Protective effect of resveratrol against caspase 3 activation in primary mouse fibroblasts.

AIM: To study the effect of resveratrol on survival and caspase 3 activation in non-transformed cells after serum deprivation. METHODS: Apoptosis was induced by serum deprivation in primary mouse embryonic fibroblasts. Caspase 3 activation and lactate dehydrogenase release were assayed as cell viability measure by using their fluorogenic substrates. The involvement of PI3K, ERK, JNK, p38, and SIRT1 signaling pathways was also examined. RESULTS: Serum deprivation of primary fibroblasts induced significant activation of caspase 3 within 3 hours and reduced cell viability after 24 hours. Resveratrol dose-dependently prevented caspase activation and improved cell viability with 50% inhibitory concentration (IC50)=66.3+/-13.81 muM. It also reduced the already up-regulated caspase 3 activity when it was added to the cell culture medium after 3 hour serum deprivation, suggesting its rescue effect. Among the major signaling pathways, p38 kinase was critical for the protective effect of resveratrol which was abolished completely in the presence of p38 inhibitor. CONCLUSION: Resveratrol showed protective effect against cell death in a rather high dose. Involvement of p38 kinase in this effect suggests the role of mild stress in its cytoprotective action. Furthermore due to its rescue effect, resveratrol may be used not only for prevention, but also treatment of age-related degenerative diseases, but in the higher dose than consumed in conventional diet

Association between metabolically healthy central obesity in women and levels of soluble receptor for advanced glycation end products, soluble vascular adhesion protein-1, and the activity of semicarbazide-sensitive amine oxidase.

AIM: To determine the levels of circulating soluble receptor for advanced glycation end products (sRAGE), as a biomarker of risk of metabolic syndrome and cardiovascular disease development in centrally obese (CO) women considered metabolically healthy (COH) in comparison with those metabolically unhealthy (COU). METHODS: 47 lean healthy, 17 COH (presenting waist-to-height ratio >/=0.5 but not elevated blood pressure, atherogenic lipid profile, and insulin resistance), and 50 COU (CO presenting >/=2 risk factors) women aged 40-45 years were included. Anthropometric characteristics, blood chemistry and hematology data, adipokines, markers of inflammation, sRAGE, soluble vascular adhesion protein-1 (sVAP-1), and the activity of semicarbazide sensitive amine oxidase (SSAO) were determined. RESULTS: Central obesity associated with low sRAGE levels (lean healthy: 1503+/-633 pg/mL; COH: 1103+/-339 pg/mL, P<0.05; COU: 1106+/-367 ng/mL, P<0.0.1), hyperleptinemia, and elevated markers of inflammation irrespective of the presence or absence of cardiometabolic risk factors. COU women presented high adiponectin levels. SVAP-1 concentrations and the activity of SSAO were similar in all 3 groups. CONCLUSION: COH women present abnormalities in non-standard markers of cardiometabolic risk (sRAGE, leptin, high sensitive C-reactive protein), supporting the view that there is no healthy pattern of obesity. The clinical impact of our findings for future prognosis of metabolically healthy obese subjects remains to be elucidated in longitudinal studies

Association between metabolically healthy central obesity in women and levels of soluble receptor for advanced glycation end products, soluble vascular adhesion protein-1, and the activity of semicarbazide-sensitive amine oxidase

Aim To determine the levels of circulating soluble receptor for advanced glycation end products (sRAGE), as a biomarker of risk of metabolic syndrome and cardiovascular disease development in centrally obese (CO) women considered metabolically healthy (COH) in comparison with those metabolically unhealthy (COU). Methods 47 lean healthy, 17 COH (presenting waist-toheight ratio ≥0.5 but not elevated blood pressure, atherogenic lipid profile, and insulin resistance), and 50 COU (CO presenting ≥2 risk factors) women aged 40-45 years were included. Anthropometric characteristics, blood chemistry and hematology data, adipokines, markers of inflammation, sRAGE, soluble vascular adhesion protein-1 (sVAP-1), and the activity of semicarbazide sensitive amine oxidase (SSAO) were determined. Results Central obesity associated with low sRAGE levels (lean healthy: 1503 ± 633 pg/mL; COH: 1103 ± 339 pg/mL, P < 0.05; COU: 1106 ± 367 ng/mL, P < 0.0.1), hyperleptinemia, and elevated markers of inflammation irrespective of the presence or absence of cardiometabolic risk factors. COU women presented high adiponectin levels. SVAP-1 concentrations and the activity of SSAO were similar in all 3 groups. Conclusion COH women present abnormalities in nonstandard markers of cardiometabolic risk (sRAGE, leptin, high sensitive C-reactive protein), supporting the view that there is no healthy pattern of obesity. The clinical impact of our findings for future prognosis of metabolically healthy obese subjects remains to be elucidated in longitudinal studies

