更新于：2024-05-01

MMP12

基质金属蛋白酶-12

更新于：2024-05-01

基本信息

别名

基质金属蛋白酶12、hME、Macrophage elastase

+ [8]

简介

May be involved in tissue injury and remodeling. Has significant elastolytic activity. Can accept large and small amino acids at the P1' site, but has a preference for leucine. Aromatic or hydrophobic residues are preferred at the P1 site, with small hydrophobic residues (preferably alanine) occupying P3.

关联

项与 MMP12 相关的药物

Aderamastat

靶点

MMP12

作用机制

MMP12抑制剂

在研机构

逸达生物科技股份有限公司

原研机构

逸达生物科技股份有限公司

在研适应症-

非在研适应症

哮喘 [+3]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

FP-020

靶点

MMP12

作用机制

MMP12抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

AZD-1236

靶点

MMP12 x MMP9

作用机制

MMP12抑制剂 [+1]

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 MMP12 相关的临床试验

NCT06334211 / Not yet recruiting临床1期

A Phase 1, Randomized, Double-blind, Placebo-controlled, Single-center, Single and Multiple Ascending Oral Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of FP-020 in Healthy Volunteers

This is a study to Investigate the Safety, Tolerability, and Pharmacokinetics, of Single (including Food Effect) and Multiple Ascending Doses of FP-020 in Healthy Adult Volunteers.

开始日期2024-04-30

申办/合作机构

逸达生物科技股份有限公司

[+1]

NCT03858686 / Completed临床2期

The Effect of FP-025, a MMP-12 Inhibitor, on Allergen-induced Airway Responses, Airway Inflammation and Aspects of Airway Remodeling in Subjects With Mild Eosinophilic House Dust Mite (HDM)-Allergic Asthma (HDM)-Allergic Asthma

This study is a Phase IIa, randomized, placebo-controlled, double-blind, 2-way crossover, 2-center (conducted in EU; The Netherlands) study in male and female subjects with stable, mild HDM-allergic asthma. The study will consist of two identical study periods of 12 treatment days each, separated by a washout period of at least 3 weeks (and no more than 7 weeks). Approximately 36 eligible subjects will be enrolled, to yield 32 evaluable subjects who will be treated with both FP-025 (400 mg BID) or matching placebo in a cross-over design from the evening of Day 1 till the morning of Day 12 (22 doses per study period in total).

开始日期2018-07-02

申办/合作机构

逸达生物科技股份有限公司

NCT03304964 / Completed临床1期

A Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the MMP-12 Inhibitor FP-025 After Multiple Oral Ascending Dose Administration, and to Evaluate the Effect of Food After a Single Oral Dose Administration in Healthy Subjects

This is a single-center, phase I study consisting of 2 parts. The first part is a multiple ascending dose (MAD) part with a randomized, double-blind, placebo-controlled design in 3 treatment groups of 8 subjects (6 active; 2 placebo). The second part is a food effect (FE) part with a randomized, open-label, 2-period, 2-way crossover, single dose design in 8 subjects.

开始日期2017-07-21

申办/合作机构

逸达生物科技股份有限公司

100 项与 MMP12 相关的临床结果

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100 项与 MMP12 相关的转化医学

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0 项与 MMP12 相关的专利（医药）

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2,544

项与 MMP12 相关的文献（医药）

2024-02-21·Nature communications

Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders.

Article

作者: Stephen J Gaudino ; Ankita Singh ; Huakang Huang ; Jyothi Padiadpu ; Makheni Jean-Pierre ; Cody Kempen ; Tej Bahadur ; Kiyoshi Shiomitsu ; Richard Blumberg ; Kenneth R Shroyer ; Semir Beyaz ; Natalia Shulzhenko ; Andrey Morgun ; Pawan Kumar

IL-22 is critical for ameliorating obesity-induced metabolic disorders. However, it is unknown where IL-22 acts to mediate these outcomes. Here we examine the importance of tissue-specific IL-22RA1 signaling in mediating long-term high fat diet (HFD) driven metabolic disorders. To do so, we generated intestinal epithelium-, liver-, and white adipose tissue (WAT)-specific Il22ra1 knockout and littermate control mice. Intestinal epithelium- and liver-specific IL-22RA1 signaling upregulated systemic glucose metabolism. Intestinal IL-22RA1 signaling also mediated liver and WAT metabolism in a microbiota-dependent manner. We identified an association between Oscillibacter and elevated WAT inflammation, likely induced by Mmp12 expressing macrophages. Mechanistically, transcription of intestinal lipid metabolism genes is regulated by IL-22 and potentially IL-22-induced IL-18. Lastly, we show that Paneth cell-specific IL-22RA1 signaling, in part, mediates systemic glucose metabolism after HFD. Overall, these results elucidate a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating systemic obesity-associated disorders.

