Current drug strategies for the treatment and control of schistosomiasis.

INTRODUCTION: Schistosomiasis, one of the current Neglected Tropical Diseases (NTDs) affects over 230 million people globally, with nearly 700 million at risk in more than 74 countries. Praziquantel (PZQ) has served as the primary treatment for the past four decades; however, its effectiveness is limited as it solely eliminates adult worms. In regions where infections are frequent, PZQ exhibits only temporary efficacy and has restricted potential to disrupt the prolonged transmission of the disease. AREAS COVERED: A comprehensive exploration using the PubMed database was conducted to review current pharmacotherapy approaches for schistosomiasis. This review also encompasses recent research findings related to potential novel therapeutics and the repurposing of existing drugs. EXPERT OPINION: Current schistosoma treatment strategies, primarily relying on PZQ, face challenges like temporary effectiveness and limited impact on disease transmission. Drug repurposing, due to economic constraints, is decisive for NTDs. Despite PZQ's efficacy, its failure to prevent reinfection highlights the need for complementary strategies, especially in regions with persistent environmental foci. Integrating therapies against diverse schistosome stages boosts efficacy and impedes resistance. Uncovering novel agents is essential to address resistance concerns in tackling this neglected tropical disease. Integrated strategies present a comprehensive approach to navigate the complex challenges.

Cardiometabolic Changes in Sirtuin1-Heterozygous Mice on High-Fat Diet and Melatonin Supplementation.

A hypercaloric fatty diet predisposes an individual to metabolic syndrome and cardiovascular complications. Sirtuin1 (SIRT1) belongs to the class III histone deacetylase family and sustains anabolism, mitochondrial biogenesis, and fat distribution. Epididymal white adipose tissue (eWAT) is involved in inflammation, whilst interscapular brown adipose tissue (iBAT) drives metabolism in obese rodents. Melatonin, a pineal indoleamine, acting as a SIRT1 modulator, may alleviate cardiometabolic damage. In the present study, we morphologically characterized the heart, eWAT, and iBAT in male heterozygous SIRT1+/- mice (HET mice) on a high-fat diet (60%E lard) versus a standard rodent diet (8.5% E fat) and drinking melatonin (10 mg/kg) for 16 weeks. Wild-type (WT) male C57Bl6/J mice were similarly fed for comparison. Cardiomyocyte fibrosis and endoplasmic reticulum (ER) stress response worsened in HET mice on a high-fat diet vs. other groups. Lipid peroxidation, ER, and mitochondrial stress were assessed by 4 hydroxy-2-nonenal (4HNE), glucose-regulated protein78 (GRP78), CCAA/enhancer-binding protein homologous protein (CHOP), heat shock protein 60 (HSP60), and mitofusin2 immunostainings. Ultrastructural analysis indicated the prevalence of atypical inter-myofibrillar mitochondria with short, misaligned cristae in HET mice on a lard diet despite melatonin supplementation. Abnormal eWAT adipocytes, crown-like inflammatory structures, tumor necrosis factor alpha (TNFα), and iBAT whitening characterized HET mice on a hypercaloric fatty diet and were maintained after melatonin supply. All these data suggest that melatonin's mechanism of action is strictly linked to full SIRT1 expression, which is required for the exhibition of effective antioxidant and anti-inflammatory properties.

Evaluation of Mitochondrial Function in Blood Samples Shows Distinct Patterns in Subjects with Thyroid Carcinoma from Those with Hyperplasia.

Metabolic adaptations are a hallmark of cancer and may be exploited to develop novel diagnostic and therapeutic tools. Only about 50% of the patients who undergo thyroidectomy due to suspicion of thyroid cancer actually have the disease, highlighting the diagnostic limitations of current tools. We explored the possibility of using non-invasive blood tests to accurately diagnose thyroid cancer. We analyzed blood and thyroid tissue samples from two independent cohorts of patients undergoing thyroidectomy at the Hospital Universitario 12 de Octubre (Madrid, Spain). As expected, histological comparisons of thyroid cancer and hyperplasia revealed higher proliferation and apoptotic rates and enhanced vascular alterations in the former. Notably, they also revealed increased levels of membrane-bound phosphorylated AKT, suggestive of enhanced glycolysis, and alterations in mitochondrial sub-cellular distribution. Both characteristics are common metabolic adaptations in primary tumors. These data together with reduced mtDNA copy number and elevated levels of the mitochondrial antioxidant PRX3 in cancer tissue samples suggest the presence of mitochondrial oxidative stress. In plasma, cancer patients showed higher levels of cfDNA and mtDNA. Of note, mtDNA plasma levels inversely correlated with those in the tissue, suggesting that higher death rates were linked to lower mtDNA copy number. In PBMCs, cancer patients showed higher levels of PGC-1α, a positive regulator of mitochondrial function, but this increase was not associated with a corresponding induction of its target genes, suggesting a reduced activity in cancer patients. We also observed a significant difference in the PRDX3/PFKFB3 correlation at the gene expression level, between carcinoma and hyperplasia patients, also indicative of increased systemic metabolic stress in cancer patients. The correlation of mtDNA levels in tissue and PBMCs further stressed the interconnection between systemic and tumor metabolism. Evaluation of the mitochondrial gene ND1 in plasma, PBMCs and tissue samples, suggested that it could be a good biomarker for systemic oxidative metabolism, with ND1/mtDNA ratio positively correlating in PBMCs and tissue samples. In contrast, ND4 evaluation would be informative of tumor development, with ND4/mtDNA ratio specifically altered in the tumor context. Taken together, our data suggest that metabolic dysregulation in thyroid cancer can be monitored accurately in blood samples and might be exploited for the accurate discrimination of cancer from hyperplasia.

