further detected and localized using cellular immunofluorescence. A total of 724 autophagy-related genes were found to be overexpressed in ovarian -cancer tissues, with high expression of PEX3, PXN, and RB1 associated with poor prognosis in patients (p < .05). PXN activates and regulates signaling pathways related to cellular autophagy, ubiquitination, lysosomes, PI3K-Akt, and mTOR. Autophagosomes were observed in all cell groups. The increase in PXN gene expression promoted the proliferation, migration, and invasion of ovarian cancer cells, increased the expression of SQSTM1/p62 protein, decreased LC3II/LC3â , inhibited the phosphorylation of Akt and mTOR proteins, and suppressed the expression of PI3K(p110ß) and Beclin1 proteins. The decrease in PXN expression also confirmed these changes. Thus, PXN is highly expressed during ovarian cancer and is associated with poor patient prognosis. It may promote ovarian cancer cell proliferation, migration, and invasion by inhibiting cellular autophagy via suppression of the p110ß/Vps34/Beclin1 pathway.
Subject(s)
Ovarian Neoplasms , Proto-Oncogene Proteins c-akt , Humans , Female , Proto-Oncogene Proteins c-akt/metabolism , Beclin-1/genetics , Beclin-1/metabolism , Beclin-1/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Prognosis , Ovarian Neoplasms/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Autophagy , Cell Proliferation , Cell Line, Tumor , Apoptosis , Paxillin/metabolism , Paxillin/pharmacologyABSTRACT
BACKGROUND AND OBJECTIVE: The pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) remain unclear. Homocysteine may reduce the compliance of intracranial arteries and damage the endothelial function of the blood-brain barrier (BBB), which may be the underlying mechanism of iNPH. The overlap cases between deep perforating arteriopathy (DPA) and iNPH were not rare for the shared risk factors. We aimed to investigate the relationship between serum homocysteine and iNPH in DPA. METHODS: A total of 41 DPA patients with iNPH and 49 DPA patients without iNPH were included. Demographic characteristics, vascular risk factors, laboratory results, and neuroimaging data were collected. Multivariable logistic regression analysis was performed to investigate the relationship between serum homocysteine and iNPH in DPA patients. RESULTS: Patients with iNPH had significantly higher homocysteine levels than those without iNPH (median, 16.34 mmol/L versus 14.28 mmol/L; P = 0.002). There was no significant difference in CSVD burden scores between patients with iNPH and patients without iNPH. Univariate logistic regression analysis demonstrated that patients with homocysteine levels in the Tertile3 were more likely to have iNPH than those in the Tertile1 (OR, 4.929; 95% CI, 1.612-15.071; P = 0.005). The association remained significant after multivariable adjustment for potential confounders, including age, male, hypertension, diabetes mellitus, atherosclerotic cardiovascular disease (ASCVD) or hypercholesterolemia, and eGFR level. CONCLUSION: Our study indicated that high serum homocysteine levels were independently associated with iNPH in DPA. However, further research is needed to determine the predictive value of homocysteine and to confirm the underlying mechanism between homocysteine and iNPH.
