Regulation of Calcitriol Biosynthesis and Activity: Focus on Gestational Vitamin D Deficiency and Adverse Pregnancy Outcomes

Vitamin D has garnered a great deal of attention in recent years due to a global prevalence of vitamin D deficiency associated with an increased risk of a variety of human diseases. Specifically, hypovitaminosis D in pregnant women is highly common and has important implications for the mother and lifelong health of the child, since it has been linked to maternal and child infections, small-for-gestational age, preterm delivery, preeclampsia, gestational diabetes, as well as imprinting on the infant for life chronic diseases. Therefore, factors that regulate vitamin D metabolism are of main importance, especially during pregnancy. The hormonal form and most active metabolite of vitamin D is calcitriol. This hormone mediates its biological effects through a specific nuclear receptor, which is found in many tissues including the placenta. Calcitriol synthesis and degradation depend on the expression and activity of CYP27B1 and CYP24A1 cytochromes, respectively, for which regulation is tissue specific. Among the factors that modify these cytochromes expression and/or activity are calcitriol itself, parathyroid hormone, fibroblast growth factor 23, cytokines, calcium and phosphate. This review provides a current overview on the regulation of vitamin D metabolism, focusing on vitamin D deficiency during gestation and its impact on pregnancy outcomes

The Interaction of Human Papillomavirus Infection and Prostaglandin E2 Signaling in Carcinogenesis: A Focus on Cervical Cancer Therapeutics

Chronic infection by high-risk human papillomaviruses (HPV) and chronic inflammation are factors associated with the onset and progression of several neoplasias, including cervical cancer. Oncogenic proteins E5, E6, and E7 from HPV are the main drivers of cervical carcinogenesis. In the present article, we review the general mechanisms of HPV-driven cervical carcinogenesis, as well as the involvement of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and downstream effectors in this pathology. We also review the evidence on the crosstalk between chronic HPV infection and PGE2 signaling, leading to immune response weakening and cervical cancer development. Finally, the last section updates the current therapeutic and preventive options targeting PGE2-derived inflammation and HPV infection in cervical cancer. These treatments include nonsteroidal anti-inflammatory drugs, prophylactic and therapeutical vaccines, immunomodulators, antivirals, and nanotechnology. Inflammatory signaling pathways are closely related to the carcinogenic nature of the virus, highlighting inflammation as a co-factor for HPV-dependent carcinogenesis. Therefore, blocking inflammatory signaling pathways, modulating immune response against HPV, and targeting the virus represent excellent options for anti-tumoral therapies in cervical cancer

Stimulatory effects of calcitriol on hCG secretion and gene expression in cultured syncytiotrophoblasts

<p><b>Copyright information:</b></p><p>Taken from "Calcitriol affects hCG gene transcription in cultured human syncytiotrophoblasts"</p><p>Reproductive biology and endocrinology : RB&E 2008;6():3-3.</p><p>Published online 22 Jan 2008</p><p>PMCID:PMC2245969.</p><p></p> A) Hormone secretion was determined by EIA after 6 hours incubation in the presence of increasing concentrations of calcitriol or its vehicle (-). B) Real time PCR analysis of hCGβ gene expression of calcitriol-treated cells. Results were normalized against GAPDH mRNA. Vehicle data were arbitrarily given a value of 1. Each bar represents the mean ± S.D. of triplicate cultures. *< 0.05 vs. control

