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FGF4 alleviates renal injury caused by ischemia-reperfusion(I/R) by inhibiting ferroptosis and pyroptosis FGF4通过抑制铁下垂和焦下垂减轻肾缺血再灌注（I/R）损伤

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-08-19 DOI: 10.1016/j.peptides.2025.171438

Tong Ding , Pengjie Zhang , Kunying Wang , Peng Du , Bin Duan

Renal ischemia-reperfusion injury can lead to severe renal function impairment, manifested by a significant increase in serum creatinine, renal tubular obstruction, and even necrosis, which can lead to acute renal failure. This injury can also trigger systemic inflammatory response syndrome and even lead to multiple organ dysfunction. It poses a serious threat to the life and health of patients, so it is urgent to find potential drugs for treatment. In our current work, we evaluated the effects of FGFs on kidney injury caused by ischemia-reperfusion. We first established a model of kidney cell injury caused by ischemia-reperfusion. The biological functions of FGFs were further evaluated through a series of biochemical techniques. The experimental data showed that, FGFs can effectively improve the damage of kidney cells caused by ischemia-reperfusion. FGFs can alleviate iron death and pyroptosis of kidney cells caused by ischemia-reperfusion. Further work showed that FGF4 also alleviated inflammation and oxidative stress damage caused by ischemia-reperfusion. Mechanism research also showed that FGFs effectively alleviated ischemia-reperfusion-induced kidney injury by activating AMPK-mediated signaling pathways. Furthermore, in vivo, we also found that FGF4 can effectively alleviate the kidney ischemia-reperfusion injury. This finding not only indicates the potential therapeutic prospects of FGF4 for ischemic diseases, but also provides a new pharmacological target for the treatment of renal ischemia-reperfusion injury.

肾缺血再灌注损伤可导致严重的肾功能损害，表现为血清肌酐显著升高，肾小管梗阻，甚至坏死，可导致急性肾功能衰竭。这种损伤还可引发全身炎症反应综合征，甚至导致多器官功能障碍。它对患者的生命和健康构成严重威胁，因此迫切需要寻找潜在的药物进行治疗。在我们目前的工作中，我们评估了FGFs对缺血再灌注引起的肾损伤的影响。我们首先建立了肾细胞缺血再灌注损伤模型。通过一系列生化技术进一步评价了FGFs的生物学功能。实验数据表明，FGFs能有效改善肾细胞缺血再灌注损伤。FGFs可减轻肾细胞缺血再灌注引起的铁死亡和焦亡。进一步的研究表明，FGF4还能减轻缺血再灌注引起的炎症和氧化应激损伤。机制研究也表明，FGFs通过激活ampk介导的信号通路，有效减轻缺血再灌注诱导的肾损伤。此外，在体内，我们还发现FGF4可以有效减轻肾脏缺血再灌注损伤。这一发现不仅显示了FGF4治疗缺血性疾病的潜在前景，也为肾缺血再灌注损伤的治疗提供了新的药理靶点。

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引用次数: 0

Correlation Between decreased mixed venous oxygen saturation and increased B-type natriuretic peptides independent of hemodynamics in pre-heart failure/heart failure patients 心衰前期/心衰患者混合静脉氧饱和度降低与独立于血流动力学的b型利钠肽增加的相关性

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-22 DOI: 10.1016/j.peptides.2025.171433

Yusuke Kashiwagi , Tomohisa Nagoshi , Ryuji Funaki , Yuto Mashitani , Satoshi Ito , Kazuo Ogawa , Makoto Kawai , Michifumi Tokuda , Michihiro Yoshimura

Previous studies have shown that natriuretic peptides (NPs) respond to hypoxia. Mixed venous oxygen saturation (SvO₂) reflects the oxygen balance and may indicate pulmonary hypoxia. In this study, we investigated whether NPs are influenced by SvO₂ and whether this effect differs between A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in heart failure patients, using structural equation modeling (SEM). We examined 179 patients with pre-heart failure/heart failure who underwent Swan-Ganz catheterization, and investigated the relationship between NP levels and various clinical parameters, including SvO₂. The path model showed that pulmonary artery wedge pressure (PAWP) and administration of angiotensin receptor-neprilysin inhibitor (ARNI) were significantly positively associated with ANP (PAWP: standardized regression coefficient [St. β] =0.281, P = 0.002; ARNI administration: St. β=0.396, P < 0.001). PAWP and ischemic heart disease (IHD) were positively associated with BNP, whereas the estimated glomerular filtration rate (eGFR) and SvO₂ were negatively associated with BNP (PAWP: St. β =0.370, P < 0.001; IHD: St. β =0.241, P < 0.001; eGFR: St. β =-0.209, P = 0.003; SvO₂: St. β =-0.528, P < 0.001). ANP was not associated with arterial oxygen saturation (SaO₂) or SvO₂, whereas BNP showed a negative relationship with SvO₂ but was not associated with SaO₂. Thus, an increased BNP, but not ANP, correlates strongly with decreased SvO₂, an indicator of hypoxia before pulmonary circulation, independent of hemodynamic indices.

