BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2018
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IF 2.559
Jianzhen Li,Wenni Zhou,Yamei Wang,Caiyan Niu
The roles of cyclic guanosine monophosphate (cGMP) signaling in oocyte maturation attracts much attention in mammals, but its roles in fish are still largely unknown. Using zebrafish as a model, we demonstrated for the first time in fish that cGMP is involved in oocyte maturation, and its functional model in oocyte maturation is different from that of mammals. The intracellular cGMP could be regulated by nitric oxide (NO), we found that all three NO synthase enzymes and four soluble guanylyl cyclases (sGC) are expressed in the zebrafish ovary. Intriguingly, either the activation or inhibition of the NO/sGC/cGMP pathway in fully grown follicles could lead to oocyte maturation. During oocyte maturation, cGMP levels increased in the follicular cell layer but decreased in oocytes, while NO levels increased in follicular cells but remained constant in oocytes. Based on these findings in zebrafish, we propose a hypothetical model on the dual role of cGMP in oocyte maturation: in follicular cells the LH signal could increase the level of NO and cGMP which induces oocyte maturation, while in the oocyte the decreased cGMP level can also induce oocyte maturation. These findings help us to understand the molecular mechanism of fish oocyte maturation.
研究领域:
生殖生物学
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分子生物学
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鱼类生理学
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DOI
PubMed
高影响因子
SMALL RUMINANT RESEARCH
·
2025
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IF 1.4
Jia Hao,Si Ouyang,Yubing Wang,Lei Cheng,Dayong Chen,Chunjuan Qiu,Riga Wu,Yongji Xie,Jianhui Tian,Lei An,Guangyin Xi
This study aims to investigate the effect of cyclic guanosine-3’,5’-monophosphate (cGMP) on ovine embryo development, thereby providing new strategies to improve the efficiency of in vitro embryo production (IVP). Following in vitro maturation (IVM) and in vitro fertilization (IVF) of ovine oocytes derived from abattoir, the presumptive zygotes were treated with different concentrations of cGMP. In order to explore the effect of cGMP on the developmental competence of embryos derived from ovum pick-up (OPU)-oocytes, the presumptive zygotes were cultured with cGMP after IVF. The cleavage rate and blastocyst rate were recorded at 24 h and on day 7 after IVF. On day 7, the blastocysts derived from slaughterhouse oocytes were collected to assess mRNA expression of development- and apoptosis-related genes. Additionally, the blastocyst quality, antioxidant capacity, mitochondrial function and lipid metabolism of blastocysts were evaluated. The results showed that cGMP significantly increased cleavage rate and blastocyst rate, with an increase in total cell number and ICM. The expression of pluripotency-related gene ( NANOG ) was upregulated and apoptosis-related gene ( CASPASE3 ) was downregulated after cGMP treatment. The administration of cGMP resulted in decreased lipid content and fatty acid levels, along with a significant decrease in reactive oxygen species (ROS) and lipid peroxidation. Additionally, mitochondrial membrane potential and ATP levels were elevated after cGMP treatment. Furthermore, cGMP also increased blastocyst rate of IVF embryos from ovine oocytes collected via OPU. These results demonstrate that cGMP can improve embryo developmental competence by enhancing lipid metabolism and reducing oxidative stress.
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DOI
高影响因子
Oxidative Medicine and Cellular Longevity
·
2019
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IF 4.868
Li-Ming Yu,Xue Dong,Jian Zhang,Zhi Li,Xiao-Dong Xue,Hong-Jiang Wu,Zhong-Lu Yang,Yang Yang,Hui-Shan Wang
Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 μmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin’s inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study.
