Publications by authors named "Yang Gao"

2,277 Publications

  • Page 1 of 1

circ-Katnal1 Enhances Inflammatory Pyroptosis in Sepsis-Induced Liver Injury through the miR-31-5p/GSDMD Axis.

Mediators Inflamm 2022 8;2022:8950130. Epub 2022 Aug 8.

Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang Province, China.

Background: Sepsis is a systemic inflammatory response that can elicit organ dysfunction as well as circulatory diseases in serious cases. When inflammatory responses are especially dysregulated, severe complications can arise, including sepsis-induced liver injury. Various microRNAs along with circular (circ) RNAs are involved in inflammatory responses; nevertheless, their functions in regulating sepsis-induced liver injury remain unknown. The cecal ligation and puncture (CLP) procedure can induce liver injury as well as polymicrobial sepsis.

Methods: In this study, CLP was used to induce liver injury as well as polymicrobial sepsis. Then, liver function, inflammatory cytokine expression, and hepatic histopathology were evaluated. High-throughput sequencing was employed to investigate the abnormal hepatic circRNA expression after CLP. Raw264.7 cells were utilized to simulation an sepsis inflammation model with LPS induce. The relative mRNA as well as protein levels of TNF-, IL-1, and IL-6 was explored by quantitative polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays. We explored functional connections among circRNAs, miR-31-5p, and gasdermin D (GSDMD) using dual-luciferase reporter assays. Western blot was employed to test GSDMD, caspase-1, and NLRP3 expression in mice and cell models.

Results: Our results showed that CLP-induced sepsis promoted liver injury via increasing inflammatory pyroptosis. The abnormal expression of circ-Katnal1 played an important role in CLP-induced sepsis. Downregulating circ-Katnal1 suppressed LPS-induced inflammatory pyroptosis in Raw264.7 cells. Bioinformatics and luciferase reporter results confirmed that miR-31-5p and GSDMD were downstream targets of circ-Katnal1. Inhibiting miR-31-5p or upregulating GSDMD reversed the protective effects of silencing circ-Katnal1.

Conclusion: Taken together, circ-Katnal1 enhanced inflammatory pyroptosis in sepsis-induced liver injury through the miR-31-5p/GSDMD axis.
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http://dx.doi.org/10.1155/2022/8950130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377930PMC
August 2022

The impact of entrepreneurs' cognitive flexibility on the business performance of New Ventures: an empirical study based on Chinese New Ventures.

Curr Psychol 2022 Aug 11:1-14. Epub 2022 Aug 11.

School of Business, Qingdao University of China, No. 93 Songling Road, Zhonghan Street, Laoshan District, 266071 Qingdao, China.

We developed a "thinking-behavior-outcome" logical framework to explore the effect of entrepreneurs' cognitive flexibility on dual innovation and the performance of new ventures, drawing on social cognitive theory, and collected data from a sample of 293 new ventures through a questionnaire to conduct an empirical analysis. We find that entrepreneurs' cognitive flexibility may indirectly affect the performance of new ventures by influencing their dual innovation activities; resource management capabilities positively moderate the relationship between entrepreneurs' cognitive flexibility and dual innovation. In addition, our study demonstrates that dual innovation equilibrium has a stronger effect on the performance of new ventures than single-dimensional innovation activities. Our study highlights the importance of entrepreneurial cognitive flexibility for new ventures to implement innovation strategies and improve performance. The findings not only help to clarify the relationship between entrepreneurs' cognitive flexibility and new venture performance and to enrich social cognitive theory, but they also provide new perspectives on responses to enhance dual innovation capabilities of new ventures under the influence of COVID-19.

Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-03532-x.
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http://dx.doi.org/10.1007/s12144-022-03532-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366834PMC
August 2022

De Novo Design of an Androgen Receptor DNA Binding Domain-Targeted peptide PROTAC for Prostate Cancer Therapy.

Adv Sci (Weinh) 2022 Aug 15:e2201859. Epub 2022 Aug 15.

Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, #277 Yanta West Road, Xi'an, China.

Androgen receptor splice variant-7 (AR-V7), one of the major driving factors, is the most attractive drug target in castration-resistant prostate cancer (CRPC). Currently, no available drugs efficiently target AR-V7 in clinical practice. The DNA binding domain (DBD) is indispensable for the transcriptional activity of AR full length and AR splice variants, including AR-V7. Based on the homodimerization structure of the AR DBD, a novel peptide-based proteolysis-targeting chimera (PROTAC) drug is designed to induce AR and AR-V7 degradation in a DBD and MDM2-dependent manner, without showing any activity on other hormone receptors. To overcome the short half-life and poor cell penetrability of peptide PROTAC drugs, an ultrasmall gold (Au)-peptide complex platform to deliver the AR DBD PROTAC in vivo is developed. The obtained Au-AR pep-PROTAC effectively degrades AR and AR-V7 in prostate cancer cell lines, particularly in CWR22Rv1 cells with DC values 48.8 and 79.2 nM, respectively. Au-AR pep-PROTAC results in suppression of AR levels and induces tumor regression in both enzalutamide sensitive and resistant prostate cancer animal models. Further optimization of the Au-AR pep-PROTAC can ultimately lead to a new therapy for AR-V7-positive CRPC.
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http://dx.doi.org/10.1002/advs.202201859DOI Listing
August 2022

Hypertension and Associated Risk Factors among Children with Intellectual Disability: A Cross-Sectional Study.

Nutrients 2022 Jul 29;14(15). Epub 2022 Jul 29.

Department of Sport, Physical Education and Health, Hong Kong Baptist University, Hong Kong 999077, China.

To investigate the prevalence of hypertension and associated risk factors in Chinese children with intellectual disability, a cross-sectional study was conducted in a sample of 558 children with intellectual disability aged 6-18 years in Hong Kong, and 452 (81.0%) with valid data were included in the data analysis. Blood pressure was measured according to a standard protocol. Hypertension was defined using the age-, gender-, and height-specific classification criteria recommended by the 2018 Chinese Guidelines for Children. Multivariate and hierarchical logistic regression was fitted to examine the associations of hypertension with potential risk factors. Overall, 31.4% of the participants were classified as having hypertension. Obese children were more likely to develop hypertension than non-obese children (adjusted OR = 2.77, 95% CI: 1.28, 5.99, = 0.010). A paternal education of college or above and a paternal occupation of clerks, sales representatives, and workers were also associated with an increased risk of hypertension. The prevalence of hypertension is high among Chinese children with intellectual disability. Obesity was the strongest risk factor. Further longitudinal studies are warranted to confirm our findings. Nevertheless, preventions against obesity are promising to receive doubled benefits in reducing both obesity and hypertension, given its strong relationship with hypertension in this special population.
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http://dx.doi.org/10.3390/nu14153127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9370698PMC
July 2022

Effectiveness and safety of ultrasound-guided intramuscular lauromacrogol injection combined with hysteroscopy in cervical pregnancy treatment: A case report.

