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Modulation of intracellular calcium activity in interstitial cells of Cajal by inhibitory neural pathways within the internal anal sphincter. 肛门内括约肌的抑制性神经通路对 Cajal 间质细胞细胞内钙活性的调节。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-01 Epub Date: 2024-06-11 DOI: 10.1152/ajpgi.00309.2023
Karen I Hannigan, Emer P Ni Bhraonain, Thomas W Gould, Kathleen D Keef, Caroline A Cobine

The internal anal sphincter (IAS) functions to maintain continence. Previous studies utilizing mice with cell-specific expression of GCaMP6f revealed two distinct subtypes of intramuscular interstitial cells of Cajal (ICC-IM) with differing Ca2+ activities in the IAS. The present study further examined Ca2+ activity in ICC-IM and its modulation by inhibitory neurotransmission. The spatiotemporal properties of Ca2+ transients in Type II ICC-IM mimicked those of smooth muscle cells (SMCs), indicating their joint participation in the "SIP" syncytium. Electrical field stimulation (EFS; atropine present) abolished localized and whole cell Ca2+ transients in Type I and II ICC-IM. The purinergic antagonist MRS2500 did not abolish EFS responses in either cell type, whereas the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine (l-NNA) abolished responses in Type I but not Type II ICC-IM. Combined antagonists abolished EFS responses in Type II ICC-IM. In both ICC-IM subtypes, the ability of EFS to inhibit Ca2+ release was abolished by l-NNA but not MRS2500, suggesting that the nitrergic pathway directly inhibits ICC-IM by blocking Ca2+ release from intracellular stores. Since inositol (1,4,5)-trisphosphate receptor-associated cGMP kinase substrate I (IRAG1) is expressed in ICC-IM, it is possible that it participates in the inhibition of Ca2+ release by nitric oxide. Platelet-derived growth factor receptor α (PDGFRα)+ cells but not ICC-IM expressed P2Y1 receptors (P2Y1R) and small-conductance Ca2+-activated K+ channels (SK3), suggesting that the purinergic pathway indirectly blocks whole cell Ca2+ transients in Type II ICC-IM via PDGFRα+ cells. This study provides the first direct evidence for functional coupling between inhibitory motor neurons and ICC-IM subtypes in the IAS, with contractile inhibition ultimately dependent upon electrical coupling between SMCs, ICC, and PDGFRα+ cells via the SIP syncytium.NEW & NOTEWORTHY Two intramuscular interstitial cells of Cajal (ICC-IM) subtypes exist within the internal anal sphincter (IAS). This study provides the first evidence for direct coupling between nitrergic motor neurons and both ICC-IM subtypes as well as indirect coupling between purinergic inputs and Type II ICC-IM. The spatiotemporal properties of whole cell Ca2+ transients in Type II ICC-IM mimic those of smooth muscle cells (SMCs), suggesting that ICC-IM modulate the activity of SMCs via their joint participation in a SIP syncytium (SMCs, ICC, and PDGFRα+ cells).

肛门内括约肌(IAS)具有维持肛门失禁的功能。之前利用细胞特异性表达 GCaMP6f 的小鼠进行的研究揭示了 IAS 中具有不同 Ca2+ 活性的两种不同亚型的 Cajal 肌肉间质细胞(ICC-IM)。本研究进一步研究了 ICC-IM 中的 Ca2+ 活性及其受抑制性神经传递的调节。II 型 ICC-IM 中 Ca2+ 瞬时特性与平滑肌细胞(SMC)相似,表明它们共同参与了 "SIP "合胞。电场刺激(EFS;存在阿托品)可消除 I 型和 II 型 ICC-IM 的局部和全细胞 Ca2+ 瞬时。嘌呤能拮抗剂 MRS2500 不能消除两种细胞类型的 EFS 反应,而 NOS 抑制剂 L-NNA 则能消除 I 型 ICC-IM 的反应,但不能消除 II 型 ICC-IM 的反应。联合拮抗剂可消除 II 型 ICC-IM 的 EFS 反应。在这两种 ICC-IM 亚型中,L-NNA 可抑制 EFS 抑制 Ca2+ 释放的能力,但 MRS2500 却不能抑制这种能力。由于 IRAG1 在 ICC-IM 中表达,它可能参与了一氧化氮对 Ca2+ 释放的抑制。PDGFRᵯC+细胞而非ICC-IM表达P2Y1R和SK3,这表明嘌呤能途径通过PDGFRᵯC+细胞间接阻断了II型ICC-IM的全细胞Ca2+瞬态。这项研究首次直接证明了 IAS 中抑制性运动神经元和 ICC-IM 亚型之间的功能耦合,收缩抑制最终取决于 SMC、ICC 和 PDGFRᵯC+ 细胞之间通过 SIP 合胞的电耦合。
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引用次数: 0
Renalase peptides reduce pancreatitis severity in mice. 肾酶肽减轻小鼠胰腺炎的严重程度
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-16 DOI: 10.1152/ajpgi.00143.2024
Thomas R Kolodecik, Xiaoyu Guo, Christine A Shugrue, Xiaojia Guo, Gary V Desir, Li Wen, Fred Gorelick

Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here, we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a 1-day post-endoscopic retrograde cholangiopancreatography (ERCP) and a 2-day severe cerulein induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development.NEW & NOTEWORTHY Renalase is a secretory protein. The prosurvival and anti-inflammatory effects of the whole molecule are contained in a 20 aa renalase site (RP220). Systemic treatment with peptides containing this renalase site reduced the severity of post-endoscopic retrograde cholangiopancreatography (ERCP) and severe cerulein pancreatitis in mouse models.