研究领域:
心脏病学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2024
·
IF 4.8
Zishan Dou,Yang Xu,Jingli Liu,Wei Chen
LVLPGE is an angiotensin-converting enzyme (ACE) inhibitory peptide extracted from broccoli protein hydrolysates. The antihypertensive mechanism of LVLPGE was explored in the present study. The results indicated that the IC 50 value of LVLPGE was 19.49 μM, and its binding to ACE occurred via a static fluorescence quenching involving the secondary structure changes of ACE. In addition, LVLPGE competitively bound to the active site of ACE through hydrogen bonding. Furthermore, LVLPGE markedly enhanced the levels of the vasodilator nitric oxide (NO) in the Ang I-induced HUVECs model, suppressed the expression of vasoconstrictor endothelin-1 (ET-1), and increased the phosphorylation of eNOS. Moreover, LVLPGE was found to enhance the production of cyclic guanosine monophosphate (cGMP), which leading to a subsequent decrease in intracellular calcium concentration, ultimately facilitating the relaxation of vascular smooth muscles and lowering the blood pressure. These results demonstrated that LVLPGE achieves the antihypertensive effects by inhibiting ACE activity and activating the eNOS/NO/cGMP signaling pathway. This study provides new insights into the antihypertensive mechanism of LVLPGE and contributes to the high-value utilization of broccoli resources.
研究领域:
药理学
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心血管科学
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功能性食品
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生物化学
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产品关联
DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2022
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IF 5.195
Jia-yi You,Xin-wei Liu,Ying-xia Bao,Zheng-nan Shen,Quan Wang,Gong-yun He,Jing Lu,Ji-guo Zhang,Jian-wen Chen,Pei-qing Liu
Background Ischemic stroke is one of the leading causes of mortality worldwide. The available treatments are not effective. Phosphodiesterase 9A (PDE9A) is an intracellular cyclic guanosine monophosphate (cGMP) hydrolase considered to be a promising therapeutic target for brain diseases. This study explored neuroprotective effects and the underlying mechanism of LW33, a novel PDE9A inhibitor, on ischemic stroke in vitro and in vivo . Methods A middle cerebral artery occlusion (MCAO) model was established in adult male Sprague-Dawley rats and an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in human SH-SY5Y cells to mimic ischemia-reperfusion injury in vitro . Results LW33 increased cell viability , reduced lactate dehydrogenase activity, and OGD/R-induced apoptosis of SH-SY5Y cells. The protective effects of LW33 against stroke occurred in the recovery phase. LW33 administration significantly reduced cerebral infarction volume in MCAO rats, without causing significant deformation or necrosis of neurons in the cortex. LW33 also improved learning and cognitive dysfunction and reduced other pathological changes in MCAO rats in the recovery period. Moreover, LW33 stimulated the cGMP/PKG/CREB pathway and up-regulated the expression of the apoptosis-related proteins, and this effect was reversed by KT5823 treatment. Conclusion LW33 inhibited cell apoptosis and promoted neuronal repair to alleviate OGD/R and MCAO induced pathological alterations via the cGMP/PKG/CREB pathway, indicating that LW33 may be a promising therapeutic target for ischemic stroke.
研究领域:
神经科学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2020
·
IF 4.225
Lv Jinpeng,An Xiaohong,Jiang Songzhou,Yang Ying,Song Guoqiang,Gao Rongyin
Protoporphyrin IX (PPIX) is a heterocyclic organic compound that is the last intermediate in the heme biosynthetic pathway. PPIX, due to its photodynamic effects, is utilized in the treatment of skin diseases. Furthermore, PPIX has been utilized as a melanogenesis-stimulating agent in various studies. However, the exact function and mechanism underlying PPIX action in melanocytes remain to be elucidated. In the present study, we sought to further investigate how PPIX affects melanocyte melanogenesis, and whether PPIX is involved in melanin transport. Our findings demonstrated that PPIX increased melanocyte dendricity and melanosome transport, in addition to increasing melanogenesis. PPIX functions primarily by activating the guanylate cyclase (GC) and cyclic guanosine 3’, 5’-monophosphate/protein kinase G (cGMP/PKG) signaling pathways. Once activated, these pathways increase tyrosinase activity and the expression of microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 and -2 (TRP-1 and TRP-2), myosin Va, melanophinin, Ras-related protein Rab-27A (Rab27a), and cell division cycle 42 (Cdc42), promoting melanogenesis, melanocyte dendricity, and melanosome transport. Furthermore, the melanogenic effects of PPIX were confirmed in vivo in a zebrafish model system. Our results indicate that PPIX is not cytotoxic and may, thus, be utilized as a pigmentation enhancer.