Subject(s)
Hydrocephalus, Normal Pressure , Vascular Diseases , Humans , Male , Hydrocephalus, Normal Pressure/diagnostic imaging , Hydrocephalus, Normal Pressure/complications , Cross-Sectional Studies , Vascular Diseases/complications , Risk Factors , NeuroimagingABSTRACT
Background: Lymphatic metastasis is a common phenomenon of cervical cancer. Tumor necrosis factor-α (TNF-α) was found to be closely associated with lymphatic cancer metastasis. However, the mechanism through which TNF-α regulates lymphatic metastasis in cervical cancer remains unclear. Methods: In this study, cervical cancer cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with or without TNF-α for 48 h, and then the corresponding conditional medium (CM-TNF-α or CM) was collected. The level of vascular endothelial growth factor (VEGFC) in the corresponding CM was then detected using an enzyme-linked immunosorbent assay (ELISA). Next, human lymphatic endothelial cells (HLECs) were cultured in CM-TNF-α or CM for 48 h. Cell viability was measured using the cell counting kit-8 (CCK-8) assay, and angiogenesis was detected using a tube formation assay. Subsequently, the expressions of AKT, p-AKT, ERK, and p-ERK in HLECs were detected using western blotting. In addition, to further investigate the effect of TNF-α on the progression of cervical cancer, a C33A subcutaneous xenograft model was established in vivo. Results: We found that TNF-α significantly stimulated cervical cancer cells to secrete VEGFC. Additionally, the CM collected from the TNF-α-treated cervical cancer cells notably promoted the proliferation, migration, and angiogenesis of HLECs; however, these changes were reversed by MAZ51, a VEGFR3 inhibitor. Moreover, TNF-α obviously elevated D2-40 and VEGFC protein expressions in tumor tissues, promoting lymphangiogenesis and lymphatic metastasis in vivo. Meanwhile, TNF-α markedly upregulated p-AKT and p-ERK expressions in tumor tissues, whereas these changes were reversed by MAZ51. Conclusion: Collectively, TNF-α could promote tumorigenesis, lymphangiogenesis, and lymphatic metastasis in vitro and in vivo in cervical cancer via activating VEGFC-mediated AKT and ERK pathways. These results may provide new directions for the treatment of cervical cancer.
Subject(s)
Uterine Cervical Neoplasms , Female , Humans , Carcinogenesis/metabolism , Cell Transformation, Neoplastic/metabolism , Endothelial Cells/metabolism , Lymphangiogenesis , Lymphatic Metastasis/pathology , MAP Kinase Signaling System , Proto-Oncogene Proteins c-akt/metabolism , Tumor Necrosis Factor-alpha/metabolism , Uterine Cervical Neoplasms/metabolism , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor C/metabolism , Vascular Endothelial Growth Factors/metabolismABSTRACT
Ischemic heart disease is the leading cause of cardiovascular mortality, which is related to cardiac myocyte apoptosis. Butorphanol is an opioid receptor agonist with potential cardioprotective function. The purpose of this work is to explore the function and mechanism of butorphanol in oxygen and glucose deprivation/reperfusion (OGD/R)-induced cardiomyocyte apoptosis. The overlapping targets of ischemic heart disease and butorphanol were analyzed according to GeneCards, ParmMapper, Cytoscape, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Human cardiomyocyte AC16 cells were incubated with butorphanol and then stimulated with OGD/R. Cell injury was investigated by Cell Counting Kit-8, lactate dehydrogenase (LDH) assay kit, TUNEL staining, caspase-3 activity assay kit, and Western blotting. The proteins in signaling pathways were measured using Western blotting. A total of 93 overlapping targets of ischemic heart disease and butorphanol were obtained. Pathway analysis exhibited that these targets might be involved in multiple signaling pathways. Butorphanol alone showed little cytotoxicity to cardiomyocytes, and it protected against OGD/R-induced viability inhibition, LDH release, cell apoptosis, and increase of caspase-3 activity and expression levels of cleaved caspase-3 and Bim. Butorphanol promoted the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/forkhead box O (FoxO) and hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathways and attenuated the activation of the mitogen-activated protein kinase (MAPK) signaling in OGD/R-treated cardiomyocytes. In conclusion, butorphanol prevents OGD/R-induced cardiomyocyte apoptosis through activating the PI3K/Akt/FoxO and HIF-1α/VEGF pathways and inactivating the MAPK pathway.