急性胰腺炎是胰腺的一种急性炎症损伤,目前尚无特效疗法。循环蛋白肾酶由肾脏和其他组织产生,具有强大的抗炎和促生存特性。重组肾酶可减轻轻度胰腺炎的严重程度;其活性包含在一个保守的 20 aa 肾酶位点(RP220)中。在此,我们使用两种临床相关的急性胰腺炎模型研究了肾酶对胰腺炎的治疗效果。我们研究了含有 RP220 位点的多肽在急性胰腺炎后一天和两天的严重脑啡肽诱导的小鼠中减轻损伤的能力。肾酶肽的初始剂量是在发病前或发病后给予的。收集样本以确定早期胰腺炎反应(组织水肿、血浆淀粉酶、活性酶原)以及后期组织损伤和炎症变化。在两种临床前模型中,肾酶肽都能显著减轻与胰腺炎相关的组织损伤,尤其是炎症、坏死和整体损伤。使用特异性免疫组化标记物对炎症进行量化显示,肾酶肽在两种模型中都能显著减少骨髓源性炎症以及中性粒细胞和巨噬细胞的数量。在重度胰胆素模型中,无论是否进行预处理,使用肾酶肽都能显著减轻损伤。胰腺炎和肾酶肽对雌性和雄性小鼠的影响似乎相同。这些研究表明,肾酶肽保留了重组肾酶的抗炎和促生存特性,能减轻急性胰腺炎的严重程度,可能成为有吸引力的候选治疗药物。
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引用次数: 0
Retraction for Glaser et al., volume 295, 2008, G124-G136. 撤回 Glaser 等人的文章,第 295 卷,2008 年,G124-G136。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-01 DOI: 10.1152/ajpgi.00536.2007_RET
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引用次数: 0
Revitalizing gut barrier integrity: role of miR-192-5p in enhancing autophagy via Rictor in enteritis. 恢复肠道屏障的完整性:miR-192-5p 在肠炎中通过 Rictor 增强自噬的作用。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-02 DOI: 10.1152/ajpgi.00291.2023
Peishan Qiu, Kezhi Zhou, Youwei Wang, Xiaoyu Chen, Cong Xiao, Wenjie Li, Yuhua Chen, Ying Chang, Jing Liu, Feng Zhou, Xiaobing Wang, Jian Shang, Lan Liu, Zhao Qiu

Intestinal inflammation and compromised barrier function are critical factors in the pathogenesis of gastrointestinal disorders. This study aimed to investigate the role of miR-192-5p in modulating intestinal epithelial barrier (IEB) integrity and its association with autophagy. A DSS-induced colitis model was used to assess the effects of miR-192-5p on intestinal inflammation. In vitro experiments involved cell culture and transient transfection techniques. Various assays, including dual-luciferase reporter gene assays, quantitative real-time PCR, Western blotting, and measurements of transepithelial electrical resistance, were performed to evaluate changes in miR-192-5p expression, Rictor levels, and autophagy flux. Immunofluorescence staining, H&E staining, TEER measurements, and FITC-dextran analysis were also used. Our findings revealed a reduced expression of miR-192-5p in inflamed intestinal tissues, correlating with impaired IEB function. Overexpression of miR-192-5p alleviated TNF-induced IEB dysfunction by targeting Rictor, resulting in enhanced autophagy flux in enterocytes (ECs). Moreover, the therapeutic potential of miR-192-5p was substantiated in colitis mice, wherein increased miR-192-5p expression ameliorated intestinal inflammatory injury by enhancing autophagy flux in ECs through the modulation of Rictor. Our study highlights the therapeutic potential of miR-192-5p in enteritis by demonstrating its role in regulating autophagy and preserving IEB function. Targeting the miR-192-5p/Rictor axis is a promising approach for mitigating gut inflammatory injury and improving barrier integrity in patients with enteritis.NEW & NOTEWORTHY We uncover the pivotal role of miR-192-5p in fortifying intestinal barriers amidst inflammation. Reduced miR-192-5p levels correlated with compromised gut integrity during inflammation. Notably, boosting miR-192-5p reversed gut damage by enhancing autophagy via suppressing Rictor, offering a potential therapeutic strategy for fortifying the intestinal barrier and alleviating inflammation in patients with enteritis.

