Protein glycosylation is a diverse form of post-translational modification. Two to three consecutive O-linked N-acetylgalactosamines (Tn-antigens) are recognized by antibodies such as MLS128. MLS128 mAb inhibited cell growth and bound to a 110 kDa glycoprotein (GP) in LS180 and HT29 colon cancer cells. However, purification and identification of the 110 kDa GP was unsuccessful due to its low abundance. The present study used a highly sophisticated and sensitive mass spectrometry method to identify proteins immunoprecipitated with MLS128 and separated by two-dimensional gel electrophoresis. Three desmosome components were identified. Of these, desmocollin and desmoglein shared many similar characteristics, including molecular mass, pI, and potential Tn-antigen sites. Western blotting analyses of LS180 cell lysates revealed a common 110 kDa band recognized by MLS128 and anti-desmocollin, but not by anti-desmoglein. Immunofluorescence microscopy of LS180 cells revealed that desmocollin is membrane-bound, while desmoglein is primarily localized in the cytosol. Confocal microscopy demonstrated colocalization of the desmocollin-specific antibody with the MLS128 antibody on the cell membrane, suggesting that desmocollin may contain Tn-antigens recognized by MLS128. Treatment of LS180 cells with siRNA to knock down desmocollin expression or a desmocollin-specific antibody decreased cell viability, suggesting a critical role for this protein in cell growth and survival. N-glycosidase F digestion of the 110 kDa GP and desmocollin suggested that although both proteins contain N-glycosylation sites, they are not identical. These findings suggest that desmocollin colocalizes with the 110 kDa GP and that growth inhibition induced by the MLS128 antibody may be mediated through a mechanism that involves desmocollin.
Newcastle disease virus (NDV), an avian paramyxovirus, causes Newcastle disease (ND) which is a highly contagious and fatal viral disease affecting poultry and most species of birds. The fusion (F) protein of NDV mediates membrane fusion, which is essential to the processes of viral entry, replication, and dissemination. Although several domains of NDV F are known to have important effects on regulating the membrane fusion activity, the role of the region around domain III (DIII) and domain I (DI) still remains ill-defined. Site-directed mutagenesis was utilized to change the conserved amino acids at 269, 274, 277, 286, 287, 290, 295, and 297 to alanine in order to investigate the effects of these conserved amino acids around the DIII and DI linker region of the NDV F protein on fusion activity. It was found that five of these substitutions almost abolished fusion activity except for mutants I269A, Q286A, and N297A, which showed 57.1%, 161.1%, and 97.7% of the wt F level, respectively. Four (I274A, D277A, V287A, and P290A) of these five mutants likely result in interfering with folding or transporting of the molecule since these proteins were minimally expressed at the cell surface, formed aggregates, or not proteolytically cleaved. However, mutant L295A almost abolished fusion activity even with a similar level of cell surface expression. These data indicated that conserved amino acids around the DIII-DI linker region are critical for the folding of the F protein and have an important influence on fusion activity.
Mitochondrial trans-2-enoyl-CoA reductase (MECR) is a protein-coding gene, and the protein encoded by this gene is an oxidoreductase that catalyzes the last step in mitochondrial fatty acid synthesis (mtFASII). Numerous studies have shown disorder of lipid metabolism is closely related with malignance, especially in liver cancer. Through pre-experiment, we found that the expression of MECR gene was highly expressed in hepatocelluar carcinoma (HCC) cell lines in vitro. This suggests that the MECR gene may play a role of oncogene in HCC. Therefore, we conducted a preliminary experimental study on the role of MECR gene in HCC cells in vitro. Objective to explore whether the MECR gene can affect the malignant biological behavior of HCC. We selected HCC cell line BEL-7404 as experimental cell, which involves the highest expression of MECR in the pre-experiment. We constructed MECR knockdwon lentivirus vector, and then infected HCC cell lines to down-regulate MECR expression, and establish negative control group (NC). Through various experiments of cytology, our study showed that knockdown of MECR inhibited cell proliferation and colony formation, promoted apoptosis, and inhibited metastasis in HCC cell lines BEL-7404. MECR might serve as a novel gene therapeutic target for the treatment of HCC. Further study is needed to elucidate the signaling pathway through which MECR functions in HCC.
