Phosphodiesterase Inhibitor Research Articles

PDE3 inhibition by cilostazol attenuated developmental hyperserotonemia induced behavioural and biochemical deficits in a rat model of autism spectrum disorder

BackgroundHyperserotonemia, in the early developmental phase generates behavioural and biochemical phenotypes associated with autism spectrum disorder (ASD) in rats. Phosphodiesterase-3 (PDE3) inhibition by cilostazol has been shown to provide benefits in various brain conditions. We investigated the role of a selective PDE3 inhibitor cilostazol on ASD related behavioural phenotypes. MethodAdministration of 5-Methoxytryptamine (5-MT) to rats perinatally (GD12-Parturition) and in early developmental stages (PND0-PND20), resulted into developmental hyperserotonemia (DHS). DHS associated behavioural changes (social behaviour deficits, repetitive behaviour, anxiety and hyperlocomotion) were assessed using a battery of behavioural examinations. Also, effect on biochemical markers related with neuronal function (BDNF – neuronal survival and pCREB – neuronal transcription factor), inflammation (IL-6, IL-10 and TNF-α) and oxidative stress (TBARS and GSH) were studied in important brain areas (frontal cortex, cerebellum, hippocampus, and striatum). Cilostazol was administered in two doses 30 & 60 mg.kg-1 p.o. each day to male rats from PND21 to PND48. ResultAdministration of cilostazol to 5-MT rats resulted in improvement of behavioural deficits. Also, cilostazol administration significantly increased the levels of BDNF, pCREB, IL-10, GSH and significantly decreased TNF-α, IL-6 and TBARS levels in different brain areas. ConclusionDHS during prenatal and early postnatal developmental stages leads to pervasive harm to the serotonergic system, leading to prolonged effects as observed via behavioural and biochemical outcomes of the study. Serotonin regulates early brain neurogenesis, synaptogenesis, and neuronal differentiation probably via the CREB/BDNF pathway and DHS is known to reduce the activity of CREB/BDNF pathway. Cilostazol administration to pups exposed to DHS perinatally has resulted in increase of neurotrophic factors, reduced inflammation and reduced oxidative stress, probably via increased cAMP/CREB/BDNF signalling. Also, improvement in behavioural profile of animals subjected to DHS. Thus, PDE3 and its inhibitors could be considered as molecules of interest for research in developmental disorders.

Compartmentation of cGMP Signaling in Induced Pluripotent Stem Cell Derived Cardiomyocytes during Prolonged Culture.

The therapeutic benefit of stimulating the cGMP pathway as a form of treatment to combat heart failure, as well as other fibrotic pathologies, has become well established. However, the development and signal compartmentation of this crucial pathway has so far been overlooked. We studied how the three main cGMP pathways, namely, nitric oxide (NO)-cGMP, natriuretic peptide (NP)-cGMP, and β3-adrenoreceptor (AR)-cGMP, mature over time in culture during cardiomyocyte differentiation from human pluripotent stem cells (hPSC-CMs). After introducing a cGMP sensor for Förster Resonance Energy Transfer (FRET) microscopy, we used selective phosphodiesterase (PDE) inhibition to reveal cGMP signal compartmentation in hPSC-CMs at various times of culture. Methyl-β-cyclodextrin was employed to remove cholesterol and thus to destroy caveolae in these cells, where physical cGMP signaling compartmentalization is known to occur in adult cardiomyocytes. We identified PDE3 as regulator of both the NO-cGMP and NP-cGMP pathway in the early stages of culture. At the late stage, the role of the NO-cGMP pathway diminished, and it was predominantly regulated by PDE1, PDE2, and PDE5. The NP-cGMP pathway shows unrestricted locally and unregulated cGMP signaling. Lastly, we observed that maturation of the β3-AR-cGMP pathway in prolonged cultures of hPSC-CMs depends on the accumulation of caveolae. Overall, this study highlighted the importance of structural development for the necessary compartmentation of the cGMP pathway in maturing hPSC-CMs.

Metabolic regulation by prostaglandin E2 impairs lung group 2 innate lymphoid cell responses.