World J Clin Cases 2022 Jun;10(18):6128-6135

Department of Gynaecology, Lishui Hospital of Traditional Chinese Medicine, Lishui 323000, Zhejiang Province, China.

Background: Cervical pregnancy is increasing in morbidity, and a definite diagnosis in early stages is challenging due to its specific onset site. Surgery is the mainstay of treatment for cervical pregnancy, but it may result in the loss of natural fertility. Therefore, it is a great challenge to pursue a safe and effective treatment for cervical pregnancy.

Case Summary: We report the case of a cervical pregnancy successfully treated by ultrasound-guided cervical-intramuscular lauromacrogol injection combined with hysteroscopy. A 23-year-old woman with minor irregular vaginal bleeding was admitted to our department with suspected ectopic pregnancy. Transvaginal ultrasound revealed a gestational sac (approximately 22 mm x 13 mm) situated in the cervical canal with a yolk sac and blood flow signals. No cardiac activity was detected. Serum beta progesterone was 17.06 ng/mL, and serum beta human chorionic gonadotropin (β-HCG) was 5077.0 IU/L. The patient was diagnosed with cervical pregnancy. She was treated by ultrasound-guided cervical-intramuscular injections of lauromacrogol (3 mL) in combination with aborting under hysteroscopic visualization. A gradual decrease in β-HCG levels and normal ultrasound findings were observed. Postoperative pathologic examination showed the presence of villi and changes in the endometrium in the secretory phase. The patient was discharged on day 6, and her β-HCG level was 0.67 mIU/mL after 1 wk. There was no statistical difference between baseline and 1-week postoperative data in terms of serum indices including liver function, renal function, and routine blood analysis after treatment. The patient subsequently became pregnant 2 mo later and no abnormalities were detected on routine screening during pregnancy.

Conclusion: Ultrasound-guided cervical-intramuscular lauromacrogol injection combined with hysteroscopy may be effective and safe in the treatment of cervical pregnancy.
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http://dx.doi.org/10.12998/wjcc.v10.i18.6128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9254199PMC
June 2022

Purely endoscopic keyhole approach for resection of a frontal falx dural arteriovenous fistula: Technical note: Endoscopic keyhole approach resection for DVAF.

World Neurosurg 2022 Aug 7. Epub 2022 Aug 7.

Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China; National Clinic Research Center for Interventional Medicine. Electronic address:

Objective: Dural arteriovenous fistulas (DAVFs) in the falx cerebri are rare. This study presents a case of DAVF in the frontal falx cerebri that was successfully resected using a purely endoscopic keyhole microsurgical technique.

Methods: A 69-year-old male patient presented to the emergency department with acute onset seizure. His condition was diagnosed as a DAVF in the frontal falx cerebri with multiple fistula points. Purely endoscopic resection was performed under neuronavigation. Postoperative angiography and clinical follow-up were performed after 10 days and 3 months, respectively.

Results: DAVF was satisfactorily observed and resected using a purely endoscopic keyhole microsurgical technique, with no deterioration of neural function or major vessel rupture. Postoperative angiogram revealed complete obliteration of the DAVF and no recurrent epilepsy during the clinical follow-up.

Conclusions: Supported by sufficient preoperative evaluation and meticulous manipulation, purely endoscopic minimally invasive resection is feasible and safe for DAVF, with the advantages of close observation and panoramic view.
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http://dx.doi.org/10.1016/j.wneu.2022.07.143DOI Listing
August 2022

Observation of a State X(2600) in the π^{+}π^{-}η' System in the Process J/ψ→γπ^{+}π^{-}η'.

Phys Rev Lett 2022 Jul;129(4):042001

Institute of High Energy Physics, Beijing 100049, People's Republic of China.

Based on (10087±44)×10^{6}  J/ψ events collected with the BESIII detector, the process J/ψ→γπ^{+}π^{-}η^{'} is studied using two largest decay channels of the η^{'} meson, η^{'}→γπ^{+}π^{-} and η^{'}→ηπ^{+}π^{-}, η→γγ. A new resonance, which we denote as the X(2600), is observed with a statistical significance larger than 20σ in the π^{+}π^{-}η^{'} invariant mass spectrum, and it has a connection to a structure around 1.5  GeV/c^{2} in the π^{+}π^{-} invariant mass spectrum. A simultaneous fit on the π^{+}π^{-}η^{'} and π^{+}π^{-} invariant mass spectra with the two η^{'} decay modes indicates that the mass and width of the X(2600) state are 2618.3±2.0_{-1.4}^{+16.3}  MeV/c^{2} and 195±5_{-17}^{+26}  MeV, where the first uncertainties are statistical, and the second systematic.
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http://dx.doi.org/10.1103/PhysRevLett.129.042001DOI Listing
July 2022

Anticancer Effect of Puerarin on Ovarian Cancer Progression Contributes to the Tumor Suppressor Gene Expression and Gut Microbiota Modulation.

J Immunol Res 2022 28;2022:4472509. Epub 2022 Jul 28.

Zhejiang Chinese Medicine Museum, Zhejiang Chinese Medical University, Hangzhou City, 310053 Zhejiang Province, China.

Ovarian cancer (OC) causes more deaths than any other cancer of the female reproductive system due to its late presentation and malignant nature. Although significant progress has been made in the diagnosis and treatment of OC over the last decade, chemotherapeutic drug resistance and cancer recurrence remain serious challenges in OC management. In the field of cancer therapy, traditional Chinese herbal medicines and their active compounds have been widely reported to have favorable therapeutic effects on cancer. Recent studies have also revealed the protective effect of puerarin in cancer, but the exact role and underlying mechanism of puerarin in OC remain unclear. Here, we established and OC models to evaluate the anticancer effect of puerarin. It was found that puerarin significantly inhibited OC cell viability and proliferation and induced cell apoptosis. In OC model mice, puerarin treatment suppressed tumor formation and modulated the gut microbiome. In addition, the expression of tumor suppressor genes was activated by puerarin and . These findings add to the existing knowledge on the usefulness of herbal active ingredients for the prevention and treatment of OC and provide a new perspective regarding the therapeutic potential of puerarin in cancer.
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http://dx.doi.org/10.1155/2022/4472509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352477PMC
August 2022

Systematic Construction and Validation of a Novel Ferroptosis-Related Gene Model for Predicting Prognosis in Cervical Cancer.