研究领域:
细胞生物学
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分子生物学
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药理学
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皮肤病学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Chuanxin Liu,Xiaobin Huang,Jiao Kong,Xuejiao Li,Yuming Wang,Fangfang Zhang,Jiajia Duan
Background Podophyllotoxin (PPT), a highly active compound extracted from the rhizome of Dysosma versipellis (DV), has been used as an effective anti-cancer drug clinically since the 1950s. It possesses various biological activities, including antiviral and antitumor effects. However, its clinical application is severely limited due to its hepatotoxicity, and the underlying mechanisms remain unclear. This study aims to elucidate the mechanisms of PPT-induced hepatotoxicity using tandem quality tag (TMT) based quantitative proteomics and phosphoproteomics, providing potential targets and directions for developing new therapeutic strategies to facilitate the safe and rational use of podophyllotoxin in clinical settings. Methods We employed a comprehensive assessment of PPT-induced hepatotoxicity based on the Toxicology Evidence Chain (TEC) concept, originally proposed by our research group in 2018. This approach involves a tiered search for evidence of Harmful Ingredients Evidence (HIE), Injury Phenotype Evidence (IPE), Adverse Outcomes Evidence (AOE), and Toxic Events Evidence (TEE) during the development of PPT-induced hepatotoxicity, thereby constructing a guiding toxicology evidence chain. Sprague-Dawley (SD) rats were administered 20 mg/kg PPT for 4 consecutive days (HIE). Indicators such as hepatic function, oxidative stress, inflammatory factors, as well as the histopathology of liver tissue were evaluated to assess liver damage and synthetic function (AOE). Proteomics and phosphoproteomics were conducted to systematically assess PPT-induced hepatotoxicity at the level of modified proteins and verify the molecular mechanisms of key molecular pathways (TEE1). Furthermore, in vitro THLE-2 cell models were used in conjunction with CCK8, immunofluorescence, and ELISA assays to validate cytotoxicity and its underlying mechanisms (TEE2). Results Our results showed that after 4 days of PPT administration at 20 mg/kg (HIE), serum levels of AST/ALT, TBA, TP, and ALB in SD rats were significantly increased ( P < 0.05), indicating severe liver damage. SOD and T-AOC levels were significantly decreased ( P < 0.05), suggesting an oxidative stress state. TNF-α levels were significantly elevated, while IL-10 and IL-3 levels were significantly reduced ( P < 0.05), indicating strong activation of the inflammatory response in the liver. Histopathological examination revealed liver sinusoidal congestion in the liver tissue (AOE). Omics analysis revealed that hepatotoxicity primarily affected the complement-pyroptosis and cGMP-PKG-autophagy pathways. Western blot (WB) and RT-qPCR results showed significant upregulation of complement-pyroptosis pathway proteins (C5a, C5aR, NLRP3) and cGMP-PKG-autophagy pathway proteins (PKG, mTOR) in the PPT group ( P < 0.05) (TEE1). In vitro cell experiments showed that PPT significantly reduced cell viability ( P < 0.05) and increased the expression of proteins associated with pyroptosis and autophagy pathways, including ROS, NLRP3, PKG, and mTOR ( P < 0.05) (TEE2). Conclusion PPT activates the complement system through the C5a/C5aR/ROS/NLRP3 pathway and induces the formation of inflammasomes, promoting pyroptosis. Simultaneously, PPT activates the cGMP-PKG pathway, inhibiting autophagy and further accelerating pyroptosis, ultimately leading to hepatotoxicity. In conclusion, this study comprehensively revealed the underlying mechanisms of PPT-induced hepatotoxicity using the TEC concept. This approach transforms fragmented toxicity indicators into systematic evidence of toxicity, presenting a hierarchical progression of toxicity evidence and avoiding data accumulation in natural drug toxicology. Our findings represent a significant breakthrough in the elucidation of the mechanisms of hepatotoxicity induced by podophyllotoxin.