Group 2 innate lymphoid cells (ILC2s) play a critical role in asthma pathogenesis. Non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is associated with reduced signaling via EP2, a receptor for prostaglandin E2 (PGE2 ). However, the respective roles for the PGE2 receptors EP2 and EP4 (both share same downstream signaling) in the regulation of lung ILC2 responses has yet been deciphered. The roles of PGE2 receptors EP2 and EP4 on ILC2-mediated lung inflammation were investigated using genetically modified mouse lines and pharmacological approaches in IL-33-induced lung allergy model. The effects of PGE2 receptors and downstream signals on ILC2 metabolic activation and effector function were examined using in vitro cell cultures. Deficiency of EP2 rather than EP4 augments IL-33-induced mouse lung ILC2 responses and eosinophilic inflammation in vivo. In contrast, exogenous agonism of EP4 and EP2 or inhibition of phosphodiesterase markedly restricts IL-33-induced lung ILC2 responses. Mechanistically, PGE2 directly suppresses IL-33-dependent ILC2 activation through the EP2/EP4-cAMP pathway, which downregulates STAT5 and MYC pathway gene expression and ILC2 energy metabolism. Blocking glycolysis diminishes IL-33-dependent ILC2 responses in mice where endogenous PG synthesis or EP2 signaling is blocked but not in mice with intact PGE2 -EP2 signaling. We have defined a mechanism for optimal suppression of mouse lung ILC2 responses by endogenous PGE2 -EP2 signaling which underpins the clinical findings of defective EP2 signaling in patients with NERD. Our findings also indicate that exogenously targeting the PGE2 -EP4-cAMP and energy metabolic pathways may provide novel opportunities for treating the ILC2-initiated lung inflammation in asthma and NERD.

ENHANCING THE SOLUBILITY OF DIPYRIDAMOLE BY LIQUISOLID COMPACTS BASED ON A FACTORIAL DESIGN APPROACH

Dipyridamole is a phosphodiesterase inhibitor used to prevent postoperative thromboembolic events. It is a poorly water-soluble drug with absolute bioavailability of 37-66 %. Water-insoluble drugs still have a poor dissolution rate, one of the biggest problems facing the pharmaceutical industry. To improve the dissolution rate of Dipyridamole, liquisolid compacts were developed in the present study. Liquidsolid formulations were prepared using Peceol, Avicel PH 112, and Aerosil, in different ratios, as a non-volatile solvent, carrier material and coating material respectively. Excipients and drug interactions were characterized through FT-IR. These studies showed no interaction between excipients and drug. 32 factorial design approach was implemented. The formulations were optimized using Design Expert version 13.00 (StatEase Inc., Minneapolis, MN, USA). An optimal formulation exhibited an angle of repose of 25.12°, a hardness of 3.1 kg/cm2 and a percentage cumulative drug release of 99.22 % after 10 minutes. The observed values were found to be similar to the predicted values. Based on these observations, DPY–O can be considered to be the optimum formulation.

Effects of Extracts and Flavonoids from Drosera rotundifolia L. on Ciliary Beat Frequency and Murine Airway Smooth Muscle.

Extracts from Drosera rotundifolia are traditionally used to treat cough symptoms during a common cold. The present study aimed to investigate the impact of extracts from D. rotundifolia and active compounds on the respiratory tract. Tracheal slices of C57BL/6N mice were used ex vivo to examine effects on airway smooth muscle (ASM) and ciliary beat frequency (CBF). Phosphodiesterase (PDE) inhibition assays were carried out to test whether PDE1 or PDE4 are targeted by the active compounds. An ethanol–water extract, as well as an aqueous fraction of this extract, exerted antispasmodic properties against acetylcholine-induced contractions. In addition, contractions induced by 60 mM K+ were abrogated by the aqueous fraction. Effects on ASM could be attributed to the flavonoids quercetin, 2″-O-galloylhyperoside and hyperoside. Moreover, the Drosera extract and the aqueous fraction increased the CBF of murine tracheal slices. Quercetin and 2″-O-galloylhyperoside were identified as active compounds involved in the elevation of CBF. Both compounds inhibited PDE1A and PDE4D. The elevation of CBF was mimicked by the subtype-selective PDE inhibitor rolipram (PDE4) and by 8-methoxymethyl-IBMX. In summary, our study shows, for the first time, that a Drosera extract and its flavonoid compounds increase the CBF of murine airways while antispasmodic effects were transferred to ASM.

Inhibition of phosphodiesterase: A novel therapeutic target for the treatment of mild cognitive impairment and Alzheimer's disease.

