Klotho improves cardiac fibrosis, inflammatory cytokines, ferroptosis, and oxidative stress in mice with myocardial infarction

The anti-aging protein Klotho has been associated with cardiovascular health protection. Nevertheless, the protective mechanism remains unknown. The present study is aimed at exploring the effect of Klotho on cardiac remodeling and its potential mechanism in mice with myocardial infarction (MI). We used left anterior coronary artery descending ligation to develop an MI model for in vivo analyses. In contrast, H9C2 cells and cardiac fibroblasts were used to establish the oxygen–glucose deprivation (OGD) model in in vitro analyses. In vivo and in vitro models were treated with Klotho. Compound C, an AMPK signaling inhibitor, was used to determine whether Klotho’s effects are mediated through the AMPK/mTOR signaling pathway. Echocardiography, Masson trichrome staining, immunofluorescence, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot were used to detect the related indicators. The findings of the in vivo model indicate that Klotho treatment improved the mice’s cardiac function, reduced cardiac fibrosis, and attenuated myocardial inflammatory factors, ferroptosis, and oxidative stress. The results of the in vitro model were in line with the findings of in vivo modeling. An AMPK inhibitor, Compound C, reversed all these effects. In conclusion, Klotho potentially improves cardiac remodeling in MI mice by regulating AMPK/mTOR signaling, demonstrating Klotho as an effective MI therapeutic agent. (AU)

Study on yanghe decoction in improving mTOR pathway and expression of inflammatory factors in female athletic patients

Purpose: A study to explore Yang He Tang chemotherapy to improve mTOR pathway and inflammatory factor expression levels in Athletic patients with acne vulgaris. Methods: Fifty-seven Athletic patients with prickly heat treated in our facility from January 2020 to June 2021 were elected as the observation group, and 20 healthy individuals from a similar period were selected as the control group. The test examined the expression levels of mTOR pathway-related wines and inflammatory factors in both groups to explore the relationship between the mTOR pathway, inflammatory factors and the development of acne vulgaris.; Athletic patient in the monitoring group received Yanghe Tang chemotherapy, and the expression levels of inflammatory factors of mTOR pathway-related proteins were differentiated before and after treatment to study the value of Yang He Tang chemotherapy in acne vulgaris. Results: The observation group (inflamed tissue) had higher levels of mTOR pathway protein expression compared to the control group (normal tissue) (p<0.05); There was no statistically significant change in IL-10 between the two groups (p>0.05), but the observation group had higher levels of IL-2/6/8/1β compared to the control group (P<0.05); compared with the pre-treatment, the mTOR pathway protein expression level was lower after treatment (P < 0.05); Levels of IL-2/6/8/10/1β were lower after treatment than before treatment (p<0.05); the efficiency rate of the observation group after treatment was 91.23%. Conclusion: The mTOR pathway and inflammatory factor expression are involved in the pathogenesis of acne vulgaris, and Yang He Tang chemotherapy can effectively inhibit their horizontal expression, with high therapeutic effect, which is worth promoting. (AU)

The prognostic and predictive values of differential expression of exosomal receptor tyrosine kinases and associated with the PI3K/AKT/mTOR signaling in breast cancer patients undergoing neoadjuvant chemotherapy