The associations of human chorionic gonadotropin (hCG), estrogen, and progesterone levels with threatened abortion have not been fully studied. Eighty women with threatened abortion were recruited sequentially, and the levels in their pregnancy hormones during the first trimester were compared with that of 160 normal early pregnancy controls. The natural logarithm transformed (Ln) hCG and Lnestrogen of women with threatened abortion and gestational age ≤ 6 weeks were significantly higher than values for the normal controls of the same gestational age (8.6 ± 1.2 vs. 7.4 ± 1.7 mIU/mL and 5.8 ± 0.4 vs. 5.4 ± 0.5 pg/mL); the two hormones reached similar levels in the groups of gestational age > 6 weeks. Among the group with gestational age ≤ 6 weeks, a univariate logistic regression showed that LnhCG and Lnestrogen were associated with threatened abortion, with odds ratios (ORs) of 1.85 [95% confidence interval (CI): 1.30-2.64] and 4.62 (95% CI: 1.67-12.80), respectively. The multivariate logistic regression model revealed that hCG and estrogen were mutually confounding factors, and only hCG was an independent factor for threatened abortion (OR 1.56; 95% CI: 1.06-2.28). None of the variables in the univariate or multivariate logistic regression was a factor associated with threatened abortion after 6 weeks gestational age. In conclusion, β-hCG and estrogen levels in the first half of the first trimester are factors associated with threatened abortion.
Paeonol extracted from the Moutan Cortex, possesses hepatoprotective activity against epirubicin (EPI)-induced liver damage. This study evaluated the protective effect of paeonol on EPI-induced hepatotoxicity and explored the underlying metabolomic mechanism. Breast tumor-bearing mice were randomly divided into three groups: control, EPI, and EPI + paeonol treatment. Mice received a tail i.v. injection of EPI every other day for 3 cycles or/and intragastrically (i.g.) administered paeonol daily for 6 days. Hematoxylin-eosin (HE) staining and biochemical detection were used to determine the degree of damage. A gas chromatography-mass spectrometry (GC-MS) technique was established to determine the metabolites. PLS-DA and PCA were used to investigate metabolic changes. HE staining and biochemical detection results showed that EPI caused serious liver damage while paeonol ameliorated it. The results of mass spectrogram, partial least squares-discriminate analysis (PLS-DA), and principal component analysis (PCA) demonstrated that lipid, amino acid, and energy metabolism involving seven metabolites were obviously changed by EPI and reversed by paeonol. Additionally, paeonol inhibited EPI-induced activation of adenosine monophosphate activated protein kinase/mammalian target of Rapamycin (AMPK/mTOR) signalling pathway. Our results demonstrated the hepatoprotective effect of paeonol on EPI-induced hepatotoxicity in mice, provided potential biomarkers for early assessment of EPI-induced liver injury and illuminated the metabolic mechanism underlying paeonol-related hepatic protection.
The current study investigated how the FOXI1 and KCNJ10 genes were affected in infants with a single-allele mutation in the SLC26A4 gene, and it determined the audiological phenotypes of infants with double heterozygous mutations (DHMs) in the three genes. Subjects were 562 infants with a single-allele SLC26A4 mutation detected during neonatal deafness genetic screening; the infants were seen as outpatients by Otology at Beijing Tongren Hospital. All subjects underwent SLC26A4 sequencing. Twenty infants had a second-allele variant while the remaining 542 had an SLC26A4 single-allele mutation. Infants also underwent FOXI1 and KCNJ10 sequencing. All patients with double heterozygous mutations in the aforementioned genes underwent an audiological evaluation and a limited imaging study; variants and audiological phenotypes were analyzed. Of 562 patients, 20 had SLC26A4 bi-allelic mutations; 8 carried single mutations in both SLC26A4 and KCNJ10. No pathogenic mutations in the FOXI1 gene were found. Four missense mutations in KCNJ10 were detected, including c.812G>A, c.800A>G, c.53G>A, and c.1042C>T. Eight individuals with a DHMs all passed universal newborn hearing screening, and all were found to have normal hearing. These data suggest that individuals with an SLC26A4 single-allele mutation, combined with FOXI1 or KCNJ10 gene mutations, do not suffer hearing loss during infancy, though this finding is worthy of further follow-up and in-depth discussion.
In the field of epigenetics, histone deacetylases (HDACs) are important members and well validated targets for anti-cancer drugs discovery. In this study, we designed and synthesized twenty-seven novel hydroxamic acid-based HDAC inhibitors (HDACis) with benzyl-triazole as the core skeleton. Most target compounds displayed excellent inhibition rates toward HDACs. Among them, compounds ZM-22 to ZM-27 with inhibition rates more than 90% toward HDACs exhibited potent inhibitory activity toward HDAC6, and ZM-23 possessed the best selectivity to HDAC6 over HDAC1. The high potency of compound ZM-23 toward HDAC6 was rationalized by molecular docking simulation. This series of compounds is worthy for further anti-cancer activity evaluation and structural optimization works.
