更新于：2024-04-01

RIPK1

受体相互作用的丝氨酸/苏氨酸蛋白激酶-1

更新于：2024-04-01

基本信息

别名

Cell death protein RIP、receptor (TNFRSF)-interacting serine-threonine kinase 1、receptor interacting serine/threonine kinase 1

+ [7]

简介

Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways (PubMed:32657447, PubMed:31827280, PubMed:31827281, PubMed:17703191, PubMed:24144979). Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival (PubMed:11101870, PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kappa-B pathway (By similarity). Kinase activity is essential to regulate necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis (By similarity). RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis (By similarity). In normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated by RIPK3 component of complex IIb, which catalyzes phosphorylation of MLKL upon induction by ZBP1 (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis (PubMed:19524512, PubMed:19524513, PubMed:29440439, PubMed:30988283). Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (By similarity). In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6) (PubMed:31827280, PubMed:31827281). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation (PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF-alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591, PubMed:15310755). Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (By similarity).

关联

项与 RIPK1 相关的药物

SAR-443820

靶点

RIPK1

作用机制

RIPK1抑制剂

在研机构

Sanofi [+3]

原研机构

Denali Therapeutics, Inc.

在研适应症

多发性硬化症 [+2]

非在研适应症-

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

LY-3871801

靶点

RIPK1

作用机制

RIPK1抑制剂

在研机构

Eli Lilly & Co.

原研机构

Rigel Pharmaceuticals, Inc.

在研适应症

类风湿关节炎

非在研适应症-

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

ABBV-668

靶点

RIPK1

作用机制

RIPK1抑制剂

在研机构

AbbVie, Inc.

原研机构

AbbVie, Inc.

在研适应症

溃疡性结肠炎 [+1]

非在研适应症-

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

项与 RIPK1 相关的临床试验

ChiCTR2400079434 / Recruiting临床1期IIT

A Phase Ib Clinical Trial to Evaluate the Safety, Tolerability, Preliminary Efficacy, and Pharmacokinetic Profile of AC-003 Capsules in Combination with Glucocorticoids for the Treatment of acute Graft-Versus-Host Disease (aGVHD)

开始日期2024-01-09

申办/合作机构-

NCT06049108 / Completed临床1期

A Phase 1, Open-label Study of the Absorption, Metabolism, and Excretion of [14C]-LY3871801 in Healthy Male Participants

The main purpose of this study is to evaluate how much of the study drug (LY3871801), administered as a single dose that has the radioactive substance 14C incorporated into it, passes from blood into urine, feces and expired air in healthy male participants. The study will also measure how much of the study drug gets into the bloodstream, how its broken down, and how long it takes the body to get rid of it. The study will last up to approximately 9 weeks including the screening period.

开始日期2023-09-15

申办/合作机构

Eli Lilly & Co.

NCT05960851 / Completed临床1期

A Phase I, Participant- and Investigator-Blind, Single-center Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of LY3871801 in Healthy Asian and Non-Asian Participants

The main purpose of this study is to evaluate the safety and tolerability of LY3871801 when administered as multiple doses in Healthy Asian and Non-Asian Participants. The study will also evaluate the amount of LY3871801 that gets into the blood stream and how long it takes the body to get rid of it in these participants. The study will be conducted in two parts (A & B). The study will last up to approximately 24 days excluding the screening period.

开始日期2023-08-09

申办/合作机构

Eli Lilly & Co.

100 项与 RIPK1 相关的临床结果

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100 项与 RIPK1 相关的转化医学

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0 项与 RIPK1 相关的专利（医药）

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2,028

项与 RIPK1 相关的文献（医药）

2024-02-24·BMC complementary medicine and therapies

JianPiYiShen formula prevents cisplatin-induced acute kidney injury in mice by improving necroptosis through MAPK pathway.

Article

作者: Zhongtang Li ; Riming He ; Jiahui Liu ; Xiaoming Jin ; Beibei Jiang ; Yunlan Lao ; Shudong Yang

BACKGROUND:

Acute kidney injury (AKI), characterized by necroptosis and activation of MAPK pathway, causes sudden declines in renal function. To date, efficacious treatments are lacking. JianPiYiShen Formula (JPYSF) has a protective effect on the kidneys. The aim of this study is to explore the mechanism of JPYSF in cisplatin-induced AKI.