Antipsychotic Drug Aripiprazole Protects Liver Cells from Oxidative Stress.

Antipsychotics used to treat schizophrenia can cause drug-induced liver injury (DILI), according to the Roussel Uclaf Causality Assessment Method. The role of oxidative stress in triggering injury in these DILI cases is unknown. We repeatedly administrated two second-generation antipsychotics, aripiprazole and olanzapine, at laboratory alert levels to study underlying mechanisms in stress prevention upon acute oxidative stress. The drugs were administered continuously for up to 8 weeks. For this, hepatoma Fao cells, which are suitable for metabolic studies, were used, as the primary hepatocytes survive in the culture only for about 1 week. Four stress responses-the oxidative stress response, the DNA damage response and the unfolded protein responses in the endoplasmic reticulum and mitochondria-were examined in H2O2-treated cells by antioxidant enzyme activity measurements, gene expression and protein quantification. Oxidant conditions increased the activity of antioxidant enzymes and upregulated genes and proteins associated with oxidative stress response in aripiprazole-treated cells. While the genes associated with DNA damage response, Gadd45 and p21, were upregulated in both aripiprazole- and olanzapine-treated cells, only aripiprazole treatment was associated with upregulation in response to even more H2O2, which also coincided with better survival. Endoplasmic reticulum stress-induced Chop was also upregulated; however, neither endoplasmic reticulum nor mitochondrial unfolded protein response was activated. We conclude that only aripiprazole, but not olanzapine, protects liver cells against oxidative stress. This finding could be relevant for schizophrenia patients with high-oxidative-stress-risk lifestyles and needs to be validated in vivo.

Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue.

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

Positively charged amino acids at the N terminus of select mitochondrial proteins mediate early recognition by import proteins αß'-NAC and Sam37.

A major challenge in eukaryotic cells is the proper distribution of nuclear-encoded proteins to the correct organelles. For a subset of mitochondrial proteins, a signal sequence at the N terminus (matrix-targeting sequence [MTS]) is recognized by protein complexes to ensure their proper translocation into the organelle. However, the early steps of mitochondrial protein targeting remain undeciphered. The cytosolic chaperone nascent polypeptide-associated complex (NAC), which in yeast is represented as the two different heterodimers αß-NAC and αß'-NAC, has been proposed to be involved during the early steps of mitochondrial protein targeting. We have previously described that the mitochondrial outer membrane protein Sam37 interacts with αß'-NAC and together promote the import of specific mitochondrial precursor proteins. In this work, we aimed to detect the region in the MTS of mitochondrial precursors relevant for their recognition by αß'-NAC during their sorting to the mitochondria. We used targeting signals of different mitochondrial proteins (αß'-NAC-dependent Oxa1 and αß'-NAC-independent Mdm38) and fused them to GFP to study their intracellular localization by biochemical and microscopy methods, and in addition followed their import kinetics in vivo. Our results reveal the presence of a positively charged amino acid cluster in the MTS of select mitochondrial precursors, such as Oxa1 and Fum1, which are crucial for their recognition by αß'-NAC. Furthermore, we explored the presence of this cluster at the N terminus of the mitochondrial proteome and propose a set of precursors whose proper localization depends on both αß'-NAC and Sam37.

