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Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension

Acta Pharmaceutica Sinica B 2021年第5期11卷 1117-1128页

作者： Nur Farah Meor Azlan Maarten P.Koeners Jinwei Zhang Institute of Biomedical and Clinical Sciences Medical SchoolCollege of Medicine and HealthUniversity of ExeterHatherly LaboratoriesExeter EX44PSUK

Hypertension is the largest risk factor for cardiovascular disease,the leading cause of mortality worldwide.As blood pressure regulation is influenced by multiple physiological systems,hypertension cannot be attributed to a single identifiable etiology.Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling,particularly the distal convoluted tubule(DCT)-native,thiazide-sensitive Na-Cl cotransporter(NCC).Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon’s and Gitelman syndromes respectively.Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC.In particular,NCC activity is controlled by phosphorylation/dephosphorylation,and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination.Studies have even found parvalbumin to be an unexpected regulator of the NCC.In recent years,there have been considerable advances in our understanding of NCC control mechanisms,particularly via the pathway containing the with-no-lysine[K](WNK)and its downstream target kinases,SPS/Ste20-related proline-alanine-rich kinase(SPAK)and oxidative stress responsive 1(OSR1),which has led to the discovery of novel inhibitory molecules.This review summarizes the currently reported regulatory mechanisms of the NCC and discusses their potential as therapeutic targets for treating hypertension.

关键词： NaCl-cotransporter NCC Cardiovascular disease CUL3/KLHL3-WNK-SPAK/OSR1 Blood pressure regulation Kinase inhibitors Membrane trafficking therapeutic targets Hypertension

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Hippo signaling:bridging the gap between cancer and neurodegenerative disorders

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Neural Regeneration Research 2021年第4期16卷 643-652页

作者： Neha Gogia Anuradha Venkatakrishnan Chimata Prajakta Deshpande Aditi Singh Amit Singh Department of Biology University of DaytonDaytonOHUSA Medical Candidate University of Toledo College of Medicine and Life SciencesToledoOHUSA Premedical Program University of DaytonDaytonOHUSA Center for Tissue Regeneration and Engineering at Dayton(TREND) University of DaytonDaytonOHUSA The Integrative Science and Engineering Center University of DaytonDaytonOHUSA Center for Genomic Advocacy(TCGA) Indiana State UniversityTerre HauteINUSA

During development,regulation of organ size requires a balance between cell proliferation,growth and cell death.Dysregulation of these fundamental processes can cause a variety of diseases.Excessive cell proliferation results in cancer whereas excessive cell death results in neurodegenerative disorders.Many signaling pathways known-to-date have a role in growth regulation.Among them,evolutionarily conserved Hippo signaling pathway is unique as it controls both cell proliferation and cell death by a variety of mechanisms during organ sculpture and development.Neurodegeneration,a complex process of progressive death of neuronal population,results in fatal disorders with no available cure to date.During normal development,cell death is required for sculpting of an organ.However,aberrant cell death in neuronal cell population can result in neurodegenerative disorders.Hippo pathway has gathered major attention for its role in growth regulation and cancer,however,other functions like its role in neurodegeneration are also emerging rapidly.This review highlights the role of Hippo signaling in cell death and neurodegenerative diseases and provide the information on the chemical inhibitors employed to block Hippo pathway.Understanding Hippo mediated cell death mechanisms will aid in development of reliable and effective therapeutic strategies in future.

关键词： animal models cell death mechanisms cell-signaling chemical inhibitors Drosophila eye Hippo pathway neurodegeneration neurological diseases therapeutic targets

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LncRNA SNHG12 ameliorates brain microvascular endothelial cell injury by targeting miR-199a

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Neural Regeneration Research 2018年第11期13卷 1919-1926页

作者： Fa-Qing Long Qing-Jie Su Jing-Xia Zhou De-Sheng Wang Peng-Xiang Li Chao-Sheng Zeng, Yi Cai The Second Affiliated Hospital of Hainan Medical University Haikou Hainan Province China

