作者: Li, Chaoliang ; Pan, Wen ; Zhang, Panrui ; Xie, Yadong ; Zhang, Kaiguang ; Zhou, Rongbin ; Zhu, Shu ; Wang, Shishan ; Song, Xinyang ; Cao, Dan ; Wei, Xiaowei ; Wang, Sheng ; Guo, Meng

Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α_2A-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis.

2023-07-16·bioRxiv : the preprint server for biology

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization.

作者: Schinke, Thorsten ; Sevecke, Jan ; Jiang, Shan ; Rahmani, Adibeh ; Tsitsilonis, Serafeim ; Tchouto, Mireille Ngokingha ; Erdmann, Cordula ; Donat, Antonia ; Köhli, Paul ; Ivanov, Andranik ; Xie, Weixin ; Witte, Jason ; Frosch, Karl-Heinz ; Graef, Frank ; Otto, Ellen ; Knapstein, Paul Richard ; Jahn, Denise ; Duda, Georg ; Keller, Johannes ; Baranowsky, Anke ; Küttner, Quin ; Beule, Dieter ; Fuchs, Melanie ; Graffmann, Christine ; Appelt, Jessika ; Revend, Lawik ; Rickert, Mayla

Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone.Abstract Figure

2016-08-01·Hypertension1区 · 医学

Catestatin Gly364Ser Variant Alters Systemic Blood Pressure and the Risk for Hypertension in Human Populations via Endothelial Nitric Oxide Pathway

1区 · 医学

Article

作者: Mohan, Viswanathan ; Munirajan, Arasambattu K. ; Sharma, Saurabh ; Sahu, Bhavani S. ; Naga Prasad, Sathyamangla V. ; Mullasari, Ajit S. ; Khullar, Madhu ; Vishnuprabu, Durairajpandian ; Martelli, Elizabeth E. ; Radha, Venkatesan ; Subramanian, Lakshmi ; Kiranmayi, Malapaka ; Allu, Prasanna K.R. ; Dixit, Madhulika ; Kumaragurubaran, Rathnakumar ; Bodhini, Dhanasekaran ; Senapati, Sanjib ; Mahapatra, Nitish R. ; Chirasani, Venkat R.

Catestatin (CST), an endogenous antihypertensive/antiadrenergic peptide, is a novel regulator of cardiovascular physiology. Here, we report case–control studies in 2 geographically/ethnically distinct Indian populations (n≈4000) that showed association of the naturally-occurring human CST-Gly364Ser variant with increased risk for hypertension (age-adjusted odds ratios: 1.483; P =0.009 and 2.951; P =0.005). Consistently, 364Ser allele carriers displayed elevated systolic (up to ≈8 mm Hg; P =0.004) and diastolic (up to ≈6 mm Hg; P =0.001) blood pressure. The variant allele was also found to be in linkage disequilibrium with other functional single-nucleotide polymorphisms in the CHGA promoter and nearby coding region. Functional characterization of the Gly364Ser variant was performed using cellular/molecular biological experiments (viz peptide–receptor binding assays, nitric oxide [NO], phosphorylated extracellular regulated kinase, and phosphorylated endothelial NO synthase estimations) and computational approaches (molecular dynamics simulations for structural analysis of wild-type [CST-WT] and variant [CST-364Ser] peptides and docking of peptide/ligand with β-adrenergic receptors [ADRB1/2]). CST-WT and CST-364Ser peptides differed profoundly in their secondary structures and showed differential interactions with ADRB2; although CST-WT displaced the ligand bound to ADRB2, CST-364Ser failed to do the same. Furthermore, CST-WT significantly inhibited ADRB2-stimulated extracellular regulated kinase activation, suggesting an antagonistic role towards ADRB2 unlike CST-364Ser. Consequently, CST-WT was more potent in NO production in human umbilical vein endothelial cells as compared with CST-364Ser. This NO-producing ability of CST-WT was abrogated by ADRB2 antagonist ICI 118551. In conclusion, CST-364Ser allele enhanced the risk for hypertension in human populations, possibly via diminished endothelial NO production because of altered interactions of CST-364Ser peptide with ADRB2 as compared with CST-WT.

