ACS Pharmacology & Translational Science
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2024
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IF 4.9
Quan Wang,Xinyue Liu,Han Yuan,Fengcai Zhang,Jiafei Wu,Dongjing Yang,Jiang Qian,Yi-You Huang,Guihong Chai,Hai-Bin Luo,Lei Guo
Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (H2S)-donor hybrid PDE10A inhibitor called COS-2080 with a well-defined mechanism of H2S-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, COS-2080 demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called COS-2080-DPI has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of COS-2080 on TGF-β1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, COS-2080 effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.
研究领域:
肺病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Cell Reports
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2025
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IF 6.9
Mingfang Wang,Jia Zeng,Binbin Cui,Guangliang Wu,Xiayu Chen,Yikai Fu,Bing Gu,Yinyue Deng
It was previously demonstrated that intestinal pathogens have evolved different mechanisms to enhance their infection and colonization in the intestines of hosts. However, it is unclear how Shigella effectively survives in the presence of bile salts. Here, we report that the biofilm formation and pathogenicity of S . sonnei are induced by primary bile salts through the two-component system EvgS/EvgA. The response regulator EvgA controls the transcription of the cyclic AMP synthase-encoding gene. Furthermore, the effector protein CRP of the cyclic AMP (cAMP) signal not only positively controls the transcription of ydeH , a gene encoding cyclic di-GMP (c-di-GMP) synthase, but also forms a complex with YdeH to improve its catalytic production of c-di-GMP. Additionally, interacting with YdeH enhances the ability of CRP to bind to the promoter of ydeH . Our work provides insights into how S . sonnei utilizes cascade amplification of c-di-GMP to promote fitness and pathogenicity in response to primary bile salts.
研究领域:
微生物学
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分子生物学
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感染与免疫
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信号转导
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病原生物学
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环境应答
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DOI
PubMed
高影响因子
Journal of Ginseng Research
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2022
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IF 5.735
Ye-ying Jiang,Rong-yun Wei,Kai Tang,Zhen Wang,Ning-hua Tan
Background Mechanisms of synaptic plasticity in retinal ganglion cells (RGCs) are complex and the current knowledge cannot explain. Growth and regeneration of dendrites together with synaptic formation are the most important parameters for evaluating the cellular protective effects of various molecules. The effect of ginsenoside Rg1 (Rg1) on the growth of retinal ganglion cell processes has been poorly understood. Therefore, we investigated the effect of ginsenoside Rg1 on the neurite growth of RGCs. Methods Expression of proteins and mRNA were detected by Western blot and qPCR. cAMP levels were determined by ELISA. In vivo effects of Rg1 on RGCs were evaluated by hematoxylin and eosin, and immunohistochemistry staining. Results This study found that Rg1 promoted the growth and synaptic plasticity of RGCs neurite by activating the cAMP/PKA/CREB pathways. Meanwhile, Rg1 upregulated the expression of GAP43, Rac1 and PAX6, which are closely related to the growth of neurons. Meantime, H89, an antagonist of PKA, could block this effect of Rg1. In addition, we preliminarily explored the effect of Rg1 on enhancing the glycolysis of RGCs, which could be one of the mechanisms for its neuroprotective effects. Conclusion Rg1 promoted neurite growth of RGCs through cAMP/PKA/CREB pathways. This study may lay a foundation for its clinical use of optic nerve diseases in the future.
