PEPTIDES
·
2024
·
IF 2.8
Yuqiao Yang,Jin Liu,Lingyan Wang,Wen Wu,Quan Wang,Yu Zhao,Xi Qian,Zhuoran Wang,Na Fu,Yanqiong Wang,Jinqiao Qian
Background The progress of cardiac hypertrophy is modulated by JAK2/STAT3 signaling pathway. Cardiac glucose metabolism derangement exacerbates the progression of cardiac hypertrophy. Oxytocin (OT) has emerged as a significant hormone involved in cardiovascular homeostasis, especially in protecting against cardiac hypertrophy. The present study aims to explore whether the anti-hypertrophy effect of oxytocin is related to the JAK2/STAT3 signaling pathway and cardiac glucose metablism. Methods Cardiac hypertrophy model was induced by angiotensin II (Ang II) in H9c2 cells and in mice with or without oxytocin treatment. Changes in cardiac histopathology were evaluated by hematoxylin and eosin (H&E), Masson staining, and wheat germ agglutinin (WGA) staining. The hypertrophy-related genes and JAK2/STAT3 pathway signaling molecules were analyzed by qRT-PCR and western blotting. The levels of glucose, pyruvic acid, lactic acid, and lactate dehydrogenase activity in H9c2 cells using the corresponding assay kits. Results The results showed that OT inhibited hypertrophic and fibrotic changes. Furthermore, OT increased intracellular levels of glucose and pyruvic acid, and decreased lactate dehydrogenase activity and lactic acid levels. Mechanistically, Ang II decreased oxytocin receptors (OXTR) expression and facilitated JAK2 and STAT3 phosphorylation. OT treatment increased OXTR expression and blocked JAK2 and STAT3 phosphorylation The OXTR-specific siRNA-mediated depleted expression could abrogate OT-induced anti-hypertrophic effects in H9c2 cells following angiotensin II insult. However, the JAK2/STAT3 inhibitor AG490 rescued the protective effects of OT against cardiac hypertrophy under OXTR downregulation. Conclusion OT exerts its protective effects against cardiac hypertrophy by improving cardiac glucose metabolism and regulating OXTR/JAK2/STAT3 axis.
研究领域:
心脏病学
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分子生物学
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内分泌学
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DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2023
·
IF 7.5
Xin-Yu Fan,Guang Shi,Yun-Peng Zhao,Jing-Jing Yang,Juan Feng
Glutamate plays a crucial role in cognitive impairments after ischemic stroke. There is a scarcity of information about how glutamate-induced activation of cAMP-response element binding (CREB) signaling pathway regulates both the negative and positive regulators of synaptic plasticity. Recent studies have demonstrated the involvement of prominent epigenetic repressors, such as MeCP2 and DNMTs, in stroke. Neuroprotective effects of oxytocin against ischemia have been previously reported, while the underlying mechanism is still elusive. In this research, the possible role of CREB-mediated DNA hypermethylation and the potential mechanism of oxytocin in a rat model of permanent middle cerebral artery occlusion (pMCAO) were assessed. Adult male Sprague-Dawley rats were pretreated with intraperitoneal injection of oxytocin at the onset of pMCAO. The effects of oxytocin on spines and the expression levels of synaptic genes were determined. The regulatory effects of oxytocin on glutamate level, N-methyl- D -aspartate receptors (NMDARs), its downstream CREB pathway, and global or gene-specific DNA methylation status were evaluated by immunofluorescence, co-immunoprecipitation, and chromatin immunoprecipitation, respectively. We found that CREB could act as a common transcription factor for MeCP2 and DNMT3B after ischemic stroke. Oxytocin dose-dependently deactivated NR2B-related CaM-CREB pathway and inhibited DNA hypermethylation at the CpG islands of Ngf gene in pMCAO-operated rats. Moreover, oxytocin prevented pMCAO-induced reduction in the number of spines and neural cells. DNA hypermethylation in Ngf gene contributed to the cognitive deficits post-stroke. The neuroprotective effects of oxytocin against ischemia could be attributed to inhibiting glutamate release, providing additional evidence on the mechanism of oxytocin against ischemic stroke.