Asociación del grupo sanguíneo ABO con complicaciones en covid-19: revisión sistemática y meta-análisis / Asociation between abo blood groups and covid-19 complications: systematic review and meta-analysis

Introducción: los grupos sanguíneos ABO han sido utilizados como marcadores de desenlace en diferentes enfermedades, otorgando al grupo O un factor protector y al A uno de riesgo. Durante el brote de SARS CoV-1 se planteó la posible relación entre riesgo de infección y tipo sanguíneo; se presume que en la pandemia por COVID-19 exista una relación entre determinados desenlaces y los grupos ABO. Objetivo: determinar la asociación entre los diferentes grupos sanguíneos y los desenlaces de mortalidad, ingreso a cuidados intensivos y requerimiento de intubación orotraqueal (IOT) en población con infección por COVID-19. Materiales y métodos: revisión sistemática y metanálisis entre enero 2020 y marzo 2021 en las bases de datos MEDLINE, EMBASE, SCOPUS, Latindex y LILACS, identificando los desenlaces mencionados en pacientes con COVID-19. Resultados: se incluyeron 16 estudios, la mayoría retrospectivos multicéntricos. Se evidenció que pacientes con grupo sanguíneo A tienen mayor riesgo de mortalidad (OR 1.08 ;1.01-0.17), frente al ingreso a UCI no hubo diferencia estadística significativa entre los grupos sanguíneos. Se encontró que el AB representa un factor de riesgo para intubación orotraqueal (OR 1.42 IC95% 1.02-1.96), en tanto que el A demostró proteger contra este desenlace (OR 0.84 IC95%0.73-0.97). Conclusiones: hay evidencia sobre la relación entre el grupo sanguíneo y los desenlaces, asociada con la infección por SARS-CoV-2. Se requieren estudios prospectivos que evalúen grupo sanguíneo, RH y desenlaces específicos.

Introduction: ABO blood groups have been used as outcome markers in various diseases, conferring group O a protective factor and group A a risk factor. During the SARS CoV-1 outbreak, it was suggested that blood type appeared to have a relationship with the risk of infection; it is believed that in the COVID-19 pandemic, ABO blood types, are relevant for certain outcomes. Objective: to determine the association between blood types and death, admission to intensive care and risk of intubation among COVID-19 patients. Materials and methods: a systematic review and meta-analysis from MEDIA, EMBASSY, SCOPUS, Latindex and LILACS databases, identifying the abovementioned outcomes among COVID 19 patients, conducted between January 2020 and March 2021. Results: 16 studies were included, most of them retrospective multicenter studies. It was evidenced that patients with blood group A have a higher mortality risk (OR 1.08:1.01-0.17). There was no statistically significant difference between blood groups for ICU admission. AB was found to be a risk factor for intubation (OR 1.42: CI95% 1.02 -1.96), while type A had a protective effect against this outcome (OR 0.84: CI95% 0.73 -0.97). Conclusions: there is evidence on a relationship between blood groups and outcomes in SARS CoV-2 infection. Prospective studies evaluating ABO and Rh(D) blood types and specific outcomes, are required.

The Thiol-Modifier Effects of Organoselenium Compounds and Their Cytoprotective Actions in Neuronal Cells.

Most pharmacological studies concerning the beneficial effects of organoselenium compounds have focused on their ability to mimic glutathione peroxidase (GPx). However, mechanisms other than GPx-like activity might be involved on their biological effects. This study was aimed to investigate and compare the protective effects of two well known [(PhSe)2 and PhSeZnCl] and two newly developed (MRK Picolyl and MRK Ester) organoselenium compounds against oxidative challenge in cultured neuronal HT22 cells. The thiol peroxidase and oxidase activities were performed using the glutathione reductase (GR)-coupled assay. In order to evaluate protective effects of the organoselenium compounds against oxidative challenge in neuronal HT22 cells, experiments based on glutamate-induced oxytosis and SIN-1-mediated peroxynitrite generation were performed. The thiol peroxidase activities of the studied organoselenium compounds were smaller than bovine erythrocytes GPx enzyme. Besides, (PhSe)2 and PhSeZnCl showed higher thiol peroxidase and lower thiol oxidase activities compared to the new compounds. MRK Picolyl and MRK Ester, which showed lower thiol peroxidase activity, showed higher thiol oxidase activity. Both pre- or co-treatment with (PhSe)2, PhSeZnCl, MRK Picolyl and MRK Ester protected HT22 cells against glutamate-induced cytotoxicity. (PhSe)2 and MRK Picolyl significantly prevented peroxinitrite-induced dihydrorhodamine oxidation, but this effect was observed only when HT22 were pre-treated with these compounds. The treatment with (PhSe)2 increased the protein expression of antioxidant defences (Prx3, CAT and GCLC) in HT22 cells. Taking together, our results suggest that the biological effects elicited by these compounds are not directly related to their GPx-mimetic and thiol oxidase activities, but might be linked to the up-regulation of endogenous antioxidant defences trough their thiol-modifier effects.

[Local and systhemic immunotherapy for bladder cáncer: from bench to bedside.] / Inmunoterapia local y sistémica en cáncer de vejiga: bases moleculares y traslación clínica.

