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High-throughput computational screening and in vitro evaluation identifies 5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione(C3),as a novel EGFR—HER2 dual inhibitor in gastric tumors

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Oncology Research 2024年第2期32卷 251-259页

作者： MESFER AL SHAHRANI REEM GAHTANI MOHAMMAD ABOHASSAN MOHAMMAD ALSHAHRANI YASSER ALRAEY AYED DERA MOHAMMAD RAJEH ASIRI PRASANNA RAJAGOPALAN department of Clinical laboratory sciences College of Applied Medical SciencesKing Khalid UniversityAbhaSaudi Arabia

Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation,adhesion,angiogenesis,and *** therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic ***,dual inhibition strategies are recommended to increase potency and reduce *** this study,we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase ***-based High-throughput Virtual Screening(D-HTVS)was used to screen the whole ChemBridge small molecular library against EGFR and *** atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand ***/HER2 kinase enzymes,KATOIII,and Snu-5 cells were used for in vitro *** atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules,identified compound C3(5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]-1H-isoindole-1,3(2H)-dione)to have a good affinity for both EGFR and *** predicted compound,C3,was promising with better binding energy,good binding pose,and optimum interactions with the EGFR and HER2 residues.C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM,*** GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM,*** on these findings,we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase,and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects,though testing in higher models with pharmacokinetic approach is required.

关键词： Dual inhibitor Drug discovery EGFR/HER2 kinase Gastric cancer High-throughput screening

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Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1726-1741页

作者： Yanjiang Xing Yangfeng Hou Tianfei Fan Ran Gao Xiaohang Feng Bolun Li Junling Pang Wenjun Guo Ting Shu Jinqiu Li Jie Yang Qilong Mao Ya Luo Xianmei Qi Peiran Yang Chaoyang Liang Hongmei Zhao Wenhui Chen Jing Wang Chen Wang State Key laboratory of Respiratory Health and Multimorbidity Institute of Basic Medical SciencesChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100005China department of Lung Transplantation National Center for Respiratory MedicineNational Clinical Research Center for Respiratory DiseasesChina–Japan Friendship HospitalInstitute of Respiratory MedicineChinese Academy of Medical SciencesBeijing 100029China Haihe laboratory of Cell Ecosystem Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300051China The State Key laboratory of Complex Severeand Rare DiseasesInstitute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of PathophysiologyPeking Union Medical CollegeBeijing 100005China department of Pharmacy West China HospitalSichuan UniversityChengdu 610044China

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

关键词： Phosphodiesterase 4B Pulmonary hypertension Endothelial-to-mesenchymal transition

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Circum-Indian Holocene sea-level database:A repository of distinct relative sea-level plots across the Indian Peninsula

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Journal of Palaeogeography 2024年第1期13卷 1-17页

作者： Shradha Menon Pankaj Khanna Santanu Banerjee REEFS lab Department of Earth SciencesIIT GandhinagarPalajGandhinagarGujarat382355India department of Earth sciences IIT BombayPowaiMumbai400076India

The Indian Peninsula is one of the most well-studied regions for Holocene sea-level fluctuations in the world, however, standardized relative sea-level datasets are missing. This study provides an archive of sealevel indicators(n = 162, 20 locations) along the western and the eastern sides of the peninsula, that have been used to develop Relative Sea Level(RSL) plots. Each dated sea-level indicator is recalibrated for its elevation based on tidal and tectonic correction, as well as age with reservoir correction, and have been separated into six zones based on coastal geomorphology and number of datasets. The database spans throughout the Holocene and covers sea-level depth/elevations from-45 m to +5 m from mean sea-level(MSL). Approximately 90 % of the dataset range from 8 ka to the present day. The first transgression is highly variable and identified between 8.5-8 ka BP in Gujarat(Zone 1), ~ 5.5 ka BP in Maharashtra(Zone 2), between 8 and 7 ka BP in Tamil Nadu(Zone 4) and between 8 and 7.5 ka BP in the Bengal coasts(Zone 6). No transgression above present sea-level is observed along Andhra Pradesh(Zone 5)(no data for Kerala-Zone 3).Further, Zones 1, 2, 4 and 6 show a strong uplift component(tectonic), whereas Zone 5 exhibits subsidence during the Holocene(Zone 3-insufficient data). Based on these findings, and given the region's coastal topography and tidal components, Zones 6 and 1 will likely undergo the largest coastal inundation, followed by Zones 5, 4, 2, and 3. These insights are critical in planning future coastal inundation measures across the Indian Peninsula.