J Immunol Res 2022 28;2022:2148215. Epub 2022 Jul 28.

Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Hubei Clinical Cancer Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, China.

Methods: Datasets containing RNA sequencing and corresponding clinical data of cervical cancer patients were obtained from searching publicly accessible databases. The "NMF" R package was conducted to calculate the matrix of the screened prognosis gene expression. Ferroptosis-related differential genes in cervical cancer were detected using the "limma" R function and WGCNA. The least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analysis were conducted to develop a novel prognostic signature. The prediction model was verified by the nomogram integrating clinical characteristics; the GSE44001 dataset was used as an external verification. Then, the immune status and tumor mutation load were explored. Finally, immunohistochemistry as well as quantitative polymerase chain reaction (RT-qPCR) was utilized to ascertain the expression of FRGs.

Results: Two molecular subgroups (cluster 1 and cluster 2) with different FRG expression patterns were recognized. A ferroptosis-related model based on 4 genes (VEGFA, CA9, DERL3, and RNF130) was developed through TCGA database to identify the unfavorable prognosis cases. Patients in cluster 1 showed significantly decreased overall survival in contrast with those in cluster 2 ( < 0.05). The LASSO technique and Cox regression analysis were both utilized to establish the independence of the prognostic model. The validity of nomogram prognostic predictions has been well demonstrated for 3- and 5-year survival in both internal and external data validation cohorts. These two subgroups showed striking differences in tumor-infiltrating leukocytes and tumor mutation burden. The low-risk subgroup showed a longer overall survival time with a higher immune cell score and higher tumor mutation rate. Gene functional enrichment analyses revealed predominant enrichment in various tumor-associated signaling pathways. Finally, the expression of each gene was confirmed by immunohistochemistry and RT-qPCR.

Conclusion: A novel and comprehensive ferroptosis-related gene model was proposed for cervical cancer which was capable of distinguishing the patients independently with high risk for poor survival, and targeting ferroptosis may represent a promising approach for the treatment of CC.
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http://dx.doi.org/10.1155/2022/2148215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352469PMC
August 2022

Assembling bacteriophage T7 leading-strand replisome for structural investigation.

Authors:
Chen-Yu Lo Yang Gao

Methods Enzymol 2022 5;672:103-123. Epub 2022 Apr 5.

Department of BioSciences, Rice University, Houston, Texas, United States. Electronic address:

Replicative helicase and polymerase form the leading-strand replisome that unwinds parental DNA and performs continuous leading-strand DNA synthesis. Uncoupling of the helicase-polymerase complex results in replication stress, replication errors, and genome instability. Although numerous replisomes from different biological systems have been reconstituted and characterized, structural investigations of the leading-strand replisome complex are hindered by its large size and dynamics. We have determined the first replisome structure on a fork substrate with bacteriophage T7 replisome as a model system. Here, we summarized our protocols to prepare and characterize the coupled T7 replisome complex. Similar methods can potentially be applied for structural investigations of more complicated replisomes.
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http://dx.doi.org/10.1016/bs.mie.2022.03.009DOI Listing
August 2022

Multiparametric MR radiomics in brain glioma: models comparation to predict biomarker status.

BMC Med Imaging 2022 08 5;22(1):137. Epub 2022 Aug 5.

Department of Imaging Diagnosis, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010000, China.

Background: Genotype status of glioma have important significance to clinical treatment and prognosis. At present, there are few studies on the prediction of multiple genotype status in glioma by method of multi-sequence radiomics. The purpose of the study is to compare the performance of clinical features (age, sex, WHO grade, MRI morphological features etc.), radiomics features from multi MR sequence (T2WI, T1WI, DWI, ADC, CE-MRI (contrast enhancement)), and a combined multiple features model in predicting biomarker status (IDH, MGMT, TERT, 1p/19q of glioma.

Methods: In this retrospective analysis, 81 glioma patients confirmed by histology were enrolled in this study. Five MRI sequences were used for radiomic feature extraction. Finally, 107 features were extracted from each sequence on Pyradiomics software, separately. These included 18 first-order metrics, such as the mean, standard deviation, skewness, and kurtosis etc., 14 shape features and second-order metrics including 24 grey level run length matrix (GLCM), 16 grey level run length matrix (GLRLM), 16 grey level size zone matrix (GLSZM), 5 neighboring gray tone difference matrix (NGTDM), and 14 grey level dependence matrix (GLDM). Then, Univariate analysis and LASSO (Least absolute shrinkage and selection operator regression model were used to data dimension reduction, feature selection, and radiomics signature building. Significant features (p < 0.05 by multivariate logistic regression were retained to establish clinical model, T1WI model, T2WI model, T1 + C (T1WI contrast enhancement model, DWI model and ADC model, multi sequence model. Clinical features were combined with multi sequence model to establish a combined model. The predictive performance was validated by receiver operating characteristic curve (ROC analysis and decision curve analysis (DCA).

Results: The combined model showed the better performance in some groups of genotype status among some models (IDH AUC = 0.93, MGMT AUC = 0.88, TERT AUC = 0.76). Multi sequence model performed better than single sequence model in IDH, MGMT, TERT. There was no significant difference among the models in predicting 1p/19q status. Decision curve analysis showed combined model has higher clinical benefit than multi sequence model.

Conclusion: Multi sequence model is an effective method to identify the genotype status of cerebral glioma. Combined with clinical models can better distinguish genotype status of glioma.

Key Points: The combined model showed the higher performance compare with other models in predicting genotype status of IDH, MGMT, TERT. Multi sequence model showed a better predictive model than that of a single sequence model. Compared with other models, the combined model and multi sequence model show no advantage in prediction of 1p/19q status.
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http://dx.doi.org/10.1186/s12880-022-00865-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9354364PMC
August 2022

Knockdown of RRM1 in tumor cells promotes radio-/chemotherapy induced ferroptosis by regulating p53 ubiquitination and p21-GPX4 signaling axis.

Cell Death Discov 2022 Aug 1;8(1):343. Epub 2022 Aug 1.

High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences; Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.