Subject(s)
Myocardial Ischemia , Myocytes, Cardiac , Apoptosis , Butorphanol/metabolism , Butorphanol/pharmacology , Caspase 3/metabolism , Glucose/metabolism , Humans , Myocardial Ischemia/metabolism , Oxygen/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Reperfusion , Vascular Endothelial Growth Factor A/metabolismABSTRACT
Four actinomycete strains isolated from the coral Acropora austera and coral sand samples from the South China Sea, were found to produce a series of halogenated compounds baring similar ultraviolet absorption based on the analysis of HPLC and LC-MS. The production titers of halogenated compounds from Streptomyces diacarni SCSIO 64983 exceeded those of other similar strains leading us to focus on SCSIO 64983. Four new thiocarbazomycins A-B (1-2), chlocarbazomycin E (3), and brocarbazomycin A (4), together with three known chlocarbazomycins A-C (5-7) containing a carbazole core were identified, and their structures were determined using a combination of spectroscopic analysis including HRESIMS, 1D and 2D NMR. Structurally speaking, compounds 1 and 2 have the rare sulfur-containing carbazole nuclei, and 3 and 4 contain Cl and Br atoms, respectively. Although these compounds have not yet been found to have obvious biological activity, their discovery highlights the role of molecular libraries in subsequent drug discovery campaigns.
Subject(s)
Actinobacteria , Anthozoa , Actinobacteria/chemistry , Actinomyces , Animals , Carbazoles , Coral Reefs , SandABSTRACT
Intrauterine adhesion (IUA) is a gynaecological disease caused by uterine cavity surgeries and infections that leads to partial or total occlusion of the uterine cavity. However, the underlying mechanism(s) and progression of the disease have not yet been identified. IUA has a high recurrence rate and poor prognosis, and effective drugs to prevent adhesion are lacking. Therefore, establishing an effective animal model of IUA is of great significance for revealing the pathogenesis of IUA and the mechanism(s) governing drug effects. Rats, mice, rabbits, and other animals are currently used to establish intrauterine adhesion models. The IUA induction methods include chemical, thermal, or mechanical damage and mechanical damage combined with an infective method. We analysed the advantages and disadvantages of various models and their clinical simulations in order to provide a precise animal model for exploring the pathogenesis, treatment strategies, and prevention of IUA.
Subject(s)
Endometrium , Uterine Diseases , Female , Humans , Rats , Animals , Mice , Rabbits , Endometrium/pathology , Uterine Diseases/pathology , Uterus/pathology , Disease Models, Animal , Tissue Adhesions/pathologyABSTRACT
Electrocatalytic nitrogen reduction reaction (NRR) under ambient conditions is still seriously impeded by the inferior NH3 yield and low Faradaic efficiency, especially at low overpotentials. Herein, we report the synthesis of nano-sized RuO2 and Bi2 O3 particles grown on functionalized exfoliated graphene (FEG) through inâ situ electrodeposition, denoted as RuO2 -Bi2 O3 /FEG. The prepared self-supporting RuO2 -Bi2 O3 /FEG hybrid with a Bi mass loading of 0.70â wt% and Ru mass loading of 0.04â wt% shows excellent NRR performance at low overpotentials in acidic, neutral and alkaline electrolytes. It achieves a large NH3 yield of 4.58±0.16â µgNH3 h-1 â cm-2 with a high Faradaic efficiency of 14.6 % at -0.2â V versus reversible hydrogen electrode in 0.1â M Na2 SO4 electrolyte. This performance benefits from the synergistic effect between Bi2 O3 and RuO2 which respectively have a fairly strong interaction of Bi 6p orbitals with the N 2p band and abundant supply of *H, as well as the binder-free characteristic and the convenient electron transfer via graphene nanosheets. This work highlights a new electrocatalyst design strategy that combines transition and main-group metal elements, which may provide some inspirations for designing low-cost and high-performance NRR electrocatalysts in the future.