背景:肠道炎症和屏障功能受损是胃肠道疾病发病机制中的关键因素。本研究旨在探讨 miR-192-5p 在调节肠上皮屏障(IEB)完整性中的作用及其与自噬的关系:方法:采用 DSS 诱导的结肠炎模型来评估 miR-192-5p 对肠道炎症的影响。体外实验涉及细胞培养和瞬时转染技术。为了评估 miR-192-5p 表达、Rictor 水平和自噬通量的变化,实验人员进行了各种检测,包括双荧光素酶报告基因检测、定量实时 PCR、Western 印迹和跨上皮电阻测量。此外还采用了免疫荧光染色、H&E 染色、TEER 测量和 FITC-葡聚糖分析:结果:我们的研究结果表明,发炎的肠道组织中 miR-192-5p 的表达量减少,这与 IEB 功能受损有关。过表达 miR-192-5p 可通过靶向 Rictor 缓解 TNF 诱导的 IEB 功能障碍,从而增强肠细胞(ECs)的自噬通量。此外,miR-192-5p 的治疗潜力在结肠炎小鼠中得到了证实,miR-192-5p 表达的增加通过调节 Rictor 增强了肠细胞的自噬通量,从而改善了肠道炎症损伤:我们的研究通过证明 miR-192-5p 在调节自噬和保护 IEB 功能方面的作用,强调了其在肠炎中的治疗潜力。靶向 miR-192-5p/Rictor 轴是减轻肠炎患者肠道炎症损伤和改善肠道屏障完整性的一种很有前景的方法。
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引用次数: 0
Secretagogue-induced pancreatitis in mice devoid of chymotrypsin. 胰蛋白酶缺失的小鼠分泌物诱发的胰腺炎
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-09-01 Epub Date: 2024-07-09 DOI: 10.1152/ajpgi.00310.2023
Alexandra Demcsák, Siavash Shariatzadeh, Miklós Sahin-Tóth

The serine protease chymotrypsin protects the pancreas against pancreatitis by degrading trypsinogen, the precursor to the digestive protease trypsin. Taking advantage of previously generated mouse models with either the Ctrb1 gene (encoding chymotrypsin B1) or the Ctrl gene (encoding chymotrypsin-like protease) disrupted, here we generated the novel Ctrb1-del × Ctrl-KO strain in the C57BL/6N genetic background, which harbors a naturally inactivated Ctrc gene (encoding chymotrypsin C). The newly created mice are devoid of chymotrypsin, yet the animals develop normally, breed well, and show no spontaneous phenotype, indicating that chymotrypsin is dispensable under laboratory conditions. When given cerulein, the Ctrb1-del × Ctrl-KO strain exhibited markedly increased intrapancreatic trypsin activation and more severe acute pancreatitis, relative to wild-type C57BL/6N mice. After the acute episode, Ctrb1-del × Ctrl-KO mice spontaneously progressed to chronic pancreatitis, whereas C57BL/6N mice recovered rapidly. The cerulein-induced pancreas pathology in Ctrb1-del × Ctrl-KO mice was highly similar to that previously observed in Ctrb1-del mice; however, trypsin activation was more robust and pancreatitis severity was increased. Taken together, the results confirm and extend prior observations demonstrating that chymotrypsin safeguards the pancreas against pancreatitis by limiting pathologic trypsin activity. In mice, the CTRB1 isoform, which constitutes about 90% of the total chymotrypsin content, is responsible primarily for the anti-trypsin defenses and protection against pancreatitis; however, the minor isoform CTRL also contributes to an appreciable extent.NEW & NOTEWORTHY Chymotrypsins defend the pancreas against the inflammatory disorder pancreatitis by degrading harmful trypsinogen. This study demonstrates that mice devoid of pancreatic chymotrypsins are phenotypically normal but become sensitized to secretagogue hyperstimulation and exhibit increased intrapancreatic trypsin activation, more severe acute pancreatitis, and rapid progression to chronic pancreatitis. The observations confirm and extend the essential role of chymotrypsins in pancreas health.

丝氨酸蛋白酶糜蛋白酶通过降解消化蛋白酶胰蛋白酶的前体--胰蛋白酶原,保护胰腺免受胰腺炎的侵害。利用以前产生的Ctrb1基因(编码糜蛋白酶B1)或Ctrl基因(编码糜蛋白酶样蛋白酶)被破坏的小鼠模型,我们在这里产生了新的Ctrb1-del ×Ctrl-KO品系,该品系是在C57BL/6N遗传背景下产生的,其中含有自然失活的Ctrc基因(编码糜蛋白酶C)。新产生的小鼠体内没有糜蛋白酶,但发育正常,繁殖能力强,没有自发表型,这表明糜蛋白酶在实验室条件下是可有可无的。与野生型 C57BL/6N 小鼠相比,当给予 Ctrb1-del ×Ctrl-KO 株小鼠胰蛋白酶时,其胰腺内胰蛋白酶活化明显增加,并表现出更严重的急性胰腺炎。急性发作后,Ctrb1-del ×Ctrl-KO 小鼠自发发展为慢性胰腺炎,而 C57BL/6N 小鼠则迅速恢复。Ctrb1-del ×Ctrl-KO小鼠的胰蛋白酶诱导的胰腺病理变化与之前在Ctrb1-del小鼠中观察到的病理变化高度相似,但胰蛋白酶活化更强,胰腺炎的严重程度更高。总之,这些结果证实并扩展了之前的观察结果,即糜蛋白酶通过限制病理性胰蛋白酶活性来保护胰腺免受胰腺炎的侵害。在小鼠体内,占糜蛋白酶总含量约 90% 的 CTRB1 异构体主要负责抗胰蛋白酶防御和保护胰腺炎,但次要的 CTRL 异构体也有相当大的贡献。
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引用次数: 0
Simultaneous Optical Imaging of Gastric Slow Waves and Contractions in the In Vivo Porcine Stomach. 体内猪胃慢波和收缩的同步光学成像
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-27 DOI: 10.1152/ajpgi.00033.2024
Haley N Patton, Hanyu Zhang, Garrett A Wood, Bijay Guragain, Nipuni D Nagahawatte, Linley A Nisbet, Leo K Cheng, Gregory P Walcott, Jack M Rogers