Ferroptosis, a type of regulated cell death brought about by lipid peroxidation, has been discovered to suppress tumor growth. Here, we report that targeting RRM1 promotes ferroptosis and affects sensitivity to radiation and chemotherapeutics in cancer cells. In vitro experiments demonstrate that RRM1 increases the accumulation of cellular reactive oxygen species (ROS) and lipid peroxidation by disrupting the activity and expression of the antioxidant enzyme GPX4. Further studies reveal the downstream mechanisms of RRM1, which can regulate the deubiquitinating enzyme USP11 and ubiquitinating enzyme MDM2 to affect the ubiquitination modification of p53. Unstable p53 then inhibited the activity and expression of GPX4 by restraining the p21 protein. Furthermore, our data reveal that targeting RRM1 also increases radiation-induced DNA damage and apoptotic signaling and causes crosstalk between ferroptosis and apoptosis. On the basis of our collective findings, we propose that RRM1 is an essential negative mediator of radiosensitivity through regulating ferroptosis, which could serve as a potential target to inhibit the tumor's antioxidant system and enhance the efficiency of radio/chemotherapy.
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http://dx.doi.org/10.1038/s41420-022-01140-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9343379PMC
August 2022

Computationally exploring the mechanism of bacteriophage T7 gp4 helicase translocating along ssDNA.

Proc Natl Acad Sci U S A 2022 Aug 1;119(32):e2202239119. Epub 2022 Aug 1.

Department of Biosciences, Rice University, Houston, TX 77005.

Bacteriophage T7 gp4 helicase has served as a model system for understanding mechanisms of hexameric replicative helicase translocation. The mechanistic basis of how nucleoside 5'-triphosphate hydrolysis and translocation of gp4 helicase are coupled is not fully resolved. Here, we used a thermodynamically benchmarked coarse-grained protein force field, Associative memory, Water mediated, Structure and Energy Model (AWSEM), with the single-stranded DNA (ssDNA) force field 3SPN.2C to investigate gp4 translocation. We found that the adenosine 5'-triphosphate (ATP) at the subunit interface stabilizes the subunit-subunit interaction and inhibits subunit translocation. Hydrolysis of ATP to adenosine 5'-diphosphate enables the translocation of one subunit, and new ATP binding at the new subunit interface finalizes the subunit translocation. The LoopD2 and the N-terminal primase domain provide transient protein-protein and protein-DNA interactions that facilitate the large-scale subunit movement. The simulations of gp4 helicase both validate our coarse-grained protein-ssDNA force field and elucidate the molecular basis of replicative helicase translocation.
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http://dx.doi.org/10.1073/pnas.2202239119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371691PMC
August 2022

Ban-xia-xie-xin-tang ameliorates hepatic steatosis by regulating Cidea and Cidec expression in HFD-fed mice.

Phytomedicine 2022 Jul 21;105:154351. Epub 2022 Jul 21.

Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. Electronic address:

Background: Ban-xia-xie-xin-tang (BXXXT) has been applied in treating metabolic diseases, such as nonalcohol fatty liver disease, diabetes mellitus, and obesity. However, the underlying molecular mechanism of BXXXT in treating diabetes mellitus is unknown.

Purpose: To clarify the underlying molecular mechanism of BXXXT in alleviating hepatic steatosis in high-fat diet (HFD)-fed mice.

Methods: After 12 weeks of HFD treatment, mice were administered BXXXT for 4 weeks. The main chemical components of BXXXT were identified by UPLC-TQ-MS/MS. Indicators associated with insulin resistance and lipid metabolism were detected. The effect of improving glucose and lipid metabolism between BXXXT and the different components was compared. Differentially expressed genes (DEGs) were identified by hepatic transcriptomics. Key DEGs and proteins were further detected by real-time quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence staining. LDs and mitochondria were detected by transmission electron microscopy.

Results: First of all, our data demonstrated that the capacity to improve glucose and lipid metabolism for BXXXT was significantly superior to different components of BXXXT. BXXXT was found to improve HFD-induced insulin resistance. Moreover, BXXXT decreased weight, serum/hepatic triglycerides, total cholesterol, and FFAs to alleviate HFD-induced hepatic steatosis. According to the results of the hepatic transcription, Cidea and Cidec were identified as critical DEGs for promoting LD fusion and reducing FFAs β-oxidation in mitochondria and peroxisome resulting in hepatic steatosis, which was reversed by BXXXT.

Conclusion: BXXXT ameliorates HFD-induced hepatic steatosis and insulin resistance by increasing Cidea and Cidec-mediated mitochondrial and peroxisomal fatty acid oxidation, which may provide a potential strategy for therapy of NAFLD and T2DM.
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http://dx.doi.org/10.1016/j.phymed.2022.154351DOI Listing
July 2022

A self-amplifying USP14-TAZ loop drives the progression and liver metastasis of pancreatic ductal adenocarcinoma.

Cell Death Differ 2022 Jul 29. Epub 2022 Jul 29.

Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China.

With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A poor understanding of the underlying biology has resulted in a lack of effective targeted therapeutic strategies. Tissue microarray and bioinformatics analyses have revealed that the downstream transcriptional coactivator of the Hippo pathway, transcriptional coactivator with PDZ-binding motif (TAZ), might be a therapeutic target in PDAC. Since pharmacological inhibition of TAZ is challenging, we performed unbiased deubiquitinase (DUB) library screening to explore the pivotal regulators of TAZ ubiquitination as potential targets in PDAC models. We found that USP14 contributed to Yes-associated protein (YAP)/TAZ transcriptional activity and stabilized TAZ but not YAP. Mechanistically, USP14 catalyzed the K48-linked deubiquitination of TAZ to promote TAZ stabilization. Moreover, TAZ facilitated the transcription of USP14 by binding to the TEA domain transcription factor (TEAD) 1/4 response element in the promoter of USP14. USP14 was found to modulate the expression of TAZ downstream target genes through a feedback mechanism and ultimately promoted cancer progression and liver metastasis in PDAC models in vitro and in vivo. In addition, depletion of USP14 led to proteasome-dependent degradation of TAZ and ultimately arrested PDAC tumour growth and liver metastasis. A strong positive correlation between USP14 and TAZ expression was also detected in PDAC patients. The small molecule inhibitor of USP14 catalytic activity, IU1, inhibited the development of PDAC in subcutaneous xenograft and liver metastasis models. Overall, our data strongly suggested that the self-amplifying USP14-TAZ loop was a previously unrecognized mechanism causing upregulated TAZ expression, and identified USP14 as a viable therapeutic target in PDAC.
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http://dx.doi.org/10.1038/s41418-022-01040-wDOI Listing
July 2022

Supramolecular Nitric Oxide Depot for Hypoxic Tumor Vessel Normalization and Radiosensitization.

Adv Mater 2022 Jul 29:e2202625. Epub 2022 Jul 29.

Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P. R. China.