METHODS:

Male C57/BL6J mice were divided into control group, cisplatin group and cisplatin + JPYSF group. Before establishing the model, the cisplatin + JPYSF group was administered JPYSF (18.35 g/kg/day) by gavage for 5 consecutive days. A single intraperitoneal injection of cisplatin (20 mg/kg) was used to establish AKI model. Measurement of renal function and H&E staining were performed to assess renal damage. WB, PCR, TUNEL staining and immunohistochemistry were used to detect related indicators of mitochondrial function, oxidative stress, necroptosis, inflammation and MAPK pathway. And one-way analysis of variance was used to compare group differences.

RESULTS:

Compared with the cisplatin group, JPYSF can attenuate AKI, reflected by the decrease in Scr and BUN levels, the improvement of renal tubular injury, and the downregulation of NGAL and KIM1. Cisplatin can induce mitochondrial dysfunction and oxidative stress, triggering necroptosis. In this study, JPYSF improved mitochondrial dysfunction to enhance oxidative stress, as manifested by upregulation of OPA1, PGC-1α, SOD and CAT, and downregulation of DRP1 and MFF. Then JPYSF showed a significant protective effect in necroptosis, as embodied by reduced number of TUNEL-positive cells, decreased the gene expression of RIPK3 and MLKL, as well as downregulation the proteins expression of P-RIPK1, P-RIPK3, and P-MLKL. Moreover, necroptosis can aggravate inflammation. JPYSF ameliorated inflammation by improving inflammatory and anti-inflammatory indexes, including downregulation of TNF-α, IL-6, MCP-1 and LY6G, and upregulation of IL-10. In addition, JPYSF also inhibited MAPK pathway to improve necroptosis by decreasing the expression of P-JNK and P-ERK.

CONCLUSION:

Our data showed that JPYSF prevents cisplatin-induced AKI by improving necroptosis through MAPK pathway, which is related to the improvement of mitochondrial dysfunction, oxidative stress, and inflammation.

2024-02-20·Microbiology spectrum

High-fat diet disrupts the gut microbiome, leading to inflammation, damage to tight junctions, and apoptosis and necrosis in Nyctereutes procyonoides intestines.

Article

作者: Chengwei Wei ; Tianchao Xu ; Yuan Geng ; Jie Yang ; Hongli Lv ; Meng-Yao Guo

Given the burgeoning Nyctereutes procyonoides breeding industry and its growing scale, it is imperative to investigate the impact of high-fat diets on the health of these animals. This study involved 30 male Nyctereutes procyonoides of comparable weights (3 kg ±0.5), randomly assigned to either a control group or a high-fat diet group (n = 15 each). The latter group was fed a mixture of lard and basal diet in a 2:5 ratio, establishing a high-fat diet model in Nyctereutes procyonoides. This diet induced diarrhea and histopathological changes in the Nyctereutes procyonoides. Analysis of the small intestine contents using 16S rRNA sequencing revealed a high-fat diet-induced disruption in the gut microbiota. Specifically, Escherichia-Shigella emerged as the biomarker in the high-fat diet group (P = 0.049), while Vagococcus was prevalent in the control group (P = 0.049), indicating a significant increase in harmful bacteria in the high-fat diet group. Furthermore, this disrupted gut flora correlated with inflammation and oxidative stress, as evidenced by marked increases in TNF-α (P < 0.01), IL-1β (P < 0.05), and IL-6 (P < 0.05) levels, measured via q-PCR, Western blot, and oxidative stress assays. In addition, q-PCR analysis revealed significant upregulation of apoptosis and necrosis markers, including Bax, Caspase3, Caspase9, Caspase12, RIPK3, and RIPK1 (P < 0.01 to P < 0.001), and a concurrent downregulation of the anti-apoptotic gene Bcl-2 (P < 0.01) in the high-fat diet group, consistent with protein expression trends. These findings suggest that a high-fat diet alters the gut microbiome toward a more harmful bacterial composition, escalating inflammatory responses and intestinal tissue permeability, culminating in intestinal cell apoptosis and necrosis.IMPORTANCEThis study examines the impact of high-fat diets on Nyctereutes procyonoides. Our research established a Nyctereutes procyonoides model on a high-fat diet, revealing significant health impacts, such as diarrhea, histological anomalies, and alterations in the gut microbiota. These findings emphasize the importance of preventing health issues and promoting sustainable industry growth. They highlight the significant impact of diet on gut microbiota and overall animal health.

2024-02-19·Dermatology and therapy

Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

Article

作者: Valerie J Ludbrook ; David C Budd ; Katie Thorn ; Debra Tompson ; Bartholomew J Votta ; Lucy Walker ; Amy Lee ; Xin Chen ; Amanda Peppercorn ; Wei Jing Loo

INTRODUCTION:

Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772.

METHODS:

This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks.

RESULTS:

GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response.

CONCLUSION:

Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.