Gastric peristalsis is governed by electrical "slow waves" generally assumed to travel from proximal to distal stomach (antegrade propagation) in symmetric rings. While alternative slow wave patterns have been correlated with gastric disorders, their mechanisms and how they alter contractions remain understudied. Optical electromechanical mapping, a developing field in cardiac electrophysiology, images electrical and mechanical physiology simultaneously. Here, we translate this technology to the in-vivo porcine stomach. Stomachs were surgically exposed and a fluorescent dye (di-4-ANEQ(F)PTEA) that transduces the membrane potential (Vm) was injected through the right gastroepiploic artery. Fluorescence was excited by LEDs and imaged with one or two 256x256 pixel cameras. Motion artifact was corrected using a marker-based motion tracking method and excitation ratiometry, which cancels common-mode artifact. Tracking marker displacement also enabled gastric deformation to be measured. We validated detection of electrical activation and Vm morphology against alternative non-optical technologies. Non-antegrade slow waves and propagation direction differences between the anterior and posterior stomach were commonly present in our data. However, sham experiments suggest they were a feature of the animal preparation and not an artifact of optical mapping. In experiments to demonstrate the method's capabilities, we found that repolarization did not always follow at a fixed time behind activation "wavefronts," which could be a factor in dysrhythmia. Contraction strength and the latency between electrical activation and contraction differed between antegrade and non-antegrade propagation. In conclusion, optical electromechanical mapping, which simultaneously images electrical and mechanical activity, enables novel questions regarding normal and abnormal gastric physiology to be explored.

胃蠕动受电 "慢波 "支配,一般假定慢波以对称环形方式从胃近端向远端传播(前向传播)。虽然另类慢波模式与胃部疾病有关,但其机制及其如何改变收缩仍未得到充分研究。光学机电图谱是心脏电生理学的一个新兴领域,可同时对电生理学和机械生理学进行成像。在这里,我们将这一技术应用于体内猪胃。手术暴露胃部,通过右胃外膜动脉注入能转导膜电位(Vm)的荧光染料(di-4-ANEQ(F)PTEA)。荧光由 LED 激发,并用一台或两台 256x256 像素相机成像。运动伪影通过基于标记的运动跟踪方法和激发比率法进行校正,从而消除共模伪影。跟踪标记物位移还能测量胃变形。我们对照其他非光学技术对电激活和 Vm 形态的检测进行了验证。在我们的数据中,前胃和后胃之间普遍存在非后向慢波和传播方向差异。然而,假实验表明它们是动物制备的一个特征,而不是光学绘图的伪影。在证明该方法能力的实验中,我们发现再极化并不总是在激活 "波前 "后的固定时间进行,这可能是导致心律失常的一个因素。收缩强度和电激活与收缩之间的潜伏期在逆行传播和非逆行传播之间存在差异。总之,光学机电绘图可同时对电活动和机械活动进行成像,从而探索有关正常和异常胃生理的新问题。
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引用次数: 0
Mechanical stress-induced connective tissue growth factor plays a critical role in intestinal fibrosis in Crohn's-like colitis. 机械应力诱导的结缔组织生长因子在克罗恩病样结肠炎的肠纤维化中起关键作用
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2024-07-02 DOI: 10.1152/ajpgi.00123.2024
You-Min Lin, Ke Zhang, Ramasatyaveni Geesala, Kenneth E Lipson, Suimin Qiu, Don W Powell, Steven Cohn, Xuan-Zheng Shi