Purpose Cancer cell-derived exosomes are the mediator of the tumor microenvironment and the molecular content of exosomes presents a promising prognostic or predictive marker in tumor progression and the treatment response of cancer patients. The aim of this study was to identify the expression levels of receptor tyrosine kinases (RTKs) and AKT1 and mTOR before and after neoadjuvant chemotherapy (NACT) in the exosomes of BC patients compared with healthy females. Methods After isolating exosomes in the serum of 25 BC patients and characterization by flow cytometry, the mRNA levels of FGFR2, FGFR3, PDGFRB, AKT1 and mTOR in the exosomes were analyzed by RT-PCR. Results Our preliminary findings showed that FGFR2, PDGFRB, AKT1 and mTOR levels were significantly upregulated in BC patients before NACT compared with the healthy group (p < 0.05). Furthermore, the mRNA levels PDGFRB and AKT1 were significantly down-regulated after NACT compared with control. PDGFRB expression level could predict pathological non-response and significantly correlated with tumor size after NACT. Conclusion Therefore, especially FGFR2, PDGFRB and AKT1 could be a therapeutic target as a prognostic marker, whereas PDGFRB may be a promising predictive indicator of therapy response in BC patients. However, the prognostic or predictive role of RTKs and PI3K/AKT/mTOR signaling in the exosomes should be further investigated in a large patient population (AU)

Galangin inhibits lipopolysaccharide-induced inflammation and stimulates osteogenic differentiation of bone marrow mesenchymal stem cells via regulation of AKT/mTOR signaling

Background: Bone marrow mesenchymal stem cells (BMSCs), with the abilities of multidirectional differentiation and self-renewal, have been widely used in bone repair and regeneration of inflammation-stimulated oral diseases. Galangin is a flavonoid isolated from Alpinia officinarum, exerts anti-obesity, antitumor, and anti-inflammation pharmacological effects. The roles of galangin in lipopolysaccharide-induced inflammation and osteogenic differentiation of BMSCs were investigated. Methods: BMSCs were isolated from rat bone marrow and identified by flow cytometry. The isolated BMSCs were treated with 1 μg/mL lipopolysaccharides or cotreated with lipopolysaccharides and different concentrations of galangin. Cell viability and apoptosis were detected by MTT (tetrazolium component) and flow cytometry. ELISA was used to detect inflammation. Alizarin red staining was used to investigate osteogenic differentiation. Results: The rat BMSCs showed negative rate of CD34, and positive rate of CD29 and CD44. Lipopolysaccharides treatment reduced cell viability of BMSCs, and promoted the cell apoptosis. Incubation with galangin enhanced cell viability of lipopolysaccharide-stimulated BMSCs, and suppressed the cell apoptosis. Galangin decreased levels of TNF-α, IL-1β, and IL-6 in lipopolysaccharide-stimulated BMSCs through down-regulation of NF-κB phosphorylation (p-NF-κB). Galangin up-regulated expression of osteo-specific proteins, collagen type I alpha 1 (COL1A1), osteopontin (OPN), and runt-related transcription factor 2 (RUNX2), to promote the osteogenic differentiation of lipopolysaccharide-stimulated BMSCs. Protein expression of p-AKT and p-mTOR in lipopolysaccharide-stimulated BMSCs were increased by galangin treatment. Conclusion: Galangin exerted an anti-inflammatory effect against lipopolysaccharide- stimulated BMSCs and promoted osteogenic differentiation through the activation of AKT/ mTOR signaling (AU)

Cinnamtannin D1 ameliorates DSS-induced colitis by preventing Th17/Treg imbalance through activation of the AMPK/mTOR pathway

Background: Inflammatory bowel disease (IBD) is a chronic idiopathic gastrointestinal dis-ease, including ulcerative colitis (UC) and Crohn’s disease (CD), which is typically charac-terized by chronicity and relapse. Cinnamtannin D1 (CTD1), extracted from Cinnamomum tamala, has been found to exert good immunosuppressive activity. However, the role of CTD1 in IBD is unclear. Methods: The colitis mice model was established by dextran sulfate sodium (DSS) treat-ment. Protein levels (p-STAT3/STAT3, ROR-γt, p-STAT5/STAT5, FOXP3, p-AMPK/AMPK, and p-mTOR/mTOR) were examined using Western blotting analysis. Changes in histopathol-ogy were detected through hematoxylin and eosin staining. The proportion of T helper 17 (Th17) cells and regulatory T (Treg) cells was measured by flow cytometry analysis.Results: CTD1 improved body weight and colon length, and alleviated inflammation and histological damage in DSS-induced colitis mice model. DSS treatment also demonstrated a negative effect on Th17–Treg cells balance whereas CTD1 restored the balance of Th17–Treg cells in DSS-induced colitis mice model. Regulatory factors (such as STAT3, ROR-γt, STAT5, and FOXP3) that closely related to the balance of Th17–Treg cells were regulated by CTD1. In addition, AMPK phosphorylation was increased and mTOR phosphorylation was inhibited by CTD1 in DSS-induced colitis mice model. Conclusion: These findings established that CTD1 improved DSS-induced colitis by suppress-ing Th17–Treg cells balance by activating the AMPK/mTOR pathway. This study provided a new strategy for developing novel treatments for patients with IBD (AU)