137

项与 RIPK1 相关的新闻（医药）

2024-03-30

·药事纵横

23项失败临床研究汇总（2024 Q1）

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。药物临床试验是新药上市的必经之路，但往往付出和回报不成正比，根据数据统计，临床I、II、III期的成功率分别为63.2%、30.7%和58.1%。据不完全统计2024年1-3月有23项失败临床研究，小编在此进行汇总，并介绍部分失败临床案例以供参考。1AMX0035 III期研究未达主要终点2024年3月8日，Amylyx Pharmaceuticals公布AMX0035治疗肌萎缩性侧索硬化症（ALS）三期临床PHOENIX的顶线数据，研究没有达到主要终点和次要终点。Amylyx将与监管进行沟通，包括自愿撤市的计划。受此消息影响，Amylyx股价暴跌83.5%。AMX0035的成分为苯丁酸钠和牛磺酸二醇，于2022年9月获得FDA批准上市，定价为每年15.8万美元。PHOENIX研究共招募了664例ALS患者，结果并未达到主要终点，第48周时，与安慰剂组比，AMX0035治疗组肌萎缩侧索硬化功能评定量表（ALSFRS-R）评分较基线变化不具有显著统计学差异（p=0.667）。此外，该研究也未达到患者报告的生活质量结果评估、总生存期以及慢肺活量（SVC）衡量的呼吸功能等次要终点。2Pimavanserin III期研究未达主要终点2024年3月11日，Acadia Pharmaceuticals公布Pimavanserin治疗精神分裂阴性症状三期临床ADVANCE-2的最新研究结果未达主要终点。研究的主要终点为NSA-16总分从基线到第26周的变化，治疗组和安慰机组26周NSA-16评分分别为-11.8 vs -11.1%，结果不具有统计学意义。安全性和耐受性与之前的临床试验一致，不良事件发生率较低。受此消息影响，Acadia Pharmaceuticals股价盘后下跌15%。3Keytruda+Lynparza III期研究未达主要终点3月21日，默沙东宣布其PD-1疗法Keytruda联合维持性PARP抑制剂Lynparza（奥拉帕利）一线治疗某些转移性非鳞状非小细胞肺癌（NSCLC）患者的III期KEYLYNK-006试验未达到总生存期（OS）和无进展生存期（PFS）的双重主要终点。除此之外，2023年12月默沙东还终止过一项K药+Lynparza用于转移性鳞状非小细胞肺癌的III期研究。终止原因是独立数据监测委员会（DMC）审查了计划中的中期分析（IA3）数据，发现与Keytruda联合化疗后进行Keytruda加安慰剂治疗相比，接受Keytruda联合化疗后进行Keytruda+Lynparza治疗的患者并没有显示出总生存期（OS）改善。而无进展生存期也没有统计学意义。早在2022年8月份，默沙东还公布了K药两项III期临床试验均未能达到终点。分别是：K药与卫材的仑伐替尼（Lenvima）联合用于新诊断肝癌的三期临床试验结果和K药+Lynparza联合用于先前治疗过的转移性去势抵抗性前列腺癌。4Enspryng III期研究未达预期3月21日，罗氏合作伙伴Chugai制药（中外制药）公布了Enspryng（萨特利珠单抗）治疗全身型重症肌无力（gMG）的III期LUMINESCE研究结果。虽在其主要终点观察到具有统计学意义的数据，但结果没有达到对临床获益程度的预期。