Crohn's disease (CD) is an inflammatory bowel disease characterized by transmural inflammation and intestinal fibrosis. Mechanisms of fibrosis in CD are not well understood. Transmural inflammation is associated with inflammatory cell infiltration, stenosis, and distention, which present mechanical stress (MS) to the bowel wall. We hypothesize that MS induces gene expression of profibrotic mediators such as connective tissue growth factor (CTGF), which may contribute to fibrosis in CD. A rodent model of CD was induced by intracolonic instillation of TNBS to the distal colon. TNBS instillation induced a localized transmural inflammation (site I), with a distended colon segment (site P) proximal to site I. We detected significant fibrosis and collagen content not only in site I but also in site P in CD rats by day 7. CTGF expression increased significantly in sites P and I, but not in the segment distal to the inflammation site. Increased CTGF expression was detected mainly in the smooth muscle cells (SMCs). When rats were fed exclusively with clear liquid diet to prevent mechanical distention in colitis, expression of CTGF in sites P and I was blocked. Direct stretch led to robust expression of CTGF in colonic SMC. Treatment of CD rats with anti-CTGF antibody FG-3149 reduced fibrosis and collagen content in both sites P and I and exhibited consistent trends toward normalizing expression of collagen mRNAs. In conclusion, our studies suggest that mechanical stress, by upregulating profibrotic mediators, i.e., CTGF, may play a critical role in fibrosis in CD.NEW & NOTEWORTHY We found that CTGF expression increased significantly not only in the inflammation site but in the distended segment proximal to inflammation in a rodent model of CD-like colitis. Release of mechanical distention prevented CTGF expression in CD rats, whereas direct stretch induced CTGF expression. Treatment with anti-CTGF antibody reduced fibrosis and collagen contents in CD rats. Thus, mechanical stress, via upregulating profibrotic mediators, i.e., CTGF, may play a critical role in fibrosis in CD.

克罗恩病(CD)是一种以跨膜炎症和肠纤维化为特征的炎症性肠病。克罗恩病纤维化的机制尚不十分清楚。跨壁炎症与炎症细胞浸润、狭窄和膨胀有关,这些因素对肠壁产生了机械应力(MS)。我们假设 MS 会诱导促纤维化介质(如结缔组织生长因子 (CTGF))的基因表达,这可能会导致 CD 的纤维化。我们通过向远端结肠灌注 TNBS 来诱导啮齿动物 CD 模型。TNBS 的灌注诱发了局部的跨膜炎症(部位 I),在部位 I 的近端有一个膨胀的结肠段(部位 P)。P部位和I部位的CTGF表达量明显增加,但炎症部位远端区段的CTGF表达量却没有增加。CTGF 表达的增加主要是在平滑肌细胞(SMC)中检测到的。当大鼠只吃清流食以防止结肠炎时的机械膨胀时,P 和 I 区段 CTGF 的表达受阻。直接拉伸导致 CTGF 在结肠 SMC 中大量表达。用抗 CTGF 抗体 FG-3149 治疗 CD 大鼠可减少 P 和 I 位点的纤维化和胶原含量,并显示出胶原 mRNA 表达正常化的一致趋势。总之,我们的研究表明,机械应力通过上调促纤维化介质(即 CTGF),可能在 CD 的纤维化过程中起到关键作用。
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引用次数: 0
IL-22 regulates MASTL expression in intestinal epithelial cells. IL-22 可调节肠上皮细胞中 MASTL 的表达。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2024-05-21 DOI: 10.1152/ajpgi.00260.2023
Kristina Pravoverov, Iram Fatima, Susmita Barman, Frank Jühling, Mark Primeaux, Thomas F Baumert, Amar B Singh, Punita Dhawan

Microtubule-associated serine-threonine kinase-like (MASTL) has recently been identified as an oncogenic kinase given its overexpression in numerous cancers. Our group has shown that MASTL expression is upregulated in mouse models of sporadic colorectal cancer and colitis-associated cancer (CAC). CAC is one of the most severe complications of chronic inflammatory bowel disease (IBD), but a limited understanding of the mechanisms governing the switch from normal healing to neoplasia in IBD underscores the need for increased research in this area. However, MASTL levels in patients with IBD and its molecular regulation in IBD and CAC have not been studied. This study reveals that MASTL is upregulated by the cytokine interleukin (IL)-22, which promotes proliferation and has important functions in colitis recovery; however, IL-22 can also promote tumorigenesis when chronically elevated. Upon reviewing the publicly available data, we found significantly elevated MASTL and IL-22 levels in the biopsies from patients with late-stage ulcerative colitis compared with controls, and that MASTL upregulation was associated with high IL-22 expression. Our subsequent in vitro studies found that IL-22 increases MASTL expression in intestinal epithelial cell lines, which facilitates IL-22-mediated cell proliferation and downstream survival signaling. Inhibition of AKT activation abrogated IL-22-induced MASTL upregulation. We further found an increased association of carbonic anhydrase IX (CAIX) with MASTL in IL-22-treated cells, which stabilized MASTL expression. Inhibition of CAIX prevented IL-22-induced MASTL expression and cell survival. Overall, we show that IL-22/AKT signaling increases MASTL expression to promote cell survival and proliferation. Furthermore, CAIX associates with and stabilizes MASTL in response to IL-22 stimulation.NEW & NOTEWORTHY MASTL is upregulated in colorectal cancer; however, its role in colitis and colitis-associated cancer is poorly understood. This study is the first to draw a link between MASTL and IL-22, a proinflammatory/intestinal epithelial recovery-promoting cytokine that is also implicated in colon tumorigenesis. We propose that IL-22 increases MASTL protein stability by promoting its association with CAIX potentially via AKT signaling to promote cell survival and proliferation.