项与 ADRA2C antagonist(Bayer AG) 相关的新闻（医药）

2023-03-30

·BioSpace

Kintor Pharma Announces 2022 Annual Results and Recent Business Progress

SUZHOU, China, March 30, 2023 /PRNewswire/ -- Kintor Pharmaceutical Limited (Kintor Pharma, HKEX: 9939), a clinical-stage biotechnology company developing innovative small molecules and biological therapeutics, today announced business highlights and financial results for the year ended 31 December 2022. Business Highlights Kintor Pharma has made rapid progress on global clinical development, and achieved positive data read-outs of core products during the reporting period. Kintor Pharma has rolled out the clinical pipeline in dermatology area globally. Kintor Pharma is actively promoting the business development opportunities in China and globally to accelerate the commercialization progress. Kintor Pharma has raised about $100 million through 2 top-up placements during the reporting period. The company's stock has been included in MSCI China Index and Shanghai-Hong Kong Stock Connect, which increased the stock's liquidity in the capital market. The company's R&D outcome has been accepted by reputable academic conferences including AACR, ASH and AAD of the U.S., which has demonstrated its R&D capabilities. Dr. Youzhi Tong, founder, Chairman, and CEO of Kintor Pharma, commented, 2022 has been a challenging year for the global biotech industry. Under the difficulty market conditions, Kintor Pharma has made rapid progress in R&D, financing and academic publications. In terms of R&D, the company has made steady progress in its pipeline and achieved positive data read-outs of its core products, including Pyrilutamide (KX-826) for androgenetic alopecia (AGA) indication, GT20029 for AGA and acne vulgaris indications. The Phase II clinical trials of KX-826 for male and female AGA in China have reached the primary endpoints, respectively. Kintor Pharma has rolled out the clinical pipeline in dermatology area globally, and is actively promoting the business development opportunities in China and globally to accelerate the commercialization progress. In capital market, the company has raised net proceeds of $100 million through two top-up placements during the reporting period. In addition, the company's stock has been included in the MSCI China Index and the Shanghai-Hong Kong Stock Connect, further enhanced the stock's liquidity in the capital market. In academics, the company's research results have been presented at important academic conferences such as AACR, ASH and AAD of the U.S., proving that the company's innovation ability and its international influence. Looking forward, Kintor Pharma will continue to execute the development of the core products in China and globally, expecting to accelerate its commercialization process. The company strives to bring safe and effective therapeutics to the patients around the globe, and create value for its shareholders and employees. Rapid Progress on Global Clinical Development and Positive Data Read-outs of Core Products As a Biotech company focusing on the R&D and industrialization of potential First-in-Class and Best-in-Class innovative drugs, Kintor Pharma has developed a diversified product pipeline including small-molecule drugs, biologics innovative drugs and combination therapies. At present, the company has seven novel drug candidates with First-in-Class or Best-in-Class potential in Phase I-III clinical stages in China and around the world. Since 2022, the company has released positive clinical results of core products, including the Phase II clinical trials of KX-826 for male and female AGA in China, respectively, and the Phase I clinical trials of GT20029 for the treatment of AGA and ance in both China and the U.S.. Pyrilutamide (KX-826) is a topical androgen receptor (AR) antagonist that is under clinical development for the potential treatment of AGA and acne. KX-826 is the world's first AR antagonist for AGA treatment which entered the Phase III clinical trial stage. On 27 August 2022, one of the leading principal investigators of the Phase II clinical trial of KX-826 in China for the treatment of male AGA adults, Professor Jianzhong Zhang (张建中) from Peking University People's Hospital, released the trial's positive results at the 6th Annual Meeting of Chinese Hair Research Society (第六届全国毛发学术会议). The results showed that after 24 weeks of treatment, the non-vellus target area hair counts (TAHC) in the 5mg (0.5% concentration) twice daily (BID) KX-826 group increased by 15.34/cm2 compared with the placebo group from baseline, with a statistical difference (P=0.024). On 1 December 2022, the company announced that the primary endpoint of Phase II clinical trial of KX-826 for female AGA adults in China was met. After 24 weeks of treatment, the non-vellus TAHC in the 5mg (0.5% concentration) once daily (QD) KX-826 group increased by 11.39/cm2 compared with the placebo group from baseline, with a statistical difference (P=0.0087). KX-826 has showed a good safety pro both trials. GT20029 is a topical AR-Proteolysis Targeting Chimera (PROTAC) compound that is under clinical development for the potential treatment of AGA and acne. GT20029 is the world's first topical PROTAC compound which entered the clinical