研究领域:
神经科学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
NEUROPHARMACOLOGY
·
2023
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IF 4.7
Rongjun Liu,Daofan Sun,Xiuzhong Xing,Qingge Chen,Bo Lu,Bo Meng,Hui Yuan,Lan Mo,Liufang Sheng,Jinwei Zheng,Qiusheng Wang,Junping Chen,Xiaowei Chen
The comorbidity of pain and depression is frequently observed in patients suffering from chronic pain and depression. However, the comorbid mechanism is not well elucidated and the therapeutic medication is still inadequate. Oxytocin is a neuropeptide synthesized in the hypothalamus. It has been reported to relieve chronic pain and depressive symptoms. However, the analgesic action and mechanisms of oxytocin have mainly been investigated using peripheral or spinal administration. Because of the advantage of intranasal delivery of oxytocin in crossing the blood-brain barrier, we investigated the effect of intranasal application of oxytocin on neuropathic pain and comorbid depressive symptoms in both female and male mice. In female and male mice receiving spared nerve injury (SNI) surgery, intranasal oxytocin (2.4 μg, daily for 28 days) attenuated depression-like behavior , but did not alleviate mechanical hyperalgesia . Intranasal oxytocin not only inhibited the activation of microglia and astrocytes, but also increased the downregulated oxytocin receptor (OTR) expression, reversed the elevated GluN2A, and restored the decreased BDNF expression in the hippocampus . SNI also decreased OTR expression in the spinal cord and increased spinal GluN2A and BDNF. However, intranasal oxytocin treatment did not change the expression levels of OTR, GluN2A, or BDNF in the spinal cord of neuropathic mice. The results suggest that the oxytocin signaling in the hippocampus is involved in the comorbidity of pain and depression, and intranasal oxytocin may have the potential to treat depressive symptoms in neuropathic pain patients.
研究领域:
神经科学
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疼痛管理
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药理学
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行为科学
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DOI
PubMed
高影响因子
Nature Communications
·
2017
·Vol. 8
·期 1
·1-15
·
IF 12.124
Wu Liufeng,Meng Jia,Shen Qing,Zhang Yi,Pan Susu,Chen Zhuo,Zhu Ling-Qiang,Lu Youming,Huang Yuan,Zhang Guo
Caffeine, an antagonist of the adenosine receptor A 1 R, is used as a dietary supplement to reduce body weight, although the underlying mechanism is unclear. Here, we report that adenosine level in the cerebrospinal fluid, and hypothalamic expression of A 1 R, are increased in the diet-induced obesity (DIO) mouse. We find that mice with overexpression of A 1 R in the neurons of paraventricular nucleus (PVN) of the hypothalamus are hyperphagic, have glucose intolerance and high body weight. Central or peripheral administration of caffeine reduces the body weight of DIO mice by the suppression of appetite and increasing of energy expenditure. We also show that caffeine excites oxytocin expressing neurons, and blockade of the action of oxytocin significantly attenuates the effect of caffeine on energy balance. These data suggest that caffeine inhibits A 1 Rs expressed on PVN oxytocin neurons to negatively regulate energy balance in DIO mice.
研究领域:
药理学
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神经科学
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肥胖研究
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产品关联
DOI
PubMed
高影响因子
BIOSCIENCE REPORTS
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2020
·Vol. 40
·期 8
·
IF 2.942
Zhu Jialei,Tang Jing
Postpartum depression (PPD) is a kind of mental disorder characterized by persistent low emotions in puerperium. The most significant physiological change in postpartum is lactation which is regulated by oxytocin receptor (OXTR). However, whether OXTR is related to pathological process of PPD and the potential mechanism still remain unclear. In the present study, we prepared hormone-simulated pregnancy (HSP)-induced PPD mouse model and found that the protein level of OXTR in hippocampus of PPD model mice was down-regulated and Nod-like receptor protein 3 (NLRP3) inflammasome was activated. We identified five long non-coding RNAs (lncRNAs) related to PPD by transcriptome sequencing, including three up-regulated and two down-regulated. The five lncRNAs were associated with the signaling pathway of OXTR according to the bioinformatics analysis. Furthermore, we focused on one of the five lncRNAs, Gm14205, and found that it targeted OXTR which inhibited astrocytic NLRP3 inflammasome activation in hippocampal primary astrocytes. These findings illustrate that OXTR has protective effects in PPD by inhibiting NLRP3 inflammasome activation and provides a new strategy for targeting lncRNA Gm14205 in the pathogenesis of PPD.