Acquired immune deficiency syndrome (AIDS), hepatitis B virus (HBV), hepatitis C virus (HCV), gonorrhea and syphilis are the major sexually transmitted diseases (STDs) in the world, which are the focus of epidemic prevention and control in China. The epidemiological trend analysis of STDs in Shanghai could reflect the epidemic situation of these diseases in high-income areas of China, providing a reference for how to control their epidemic. Although the overall incidence rate of infectious diseases levelled off after 2009, Shanghai still faces many new obstacles in the fight against STDs. Without effective prevention and control strategies for high-risk behaviors, such as active sexual activity without protection, for key susceptible populations, there may be a more serious epidemic of STDs in the future. Given these situations, strategies for controlling STDs in Shanghai should be more targeted with the development of epidemics, focusing on the following key areas for future work: i) attaching importance to health education; ii) strengthening epidemic surveillance; and iii) developing Community Health Service Centers (CHSC) as intervention subjects.
As the super-aged society, Japan is facing challenges in health care system. As one of measures to cope with challenges, the Ministry of Health, Labor, and Welfare started to construct an open medical information platform, named PeOPLe, in 2016 for personalized medical care, improvement of medical services, and the redistribution of medical resources. The Ministry plans to build the platform infrastructure by 2020 and put the platform into full-scale operation by 2025. PeOPLe collects only medical records, but it should collect lifelogs as well in order to better improve the health, especially for elderly. A lifelog is a record of a person's activity and it has potential to predict the probability a person will suffer a lifestyle-related disease as a result of the person's lifestyle. This prediction could help to maintain the health of the elderly. In addition, constructing a self-recording platform integrated with the medical platform is the best way to collect lifelogs since collecting a large amount of lifelogs for a long time from various people at public or medical agencies is difficult. A self-recording platform is a place where people can post and manage their lifelogs. In return for posting lifelogs, people will receive personalized health advice, which will attract more people.
Japan is experiencing unprecedented aging of its population. People age 65 years or older accounted for 28.1% of the total population in 2018, and that proportion is expected to reach 33.3% in 2036 and 38.4% in 2065. In 2017, the average life expectancy in Japan was 81.09 years for men and 87.26 years for women. By 2065, it is expected to reach 84.95 years for men and 91.35 years for women. Population aging affects health and long-term care systems. The government proposed the establishment of "a community-based integrated care system" by 2025 with the purpose of comprehensively ensuring the provision of health care, nursing care, preventive care, housing, and livelihood support. This will require health care and nursing care professionals who are capable of fully understanding the physical and mental characteristics of elderly people and the fostering of organic collaboration with others professionals in the community-based integrated care system. A department of gerontology or geriatric medicine is desired to be established in each medical school to teach students medicine and efficient medical care, to conduct research, and to develop personnel to facilitate this paradigm shift. In 2018, there were 263 colleges of nursing with an admissions capacity of 23,667. In Japan, Certified Nurse Specialists can specialize in 13 areas as of December 2016. The number of Certified Nurse Specialists increased to 2,279 as of December 2018. One hundred and forty-four of those specialists specialized in Gerontological Nursing while 53 specialized in Home Care Nursing. The number of nurses specializing in Gerontological Nursing and Home Care Nursing is desired to be increased in order to implement and improve community-based comprehensive care.
Hepatocellular carcinoma (HCC) is a prevalent and refractory cancer in the world and very few drugs are available for the disease treatment currently. Programmed cell death protein-1 (PD-1) monoclonal antibodies including nivolumab and pembrolizumab has received accelerated approval for treatment of advanced HCC based on phase 1/2 clinical trials. However, the recently disclosed results of phase 3 clinical trials showed that both nivolumab and pembrolizumab as monotherapy failed to meet the primary objectives, which might overshadow the prospect of PD-1 inhibitors as monotherapy in treatment of advanced and unresectable HCC. The feasibility of PD-1 inhibitors in combination with other therapies or in other HCC settings requires further verification in the future.
Threatened abortion is a common complication of pregnancy. Since the underlying mechanisms behind this condition are complicated, predicting and treating threatened abortion is a challenge for clinicians. Interestingly, a recent article in Bioscience Trends (Biosci Trends 2019; DOI: 10.5582/bst.2019.01111) revealed a higher, not lower, level of ꞵ-human chorionic gonadotropin (hCG) and estrogen during the first 6 weeks of pregnancy, suggesting a novel association between ꞵ-hCG, estrogen, and threatened abortion. Unfortunately, this study was limited by its small sample size, unconvincing trial design, and inadequate exploration of the underlying mechanisms. This low-quality evidence indicates that a higher level of ꞵ- hCG and estrogen is associated with threatened abortion. However, that work provided some new insights for further studies of threatened abortion.