先前的研究表明，利钠肽（NPs）对缺氧有反应。混合静脉氧饱和度（SvO₂）反映氧平衡，可能提示肺缺氧。在本研究中，我们利用结构方程模型（SEM）研究了心力衰竭患者的NPs是否受到SvO₂的影响，以及这种影响在a型利钠肽（ANP）和b型利钠肽（BNP）之间是否存在差异。我们检查了179例接受Swan-Ganz导管置入的心衰前期/心衰患者，并研究了NP水平与包括SvO₂在内的各种临床参数的关系。路径模型显示肺动脉楔压（PAWP）和血管紧张素受体-neprilysin抑制剂（ARNI）给药与ANP呈显著正相关(PAWP：标准化回归系数[St. β] =0.281， P=0.002；ARNI给药：St. β=0.396， P

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引用次数: 0

Ghrelin/GHSR-1a promotes angiogenesis after myocardial infarction through the glycolytic process Ghrelin/GHSR-1a通过糖酵解过程促进心肌梗死后血管生成

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-22 DOI: 10.1016/j.peptides.2025.171434

Ming-Jie Yuan , Peng Zhong , Zhi-Xuan Shu , Li-Hua Zheng , Tao Liu , Song Dang

Background

Therapeutic angiogenesis has demonstrated efficacy in revascularizing ischemic heart tissue and reducing the progression of cardiac remodeling following myocardial infarction. Recent studies have highlighted the significance of the glycolytic process in maintaining endothelial cell function and cardiac homeostasis. However, the specific role of glycolysis in angiogenesis post-myocardial infarction remains poorly understood. This study aims to explore whether ghrelin/GHSR-1a promotes angiogenesis after myocardial infarction through glycolysis.

Methods and results

Myocardial infarction was induced in mice, and our experiments showed that GHSR-1a overexpression led to a significant increase in the density of α-SMA-positive vessels in the peri-infarct zones, compared to the MI group, at day 7 post-infarction. Furthermore, elevated FGF-21 levels were observed in the border zone of the infarcted area seven days post-acute myocardial infarction. We also identified a modified GHSR-1a/FGF-21 axis in cardiac endothelial cells, where GHSR-1a knockdown reduced the expression of both FGF-21 and AMPK. In vitro, ghrelin enhanced glycolytic activity by increasing the expression of glycolytic enzymes. Moreover, ghrelin significantly stimulated endothelial tube formation and enhanced cell viability; however, these effects were attenuated following FGF-21 knockdown.

Conclusion

Our findings demonstrate that ghrelin/GHSR-1a improves neovascularization and enhances glycolysis in cardiac endothelial cells by modulating FGF-21. These results lay the groundwork for further experimental and clinical investigations to explore pharmaceutical approaches for treating ischemic heart disease.

研究背景：治疗性血管生成在缺血心脏组织血运重建和减少心肌梗死后心脏重构进展方面已被证明有效。最近的研究强调了糖酵解过程在维持内皮细胞功能和心脏稳态中的重要性。然而，糖酵解在心肌梗死后血管生成中的具体作用仍然知之甚少。本研究旨在探讨ghrelin/GHSR-1a是否通过糖酵解促进心肌梗死后血管生成。方法和结果小鼠心肌梗死后第7天，与心肌梗死组相比，GHSR-1a过表达导致梗死周围α- sma阳性血管密度显著增加。此外，急性心肌梗死后7天，在梗死区边界区观察到FGF-21水平升高。我们还在心脏内皮细胞中发现了一个修饰的GHSR-1a/FGF-21轴，其中GHSR-1a敲低降低了FGF-21和AMPK的表达。在体外，胃饥饿素通过增加糖酵解酶的表达来增强糖酵解活性。此外，胃饥饿素显著刺激内皮管形成，提高细胞活力；然而，FGF-21敲除后，这些作用减弱。结论ghrelin/GHSR-1a通过调节FGF-21促进心脏内皮细胞新生血管和糖酵解。这些结果为进一步的实验和临床研究探索治疗缺血性心脏病的药物途径奠定了基础。