Long non-coding RNAs regulate brain microvascular endothelial cell death, the inflammatory response and angiogenesis during and after ischemia/reperfusion and oxygen-glucose deprivation/reoxygenation（OGD/R） insults. The long non-coding RNA, SNHG12, is upregulated after ischemia/reperfusion and OGD/R in microvascular endothelial cells of the mouse brain. However, its role in ischemic stroke has not been studied. We hypothesized that SNHG12 positively regulates ischemic stroke, and therefore we investigated its mechanism of action. We established an OGD/R mouse cell model to mimic ischemic stroke by exposing brain microvascular endothelial cells to OGD for 0, 2, 4, 8, 16 or 24 hours and reoxygenation for 4 hours. Quantitative real-time polymerase chain reaction showed that SNHG12 levels in brain microvascular endothelial cells increased with respect to OGD exposure time. Brain microvascular endothelial cells were transfected with pc DNA-control, pc DNA-SNHG12, si-control, or si-SNHG12. After exposure to OGD for 16 hours, these cells were then analyzed by 3-（4,5-dimethyl-2-thiazolyl）-2,5-diphenyl-2-H-tetrazolium bromide, trypan blue exclusion, western blot, and capillary-like tube formation assays. Overexpression of SNHG12 inhibited brain microvascular endothelial cell death and the inflammatory response but promoted angiogenesis after OGD/R, while SNHG12 knockdown had the opposite effects. miR-199a was identified as a target of SNHG12, and SNHG12 overexpression reversed the effect of miR-199a on brain microvascular endothelial cell death, the inflammatory response, and angiogenesis. These findings suggest that SNHG12 suppresses endothelial cell injury induced by OGD/R by targeting miR-199a.

关键词： nerve regeneration ischemic stroke microRNA brain microvascular endothelial cell death inflammatory response angiogenesis oxygen-glucose deprivation/reoxygenation ischemia/reperfusion therapeutic targets neural regeneration gene regulation neural regeneration

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Notch signalling pathway in development of cholangiocarcinoma

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World Journal of Gastrointestinal Oncology 2020年第9期12卷 957-974页

作者： Bisma Rauff Arif Malik Yasir Ali Bhatti Shafiq Ahmad Chudhary Ishtiaq Qadri Shafquat Rafiq Institute of Molecular Biology and Biotechnology University of LahoreLahore 54000Pakistan Institute of Biomedical and Allied Health Sciences University of Health SciencesLahore 54000Pakistan Department of Biology Faculty of ScienceKing Abdulaziz University Jeddah Kingdom of Saudi Arabia Department of Gastrointestinal medicine Croydon University HospitalCroydon CR77YEUnited Kingdom

Cholangiocarcinoma(CCA)comprises of extra-hepatic cholangiocarcinoma and intrahepatic cholangiocarcinoma cancers as a result of inflammation of epithelium cell lining of the bile duct.The incidence rate is increasing dramatically worldwide with highest rates in Eastern and South Asian regions.Major risk factors involve chronic damage and inflammation of bile duct epithelium from primary sclerosing cholangitis,chronic hepatitis virus infection,gallstones and liver fluke infection.Various genetic variants have also been identified and as CCA develops on the background of biliary inflammation,diverse range of molecular mechanisms are involved in its progression.Among these,the Notch signalling pathway acts as a major driver of cholangiocarcinogenesis and its components(receptors,ligands and downstream signalling molecules)represent a promising therapeutic targets.Gamma-Secretase Inhibitors have been recognized in inhibiting the Notch pathway efficiently.A comprehensive knowledge of the molecular pathways activated by the Notch signalling cascade as well as its functional crosstalk with other signalling pathways provide better approach in developing innovative therapies against CCA.

关键词： Cholangicarcinoma Notch receptors therapeutic targets Notch signalling pathway Gamma secretase inhibitor Cholangiocytes

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Neutrophil extracellular traps in gastrointestinal cancer

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World Journal of Gastroenterology 2021年第33期27卷 5474-5487页

作者： Zi-Qiang Chu Ke-Cheng Zhang Lin Chen Graduate School Chinese PLA General HospitalBeijing 100853China Institute of Basic Medical Sciences Chinese PLA General HospitalBeijing 100853China Department of General Surgery Chinese PLA General Hospital First Medical CenterBeijing 100853China

Gastrointestinal(GI)cancer is a high-risk malignancy and is characterized by high mortality and morbidity worldwide.Neutrophil extracellular traps(NETs),a weblike structure consisting of chromatin DNA with interspersed cytoplasmic and granule proteins,are extruded by activated neutrophils to entrap and kill bacteria and fungi.However,accumulating evidence shows that NETs are related to the progression and metastasis of cancer.In clinical studies,NETs infiltrate primary GI cancer tissues and are even more abundant in metastatic lesions.The quantity of NETs in peripheral blood is revealed to be associated with ascending clinical tumour stages,indicating the role of NETs as a prognostic markers in GI cancer.Moreover,several inhibitors of NETs or NET-related proteins have been discovered and used to exert anti-tumour effects in vitro or in vivo,suggesting that NETs can be regarded as targets in the treatment of GI cancer.In this review,we will focus on the role of NETs in gastric cancer and colorectal cancer,generalizing their effects on tumour-related thrombosis,invasion and metastasis.Recent reports are also listed to show the latest evidences of how NETs affect GI cancer.Additionally,notwithstanding the scarcity of systematic studies elucidating the underlying mechanisms of the interaction between NETs and cancer cells,we highlight the potential importance of NETs as biomarkers and anti-tumour therapeutic targets.

