Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats.

Aging is accompanied by an increased prevalence of degenerative conditions, including those affecting ocular health, which significantly impact quality of life and increase the burden on healthcare systems. Among these, retinal aging is of particular concern due to its direct link to vision impairment, a leading cause of disability in the elderly. Vision loss in the aging population is associated with heightened risks of cognitive decline, social isolation, and morbidity. This study addresses the critical gap in our understanding of modifiable lifestyle factors, such as physical exercise, that may mitigate retinal aging and its related pathologies. We investigated the effects of different exercise regimens-voluntary (recreational-type) and forced (high-intensity)-on the retinal health of aging Wistar rats (18-month-old), serving as a model for studying the translational potential of exercise interventions in humans. Male Wistar rats were divided into four groups: a young control (3-month-old) for baseline comparison, an aged sedentary control, an aged group engaging in voluntary exercise via a running wheel in their cage, and an aged group subjected to forced exercise on a treadmill for six sessions of 20 min each per week. After a 6-month experimental period, we assessed retinal function via electroretinography (ERG), measured retinal thickness histologically, and analyzed protein expression changes relevant to oxidative stress, inflammation, and anti-aging mechanisms. Our findings reveal that voluntary exercise positively impacts retinal function and morphology, reducing oxidative stress and inflammation markers while enhancing anti-aging protein expression. In contrast, forced exercise showed diminished benefits. These insights underscore the importance of exercise intensity and preference in preserving retinal health during aging. The study highlights the potential of recreational physical activity as a non-invasive strategy to counteract retinal aging, advocating for further research into exercise regimens as preventative therapies for age-related ocular degenerations.

The influence of the way of regression on the results obtained by the receptorial responsiveness method (RRM), a procedure to estimate a change in the concentration of a pharmacological agonist near the receptor.

The receptorial responsiveness method (RRM) enables the estimation of a change in concentration of an (even degradable) agonist, near its receptor, via curve fitting to (at least) two concentration-effect (E/c) curves of a stable agonist. One curve should be generated before this change, and the other afterwards, in the same system. It follows that RRM yields a surrogate parameter ("cx") as the concentration of the stable agonist being equieffective with the change in concentration of the other agonist. However, regression can be conducted several ways, which can affect the accuracy, precision and ease-of-use. This study utilized data of previous ex vivo investigations. Known concentrations of stable agonists were estimated with RRM by performing individual (local) or global fitting, this latter with one or two model(s), using a logarithmic (logcx) or a nonlogarithmic (cx) parameter (the latter in a complex or in a simplified equation), with ordinary least-squares or robust regression, and with an "all-at-once" or "pairwise" fitting manner. We found that the simplified model containing logcx was superior to all alternative models. The most complicated individual regression was the most accurate, followed closely by the moderately complicated two-model global regression and then by the easy-to-perform one-model global regression. The two-model global fitting was the most precise, followed by the individual fitting (closely) and by the one-model global fitting (from afar). Pairwise fitting (two E/c curves at once) improved the estimation. Thus, the two-model global fitting, performed pairwise, and the individual fitting are recommended for RRM, using the simplified model containing logcx.

Electroretinographical Analysis of the Effect of BGP-15 in Eyedrops for Compensating Global Ischemia-Reperfusion in the Eyes of Sprague Dawley Rats.

Retinal vascular diseases and consequential metabolic disturbances in the eye are major concerns for healthcare systems all around the world. BGP-15, a drug candidate small-molecule [O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime dihydrochloride], has been formerly demonstrated by our workgroup to be retinoprotective both in the short and long term. Based on these results, the present study was performed to investigate the efficacy of BGP in an eyedrop formulation containing sulfobutylether-ß-cyclodextrin (SBECD), which is a solubility enhancer as well. Electroretinographical evaluations were carried out and BGP was demonstrated to improve both scotopic and photopic retinal a- and b-waves, shorten their implicit times and restore oscillatory potentials after ischemia-reperfusion. It was also observed to counteract retinal thinning after ischemia-reperfusion in the eyes of Sprague Dawley rats. This small-molecule drug candidate is able to compensate for experimental global eye ischemia-reperfusion injury elicited by ligation of blood vessels in rats. We successfully demonstrated that BGP is able to exert its protective effects on the retina even if administered in the form of eyedrops.

Assessing the Impact of Influenza Vaccination Timing on Experimental Arthritis: Effects on Disease Progression and Inflammatory Biomarkers.

