Neuropeptides最新文献_第3页

Substance P mitigates lipopolysaccharide induced cognitive impairment in rats in a dose dependent manner P物质以剂量依赖的方式减轻脂多糖诱导的大鼠认知功能障碍

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-08-23 DOI: 10.1016/j.npep.2025.102551

Prasada Chowdari Gurram , Suman Manandhar , Sairaj Satarker , Ajmal Nassar , Farmiza Begum , Jayesh Mudgal , Devinder Arora , Madhavan Nampoothiri

Neuroinflammation contributes to cognitive decline in Alzheimer's disease (AD), and the neurokinin pathway has been implicated in the pathophysiology of AD. Although Substance P (SP), an endogenous ligand to the neurokinin 1 receptor (NK1R), is primarily known as a neurotransmitter, but emerging evidence indicates it has shown both pro and anti-inflammatory actions. However, the dose-dependent nature of the SP–NK1R axis’s functional role remains to be fully elucidated. In this study, we examined the effects of SP in a rat model of AD induced by lipopolysaccharide (LPS).

A dose of 150 μg/10 μl of LPS was administered through intracerebroventricular injection to induce cognitive impairment in the rats. Two doses of SP, 50 μg/kg and 500 μg/kg were administered intraperitoneally once a day for 21 days. Behavioral assessments included the Morris water maze test and novel object recognition test to investigate cognitive defects, and the open field test evaluated locomotion. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), amyloid-beta (Aβ), acetylcholinesterase (AChE), lipid peroxidation, and catalase were estimated in the frontal cortex and hippocampus. The cAMP-responsive element-binding (CREB) protein levels in the whole brain were estimated by western blot. The LPS treatment significantly impaired cognition, increased levels of cytokines, Aβ, oxidative stress, and AChE, while decreasing CREB levels. Notably, the lower dose of SP (50 μg/kg) restored cognitive performance and markers of AD. In contrast, the higher dose of SP (500 μg/kg) failed to reverse spatial memory impairment and neuroinflammation. Thus, our data propose the dose-dependent effect of SP on neuroinflammation-induced cognitive deficits in AD.

神经炎症有助于阿尔茨海默病（AD）的认知能力下降，神经激肽途径与AD的病理生理有关。虽然P物质（SP）是神经激肽1受体（NK1R）的内源性配体，主要被认为是一种神经递质，但越来越多的证据表明它具有促炎和抗炎作用。然而，SP-NK1R轴的功能作用的剂量依赖性仍有待充分阐明。在本研究中，我们研究了SP对脂多糖（LPS）诱导的AD大鼠模型的作用。采用脑室内注射150 μg/10 μl LPS诱导大鼠认知功能障碍。SP 50 μg/kg和500 μg/kg 2剂量腹腔注射，每天1次，连用21 d。行为评估包括Morris水迷宫测试和新物体识别测试以调查认知缺陷，开放场测试评估运动。在额叶皮质和海马中检测肿瘤坏死因子-α (TNF-α)、白细胞介素-6 （IL-6）、淀粉样蛋白- β (Aβ)、乙酰胆碱酯酶（AChE）、脂质过氧化和过氧化氢酶。western blot检测全脑cAMP-responsive element-binding （CREB）蛋白水平。LPS治疗显著损害认知能力，增加细胞因子、Aβ、氧化应激和AChE水平，同时降低CREB水平。值得注意的是，低剂量SP （50 μg/kg）可恢复认知能力和AD标志物。而高剂量SP （500 μg/kg）对大鼠空间记忆损伤和神经炎症反应无明显逆转作用。因此，我们的数据表明SP对阿尔茨海默病中神经炎症引起的认知缺陷有剂量依赖性作用。

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引用次数: 0

Catestatin attenuates cerebral ischemia/reperfusion injury and suppresses endoplasmic reticulum stress Catestatin减轻脑缺血/再灌注损伤和抑制内质网应激

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-08-11 DOI: 10.1016/j.npep.2025.102550

Xiaodong Zhang, Jiaxin Fan, Shuyin Ma, Nan Zhang, Kaili Shi, Mengying Chen, Minyu Duan, Qingling Yao, Yuxuan Cheng, Shuang Du, Huiyang Qu, Han Yang, Tiantian Gao, Shuqin Zhan

