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1. A Longitudinal Study of the Relationship of Adiponectin with Reproduction in Infertile Women Undergoing IVF/ICSI Treatment, and an Experimental Study in Human Granulosa Cells

Author

Lixian Qin, Chantacha Sitticharoon, Somsin Petyim, Issarawan Keadkraichaiwat, Rungnapa Sririwichitchai, Pailin Maikaew, and Malika Churintaraphan

Subjects
adiponectin, IVF/ICSI treatment, granulosa cells, aromatase, FSH, Science
Abstract

This study investigated the roles of adiponectin in IVF treatment during Phase I (the basal stage before gonadotropin administration), Phase II (approximately 8 days after gonadotropin administration), and Phase III (on the ovum pick-up day), as well as the effects of adiponectin on CYP19A1 and the FSH receptor (FSHR) mRNA expression in a human granulosa-like tumor cell line (KGN). In human subjects (a longitudinal study, n = 30), blood samples were collected in all phases, while follicular fluid (FF) was only collected in Phase III. The participants were classified into successful and unsuccessful groups based on the determination of fetal heartbeats. KGN cells were treated with adiponectin/FSH/IGF-1 (an experimental study, n = 3). There was no difference in the adiponectin levels between successful and unsuccessful pregnancies in the FF (Phase III) and in serum (all phases), as well as among the three phases in both groups. Serum FSH (Phase I) was positively associated with serum adiponectin in the unsuccessful group, but it had a negative association in the successful group (all phases). Serum adiponectin and serum FSH (Phase I) were positively correlated in the unsuccessful group, whereas they were negatively correlated (all phases) in the successful group. The serum adiponectin levels (Phase III) were significantly higher than in the FF in unsuccessful pregnancies, but there was no difference in successful pregnancies. FF adiponectin concentrations were negatively correlated with serum LH in successful subjects. In KGN cells, adiponectin had no influence on CYP19A1 and FSHR mRNA expression. High adiponectin levels in serum compared to FF (Phase III) in unsuccessful subjects might negatively impact IVF treatment.

Published
2023
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2. Plasma gp96 is a Novel Predictive Biomarker for Severe COVID-19

Author

Rongguo Wei, Biyan Zhou, Shaohua Li, Debin Zhong, Boan Li, Jianqiu Qin, Liping Zhao, Lixian Qin, Jun Hu, Jiuru Wang, Shixiong Yang, Jingming Zhao, and Songdong Meng

Subjects
plasma gp96, predictive biomarker, COVID‐19, IL-6, Microbiology, QR1-502
Abstract

ABSTRACT Early and effective identification of severe coronavirus disease 2019 (COVID-19) may allow us to improve the outcomes of associated severe acute respiratory illness with fever and respiratory symptoms. This study analyzed plasma concentrations of heat shock protein gp96 in nonsevere (including mild and typical) and severe (including severe and critical) patients with COVID-19 to evaluate its potential as a predictive and prognostic biomarker for disease severity. Plasma gp96 levels that were positively correlated with interleukin-6 (IL-6) levels were significantly elevated in COVID-19 patients admitted to the hospital but not in non-COVID-19 patients with less severe respiratory impairment. Meanwhile, significantly higher gp96 levels were observed in severe than nonsevere patients. Moreover, the continuous decline of plasma gp96 levels predicted disease remission and recovery, whereas its persistently high levels indicated poor prognosis in COVID-19 patients during hospitalization. Finally, monocytes were identified as the major IL-6 producers under exogenous gp96 stimulation. Our results demonstrate that plasma gp96 may be a useful predictive and prognostic biomarker for disease severity and outcome of COVID-19. IMPORTANCE Early and effective identification of severe COVID-19 may allow us to improve the outcomes of associated severe acute respiratory illness with fever and respiratory symptoms. Some heat shock proteins (Hsps) are released during oxidative stress, cytotoxic injury, and viral infection and behave as danger-associated molecular patterns (DAMPs). This study analyzed plasma concentrations of Hsp gp96 in nonsevere and severe patients with COVID-19. Significantly higher plasma gp96 levels were observed in severe than those in nonsevere patients, and its persistently high levels indicated poor prognosis in COVID-19 patients. The results demonstrate that plasma gp96 may be a useful predictive and prognostic biomarker for disease severity and outcome of COVID-19.