Enspryng是一种白介素6(IL-6)受体拮抗剂，2020年8月获得美国FDA批准用于治疗抗水通道蛋白-4(AQP4)抗体阳性的视神经脊髓炎谱系障碍(NMOSD)成人患者。此后，萨特利珠单抗于 2021年5月在国内获批上市，成为国内首个视神经脊髓炎谱系疾病治疗药物。中外制药表示此次研究结果不影响Enspryng在NMOSD患者中的使用。该公司还在开发Enspryng用于其他神经自身免疫性和炎症性疾病。5DNL788 II期研究未达主要终点2月16日，Denali Therapeutics在SEC文件中透露，DNL788（SAR443820）治疗肌萎缩侧索硬化症（ALS）的II期HIMALAYA研究未能达到显著改善修订版ALS功能评定量表（ALSFRS-R）评分的主要终点。受此消息影响，Denali的股价下跌了近8%。2018年10月，赛诺菲和Denali公司就RIPK1抑制剂的全球开发和商业化展开广泛合作。赛诺菲将领导SAR443820/DNL788治疗ALS和MS的1期临床和2期临床开发，并与Denali公司一起进行该药治疗ALS、MS和阿尔茨海默病的3期临床试验。SAR443820/DNL788是由赛诺菲和Denali共同开发的一款有效的、选择性的、具有脑渗透性的RIPK1抑制剂。赛诺菲将继续在多发性硬化症患者中开展SAR443820/DNL788的K2 2期研究；1月8日，Denali在新闻稿中透露，赛诺菲已完成SAR443820/DNL788治疗多发性硬化症（MS）的2期试验，共招募174名参与者。6Yupelri IV期研究未达主要终点2024年1月5日，Theravance Biopharma宣布Yupelri（revfenacin）吸入溶液用于慢性阻塞性肺病（COPD）维持治疗的IV期PIFR-2研究未达主要终点。Yupelri 是美国批准用于慢阻肺维持治疗的唯一每日一次的雾化长效毒蕈碱拮抗剂（LAMA）。这项PIFR-2研究旨在评估，Yupelri较噻托溴铵（Spiriva，粉雾剂）在严重至极为严重COPD患者的肺功能改善情况。研究结果显示，第85天时第一秒用力呼气谷值较基线变化的主要终点指标方面，与对照组相比，Yupelri并未有统计学显著差异。Yupelri的安全性与耐受性与既往研究一致。本次研究的失败也导致Theravance股价下跌10%。总结新药的研发是现实且残酷的，没有主角光环，研究的失败不仅使巨额研究费用打水漂，往往也伴随着股价的大幅下跌。但凡事都有两面性，没有这些负重前行的研发企业，患者也便失去了一线希望，失败也是探索路上的重要部分，为成功奠定基石。2024年第一季度也有很多临床成功的好消息，比如：1月，Vertex公布Nav1.8抑制剂VX-548治疗中至重度急性疼痛三期临床达到主要终点；2月，信达生物宣布IGF-1R抗体治疗甲状腺眼病的三期临床达到主要终点，将向NMPA递交上市申请；强生宣布FcRn抗体Nipocalimab治疗全身性重症肌无力（gMG）三期临床达到主要终点；3月，Acelyrin公布IL-17类抗体Izokibep治疗银屑病关节炎（PsA）的2b/3期临床达到主要终点。参考资料：各公司官网往期文章：全球失败临床研究TOP18（1-2月）活动推荐【4.12日上海】Focus抗体/XDC类系列见面会:生物偶联药物，早期研发专场-上海首站蓄势待发，精准聚焦ADC/XDC早期研发最新进展与难点案例，面对面学习头部领先经验，了解行业新兴项目最新数据与趋势，与行业专家共同探索更多市场空间，创造更多产业商机与价值！现场特设新兴项目路演及点评交流，更有大咖点评互动。席位有限，机不可失~