Ischemic stroke is one of the leading causes of death worldwide. Catestatin (CST), as a pleiotropic hormone, displays an anti-apoptotic effect, in addition to its known roles in cardiovascular regulation. However, the role of CST in ischemic stroke remains unclear. In this study, we investigated the temporal changes of CST levels in the cortex and serum of middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Intracerebroventricular administration of CST significantly alleviated neurological deficits, reduced cerebral infarct volume, cerebral edema, and pathological damage, while attenuating neuronal apoptosis and modulating apoptosis-related proteins. Notably, CST suppressed endoplasmic reticulum stress (ERS) by inhibiting the PERK pathway. Furthermore, in vitro experiments using the oxygen-glucose deprivation/reperfusion (OGD/R) model of PC12 cells demonstrated that CST similarly inhibited apoptosis, as evidenced by flow cytometry and consistent changes in apoptosis-related proteins. These findings collectively demonstrate that CST exerts neuroprotective effects against cerebral ischemia-reperfusion injury (CIRI), with these effects potentially mediated through inhibition of ERS via the PERK signaling pathway.

缺血性中风是世界范围内死亡的主要原因之一。Catestatin （CST）作为一种多效性激素，除了已知的心血管调节作用外，还具有抗凋亡作用。然而，CST在缺血性卒中中的作用尚不清楚。本研究观察了大脑中动脉闭塞/再灌注（MCAO/R）大鼠皮层和血清中CST水平的变化。脑室内给药CST可显著减轻神经功能缺损，减少脑梗死体积、脑水肿和病理损伤，同时减轻神经元凋亡和调节凋亡相关蛋白。值得注意的是，CST通过抑制PERK途径抑制内质网应激（ERS）。此外，体外氧-葡萄糖剥夺/再灌注（OGD/R）模型实验表明，CST对PC12细胞的凋亡具有相似的抑制作用，流式细胞术和凋亡相关蛋白的一致变化证明了这一点。这些发现共同表明，CST对脑缺血再灌注损伤（CIRI）具有神经保护作用，这些作用可能是通过PERK信号通路抑制ERS介导的。

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引用次数: 0

Chromogranin B: A versatile neuroendocrine protein regulating physiological and metabolic functions 嗜铬粒蛋白B：一种调节生理和代谢功能的多功能神经内分泌蛋白

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-08-07 DOI: 10.1016/j.npep.2025.102548

Chandramouli Mukherjee, Palki Chauksey, Aamna Jain, Bhavani S. Sahu

Chromogranin B (CHGB) is a key member of the granin family of acidic proteins, predominantly localized in the secretory granules of professional secretory cells, such as neurons and neuroendocrine cells. It plays a crucial role in the regulated secretory pathway, influencing hormone storage, processing, and release. CHGB's role extends from cellular processes to systemic physiology, encompassing vesicular trafficking, calcium homeostasis, and immune regulation. CHGB dysfunction is linked to pathological conditions such as neurodegenerative diseases, cardiovascular disorders, and metabolic disorders. This review examines the multifaceted functions of CHGB at both the cellular and organismal levels, highlighting its role in maintaining cellular homeostasis and its potential link to metabolic dysfunction and related pathophysiology.

嗜铬颗粒蛋白B （Chromogranin B， CHGB）是酸性颗粒蛋白家族的关键成员，主要存在于专业分泌细胞的分泌颗粒中，如神经元和神经内分泌细胞。它在受调节的分泌途径中起着至关重要的作用，影响激素的储存、加工和释放。CHGB的作用从细胞过程延伸到全身生理，包括囊泡运输、钙稳态和免疫调节。CHGB功能障碍与神经退行性疾病、心血管疾病和代谢紊乱等病理状况有关。本文综述了CHGB在细胞和机体水平上的多方面功能，强调了它在维持细胞稳态中的作用，以及它与代谢功能障碍和相关病理生理的潜在联系。

引用次数: 0

Inhibition of neurokinin B promotes functional recovery in traumatic brain injury by increasing M2 microglia 抑制神经激肽B通过增加M2小胶质细胞促进外伤性脑损伤的功能恢复

IF 2.7 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-08-06 DOI: 10.1016/j.npep.2025.102549

