ABSTRACT
Metastasis is the leading cause of death in breast cancer patients. Osthole, as an active compound detected in the traditional Chinese medicine Wenshen Zhuanggu Formula, has shown a promising anti-metastatic activity in human breast cancer cells, but the underlying mechanisms remain ambiguous. In this study we elucidated the anti-metastatic mechanisms of osthole in highly metastatic breast cancer cells and a zebrafish xenograft model. We showed that the expression of integrin α3 (ITGα3) and integrin ß5 (ITGß5) was upregulated in highly metastatic MDA-MB-231, MDA-MB-231BO breast cancer cell lines but was downregulated in poorly metastatic MCF-7 breast cancer cell line, which might be the key targets of osthole's anti-metastatic action. Furthermore, we showed that knockdown of ITGα3 and ITGß5 attenuated breast cancer cell migration and invasion possibly via suppression of FAK/Src/Rac1 pathway, whereas overexpression of ITGα3 and ITGß5 caused the opposite effects. Consistently, osthole significantly inhibited breast cancer metastasis by downregulating ITGα3/ITGß5 signaling in vitro and in vivo. These results provide new evidence that osthole may be developed as a candidate therapeutic drug for metastatic breast cancer.
Subject(s)
Breast Neoplasms , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Movement , Coumarins/pharmacology , Coumarins/therapeutic use , Female , Humans , Neoplasm Invasiveness/prevention & control , ZebrafishABSTRACT
Non-small-cell carcinoma (NSCLC) is the most common cancer along with high mortality rate worldwide. In the present study, our data showed that lncRNA MAF BZIP Transcription Factor G Antisense RNA 1 (MAFG-AS1) was over-expressed in NSCLC tissues and cell lines. Overexpression of MAFG-AS1 promoted the migration, invasion and enhanced epithelial-mesenchymal transition (EMT) of NSCLC cell. In addition, miR-339-5p was predicted to be a target of MAFG-AS1 and the level of miR-339-5p was down-regulated in NSCLC. Over-expression of MAFG-AS1 significantly decreased the level of miR-339-5p in NSCLC cell. Moreover, the matrix metalloproteinase 15 (MMP15) was identified to be a target of miR-339-5p. The level of MMP15 was negatively regulated by miR-339-5p whereas positively controlled by MAFG-AS1. In addition, up-regulation of miR-339-5p neutralized the promoting impact of MAFG-AS1 on the migration, invasion and EMT of NSCLC cell. Finally, the xenograft model suggested that MAFG-AS1 promoted the metastasis of NSCLC cell in vivo. Altogether, we proved that MAFG-AS1-miR-339-5p-MMP15 axis might be a promising therapeutic target for the treatment of patients with NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/genetics , Matrix Metalloproteinase 15/metabolism , MicroRNAs/metabolism , RNA, Antisense/metabolism , Animals , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Epithelial-Mesenchymal Transition/genetics , Heterografts , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , MafG Transcription Factor/genetics , MafG Transcription Factor/metabolism , Matrix Metalloproteinase 15/genetics , Mice , Mice, Inbred BALB C , MicroRNAs/genetics , Neoplasm Invasiveness , RNA, Antisense/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolismABSTRACT
The purpose of this study was to test the hypothesis that the incidence of crochetage on the R wave in inferior limb leads can be used for the diagnosis of pediatric secundum atrial septal defect (ASD). Two hundred fifty-six children with secundum ASD (case cohort) and 256 age- and gender-matched children without heart disease (control cohort) were included in the study. Statistical analyses were performed to test the relationship between the ASD and the crochetage on the R wave with a single lead and three leads, respectively. The impact of incomplete right bundle branch block (IRBBB) and ASD diameter (≥ 5 and < 5 mm) on ASD diagnosis were also explored. Crochetage on the R wave was observed in all three inferior limb leads on 28.13% (72/256, 28 with IRBBB) of subjects with secundum ASD, while it was seen in only 2.73% (7/256, one with IRBBB) of control subjects (P < 0.001). Subgroup analysis showed that the incidence of R wave crochetage correlated with ASD size in both the single inferior limb lead (26.14%, 23/88 on ASD ≥ 5 mm vs. 10.71%, 18/168 on ASD < 5 mm; P = 0.001) and all three inferior limb leads (44.32%, 39/88 on ASD ≥ 5 mm vs. 19.64%, 33/168 on ASD < 5 mm; P < 0.001). Our findings suggest that crochetage on the R wave in inferior limb leads can serve as an independent marker for ASD diagnosis.