Published
2021
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3. Roles of kisspeptin in IVF/ICSI-treated infertile women and in human granulosa cells

Author

Rungnapa Sririwichitchai, Chantacha Sitticharoon, Somsin Petyim, Chanakarn Sripong, Lixian Qin, Malika Churintaraphan, Pailin Maikeaw, and Issarawan Keadkraichaiwat

Subjects
Adult, Infertility, endocrine system, media_common.quotation_subject, medicine.medical_treatment, Regulator, 030209 endocrinology & metabolism, Biology, General Biochemistry, Genetics and Molecular Biology, Andrology, 03 medical and health sciences, Aromatase, 0302 clinical medicine, Kisspeptin, medicine, Humans, Sperm Injections, Intracytoplasmic, Insulin-Like Growth Factor I, Original Research, media_common, Kisspeptins, Granulosa Cells, 030219 obstetrics & reproductive medicine, In vitro fertilisation, Ivf icsi, medicine.disease, Follicular Fluid, Female, Reproduction, Infertility, Female, hormones, hormone substitutes, and hormone antagonists
Abstract

Kisspeptin, a crucial central regulator of reproduction, has been used as a trigger in in vitro fertilization (IVF) treatment. This study aimed to investigate the roles of kisspeptin in IVF treatment in infertile females ( n = 30); and in steroidogenesis in human granulosa-like tumor cell line (KGN). In the human study, blood was collected at three time points including (1) the beginning of gonadotropin stimulation (Phase I), (2) around eight days after gonadotropin stimulation (Phase II), and (3) on the day of ovum pick-up (Phase III). Follicular fluid (FF) was collected at Phase III. Serum human chorionic gonadotropin (hCG) was measured 15 days after embryo transfer and fetal heart beats were determined around 42 days of menstrual cycle to classify the subjects into successful and unsuccessful groups. FF kisspeptin levels were higher in successful compared with unsuccessful subjects ( P -2 mmol/L with FSH enhanced aromatase concentrations in the supernatant compared with FSH alone ( P

Published
2020
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4. Plasma gp96 is a Novel Predictive Biomarker for Severe COVID-19

Author

Songdong Meng, Liping Zhao, Jianqiu Qin, Jun Hu, Debin Zhong, Jiuru Wang, Shixiong Yang, Rongguo Wei, Shaohua Li, Biyan Zhou, Lixian Qin, Boan Li, and Jingming Zhao

Subjects
Male, Physiology, medicine.disease_cause, Severity of Illness Index, Gastroenterology, Monocytes, Cohort Studies, COVID-19 Testing, Medicine, Respiratory system, predictive biomarker, Aged, 80 and over, Membrane Glycoproteins, Ecology, biology, Middle Aged, plasma gp96, QR1-502, Infectious Diseases, Cytokines, Female, Research Article, Adult, Microbiology (medical), Poor prognosis, medicine.medical_specialty, Adolescent, Coronavirus disease 2019 (COVID-19), macromolecular substances, Microbiology, Young Adult, Disease severity, COVID‐19, Internal medicine, Heat shock protein, Genetics, Humans, Interleukin 6, Aged, Predictive biomarker, IL-6, General Immunology and Microbiology, Interleukin-6, SARS-CoV-2, business.industry, COVID-19, Cell Biology, biology.protein, business, Biomarkers, Oxidative stress
Abstract