Therapeutic approaches for treatment of urothelial transitional cell carcinoma based on immune system modulation, as well as the contribution of intravesica Bacillus de Calmette-Guérin (BCG) and the recentin corporation of checkpoint inhibitors had found irrefutable proofs of concept for the indication of antitumoral immunontherapy in such tumors. Its extension and development at the present time covers all the locations of the wide spectrum of presentation and evolution of these tumors. Nowadays, apart for the low grade non muscle-invasive tumors, we are facingan unpredictable development of antitumoral immunotherapy in bladder cancer not only as an option in the primary treatment, but also in other scenarios such asnon-responders when it comes to BCG, or the situation of ineligibility for systemic chemotherapy indication. The main objective of this review article is trying to translate the current basic mechanisms involved in different phases of transitional cell carcinomas antitumoral response, regardless of whether they are muscle-invasive or not, and to establish the rationale for their therapeutic intravesical or systemic administration. The role of the interactions established between urothelial tumor cells and the cellular and molecular elements of the immune system of patients is described, incorporating the relevant and recent advances in immunobiology and the molecular characterization of these tumors thatwill undoubtedly introduce far-reaching modifications intherapeutic regimes that will contrast with the traditional options available. Investigational lines that are already active in the clinical research phase with BCG and, checkpoints inhibitors ofthe immune response are also analyzed, high lighting theneed to find predictive response markers as a real option for treatments personalization. The approach to the knowledge of the individual reactivity of the immune system of each patient as a determining factor to achieve it is proposed.

Los abordajes terapéuticos para los carcinomas de células transicionales del urotelio desarrollados en torno a la modulación del sistema inmune encuentran, en la contribución del Bacillus de Calmettey Guérin (BCG) intravesical y más reciente la de los fármacos inhibidores de los puntos de control de la respuesta inmunitaria, indiscutibles pruebas de concepto de la indicación inmunoterapia antitumoral. Su extensión y desarrollo en el momento actual abarca todas las localizaciones del amplio espectro de presentación y evolución de estos tumores. A excepción, por el momento, de los tumores no-músculo infiltrantes debajo grado, acudimos a un desarrollo impredecible de la inmunoterapia antitumoral en el cáncer de vejiga no solo como opción en el tratamiento primario de alguno de ellos sino también en pacientes no-respondedores cuando se trata del BCG, de la quimioterapia sistémicao la situación de no-elegibilidad para su indicación. El objetivo de este artículo de revisión es intentar trasladar los mecanismos básicos actuales implicados en las distintas fases de la respuesta antitumoral de los carcinomas de células transicionales con independencia de que sean o no músculo infiltrantes y establecer los fundamentos para su traslación terapéutica por vía intravesical o sistémica. Se describe el papel de las interacciones que se establecen entre las células tumorales uroteliales y los elementos celulares y moleculares del sistema inmune de los pacientes incorporando los relevantes y recientes avances de la inmunobiológica y la caracterización molecular de estos tumores que sin duda introducirán modificaciones de alcance en su evolución y tratamiento que contrastaran con las opciones hasta hace poco tiempo disponibles. También se analizan las líneas de futuro ya activas en fase de investigación clínica con BCG y con inhibidores de los puntos de control de la respuesta inmunitaria destacando la necesidad de avanzar en la búsqueda de marcadores predictivos de respuesta como opción real para la personalización de los tratamientos planteando la aproximación al conocimiento de la reactividad individual del sistema inmune de cada paciente como factor determinante para poder alcanzarla.

Coagulopatía asociada a síndrome de malabsorción por enfermedad celíaca / Coagulopathy associated with celiac disease malabsorption syndrome

This article describes a 19-y-old patient with abdominal pain and signs of malnutrition. She had been treated previously with an antibiotic for chronic diarrhea. Laboratory analyses showed the presence mild hypoalbuminemia, and considerably prolonged prothrombin time. Tests revealed that hemostasis improved after the patient received fresh frozen plasma and vitamin k. A coagulation profile showed a decrease in clotting factors V, VII, IX, and fibrinogen. Positive serology (immunoglobulin A antitissue transglutaminase and immunoglobulin A antiendomysial antibodies) and small bowel mucosal histopathology confirmed the presence of celiac disease (CD). The girl recovered completely after she was put on a gluten-free diet. Vitamin K­deficiency is a rare complication that occurs in celiac disease manifestations. In addition to antibiotic therapy, treatment with other drugs that influence vitamin K resorption and metabolism may increase the risk of bleeding in patients with CD with hypoprothrombinemia.

Targeting Lipid Peroxidation for Cancer Treatment.