Cordycepin alleviates myocardial ischemia/reperfusion injury by enhancing autophagy via AMPK-mTOR pathway

To estimate the cardioprotective mechanism of cordycepin on myocardial ischemia/reperfusion (I/R) injury. The left anterior descending artery of mice was ligated transiently to establish the myocardial I/R model. TTC/Evans Blue staining and TUNEL assay were performed to quantify the infarct size and apoptosis index. The cardiac function was evaluated by echocardiography. Neonatal rat ventricular cardiomyocytes (NRVCs) underwent hypoxia and reoxygenation (H/R). MTS and LDH were detected to measured cell viability and necrosis respectively. The results suggested that cordycepin could markedly decrease apoptosis, reduce infarct size, and improve cardiac function in mice subjected to I/R injury, alongside with enhanced autophagy. In NRVCs, cordycepin treatment obviously reduced ROS production. In addition, cordycepin partly promoted autophagy in the context of H/R injury by regulating AMPK/mTOR pathway. Our data demonstrated that cordycepin exerts cardio-protective effect and promotes cardiac functional recovery following myocardial I/R by enhancing autophagy via AMPK-mTOR signaling pathway. (AU)

Calcium/calmodulin-dependent protein kinase IV regulates vascular autophagy and insulin signaling through Akt/mTOR/CREB pathway in ob/ob mice

Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and vascular function, but the underlying mechanism is not fully understood. Recently, we revealed that CaMKIV limits metabolic disorder and liver insulin resistance and regulates autophagy in high-fat diet-induced obese mice. In the present study, we demonstrated that CaMKIV was not only associated with improvement of glucose tolerance and insulin sensitivity in ob/ob mice but also involved in the regulation of vascular autophagy and mitochondrial biogenesis. Our in vitro data indicated that CaMKIV reversed autophagic imbalance and restored insulin sensitivity in palmitate-induced A7r5 cells with insulin resistance. However, the protective effects of CaMKIV were nullified by suppression of Akt, mTOR, or CREB, suggesting that CaMKIV inhibits autophagy and improves insulin signaling in insulin resistance cell models in an Akt/mTOR/CREB-dependent manner. CaMKIV reversed autophagic imbalance and insulin sensitivity in vascular tissues and vascular cells through Akt/mTOR/CREB signaling, which could be regarded as a novel opportunity for the treatment of insulin resistance. (AU)

Procyanidin A1 alleviates DSS-induced ulcerative colitis via regulating AMPK/mTOR/p70S6K-mediated autophagy