Early and effective identification of severe coronavirus disease 2019 (COVID-19) may allow us to improve the outcomes of associated severe acute respiratory illness with fever and respiratory symptoms. This study analyzed plasma concentrations of heat shock protein gp96 in nonsevere (including mild and typical) and severe (including severe and critical) patients with COVID-19 to evaluate its potential as a predictive and prognostic biomarker for disease severity. Plasma gp96 levels that were positively correlated with interleukin-6 (IL-6) levels were significantly elevated in COVID-19 patients admitted to the hospital but not in non-COVID-19 patients with less severe respiratory impairment. Meanwhile, significantly higher gp96 levels were observed in severe than nonsevere patients. Moreover, the continuous decline of plasma gp96 levels predicted disease remission and recovery, whereas its persistently high levels indicated poor prognosis in COVID-19 patients during hospitalization. Finally, monocytes were identified as the major IL-6 producers under exogenous gp96 stimulation. Our results demonstrate that plasma gp96 may be a useful predictive and prognostic biomarker for disease severity and outcome of COVID-19. IMPORTANCE Early and effective identification of severe COVID-19 may allow us to improve the outcomes of associated severe acute respiratory illness with fever and respiratory symptoms. Some heat shock proteins (Hsps) are released during oxidative stress, cytotoxic injury, and viral infection and behave as danger-associated molecular patterns (DAMPs). This study analyzed plasma concentrations of Hsp gp96 in nonsevere and severe patients with COVID-19. Significantly higher plasma gp96 levels were observed in severe than those in nonsevere patients, and its persistently high levels indicated poor prognosis in COVID-19 patients. The results demonstrate that plasma gp96 may be a useful predictive and prognostic biomarker for disease severity and outcome of COVID-19.

Published
2021
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5. SAT-019 The Associations of Kisspeptin with Reproductive Hormones and Oocyte Maturation in Infertile Patients Who Underwent IVF Treatment

Author

Somsin Petyim, Rungnapa Sririwichitchai, Issarawan Keadkraichaiwat, Chanakarn Sripong, Pailin Maikaew, Chantacha Sitticharoon, Lixian Qin, and Malika Churintaraphan

Subjects
Ivf treatment, business.industry, Endocrinology, Diabetes and Metabolism, Reproductive hormones, Oocyte, Andrology, medicine.anatomical_structure, Kisspeptin, medicine, Reproductive Endocrinology, Clinical Studies in Female Reproduction I, business, hormones, hormone substitutes, and hormone antagonists, AcademicSubjects/MED00250
Abstract

Kisspeptin has been recognized as a stimulatory factor of the hypothalamic-pituitary-gonadal (HPG) axis. Kisspeptin has been successfully used to trigger ovulation in in vitro fertilization (IVF) treatment (1). This study aimed to 1)compare reproductive hormones (FSH, LH, estradiol, progesterone, and AMH), serum and follicular fluid kisspeptin between successful and unsuccessful clinical pregnancy in different stages of IVF treatment; 2) determine the correlations of serum or follicular fluid kisspeptin with reproductive hormones as well as biochemical and clinical outcomes; and 3) compare the levels of kisspeptin between serum and follicular fluid. In this study, 30 infertile female patients (age 26–40 years old) undergoing IVF treatment were recruited. Blood samples were collected at 3 different time points, the beginning of gonadotropin stimulation (the early follicular phase or T1), the scheduled day for ovum pick-up (OPU) (the late follicular phase or T2), and the day of OPU (T3). Meanwhile, biochemical and clinical parameters including the number of retrieved oocytes, matured oocytes, 2 pronuclear (2PN), and serum hCG were also determined. Moreover, fetus heart beat at 6 weeks of gestation was measured to classify the subjects into successful (n=10) and unsuccessful (n=20) clinical pregnancies. Serum AMH at T1 was significantly higher but serum FSH at T1 and T2 was significantly lower in the success group compared with the unsuccess group (P Thus, kisspeptin might be used as a potential predictor of successful IVF treatment. Reference: (1) Abbara A, et al. J Clin Endocrinol Metab. 2015;100(9):3322–31.