Numerous studies have indicated a link between vaccines and the exacerbation of autoimmune diseases including rheumatoid arthritis (RA). However, there is no consensus in clinical practice regarding the optimal timing of immunization. Therefore, this study aimed to investigate the impact of the 3Fluart influenza vaccine on the complete Freund's adjuvant (CFA)-induced chronic arthritis rat model and to identify new biomarkers with clinical utility. CFA was injected into the plantar surface of one hind paw and the root of the tail on day 0, and the tail root injection was repeated on day 1. Flu vaccination was performed on day 1 or 7. Paw volume was measured by plethysmometry, mechanonociceptive threshold by dynamic plantar aesthesiometry, neutrophil myeloperoxidase (MPO) activity, and vascular leakage using in vivo optical imaging throughout the 21-day experiment. Inflammatory markers were determined by Western blot and histopathology. CFA-induced swelling, an increase in MPO activity, plasma extravasation in the tibiotarsal joint. Mechanical hyperalgesia of the hind paw was observed 3 days after the injection, which gradually decreased. Co-administration of the flu vaccine on day 7 but not on day 1 resulted in significantly increased heme oxygenase 1 (HO-1) expression. The influenza vaccination appears to have a limited impact on the progression and severity of the inflammatory response and associated pain. Nevertheless, delayed vaccination could alter the disease activity, as indicated by the findings from assessments of edema and inflammatory biomarkers. HO-1 may serve as a potential marker for the severity of inflammation, particularly in the case of delayed vaccination. However, further investigation is needed to fully understand the regulation and role of HO-1, a task that falls outside the scope of the current study.

Therapeutic Aspects of Prunus cerasus Extract in a Rabbit Model of Atherosclerosis-Associated Diastolic Dysfunction.

This study evaluates the potential therapeutic effects of anthocyanin-rich Prunus cerasus (sour cherry) extract (PCE) on atherosclerosis-associated cardiac dysfunction, described by the impairment of the NO-PKG (nitric oxide-protein kinase G) pathway and the antioxidant capacity. Initially, a rabbit model of atherosclerotic cardiovascular disease was established by administering a cholesterol-rich diet, enabling the examination of the impact of 9 g/kg PCE on the pre-existing compromised cardiovascular condition. After that, the animals were divided into four groups for 12 weeks: the (1) untreated control group; (2) PCE-administered healthy rabbits; (3) hypercholesterolemic (HC) group kept on an atherogenic diet; and (4) PCE-treated HC group. Dyslipidemia, impaired endothelial function, and signs of diastolic dysfunction were evident in hypercholesterolemic rabbits, accompanied by a reduced cardiac expression of eNOS (endothelial nitric oxide synthase), PKG, and SERCA2a (sarco/endoplasmic reticulum calcium ATPase 2a). Subsequent PCE treatment improved the lipid profile and the cardiac function. Additionally, PCE administration was associated with elevated myocardial levels of eNOS, PKG, and SERCA2a, while no significant changes in the vascular status were observed. Western blot analysis further revealed hypercholesterolemia-induced increase and PCE-associated reduction in heme oxygenase-1 expression. The observed effects of anthocyanins indicate their potential as a valuable addition to the treatment regimen for atherosclerosis-associated cardiac dysfunction.

Drug Candidate BGP-15 Prevents Isoproterenol-Induced Arrhythmias and Alters Heart Rate Variability (HRV) in Telemetry-Implanted Rats.

Multi-target drug candidate BGP-15 has shown cardioprotective and antiarrhythmic actions in diseased models. Here, we investigated the effects of BGP-15 on ECG and echocardiographic parameters, heart rate variability (HRV), and arrhythmia incidence in telemetry-implanted rats, under beta-adrenergic stimulation by isoproterenol (ISO). In total, 40 rats were implanted with radiotelemetry transmitters. First, dose escalation studies (40-160 mg/kg BGP-15), ECG parameters, and 24 h HRV parameters were assessed. After, rats were divided into Control, Control+BGP-15, ISO, and ISO+BGP-15 subgroups for 2 weeks. ECG recordings were obtained from conscious rats, arrhythmias and HRV parameters were assessed, and echocardiography was carried out. ISO-BGP-15 interaction was also evaluated on an isolated canine cardiomyocyte model. BGP-15 had no observable effects on the ECG waveforms; however, it decreased heart rate. HRV monitoring showed that BGP-15 increased RMSSD, SD1, and HF% parameters. BGP-15 failed to counteract 1 mg/kg ISO-induced tachycardia, but diminished the ECG of ischemia and suppressed ventricular arrhythmia incidence. Under echocardiography, after low-dose ISO injection, BGP-15 administration lowered HR and atrial velocities, and increased end-diastolic volume and ventricle relaxation, but did not counteract the positive inotropic effects of ISO. Two weeks of BGP-15 treatment also improved diastolic function in ISO-treated rats. In isolated cardiomyocytes, BGP-15 prevented 100 nM ISO-induced aftercontractions. Here, we show that BGP-15 increases vagally mediated HRV, reduces arrhythmogenesis, enhances left ventricle relaxation, and suppresses the aftercontractions of cardiomyocytes. As the drug is well tolerated, it may have a clinical value in preventing fatal arrhythmias.