stage. On 24 November 2022, the company announced the top-line data of the Phase I clinical trial of GT20029 for the treatment of AGA and acne in China. The results showed that GT20029 demonstrated good safety, tolerability and pharmacokinetics in healthy subjects. On 10 February 2023, the company announced the top-line data of the Phase I clinical trial of GT20029 for the treatment of AGA and acne in the U.S.. The results showed that GT20029 demonstrated good safety, tolerability and pharmacokinetics following topical single ascending dose (SAD) administration in healthy subjects and multiple ascending dose (MAD) administration in subjects with AGA or acne. In addition, the company's product pipeline includes Pruxelutamide, GT1708F, GT0486, ALK-1 antibody (GT90001) and GT90008 in the clinical stage, and c-Myc inhibitor, compound of other targets out of PROTAC platform and ALK-1/VEGF bispecific antibody in the preclinical stage. The company's Hedgehog/SMO inhibitor GT1708F is being explored for both idiopathic pulmonary fibrosis (IPF) indication and combination therapy in blood cancer. The company is now preparing for clinical trial application for the IPF indication. The Growing Visibility in the Capital Market Since its listing on the Hong Kong Stock Exchange on 22 May 2020, the company's development has received long-term support from investors around the world. In 2022, the company successfully completed two top-up placements in the capital market and raised about $100 million. After being included in the Hong Kong Stock Connect program in September 2021, the company's stock has been included in the Shanghai-Hong Kong Stock Connect in March 2023, further expanding the company's mainland investor pool, improving its liquidity and the market influence. Thus benefits the company's future development prospects. In addition, Kintor Pharma's stock have been included in the MSCI China Index during the reporting period. Increasing Presence in Reputable Academic Seminars and Conferences Since 2022, Kintor Pharma's R&D outcome has been accepted by reputable academic conferences and journals, proving that the company's innovation ability and its international influence, and further demonstrating the First-in-Class and Best-in-Class potential of the company's product pipeline. Kintor Pharma's KX-826 and GT20029 for treatment of AGA and acne presented at AAD 2023 Kintor Pharma's Hedgehog/SMO inhibitor GT1708F for the treatment of Acute Myeloid Leukemia (AML) presented at AACR 2023 Oral Presentation highlighting the data from novel dual c-Myc/GSPT1 degrader GT19715 at ASH 2022 Pruxelutamide for treatment of COVID-19 and a c-Myc degrader for treatment of blood cancer and small cell lung cancers (SCLC) presented at AACR 2022 The study result of GT19715, a novel dual-target degrader of C-Myc/GSPT1, was published in the journal Clinical Lymphoma, Myeloma & Leukemia The study result of the Phase Ib clinical trial of Pruxelutamide for treatment of breast Cancer was published in the European Journal of Cancer (EJC) Industry and Capital Market Awards Kintor Pharma's persistent efforts in R&D has been widely recognized in the industry and has won many industry and capital market awards. Top 15 Biotech of the Top 100 Hong Kong Listed Companies Top 10 Innovative Pharmaceutical Companies in 2022 R&D Innovation Outstanding Contribution Award in 2021 Top 20 Biomedical Innovation Potential List in 2022 TOP 30 Innovative Small Molecule Pharmaceutical Companies in China in 2021 TOP 20 Most Influential Small Molecule Pharmaceutical Innovation Companies in 2022 Jishi Cup Top 10 Pharmaceutical Innovation Companies in 2021 Most Valuable Pharmaceutical and Medical Companies Other Business Updates In August 2022, Dr. Lu Qun, our Chief Technology Officer, was elected as a "2022 Gusu Innovation and Entrepreneurship Leading Talent". In May 2022, the company has received the approval to set up a Doctors workstation in Guangdong Province by the Human Resources and Social Security Department of Guangdong Province. Financial Highlights As of 31 December 2022, the company's research and development costs increased by RMB828 million, up by 7.8%, from RMB767.9 million for the year ended 31 December 2021. The increased R&D costs were mainly attributable to the ongoing Phase III clinical trials, including those of Pruxelutamide for the indication of COVID-19 and mCRPC, and KX-826 for the indication of AGA during the reporting period. The company had cash and cash equivalents and time deposits of RMB875.3 million as at 31 December 2022, including utilised bank facilities of RMB 276.5 million. In addition, the company also had unutilised bank facilities of RMB 120.0 million as at 31 December 2022. The company has sufficient cash on hand to support the advancement of the clinical trials and R&D. *For more details, please refer to the 2022 annual results announcement. About Kintor Pharmaceutical Limited Kintor Pharmaceutical Limited is developing and commercializing a robust pipeline of innovative small molecule and biological therapeutics for androgen-receptor-related disease areas with unmet medical needs, including COVID-19, prostate, breast and liver cancers, alopecia and acne. For more information, visit . Company Codes: HongKong:9939