微管相关丝氨酸-苏氨酸激酶样(MASTL)最近被确定为一种致癌激酶,因为它在许多癌症中过度表达。我们的研究小组发现,在散发性 CRC 和结肠炎相关癌症(CAC)的小鼠模型中,MASTL 的表达上调。CAC 是慢性 IBD 最严重的并发症之一,但人们对 IBD 从正常愈合到肿瘤发生的机制了解有限,这凸显了加强该领域研究的必要性。然而,MASTL在IBD患者中的表达及其在IBD和CAC中的分子调控尚未得到研究。本研究揭示了 MASTL 受细胞因子白细胞介素(IL)-22 的上调,而白细胞介素(IL)-22 可促进增殖并在结肠炎恢复过程中发挥重要作用;然而,IL-22 长期升高也可促进肿瘤发生。在查阅公开资料后,我们发现与对照组相比,晚期溃疡性结肠炎患者活检组织中的 MASTL 和 IL-22 水平明显升高,而且 MASTL 的上调与 IL-22 的高表达有关。我们随后的体外研究发现,IL-22 会增加肠上皮细胞系中 MASTL 的表达,促进 IL-22 介导的细胞增殖和下游生存信号转导。抑制 AKT 的活化可减轻 IL-22 诱导的 MASTL 上调。我们进一步发现,在IL-22处理的细胞中,碳酸酐酶IX(CAIX)与MASTL的结合增加,从而稳定了MASTL的表达。抑制 CAIX 可阻止 IL-22 诱导的 MASTL 表达和细胞存活。总之,我们的研究表明,IL-22/AKT 信号传导会增加 MASTL 的表达,从而促进细胞存活和增殖。此外,CAIX在IL-22刺激下与MASTL结合,从而稳定MASTL。
{"title":"IL-22 regulates MASTL expression in intestinal epithelial cells.","authors":"Kristina Pravoverov, Iram Fatima, Susmita Barman, Frank Jühling, Mark Primeaux, Thomas F Baumert, Amar B Singh, Punita Dhawan","doi":"10.1152/ajpgi.00260.2023","DOIUrl":"10.1152/ajpgi.00260.2023","url":null,"abstract":"<p><p>Microtubule-associated serine-threonine kinase-like (MASTL) has recently been identified as an oncogenic kinase given its overexpression in numerous cancers. Our group has shown that MASTL expression is upregulated in mouse models of sporadic colorectal cancer and colitis-associated cancer (CAC). CAC is one of the most severe complications of chronic inflammatory bowel disease (IBD), but a limited understanding of the mechanisms governing the switch from normal healing to neoplasia in IBD underscores the need for increased research in this area. However, MASTL levels in patients with IBD and its molecular regulation in IBD and CAC have not been studied. This study reveals that MASTL is upregulated by the cytokine interleukin (IL)-22, which promotes proliferation and has important functions in colitis recovery; however, IL-22 can also promote tumorigenesis when chronically elevated. Upon reviewing the publicly available data, we found significantly elevated MASTL and IL-22 levels in the biopsies from patients with late-stage ulcerative colitis compared with controls, and that MASTL upregulation was associated with high IL-22 expression. Our subsequent in vitro studies found that IL-22 increases MASTL expression in intestinal epithelial cell lines, which facilitates IL-22-mediated cell proliferation and downstream survival signaling. Inhibition of AKT activation abrogated IL-22-induced MASTL upregulation. We further found an increased association of carbonic anhydrase IX (CAIX) with MASTL in IL-22-treated cells, which stabilized MASTL expression. Inhibition of CAIX prevented IL-22-induced MASTL expression and cell survival. Overall, we show that IL-22/AKT signaling increases MASTL expression to promote cell survival and proliferation. Furthermore, CAIX associates with and stabilizes MASTL in response to IL-22 stimulation.<b>NEW & NOTEWORTHY</b> MASTL is upregulated in colorectal cancer; however, its role in colitis and colitis-associated cancer is poorly understood. This study is the first to draw a link between MASTL and IL-22, a proinflammatory/intestinal epithelial recovery-promoting cytokine that is also implicated in colon tumorigenesis. We propose that IL-22 increases MASTL protein stability by promoting its association with CAIX potentially via AKT signaling to promote cell survival and proliferation.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights. 裸鼹鼠的肠道屏障功能:洞察胃肠道的新兴模型。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2024-06-25 DOI: 10.1152/ajpgi.00080.2024
Javier Aguilera-Lizarraga, Anne Ritoux, David C Bulmer, Ewan St John Smith