Examination of Preferences for COVID-19 Vaccines in Hungary Based on Their Properties-Examining the Impact of Pandemic Awareness with a Hybrid Choice Approach.

The COVID-19 pandemic has posed a huge challenge to the world in recent years. The development of vaccines that are as effective as possible and accessible to society offers a promising alternative for addressing the problems caused by this situation as soon as possible and to restore the pre-epidemic system. The present study investigated the preferences of residents in Hungary's second-largest city (Debrecen) for the COVID-19 vaccine. To achieve this aim, a discrete choice experiment was conducted with 1011 participants, and the vaccine characteristics included in the design of the experiment were determined by qualitative methods and a pilot survey: (1) country of origin; (2) efficiency; (3) side effect; and (4) duration of protection. During the data collection at three vaccination sites, respondents were asked to choose between three vaccine alternatives and one "no choice" option in eight decision situations. Discrete choice model estimations were performed using a random parameter logit (RPL) specification with the final model extended to include a latent variable measuring pandemic awareness. The results showed that the vaccine with a Chinese country of origin is the least preferred among the respondents, while the Hungarian and the European vaccines are the most preferred. Furthermore, the increase in the vaccine efficiency level increased the respondents' sense of utility for the vaccine; the short-term side effect was preferred to the long-term one; and the increase in the duration of protection provided by the vaccine increased the respondents' sense of utility for the vaccine. Based on the parameter estimated for the latent variable, it can be concluded that as the level of pandemic awareness (which is more positive among people with chronic diseases and less important among health workers) increases, the choice of a vaccine option becomes more preferred among respondents compared to the "no choice". The results of our investigation could contribute towards increasing compliance in the case of the vaccination-rejecting population, not only for COVID-19, but for any kind of vaccination procedure.

Corrigendum: Improved survival and retinal function of aging ZDF rats in long-term, uncontrolled diabetes by BGP-15 treatment.

[This corrects the article DOI: 10.3389/fphar.2021.650207.].

Therapeutic Properties of Ayahuasca Components in Ischemia/Reperfusion Injury of the Eye.

Ischemic eye diseases are major causes of vision impairment. Thus, potential retinoprotective effects of N'N-dimethyltryptamine (DMT) were investigated. To inhibit its rapid breakdown by monoamine-oxidase A (MAO-A) enzyme, DMT was co-administered with harmaline, a ß-carboline in the Amazonian Ayahuasca brew. Using ligation, 60 min of ischemia was provoked in eyes of rats, followed by 7 days of reperfusion whilst animals received harmaline alone, DMT + harmaline, or vehicle treatment. After 1 week of reperfusion, electroretinographical (ERG) measurements, histological analysis, and Western blot were performed. Harmaline alone exhibited retinoprotection in ischemia-reperfusion (I/R) which was, surprisingly, counterbalanced by DMT in case of co-administration. As both MAO-A inhibition and DMT increase serotoninergic tone synergistically, communicated to be anti-ischemic, thus, involvement of other pathways was investigated. Based on our experiments, DMT and harmaline exert opposite effects on important ocular proteins such as PARP1, NFκB, MMP9, or HSP70, each having a critical role in a different mechanism of eye-ischemia-related pathologies, e.g., cell death, inflammation, tissue destruction, and oxidative stress. Since DMT is proclaimed to be a promising drug candidate, its potentially undesirable effect on eye-ischemia should be further investigated. Meanwhile, this experiment revealed the potential therapeutic effect of MAO-A inhibitor harmaline in I/R-related eye diseases.