Rhabdomyolysis caused by exercise

Introduction: rhabdomyolysis is a clinical and paraclinical syndrome characterized by the presence ofskeletal muscle necrosis that leads to the consequent release of intracellular muscle components witha variable clinical presentation and complications that put life at risk such as acute kidney injury. Methods: we present a case report of a patient with rhabdomyolysis with severe elevation of muscle enzymes and secondary acute kidney injury who was subsequently documented (initial Total CK189,000 u/L) after extreme physical activity (CrossFit), who developed multiple complications and theneed for support in the Intensive Care Unit (ICU) with satisfactory outcome. Results: Patient with kidney failure, receiving renal therapy with a favorable evolution and survival atdischarge from the intensive care unit of a third-level hospital in the city of Pereira, Risaralda, Colombia. Conclusions: Rhabdomyolysis is a clinical and paraclinical syndrome characterized by the presence ofskeletal muscle necrosis. The main cause is severe direct traumatic injury or crushes injuries; however,other conditions such as infections, intoxication, muscle ischemia, neuroleptic malignant syndrome, malignant hyperthermia, metabolic disorders, and genetic pathologies can also cause it, and particularly, extended rest, immobilization or strenuous exercise. The clinical presentation and complications are variable.Introducción: la rabdomiólisis es un síndrome clínico y paraclínico caracterizado por la presencia de necrosis del músculo esquelético que lleva a la liberación de componentes muscularesintracelulares, con una presentación clínica variable y complicaciones que ponen en riesgo lavida, como la insuficiencia renal aguda. Métodos: presentamos un caso clínico de un paciente con rabdomiólisis con elevación severade enzimas musculares y lesión renal aguda secundaria que posteriormente se documentó (CKTotal inicial 189.000 u/L) luego de actividad física extrema (CrossFit), quien desarrolló múltiplescomplicaciones y la necesidad de apoyo en la Unidad de Cuidados Intensivos (UCI) con evolución satisfactoria. Resultados: Paciente con insuficiencia renal, que recibe terapia renal con una evolución favorable y supervivencia al egreso de la unidad de cuidados intensivos de un hospital de tercer nivelde la ciudad de Pereira, Risaralda, Colombia. Conclusiones: La rabdomiólisis es un síndrome clínico y paraclínico caracterizado por la presencia de necrosis del músculo esquelético. La causa principal son las lesiones traumáticas directasseveras o las lesiones por aplastamiento; sin embargo, otras condiciones como las infecciones,la intoxicación, la isquemia muscular, el síndrome neuroléptico maligno, la hipertermia maligna,los trastornos metabólicos y las patologías genéticas también pueden causarla, y en particular,el reposo prolongado, la inmovilización o el ejercicio extenuante. La presentación clínica y lascomplicaciones son variables

The Inhibition of the FGFR/PI3K/Akt Axis by AZD4547 Disrupts the Proangiogenic Microenvironment and Vasculogenic Mimicry Arising from the Interplay between Endothelial and Triple-Negative Breast Cancer Cells

Vasculogenic mimicry (VM), a process in which aggressive cancer cells form tube-like structures, plays a crucial role in providing nutrients and escape routes. Highly plastic tumor cells, such as those with the triple-negative breast cancer (TNBC) phenotype, can develop VM. However, little is known about the interplay between the cellular components of the tumor microenvironment and TNBC cells’ VM capacity. In this study, we analyzed the ability of endothelial and stromal cells to induce VM when interacting with TNBC cells and analyzed the involvement of the FGFR/PI3K/Akt pathway in this process. VM was corroborated using fluorescently labeled TNBC cells. Only endothelial cells triggered VM formation, suggesting a predominant role of paracrine/juxtacrine factors from an endothelial origin in VM development. Via immunocytochemistry, qPCR, and secretome analyses, we determined an increased expression of proangiogenic factors as well as stemness markers in VM-forming cancer cells. Similarly, endothelial cells primed by TNBC cells showed an upregulation of proangiogenic molecules, including FGF, VEGFA, and several inflammatory cytokines. Endothelium-dependent TNBC-VM formation was prevented by AZD4547 or LY294002, strongly suggesting the involvement of the FGFR/PI3K/Akt axis in this process. Given that VM is associated with poor clinical prognosis, targeting FGFR/PI3K/Akt pharmacologically may hold promise for treating and preventing VM in TNBC tumors

α-Mangostin Synergizes the Antineoplastic Effects of 5-Fluorouracil Allowing a Significant Dose Reduction in Breast Cancer Cells

Breast cancer is the most common neoplasm and the leading cause of cancer death in women worldwide. Although 5-fluorouracil is a conventional chemotherapeutic agent for breast cancer treatment, its use may result in severe side effects. Thus, there is widespread interest in lowering 5-fluorouracil drawbacks, without affecting its therapeutic efficacy by the concomitant use with natural products. Herein, we aimed at evaluating whether α-mangostin, a natural antineoplastic compound, could increase the anticancer effect of 5-fluorouracil in different breast cancer cell lines, allowing for dose reduction. Cell proliferation was evaluated by sulforhodamine-B assays, inhibitory concentrations and potency were calculated by dose-response curves, followed by analysis of their pharmacological interaction by the combination-index method and dose-reduction index. Cell cycle distribution was evaluated by flow cytometry. Each compound inhibited cell proliferation in a dose-dependent manner, the triple negative breast cancer cells being the most sensitive. When 5-fluorouracil and α-mangostin were used concomitantly, synergistic antiproliferative effect was observed. The calculated dose-reduction index suggested that this combination exhibits therapeutic potential for reducing 5-fluorouracil dosage in breast cancer. Mechanistically, the cotreatment induced cell death in a greater extent than each drug alone. Therefore, α-mangostin could be used as a potent co-adjuvant for 5-fluorouracil in breast cancer