Alzheimer’s disease (AD) is the most common form of dementia and is ranked as the 6th leading cause of death in the US. The prevalence of AD and dementia is steadily increasing and expected cases in USA is 14.8 million by 2050. Neuroinflammation and gradual neurodegeneration occurs in Alzheimer’s disease. However, existing medications has limitation to completely abolish, delay, or prevent disease progression. Phosphodiesterases (PDEs) are large family of enzymes to hydrolyze the 3’-phosphodiester links in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in signal-transduction pathways for generation of 5’-cyclic nucleotides. It plays vital role to orchestrate several pharmacological activities for proper cell functioning and regulating the levels of cAMP and cGMP. Several evidence has suggested that abnormal cAMP signaling is linked to cognitive problems in neurodegenerative disorders like AD. Therefore, the PDE family has become a widely accepted and multipotential therapeutic target for neurodegenerative diseases. Notably, modulation of cAMP/cGMP by phytonutrients has a huge potential for the management of AD. Natural compounds have been known to inhibit phosphodiesterase by targeting key enzymes of cGMP synthesis pathway, however, the mechanism of action and their therapeutic efficacy has not been explored extensively. Currently, few PDE inhibitors such as Vinpocetine and Nicergoline have been used for treatment of central nervous system (CNS) disorders. Considering the role of flavonoids to inhibit PDE, this review discussed the therapeutic potential of natural compounds with PDE inhibitory activity for the treatment of AD and related dementia.

PDE2A Inhibition Enhances Axonal Sprouting, Functional Connectivity, and Recovery after Stroke.

Phosphodiesterase (PDE) inhibitors have been safely and effectively used in the clinic and increase the concentration of intracellular cyclic nucleotides (cAMP/cGMP). These molecules activate downstream mediators, including the cAMP response element-binding protein (CREB), which controls neuronal excitability and growth responses. CREB gain of function enhances learning and allocates neurons into memory engrams. CREB also controls recovery after stroke. PDE inhibitors are linked to recovery from neural damage and to stroke recovery in specific sites within the brain. PDE2A is enriched in cortex. In the present study, we use a mouse cortical stroke model in young adult and aged male mice to test the effect of PDE2A inhibition on functional recovery, and on downstream mechanisms of axonal sprouting, tissue repair, and the functional connectivity of neurons in recovering cortex. Stroke causes deficits in use of the contralateral forelimb, loss of axonal projections in cortex adjacent to the infarct, and functional disconnection of neuronal networks. PDE2A inhibition enhances functional recovery, increases axonal projections in peri-infarct cortex, and, through two-photon in vivo imaging, enhances the functional connectivity of motor system excitatory neurons. PDE2A inhibition after stroke does not have an effect on other aspects of tissue repair, such as angiogenesis, gliogenesis, neurogenesis, and inflammatory responses. These data suggest that PDE2A inhibition is an effective therapeutic approach for stroke recovery in the rodent and that it simultaneously enhances connectivity in peri-infarct neuronal populations.SIGNIFICANCE STATEMENT Inhibition of PDE2A enhances motor recovery, axonal projections, and functional connectivity of neurons in peri-infarct tissue. This represents an avenue for a pharmacological therapy for stroke recovery.

Effects of cilostazol, a Phosphodiesterase-3 inhibitor, on kidney function and redox imbalance in acute kidney injury caused by Bothrops alternatus venom

The mechanisms of pathogenesis of acute kidney injury (AKI) in snakebites is multifactorial and involves hemodynamic disturbances, with release of free radical causing cytotoxic effects. The phosphodiesterase-3 (PDE3) inhibitor, Cilostazol, has been reported to provide protection against renal oxidative stress.Objective: We evaluated the protective effects of cilostazol against Bothrops alternatus snake venom (BaV)-induced nephrotoxicity.Methods: Wistar rat kidneys (n = 6, 260–300 g) were isolated and perfused with Krebs-Henseleit solution containing 6 g/100 mL of bovine serum albumin. After 30 min, the kidneys were perfused with BaV to a final concentration of 1 and 3 μg/mL, and subsequently evaluated for perfusion pressure (PP), renal vascular resistance (RVR), urinary flow (UF), glomerular filtration rate (GFR), and percentage of electrolyte tubular sodium and chloride transport (%TNa+, %TCl–). Oxidative stress and renal histological analyses were performed.Results:BaV caused a reduction in all the evaluated renal parameters (PP, RVR, GFR, UF, %TNa+, and %TCl–). Although only the effects on PP and UF were reversed with cilostazol treatment, the decrease in the malondialdehyde levels, without changes in glutathione levels, further reduced the venom-induced renal tissue changes.Conclusion: Our data suggest that PDE3 is involved in BaV-induced nephrotoxicity, as cilostazol administration significantly ameliorated these effects.

