Redox modulation of stress resilience by Crocus sativus L. for potential neuroprotective and anti-neuroinflammatory applications in brain disorders: From molecular basis to therapy.

Recent evidence demonstrates that Crocus sativus L. (saffron) counteracts oxidative stress, mitochondrial dysfunction and neuroinflammation, closely linked to initiation and progression of major brain pathologies. Interestingly, saffron constituents such as crocin, crocetin and safranal can exert antioxidant or toxic effects depending on their endogenous concentration. According to the hormesis principles, at low dose they act as antioxidants in a wide range of brain diseases by upregulating Nrf2 signaling pathway and the expression of vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system. Importantly, neuronal dysregulation of Nrf2 pathway can be a prominent cause of selective susceptibility, under neuroinflammatory conditions, due to the high vulnerability of brain cells to oxidative stress. Here we discuss natural inducers from saffron targeting Nrf2/vitagene pathway for development of new therapeutical strategies to suppress oxidative stress and neuroinflammation and consequently cognitive dysfunction. In this review we also focus on the hormetic effect of saffron active constituents, summarizing their neuroprotective and anti-neuroinflammatory properties, as well as pharmacological perspectives in brain disorders.

[Diagnostic and therapeutic procedures by doctors for patients in a hypertensive crisis. An inquiry in 56 internal medicine clinics]. / Diagnostisches und therapeutisches Vorgehen von Arzten bei Patienten mit hypertensiver Krise. Eine Umfrage an 56 internistischen Kliniken.

BACKGROUND AND OBJECTIVE: Despite official guidelines on the diagnosis and treatment of hypertensive crisis, the extent to which they are being followed in routine medical practice is unknown. This study was undertaken to discover how hospital doctors were handling cases of hypertensive crisis (HC). MATERIALS AND METHODS: Physicians were requested to participate in a multiple-choice questionnaire study, relating to the diagnosis of HC, any emergency diagnosis and choice of antihypertensive drugs, these questionnaires to be distributed among the medical staff. Ultimately 463 questionnaires (one per doctor) were sent out and 325 were completed (response rate of 70%). RESULTS: The most frequently mentioned blood pressure values characteristics for HC were > 200 systolic and > 120 diastolic. 160/90 was given most often as the therapeutic goal, which most doctors wanted to reach in an HC within 30 to 60 min. The calcium-antagonist nifedipine was the drug of first choice for almost all clinical presentations. Second was intravenously urapidil, an alpha-agonist. Nitroglycerin was named as first choice only for pulmonary oedema or myocardial infarction. In everyone of the stated conditions most doctors were eager to avoid using beta-blockers. As for the drug of first choice in associated myocardial infarction, 111 doctors named nifedipine, 28 wanted to avoid it and 45 considered it contraindicated. CONCLUSION: These data show a marked discrepancy between recommended guidelines and actual practice in the management of hypertensive crisis.

L-arginine suppresses lipopolysaccharide-induced expression of RANTES in glomeruli.

Endotoxemia leads to the infiltration of inflammatory cells in glomeruli and the tubulointerstitium of the kidney. The ultimate mechanisms for this infiltration, however, are not entirely clear. In this study, the glomerular formation of the chemokine RANTES (regulated upon activation normal T cell expressed and secreted) was examined in an in vivo model of endotoxemia to evaluate the role the local release of chemokines might play in the regulation of this inflammatory cell infiltrate. Since the beneficial effects of nitric oxide (NO) on immune-mediated tissue injury have been reported, we also examined possible interactions between the chemokine RANTES and the L-arginine/NO pathway. To induce endotoxemia, rats were injected intraperitoneally with lipopolysaccharide (LPS). Glomeruli were isolated over a 24-h time period, and RANTES was assessed by Northern blotting, a chemotactic assay, and a specific enzyme-linked immunosorbent assay. The chemokine release was associated with increased glomerular infiltration of monocytes/macrophages. LPS also stimulated the mRNA expression of inducible NO synthase and increased the release of nitrite into the supernatants of isolated glomeruli. Supplementation of L-arginine intake increased the release of glomerular nitrite and reduced glomerular RANTES expression after the injection of LPS. Inhibition of the L-arginine/NO pathway by the unspecific NO synthase inhibitor N(G)-nitro-L-arginine methylester significantly increased glomerular RANTES mRNA expression and the number of infiltrating glomerular macrophages. These data demonstrate that L-arginine suppresses glomerular RANTES formation and suggest that the chemokine-mediated recruitment of glomerular macrophages in LPS-induced endotoxemia can be modulated by the L-arginine/NO pathway.