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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DOI
PubMed
高影响因子
SCHIZOPHRENIA BULLETIN
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2025
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IF 4.8
Fan Rui,Pu Jianlin,Zhang Jin,Yu Minglan,Wang Tingting,Geng Xiaoqi,Dong Wei,Ma Rong,Wang Binglong,Wu Jianfei,Liu Kezhi,Hashimoto Kenji,Xiang Bo
BackgroundSocial withdrawal is a core symptom of schizophrenia (SCZ), yet its underlying molecular mechanisms remain unclear. Gα13 (GNA13), a G protein alpha subunit, has been implicated in SCZ susceptibility. This study investigated the role of Gα13 in social behavior by overexpressing it in the medial prefrontal cortex (mPFC) pyramidal neurons of mice.Study DesignIn this study, we first constructed CRE recombinase overexpressing Gα13 gene mice using CRISPR/Cas9 technology, tested the social behaviors by three-box socialization test, detected the changes of neuronal activities during social activities in mice by calcium signal fiber-optic recordings, observed the changes of dendritic spines by Golgi staining, applied RNA sequencing (RNA-Seq) to find the relevant targets, and observed whether it could reverse the abnormalities by pharmacological experiments social behavior. The electrophysiological characteristics of Gα13 overexpression were investigated using the whole-cell membrane clamp technique, followed by assessment of the severity of SCZ patients and social withdrawal using the PANSS scale and measurement of human plasma Gα13 protein levels using the ELISA technique, and the clinical correlation between the two was assessed.Study ResultsGα13 overexpression (Gα13-OE) mice exhibited significant social deficits in the three-chamber test, showing reduced sociability but normal social novelty recognition. Fiber photometry recordings revealed decreased neuronal activity during social interactions, and Golgi staining showed reduced dendritic spine density in mPFC pyramidal neurons. RNA-Seq identified downregulation of Adcyap1, affecting the cAMP/PKA signaling pathway and NMDA receptor (NMDAR) function. Pharmacological activation of Adcyap1 with PACAP-38 or NMDAR with D-cycloserine rescued the social deficits and restored synaptic function. Conversely, knockdown of Gα13 in an MK-801-induced SCZ mouse model ameliorated social behavior abnormalities. Clinically, patients with SCZ exhibited elevated plasma levels of Gα13, which positively correlated with the severity of social withdrawal symptoms measured by the PANSS G16 item.ConclusionsThese findings suggest that overexpression of Gα13 in the mPFC impairs social behavior by disrupting neuronal function and synaptic plasticity via the Adcyap1/cAMP/PKA/NMDAR pathway. Targeting Gα13 may offer a novel therapeutic strategy for addressing social deficits in SCZ.
研究领域:
神经生物学
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精神病学
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分子神经科学
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信号转导
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行为神经科学
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转化医学
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突触生物学
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2023
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IF 14.5
Yue Zhang,Jingwen Gao,Na Li,Peng Xu,Shimeng Qu,Jinqian Cheng,Mingrui Wang,Xueru Li,Yaheng Song,Fan Xiao,Xinyu Yang,Jihong Liu,Hao Hong,Ronghao Mu,Xiaotian Li,Youmei Wang,Hui Xu,Yuan Xie,Tianming Gao,Guangji Wang,Jiye Aa
Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.
研究领域:
神经科学
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药理学
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精神病学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2023
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IF 5.6
Gao Rongyin,Zhang Ximei,Zou Kun,Meng Duo,Lv Jinpeng
Cutaneous pigmentation was recently shown to be an event regulated by clock proteins. Cryptochrome (CRY) is a key protein composing the feedback loop of circadian clock, however, the function of CRY in melanocytes remains unclear. Here, we found that KL001, a synthetic small molecule modulator of CRY1, inhibited melanin synthesis, as well as reduced melanocyte dendrite elongation and melanosome transport. In addition, the dominant role of CRY1 in KL001-induced anti-melanogenesis was revealed by small interfering RNA transfection. Cellular tyrosinase activity and expression level of melanogenic proteins, including tyrosinase, TRP-1, TRP-2, and transport proteins like Rab27a, Cdc42 and Myosin Va induced by α-MSH were remarkably reversed after KL001 treatment. Mechanistically, CRY1 activation inhibited melanogenesis through CREB-dependent downregulation of MITF and CREB phosphorylation was mediated by classical cAMP/PKA pathway. In addition, the other CRY1 activator, KL044 also suppressed cAMP/PKA/CREB pathway and inhibited melanogenesis. Finally, anti-melanogenic efficacy of KL001 was confirmed by determination of melanin contents in UVB-tanning model of brown guinea pigs, which indicated that targeting CRY1 activity, via topical application of small molecule activator, can be utilized therapeutically to manage human pigmentary disorders.
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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皮肤科
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
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IF 8.2
Qiuyang Huang,Xiaoling Zang,Zhiwei Zhang,Hang Yu,Baoyan Ding,Zhuangzhuang Li,Simin Cheng,Xin Zhang,Mustafa R.K. Ali,Xue Qiu,Zhihua Lv
The discovery of new anti-cancer drugs targeting the PD-1/PD-L1 pathway has been a research hotspot in recent years. In this study, biological affinity ultrafiltration (BAU), UPLC-HRMS, molecular dynamic (MD) simulations and molecular docking methods were applied to search for endogenous active compounds that can inhibit the binding of PD-L1 to PD-1. We screened dozens of potential cancer related endogenous compounds. Surprisingly, cyclic adenosine monophosphate (cAMP) was found to have a direct inhibitory effect on the PD-1/PD-L1 binding with an in vitro IC 50 value of about 36.4 ± 9.3 μM determined by homogeneous time-resolved fluorescence (HTRF) assay. cAMP could recover the proliferation of Jurkat T cells co-cultured with DU-145 cells and may suppress PD-L1 expression of DU-145 cells. cAMP was demonstrated to bind and induce PD-L1 dimerization by FRET assay, and also predicted by MD simulations and molecular docking. The finding of cAMP as a potential inhibitor directly targeting the PD-1/PD-L1 interaction could advance our understanding of the activity of endogenous compounds regulating PD-L1.