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引用次数: 0

Liraglutide suppresses ferroptosis by upregulation NRF2 in type 2 diabetic cardiomyopathy 利拉鲁肽通过上调2型糖尿病心肌病患者的NRF2抑制铁下垂

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-16 DOI: 10.1016/j.peptides.2025.171429

Xuepin Chen , Tianying Wang , Yan Gao , Guo an Wang , Jun Guan , Hongyan Dai

Recent research indicates that inhibiting myocardial ferroptosis may help alleviate diabetic cardiomyopathy (DCM). Liraglutide (LIRA), a glucagon-like peptide-1 receptor agonist, has been shown to offer cardiovascular protective effects. Nevertheless, the specific role of LIRA and its relationship with myocardial ferroptosis in type 2 DCM is still not well understood. An in vivo model of type 2 diabetes mellitus (T2DM) was created using spontaneous diabetes Goto-Kakizaki (GK) rats. These rats received LIRA at a dose of 200 μg/kg/day through daily subcutaneous injections for 8 weeks. In vitro experiments involved treating H9C2 cells with different concentrations of glucose, LIRA, siRNA-Nrf2, Fer-1, or their combinations. The results demonstrated that LIRA enhanced glucose metabolism, improved cardiac remodeling and function, reduced lipid peroxidation, and mitigated myocardial ferroptosis in diabetic rats. Additionally, LIRA was found to increase the levels of proteins associated with ferroptosis, such as Cyto-NRF2, Nu-NRF2, PTGS2, FTH-1, and GPX4 in DCM. In vitro, high glucose levels intensified the production of lipid reactive oxygen species (ROS) and lipid peroxidation, diminished mitochondrial mass, and lowered the levels of ferroptosis-related proteins, ultimately triggering ferroptosis. Notably, these detrimental effects were mitigated by LIRA treatment. Overall, these results indicate that LIRA may serve as a valuable therapeutic option for addressing myocardial ferroptosis by promoting NRF2 expression in type 2 DCM.

最近的研究表明，抑制心肌铁下垂可能有助于减轻糖尿病性心肌病（DCM）。利拉鲁肽（Liraglutide， LIRA）是一种胰高血糖素样肽-1受体激动剂，已被证明具有心血管保护作用。然而，LIRA在2型DCM中的具体作用及其与心肌铁下垂的关系尚不清楚。以自发性糖尿病大鼠Goto-Kakizaki （GK）建立2型糖尿病（T2DM）体内模型。这些大鼠每天皮下注射200 μg/kg/天的LIRA，持续8周。体外实验包括用不同浓度的葡萄糖、LIRA、siRNA-Nrf2、Fer-1或它们的组合处理H9C2细胞。结果表明，LIRA可增强糖尿病大鼠的糖代谢，改善心脏重塑和功能，减少脂质过氧化，减轻心肌下垂。此外，研究发现LIRA可增加DCM中与铁下垂相关的蛋白水平，如Cyto-NRF2、Nu-NRF2、PTGS2、FTH-1和GPX4。在体外实验中，高葡萄糖水平增强了脂质活性氧（ROS）的产生和脂质过氧化，减少了线粒体质量，降低了铁中毒相关蛋白的水平，最终引发铁中毒。值得注意的是，LIRA治疗减轻了这些有害影响。总之，这些结果表明，LIRA可能通过促进NRF2在2型DCM中的表达，作为解决心肌铁下垂的有价值的治疗选择。

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引用次数: 0

Protective effects of PACAP against high glucose-induced inflammation on air-liquid interface corneal epithelium barrier PACAP对高糖诱导炎症对角膜气液界面上皮屏障的保护作用

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-16 DOI: 10.1016/j.peptides.2025.171432

Grazia Maugeri , Agata Grazia D’Amico , Nicoletta Palmeri , Elisabetta Pricoco , Desiree Brancato , Concetta Federico , Velia D’Agata

