Publications by authors named "Yan Jiang"

1,583 Publications

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Comparative Evaluation of the Effect of Metformin and Insulin on Gut Microbiota and Metabolome Profiles of Type 2 Diabetic Rats Induced by the Combination of Streptozotocin and High-Fat Diet.

Front Pharmacol 2021 3;12:794103. Epub 2022 Jan 3.

Department of Pharmacy, The Third Affiliated Hospital of Soochow University/The First People's Hospital of Changzhou, Changzhou, China.

Lately, an increasing number of studies have investigated the relationship between metformin and gut microbiota, suggesting that metformin exerts part of its hypoglycemic effect through the microbes. However, its underlying mechanism remains largely undetermined. In the present study, we investigated the effects of metformin on gut microbiota and metabolome profiles in serum and compared it with insulin treatment in rats with type 2 diabetes mellitus (T2DM). Diabetic rats (DM group) were induced by a combination of streptozotocin and high-fat diet (HFD). After 7 days, DM rats were treated with metformin (MET group) or insulin (INS group) for 3 weeks. The 16S rRNA sequencing of the gut microbiota and non-targeted metabolomics analysis of serum were conducted. A total of 13 bile acids (BAs) in serum were further determined and compared among different groups. The rat model of T2DM was well established with the typical diabetic symptoms, showing significantly increased blood glucose, AUC of OGTT, HOMA-IR, TC, TG, LDL-C and TBA. Metformin or insulin treatment could ameliorate symptoms of diabetes and partly recover the abnormal biochemical indicators. Compared with DM rats, the relative abundances of 13 genera were significantly changed after metformin treatment, while only three genera were changed after insulin treatment. The metformin and insulin treatments also exhibited different serum metabolome profiles in T2DM rats. Moreover, 64 differential metabolites were identified between MET and DM groups, whereas 206 were identified between INS and DM groups. Insulin treatment showed greater influence on amino acids, glycerophospholipids/glycerolipids, and acylcarnitine compared with the metformin treatment, while metformin had an important impact on BAs. Furthermore, metformin could significantly decrease the serum levels of CA, GCA, UDCA, and GUDCA, but increase the level of TLCA in DM rats. Insulin treatment significantly decreased the levels of CA, UDCA, and CDCA. Besides, several metabolites in serum or microbiota were positively or negatively correlated with some bacteria. Collectively, our findings indicated that metformin had a stronger effect on gut microbiota than insulin, while insulin treatment showed greater influence on serum metabolites, which provided novel insights into the therapeutic effects of metformin on diabetes.
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http://dx.doi.org/10.3389/fphar.2021.794103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762251PMC
January 2022

Nursing allocation in isolation wards of COVID-19 designated hospitals: a nationwide study in China.

BMC Nurs 2022 Jan 19;21(1):23. Epub 2022 Jan 19.

Nursing Department of West China Hospital, Sichuan University, NO. 37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan Province, China.

Background: Appropriate allocation of nursing staff is key to ensuring efficient nursing in hospitals, and is significantly correlated with patient safety, nursing quality, and nurse job satisfaction. However, there are few studies on nursing workforce allocation in the isolation wards of COVID-19 designated hospitals globally. This study aims to better understand the nursing workforce allocation in the isolation wards of COVID-19 designated hospitals in China, and provide a theoretical basis for efficiently deploying first-line nurses in China and across the world in the future.

Methods: An online survey was conducted among the head nurses (n = 229) and nurses (n = 1378) in the isolation wards of 117 hospitals (selected by stratified sampling), using a self-reported human resource allocation questionnaire.

Results: The average bed-to-nurse ratios of different isolation wards were different (Z = 36.742, P = 0.000). The bed-to-nurse ratios of the ICU, suspected COVID-19 cases ward, and confirmed COVID-19 cases ward, were 1:1.88, 1:0.56, and 1:0.45, respectively. The nurse work hours per shift in different isolation wards were also different (Z = 8.468, P = 0.014), with the specific values of the ICU, suspected COVID-19 cases ward, and confirmed COVID-19 cases ward, being 5, 6, and 6 h, respectively. A correlation analysis showed that the average work hours per shift was proportional to the overtime work of nurses (r = 0.146), the proportion of nurse practitioners was proportional to the overall utilization rate of nursing human resources in the wards (r = 0.136), and the proportion of nurses with college degrees was proportional to teamwork (r = 0.142). The proportion of nurses above grade 10 was inversely proportional to teamwork and psychological problems (r = 0.135, r = 0.203). The results of multiple stepwise regression analyses showed that the work hours of nurses per shift was the main factor affecting nurse satisfaction and that the proportion of nurses and the work hours of nurses per shift were both independent factors affecting the length of stay (LOS) of patients.

Conclusion: Hospitals in China have made good nursing workforce allocations during the COVID-19 pandemic, but there are certain shortcomings. Therefore, scientific and efficient nursing workforce allocation practice plans should be established to improve the ability of hospitals to deal with public health emergencies and are urgent problems that need to be addressed soon.
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http://dx.doi.org/10.1186/s12912-021-00795-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766220PMC
January 2022

Vitexin attenuates non-alcoholic fatty liver disease (NAFLD) lipid accumulation in high fat-diet fed mice by activating autophagy and reducing endoplasmic reticulum (ER) stress in liver.

Biol Pharm Bull 2022 Jan 15. Epub 2022 Jan 15.

Medical College, Guangxi University.

Non-alcoholic fatty liver disease (NAFLD) has become prevalent worldwide, but sufficient pharmaceutical treatments for this condition are lacking. Previous literature suggests that vitexin offers beneficial effects in the treatment of NAFLD, but the underlying mechanisms are not well understood. In this study, the in vivo effects of vitexin were investigated in high-fat-diet (HFD)-induced NAFLD mice. Liver pathology, biochemical parameters, lipid levels, hepatocyte ultrastructure, and related regulatory proteins were measured at the end of treatment. Treatment consisted of four weeks of daily administration of vitexin at a dose of 6 mg/kg of body weight. This treatment markedly improved hepatic architecture, attenuated lipid accumulation, and regulated lipid abnormalities. In addition, the treatment reduced endoplasmic reticulum (ER) stress, restored mitochondrial biological proteins, and increased autophagy. Furthermore, the treatment increased PPAR-r protein, which was inhibited by HFD. Thus, it was speculated that vitexin degraded lipids in HFD-induced NAFLD mice liver by inducing autophagy and restoring both ER and mitochondrial biological proteins.
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http://dx.doi.org/10.1248/bpb.b21-00716DOI Listing
January 2022

Paternal acrylamide exposure induces transgenerational effects on sperm parameters and learning capability in mice.

Food Chem Toxicol 2022 Jan 13;161:112817. Epub 2022 Jan 13.