研究领域:
神经科学
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分子生物学
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药理学
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精神病学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2025
·
IF 5.2
Honglin Li,Ya Chen,Yue Qiu
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms. Oxytocin, an endogenous polypeptide known as the “social hormone”, has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood–brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among these analogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.
研究领域:
神经科学
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药理学
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行为科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2018
·
IF 3.115
Yue Wei,Tingyun Ma,Hanxue Wang,Jianguo Xing,Yuwen Wang,Zhengyi Gu,Dandan Mu,Qiang Yin,Xuemei Cheng,Changhong Wang
Ethnopharmacological relevance Compound Muniziqi granule (CMG) is usually used as a traditional Uighur medicine to treat acne, chloasma , skin inflammation, primary dysmenorrhea (PDM), and menopausal syndrome . However, there are no sufficient data to support the clinic uses of CMG in PDM. Aim of the study This work aims to examine the effect of CMG as a treatment for PDM and reveal its possible therapeutic mechanism. Materials and methods In vivo and in vitro mouse PDM models were utilized in this study. The mouse uterine contraction was induced by oxytocin after progynova or estradiol benzoate pretreatment. CMG, alkaloid extracts from seeds of Peganum harmala (AEP), and 10% and 95% ethanol extracts from seeds of Nigella glandulifera (EEN10 and EEN95) were given to mice in three doses by gavage. The writhing times within 30 min after oxytocin treatment were recorded to evaluate the analgesic effect, and the glutathione peroxidase (GSH-Px), malondialdehyde (MDA), 6-keto-prostaglandin F 1α (6-k-PGF 1α ), prostaglandin F 2α (PGF 2α ), thromboxane B2 (TXB 2 ), and nitric oxide (NO) levels in uterine tissues and PGF 2α and MDA in serum were determined. The effects (contractile curve) of CMG, AEP, EEN10, and EEN95 on uterus contraction induced by oxytocin in isolated mouse uterus were recorded. Results In contrast to the control group, CMG, AEP, N10, and N95 could display analgesic activities dose dependently by reducing the writhing response of the PDM model mice. CMG, AEP, EEN10, and EEN95 could also remarkably decrease the level of PGF 2α , 6-k-PGF 1α , TXB 2 , NO and MDA in uterine tissues and PGF 2α and MDA in serum, whereas the activity of GSH-Px in uterine tissues was increased. Furthermore, CMG, AEP, EEN10, and EEN95 could significantly inhibit the frequency and amplitude of isolated uterus induced by oxytocin in a concentration-dependent manner. Conclusions CMG exhibited a significant protective effect on experimental PDM. The mechanisms are probably associated with abating lipid peroxidation and over-inflammatory reaction, and alleviating the contraction of isolated mouse uterus. The seeds of P. harmala and N. glandulifera in the CMG may play an important role in exerting protective effects on PDM. This study provides pre-clinic proof to the use of CMG in clinical practice of PDM.
研究领域:
药理学
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传统医学
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民族药理学
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生殖健康
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2022
·
IF 10.383
Caihua Ye,Meng Cheng,Lin Ma,Tianzhu Zhang,Zuhao Sun,Chunshui Yu,Junping Wang,Yan Dou
Prevention of Alzheimer’s disease (AD) is a global imperative, but reliable early interventions are currently lacking. Microglia-mediated chronic neuroinflammation is thought to occur in the early stage of AD and plays a critical role in AD pathogenesis. Here, oxytocin (OT)-loaded angiopep-2-modified chitosan nanogels (AOC NGs) were designed for early treatment of AD via inhibiting innate inflammatory response. Through the effective transcytosis of angiopep-2, AOC NGs were driven intravenously to cross the blood-brain barrier, enter the brain, and enrich in brain areas affected by AD. A large amount of OT was then released and specifically bound to the pathological upregulated OT receptor, thus effectively inhibiting microglial activation and reducing inflammatory cytokine levels through blocking the ERK/p38 MAPK and COX-2/iNOS NF-κB signaling pathways. Consecutive weekly intravenous administration of AOC NGs into 12-week-old young APP/PS1 mice, representing the early stage of AD, remarkably slowed the progression of Aβ deposition and neuronal apoptosis in the APP/PS1 mice as they aged and ultimately prevented cognitive impairment and delayed hippocampal atrophy. Together, the findings suggest that AOC NGs, which show good biosafety, can serve as a promising therapeutic candidate to combat neuroinflammation for early prevention of AD.