临床3期临床失败临床成功上市批准

2024-03-25

·MedCity News

AbbVie Gets Another Ulcerative Colitis Contender via $137M Landos Acquisition

AbbVie already has blockbuster drugs for ulcerative colitis, but that isn’t stopping the pharmaceutical giant from trying to expand its scope in this disease. To that end, the company is acquiring Landos Biopharma, a clinical-stage biotech whose lead asset brings a different approach to treating this prevalent inflammatory disorder of the gut. According to deal terms announced Monday deal, AbbVie will pay $20.42 for each share of Blacksburg, Virginia-based Landos, which represents a 155% premium to the biotech’s closing stock price on Friday. Landos’s drug, named NX-13, is a small molecule designed to target and activate the NOD-like receptor X1, or NLRX1. This receptor is associated with the modulation of inflammatory proteins involved in ulcerative colitis and Crohn’s disease. As a once-daily oral drug, NX-13 would provide a more convenient dosing alternative to many inflammatory bowel disorder drugs that are administered as injections or infusions, including some products currently marketed by AbbVie. In a Phase 1b test enrolling patients with active ulcerative colitis, the Landos drug posted results showing it was safe and well tolerated across a range of doses. Furthermore, the results showed signals of clinical improvement. Results were published last November in the Journal of Crohn’s and Colitis. A placebo-controlled Phase 2 proof-of-concept clinical trial is underway testing two doses of the drug. The study has a targeted enrollment of 80 patients who have moderate-to-severe ulcerative colitis. Preliminary data are expected in the fourth quarter of this year. “With this acquisition, we aim to advance the clinical development of NX-13, a differentiated, first-in-class, oral asset with the potential to make a difference in the lives of people living with ulcerative colitis and Crohn’s disease,” AbbVie’s Roopal Thakkar, senior vice president, chief medical officer, global therapeutics, said in a prepared statement. AbbVie brings several different approaches to the intestinal inflammation, irritation, and ulcers caused by ulcerative colitis. Humira an antibody drug designed to bind to and block tumor necrosis factor alpha, a protein associated with several inflammatory disorders. Rinvoq, approved for both Crohn’s disease and ulcerative colitis, belongs to a class of drugs that block a different set of inflammatory proteins called Janus kinases. The antibody drug Skyrizi blocks IL-23, a signaling protein associated with inflammation. Skyrizi, whose approved indications include the treatment of Crohn’s disease, is currently under regulatory review for ulcerative colitis. The AbbVie pipeline includes ABBV-668, a RIPK1 inhibitor currently in Phase 2 testing in ulcerative colitis. AbbVie also holds an option to a biologic drug that Calibr, a division of Scripps Research, is developing for inflammatory bowel disease. This program is in Phase 1 testing. Founded in 2017, Landos was one of the first startups in Xontogeny, an accelerator run by Chairman and CEO Chris Garabedian, a biotech industry veteran. While the per share price of AbbVie’s Landos acquisition is a premium to its closing stock price last Friday as well as its $16 per share IPO price in 2021, the biotech’s shares have not traded anywhere near that price for more than two years. Last May, the company completed a 1-for-10 reverse stock split that consolidated shares in order to boost the stock price to maintain compliance with the Nasdaq’s listing requirements. On a split-adjusted basis, the per-share acquisition price is still below Landos’s IPO price. However, Landos shareholders could receive more. The deal includes a contingent value right that will pay up to $11.14 per share, adding $75 million to the purchase price. That additional payment is tied to the achievement of a clinical development milestone. In a regulatory filing, Landos said the milestone is the start of Phase 3 testing of NX-13 or any other drug candidate addressing the NRLX1 pathway for the treatment of ulcerative colitis. This study must start before March 31, 2029, according to the agreement. In research note sent to investors on Monday research, Leerink Partners analyst Thomas Smith wrote that Landos is a logical strategic fit for AbbVie, providing the pharma giant with optionality in its inflammatory bowel disorder pipeline for a relatively modest upfront cash payment. While acknowledging some overlap with AbbVie’s Rinvoq, Skyrizi, and Humira as well as the clinical-stage assets for inflammatory bowel disease, Smith said Leerink believes there is high probability of the acquisition closing and low risk of opposition from the Federal Trade Commission.