Fangjie Luo , Xiaoyun Li , Zhanpeng Zhu

Microglial polarization into pro-inflammatory M1 and anti-inflammatory M2 phenotypes is critical for regulating neuroinflammation and tissue repair following traumatic brain injury (TBI). The M1/M2 balance determines neurological outcomes, yet the mechanisms governing this polarization remain unclear. This study identifies neurokinin B (NKB) as a novel regulator of microglial M1/M2 polarization in TBI. Using a murine TBI model, we demonstrated significant upregulation of NKB and its receptor NK3R. Genetic knockdown of NKB enhanced functional recovery and shifted microglial polarization from the detrimental M1 to the beneficial M2 phenotype. Conversely, NKB administration promoted M1 activation while suppressing M2 markers in microglial cultures, potentially through inhibition of the STAT6 pathway. Overexpression of STAT6 reversed NKB's suppressive effects on M2 polarization, while NK3R antagonism with SB222200 promoted M2 polarization and improved functional outcomes. These findings establish NKB signaling as a key modulator of microglial dynamics after TBI, suggesting that targeting this pathway may promote neuroprotective M2 polarization while inhibiting damaging M1 responses. This dual regulation, combined with improved cognitive recovery, positions NKB as a promising target for developing novel TBI therapies aimed at modulating neuroinflammation.

小胶质细胞分化为促炎M1和抗炎M2表型对于调节创伤性脑损伤（TBI）后的神经炎症和组织修复至关重要。M1/M2平衡决定神经预后，但控制这种极化的机制尚不清楚。本研究发现神经激肽B （NKB）是脑外伤中小胶质细胞M1/M2极化的一种新的调节因子。通过小鼠TBI模型，我们证实了NKB及其受体NK3R的显著上调。基因敲低NKB增强了功能恢复，并将小胶质细胞极化从有害的M1表型转移到有益的M2表型。相反，在小胶质细胞培养中，NKB可能通过抑制STAT6通路促进M1激活，同时抑制M2标记物。STAT6的过表达逆转了NKB对M2极化的抑制作用，而NK3R与SB222200的拮抗促进了M2极化并改善了功能结果。这些发现证实了NKB信号是脑外伤后小胶质细胞动力学的关键调节剂，表明靶向这一通路可能促进神经保护性M2极化，同时抑制损伤性M1反应。这种双重调节，结合改善的认知恢复，使NKB成为开发旨在调节神经炎症的新型TBI疗法的有希望的靶点。

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引用次数: 0

Interplay of neuropeptide Y and autophagy in Alzheimer's disease: Therapeutic perspectives and mechanistic insights 神经肽Y和自噬在阿尔茨海默病中的相互作用：治疗观点和机制见解

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-07-17 DOI: 10.1016/j.npep.2025.102547

Dhiraj Lanjewar, Raj Katariya, Vinita Kale, Brijesh Taksande, Milind Umekar, Madhura Vinchurney

Alzheimer's disease (AD) is a progressive, chronic, neurodegenerative disorder involving cognitive impairment, neuronal loss, autophagy dysregulation, and toxic protein aggregates build-up, including amyloid-β plaques and hyperphosphorylated tau tangles. Autophagy dysregulation is a central driving force behind AD pathogenesis, interfering with the clearance of these aggregates and resulting in synaptic disruption and enhanced neurodegeneration. Neuropeptide Y (NPY) is abundantly present in the CNS. NPY has been identified as a promising candidate due to its neuropeptidergic activity. It plays a central role in regulating autophagy, anti-inflammation, and the induction of synaptic plasticity. NPY regulates the AMPA-mTOR pathway to restore cellular homeostasis and enhance neuronal survival through improved autophagic flux. It facilitates the clearance of aggregate proteins and dysfunctional cellular components, which lessen the signs of AD pathology. Moreover, NPY plays an important role in stabilizing the mitochondria and enhancing antioxidant action, in effect sustaining cognitive function. The modulatory influence of NPY on autophagy represents a potential novel direction in AD therapy, advanced delivery systems, such as nanoparticle-based carriers, offer promising targeted brain delivery mechanisms. However, clinical application is hindered by the need for a receptor-specific agonist to mitigate side effects and the lengthy trials necessary to assess long-term efficiency. Further research should aim to optimise NPY delivery and autophagy-targeted therapies to develop more effective treatments; such research challenges may position NPY as a breakthrough candidate for slowing cognitive and functional impairment in AD.

