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Role of doxycycline in the treatment of dengue infection: An open-label, randomized, controlled, pilot trial

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Asian Pacific Journal of Tropical medicine 2024年第4期17卷 160-165页

作者： Banothu Vinod Kumar Kajal Kamboj Ashok Kumar Pannu Ashok Kumar Yadav Mandip Bhatia Atul Saroch department of Internal medicine PGIMER ChandigarhIndia department of experimental medicine&Biotechnology PGIMER ChandigarhIndia

Objective:To measure the effect of doxycycline on inflammatory marker[IL-6,TNF-α,ferritin and C reactive protein(CRP)]levels in patients with dengue ***:A single-centre,open-label,parallel-group randomized controlled trial was done in PGIMER Chandigarh from June 2021 to October *** were randomized using a simple randomization process into two groups:the doxycycline treatment group(n=35)and the control group(n=34).Patients in the treatment group were given oral doxycycline 100 mg twice daily for five days along with standard treatment,whereas patients in the control group received only standard *** objective was to measure the effect of doxycycline on inflammatory markers in dengue ***:On comparative analysis at day 5,there was a statistically significant reduction in the median values of ferritin and CRP in cases compared to the control group(ferritin:P=0.006 and CRP:P=0.006).No significant reduction was noted in the levels of IL-6 and TNF-α.Conclusions:Doxycycline treatment led to a reduction of inflammatory markers in dengue infection.

关键词： Dengue Cytokine Doxycycline Serum ferritin C reactive protein

Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern

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Journal of Molecular Cell biology 2024年第3期16卷 9-23页

作者： Ilaria Frasson Linda Diamante Manuela Zangrossi Elena Carbognin Anna Dalla Pietà Alessandro Penna Antonio Rosato Ranieri Verin Filippo Torrigiani Cristiano Salata Marìa Paula Dizanzo Lorenzo Vaccaro Davide Cacchiarelli Sara N.Richter Marco Montagner Graziano Martello department of Molecular medicine University of PaduaPadua 35121Italy department of biology Armenise/Harvard Pluripotent Stem Cell Biology LaboratoryUniversity of PaduaPadua 35131Italy department of Surgery Oncology and GastroenterologyUniversity of PaduaPadua 35128Italy Veneto Institute of Oncology IOV-IRCCS Padua 35128Italy department of comparative Biomedicine and Food Science University of PaduaPadua 35020Italy Telethon Institute of Genetics and medicine(TIGEM) Armenise/Harvard Laboratory of Integrative GenomicsPozzuoli 80078Italy department of Translational medicine University of Naples Federico IINaples 80138Italy School for Advanced Studies Genomics and Experimental Medicine ProgramUniversity of Naples Federico IINaples 80138Italy Microbiology and Virology Unit Padua University HospitalPadua 35128Italy

The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants,some of which are resistant to vaccines and drugs targeting viral *** host dependency factors,*** proteins required for viral replication,would help prevent the development of ***,it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host *** this end,we compared three variants of concern and found that the host transcriptional response was conserved,differing only in kinetics and *** regularly interspaced short palindromic repeats screening identified host genes required for each variant during *** of the genes were shared by multiple *** validated our hits with small molecules and repurposed the US Food and Drug Administration-approved *** the drugs were highly active against all the tested variants,including new variants that emerged during the study(Delta and Omicron).Mechanistically,we identified reactive oxygen species production as a key step in early viral *** such as N-acetyl cysteine(NAC)were effective against all the variants in both human lung cells and a humanized mouse *** study supports the use of available antioxidant drugs,such as NAC,as a general and effective anti-COVID-19 approach.