Subject(s)
Bundle-Branch Block/diagnosis , Electrocardiography/methods , Heart Septal Defects, Atrial/diagnosis , Child , Child, Preschool , Early Diagnosis , Echocardiography/methods , Female , Heart Septal Defects, Atrial/physiopathology , Humans , Male , Sensitivity and SpecificityABSTRACT
Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by decreased bone mass and increased fracture risk. The majority of OI cases have an autosomal dominant pattern of inheritance and are usually caused by mutations in genes encoding type I collagen. OI cases of autosomal recessive inheritance are rare, and OI type XI is attributable to mutation of the FKBP10 gene. Here, we used next-generation sequencing and Sanger sequencing to detect mutations in FKBP10 and to analyze their relation to the phenotypes of OI type XI in three Chinese patients. We also evaluated the efficacy of zoledronic acid treatment in these patients. Two of the affected patients had novel compound heterozygous mutations, one patient with c.343C>T (p.R115X) in exon 2 and c.1085delC (p.A362fsX1) in exon 7, and the other patient with c.879C>G (p.Y293X) in exon 5 and c.918-3C>G in intron 5. In the third proband, we identified a homozygous single base-pair duplication, c.831dupC (p.G278RfsX95) in exon 5. In conclusion, we report for the first time that these novel pathogenic mutations of FKBP10 can lead to the extremely rare type XI OI without contractures, which expands the genotypic spectrum of OI. The phenotypes of these patients are similar to patients with types III or IV OI, and zoledronic acid is effective in increasing BMD, inhibiting bone resorption biomarkers and reducing fractures of these patients.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Diphosphonates/therapeutic use , Fractures, Bone/prevention & control , Imidazoles/therapeutic use , Osteogenesis Imperfecta/drug therapy , Osteogenesis Imperfecta/genetics , Tacrolimus Binding Proteins/genetics , Adult , Asian People/genetics , Base Sequence , Bone Density/drug effects , Bone Density/genetics , Bone Resorption/prevention & control , Child , Child, Preschool , China/epidemiology , Collagen Type I/genetics , Collagen Type I, alpha 1 Chain , Female , Fractures, Bone/drug therapy , Fractures, Bone/epidemiology , High-Throughput Nucleotide Sequencing , Humans , Male , Membrane Proteins/genetics , Sequence Analysis, DNA , Young Adult , Zoledronic AcidABSTRACT
Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is known to cause a distinct, extremely rare autosomal recessive form of type VI OI. Here we report, for the first time, the detection of SERPINF1 mutations in Chinese OI patients. We designed a novel targeted next-generation sequencing panel of OI-related genes to identify pathogenic mutations, which were confirmed with Sanger sequencing and by co-segregation analysis. We also investigated the phenotypes of OI patients by evaluating bone mineral density, radiological fractures, serum bone turnover markers, and pigment epithelium-derived factor (PEDF) concentration. Six patients with moderate-to-severe bone fragility, significantly low bone mineral density, and severe deformities of the extremities were recruited from five unrelated families for this study. Six pathogenic mutations in SERPINF1 gene were identified, five of which were novel: (1) a homozygous in-frame insertion in exon 3 (c.271_279dup, p.Ala91_Ser93dup); (2) compound heterozygous mutations in intron 3 (c.283 + 1G > T, splicing site) and exon 5 (c.498_499delCA, p.Arg167SerfsX35, frameshift); (3) a homozygous frameshift mutation in exon 8 (c.1202_1203delCA, p.Thr401ArgfsX); (4) compound heterozygous missense mutation (c.184G > A, p.Gly62Ser) and in-frame insertion (c.271_279dup, p.Ala91_Ser93dup) in exon 3; and (5) a heterozygous nonsense mutation in exon 4 (c.397C>T + ?, p.Gln133X + ?). Serum PEDF levels were barely detectable in almost all subjects. We identified five novel mutations in SERPINF1 and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.
Subject(s)
Eye Proteins/genetics , Fractures, Bone/genetics , Genetic Predisposition to Disease/genetics , Mutation/genetics , Nerve Growth Factors/genetics , Osteogenesis Imperfecta/genetics , Serpins/genetics , Adolescent , Bone Density/genetics , Female , Heterozygote , Homozygote , Humans , Male , PhenotypeABSTRACT
Wenshen Zhuanggu formula (WSZG) is a traditional Chinese medicine used as an adjuvant for the prevention of bone metastases in breast cancer patients. In this study we investigated the efficacy of WSZG in preventing bone metastases and the potential mechanisms in a mouse xenograft model of breast cancer bone metastases. This model was established by injection of human MDA-MB-231BO-Luc breast cancer cells alone or a mixture of the cancer cells with bone marrow-derived mesenchymal stem cells (BMSCs) into left ventricle of the heart in female nude mice. Then the mice were treated with WSZG (3.25, 6.5 or 13.0 mg·kg-1·d-1, ig) for four weeks, whereas zoledronic acid (100 µg/kg per week, ig) was used as a positive control. The occurrence and development of bone metastases were monitored via bioluminescent imaging, and bone lesions were assessed using micro-CT. Intracardiac injection of the mixture of MDA-MB-231BO-Luc breast cancer cells with BMSCs significantly facilitated the bone metastatic capacity of the breast cancer cells, and aggravated bone lesions in the mouse xenograft model of breast cancer bone metastases. Administration of WSZG dose-dependently inhibited the incidence and intensity of bone metastases and protected against bone lesions by suppressing osteoclast formation and tumor cell infiltration. Furthermore, administration of WSZG caused a marked reduction in the expression of CCL5/CCR5 and IL-17B/IL-17BR in bone metastatic tissues. The results demonstrate that WSZG exerts potential therapeutic effects in a mouse xenograft model of breast cancer bone metastases, which are partially mediated by weakening the interaction between BMSCs and breast cancer cells in the tumor microenvironment.
Subject(s)
Antineoplastic Agents/pharmacology , Bone Neoplasms/prevention & control , Breast Neoplasms/drug therapy , Plant Extracts/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Bone Neoplasms/secondary , Breast Neoplasms/pathology , Diphosphonates/pharmacology , Dose-Response Relationship, Drug , Female , Humans , Imidazoles/pharmacology , Mesenchymal Stem Cells/cytology , Mice , Mice, Inbred BALB C , Mice, Nude , Osteoclasts/metabolism , Plant Extracts/administration & dosage , Tumor Microenvironment , Xenograft Model Antitumor Assays , Zoledronic AcidABSTRACT
Osteogenesis imperfecta (OI) is a group of clinically and genetically heterogeneous disorders characterized by decreased bone mass and recurrent bone fractures. Transmembrane protein 38B (TMEM38B) gene encodes trimeric intracellular cation channel type B (TRIC-B), mutations of which will lead to the rare form of autosomal recessive OI. Here we detected pathogenic gene mutations in TMEM38B and investigated its phenotypes in three children with OI from two non-consanguineous families of Chinese Han origin. The patients suffered from recurrent fractures, low bone mass, mild bone deformities and growth retardation, but did not have impaired hearing or dentinogenesis imperfecta. Next-generation sequencing and Sanger sequencing revealed a homozygous novel acceptor splice site variant (c.455-7T>G in intron 3, p.R151_G152insVL) in family 1 and a homozygous novel nonsense variant (c.507G>A in exon 4, p.W169X) in family 2. The parents of the probands were all heterozygous carriers of these mutations. We reported the phenotype and novel mutations in TMEM38B of OI for the first time in Chinese population. Our findings of the novel mutations in TMEM38B expand the pathogenic spectrum of OI and strengthen the role of TRIC-B in the pathogenesis of OI.
Subject(s)
Genes, Recessive , Ion Channels/genetics , Mutation , Osteogenesis Imperfecta/diagnosis , Osteogenesis Imperfecta/genetics , Alternative Splicing , Biomass , Bone and Bones/pathology , Child, Preschool , DNA Mutational Analysis , Female , High-Throughput Nucleotide Sequencing , Homozygote , Humans , Male , Pedigree , Phenotype , RNA, Messenger , RadiographyABSTRACT
OBJECTIVE: Osteogenesis imperfecta (OI) is characterized by low bone mass and recurrent fractures. Adults with OI are often treated with oral or intravenous bisphosphonates (BPs). We investigated the clinical phenotypes of adult OI patients and prospectively compared the efficacy of oral alendronate (ALN) with intravenous zoledronic acid (ZOL) in OI patients. METHODS: This 24-month, observational, randomized clinical study included 60 adult patients with OI. We compared the differences in bone mineral density (BMD) and bone turnover biomarkers between OI adults and healthy subjects. Thereafter, OI patients were randomized at a 2:1 ratio to receive either weekly oral ALN 70 mg or once-yearly infusion of ZOL 5 mg. The efficacy outcomes were changes in BMD, bone turnover biomarkers, and fracture incidence. RESULTS: Adult OI patients had significantly lower BMD and significantly higher cross-linked C-telopeptide of type I collagen (ß-CTX) levels than age-/sex-/BMI-matched healthy subjects. A total of 52 patients completed the 24-month clinical study. BMD at lumbar spine, femoral neck, and total hip were equivalently elevated in the ALN (10.5, 13.2, and 14.7%, respectively) and ZOL (11.3, 13.7, and 11.7%, respectively; all P>.05) groups. Serum alkaline phosphatase decreased by 30.3% in the ALN group and 37.3% in the ZOL group (P = .12), and ß-CTX decreased by 58.0% in the ALN group and 63.6% in the ZOL group (P = .48). Compared to the prior fracture rates, clinical fracture incidences were decreased in the ALN and ZOL groups (both P<.05). CONCLUSION: Adults with OI present significantly lower bone mass and higher bone resorption biomarkers than healthy populations. Oral ALN and intravenous ZOL are equally effective at increasing BMD and inhibiting bone turnover in adults with OI. The treatment may reduce fractures in this study, but further efforts are still needed to demonstrate the anti-fracture efficacy of BPs. ABBREVIATIONS: 25OHD = 25-hydroxyvitamin D ALN = alendronate ALP = alkaline phosphatase BMD = bone mineral density BMI = body mass index BP = bisphosphonate ß-CTX = cross-linked C-telopeptide of type I collagen FN = femoral neck LS = lumbar spine OI = osteogenesis imperfecta RCT = randomized controlled trial TH = total hip ZOL = zoledronic acid.