阿尔茨海默病（AD）是一种进行性、慢性、神经退行性疾病，涉及认知障碍、神经元丧失、自噬失调和有毒蛋白聚集体积聚，包括淀粉样蛋白-β斑块和过度磷酸化的tau缠结。自噬失调是阿尔茨海默病发病机制背后的主要驱动力，它干扰了这些聚集体的清除，导致突触破坏和神经变性加剧。神经肽Y （NPY）在中枢神经系统中大量存在。由于其神经肽能活性，NPY已被确定为有希望的候选药物。它在调节自噬、抗炎症和诱导突触可塑性中起核心作用。NPY调节AMPA-mTOR通路，通过提高自噬通量，恢复细胞稳态，提高神经元存活。它促进了聚集蛋白和功能失调的细胞成分的清除，从而减轻了AD病理的迹象。此外，NPY在稳定线粒体和增强抗氧化作用方面发挥重要作用，有效地维持认知功能。NPY对自噬的调节作用代表了AD治疗的一个潜在的新方向，先进的递送系统，如纳米颗粒载体，提供了有希望的靶向脑递送机制。然而，由于需要受体特异性激动剂来减轻副作用和评估长期疗效所需的漫长试验，临床应用受到阻碍。进一步的研究应着眼于优化NPY递送和自噬靶向治疗，以开发更有效的治疗方法；这些研究挑战可能使NPY成为减缓AD认知和功能损害的突破性候选药物。

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引用次数: 0

Irisin alleviates anxiety and deficits in fear extinction in PTSD within SPS mouse model 鸢尾素可减轻SPS小鼠创伤后应激障碍的焦虑和恐惧消退缺陷

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-07-14 DOI: 10.1016/j.npep.2025.102537

Xupei Xie , Yandi Ding , Qizhi Yan , Jiadan Zhao , Lingdi Zhang

Post-Traumatic Stress Disorder (PTSD), a prevalent psychological disorder, emerges subsequent to a grave traumatic incident or a succession of such events. Irisin is expressed in brain regions such as the hippocampus and prefrontal cortex and is found to have a neuroprotective function by suppressing neuroinflammation through the AMPK pathway, demonstrating its potential in treating cognitive decline, having antidepressant effects, and intervening in stress-related disorders. This study aims to explore the potential therapeutic effects of irisin on PTSD, as well as investigate the underlying mechanisms. Results showed that SPS caused anxiety-like behaviors and deficit in fear memory extinction of the mice. These SPS-induced abnormalities of the mice were reversed by exogenous irisin treatment. However, the AMPK inhibitor abolished the protective effects of irisin, indicating that irisin's therapeutic effects on SPS mice were achieved by activating AMPK. Further biochemical experiments demonstrated that irisin could increase pAMPK levels and ameliorate the overexpression of NF-κB and its downstream factors, including inflammatory factors and neurotoxic mediators, in the hippocampus, frontal cortex, and amygdala of the SPS mice. These effects of irisin were also reversed by AMPK inhibitor. Cell experiments suggest that irisin exerts anti-inflammatory effects on BV2 cells (microglia) via the AMPK/NF-κB pathway and subsequently confers anti-inflammatory benefits while enhancing cell viability in PC12 cells. The cumulative results indicate that irisin can improve behavioral deficits induced by SPS in mice by exerting anti-neuroinflammation function, and this function may be associated with the modulation of AMPK/NF-κB pathway in microglia in the brain tissues including hippocampus, cerebral cortex, and amygdala.

创伤后应激障碍（PTSD）是一种普遍的心理障碍，发生在严重的创伤事件或连续的创伤事件之后。鸢尾素在海马和前额叶皮层等大脑区域表达，并通过AMPK通路抑制神经炎症，具有神经保护功能，证明其在治疗认知能力下降、抗抑郁作用和干预压力相关疾病方面的潜力。本研究旨在探讨鸢尾素对PTSD的潜在治疗作用，并探讨其作用机制。结果表明，SPS引起小鼠焦虑样行为和恐惧记忆消退缺陷。通过外源性鸢尾素处理，这些sps诱导的小鼠异常被逆转。然而，AMPK抑制剂消除了鸢尾素的保护作用，表明鸢尾素对SPS小鼠的治疗作用是通过激活AMPK来实现的。进一步的生化实验表明，鸢尾素可以提高SPS小鼠海马、额叶皮层和杏仁核中pAMPK水平，改善NF-κB及其下游因子（包括炎症因子和神经毒性介质）的过度表达。鸢尾素的这些作用也被AMPK抑制剂逆转。细胞实验表明，鸢尾素通过AMPK/NF-κB通路对BV2细胞（小胶质细胞）发挥抗炎作用，随后在增强PC12细胞活力的同时具有抗炎作用。综上所述，鸢尾素可通过发挥抗神经炎症功能改善SPS诱导的小鼠行为缺陷，该功能可能与海马、大脑皮层、杏仁核等脑组织小胶质细胞中AMPK/NF-κB通路的调节有关。