In cancer radiotherapy, the lack of fixed DNA damage by oxygen in hypoxic microenvironment of solid tumors often leads to severe radioresistance. Nitric oxide (NO) is a potent radiosensitizer that acts in two ways. It can directly react with the radical DNA thus fixing the damage. It also normalizes the abnormal tumor vessels, thereby increasing blood perfusion and oxygen supply. To achieve these functions, the dosage and duration of NO treatment need to be carefully controlled, otherwise it will lead to the exact opposite outcomes. However, a delivery method that fulfills both requirements is still lacking. A NO depot is designed for the control of NO releasing both over quantity and duration for hypoxic tumor vessel normalization and radiosensitization. In B16-tumor-bearing mice, the depot can provide low dosage NO continuously and release large amount of NO immediately before irradiation for a short period of time. These two modes of treatment work in synergy to reverse the radioresistance of B16 tumors more efficiently than releasing at single dosage.
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http://dx.doi.org/10.1002/adma.202202625DOI Listing
July 2022

Analysis of clinical characteristics, pathogen infection, and drug sensitivity of Marine injury patients: A cross-sectional study.

Medicine (Baltimore) 2022 Jul 29;101(30):e29943. Epub 2022 Jul 29.

Department of Emergency, People's Hospital of Rizhao, Jining Medical University, Shandong, China.

The infection rate is high in patients injured at sea, and because of the unique distribution of marine microorganisms, the infection is often not easily controlled effectively with the empirical application of antibiotics. This study aims to consider the clinical characteristics and pathogen infection and drug susceptibility of patients injured at sea. From 2019 to 2021, there were 635 patients injured at sea in Rizhao People's Hospital. We assess the patient's basic condition, while performing bacterial culture and drug susceptibility testing on wound exudate or pus from infected patients. Among the 635 patients injured at sea, 195 people were infected, and the infection rate was 30.71%. Infected patients are usually older, have longer prehospital visits, and have lower normal levels of red blood cells, hemoglobin, total protein, and albumin. The causes of injury in infected patients were mainly avulsion and puncture injuries, and the types of injuries were mainly bone fracture, vascular injury, and nerve injury. A total of 305 strains of pathogenic bacteria were cultured in 195 patients. Gram-negative bacteria accounted for 77.05% (235 strains), of which Proteus was the most. Gram-positive bacteria accounted for 22.95% (70 strains), of which Staphylococcus aureus was the most. Gram-negative bacilli were sensitive to aminoglycosides, lactam antibiotics, carbapenems antibiotics, sulfonamides, quinolones, fourth-generation cephalosporins, and antibacterial drugs containing enzyme inhibitors, while most of the bacteria were resistant to penicillins, first-generation cephalosporins, and second-generation cephalosporins. Gram-positive bacteria were sensitive to quinuptin/dafoptin, rifampicin, linezolid, gentamicin, tigacycline, and vancomycin but resistant to penicillin antibiotics. Due to the particularity of marine injuries, patients are prone to infection. Pathogen culture and drug sensitivity analysis play an important role in guiding antiinfective treatment for marine injured patients.
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http://dx.doi.org/10.1097/MD.0000000000029943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9333461PMC
July 2022

Efficient epidermal delivery of antibiotics by self-assembled lecithin/chitosan nanoparticles for enhanced therapy on epidermal bacterial infections.

Int J Biol Macromol 2022 Jul 25;218:568-579. Epub 2022 Jul 25.

School of Pharmacy, Qingdao University, Qingdao 266071, China. Electronic address:

The treatment for epidermal bacterial infections has become a primary healthy concern, producing a significant therapeutic challenge. Here we present a facile strategy to fabricate lecithin/chitosan nanoparticles (LCNPs) for efficient epidermal drug delivery over epidermal bacterial infections. The central rotatable composite design method was used for the optimization of the preparation, and that the optimal size (212.63 ± 1.95 nm) was obtained via analysis of variance (ANOVA). The prepared CIP-LCNPs show an average diameter of 325.9 ± 7.4 nm and a zeta potential of 26.6 ± 1.2 mV. Antibiotics can be well encapsulated in LCNPs and its release kinetics is studied with cumulative release of 93.81 ± 2.05 % for 48 h. The hemolytic activity, cytotoxicity, and skin irritation are further investigated. The zones of inhibition are 2.16 ± 0.04 cm and 2.92 ± 0.03 cm for Escherichia coli and Staphylococcus aureus, respectively. Moreover, in vitro permeation studies demonstrate that LCNPs can increase the accumulation of antibiotics in the epidermis with retention ratio 2-3 fold higher than commercial formulations. The in vivo result over epidermal-infected wound demonstrates the superior therapeutic effects of LCNPs. The developed LCNPs represent an important advance in fabricating therapeutic materials for enhanced therapy over epidermal bacterial infections.
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http://dx.doi.org/10.1016/j.ijbiomac.2022.07.165DOI Listing
July 2022

Unveiling the spatial and sectoral characteristics of a high-resolution emission inventory of CO and air pollutants in China.

Sci Total Environ 2022 Jul 25:157623. Epub 2022 Jul 25.

Appraisal Center for Environment and Engineering, Ministry of Ecology and Environment, Beijing 100012, China.

Under the target of carbon neutrality as well as stringent air quality guideline, understanding the spatial characteristics of both greenhouse gases and air pollutants emissions, in particular of their mutual sources, is crucial for assessing the feasibility of achieving their concomitant emission control, which, nevertheless, remains to be unclear yet. To this end, we construct a high-resolution (10 km * 10 km) emission inventory including both CO and air pollutants in China, which fosters us an opportunity to examine their spatial and sectoral characteristics. The primary sources for both CO and air pollutant emissions are power and industry. Among different subsectors in industry, detailed information indicates cement, iron and steel are the major subsectors for both CO and majority of air pollutants. Analysis of the high-resolution spatial distribution indicates that for CO, 5 % of the grids account for 90 % of the total CO emissions, indicative of the existence of spatial heterogeneity. These grids are the major locations with air pollutant emissions as well, i.e., 73 % for SO emissions, and more than 50 % for VOCs, CO, NOx, PM and PM, stressing the spatial consistency between greenhouse gases and air pollutant emissions. A large portion of emissions concentrate in a relatively small number of grids further implies the possibility to achieve the mutual control of both greenhouse gas emissions and air pollutant emissions, which is useful for future policy in particular of achieving the carbon neutrality and air quality improvement.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157623DOI Listing
July 2022

Retinal Microvascular Signs in Pre- and Early-Stage Diabetic Retinopathy Detected Using Wide-Field Swept-Source Optical Coherence Tomographic Angiography.

J Clin Med 2022 Jul 26;11(15). Epub 2022 Jul 26.

Department of Ophthalmology, Qilu Hospital, Shandong University, Jinan 250012, China.