关键词： Neutrophil extracellular traps Gastric cancer Colorectal cancer Biomarkers therapeutic targets

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Interplay between nuclear factor erythroid 2-related factor 2 and inflammatory mediators in COVID-19-related liver injury

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World Journal of Gastroenterology 2021年第22期27卷 2944-2962页

作者： Dan-Dan Zhu Xue-Mei Tan Li-Qing Lu Si-Jia Yu Ru-Li Jian Xin-Fang Liang Yi-Xuan Liao Wei Fan LucíiaBarbier-Torres Austin Yang He-Ping Yang Ting Liu Department of Gastroenterology Xiangya HospitalCentral South UniversityChangsha 410008Hunan ProvinceChina Key Laboratory of Cancer proteomics of Chinese Ministry of Health Xiangya HospitalCentral South UniversityChangsha 410008Hunan ProvinceChina Department of Medicine Division of Digestive and Liver DiseasesCedars-Sinai Medical CenterLos AngelesCA 90048United States Department of Biology East Los Angeles CollegeLos AngelesCA 91008United States

Coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2 is a global pandemic and poses a major threat to human health worldwide.In addition to respiratory symptoms,COVID-19 is usually accompanied by systemic inflammation and liver damage in moderate and severe cases.Nuclear factor erythroid 2-related factor 2(NRF2)is a transcription factor that regulates the expression of antioxidant proteins,participating in COVID-19-mediated inflammation and liver injury.Here,we show the novel reciprocal regulation between NRF2 and inflammatory mediators associated with COVID-19-related liver injury.Additionally,we describe some mechanisms and treatment strategies.

关键词： COVID-19-related liver injury Nuclear factor erythroid 2-related factor 2 Inflammatory mediator Oxidative stress therapeutic targets

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Targeting IKKαkinase to prevent tumor progression and therapy resistance

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Cancer Drug Resistance 2020年第3期3卷 482-490页

作者： Carlota Colomer Irene Pecharroman Anna Bigas Lluís Espinosa Cancer Research Program Institut Mar d’Investigacions MèdiquesCIBERONCHospital del MarBarcelona 08003Spain.

Cancer therapy has improved considerably in the last years;however,therapeutic resistance is still a major problem that impedes full response to the treatment and the main cause of patient relapse and death.Numerous kinases have been reported to be overactivated in cancer and induce resistance to current therapies.Targeting kinases has proven to be useful for overcoming chemotherapy resistance and thus improving patient outcomes.Inhibitor of kappaB kinase alpha(IKKα)is a serine/threonine kinase that was first described as part of the IKK complex in the nuclear factor-κB(NF-κB)pathway,which regulates several physiological and physiopathological processes such as immunity,inflammation,and cancer.However,the IKKαsubunit has been shown to be dispensable for NF-κB activation and responsible of multiple pro-tumorigenic functions.Furthermore,we identified a nuclear active form of IKKαkinase IKKα(p45)that promotes tumor growth and therapy resistance,independent of canonical NF-κB.Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies.Here,we review the recent publications on the implications of IKKαin cancer initiation,development,and resistance.

关键词： IKKα cancer therapeutic targets chemoresistance

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Research advances and new challenges in overcoming triple-negative breast cancer

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Cancer Drug Resistance 2021年第3期4卷 517-542页

作者： Yu Zong Mark Pegram Stanford Cancer Institute Stanford University School of MedicineStanfordCA 94305USA