Diabetes mellitus (DM) is a chronic metabolic disease considered the “epidemic” of the new millennium, with devastating impacts on quality of life and global prevalence. One of the most common ocular complications is diabetic keratopathy (DK), often overlooked compared to other diabetes-related diseases. This disease causes significant corneal damage and is characterized by an overactive inflammatory condition, alteration of the corneal epithelial barrier, and delayed wound healing. Current therapies do not always ensure effective restoration of corneal function. In our previous study, we found that changes in the endogenous pituitary adenylate cyclase-activating polypeptide (PACAP) expression can concur for delayed epithelial wound healing in diabetic cornea. Moreover, the peptide showed cytoprotective effects on the corneal epithelium, promoting cell viability and wound healing under high glucose conditions, suggesting its potential effect in this diabetes-related disease. Therefore, this study aims to investigate the effect of PACAP against hyperglycemia-induced inflammation. To better resemble the natural conditions of corneal epithelium in vivo, an air-liquid interface (ALI) culture of the corneal epithelial cells was performed. The ALI corneal epithelium was cultured under high-glucose conditions to generate a model of DK. Our model reproduced well-established molecular and cellular characteristics of this pathology, including barrier thickness decrease and inflammation, with increased expression of IL-1β, TNF-α, and p-NF-kB. Our results indicated that PACAP significantly reduced the levels of proinflammatory cytokines IL-1β and TNF-α and inhibited the activation of NF-kB, an important mediator of inflammation. Moreover, PACAP improved epithelial morphology and corneal barrier thickness, suggesting its therapeutic potential in the treatment of DK.

糖尿病（DM）是一种慢性代谢性疾病，被认为是新千年的“流行病”，对生活质量和全球患病率具有破坏性影响。糖尿病性角膜病变（DK）是最常见的眼部并发症之一，与其他糖尿病相关疾病相比，它往往被忽视。这种疾病引起严重的角膜损伤，其特征是炎症过度活跃，角膜上皮屏障改变，伤口愈合延迟。目前的治疗方法并不能保证角膜功能的有效恢复。在我们之前的研究中，我们发现内源性垂体腺苷酸环化酶激活多肽（PACAP）表达的变化与糖尿病角膜上皮伤口愈合延迟有关。此外，该肽对角膜上皮具有细胞保护作用，在高糖条件下促进细胞活力和伤口愈合，提示其在糖尿病相关疾病中的潜在作用。因此，本研究旨在探讨PACAP对高血糖性炎症的作用。为了更好地模拟角膜上皮在体内的自然状态，我们对角膜上皮细胞进行了气液界面（ALI）培养。在高糖条件下培养ALI角膜上皮，形成DK模型。我们的模型再现了这种病理的分子和细胞特征，包括屏障厚度减少和炎症，以及IL-1β、TNF-α和p-NF-kB的表达增加。我们的研究结果表明，PACAP显著降低了促炎细胞因子IL-1β和TNF-α的水平，并抑制了NF-kB的激活，NF-kB是炎症的重要介质。此外，PACAP改善上皮形态和角膜屏障厚度，提示其治疗DK的治疗潜力。

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引用次数: 0

Substitution of a proline residue in the frog skin host-defense peptide, figainin-2PL by D-lysine generates an analog with potent activity against antibiotic-resistant ESKAPE pathogens 用d -赖氨酸取代青蛙皮肤宿主防御肽中的脯氨酸残基，可以产生一种对耐抗生素ESKAPE病原体具有有效活性的类似物。

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-12 DOI: 10.1016/j.peptides.2025.171430

Laure Guilhaudis , Taylor S. Cunning , Jack J. Delaney , Nigel G. Ternan , Milena Mechkarska , Samir Attoub , J. Michael Conlon

Figainin-2PL (FLGTVLKLGKAIAKTVVPMLTNAMQPKQ.NH₂) is active against a range of antibiotic-resistant bacteria as well as human tumor-derived cells. The study aimed to determine the effects of a proline-substitution on the biological potency of the peptide. Secondary structure predictions indicate that figainin-2PL can adopt a helix-turn-helix conformation in membrane-mimetic environments. Circular dichroism spectra are consistent with these predictions. Replacement of the Pro¹⁸ residue by either L-Ala, L-Lys or D-Lys increased the extent and stability of the helical domains. All substitutions increased cytotoxic activity against a range of human tumor-derived cells (between 1.5- and 3-fold) but major (between 4- and 10-fold) increases in hemolytic activity against mouse erythrocytes were also observed. While the substitutions Pro¹⁸ → L-Ala and Pro¹⁸ → L-Ala produced only minor and inconsistent changes in antibacterial activity, the [P18k] analog displayed a 2- to 4-fold greater (MIC and MBC in the range 1–8 µM) against the ESKAPE pathogens Enterococcus faecalis, Enterococcus faecium, Klebsiella pneumoniae and Pseudomonas aeruginosa compared with figainin-2PL and the peptide retained high potency against Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus and Clostridium difficile (MIC and MBC = 2 µM). Consequently, the [P18k] peptide shows therapeutic potential for development into a broad-spectrum, topical antimicrobial agent.

