Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions.

Lipid droplets (LD) have long been considered as mere fat drops; however, LD have lately been revealed to be ubiquitous, dynamic and to be present in diverse organelles in which they have a wide range of key functions. Although incompletely understood, the biogenesis of eukaryotic LD initiates with the synthesis of neutral lipids (NL) by enzymes located in the endoplasmic reticulum (ER). The accumulation of NL leads to their segregation into nanometric nuclei which then grow into lenses between the ER leaflets as they are further filled with NL. The lipid composition and interfacial tensions of both ER and the lenses modulate their shape which, together with specific ER proteins, determine the proneness of LD to bud from the ER toward the cytoplasm. The most important function of LD is the buffering of energy. But far beyond this, LD are actively integrated into physiological processes, such as lipid metabolism, control of protein homeostasis, sequestration of toxic lipid metabolic intermediates, protection from stress, and proliferation of tumours. Besides, LD may serve as platforms for pathogen replication and defense. To accomplish these functions, from biogenesis to breakdown, eukaryotic LD have developed mechanisms to travel within the cytoplasm and to establish contact with other organelles. When nutrient deprivation occurs, LD undergo breakdown (lipolysis), which begins with the LD-associated members of the perilipins family PLIN2 and PLIN3 chaperone-mediated autophagy degradation (CMA), a specific type of autophagy that selectively degrades a subset of cytosolic proteins in lysosomes. Indeed, PLINs CMA degradation is a prerequisite for further true lipolysis, which occurs via cytosolic lipases or by lysosome luminal lipases when autophagosomes engulf portions of LD and target them to lysosomes. LD play a crucial role in several pathophysiological processes. Increased accumulation of LD in non-adipose cells is commonly observed in numerous infectious diseases caused by intracellular pathogens including viral, bacterial, and parasite infections, and is gradually recognized as a prominent characteristic in a variety of cancers. This review discusses current evidence related to the modulation of LD biogenesis and breakdown caused by intracellular pathogens and cancer.

High-throughput drug repositioning for the discovery of new treatments for Chagas disease.

Despite affecting around 8 million people worldwide and representing an economic burden above $7 billion/ year, currently approved medications to treat Chagas disease are still limited to two drugs, nifurtimox and benznidazole, which were developed more than 40 years ago and present important efficacy and safety limitations. Drug repositioning (i.e. finding second or further therapeutic indications for known drugs) has raised considerable interest within the international drug development community. There are many explanations to the current interest on drug repositioning including the possibility to partially circumvent clinical trials and the consequent saving in time and resources. It has been suggested as a particular attractive approach for the development of novel therapeutics for neglected diseases, which are usually driven by public or non-profit organizations. Here we review current computer-guided approaches to drug repositioning and reports on drug repositioning stories oriented to Chagas disease, with a focus on computer-guided drug repositioning campaigns.

Computer-guided drug repurposing: identification of trypanocidal activity of clofazimine, benidipine and saquinavir.

In spite of remarkable advances in the knowledge on Trypanosoma cruzi biology, no medications to treat Chagas disease have been approved in the last 40 years and almost 8 million people remain infected. Since the public sector and non-profit organizations play a significant role in the research efforts on Chagas disease, it is important to implement research strategies that promote translation of basic research into the clinical practice. Recent international public-private initiatives address the potential of drug repositioning (i.e. finding second or further medical uses for known-medications) which can substantially improve the success at clinical trials and the innovation in the pharmaceutical field. In this work, we present the computer-aided identification of approved drugs clofazimine, benidipine and saquinavir as potential trypanocidal compounds and test their effects at biochemical as much as cellular level on different parasite stages. According to the obtained results, we discuss biopharmaceutical, toxicological and physiopathological criteria applied to decide to move clofazimine and benidipine into preclinical phase, in an acute model of infection. The article illustrates the potential of computer-guided drug repositioning to integrate and optimize drug discovery and preclinical development; it also proposes rational rules to select which among repositioned candidates should advance to investigational drug status and offers a new insight on clofazimine and benidipine as candidate treatments for Chagas disease. One Sentence Summary: We present the computer-guided drug repositioning of three approved drugs as potential new treatments for Chagas disease, integrating computer-aided drug screening and biochemical, cellular and preclinical tests.

Sequence variation in CYP51A from the Y strain of Trypanosoma cruzi alters its sensitivity to inhibition.

CYP51 (sterol 14α-demethylase) is an efficient target for clinical and agricultural antifungals and an emerging target for treatment of Chagas disease, the infection that is caused by multiple strains of a protozoan pathogen Trypanosoma cruzi. Here, we analyze CYP51A from the Y strain T. cruzi. In this protein, proline 355, a residue highly conserved across the CYP51 family, is replaced with serine. The purified enzyme retains its catalytic activity, yet has been found less susceptible to inhibition. These biochemical data are consistent with cellular experiments, both in insect and human stages of the pathogen. Comparative structural analysis of CYP51 complexes with VNI and two derivatives suggests that broad-spectrum CYP51 inhibitors are likely to be preferable as antichagasic drug candidates.

[Relation between selenium plasma levels and different prostatic pathologies]. / Relación entre los niveles plasmáticos de selenio y las diferentes enfermedades prostáticas.