2024-02-18·Scientific reports

Fructose regulates the pentose phosphate pathway and induces an inflammatory and resolution phenotype in Kupffer cells.

Article

作者: Mareca Lodge ; Grace Scheidemantle ; Victoria R Adams ; Matthew A Cottam ; Daniel Richard ; Denitra Breuer ; Peter Thompson ; Kritika Shrestha ; Xiaojing Liu ; Arion Kennedy

Over-consumption of fructose in adults and children has been linked to increased risk of non-alcoholic fatty liver disease (NAFLD). Recent studies have highlighted the effect of fructose on liver inflammation, fibrosis, and immune cell activation. However, little work summarizes the direct impact of fructose on macrophage infiltration, phenotype, and function within the liver. We demonstrate that chronic fructose diet decreased Kupffer cell populations while increasing transitioning monocytes. In addition, fructose increased fibrotic gene expression of collagen 1 alpha 1 (Col1a1) and tissue metallopeptidase inhibitor 1 (Timp1) as well as inflammatory gene expression of tumor necrosis factor alpha (Tnfa) and expression of transmembrane glycoprotein NMB (Gpnmb) in liver tissue compared to glucose and control diets. Single cell RNA sequencing (scRNAseq) revealed fructose elevated expression of matrix metallopeptidase 12 (Mmp12), interleukin 1 receptor antagonist (Il1rn), and radical S-adenosyl methionine domain (Rsad2) in liver and hepatic macrophages. In vitro studies using IMKC and J774.1 cells demonstrated decreased viability when exposed to fructose. Additionally, fructose increased Gpnmb, Tnfa, Mmp12, Il1rn, and Rsad2 in unpolarized IMKC. By mass spectrometry, C13 fructose tracing detected fructose metabolites in glycolysis and the pentose phosphate pathway (PPP). Inhibition of the PPP further increased fructose induced Il6, Gpnmb, Mmp12, Il1rn, and Rsad2 in nonpolarized IMKC. Taken together, fructose decreases cell viability while upregulating resolution and anti-inflammatory associated genes in Kupffer cells.

2024-02-14·BMC pharmacology & toxicology

New tricks for old drugs- praziquantel ameliorates bleomycin-induced pulmonary fibrosis in mice.

Article

作者: Yanjun Zeng ; Rui Hu ; Wei Ma ; Ying Ding ; Yi Zhou ; Xin Peng ; Lixin Feng ; Qingmei Cheng ; Ziqiang Luo

BACKGROUND:

Pulmonary fibrosis is a chronic progressive disease with complex pathogenesis, short median survival time, and high mortality. There are few effective drugs approved for pulmonary fibrosis treatment. This study aimed to evaluate the effect of praziquantel (PZQ) on bleomycin (BLM)-induced pulmonary fibrosis.

METHODS:

In this study, we investigated the role and mechanisms of PZQ in pulmonary fibrosis in a murine model induced by BLM. Parameters investigated included survival rate, lung histopathology, pulmonary collagen deposition, mRNA expression of key genes involved in pulmonary fibrosis pathogenesis, the activity of fibroblast, and M2/M1 macrophage ratio.

RESULTS:

We found that PZQ improved the survival rate of mice and reduced the body weight loss induced by BLM. Histological examination showed that PZQ significantly inhibited the infiltration of inflammatory cells, collagen deposition, and hydroxyproline content in BLM-induced mice. Besides, PZQ reduced the expression of TGF-β and MMP-12 in vivo and inhibited the proliferation of fibroblast induced by TGF-β in vitro. Furthermore, PZQ affected the balance of M2/M1 macrophages.

CONCLUSIONS:

Our study demonstrated that PZQ could ameliorate BLM-induced pulmonary fibrosis in mice by affecting the balance of M2/M1 macrophages and suppressing the expression of TGF-β and MMP-12. These findings suggest that PZQ may act as an effective anti-fibrotic agent for preventing the progression of pulmonary fibrosis.

