Serum OPG and RANKL Levels as Risk Factors for the Development of Cardiovascular Calcifications in End-Stage Renal Disease Patients in Hemodialysis.

Cardiovascular calcifications (CVC) are frequently observed in chronic kidney disease (CKD) patients and contribute to their cardiovascular mortality. The aim of the present study was to investigate the impact of osteoprotegerin (OPG)/Receptor Activator of NF-κΒ (RANK)/RANK ligand (RANKL) pathway in the development and evolution of CVCs in hemodialysis patients. In total, 80 hemodialysis patients were assessed for the presence of vascular (abdominal aorta and muscular arteries) calcifications and results were correlated to serum OPG and RANKL levels and the OPG/RANKL ratio. Traditional cardiovascular risk factors and mineral bone disease parameters were also estimated. The presence of VCs was also evaluated 5 years after the initiation of the study, and results were correlated to the initial serum OPG levels. Age, diabetes mellitus, coronary artery disease and OPG levels (p < 0.001) were associated with VCs, whereas RANKL levels were not. Multivariate analysis though revealed that only OPG levels were significantly associated with abdominal aorta calcifications (p = 0.026), but they were not correlated with the progression of VCs. Serum OPG levels are positively and independently associated with VCs in HD patients, but not with their progression. RANKL levels did not show any associations, whereas further studies are needed to establish the significance of OPG/RANKL ratio.

Neurotoxic effects of aluminum are associated with its interference with estrogen receptors signaling.

Aluminum compounds have been observed in various brain regions, and their accumulation has been associated with many neurodegenerative disorders. Neurotoxic effects of aluminum are attributed to reactive oxygen species generation, induction of apoptosis and inflammatory reactions activation. Metalloestrogen activity of aluminum has also been linked to breast cancer progression and metastasis. In this study, taking into account the anti-apoptotic and anti-oxidant activities of estrogens in neuronal cells, which are mediated by estrogen receptors, the possible estrogenic activity of aluminum in SH-SY5Y neuroblastoma cells was studied. Our results showed that aluminum in the form of aluminum chlorohydrate (ACH) exhibited no effect on estrogen receptors transcriptional activation, and differential effect on estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) protein levels. ACH caused reduction in ERß protein levels, and increase in its mitochondrial localization. ACH-induced reduction in ERß protein level may be linked, at least in part, to the ACH-induced increase in ERα protein level. This statement is based on our observations showing aluminum-induced reduction in the E2-induced increase in ERα S118 phosphorylation, in MCF-7 and SH-SH5Y cells. Phosphorylation at S118 residue is known to be associated with inhibition of the ubiquitin-induced proteolytic degradation of ERα, leading to its accumulation. Since it is known that ERα negatively regulate ERß expression, increase in ERα, may contribute to reduction in ERß levels and subsequent weakening of its anti-apoptotic and anti-oxidant activity, justified by the observed reduction in procaspase 9, mitochondrial cytochrome c, Bcl-2, Bcl-xL and mitochondrial thioredoxin protein level, as well as by the increase in proapoptotic BAX level, in ACH treated SH-SY5Y cells. In addition, increase in mitochondrial ERß localization may also trigger mitochondrial metabolism, suppress biosynthetic process of gluconeogenesis, as indicated by the observed reduction in the phosphoenolpyruvate carboxykinase protein level, and eventually lead to increase in reactive oxygen species (ROS) generation, known to be implicated in aluminum induced neurodegeneration. This statement was verified by the observed ACH-induced increase in ERß mitochondrial localization, induction of the mitochondrial membrane depolarization and increase in ROS production, in neuronal-like differentiated SH-SY5Y cells.

Replacement of Male Mini-Puberty.

CONTEXT: Clinical management of congenital hypogonadotropic hypogonadism (CHH) remains a challenge in pediatric endocrinology. OBJECTIVE: To investigate whether daily subcutaneous injections of the recombinant human LH/FSH preparation could mimic the physiological male mini-puberty. DESIGN AND SETTING: The REMAP (REplacement of MAle mini-Puberty) study with up to 10 years of follow-up. PATIENTS AND INTERVENTION: Ten neonates or infants, all with bilateral cryptorchidism in intra-abdominal/inguinal position and micropenis with the absence of neonatal male mini-puberty, received daily subcutaneous injections of Pergoveris® (LH/FSH 75/150 IU) for 3 months. MAIN OUTCOME MEASURES: Restoration of bilateral cryptorchidism/micropenis and the Leydig/Sertoli cells function. RESULTS: At the end of treatment, median LH and FSH, both undetectable before treatment, reached high normal levels of 4.45 IU/L and supranormal levels 83 IU/L, respectively; median inhibin-b and anti-Mullerian hormone levels increased from subnormal (27.8 and 1.54 ng/mL, respectively) to normal levels (365 and 150 ng/mL, respectively); median testosterone increased from just detectable (0.02 ng/mL) to normal levels (3.3 ng/mL). Stretched penile length increased from a median of 2 to 3.8 cm. During therapy, all testes descended to the scrotal position (by the end of the first month in three patients, the second month in four patients, and the third month in three patients), measuring 1.5 mL and appearing normal in ultrasonography. Three infants received additional treatment with testosterone enanthate. In two infants, one of two testes regressed in the low inguinal area; both infants were successfully treated surgically. After 1 to 10 years of follow-up, all testes are still in scrotal position and have slightly regressed in size. CONCLUSIONS: The proposed regimen mimics neonatal male mini-puberty and successfully treats infants with micropenis and cryptorchidism in CHH.

Ionizing radiation-mediated premature senescence and paracrine interactions with cancer cells enhance the expression of syndecan 1 in human breast stromal fibroblasts: the role of TGF-ß.

The cell surface proteoglycan syndecan 1 (SDC1) is overexpressed in the malignant breast stromal fibroblasts, creating a favorable milieu for tumor cell growth. In the present study, we found that ionizing radiation, a well-established treatment in human breast cancer, provokes premature senescence of human breast stromal fibroblasts in vitro, as well as in the breast tissue in vivo. These senescent cells were found to overexpress SDC1 both in vitro and in vivo. By using a series of specific inhibitors and siRNA approaches, we showed that this SDC1 overexpression in senescent cells is the result of an autocrine action of Transforming Growth Factor-ß (TGF-ß) through the Smad pathway and the transcription factor Sp1, while the classical senescence pathways of p53 or p38 MAPK - NF-kB are not involved. In addition, the highly invasive human breast cancer cells MDA-MB-231 (in contrast to the low-invasive MCF-7) can also enhance SDC1 expression, both in early-passage and senescent fibroblasts via a paracrine action of TGF-ß. The above suggest that radiation-mediated premature senescence and invasive tumor cells, alone or in combination, enhance SDC1 expression in breast stromal fibroblasts, a poor prognostic factor for cancer growth, and that TGF-ß plays a crucial role in this process.

Screening of Panamanian Plants for Cosmetic Properties, and HPLC-Based Identification of Constituents with Antioxidant and UV-B Protecting Activities.

A library of 600 taxonomically diverse Panamanian plant extracts was screened for DPPH scavenging and UV-B protective activities, and the methanolic extracts of Mosquitoxylum jamaicense, Combretum cacoucia, and Casearia commersionia were submitted to HPLC-based activity profiling. The compounds located in the active time windows were isolated and identified as gallic acid derivatives and flavonoids. Gallic acid methyl ester (3) and digallic acid derivatives (2, 6) showed the highest DPPH scavenging activity (<10 µg/mL), while protocatechuic acid (7) and isoquercitrin (10) exhibited the highest UV-B protective properties.