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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细胞生物学
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DOI
PubMed
高影响因子
FASEB JOURNAL
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2025
·Vol. 39
·期 8
·e70510
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IF 4.2
Songlun Jiang,Xu Zhang,Fanfan Chen,Zifan Zhao,Chenglong Zhang,Yuchun Sun
Bone organoids offer potential for bone regeneration and in vitro organ models. Current limitations in bone organoid culture systems include low efficiency in construction and functionality, as well as increased apoptosis in prolonged cultures of larger sizes. The ketone body 3-hydroxybutyrate (3HB), synthesized in the liver, addresses these challenges effectively. Our findings suggest that 3HB increases intracellular calcium ion (Ca 2+ ) levels in human bone marrow-derived mesenchymal stem cells (hBMSCs) by activating the hydroxycarboxylic acid receptor 2 (HCAR2). This activation initiates the cAMP/PKA/CREB pathway, which elevates the expression of anti-apoptotic genes such as myeloid cell leukemia 1 (MCL1) and B cell lymphoma 2-related protein A1 (BCL2A1), thereby reducing apoptosis. Furthermore, this pathway boosts the expression of osteogenic proteins, including Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2), facilitating osteogenesis in bone organoids. Consequently, 3HB may enhance the construction of bone organoids that are more mature, larger, and have longer viability. Graphical Our study demonstrates that 3-Hydroxybutyrate (3HB) activates the HCAR2 receptor in hBMSCs, leading to an increase in intracellular calcium levels and subsequent activation of the cAMP/PKA/CREB signaling pathway. This pathway upregulates the expression of the anti-apoptotic molecule MCL1 and early osteogenic factors RUNX2 and BMP2. These dual effects of 3HB, promoting osteogenesis and inhibiting apoptosis, provide a promising strategy for constructing more viable and mature bone organoids with higher efficiency.
研究领域:
再生医学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2024
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IF 2.5
Le Wang,Zhaobin Lei,Guanjie Zhang,Yang Cheng,Mingwei Zhong,Guangyong Zhang,Sanyuan Hu
The escalating incidence of metabolic pathologies such as obesity and diabetes mellitus underscores the imperative for innovative therapeutics targeting lipid metabolism modulation. Within this context, augmenting thermogenic processes in adipose cells emerges as a viable therapeutic approach. Given the limitations of previous β3-adrenergic receptor (β3-AR) agonist treatments in human diseases, there is an increasing focus on therapies targeting the β2-adrenergic receptor (β2-AR). Olodaterol (OLO) is a potent β2-AR agonist that is a potential novel pharmacological candidate in this area. Our study explores the role and underlying mechanisms of OLO in enhancing brown adipose thermogenesis, providing robust evidence from in vitro and in vivo studies. OLO demonstrated a dose-dependent enhancement of lipolysis, notably increasing the expression of Uncoupling Protein 1 (UCP1) and raising the rate of oxygen consumption in primary brown adipocytes. This suggests a significant increase in thermogenic potential and energy expenditure. The administration of OLO to murine models noticeably enhanced cold-induced nonshivering thermogenesis. OLO elevated UCP1 expression in the brown adipose tissue of mice. Furthermore, it promoted brown adipocyte thermogenesis by activating the β2-AR/cAMP/PKA signaling cascades according to RNA sequencing, western blotting, and molecular docking analysis. This investigation underscores the therapeutic potential of OLO for metabolic ailments and sheds light on the intricate molecular dynamics of adipocyte thermogenesis, laying the groundwork for future targeted therapeutic interventions in human metabolic disorders.