Cancer is one of the highest prevalent diseases in humans. The chances of surviving cancer and its prognosis are very dependent on the affected tissue, body location, and stage at which the disease is diagnosed. Researchers and pharmaceutical companies worldwide are pursuing many attempts to look for compounds to treat this malignancy. Most of the current strategies to fight cancer implicate the use of compounds acting on DNA damage checkpoints, non-receptor tyrosine kinases activities, regulators of the hedgehog signaling pathways, and metabolic adaptations placed in cancer. In the last decade, the finding of a lipid peroxidation increase linked to 15-lipoxygenases isoform 1 (15-LOX-1) activity stimulation has been found in specific successful treatments against cancer. This discovery contrasts with the production of other lipid oxidation signatures generated by stimulation of other lipoxygenases such as 5-LOX and 12-LOX, and cyclooxygenase (COX-2) activities, which have been suggested as cancer biomarkers and which inhibitors present anti-tumoral and antiproliferative activities. These findings support the previously proposed role of lipid hydroperoxides and their metabolites as cancer cell mediators. Depletion or promotion of lipid peroxidation is generally related to a specific production source associated with a cancer stage or tissue in which cancer originates. This review highlights the potential therapeutical use of chemical derivatives to stimulate or block specific cellular routes to generate lipid hydroperoxides to treat this disease.

The gonadal expression pattern of lipocalin­2 and 24p3 receptor is modified in the gonads of the offspring of obese rats.

Obesity represents a global health and economic burden, affecting millions of individuals worldwide. This pathology is associated with a chronic low­grade inflammatory state that is partially responsible for the development of other cardiometabolic complications. Clinical studies have reported an association between high circulating levels of lipocalin­2 (Lcn2) and increased body weight. Additionally, there is scientific evidence demonstrating the impact of maternal obesity on fetal programming. The latter and the fact that the authors previously found that Lcn2 and its receptor (24p3R) are expressed in the gonads of wild­type rats, led to the analysis of their mRNA profile and cellular localization in gonads collected from the offspring of obese rats at 21 days postconception (dpc), and 0, 2, 4, 6, 12, 20 and 30 days postnatal (dpn) in the present study. Semi­quantitative PCR revealed a statistically significant downregulation of Lcn2 and 24p3R mRNA at 21 dpc in the ovaries (P<0.01) and testicles (P<0.001) of the offspring of obese mothers. At 30 dpn, the relative expression of Lcn2 mRNA decreased significantly in the ovaries of the experimental group (P<0.05), while Lcn2 mRNA expression was not detectable in testicles. Regarding 24p3R, its mRNA was only significantly decreased at 21 dpc in ovaries of pups of obese mothers. At 30 dpn, the change in females was not significant. Conversely, in testicles, 24p3R mRNA levels increased slightly in the experimental group at 30 dpn. The Lcn2 protein signal was less intense in gonadal tissue sections from 30 dpn offspring of obese rats (P<0.001), whereas the 24p3R signal was downregulated in ovaries (P<0.001) and slightly upregulated in testicles. It was concluded that maternal obesity changes the expression of Lcn2 and 24p3R in the gonads of the offspring of obese rats, possibly through fetal programming. The consequences of this dysregulation for the offspring's gonadal function remains to be determined.

Metabolic adaptations in spontaneously immortalized PGC-1α knock-out mouse embryonic fibroblasts increase their oncogenic potential.

PGC-1α controls, to a large extent, the capacity of cells to respond to changing nutritional requirements and energetic demands. The key role of metabolic reprogramming in tumor development has highlighted the potential role of PGC-1α in cancer. To investigate how loss of PGC-1α activity in primary cells impacts the oncogenic characteristics of spontaneously immortalized cells, and the mechanisms involved, we used the classic 3T3 protocol to generate spontaneously immortalized mouse embryonic fibroblasts (iMEFs) from wild-type (WT) and PGC-1α knockout (KO) mice and analyzed their oncogenic potential in vivo and in vitro. We found that PGC-1α KO iMEFs formed larger and more proliferative primary tumors than WT counterparts, and fostered the formation of lung metastasis by B16 melanoma cells. These characteristics were associated with the reduced capacity of KO iMEFs to respond to cell contact inhibition, in addition to an increased ability to form colonies in soft agar, an enhanced migratory capacity, and a reduced growth factor dependence. The mechanistic basis of this phenotype is likely associated with the observed higher levels of nuclear ß-catenin and c-myc in KO iMEFs. Evaluation of the metabolic adaptations of the immortalized cell lines identified a decrease in oxidative metabolism and an increase in glycolytic flux in KO iMEFs, which were also more dependent on glutamine for their survival. Furthermore, glucose oxidation and tricarboxylic acid cycle forward flux were reduced in KO iMEF, resulting in the induction of compensatory anaplerotic pathways. Indeed, analysis of amino acid and lipid patterns supported the efficient use of tricarboxylic acid cycle intermediates to synthesize lipids and proteins to support elevated cell growth rates. All these characteristics have been observed in aggressive tumors and support a tumor suppressor role for PGC-1α, restraining metabolic adaptations in cancer.