Selegiline : a molecule with innovative potential

Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on-off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson's disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors

Effects of Cariprazine, Aripiprazole, and Olanzapine on Mouse Fibroblast Culture: Changes in Adiponectin Contents in Supernatants, Triglyceride Accumulation, and Peroxisome Proliferator-Activated Receptor-γ Expression

Background and Objectives: The use of the dopamine-partial agonist subclass (also termed dopamine stabilizers) of atypical antipsychotics for the treatment of negative schizophrenia symptoms and some mood disorders has increased recently. Similar to other second-generation antipsychotics (SGAs), aripiprazole (ARI) and cariprazine (CAR) also influence food intake, but the peripheral effects of these drugs on adipose&#8722;tissue homeostasis, including adipokine secretion as well as lipo- and adipogenesis, are not fully elucidated. In this study, we explored the adipocyte-related mechanisms induced by second-generation antipsychotics (SGAs), leading to changes in peripheral signals involved in energy homeostasis. Materials and Methods: CAR, a new SGA, was compared with ARI and olanzapine (OLA), using cell cultures to study adipogenesis, and the expression levels of peroxisome proliferator-activated receptor-&#947; (PPAR-&#947;) was measured in adipocytes derived from mouse fibroblasts, by western blotting on days 7, 14, and 21 postinduction. The triglyceride (TG) content of the cells was also evaluated on day 15 using Oil Red O staining, and the adiponectin (AN) content in the cell culture supernatants was quantified on days 7 and 15 by enzyme-linked immunosorbent assay. Cells were treated with two concentrations of ARI (0.5 and 20 &#181;g/mL), OLA (1 and 20 &#181;g/mL), and CAR (0.1 and 2 &#181;g/mL). Results: Both concentrations of ARI and OLA, as well as the lower concentration of CAR, significantly increased the TG contents. The AN levels in the supernatants were significantly increased by the higher concentration of ARI on days 7 and 15 (p &lt; 0.05). Although PPAR-&#947; levels were not significantly affected by ARI and OLA, the lower concentration of CAR induced a significant time-dependent decrease in PPAR-&#947; expression (p &lt; 0.05). Conclusions: The in vitro adipogenesis considered from TG accumulation, AN secretion, and PPAR-&#947; expression was differently influenced by ARI, CAR, and OLA. Understanding the adipocyte-related mechanisms of antipsychotics could contribute to understanding their weight-influencing effect

Prenatal dietary load of Maillard reaction products combined with postnatal Coca-Cola drinking affects metabolic status of female Wistar rats.

AIM: To assess the impact of prenatal exposure to Maillard reaction products (MRPs) -rich diet and postnatal Coca-Cola consumption on metabolic status of female rats. Diet rich in MRPs and consumption of saccharose/fructose sweetened soft drinks is presumed to impose increased risk of development of cardiometabolic afflictions, such as obesity or insulin resistance. METHODS: At the first day of pregnancy, 9 female Wistar rats were randomized into two groups, pair-fed either with standard rat chow (MRP-) or MRPs-rich diet (MRP+). Offspring from each group of mothers was divided into two groups and given either water (Cola-) or Coca-Cola (Cola+) for drinking ad libitum for 18 days. Oral glucose tolerance test was performed, and circulating markers of inflammation, oxidative stress, glucose and lipid metabolism were assessed. RESULTS: MRP+ groups had higher weight gain, significantly so in the MRP+/Cola- vs MRP-/Cola-. Both prenatal and postnatal intervention increased carboxymethyllysine levels and semicarbazide-sensitive amine oxidase activity, both significantly higher in MRP+/Cola + than in MRP-/Cola-. Total antioxidant capacity was lower in MRP+ groups, with significant decrease in MRP+/Cola + vs MRP-/Cola+. Rats drinking Coca-Cola had higher insulin, homeostatic model assessment of insulin resistance, heart rate, advanced oxidation of protein products, triacylglycerols, and oxidative stress markers measured as thiobarbituric acid reactive substances compared to rats drinking water, with no visible effect of MRPs-rich diet. CONCLUSION: Metabolic status of rats was affected both by prenatal and postnatal dietary intervention. Our results suggest that combined effect of prenatal MRPs load and postnatal Coca-Cola drinking may play a role in development of metabolic disorders in later life

Neuro- és citoprotektív mechanizmusok kutatása. = Studies on neuro- and cytoprotective mechanisms.