项与 MMP12 相关的新闻（医药）

2024-04-06

·佰傲谷BioValley

肿瘤细胞“主动寻死”

诱导肿瘤细胞凋亡，一直以来是各类肿瘤免疫治疗的根本目标。但这一定是对的吗？如果不对，我们是否需要改变药物研发和临床治疗的策略？肿瘤细胞主动死亡近年来，科学家们发现一些预后不良的高级别癌症往往包含相对高水平凋亡细胞。有人提出死亡的肿瘤细胞有助于肿瘤种群整体的净生存、扩张和进化，可能是肿瘤的一个主动行为。Cancer Cell上，阿拉巴马大学伯明翰分校的一些研究者就发现，凋亡的胶质母细胞瘤会释放胞外囊泡，含有恶性促肿瘤的剪切碎片，它再转入存活的胶质母细胞瘤细胞，促进他们发生恶性表型改变，并对治疗产生抗性。作者发现胶质母细胞瘤中超过70%的肿瘤细胞会发生凋亡。Cancer Cell. 2018英国爱丁堡大学Catriona A. Ford等则认为凋亡的淋巴瘤细胞和肿瘤相关巨噬细胞会促进肿瘤细胞生长，血管生成，对抗肿瘤免疫产生抑制。凋亡的淋巴瘤细胞会激活肿瘤相关巨噬细胞，释放基质金属蛋白酶（MMP2和MMP12等）促进组织重构和转移。伯基特淋巴瘤是增长最快的人类癌症之一，但是其通过凋亡丢失的细胞约占总增量细胞的70%。Curr. Biol. 2015促进肿瘤细胞凋亡和抗肿瘤作用在某些条件下是一个悖论（Apoptosis Paradox）。目前至少发现在10种肿瘤存在这种悖论，包括膀胱癌、乳腺癌、结肠直肠癌、胃癌、胶质母细胞瘤、恶性间皮瘤、NHL、非小细胞肺癌、胰腺管癌、舌鳞状癌。 Int. J. Mol. Sci. 2022凋亡创造促肿瘤生态位根据Paget’s的种子和土壤概念，原发性和转移性癌症的发展从根本上依赖于肿瘤的“生态位”，即肿瘤微环境。凋亡是肿瘤微环境的一个共同特征，其次，在多个较高凋亡水平的肿瘤更具侵袭性。虽然恶性疾病的侵袭性和肿瘤细胞凋亡水平之间的因果关系仍然很大程度上是理论上的，即促凋亡分子的高表达可能与疾病的低侵袭性不相关，反之亦然。比如，促凋亡的Bax表达或Caspase激活与侵袭性疾病相关，而抗凋亡的Bcl-2与较低的侵袭性状态相关。细胞死亡可能促进基因组的不稳定性和创建新的生态位(Onco-Regenerative Niche ,ORN)，导致更具有侵袭性的肿瘤细胞增殖，形成新克隆重新聚集。分泌的凋亡囊泡可以促进血管新生，激活肿瘤相关巨噬细胞，诱导肿瘤微环境重构，转移。 Int. J. Mol. Sci. 2022简评：诱导凋亡是我们抗肿瘤治疗一直以来的目标和策略。但是肿瘤细胞也通过主动诱导凋亡形成促进其生长转移的新生态位。所以，单纯的凋亡可能无法给我抗肿瘤治疗成或败的信息。那么，诱导凋亡的细胞毒性药物（小分子或者大分子）还会是研究和开发的重点吗？参考文献Pavlyukov, M.S.; Yu, H.; Bastola, S.; Minata, M.; Shender, V.O.; Lee, Y.; Zhang, S.; Wang, J.; Komarova, S.; Wang, J.; et al. Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors. Cancer Cell. 2018, 34, 119–135.e10Ford, C.A.; Petrova, S.; Pound, J.D.; Voss, J.J.; Melville, L.; Paterson, M.; Farnworth, S.L.; Gallimore, A.M.; Cuff, S.; Wheadon, H.; et al. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma. Curr. Biol. 2015, 25, 577–588Morana, O.; Wood, W.; Gregory, C.D. The Apoptosis Paradox in Cancer. Int. J. Mol. Sci. 2022, 23, 1328. https://doi.org/10.3390/ ijms23031328本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处···

免疫疗法临床研究

2024-04-01

·PRNewswire

Foresee Pharmaceuticals Receives Positive Recommendation from DSMB to Continue the Casppian Study, a Phase 3 Clinical Trial of Leuprolide (FP-001) Injectable Emulsion for the Treatment of Central Precocious Puberty