临床2期临床1期临床结果并购上市批准

2024-03-23

·今日头条

Lancet+JAMA领衔，聚焦炎症性肠病诊断与治疗

本期话题：IBD，治疗，诊断，生物制剂，药物研发，治疗靶点，纳米医学，整合素，椰水，Parvus Therapeutics，艾伯维，德琪医药，依拉环素，科迪乳业，Triplebar，菲仕兰该篇日报由R·AI辅助创作生成，人工审核校对。 Lancet：克罗恩病—希望与挑战（综述） Lancet——[168.9] ① 克罗恩病是一种慢性胃肠道炎症性疾病，通常影响回肠末端和结肠近端，以透壁性炎症为主要特征；② 克罗恩病的病因尚不完全清楚，目前认为是多因素相互作用的结果，由环境因素作用于遗传易感者，在肠道菌群参与下，启动肠道异常免疫应答，最终引起免疫损伤和炎症；③ 克罗恩病的主要症状为腹痛、腹泻、体重下降，病程隐匿且进展缓慢，伴随一系列肠外病症，包括口腔溃疡、脊柱关节炎、眼炎、皮肤损害、肝胆疾病等；④ 克罗恩病缺乏诊断的金标准，消化道内镜加组织活检是帮助确诊的重要手段，治疗策略不仅是达到临床缓解，还包括更深层次的内窥镜愈合、考虑辅助组织学和跨壁靶标以及心理舒缓等；⑤ 目前可以通过药物和手术来治疗，未来可能通过饮食与生物或小分子药物相结合，以及改进监测工具和预测生物标志物来改善克罗恩病。【原文信息】 Crohn's disease 2024-03-01 , doi: 10.1016/S0140-6736(23)02586-2 JAMA：溃疡性结肠炎的症状、诊断和治疗 JAMA——[120.7] ① 本文全面介绍了溃疡性结肠炎的症状、诊断和治疗方法，为患者和医疗专业人员提供了宝贵的信息；② 溃疡性结肠炎是一种慢性炎症性肠道疾病，常见症状包括腹泻、直肠出血、腹痛等，且可能引发关节炎、胆管炎或眼部炎症；③ 溃疡性结肠炎患者抑郁、焦虑、睡眠障碍和性功能障碍增加，诊断后20年内患结肠癌的风险是普通人群的1.7倍；④ 诊断依据包括胃肠道症状、血液和粪便检测以及结肠镜检查，治疗方法根据疾病严重程度和受影响的结肠部位而定，包括药物治疗和结肠切除手术；⑤ 患者应1-5年进行一次结肠镜检查，以预防病情恶化或筛查结直肠癌。【原文信息】 What Is Ulcerative colitis? 2024-02-02 , doi: 10.1001/jama.2023.23814 Lancet子刊：新诊断的克罗恩病患者应采用自上而下治疗策略 Lancet Gastroenterology & Hepatology——[35.7] ① 招募386名新诊断的活动性克罗恩病患者，抽取血液来检测由T细胞转录特征定义的预后生物标志物，然后随机分配到自上向下的治疗策略（即早期联合使用英夫利昔单抗和免疫调节剂）或加速逐步治疗（传统方法），其中379名参与者（自上而下组189名；加速逐步升级组190名）的主要结果数据是可用的；② 相比加速分级治疗组，自上向下治疗组的患者的持续性无类固醇和无手术缓解（79%对比15%）比例更高；③ 在自上向下治疗组中，不良事件（包括疾病复发）和严重不良事件更少，需要腹部手术的并发症更少，且严重感染的发生率没有差异；④ 所测试的预后生物标志物与治疗没有相互作用效应，不能应用于临床；⑤ 研究结果表明，对于新诊断的活动性克罗恩病患者，联合使用英夫利昔单抗和免疫调节剂的自上而下治疗在1年内取得了明显更好的结果，应考虑将自上而下治疗作为标准护理。【原文信息】 A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial 2024-02-21 , doi: 10.1016/S2468-1253(24)00034-7 Lancet子刊：治疗急性重症溃疡性结肠炎的新进展和未解之谜（综述） Lancet Gastroenterology & Hepatology——[35.7] ① 观点、治疗效果预测及新兴治疗方案的最新进展；② 重点总结了ASUC临床管理中一线类固醇静脉注射、二线抗体类药物在临床实践中尚未解决的问题和最新的改进及效果的评价，一线或二线治疗失败的早期预测，以及JAK抑制剂作为新兴治疗角色的重要性；③ 尽管对ASUC的病理机制尚不清楚，但宿主-微生物相互作用的失调可能是ASUC的关键因素；④ 基于多组学工具的个性化治疗框架的开发是未来ASUC临床管理的重要方向。【原文信息】 Acute severe ulcerative colitis management: unanswered questions and latest insights 2024-03-01 , doi: 10.1016/S2468-1253(23)00313-8 尽早使用生物制剂治疗克罗恩病，临床愈后更佳 Gastroenterology——[29.4] ① 本研究探讨了早期使用生物制剂对克罗恩病（CD）和溃疡性结肠炎（UC）患者（包括儿童和成人）疾病结果的影响，发现早期生物制剂治疗对CD患者减少手术风险和类固醇依赖性有显著效果，而对UC患者的影响不明显；② 纳入34375名患者（5240名为儿童），7,452/19,264名CD和2,235/15,111名UC患者接受生物制剂治疗；③ 早期使用生物制剂治疗的CD患者，诊断后10年内CD相关手术概率逐渐减少但幅度不大，其中治疗时间>2-3年和0-3个月之间存在显著差异，而0-3个月与>3-12个月之间没有差异；④ UC患者10年内发展成类固醇依赖的概率，0-3个月（19%）显著低于>2-3年(31%)和1-2年期间（37%）；⑤ UC患者中，治疗起始期间在结肠切除术或类固醇依赖率之间没有显著差异；⑥ 儿童患者中也观察到类似的趋势。