关键词： Indian ocean Terraces Relative sea level curve Holocene Arabian sea Bay of Bengal

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The anti-neoplastic effects of metformin modulate the acquired phenotype of fbroblast cells in the breast cancer-normal fbroblast co-culture system

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Oncology Research 2024年第3期32卷 477-487页

作者： SAMANEH MOSTAFAVI ZUHAIR MOHAMMAD HASSAN department of Immunology Faculty of Medical SciencesTarbiat Modares UniversityTehranIran

Intracellular communications between breast cancer and fibroblast cells were reported to be involved in cancer proliferation,growth,and therapy *** hallmarks of cancer fibroblast interactions,consisting of caveolin 1(Cav1)and mono-carboxylate ransporter 4(MCT4)(metabolic coupling markers),along with IL-6,TGFB,and lactate secretion,are considered robust biomarkers predicting recurrence and *** order to promote a novel phenotype in normal fibroblasts,we predicted that breast cancer cells could be able to cause loss of Cavl and increase of MCT4,as well as elevate IL 6 and TGF in nearby nomal *** created a co culture model using breast cancer(4T1)and normal fibroblast(NIH3T3)cell lines cultured under specific experimental conditions in order to directly test our ***,we show that long-term co-culture of breast cancer cells and normal fibroblasts promotes loss of Cavl and gain of MCT4 in adjacent fibroblasts and increase lactate *** results were validated using the monoculture of each group separately as a *** this system,we show that me tformin inhibits IL-6 and TGFB secretion and re expresses Cavl in both ***,MCT4 and lactate stayed high after treatment with *** conclusion,our work shows that co-culture with breast cancer cells may cause signifcant alterations in the phenotype and secretion of normal ***,however,may change this state and affect fibroblasts'acquired ***,mitochondrial inhibition by metformin after 8 days of treatment,signi ficantly hinders tumor growth in mouse model of breast cancer.

关键词： Caveolin 1 Lactic acid Metformin NIH 3T3 cells Neoplasms

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Dysregulated N6-methyladenosine modification in peripheral immune cells contributes to the pathogenesis of amyotrophic lateral sclerosis

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Frontiers of Medicine 2024年第2期18卷 285-302页

作者： Di He Xunzhe Yang Liyang Liu Dongchao Shen Qing Liu Mingsheng Liu Xue Zhang Liying Cui department of Neurology Peking Union Medical College Hospital(PUMCH)Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China medical Doctor Program Chinese Academy of Medical Science and Peking Union Medical CollegeBeijing100730China McKusick-Zhang Center for Genetic Medicine State Key Laboratory of Medical Molecular BiologyInstitute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing100730China Neuroscience Center Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China

Amyotrophic lateral sclerosis(ALS)is a progressive neurogenerative disorder with uncertain *** evidence implicates N6-methyladenosine(m6A)modification in ALS *** RNA immunoprecipitation sequencing(MeRIP-seq)and liquid chromatography–mass spectrometry were utilized for m6A profiling in peripheral immune cells and serum proteome analysis,respectively,in patients with ALS(n=16)and controls(n=6).The single-cell transcriptomic dataset(GSE174332)of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication *** of peripheral immune cells revealed extensive RNA hypermethylation,highlighting candidate genes with differential m6A modification and expression,including C-X3-C motif chemokine receptor 1(CX3CR1).In RAW264.7 macrophages,disrupted CX3CR1 signaling affected chemotaxis,potentially influencing immune cell migration in *** proteome analysis demonstrated the role of dysregulated immune cell migration in *** type-specific expression variations of these genes in the central nervous system(CNS),particularly microglia,were *** communication between neurons and glial cells was selectively altered in ALS *** integrated approach underscores m6A dysregulation in immune cells as a potential ALS contributor.