临床1期临床结果临床2期财报

2023-03-21

·BioSpace

Kintor Pharma's KX-826 and GT20029 for Treatment of Androgenetic Alopecia (AGA) and Acne Presented at AAD 2023

SUZHOU, China, March 21, 2023 /PRNewswire/ -- The 2023 Annual Meeting of American Academy of Dermatology Association (AAD 2023) was held from 17 to 21 March 2023 in New Orleans, Louisiana, United States. As one of the largest, most influential and representative of all dermatologic associations, dermatologists from around the world shared the latest research advances in the field of dermatology. Kintor Pharmaceutical Limited ("Kintor Pharma", HKEX: 9939)'s self-developed and potential first-in-class topical drug candidates pyrilutamide (KX-826) and GT20029 have attracted a lot of attention at the meeting, demonstrating the company's innovative capabilities and the therapeutic potential of its androgenetic alopecia (AGA) and acne pipelines. At AAD 2023, Ken Washenik, M.D., Ph.D., FISHRS, FAAD, President and Chief Medical Officer of Bosley Medical Group and Clinical Assistant Professor of Ronald O. Perelman Department of Dermatology at New York University Grossman School of Medicine, shared the MoA and data of KX-826 and GT20029 for treatment of AGA in a presentation entitled "The Emerging Potential of Topical Androgen Modulators in Androgenetic Alopecia". Dr. Ken Washenik highlighted the emerging potential of topical androgen receptor (AR) modulators in AGA. He said that the potential of an effective topical AR blocker without systemic side-effects has long been promising. In addition, Adelaide Hebert, M.D., Director of Pediatric Dermatology at McGovern School of Medicine, University of Texas Health Science Center at Houston, shared the MoA and clinical trial design of KX-826 for treatment of acne in a presentation entitled "The Role of Topical Therapies Involving Androgen Hormones in Acne: Available and Future Therapies". Dr. Adelaide Hebert said that androgens and androgen receptors would play a key role in acne pathogenesis and represent important treatment targets. KX-826 is a topical AR antagonist under development by Kintor Pharma. The MoA of KX-826 for treatment of AGA is to locally block the androgen mediated signaling by competing with Dihydrotestosterone (DHT), limit the miniaturization of hair follicles and promote the growth of terminal hairs. KX-826 is quickly metabolized to the deactivated metabolite when arriving at the circulation system, contributing to least impact on systemic AR signaling pathway and a favorable safety profile. The Phase II clinical trial of KX-826 for male AGA adults in China showed that, after 24 weeks of treatment, the non-vellus target area hair count (TAHC) in the 5mg (0.5% concentration) twice daily (BID) KX-826 group increased by 15.34/cm2 compared with the placebo group from baseline, with a statistical difference (P=0.024). At present, Kintor Pharma is conducting the Phase III clinical trial in China and the Phase II clinical trial in the US of KX-826 for male AGA, and planning to conduct the Phase III clinical trial in China of KX-826 for female AGA and the global multi-center Phase III clinical trials of KX-826 for male and female AGA. The MoA of KX-826 for treatment of acne is to compete with DHT for binding to ARs, inhibiting gene expression that reduces sebum production and inflammation. The Phase II clinical trial of KX-826 for acne in China is ongoing, and the enrollment of all subjects has been completed in October 2022. GT20029 is a topical AR-Proteolysis Targeting Chimera (PROTAC) owned by Kintor Pharma. In preclinical studies, by degrading AR protein, GT20029 could block the shrinkage and miniaturization of hair follicles which was caused by the activation of AR signaling pathway. As the result, it prevented the hair from thinning, softening and falling out. GT20029 could also effectively inhibit sebaceous gland development and sebum secretion. GT20029 could avoid high systemic exposure and achieve a better safety profile. GT20029's Phase I clinical trials for treatment of AGA and acne in China and the US have been completed. About Kintor Pharmaceutical Limited Kintor Pharmaceutical Limited is developing and commercializing a robust pipeline of innovative small molecule and biological therapeutics for oncology and androgen-receptor-related disease areas with unmet medical needs, including COVID-19, prostate cancer, alopecia, acne, liver and breast cancers. For more information, visit . View original content to download multimedia: SOURCE Kintor Pharma Company Codes: HongKong:9939