Inhibition of Phosphodiesterase 2 Ameliorates Post-Traumatic Stress-Induced Alcohol Intake Disorder by Regulating cAMP/cGMP Signaling.

Post-traumatic stress disorder (PTSD) is the prevalent psychiatric disorder that induces alcohol use disorders (AUD) such as abnormal alcohol intake and anxiety. However, little is known about whether phosphodiesterase 2 (PDE2)-cAMP/cGMP signaling is involved in PTSD-induced AUD. The present study used single-prolonged stress (SPS) to mimic PTSD that induced increases in ethanol intake and preference (2-bottle choice test) and anxiety-like behavior (elevated-plus maze test and novelty suppressed feeding test). PDE2 inhibitor Bay 60-7550 (Bay) was administered to the mice and protein kinase A (PKA) inhibitor H89 and PKG inhibitor KT5823 were micro-injected into dorsolateral striatum (DLS) and central amygdala (CA) of mice to determine whether the effects of Bay on anxiety-like behavior in SPS mice are brain region dependent. PDE2 inhibitor Bay rescued SPS-induced decreases in open arm entries and open arm time exposure in elevated-plus maze test and reversed increased latency to feed in the novelty suppressed feeding test. Moreover, SPS-induced ethanol use disorder was reversed by Bay as evidenced by decreased ethanol intake and preference without changing total fluid intake in the SPS mice after treatment with Bay. However, Bay did not change the ethanol metabolism or sucrose or quinine intake and preference. The locomotor activity was not affected after treatment with Bay. Interestingly, microinjection of PKA or PKG inhibitor H89 or KT5823 into DLS prevented the effects of Bay on alcohol intake and preference and cAMP-response element binding proteins phosphorylation and brain derived neurotrophic factor expression in DLS but not on the anxiety-like behavior in SPS mice. Microinjection of these inhibitors into CA prevented Bay-induced anxiolytic-like effects and cAMP-response element binding proteins phosphorylation and brain derived neurotrophic factor levels in CA but did not affect ethanol intake in SPS mice, indicating that the effects of Bay on different behaviors are brain region dependent. These findings support the hypothesis that PDE2-cAMP/cGMP signaling may differentially mediate PTSD-induced AUD and anxiety-like behavior.

Cyclic Nucleotide Phosphodiesterases in Alcohol Use Disorders: Involving Gut Microbiota.

Alcohol abuse is 1 of the most significant public health problems in the world. Chronic, excessive alcohol consumption not only causes alcohol use disorder (AUD) but also changes the gut and lung microbiota, including bacterial and nonbacterial types. Both types of microbiota can release toxins, further damaging the gastrointestinal and respiratory tracts; causing inflammation; and impairing the functions of the liver, lung, and brain, which in turn deteriorate AUD. Phosphodiesterases (PDEs) are critical in the control of intracellular cyclic nucleotides, including cyclic adenosine monophosphate and cyclic guanosine monophosphate. Inhibition of certain host PDEs reduces alcohol consumption and attenuates alcohol-related impairment. These PDEs are also expressed in the microbiota and may play a role in controlling microbiota-associated inflammation. Here, we summarize the influences of alcohol on gut/lung bacterial and nonbacterial microbiota as well as on the gut-liver/brain/lung axis. We then discuss the relationship between gut and lung microbiota-mediated PDE signaling and AUD consequences in addition to highlighting PDEs as potential targets for treatment of AUD.

Piezo1 stimulates mitochondrial function via cAMP signaling.

Mechanical signals stimulate mitochondrial function but the molecular mechanisms are not clear. Here, we show that the mechanically sensitive ion channel Piezo1 plays a critical role in mitochondrial adaptation to mechanical stimulation. The activation of Piezo1 induced mitochondrial calcium uptake and oxidative phosphorylation (OXPHOS). In contrast, loss of Piezo1 reduced the mitochondrial oxygen consumption rate (OCR) and adenosine triphosphate (ATP) production in calvarial cells and these changes were associated with increased expression of the phosphodiesterases Pde4a and lower cyclic AMP (cAMP) levels. In addition, Piezo1 increased cAMP production and the activation of a cAMP-responsive transcriptional reporter. Consistent with this, cAMP was sufficient to increase mitochondrial OCR and the inhibition of phosphodiesterases augmented the increase in OCR induced by Piezo1. Moreover, the inhibition of cAMP production or activity of protein kinase A, a kinase activated by cAMP, prevented the increase in OCR induced by Piezo1. These results demonstrate that cAMP signaling contributes to the increase in mitochondrial OXPHOS induced by activation of Piezo1.