关键词： amyotrophic lateral sclerosis N^(6)-methyladenosine epi-transcriptome proteome single cell RNA sequencing analysis CX3CR1

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Therapeutic effects of Coriandrum sativum extracts:A review

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Asian Pacific Journal of Tropical Biomedicine 2024年第5期14卷 181-186页

作者： Akbar Anaeigoudari department of Physiology School of MedicineJiroft University of Medical SciencesJiroftIran

Medicinal plants,as a good therapeutic strategy,can be used to treat a wide spectrum of *** sativum(***)is a plant from Apiaceae *** reports indicate that *** has positive effects on anxiety,seizure,learning and memory ability,as well as *** annual plant can also treat colitis,increase appetite,reduce blood pressure,and attenuate myocardial ***,it improves liver and kidney function and diabetes mellitus and inhibits osteoclast *** beneficial effects of *** mainly are attributed to its antioxidant and anti-inflammatory *** present paper reviews the impacts of *** on different body *** was extracted by searching the Web of Science,PubMed,Scopus,and Google Scholar from January 2010 until the end of February 2024.

关键词： Coriandrum sativum Inflammation Antioxidant Oxidative stress Nervous system Liver

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Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1711-1725页

作者： Yingting Wu Jiaqi Xin Xinyu Li Ting Yang Yi Liu Yongsheng Zhao Wen Xie Mengxi Jiang department of Pharmacology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China department of Traditional Chinese Medicine Capital Medical UniversityBeijing 100069China Center for Pharmacogenetics and department of Pharmaceutical sciences University of PittsburghPittsburghPA 15261USA Advanced Innovation Center for Human Brain Protection Capital Medical UniversityBeijing 100069China

Drug repurposing offers an efficient approach to therapeutic *** this study,our bioinformatic analysis first predicted an association between obesity and lansoprazole(LPZ),a commonly prescribed drug for gastrointestinal *** went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity,insulin resistance,and hepatic stea-tosis in *** with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes,and induced cold tolerance in cold-exposed mice,suggesting the activity of LPZ in promoting adipose thermogenesis and energy ***,LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1(PHOSPHOI)and produces metabolic benefits in a PHOS-PHO1-dependent *** results suggested that LPZ may stimulate adipose thermogenesis by inhi-biting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid(2-AG-LPA)to 2-arachidonoylglycerol(2-AG)and reduce the activity of the thermogenic-suppressive cannabinoid recep-tor *** summary,we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome,and identified a potential metabolic basis by which LPZ improves energy metabolism.

关键词： Lansoprazole Proton pump inhibitors Adipose thermogenesis Energy expenditure Metabolic syndrome PHOSPHO1 inhibitor Cannabinoid receptor signaling Drug repurposing

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Hippo-YAP/TAZ signaling in breast cancer:Reciprocal regulation of microRNAs and implications in precision medicine

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Genes & Diseases 2024年第2期11卷 760-771页

作者： Farzad Sadri Seyede fatemeh Hosseini Zohreh Rezaei Mohammad Fereidouni Student Research Committee Birjand University of Medical SciencesBirjand ***Iran Tabas School of Nursing Birjand University of Medical SciencesBirjand ***Iran department of Biology University of Sistan and BaluchestanZahedan ***Iran Cellular and Molecular Research Center Birjand University of Medical SciencesBirjand ***Iran

Breast cancer is a molecularly heterogeneous disease and the most common female *** recent years,therapy approaches have evolved to accommodate molecular diversity,with a focus on more biologically based therapies to minimize negative *** regulate cell fate in human breast cells,the Hippo signaling pathway has been associated with the alpha subtype of estrogen *** pathway regulates tissue size,regeneration,and healing,as well as the survival of tissue-specific stem cells,proliferation,and apoptosis in a variety of organs,allowing for cell *** signaling is mediated by the kinases MST1,MST2,LATS1,and LATS2,as well as the adaptor proteins SAV1 and *** kinases phosphorylate the downstream effectors of the Hippo pathway,yes-associated protein(YAP),and transcriptional coactivator with PDZ-binding motif(TAZ),suppressing the expression of their downstream target *** Hippo signaling pathway kinase cascade plays a significant role in all *** the principles of this kinase cascade would prevent the occurrence of breast *** recent years,small noncoding RNAs,or microRNAs,have been implicated in the development of several malignancies,including breast *** interconnections between miRNAs and Hippo signaling pathway core proteins in the breast,on the other hand,remain poorly *** this review,we focused on highlighting the Hippo signaling system,its key parts,its importance in breast cancer,and its regulation by miRNAs and other related pathways.