关键词： SARS-CoV-2 variants of concern host dependency factors antivirals N-acetyl cysteine

Investigation of HCAR2 antagonists as a potential strategy to modulate bovine leukocytes

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Journal of Animal Science and Biotechnology 2024年第4期15卷 1567-1577页

作者： Laman K.Mamedova Kirby C.Krogstad Paiton O.McDonald Laxman Pokhrel Duy H.Hua Evan C.Titgemeyer Barry J.Bradford department of Animal Science Michigan State UniversityEast LansingMichigan 48824USA department of Animal Sciences and Industry Kansas State UniversityManhattanKS 66506USA comparative medicine and Integrative biology East LansingMI 48824USA department of Chemistry Kansas State UniversityManhattanKS 66506USA

Background Dairy cows experiencing ketosis after calving suffer greater disease incidence and are at greater risk of leaving the herd. In vitro administration of beta-hydroxybutyric acid(BHBA;the primary blood ketone) has inhibitory effects on the function of bovine leukocytes. BHBA is a ligand of HCAR2 and the activation of these receptors promotes an anti-inflammatory response which may be related with immunosuppression observed in transition dairy cattle. The objective of this study was to identify and test antagonists for HCAR2 in bovine immune cells cultured with *** We observed expression of HCAR2 at the protein level within lymphocytes, monocytes, and granulocytes. The proportion of cells expressing HCAR2 tended to be greater in mid-lactation compared to early lactation cows;the increase was a result of increased proportion of T and B cells expressing HCAR2. Stimulation of HCAR2 with niacin or BHBA promoted Ca^(2+) mobilization in neutrophils and mononuclear cells. Mononuclear cells treated with BHBA had diminished intracellular Ca^(2+) responses when HCAR2 was knocked down by si RNA silencing, indicating Ca^(2+) mobilization was mediated by HCAR2 signaling. Two candidate antagonists for HCAR2, synthesized from niacin(NA-1 and NA-5), were tested;monocytes and neutrophils pre-treated with NA-1 and NA-5 had reduced Ca^(2+) mobilization after incubation with BHBA. Furthermore, NA-5 but not NA-1 prevented BHBA-associated reductions in cyclic *** We demonstrated that HCAR2 is present on bovine leukocytes and has greater expression later in lactation. We confirmed that BHBA and niacin derived HCAR2 antagonists alter bovine leukocyte activity. Our results demonstrate that both BHBA and niacin affect bovine leukocyte Ca^(2+) mobilization in a HCAR2-dependent manner.

关键词： Flow cytometry GPR109A HM74A Ketosis

UBE2T mediates the stemness properties of breast cancer cells through the mTOR signaling pathway

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BIOCELL 2024年第6期48卷 959-970页

作者： JIAWEI YIN YONGSHENG WANG GUANGWEI WEI MINGXIN WEN department of Traumatology The Second Hospital of Shandong UniversityJinan250033China department of Pathology Weifang People’s HospitalWeifang261000China department of Human Anatomy Shandong University School of MedicineJinan250012China department of Cell biology and Key Laboratory of experimental Teratology Shandong University School of MedicineJinan250012China

Objectives:This study aimed to reveal the role and possible mechanism of the ubiquitin-conjugating enzyme 2T(UBE2T)in the biological activities of breast cancer stem cells(BCSCs).Methods:The specific protein and gene expression were quantified by Western blotting and quantitative real-time polymerase chain reaction,the proportion of BCSCs was examined by flow cytometry,and the self-renewal and proliferation of BCSCs were verified by serial sphere formation and soft ***:Increasing expression of UBE2T was drastically found in breast cancer than that in adjacent ***,UBE2T overexpression significantly increased the proportion of BCSCs in breast cancer cells and promoted their self-renewal and *** UBE2T exhibited the opposite ***2T increased the levels of the mammalian target of rapamycin and the phosphorylated mammalian target of *** target of rapamycin(mTOR)inhibitor rapamycin inhibited the function of UBE2T in ***:UBE2T plays a role in BCSCs through mTOR pathway and may suggest a novel therapeutic strategy for breast cancer.