Pgc1a is responsible for the sex differences in hepatic Cidec/Fsp27ß mRNA expression in hepatic steatosis of mice fed a Western diet.

Hepatic fat-specific protein 27 [cell death-inducing DNA fragmentation effector protein C (Cidec)/Fsp27] mRNA levels have been associated with hepatic lipid droplet extent under certain circumstances. To address its hepatic expression under different dietary conditions and in both sexes, apolipoprotein E (Apoe)-deficient mice were subjected to different experimental conditions for 11 wk to test the influence of cholesterol, Western diet, squalene, oleanolic acid, sex, and surgical castration on Cidec/Fsp27 mRNA expression. Dietary cholesterol increased hepatic Cidec/Fsp27ß expression, an effect that was suppressed when cholesterol was combined with saturated fat as represented by Western diet feeding. Using the latter diet, neither oleanolic acid nor squalene modified its expression. Females showed lower levels of hepatic Cidec/Fsp27ß expression than males when they were fed Western diets, a result that was translated into a lesser amount of CIDEC/FSP27 protein in lipid droplets and microsomes. This was also confirmed in low-density lipoprotein receptor (Ldlr)-deficient mice. Incubation with estradiol resulted in decreased Cidec/Fsp27ß expression in AML12 cells. Whereas male surgical castration did not modify the expression, ovariectomized females did show increased levels compared with control females. Females also showed increased expression of peroxisome proliferator-activated receptor-γ coactivator 1-α (Pgc1a), suppressed by ovariectomy, and the values were significantly and inversely associated with those of Cidec/Fsp27ß. When Pgc1a-deficient mice were used, the sex differences in Cidec/Fsp27ß expression disappeared. Therefore, hepatic Cidec/Fsp27ß expression has a complex regulation influenced by diet and sex hormonal milieu. The mRNA sex differences are controlled by Pgc1a.

Nuclear Factor Kappa B Signaling Complexes in Acute Inflammation.

Significance: Nuclear factor kappa B (NF-κB) is a master regulator of the inflammatory response and represents a key regulatory node in the complex inflammatory signaling network. In addition, selective NF-κB transcriptional activity on specific target genes occurs through the control of redox-sensitive NF-κB interactions. Recent Advances: The selective NF-κB response is mediated by redox-modulated NF-κB complexes with ribosomal protein S3 (RPS3), Pirin (PIR). cAMP response element-binding (CREB)-binding protein (CBP)/p300, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), early growth response protein 1 (EGR-1), and SP-1. NF-κB is cooperatively coactivated with AP-1, STAT3, EGR-1, and SP-1 during the inflammatory process, whereas NF-κB complexes with CBP/p300 and PGC-1α regulate the expression of antioxidant genes. PGC-1α may act as selective repressor of phospho-p65 toward interleukin-6 (IL-6) in acute inflammation. p65 and nuclear factor erythroid 2-related factor 2 (NRF2) compete for binding to coactivator CBP/p300 playing opposite roles in the regulation of inflammatory genes. S-nitrosylation or tyrosine nitration favors the recruitment of specific NF-κB subunits to κB sites. Critical Issues: NF-κB is a redox-sensitive transcription factor that forms specific signaling complexes to regulate selectively the expression of target genes in acute inflammation. Protein-protein interactions with coregulatory proteins, other transcription factors, and chromatin-remodeling proteins provide transcriptional specificity to NF-κB. Furthermore, different NF-κB subunits may form distinct redox-sensitive homo- and heterodimers with distinct affinities for κB sites. Future Directions: Further research is required to elucidate the whole NF-κB interactome to fully characterize the complex NF-κB signaling network in redox signaling, inflammation, and cancer.

Complications of ureteroscopy: a complete overview.

INTRODUCTION: The aim of this paper was to give a complete overview of all published complications associated with ureteroscopy and their according management and prevention in current urological practice. MATERIALS AND METHODS: This review was registered in PROSPERO with registration number CRD42018116273. A bibliographic search of the Medline, Scopus, Embase and Web of Science databases was performed by two authors (V.D.C. and E.X.K.). According to the Population, Intervention, Comparator, Outcome (PICO) study design approach and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) standards, a consensus between these authors was found relating to the thematic structure of this review. RESULTS: Ureteral stent discomfort, ureteral wall injury and stone migration are the most frequently reported complications. The worst complications include urosepsis, multi-organ failure and death. Incidence rates on these and other complications varied extensively between the reviewed reports. CONCLUSION: Ureteroscopy seems to be associated with more complications than currently reported. The present overview may help urologists to prevent, recognize and solve complications of ureteroscopy. It may also stimulate colleagues to perform prospective studies using standardized systems for classifying complications. These are warranted to compare results among different studies, to conduct meta-analyses, to inform health care workers and to counsel patients correctly about possible risks of ureteroscopy.