Ulcerative colitis (UC) is a recurrent chronic inflammatory disease. The symptom of UC is mainly diarrhea including bloody stools. Increasing evidence has suggested that procyanidin A1 (PCA1) exerts an anti-inflammatory effect in several diseases. However, the role of PCA1 in UC is still a mystery. In our study, we explored the effect of PCA1 in dextran sulfate sodium (DSS)–induced UC mice and lipopolysaccharide (LPS)-stimulated HT-29 and IEC-6 cells. Then, cell proliferation, apoptosis, the production of proinflammatory cytokines, and autophagy-related markers were determined. Furthermore, the AMPK/mTOR/p70S6K signaling pathway was assayed by Western blot assay. In in vivo study, we found that PCA1 administration alleviated DSS-induced UC, as evidenced by reducing weight loss, clinical scores, colon weight/length ratio, histological damage, proinflammatory cytokines, and apoptosis. Moreover, we showed that the expression of Beclin-1 and LC3II/I ratio was increased, whereas the level of p62 was decreased after PCA1 treatment in vivo. Meanwhile, the reduced AMP/ATP ratio, enhanced expression of p-AMPK, and decreased p-p70S6K and p-mTOR levels indicate the activation of AMPK/mTOR/p70S6K signaling pathway. In in vitro study, PCA1 promoted cell proliferation and inhibited cell apoptosis in LPS-stimulated HT-29 and IEC-6 cells. Pro-inflammatory cytokines and autophagy-related factors exhibited the same trend as in in vivo results. Mechanically, PCA1 activated the AMPK/mTOR/p70S6K signaling pathway. The treatment with an AMPK inhibitor compound C significantly reversed the anti-inflammatory effect of PCA1 in LPS-stimulated cells. Taken together, these data indicated that PCA1 alleviated UC through induction of AMPK/mTOR/p70S6K-mediated autophagy. (AU)

ST8SIA1 inhibition sensitizes triple negative breast cancer to chemotherapy via suppressing Wnt/B-catenin and FAK/Akt/mTOR

Background Chemoresistance is the major cause of therapeutic failure in triple negative breast cancer (TNBC). In this work, we investigated the molecular mechanism for the development of TNBC chemoresistance. Methods mRNA and protein levels of ST8SIA1 were analyzed in chemosensitive and chemoresistant TNBC cells and tissues. Proliferation and survival assays were performed to determine the role of ST8SIA1 in TNBC chemoresistance. Results We found that ST8SIA1 mRNA and protein levels were increased in multiple TNBC cell lines after prolonged exposure to chemotherapeutic drugs. Consistently, retrospective study demonstrated that the majority of TNBC patients who developed chemoresistance displayed upregulation of ST8SIA1. We further found that chemoresistant TNBC cells were more sensitive than chemosensitive cells to ST8SIA1 inhibition in decreasing growth and viability. Consistently, ST8SIA1 inhibition augmented the efficacy of chemotherapy in TNBC cells. Mechanism studies demonstrated that ST8SIA1 inhibition led to suppression of FAK/Akt/mTOR and Wnt/β-catenin signalling pathways. Conclusions These findings provide an explanation for the heterogeneity of chemotherapy responses across TNBC individuals and reveal the supportive roles of ST8SIA1in TNBC chemoresistance (AU)

CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT/mTOR pathway

Purpose The current study aims to explore the effects of CDKN2A on cell proliferation and cycle, and investigate the underlying mechanisms. Methods Expression of CDKN2A in cervical cancer cell lines was evaluated by real-time quantitative PCR (RT-qPCR) and western blotting. Apoptotic rate was detected by Annexin V assay. MTT assay, Transwell assay and cell cycle assay kit were applied to examine the effect of CDKN2A on cell viability, invasion and cell cycle. Co-immunoprecipitation and western blotting were devoted to explore the mechanism by which CDKN2A contributes to cell function. Results CDKN2A was expressed at a low level in cervical cancer cell lines. Overexpression of CDKN2A inhibited cell proliferation and invasion, and caused cell cycle arrest in the G1 phase. CDKN2A mediates the AKT–mTOR signaling pathway by suppressing lactate dehydrogenase (LDHA). Taken together, our data revealed that CDKN2A can be applied as a therapeutic target for the treatment of cervical cancer in future. Conclusions CDKN2A inhibits cell proliferation and invasion in cervical cancer through LDHA-mediated AKT–mTOR pathway (AU)

