Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that regulate the cellular levels of the second messengers, cAMP and cGMP, by controlling their rates of degradation. There are 11 different PDE families, with each family typically having several different isoforms and splice variants. These unique PDEs differ in their three-dimensional structure, kinetic properties, modes of regulation, intracellular localization, cellular expression, and inhibitor sensitivities. Current data suggest that individual isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the opportunity for selectively targeting specific PDEs for treatment of specific disease states. The feasibility of these enzymes as drug targets is exemplified by the commercial and clinical successes of the erectile dysfunction drugs, sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra). PDE inhibitors are also currently available or in development for treatment of a variety of other pathological conditions. In this review the basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed. How these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered. PDEs hold great promise as drug targets and recent research advances make this an exciting time for the field of PDE research.

Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K Ay and ob/ob (also known as Lep/Lep) micetwo genetic models of obesityhave markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(13)00229-0.pdf

Zebrafish as an emerging model for studying complex brain disorders.

Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents.

More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.

/pdf/animal-models-of-obesity-and-diabetes-mellitus-yeum7tysn3.pdf

Animal models of obesity and diabetes mellitus

A method of arranging a large number of living bodies, such as cells, embryos, or organisms rapidly, individually, and one by one, a holding sheet for the method, and a device for processing the living bodies. The method of holding living bodies includes using a sheet in which multiple through-holes with a size capable of holding one of the target living bodies, but not capable of holding two or more of the living bodies, are provided, to thereby arrange and hold the living bodies one by one in the multiple through-holes in the sheet together with a liquid.

Living body holding method, living body test method, living body growing method, living body holding sheet, and living body processing device

A probe for a hair cell comprises, as an active agent, at least one kind selected from staining compounds represented by the general formula (II):
 
where R 11 and R 12 each independently represent one of a carboxylic acid group, a carboxylic acid ester group, a carboxylic acid amide group, a sulfonic acid group, a sulfonic acid ester group, a sulfonic acid amide group, a carboxylic acid salt, and a sulfonic acid salt; R 13 and R 14 each independently represent one of a hydrogen atom, an alkyl group, and an aryl group, and R 15 , R 16 , R 17A , and R 17B each independently represent one of a hydrogen atom, an alkyl group, an aryl group, and a heterocyclic group; and X 2 - represents an anionic group. The staining compound fluoresces in a near-infrared area. The probe is used as a probe for a hair cell, such as for evaluating auditory toxicity of a chemical substance, for screening and/or evaluating a therapeutic drug and a preventive drug for hearing loss.

Probe for auditory hair cells.

To provide a central nervous system tissue-labeling composition labeling the central nervous tissue system. Also, another object of the present invention is to provide a method for non-invasively labeling the central nervous tissue system. Further, another object of the present invention is to provide a screening method using the above central nervous system tissue-labeling composition. A central nervous system tissue-labeling composition containing, as an active ingredient, at least one of compounds represented by the general formula (1) or (7).

Composition for labeling tissues of central nervous system, method for labeling tissues of central nervous system, and screening method using the composition for labeling tissues of central nervous system

From zebrafish to clinical: Rhamnan sulfate improves constipation with gut microbiota alteration in double-blind placebo-controlled trial.

Anemia, characterized by reduced hemoglobin (Hb), remains a major health concern. Although iron and erythropoietin (EPO) therapies are effective, limitations in safety and accessibility have prompted interest in nutritional alternatives. Hydrolyzed milk-derived peptides (H-MDPs) contain bioactive sequences with diverse physiological effects, yet their role in erythropoiesis remains poorly defined. This study investigated the hematopoietic actions of H-MDP using zebrafish and mouse models. Adult zebrafish underwent phlebotomy-induced anemia and received oral H-MDP for 3 weeks. Hb levels, erythrocyte morphology, and expression of erythropoiesis- and iron-metabolism genes were assessed. In healthy mice, renal Epo expression, circulating EPO, and serum cytokines were measured after 2 weeks of H-MDP administration. H-MDP significantly accelerated Hb recovery in anemic zebrafish (4.6 ± 0.64 g/dL vs. 3.4 ± 0.66 g/dL in untreated fish at week 1) and markedly improved erythrocyte maturation. These effects coincided with strong induction of epo, hif1aa/b, igf1, csf1a, and csf3b in the heart and liver, as well as normalization of anemia-induced hepatic iron-transport genes (tfa, fpn1, tfr2) and reactivation of hamp. In mice, H-MDP elevated renal Epo mRNA and circulating EPO (approximately 2.3-fold) without altering steady-state Hb, and cytokine profiling with IPA-predicted activation of the erythropoietin signaling pathway. Collectively, these findings indicate that H-MDPs modulate erythropoiesis by coordinating the activation of EPO-related and iron-regulatory networks, supporting their potential as functional food ingredients for hematologic recovery and anemia management.

Hydrolyzed Milk-Derived Peptides Promote Erythropoietin Pathways and Hematologic Recovery: A Cross-Species Analysis

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