Cardioprotective Role of BGP-15 in Ageing Zucker Diabetic Fatty Rat (ZDF) Model: Extended Mitochondrial Longevity.

Impaired mitochondrial function is associated with several metabolic diseases and health conditions, including insulin resistance and type 2 diabetes (T2DM), as well as ageing. The close relationship between the above-mentioned diseases and cardiovascular disease (CVD) (diabetic cardiomyopathy and age-related cardiovascular diseases) has long been known. Mitochondria have a crucial role: they are a primary source of energy produced in the form of ATP via fatty acid oxidation, tricarboxylic acid (TCA) cycle, and electron transport chain (ETC), and ATP synthase acts as a key regulator of cardiomyocyte survival. Mitochondrial medicine has been increasingly discussed as a promising therapeutic approach in the treatment of CVD. It is well known that vitamin B3 as an NAD+ precursor exists in several forms, e.g., nicotinic acid (niacin) and nicotinamide (NAM). These cofactors are central to cellular homeostasis, mitochondrial respiration, ATP production, and reactive oxygen species generation and inhibition. Increasing evidence suggests that the nicotinic acid derivative BGP-15 ((3-piperidine-2-hydroxy-1-propyl)-nicotinic amidoxime) improves cardiac function by reducing the incidence of arrhythmias and improves diastolic function in different animal models. Our team has valid reasons to assume that these cardioprotective effects of BGP-15 are based on its NAD+ precursor property. Our hypothesis was supported by an animal experiment where ageing ZDF rats were treated with BGP-15 for one year. Haemodynamic variables were measured with echocardiography to detect diabetic cardiomyopathy (DbCM) and age-related CVD as well. In the ZDF group, advanced HF was diagnosed, whereas the BGP-15-treated ZDF group showed diastolic dysfunction only. The significant difference between the two groups was supported by post-mortem Haematoxylin and eosin (HE) and Masson's trichrome staining of cardiac tissues. Moreover, our hypothesis was further confirmed by the significantly elevated Cytochrome c oxidase (MTCO) and ATP synthase activity and expression detected with ELISA and Western blot analysis. To the best of our knowledge, this is the first study to demonstrate the protective effect of BGP-15 on cardiac mitochondrial respiration in an ageing ZDF model.

The effect of a long-term treatment with cannabidiol-rich hemp extract oil on the adenosinergic system of the zucker diabetic fatty (ZDF) rat atrium.

Cannabidiol (CBD), the most extensively studied non-intoxicating phytocannabinoid, has been attracting a lot of interest worldwide owing to its numerous beneficial effects. The aim of this study was to explore the effect that CBD exerts on the adenosinergic system of paced left atria isolated from obese type Zucker Diabetic Fatty (ZDF) rats, maintained on diabetogenic rat chow, received 60 mg/kg/day CBD or vehicle via gavage for 4 weeks. We found that N6-cyclopentyladenosine (CPA), a relatively stable and poorly transported A1 adenosine receptor agonist, elicited a significantly weaker response in the CBD-treated group than in the vehicle-treated one. In contrast, adenosine, a quickly metabolized and transported adenosine receptor agonist, evoked a significantly stronger response in the CBD-treated group than in the vehicle-treated counterpart (excepting its highest concentrations). These results can be explained only with the adenosine transport inhibitory property of CBD (and not with its adenosine receptor agonist activity). If all the effects of CBD are attributed to the interstitial adenosine accumulation caused by CBD in the myocardium, then a significantly increased adenosinergic activation can be assumed during the long-term oral CBD treatment, suggesting a considerably enhanced adenosinergic protection in the heart. Considering that our results may have been influenced by A1 adenosine receptor downregulation due to the chronic interstitial adenosine accumulation, an adenosinergic activation smaller than it seemed cannot be excluded, but it was above the CBD-naïve level in every case. Additionally, this is the first study offering functional evidence about the adenosine transport inhibitory action of CBD in the myocardium.

The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications.