The Science of IVM

Oocyte in vitro maturation (IVM) makes use of oocytes from patients that have received minimal or no gonadotrophin stimulation. Whilst this brings many advantages to patients, this typically means oocytes are collected from small-medium sized (4-12 mm) antral follicles. These oocytes are under-developed, and yet removal of these from the follicle and culture in vitro leads to spontaneous oocyte meiotic maturation, without the benefit of the physiological signals that naturally induce oocyte maturation at ovulation. Using animals models, over the past decade seminal advances have been made in our understanding of the fundamental mechanisms regulating oocyte maturation in vivo. Most IVM systems, as practised clinically today, typically do not recapitulate these key cellular processes, possibly accounting for the lower efficiency of IVM compared to IVF. A key objective of modern approaches to IVM is to restore in vitro, as far as possible, the natural processes that occur during oocyte maturation in vivo. One strategy to achieve this in IVM is to: 1) prevent spontaneous meiotic resumption at oocyte collection using phosphodiesterase inhibitors, then 2) artificially maintain or elevate cumulus-oocyte complex (COC) cAMP levels, and finally to 3) induce oocyte meiotic resumption using EGF-like peptides. This typically requires the use of biphasic or 2-step IVM systems. One such biphasic IVM system is called capacitation-IVM (CAPA-IVM), as the oocyte is “capacitated” for development in vitro. CAPA-IVM uses the follicle’s natural oocyte meiotic inhibitor, c-type natriuretic peptide (CNP), in the pre-IVM phase, and amphiregulin as the oocyte meiotic inducer in the second IVM phase. Such biphasic-IVM systems typically lead to subsequent improvements in embryo yield compared to standard IVM, and indeed this is the case for CAPA-IVM. Several pilot RCTs and a large RCT of CAPA-IVM vs conventional IVF have been completed, and CAPA-IVM is now practiced in a few centres globally and is commencing in Sydney. The development and clinical application of modern IVM systems, built on decades of animal scientific research, is a bench-to-bedside success story of biomedical research. IVM is now a viable minimally invasive procedure for the treatment of infertility and for fertility preservation in female cancer patients.

Advancements in the Treatment of Cutaneous Lupus Erythematosus and Dermatomyositis: A Review of the Literature.

BackgroundCutaneous lupus erythematosus (CLE) and dermatomyositis (DM) are autoimmune diseases that present with a wide variety of cutaneous manifestations. In both cases, first-line therapy includes topical corticosteroids. Patients may present with more widespread disease requiring systemic treatments, including corticosteroids, traditional immunosuppressants, or antimalarials. Due to their complex nature, both CLE and DM remain difficult to treat and continue to cause significant distress to patients.ObjectiveTo summarize the most recent literature on the safety and efficacy of novel treatment modalities for CLE and DM.MethodsA literature search was conducted on PubMed using search terms “(dermatomyositis) AND (treatment)” and “(cutaneous lupus) AND (treatment)”. Additional search terms included specific names of biologic agents, phosphodiesterase inhibitors (apremilast), and JAK inhibitors.ResultsJAK inhibitors, PDE-4 inhibitors, and biologics have shown promise in reducing cutaneous symptoms of both CLE and DM, including reduction in SLE Disease Activity Index 2000 (SLEDAI-2K), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), British Isles Lupus Assessment Group (BILAG), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), and Disease Activity Score (DAS).ConclusionWhile there have been recent advancements in the treatment for CLE and DM, further research and clinical trials are required to better elucidate which therapy is best for individual patients.

Cyclic nucleotide phosphodiesterases as therapeutic targets in cardiac hypertrophy and heart failure.

