Abstract

Cisplatin is a potent widely-used chemotherapeutics; however, its clinical use is associated with nephrotoxicity. Renoprotective approaches are being discovered to halt the tubular cell death due to inflammatory and apoptotic burdens. In the present study, the renoprotective effects of different doses of biochanin A (10, 20 or 40?mg/kg) in mice treated with a single injection of cisplatin (10?mg/kg) were reported. Cisplatin administration resulted in marked increases in serum creatinine and blood urea nitrogen. Further, renal homogenates showed increased level of inflammatory cytokines and upregulation of the expression of p53 up-regulated modulator of apoptosis (PUMA), p53 and caspase 3 but downregulation in Nrf2 expression. Furthermore, cisplatin group showed marked necrosis and degenerated tubular lining epithelial cells with frequently detected apoptotic bodies. Mice treated with biochanin A (10, 20 or 40?mg/kg) for 14?days prior to cisplatin abrogated cisplatin-mediated damage. Furthermore, the elevated serum creatinine and urea levels were lessened by some doses of biochanin A, indicating protection against renal injury. Similarly, the changes in apoptosis and inflammatory markers have ameliorated to significant levels (P?<?0.05). The results suggest biochanin A as a nephroprotective agent against cisplatin toxicity. Overall, this nephroprotective effect of biochanin A involved anti-inflammatory and antiapoptotic activities.

Keywords

Acute kidney injury; Biochanin A; Cisplatin; Inflammation; p53 apoptosis; PUMA

Abstract

Midbrain dopamine neuronal loss and neuroinflammation are two phenomena that are associated with brain senescence. Neurotrophic factor changes and oxidative stress could subserve these phenomena. Aging-related brain changes can be well monitored through the cerebrospinal fluid (CSF). The objective was to analyze neurotrophic and oxidative parameters that could be related to midbrain dopamine neuronal loss or brain inflammation in the CSF of elderly subjects: 1) levels of the dopaminotrophic factors BDNF, GDNF, persephin, and neurturin, 2) levels of the proinflammatory factors TGFβ1 and TGFβ2; 3) activity of main antioxidant enzymes (catalases, glutathione-peroxidase, glutathione-reductase, glutathione-S-transferases, peroxirredoxins, and superoxide-dismutases), 4) ferritin content, antioxidant protein which reduces reactive free iron, and 5) antioxidant potential of the cerebrospinal fluid. ELISA and PAO tests were used. Subjects were also evaluated clinically, and the group of old subjects with mild cognitive impairment was studied separately. The findings indicate that normal elderly CSF is devoid of changes in either dopaminotrophic or proinflammatory factors. The antioxidant efficacy is slightly reduced with normal aging, through a reduction of glutathione-S-transferase activity in people older than 74?years (p?<?0.05). However old people with mild cognitive impairment show reduced BDNF levels, and stronger signs of oxidative stress such as low antioxidant potential and glutathione-S-transferase activity (p?<?0.05). To sum up, the present study demonstrates that, in CSF of normal senescence, dopaminotrophic factors and proinflammatory TGF-family ligands are not affected, and antioxidant efficacy is slightly reduced. CSF of elderly subjects with mild cognitive impairment shows more oxidative and trophic changes that are characterized by reduction of BDNF content, glutathione-S-transferase activity, and antioxidant potential.

Abstract

The present study was designed to evaluate the effect of cranberry extract (CRAN) and/or losartan (LOS) against aluminium chloride (AlCl3) induced hepatorenal damage associated cardiomyopathy in rats. To induce hepatorenal and cardiotoxicity, animals were received (AlCl3; 70?mg/kg i.p.) for 8?weeks day after day and treated with CRAN (100?mg/kg b.wt.) orally daily for 4?weeks started after 4?weeks from AlCl3 injection accompanied with an administration of LOS (5?mg/kg i.p.) three times weekly for 4?weeks. Our data revealed that, compared to AlCl3, administration of CRAN extract and LOS produced a significant improvement which was evidenced by a significant amelioration in myocardial and vascular indices, kidney and liver markers, lipid profile and oxidative stress indices. Furthermore, histopathological and immunohistochemical examination reinforced the previous results. It could be concluded that combination of CRAN extract and LOS hindered AlCl3 induced hepatorenal damage complicated cardiomyopathy in rats.

Abstract

Objective: The aim of this study was to compare the laeverin level in maternal serum from first trimester (11–14 weeks) of pregnancy between normal pregnancies and pregnancies that later developed preeclampsia (PE).

Material and methods: This was a case-cohort study. The laeverin concentration was measured in cases with preterm PE (n?=?55), term PE (n?=?95), and a reference group of randomly selected women with normal pregnancy outcome (n?=?200) in stored serum samples collected from the double-test as part of the combined first trimester trisomy 21 screening program. The samples were thawed and analyzed for laeverin. The median gestational age at blood sampling was 77 days (range 57–96 days). Multiple regression analysis was performed to establish a normal median. Concentrations were converted to multiples of the median (MoM) and groups were compared using the Mann–Whitney U-test.

Results: In the reference group, laeverin was significantly correlated with gestational age (r?=?0.18, p?=?.01) and its concentration ranged from 41–393 μg/L. No significant differences in the median laeverin MoM were found between the reference group (1.01 MoM) and cases with preterm PE (0.98 MoM) or term PE (0.96 MoM).

Conclusions: First trimester maternal serum laeverin level cannot be used to predict preeclampsia.

ABSTRACT

Background and Purpose

Microglia phenotype and phagocytic activity are deregulated in Parkinson disease (PD). Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are neuroprotective in experimental PD, but their role in regulating microglial phenotype and phagocytosis has been poorly investigated. We addressed it by using the PPAR gamma agonist MDG548.

Experimental Approach

Murine microglial cell line MMGT12 was stimulated with LPS and/or MDG548 and their effect on phagocytosis of fluorescent microspheres or necrotic neurons was investigated by flow cytometry. Cytokines and markers of microglia phenotype such as Mannose Receptor C-Type 1 (MRC1), Ym1 and CD68 were measured by ELISA and fluorescent immunohistochemistry. Levels of Beclin-1, recently shown to play a role in microglial phagocytosis, were measured by western blotting. In the In vivo MPTP-probenecid (MPTPp) model of PD in mice, MDG548 was tested on motor impairment, nigral neurodegeneration, microglial activation and phenotype.

Key Results

MDG548, applied to LPS-stimulated microglia, increased the phagocytosis of both latex beads and necrotic cells, upregulated the expression of MRC1, CD68 and to a lesser extent IL-10, while counteracted the LPS-induced increase of TNF-alpha and iNOS. MDG548 also caused the induction of Beclin-1. The chronic MPTPp treatment in mice downregulated MRC1 and TGF-beta and upregulated TNF-alpha and IL-1beta immunoreactivity in activated CD11bpositive microglia, causing the death of nigral dopaminergic neurons. MDG548 arrested the MPTPp-induced cell death, enhanced MRC1 and restored cytokines levels.

Conclusion and Implications

This study adds a novel mechanism for PPAR gamma-mediated neuroprotection in PD, and suggests that boosting the phagocytic activity and anti-inflammatory markers may represent an effective disease-modifying approach.