Figainin-2PL （FLGTVLKLGKAIAKTVVPMLTNAMQPKQ.NH2）对一系列耐药细菌和人类肿瘤源性细胞具有活性。该研究旨在确定脯氨酸替代对肽的生物效力的影响。二级结构预测表明，在膜模拟环境中，figainin-2PL可以采用螺旋-转-螺旋构象。圆二色光谱与这些预测一致。用L-Ala、L-Lys或D-Lys取代Pro18残基增加了螺旋结构域的范围和稳定性。所有的替代都增加了对一系列人类肿瘤来源细胞的细胞毒活性（在1.5到3倍之间），但对小鼠红细胞的溶血活性也显著增加（在4到10倍之间）。虽然替换Pro18→L-Ala和Pro18→L-Ala对ESKAPE病原菌的抗菌活性仅产生微小且不一致的变化，但与figainin-2PL相比，[P18k]类似物对粪肠球菌、粪肠球菌、肺炎克雷伯菌和铜绿假单胞菌的MIC和MBC在1- 8µM范围内提高了2- 4倍，对鲍曼不动杆菌、大肠杆菌、金黄色葡萄球菌和艰难梭菌（MIC和MBC = 2µM）。因此，[P18k]肽显示出发展成为广谱局部抗菌剂的治疗潜力。

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引用次数: 0

Phoenixin-14 ameliorates acetic acid-induced ulcerative colitis in rats via antioxidant, anti-inflammatory and anti-apoptotic mechanisms 凤凰素-14通过抗氧化、抗炎和抗凋亡机制改善醋酸诱导的大鼠溃疡性结肠炎

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-12 DOI: 10.1016/j.peptides.2025.171431

Hülya Buzcu , Meral Yüksel , Seda Kırmızıkan , Esra Çikler , Berna Karakoyun

Phoenixin (PNX), first discovered in the rat hypothalamus, was initially identified as a reproductive peptide. PNX-14 (14 amino acid isoform) has also been shown to function in cardiovascular regulation, neuroprotection, glucose metabolism, appetite, anxiety, and memory. We aimed to investigate the potential therapeutic role of PNX-14 in acetic acid (AA)-induced ulcerative colitis. Rats were given intrarectally 1 ml saline (control) or 5 % AA (colitis groups). The control group was treated intraperitoneally with saline, while the colitis groups were treated intraperitoneally with saline or PNX-14 (50 μg/kg/d) or gonadotrophin-releasing hormone (GnRH)-antagonist cetrorelix (CTX; 100 µg/kg/d) or CTX and PNX-14 or sulfasalazine as a positive control (100 mg/kg/d) instantly and once a day for 3 days following colitis induction. Colonic samples were evaluated histologically and biochemically [malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), chemiluminescence (CL), pro-inflammatory cytokines (tumor necrosis factor-α, interferon-γ, interleukin (IL)-1β, IL-6, IL-8), caspase-3, and 8-hydroxy-2’-deoxyguanosine (8-OHdG) measurements] on the 3rd day. Elevated damage scores (macroscopic and microscopic), MPO, MDA, caspase-3, cytokines, and CL values, and decreased GSH levels of the colitis group were reversed by PNX-14 treatment (p < 0.05–0.001). CTX or CTX plus PNX-14 reduced damage scores, caspase-3, 8-OHdG, cytokines, and CL values (p < 0.05–0.001). Sulfasalazine treatment improved all parameters except MDA and GSH. PNX-14, which alleviates macroscopic, histological and biochemical parameters, can be considered as a potential therapeutic agent in ulcerative colitis with its anti-inflammatory, antioxidant and anti-apoptotic actions. Furthermore, despite its effects as an GnRH-antagonist, CTX has also revealed a similar beneficial role as PNX-14 in this ulcerative colitis model.