研究领域:
药理学
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代谢学
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内分泌学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2016
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IF 2.326
Tongliang Xia,Bin Huang,Shilei Ni,Lei Gao,Jiangang Wang,Jian Wang,Anjing Chen,Shaowei Zhu,Benlin Wang,Gang Li,Shugan Zhu,Xingang Li
This study describes the use of poly(propylene carbonate) (PPC) electrospun microfibres impregnated with a combination of dibutyryl cyclic adenosine monophosphate (db-cAMP) and chondroitinase ABC (ChABC) in the treatment of right-side hemisected spinal cord injury (SCI). Release of db-cAMP and/or ChABC from the microfibres was assessed in vitro using high-performance liquid chromatography (HPLC). Drug-impregnated microfibres were implanted into the hemisected thoracic spinal cord of rats, and treatment was evaluated using functional recovery examinations and immunohistochemistry . Our results demonstrated that the microfibres containing db-cAMP and/or ChABC displayed a stable and prolonged release of each agent. Sustained delivery of db-cAMP and/or ChABC was found to promote axonal regenerative sprouting , functional recovery, and reduced glial scar formation when compared to untreated control animals. The combination of both db-cAMP and ChABC was determined to be more effective than using either drug alone in the treatment of SCI. These findings demonstrate the feasibility of using PPC electrospun microfibres for multi-drug combination therapy in SCI.
研究领域:
神经科学
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再生医学
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药理学
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产品关联
DOI
PubMed
高影响因子
RESEARCH IN MICROBIOLOGY
·
2025
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IF 3.4
Haoying Zhang,Qi Zhang,Ting Zuo,Ziqi Wang,Jianmin Liao,Yuanyuan Lu
Candida albicans is an opportunistic pathogen, and the formation of its biofilm makes it resistant to traditional antifungal therapy. Anthraquinones have universal antibacterial activity. We evaluated the inhibitory effects of 2-chloromethyl anthraquinone on C. albicans adhesion, mycelial morphology transformation, and biofilm formation. The results showed that 2-chloromethyl anthraquinone could inhibit C. albicans adhesion, mycelium formation, and biofilm formation in a dose-dependent manner at 2 μg/mL. In addition, 2-chloromethyl anthraquinone significantly inhibited the expression of biofilm formation-related genes in C. albicans , including ALS1 , CPH1 , ECE1, HWP1 , TEC1 , BCR1 , and UME6 . In addition, Ras1-cAMP-Efg1 pathway-related genes ( RAC1 , CYR1 , and TPK2) were also significantly down-regulated, indicating that the inhibitory effect of 2-chloromethyl anthraquinone on C. albicans biofilms may be related to the Ras1-cAMP-Efg1 signaling pathway. In summary, the results of this study confirmed the inhibitory mechanism of 2-chloromethyl anthraquinone on the virulence factors of C. albicans , which laid a theoretical foundation for its use as an anti-biofilm agent against C. albicans .
研究领域:
微生物学
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真菌学
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药理学
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产品关联
DOI
PubMed
高影响因子
Molecular Metabolism
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2024
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IF 7
Junyong Wang,Yaping Guo,Yunduan He,Yifan Qin,Xiuling Li,Ling Yang,Kangdong Liu,Li Xiao
Objective Nonalcoholic fatty liver disease (NAFLD) is an emerging public health threat as the most common chronic liver disease worldwide. However, there remains no effective medication to improve NAFLD. G protein-coupled receptors (GPCRs) are the most frequently investigated drug targets family. The Regulator of G protein signaling proteins 14 (RGS14), as an essential negative modulator of GPCR signaling, play important regulatory roles in liver damage and inflammatory responses. However, the role of RGS14 in NAFLD remains largely unclear. Methods and Results In this study, we found that RGS14 was decreased in hepatocytes in NAFLD individuals in a public database. We employed genetic engineering technique to explore the function of RGS14 in NAFLD. We demonstrated that RGS14 overexpression ameliorated lipid accumulation, inflammatory response and liver fibrosis in hepatocytes in vivo and in vitro . Whereas, hepatocyte specific Rgs14 -knockout ( Rgs14 -HKO) exacerbated high fat high cholesterol diet (HFHC) induced NASH. Further molecular experiments demonstrated that RGS14 depended on GDI activity to attenuate HFHC-feeding NASH. More importantly, RGS14 interacted with Guanine nucleotide-binding protein (Gi) alpha 1 and 3 (Giα1/3, gene named GNAI1/3 ), promoting the generation of cAMP and then activating the subsequent AMPK pathways. GNAI1/3 knockdown abolished the protective role of RGS14, indicating that RGS14 binding to Giα1/3 was required for prevention against hepatic steatosis. Conclusions RGS14 plays a protective role in the progression of NAFLD. RGS14-Giα1/3 interaction accelerated the production of cAMP and then activated cAMP-AMPK signaling. Targeting RGS14 or modulating the RGS14-Giα1/3 interaction may be a potential strategy for the treatment of NAFLD in the future.
研究领域:
分子生物学
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药理学
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肝病学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
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