Published
2020

6. MON-012 The Direct Effect of Kisspeptin on Human Ovarian Granulosa Cells to Regulate Steroidogenesis

Author

Pailin Maikaew, Rungnapa Sririwichitchai, Malika Churintaraphan, Issarawan Keadkraichaiwat, Chantacha Sitticharoon, and Lixian Qin

Subjects
endocrine system, Kisspeptin, Endocrinology, Diabetes and Metabolism, Reproductive Endocrinology, Biology, Female Reproduction: Basic Mechanisms, hormones, hormone substitutes, and hormone antagonists, AcademicSubjects/MED00250, Cell biology
Abstract

Kisspeptin has a central role to stimulate the hypothalamic-pituitary-gonadal (HPG) axis. Furthermore, a previous study has suggested that kisspeptin might have a peripheral role in follicular development (1). This study aimed to 1) explore the effect of kisspeptin on CYP19A1 (aromatase) mRNA expression in human granulosa cells and aromatase concentrations in the supernatant; and 2) investigate the effect of kisspeptin on FSHR mRNA expression in human granulosa cells. In this study, human granulosa-like tumor cell line (KGN) (n=3) was incubated for 24 hours with FSH (10-8 M); FSH with IGF-1 (10-8 M); different doses of kisspeptin including 1, 10, 100, 1,000, and 10,000 nM; FSH with different doses of kisspeptin; and FSH with IGF-1 together with different doses of kisspeptin. FSH treatment alone or FSH with IGF-1 did not increase CYP19A1 mRNA expression when compared to control. Interestingly, kisspeptin treatment at the doses of 100 nM (P=0.028), 1,000 nM (P=0.005), and 10,000 nM (P=0.009) in the presence of FSH together with IGF-1 enhanced CYP19A1 mRNA expression when compared with control. Furthermore, FSH or FSH with IGF-1 or FSH with all doses of kisspeptin or FSH with IGF-1 together with all doses of kisspeptin increased aromatase concentrations in the supernatant when compared to control (P

Published
2020

7. The Effects of Adiponectin on Infertile Women Undergoing IVF/ICSI Treatment and on Human Granulosa Cells

Author

Somsin Petyim, Malika Churintaraphan, Pailin Maikeaw, Issarawan Keadkraichaiwat, Chantacha Sitticharoon, Rungnapa Sririwhitchai, and Lixian Qin

Subjects
Andrology, Ovary, Testes, and Impact of Hormones on Metabolic Function, Adiponectin, business.industry, Endocrinology, Diabetes and Metabolism, Medicine, Reproductive Endocrinology, Ivf icsi, business, hormones, hormone substitutes, and hormone antagonists, AcademicSubjects/MED00250
Abstract

Adiponectin, one of the most abundant adipocyte-secreted protein, has been involved in female reproductive regulation. This study aimed to 1) compare serum adiponectin levels in various phases of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment including Phase I (the beginning of gonadotropin stimulation), Phase II (around 8 days after gonadotropin stimulation), and Phase III (on the day of ovum pick-up) between success and unsuccess subjects; 2) compare follicular fluid (FF) adiponectin levels between success and unsuccess groups; 3) compare serum adiponectin levels among different phases of IVF/ICSI treatment in success and unsuccess groups; 4) compare the levels of adiponectin between serum and FF; and 5) investigate the effects of adiponectin on mRNA expressions of follicle stimulating hormone receptor (FSHR) and CYP19A1 (aromatase) in human granulosa-like tumor cell line (KGN) (n=3). In the human study, recruited participants (n=30) with age of 26-40 years were enrolled between April 2018 - May 2019. Blood samples were collected at Phases I, II, and III while FF samples were collected at Phase III. Adiponectin levels were comparable between success and unsuccess subjects in both serum (all phases) and FF (Phase III). Furthermore, serum adiponectin levels were comparable among Phase I, II, and III in success and unsuccess groups. In Phase III, serum adiponectin showed positive correlations with serum adiponectin in Phase I and II and serum FSH in Phase I. Interestingly, adiponectin levels in FF were significantly lower than serum at Phase III in unsuccessful pregnancies but were comparable in successful pregnancies. Moreover, FF adiponectin had a negative correlation with serum LH at Phase III in success subjects. In the KGN cell study, adiponectin had no effects on FSHR and CYP19A1 (aromatase) mRNA expression compared with control. In conclusion, high adiponectin levels in serum compared to FF might contribute to unsuccessful IVF/ICSI treatment.