UNLABELLED: Several studies have demonstrated an inverse relation between serum selenium levels (Se) and advanced prostate cancer (PCa). OBJECTIVE: To determine and compare selenium plasma levels in patients with different prostatic pathologies. MATERIAL AND METHODS: It is a transversal, descriptive and comparative study. A sample of 64 men between 50 and 80 years old were selected for the study between 2007 and 2009. All volunteers underwent a digital rectal examination, prostate specific antigen level, ultrasound and transrectal prostate biopsy (12-14 chips). Prostate cancer was subclassified according to Gleason Score. Selenium was determined indirectly by serum Glutathione peroxidase (Kit Ransel, Randox SRL, Crumlin, UK). Statistical analysis was performed using ANOVA I (p<0.05). RESULTS: Glutathione Peroxidase level was 33.75+/-2.36 mg/ml in control patients. A decrease of 31.6% was observed in patients with BPH (23.08+/-1.57 mg/ml) and of (63.6%) in subjects with prostate cancer (12.28+/-1.03 mg/ml) (p<0,0001). There was no correlation with the Gleason Score. CONCLUSION: Serum Seleniun is lower in patients with prostatic pathologies being even more important in cancer patients regardless the Gleason Score.

[Implantation of a hospital registry of hereditary nonpolyposis colorectal cancer]. / Implantación de un registro hospitalario de cáncer colorrectal hereditario sin poliposis.

INTRODUCTION: Identification of patients with hereditary nonpolyposis colorectal cancer (HNPCC) can allow colorectal cancer (CRC) prevention through colonoscopy and polypectomies. The purpose of this study was to report the clinical characteristics of HNPCC families in our registry. PATIENTS AND METHOD: HNPCC was identified using the Amsterdam criteria. Familial clustering of CRC and extracolonic cancers were investigated in families. Individuals at risk were offered annual colonoscopy, starting from the age of 25 years. RESULTS: Twelve HNPCC families were identified. There were 46 cases of CRC in 38 patients. The mean age at diagnosis of CRC was 45.4 +/- 12.7 years (range 25-73 years). In patients with documented disease, right-sided tumors predominated. Eleven patients with extracolonic cancer were identified (six tumors located in the endometrium). Of 43 at-risk individuals, 29 accepted surveillance. CONCLUSIONS: Our data confirm the importance of the family history in identifying HNPCC. This study confirms previously described characteristics in HNPCC, namely, early age at onset of CRC, right-sided predominance, multiple synchronous and metachronous neoplasms, and increased extracolonic cancers. This is the first study of clinical data in a Spanish HNPCC registry.

Implantación de un registro hospitalario de cáncer colorrectal hereditario sin poliposis / Implantation of a hospital registry of hereditary nonpolyposis colorectal cancer

Introducción: La identificación de los pacientes afectados de cáncer colorrectal hereditario sin poliposis (CCRHSP) hace posible la prevención del cáncer colorrectal (CCR), mediante el cribado endoscópico y las polipectomías endoscópicas. La finalidad de nuestro estudio es presentar los datos clínicos de las familias incluidas en nuestro registro de CCRHSP. Pacientes y método: El CCRHSP se identifica mediante los criterios de Ámsterdam. Se analiza la historia familiar de CCR y de neoplasias extracolónicas. Entre las familias identificadas, a los familiares en situación de riesgo se les ofrece la realización de cribado mediante colonoscopia anual, a partir de los 25 años de edad. Resultados: Se identifica a 12 familias que cumplen los criterios de Ámsterdam. En total se presentan 46 casos de CCR en 38 pacientes. La edad media en el momento del diagnóstico es de 45,4 ± 12,7 años, con un rango de entre 25 y 73 años. Entre los pacientes con histología documentada, predominan las lesiones del colon derecho. Se identifica a 11 pacientes con neoplasias extracolónicas (6 localizadas en el endometrio). En total, 29 de 43 familiares de riesgo aceptaron el cribado endoscópico. Conclusiones: Los datos confirman la importancia de la historia familiar para la identificación del CCRHSP. Este estudio confirma las características previamente descritas para el CCRHSP, como la edad temprana de presentación del CCR, la localización preferente en el colon derecho, la presencia de múltiples lesiones sincrónicas o metacrónicas y el incremento de las neoplasias extracolónicas. Éste es el primer estudio con datos clínicos de un registro de CCRHSP en España

Introduction: Identification of patients with hereditary nonpolyposis colorectal cancer (HNPCC) can allow colorectal cancer (CRC) prevention through colonoscopy and polypectomies. The purpose of this study was to report the clinical characteristics of HNPCC families in our registry. Patients and method: HNPCC was identified using the Amsterdam criteria. Familial clustering of CRC and extracolonic cancers were investigated in families. Individuals at risk were offered annual colonoscopy, starting from the age of 25 years. Results: Twelve HNPCC families were identified. There were 46 cases of CRC in 38 patients. The mean age at diagnosis of CRC was 45.4 ± 12.7 years (range 25-73 years). In patients with documented disease, right-sided tumors predominated. Eleven patients with extracolonic cancer were identified (six tumors located in the endometrium). Of 43 at-risk individuals, 29 accepted surveillance. Conclusions: Our data confirm the importance of the family history in identifying HNPCC. This study confirms previously described characteristics in HNPCC, namely, early age at onset of CRC, right-sided predominance, multiple synchronous and metachronous neoplasms, and increased extracolonic cancers. This is the first study of clinical data in a Spanish HNPCC registry

Distrofia simpático refleja asociada al tratamiento con tacrolimus / Reflex sympathetic dystrophy associated to treatment with tacrolimus

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