【原文信息】 Early initiation of biologics and disease outcomes in children and adults with inflammatory bowel diseases: results from the nationwide epi-IIRN cohort 2024-02-06 , doi: 10.1053/j.gastro.2024.01.041 国内团队：酵母微囊搭载抗氧化物质缓解溃疡性结肠炎 Bioactive Materials——[18.9] ① 西安交通大学Li Runqing、张明真团队联合西安医学院张明鑫团队成功开发了一种基于金属多酚网络（MPN）的新型药物递送系统，有效缓解溃疡性结肠炎（UC），通过三重肠道微环境改造实现了抗氧化、抗炎和调节肠道菌群的同步治疗；② MPN装载抗炎活性多酚化合物姜黄素（Cur）生成Cur-MPN，并通过酵母微囊（YM）包裹形成CM@YM，保护Cur-MPN抵御恶劣的胃肠环境，并增强对炎症结肠的靶向和滞留能力；③ CM@YM通过口服给药，能够通过清除ROS、降低促炎细胞因子、调节巨噬细胞向M1极化，恢复屏障功能并维持肠道稳态，缓解DSS诱导的结肠炎并具有保护和治疗效果；④ CM@YM通过改善细菌多样性及增加短链脂肪酸含量，将肠道微生物组调整至有利状态。【原文信息】 Robust reactive oxygen species modulator hitchhiking yeast microcapsules for colitis alleviation by trilogically intestinal microenvironment renovation 2024-03-05 , doi: 10.1016/j.bioactmat.2024.02.033 国内团队Nature子刊：P2Y14R或是治疗炎症性肠病的潜在靶点 Nature Communications——[16.6] ① 苏州大学的李环球和中国药科大学的胡庆华团队合作发表文章，揭示嘌呤受体P2Y14R参与溃疡性结肠炎的作用机制，为炎症性肠病的治疗提供了潜在的治疗靶点；② P2Y14R与UC患者黏膜活检的炎症评分呈正相关，且在实验性结肠炎小鼠的肠上皮细胞中过表达，而肠上皮细胞特异性缺乏P2Y14R的雄性小鼠显示出较少的肠道损伤；③ P2Y14R的缺失通过cAMP/PKA轴限制了cAMP响应元件结合蛋白的转录活性，后者结合到Ripk1的启动子上，抑制肠上皮细胞的坏死；④ 通过虚拟筛选和化学优化设计了P2Y14R拮抗剂HDL-16，表现出显著的抗结肠炎效果。【原文信息】 Targeting P2Y14R protects against necroptosis of intestinal epithelial Cells through PKA/CREB/RIPK1 axis in ulcerative colitis 2024-03-07 , doi: 10.1038/s41467-024-46365-x 陆军医大Nature子刊：新型纳米粒子靶向输送PD-L1-Fc治疗IBD Nature Communications——[16.6] ① 陆军军医大学的陈磊、张定林与团队发表文章，表明用活性氧响应性纳米粒子递送PD-L1到肠道炎症部位，可增加PD-L1的疗效与安全性，为炎症性肠病（IBD）的靶向治疗提供了新思路；② 这种纳米颗粒能够控制PD-L1-Fc在结肠炎症部位的积累与释放，比系统性给药更有效地缓解炎症症状，减少不良反应；③ 纳米颗粒递送的PD-L1-Fc影响促炎和抗炎细胞因子的产生，减少了巨噬细胞、中性粒细胞和树突状细胞的浸润，增加调节性T细胞、Th1和Tfh细胞的频率；④ 此外，它还重塑肠道菌群组成，并增加短链脂肪酸的产生，为IBD的靶向治疗提供了一种有效且安全的策略。【原文信息】 Targeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis 2024-02-23 , doi: 10.1038/s41467-024-46025-0 Nature子刊：多组学分析抗整合素治疗对溃疡性结肠炎细胞的影响 Nature Communications——[16.6] ① 本研究通过单细胞转录组和蛋白质组分析，揭示了抗整合素抗体Vedolizumab（VDZ）在治疗溃疡性结肠炎（UC）时对不同细胞亚群的广泛影响；② VDZ治疗与循环和组织中的单核吞噬细胞（MNP）亚群的变化相关，同时也观察到淋巴细胞的轻微变化；③ 空间多组学分析显示，在活动性结肠炎中，MNP和成纤维细胞亚群的丰度和邻近性趋于增加；④ 对存档样本进行空间转录组学分析，发现与VDZ响应性相关的上皮细胞、MNP和成纤维细胞富集基因，强调了这些亚群在UC中的重要作用；⑤ 本研究有助于增强对UC治疗有反应和无反应的理解。