The intestinal barrier plays a crucial role in homeostasis by both facilitating the absorption of nutrients and fluids and providing a tight shield to prevent the invasion by either pathogen or commensal microorganisms. Intestinal barrier malfunction is associated with systemic inflammation, oxidative stress, and decreased insulin sensitivity, which may lead to the dysregulation of other tissues. Therefore, a deeper understanding of physiological aspects related to an enhanced barrier function is of significant scientific and clinical relevance. The naked mole-rat has many unusual biological features, including attenuated colonic neuron sensitivity to acid and bradykinin and resistance to chemical-induced intestinal damage. However, insight into their intestinal barrier physiology is scarce. Here, we observed notable macroscopic and microscopic differences in intestinal tissue structure between naked mole-rats and mice. Moreover, naked mole-rats showed increased number of larger goblet cells and elevated mucus content. In measuring gut permeability, naked mole-rats showed reduced permeability compared with mice, measured as transepithelial electrical resistance, especially in ileum. Furthermore, intestinal ion secretion induced by serotonin, bradykinin, histamine, and capsaicin was significantly reduced in naked mole-rats compared with mice, despite the expression of receptors for all these agonists. In addition, naked mole-rats exhibited reduced prosecretory responses to the nonselective adenylate cyclase activator forskolin. Collectively, these findings indicate that naked mole-rats possess a robust and hard-to-penetrate gastrointestinal barrier that is resistant to environmental and endogenous irritants. Naked mole-rats may therefore provide valuable insights into the physiology of the intestinal barrier and set the stage for the development of innovative and effective therapies.NEW & NOTEWORTHY This is the first study to characterize the intestinal function of naked mole-rats. We found that these animals show a robust gut tissue structure, displaying thicker intestinal layers, longer villi, and larger crypts. Naked mole-rats showed more and larger goblet cells, with increased mucus content. Intestinal permeability, especially in the ileum, was substantially lower than that of mice. Finally, naked mole-rats showed reduced intestinal anion secretion in response to serotonin, bradykinin, histamine, capsaicin, and forskolin.

肠道屏障在体内平衡中起着至关重要的作用,它既能促进营养和液体的吸收,又能提供一个严密的屏障,防止病原体或共生微生物的入侵。肠道屏障功能失调与全身炎症、氧化应激和胰岛素敏感性降低有关,可能导致其他组织的调节失调。因此,深入了解与屏障功能增强有关的生理方面具有重要的科学和临床意义。裸鼹鼠具有许多不同寻常的生物学特征,包括结肠神经元对酸和缓激肽的敏感性减弱,以及对化学物质引起的肠道损伤具有抵抗力。然而,对其肠道屏障生理学的了解却很少。在这里,我们观察到裸鼹鼠和小鼠肠道组织结构在宏观和微观上的显著差异。此外,裸鼹鼠表现出更大的鹅口疮细胞数量增加和粘液含量升高。在测量肠道通透性时,裸鼹鼠的通透性(以经皮电阻测量)比小鼠低,尤其是在回肠。此外,与小鼠相比,裸鼹鼠在血清素、缓激肽、组胺和辣椒素诱导下的肠离子分泌显著减少,尽管裸鼹鼠表达了所有这些激动剂的受体。此外,裸鼹鼠对非选择性腺苷酸环化酶激活剂福斯可林的促分泌反应也有所降低。总之,这些研究结果表明,裸鼹鼠拥有坚固且难以穿透的胃肠道屏障,能够抵御环境和内源性刺激物。因此,裸鼹鼠可以为了解肠道屏障的生理学提供宝贵的信息,并为开发创新和有效的疗法创造条件。
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引用次数: 0
Alterations in gastrointestinal motility assessed by high-resolution antroduodenal manometry in patients with severe disorders of gut-brain interaction. 通过高分辨率十二指肠测压法评估严重肠脑交互障碍患者胃肠道运动的变化。
IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-08-01 Epub Date: 2024-06-11 DOI: 10.1152/ajpgi.00039.2024
Heithem Soliman, Fabien Wuestenberghs, Charlotte Desprez, Anne-Marie Leroi, Chloé Melchior, Guillaume Gourcerol

Data are limited regarding gastrointestinal motility disturbance in disorders of gut-brain interaction (DGBI). This study aimed to characterize antroduodenal motor alterations in patients with high-resolution antroduodenal manometry (HR-ADM). HR-ADM was performed in patients with severe DGBI and compared with healthy volunteers (HV). HR-ADM used a commercially available probe composed of 36 electronic sensors spaced 1 cm apart and positioned across the pylorus. Antral and duodenal motor high-resolution profiles were analyzed, based on the frequency, amplitude, and contractile integral/sensor (CI/s) calculated for each phase of the migrating motor complex (MMC). Eighteen HV and 64 patients were investigated, 10 with irritable bowel syndrome (IBS), 24 with functional dyspepsia (FD), 15 with overlap IBS-FD, and 15 with other DGBI. Compared with HV, patients had a lower frequency of phase II duodenal contractions (27 vs. 51 per hour; P = 0.002) and a lower duodenal phase II contraction amplitude (70 vs. 100 mmHg; P = 0.01), resulting in a lower CI/s of phase II (833 vs. 1,901 mmHg·cm·s; P < 0.001) in the duodenum. In addition, the frequency of phase II propagated antroduodenal contractions was lower (5 vs. 11 per hour; P < 0.001) in patients compared with HV. Interestingly, the antral CI/s of phase III was decreased in FD patients but not in IBS patients. Patients with severe DGBI display alterations in antral and intestinal motility assessed by commercially available HR-ADM. Whether these alterations may explain symptom profiles in such patients remains to be confirmed (NCT04918329 and NCT01519180).NEW & NOTEWORTHY Gastrointestinal dysmotility has been assessed poorly in disorders of gut-brain interaction (DGBI), especially with high-resolution antroduodenal manometry. Plots of DGBI patients showed lower duodenal contractions during phase II regarding amplitude, frequency, and contractile integral/sensor (CI/s) compared with healthy volunteers. A lower frequency of propagated antroduodenal contractions was also reported. Finally, antral CI/s was lower in patients with functional dyspepsia during phase III. Further studies are needed to assess the clinical significance of these alterations.

