Growth hormone releasing peptide-6 (GHRP-6) prevents doxorubicin-induced myocardial and extra-myocardial damages by activating prosurvival mechanisms.

Introduction: Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart failure (HF). DCM is a frequent complication in oncologic patients receiving Doxorubicin (Dox). Dox is a highly cardiotoxic drug, whereas its damaging spectrum affects most of the organs by multiple pathogenic cascades. Experimentally reproduced DCM/HF through Dox administrations has shed light on the pathogenic drivers of cardiotoxicity. Growth hormone (GH) releasing peptide 6 (GHRP-6) is a GH secretagogue with expanding and promising cardioprotective pharmacological properties. Here we examined whether GHRP-6 administration concomitant to Dox prevented the onset of DCM/HF and multiple organs damages in otherwise healthy rats. Methods: Myocardial changes were sequentially evaluated by transthoracic echocardiography. Autopsy was conducted at the end of the administration period when ventricular dilation was established. Semiquantitative histopathologic study included heart and other internal organs samples. Myocardial tissue fragments were also addressed for electron microscopy study, and characterization of the transcriptional expression ratio between Bcl-2 and Bax. Serum samples were destined for REDOX system balance assessment. Results and discussion: GHRP-6 administration in parallel to Dox prevented myocardial fibers consumption and ventricular dilation, accounting for an effective preservation of the LV systolic function. GHRP-6 also attenuated extracardiac toxicity preserving epithelial organs integrity, inhibiting interstitial fibrosis, and ultimately reducing morbidity and mortality. Mechanistically, GHRP-6 proved to sustain cellular antioxidant defense, upregulate prosurvival gene Bcl-2, and preserve cardiomyocyte mitochondrial integrity. These evidences contribute to pave potential avenues for the clinical use of GHRP-6 in Dox-treated subjects.

Carcinogenic effect of human tumor-derived cell-free filtrates in nude mice.

Cancer remains a worldwide cause of morbidity and mortality. Investigational research efforts have included the administration of tumor-derived extracts to healthy animals. Having previously demonstrated that the administration of non-transmissible, human cancer-derived homogenates induced malignant tumors in mice, here, we examined the consequences of administering 50 or 100 µg of protein of crude homogenates from mammary carcinoma, pancreatic adenocarcinoma, and melanoma samples in 6 inoculations per week during 2 months. The concurrent control mice received homogenates of healthy donor-skin cosmetic surgery fragments. Mammary carcinoma homogenate administration did not provoke the deterioration or mortality of the animals. Multiple foci of lung adenocarcinomas with a broad expression of malignity histomarkers coexisting with small cell-like carcinomas were found. Disseminated cells, positive to classic epithelial markers, were detected in lymphoid nodes. The administration of pancreatic tumor and melanoma homogenates progressively deteriorated animal health. Pancreatic tumor induced poorly differentiated lung adenocarcinomas and pancreatic islet hyperplasia. Melanoma affected lungs with solid pseudopapillary adenocarcinomas. Giant atypical hepatocytes were also observed. The kidney exhibited dispersed foci of neoplastic cells within a desmoplastic matrix. Nuclear overlapping with hyperchromatic nuclei, mitotic figures, and prominent nuclear atypia was identified in epidermal cells. None of these changes were ever detected in the control mice. Furthermore, the incubation of zebrafish embryos with breast tumor homogenates induced the expression of c-Myc and HER-2 as tumor markers, contrasting to embryos exposed to healthy tissue-derived material. This study confirms and extends our hypothesis that tumor homogenates contain and may act as vectors for "malignancy drivers," which ultimately implement a carcinogenesis process in otherwise healthy mice.

Evidence of SARS-CoV-2 infection in postmortem lung, kidney, and liver samples, revealing cellular targets involved in COVID-19 pathogenesis.

