We evaluated the effect of melatonin (Mel), a potent scavenger of reactive oxygen species, in the course of HgCl(2)-induced acute renal failure. Rats received by gastric gavage 1 mg/kg of Mel (n = 21) or vehicle (n = 21), 30 min before the subcutaneous injection of HgCl(2) (2.5 mg/kg). Rats were killed at 24, 48, and 72 h, and plasma creatinine (S(cr)), renal histology, proliferative activity, apoptosis, and superoxide-producing cells were studied. We also determined the renal content of malondialdehyde (MDA) and glutathione (GSH) and the activities of glutathione peroxidase and catalase. Mel pretreatment (Mel plasma levels of 3.40 +/- 3.15 microgram/ml at the time of HgCl(2) injection) prevented the increment in S(cr) and reduced tubular necrosis from 41.0 +/- 10.5 to 4.2 +/- 5.1% of proximal tubules (P < 0.01). Apoptosis and postnecrotic proliferative activity were twice more intense in the group untreated with Mel. Increment in renal content of MDA and decrease in GSH resulting from HgCl(2) toxicity were prevented by Mel. Mel also induced an important reduction in superoxide-positive cells. In contrast to the beneficial effects of pretreatment with Mel, the administration of Mel in conjunction with HgCl(2) had no effect on the oxidative damage and did not prevent nephrotoxicity. We conclude that the beneficial effects of pharmacological doses of Mel are due to its antioxidant properties.

ObjectiveCD5 plays a crucial role in autoimmunity and is a well-established genetic risk factor of developing RA. Recently, evidence of positive selection has been provided for the CD5 Pro224-Val471 haplotype in East Asian populations. The aim of the present work was to further analyze the functional relevance of non-synonymous CD5 polymorphisms conforming the ancestral and the newly derived haplotypes (Pro224-Ala471 and Pro224-Val471, respectively) as well as to investigate the potential role of CD5 on the development of SLE and/or SLE nephritis.MethodsThe CD5 SNPs rs2241002 (C/T; Pro224Leu) and rs2229177 (C/T; Ala471Val) were genotyped using TaqMan allelic discrimination assays in a total of 1,324 controls and 681 SLE patients of Spanish origin. In vitro analysis of CD3-mediated T cell proliferative and cytokine response profiles of healthy volunteers homozygous for the above mentioned CD5 haplotypes were also analyzed.ResultsT-cell proliferation and cytokine release were significantly increased showing a bias towards to a Th2 profile after CD3 cross-linking of peripheral mononuclear cells from healthy individuals homozygous for the ancestral Pro224-Ala471 (CC) haplotype, compared to the more recently derived Pro224-Val471 (CT). The same allelic combination was statistically associated with Lupus nephritis.ConclusionThe ancestral Ala471 CD5 allele confers lymphocyte hyper-responsiveness to TCR/CD3 cross-linking and is associated with nephritis in SLE patients.

CD5 is a lymphocyte surface coreceptor of still incompletely understood function. Currently available information indicates that CD5 participates not only in cell-to-cell immune interactions through still poorly defined endogenous ligands expressed on hemopoietic and nonhemopoietic cells but also in recognition of exogenous and highly conserved microbial structures such as fungal β-glucans. Preceding single nucleotide polymorphism (SNP) data analysis provided evidence for a recent selective sweep in East Asia and suggested a nonsynonymous substitution at position 471 (A471V; rs2229177) of the cytoplasmatic region of the CD5 receptor as the most plausible target of selection. The present report further investigates the role of natural selection in the CD5 gene by a resequencing approach in 60 individuals representing populations from 3 different continents (20 Africans, 20 Europeans and 20 East Asians) and by functionally assaying the relevance of the A471V replacement on CD5 signaling. The high differentiation pattern found at the nonsynonymous A471V site together with the low diversity, most of the performed neutrality tests (Tajima's D, Fu and Li's F* and D*, and Fu's Fs) and the predominance of a major haplotype in East Asians strongly argue in favor of positive selection for the A471V site. Importantly, anti-CD5 monoclonal antibody cross-linking unveiled significant differences among A471V variants regarding the mitogen-activated protein kinase (MAPK) cascade activation on COS7 and on human peripheral blood mononuclear cells. Similar differences on MAPK activation and IL-8 cytokine release were also observed upon exposure of HEK293 cell transfectants expressing the A471V variants to Zymosan, a β-glucan-rich fungal particle. Taken together, the results provide evidence for the hypothesis of an adaptive role of the A471V substitution to environmental challenges, most likely infectious pathogens, in East Asian populations.

a b s t r a c t CD6 is a transmembrane receptor expressed by all T and a subset of B lymphocytes, where it physically associates with the antigen-specific receptor to modulate activation and differentiation processes through still poorly understood mechanisms. Its cytoplasmic tail lacks intrinsic catalytic activity but presents several consensus motifs for phosphorylation. The present work reports on the identification of two constitutively phosphorylated serine clusters (S480/482/484 and S560/ 562/565/567/568), which are embedded into Casein Kinase 2 consensus motifs, and are indispensable for proper mitogen-activated protein kinase activation following CD6 ligation. The data point to a novel level of regulation of CD6 function by intracytoplasmic serine phosphorylation.

studies could probably be helpful in this setting. M component reductions to the IV formulation were brief and further studies are warranted to confirm these findings. Interestingly, a recent German Myeloma Group study (Merz et al, 2015) compared the IV versus the SC route retrospectively for VCD and PAD induction therapy in newly diagnosed multiple myeloma patients. The analysis of high quality responses revealed that IV-treated patients achieved higher rates of ≥very good partial response than SC-treated patients (42% vs. 29%, P = 0Á02) after 3 cycles of therapy. These data are in favour of a faster mechanism of action of the IV route, confirming a different pharmacokinetic profile at least in untreated patients, and multicentre studies are on-going to better clarify this aspect. In conclusion, to our knowledge, this is the first report regarding IV bortezomib efficacy after SC administration failure.