[The role of intraoperatory ultrasound in laparoscopic partial nephrectomy for intrarenal tumors.] / Nefrectomía parcial laparoscópica en tumores intrarrenales. Papel de la ecografía intraoperatoria.

OBJECTIVES: The use of intraoperatory laparoscopic ultrasound for nephron sparring surgery (partial nephrectomy) in patients with technically challenging tumors has emerged during the last years. The objective of this work is to present a literature review and analysis of the published series, as well as the surgical technique of intraoperatory laparoscopic guided partial nephrectomy. METHODS: Pubmed and Scopus serch was performed in January 2019 including the following keywords: "intraoperative ultrasonography", "laparoscopic ultrasonography" and "partial nephrectomy", the published series are presented. We describe the laparoscopic technique of intraoperatory ultrasound during partial nephrectomy. RESULTS: All the published series present similar results in terms of tumour size which varies from 2.3 to 4 cm. Complications results are also very similar in the comparative series to the ones published in partial nephrectomies. They show promising oncological results during follow up with a rate superior to 90% of negative margins, comparable to those of exophytic tumor partial nephrectomies. CONCLUSIONS: The use of intraoperatory ultrasound during laparoscopic surgery to localize intraparenchymatous renal lesions can expand the indications of partial nephrectomy to more technically challenging tumors. These indications are not yet well standardized. Due to its complexity, the need of previous surgical experience is required to achieve good results and corroborate the security and feasibility of this procedure. Prospective randomized trials are needed to confirm the benefits of intraoperatory laparoscopic ultrasound for nephron sparring surgery (partial nephrectomy).

OBJETIVO: En los últimos años ha emergido el uso de la ecografía laparoscópica intraoperatoria en pacientes con tumores inicialmente complejos para la realización de nefrectomías parciales. El objetivo es realizar una revisión bibliográfica de las series publicadas analizando sus resultados y presentar la técnica quirúrgica de la nefrectomía parcial laparoscópica en los tumores intrarrenales.MÉTODOS: Se realiza una búsqueda bibliográfica en Pumbed y Scopus en Enero de 2019 incluyendo los términos "intraoperative ultrasonography", "laparoscopic ultrasonography" y "partial nephrectomy" en lengua inglesa y se presentan las series de casos publicadas. Descripción de la técnica laparoscópica de ecografía intraoperatoria renal durante la nefrectomía parcial. RESULTADOS: Las diez series publicadas presentan resultados acerca del tamaño medio de las masas intervenidas que oscilan entre los 2,3 y 4 cm. Los resultados de complicaciones son muy similares en las series comparativas a los del resto de nefrectomías parciales. Respecto a la tasa de márgenes negativos en todas las series presenta una tasa superior al 90% con buenos resultados oncológicos en el seguimiento equiparables a la nefrectomía parcial de tumores periféricos. CONCLUSIONES: La utilización durante la cirugía laparoscópica renal de la ecografía intraoperatoria para localización de masas intraparenquimatosas puede expandir la indicación de la nefrectomía parcial a tumores técnicamente más complejos. Las indicaciones de uso de esta técnica no están aún estandarizadas y dada la complejidad precisan de una experiencia quirúrgica previa para ser llevadas a cabo asegurando buenos resultados que corroboren la seguridad y factibilidad de este procedimiento. Son necesarios estudios prospectivos randomizados para confirmar los beneficios de la nefrectomía parcial asistida con ecografía intraoperatoria.

Virtual reality and intracorporeal navigation in urology. / Realidad virtual y navegación intraquirúrgica en urología.

OBJECTIVE: To provide an overview of the meaning and types of virtual reality (VR) system, its current applications in the field of urology and future implications. SYNTHESIS OF THE EVIDENCE: The concept of VR involves the generation of computer environments with which a user can interact directly. Urology technologies and surgical practices are constantly evolving and RV simulation has become an important complement in urologist training curricula, taking into account not only simulations in surgical techniques, but also in non-surgical techniques such as communication and decision making. VR approaches for image-guided surgery have demonstrated potential in the field of urology by supporting guidance for various disorders. An increasing number of pre and intraoperative imaging modalities have been used to create detailed surgical route maps. The tracing of these surgical roadmaps with the surgical vision of real life has been produced in different ways (electromagnetic, acoustic, optical ...), recommending the combination of several approaches to provide a superior result. One of the disadvantages of navigation systems is soft tissue deformations, requiring confirmatory images. Although early studies report that navigation surgeries provide results equal to or greater than conventional approaches, most of the work has been done in relatively small groups of patients, thus requiring studies with larger sample sizes. CONCLUSIONS: The development of VR offers urologists many opportunities, with surgical simulation being one of its most important applications today. Likewise, the first clinical studies have demonstrated the potential of augmented reality (2D and 3D models) to improve surgical accuracy, describing different navigation systems for different urological surgical interventions.