Az elmúlt négy évtized magyar gyógyszerkutatásának sikervegyületét, a (-)-deprenylt tanulmányoztuk a neuroprotektív hatás újabb lehetőségeinek feltárására. Vizsgáltuk a deprenyl-N-oxid képződését és farmakokinetikáját. Megállapítottuk, hogy a propargyl-csoporttal rendelkező deprenyl metabolit, a deprenyl-N-oxid nagy koncentrációban sem idéz elő apoptózist, ugyanakkor a belőle kis mennyiségben visszaalakuló deprenyl hatékonyan kivédheti az apoptotikus sejtpusztulást. A neurodegeneratív betegségek gyógykezelésére használt deprenylt p.o. adják 5-10 mg dózisban, melynek 75 %-a "first-pass" metabolizmust szenved. A szokványos dózisban parenterálisan adott (-)-deprenyl elkerülve a "first-pass" metabolizmust bénítja a MAO-A-t is és alkalmas antidepresszív hatás kiváltására. Ebből a szempontból a transzdermális vagy liposzóma készítmény tűnik előnyösebbnek. Az SSAO fiziológiai és pathofiziológiai szerepének megismerését hátráltatja egy szelektív, hatékony és emberi terápiában alkalmazható gátlószer hiánya. Duellinnel kezelt parkinsonos betegeken követtük az SSAO enzim aktivitását. A Duellin carbidopa komponense olyan tartós SSAO-gátolt állapotot hoz létre, mely alkalmas lehet különböző kórképekben az ok-okozat elemzésére. Kapilláris elektroforézis módszert dolgoztunk ki az oxidatív károsodást előidéző reaktív gyökök stabil végtermékeinek meghatározására. A módszer lehetővé teszi új targetek vizsgálatát, melyek szerepe fontosnak tűnik a neuroprotekció kialakulásában. | (-)-Deprenyl, the success compound of the Hungarian drug research in the last four decades, has been studied to reveal new ways of neuroprotection. Metabolic formation and pharmacokinetics of deprenyl-N-oxide have been clarified. This propargyl derivative does not induce apoptosis even at a high concentration, however its small portion is converted back to deprenyl, low concentration of which may prevent apoptotic cell death. Daily 5-10 mg oral deprenyl is used in neurodegenerative diseases, although 75% of the dose undergoes first pass metabolism, and only 25% reaches the systemic circulation. Similar dose of deprenyl given parenterally provides the inhibition of both monoamine oxidase A and B (because of its much less first pass metabolism), resulting in antidepressant effect. Transdermal or liposome formulations seem to be preferred. The lack of effective, selective SSAO inhibitor makes the elucidation of the physiological and pathophysiological role of the enzyme difficult. Serum SSAO activity in parkinsonian patients treated with Duellin was measured. As the hydrazine derivative carbidopa in Duellin provided long-term inhibition of SSAO, it could be used in further studies to clarify SSAO function. Capillary electrophoresis methods have been developed to measure the stable end-products of the cytotoxic reactive oxygen and nitrogen species. These methods allow the study of new targets in neuroprotection

Az amin oxidázok és a NADPH-oxidáz szerepe az ér- és neuronkárosodások kialakulásában (patomechanizmus és gyógyszeres befolyásolás) = Amine-oxidases and NADPH-oxidase-studies on their contribution to vascular and neuronal damages (pathomechanism and drug targets)