凤凰素（Phoenixin， PNX）最早发现于大鼠下丘脑，是一种生殖肽。PNX-14（14个氨基酸异构体）也被证明在心血管调节、神经保护、葡萄糖代谢、食欲、焦虑和记忆中起作用。我们的目的是研究PNX-14在醋酸（AA）诱导的溃疡性结肠炎中的潜在治疗作用。大鼠直肠内注射1 ml生理盐水（对照组）或5 % AA（结肠炎组）。对照组腹腔注射生理盐水，结肠炎组腹腔注射生理盐水或PNX-14 （50 μg/kg/d）或促性腺激素释放激素（GnRH）拮抗剂cetrorelix (CTX；100 µg/kg/d)或CTX和PNX-14或柳氮磺胺吡啶作为阳性对照（100 mg/kg/d），在结肠炎诱导后立即，每天1次，连续3天。在第3天对结肠样本进行组织学和生化评价[丙二醛（MDA）、谷胱甘肽（GSH）、髓过氧化物酶（MPO）、化学发光（CL）、促炎细胞因子（肿瘤坏死因子-α、干扰素-γ、白细胞介素(IL)-1β、IL-6、IL-8）、半胱天冬酶-3和8-羟基-2′-脱氧鸟苷（8-OHdG）测定]。PNX-14治疗可逆转结肠炎组损伤评分（宏观和微观）、MPO、MDA、caspase-3、细胞因子和CL值升高以及GSH水平降低（p <； 0.05-0.001）。CTX或CTX加PNX-14可降低损伤评分、caspase- 3,8 - ohdg、细胞因子和CL值（p <； 0.05-0.001）。除丙二醛（MDA）和谷胱甘肽（GSH）外，磺胺吡啶处理改善了所有参数。PNX-14具有抗炎、抗氧化、抗凋亡等作用，可作为治疗溃疡性结肠炎的潜在药物。此外，尽管CTX具有gnrh拮抗剂的作用，但在溃疡性结肠炎模型中，CTX也显示出与PNX-14相似的有益作用。

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引用次数: 0

Maximizing cost savings in heart failure management: The economic value of natriuretic peptide testing 心力衰竭管理的成本节约最大化：利钠肽检测的经济价值。

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-11 DOI: 10.1016/j.peptides.2025.171428

Damien Gruson , Gaetano Caforio , Daniel D’Angela

Heart failure (HF) remains a significant global health challenge, requiring cost-effective strategies to optimize patient outcomes and resource allocation. Natriuretic peptide (NP) testing has demonstrated substantial clinical and economic value in HF diagnosis, risk stratification, and management. This article examines the international evidence supporting NP testing, highlighting its role in reducing hospitalizations, optimizing medication use, and lowering healthcare expenditures. Addressing disparities in access and reimbursement policies can further enhance its adoption and impact across healthcare systems.

心力衰竭（HF）仍然是一个重大的全球健康挑战，需要具有成本效益的战略来优化患者的结果和资源分配。利钠肽（NP）检测在心衰诊断、风险分层和管理方面具有重要的临床和经济价值。本文研究了支持NP测试的国际证据，强调了其在减少住院、优化药物使用和降低医疗保健支出方面的作用。解决可及性和报销政策方面的差异，可以进一步加强其在整个医疗保健系统中的采用和影响。

引用次数: 0

Effect of central UAG on metabolic associated fatty liver disease: A possible mechanism involving in GLP-1 neural pathway 中枢UAG对代谢性脂肪性肝病的影响：涉及GLP-1神经通路的可能机制

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-03 DOI: 10.1016/j.peptides.2025.171427

Wenxiu Xu , Zixin Du , Jing Wang , Yating Gong , Jiantong Yu , Xueyuying Wang , Xiangrong Sun , Yanling Gong

Objective

The study aimed to investigate the possible effect of central unacylated ghrelin (UAG) on metabolic associated fatty liver disease (MAFLD) and its underlying mechanism.

Methods

A high fat diet (HFD) was fed to rat to construct MAFLD model. UAG was administered via intra-cerebroventricular injection (ICV) and its effect on MAFLD was observed. Glucagon-like peptide-1 (GLP-1) neural pathway was observed via FluoroGold (FG) retrograde tracking combined with immunofluorescence. To assess the involvement of the GLP-1 pathway, GLP-1 receptor (GLP-1R) inhibitor Exendin (9−39) was injected prior to ICV of UAG.

Results

ICV administration of UAG significantly reduced lipid accumulation in liver and liver injury in MAFLD rats which was partially attenuated by Exendin(9−39). Central UAG upregulated and activated GLP-1 neurons in nucleus tractus solitarii (NTS), and increased GLP-1 projections from NTS to paraventricular hypothalamic nucleus (PVN) and ventral tegmental area (VTA), respectively. Consequently, GLP-1R in PVN and VTA was activated, resulting in decreased food intake and reward behavior, as well as increased hepatic insulin sensitivity via activation of IRS-1/PI3K/Akt signaling pathway. These changes downregulated key lipogenic enzymes, including fatty acid synthase (FAS), acetyl-CoA Carboxylase (ACC) and stearoyl-CoAdesaturase-1 (SCD-1), thereby alleviating MAFLD.

Conclusion

These findings suggest that central UAG might alleviate MAFLD by modulating GLP-1 neuronal pathway from NTS to PVN and VTA. Further studies are needed to identify the specific receptor for UAG and its potential interaction with GLP-1 or GLP-1R, which could provide direct evidence for the role of central UAG in regulating food intake and lipid metabolism in MAFLD.

目的：探讨中枢unacylated ghrelin （UAG）对代谢性脂肪性肝病（MAFLD）的可能作用及其机制。方法：采用高脂饲料（HFD）建立mald模型。通过脑室注射（ICV）给药，观察UAG对MAFLD的影响。采用FluoroGold （FG）逆行跟踪联合免疫荧光法观察胰高血糖素样肽-1 （GLP-1）神经通路。为了评估GLP-1通路的参与，在UAG的ICV之前注射GLP-1受体（GLP-1R）抑制剂Exendin（9-39）。结果：ICV给药UAG可显著降低mfld大鼠肝脏脂质积累和肝损伤，Exendin可部分减弱这种作用（9-39）。中央UAG上调和激活孤束核（NTS）的GLP-1神经元，增加GLP-1从NTS到室旁下丘脑核（PVN）和腹侧被盖区（VTA）的投射。因此，PVN和VTA中的GLP-1R被激活，导致食物摄入和奖励行为减少，并通过激活IRS-1/PI3K/Akt信号通路增加肝脏胰岛素敏感性。这些变化下调了关键的脂肪生成酶，包括脂肪酸合成酶（FAS）、乙酰辅酶a羧化酶（ACC）和硬脂酰辅酶饱和酶-1 (SCD-1)，从而减轻了MAFLD。结论：中枢性UAG可能通过调节GLP-1神经元从NTS到PVN和VTA的通路来缓解mald。UAG的特异性受体及其与GLP-1或GLP-1R的潜在相互作用有待进一步研究，这可能为中枢UAG在MAFLD中调节食物摄入和脂质代谢中的作用提供直接证据。

{"title":"Effect of central UAG on metabolic associated fatty liver disease: A possible mechanism involving in GLP-1 neural pathway","authors":"Wenxiu Xu , Zixin Du , Jing Wang , Yating Gong , Jiantong Yu , Xueyuying Wang , Xiangrong Sun , Yanling Gong","doi":"10.1016/j.peptides.2025.171427","DOIUrl":"10.1016/j.peptides.2025.171427","url":null,"abstract":"<div><h3>Objective</h3><div>The study aimed to investigate the possible effect of central unacylated ghrelin (UAG) on metabolic associated fatty liver disease (MAFLD) and its underlying mechanism.</div></div><div><h3>Methods</h3><div>A high fat diet (HFD) was fed to rat to construct MAFLD model. UAG was administered via intra-cerebroventricular injection (ICV) and its effect on MAFLD was observed. Glucagon-like peptide-1 (GLP-1) neural pathway was observed via FluoroGold (FG) retrograde tracking combined with immunofluorescence. To assess the involvement of the GLP-1 pathway, GLP-1 receptor (GLP-1R) inhibitor Exendin (9−39) was injected prior to ICV of UAG.</div></div><div><h3>Results</h3><div>ICV administration of UAG significantly reduced lipid accumulation in liver and liver injury in MAFLD rats which was partially attenuated by Exendin(9−39). Central UAG upregulated and activated GLP-1 neurons in nucleus tractus solitarii (NTS), and increased GLP-1 projections from NTS to paraventricular hypothalamic nucleus (PVN) and ventral tegmental area (VTA), respectively. Consequently, GLP-1R in PVN and VTA was activated, resulting in decreased food intake and reward behavior, as well as increased hepatic insulin sensitivity via activation of IRS-1/PI3K/Akt signaling pathway. These changes downregulated key lipogenic enzymes, including fatty acid synthase (FAS), acetyl-CoA Carboxylase (ACC) and stearoyl-CoAdesaturase-1 (SCD-1), thereby alleviating MAFLD.</div></div><div><h3>Conclusion</h3><div>These findings suggest that central UAG might alleviate MAFLD by modulating GLP-1 neuronal pathway from NTS to PVN and VTA. Further studies are needed to identify the specific receptor for UAG and its potential interaction with GLP-1 or GLP-1R, which could provide direct evidence for the role of central UAG in regulating food intake and lipid metabolism in MAFLD.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"191 ","pages":"Article 171427"},"PeriodicalIF":2.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Characterization of thyrotropin-releasing hormone (TRH) and its receptors (TRHRs) in Nile tilapia: Molecular identification, ligand-receptor interaction and expression profile 尼罗罗非鱼促甲状腺激素释放激素（TRH）及其受体（TRHRs）的分子鉴定、配体-受体相互作用和表达谱