Medical College of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China. Electronic address:

Acrylamide (AA) has been shown to have neurological and reproductive toxicities, but little is known about transgenerational effects of AA. In this study, male C57BL/6 mice were exposed to AA (0.01, 1, 10 μg/mL) and its metabolite glycidamide (GA, 10 μg/mL) in drinking water, which were then mated with unexposed female mice to produce F1 and F2 generations. We found that both AA and GA at high concentrations decreased sperm motility in F0 mice and increased sperm malformation rates in mice from all the three generations. In addition, AA and GA increased sperm reactive oxygen species as well as decreased serum testosterone levels, and increased the escape latency time in exposed mice and their offspring. We further found that AA-induced mRNA expression changes in the hippocampus of F0 mice persist to the F2 generation. In the sperm of F0 mice, AA induced significant DNA methylation changes in genes involved in neural and reproduction; the mRNA expression levels of Dnmt3b, a DNA methyltransferase, were dramatically decreased in the testes of F0 and F1 mice. In conclusion, our study indicates that paternal AA exposure leads to DNA methylation-mediated transgenerational adverse effects on sperm parameters and leaning capability in mice.
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http://dx.doi.org/10.1016/j.fct.2022.112817DOI Listing
January 2022

Emergence of a KPC-90 Variant that Confers Resistance to Ceftazidime-Avibactam in an ST463 Carbapenem-Resistant Pseudomonas aeruginosa Strain.

Microbiol Spectr 2022 Jan 12:e0186921. Epub 2022 Jan 12.

Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital, Zhejiang Universitygrid.13402.34 School of Medicine, Hangzhou, Zhejiang, China.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has become a serious challenge in the clinic. Recently, the prevalence of CRPA isolates carrying the gene has been increasing in China. Ceftazidime-avibactam (CZA) has shown good efficacy against large portions of KPC-2-producing CRPA strains. However, with the increasing usage of this drug, CZA resistance in CRPA strains has been reported. Here, we reported for the first time that resistance of the ST463 CRPA strain to CZA was caused by a novel variant in the KPC gene that arose after CZA exposure. The CRPA strain PA2207 is a carbapenem- and CZA-resistant strain that harbors a mutated gene, named . Cloning and expression of in Escherichia coli DH5α revealed that KPC-90 led to a 64-fold increase in the MIC value of CZA. Conjugation experiments further confirmed that was located on a conjugative plasmid. Whole-genome sequencing analysis showed that this plasmid had high sequence similarity to a previously reported novel -harboring plasmid in a clinical P. aeruginosa strain isolated in China. In addition, overexpression of an efflux pump (MexXY-OprM) might be associated with the CZA resistance phenotype, as determined by reverse transcription-quantitative PCR and efflux pump inhibition experiments. For the first time, we reported a KPC variant, KPC-90, in a clinical ST463 CRPA strain with CZA resistance that was mediated by a 2 amino acid insertion outside the KPC omega-loop region. Our study further highlights that diverse KPC variants that mediate CZA resistance have emerged in the CRPA strain. Furthermore, KPC-90 mutation combined with efflux pump overexpression resulted in a high level of resistance to CZA in the PA2207 isolate. Effective surveillance should be conducted to prevent CZA resistance from spreading in the CRPA strain. For the first time, we reported a KPC variant, KPC-90, in a clinical ST463 CRPA strain with CZA resistance. CZA resistance was mediated by a 2 amino acid insertion outside the KPC omega-loop region in CRPA. Our study further emphasized that CZA resistance caused by gene mutation could be selected in CRPA after CZA therapy. Considering the widespread presence of the ST463 CRPA strain in China, clinicians should pay attention to the risk of the development of CZA resistance in CRPA strains under treatment pressure.
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http://dx.doi.org/10.1128/spectrum.01869-21DOI Listing
January 2022

The combination of computed tomography features and circulating tumor cells increases the surgical prediction of visceral pleural invasion in clinical T1N0M0 lung adenocarcinoma.

Transl Lung Cancer Res 2021 Nov;10(11):4266-4280

Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Visceral pleural invasion (VPI) is a clinical manifestation associated with a poor prognosis, and diagnosing it preoperatively is highly imperative for successful sublobar resection of these peripheral tumors. We evaluated the roles of computed tomography (CT) features and circulating tumor cells (CTCs) for improving VPI detection in patients with clinical T1N0M0 invasive lung adenocarcinoma.

Methods: Three hundred and ninety-one patients were reviewed retrospectively in this study, of which 234 presented with a pleural tag or pleural contact on CT images. CTCs positive for the foliate receptors were enriched and analyzed prior to surgery. Logistic regression analyses were performed to assess the association of CT features and CTCs with VPI, and the receiver operating characteristic (ROC) curve was generated to compare the predictive power of these variables.

Results: Patients mostly underwent either segmentectomies (18.9%) or lobectomies (79.0%). Only 49 of the 234 patients with pleural involvement on CT showed pathologically confirmed VPI. Multivariate logistic regression analysis revealed that CTC level ≥10.42 FU/3 mL was a significant VPI risk factor for invasive adenocarcinoma cases ≤30 mm [adjusted odds ratio (OR) =4.62, 95% confidence interval (CI): 2.05-10.44, P<0.001]. Based on CT features, subgroup analyses showed that the solid portion size was a statistically significant independent predictor of VPI for these peripheral nodules with pleural tag, while the solid portion length of the interface was an independent predictor of pleural contact. The receiver operating curve analyses showed that the combination of CTC and CT features were highly predictive of VPI [area under the curve (AUC) =0.921 for pleural contact and 0.862 for the pleural tag, respectively].

Conclusions: CTC, combined with CT features of pleural tag or pleural contact, could significantly improve VPI detection in invasive lung adenocarcinomas at clinical T1N0M0 stage prior to the patient's surgery.
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http://dx.doi.org/10.21037/tlcr-21-896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674597PMC
November 2021

Relation of circulating lncRNA GAS5 and miR-21 with biochemical indexes, stenosis severity, and inflammatory cytokines in coronary heart disease patients.

Authors:
Yan Jiang Tian Du

J Clin Lab Anal 2022 Jan 8:e24202. Epub 2022 Jan 8.

Department of Thoracic and Cardiovascular Surgery, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Edong Healthcare Group, Huangshi, China.

Background: Long noncoding RNA GAS5 (lnc-GAS5) and its target microRNA-21 (miR-21) regulate blood lipid, macrophages, Th cells, vascular smooth muscle cells to participate in atherosclerosis, and related coronary heart disease (CHD). The study aimed to further explore the linkage of their circulating expressions with common biochemical indexes, stenosis severity and inflammatory cytokines in CHD patients.

Methods: Ninety-eight CHD patients and 100 controls confirmed by coronary angiography were enrolled. Plasma samples were collected for lnc-GAS5 and miR-21 detection by reverse transcription-quantitative polymerase chain reaction and inflammatory cytokines determination by enzyme-linked immunosorbent assay.

