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Senescent mesenchymal stem/stromal cells in pre-metastatic bone marrow of untreated advanced breast cancer patients

Oncology Research 2023年第3期31卷 361-374页

作者： FRANCISCO RAÚL BORZONE MARÍA BELÉN GIORELLO LEANDRO MARCELO MARTINEZ MARÍA CECILIA SANMARTIN LEONARDO FELDMAN FEDERICO DIMASE EMILIO BATAGELJ GUSTAVO YANNARELLI norma alejandra chasseing Laboratorio de Inmunohematología Instituto de Biología y Medicina Experimental(IBYME)Consejo Nacional de Investigaciones Científicas y Técnicas(CONICET)Buenos AiresArgentina Division of Hematology and Medical Oncology Department of MedicineWeill Cornell Medical CollegeNew YorkUSA Laboratorio de Regulación Génica y Células Madre Instituto de Medicina TraslacionalTrasplante y Bioingeniería(IMeTTyB)Universidad Favaloro-CONICETBuenos AiresArgentina Facultad de Ciencias de la Salud Universidad Nacional del Centro de la Provincia de Buenos Aires(UNCPB)TandilBuenos AiresArgentina Servicio de Hematología Hospital Militar CentralBuenos AiresArgentina Servicio de Oncología Hospital Militar CentralBuenos AiresArgentina

Breast cancer is the predominant form of carcinoma among women worldwide,with 70%of advanced patients developing bone metastases,with a high mortality *** this sense,the bone marrow(BM)mesenchymal stem/stromal cells(MSCs)are critical for BM/bone homeostasis,and failures in their functionality,transform the BM into a premetastatic niche(PMN).We previously found that BM-MSCs from advanced breast cancer patients(BCPs,infiltrative ductal carcinoma,stage III-B)have an abnormal *** work aims to study some of the metabolic and molecular mechanisms underlying MSCs shift from a normal to an abnormal profile in this group of patients.A comparative analysis was undertaken,which included self-renewal capacity,morphology,proliferation capacity,cell cycle,reactive oxygen species(ROS)levels,and senescence-associatedβ‑galactosidase(SA‑β‑gal)staining of BMderived MSCs isolated from 14 BCPs and 9 healthy volunteers(HVs).Additionally,the expression and activity of the telomerase subunit TERT,as well as telomere length,were *** levels of pluripotency,osteogenic,and osteoclastogenic genes(OCT-4,SOX-2,M-CAM,RUNX-2,BMP-2,CCL-2,M-CSF,and IL-6)were also *** results showed that MSCs from BCPs had reduced,self-renewal and proliferation *** cells also exhibited inhibited cell cycle progression and phenotypic changes,such as an enlarged and flattened ***,there was an increase in ROS and senescence levels and a decrease in the functional capacity of TERT to preserve telomere *** also found an increase in pro-inflammatory/pro-osteoclastogenic gene expression and a decrease in pluripotency gene *** conclude that these changes could be responsible for the abnormal functional profile that MSCs show in this group of patients.

关键词： Mesenchymal stem/stromal cells Senescence Breast cancer Bone marrow Pre-metastatic niche Bone metastasis

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Immunomodulatory oligonucleotide IMT504:Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

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World Journal of Stem Cells 2017年第3期9卷 45-67页

作者： Jorge Zorzopulos Steven M Opal Andrés Hernando-Insúa Juan M Rodriguez Fernanda Elías Juan Fló Ricardo A López norma A chasseing Victoria A Lux-Lantos Maria F Coronel Raul Franco Alejandro D Montaner David L Horn Immunotech S.A. Ciudad de Buenos Aires C1440FFXArgentina Infectious Disease Division Memorial Hospital of Rhode Island and Alpert Medical SchoolProvidenceRI 02905United States Fundación Pablo Cassara Ciudad Autonoma de Buenos Aires C1440FFXArgentina Instituto de Biología y Medicina Experimental(IBYME-CONICET) Ciudad Autónoma de Buenos Aires C1428ADNArgentina Instituto de Ciencia y Tecnolog'DR.Cesar Milstein” Fundación Pablo CassaráCiudad Autonoma de Buenos Aires C1440FFXArgentina David Horn LLC DoylestownPA 18902United States

The immune responses of humans and animals to insults(i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged proinflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell(MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.

关键词： Immunohomeostasis Immunoprotection Immunoregeneration Inflammation Mesenchymal stem cells IMT504

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Comparison of Apigenin,Quercetin and Kaempferol Accumulation and Total Flavonoid Content in Leaves,Embryogenic Cultures and Cell Suspension Cultures of Parsley(Petroselinum crispum)

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国际实验植物学杂志(英文) 2023年第10期92卷 2807-2823页

作者： Laura Isabel Arias-Rodríguez Martha Alicia Rodríguez-Mendiola Carlos Arias-Castro Federico Antonio Gutiérrez Miceli Diana Reséndez Pérez María Celina Luján Hidalgo Juan JoséVillalobos Maldonado norma alejandra Mancilla Margalli Analytical Laboratory National Technological Institute of MexicoTuxtla Gutierrez CampusTuxtla GutierrezMexico Plant Biotechnology Laboratory Instrumental Analysis LaboratoryPlant Biochemistry LaboratoryNational Technological Institute of MexicoTlajomulco de ZunigaMexico Department of Cellular Biology and Genetics Faculty of Biological SciencesAutonomous University of Nuevo LeonSan Nicolas delos GarzaMexico

In recent years,there has been a growing interest in exploring alternative treatments for bone *** tissue engineering has turned its attention to plant extracts containing osteogenic flavonoids as potential promoters of bone *** our study,we specifically investigated the extract of Petroselinum crispum,a plant known for its abundance of osteogenic flavonoids such as apigenin,quercetin,and *** objective was to compare the total flavonoid content(TFC)and their accumulation in different *** obtained hydrolyzed aqueous extracts from the leaves of parsley plants(grown for 12 weeks in the field),weekly embryogenic cultures,and suspension cell *** TFC,measured in mg quercetin equivalent per gram of dry weight(QE mg/g dw),was found to be 53.81±0.97 for 52 g dw of leaves(1 kg plant fw),31.10±1.52 for 420 g dw of embryogenic cultures,and 11.80±0.76 for 210 g dw of cell ***,only the leaves and embryogenic cultures showed significant accumulation of osteogenic flavonoids,with apigenin levels of 1.8±0.3 and 0.32±0.02 mg/g dw,and kaempferol levels of 1.0±0.18 and 0.2±0.01 mg/g dw,*** findings indicate that embryogenic cultures have the potential to produce up to 40%more apigenin in 12 weeks compared to 1 kg of parsley plant,thanks to their superior biomass reproductive *** results present a promising biotechnological approach for generating extracts enriched with bioactive compounds,which can be further utilized in in vitro osteogenic testing.

关键词： Parsley(Petroselinum crispum)cultures osteogenic flavonoids bone regeneration aqueous extracts

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