There is an urgent need to understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-host interactions involved in virus spread and pathogenesis, which might contribute to the identification of new therapeutic targets. In this study, we investigated the presence of SARS-CoV-2 in postmortem lung, kidney, and liver samples of patients who died with coronavirus disease (COVID-19) and its relationship with host factors involved in virus spread and pathogenesis, using microscopy-based methods. The cases analyzed showed advanced stages of diffuse acute alveolar damage and fibrosis. We identified the SARS-CoV-2 nucleocapsid (NC) in a variety of cells, colocalizing with mitochondrial proteins, lipid droplets (LDs), and key host proteins that have been implicated in inflammation, tissue repair, and the SARS-CoV-2 life cycle (vimentin, NLRP3, fibronectin, LC3B, DDX3X, and PPARγ), pointing to vimentin and LDs as platforms involved not only in the viral life cycle but also in inflammation and pathogenesis. SARS-CoV-2 isolated from a patient´s nasal swab was grown in cell culture and used to infect hamsters. Target cells identified in human tissue samples included lung epithelial and endothelial cells; lipogenic fibroblast-like cells (FLCs) showing features of lipofibroblasts such as activated PPARγ signaling and LDs; lung FLCs expressing fibronectin and vimentin and macrophages, both with evidence of NLRP3- and IL1ß-induced responses; regulatory cells expressing immune-checkpoint proteins involved in lung repair responses and contributing to inflammatory responses in the lung; CD34+ liver endothelial cells and hepatocytes expressing vimentin; renal interstitial cells; and the juxtaglomerular apparatus. This suggests that SARS-CoV-2 may directly interfere with critical lung, renal, and liver functions involved in COVID-19-pathogenesis.

Infestation of rabbits with just-molted adults of the cattle tick Rhipicephalus microplus: biological parameters and efficiency.

In this study, we report for the first time the successful infestation of rabbits with just-molted, unfed adults of Rhipicephalus microplus. Six New Zealand White rabbits were experimentally infested with 20 female and 20 male unfed adult ticks released into plastic chambers fixed on the shaved backs of each host. The attachment and feeding processes were successful. The biological characteristics of the ticks and the occurrence of adverse events in the tick-attachment area were studied. The average engorgement period was 10.7 days, and 33.3% of the engorged females completed the parasitic phase. The average weight of the recovered engorged females was 149.8 mg, with an average egg mass weight of 70.9 mg, a conversion efficiency index of 47.3%, and a hatching percentage of 88.31%. The adverse reactions found in the tick-attachment area were the usual inflammatory responses of the organism to infestation by these ectoparasites; however, it did not prevent the ticks from feeding and completing their life cycle. These data indicate that the infestation of rabbits with just-molted, unfed adult ticks could be a valuable, alternative animal model for rapid and economical evaluation of vaccine candidates and new molecules with acaricidal activity against Rhipicephalus microplus.

Preliminary safety assessment of CIGB-210, an investigational peptide for HIV infection.

Current human immunodeficiency virus treatments need to be periodically administered lifelong. In this study we assess the effect of repeated doses of an anti-HIV peptide drug candidate in C57BL6 strain. Two schemes of up to 15 administrations and one of 30, daily dosing for 5 days per week, all by the subcutaneous route were evaluated. Different dose concentrations of the peptide were assayed. CIGB-210 treated animals showed no symptoms or abnormal behavior as compared with placebo. All the animals gained weight during the study. Macroscopic evaluation showed no alterations in any of the organs studied. Microscopic analysis of the tissues did not show morphological changes in thymus, stomach, small and large intestines, kidney, brain, or cerebellum. The proliferative response of splenocytes and their capacity to secrete gamma interferon were not compromised by the repeated administration of CIGB-210. There were not statistically significant differences for any of the parameters evaluated during the study among treated and non-treated groups. We can conclude that CIGB-210 is well tolerated in C57BL6 mice in the dose concentration range explored and merits subsequent toxicological studies.

Coadministration of epidermal growth factor and growth hormone releasing peptide-6 improves clinical recovery in experimental autoimmune encephalitis.