Vías moleculares de regulación de la autofagia por BRCA1: implicaciones en cáncer / Molecular pathways of autophagy regulation by BRCA1: implications in cancer

La proteína BRCA1 contribuye a mantener la integridad genómica, a través de la regulación transcripcional de proteínas que controlan el ciclo celular y la reparación del ADN o por interacción directa con estas proteínas. La inestabilidad genética generada por mutaciones que dan lugar a un déficit de la actividad de BRCA1 confiere un riesgo incrementado de padecer, fundamentalmente, cánceres de mama y ovario. En los últimos años, se ha demostrado que la autofagia tiene un papel dual en el desarrollo tumoral, y agentes químicos como lucanthone, cloroquina, Z-ligustilide, spautin-1, tunicamicina, T-12, y olaparib, regulan la supervivencia/muerte del tumor dependiente de autofagia. Aquí revisamos también las diferentes vías moleculares por las que BRCA1 regula (mayoritariamente de forma negativa) la autofagia, fundamentalmente en cánceres de mama y ovario, y donde el estado rédox celular (ROS, GSH) y las proteínas mTOR, p53-Mdm2, STAT3, y Parkin, se ha demostrado que tienen un papel esencial

The BRCA1 protein contributes to maintain genomic integrity, through transcriptional regulation of proteins that control the cell cycle and DNA repair or by direct interaction with these proteins. The genetic instability caused by mutations that result in a deficit of BRCA1 activity, confers an increased risk of mainly breast and ovarian cancers. In recent years, it has been shown that autophagy has a dual role in tumor development, and chemical agents such as lucanthone, chloroquine, Z-ligustilide, spautin-1, tunicamycin, T-12, and olaparib, regulate tumor survival/death autophagy-dependent. Here we also review the different molecular pathways by which BRCA1 regulates (mostly negatively) autophagy, mainly in breast and ovarian cancers, and where the cellular redox state (ROS, GSH) and proteins mTOR, p53-Mdm2, STAT3, and Parkin, have been shown to play an essential role

Inmunosupresión en el trasplante hepático en la era covid-19 / Liver transplant immunosuppression during the covid-19 pandemic

La infección por el virus SARS-CoV-2 ha producido una pandemia con graves consecuencias sobre nuestro sistema sanitario. Aunque el colectivo de pacientes trasplantados hepáticos representa solo una minoría de la población, los hepatólogos que seguimos a estos pacientes hemos intentado coordinar esfuerzos para protocolizar el manejo de la inmunosupresión durante la infección por SARS-CoV-2. Aunque no hay estudios sólidos que avalen recomendaciones generales, las experiencias con otras infecciones víricas (hepatitis C, citomegalovirus) sugieren que el manejo de la inmunosupresión sin micofenolato mofetilo ni inhibidores m-Tor (fármacos que además se asocian a leucopenia y linfopenia) puede resultar beneficiosa. Es importante además prestar atención a las posibles interacciones farmacológicas, especialmente en el caso de tacrolimus, con algunos de los tratamientos con efecto antiviral que se administran en el contexto de la covid-19 (lopinavir/ritonavir, azitromicina). Finalmente, deberá tenerse en cuenta el efecto inmunosupresor de fármacos inmunomoduladores (tocilizumab y similares) que se administran en pacientes con enfermedad pulmonar severa. En el artículo se revisan los mecanismos de actuación de los diferentes fármacos inmunosupresores, su potencial efecto sobre la infección por SARS-CoV-2 y se sugieren unas pautas en el manejo de la inmunosupresión

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression

FR- Rapamicina tópica adyuvante al tratamiento con láser en malformaciones capilares / RF-Topical Rapamycin as an Adjuvant to Laser Treatment in Capillary Malformations

No disponible

Evaluación del efecto sinérgico de la metformina y los inhibidores mTOR sobre la endotelización de los stents farmacoactivos en pacientes diabéticos / In vivo evaluation of the synergic effect of metformin and mTOR inhibitors on the endothelial healing of drug-eluting stents in diabetic patients

