Can the electrophysiological action of rosiglitazone explain its cardiac side effects?

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A diabetes mellitus immunológiája: a hő-shock proteinek, egyéb endogén anyagok és gyógyszerek kölcsönhatása kardiovaszkuláris szövődmények kialakulására = The immunological aspect of diabetes mellitus: the interactions between heat-shock proteins, endogeneous substances and drugs in cardiovascular complications of diabetes mellitus

Autoimmun diabetes mellitust (DM) váltottunk ki streptozotocin (STZ) kis dózisával (3x30 mg/kg, 40mg/kg) patkányon és histidin dekarboxiláz knock-out (KO) egéren és vizsgáltuk a hőshock fehérjék(hsp) szerepét a DM kialakulásában. Vizsgálatainkat kiterjesztettük az endogén nociceptinerg és a hisztamin rendszer valamint a DM kapcsolatának kutatására. Patkányon a hsp65-el történő immunizálás (mind 1x, mind 2x) nem befolyásolta a magas vércukor értéket , de jelentősen növelte a túlélési százalékot . A hsp-vel történő kezelés hatása a DM-os állatok túlélésére szignifikánsnak bizonyult, azonban a hsp65 ellenanyag szint nem változott, továbbá nem befolyásolta a diabeteszes szívfunkció változást. A KO és vad egerek esetén a STZ kevésbé volt hatékony. A hsp-vel immunizált állatokban a vércukorérték csökkent, de az immunizálás csak a vad egerekben okozott szignifikáns hsp elleni antitest szint növekedést. Humán vizsgálatainkban az IDDM-ban szignifikáns eltolódás találtunk Th1 immunválasz irányába p277 esetén. A patkányokban a nociceptin (NC) a liquorban(CSF) a vizsgált agy részekben jelentős hisztamin szint növekedést okozott. A NC plazma koncentrációja életkorfüggő, a 14. hétre stabilizálódik. A CSF magasabb NC szintet mutat, mint a plazma, viszont a nocistatin (NS) a plazmában található magasabb koncentrációban, mint a CSF-ben. A STZ indukálta DM a NC szintre nincs hatással, viszont a NS koncentrációját mind a három vizsgált szövetben (plazma, CSF, májszövet) jelentősen megemelte. | Diabetes mellitus (DM) considered as autoimmune disease was induced by low dose of streptozotocin (STZ) in rats and histidine decarboxylase knock out (KO) mice. The role of different heat shock proteins (hsp65, p277) in the pathophysiology of DM was investigated. The aim was also to study the relationship between histaminergic and nociceptinegic systems and DM. In the rats STZ (3x30 mg/kg) was able to cause diabetes and the hsp65 treatment significantly increased the survival of the diabetic animals. However, the vaccination with hsp65 cause any significant change in the antibody level. In the case of KO and WT mice the STZ dose (3x 40 mg/kg) was not so effective, a less massive diabetes was observed. Vaccination with both hsp65 and p277 caused a significant decrease of glucose level, but the antibody level increased only in WT animals. Determining Th1 and Th2 cytokine levels in Type 1 diabetic patients we found a shift towards Th1 immun response in the case of p277. Nociceptin (NC) significantly increased the histamine levels in various brain region. In DM in rats NC and nocistatin (NS) levels in plasma and liquor(CSF) were measured. Age dependence of both plasma and CSF NC levels reached the adult level in 14 weeks old rats. NC level was higher in CSF than in plasma, while the NS level showed a contrary tendency. Neither plasma nor CSF NC levels showed significant difference from control in DM, while in the case of NS increased levels were observed in DM

Diabetes mellitus attenuates the repolarization reserve in mammalian heart

Objective: In diabetes mellitus several cardiac electrophysiological parameters are known to be affected. In rodent experimental diabetes models changes in these parameters were reported, but no such data are available in other mammalian species including the dog. The present study was designed to analyse the effects of experimental type I diabetes on ventricular repolarization and its underlying transmembrane ionic currents and channel proteins in canine hearts. Methods and results: Diabetes was induced by a single injection of alloxan, a subgroup of dogs received insulin substitution. After the development of diabetes (8 weeks) electrophysiological studies were performed using conventional microelectrodes, whole cell voltage clamp, and ECG. Expression of ion channel proteins was evaluated by Western blotting. The QT(c) interval and the ventricular action potential duration in diabetic dogs Were moderately prolonged. This was accompanied by significant reduction in the density of the transient outward K+ current (I-to) and the slow delayed rectifier K+ current (I-Ks), to 54.6% and 69.3% of control, respectively. No differences were observed in the density of the inward rectifier K+ current (I-K1), rapid delayed rectifier K+ current (I-Kr), and L-type Ca2+ current (I-Ca). Western blot analysis revealed a reduced expression of Kv4.3 and MinK (to 25 +/- 21% and 48 +/- 15% of control, respectively) in diabetic dogs, while other channel proteins were unchanged (HERG, MiRP1, alpha(1c)) or increased (Kv1.4, KChIP2, KvLQT1). Insulin substitution fully prevented the diabetes-induced changes in I-Ks, KvLQT1 and MinK, however, the changes in I-to, Kv4.3, and Kv1.4 were only partially diminished by insulin. Conclusion: It is concluded that type I diabetes mellitus, although only moderately, lengthens ventricular repolarization, attenuates the repolarization reserve by decreasing I-to and I-Ks currents, and thereby may markedly enhance the risk of sudden cardiac death

Carnosic Acid Inhibits Herpes Simplex Virus Replication by Suppressing Cellular ATP Synthesis

Acquiring resistance against antiviral drugs is a significant problem in antimicrobial therapy. In order to identify novel antiviral compounds, the antiviral activity of eight plants indigenous to the southern region of Hungary against herpes simplex virus-2 (HSV-2) was investigated. The plant extracts and the plant compound carnosic acid were tested for their effectiveness on both the extracellular and intracellular forms of HSV-2 on Vero and HeLa cells. HSV-2 replication was measured by a direct quantitative PCR (qPCR). Among the tested plant extracts, Salvia rosmarinus (S. rosmarinus) exhibited a 90.46% reduction in HSV-2 replication at the 0.47 μg/mL concentration. Carnosic acid, a major antimicrobial compound found in rosemary, also demonstrated a significant dose-dependent inhibition of both extracellular and intracellular forms of HSV-2. The 90% inhibitory concentration (IC90) of carnosic acid was between 25 and 6.25 μg/mL. Proteomics and high-resolution respirometry showed that carnosic acid suppressed key ATP synthesis pathways such as glycolysis, citrate cycle, and oxidative phosphorylation. Inhibition of oxidative phosphorylation also suppressed HSV-2 replication up to 39.94-fold. These results indicate that the antiviral action of carnosic acid includes the inhibition of ATP generation by suppressing key energy production pathways. Carnosic acid holds promise as a potential novel antiviral agent against HSV-2