Subject(s)
Alendronate/pharmacology , Bone Density Conservation Agents/pharmacology , Bone Density/drug effects , Bone Remodeling/drug effects , Diphosphonates/pharmacology , Imidazoles/pharmacology , Osteogenesis Imperfecta/drug therapy , Outcome Assessment, Health Care , Absorptiometry, Photon , Adolescent , Adult , Alendronate/administration & dosage , Biomarkers/blood , Bone Density Conservation Agents/administration & dosage , Diphosphonates/administration & dosage , Female , Humans , Imidazoles/administration & dosage , Male , Middle Aged , Osteogenesis Imperfecta/blood , Osteogenesis Imperfecta/diagnostic imaging , Young Adult , Zoledronic AcidABSTRACT
Vasovagal syncope (VVS) causes accidental harm for susceptible patients. However, pathophysiology of this disorder remains largely unknown. In an effort to understanding of molecular mechanism for VVS, genome-wide gene expression profiling analyses were performed on VVS patients at syncope state. A total of 66 Type 1 VVS child patients and the same number healthy controls were enrolled in this study. Peripheral blood RNAs were isolated from all subjects, of which 10 RNA samples were randomly selected from each groups for gene expression profile analysis using Gene ST 1.0 arrays (Affymetrix). The results revealed that 103 genes were differently expressed between the patients and controls. Significantly, two G-proteins related genes, GPR174 and GNG2 that have not been related to VVS were among the differently expressed genes. The microarray results were confirmed by qRT-PCR in all the tested individuals. Ingenuity pathway analysis and gene ontology annotation study showed that the differently expressed genes are associated with stress response and apoptosis, suggesting that the alteration of some gene expression including G-proteins related genes is associated with VVS. This study provides new insight into the molecular mechanism of VVS and would be helpful to further identify new molecular biomarkers for the disease.
Subject(s)
GTP-Binding Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Syncope, Vasovagal/genetics , Adolescent , Case-Control Studies , Child , Female , Gene Expression Profiling/methods , Genetic Predisposition to Disease , Humans , Male , Microarray Analysis/methods , Real-Time Polymerase Chain Reaction , Syncope, Vasovagal/physiopathologyABSTRACT
Despite their crucial role in determining the fate of seeds, the type and breaking mode of seed dormancy in peatland plants in temperate Asia with a continental monsoon climate are rarely known. Fifteen common peatland plant species were used to test their seed germination response to various dormancy-breaking treatments, including dry storage (D), gibberellin acid soaking (GA), cold stratification (CS), warm followed cold stratification (WCS), GA soaking + cold stratification (GA + CS) and GA soaking + warm followed cold stratification (GA + WCS). Germination experiment, viability and imbibition test, and morphological observation of embryos were conducted. Of the 15 species, nine showed physiological dormancy (PD), with non-deep PD being the dominant type. Four species, Angelica pubescens, Cicuta virosa, Iris laevigata, and Iris setosa exhibited morphophysiological dormancy. Two species, Lycopus uniflorus and Spiraea salicifolia, demonstrated nondormancy. Overall, the effect hierarchy of dormancy-breaking is: CS > GA > WCS > GA + CS > D > GA + WCS. Principal component analysis demonstrated that seed traits, including embryo length: seed length ratio, seed size, and monocot/eudicot divergence, are more likely to influence seed dormancy than environmental factors. Our study suggests that nearly 90% of the tested peatland plant species in the Changbai Mountains demonstrated seed dormancy, and seed traits (e.g. embryo-to-seed ratio and seed size) and abiotic environmental factors (e.g. pH and temperature seasonality) are related to germination behavior, suggesting seed dormancy being a common adaptation strategy for the peatland plants in the temperate montane environment.
