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Gene regulatory network stabilized by pervasive weak repressions: micro RNA functions revealed by the May–Wigner theory

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National Science Review 2019年第6期6卷 1176-1188页

作者： Yuxin Chen Yang Shen Pei Lin Ding Tong Yixin Zhao Stefano Allesina Xu Shen Chung-I Wu School of Life Science Sun Yat-Sen University Target Discovery Research Boehringer Ingelheim Pharma Gmb H & Co KG Department of Biostatistics School of Public Health Yale University Department of Ecology and Evolution University of Chicago

Food web and gene regulatory networks(GRNs) are large biological networks, both of which can be analyzed using the May–Wigner theory. According to the theory, networks as large as mammalian GRNs would require dedicated gene products for stabilization. We propose that micro RNAs(mi RNAs) are those products. More than 30% of genes are repressed by mi RNAs, but most repressions are too weak to have a phenotypic consequence. The theory shows that(i) weak repressions cumulatively enhance the stability of GRNs, and(ii) broad and weak repressions confer greater stability than a few strong ones. Hence, the diffuse actions of mi RNAs in mammalian cells appear to function mainly in stabilizing GRNs. The postulated link between m RNA repression and GRN stability can be seen in a different light in yeast, which do not have mi RNAs. Yeast cells rely on non-specific RNA nucleases to strongly degrade m RNAs for GRN stability. The strategy is suited to GRNs of small and rapidly dividing yeast cells, but not the larger mammalian cells. In conclusion, the May–Wigner theory, supplanting the analysis of small motifs, provides a mathematical solution to GRN stability, thus linking mi RNAs explicitly to ’developmental canalization’.

关键词： micro RNAs network stability canalization May–Wigner theory systems biology RNA crosstalk

Metabolic reprogramming as an emerging mechanism of resistance to endocrine therapies in prostate cancer

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Cancer Drug Resistance 2021年第1期4卷 143-162页

作者： Paolo Chetta Giorgia Zadra University of Milan Milan 20122Italy Current Address:boehringer ingelheim rcv gmbh&co.kg Dr.-Boehringer-Gasse 5-11Vienna 1121Austria Department of Oncologic Pathology Dana-Farber Cancer Institute and Brigham Women’s HospitalHarvard Medical SchoolBostonMA 02215USA Current Address:Institute of Molecular Genetics National Research CouncilPavia 27100Italy

Prostate cancer(PCa)is the second leading cause of cancer-related death in the *** receptor(AR)signaling is the driver of both PCa development and progression and,thus,the major target of current in-use ***,despite the survival benefit of second-generation inhibitors of AR signaling in the metastatic setting,resistance mechanisms inevitably ***,novel strategies are required to circumvent resistance occurrence and thereby to improve PCa *** the key cellular processes that are regulated by androgens,metabolic reprogramming stands out because of its intricate links with cancer cell *** this review,we discuss how cancer metabolism and lipid metabolism in particular are regulated by androgens and contribute to the acquisition of resistance to endocrine *** describe the interplay between genetic alterations,metabolic vulnerabilities and castration *** PCa cells adapt their metabolism to excess nutrient supply to promote cancer progression,we review our current knowledge on the association between diet/obesity and resistance to anti-androgen *** briefly describe the metabolic symbiosis between PCa cells and tumor microenvironment and how this crosstalk might contribute to PCa *** discuss how tackling PCa metabolic vulnerabilities represents a potential approach of synthetic lethality to endocrine ***,we describe how the continuous advances in analytical technologies and metabolic imaging have led to the identification of potential new prognostic and predictive biomarkers,and non-invasive approaches to monitor therapy response.