ABSTRACT
OBJECTIVE: To explore the application effects of hierarchical, diversified soft skills training in clinical nursing training. METHODS: This is a prospective study. There involved a total of 124 nurses who participated in the training in our hospital. The participants were randomly allocated to the study group and the control group, with 62 nurses in each group. Study group received hierarchical, diversified nursing soft skills training and control group received conventional nursing training only. The core competence, knowledge, operation skills and clinical competence of nurses in the two groups before and after training were measured and compared, and the satisfaction of doctors and patients in the two groups after training were observed. RESULTS: The scores of education and consultation, professional development, legal and ethical practice, interpersonal relationship, leadership, clinical nursing and critical thinking were compared between the two groups before the training (P > .05). After the training, however, the scores of abovementioned items in the two groups were higher than those before treatment, and compared with the control group, the scores in the study group were significantly higher (P < .05). Before the training, the scores of theoretical knowledge, operation skills and clinical competence of nurses in the two groups were compared (P > .05). After training, the scores of those items of nurses in the two groups were higher than those before treatment. Compared with the control group, the scores of theory, operation skills and clinical competence of nurses in the study group were significantly higher (P < .05). Moreover, the study group showed significant higher satisfaction of doctors and patients (P < .05). CONCLUSION: Hierarchical, diversified soft skills training in clinical nursing training programme obtained better outcomes in the core competence, knowledge, operation skills and clinical competence of nursing staff, and promoted the satisfaction of doctors and patients, which can be utilised for clinical practice.
Subject(s)
Clinical Competence , Humans , Prospective StudiesABSTRACT
Tuberculosis (TB) ranks as the leading cause of death from a single infectious agent (ranking more lethal than HIV/AIDS) over the course of the past decade. More concerning is that reports of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB have been dramatically increasing. It continues to become ever more clear that novel anti-TB drugs with improved efficacies and reduced toxicities are urgently needed. We report here the discovery of 12 new ilamycin analogues, ilamycins G-R (1-12), bearing various nonproteinogenic amino acids, along with ilamycins E1 (13) and F (14), from a 200 L scale culture of the marine-derived mutant actinomycete Streptomyces atratus SCSIO ZH16 ΔilaR. Importantly, bioassays against Mycobacterium tuberculosis H37Rv revealed that all 12 new agents displayed antitubercular activities with MIC values ranging from 0.0096 to 10 µM. The structures of 1-12 were elucidated on the basis of HRESIMS, 1D and 2D NMR, and X-ray single-crystal diffraction studies. In addition, compound 10 was found to be moderately cytotoxic against a panel of tumor human cell lines. From these data we can formulate tentative structure-activity relationships for the antitubercular and antitumor activities of the ilamycins.
Subject(s)
Antineoplastic Agents/pharmacology , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Streptomyces/chemistry , Antineoplastic Agents/chemistry , Antitubercular Agents/chemistry , Cell Line, Tumor , Drug Design , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Borrelidins M-O (1-3), along with four previously known family members (4-7), were isolated from marine pulmonated mollusks Onchidium sp. associated Streptomyces olivaceus SCSIO LO13. The structures of 1-3 were elucidated by extensive spectral analyses of HR-ESI-MS, 1D and 2D NMR data. In addition, the cytotoxic and antibacterial activities of 1-7 were evaluated enabling us to propose some tentative structure-activity relationships (SARs), especially those involving modifications at C(22) and the moieties at C(7) and C(8) of the borrelidin scaffold.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Gastropoda/chemistry , Streptomyces/chemistry , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Fatty Alcohols/chemistry , Fatty Alcohols/isolation & purification , Fatty Alcohols/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