PURPOSE: Multiple sclerosis is a complex and devastating autoimmune disease of the central nervous system. Up to now, a constellation of candidate drugs have been evaluated with no major success. Experimental Autoimmune Encephalitis (EAE) is the animal counterpart that reproduces critical features of the human MS process. The aim of the present work is to study a possible therapeutic effect of epidermal growth factor (EGF) and growth hormone releasing peptide-6 (GHRP(6)) coadministration in mild and severe EAE. METHODS: Mild and severe forms of EAE were generated immunizing rats and mice with xenogeneic spinal cord homogenate and with the encephalitogenic peptide MOG(p35-35), respectively. EGF and GHRP(6) alone or combined were administered in therapeutic and prophylactic schedules. A clinical score was established to follow-up the animals during the disease period. Malondialdehyde (MDA) serum concentration and insulin like growth factor-1 (IGF-1) relative level from brain tissue were determined. RESULTS: Only the combined EGF+GHRP(6) therapy reduced the clinical score in mild as well in severe EAE forms. The combination also improved the survival rate in nearly 100% of the severe EAE animals. In addition to these effects, there was an increase in the brain IGF-1 transcript and a decrease of serum MDA. CONCLUSIONS: EGF+GHRP(6) proved to be effective in improving the natural course of both mild and severe EAE. Accordingly, the treatment reduces inflammatory infiltration and microvascular damage, which may be associated to the attenuation of the lipid peroxidation process and the transcriptional enhancement of IGF-1, a major pro-survival factor for brain cells.

Pesquisaje del síndrome de Klinefelter en pacientes con retraso mental: algunas características clínicas / Screening for Klinefeltr's syndrome in patients with mental retardation: some clinical characteristics

Se estudiaron 120 pacientes en las edades comprendidas entre 10 y 18 años, 40 de ellos procedentes de la institución de salud pública "Rubén Martínez Villena" y, el resto, de los pacientes que concurren a consulta de psiquiatría del hospital docente pediátrico del Cerro. A cada paciente se le tomó dos muestras de la extensión (smear) bucal. La técnica utilizada y el procedimiento para la coloración fue el método de Junis. Se detectaron 3 pacientes para un 25 de la población estudiada. Se clasificaron, como retraso mental ligero, 2 de ellos y 1 retraso mental severo. En los 3 pacientes se encontró daño perinatal, con anoxia y oxigenoterapia. La edad de la madre, al nacer el niño, fluctuaba entre 17 y 32 años. Aparecen trastornos psiquiátricos entre los antecedentes patológicos familiares en los 3 pacientes estudiados. Predominaron los rasgos esquizotpimicos de personalidad, además de la intranquilidad y enuresis. Entre las enfermedades asociadas aparecen las broncopulmonares, la epilepsia y los trastornos ortopédicos. El electroencefalograma fue anormal en uno de ellos. Se compara nuestros hallazgos con los informados en la literatura y se hacen comentarios

Pesquisaje del síndrome de Klinefelter en pacientes con retraso mental: algunas características clínicas / Screening for Klinefeltr's syndrome in patients with mental retardation: some clinical characteristics

Se estudiaron 120 pacientes en las edades comprendidas entre 10 y 18 años, 40 de ellos procedentes de la institución de salud pública "Rubén Martínez Villena" y, el resto, de los pacientes que concurren a consulta de psiquiatría del hospital docente pediátrico del Cerro. A cada paciente se le tomó dos muestras de la extensión (smear) bucal. La técnica utilizada y el procedimiento para la coloración fue el método de Junis. Se detectaron 3 pacientes para un 25 de la población estudiada. Se clasificaron, como retraso mental ligero, 2 de ellos y 1 retraso mental severo. En los 3 pacientes se encontró daño perinatal, con anoxia y oxigenoterapia. La edad de la madre, al nacer el niño, fluctuaba entre 17 y 32 años. Aparecen trastornos psiquiátricos entre los antecedentes patológicos familiares en los 3 pacientes estudiados. Predominaron los rasgos esquizotpimicos de personalidad, además de la intranquilidad y enuresis. Entre las enfermedades asociadas aparecen las broncopulmonares, la epilepsia y los trastornos ortopédicos. El electroencefalograma fue anormal en uno de ellos. Se compara nuestros hallazgos con los informados en la literatura y se hacen comentarios