临床2期临床结果临床1期

2022-10-17

·PRNewswire

Kintor Pharma Announces Completion of Patient Enrollment in Phase II Clinical Trial of KX-826 for Acne Vulgaris in China

SUZHOU, China, Oct. 16, 2022 /PRNewswire/ -- Kintor Pharmaceutical Limited ("Kintor Pharma", HKEX: 9939), a clinical-stage biotechnology company developing innovative small molecules and biological therapeutics, today announced that the company has completed the enrollment of 160 patients for its phase II clinical trial of KX-826 ("pyrilutamide") in China for the treatment of acne vulgaris on 14 October 2022. The phase II clinical trial is a randomized, double-blind, placebo-controlled, multi-regional clinical study to evaluate the safety and efficacy of KX-826 (gel) in patients with mild to moderate acne vulgaris. The primary endpoint is the treatment success rate in each group at the end of week 12 (according to the 5-point Investigator Global Assessment ("IGA") scale, subjects whose IGA scale decreases by not less than two levels to 0-1 defined as "success".). Dr. Youzhi Tong, founder, Chairman, and Chief Executive Officer of Kintor Pharma, commented, "We are delighted to see the completion of the enrollment of all patients in its phase II clinical trial of KX-826 for acne vulgaris in China. And I would like to give special thanks to all the investigators and my team who participated in this clinical trial, especially Professor Leihong Xiang from Huashan Hospital affiliated to Fudan University as the leading principal investigator (leading PI). KX-826's clinical trial in China for treating acne vulgaris was the combined design of phase I and phase II clinical trials. KX-826's phase I clinical trial has demonstrated a preliminary positive safety and tolerability profile in terms of dose-escalation and multiple topical doses applications per day for local use. We expect that KX-826 continues to demonstrate good efficacy and safety in phase II clinical trial to benefit more people suffering from acne vulgaris." About Acne Vulgaris Acne vulgaris is the eighth most prevalent disease in the world, which is a common disease in particular in adolescents and young adults. Acne vulgaris affects more than 740 millions people. The pathogenesis of acne vulgaris is complicated. The influence of androgen and its receptor signaling pathway on sebaceous glands and sebum secretion is one of the important factors causing acne vulgaris. The U.S. FDA approved the first androgen receptor (AR) antagonist in the past 40 years for the treatment of acne in August 2020, which had paved the way for our AR antagonist to conduct clinical trials in China. To date, there has been significant unmet medical needs as no effective topical AR antagonist was approved for the acne vulgaris treatment in China. About KX-826 KX-826 is an AR antagonist and a potential first-in-class topical drug for the treatment of androgenetic alopecia (AGA) and acne vulgaris. For the acne vulgaris indication, KX-826 could inhibit the combination of androgen receptor and androgen in hair follicle sebaceous glands that reduces sebum production, thereby treating acne vulgaris. For the AGA indication, Kintor Pharma now is conducting a phase III clinical trial of KX-826 in China and a phase II clinical trial of KX-826 in the US for male AGA patients. Kintor is also conducting a phase II clinical trial of KX-826 for female AGA patients in China. About Kintor Pharmaceutical Limited Kintor Pharmaceutical Limited is developing and commercializing a robust pipeline of innovative small molecule and biological therapeutics for androgen-receptor-related disease areas with unmet medical needs, including COVID-19, prostate, breast and liver cancers, alopecia and acne. For more information, visit www.kintor.com.cn. SOURCE Kintor Pharmaceuticals