ABSTRACT
OBJECTIVE: To explore attenuation and mechanism of endoplasmic reticulum stress (ERS)-mediated hepatocyte apoptosis in rats with alcohol-induced liver injury by Qinggan Huoxue Recipe (QGHXR) and its disassembled formulas (Qinggan Recipe and Huoxue Recipe respectively). METHODS: A rat model of chronic alcoholic liver injury was successfully established using a compound reagent of alcohol, corn oil, and pyrazol. The modeled rats were randomly divided into the model group, the QGHXR group, the Qinggan Recipe (QGR) group, and the Huoxue Recipe group (HXR). The CCl4 control group and the normal control group were also set up. There were ten rats in each group. All rats of modeled groups were gastrogavaged with alcohol compound reagent every morning. Rats in the QGHXR group (at the daily dose of 9. 5 g/kg, QGR group (at the daily dose of 3.0 g/kg), and HXR group (at the daily dose of 6.5 g/kg) were administered with corresponding medicines by gastrogavage every afternoon. Equal volume of normal saline was given to rats of the model group by gastrogavage. CCl4 was intraperitoneally injected at the dose of 0.3 mL/kg to rats in the CCl4 control group, once per week. Normal saline was given to rats in the normal control group by gastrogavage. The treatment was lasted for two weeks. Pathological changes of the liver were observed by histopathology. Serum total homocysteine (tHCY) level was detected by ELISA. The hepatocyte apoptosis rate was detected using flow cytometry. The gene and protein expressions of eukaryotic translation initiation factor 2 alpha (elF-2alpha), phosphorylation elF-2alpha (pelF-2alpha), glucose-regulated protein 78 (GRP78), and Caspase-3 in the liver were examined using Real-time PCR and Westen blot respectively. RESULTS: Compared with the normal control group, typical pathological changes of chronic alcoholic liver injury such as steatosis, inflammation, and even fibrosis occurred in model rats. The hepatocyte apoptosis obviously increased, with the apoptosis rate reaching the five-fold of that in normal rats. Besides, early apoptosis dominated. The serum tHCY level significantly increased. The expressions of p-elF-2alpha, GRP78, and Caspase-3 protein obviously increased (P < 0.01). Expressions of GRP78 and Caspase-3 mRNA significantly increased (P < 0.05, P < 0.01). Compared with the model group, the degrees of the liver injury and the hepatocyte apoptosis in the QGHXR group, the QGR group, and the HXR group were significantly alleviated. The serum tHCY level was significantly lowered. The protein expressions of p-elF-2a, GRP78, and Caspase-3 obviously decreased (P < 0.01). mRNA expressions of GRP78 and Caspase-3 obviously decreased in the QGHXR group (P < 0.05, P < 0.01). Only GRP78 mRNA expression obviously decreased in the QGR group (P < 0.05). CONCLUSION: QGHXR and its disassembled formulas could attenuate ERS-mediated hepatocyte apoptosis in alcohol-induced liver injury rats by lowering the serum tHCY level and expressions of ERS apoptosis correlated factors.
Subject(s)
Apoptosis/drug effects , Drugs, Chinese Herbal/pharmacology , Endoplasmic Reticulum Stress/drug effects , Hepatocytes/drug effects , Liver Diseases, Alcoholic/pathology , Animals , Caspase 3/metabolism , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/therapeutic use , Eukaryotic Initiation Factor-2/metabolism , Heat-Shock Proteins/metabolism , Hepatocytes/pathology , Homocysteine/blood , Liver Diseases, Alcoholic/blood , Liver Diseases, Alcoholic/drug therapy , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: To investigate the role of PERK/eIF2alpha signaling pathway in hepatocyte apoptosis of alcoholic liver injury rats. METHODS: Rat models with ethanol-induced liver injury were successfully developed by gastric gavage with ethanol-corn oil mixtures for 12 weeks. At different time points (4, 6, 10, 12 week), liver pathology was dynamically observed. The hepatocyte apoptosis was quantitatively analyzed by Annexin V-FITC/PI double-labeled flow cytometry, the serum total homocysteine (tHCY) level was detected by ELISA and the expressions of eIF2a, p-eIF2a, GRP78/Bip, GRP94, caspase-3 and caspase-12 in liver were examined using Real-time PCR and Western blot. RESULTS: Typical acute liver injury and chronic liver injury were observed at week 4 and week 12 respectively. The hepatocyte apoptosis rates in 6-week model rats significantly increased compared with normal rats (P value less than 0.05), and the degree of hepatocyte apoptosis continued to increase with the modeling time, and the percentages of early and total apoptosis reached 26% and 29% at week 12. From week 6 to week 12, the serum tHCY levels in model rats were obviously higher than in normal rats (P value less than 0.01). Since week 4, eIF2a protein phosphorylation in model rat livers remarkably elevated compared with that in normal rat livers (P value less than 0.01), and at week 12 the peIF2a protein expression in model rat livers increased by 2.81-fold. Since week 4 the expressions of GRP78/Bip, GRP94, caspase-12 and caspase-3 mRNA and protein in model rat livers showed a significant increase as compared to normal rat livers, and at week 12, these gene and protein levels increased 4.70, 12.95, 3.83, 4.05 fold and 3.93, 6.93, 9.88, 3.31 fold, respectively (P value less than 0.01). CONCLUSION: Activation of PERK/eIF2a signaling pathway contributes to the occurrence and development of hepatocyte apoptosis in alcoholic liver injury rats and it might be as a potential target for therapeutic applications in alcoholic liver diseases.