The independent Data and Safety Monitoring Board (DSMB) recommended the continuation of patient enrollment as planned. There has been no safety concern with the use of Leuprolide (FP-001) injectable Emulsion in pediatric CPP patients. TAIPEI, April 1, 2024 /PRNewswire/ -- Foresee Pharmaceuticals (TPEx: 6576), ("Foresee") today announces the positive safety review by the independent Data and Safety Monitoring Board for its Casppian Phase 3 registration study. The DSMB recommended that Foresee Pharmaceuticals continue the trial with a minor amended protocol. The Casppian Phase 3 study is an open-label, multicenter, multinational clinical trial to evaluate the efficacy, safety, and pharmacokinetics of Leuprolide (FP-001) 42 mg-controlled release in patients with central (Gonadotropin-Dependent) precocious puberty (CPP). Foresee's Leuprolide injectable emulsion, 42 mg (marketed under the brand name CAMCEVI®), is currently approved for the treatment of adult patients with advanced prostate cancer and has demonstrated positive efficacy and safety results with statistically significant treatment effects in adult male patients with advanced prostate cancer. "We are pleased to receive the positive recommendation from the DSMB to continue our clinical trial. Ensuring the safety of the children participating in our trial is paramount and we continue to be dedicated to maintaining the highest standards of safety and ethical conduct throughout this clinical trial. The top-line results from this trial are anticipated in 2025.", said Bassem Elmankabadi, M.D., Senior Vice President of Clinical Development at Foresee Pharmaceuticals. "Foresee's Leuprolide 42 mg formulation (FP-001) dosed subcutaneously every 6 months, has the potential to become the only ready-to-use Leuprolide 6-month long-acting injection on the market, providing benefit to stakeholders in the CPP community. This positive recommendation brings us closer to our goal of delivering safe and effective treatment for children in need," said Dr. Ben Chien, Foresee's Chairman and CEO. "We look forward to establishing commercial partnership soon for the potential future commercialization of FP-001, in CPP indication." About CPP GnRH-dependent CPP is a condition that causes early sexual development in girls and boys, as their "hypothalamus - pituitary gland - gonadal axis" is activated too early, causing children to enter puberty prematurely, between 2 years and 9 years of age. CPP patients are at risk of having significantly short stature as adults in addition to social, psychological, and emotional issues, including lower self-esteem, stress, anxiety, and depression, which may negatively impact their quality of life. According to the NORD (National Organization for Rare Disorders) website, CPP occurs in 1 out of 5,000 to 10,000 children. It is estimated that approximately 80% - 90% of CPP cases are idiopathic, especially in females, with a female-to-male ratio of around 20. Gonadotropin-releasing hormone (GnRH) agonists, including leuprolide, are the most widely used treatment for CPP. About Foresee Pharmaceuticals Co., Ltd. Foresee is a Taiwan and US-based biopharmaceutical company listed on the Taipei Exchange (TPEx: 6576). Foresee's R&D efforts are focused on two key areas, namely its unique Stabilized Injectable Formulation (SIF) long-acting injectable technology with derived drug products targeting specialty markets and secondly, its transformative preclinical and clinical first-in-class NCE programs targeting rare and severe disease areas with high unmet needs. Foresee's product portfolio includes late and early-stage programs. CAMCEVI® 42 mg, for the treatment of advanced prostate cancer, is now approved in the U.S., Canada, EU, and Taiwan and launched in the U.S. in April 2022. Additionally, U.S. and EU regulatory submissions are being prepared for CAMCEVI® 21 mg. The second indication of CAMCEVI® 42 mg – central precocious puberty (CPP), the Casppian phase 3 clinical study, has been initiated. FP-025 – a highly selective oral MMP-12 inhibitor targeting inflammatory and fibrotic diseases, a Phase 2 proof-of-concept study in allergic asthmatic patients has been completed with positive outcomes, with future development in rare immune-fibrotic diseases. FP-020, a follow-on oral MMP-12 inhibitor currently in Phase 1, with development targeted in severe asthma and COPD. FP-045 – a highly selective oral small molecule allosteric activator of ALDH2, a mitochondrial enzyme, for which the FuschiA Phase 1b/2 Fanconi Anemia study is currently being initiated, and a Phase 2 study in pulmonary hypertension-interstitial lung disease (PH-ILD) patients is in planning. SOURCE Foresee Pharmaceuticals Co., Ltd.

