Article
Chemistry, Medicinal
Leila Gobejishvili, Walter E. Rodriguez, Philip Bauer, Yali Wang, Chirag Soni, Todd Lydic, Shirish Barve, Craig McClain, Claudio Maldonado
Summary: Low and moderate doses of FLVs-Rol were effective in reducing anesthesia duration, while high doses were not. FLVs were found to affect the rate of rolipram uptake by liver and brain, and a moderate dose of FLVs-Rol attenuated endotoxin-induced PDE4 activity in the liver without affecting the brain. Therefore, FLVs-Rol has potential for clinical application in liver disease treatment with minimal side effects.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2022)
Review
Chemistry, Medicinal
Gang Li, Dengqin He, Xiaojia Cai, Wen Guan, Yali Zhang, Jia-Qiang Wu, Hongliang Yao
Summary: Phosphodiesterase 4 (PDE4) is crucial in various biological processes by hydrolyzing cyclic adenosine monophosphate (cAMP). PDE4 inhibitors have been extensively studied as potential therapeutics for diseases like asthma, chronic obstructive pulmonary disease (COPD), and psoriasis. However, the development of PDE4 inhibitors for COPD and psoriasis has been hindered by side effects such as emesis. This review summarizes the recent advancements in the development of PDE4 inhibitors, focusing on PDE4 sub-family selectivity, dual target drugs, and therapeutic potential, with the aim of facilitating the development of novel PDE4 inhibitors as potential drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Zhihui Fong, Caoimhin S. Griffin, Roddy J. Large, Mark A. Hollywood, Keith D. Thornbury, Gerard P. Sergeant
Summary: P2X1 receptors are inhibited by EPAC activators, while P2X2 current amplitudes are enhanced. PKA activators have no effect on P2X1 receptors but inhibit P2X2 receptors. The inhibitory effects of EPAC on P2X1 receptors can be prevented through mutations and an inhibitor of Rac1.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Neurosciences
Ahmed Maher, Nesrine El Sayed, Heba Nafea, Mohamed Gad
Summary: This study demonstrated that PDE4 inhibitors restore memory through a dual mechanism involving PKA and Epac pathways.
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS
(2022)
Editorial Material
Cell Biology
Liliana Felicia Iannucci, Giulietta Di Benedetto, Konstantinos Lefkimmiatis
Summary: Macroautophagy/autophagy is a cellular process responsible for eliminating and recycling aggregated proteins and damaged organelles. The compartmentalization of PRKA/PKA determines its effects on autophagy, with increased cAMP levels generating different PRKA activity signatures. The distribution of PRKA holoenzymes plays a role in affecting the autophagic flux in specific cell types.
Article
Biochemistry & Molecular Biology
Issaka Yougbare, Therese Keravis, Claire Lugnier
Summary: The study identified the therapeutic effects of NCS 613 on lupus nephritis, demonstrating its ability to reduce systemic inflammation, increase kidney cAMP levels, and improve kidney PDE4 alterations, thereby effectively preventing disease progression.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Review
Cell Biology
Dhritiman Roy, Shivaramakrishnan Balasubramanian, Praveen Thaggikuppe Krishnamurthy, Piyong Sola, Emdormi Rymbai
Summary: Clinicians and researchers are actively exploring safer and novel treatment strategies for Parkinson's disease (PD). Different therapeutic approaches, including dopamine replacement therapy, surgery, and drug interventions, have been used to alleviate symptoms of PD but do not provide a long-term solution. This review focuses on the role of cyclic adenosine monophosphate (cAMP) and the overexpression of phosphodiesterase 4 (PDE4) in the substantia nigra of the brain. It discusses the potential of PDE4 inhibitors (PDE4Is) as neuroprotective and disease-modifying targets for PD.
CELLULAR AND MOLECULAR NEUROBIOLOGY
(2023)
Article
Biology
Abigail Boyd, Ileana V. Aragon, Justin Rich, Will McDonough, Marianna Oditt, Daniel Irelan, Edward Fiedler, Lina Abou Saleh, Wito Richter
Summary: PDE4 inhibitors can cause side effects like nausea and emesis, but targeting individual subtypes may prevent these effects.
Review
Biochemistry & Molecular Biology
Laura Ponsaerts, Lotte Alders, Melissa Schepers, Rubia Maria Weffort de Oliveira, Jos Prickaerts, Tim Vanmierlo, Annelies Bronckaers
Summary: Ischemic stroke is caused by a blocked major cerebral artery, leading to neuroinflammation and neuronal damage. Inhibiting cAMP-specific PDEs shows promise in reducing neuroinflammation and improving functional recovery, with PDE4 inhibition being extensively studied for acute neuroinflammation post-stroke.
Article
Cell Biology
Mitsugi Ookawara, Yasunori Nio
Summary: Phosphodiesterase subtype 4 (PDE4) plays key roles in inflammatory and fibrotic responses by hydrolyzing cyclic AMP, but its inhibition with PDE4 inhibitors can also lead to adverse effects. Studies have shown that PDE4 inhibitors may have beneficial effects on improving symptoms of diabetes, particularly in relation to hyperglycemia and insulin resistance, yet the mechanisms of action in diabetic nephropathy are still unknown.
CELLULAR SIGNALLING
(2022)
Article
Biochemistry & Molecular Biology
Anna Signorile, Consiglia Pacelli, Luigi Leonardo Palese, Arcangela Santeramo, Emilio Roca, Tiziana Cocco, Domenico De Rasmo
Summary: The oxidative phosphorylation system couples electron transfer to oxygen with proton pumping to ensure ATP production. Evidence suggests that the assembly of respiratory chain complexes into supercomplexes can increase efficiency and reduce reactive oxygen species production. Complex I plays a key role in both supercomplex formation and cellular energy production. Activation of the cAMP/PKA cascade enhances supercomplex formation, electron flux, and ATP production rate, accompanied by phosphorylation of the NDUFS4 subunit of complex I.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Plant Sciences
Yinsi Lin, Jianhui Su, Mingqiang Wang, Yanzhen Li, Zhongxiang Zhao, Zhanghua Sun
Summary: This study investigates the therapeutic effects and molecular mechanisms of Hypericum sampsonii in a mouse model of ulcerative colitis. The results demonstrate that Hypericum sampsonii can alleviate ulcerative colitis by improving inflammation, protecting intestinal barrier function, inhibiting PDE4, and activating the PKA/CREB signaling pathway.
JOURNAL OF ETHNOPHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Pritha Mukherjee, Arka Bagchi, Ananya Banerjee, Himansu Roy, Arijit Bhattacharya, Arunima Biswas, Urmi Chatterji
Summary: Ineffective cancer treatment is closely related to the persistence of cancer stem cells (CSCs). The study found that the expression of phosphatidylinositol-3-kinase (PI3K) was upregulated in breast CSCs, while phosphodiesterase 4 (PDE4) levels were higher in breast CSCs compared to normal stem cells. The PDE4 inhibitor rolipram was able to induce cell cycle arrest and apoptosis in CSCs by modulating the PI3K signaling pathway.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Carlos Alberto Arcaro, Renata Pires Assis, Juliana Oriel Oliveira, Neusa Maria Zanon, Silvia Paula-Gomes, Luiz Carlos Carvalho Navegantes, Isis Carmo Kettelhut, Iguatemy Lourenco Brunetti, Amanda Martins Baviera
Summary: The study showed that rolipram, a selective PDE4 inhibitor, can inhibit protein breakdown in skeletal muscles of diabetic rats by activating cAMP downstream effectors, ultimately leading to the preservation of muscle mass.
Review
Biochemistry & Molecular Biology
Claire Lugnier
Summary: Cyclic nucleotide phosphodiesterases (PDEs) play a crucial role in regulating intracellular cAMP and/or cGMP levels by converting cyclic nucleotides to 5'-nucleotides. Among the PDEs, PDE4 represents the largest family and is involved in various tissues and pathologies. Recent development in PDE4 inhibitors has focused on targeting cardiovascular diseases, obesity, diabetes, and other conditions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Yang He, Jun Tang, Meng Zhang, Junjie Ying, Dezhi Mu
Summary: This study investigated the protective effects and mechanisms of human placenta derived mesenchymal stem cells (hPMSCs) transplantation in a rat model of hypoxic-ischemic encephalopathy (HIE). The results showed that hPMSCs transplantation reduced apoptosis and improved long-term neurological prognosis. Furthermore, the downregulation of Sema 3A/NRP-1 expression and activation of the PI3K/Akt/mTOR signaling pathway played a key role in the protective effects of hPMSCs.
Article
Neurosciences
Emily L. Isenstein, Edward G. Freedman, Jiayi Xu, Ian A. DeAndrea-Lazarus, John J. Foxe
Summary: This study evaluated electrophysiological discrimination of parametric somatosensory stimuli in healthy young adults to understand how the brain processes the duration of tactile information. The results showed that participants did not electrophysiologically discriminate between 100 and 115 ms, but they exhibited distinct electrophysiological responses when the deviant stimuli were 130, 145, and 160 ms. These findings contribute to a better understanding of tactile sensitivity in different clinical conditions.
Article
Neurosciences
Juliana R. Souza, Ludmila Lima-Silveira, Daniela Accorsi-Mendonca, Benedito H. Machado
Summary: This study demonstrates that A2A receptors play a crucial role in modulating synaptic transmission in the NTS neurons and are required for the enhancement of glutamatergic transmission observed under short-term sustained hypoxia conditions.
Article
Neurosciences
Miki Hashizume, Rina Ito, Rie Suge, Yasushi Hojo, Gen Murakami, Takayuki Murakoshi
Summary: The basolateral amygdaloid complex (BLA) is closely involved in the formation of emotional memories, including both aversive memory and contextual fear memory. Acute sleep deprivation (SD) disrupts the acquisition of tone-associated fear memory in juvenile rats, but has no significant effect on contextual fear memory. Slow network oscillation in the amygdala contributes to the formation of amygdala-dependent fear memory in relation to sleep.
Article
Neurosciences
Qunxian Wang, Shipeng Guo, Dongjie Hu, Xiangjun Dong, Zijun Meng, Yanshuang Jiang, Zijuan Feng, Weihui Zhou, Weihong Song
Summary: GSDME plays a crucial role in the pathogenesis of Alzheimer's disease by regulating the switch from apoptosis to pyroptosis and participating in neuroinflammatory response. Knockdown of GSDME has been shown to improve cognitive impairments, indicating that GSDME could be a therapeutic target for Alzheimer's disease.