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Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs

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Science China(Life Sciences) 2022年第2期65卷 309-327页

作者： Ning Wang Yuchen He Silvia Liu Meagan J.Makarcyzk Guanghua Lei Alexander Chang Peter G Alexander Tingjun Hao Anne-Marie Padget nuria de pedro Tsapekos Menelaos Hang Lin department of Orthopaedic Surgery University of Pittsburgh School of MedicinePittsburgh PA 15219USA department of Orthopedic Surgery Xiangya HospitalCentral South UniversityChangsha 410008China department of Pathology University of Pittsburgh School of MedicinePittsburgh PA 15219USA department of Bioengineering University of Pittsburgh Swanson School of EngineeringPittsburgh PA 15219USA department of Bioinformatics University of Pittsburgh School of MedicinePittsburgh PA 15219USA McGowan Institute for Regenerative Medicine University of Pittsburgh School of MedicinePittsburgh PA 15219USA department of Biology University of Pittsburgh Dietrich School of Arts and SciencePittsburgh PA 15219USA department of Research B2B Life Length SLMadrid 28010Spain Xiangya Third Hospital Central South UniversityChangsha 410013China

Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic *** from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-***,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis ***,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and *** results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in *** P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.

关键词： osteoarthritis MSC senescence cartilage tissue engineering disease-modifying OA drug senolytic

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HCS strategy targeting dysregulation of the VHL/HIF pathway for drug discovery

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Advances in Bioscience and Biotechnology 2013年第3期4卷 398-405页

作者： Bastien Cautain nuria de pedro Maria Munoz de Escalona Jose R.Tormo Olga Genilloud Francisca Vicente Screening and Target Validation department Fundacion MedinaGranadaSpain

One-third of top-selling drugs are derived from natural products. When only a fraction of the bioactive natural products diversity has been explored, huge opportunities still remain for discovering novel leads for the development of new drugs. Clear cell renal cell carcinoma (ccRCC) is a highly vascular tumour arising from epithelial elements. Mutations in the Von Hippel-Lindau (VHL) gene are responsible for VHL disease and arise in the majority of Renal Cell Carcinoma (RCC) as well as in other types of cancer. Renal carcinoma cell lines with naturally occurring VHL mutations (RCC4 VA) and their genetically matched wild-type VHL (RCC4 VHL) counterparts were seeded onto 96-well plates and allowed to attach overnight. Fungal extracts were tested on both cell lines. Clinically useful antitumor agents were used as positive controls and as reference points to establish the efficacy and selectivity of the new compounds. Renal cell carcinoma cell lines expressing VHL or not were treated with Carboxyfluorescein succinimidyl ester (CFSE). The day after cell inoculation, extracts were added and during the following days of incubation, fluorescence intensity was measured as a surrogate marker for cell viability. The most promising extracts selectively inhibited growth of pVHL-defi- cient cells but not of wild-type VHL cells. We used High Content Bio-imaging, a complete cellular imaging workflow that integrates instruments and software to acquire and analyze images, to evaluate their effect. Cell imaging can reveal effects that would be overlooked by other cell assay approaches. This target-based whole cell screen is a new strategy, which ensures cell permeability and target selectivity especially in natural product screening where natural product purification is a labour of extensive work. This approach permitted a dynamic study where fluorescence was measured without affecting cell viability and enabling a better detection of cytotoxic effects such as autophagy, senescence or

关键词： High Content Screening Natural Products HIF Drug Discovery

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Short-term effectiveness of golimumab for ulcerative colitis: Observational multicenter study

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World Journal of Gastroenterology 2016年第47期22卷 10432-10439页

作者： Marta Maia Bosca-Watts Xavier Cortes Marisa Iborra Jose Maria Huguet Laura Sempere Gloria Garcia Rafa Gil Mari Fe Garcia Marga Munoz pedro Almela nuria Maroto Jose Maria Paredes Inflammatory Bowel Disease Unit Digestive Disease DepartmentUniversity of ValenciaUniversity Clinic Hospital of Valencia46010 ValenceiaSpain Digestive Disease department Hospital of Sagunto46010 ValenciaSpain Gastroenterology department and CIBEREHD Hospital Universitari i Politecnic La Fe46026 ValenciaSpain Digestive Disease department General Hospital of Valencia46014 ValenciaSpain Digestive Disease department General Hospital of Alicante03010 AlacantSpain Digestive Disease department San Juan University Hospital of Alicante46015 ValenciaSpain Digestive Disease department Arnau Hospital of Valencia Digestive Disease department General University Hospital of Elche03203 AlicaneSpain Digestive Disease department General Hospital of Castellon12004 Castellón de la PlanaSpain Digestive Disease department Hospital of Manises46940 ManisesSpain Digestive Disease department Peset University Hospital of Valencia46017 ValenciaSpain