Published
2021

9. Toward the First Class of Suicide Inhibitors of Kallikreins Involved in Skin Diseases

Author

Michèle Reboud-Ravaux, Bernard Pirotte, Xiao Tan, Jean-François Renard, Maurice Pagano, I. Kempen, Feryel Soualmia, Laetitia Furio, Lixian Qin, Alain Hovnanian, Chahrazade El Amri, Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National pour la Recherche Medicale (INSERM), Universite Pierre et Marie Curie (UPMC), Centre National de la Recherche Scientifique (CNRS), Agence Nationale de Recherche (ANR-GENOPAT), French Ministery of Research and Education, Agence Nationale de Recherche, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Genetically modified mouse, Serine Proteinase Inhibitors, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Skin Diseases, Structure-Activity Relationship, In situ zymography, Coumarins, Drug Discovery, medicine, Humans, Structure–activity relationship, Netherton syndrome, Matriptase, Cytotoxicity, chemistry.chemical_classification, biology, urogenital system, Chemistry, Serine Endopeptidases, Kallikrein, medicine.disease, Molecular biology, Enzyme, Biochemistry, biology.protein, Molecular Medicine, Kallikreins, circulatory and respiratory physiology
Abstract

International audience; The inhibition of kallikreins 5 and 7, and possibly kallikrein 14 and matriptase, (that initiates the kallikrein proteolytic cascade) constitutes an innovative way to treat some skin diseases such as Netherton syndrome. We present here the inhibitory properties of coumarin-3-carboxylate derivatives against these enzymes. Our small collection of these versatile organic compounds was enriched by newly synthesized derivatives in order to obtain molecules selective against one, two, three enzymes or acting on the four ones. We evidenced a series of compounds with IC50 values in the nanomolar range. A suicide mechanism was observed against kallikrein 7 whereas the inactivation was either definitive (suicide type) or transient for kallikreins 5 and 14, and matriptase. Most of these potent inhibitors were devoid of cytotoxicity toward healthy human keratinocytes. In situ zymography investigations on skin sections from human kallikrein 5 transgenic mouse revealed significant reduction of the global proteolytic activity by several compounds.

Published
2014
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10. Involvement of the Ivr2-invertase in the perianth during maize kernel development under water stress

Author

Jean-Louis Prioul, Jacques Trouverie, Claudine Thévenot, Elizabeth Simond-Côte, Lixian Qin, and Sophie Chateau-Joubert

Subjects
Untranslated region, food and beverages, Locus (genetics), Plant Science, General Medicine, Molecular cloning, Biology, Endosperm, Cell biology, Cell wall, Invertase, Biochemistry, Genetics, Perianth, Agronomy and Crop Science, Gene
Abstract

The susceptibility of early developing grain to water stress is a major problem in maize, assimilate shortage being a likely cause for insufficient grain filling. Both cell wall and vacuolar invertases appear to be involved in this failure. To date, most data concern molecular analysis of the Incw2 cell wall invertase expressed in the basal endosperm and its association with the miniature mutation. Here the predominant role, at early post-pollination stage, 4 days after pollination (DAP), of a vacuolar invertase located in the perianth adhering to the kernels is presented. Both Ivr2 mRNA and the corresponding vacuolar invertase activity were strongly reduced by a mild water stress while Incw2 transcripts and the kernel cell wall invertase activity were hardly modified. Hybridisation with an Ivr2 3′UTR-probe strongly suggested that the same gene was expressed in perianth and leaf although its response to water stress was the opposite. In order to check for a perianth specific gene, cloning of genomic Ivr2 DNA was performed. A partial gene covering ca. 80% of the coding region and the specific UTR sequence was obtained. It mapped to a unique locus on chromosome 5 where a QTL for vacuolar invertase activity has been previously detected.