研究领域:
药理学
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毒理学
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分子生物学
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蛋白质组学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Dongchao Xu,Ajuan Liu,Qiang Liu,Hongchen Zhang,Mengyao Tian,Ying Bian,Xiaofeng Zhang,Meidan Ying,Hongzhang Shen
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating diseases; it has a considerably poor prognosis and may become the second most lethal malignancy in the next 10 years. Chemotherapeutic resistance is common in PDAC; thus, it is necessary to exploit effective alternative drugs. In recent years, traditional folk medicines and their extracts have shown great potential in cancer treatment. The seed of Lagenaria siceraria (Molina) Standl. is a traditional medicine in Asia. Because of its analgesic effects and ability to reduce swelling, it is often used as an adjuvant treatment for abdominal tumors. Cucurbitacin compounds are extracts abundant in Lagenaria siceraria (Molina) Standl. Here, we found that cucurbitacin C (CuC), a member of the cucurbitacin family, has apparent anti-PDAC therapeutic properties. CuC decreased the viability and suppressed the proliferation of PDAC cells in a time- and dose-dependent manner. Further studies revealed that CuC inhibited cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT). In addition, G2/M arrest was induced, and the apoptotic pathway was activated. Transcriptomic and bioinformatic analyses showed that CuC inhibited the cGMP-PKG-VASP axis, increasing the content of cGMP to restore tumor characteristics. The antitumor activity of CuC in vivo was verified through animal experiments, and no obvious side effects were observed. Overall, our study indicates a candidate therapeutic compound for PDAC that is worthy of further development.
研究领域:
肿瘤学
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药理学
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分子生物学
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传统医学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2022
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IF 5.195
Liqian Chen,Xinghong Zhou,Yijian Deng,Ying Yang,Xiaohu Chen,Qinghong Chen,Yanyan Liu,Xiuqiong Fu,Hiu Yee Kwan,Yanting You,Wen Jin,Xiaoshan Zhao
Ethnopharmacological relevance Zhenwu Decoction (ZWD) is a traditional Chinese medicine (TCM) formula which has wide scope of indications related to Yang deficiency and dampness retention in TCM syndrome. Cardiac hypertrophy can induce similar symptoms and signs to the clinical features of Yang deficiency and dampness retention syndrome. ZWD can increase the left ventricular ejection fraction, reduce cardiac hypertrophy of patients with chronic heart failure. However, its underlying pharmacological mechanism remains unclear. Aim of the study The study aimed to confirm the protective effects of ZWD on cardiac hypertrophy and explore the underlying mechanisms. Materials and methods The potential targets and pathways of ZWD in cardiac hypertrophy were highlighted by network pharmacology and validated by mechanistic and functional studies. Results Our network pharmacology analysis suggests that the protective effects of ZWD on cardiac hypertrophy are related to cyclic guanosine monophosphate (cGMP) - protein kinase G (PKG) pathway. Subsequent animal studies showed that ZWD significantly ameliorated cardiac function decline, cardiac hypertrophy, cardiac fibrosis and cardiomyocyte apoptosis. To explore the underlying mechanisms of action, we performed Western blotting, immunohistochemical analysis, and detection of inflammatory response and oxidative stress. Our results showed that ZWD activated the soluble guanylate cyclase (sGC) - cGMP - PKG signaling pathway. The sGC inhibitor ODQ that blocks the sGC-cGMP-PKG signaling pathway in zebrafish abolished the protective effects of ZWD, suggesting sGC-cGMP-PKG is the main signaling pathway mediates the protective effect of ZWD in cardiac hypertrophy. In addition, three major ingredients from ZWD, poricoic acid C, hederagenin and dehydrotumulosic acid, showed a high binding energy with prototype sGC. Conclusion ZWD reduces oxidative stress and inflammation and exerts cardioprotective effects by activating the sGC-cGMP-PKG signaling pathway.