Introducción y objetivos: Estudios recientes en animales han demostrado que la metformina (MF) perjudica la endotelización de los stents farmacoactivos (SFA). Se evaluó el efecto de la MF en el recubrimiento neointimal de los SFA en pacientes diabéticos por tomografía de coherencia óptica (OCT). Métodos: El ensayo RESERVOIR aleatorizó 116 lesiones en 112 pacientes con diabetes mellitus a stents liberadores de amphilimus o everolimus, a los que se realizó una OCT a los 9 meses. Los pacientes se dividieron en 3 grupos según el tratamiento hipoglucemiante recibido: a) no MF; b) MF sin insulina, y c) MF con insulina. El objetivo primario fue el porcentaje de struts no recubiertos. Resultados: Diecisiete pacientes (19 lesiones) al grupo sin MF; 53 pacientes (54 lesiones) al grupo MF sin insulina y 28 pacientes (28 lesiones) al grupo MF con insulina. Las características basales fueron comparables, aunque los pacientes del grupo MF sin insulina tuvieron un mejor control glucémico (p < 0,01). Por OCT la frecuencia relativa de struts no recubiertos fue comparable entre grupos (3,07 ± 4,80% frente a 2,23 ± 4,73% frente a 3,43 ± 6,69% respectivamente, p = 0,48). El análisis multivariante confirmó que la MF no altera el recubrimiento de los SFA (OR = 1,49; IC95%, 0,71-3,08, p = 0,29). La angiografía cuantitativa tampoco mostró efecto de la MF sobre la pérdida luminal tardía, mientras que el tratamiento con insulina si se asoció a una mayor pérdida luminal tardía (p = 0,02). Conclusiones: El uso de MF no perjudica el recubrimiento neointimal de los SFA en diabéticos independientemente de que reciban o no tratamiento con insulina. De acuerdo a nuestros resultados, el uso de MF parece no estar desaconsejado en estos pacientes

Introduction and objectives: Recent animal studies have shown metformin (MF) to impair endothelialization of drug-eluting stents (DES). The aim of this study was to evaluate the effect of MF on the healing of DES in human coronary arteries of patients with diabetes mellitus by optical coherence tomography (OCT). Methods: The RESERVOIR trial randomized 116 lesions in 112 patients with diabetes mellitus to amphilimus- or everolimus-eluting stents and included mandatory OCT at 9 months of follow-up. Patients were divided in 3 groups according to the glucose-lowering agents received: a) no MF; b) MF in noninsulin treated patients, and c) MF in insulin-treated patients. The primary safety endpoint was the rate of uncovered stents. Results: Seventeen patients with 19 lesions did not receive MF, whereas MF was administered to 53 noninsulin treated patients (54 lesions) and 28 insulin-treated patients (28 lesions). Baseline characteristics were comparable, although noninsulin treated patients who received MF had better glycemic control (P < .01). By OCT, rates of uncovered struts were comparable between groups (3.07 ± 4.80% vs 2.23 ± 4.73% vs 3.43 ± 6.69%, respectively; P = .48). Multivariate models confirmed that MF had no effect on the healing of DES (OR, 1.49, 95%CI, 0.71-3.08; P = .29). Similarly, quantitative angiography showed no effect of MF on late lumen loss, whereas patients treated with exogenous insulin had greater late lumen loss (P = .02). Conclusions: Metformin use does not impair endothelial healing of DES in patients with both insulin- and noninsulin-treated diabetes mellitus. According to these results, MF should not be discouraged in these patients

Comparación del perfil de expresión de la vía PI3K-AKT-mTOR en muestras de tejido tumoral y no tumoral de pacientes sometidos a trasplante cardiaco / Comparison of the PI3K-AKT-mTOR pathway expression profile in tumoral versus nontumoral tissue samples from heart transplant recipients