A selegilinnek és N-proragyl származékainak (dezmetil-deprenyl, deprenyl-N-oxid) neuroprotektív hatását tanulmányoztuk A-2058 melanóma sejtkultúrán. A sejtkárosodást BSO toxinnal váltottuk ki, mely gátolja a glutation szintézisét, valamint csökkenti az élősejtek számát és a sejt mitózist, miközben növeli az apoptotikus indexet. A selegiline és metabolitjai csökkentik a sejt veszteséget és az apoptotikus indexet. A leghatásosabb antiapoptotikus hatású vegyületnek a dezmetil-deprenyl bizonyult, míg a deprenyl-N-oxid kontroll szinten stabilizálta az élősejtek arányát, növelve a mitotikus indexet a kontrollhoz viszonyítva. A deprenyl-N-oxid ígéretes neuroprotektív vegyületnek tűnik. A selegiline ’first pass’ metabolizmusa jelentős. Jó hatásfokú, tolerálható parenterális út kimunkálása növelhetné a vegyület antidepresszív hatását „sajtreakció” nélkül. A selegiline növelte a magas zsírtartalmú tápon tartott patkányok teljes scavanger kapacitását és kivédte a máj elzsírosodását. Az SSAO enzim exogén szubsztrátja a benzilamin, gátolja az inzulinrezisztencia kialakulását és a glukóz-toleranciát. Az elhízásos és diabéteszes rágcsálómodelleken kapott eredményeink megerősítették az SSAO enzim szubsztrátjának, az orálisan adagolt benzilaminnak a kedvező hatását a szénhidrát- és zsíranyagcserére. A kezelés nem rontotta, inkább javította a nitrogén-monoxid hasznosíthatóságát az aortában. | The neuroprotective effect of selegiline and its N-propargyl derivatives (desmethyl-deprenyl, deprenyl-N-oxide) has been investigated on A-2058 melanoma cell culture. Cell damage was induced by BSO toxicity. BSO inhibits glutation synthesis, decreases viable cell number and mitotic rate, while increased the apoptotic index. Selegiline with its metabolites decreased cell loss and the apoptotic ratio. Desmethyl-deprenyl was the most effective compound decreasing apoptotic activity, while deprenyl-N-oxide stabilized cell number on control level and increased the ratio of mitotic cells above the serum deprived control. Desmethyl-deprenyl supposed to be promising neuroprotective agent. Selegiline has a high rate of ‘first pass’ metabolism. An efficient route of parenteral administration could establish antidepressive activity, without “cheese reaction”. Selegiline treatment of rats kept on high fat diet increased total scavenger capacity and decreased fat content of rat liver. Our results have confirmed the insulinomimetic effect of oral treatment with benzylamine, exogenous substrate of SSAO, using various rodent models of diabetes and obesity. The treatment also improved the bioavailability of nitric oxide in the aorta. Based on these results, further studies on the effect of SSAO substrate amines on carbohydrate and lipid metabolism is reasonable, especially as insulin resistance, obesity and their vascular complications are major health problems

Gyógyszerrosta: a racionális gyógyszeres terápia meghatározó eleme [Deprescribing: an essential part of rational pharmacotherapy]

A gyógyszerrosta (az angol deprescribing magyar megfelelője) tervezett, szisztematikus gyógyszerleépítési folyamat, amely egészségügyi szakember felügyeletével zajlik, és lényegében a helyes gyógyszerrendelési gyakorlat részének tekintendő. A gyógyszerrosta nemcsak a teljes gyógyszerelhagyást jelentheti, hanem a dóziscsökkentés folyamata is lehet. Megtervezése során létfontosságú figyelembe venni a terápiás célkitűzéseket, valamint a beteg egészségi állapotát, időbeli életkilátását, értékrendjét és igényeit. A gyógyszerrosta célja betegenként változhat, alapvetően azonban prioritásnak tekinthető a beteg számára fontos célok elérése, a beteg életminőségének javítása. Közleményünkben a nemzetközi szakirodalom alapján áttekintjük a gyógyszerrosta folyamatának lehetséges célpontjait: azokat a nagy egészségügyi kockázatú betegcsoportokat, amelyeknél előnyös lehet a gyógyszerleépítés; a gyógyszereket és gyógyszercsoportokat, amelyek szedése esetén szükség lehet a terápia felülvizsgálatára; valamint összefoglaljuk a folyamat lehetséges színtereit. Ezenkívül kitérünk a folyamat általános lépéseire, előnyeire, kockázataira, és ismertetjük a rendelkezésre álló specifikus irányelveket, algoritmusokat. Részletesen tárgyaljuk a folyamatot segítő és hátráltató tényezőket, mind az egészségügyi szakemberek, mind pedig a betegek szemszögéből, végül pedig kitérünk a nemzetközi kezdeményezésekre és a gyógyszerrosta jövőjére is. Orv Hetil. 2023; 164(24): 931–941

Shedding light on the pharmacological interactions between µ-opioid analgesics and angiotensin receptor modulators:A new option for treating chronic pain

The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia