Dysregulation of Cyclic AMP and Cyclic PIP Synthesis: Implications for Disease and Advances in Therapeutic Development

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 25 January 2026 | Viewed by 283

Special Issue Editor


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Guest Editor
BioReg Biopharm, Technology Innovation Laboratory, University of Illinois at Chicago, Chicago, IL 60612, USA
Interests: regulation of metabolism; cyclic AMP and the cyclic AMP antagonist prostaglandylinositol cyclic phosphate (cyclic PIP); the development of type-2 diabetes and hypertension

Special Issue Information

Dear Colleagues,

The reversible phosphorylation of proteins is a key control mechanism that regulates cellular processes such as metabolism, cell division, and neurotransmission. Two intracellular regulators, cyclic AMP and cyclic PIP (prostaglandylinositol cyclic phosphate), control the equilibrium between the phospho- and de-phospho-form of key enzymes and, thus, control the activity of these enzymes. Derailing this equilibrium has serious consequences on the well-being of the human body. A simple example from our everyday life is as follows: We know to take the foot from the gas pedal when we want to stop a car because leaving one foot on the gas pedal and the other foot on the brake will use up the brakes too fast. However, we do not apply this knowledge to our bodies. To be fit enough to handle daily stress overloads, we push our bodies, for instance, by drinking a lot of coffee, to stay in shape, or, in biochemical terms, to prepare for an overload of catabolic processes. Generally, we do not give the body enough time and appropriate conditions for anabolic recovery. Besides from this unhealthy lifestyle, some illnesses can derail these control mechanisms. The dysregulation of protein phosphorylation is known to be related, for instance, to illnesses as Alzheimer’s disease, chronic inflammatory disease, cancer, and type 2 diabetes.

Generally, we divide signal transduction into three levels: First, the receptor to which a hormone or neurotransmitter binds. Second, the synthesis of intracellular regulators, which spread the signal inside the cell. Third, resulting regulatory changes. Illnesses such as hypertension are treated with selective beta-adrenoceptor antagonists; illnesses such as asthma are treated with highly selective beta-adrenoceptor agonists. The treatment of illnesses such as type 2 diabetes is more diverse, since patients are treated either with overloads of insulin or with synthetic drugs with different mechanisms of action. Cancer-related hyperphosphorylation has also been subjected to attempted treatment with synthetic protein kinase A inhibitors.

This Special Issue will invite scientists engaged in these or closely related research fields to contribute their views/results. We aim to combine newer research results related to broken signal transduction in this publication. This will give not only an overview on where we stand presently, but, more importantly, these data will show convincing results suggestive of progress. This progress will provide a means for achieving further success, not only for treating single illnesses but also for multiple illnesses. Insofar as they are related to changes of the synthesis of these two regulators, cyclic AMP or cyclic PIP, improvements in treatments for one of these illnesses may inspire improvements in treatments for comparable illnesses.

Dr. Heinrich K Wasner
Guest Editor

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Keywords

  • reversible protein phosphorylation
  • cyclic AMP
  • cyclic PIP
  • signal transduction
  • cyclic AMP antagonist

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Published Papers (1 paper)

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Research

25 pages, 4241 KB  
Article
VDAC1 Intervention Alleviates Bisphenol AF-Induced Succinate Metabolism Dysregulation and Inflammatory Responses
by Xinyu Hong, Ning Wang, Jing Leng, Jing Xu, Kelei Qian, Zhiqing Zheng, Gonghua Tao and Ping Xiao
Pharmaceuticals 2025, 18(11), 1600; https://doi.org/10.3390/ph18111600 - 22 Oct 2025
Abstract
Background/Objectives: Bisphenol AF (BPAF) is a prevalent environmental contaminant with demonstrated metabolic and immunological toxicity. This study aimed to investigate whether VDAC1 (Voltage-Dependent Anion Channel 1) mediates BPAF-induced succinate dysmetabolism and inflammatory responses in macrophages, and to evaluate the therapeutic potential of [...] Read more.
Background/Objectives: Bisphenol AF (BPAF) is a prevalent environmental contaminant with demonstrated metabolic and immunological toxicity. This study aimed to investigate whether VDAC1 (Voltage-Dependent Anion Channel 1) mediates BPAF-induced succinate dysmetabolism and inflammatory responses in macrophages, and to evaluate the therapeutic potential of VDAC1 silencing. Methods: RAW264.7 macrophages were exposed to BPAF (0–2500 nM, 24 h) with or without VDAC1 siRNA transfection. Succinate levels, SDH activity, mitochondrial function (complexes I–V, ATP, membrane potential), and inflammatory markers (TNF-α, IL-6, IL-1β, ROS, MDA) were quantified. A 90-day oral toxicity study in C57BL/6J mice (0–32 mg kg−1) assessed systemic inflammation and hepatic ultrastructure. p38 MAPK/NF-κB signaling was evaluated by Western blot and immunofluorescence. Results: BPAF elevated succinate 2.3-fold and decreased SDH activity by 48%, coinciding with reduced mitochondrial membrane potential and ATP synthesis (p < 0.01). Inflammatory cytokines and ROS were markedly increased. VDAC1 siRNA reversed these perturbations, restored complex II activity, and blunted p38 MAPK/NF-κB activation. In vivo, BPAF dose-dependently increased serum TNF-α, IL-6 and IL-1β, promoted NF-κB nuclear translocation and mitochondrial swelling, without altering body or liver weight; VDAC1 knockdown mitigated these effects. Conclusions: VDAC1 orchestrates BPAF-elicited succinate accumulation and macrophage inflammation via p38 MAPK/NF-κB signaling. Targeted VDAC1 silencing alleviates metabolic and inflammatory injury, offering a promising therapeutic strategy against BPAF-related diseases. Full article
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