No disponible

Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy

Aim: to analyze the effect of metformin on ammonia production derived from glutamine metabolism in vitro and in vivo. Methods: twenty male Wistar rats were studied for 28 days after a porto-caval anastomosis (n = 16) or a sham operation (n = 4). Porto-caval shunted animals were randomized into two groups (n = 8) and either received 30 mg/kg/day of metformin for two weeks or were control animals. Plasma ammonia concentration, Gls gene expression and K-type glutaminase activity were measured in the small intestine, muscle and kidney. Furthermore, Caco2 were grown in different culture media containing glucose/glutamine as the main carbon source and exposed to different concentrations of the drug. The expression of genes implicated in glutamine metabolism were analyzed. Results: metformin was associated with a significant inhibition of glutaminase activity levels in the small intestine of porto-caval shunted rats (0.277 ± 0.07 IU/mg vs 0.142 ± 0.04 IU/mg) and a significant decrease in plasma ammonia (204.3 ± 24.4 µg/dl vs 129.6 ± 16.1 µg/dl). Glucose withdrawal induced the expression of the glutamine transporter SLC1A5 (2.54 ± 0.33 fold change; p < 0.05). Metformin use reduced MYC levels in Caco2 and consequently, SLC1A5 and GLS expression, with a greater effect in cells dependent on glutaminolytic metabolism. Conclusion: metformin regulates ammonia homeostasis by modulating glutamine metabolism in the enterocyte, exerting an indirect control of both the uptake and degradation of glutamine. This entails a reduction in the production of metabolites and energy through this pathway and indirectly causes a decrease in ammonia production that could be related to a decreased risk of HE development

No disponible

Muscle-specific deletion of Prkaa1 enhances skeletal muscle lipid accumulation in mice fed a high-fat diet

Excessive intramyocellular triacylglycerols (IMTGs, muscle lipids) are associated with the abnormal energy metabolism and insulin resistance of skeletal muscle. AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, consists of α, β and γ subunits. Researchers have not clearly determined whether Prkaa1 (also known as AMPKα1) affects IMTG accumulation in skeletal muscle. Here, we show an important role of Prkaa1 in skeletal muscle lipid metabolism. Deletion of muscle Prkaa1 leads to the delayed development of skeletal muscles but does not affect glucose tolerance or insulin sensitivity in animals fed a normal diet. Notably, when animals are fed a high-fat diet, the skeletal muscle of muscle-specific Prkaa1 knockout mice accumulates more lipids than the skeletal muscle of wild-type (WT) mice, with concomitant upregulation of adipogenic gene expressions and downregulation of the expression of genes associated with mitochondrial oxidation. Muscle-specific Prkaa1 ablation also results in hyperlipidemia, which may contribute to the increased IMTG levels. Furthermore, Prkaa1 deletion activates skeletal muscle mTOR signalling, which has a central role in lipid metabolism and mitochondrial oxidation. Collectively, our study provides new insights into the role of Prkaa1 in skeletal muscle. This knowledge may contribute to the treatment of related metabolic diseases

Prognostic and predictive role of the PI3K-AKT-mTOR pathway in neuroendocrine neoplasms

Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K-AKT-mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K-AKT-mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials' design to identify potential predictive or prognostic biomarkers

No disponible

Opciones terapéuticas y factores predictivos de recurrencia y mortalidad cáncer-específica en pacients con tumor vesical después de traspante renal: análisis multiinstitucional / Treatment options and predictive factors for recurrence and cancer-specific mortality in bladder cancer after renal transplantation: A multi-institutional analysis