关键词： Metabolic reprogramming prostate cancer castration resistance endocrine therapies metabolomics metabolic imaging therapy respo nse

The many faces of cGAS:how cGAS activation is controlled in the cytosol,the nucleus,and during mitosis

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Signal Transduction and Targeted Therapy 2021年第8期6卷 2261-2263页

作者： Anna-Maria Herzner Martin Schlee Eva Bartok Department of Cancer Immunology and Immune Modulation Boehringer Ingelheim Pharma GmbH&Co.KGBiberach an der RiBGermany lnstitute of Clinical Chemistry and Clinical Pharmacology University HospitalUniversity of BonnBonnGermany Unit of Experimental Immunology Department of Biomedical SciencesInstitute of Tropical MedicineAntwerpBelgium

In their recently published study in Science,Li et al.1 unravel how hyperphosphorylation and chromatin-tethering of the double-stranded(dsDNA)sensor cGAMP synthase(cGAS)prevent self DNA recognition during mitosis(Fig.1);providing important insight into how this innate immune sensor balances its essential function for pathogen defense against potential autoinflammation.

关键词： activation sensor insight

Adjuvant effects of different TLR agonists on the induction of allergen-specific Th2 responses

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Open Journal of Immunology 2012年第1期2卷 17-24页

作者： Matthias J. Duechs James E. Brunt Florian Gantner Klaus J. Erb Respiratory Diseases Research Boehringer Ingelheim Pharma GmbH & Co. KG Biberach an der Riss Germany

Currently different Toll-like receptor (TLR) agonists are tested in humans for their ability to enhance the efficacy of specific immunotherapy (SIT). Recent clinical data suggest that this may be achieved by increasing allergen-specific Th1 responses. However, it is not clear which TLR agonist is best suited to be used in combination with SIT. We tested the ability of five TLR agonists, LTA, poly(I:C), LPS, R848, and CpG-ODN, activating TLR2, 3, 4, 7, and 9, to induce allergen-specific Th1 and suppress allergen-specific Th2 responses in a preclinical setting. Mice were immunized by intraperitoneal injection of ovalbumin (OVA)/Al(OH)3 together with different doses (0.0025, 0.025, 0.25, and 2.5 mg/kg) of agonists followed by two OVA aerosol challenges. The results of these experiments showed, that the suppression of allergen-specific Th2 responses and the induction of Th1 responses dependedon the dose and the agonists used. All TLR agonists increased allergen-specific IgG2a, and with the exception of poly(I:C), reduced allergen-specific IgE levels in the serum. Allergic cutaneous anaphylaxis was also suppressed in mice when LPS or CpG was given together with OVA/alum. The strongest Th1 responses were induced by CpG and poly(I:C), characterized by the presence of IFN-g in the BAL and the highest OVA-specific IgG2a levels in the serum. This study suggests that the TLR9 agonist CpG-ODN and TLR4 agonist LPS have the strongest suppressive effects on the development of aller-gen-specific Th2 responses in mice and CpG-ODN induces the strongest allergen-specific Th1 responses. Therefore these two TLR agonists may be good candidates to combine with allergen in novel SIT formulations in humans.

关键词： Asthma TLR-Agonists Innate-Inflammation Inhibition

Optimizing Growth conditions for Digoxin Production in Digitalis lanata Ehrh

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World Journal of Traditional Chinese Medicine 2016年第2期2卷 24-35页

作者： Herman A.van Wietmarschen Hansj?rg Hagels Ron Peters Jolanda Heistek Jan van der Greef Mei Wang TNO Netherlands Organization for Applied Scientific Research Microbiology & Systems Biology Sino-Dutch Centre for Preventive and Personalized Medicine boehringer ingelheim Pharma Gmb H & co.kg Business Center Klazienaveen Jolanda: Heistek Result Groenloper SU Bio Medicine

Objective: Digoxin is a therapeutic cardenolide widely used to treat various heart conditions such as atrial flutter, atrial fibrillation and heart failure in both Western as well as Chinese medicine. Digoxin is extracted from cultivated Digitalis lanata Ehrh. plants, known as Mao Hua Yang Di Huang in Chinese medicine. This manuscript presents two studies that were conducted to optimize the cultivation conditions for digoxin production in the TCM Mao Hua Yan Di Huang in a greenhouse under GAP ***: Two experiments were designed in which 4 growth conditions were compared. Levels of digoxin, gitoxin, digitoxin, α-acetyldigoxin, β-acetyl-digoxin were measured using HPLC-UV and compared between the ***: Normal soil, no co_2 enrichment combined with a cold shock was found to be the optimal condition for producing digoxin in the first experiment. Gitoxin content was significantly lower in plants grown in this condition. Mechanical stress as well as the time of harvesting showed no statistically significant differences in the production of cardenolides. In the second experiment the optimal condition was found to be a combination of cold nights, sun screen, fertilizer use and no milled ***: This study shows that digoxin production can be increased by controlling the growth conditions of D. lanata Ehrh. The effect of cold was important in both experiments for improving digoxin production. Cultivating Chinese herbal medicines in optimized greenhouse conditions might be an economically attractive alternative to regular open air cultivation.