Using a wide-field, high-resolution swept-source optical coherence tomographic angiography (OCTA), this study investigated microvascular abnormalities in patients with pre- and early-stage diabetic retinopathy. 38 eyes of 20 people with diabetes mellitus (DM) type 2 without diabetic retinopathy (DR) and 39 eyes of 21 people with DR were enrolled in this observational and cross-sectional cohort study, and a refractive error-matched group consisting of 42 eyes of 21 non-diabetic subjects of similar age were set as the control. Each participant underwent a wide-field swept-source OCTA. On OCTA scans (1.2 × 1.2 cm), the mean central macular thickness (CMT), the vessel density of the inner retina, superficial capillary plexus (SCP), and deep capillary plexus (DCP) were independently measured in the whole area (1.2 cm diameter) via concentric rings with varying radii (0-0.3, 0.3-0.6, 0.6-0.9, and 0.9-1.2 cm). Patients whose eyes had pre-and early-stage DR showed significantly decreased vessel density in the inner retina, SCP, DCP and CMT (early-stage DR) compared with the control. In addition, compared with the average values upon wide-field OCTA, the decreases were even more pronounced for concentric rings with a radius of 0.9-1.2 cm in terms of the inner retina, SCP, DCP and CMT. Widefield OCTA allows for a more thorough assessment of retinal changes in patients with pre- and early-stage DR.; retinal microvascular abnormalities were observed in both groups. In addition, the decreases in retinal vessel density were more significant in the peripheral concentric ring with a radius of 0.9-1.2 cm. The application of novel and wide-field OCTA could potentially help to detect earlier diabetic microvascular abnormalities.
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http://dx.doi.org/10.3390/jcm11154332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329884PMC
July 2022

Preliminary Study on Phytochemical Constituents and Biological Activities of Essential Oil from Less.

Molecules 2022 Jul 20;27(14). Epub 2022 Jul 20.

Marine College, Shandong University, Weihai 264209, China.

In response to the need for novel therapeutic strategies to combat the development of microbial resistance, plant essential oils may represent a promising alternative source. This study set out to characterize the chemical composition and assess the antibacterial potential of Less. essential oil (MNEO). Essential oil isolated from by hydrodistillation was analyzed using a GC-MS technique. The antibacterial properties of MNEO alone and combined with antibiotics (chloramphenicol and streptomycin) were tested via the disc diffusion, microbroth dilution, and checkerboard methods. MNEO was represented by oxygenated sesquiterpenes (60.3%) and sesquiterpene hydrocarbons (28.6%), with caryophyllene oxide, spathulenol, humulene epoxide II, β-elemene, neointermedeol, and β-caryophyllene as the main compounds. MNEO exhibited a strong antibacterial effect against Gram-positive bacteria, with MIC and MBC values of 0.039 mg/mL and 0.039-0.156 mg/mL, respectively, and synergistic effects were observed in both combinations with chloramphenicol and streptomycin. Furthermore, the antibiofilm and cytotoxic activities of MNEO were also evaluated. The crystal violet assay was used for quantification of biofilm formation, and an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was conducted to determine cell viability. The results revealed MNEO could dose-dependently inhibit biofilm formation and possessed potential cytotoxic on both normal and cancer cells (IC values from 13.13 ± 1.90 to 35.22 ± 8.36 μg/mL). Overall, the results indicate that MNEO may have promising applications in the field of bacterial infections.
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http://dx.doi.org/10.3390/molecules27144631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9324352PMC
July 2022

The Bifunctional Silyl Reagent Me (CH Cl)SiCF Enables Highly Enantioselective Ketone Trifluoromethylation and Related Tandem Processes.

Angew Chem Int Ed Engl 2022 Jul 26:e202208861. Epub 2022 Jul 26.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663N Zhongshan Road, Shanghai, 200062, China.

We report the development of bifunctional trifluoromethylsilyl reagents for selective trifluoromethylation. The newly developed reagent, Me (CH Cl)SiCF , allows highly enantioselective trifluoromethylations of ketones with broad scope. Notably, by taking advantage of the chloromethyl group, a tandem synthesis of chiral trifluoromethylated oxasilacyclopentanes is developed, paving way to α-CF tertiary alcohols with vicinal tertiary or quaternary stereocenters. Theoretical studies revealed the important role of nonclassical C-H⋅⋅⋅F-C interactions in stabilizing the transition state, and that the presence of the chlorine atom enhances such interactions for better enantiofacial control.
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http://dx.doi.org/10.1002/anie.202208861DOI Listing
July 2022

Risk Factors and Treatments of Suprachoroidal Hemorrhage.

Biomed Res Int 2022 14;2022:6539917. Epub 2022 Jul 14.

The First People's Hospital of Yunnan Province (Kunhua Hospital Affiliated with Kunming University of Science and Technology), Kunming, China.

Suprachoroidal hemorrhage (SCH) is a rare but serious sight-threatening complication of inner eye surgery. Despite continuous advances in treatment, visual prognosis remains poor. The disease has a more typical clinical presentation, the etiology and pathogenesis are not well defined, and intraoperative ocular and systemic factors may induce fulminant SCH. To investigate risk factors and treatments of SCH-associated intraocular surgeries, summarize diagnosis, characteristics, management, and prevention of SCH developed during and after intraocular surgeries. A retrospective study of SCH occurred in six cases of intraocular surgeries including cataract, glaucoma, pars plana vitrectomy (PPV), and silicone oil removal surgery. Assess baseline systemic and ocular characteristics of SCH eyes. Analyze the second surgery timing and technique, and visual outcomes were measured. SCH occurred in six patients including five eyes during surgeries and one eye after the surgery. Three eyes that underwent cataract surgery had hard nucleuses (nuclear sclerotic 4+). One eye was due to hypotony during the vitrectomy procedure. One eye developed SCH when silicone oil was extracted from the eyeball. One eye developed delayed SCH after glaucoma surgery. Incision closure and anterior chamber deepening were performed. B-scan ultrasonography was used to diagnose SCH, and determine the timing and location of sclerotomy for the second surgery. Vitrectomy and sclerotomy were performed in five eyes. The median follow-up time was six months. The final best-corrected visual acuity (BCVA) was 0.3 in one eye, one eye had light perception with retinal adherence, and four eyes had no light perception with retinal detachment. The results showed that risk factors including advanced age, hypertension, taking anticoagulants, antiplatelet drugs, and cardiovascular drugs were systemic risk factors, and hard nucleus (nuclear sclerosis 4 +) cataract, long-term uncontrolled ocular hypertension glaucoma, vitrectomy, silicone oil removal, high myopia, aphakia, previous intraocular surgery, intraocular pressure during surgery, and others were ocular risk factors. The most important risk factor is a sudden drop in intraocular pressure during or after surgery. The outcome of visual acuity depends on retinal status. Because of the poor prognosis, the prevention of SCH is of utmost importance during intraocular surgery.
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http://dx.doi.org/10.1155/2022/6539917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303137PMC
July 2022

Mesenchymal stem cells derived from adipose accelerate the progression of colon cancer by inducing a MT-CAFs phenotype via TRPC3/NF-KB axis.