AIM To evaluate the real-world effectiveness of golimumab in ulcerative colitis(UC) and to identify predictors of *** We conducted an observational, prospective and multi-center study in UC patients treated with golimumab, from September 2014 to September 2015. Clinical activity was assessed at wk 0 and 14 with the physician's global clinical assessment(PGA) and the partial Mayo score. Colonoscopies and blood tests were performed, following daily-practice clinical criteria, and the results were recorded in an SPSS *** Thirty-three consecutive patients with moderately to severely active UC were included. Among them, 54.5% were female and 42 years was the average age. Thirty percent had left-sided UC(E2) and 70% had extensive UC(E3). All patients had an endoscopic Mayo score of 2 or 3 at baseline. Twenty-seven point three percent were anti-tumor necrosis factor(TNF) treatment na?ve, whereas 72.7% had previously received infliximab and/or adalimumab. Sixty-nine point seven percent showed clinical response and were steroid-free at wk 14(a decrease from baseline in the partial Mayo score of at least 3 points). Based on PGA, the clinical remission and clinical response rates were 24% and 55% respectively. Withdrawal of corticosteroids was observed in 70.8% of steroid-dependent patients at the end of the study. Three out of 10 clinical non-responders needed a colectomy. Mean fecal calprotectin value at baseline was 300 μg/g, and 170.5 μg/g at wk 14. Being anti-TNF treatment na?ve was a protection factor, which was related to better chances of reaching clinical remission. Twenty-seven point three percent of the patients required treatment intensification at 14 wk of followup. Only three adverse effects(AEs) were observed during the study; all were mild and golimumab was not *** This real-life practice study endorses golimumab's promising results, demonstrating its short-term effectiveness and confirming it as a safe drug during t

关键词： Golimumab Ulcerative colitis Real-life results

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dendritic cell deficiencies persist seven months after SARS-CoV-2 infection

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Cellular & Molecular Immunology 2021年第9期18卷 2128-2139页