研究领域:
神经科学
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药理学
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神经炎症
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药物递送系统
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阿尔茨海默病研究
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产品关联
DOI
PubMed
高影响因子
Bioactive Materials
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2023
·
IF 18.9
Meng Cheng,Caihua Ye,Chunxiao Tian,Dongju Zhao,Haonan Li,Zuhao Sun,Yuyang Miao,Qiang Zhang,Junping Wang,Yan Dou
Immune recognition of excessive neurotoxins by microglia is a trigger for the onset of neuroinflammation in the brain, leading to neurodegeneration in Alzheimer's disease (AD). Blocking active recognition of microglia while removing neurotoxins holds promise for fundamentally alleviating neurotoxin-induced immune responses, but is very challenging. Herein, an engineered macrophage-biomimetic versatile nanoantidote ( [email protected] ) is developed for inflammation-targeted therapy against AD by neurotoxin neutralization and immune recognition suppression. Coating macrophage membranes can not only endow [email protected] with anti-phagocytic and inflammation-tropism capabilities to target inflammatory lesions in AD brain, but also efficiently reduce neurotoxin levels to prevent them from activating microglia. The loaded oxytocin (OT) can be slowly released to downregulate the expression of immune recognition site Toll-like receptor 4 (TLR4) on microglia, inhibiting TLR4-mediated pro-inflammatory signalling cascade. Benefiting from this two-pronged immunosuppressive strategy, [email protected] exhibits outstanding therapeutic effects on ameliorating cognitive deficits, inhibiting neuronal apoptosis, and enhancing synaptic plasticity in AD mice, accompanied by the delayed hippocampal atrophy and brain microstructural disruption by in vivo 9.4T MR imaging. This work provides new insights into potential AD therapeutics targeting microglia-mediated neuroinflammation at the source.
研究领域:
神经科学
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药理学
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纳米技术
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免疫学
·
神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2020
·
IF 3.69
Baolian Ma,Shilin Yang,Ting Tan,Junmao Li,Xiaoyong Zhang,Hui Ouyang,Mingzhen He,Yulin Feng
Ethnopharmacological relevance Akebiae Fructus, a Tujia minority folk medicine and a well-known traditional Chinese medicine for soothing the liver, regulating Qi, promoting blood circulation and relieving pain, is widely used in the treatment of primary dysmenorrhea . However, little is known about its underlying mechanism. Aim of the study To explore the effect of Akebiae Fructus on primary dysmenorrhea model induced by estradiol benzoate and oxytocin, and to provide better understanding of the mechanism of Akebiae Fructus for primary dysmenorrhea treatment. Materials and methods The primary dysmenorrhea mouse model was used in this study. Except for the control group and the normal administration group, the mice of other groups were subcutaneously injected with estradiol benzoate (10 mg/kg/d) for 10 consecutive days. From the 5th day of the ten-day model period, the positive control groups were given 0.075 g/kg ibuprofen and 7.5 g/kg Leonurus granule, the drug groups were given 0.2 g/kg, 0.4 g/kg, 0.8 g/kg Akebiae Fructus extract, the normal administration group was given 0.8 g/kg Akebiae Fructus extract, and the same volume saline was given in the control group. On the tenth day, oxytocin (10 U/kg) was peritoneally injected after estradiol benzoate injected 1 h. After the oxytocin injection, writhing behavior was observed for 30 min. Then the uterine tissue was collected to measure the level of PGF 2α and PGE 2 , and for histological analysis and transcriptomics analysis. Meanwhile, plasma and urine samples were collected for metabolomic analysis. Results Akebiae Fructus inhibited the writhing, decreased the PGF 2α level and ameliorated the morphological changes. 32 potential metabolic biomarkers in plasma and 17 in urine were found for primary dysmenorrhea, and after Akebiae Fructus treatment, 25 metabolites in plasma and 14 in urine were restored. These altered metabolites were mainly involved in lipid, amino acid and organic acid metabolism. For the transcriptomic study, a total of 2244 differentially expressed genes (1346 up-regulated and 898 down-regulated) were obtained between the control and model group, and 148 differentially expressed genes (DEGs) were found related with Akebiae Fructus treatment of primary dysmenorrhea. Correlation analysis was carried out based on the transcriptomic and metabolomic data. 5 differentially expressed genes (Plpp3, Sgpp2, Arg1, Adcy8, Ak5) were found related with the enrichment metabolic pathways. The mechanism by which Akebiae Fructus ameliorates primary dysmenorrhea may account for the regulation of the gene expression to control the key enzymes in the sphingolipid metabolism, arginine and proline metabolism, glycerophospholipid metabolism and purine metabolism, inhibiting the abnormal secretion of PGF 2α , alleviating the uterine contraction and reducing inflammation and pain. Conclusions Akebiae Fructus could effectively alleviate the symptoms of primary dysmenorrhea, regulate metabolic disorders , and control the related gene expression in primary dysmenorrhea. The study may provide clues for further study of Akebiae Fructus treatment on primary dysmenorrhea.