OBJETIVO: Proporcionar una visión general sobre el significado y tipos de sistemas de realidad virtual (RV), sus aplicaciones actuales en el campo de la urología y las implicaciones futuras.SÍNTESIS DE LA EVIDENCIA: El concepto de RV implica la generación de entornos informáticos con los que un usuario puede interactuar directamente. Las tecnologías de urología y las prácticas quirúrgicas están en constante evolución y la simulación de RV se ha convertido en un complemento importante en los planes de estudio de formación de urólogos, teniendo en cuenta no sólo simulaciones en técnicas quirúrgicas, sino también en técnicas no quirúrgicas como comunicación y toma de decisiones.Los enfoques de la RV para la cirugía guiada por imagen han demostrado potencial en el campo de la urología, al apoyar la orientación para diversos trastornos. Se ha utilizado un número cada vez mayor de modalidades de imagen pre e intraoperatorias para crear mapas de ruta quirúrgicos detallados. El rastreo de estas hojas de ruta quirúrgicas, con la visión quirúrgica de la vida real, se ha producido de diferentes formas (electromagnético, acústico, óptico….), recomendándose la combinación de varios enfoques para proporcionar un resultado superior. Uno de los inconvenientes de los sistemas de navegación son las deformaciones de los tejidos blandos, precisando imágenes confirmatorias. Aunque los primeros estudios reportan que las cirugías con navegación proporcionan resultados iguales o superiores a los enfoques convencionales, la mayoría de los trabajos se han realizado en grupos de pacientes relativamente pequeños, precisando por tanto, estudios con mayor tamaño muestral. CONCLUSIONES: El desarrollo de la RV ofrece a los urólogos muchas oportunidades, siendo la simulación quirúrgica una de sus aplicaciones más importantes actualmente. Así mismo, los primeros estudios clínicos han demostrado el potencial de la realidad aumentada (modelos 2D y 3D) para mejorar la precisión quirúrgica, describiéndose diferentes sistemas de navegación para diferentes intervenciones quirúrgicas urológicas.

Melatonin Effects on Non-Alcoholic Fatty Liver Disease Are Related to MicroRNA-34a-5p/Sirt1 Axis and Autophagy.

Melatonin, an indole produced by pineal and extrapineal tissues, but also taken with a vegetarian diet, has strong anti-oxidant, anti-inflammatory and anti-obesogenic potentials. Non-alcoholic fatty liver disease (NAFLD) is the hepatic side of the metabolic syndrome. NAFLD is a still reversible phase but may evolve into steatohepatitis (NASH), cirrhosis and carcinoma. Currently, an effective therapy for blocking NAFLD staging is lacking. Silent information regulator 1 (SIRT1), a NAD+ dependent histone deacetylase, modulates the energetic metabolism in the liver. Micro-RNA-34a-5p, a direct inhibitor of SIRT1, is an emerging indicator of NAFLD grading. Thus, here we analyzed the effects of oral melatonin against NAFLD and underlying molecular mechanisms, focusing on steatosis, ER stress, mitochondrial shape and autophagy. Male C57BL/6J (WT) and SIRT1 heterozygous (HET) mice were placed either on a high-fat diet (58.4% energy from lard) (HFD) or on a standard maintenance diet (8.4% energy from lipids) for 16 weeks, drinking melatonin (10 mg/kg) or not. Indirect calorimetry, glucose tolerance, steatosis, inflammation, ER stress, mitochondrial changes, autophagy and microRNA-34a-5p expression were estimated. Melatonin improved hepatic metabolism and steatosis, influenced ER stress and mitochondrial shape, and promoted autophagy in WT HFD mice. Conversely, melatonin was ineffective in HET HFD mice, maintaining NASH changes. Indeed, autophagy was inconsistent in HET HFD or starved mice, as indicated by LC3II/LC3I ratio, p62/SQSTM1 and autophagosomes estimation. The beneficial role of melatonin in dietary induced NAFLD/NASH in mice was related to reduced expression of microRNA-34a-5p and sterol regulatory element-binding protein (SREBP1) but only in the presence of full SIRT1 availability.