Isoflurane, one of the commonly used inhalation anesthetics worldwide in clinical practice, may generate substantial risks of neurotoxicity in the developing brains. The present study aimed to illustrate the effects and underlying mechanisms of miR-214 on isoflurane-induced neurotoxicity in human neuroblastoma cell line SH-SY5Y. SH-SY5Y cells were transfected with miR-214 or miR-con alone or in combination with pcDNA empty vector or pcDNA-PTEN in the presence of 3% isoflurane and incubated for 48â¯h. Cell viability, lactate dehydrogenase (LDH) release, apoptosis, and caspase-3/7 activity were evaluated using CCK-8, LDH release assay, flow cytometry analysis, and caspase-3/7 activity assay, respectively. The superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) activities were measured using commercial kits. miR-214 expression and alterations of the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway were detected by qRT-PCR and Western blot, respectively. The interaction between miR-214 and PTEN was explored by luciferase reporter assay. We found that isoflurane exposure induced neurotoxicity in SH-SY5Y cells, as evidenced by the reduced cell viability, increased LDH release, apoptotic rate, caspase-3/7 activity, and oxidative stress levels. Moreover, isoflurane exposure decreased the expression of miR-214 and affected the PTEN/PI3K/Akt pathway in SH-SY5Y cells. miR-214 overexpression significantly suppressed isoflurane-induced viability reduction, LDH release, apoptosis and oxidative stress, as well as inactivation of the PI3K/Akt pathway in SH-SY5Y cells. Interestingly, PTEN was identified as a target of miR-214. Moreover, PTEN upregulation blocked the effects of miR-214 on isoflurane-induced neurotoxicity in SH-SY5Y cells. In conclusion, miR-214 protected against isoflurane-induced neurotoxicity in SH-SY5Y cells via regulation of PI3K/Akt pathway by targeting PTEN, contributing to better understanding the underlying mechanisms of anesthetics-induce neurotoxicity.
Subject(s)
Isoflurane/toxicity , MicroRNAs/genetics , Neuroprotection/genetics , Neurotoxins/toxicity , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Base Sequence , Cell Line, Tumor , Humans , Oxidative Stress/drug effects , Oxidative Stress/genetics , PTEN Phosphohydrolase/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Up-Regulation/drug effects , Up-Regulation/geneticsABSTRACT
As an ω-conopeptide originally discovered from Conus striatus, SO-3 contains 25 amino acid residues and three disulfide bridges. Our previous study has shown that this peptide possesses potent analgesic activity in rodent pain models (mouse and rat), and it specifically inhibits an N-type calcium ion channel (Cav2.2). In the study presented here, we investigated the key amino acid residues for their inhibitory activity against Cav2.2 expressed in HEK 293 cells and analgesic activity in mice. To improve the inhibitory activity of SO-3, we also evaluated the effects of some amino acid residues derived from the corresponding residues of ω-peptide MVIIA, CVID, or GVIA. Our data reveal that Lys6, Ile11, and Asn14 are the important functional amino acid residues for SO-3. The replacement of some amino acid residues of SO-3 in loop 1 with the corresponding residues of CVID and GVIA improved the inhibitory activity of SO-3. The binding mode of Cav2.2 with SO-3 amino acids in loop 1 and loop 2 may be somewhat different from that of MVIIA. This study expanded our knowledge of the structure-activity relationship of ω-peptides and provided a new strategy for improving the potency of Cav2.2 inhibitors.