Recent cardiotropic drug developments have focused on cardiac myofilaments. Danicamtiv, the second direct myosin activator, has achieved encouraging results in preclinical and clinical studies, thus implicating its potential applicability in the treatment of heart failure with reduced ejection fraction (HFrEF). Here, we analyzed the inotropic effects of danicamtiv in detail. To this end, changes in sarcomere length and intracellular Ca2+ levels were monitored in parallel, in enzymatically isolated canine cardiomyocytes, and detailed echocardiographic examinations were performed in anesthetized rats in the absence or presence of danicamtiv. The systolic and diastolic sarcomere lengths decreased; contraction and relaxation kinetics slowed down with increasing danicamtiv concentrations without changes in intracellular Ca2+ transients in vitro. Danicamtiv evoked remarkable increases in left ventricular ejection fraction and fractional shortening, also reflected by changes in systolic strain. Nevertheless, the systolic ejection time was significantly prolonged, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also observed upon danicamtiv treatment in vivo. Taken together, danicamtiv improves cardiac systolic function, but it can also limit diastolic performance, especially at high drug concentrations.

Nicotinic-acid derivative BGP-15 improves diastolic function in a rabbit model of atherosclerotic cardiomyopathy.

BACKGROUND AND PURPOSE: The small molecule BGP-15 has been reported to alleviate symptoms of heart failure and improve muscle function in murine models. Here, we investigated the acute and chronic effects of BGP-15 in a rabbit model of atherosclerotic cardiomyopathy. EXPERIMENTAL APPROACH: Rabbits were maintained on standard chow (control) or atherogenic diet (hypercholesterolemic) for 16 weeks. BGP-15 was administered intravenously (once) or orally (for 16 weeks), to assess acute and chronic effects. Cardiac function was evaluated by echocardiography, endothelium-dependent vasorelaxation was assessed and key molecules in the protein kinase G (PKG) pathway were examined by enzyme-linked immunosorbent assay (ELISA) and western blot. Passive force generation was investigated in skinned cardiomyocytes. KEY RESULTS: Both acute and chronic BGP-15 treatments improved the diastolic performance of the diseased heart. However, vasorelaxation and serum lipid markers were unaffected. Myocardial cyclic guanosine monophosphate (cGMP) levels were elevated in the BGP-15-treated group, along with preserved PKG activity and increased phospholamban Ser16-phosphorylation. PDE5 expression decreased in the BGP-15-treated group and PDE1 was inhibited. Cardiomyocyte passive tension reduced in BGP-15-treated rabbits, the ratio of titin N2BA/N2B isoforms increased and PKG-dependent N2B-titin phosphorylation elevated. CONCLUSIONS AND IMPLICATIONS: BGP-15 treatment improves diastolic function, reduces cardiomyocyte stiffness and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP-PKG pathway. As BGP-15 has been proven to be safe, it may be clinically useful in the treatment of diastolic dysfunction.

Changes in the SARS-CoV-2 cellular receptor ACE2 levels in cardiovascular patients: a potential biomarker for the stratification of COVID-19 patients.

Angiotensin-converting enzyme 2 (ACE2) is essential for SARS-CoV-2 cellular entry. Here we studied the effects of common comorbidities in severe COVID-19 on ACE2 expression. ACE2 levels (by enzyme activity and ELISA measurements) were determined in human serum, heart and lung samples from patients with hypertension (n = 540), heart transplantation (289) and thoracic surgery (n = 49). Healthy individuals (n = 46) represented the controls. Serum ACE2 activity was increased in hypertensive subjects (132%) and substantially elevated in end-stage heart failure patients (689%) and showed a strong negative correlation with the left ventricular ejection fraction. Serum ACE2 activity was higher in male (147%), overweight (122%), obese (126%) and elderly (115%) hypertensive patients. Primary lung cancer resulted in higher circulating ACE2 activity, without affecting ACE2 levels in the surrounding lung tissue. Male sex resulted in elevated serum ACE2 activities in patients with heart transplantation or thoracic surgery (146% and 150%, respectively). Left ventricular (tissular) ACE2 activity was unaffected by sex and was lower in overweight (67%), obese (62%) and older (73%) patients with end-stage heart failure. There was no correlation between serum and tissular (left ventricular or lung) ACE2 activities. Neither serum nor tissue (left ventricle or lung) ACE2 levels were affected by RAS inhibitory medications. Abandoning of ACEi treatment (non-compliance) resulted in elevated blood pressure without effects on circulating ACE2 activities. ACE2 levels associate with the severity of cardiovascular diseases, suggestive for a role of ACE2 in the pathomechanisms of cardiovascular diseases and providing a potential explanation for the higher mortality of COVID-19 among cardiovascular patients. Abandoning RAS inhibitory medication worsens the cardiovascular status without affecting circulating or tissue ACE2 levels.