Objetivos: El tumor vesical (TV) en la población trasplantada representa un desafío debido al estado de inmunosupresión de los pacientes y a la mayor tasa de comorbilidades. El objetivo de este estudio fue analizar el tratamiento del TV tras el trasplante renal (TR), centrándose en el modo de presentación, diagnóstico, opciones de tratamiento, factores predictivos de recurrencia y mortalidad cáncer-específica. Material y métodos: Se realizó un estudio observacional prospectivo con un análisis retrospectivo de 88 pacientes con TV después de TR en 10 centros europeos. Se recogieron datos clínicos y oncológicos y se revisaron las indicaciones y los resultados del tratamiento adyuvante. Se aplicó el método de Kaplan-Meier para el análisis de la supervivencia y regresión de Cox uni- y multivariante para identificar los factores de riesgo. Resultados: En la revisión se incluyeron un total de 10.000 TR, identificando 87 pacientes con TV de novo, tras una mediana de seguimiento de 126 meses. La mediana del tiempo al diagnóstico fue 73 meses posterior al TR. Setenta y un pacientes (81,6%) fueron diagnosticados de TV no músculo-invasivo, de los cuales 29 (40,8%) recibieron tratamiento adyuvante: 6 de ellos (20,6%) recibieron el bacilo Calmette-Guérin (BCG) y 20 (68,9%) mitomicina C. En el análisis univariado los pacientes que recibieron BCG presentaron una tasa de recurrencia del TV significativamente menor (p = 0,043). En el análisis multivariante, el cambio de la inmunosupresión a inhibidores de mTOR redujo significativamente el riesgo de recurrencia (HR: 0,24; IC del 95%: 0,053-0,997; p = 0,049), mientras que la presencia de múltiples tumores lo aumentó (HR: 6,31; IC del 95%: 1,78-22,3; p = 0,004). Globalmente, 26 pacientes (29,88%) se sometieron a cistectomía, sin registrarse complicaciones mayores. La mortalidad global fue del 32,2% (28 pacientes) y la mortalidad cáncer-específica del 13,8%. Conclusiones: El tratamiento con bacilo Calmette-Guérin adyuvante y el cambio a inhibidores de mTOR reduce significativamente el riesgo de recurrencia de TV en TR, mientras que la presencia de tumores múltiples aumenta el riesgo

Objectives: Bladder cancer (BC) in the transplanted population can represent a challenge owing to the immunosuppressed state of patients and the higher rate of comorbidities. The objective was to analyze the treatment of BC after renal transplant (RT), focusing on the mode of presentation, diagnosis, treatment options and predictive factors for recurrence. Material and methods:We conducted an observational prospective study with a retrospective analysis f 88 patients with BC after RT at 10 European centers. Clinical and oncologic data were collected, and indications and results of adjuvant treatment reviewed. The Kaplan-Meier method and uni- and multivariate Cox regression analyses were performed. Results: A total of 10,000 RTs were performed. Diagnosis of BC occurred at a median of 73 months after RT. Median follow-up was 126 months. Seventy-one patients (81.6%) had non-muscle invasive bladder cancer, of whom 29 (40.8%) received adjuvant treatment; of these, six (20.6%) received bacillus Calmette-Guérin and 20 (68.9%) mitomycin C. At univariate analysis, patients who received bacillus Calmette-Guérin had a significantly lower recurrence rate (P = .043). At multivariate analysis, a switch from immunosuppression to mTOR inhibitors significantly reduced the risk of recurrence (HR 0.24, 95% CI: 0.053-0.997, P = .049) while presence of multiple tumors increased it (HR 6.31, 95% CI: 1.78-22.3, P = .004). Globally, 26 patients (29.88%) underwent cystectomy. No major complications were recorded. Overall mortality (OM) was 32.2% (28 patients); the cancer-specific mortality was 13.8%. Conclusions: Adjuvant bacillus Calmette-Guérin significantly reduces the risk of recurrence, as does switch to mTOR inhibitors. Multiple tumors increase the risk

Kaposi Sarcoma and Lung Transplant: Two Case Reports / Sarcoma de Kaposi y trasplante pulmonar: dos casos clínicos

No disponible