临床3期临床1期临床2期上市批准临床结果

2024-03-19

·今日头条

今日Cell：国内团队发现新肠道激素，连起肠肝轴胆固醇代谢调控

03月19日的《热心肠日报》，我们解读了 15 篇文献，关注：肠肝轴，胆固醇，免疫耐受，IL-22，肠道应激，阿司匹林，IBD，肠脑轴，乳糜泻，Novonesis，Slimbiotics，i-Health，英赛飞影，海南三叶制药厂，百奥泰。该篇日报由R·AI辅助创作生成，人工审核校对。国内团队Cell：发现调控胆固醇代谢的新肠道激素 Cell——[64.5] ① 清华大学王一国、南方医科大学南方医院张惠杰与团队研究发现了一种新肠道激素Cholesin（肠抑脂素），其具有抑制肝脏胆固醇合成、降低血液胆固醇水平的作用；② Cholesin由此前功能未知的基因编码（人类 C7orf50 ，小鼠 3110082I17Rik ）；③ 肠道的胆固醇吸收可诱导Cholesin生成，肠细胞中，NPC1L1介导的胆固醇摄取促进Cholesin分泌；④ SNP变异rs1007765（位于 Cholesin 基因3'端附近）能上调 Cholesin 表达，并与人类血浆胆固醇水平呈负相关；⑤ 机制上，Cholesin进入肝脏后，通过结合孤儿G蛋白偶联受体GPr146，抑制cAMP/PKA-ERK1/2信号通路，从而抑制肝脏中SREBP2控制的胆固醇合成，减少极低密度脂蛋白分泌，降低血浆胆固醇水平；⑥ Cholesin治疗可改善模型小鼠血脂和动脉粥样硬化，与他汀类药物联用效果更佳；⑦ 因此，肠道胆固醇吸收通过Cholesin-GPR146轴抑制肝脏胆固醇合成，为治疗相关疾病提供了新思路。【原文信息】 A gut-derived hormone regulates cholesterol metabolism 2024-03-18 , doi: 10.1016/j.cell.2024.02.024 Science子刊：肠道细菌衍生的血清素促进生命早期的免疫耐受 Science Immunology——[24.8] ① 本研究揭示了特定肠道细菌通过增加血清素的可用性，在新生儿肠道中塑造T细胞对膳食抗原和共生菌的反应，从而促进早期生命中的免疫耐受；② 新生儿肠道中富含包括血清素在内的神经递质，且特定细菌直接产生血清素，并通过下调单胺氧化酶A以限制血清素的分解；③ 血清素直接作用于T细胞，增加细胞内吲哚-3-乙醛并抑制mTOR激活，从而促进调节性T细胞的分化；④ 新生小鼠口服血清素可产生T细胞介导的针对膳食抗原和共生菌的长期特异性免疫耐受；⑤ 本研究表明新生儿肠道细菌衍生的血清素在生命早期免疫耐受中的关键作用。【原文信息】 Gut bacteria-derived serotonin promotes immune tolerance in early life 2024-03-15 , doi: 10.1126/sciimmunol.adj4775 Nature子刊：IL-22如何调节肠道，改善肥胖相关代谢紊乱？ Nature Communications——[16.6] ① 通过构建肠上皮、肝脏和白色脂肪组织（WAT）特异性Il22ra1敲除小鼠，研究组织特异性IL-22RA1信号在介导长期高脂饮食（HFD）驱动的代谢紊乱中的重要性；② 肠上皮和肝脏特异性IL-22RA1信号可提全身高性的糖代谢；③ 肠道IL-22RA1信号以菌群依赖方式介导肝脏和WAT代谢；④ 颤杆菌属与WAT炎症增加有关，并由表达Mmp12的巨噬细胞引起；⑤ 机制上，IL-22及其诱导的IL-18调控肠道脂质代谢基因的转录，而潘氏细胞特异性IL-22RA1信号部分介导HFD后的全身性糖代谢；⑥ 本研究揭示了肠道特异性IL-22RA1信号在调节肠道代谢及缓解系统性肥胖相关疾病中的关键作用。【原文信息】 Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders 2024-02-21 , doi: 10.1038/s41467-024-45568-6 肠道应激如何导致血脂异常？ Theranostics——[12.4] ① 本研究评估核糖体应激反应在肠肝脂质调节中的作用；② 利用化学核糖体失活应激剂（RIS）处理模型，发现RIS促进肠肝脂质积累，同时降低正常和饮食诱导肥胖小鼠血液中的低密度脂蛋白胆固醇；③ 核糖体应激显著调节胆固醇输入相关途径，尤其是通过转录和转录后调控增加肠道低密度脂蛋白受体（LDLR）的水平；④ LDLR增加可促进肠肝胆固醇的积累，导致核糖体应激响应下的血脂异常；⑤ 炎症和肥胖相关的肠道模型中进一步证实以上结论；⑥ 本研究为理解慢性人类疾病中应激响应性代谢重编程提供了新的分子机制。