Results: Lnc-GAS5 was increased in CHD patients compared with controls (2.270 (interquartile range [IQR]: 1.676-3.389) vs. 0.999 ([IQR: 0.602-1.409], p < 0.001), whereas miR-21 showed opposite tread (0.442 [IQR: 0.318-0.698] vs. 0.997 [IQR: 0.774-1.368], p < 0.001). In aspect of their intercorrelation, lnc-GAS5 negatively linked with miR-21 in CHD patients (p < 0.001) instead of controls (p = 0.211). Interestingly, among the common biochemical indexes, lnc-GAS5 related to decreased high-density lipoprotein cholesterol (p = 0.008) and increased C-reactive protein (CRP) (p < 0.001), while miR-21 correlated with lower total cholesterol (p = 0.024) and CRP (p < 0.001) in CHD patients. As stenosis degree, lnc-GAS5 positively correlated with Gensini score (p < 0.001), but miR-21 exhibited negative association (p = 0.003) in CHD patients. In terms of inflammatory cytokines, lnc-GAS5 positively related to tumor necrosis factor α (TNF-α) and interleukin (IL)-17A, while miR-21 negatively linked with TNF-α, IL-1β, IL-6, and IL-17 in CHD patients (all p < 0.05).

Conclusion: Circulating lnc-GAS5 and its target miR-21 exhibit potency to serve as biomarkers for CHD management.
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http://dx.doi.org/10.1002/jcla.24202DOI Listing
January 2022

Specific Characteristic of Hyperplastic Callus in a Larger Cohort of Osteogenesis Imperfecta Type V.

Calcif Tissue Int 2022 Jan 6. Epub 2022 Jan 6.

Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Chinese Academy of Medical Sciences and Peking Union Medical College, Shuaifuyuan No. 1, Dongcheng District, Beijing, 100730, China.

Hyperplastic callus (HPC) is the most conspicuous features of osteogenesis imperfecta (OI) type V, of which accurate diagnosis and treatment are facing challenges. We investigate the clinical features, and impact factors of HPC in OI type V patients. In this retrospective single-center study, a total of 21 patients with type V OI confirmed by IFITM5 mutation were included. Radiological characteristics of bone were evaluated by X-rays, dual-energy X-ray absorptiometry, and computed tomography scan. Bone biopsy specimens were performed and stained by routine hematoxylin-eosin. The effects of bisphosphonates on HPC were investigated. Eleven patients (52.3%) had HPCs at 19 skeletal sites, 11 of which affected the femur. Three patients developed four (21.1%) HPCs after fractures, and 15 (78.9%) HPCs occurred in absence of bone fracture. The progress of HPCs was variable, of which most HPCs enlarged in the initial phase and remained stable, and only one HPC dwindled in size. One patient had a rapidly growing mass on the right humerus, and biopsy showed irregular trabeculae of woven bone and immature bone and cartilage in the loose and edematous collagenous network without signs of tumor. Bisphosphonates treatment had no significant effects on HPC of OI patients. HPC is the specific characteristic of OI type V patients, and its location, shape, size, and progression are variable, and the femur is the most frequently involved site. It is very important to make a diagnosis of HPC through detecting IFITM5 mutation and completing pathological diagnosis if necessary. The treatment of HPC is worth further exploration.
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http://dx.doi.org/10.1007/s00223-021-00932-2DOI Listing
January 2022

Anticolonization of Carbapenem-Resistant by LP1812 Through Accumulated Acetic Acid in Mice Intestinal.

Front Cell Infect Microbiol 2021 15;11:804253. Epub 2021 Dec 15.

Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Sir Run Run Shaw Hospital, Hangzhou, China.

Carbapenem-resistant (CRKP) is highly prevalent and poses a significant threat to public health. In critically ill patients, gut colonization is considered to be the reservoir of recurrent CRKP infection. Therefore, eliminating CRKP carriage in the intestine is critical for preventing subsequent CRKP infection. In the present study, LP1812, a probiotic that can inhibit CRKP , was used as a candidate probiotic to investigate its efficacy for CRKP anticolonization. Compared with the control, mice fed with 1×10 CFU LP1812 exhibited significant CRKP clearance from 1×10 CFU/mg to less than 10 CFU/mg in mice feces. Furthermore, 16S RNA gene sequencing revealed that LP1812 modulated mice microbiota by increasing the relative abundance of the genus , , and . Further KEGG pathway enrichment analysis revealed that fatty acid-utilizing bacteria, such as acetate-producing and flourished in mice fed with LP1812. Moreover, we found that the concentration of acetic acid was higher in LP1812, which inhibited the growth of strains . Meanwhile, mice intragastrically administered with acetic acid exhibited significantly increased CRKP elimination . In conclusion, LP1812 is a potential candidate for intestinal CRKP anticolonization by regulating the intestinal microbiota and inhibiting CRKP increased acetic acid in the intestinal lumen.
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http://dx.doi.org/10.3389/fcimb.2021.804253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8714838PMC
December 2021

Long non-coding RNA GAS6-AS1 enhances breast cancer cell aggressiveness by functioning as a competing endogenous RNA of microRNA-215-5p to enhance SOX9 expression.

Exp Ther Med 2022 Jan 2;23(1):109. Epub 2021 Dec 2.

Department of Radiation Oncology, Zhangzhou Hospital Affiliated to Fujian Medical University, Zhangzhou, Fujian 363000, P.R. China.

Long non-coding (lnc) RNAs play crucial functions in human cancer. However, until recently, the involvement of the lncRNA GAS6-AS1 in breast cancer (BCa) malignancy has not been studied exhaustively. The roles and underlying mode of action of GAS6-AS1 action in BCa progression were examined through functional experiments. A decline in GAS6-AS1 level led to a significant decrease in BCa cell proliferation, and the ability for colony formation. Here, GAS6-AS1 competed as endogenous RNA by sequestering microRNA-215-5p (miR-215-5p) causing an enhanced expression of SRY-box transcription factor 9 (SOX9). The effects of silencing GAS6-AS1 on BCa malignant phenotypes could be ameliorated by inhibiting miR-215-5p or restoring SOX9. Thus, GAS6-AS1 acted as a lncRNA that drives tumor in BCa, and enabled progression of BCa through miR-215-5p /SOX9 axis regulation. These outcomes show that the GAS6-AS1/miR-215-5p/SOX9 axis is a potentially effective target for cancer treatment and management.
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http://dx.doi.org/10.3892/etm.2021.11032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8674965PMC
January 2022

Dietary exposure of copper and zinc oxides nanoparticles affect the fitness, enzyme activity, and microbial community of the model insect, silkworm Bombyx mori.

Sci Total Environ 2021 Dec 30;813:152608. Epub 2021 Dec 30.