Cyclic nucleotide phosphodiesterases (PDEs) modulate the neurohormonal regulation of cardiac function by degrading cAMP and cGMP. In cardiomyocytes, multiple PDE isozymes with different enzymatic properties and subcellular localization regulate local pools of cyclic nucleotides and specific functions. This organization is heavily perturbed during cardiac hypertrophy and heart failure (HF), which can contribute to disease progression. Clinically, PDE inhibition has been considered a promising approach to compensate for the catecholamine desensitization that accompanies HF. Although PDE3 inhibitors, such as milrinone or enoximone, have been used clinically to improve systolic function and alleviate the symptoms of acute HF, their chronic use has proved to be detrimental. Other PDEs, such as PDE1, PDE2, PDE4, PDE5, PDE9 and PDE10, have emerged as new potential targets to treat HF, each having a unique role in local cyclic nucleotide signalling pathways. In this Review, we describe cAMP and cGMP signalling in cardiomyocytes and present the various PDE families expressed in the heart as well as their modifications in pathological cardiac hypertrophy and HF. We also appraise the evidence from preclinical models as well as clinical data pointing to the use of inhibitors or activators of specific PDEs that could have therapeutic potential in HF.

What's New in Topicals for Atopic Dermatitis?

Atopic dermatitis (AD) is a chronic inflammatory skin condition that can have tremendous impact on quality of life for affected children and adults. First-line therapy for acute management of AD includes topical therapies such as corticosteroids, calcineurin inhibitors, and, more recently, the phosphodiesterase inhibitor crisaborole. Topical agents have remained the mainstay therapy for decades; however, there has been a longstanding need for topical therapies with high efficacy and low risk of adverse effects with long-term use. Given the ongoing advances in understanding the pathogenesis of AD, there are novel targets for pharmacological intervention. We are now in an unprecedented time with more than 40 topical treatments in the pipeline for AD in addition to many developments and treatments on the horizon. This review summarizes selected therapeutic topical agents in later phases of development that target various aspects in the pathogenesis of AD such as Janus kinase inhibition (ruxolitinib and delgocitinib), phosphodiesterase-4 inhibition (roflumilast and difamilast), aryl hydrocarbon modulation (tapinarof), and modulation of the microbiome. We also review novel targeted therapies that are in early phase clinical trials, including AMTX-100, BEN-2293, and PRN473. Preliminary findings on efficacy and tolerability of most of these agents are promising, but further studies are warranted to evaluate the long-term safety and efficacy of these novel agents against the current standard of care.

Exercise During Pregnancy Improves PDE-BKCa Coupling In Cerebral Arteries In Offspring Of Spontaneously Hypertensive Rats

In numerous cardiovascular diseases, Phosphodiesterases (PDEs) mediate ion channel pathological compensation in vascular smooth muscle cells (VSMCs). Our previous studies showed that exercise during pregnancy improves ion channel function in VSMCs of offspring in spontaneously hypertensive rats (SHR). The hypothesis that the pathological compensation of large-conductance Ca2+-activated K+ (BKCa) channels mediated by PDE in cerebral arteries of SHR is tested here. It is further demonstrated that exercise during pregnancy enhances the functional coupling of PDE to BKCa channels to improve cerebral arterial function in the offspring of SHR. PURPOSE: To investigate the effect of exercise during pregnancy on BKCa channel and the role of PDE in regulating BKCa function of cerebral arteries in the offspring of SHR. Methods: Pregnant SHR and Wistar-Kyoto rats (WKY) were separated into a sedentary group (p-WKY-SED, p-SHR-SED) and an exercise group (p-WKY-EX, p-SHR-EX) at random. Exercise group were subjected to swimming (60 min/day, 6 day/week, gestation day 1-19), and the BKCa channel function of the cerebral arteries from the 3-month-old (3 M) offspring were evaluated. Results: Exercise during pregnancy significantly decreased the resting mean arterial blood pressure at 3 M in the offspring of SHR (SHR-EX, 153.2 ± 7.5 vs. SHR-SED, 164.6 ± 3.6 mmHg, p < 0.05). The BKCa current density in p-SHR-SED offspring (49.8 ± 7.3 pA/pF) was markedly higher than that in p-WKY-SED (36.8 ± 6.1 pA/pF, p < 0.05). Exercise during pregnancy significantly decreased BKCa channel currents in p-SHR-EX (33.4 ± 11.2 pA/pF, p < 0.05 vs. p-SHR-SED). After application of PDE inhibitor (cilostamide and Ro-20-1724), the percentage of current enhancement was higher in p-WKY-SED (44.3 ± 15.1%) than in p-SHR-SED (13.5 ± 12.1%, p < 0.05), whereas exercise during pregnancy significantly increased it in p-SHR-EX (45.2 ± 3.1%, p < 0.05 vs. p-SHR-SED). Conclusions: These data suggest that the loss of PDE-BKCa coupling mediates pathological compensation of BKCa channels in the cerebral arteries of SHR offspring. Exercise during pregnancy enhances the coupling, and delays the development of hypertension. Supported by the National Natural Science Foundation of China 32071174.