关键词： UBE2T Breast cancer Breast cancer stem cell mTOR

Metabolic cell death in cancer:ferroptosis,cuproptosis,disulfidptosis,and beyond

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Protein & Cell 2024年第9期15卷 642-660页

作者： Chao Mao Min Wang Li Zhuang Boyi Gan department of experimental Radiation Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA department of Molecular and Cellular biology Baylor College of MedicineHoustonTX 77030USA The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences HoustonTX 77030USA

Cell death resistance represents a hallmark of *** studies have identified metabolic cell death as unique forms of regulated cell death resulting from an imbalance in the cellular *** review discusses the mechanisms of metabolic cell death—ferroptosis,cuproptosis,disulfidptosis,lysozincrosis,and alkaliptosis—and explores their potential in cancer *** review underscores the complexity of the metabolic cell death pathways and offers insights into innovative therapeutic avenues for cancer treatment.

关键词： cell death cancer treatment ferroptosis cuproptosis disulfidptosis

Recombinant adeno-associated virus 8-mediated inhibition of microRNA let-7a ameliorates sclerosing cholangitis in a clinically relevant mouse model

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World Journal of Gastroenterology 2024年第5期30卷 471-484页

作者： Hui Hua Qian-Qian Zhao Miriam Nkesichi Kalagbor Guo-Zhi Yu Man Liu Zheng-Rui Bian Bei-Bei Zhang Qian Yu Yin-Hai Xu Ren-Xian Tang Kui-Yang Zheng Chao Yan Jiangsu Key Laboratory of Immunity and Metabolism Department of Pathogenic Biology and ImmunologyNational Demonstration Center for Experimental Basic Medical Science EducationLaboratory of Infection and ImmunityXuzhou Medical UniversityXuzhou 221004Jiangsu ProvinceChina department of Laboratory medicine The Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221002Jiangsu ProvinceChina

BACKGROUND Primary sclerosing cholangitis(PSC)is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment *** adeno-associated virus(rAAV)provides a promising platform for gene therapy on such kinds of diseases.A microRNA(miRNA)let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been *** To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8(rAAV8)on a xenobiotic-induced mouse model of sclerosing *** A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine(DDC)feeding for 2 wk or 6 wk.A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC *** sacrifice,the liver and the serum were collected from each *** hepatobiliary injuries,hepatic inflammation and fibrosis were *** targets of let-7a-5p and downstream molecule NF-κB were detected using Western *** rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 *** reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers,and prevent the proliferation of cholangiocytes and biliary ***,inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1,which consequently inhibit of NF-κB-mediated hepatic *** Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis,which provides a possible clinical translation of PSC of human.

关键词： Primary sclerosing cholangitis Recombinant adeno-associated virus 8 Let-7a-5p Therapeutic effects Inflammation

Fetal lung growth predicts the risk for early-life respiratory infections and childhood asthma

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World Journal of Pediatrics 2024年第5期20卷 481-495页

作者： Dimitra E.Zazara Olympia Giannou Steven Schepanski Mirja Pagenkemper Anastasios D.Giannou Maike Pincus Ioannis Belios Stefan Bonn Ania C.Muntau Kurt Hecher Anke Diemert Petra Clara Arck Division for experimental Feto-Maternal medicine Department of Obstetrics and Fetal MedicineUniversity Medical Center Hamburg-Eppendorf(UKE)Martinistraße 5220251HamburgGermany University Children’s Hospital UKEHamburgGermany Computer Engineering and Informatics department Polytechnic SchoolUniversity of PatrasPatrasGreece Institute of Developmental Neurophysiology Center for Molecular Neurobiology Hamburg(ZMNH)UKEHamburgGermany department of Obstetrics and Fetal medicine UKEHamburgGermany department of General Visceral and Thoracic SurgeryUKEHamburgGermany Section of Molecular Immunology and Gastroenterology Ⅰ.Department of MedicineUKEHamburgGermany Pediatrics and Pediatric Pneumology Practice BerlinGermany Institute of Medical Systems biology ZMNHUKEHamburgGermany Hamburg Center for Translational Immunology UKEHamburgGermany