关键词： Breast cancer Hippo signaling Large tumor suppressor kinase 1 microRNAs PDZ-binding motif Yes-associated protein

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Therapeutic and regenerative potential of different sources of mesenchymal stem cells for cardiovascular diseases

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BIOCELL 2024年第4期48卷 559-569页

作者： YARA ALZGHOUL HALA J.BANI ISSA AHMAD K.SANAJLEH TAQWA AlabDUH FATIMAH RABABAH MAHA AL-SHDAIFAT EJLAL ABU-EL-RUB FATIMAH ALMAHASNEH RAMADA R.KHASAWNEH AYMAN ALZU’BI HUTHAIFA MAGABLEH department of Basic medical sciences Faculty of MedicineYarmouk UniversityIrbidJordan

Mesenchymalstemcells(MSCs)*** the internal cardiac microenvironment to facilitate their immunomodulatory and differentiation abilities,which are essential to restore heart *** can be easily isolated from different sources,including bone marrow,adipose tissues,umbilical cord,and dental *** from various sources differ in their regenerative and therapeutic abilities for cardiovascular *** this review,we will summarize the therapeutic potential of each MSC source for heart diseases and highlight the possible molecular mechanisms of each source to restore cardiac function.

关键词： Bone marrow mesenchymal stem cells Adipose tissue mesenchymal stem cells Dental pulp stem cells Umbilical cord mesenchymal stem cells Cardiomyocytes Regeneration Myocardial infarction Mesenchymal stem cells Differentiation Immunomodulation

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Effectiveness of aromatherapy with lavender compared to progressive muscle relaxation on anxiety and vital signs in patients under spinal anesthesia:A randomized clinical trial

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Journal of Integrative Nursing 2024年第2期6卷 90-95页

作者： Nazanin AMINI Safoora OMIDVAR Masoomeh Noruzi ZAMENJANI Mehdi HARORANI Hesameddin MODIR department of Paramedicine Arak University of Medical SciencesArakIran department of Nursing Shazand School of NursingArak University of Medical SciencesArakIran department of Anesthesiology Arak University of Medical SciencesArakIran

Objective:This study aimed to determine the effectiveness of aromatherapy with lavender essential oil compared to progressive muscle relaxation(PMR)on anxiety and vital signs of patients under spinal *** and Methods:This clinical trial was conducted on 120 spinal anesthesia candidates who were randomly assigned into three groups of 40 including control,PMR(Jacobsen group),and *** state-trait anxiety inventory was completed on surgery day and 15 min after the end of the intervention by the samples of all three groups,and at the same time as completing the questionnaire,vital signs were also measured and ***:The mean score of anxiety after intervention was lower than that before the intervention in the aromatherapy group(P<0.001).The mean score of anxiety in the aromatherapy group was significantly lower than that in the Jacobsen group(P<0.001).Moreover,data analysis showed a significant decrease in the mean arterial blood pressure scores of the PMR(P=008)and aromatherapy(P<0.001)groups and a statistically significant increase in the mean heart rate scores in the control group(P=0.002).Conclusion:The use of aromatherapy with lavender is more effective than PMR therapy in reducing the anxiety level of patients undergoing spinal *** to the high level of anxiety and its serious effects on the patient’s hemodynamics,aromatherapy with lavender can be used as an easy and cheap method to reduce anxiety in operation rooms.

关键词： Anxiety aromatherapy lavender essential oil massage progressive muscle relaxation spinal anesthesia vital signs

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