Sexual dysfunctions and their treatment in liver diseases.

Sexual dysfunction (SD) is a prevalent but very commonly ignored aspect in the treatment of liver diseases and cirrhosis. The etiology of SD is multifactorial and therefore treatment strategies are complex, especially in females. Phosphodiesterase inhibitors are useful and effective in erectile dysfunction in males but in females, no single drug is available for SD, therefore multimodal treatment is required depending upon the cause. The foremost and fundamental requirement in both genders is to be stress-free and have adequate control of liver diseases. Improved quality of life is helpful in improving SD and vice versa is also true. Therefore, patients suffering from liver diseases should come forward and ask for treatment for SD, and physicians should actively enquire about SD while history taking and evaluating these patients. SD results in deterioration of quality of life, and both are modifiable and treatable aspects of liver diseases, which are never addressed actively, due to social taboos and fears of SD treatment in the presence of liver diseases. The diagnosis of SD does not require costly investigations, as the diagnosis can be established based on validated questionnaires available for both genders, therefore detailed targeted history taking using questionnaires is essential. Data are emerging in this area but is still at an early stage. More studies should be dedicated to SD in liver diseases.

Editorial: The relationship between sarcopenia and metabolic diseases: Its formation mechanism and intervention means

hormone and DHEAS levels in elderly men. If the study is confirmed in a larger population, the results obtained may shift the paradigm of drug intervention strategy of sarcopenia [22] . The Ghrelin secret-promoting agent capromorelin increases weight and muscle mass in older adults and improves walking and stair climbing [23,24] . These data suggest that Ghrelin has a potential therapeutic effect on sarcopenia, but more prospective studies are needed to confirm it. Other drugs, such as metformin, anti-Myostain Activin ⅱ receptor, estrogen, and angiotensin converting enzyme inhibitors, are all being studied for intervention of sarcopenia [21] . Other potential targets include PGC-1A, phosphodiesterase inhibitors (PDE), skeletal muscle stem cells, and gene recombination [21,23,24] .In summary, the research on sarcopenia is still in its exploratory stage, and the pathogenesis of sarcopenia is not well understood. For future studies, it is necessary to enhance the efforts on elucidating the underlying cellular and molecular mechanisms, developing validate biomarkers, improving the accuracy of diagnostic tests, solving the problem of consistency of diagnostic criteria, and designing effective strategies for the prevention and treatment of sarcopenia. The editors thank all authors and reviewers for their scientific contributions.

Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors.

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, “precapillary” alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment.

Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs stalled type I topoisomerase (TOP1)-DNA complexes by hydrolyzing the phosphodiester bond between the TOP1 Y723 residue and the 3′-phosphate of its DNA substrate. Although TDP1 antagonists could potentially reduce the dose of TOP1 inhibitors needed to achieve effective anticancer effects, the development of validated TDP1 inhibitors has proven to be challenging. This may, in part, be due to the open and extended nature of the TOP1 substrate binding region. We have previously reported imidazopyrazines and imidazopyridines that can inhibit TDP1 catalytic function in vitro. We solved the TDP1 crystal structures with bound inhibitors of this class and found that the dicarboxylic acid functionality within the N-(3,4-dicarboxyphenyl)-2-diphenylimidazo [1,2-a]pyridin-3-amine platform overlaps with aspects of phosphoryl substrate recognition. Yet phosphonic acids could potentially better-replicate cognate TOP1-DNA substrate binding interactions than carboxylic acids. As reported herein, we designed phosphonic acid-containing variants of our previously reported carboxylic acid-containing imidazopyrazine and imidazopyridine inhibitors and effected their synthesis using one-pot Groebke–Blackburn–Bienayme multicomponent reactions. We obtained crystal structures of TDP1 complexed with a subset of inhibitors. We discuss binding interactions of these inhibitors within the context of phosphate-containing substrate and carboxylic acid-based inhibitors. These compounds represent a new structural class of small molecule ligands that mimic aspects of the 3′-processed substrate that results from TDP1 catalysis.