Max Planck Partner Group, Institute of Sericulture and Apiculture, College of Animal Sciences, Zhejiang University, Hangzhou, China; Key Laboratory for Molecular Animal Nutrition, Ministry of Education, China. Electronic address:

Copper and Zinc oxides nanoparticles (CuO and ZnO NPs, respectively) are among the most produced and commonly used engineered nanomaterials. They can be released into the environment, thereby causing health concerns and risks to biodiversity that indicate a need to evaluate their toxicological effects in a complex situation. Here, we used the insect model organism silkworm Bombyx mori to address the concerns about the biological effects associated with dietary exposure of CuO and ZnO NPs. ICP-MS analysis revealed significant accumulation of Cu and Zn (the latter being more accumulated) in silkworms' tissues (gut, fat body, silk gland, and malpighian tubule), and some elimination through feces in the respective NPs-exposed groups. NPs-exposures led to a decrease in larval body mass, survivorship, and cocoon production, where the effects of ZnO NPs were more pronounced. We also found that NPs-exposure induced gene expression changes (Attacin, lysozyme, SOD, and Dronc) and altered the activities of antioxidant enzymes (SOD, GST, and CAT), as well as impaired nutrient metabolism (alpha-amylase). Given their antibacterial property, CuO and ZnO NPs decreased species richness and diversity of the gut bacterial community and shifted their configuration to overt microbiome i.e., decreased abundance of probiotics (e.g., Acetobacter) and increased pathobionts (e.g., Pseudomonas, Bacillus, Escherichia, Enterococcus, Ralstonia, etc.) proportions. Overall, this integrated study revealed the unintended negative effects of CuO and ZnO NPs on silkworms and highlighted the potential to inevitably affect all living things due to intensive and possible mishandling of nanomaterials.
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http://dx.doi.org/10.1016/j.scitotenv.2021.152608DOI Listing
December 2021

Evaluation of Four Lymph Node Classifications for the Prediction of Survival in Hilar Cholangiocarcinoma.

J Gastrointest Surg 2022 Jan 1. Epub 2022 Jan 1.

Department of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), No. 30 Gaotanyan Road, Chongqing, 400038, China.

Background: An important prognostic indicator of hilar cholangiocarcinoma (HCCA) in patients after surgery is metastasis of lymph nodes (LN). However, there are many types of LN staging systems to the issue of a better determination of the prognosis of patients through the lymphatic staging system which needs research. Based on the above, we tried to re-evaluate the staging system of HCCA LNs. We compared the American Joint Committee on Cancer (AJCC), number of metastatic LNs (MLN), ratio of LN (LNR), and log odds of MLNs (LODDS) in individuals undergoing curative resection to determine the best LN staging system.

Methods: In the current study, we retrospectively analyzed 229 patients undergoing curative resection. We evaluated the impact of the stage of AJCC pN, LNR, LODDS, and MLN on OS (overall survival) and RFS (recurrence-free survival). According to the curve of receiver operating characteristic (ROC), we compared the predictive capacity of different staging systems of LN for survival and recurrence.

Results: Multivariate analysis results revealed that LODDS >  - 0.45 (95% CI = 1.115-2.709, P = 0.015; 95% CI = 1.187-2.780, P = 0.006) are independent risk factors affecting OS and RFS, respectively. Compared with LN status, AJCC pN stage, MLN, and LNR, the variable having the highest area under the ROC curve (AUC) was LODDS when predicting 1-year, 3-year, and 5-year OS and RFS.

Conclusion: This study shows that metastasis of LNs is a key indicator for predicting patient death and recurrence. Among them, LODDS is the best LN staging system for the prognostic evaluation of HCCA patients after surgery. Clinicians can incorporate LODDS into HCCA patient lymphatic staging system for a more accurate prognosis of HCCA patients post-surgery.
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http://dx.doi.org/10.1007/s11605-021-05211-xDOI Listing
January 2022

Effects of Bisphosphonates on Bone of Osteoporotic Men With Different Androgen Levels: A Case-Control Study.

Endocr Pract 2021 Dec 27. Epub 2021 Dec 27.

Department of Endocrinology, National Health Commission Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address:

Objective: Osteoporosis in men has been neglected despite its association with disability and mortality. We evaluated the effect of bisphosphonates (BPs) on bone mineral density (BMD) and bone turnover biomarkers of osteoporotic men with different androgen levels.

Methods: This case-control study included 136 osteoporotic men who were divided into normal group (n = 75) and hypogonadism group (n = 61) (patients treated with testosterone were excluded) according to their serum testosterone levels (cutoff value, 350 ng/dL). BMD, serum testosterone, total alkaline phosphatase, and cross-linked C-telopeptide of type I collagen were detected. The relationship between testosterone levels and BMD at baseline was evaluated. All patients were treated with BPs for 2 years. We compared the effects of BPs on BMD and bone turnover biomarkers between the 2 groups.

Results: At baseline, there were no significant differences in BMD and bone turnover biomarkers between the 2 groups. Testosterone levels were positively correlated with BMD in the hypogonadism group. After treatment, the lumbar BMD increased by 7.65% ± 1.54% and 7.47% ± 1.88% in normal and hypogonadism groups, respectively (both P < .01 vs baseline) and hip BMD increased without significant differences between the 2 groups. Serum cross-linked C-telopeptide of type I collagen and alkaline phosphatase levels decreased without significant differences between the 2 groups (all P < .01 vs baseline).

Conclusion: Testosterone level is positively correlated with BMD in men with hypogonadism. In osteoporotic men, BPs significantly increase spine and hip BMD and decrease bone resorption. The efficacy of BPs is similar in men with or without hypogonadism.
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http://dx.doi.org/10.1016/j.eprac.2021.12.013DOI Listing
December 2021

Impedance Analysis and Noise Measurements on Multi Walled Carbon Nanotube Networks.

Materials (Basel) 2021 Dec 7;14(24). Epub 2021 Dec 7.

Department of Physics, University of North Texas, Denton, TX 75077, USA.

The electrical impedance characteristics of multi-walled carbon nanotube (MWCNTs) networks were studied as a function of CNT concentrations in the frequency range of 1 kHz-1 MHz. The novelty of this study is that the MWCNTs were not embedded in any polymer matrix and so the response of the device to electrical measurements are attributed to the CNTs in the network without any contribution from a polymer host matrix. Devices with low MWCNT packing density (0.31-0.85 µg/cm) exhibit a frequency independent plateau in the low-frequency regime. At higher frequencies, the AC conductivity of these devices increases following a power law, characteristic of the universal dynamic response (UDR) phenomenon. On the other hand, devices with high MWCNT concentrations (>1.0 µg/cm) exhibit frequency independent conductivity over the entire frequency range (up to 1 MHz), indicating that conduction in these devices is due to direct contact between the CNTs in the network. A simple single-relaxation time electrical equivalent circuit with an effective resistance and capacitance is used to describe the device performance. The electrical noise measurements on devices with different MWCNT packing densities exhibit bias-dependent low-frequency 1/f noise, attributed to resistance fluctuations.
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http://dx.doi.org/10.3390/ma14247509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708505PMC
December 2021

A missense mutation in WRKY32 converts its function from a positive regulator to a repressor of photomorphogenesis.

New Phytol 2021 Dec 21. Epub 2021 Dec 21.

State Key Laboratory of Crop Genetics and Germplasm Enhancement, National Center for Soybean Improvement, College of Agriculture, Nanjing Agricultural University, Nanjing, 210095, China.

CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) mediates various cellular and physiological processes in plants by targeting a large number of substrates for ubiquitination and degradation. In this study, we reveal that a substitution of Pro for Leu at amino acid position 409 in WRKY32 largely suppresses the short hypocotyls and expanded cotyledon phenotypes of cop1-6. WRKY32 promotes hypocotyl growth and inhibits the opening of cotyledons in Arabidopsis. Loss of WRKY32 function mutant seedlings display elongated hypocotyls, whereas overexpression of WRKY32 leads to shortened hypocotyls. WRKY32 directly associates with the promoter regions of HY5 to activate its transcription. COP1 interacts with and targets WRKY32 for ubiquitination and degradation in darkness. WRKY32 exhibits enhanced DNA binding ability and affects the expression of more genes compared with WRKY32 in Arabidopsis. Our results not only reveal the basic role for WRKY32 in promoting photomorphogenesis, but also provide insights into manipulating plant growth by engineering key components of light signaling.
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http://dx.doi.org/10.1111/nph.17932DOI Listing
December 2021

Qiu's Neiyi Recipe Regulates the Inflammatory Action of Adenomyosis in Mice via the MAPK Signaling Pathway.

Evid Based Complement Alternat Med 2021 11;2021:9791498. Epub 2021 Dec 11.

Department of Gynecology and Obstetrics, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, China.

Background: The management of adenomyosis is challenging and limiting. Qiu's Neiyi recipe (Qiu) is a traditional Chinese medicine (TCM) prescription clinically used for endometriosis treatment in China, but the effect and mechanism of Qiu on adenomyosis are undefined.

Methods: An experimental adenomyosis model was induced in female neonatal ICR mice administrated with tamoxifen. The adenomyosis mice were divided into five groups: high-, middle-, and low-Qiu's group, danazol group, and model group. The mice just administrated with the solvent only (no tamoxifen or drugs) were served as the control group. After 28 days of administration, the body, uterine, spleen, and thymus weights of all mice were examined. Then, the myometrial infiltration and the expression of inflammatory factors were detected by histology examination, ELISA, and qRT-PCR in the uterus. In addition, the MAPK/ERK signaling pathway-related protein expression in adenomyosis mice was detected by immunohistochemical (IHC) staining, qRT-PCR, and western blotting.

Results: In experimental adenomyosis mice, Qiu treatment improved the symptoms of adenomyosis by reducing the myometrial infiltration and increasing the index of spleen and thymus. The elevated levels of IL-1, IL-6, and TNF- in serum and uterus tissues of adenomyosis model mice were also decreased after Qiu treatment. The improvement of Qiu on the adenomyosis was achieved by inhibiting the activated MAPK/ERK signaling pathway, including reducing the mRNA and protein expressions of p-ERK/ERK, p-JNK/JNK, and p-p38/38 in the uterus tissues.

Conclusion: Qiu alleviated the inflammatory reaction and uterus histological changes in mice with adenomyosis, and the potential mechanism is through the inhibition of the MAPK/ERK signaling pathway. Qiu may be a promising treatment for adenomyosis.
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http://dx.doi.org/10.1155/2021/9791498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684508PMC
December 2021

Synergistic effects of crop residue and microbial inoculant on soil properties and soil disease resistance in a Chinese Mollisol.

Sci Rep 2021 12 20;11(1):24225. Epub 2021 Dec 20.

Key Laboratory of Straw Biology and Utilization, Ministry of Education, Jilin Agricultural University, Changchun, Jilin, China.

The soil-borne disease caused by Fusarium graminearum seriously affects the corn quality. Straw can greatly improve soil quality, but the effect is limited by its nature and environmental factors. This study explored the impact of straw-JF-1(biocontrol bacteria) combination on soil environment and soil disease resistance. The results showed that the combined treatment increased the proportion of soil large and small macro-aggregates by 22.50 and 3.84%, with soil organic carbon (SOC) content by 16.18 and 16.95%, respectively. Compared to treatment with returning straw to the field alone, the straw-JF-1 combination increased the soil content of humic acid, fulvic acid, and humin by 14.06, 5.50, and 4.37%, respectively. Moreover, A metagenomics showed that returning straw to the field alone increased the abundance of disease-causing fungi (Fusarium and Plectosphaerella), however, the straw-JF-1 combination significantly suppressed this phenomenon as well as improved the abundance of probiotic microorganisms such as Sphingomonas, Mortierella, Bacillus, and Pseudomonas. Functional analysis indicated that the combination of straw and JF-1 improved some bacterial functions, including inorganic ion transport and metabolism, post-translational modification/protein turnover/chaperones and function unknown, fungal functions associated with plant and animal pathogens were effectively inhibited. Pot experiments showed that the straw-JF-1 combination effectively inhibited the Fusarium graminearum induced damage to maize seedlings. Therefore, the combination of straw and JF-1 could be a practical method for soil management.
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http://dx.doi.org/10.1038/s41598-021-03799-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688499PMC
December 2021

The role of CEMIP in tumors: An update based on cellular and molecular insights.

Biomed Pharmacother 2022 Feb 15;146:112504. Epub 2021 Dec 15.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life, Sciences and Medicine, University of Science and Technology of China, Hefei 230031, China. Electronic address:

CEMIP was initially identified as an inner-ear specific protein in which three-point mutations cause folding changes in protein structure associated with non-syndromic hearing loss. CEMIP was also involved in other cellular activities, such as hyaluronan depolymerization independent of CD44 and other hyaluronidases. Growing evidence has demonstrated that CEMIP is involved in the progression of various tumors. However, whether the oncogenic effects of CEMIP relies on its enzymatic activity remain elusive. CEMIP is significantly related to metastasis and poor prognosis in patients with various tumors, suggesting that CEMIP is a potential, highly specific diagnostic tumor marker. Most preclinical experiments have shown that the overexpression of CEMIP in tumors mainly affects the adhesion, metastasis, and invasion of tumor cells and EMT. Other studies have also demonstrated that CEMIP can promote a variety of tumor processes by affecting tumor proliferation, dedifferentiation, and the tumor microenvironment. In terms of molecular mechanisms, existing research has shown that CEMIP mainly affects the WNT and EGFR signaling pathways. In addition, a variety of miRNAs have been shown to inhibit CEMIP in tumors. This paper elaborates on the clinical characteristics and regulatory dysfunction of CEMIP in different cancers. CEMIP provides a new potential target for therapy of multiple tumors, which is worthy of further study.
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http://dx.doi.org/10.1016/j.biopha.2021.112504DOI Listing
February 2022

Simultaneously screening multiple UGT1A1 inhibitors from Polygonum multiflorum root using ultrafiltration LC-MS.

Biomed Chromatogr 2021 Dec 17:e5300. Epub 2021 Dec 17.

State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

Liver injury induced by Polygonum multiflorum root (PMR) is an immediate issue requiring global attention. UDP-glucuronosyltransferase 1A1 (UGT1A1) inhibitors are suspected to additively contribute to the hepatotoxicity of PMR. This study was deliberately designed to simultaneously screen UGT1A1 inhibitors from PMR, and their co-contribution to hepatotoxicity was determined. Using ultrafiltration coupled to LC-MS method, four compounds, namely cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-glucoside, trans-2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside, emodin-8-O-β-d-glucoside, and emodin, were screened, exhibiting the in vitro inhibitory activities against UGT1A1 with IC values of 76.23, 18.70, 62.18, and 34.02 μM, respectively. The varying activities of the screened UGT1A1 inhibitors were demonstrated by performing a molecular docking simulation. Finally, zebrafish larvae and mice assays demonstrated that the UGT1A1 inhibitors co-contributed to the hepatotoxicity of PMR. These findings are conducive to understand the role of UGT1A1 inhibitors in PMR-induced hepatotoxicity.
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http://dx.doi.org/10.1002/bmc.5300DOI Listing
December 2021

Genetic Characterization and Passage Instability of a Hybrid Plasmid Co-Harboring and Reveal the Contribution of Insertion Sequences During Plasmid Formation and Evolution.

Microbiol Spectr 2021 12 15;9(3):e0157721. Epub 2021 Dec 15.

Department of Clinical Laboratory, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.

Carbapenemase is the predominant enzyme in the mechanism leading to resistance to carbapenems, but only a limited number of isolates harbor double classes/types of carbapenemase. Here, an IMP-4 and NDM-1 producer named Klebsiella michiganensis 7525 is reported, and the co-harboring plasmid is further characterized. K. michiganensis 7525 was positive for the and genes by the NG-Test Carba-5 method and PCR followed by sequencing, and both were located on the same plasmid (designated pKOX7525_1) according to S1-PFGE with Southern blot experiments. pKOX7525_1 was capable of transconjugation with an efficiency of 4.3 × 10 in a filter mating experiment. Whole-genome sequencing and bioinformatics analysis confirmed that the plasmid was novel, clustered to the incompatibility type of IncHIB/IncFIA/IncR and presented high similarity to a -carrying IncHIB plasmid (pA) published with 79% coverage and 100% sequence identify. In contrast, a large-fragment insertion and inversion mediated by IS was observed on the plasmid, which introduced a genetic hybrid zone with multiple resistance genes, including , to the plasmid. In the transconjugants, the presence of pKOX7525_1 had a negative impact on bacterial fitness. evolution experiments showed that pKOX7525_1 in the transconjugant could not be stably inherited after 10 days of passage and that could be lost during repeated laboratory passage. Our study not only reports a novel plasmid co-harboring and but also highlights the putative pathway of plasmid formation and evolution by means of genetic rearrangement through sequence insertion and homologue recombination, which may have critical value for plasmid research and increase awareness of carbapenem-resistant (CRE). In this study, we characterized a novel plasmid from a carbapenem-resistant K. michiganensis (CRKM) isolate, which harbors two metallo-β-lactamases (MBLs), IMP-4 and NDM-1, is capable of transconjugation and contains three replicons. Our results first expand the diversity of plasmids co-harboring carbapenemase genes in , which exhibits epidemic importance in bacterial resistance. Additionally, we investigated the origin and formation of this MBL double-positive plasmid based on comparative genomics analysis, which indicated that IS plays a vital role through continuous genetic rearrangements. Moreover, this plasmid is unstable in transconjugants during passage at the multidrug-resistant (MDR) region of , with fluctuating stability under varying antibiotic selection, highlighting auspicious considerations regarding recognition of the complexity and plasticity of plasmids in evolution and re-emphasizing clinical infection control inspired by CRE.
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http://dx.doi.org/10.1128/Spectrum.01577-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672901PMC
December 2021

Serum metabolomics reveals dysregulation and diagnostic potential of oxylipins in tumor-induced osteomalacia.

J Clin Endocrinol Metab 2021 Dec 14. Epub 2021 Dec 14.

Department of Endocrinology, Key Laboratory of Endocrinology, National Commission of Health, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.

Context: Excessive production of fibroblast growth factor 23 (FGF23) by tumor was considered as the main pathogenesis in tumor-induced osteomalacia (TIO). Despite its importance to comprehensive understanding of pathogenesis and diagnosis, the regulation of systemic metabolism in TIO remains unclear.

Objectives: We aimed to systematically characterize the metabolome alteration associated with TIO.

Methods: By means of liquid chromatography-tandem mass spectrometry (LC-MS) based metabolomics, we analyzed the metabolic profile from 96 serum samples (32 initial diagnosis TIO patients, pairwise samples after tumor resection and 32 matched healthy control subjects). In order to screen and evaluate potential biomarkers, statistical analyses, pathway enrichment and receiver operating characteristic (ROC) were performed.

Results: Metabolomic profiling revealed distinct alterations between TIO and HC cohort. Differential metabolites were screened and conducted to functional clustering and annotation. Significantly enriched pathway was found involved in arachidonic acid metabolism. A combination of 5 oxylipins, 4-HDoHE, leukotriene B4, 5-HETE, 17-HETE and 9,10,13-TriHOME, demonstrated a high sensitivity and specificity panel for TIO prediction screened by random forest (RF) algorithm (AUC=0.951, 95% confidence interval, CI 0.827-1). Supported vector machine (SVM) model and partial least-squares (PLS) model were conducted to validate the predictive capabilities of the diagnostic panel.

Conclusions: Metabolite profiling of TIO altered significant compared with HC. A high sensitivity and specificity panel with 5 oxylipins were tested as diagnostic predictor. For the first time, we provide the global profile of metabolomes and identify potential diagnostic biomarkers of TIO. The present work may offer novel insights into the pathogenesis of TIO.
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http://dx.doi.org/10.1210/clinem/dgab885DOI Listing
December 2021

Neuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions.

Nat Commun 2021 12 13;12(1):7243. Epub 2021 Dec 13.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Regulatory mechanisms associated with repeat-rich sequences and chromosomal conformations in mature neurons remain unexplored. Here, we map cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic B megabase-scaling subcompartment. Single molecule long-read sequencing and comparative Hi-C chromosomal contact mapping in wild-derived SPRET/EiJ (Mus spretus) and laboratory inbred C57BL/6J (Mus musculus) reveal neuronal reconfigurations tracking recent ERV2 expansions in the murine germline, with significantly higher B contact frequencies at sites with ongoing insertions in Mus musculus. Neuronal ablation of the retrotransposon silencer Kmt1e/Setdb1 triggers B disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly with infiltration of dendrites . We conclude that neuronal megabase-scale chromosomal architectures include an evolutionarily adaptive heterochromatic organization which, upon perturbation, results in transcriptional dysregulation and unleashes ERV2 proviruses with strong neuronal tropism.
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http://dx.doi.org/10.1038/s41467-021-26862-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669064PMC
December 2021

Evaluation of Liquid Biopsy in Patients with HER2-Positive Breast Cancer.

Biomed Res Int 2021 3;2021:6388492. Epub 2021 Dec 3.

Department of Breast Surgery, Wuhu No. 1 People's Hospital, Wuhu 241000, China.