Published
2004
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11. Bisbenzimidazole derivatives as potent inhibitors of the trypsin-like sites of the immunoproteasome core particle

Author

Olga N. Koroleva, The Hien Pham, Dominique Bouvier, Laure Dufau, Lixian Qin, Michèle Reboud-Ravaux, Alexander A. Ivanov, Alexei L. Zhuze, Elizaveta S. Gromova, Michelle Bouvier-Durand, Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Russian Foundation of Basic Researches [12-04-01229, 13-04-01504, 13-04-00727, 14-04-00388], Vietnamian Ministery for Education (Doctoral Fellowship), Pierre and Marie Curie University (UPMC, Paris 6) (UMR 8256), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteasome Endopeptidase Complex, Constitutive proteasome, Molecular model, Protein Data Bank (RCSB PDB), [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biochemistry, Immunoproteasome, Cathepsin B, In silico docking, Mice, Catalytic Domain, medicine, Animals, Humans, Trypsin, chemistry.chemical_classification, biology, Chemistry, Calpain, Active site, General Medicine, Ligand (biochemistry), Isoenzymes, Molecular Docking Simulation, Bisbenzimidazole, Enzyme, Proteasome, biology.protein, Specific inhibitors of the trypsin-like sites, Proteasome Inhibitors, Bisbenzimidazole derivatives, medicine.drug, HeLa Cells
Abstract

International audience; In this study, a monomeric (MB) and a dimeric (DB) bisbenzimidazoles were identified as novel proteasome inhibitors of the trypsin-like activity located on beta 2c sites of the constitutive 20S proteasome (IC50 values at 2-4 mu M range). Remarkably, they were further shown to be 100- and 200-fold more potent inhibitors of the immunoproteasome trypsin-like activity (beta 2i sites, IC50 = 24 nM) than of the homologous constitutive activity. Molecular models of inhibitor/enzyme complexes in the two types of trypsin-like sites and corresponding computed binding energy values corroborated kinetic data. Different binding modes were suggested for MB and DB to the beta 2c and beta 2i trypsic sites. Each pointed to better contacts of the ligand inside the beta 2i active site than for beta 2c site. MB and DB represent the first selective inhibitors of the immunoproteasome trypsin-like activity described to date and can be considered as prototypes for inhibiting this activity.

Published
2015
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12. New C-4-and C-1-derivatives of furo[3,4-c] pyridine-3-ones and related compounds: Evidence for site-specific inhibition of the constitutive proteasome and its immunoisoform

Author

Yan Cheng, Anna Hovhannisyan, Dominique Bouvier, Lixian Qin, Michelle Bouvier-Durand, Alexander Piroyan, Michèle Reboud-Ravaux, Laure Dufau, Gagik Melikyan, Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Yerevan University, State Committee Science MES RA [SCS 131D330], Vietnamian Ministery for Education, Pierre et Marie Curie University (UPMC, Paris), French Association against myopathies, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteasome Endopeptidase Complex, Pyridones, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, CT-L, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Ring (chemistry), Biochemistry, Furo-and thieno[2, In silico docking, Mice, chemistry.chemical_compound, Nucleophile, Catalytic Domain, Drug Discovery, Pyridine, Animals, Protein Isoforms, Constitutive c20S proteasome, Molecular Biology, Furo[3, 4-c] pyridine-3-ones, Binding Sites, Organic Chemistry, Immunoproteasome i20S, Carbon, In vitro, Molecular Docking Simulation, Proteasome, chemistry, 3-d] pyrimidine-4-ones, Molecular Medicine, Proteasome Inhibitors, T-L and PA proteolytic activities, Protein Binding
Abstract