研究领域:
药理学
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心脏病学
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中医药
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网络药理学
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产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2025
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IF 5.1
Yudong Su,Jinman Shui,Danshi Qi,Jie Bai,Xiaoxia Xu,Yongchun Huang,Ruilian Li,Qiong Wu,Haiyan Wang,Chengzhu Cao,Zhanhai Su,Shoude Zhang
Purpose Erectile dysfunction (ED), a prevalent form of male sexual dysfunction, is predominantly treated with Phosphodiesterase type 5 inhibitors (PDE5Is). Our previous research highlighted procyanidin, a natural compound, as a notably effective PDE5I. In the current study, we intend to further validate the inhibitory activity of procyanidin on PDE5A through in vitro and in vivo assessments. This study aims to validate the efficacy of procyanidin as a treatment for ED.Methods The binding affinity of procyanidin for PDE5A was assessed by molecular docking, molecular dynamics (MD) simulations, and microscale thermophoresis (MST) assay. The toxicity of procyanidin on penile corpus cavernosum smooth muscle (CCSM) cells (n=5) was evaluated. Additionally, its effects on intracellular cyclic guanosine monophosphate (cGMP) levels in CCSM cells (n=5) were evaluated. The absorption of procyanidin was evaluated by measuring plasma levels at various times after oral gavage to Sprague-Dawley (SD) rats (n=6). Subsequently, the effects of procyanidin on intracavernous pressure (ICP) and cGMP levels in penile cavernous tissue were evaluated in SD rats (n=6).Results Procyanidin forms three hydrogen bonds with PDE5A and stabilizes the complex structure, exhibiting equilibrium dissociation constants (KD) value of 7.77 ± 2.39 µmol/L. Additionally, procyanidin exhibits minimal cytotoxicity toward CCSM cells and significantly elevates intracellular cGMP levels compared to the control group. In vivo studies demonstrate that procyanidin is rapidly absorbed, achieving peak blood concentrations within one hour. Simultaneously, procyanidin significantly increases ICP and cGMP levels in rats compared to the control group.Conclusion These findings indicate that procyanidin sustains elevated cGMP levels within cells by targeting PDE5A, thereby exhibiting therapeutic efficacy in improving ICP. Procyanidin emerges as a promising PDE5I for treating ED and potentially other related conditions.
研究领域:
药理学
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泌尿学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
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IF 5.6
Chengsi Li,Jing Li,Chengyingjie Yang,Zhenghao Zhu,Yachen Zhang,Yin Xiang
Chronic kidney disease (CKD) is a condition characterized by progressive loss of kidney function. Vascular calcification is not only a common late-stage complication of CKD but also serves as an independent predictor of cardiovascular events and mortality in CKD patients. This study investigates the mechanism by which vericiguat (VER), a soluble guanylyl cyclase (sGC) sensitizer, attenuates CKD-associated vascular calcification. The hypothesis that vericiguat alleviates the decrease of sGC activity mediated by calcium and phosphorus metabolism was verified in both in vitro and in vivo experimental models. The calcium levels were increased in the aorta of CKD rats and VSMCs in vitro, and the expression of osteogenic differentiation-related markers, eNOS and PKG was upregulated. Nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) levels were downregulated, while VER significantly improved calcification by activating the NO/cGMP/PKG pathway. Meanwhile, L-NAME antagonized the positive effects of VER in either CKD rats or calcified VSMCs.
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DOI
PubMed
高影响因子
ENDOCRINOLOGY
·
2020
·Vol. 162
·期 3
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IF 3.934
Jiang Jingle,Liu Siyi,Qi Lina,Wei Quanwei,Shi Fangxiong
Taste receptors are not only expressed in the taste buds, but also in other nongustatory tissues, including the reproductive system. Taste receptors can be activated by various tastants, thereby exerting relatively physiologic functions. The aim of this study was to investigate the effects and potential mechanisms underlying ovarian taste receptor activation on progesterone production using saccharin sodium as the receptor agonist in a pseudopregnant rat model. Taste 1 receptor member 2 (TAS1R2) and taste 2 receptor member 31 (TAS2R31) were demonstrated to be abundantly expressed in the corpora lutea of rats, and intraperitoneal injection of saccharin sodium can activate both of them and initiate their downstream signaling cascades. The activation of these ovarian taste receptors promoted nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS). NO production then increased ovarian cyclic guanosine 3′,5′-monophosphate (cGMP) levels, which, in turn, decreased ovarian cyclic adenosine 3′,5′-monophosphate levels. In addition, the activation of ovarian taste receptors induced apoptosis, possibly through NO and mitogen-activated protein kinase signaling. As a result, the activation of ovarian taste receptors reduced the protein expression of steroidogenesis-related factors, causing the inhibition of ovarian progesterone production. In summary, our data suggest that the activation of ovarian taste receptors inhibits progesterone production in pseudopregnant rats, potentially via NO/cGMP and apoptotic signaling.
研究领域:
生殖生物学
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药理学
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）