Combination treatment of enalapril with nitrendipine in rats with renovascular hypertension.

We have recently shown that treatment with the calcium channel blocker nitrendipine may aggravate albuminuria and glomerular injury in rats with two-kidney, one clip renovascular hypertension if arterial blood pressure is not reduced. To test whether nitrendipine also exerts its adverse renal effects when normotension is achieved, we examined the effect of combined therapy with nitrendipine and the converting enzyme inhibitor enalapril on blood pressure, albuminuria, glomerular filtration rate, and morphology of the nonclipped kidney. Rats treated with enalapril alone or in combination with the diuretic hydrochlorothiazide or rats treated with nitrendipine alone served as controls. Therapy was started 6 weeks after clipping of one renal artery. Nitrendipine alone did not reduce blood pressure but significantly increased albuminuria, diuresis, glomerular filtration rate, and glomerular volume and injury compared with untreated hypertensive controls. Increase of glomerular filtration rate, diuresis, and albuminuria was reversible after withdrawal of nitrendipine. Treatment with enalapril alone decreased blood pressure significantly but not to normotensive levels and was without significant effect on albuminuria and glomerular morphology. The combination of nitrendipine and enalapril reduced blood pressure to normotensive levels and not only prevented the increase of glomerular volume, glomerular filtration rate, diuresis, and albuminuria caused by nitrendipine alone but furthermore improved glomerular injury and albuminuria to levels not significantly different from normotensive controls. Enalapril in combination with the diuretic had similar beneficial effects on blood pressure, albuminuria, and glomerular injury. These data demonstrate that the adverse effects of nitrendipine monotherapy on glomerular structure and function can be prevented by the combination of nitrendipine and enalapril when blood pressure is normalized.

[Morphology and biochemistry of blood of various mustelids. 4. Determination of various metabolites in the arterial plasma of mink--principles of the preparation of standard values for laboratory diagnosis in farm mink (Mustela vison Schreber, 1777)]. / Beiträge zur Morphologie und Biochemie des Blutes einiger Musteliden. 4. Mitteilung: Zur Bestimmung einiger Stoffwechselprodukte im arteriellen Nerzplasma--Grundlagen zur Erstellung labordiagnostischer Arbeitswerte für den Farmnerz (Mustela vison Schreber, 1777).

An account is first given of latest knowledge on how to determine clinico-diagnostic applicability of certain metabolites in mink plasma and serum. Then, statistically treated results obtained from analysis of levels of total protein, albumin, creatinine, urea, total cholesterin, triglyceride, and total bilirubin are tabulated and discussed, with due consideration being given to sexual dimorphism, following determination of those values from arterial plasma of 118 male and 124 female minks, aged between six and seven months and kept under anaesthesia. The following preliminary findings are somewhat worth mentioning: (a) Total cholesterin concentrations in plasma of females were found to be higher than those recorded from the males tested. However, no sex-related differences were established for any of the other parameters. (b) Creatinine, urea, and total cholesterin followed simple normal distribution. However, plasma protein concentrations exhibited no Gaussian distribution until all individual data had been logarithmically transformed. (c) In a complementary model experiment, in which the above plasma data were determined from nine male ferrets, aged between six and seven months, evidence was produced to differentiated effects of neuroleptanalgesia on metabolite concentrations.