IF 2.8 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-07-02 DOI: 10.1016/j.peptides.2025.171426

Guixian Bu , Tao Yong , Yuqing Tang , Jingyan Luo , Yu Ji , Li Guo , Shasha Guo , Shuai Yang , Linyan Huang , Xianyin Zeng , Caiyun Sun , Fengyan Meng

Thyrotropin-releasing hormone (TRH) is a highly conserved tripeptide across vertebrates and regulates various biological processes, including energy metabolism, appetite, and reproduction. The functions of TRH are mediated by TRH receptors (TRHRs). In vertebrates, three TRHR subtypes have been identified, namely TRHR1, TRHR2, and TRHR3. However, TRHR2 and TRHR3 are often lost in some vertebrate lineages, highlighting the evolutionary divergence of the TRH-TRHR system. Although extensive research has been conducted in mammals, studies concerning the biological roles of TRH-TRHR system remain limited in fish. Therefore, using Nile tilapia (ti-) as a teleost model, we cloned the full-length cDNA of TRH and its receptors. Based on sequence alignment, synteny analysis and phylogenetic tree construction, we observed that TRHR2 has been lost in Nile tilapia. The cloned tiTRHRs were designated as tiTRHR1a, tiTRHR1b, and tiTRHR3. Using luciferase reporter assays, signal pathway inhibitors and western blot analysis, we demonstrated that tiTRH could effectively activate tiTRHR1a, tiTRHR1b, and tiTRHR3, leading to the stimulation of intracellular calcium mobilization, MAPK/ERK, and cAMP/PKA signaling cascades. However, the efficiencies in activating signaling pathways differed between tiTRHR subtypes upon tiTRH treatment. Quantitative real-time PCR revealed that tiTRH and tiTRHRs were mainly expressed in the central nervous system (CNS) including the hypothalamus. Moreover, hypothalamic mRNA levels of tiTRH and tiTRHR1b were significantly downregulated in response to short-term fasting and acute cold exposure, while tiTRHR1a expression was only responsive to acute cold stress. Collectively, our data will facilitate a better understanding of the components and functions of the TRH-TRHR system in teleost.

促甲状腺素释放激素（TRH）是一种高度保守的三肽，调节多种生物过程，包括能量代谢、食欲和生殖。TRH的功能是由TRH受体介导的。在脊椎动物中，已经鉴定出三种TRHR亚型，即TRHR1、TRHR2和TRHR3。然而，TRHR2和TRHR3在一些脊椎动物谱系中经常丢失，这突出了TRH-TRHR系统的进化分化。尽管在哺乳动物中进行了广泛的研究，但关于TRH-TRHR系统在鱼类中的生物学作用的研究仍然有限。因此，我们以尼罗罗非鱼（ti-）为硬骨鱼模型，克隆了TRH及其受体的全长cDNA。通过序列比对、同源性分析和系统发育树构建，我们发现TRHR2在尼罗罗非鱼中已经丢失。克隆的titrhr被命名为tiTRHR1a、tiTRHR1b和tiTRHR3。通过荧光素酶报告基因检测、信号通路抑制剂和western blot分析，我们证明了tiTRH可以有效激活tiTRHR1a、tiTRHR1b和tiTRHR3，从而刺激细胞内钙动员、MAPK/ERK和cAMP/PKA信号级联。然而，在tiTRHR治疗后，激活信号通路的效率在tiTRHR亚型之间存在差异。实时荧光定量PCR结果显示，tiTRH和tiTRHRs主要在包括下丘脑在内的中枢神经系统（CNS）表达。此外，下丘脑tiTRH和tiTRHR1b的mRNA水平在短期禁食和急性冷暴露下显著下调，而tiTRHR1a的表达仅对急性冷应激有反应。总的来说，我们的数据将有助于更好地理解硬骨鱼TRH-TRHR系统的组成和功能。

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引用次数: 0