Breast cancer is one of the common malignant tumors, and liquid biopsy has become a hot spot for clinical testing. To clarify the detection effect of liquid biopsy in breast cancer, we collected peripheral blood of HER2-positive (human epidermal growth factor receptor 2-positive) patients. Circulating tumor cells (CTCs) were isolated and analyzed. HER2 expression on CTCs was detected. The results showed that in the 198 HER2-positive samples, the CTC detection rate was 79.8% (158/198), and the mean number of CTCs was 21, ranging from 1 to 63/7.5 mL peripheral blood. Only 41.1% (65/158) of patients had histology and CTC HER2 status consistent with the remaining 58.9% (93/158) of patients, although their histological HER2 was positive, and CTC HER2 was negative. Our study confirmed the value of CTC HER2 real-time status testing in HER2-positive breast cancer patients. The inconsistency in HER2 status between CTCs and histology may be related to the time interval between CTCs and histological HER2 detection, suggesting that real-time HER2 detection is necessary for histological HER2-positive patients.
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http://dx.doi.org/10.1155/2021/6388492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8664526PMC
January 2022

ZFP36 protects against oxygen-glucose deprivation/reoxygenation-induced mitochondrial fragmentation and neuronal apoptosis through inhibiting NOX4-DRP1 pathway.

Brain Res Bull 2022 Feb 9;179:57-67. Epub 2021 Dec 9.

Department of Anesthesiology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200062, China. Electronic address:

The imbalance of mitochondrial dynamics plays an important role in the pathogenesis of cerebral ischemia/reperfusion (I/R) injury. Zinc-finger protein 36 (ZFP36) has been documented to have neuroprotective effects, however, whether ZFP36 is involved in the regulation of neuronal survival during cerebral I/R injury remains unknown. In this study, we found that the transcriptional and translational levels of ZFP36 were increased in immortalized hippocampal HT22 neuronal cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ZFP36 gene silencing exacerbated OGD/R-induced dynamin-related protein 1 (DRP1) activity, mitochondrial fragmentation, oxidative stress and neuronal apoptosis, whereas ZFP36 overexpression exhibited the opposite effects. Besides, we found that NADPH oxidase 4 (NOX4) was upregulated by OGD/R, and NOX4 inhibition remarkably attenuated OGD/R-instigated DRP1 activity, mitochondrial fragmentation and neuronal apoptosis. Further study demonstrated that ZFP36 targeted NOX4 mRNA directly by binding to the AU-rich elements (AREs) in the NOX4 3'-untranslated regions (3'-UTR) and inhibited NOX4 expression. Taken together, our data indicate that ZFP36 protects against OGD/R-induced neuronal injury by inhibiting NOX4-mediated DRP1 activation and excessive mitochondrial fission. Pharmacological targeting of ZFP36 to suppress excessive mitochondrial fission may provide new therapeutic strategies in the treatment of cerebral I/R injury.
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http://dx.doi.org/10.1016/j.brainresbull.2021.12.003DOI Listing
February 2022

Cx43 overexpression is involved in the hyper-proliferation effect of trichloroethylene on human embryonic stem cells.

Toxicology 2022 Jan 9;465:153065. Epub 2021 Dec 9.

School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China. Electronic address:

Trichloroethylene (TCE) is a major environmental contaminant. Maternal exposure of TCE is linked to developmental defects, but the mechanisms remain to be elucidated. Along with a strategy of 3Rs principle, human embryonic stem cells (hESCs) are regarded as most promising in vitro models for developmental toxicity studies. TCE interfered with hESCs differentiation, but no report was available for TCE effects on hESCs proliferation. Here, we aimed to explore the toxic effects and mechanisms of TCE on hESCs proliferation. Treatment with TCE, did not affect the pluripotency genes expression. However, TCE enhanced hESCs proliferation, manifested by increased cell number, PCNA expression and EdU incorporation. Moreover, TCE exposure upregulated the protein expression levels of Cx43 and cyclin-dependent kinases. Knockdown of Cx43 attenuated the TCE-induced cell hyper-proliferation and CDK2 upregulation. Furthermore, TCE increased Akt phosphorylation, and the inhibition of Akt blocked the TCE-induced Cx43 overexpression and cell proliferation. In conclusion, TCE exposure resulted in upregulation of Cx43 via Akt phosphorylation, consequently stimulated CDK2 expression, contributing to hyper-proliferation in hESCs. Our study brings to light that TCE stimulated the proliferation of hESCs via Cx43, providing a new research avenue for the causes of TCE-induced developmental toxicity.
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http://dx.doi.org/10.1016/j.tox.2021.153065DOI Listing
January 2022

Bone Geometry, Density, Microstructure, and Biomechanical Properties in the Distal Tibia in Patients With Primary Hypertrophic Osteoarthropathy Assessed by Second-Generation High-Resolution Peripheral Quantitative Computed Tomography.

J Bone Miner Res 2021 Dec 10. Epub 2021 Dec 10.

Department of Endocrinology, Key Laboratory of Endocrinology, NHC, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Periosteosis refers to pathological woven bone formation beneath the cortical bone of the long bones. It is an imaging hallmark of primary hypertrophic osteoarthropathy (PHO) and also considered as one of the major diagnostic criteria of PHO patients. Up to date, detailed information on bone quality changes in long bones of PHO patients is still missing. This study aimed to evaluate bone microarchitecture and bone strength in PHO patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT). The study comprised 20 male PHO patients with the average age of 27.0 years and 20 age- and sex-matched healthy controls. The areal bone mineral density (aBMD) was assessed at the lumbar spine (L -L ) and hip (total hip and femoral neck) by dual-energy X-ray absorptiometry (DXA). Bone geometry, volumetric bone mineral density (vBMD), and microstructure parameters at the distal tibia were evaluated by using HR-pQCT. Bone strength was evaluated by finite element analysis (FEA) based on HR-pQCT screening at distal tibia. Urinary prostaglandin E (PGE ), serum phosphatase (ALP), beta-C-telopeptides of type I collagen (β-CTX), soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and neuronal calcitonin gene-related peptide (CGRP) were investigated. As compared with healthy controls, PHO patients had larger bone cross-sectional areas; lower total, trabecular, and cortical vBMD; compromised bone microstructures with more porous cortices, thinned trabeculae, reduced trabecular connectivity, and relatively more significant resorption of rod-like trabeculae at distal tibia. The apparent Young's modulus was significantly lower in PHO patients. The concentration of PGE , biomarkers of bone resorption (β-CTX and sRANKL/OPG ratio), and the neuropeptide CGRP were higher in PHO patients versus healthy controls. PGE level correlated negatively with vBMD and estimated bone strength and positively with bone geometry at distal tibia. The present HR-pQCT study is the first one illustrating the microarchitecture and bone strength features in long bones. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4488DOI Listing
December 2021

A 2-oxoglutarate dependent dioxygenase converts dihydrofuran to furan in Salvia diterpenoids.

Plant Physiol 2021 Dec 6. Epub 2021 Dec 6.