作者： Alberto Pérez-Gómez Joana Vitallé Carmen Gasca-Capote Alicia Gutierrez-Valencia María Trujillo-Rodriguez Ana Serna-Gallego Esperanza Muñoz-Muela María de los Reyes Jiménez-Leon Mohamed Rafii-El-Idrissi Benhnia Inmaculada Rivas-Jeremias Cesar Sotomayor Cristina Roca-Oporto nuria Espinosa Carmen Infante-Domínguez Juan Carlos Crespo-Rivas Alberto Fernández-Villar Alexandre Pérez-González Luis Fernando López-Cortés Eva Poveda Ezequiel Ruiz-Mateos JoséMiguel Cisneros Sonsoles Salto-Alejandre Judith Berastegui-Cabrera pedro Camacho-Martínez Carmen Infante-Domínguez Marta Carretero-Ledesma Juan Carlos Crespo-Rivas Eduardo Márquez JoséManuel Lomas Claudio Bueno Rosario Amaya JoséAntonio Lepe Jerónimo Pachón Elisa Cordero Javier Sánchez-Céspedes Manuela Aguilar-Guisado Almudena Aguilera Clara Aguilera Teresa Aldabo-Pallas Verónica Alfaro-Lara Cristina Amodeo Javier Ampuero María Dolores Avilés Maribel Asensio Bosco Barón-Franco Lydia Barrera-Pulido Rafael Bellido-Alba Máximo Bernabeu-Wittel Candela Caballero-Eraso Macarena Cabrera Enrique Calderón Jesús Carbajal-Guerrero Manuela Cid-Cumplido Yael Corcia-Palomo Juan delgado Antonio Domínguez-Petit Alejandro deniz Reginal Dusseck-Brutus Ana Escoresca-Ortega Fátima Espinosa nuria Espinosa Michelle Espinoza Carmen Ferrándiz-Millón Marta Ferrer Teresa Ferrer Ignacio Gallego-Texeira Rosa Gámez-Mancera Emilio García Horacio García-delgado Manuel García-Gutiérrez María Luisa Gascón-Castillo Aurora González-Estrada demetrio González Carmen Gómez-González Rocío González-León Carmen Grande-Cabrerizo Sonia Gutiérrez Carlos Hernández-Quiles Inmaculada Concepción Herrera-Melero Marta Herrero-Romero Luis Jara Carlos Jiménez-Juan Silvia Jiménez-Jorge Mercedes Jiménez-Sánchez Julia Lanseros-Tenllado Carmina López Isabel López Álvaro López-Barrios Luis F.López-Cortés Rafael Luque-Márquez Daniel Macías-García Guillermo Martín-Gutiérrez Luis Martín-Villén JoséMolina Aurora Morillo María Dolores Navarro-Amuedo Dolores Nieto-Martín Francisco Ortega María Paniagua-García Amelia Peña-Rodríguez E Clinical Unit of Infectious Diseases Microbiology and Preventive MedicineInstitute of Biomedicine of Seville(IBiS)Virgen del Rocío University HospitalCSICUniversity of SevilleSevilleSpain department of Medical Biochemistry Molecular Biologyand ImmunologySchool of MedicineUniversity of SevilleSevilleSpain Pneumology Service Galicia Sur Health Research Instituto(IIS Galicia Sur)SERGAS-UVigoVigoSpain Infectious Diseases Unit Department of Internal MedicineComplexo HospitalarioUniversitario de VigoIIS Galicia SurSERGAS-UVigoVigoSpain Group of Virology and Pathogenesis Galicia Sur Health Research Institute(IIS Galicia Sur)-Complexo Hospitalario Universitario de VigoSERGAS-UVigoVigoSpain Unit of Infectious Diseases Microbiologyand Preventive MedicineVirgen del Rocío University HospitalSevilleSpain Institute of Biomedicine of Seville(IBiS) Virgen del Rocío University Hospital/CSIC/University of SevilleSevilleSpain Medico-Surgical Unit of Respiratory Diseases Virgen del Rocío University HospitalSevilleSpain Unit of Emergencies Virgen del Rocío University HospitalSevilleSpain Intensive Care Unit Virgen del Rocío University HospitalSevilleSpain department of Medicine University of SevilleSevilleSpain Cardiology and Cardiovascular Surgery Unit Virgen del Rocío University HospitalSevilleSpain Rheumatology Unit Virgen del Rocío University HospitalSevilleSpain Internal Medicine Unit Virgen del Rocío University HospitalSevilleSpain Digestive and Hepatobiliary Unit Virgen del Rocío University HospitalSevilleSpain Neurology and Clinical Neurophysiology Unit Virgen del Rocío University HospitalSevilleSpain Endocrinology and Nutrition Unit Virgen del Rocío University HospitalSevilleSpain Urology and Nephrology Unit Virgen del Rocío University HospitalSevilleSpain Unit of Clinical Investigation and Clinical Trials Virgen del Rocío University HospitalSevilleSpain

Severe Acute Respiratory Syndrome Coronavirus(SARS-CoV)-2 infection induces an exacerbated inflammation driven by innate immunity *** cells(DCs)play a key role in the defense against viral infections,for instance plasmacytoid DCs(pDCs),have the capacity to produce vast amounts of interferon-alpha(IFN-α).In COVID-19 there is a deficit in DC numbers and IFN-αproduction,which has been associated with disease *** this work,we described that in addition to the DC deficiency,several DC activation and homing markers were altered in acute COVID-19 patients,which were associated with multiple inflammatory ***,previously hospitalized and nonhospitalized patients remained with decreased numbers of CD1c+myeloid DCs and pDCs seven months after SARS-CoV-2 ***,the expression of DC markers such as CD86 and CD4 were only restored in previously nonhospitalized patients,while no restoration of integrinβ7 and indoleamine 2,3-dyoxigenase(IDO)levels were *** findings contribute to a better understanding of the immunological sequelae of COVID-19.

关键词： SARS-CoV-2 COVID-19 dendritic cell Long-COVID

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