【原文信息】 Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis 2024-02-19 , doi: 10.1038/s41467-024-45665-6 椰水或可作为溃疡性结肠炎的辅助治疗 Clinical Gastroenterology and Hepatology——[12.6] ① 椰子水具有抗炎作用，可以调节肠道微生物组，并且是丰富的钾来源，而这项研究发现，椰子水作为轻至中度溃疡性结肠炎（UC）患者的辅助治疗，能显著提高临床缓解率；② 纳入121名轻度至中度活动性UC患者，随机接受椰子水+标准医学治疗或安慰剂+标准医学治疗，治疗8周；③ 椰子水组，临床反应率、临床缓解率和粪便钙卫蛋白<150μg/g的比例均显著高于安慰剂组；④ 椰子水组，与临床指标显著或趋势性负相关的细菌分类群的相对丰度在8周时增加，这种效应与疾病活动和膳食纤维无关；⑤ 不良事件相当，并且没有患者出现高钾血症；⑥ 这项研究为UC的治疗提供了新的思路，值得进一步深入研究和临床应用。【原文信息】 Coconut water induces clinical remission in mild to moderate ulcerative colitis: double-blind placebo controlled trial 2024-01-24 , doi: 10.1016/j.cgh.2024.01.013 Parvus Therapeutics与艾伯维达成IBD药物开发合作 ① 近日，Parvus Therapeutics公司宣布与艾伯维公司达成一项全球独家许可合作协议；② 艾伯维将获得Parvus Therapeutics公司通过Navacim平台开发的炎症性肠病（IBD）疗法开发和商业化选择权；③ Parvus Therapeutics公司将获得预付款和潜在投资，并有资格获得未来开发和商业里程碑款项；④ 目前，Parvus Therapeutics公司通过Navacim平台开发的管线涵盖IBD、1型糖尿病、多发性硬化、类风湿关节炎、预防移植排斥反应和乳糜泻等项目。【原文信息】速递 | 联手抗击自身免疫疾病，艾伯维达成合作 2024-03-22 , 药明康德依拉环素被列入世卫组织更新的MIA清单 ① 近期，世界卫生组织在更新的“医学上重要的抗微生物药物”（MIA）清单中，将氟环素单独归类为新的抗菌药物类别；② 氟环素对四环素侧链全新改造，耐药机制发生变化，依拉环素成为氟环素类中唯一的抗菌药物；③ 依拉环素用于治疗多重耐药菌在内的革兰阴性菌、革兰阳性菌、厌氧菌等所引起的感染；④ 云顶新耀旗下依拉环素于2023年3月获得国家药监局的批准，并于当年7月成功商业化上市。【原文信息】依拉环素被列入世界卫生组织更新的具有重要医学意义的抗微生物药物清单，并成为氟环素类唯一的抗菌药物 2024-03-21 , 云顶新耀德琪医药启动TG-022 2期剂量扩展阶段研究 ① 3月20日，德琪医药宣布，在中国和澳大利亚启动ATG-022的CLINCH研究剂量扩展阶段试验；② 该研究的剂量扩展阶段计划入组胃癌和其他实体瘤患者；③ ATG-022是一款作用于紧密连接蛋白18.2（Claudin 18.2）的抗体偶联药物，在治疗胰腺癌和胃癌上分别获得FDA颁发的孤儿药资格认定；④ 此前，正在进行中的CLINCH研究已经取得了优异的初步临床数据，患者达到部分缓解和完全缓解。【原文信息】德琪医药在中国和澳大利亚启动Claudin 18.2抗体偶联药物的II期剂量扩展阶段研究 2024-03-21 , 医药魔方科迪乳业股票在退市板块恢复转让 ① 3月19日，科迪乳业宣布，其股票将在退市板块恢复转让，转让方式为每周三次；② 股票转让首日开盘参考价定为0.82元/股，首日成交不设价格涨跌幅限制；③ 投资者参与股票转让需通过中原证券或其他合格券商，且买卖单位需为100股的整数倍；④ 2022年9月，科迪乳业因无法清偿到期债务申请破产重整；⑤ 经过破产重整程序，科迪乳业及三家子公司合并重整计划已于2023年12月执行完毕，暂停转让因素已消除。【原文信息】这家乳企的股票，将在退市板块恢复转让！ 2024-03-19 , 新乳业 Triplebar与菲仕兰合作生产乳铁蛋白 ① 近日，Triplebar Bio公司宣布与菲仕兰达成一项合作，双方将通过精密发酵技术合作生产乳铁蛋白；② 该合作旨在满足乳铁蛋白日益增长的市场需求，预计到2030年乳铁蛋白的市场规模将翻倍；③ 乳铁蛋白通常用于高端婴儿配方奶粉，可以促进婴幼儿肠道成熟和免疫力发育，并且也因其抗菌效果而受到青睐；④ 精密发酵技术带来的乳铁蛋白产量是传统方法无法达到的，并且可以减少对牛奶、水资源和土地使用的影响。【原文信息】 Triplebar Announces Partnership with FrieslandCampina Ingredients on Lactoferrin 2024-03-20 , Daily Caller 感谢本期日报的审核者：RZN，章台柳，Zhonghua，圆圈儿，Richard，lxx 点击阅读过去10天的日报： 0322 | 陈豪燕/洪洁等Cell子刊：免疫治疗对老年人更有效，肠道菌群或是隐藏功臣 0321 | 今日Nature双发：促肠癌菌和宿主-菌群互作研究均有新突破 0320 | 12页高分综述解析：抗生素扰乱菌群，对宿主代谢有何影响？ 0319 | 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 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？

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