Subject(s)
Analgesics/pharmacology , Behavior, Animal/drug effects , Calcium Channels, N-Type/chemistry , Calcium Channels, N-Type/metabolism , Pain/drug therapy , Peptides/pharmacology , Analgesics/chemistry , Animals , HEK293 Cells , Humans , Mice , Models, Molecular , Pain/metabolism , Peptides/chemistry , Protein Conformation , Rats , Structure-Activity RelationshipABSTRACT
OBJECTIVE: To explore distinctive manifestations of rheumatoid arthritis (RA) patients of cold syndrome and heat syndrome using wrist joints ultrasound. METHOD: s Totally 65 RA patients were syndrome typed as cold syndrome (29 cases, cold-damp blockage syndrome) and heat syndrome (36 cases, damp-heat obstruction syndrome). Grey-scale synovitis, power doppler (PD) signals, tenosynovitis, and bone erosion were observed using wrist ultrasound. Distinctive manifestations of cold syndrome and heat syndrome were analyzed using wrist ultrasound. RESULTS: In RA patients of cold syndrome, the positive rate of synovitis, PD, tenosynovitis, and bone erosion was 51.72%, 20.68%, 51.72%, and 37.93%, respectively, while they were 97.22%, 91.67%, 75.0%, and 63.89%, respectively in RA patients of heat syndrome. Compared with patients of cold syndrome, the positive rate of synovitis, PD, and bone erosion increased in patients of heat syndrome (P < 0.01, P < 0.01, P < 0.05). There was no statistical difference in the positive rate of tenosynovitis between the two groups (P > 0.05). Compared with the cold syndrome group, there was statistical difference in the constituent ratio of synovitis, PD, and bone erosion in the heat syndrome group (P < 0.01, P < 0.01, P < 0.05), but with no statistical difference in the constituent ratio of tenosynovitis (P > 0.05). Results of the ROC curve showed that the sensitivity was 86.1% and the specificity was 62.1% in judging heat syndrome, when the total score of synovitis in two wrists was more than 1.5; the sensitivity was 80.0% and the specificity was 93.1% in judging heat syndrome, when the total score of PD in two wrists was more than 1.5. CONCLUSIONS: Positive rates of synovitis, PD, and bone erosion were significantly higher in RA patients of heat syndrome than those of cold syndrome. Especially serious manifestations were more often seen in RA patients of heat syndrome. The total score of synovitis or PD in the two wrist joints higher than 1.5 was characteristic manifestations of heat syndrome using wrist ultrasound.
Subject(s)
Arthritis, Rheumatoid/therapy , Wrist Joint/diagnostic imaging , Hot Temperature , Humans , Medicine, Chinese Traditional , ROC Curve , Sensitivity and Specificity , Syndrome , Synovitis , Ultrasonography , Wrist/diagnostic imagingABSTRACT
OBJECTIVE: To study the effect of Shenfu Injection (SF) on the apoptosis of prostate cancer PC-3 cells and its possible mechanism. METHODS: We divided prostate cancer PC-3 cells into a blank control group and three experimental groups, the latter treated with SF at 50, 100, and 200 microl/ml, respectively, for 24, 48, and 72 hours. Then we determined the proliferation of the cells by MTT assay, measured their apoptosis by Annexin V/PI flow cytometry, and detected the expression of P53 mRNA by RT-qPCR. RESULTS: Compared with the blank control group, the survival rates of the prostate cancer PC-3 cells in the 50, 100, and 200 microl/ml SF groups were (93.76 +/- 2.63)%, (81.21 +/- 1.80)% and (18.01 +/- 3.84)% at 24 hours, (94.67 +/-1.11)%, (78.33 +/- 2.89)% and (10.34 +/- 1.44)% at48 hours, and (91.30 +/- 0.47)%, (36.67 +/- 1.56)% and (1.33 +/- 0.32)% at 72 hours, all significantly increased in a dose- and time-dependent manner (P < 0.05). The expression of p53 mRNA was also markedly increased in all the three experimental groups at 48 hours (P < 0. 05). CONCLUSION: SF can inhibit the proliferation and induce the apoptosis of PC-3 cells, which may due to its upregulation of the p53 mRNA expression.