【原文信息】 Gut ribotoxic stress responses facilitate dyslipidemia via metabolic reprogramming: an environmental health prediction 2024-01-20 , doi: 10.7150/thno.88586 国内团队：阿司匹林如何维持肠道免疫稳态？ Advanced Science——[15.1] ① 复旦大学余巍、于肖飞团队揭示了阿司匹林通过乙酰化组蛋白去乙酰化酶（HDACs）SIRT1以维持肠道免疫稳态的新机制；② 通过同位素标记的阿司匹林和质谱分析，发现阿司匹林可直接乙酰化包括SIRT1在内的10种HDACs蛋白；③ 阿司匹林乙酰化SIRT1的第408位赖氨酸，破坏其去乙酰化活性，影响底物结合亲和力；④ 阿司匹林通过抑制SIRT1，增加乙酰化p53水平，促进p53依赖的细胞凋亡；⑤ SIRT1乙酰化模拟突变小鼠中促炎细胞因子产生减少，并有助于维持肠道免疫稳态；⑥ 本研究表明SIRT1乙酰化内部功能位点在维持肠道免疫稳态中的重要性，并解释了阿司匹林作为传统抗炎药发挥作用。【原文信息】 Aspirin-Mediated Acetylation of SIRT1 Maintains Intestinal Immune Homeostasis 2024-03-14 , doi: 10.1002/advs.202306378 国内团队：自噬相关蛋白AMBRA1抑制生物制剂疗效，加重肠炎 Cell Death and Differentiation——[12.4] ① 上海交通大学医学院附属新华医院杜鹏、刘辰莹、陈颖伟与团队揭示了自噬相关蛋白AMBRA1在肠道炎症反应中的促炎作用和自噬非依赖的NF-κB激活分子机制，提示靶向AMBRA1是增强生物制剂IFX抗炎疗效的新策略；② 首先构建 Villin-Ambra1flox/flox 肠上皮细胞特异性敲除小鼠，在DSS急性小鼠肠炎模型中，证实敲除 Ambra1 显著抑制肠炎反应，并增强抗TNF-α生物制剂夫利西单抗（IFX）的靶向抗炎作用；③ AMBRA1与IKK激酶复合物及PP4R1/PP4c蛋白磷酸酶复合体互作，通过N端结构域（1-532 AA）竞争性抑制PP4R1/PP4c与IKK复合物的结合，从而拮抗了PP4R1/PP4c对IKK的去磷酸化作用，进而促进NF-κB通路激活，加重肠道炎症反应；④ 在炎症刺激条件下，IKKα通过磷酸化AMBRA1第1043位丝氨酸，抑制CUL4A与AMBRA1的蛋白互作以及CUL4A对AMBRA1的K48多聚泛素化修饰，从而增强AMBRA1的蛋白稳定性；⑤ 通过对IBD患者的IFX治疗后临床缓解及无缓解的肠道组织分析发现，AMBRA1在IFX治疗临床无缓解的肠道炎症组织中显著增高，而在IFX治疗后临床缓解的组织中表达明显减少，与IBD患者的临床治疗预后相关。【原文信息】 AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner 2024-02-29 , doi: 10.1038/s41418-024-01275-9 全面解析炎症性肠病的肠外表现 Gastroenterology——[29.4] ① 本研究是迄今为止最大规模的关于炎症性肠病（IBD）患者肠外表现（EIM）的多队列综合性分析，揭示了与EIM并发症相关的临床、血清学和遗传因素；② 大多数EIM在女性、患有结肠病变的CD患者以及需要手术的患者中更为常见，吸烟增加EIM的风险，除了原发性硬化性胆管炎PSC；③ 观察到多个血清学关联，包括PSC（ANCA, ASCA, anti-CBir1）和任何EIM（ANCA, ASCA, anti-I2）；④ 在MHC和CPEB4中发现了全基因组显著关联，遗传关联提示TNF、JAK-STAT和IL6可能是EIM的潜在治疗靶点；⑤ 与先前报道相反，这项研究的受试者中只有2%有多个EIMs，且大多数共存现象是负相关的；⑥ 研究确定了与EIMs相关的人口统计学、临床和遗传学关联，揭示了潜在的机制，并涉及新颖和现有的药物靶点，为IBD管理提供了更个性化的方法。