关键词： Digitalis lanata Ehrh mao hua yang di huang cardenolides content optimisation TCM

利格列汀在二甲双胍和磺脲类联合治疗血糖控制不佳的2型糖尿病患者中的疗效和安全性:一项24周的随机对照研究

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利格列汀在二甲双胍和磺脲类联合治疗血糖控制不佳的2型糖尿病患...

Symptoms and Their Interpretation in Patients Self-Treating Abdominal Cramping and Pain with a Spasmolytic(Butylscopolamine Bromide)—A Pharmacy-Based Survey

中华医学会糖尿病学分会第十六次全国学术会议

作者： Owens DR Swallow R Dugi KA Woerle HJ University Hospital Llandough Cardiff boehringer ingelheim Ltd BracknellBerkshireUK boehringer ingelheim gmbh Ingelheim boehringer ingelheim Pharma gmbh and co.kg BiberachGermany

目的评估DPP-4抑制剂利格列汀在二甲双胍和磺脲类联合治疗血糖控制不佳[HbA1c 53～86 mmol/mol(7.0%～10.0%)]的2型糖尿病患者中的疗效和安全性。方法一项24周的多中心,随机,双盲,平行对照研究,纳入1058例患者,在二甲双胍和磺脲类治疗...

目的评估DPP-4抑制剂利格列汀在二甲双胍和磺脲类联合治疗血糖控制不佳[HbA1c 53～86 mmol/mol(7.0%～10.0%)]的2型糖尿病患者中的疗效和安全性。方法一项24周的多中心,随机,双盲,平行对照研究,纳入1058例患者,在二甲双胍和磺脲类治疗基础上的分别加用利格列汀(每日5 mg)和安慰剂,进行比较。主要终点是24周后的HbA1c改变。

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Pharmacology & Pharmacy 2011年第2期2卷 82-87页

作者： Stefan Müller-Lissner Eckhard Schafer Anke Kondla Park-Klinik Weissensee Charite-Universitatsmedizin BerlinGermany boehringer ingelheim IngelheimGermany

Background: A majority of people suffering from functional abdominal complaints treat themselves with OTC medication. Aim: To gain information on symptoms and their interpretation in patients self-treating abdominal cramping and pain with a spasmolytic (butylscopolamine). Method: 4,680 questionnaires were distributed by 306 pharmacists in Germany to patients suffering from abdominal complaints and buying butylscopolamine. Key findings: Questionnaires from 1,539 respondents were returned, and 1,417 could be evaluated. Abdominal cramping was the major reason for buying butylscopolamine. Only a minority of respondents had consulted a general practitioner (27.3%) and even less a specialist (12.5%). Only a minority of subjects met expert criteria for irritable bowel syndrome (13%). There was a large overlap between self-reported dysmenorrhoea and bowel symptoms (35%). conclusions: Real life conditions do not seem to be well covered by expert criteria. Differentiating bowel origin from uterine origin in pelvic pain syndromes seems especially problematic. This may particularly apply to the OTC market.

关键词： Abdominal Pain Butylscopolamine Bromide Irritable Bowel Syndrome(IBS) Dysmenorrhoea

利格列汀单药治疗对血糖控制不佳2型糖尿病患者的血糖控制和β细胞功能指标的影响:一项随机对照研究

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利格列汀单药治疗对血糖控制不佳2型糖尿病患者的血糖控制和β细...

Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice

中华医学会糖尿病学分会第十六次全国学术会议

作者： Del Prato S Barnett AH Huisman H Neubacher D Woerle HJ Dugi KA Department of Endocrinology and Metabolism Section of Metabolic DiseasesUniversity of PisaPisaItaly University of Birmingham and Heart of England NHS Foundation Trust BirminghamUK boehringer ingelheim BV AlkmaarThe Netherlands boehringer ingelheim Pharma gmbh & co kg Biberach/RisGermany corporate Medicine Boehringer Ingelheim GmbHIngelheimGermany

目的评估在首次治疗或已接受一种口服降糖药物治疗的2型糖尿病患者中,给予24周的强效及选择性DPP-4抑制剂利格列汀5 mg治疗的安全性和有效性。方法一项针对2型糖尿病患者,为期24周、多中心、随机、平行Ⅲ期研究,将利格列汀(5 mg,每日1次...

目的评估在首次治疗或已接受一种口服降糖药物治疗的2型糖尿病患者中,给予24周的强效及选择性DPP-4抑制剂利格列汀5 mg治疗的安全性和有效性。方法一项针对2型糖尿病患者,为期24周、多中心、随机、平行Ⅲ期研究,将利格列汀(5 mg,每日1次,n=336)与安慰剂(n=167)进行比较。随机化之前,已接受一种口服降糖药物治疗的患者需经过6周的洗脱期,其中包括2周的安慰剂导入期。未接受过口服降糖药物治疗的患者经过2周的安慰剂导入

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World Journal of Diabetes 2020年第12期11卷 596-610页

作者： Vadim V Klimontov Anton I Korbut Iuliia S Taskaeva Nataliya P Bgatova Maksim V Dashkin Nikolai BOrlov Anna S Khotskina Evgenii L Zavyalov Thomas Klein Laboratory of Endocrinology Research Institute of Clinical and Experimental Lymphology–Branch of the Institute of Cytology and GeneticsSiberian Branch of Russian Academy of Sciences(RICEL–Branch of IC&G SB RAS)Novosibirsk 630060Russia Laboratory of Ultrastructural Research Research Institute of Clinical and Experimental Lymphology–Branch of the Institute of Cytology and GeneticsSiberian Branch of Russian Academy of Sciences(RICEL–Branch of IC&G SB RAS)Novosibirsk 630060Russia Laboratory of Clinical Immunogenetics Research Institute of Clinical and Experimental Lymphology–Branch of the Institute of Cytology and GeneticsSiberian Branch of Russian Academy of Sciences(RICEL–Branch of IC&G SB RAS)Novosibirsk 630060Russia Center for Genetic Resources of Laboratory Animals Institute of Cytology and GeneticsSiberian Branch of Russian Academy of SciencesNovosibirsk 630090Russia Department of Cardiometabolic Diseases Research Boehringer Ingelheim Pharma GmbHBiberach 88397Germany

BACkgROUND Modern guidelines recommend sodium-glucose cotransporter-2(SGLT2)inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney ***,the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully *** of podocytes and nephrin expression in glomeruli in db/db diabetic *** We treated 8-wk-old male db/db mice with EMPA(10 mg/kg/d)or vehicle for 8 ***-matched male db/+mice were included as non-diabetic *** of body composition,glycemic and lipid control,and plasma concentrations of leptin,insulin and glucagon were *** evaluated renal hypertrophy as kidney weight adjusted to lean mass,renal function as plasma levels of creatinine,and albuminuria as the urinary albumin-to-creatinine ratio(UACR).Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure,*** nephrin and transforming growth factor beta(TGF-β)were assessed by *** Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment;increased plasma concentrations of fructosamine,glycated albumin,cholesterol,leptin,and insulin,and elevated UACR were *** expansion,glomerular basement membrane thickening,and increased area of TGF-βstaining in glomeruli were revealed in vehicle-treated *** was manifested by effacement of foot processes;nephrin-positive areas in glomeruli were *** decreased the levels of glucose,fructosamine and glycated albumin,UACR,kidney hypertrophy,mesangial expansion,glomerular basement membrane thickening,and glomerular TGF-βstaining,alleviated podocytopathy and restored glomerular staining of *** These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney *** anti-albuminuric effect of EMPA could be attributed to mitigation o

关键词： Diabetes Chronic kidney disease Albuminuria Podocyte Sodium-glucose transporter 2 inhibitors Empagliflozin