Triple-negative breast cancer(TNBC)is a pathological term used to identify invasive breast cancers that lack expression of estrogen and progesterone receptors and do not have pathologic overexpression of the HER2 receptor or harbor ERBB2 gene amplification.TNBC includes a collection of multiple distinct disease entities based upon genomic,transcriptomic and phenotypic characterization.Despite improved clinical outcomes with the development of novel therapeutics,TNBC still yields the worst prognosis among all clinical subtypes of breast cancer.We will systematically review evidence of the genomic evolution of TNBC,as well as potential mechanisms of disease progression and treatment resistance,defined in part by advances in next-generation DNA sequencing technology(including single cell sequencing),providing a new perspective on treatment strategies,and promise to reveal new potential therapeutic targets.Moreover,we review novel therapies aimed at homologous recombination deficiency,PI3 kinase/AKT/PTEN pathway activation,androgen receptor blockade,immune checkpoint inhibition,as well as antibody-drug conjugates engaging novel cell surface targets,including recent progress in pre-clinical and clinical studies which further validate the role of targeted therapies in TNBC.Despite major advances in treatment for TNBC,including FDA approval of 2 PARP inhibitors for metastatic TNBC,the crossing of the superiority boundary in a phase 3,placebo-controlled study of adjuvant olaparib in early-stage patients with germline BRCA-mutated high-risk HER2-negative early breast cancer,the FDA approval of 2 PD-(L)1 checkpoint antibodies for metastatic TNBC,and the FDA approval of the first antibody drug conjugate for TNBC,significant challenges remain.For example,despite the dawn of immunotherapy in metastatic TNBC,durable responses are limited to a small subset of patients,definitive biomarkers for patient selection are lacking,and the Oncology Drug Advisory Committee to the FDA has recently voted against approval of an anti-PD-1 ch

关键词： Triple negative breast cancer subtypes genomic evolution therapeutic targets homologous recombination deficiency antibody-drug conjugates immunotherapy tumor immune microenvironment

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Nine-long non-coding ribonucleic acid signature can improve the survival prediction of colorectal cancer

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World Journal of Gastrointestinal Surgery 2021年第2期13卷 210-221页

作者： Zhen Zong Ce-Gui Hu Tai-Cheng Zhou Zhuo-Min Yu Fu-Xin Tang Hua-Kai Tian Hui Li He Wang Department of Gastrointestinal Surgery The Second Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina Department of Gastrointestinal Surgery and Hernia Center The Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510655Guangdong ProvinceChina Department of Rheumatology The First Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina Department of Cardiovascular Medicine The Second Affiliated Hospital of Nanchang UniversityNanchang 330006Jiangxi ProvinceChina

BACKGROUND Investigating molecular biomarkers that accurately predict prognosis is of considerable clinical significance.Accumulating evidence suggests that long noncoding ribonucleic acids(lncRNAs)are frequently aberrantly expressed in colorectal cancer(CRC).AIM To elucidate the prognostic function of multiple lncRNAs serving as biomarkers in CRC.METHODS We performed lncRNA expression profiling using the lncRNA mining approach in large CRC cohorts from The Cancer Genome Atlas(TCGA)database.Receiver operating characteristic analysis was performed to identify the optimal cutoff point at which patients could be classified into the high-risk or low-risk groups.Based on the Cox coefficient of the individual lncRNAs,we identified a ninelncRNA signature that was associated with the survival of CRC patients in the training set(n=175).The prognostic value of this nine-lncRNA signature was validated in the testing set(n=174)and TCGA set(n=349).The prognostic models,consisting of these nine CRC-specific lncRNAs,performed well for risk stratification in the testing set and TCGA set.Time-dependent receiver operating characteristic analysis indicated that this predictive model had good performance.RESULTS Multivariate Cox regression and stratification analysis demonstrated that this nine-lncRNA signature was independent of other clinical features in predicting overall survival.Functional enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology terms further indicated that these nine prognostic lncRNAs were closely associated with carcinogenesis-associated pathways and biological functions in CRC.CONCLUSION A nine-lncRNA expression signature was identified and validated that could improve the prognosis prediction of CRC,thereby providing potential prognostic biomarkers and efficient therapeutic targets for patients with CRC.

关键词： Colorectal cancer Long non-coding ribonucleic acid Biomarkers Survival prediction The Cancer Genome Atlas therapeutic targets

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Mechanisms and therapeutic advances of myocardial ischemia-reperfusion injury

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South China Journal of Cardiology 2022年第1期23卷 14-18,38页

作者：张萌高山李丹阳饶宏宇 Jiamusi University Heilongjiang 154000China The First Affiliated Hospital of Jiamusi University Heilongjiang 154002China

Background The most effective treatment for Acute myocardial infarction(AMI)is timely and effective reperfusion therapy;however,the process of reperfusion therapy can worsen the myocardial damage.This pathological process is known as myocardial ischemia-reperfusion injury(I/R).But,the mechanism of I/R is not fully understood and there is no available effective treatment for I/R.This article will review the mechanisms of occurrence and treatments currently found for I/R.

关键词： myocardial ischemia/reperfusion injury acute myocardial infarction therapeutic targets

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