Background Early-life respiratory infections and asthma are major health burdens during *** predicting an increased risk for early-life respiratory diseases are ***,we identified the predictive value of ultrasound-monitored fetal lung growth for the risk of early-life respiratory infections and *** Fetal lung size was serially assessed at standardized time points by transabdominal ultrasound in pregnant women participating in a pregnancy *** between fetal lung growth and respiratory infections in infancy or early-onset asthma at five years were ***-learning models relying on extreme gradient boosting regressor or classifier algorithms were developed to predict respiratory infection or asthma risk based on fetal lung *** model development and validation,study participants were randomly divided into a training and a testing group,respectively,by the employed *** Enhanced fetal lung growth throughout pregnancy predicted a lower early-life respiratory infection *** sex was associated with a higher risk for respiratory infections in *** lung growth could also predict the risk of asthma at five years of *** designed three machine-learning models to predict the risk and number of infections in infancy as well as the risk of early-onset *** models’R2 values were 0.92,0.90 and 0.93,respectively,underscoring a high accuracy and agreement between the actual and predicted *** variables included known risk factors and novel predictors,such as ultrasound-monitored fetal lung *** Sonographic monitoring of fetal lung growth allows to predict the risk for early-life respiratory infections and asthma.

关键词： Asthma Child risk Early-life respiratory infections Prenatal lung development Sexual dimorphism

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

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Oncology Research 2024年第4期32卷 769-784页

作者： HUAN GAO JIE ZHANG TONY GKLEIJN ZHAOYONG WU BING LIU YUJIN MA BAOYUE DING DONGFENG YIN Jiaxing Key Laboratory for Photonanomedicine and experimental Therapeutics Department of PharmaceuticsCollege of MedicineJiaxing UniversityJiaxing314001China department of Pharmacy The General Hospital of Xinjiang Military RegionUrumqi830000China department of Pathology and Medical biology University Medical Center GroningenUniversity of GroningenGroningen9713 GZThe Netherlands department of Pathology Laboratory of Experimental OncologyErasmus MCRotterdam3015 GDThe Netherlands department of Pharmacy Jiaxing Maternal and Child Health Care HospitalAffiliated Hospital of Jiaxing UniversityJiaxing314001China Qinghai Enlu Biotechnology Co. Ltd.Haidong810700China

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and *** treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic *** improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone ***(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size *** in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX *** micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated *** binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis *** vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic *** conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

关键词： Pluronic micelles Targeted nanotherapeutics Nanoparticulate drug delivery system Breast cancer with bone metastasis Therapeutic efficacy

Targeting PKM2 signaling cascade with salvianic acid A normalizes tumor blood vessels to facilitate chemotherapeutic drug delivery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2077-2096页

作者： Cheng Qian Yueke Zhou Teng Zhang Guanglu Dong Mengyao Song Yu Tang Zhonghong Wei Suyun Yu Qiuhong Shen Wenxing Chen Jaesung P.Choi Juming Yan Chongjin Zhong Li Wan Jia Li Aiyun Wang Yin Lu Yang Zhao Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China School of medicine&Holistic Integrative medicine Nanjing University of Chinese MedicineNanjing 210023China Centre for Inflammation Faculty of ScienceCentenary InstituteSchool of Life SciencesUniversity of Technology SydneySydney NSW 2050Australia Jiangsu Key Laboratory of Immunity and Metabolism Department of Pathogenic Biology and ImmunologyNational Experimental Demonstration Center for Basic Medicine EducationXuzhou Laboratory of Infection and ImmunityXuzhou Medical UniversityXuzhou 221004China department of General Surgery Jiangsu Province Hospital of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjing 210029China Macquarie Medical School Faculty of MedicineHuman Health SciencesMacquarie UniversitySydney NSW 2109Australia

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor ***,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic *** was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to ***,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial *** importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent *** findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.

关键词： Salvianic acid A Tumor vascular normalization PKM2 β-Catenin Claudin-5 Endothelial glycolysis Tight junctions Doxorubicin