Subject(s)
Apoptosis , Eukaryotic Initiation Factor-2/metabolism , Hepatocytes/pathology , Liver Diseases, Alcoholic/pathology , Signal Transduction , eIF-2 Kinase/metabolism , Animals , Hepatocytes/cytology , Liver Diseases, Alcoholic/metabolism , Male , Rats , Rats, Sprague-DawleyABSTRACT
Calophaca sinica Rehd. is a tree species with high economic value, whose resource has been declining due to unreasonable exploitation. In this study, we sequenced, assembled, and annotated the complete chloroplast genome of C. sinica. The whole chloroplast genome size is 129,345 bp, it lacks an inverted repeat (IR) region. The GC content of the whole chloroplast genome is 34.51%. The chloroplast genome comprises 112 unique genes, including 77 protein-coding genes (PCGs), 30 transfer RNA (tRNA) genes, and 5 ribosomal RNA (rRNA) genes. Phylogenetic analyses of chloroplast genomes derived from 15 species indicated that C. sinica is close to Caragana and Tibetia species in Papilionoideae.
ABSTRACT
OBJECTIVE: To explore the optimized clinical management and therapeutic strategies for the survived human case infected by influenza A (A/H5N1). METHODS: All the data of the first human case infected by A/H5N1 in Guizhou province was collected and analyzed. RESULTS: The first case infected by A/H5N1 in Guizhou Province was confirmed by laboratory findings with reverse-transcription polymerase chain reaction (RT-PCR) and A/H5N1 isolation. Patient was healthy in the past and exposed in the environment of living poultry. The initial symptoms was high fever without influenza-like presentation, but with extremity hyperspasmia and conscious disturbance sometimes. A productive cough with a large mount of pink foaming sputum then appeared. The clinical situation was rapidly deteriorated with dyspnea, acute respiratory distress syndrome and atrial fibrillation. Multiple infiltration in bilateral lungs was progressively developed with moderate bilateral pleural effusion. Invasive ventilation was intervened since ARDS on day 8 after sickness. Oseltamivir was kicked off since day 9 after sickness. However, the clinical condition was still exacerbated. High titering antibody of A/H5N1 vaccinated plasma was administrated on day 10 after sickness. The clinical condition (including oxygen saturation, respiratory symptoms, etc.) was improved rapidly. The weaning of ventilation was carried out in two days. Atrial fibrillation was back to normal. The patient was clinical recovery and was discharged from hospital on day 23 after sickness. CONCLUSIONS: The prognosis was poor if A/H5N1 infected human cases developed as acute respiratory distress syndrome with heart injury. However, it could be ameliorated if the plasma of A/H5N1 vaccinated neutralizing antibody was administrated in time or within two weeks after sickness.
Subject(s)
Influenza, Human/diagnosis , Influenza, Human/therapy , Adult , China , Humans , Immune Sera , Influenza A Virus, H5N1 Subtype , Influenza, Human/virology , Male , Prognosis , Respiratory Distress Syndrome/diagnosis , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapyABSTRACT
OBJECTIVE: To discuss the tactics of mechanical ventilation in a human severe case of influenza A (H5N1) complicated with acute respiratory distress syndrome (ARDS). METHODS: The data of the patient infected by the influenza A (H5N1) admitted to People's Hospital of Guizhou Province on January 15, 2009, were analyzed and summarized. RESULTS: The patient, a 29-year-old man, had been healthy in the past, but had exposed to the environment of bird flu before illness. The initial symptom was unremitting high fever, and then the clinical situation deteriorated progressively with occurrence of dyspnea. Pulmonary infiltrates were evident in the left lower lobe on January 19, and rapidly progressed to involve bilateral lungs presenting ARDS-like changes. Mechanical ventilation became the most important treatment among others. The ventilation mode was synchronized intermittent mandatory ventilation (SIMV)+ pressure support (PS) + positive end expiratory pressure (PEEP), following lung protective ventilatory strategies, with low tidal volume. The patient's condition improved day by day without developing multiple organ dysfunction. The patient fully recovered and was discharged on February 6. CONCLUSION: Early detection, early diagnosis, and finely effective intervention are to improve oxygenation by mechanical ventilation with low tidal volume and adequate PEEP are critical to reducing the mortality.
Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza, Human/complications , Respiration, Artificial/methods , Respiratory Distress Syndrome/therapy , Adult , China , Humans , Male , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/virologyABSTRACT
BACKGROUNDS: SERPINF1 mutations caused deficiency of pigment epithelium-derived factor (PEDF) and would lead to osteogenesis imperfecta (OI) type VI. However, serum PEDF levels were unclear in Chinese OI patients who had clear molecular diagnosis. OBJECTIVE: To assess PEDF levels in different genotypes of OI, to evaluate the influencing factors of PEDF in Chinese OI patients with clear molecular diagnosis. METHODS: Known candidate genes of OI were examined by a targeted next generation sequence. Serum PEDF levels were measured by ELISA in 6 OI patients with SERPINF1 mutations, 6 carriers of one copy of the SERPINF1 mutation, 88 OI patients with COL1A1, CLO1A2, IFITM5 and other pathogenic mutations of OI and 24 healthy controls. We compared the differences in serum PEDF levels among different OI patients and normal controls. RESULTS: Serum PEDF levels were extremely low in OI patients with SERPINF1 mutations (0.66±1.60µg/ml) than in OI patients with other pathogenic mutations (4.88±1.43-7.07±2.43µg/ml), carriers of one copy of SERPINF1 mutation (4.94±2.35µg/ml), and normal controls (7.29±2.31µg/m) (P<0.001). No significant differences in serum PEDF concentrations were found among patients with OI type I, III or IV, and between patients with or without bisphosphonate treatment. Serum PEDF level was positively correlated with Z-score of weight (r=0.310, P=0.004), BMI (r=0.253, P=0.020) and alanine aminotransferase (r=0.291, P=0.007). CONCLUSIONS: Extremely low level of PEDF was demonstrated as a specific, convenient, and inexpensive diagnostic biomarker for OI patients with SERPINF1 mutations, but it could not provide information regarding the clinical severity of OI and the efficacy of bisphosphonates treatment.
Subject(s)
Eye Proteins/blood , Mutation , Nerve Growth Factors/blood , Osteogenesis Imperfecta/genetics , Serpins/blood , Adult , Asian People , Biomarkers/blood , Case-Control Studies , Diphosphonates/therapeutic use , Eye Proteins/genetics , Humans , Nerve Growth Factors/deficiency , Nerve Growth Factors/genetics , Osteogenesis Imperfecta/blood , Osteogenesis Imperfecta/classification , Serpins/deficiency , Serpins/genetics , Young AdultABSTRACT
A lithium-sulfur (Li-S) battery is regarded as the most promising candidate for next generation energy storage systems, because of its high theoretical specific capacity (1675 mA h g-1) and specific energy (2500 W h kg-1), as well as the abundance, low cost and environmental benignity of sulfur. However, the soluble polysulfides Li2Sx (4 ≤ x ≤ 8) produced during the discharge process can cause the so-called "shuttle effect" and lead to low coulombic efficiency and rapid capacity fading of the batteries, which seriously restrict their practical application. Using porous materials as hosts to immobilize the polysulfides is proved to be an effective strategy. In this article, a dual functional cage-like metal-organic framework (Cu-MOF), Cu-TDPAT, combining the Lewis basic sites from the nitrogen atoms of the ligand H6TDPAT with the Lewis acidic sites from Cu(ii) open metal sites (OMSs), was employed as the sulfur host in a Li-S battery for lithium ions and polysulfide anions (Sx2-). In addition, the size of nano-Cu-TDPAT was also optimized by microwave synthesis to reduce the internal resistance of the batteries. The electrochemical test results showed that the optimized Cu-TDPAT material can efficiently confine the polysulfides within the MOF, and the resultant porous S@Cu-TDPAT composite cathode material with the size of 100 nm shows good cycling performance with a reversible capacity of about 745 mA h g-1 at 1C (1C = 1675 mA g-1) after 500 cycles, to the best of our knowledge, which is higher than those of all reported S@MOF cathode materials. The DFT calculation and XPS data indicate that the good cycling performance mainly results from the dual functional binding sites (that is, Lewis acid and base sites) in nanoporous Cu-TDPAT, providing the comprehensive and robust interaction with the polysulfides to overcome their dissolution and diffusion into the electrolyte. Clearly, our work provides a good example of designing MOFs with suitable interaction sites for the polysulfides to achieve S@MOF cathode materials with excellent cycling performance by multiple synergistic effects between nanoporous host MOFs and the polysulfides.