Shanghai Key Laboratory of Plant Functional Genomics and Resources, Shanghai Chenshan Botanical Garden, Shanghai 201602, China.

Tanshinone IIA (TIIA), a diterpene quinone with a furan ring, is a bioactive compound found in the medicinal herb redroot sage (Salvia miltiorrhiza Bunge), in which both furan and dihydrofuran analogs are present in abundance. Progress has been made recently in elucidating the tanshinone biosynthetic pathway, including heterocyclization of the dihydrofuran D-ring by cytochrome P450s (CYPs); however, dehydrogenation of dihydrofuran to furan, a key step of furan ring formation, remains uncharacterized. Here, by differential transcriptome mining, we identified six 2-oxoglutarate-dependent dioxygenase (2-ODD) genes whose expressions corresponded to tanshinone biosynthesis. We showed that Sm2-ODD14 acts as a dehydrogenase catalyzing the furan ring aromatization. In vitro Sm2-ODD14 converted cryptotanshinone (CT) to TIIA and thus was designated TIIA synthase (SmTIIAS). Further, SmTIIAS showed a strict substrate specificity, and repression of SmTIIAS expression in hairy root by RNAi led to increased accumulation of total dihydrofuran-tanshinones and decreased production of furan-tanshinones. We conclude that SmTIIAS controls the metabolite flux from dihydrofuran- to furan-tanshinones, which influences medicinal properties of S. miltiorrhiza.
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http://dx.doi.org/10.1093/plphys/kiab567DOI Listing
December 2021

Preclinical evaluation of the dual mTORC1/2 inhibitor sapanisertib in combination with cisplatin in nasopharyngeal carcinoma.

Eur J Pharmacol 2022 Jan 6;915:174688. Epub 2021 Dec 6.

Department of Otolaryngology & Head and Neck Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, 441021, China. Electronic address:

A wide range of investigational drugs are being investigated in clinical trials for the treatment of nasopharyngeal carcinoma (NPC), including PI3K-mTOR inhibitor. The purpose of this study was to evaluate the effective combination of TORC1/2 inhibitor sapanisertib and chemotherapy drug cisplatin in preclinical models of NPC. In our work, sapanisertib at nanomolar concentrations decreases viability and proliferation in NPC cells regardless of varying genetic backgrounds. Sapanisertib acts synergistically with cisplatin via induces more G0/G1 arrest and apoptosis. At the same concentration, sapanisertib neither decreases viability nor proliferation in normal nasal epithelial cells. Sapanisertib also decreases NPC cell migration. It decreases phosphorylation of Akt, mTOR, p70S6K and 4EBP1 in NPC cells. The in vitro findings on the inhibitory effects of sapanisertib on NPC growth and mTOR signaling were also evident in the NPC xenograft mouse model. In addition, combination of sapanisertib with cisplatin resulted in better efficacy than monotherapy to inhibit NPC growth in mice without causing significant toxicity. These data clearly demonstrate efficacy and insignificant toxicity of sapanisertib alone and its combination with cisplatin in NPC preclinical models. Our findings will accelerate clinical trials evaluating combination of sapanisertib and chemotherapy for NPC treatment.
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http://dx.doi.org/10.1016/j.ejphar.2021.174688DOI Listing
January 2022

Single-molecule imaging of von Willebrand factor reveals tension-dependent self-association.

Blood 2021 12;138(23):2425-2434

Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.

von Willebrand factor (VWF) is an ultralong concatemeric protein important in hemostasis and thrombosis. VWF molecules can associate with other VWF molecules, but little is known about the mechanism. Hydrodynamic drag exerts tensile force on surface-tethered VWF that extends it and is maximal at the tether point and declines linearly to 0 at the downstream free end. Using single-molecule fluorescence microscopy, we directly visualized the kinetics of binding of free VWF in flow to surface-tethered single VWF molecules. We showed that self-association requires elongation of tethered VWF and that association increases with tension in tethered VWF, reaches half maximum at a characteristic tension of ∼10 pN, and plateaus above ∼25 pN. Association is reversible and hence noncovalent; a sharp decrease in shear flow results in rapid dissociation of bound VWF. Tethered primary VWF molecules can recruit more than their own mass of secondary VWF molecules from the flow stream. Kinetics show that instead of accelerating, the rate of accumulation decreases with time, revealing an inherently self-limiting self-association mechanism. We propose that this may occur because multiple tether points between secondary and primary VWF result in lower tension on the secondary VWF, which shields more highly tensioned primary VWF from further association. Glycoprotein Ibα (GPIbα) binding and VWF self-association occur in the same region of high tension in tethered VWF concatemers; however, the half-maximal tension required for activation of GPIbα is higher, suggesting differences in molecular mechanisms. These results have important implications for the mechanism of platelet plug formation in hemostasis and thrombosis.
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http://dx.doi.org/10.1182/blood.2021012595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662069PMC
December 2021

Prevalence and Characteristics of Ceftriaxone-Resistant in Children's Hospital in Hangzhou, China.

Front Microbiol 2021 22;12:764787. Epub 2021 Nov 22.

Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

The non-Typhi (NTS) infection is critical to children's health, and the ceftriaxone is the important empirical treatment choice. With the increase resistance rate of ceftriaxone in , the molecular epidemiology and resistance mechanism of ceftriaxone-resistant needs to be studied. From July 2019 to July 2020, a total of 205 NTS isolates were collected, 195 of which (95.1%) were cultured from stool, but 10 isolates were isolated from an extraintestinal site. Serogroup B accounted for the vast majority (137/205) among the isolates. Fifty-three isolates were resistant to ceftriaxone, and 50 were isolated from children younger than 4years of age. The resistance rates for ceftriaxone, ciprofloxacin, and levofloxacin were significantly higher in younger children than the older children. The resistance genes in the ceftriaxone-susceptible isolates were detected by PCR, and ceftriaxone-resistant were selected for further whole-genome sequencing. Whole-genome analysis showed that serotype Typhimurium and its monophasic variant was the most prevalent in ceftriaxone-resistant isolates (37/53), which comprised ST34 (33/53), ST19 (2/53), and ST99 (2/53), and they were close related in the phylogenetic tree. However, the other isolates were diverse, which included one Enteritidis (ST11), one Indiana (ST17), one Derby (ST40), four Kentucky (ST198), two Goldcoast (ST2529, ST358), one Muenster (ST321), one Virchow (ST359), one Rissen (ST469), one Kedougou (ST1543), two Uganda (ST684), and one Kottbus (ST8839). Moreover, CTX-M-55 ESBLs production (33/53) was found to be mainly responsible for ceftriaxone resistance, followed by (12/53), (4/53), (2/53), (1/53), (1/53), and (1/53). IS, IS, IS , IS, and IS were connected to antimicrobial resistance genes transfer. In conclusion, the dissemination of ESBL-producing isolates resulted in an increased prevalence of ceftriaxone resistance in young children. The high rate of multidrug resistance should be given additional attention.
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http://dx.doi.org/10.3389/fmicb.2021.764787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645868PMC
November 2021
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