Stem Cell Res Ther 2022 07 23;13(1):335. Epub 2022 Jul 23.

Beijing Key Laboratory (No.BZO38 1), Center of Excellence in Tissue Engineering Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, No. 1 Shuaifuyuan Hutong, Dongcheng District, Beijing, 100730, People's Republic of China.

Background: There is increasing evidence that mesenchymal stem cells (MSCs) help shape the tumor microenvironment and promote tumor progression, and ion channels might play a critical role in this process. The objective of the present study was to explore the function and mechanism of MT-CAFs on progression of colon cancer.

Methods: Here, a gene chip was used for a general analysis of gene expression changes in MSC-transformed CAF cells (MT-CAFs). Bioinformatic tool and western blot screened out the ion channel protein TRPC3 with significantly increased expression, and identify the function through two-photon microscope. The progression of cancer was detected via MTS, transwell and Wound Healing. ELISA deected the secretion of inflammation factors. TRPC3/NF-KB axis was identified by western blot and immunofluorescence.

Results: TRPC3 can caused calcium influx, which further activated the NF-KB signaling pathway. Knockdown or inhibition of TRPC3 in MSCs significantly reduced the activation of NF-KB, and decreased the growth, migration, and invasion of MT-CAFs. After TRPC3 knockdown, the ability of MT- CAFs to promote tumor migration and invasion was impaired. Conversely, the upregulation of TRPC3 expression in MT-CAFs had the opposite effect. In vivo, TRPC3 expressed on MSCs also contributed to the tumorigenesis and progression of cancer cells. In addition, the Oncomine and GEPIA databases showed that TRPC3 expression is higher in colon cancer tissues compared with normal colon tissues, and was positively correlated with the expression of the CAF genes alpha-smooth muscle (α-SMA/ACTA2) and fibroblast activation protein Alpha. The disease-free survival of patients with positive TRPC3 expression in MSCs was significantly shorter than those with negative expression.

Conclusions: These results indicate that TRPC3 expressed on MT-CAFs plays a critical role in tumor progression via the NF-KB signaling pathway, and is correlated with poor prognosis in colon cancer patients. Therefore, TRPC3 may be a novel therapeutic target for the treatment of colon cancer.
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http://dx.doi.org/10.1186/s13287-022-03017-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308187PMC
July 2022

Systemic pharmacological verification of Guizhi Fuling decoction in treating endometriosis-associated pain.

J Ethnopharmacol 2022 Oct 20;297:115540. Epub 2022 Jul 20.

Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address:

Ethnopharmacological Relevance: Guizhi Fuling decoction (GZFL decoction) is a famous formula in the Synopsis of the Golden Chamber, which has a long history in treating endometriosis. However, its exact mechanism remains unclear.

Aim Of Study: This study aims to explore the mechanism of GZFL decoction in treating endometriosis, especially in alleviating endometriosis-associated pain.

Materials And Methods: A combination of system pharmacology and pharmacodynamics was used to explore the specific mechanism of GZFL decoction in the treatment of endometriosis-associated pain. First, the TCMSP database was used to search the components of the GZFL decoction; the parameter index was set as oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18, while the active ingredients of the drug were screened out. The disease targets of endometriosis were obtained from the TTD, OMIM, Genecards, and DisGeNET databases; the keyword was "endometriosis pain". Network construction and analysis were performed using Cytoscape 3.7.2 software; the David database was used to enrich and analyze the pathways for alleviating endometriosis pain after GZFL decoction treatment. In addition, the network results were verified using experimental animal and cell research.

Results: The results showed the following targets: 76 for the effective chemical components in the prescription, 1329 for disease pain, and 278 for the intersection of drugs and endometriosis pain. The enrichment results for these targets showed that the TNF-PI3K/Akt pathway exhibited research significance. In endometriosis rat models, the GZFL decoction reduced the volume of lesions and relieved pain symptoms. It also reduced the serum levels of IL-6, IL-1β, and TNF-α as well as their expression in the lesion tissues. The GZFL decoction also suppressed the activation of PI3K/Akt downstream signaling proteins.

Conclusions: GZFL decoction could reduce the volume of lesions, suppress inflammation, and decrease the sensitivity to pain in endometriosis rat models through inhibiting PI3K/Akt pathway. This study provides a possible target for traditional Chinese medicine in treating endometriosis-associated pain.
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http://dx.doi.org/10.1016/j.jep.2022.115540DOI Listing
October 2022

Current knowledge of pyroptosis in heart diseases.

J Mol Cell Cardiol 2022 Jul 20;171:81-89. Epub 2022 Jul 20.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Institute of Biomedical Science, Fudan University, Shanghai, China; NHC Key Laboratory of Viral Heart Diseases, Shanghai, China; Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, China. Electronic address:

Pyroptosis is a form of pro-inflammatory, necrotic cell death mediated by proteins of the gasdermin family. Various heart diseases, including myocardial ischemia/reperfusion injury, myocardial infarction, and heart failure, involve cardiomyocyte and non-myocyte pyroptosis. Cardiomyocyte pyroptosis also causes the release of pro-inflammatory cytokines. Recent studies have confirmed that pyroptosis is predominantly triggered by both the canonical and non-canonical inflammasome pathways, which independently facilitate caspase-1 or caspase-11/4/5 activation and gasdermin D (GSDMD) cleavage. Cardiac fibroblast and myeloid cell pyroptosis also contributes to the pathogenesis and development of heart diseases. This review summarizes the recent studies on pyroptosis in heart diseases and discusses the associated therapeutic targets.
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http://dx.doi.org/10.1016/j.yjmcc.2022.07.005DOI Listing
July 2022

Characterization of the Immunologic Phenotype of Dendritic Cells Infected With Herpes Simplex Virus 1.

Front Immunol 2022 5;13:931740. Epub 2022 Jul 5.

Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, China.