ABSTRACT
AIM: To investigate the correlation between DKK1 polymorphisms with bone phenotypes and response to alendronate treatment. MATERIALS & METHODS: Five tag single nucleotide polymorphisms of DKK1 were analyzed in 639 Chinese postmenopausal women with osteoporosis or osteopenia. Bone mineral density (BMD), ß-CTX and ALP were measured before and after alendronate treatment. RESULTS: Genotypes at rs1896367, rs1528877 and rs2241529 correlated to baseline BMD (p < 0.05). rs1528877 and rs2241529 polymorphisms correlated to baseline ß-CTX levels (p < 0.05). rs2241529 polymorphisms of DKK1 had a small influence on the skeletal response to alendronate treatment (p < 0.05). CONCLUSION: DKK1 polymorphisms may correlate to baseline BMD and serum ß-CTX levels, but present a weak effect on the response to alendronate.
Subject(s)
Alendronate/therapeutic use , Bone Density Conservation Agents/therapeutic use , Bone Density/drug effects , Bone Remodeling/drug effects , Intercellular Signaling Peptides and Proteins/genetics , Alanine Transaminase/blood , Alkaline Phosphatase/blood , Asian People , Biomarkers/blood , Bone Diseases, Metabolic/drug therapy , Bone Diseases, Metabolic/genetics , Bone Diseases, Metabolic/physiopathology , Collagen Type I/blood , Creatinine/blood , Genetic Association Studies , Humans , Osteoporosis, Postmenopausal/drug therapy , Osteoporosis, Postmenopausal/genetics , Osteoporosis, Postmenopausal/physiopathology , Peptides/blood , Polymorphism, Single Nucleotide , Prospective StudiesABSTRACT
BACKGROUND: Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessively inherited disease characterized by excessive wasting of renal tubular magnesium and calcium. FHHNC is associated with various mutations in CLDN16 and CLDN19. CASES: Two children from a consanguineous family of Chinese Han origin demonstrated manifestations of rickets, polyuria, polydipsia, hematuria and failure to thrive. Hypomagnesaemia (0.49-0.50mmol/L), hypercalciuria or a trend to hypercalciuria (24hour urine calcium: 3.8-5.1mg/kg/day), and secondary hyperparathyroidism (serum PTH level: 94.7-200pg/mL) were revealed upon laboratory examination. Using targeted next-generation sequencing and subsequent confirmation by Sanger sequencing, a novel homozygous mutation was identified in the CLDN16 gene of both FHHNC patients. This specific mutation, a 16bp deletion followed by a 23bp insertion in exon 3, led to the generation of a premature termination codon. The parents and an unaffected sister were all heterozygous carriers of this mutation. CONCLUSIONS: We detected a novel mutation in CLDN16 for the first time. The clinical and genetic findings from this study will help to expand the understanding of this rare disease, FHHNC.
Subject(s)
Claudins/genetics , Hypercalciuria/complications , Magnesium/blood , Mutation , Nephrocalcinosis/complications , Adolescent , Child , China , Ethnicity , Female , Humans , Male , PedigreeABSTRACT
BACKGROUND: Osteogenesis imperfecta (OI) is a group of hereditary disorders characterized by low bone mass and recurrent fractures. Most OI cases follow an autosomal dominant pattern of inheritance and are attributed to mutations in genes encoding type I collagen (COL1A1/COL1A2). Genomic structural variations involving type I collagen genes are extremely rare in OI. CASE REPORT: In this study, we characterized a de novo balanced translocation of t(5;7)(q32;q21.3) that caused an extremely rare type of OI in a patient from a non-consanguineous family. The clinical phenotypes of this OI included recurrent fractures, low bone mass, macrocephaly, blue sclera and failure to thrive. Next-generation sequencing was used to identify the translocation, and Sanger sequencing was used to validate and map the breakpoints. The breakpoint on chromosome 7 disrupted the COL1A2 gene in the 17th exon, presumed to affect type I collagen production and give rise to OI. The breakpoint on chromosome 5 disrupted the protein phosphatase 2 regulatory subunit B, beta gene (PPP2R2B) within the first intron. CONCLUSIONS: This is the first report of a copy-neutral structural variant involving COL1A2 that leads to a rare type of OI. This study expands the genotypic spectrum of OI and demonstrates the effectiveness of targeted sequencing for breakpoint mapping.