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引用次数: 0

Neuropeptide Y as a multifaceted modulator of neuroplasticity, Neuroinflammation, and HPA axis dysregulation: Perceptions into treatment-resistant depression 神经肽Y作为神经可塑性、神经炎症和HPA轴失调的多方面调节剂：对治疗抵抗性抑郁症的感知

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-07-12 DOI: 10.1016/j.npep.2025.102538

Priyanka Singanwad , Amol Tatode , Mohammad Qutub , Brijesh Taksande , Milind Umekar , Rashmi Trivedi , Tanvi Premchandani

Treatment-resistant depression (TRD) is a severe neurobiological and clinical category in which common antidepressants do not induce an adequate response. Neuropeptide Y (NPY), a neuropeptide highly conserved through evolution, is known to be involved in the regulation of stress responses, emotional processing, neuroinflammation, and neuroplasticity. This review synthesizes the importance of NPY in TRD by describing NPY's physiological (central nervous system) functions and roles. Experimental data suggest that NPY is dysregulated in animal models of chronic stress and TRD, which include changes in hippocampal NPY signaling, neurotrophic factor expression, and HPA axis activity. Clinical studies have, in turn, shown decreased cerebrospinal NPY concentrations in TRD patients as well as decreased expression of NPY receptors in stress-related regions of their brains. Finally, we discuss new therapeutic avenues targeting NPY pathology, such as intranasal NPY administration and receptor-selective modulation. Thus, preclinical and clinical data jointly suggest that restoration of NPY signaling pathways might offer a novel and biologically grounded intervention for TRD.

难治性抑郁症（TRD）是一种严重的神经生物学和临床类别，其中常见的抗抑郁药物不能诱导足够的反应。神经肽Y （NPY）是一种在进化过程中高度保守的神经肽，参与调节应激反应、情绪加工、神经炎症和神经可塑性。本文通过描述NPY的生理（中枢神经系统）功能和作用，综合了NPY在TRD中的重要性。实验数据表明，慢性应激和TRD动物模型中NPY失调，包括海马NPY信号、神经营养因子表达和HPA轴活性的改变。反过来，临床研究表明，TRD患者的脑脊液中NPY浓度降低，大脑应激相关区域中NPY受体表达减少。最后，我们讨论了针对NPY病理的新治疗途径，如鼻内NPY给药和受体选择性调节。因此，临床前和临床数据共同表明，恢复NPY信号通路可能为TRD提供一种新颖的、基于生物学的干预措施。

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引用次数: 0

Tauopathies: Emerging discoveries on tau protein, with a special focus on Alzheimer's disease tau病：关于tau蛋白的新发现，特别关注阿尔茨海默病

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-07-02 DOI: 10.1016/j.npep.2025.102536

Aishwarya Hattiholi , Harsha Hegde , Suhas Kumar Shetty

Tauopathies encompass a group of neurodegenerative disorders (NDDs) driven by the abnormal accumulation of mutated tau protein, leading to hyperphosphorylation, neuronal damage, and neuroinflammation. The protein plays essential roles in brain function but undergoes hyperphosphorylation and aggregation into toxic oligomers in NDDs. Recent research emphasizes the need to understand tau's post-translational modifications (PTMs) and their role in pathological states. Insights into tau's structure, isoform-specific properties, and aggregation mechanisms are critical for elucidating its propagation in neurodegeneration. Moreover, tau's potential as a biomarker and the development of targeted therapies to mitigate tauopathies, particularly in AD, remain promising avenues. However, many strategies targeted at tau have repeatedly failed, which continues the search for better alternatives. This review focuses on recent advances in tau research, highlighting its structural and functional characteristics, and roles in disease, that may be critical to understanding their implications for new therapeutic strategies. PTMs are important for the stable structure and physiological functions of a protein. However, dysfunctional PTMs are the leading causes of tau protein aggregation. The recent shift on tau hyperphosphorylation has resulted in many discoveries related to their functions in AD. Therapeutic strategies targeting phosphorylated tau are being extensively studied worldwide. This paper gives a comprehensive view on these aspects.