A set of 18 new C4 and C1 derivatives of nor-cerpegin (1,1-dimethyl furo[3,4-c]pyridine-3-one), 6 model compounds (γ- and δ-lactones) and 20 furo- or thieno[2,3-d]-pyrimidine-4-one related compounds were designed and synthesized. Each compound was assayed for inhibition of CT-L, T-L and PA proteolytic activities of 20S constitutive proteasome (c20S). Most performant compounds were also assayed on 20S immunoproteasome (i20S). Compound 10 with a benzylamino group at C4 and dimethylated at C1 of the furopyridine ring was the most efficient PA site-specific inhibitor of the c20S ( IC 50 cPA of 600 nM) without noticeable inhibition of the i20S PA site (iPA). In silico docking assays for 10 at the iPA catalytic site revealed the absence of poses normally observed for this compound and related ones at the constitutive PA site (cPA). The thieno[2,3-d]pyrimidine-4-one 40 was T-L site-specific with a mild inhibition of both c20S and i20S in vitro ( IC 50 cT-L of 9.9 μM and IC 50 iT-L of 6.7 μM). In silico docking assays of 40 at T-L sites of c20S and i20S revealed almost identical first rank poses in the two types of sites with no possibility left for nucleophilic attack by Thr1 as observed for the fused furopyridine-3-one 10.

Published
2014
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13. Identification by in silico and in vitro screenings of small organic molecules acting as reversible inhibitors of kallikreins

Author

Chahrazade El Amri, Xiao Tan, Lixian Qin, Claudia Bertonati, Laetitia Furio, Michèle Reboud-Ravaux, Bruno O. Villoutreix, Alain Hovnanian, Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National pour la Recherche Medicale (INSERM), Universite Pierre et Marie Curie (UPMC), Agence Nationale de Recherche (grant ANR-GENOPAT), French Ministry of Research and Education, Agence Nationale de Recherche, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Virtual screening, Models, Molecular, Proteases, Serine Proteinase Inhibitors, In silico, Serine Peptidase Inhibitor Kazal-Type 5, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, In vitro screening, Small Molecule Libraries, Structure-Activity Relationship, Drug Discovery, medicine, Humans, Netherton syndrome, Matriptase, Pharmacology, Serine protease, biology, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Organic Chemistry, Reversible inhibitors, General Medicine, Kallikrein, medicine.disease, High-Throughput Screening Assays, Skin diseases, LEKTI, Biochemistry, Small organic molecules, biology.protein, Kallikreins
Abstract

International audience; Netherton syndrome is caused by loss-of-function mutations in SPINK5 encoding the Kazal-type inhibitor LEKTI-1 leading to dysregulation of proteolytic cascades involving several kallikreins. We used both structure-based and ligand-based virtual screening computations to identify commercially available non-covalent inhibitors of human kallikrein 5 (hK5), a serine protease (trypsin-like) that plays a central role in the initiation of the molecular cascades leading to the Netherton syndrome phenotype. The efficacy and mechanism of inhibition of the identified new families of organic compounds were analyzed not only for hK5 but also on other proteases implicated in the cascades (hK7, hK14 and matriptase). These inhibitors are nontoxic on healthy human keratinocytes and are structurally different from traditional serine protease inhibitors validating their potential utility as initial hits to control proteolytic disorders observed in dermatological pathologies such as Netherton syndrome.

Published
2013
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14. C-1 and N-5 derivatives of cerpegin: Synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome

Author

Anna Hovhannisyan, The Hien Pham, Dominique Bouvier, Lixian Qin, Gagik Melikyan, Michèle Reboud-Ravaux, Michelle Bouvier-Durand, Vieillissement Cellulaire Intégré et Inflammation (VCII), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Yerevan University, Vietnamian Ministery for Education, Universities of Yerevan, Pierre et Marie Curie (UPMC, Paris 6), French Association Against Myopathies, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteasome Endopeptidase Complex, Alkaloid cerpegin, 4-c]pyridine-3, Stereochemistry, Pyridones, Clinical Biochemistry, Protein Data Bank (RCSB PDB), Pharmaceutical Science, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Proteasome inhibitors, Biochemistry, 20s proteasome, Cathepsin B, Catalysis, In silico docking, Structure-Activity Relationship, Catalytic Domain, Drug Discovery, Molecule, Selective inhibition of PA activity, Molecular Biology, Inhibitory effect, Furo[3, Binding Sites, biology, Chemistry, Organic Chemistry, Calpain, 4-dione, Benzenesulfanilamide, Molecular Docking Simulation, Yield (chemistry), Drug Design, biology.protein, Molecular Medicine, Protein Binding
Abstract

International audience; Thirty-two new derivatives of cerpegin (1,1,5-trimethylfuro[3,4-c]pyridine-3,4-dione) were designed and synthesized in high yield by a new method, combining several C-1 and N-5 substituents. All compounds were tested for their inhibitory effect on the CT-L, T-L and PA proteolytic activities of a purified mammalian 20S proteasome. Only one molecule inhibited both CT-L and PA activities. Sixteen molecules specifically inhibited PA at the micromolar range, out of which fourteen had IC50 values around 5 mu M and two had IC50 values closer to 2 mu M. Except in one case, neither calpain I nor cathepsin B was inhibited. In silico docking suggests a unique mode of binding of the most efficient compounds to the beta 1 catalytic site (PA activity) in relation to the chemical nature of C-1 substituents.

Published
2013
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15. Novel Organic Proteasome Inhibitors Identified by Virtual and in Vitro Screening

Author

Michèle Reboud-Ravaux, Matthieu Montes, Bruno O. Villoutreix, Lixian Qin, Joëlle Vidal, Xavier Maréchal, Michelle Bouvier-Durand, Emilie Genin, Nicolas Basse, Enzymologie Moléculaire et Fonctionnelle, Université Pierre et Marie Curie - Paris 6 (UPMC), Pharmacochimie Moléculaire et Cellulaire (PMC - UMR_S 648), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Molécules Thérapeutiques in silico (MTI), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Lab Animal Sciences, China Academy of Medical Sciences, Chimie et Photonique Moléculaires (CPM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Proteines Biochimie Structurale et Fonctionnelle (FRE 2852), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Pharmacochimie Moléculaire et Cellulaire ( PMC - UMR_S 648 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Molécules Thérapeutique in silico, Recherche de molécules à visée thérapeutique par approches In Silico ( MTI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Chimie et Photonique Moléculaires ( CPM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Proteines Biochimie Structurale et Fonctionnelle ( FRE 2852 ), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Models, Molecular, Databases, Factual, Antineoplastic Agents, Crystallography, X-Ray, 01 natural sciences, Piperazines, Cell Line, Sulfone, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, [ CHIM.ORGA ] Chemical Sciences/Organic chemistry, Drug Discovery, medicine, Animals, Humans, Protease Inhibitors, Sulfones, Piperazine, Cell Proliferation, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Virtual screening, Molecular Structure, biology, 010405 organic chemistry, Chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Stereoisomerism, Ligand (biochemistry), In vitro, 3. Good health, 0104 chemical sciences, Enzyme, Proteasome, Biochemistry, Enzyme inhibitor, Proteasome inhibitor, biology.protein, Molecular Medicine, Rabbits, Drug Screening Assays, Antitumor, Proteasome Inhibitors, HeLa Cells, medicine.drug
Abstract

International audience; Proteasome inhibition is a promising strategy for treating cancers. Herein, we report the discovery of novel drug-like inhibitors of mammalian proteasome 20S using a multistep structure-based virtual ligand screening strategy. Sulfone- or piperazine-containing hits essentially belong to the under-represented class of noncovalent and nonpeptidic proteasome inhibitors. Several of our compounds act in the micromolar range and are cytotoxic on human tumoral cell lines. Optimization of these molecules could lead to better anticancer therapy.

Published
2009
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