BGP-15 Inhibits Hyperglycemia-Aggravated VSMC Calcification Induced by High Phosphate.

Vascular calcification associated with high plasma phosphate (Pi) level is a frequent complication of hyperglycemia, diabetes mellitus, and chronic kidney disease. BGP-15 is an emerging anti-diabetic drug candidate. This study was aimed to explore whether BGP-15 inhibits high Pi-induced calcification of human vascular smooth muscle cells (VSMCs) under normal glucose (NG) and high glucose (HG) conditions. Exposure of VSMCs to Pi resulted in accumulation of extracellular calcium, elevated cellular Pi uptake and intracellular pyruvate dehydrogenase kinase-4 (PDK-4) level, loss of smooth muscle cell markers (ACTA, TAGLN), and enhanced osteochondrogenic gene expression (KLF-5, Msx-2, Sp7, BMP-2). Increased Annexin A2 and decreased matrix Gla protein (MGP) content were found in extracellular vesicles (EVs). The HG condition markedly aggravated Pi-induced VSMC calcification. BGP-15 inhibited Pi uptake and PDK-4 expression that was accompanied by the decreased nuclear translocation of KLF-5, Msx-2, Sp7, retained VSMC markers (ACTA, TAGLN), and decreased BMP-2 in both NG and HG conditions. EVs exhibited increased MGP content and decreased Annexin A2. Importantly, BGP-15 prevented the deposition of calcium in the extracellular matrix. In conclusion, BGP-15 inhibits Pi-induced osteochondrogenic phenotypic switch and mineralization of VSMCs in vitro that make BGP-15 an ideal candidate to attenuate both diabetic and non-diabetic vascular calcification.

A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far.

In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A1 adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A1 adenosine receptor agonists (determined using concentration/effect (E/c) curves) if NBTI, a nucleoside transport inhibitor, was present. Based on mathematical modeling, we hypothesized that FSCPX blunted the cardiac interstitial adenosine accumulation in response to nucleoside transport blockade, probably by inhibiting CD39 and/or CD73, which are the two main enzymes of the interstitial adenosine production in the heart. The goal of the present study was to test this hypothesis. In vitro CD39 and CD73 inhibitor assays were carried out; furthermore, E/c curves were constructed in isolated, paced rat and guinea pig left atria using adenosine, CHA and CPA (two A1 adenosine receptor agonists), FSCPX, NBTI and NBMPR (two nucleoside transport inhibitors), and PSB-12379 (a CD73 inhibitor), measuring the contractile force. We found that FSCPX did not show any inhibitory effect during the in vitro enzyme assays. However, we successfully reproduced the paradox effect of FSCPX in the rat model, mimicked the "paradox" effect of FSCPX with PSB-12379, and demonstrated the lipophilia of FSCPX, which could explain the negative outcome of inhibitor assays with CD39 and CD73 dissolved in a water-based solution. Taken together, these three pieces of indirect evidence are strong enough to indicate that FSCPX possesses an additional action besides the A1 adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.

Improved Survival and Retinal Function of Aging ZDF Rats in Long-Term, Uncontrolled Diabetes by BGP-15 Treatment.

Retinal complications of diabetes often lead to deterioration or even loss of vision. This hastens discovery of pharmacological agents able to counterbalance diabetic retinopathy. BGP-15, an emerging small molecule agent, was formerly proven by our workgroup to be retinoprotective on nonobese diabetic animals, Goto-Kakizaki rats. In the present study, we aimed to examine its long-term tolerability or incidental side effects on obese-prone Zucker diabetic fatty (ZDF) rats to further increase the rationale for a future human translation. To make terminal visual status comparable with our other investigations, we also carried out electroretinography (ERG) at the end of the experiment. Our study was started on 16-week-old ZDF rats and lasted for 52 weeks, while BGP was administered daily by gavage. During the 12 months of treatment, 100% of BGP-treated animals survived compared to the non-treated ZDF group, where 60% of the animals died, which was a statistically significant difference. Based on ERG results, BGP-15 was able to counterbalance visual deterioration of ZDF rats caused by long-term diabetes. Some moderate but significant changes were seen in OGTT results and some relationship to oxidative stress by the western blot method: BGP-15 was able to increase expression of HSP70 and decrease that of NFkB in eyes of rats. These were in concert with our previous observations of SIRT1 increment and MMP9 decrement in diabetic eyes by BGP. In summary, not only is BGP-15 not harmful in the long run but it is even able to reduce the related mortality and the serious consequences of diabetes. BGP-15 is an excellent candidate for future drug development against diabetic retinopathy.