【原文信息】 Comprehensive association analyses of extraintestinal manifestations in inflammatory bowel disease 2024-02-27 , doi: 10.1053/j.gastro.2024.02.026 溃疡性结肠炎患者的焦虑抑郁症状或与肠道菌群有关 Gut Microbes——[12.2] ① 本研究揭示出溃疡性结肠炎（UC）患者肠道菌群通过降低结肠中神经肽Y（NPY）表达，从而导致焦虑和抑郁行为；② 将UC患者（UC-FMT）和对照（HC-FMT）的粪菌移植到小鼠，通过RNA-seq检测小鼠结肠基因的表达，结果显示两组小鼠的结肠基因表达具有显著差异，UC-FMT小鼠结肠中神经肽信号通路下调，包括NPY表达下调；③ 相比于HC-FMT，UC-FMT小鼠的结肠和血浆中NPY蛋白水平也降低；④ 口服给予从UC患者粪便中分离的蒙氏肠球菌（EM）能够降低小鼠结肠中的NPY表达，并诱发肠炎、焦虑和抑郁样行为，而腹腔注射外源性NPY能显著缓解EM诱发的焦虑和抑郁样行为；⑤ EM给药的小鼠其血浆和海马中NPY蛋白水平也降低，且荚膜多糖与EM诱导的NPY表达下调相关；⑥ 与健康对照组相比，UC患者炎症性结肠中NPY表达显著降低。【原文信息】 Regulation of colonic neuropeptide Y expression by the gut microbiome in patients with ulcerative colitis and its association with anxiety- and depression-like behavior in mice 2024-02-25 , doi: 10.1080/19490976.2024.2319844 肠道菌群影响IBD相关脊柱关节炎的治疗效果 Cell Reports Medicine——[14.3] ① 本研究揭示了硫唑嘌呤治疗炎症性肠病（IBD）相关的外周脊柱关节炎（pSpA）的临床疗效与肠道菌群之间的机制联系；② 纳入22名IBD-pSpA患者中，使用硫唑嘌呤治疗后，临床反应者的肠道菌群中富含产丁酸的普拉梭菌Fp；③ 硫唑嘌呤能促进Fp中丁酸合成基因的转录和丁酸的产生，但过量的叶酸会抑制这一过程；④ 硫唑嘌呤治疗可增强粪便中丁酸的产生，并限制野生型和反应者（而非非反应者）菌群定植的小鼠结肠炎；⑤ Fp足以恢复硫唑嘌呤对非反应者菌群定植的无菌小鼠结肠炎的保护作用；⑥ 本研究为IBD-pSpA的诊断和治疗提供了新的指导。【原文信息】 The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis 2024-02-12 , doi: 10.1016/j.xcrm.2024.101431 乳糜泻自身免疫的机制（综述） Gut——[24.5] ① 乳糜泻是一种食物不耐受，也是一种自身免疫性疾病，具有高度疾病特异性的转谷氨酰胺酶2自身抗体；② 目前，如果儿童血清中含有高水平的抗转谷氨酰胺酶2的IgA抗体，就可诊断为乳糜泻；③ 抗转谷氨酰胺酶2抗体是谷蛋白免疫反应的一部分，这一过程的分子机制已经被破解；④ 谷蛋白肽是转谷氨酰胺酶2的良好底物，会被转谷氨酰胺酶2捕获，然后通过乳糜泻相关HLA分子HLA-DQ2和HLA-DQ8以脱酰胺肽的形式呈递给CD4+ T细胞；⑤ 转谷氨酰胺酶2特异性B细胞及其B细胞受体（膜结合免疫球蛋白）在谷蛋白肽呈递到T细胞的过程中至关重要；⑥ 转谷氨酰胺酶2特异性B细胞会与捕获谷蛋白肽的转谷氨酰胺酶2结合（半抗原载体样复合物），进而在T细胞的帮助下，变成产生抗转谷氨酰胺酶2抗体的浆细胞。【原文信息】 Coeliac disease: the paradox of diagnosing a food hypersensitivity disorder with autoantibodies 2024-02-20 , doi: 10.1136/gutjnl-2023-331595 Novonesis旗下益生菌新健康声明获加拿大卫生部批准 ① 3月15日，Novonesis宣布，旗下植物乳杆菌Clepius L. plantarum的2项健康声明获得加拿大卫生部批准，成为加拿大首株被认为具有缓解压力和促进胃肠健康双重益处的益生菌；② 临床前实验数据表明，该菌株具有良好的胃肠耐受性，并展现出有助于维持肠道屏障完整性以及抗病原体、抗炎和产胆盐水解酶等特性；③ 此次批准基于一系列临床研究和数据，其中一项随机双盲、安慰剂对照、多中心和剂量范围研究结果显示，该菌株无论是低剂量（1010 CFU）还是高剂量（1011 CFU）均可显著改善胃肠道症状，如腹痛和腹胀等；④ 此外，据报道，该菌株还有望通过日常补充来缓解压力。