tau病包括一组由突变tau蛋白异常积累驱动的神经退行性疾病（ndd），导致过度磷酸化、神经元损伤和神经炎症。该蛋白在脑功能中起着至关重要的作用，但在ndd中会发生过度磷酸化并聚集成有毒的低聚物。最近的研究强调需要了解tau蛋白的翻译后修饰（PTMs）及其在病理状态中的作用。深入了解tau蛋白的结构、亚型特异性和聚集机制对于阐明其在神经退行性疾病中的传播至关重要。此外，tau作为生物标志物的潜力和靶向治疗的发展，以减轻tau病变，特别是在AD中，仍然是有希望的途径。然而，许多针对tau蛋白的策略一再失败，这促使人们继续寻找更好的替代方案。本文综述了tau蛋白研究的最新进展，强调了其结构和功能特征，以及在疾病中的作用，这可能对理解它们对新的治疗策略的影响至关重要。PTMs对蛋白质的稳定结构和生理功能至关重要。然而，功能失调的ptm是tau蛋白聚集的主要原因。最近对tau过度磷酸化的转变导致了许多与其在AD中的功能相关的发现。针对磷酸化tau蛋白的治疗策略正在世界范围内被广泛研究。本文对这些方面进行了全面的论述。

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引用次数: 0

Dynorphin B induces mitochondrial fragmentation in NSCLC through the PKD/DRP-1 signaling pathway Dynorphin B通过PKD/DRP-1信号通路诱导NSCLC线粒体断裂

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-06-25 DOI: 10.1016/j.npep.2025.102535

Yunxiao Li , Bin Zhou , Yuenan Yang , Kexin Liu , Shichao Zhou

Mitochondrial fragmentation and impairment are essential targets for therapeutic approach for non-small cell lung cancer (NSCLC), given their significant contributions to the persistence and progression of malignant cells. Dynorphin B (Dyn B), an endogenous opioid peptide, has been demonstrated for its involvement in an extensive array of cellular activities; however, its specific functions and mechanisms within the context of cancer remain largely undefined. To address this, we employed NCI-H2087 NSCLC cells treated with Dyn B (0.01–100 μM) and utilized lactate dehydrogenase (LDH) release and γ-glutamyl transpeptidase (GPT) activity assays to evaluate cytotoxicity. Mitochondrial function was assessed via Complex I activity assays, adenosine triphosphate (ATP) production measurements, and MitoSOX Green staining for reactive oxygen species (ROS). MitoTracker Red staining with ImageJ quantification characterized mitochondrial morphology, while Western blot analysis probed phosphorylation of dynamin-related protein 1 (DRP1) and protein kinase D (PKD). Lentiviral shRNA-mediated PKD silencing was used to validate functional rescue of mitochondrial dynamics. This investigation reveals that Dyn B induces cytotoxic effects in NCI-H2087 NSCLC cells by facilitating mitochondrial dysfunction and fragmentation. Treatment with Dyn B resulted in a significant augmentation of LDH and elevated GPT activity, indicating cellular injury. Additionally, Dyn B compromised mitochondrial functionality by reducing Complex I activity, diminishing ATP synthesis, and promoting mitochondrial ROS generation. Mechanistically, Dyn B triggered mitochondrial fragmentation through activation of DRP1 and PKD, without affecting protein kinase C (PKC). Silencing of PKD reversed Dyn B–induced mitochondrial fragmentation and restored mitochondrial functionality. These findings underscore the promising role of Dyn B as a prospective therapeutic agent in NSCLC, targeting mitochondrial dynamics via the PKD-DRP1 signaling pathway.