导言:有关肠脑交互作用紊乱(DGBI)患者胃肠道运动障碍的数据十分有限。本研究旨在利用高分辨率十二指肠测压法(HR-ADM)描述患者的十二指肠运动变化。方法:对严重 DGBI 患者进行 HR-ADM,并与健康志愿者(HV)进行比较。HR-ADM 使用的是市场上销售的由 36 个电子传感器组成的探头,这些传感器间距 1 厘米,横跨幽门。根据移行运动复合体(MMC)每个阶段计算出的频率、振幅和收缩积分/传感器(CI/s)对前胃和十二指肠运动高分辨率剖面进行分析:研究了 18 位 HV 和 64 位患者,其中 10 位患有肠易激综合征 (IBS),24 位患有功能性消化不良 (FD),15 位患有 IBS-FD 重叠,15 位患有其他 DGBI。与 HV 相比,患者的十二指肠二期收缩频率较低(每小时 27 次 vs 51 次;P=0.002),十二指肠二期收缩幅度较低(70 mmHg vs 100;P=0.01),导致二期收缩的 CI/s 较低(833 mmHg.cm.s vs 1901;P=0.01):使用市售的 HR-ADM 评估,严重 DGBI 患者的前胃和肠道运动发生了改变。这些改变是否能解释此类患者的症状特征还有待证实。(NCT04918329和NCT01519180)。
{"title":"Alterations in gastrointestinal motility assessed by high-resolution antroduodenal manometry in patients with severe disorders of gut-brain interaction.","authors":"Heithem Soliman, Fabien Wuestenberghs, Charlotte Desprez, Anne-Marie Leroi, Chloé Melchior, Guillaume Gourcerol","doi":"10.1152/ajpgi.00039.2024","DOIUrl":"10.1152/ajpgi.00039.2024","url":null,"abstract":"<p><p>Data are limited regarding gastrointestinal motility disturbance in disorders of gut-brain interaction (DGBI). This study aimed to characterize antroduodenal motor alterations in patients with high-resolution antroduodenal manometry (HR-ADM). HR-ADM was performed in patients with severe DGBI and compared with healthy volunteers (HV). HR-ADM used a commercially available probe composed of 36 electronic sensors spaced 1 cm apart and positioned across the pylorus. Antral and duodenal motor high-resolution profiles were analyzed, based on the frequency, amplitude, and contractile integral/sensor (CI/s) calculated for each phase of the migrating motor complex (MMC). Eighteen HV and 64 patients were investigated, 10 with irritable bowel syndrome (IBS), 24 with functional dyspepsia (FD), 15 with overlap IBS-FD, and 15 with other DGBI. Compared with HV, patients had a lower frequency of phase II duodenal contractions (27 vs. 51 per hour; <i>P</i> = 0.002) and a lower duodenal phase II contraction amplitude (70 vs. 100 mmHg; <i>P</i> = 0.01), resulting in a lower CI/s of phase II (833 vs. 1,901 mmHg·cm·s; <i>P</i> < 0.001) in the duodenum. In addition, the frequency of phase II propagated antroduodenal contractions was lower (5 vs. 11 per hour; <i>P</i> < 0.001) in patients compared with HV. Interestingly, the antral CI/s of phase III was decreased in FD patients but not in IBS patients. Patients with severe DGBI display alterations in antral and intestinal motility assessed by commercially available HR-ADM. Whether these alterations may explain symptom profiles in such patients remains to be confirmed (NCT04918329 and NCT01519180).<b>NEW & NOTEWORTHY</b> Gastrointestinal dysmotility has been assessed poorly in disorders of gut-brain interaction (DGBI), especially with high-resolution antroduodenal manometry. Plots of DGBI patients showed lower duodenal contractions during phase II regarding amplitude, frequency, and contractile integral/sensor (CI/s) compared with healthy volunteers. A lower frequency of propagated antroduodenal contractions was also reported. Finally, antral CI/s was lower in patients with functional dyspepsia during phase III. Further studies are needed to assess the clinical significance of these alterations.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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American journal of physiology. Gastrointestinal and liver physiology
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