【原文信息】 Novonesis touts pioneering probiotic Clepius L. Plantarum’s approval for gut and brain health claims 2024-03-15 , nutrition insight Slimbiotics与i-Health达成益生菌商业化新合作 ① 近日，奥地利初创公司Slimbiotics与DSM旗下子公司i-Health宣布达成合作，后者将帮助前者把代谢健康益生菌引入北美和中国市场；② Slimbiotics的代谢健康益生菌为发酵乳杆菌（ L. fermentum ）K7-Lb1、K8-Lb1和K11-Lb3，筛选自肯尼亚Mbeere地区的自然发酵面团Kimere；③ 三株菌株将通过Culturelle和Estroven品牌实现商业化；④ 发表于 Nutrients 杂志上的临床研究结果显示，补充三株菌株组合3个月，能显著降低体脂肪量、体重、腰围、BMI等指标。【原文信息】 DSM i-Health partners with Slimbiotics for metabolic health probiotics 2024-03-14 , nutraingredients-usa 无线内镜厂商「英赛飞影」宣布完成天使轮融资 ① 近日，苏州英赛飞影医疗科技有限公司宣布完成天使轮融资；② 本轮融资由国仟创投、接力基金及苏州器械产业集团共同投资；③ 融资资金将用于公司核心产品智能无线硬镜和软镜的研发投入、产能扩建及市场开拓等；④ 英赛飞影的智能无线内镜产品具备无线、超低延迟、易携、高清晰度等特点，适用于多种医疗场景；⑤ 目前，两款核心产品已完成开发并进入临床试验阶段，预计将于2024年下半年获批。【原文信息】英赛飞影完成天使轮融资，开启“无线”创新之路 2024-03-18 , 动脉网海南三叶制药厂：奥美拉唑肠溶胶囊过评 ① 3月18日，国家药监局发布了新一批药品批准证明文件送达信息；② 本批次共16个受理号获批，其中海南三叶制药厂的奥美拉唑肠溶胶囊的一致性评价受理号获批；③ 奥美拉唑肠溶胶囊由阿斯利康研发，用于治疗胃、十二指肠溃疡、反流性食管炎等疾病；④ 其于1988年在欧盟和中国获批上市，是第一个上市的质子泵抑制剂。【原文信息】刚刚，国家药监局发布16个新批件，1个大品种过评！ 2024-03-18 , 新康界百奥泰2款生物类似药授权海外，达成600万美元协议 ① 3月18日，百奥泰生物宣布，已与SteinCares就2款在研生物类似药签订授权许可与商业化协议；② 百奥泰将BAT2506注射液和BAT2606注射液在巴西及拉丁美洲地区的商业化权益许可授予SteinCares；③ 此次协议总金额最高达600万美元（约合人民币4318.86万），包括120万美元首付款和最高480万美元的里程碑付款；④ 此外，双方还约定了将净销售额的两位数百分比作为收入分成；⑤ BAT2506是一款戈利木单抗生物类似药，原研戈利木单抗（Simponi）来自强生，靶向TNF-α，获批用于类风湿性关节炎、强直性脊柱炎、银屑病关节炎、溃疡性结肠炎等自免疾病；⑥ BAT2606是一款美泊利珠单抗生物类似药，原研美泊利珠单抗（Nucala）由GSK开发，主要用于嗜酸性粒细胞哮喘、支气管哮喘等免疫炎症性疾病。【原文信息】 600万美元！百奥泰2款生物类似药授权海外 2024-03-18 , 医药魔方感谢本期日报的审核者：mildbreeze，圆圈儿，章台柳，九卿臣，lxx，Alex Zhang 点击阅读过去10天的日报： 0318 | NEJM双发：大肠癌无创检测取得新突破 0317 | Cell子刊：多组学+长追踪，深度解析人体菌群动态和与宿主的互作 0316 | 国内团队34页综述详解：用饮食干预对抗疾病 0315 | 顶刊小高潮：王良静等Cell重磅突破，Science三文聚焦肠菌 0314 | 今日Nature：抵御肠道感染，菌群色氨酸代谢物有新招 0313 | 朱书/潘文等Cell子刊新发现：肠菌胆汁酸代谢如何影响大肠癌抗肿瘤免疫？ 0312 | 65分综述详解ILC3：守护肠道健康的重要免疫细胞 0311 | 分析81万人数据：根除幽门螺杆菌，还能防肠癌？ 0310 | 癌症治疗中的饮食干预：评估252项临床试验有何发现？ 0309 | AGA最新指南：基于粪便菌群的疗法在胃肠疾病中的应用

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