Subject(s)
Apoptosis/drug effects , Drugs, Chinese Herbal/pharmacology , Prostatic Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Male , Prostatic Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally and often develops on the foundation of chronic liver disease or cirrhosis. Cirrhosis is a clinically prevalent chronic progressive liver disease characterized by diffuse liver damage resulting from long-term or repeated actions of 1 or more etiological factors. However, the impact of CENPF and nuclear division cycle 80 (NDC80) genes on rehabilitation nursing of HCC and cirrhosis remains unclear. HCC and cirrhosis datasets GSE63898 and GSE89377 profile files were downloaded from the gene expression omnibus database generated on platforms GPL13667 and GPL6947, respectively. Differentially expressed genes (DEGs) screening, weighted gene co-expression network analysis (WGCNA), construction and analysis of protein-protein interaction (PPI) networks, functional enrichment analysis, gene set enrichment analysis (GSEA), survival analysis, immune infiltration analysis, and comparative toxicogenomics database (CTD) analysis were conducted. Gene expression heatmaps were plotted. miRNAs regulating central DEGs were selected through TargetScan. A total of 626 DEGs were identified. According to gene ontology (GO) analysis, they were primarily enriched in small molecule metabolic processes, drug metabolic processes, binding of identical proteins, and lipid metabolic processes. Kyoto Encyclopedia of Gene and Genome (KEGG) analysis results indicated that the target genes were mainly enriched in metabolic pathways, phagosomes, glycine, serine, and threonine metabolism. The construction and analysis of the PPI network revealed 3 core genes (NDC80, CENPF, RRM2). Gene expression heatmaps showed that core genes (CENPF, NDC80) were highly expressed in HCC and cirrhosis samples. CTD analysis found that 2 genes (CENPF and NDC80) were associated with liver, jaundice, ascites, fever, dyspepsia, and hepatic encephalopathy. CENPF and NDC80 are highly expressed in HCC and cirrhosis, and CENPF and NDC80 might be the biomarkers of rehabilitation nursing of HCC and cirrhosis.
Subject(s)
Carcinoma, Hepatocellular , Cytoskeletal Proteins , Liver Cirrhosis , Liver Neoplasms , Carcinoma, Hepatocellular/genetics , Humans , Liver Neoplasms/genetics , Liver Cirrhosis/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Protein Interaction Maps , Gene Expression ProfilingABSTRACT
Previous published data have confirmed that the addition of a citric acid meal improves the accuracy of the 13C-urea breath test (13C-UBT). However, some studies have suggested that a citric acid test meal may not be necessary. Thus, the aim of this study was to evaluate the combination of a 13C-UBT with a citric acid meal for the diagnosis of Helicobacter pylori (Hp) infection in a Chinese population, particularly for patients with results in the gray zone. In this paired self-controlled study, all subjects had previously undergone 13C-UBTs without citric acid meals and were randomly divided into two groups based on different doses of citric acid (a low-dose citric acid group and a high-dose citric acid group, comprising meals with 0.68 g and 3.84 g citric acid powder, respectively). Positive rapid urease test (CLO) test and histology results were considered the 'gold standard'. The mean delta over baseline (DOB) value, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were compared between the two groups, particularly for patients with results in the gray zone. In total, 285 patients were tested. Of these patients, 189 were included in the low-dose citric acid group, and 96 were included in the high-dose citric acid group. Among patients with a positive 13C-UBT result without citric acid [delta over baseline (DOB) value ≥ 4, n = 174] and a negative 13C-UBT result without citric acid (DOB value < 4, n = 111), 8.0% (14/174) were false positive, and 0.9% (1/111) was false negative as determined by gold standard. Of 14 patients with false positive, 78.6% (11/14) false positive were in the gray zone of 4-10. However, there were no false positive 13C-UBT results with citric acid in the the gray zone of 4-10. In the comparison of the commercial 13C-UBT with the 13C-UBT in the low-dose citric acid group, the sensitivity, specificity, PPV, NPV and accuracy at 15 min were as follows: 99.1% vs. 99.1%, 97.5% vs. 88.9%, 98.2% vs. 92.2%, 98.8% vs. 98.6% and 98.4% vs. 94.7%, respectively. In the the gray zone of 4.0-10.0, the comparison of the commercial 13C-UBT with the 13C-UBT in the low-dose citric acid group, the sensitivity, specificity, PPV, and accuracy at 15 min were as follows: 94.4% vs. 100.0%, 100.0% vs. 0%, 100.0% vs. 75.0% and 95.8% vs. 75.0%, respectively. No significant difference was observed between the 15-min and 30-min measurement intervals in the low- and high-dose citric acid groups, including patients with results in the gray zone. The low-dose citric acid test, with an optimal measurement interval of 15 min, was highly accurate in the diagnosis of Hp infection in the Chinese population, especially for individuals with results in the gray zone.