Compounds with Antiviral, Anti-Inflammatory and Anticancer Activity Identified in Wine from Hungary's Tokaj Region via High Resolution Mass Spectrometry and Bioinformatics Analyses.

(1) Background: Wine contains a variety of molecules with potential beneficial effects on human health. Our aim was to examine the wine components with high-resolution mass spectrometry including high-resolution tandem mass spectrometry in two wine types made from grapes with or without the fungus Botrytis cinerea, or "noble rot". (2) For LC-MS/MS analysis, 12 wine samples (7 without and 5 with noble rotting) from 4 different wineries were used and wine components were identified and quantified. (3) Results: 288 molecules were identified in the wines and the amount of 169 molecules was statistically significantly different between the two wine types. A database search was carried out to find the molecules, which were examined in functional studies so far, with high emphasis on molecules with antiviral, anti-inflammatory and anticancer activities. (4) Conclusions: A comprehensive functional dataset related to identified wine components is also provided highlighting the importance of components with potential health benefits.

SIRT1 Activation by Equisetum Arvense L. (Horsetail) Modulates Insulin Sensitivity in Streptozotocin Induced Diabetic Rats.

BACKGROUND: Equisetum arvense L., commonly known as field horsetail is a perennial fern of which extracts are rich sources of phenolic compounds, flavonoids, and phenolic acids. Activation of SIRT1 that was shown to be involved in well-known signal pathways of diabetic cardiomyopathy has a protective effect against oxidative stress, inflammatory processes, and apoptosis that are the basis of diseases such as obesity, diabetes mellitus, or cardiovascular diseases. The aim of our study was to evaluate the antidiabetic and cardioprotective effects of horsetail extract in streptozotocin induced diabetic rats. METHODS: Diabetes was induced by a single intraperitoneal injection of 45 mg/kg streptozotocin. In the control groups (healthy and diabetic), rats were administered with vehicle, whilst in the treated groups, animals were administered with 50, 100, or 200 mg/kg horsetail extract, respectively, for six weeks. Blood glucose levels, glucose tolerance, and insulin sensitivity were determined, and SIRT1 levels were measured from the cardiac muscle. RESULTS: The horsetail extract showed moderate beneficial changes in blood glucose levels and exhibited a tendency to elevate SIRT1 levels in cardiomyocytes, furthermore a 100 mg/kg dose also improved insulin sensitivity. CONCLUSIONS: Altogether our results suggest that horsetail extract might have potential in ameliorating manifested cardiomyopathy acting on SIRT1.

Negative Inotropic Effect of BGP-15 on the Human Right Atrial Myocardium.

Cardiovascular morbidity and mortality carry great socioeconomic burden worldwide that mandates the development of new, efficacious therapeutic agents with limited adverse effects. O-(3-piperidino-2-hydroxy-1-propyl) nicotinic acid amidoxime (BGP-15) is a known, well-tolerable drug candidate that exerts beneficial effects in several disease models. As BGP-15 has a significant structural similarity with propranolol, it arose that BGP-15 might also have a direct effect on the heart. Thus, in the present work, we investigated the effect of BGP-15 and propranolol on the contractility of isolated, paced, human right atrial samples (obtained from patients undergone open-heart surgery), with or without previous isoproterenol (ISO) stimulation (evoking an indirect or direct effect, respectively). We found that both BGP-15 and propranolol exerted direct as well as indirect negative inotropic effects on the atrial myocardium, reaching similar maximal response. However, BGP-15 had considerably smaller potency than propranolol regarding both types of negative inotropy. In addition, BGP-15, in contrast to propranolol, had a significantly greater indirect negative inotropic effect on samples exhibiting strong response to ISO. Moreover, the indirect negative inotropic effect of BGP-15 was significantly greater on samples derived from diabetic patients than on samples obtained from non-diabetic ones. Our results suggest that the enhanced ISO sensitivity is associated with the diabetic state, and BGP-15 exerts greater negative inotropic effect on the human atrial myocardium in both conditions (as compared to the atrial tissue that is not ISO oversensitive and/or diabetic). Additionally, the negative inotropic effects of BGP-15 and propranolol seem to be mediated by in part different molecular pathways in the atrial myocardium.