线粒体断裂和损伤是治疗非小细胞肺癌（NSCLC）的重要靶点，因为它们对恶性细胞的持续和进展有重要贡献。肌啡肽B （Dyn B）是一种内源性阿片肽，已被证明参与广泛的细胞活动；然而，其在癌症中的具体功能和机制在很大程度上仍未明确。为了解决这个问题，我们使用Dyn B （0.01-100 μM）处理NCI-H2087 NSCLC细胞，并利用乳酸脱氢酶（LDH）释放和γ-谷氨酰转肽酶（GPT）活性测定来评估细胞毒性。通过复合体I活性测定、三磷酸腺苷（ATP）生成测定和MitoSOX绿色活性氧（ROS）染色来评估线粒体功能。MitoTracker Red用ImageJ定量染色表征线粒体形态，Western blot分析检测动力蛋白相关蛋白1 （DRP1）和蛋白激酶D （PKD）的磷酸化。慢病毒shrna介导的PKD沉默被用来验证线粒体动力学的功能拯救。本研究表明，Dyn B通过促进线粒体功能障碍和断裂，诱导NCI-H2087 NSCLC细胞的细胞毒性作用。Dyn B治疗导致LDH显著增加，GPT活性升高，表明细胞损伤。此外，Dyn B通过降低复合物I活性、减少ATP合成和促进线粒体ROS生成来损害线粒体功能。在机制上，Dyn B通过激活DRP1和PKD触发线粒体断裂，而不影响蛋白激酶C （PKC）。PKD的沉默逆转了Dyn b诱导的线粒体断裂并恢复了线粒体功能。这些发现强调了Dyn B作为一种有前景的治疗药物在NSCLC中的作用，通过PKD-DRP1信号通路靶向线粒体动力学。

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引用次数: 0

Neuroprotective effect of Ac-SDKP peptide in SH-SY5Y cells and rat model of Parkinson's disease against 6-OHDA-induced oxidative stress and ER stress Ac-SDKP肽对SH-SY5Y细胞和帕金森病大鼠模型抗6- ohda诱导的氧化应激和内质网应激的神经保护作用

IF 2.5 3区医学 Q3 ENDOCRINOLOGY & METABOLISM

Neuropeptides

Pub Date : 2025-06-16 DOI: 10.1016/j.npep.2025.102534

Maryam Kamarehei , Hamid Zahednasab

Oxidative stress and endoplasmic reticulum (ER) stress are key contributors to the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD), for which no definitive cure currently exists. This study investigated the neuroprotective potential of the N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) tetrapeptide in both in vitro and in vivo PD models. In cell-based analyses, pre-treatment with 20 nM Ac-SDKP provided significant protection against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. In vivo, the neuroprotective potential of the peptide was also supported through daily administration of rats with Ac-SDKP (800 μg/kg) after 6-OHDA lesioning, which unveiled a series of significant observations. Treated animals demonstrated highly preserved dopaminergic neurons through reduced activation of apoptotic markers such as caspase-3 and caspase-12. In addition to cytoprotection, Ac-SDKP also produced striking behavioral improvement. Treated animals exhibited improved motor coordination and ability on spatial memory tasks, as well as the significant attenuation of anxiety-like and depressive-like behaviors. Such behavioral improvement is probable because Ac-SDKP possesses the ability to modulate several pathological features of PD. In fact, the peptide was able to decrease oxidative stress, diminish ER stress, and inhibit neuroinflammatory signaling. Collectively, these findings position Ac-SDKP as a promising neuroprotection candidate, and as a candidate with potential to be developed as a multifactorial treatment for the complex pathophysiology of PD.

氧化应激和内质网（ER）应激是神经退行性疾病发病机制的关键因素，包括帕金森病（PD），目前尚无明确的治疗方法。本研究研究了n -乙酰-seryl-天冬氨酸-赖氨酸-脯氨酸（Ac-SDKP）四肽在体内和体外PD模型中的神经保护作用。在基于细胞的分析中，20 nM Ac-SDKP预处理对SH-SY5Y细胞6-羟基多巴胺（6-OHDA）诱导的神经毒性具有显著的保护作用。在体内，6-OHDA损伤后，每天给大鼠注射Ac-SDKP (800 μg/kg)，也支持了该肽的神经保护潜力，这揭示了一系列显著的观察结果。通过减少凋亡标记物如caspase-3和caspase-12的激活，治疗动物表现出高度保存的多巴胺能神经元。除了细胞保护外，Ac-SDKP还产生了显著的行为改善。治疗后的动物在空间记忆任务中表现出运动协调和能力的改善，以及焦虑和抑郁样行为的显著减弱。这种行为改善可能是因为Ac-SDKP具有调节PD的几种病理特征的能力。事实上，这种肽能够减少氧化应激，减少内质网应激，并抑制神经炎症信号。总的来说，这些发现将Ac-SDKP定位为一种有前途的神经保护候选药物，并有可能成为PD复杂病理生理的多因素治疗药物。

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