研究领域:
药理学
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中药学
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分子生物学
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代谢组学
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转录组学
·
疼痛管理
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Junling Ren,Xia Wang,Yuran Sun,Le Yang,Hui Sun,Ye Sun,Ling Kong,Guangli Yan,Ying Han,Xijun Wang
Background Danggui Sini Decoction (DGSND) is a classic prescription for treating primary dysmenorrhea (PD), while, the ameliorating effects of DGSND on PD and its mechanisms are not yet fully understood. Purpose The present study is devoted to investigate the protective effect of DGSND against PD and the possible mechanism from the perspective of metabolomics as well as lipidomics. Methods DGSND was characterized by UPLC-Q-TOF/MS. The PD rat model was induced by estradiol benzoate and oxytocin, and traditional pharmacology, including writhing times, latency time, biochemical index, organ index, and histopathology were performed to evaluated the efficacy of DGSND on PD. Urine metabolomics strategy combined with functional analysis was adopted to delineate the therapeutic effect of DGSND on PD rats and anchor the crucial pathway, and lipidomics analysis was further performed with the uterine tissue as the research object to elucidate the protective mechanism of DGSND from the perspective of lipid homeostasis. Finally, western blot analysis was used to validate the expression of key metabolic enzymes in lipid metabolism. Results DGSND was effective in ameliorating writhing times, latency time, the value of prostaglandin F 2α (PGF 2α )/PGE 2 , uterus index, and morphological changes of PD rats. Metabolic signature of PD rats was primarily characterized by the disturbance of steroid hormone metabolism, amino acid metabolism, and lipid metabolism. Functional analysis revealed the urine biomarkers of PD were most related with lipid abnormality. Further lipidomics analysis indicated DGSND exerted anti-PD effects by remodeling lipid homeostasis, which might be due to the significant correlations between different kinds of lipids, especially the extremely high correlation of phosphatidylethanolamine, phosphatidylcholine, and fatty acids. Moreover, the key metabolic enzymes expression of CK, PLA 2 , LPCAT3, COX-2, and 5-LOX can be greatly downregulated by DGSND. Conclusion Our findings demonstrated a novel protective mechanism of DGSND against PD by regulating lipid homeostasis.
研究领域:
药理学
·
代谢组学
·
脂质组学
·
中医
·
动物模型
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2018
·
IF 3.457
Yu Wang,Shanshan Zhao,Xu Liu,Yumin Zheng,Lei Li,Su Meng
Objective Autism is a neurodevelopmental disorder which significantly impacts the quality of people’s life. Oxytocin is a hormone impacting the social cognition and interpersonal trust. In this study, we aimed to explore the role of oxytocin in autism. Methods Autistic mice models were established by valproate . Animal behaviors were assessed by open field test, tail suspension test , marble burying test and three-chamber social interaction test. Oxidative stress was evaluated by the levels or activities of malondialdehyde , superoxide dismutase , glutathion peroxidase , reduced glutathione and reactive oxygen species . Inflammation was assessed by the levels of tumor necrosis factor-α, interleukin-1β and interleukin-6. The number of activated microglia was detected by immunofluorescence with an Iba-1 antibody. Results Our results showed that oxytocin improved the behaviors of autistic mice, with less anxiety, depression and repetitive behavior , and ameliorated social interaction. Further study showed that the elevated oxidative stress and inflammation in autistic mice were alleviated after treatment of oxytocin. Conclusion Our study demonstrates that oxytocin treatment ameliorates autism in a mouse model, maybe through its modulation on oxidative stress and inflammation. It is indicated that oxytocin may beneficial to autism.
研究领域:
神经科学
·
药理学
·
行为科学
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
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