Due to viral envelope glycoprotein D binding to cellular membrane HVEM receptor, HSV-1 can infect certain dendritic cells, which becomes an event in the viral strategy to interfere with the host's immune system. We previously generated the HSV-1 mutant strain M6, which produced an attenuated phenotype in mice and rhesus monkeys. The attenuated M6 strain was used to investigate how HSV-1 infection of dendritic cells interferes with both innate and adaptive immunity. Our study showed that dendritic cells membrane HVEM receptors could mediate infection of the wild-type strain and attenuated M6 strain and that dendritic cells infected by both viruses in local tissues of animals exhibited changes in transcriptional profiles associated with innate immune and inflammatory responses. The infection of pDCs and cDCs by the two strains promoted cell differentiation to the CD103 phenotype, but varied transcriptional profiles were observed, implying a strategy that the HSV-1 wild-type strain interferes with antiviral immunity, probably due to viral modification of the immunological phenotype of dendritic cells during processing and presentation of antigen to T cells, leading to a series of deviations in immune responses, ultimately generating the deficient immune phenotype observed in infected individuals in the clinical.
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http://dx.doi.org/10.3389/fimmu.2022.931740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294641PMC
July 2022

Genetic evidence of tri-genealogy hypothesis on the origin of ethnic minorities in Yunnan.

BMC Biol 2022 07 21;20(1):166. Epub 2022 Jul 21.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Center for Evolutionary Biology, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Background: Yunnan is located in Southwest China and consists of great cultural, linguistic, and genetic diversity. However, the genomic diversity of ethnic minorities in Yunnan is largely under-investigated. To gain insights into population history and local adaptation of Yunnan minorities, we analyzed 242 whole-exome sequencing data with high coverage (~ 100-150 ×) of Yunnan minorities representing Achang, Jingpo, Dai, and Deang, who were linguistically assumed to be derived from three ancient lineages (the tri-genealogy hypothesis), i.e., Di-Qiang, Bai-Yue, and Bai-Pu.

Results: Yunnan minorities show considerable genetic differences. Di-Qiang populations likely migrated from the Tibetan area about 6700 years ago. Genetic divergence between Bai-Yue and Di-Qiang was estimated to be 7000 years, and that between Bai-Yue and Bai-Pu was estimated to be 5500 years. Bai-Pu is relatively isolated, but gene flow from surrounding Di-Qiang and Bai-Yue populations was also found. Furthermore, we identified genetic variants that are differentiated within Yunnan minorities possibly due to the living circumstances and habits. Notably, we found that adaptive variants related to malaria and glucose metabolism suggest the adaptation to thalassemia and G6PD deficiency resulting from malaria resistance in the Dai population.

Conclusions: We provided genetic evidence of the tri-genealogy hypothesis as well as new insights into the genetic history and local adaptation of the Yunnan minorities.
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http://dx.doi.org/10.1186/s12915-022-01367-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306206PMC
July 2022

A double-network strategy for the tough tissue adhesion of hydrogels with long-term stability under physiological environment.

Soft Matter 2022 Jul 20. Epub 2022 Jul 20.

State Key Lab for Strength and Vibration of Mechanical Structures, Soft Machines Lab, School of Aerospace Engineering, Xi'an Jiaotong University, Xi'an 710049, China.

Achieving tough and stable tissue adhesion under a physiological environment is of great significance for the clinical applications of hydrogel adhesives. The current tough hydrogel adhesives face challenges in the preservation of the maximal adhesion for a long time due to swelling. Here, we propose a double-network strategy for tough tissue adhesion by a hydrogel with long-term stability under a physiological environment. A double-network hydrogel consisting of a covalently crosslinked primary network with tunable hydrophilicity and a non-covalently crosslinked secondary network with functional groups is designed. The primary network exhibited hydrophobicity in the physiological environment, which could constrict the secondary network and limit the swelling of the entire hydrogel. The secondary network could form strong interlinks with tissue and provide large energy dissipation through the unzipping of its noncovalent crosslinks when separated by a force. The combination of the two networks resulted in a tough and stable tissue adhesion. A poly(-isopropylacrylamide)/calcium alginate hydrogel synthesized based on this strategy realized an adhesion energy of 300-500 J m with porcine tissues, and the maximal adhesion could be maintained for over 1000 min after submerging in a PBS solution at 37 °C. The swelling behavior of the hydrogel and changes in mechanical properties under the physiological environment are studied, and its application in repairing the aorta wound is demonstrated.
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http://dx.doi.org/10.1039/d2sm00688jDOI Listing
July 2022

New brefeldin A-cinnamic acid ester derivatives as potential antitumor agents: Design, synthesis and biological evaluation.

Eur J Med Chem 2022 Oct 11;240:114598. Epub 2022 Jul 11.

Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts of Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China. Electronic address:

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and ranks third in mortality rate worldwide. Brefeldin A (BFA, 1), a natural Arf1 inhibitor, qualifies extremely superior antitumor activity against HCC while its low aqueous solubility, poor bioavailability, and high toxicity have greatly hindered its translation to the clinic. Herein, a series of BFA-cinnamic acid ester derivatives was rationally designed and synthesized via introducing active cinnamic acid and its analogues into the structure of 1. Their in vitro cytotoxic activities on five cancer cell lines, including HepG2, BEL-7402, HeLa, Eca-109 and PANC-1, were evaluated using MTT assay. As expected, favorable cytotoxic activity was observed on majority of the mono-substituted derivatives. Especially, the most potent brefeldin A 4-O-(4)-dimethylaminocinnamate (CHNQD-01269, 33) with improved aqueous solubility, demonstrated the strong cytotoxic activity against HepG2 and BEL-7402 cell lines with IC values of 0.29 and 0.84 μM, respectively. More importantly, 33 performed low toxicity on normal liver cell line L-02 with the selectivity index (SI) of 9.69, which was more than 17-fold higher than that of 1. Results from mechanistic studies represented that 33 blocked the cell cycle in the G1 phase, and induced apoptosis via elevating reactive oxygen species (ROS) production and increasing expression of apoptosis-related proteins of HepG2 cells. Docking experiment also suggested 33 a promising Arf1 inhibitor, which was confirmed by the cellular thermal shift assay that 33 displayed a significant effect on the stability of Arf1 protein. Furthermore, 33 possessed high safety profile (MTD >100 mg/kg, ip) and favorable pharmacokinetic properties. Notably, the superior antiproliferative activity was verified in HepG2 tumor-bearing xenograft model in which 33 markedly suppressed the tumor growth (TGI = 46.17%) in nude mice at a dose of 10 mg/kg once a day for 16 d. The present study provided evidence of exploiting this series of highly efficacious derivatives, especially 33, for the treatment of HCC.
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http://dx.doi.org/10.1016/j.ejmech.2022.114598DOI Listing
October 2022
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