RESUMO
Protein biogenesis within the endoplasmic reticulum (ER) is crucial for organismal function. Errors during protein folding necessitate the removal of faulty products. ER-associated protein degradation and ER-phagy target misfolded proteins for proteasomal and lysosomal degradation. The mechanisms initiating ER-phagy in response to ER proteostasis defects are not well understood. By studying mouse primary cells and patient samples as a model of ER storage disorders (ERSDs), we show that accumulation of faulty products within the ER triggers a response involving SESTRIN2, a nutrient sensor controlling mTORC1 signaling. SESTRIN2 induction by XBP1 inhibits mTORC1's phosphorylation of TFEB/TFE3, allowing these transcription factors to enter the nucleus and upregulate the ER-phagy receptor FAM134B along with lysosomal genes. This response promotes ER-phagy of misfolded proteins via FAM134B-Calnexin complex. Pharmacological induction of FAM134B improves clearance of misfolded proteins in ERSDs. Our study identifies the interplay between nutrient signaling and ER quality control, suggesting therapeutic strategies for ERSDs.
Assuntos
Retículo Endoplasmático , Alvo Mecanístico do Complexo 1 de Rapamicina , Dobramento de Proteína , Proteína 1 de Ligação a X-Box , Animais , Retículo Endoplasmático/metabolismo , Humanos , Camundongos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Proteína 1 de Ligação a X-Box/genética , Transdução de Sinais , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Lisossomos/metabolismo , Estresse do Retículo Endoplasmático , Sestrinas/metabolismo , Sestrinas/genética , Fosforilação , Proteostase , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix BásicosRESUMO
TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive. By integrating in vivo analyses with multi-omics approaches and functional assays, we have uncovered an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Our findings demonstrate that constitutive loss of TFEB in knock-out mice is associated with defective formation of the syncytiotrophoblast layer. Indeed, using in vitro models of syncytialization, we demonstrated that TFEB translocates into the nucleus during syncytiotrophoblast formation and binds to the promoters of crucial placental genes, including genes encoding fusogenic proteins (Syncytin-1 and Syncytin-2) and enzymes involved in steroidogenic pathways, such as CYP19A1, the rate-limiting enzyme for the synthesis of 17ß-Estradiol (E2). Conversely, TFEB depletion impairs both syncytial fusion and endocrine properties of syncytiotrophoblast, as demonstrated by a significant decrease in the secretion of placental hormones and E2 production. Notably, restoration of TFEB expression resets syncytiotrophoblast identity. Our findings identify that TFEB controls placental development and function by orchestrating both the transcriptional program underlying trophoblast fusion and the acquisition of endocrine function, which are crucial for the bioenergetic requirements of embryonic development.
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Introducción. El cáncer colorrectal es uno de los tipos de cáncer más comunes y mortales a nivel mundial. Aunque los avances médicos han mejorado el manejo, la cirugía sigue siendo fundamental. La resección anterior baja (RAB) de recto ha ganado relevancia, a pesar de que puede llevar al síndrome de resección anterior baja de recto (LARS, por sus siglas en inglés), afectando la calidad de vida. Métodos. Estudio de corte transversal con intención analítica en un centro de referencia en Medellín, Colombia. Los pacientes con cáncer de recto sometidos a RAB entre enero de 2016 y diciembre de 2022 completaron el cuestionario LARS para evaluar disfunción intestinal. Se evaluaron factores relacionados con la presencia de LARS por medio de un análisis bivariado. Resultados. De 234 pacientes elegibles, 110 (47 %) respondieron la encuesta, predominantemente mujeres (58,2 %). La edad promedio fue 62 años. Dos tercios de los pacientes recibieron neoadyuvancia y el 69 % requirieron ileostomía. La prevalencia de LARS fue 47,3 %. El 80,9 % llevaban más de 12 meses desde la cirugía o el cierre del estoma. Factores estadísticamente significativos asociados a LARS fueron edad mayor de 65 años (p=0,03), estadío patológico avanzado (p=0,02) y requerimiento de estoma (p=0,03). Conclusiones. El LARS afecta a casi la mitad de los pacientes en diferentes etapas posquirúrgicas. El LARS scorees una herramienta práctica para evaluar la función intestinal en el seguimiento del paciente. La prevalencia y los factores de riesgo identificados contribuyen a la comprensión del impacto de la cirugía conservadora del esfínter en la calidad de vida de los pacientes.
Introduction. Colorectal cancer is one of the most common and deadly types of cancer worldwide, with a high incidence of rectal cancer. Although medical advances have improved management, surgery remains crucial. Low anterior resection of the rectum (LAR) has gained significance, despite its potential to lead to low anterior resection syndrome (LARS), affecting quality of life. Methods. A cross-sectional study with analytical intent was conducted at a referral center in Medellín, Colombia. Patients with rectal cancer who underwent LAR between January 2016 and December 2022 completed the LARS questionnaire to assess intestinal dysfunction. Factors related to the presence of LARS were analyzed using bivariate analysis. Results. Of 234 eligible patients, 110 (47%) responded, predominantly women (58.2%). The average age was 62 years. Two-thirds of patients received neoadjuvant therapy and 69% required ileostomy. The prevalence of LARS was 47.3%. 80.9% had been more than 12 months post-surgery or stoma closure. Statistically significant factors associated with LARS included age over 65 years (p=0.03), advanced pathological stage (p=0.02), and stoma requirement (p=0.03). Conclusions. LARS affects almost half of the patients in various post-surgical stages. The LARS score is a practical tool for assessing intestinal function in patient follow-up. The prevalence and risk factors identified contribute to the understanding of the impact of sphincter-conserving surgery on patients' quality of life.
Assuntos
Humanos , Doenças Retais , Protectomia , Complicações Pós-Operatórias , Neoplasias Retais , Cirurgia Colorretal , Estomas CirúrgicosRESUMO
Lysosomes are the terminal end of catabolic pathways in the cell, as well as signaling centers performing important functions such as the recycling of macromolecules, organelles, and nutrient adaptation. The importance of lysosomes in human health is supported by the fact that the deficiency of most lysosomal genes causes monogenic diseases called as a group Lysosomal Storage Diseases (LSDs). A common phenotypic hallmark of LSDs is the expansion of the lysosomal compartment that can be detected by using conventional imaging methods based on immunofluorescence protocols or overexpression of tagged lysosomal proteins. These methods require the alteration of the cellular architecture (i.e., due to fixation methods), can alter the behavior of cells (i.e., by the overexpression of proteins), and require sample preparation and the accurate selection of compatible fluorescent markers in relation to the type of analysis, therefore limiting the possibility of characterizing cellular status with simplicity. Therefore, a quantitative and label-free methodology, such as Quantitative Phase Imaging through Digital Holographic (QPI-DH), for the microscopic imaging of lysosomes in health and disease conditions may represent an important advance to study and effectively diagnose the presence of lysosomal storage in human disease. Here we proof the effectiveness of the QPI-DH method in accomplishing the detection of the lysosomal compartment using mouse embryonic fibroblasts (MEFs) derived from a Mucopolysaccharidosis type III-A (MSP-IIIA) mouse model, and comparing them with wild-type (WT) MEFs. We found that it is possible to identify label-free biomarkers able to supply a first pre-screening of the two populations, thus showing that QPI-DH can be a suitable candidate to surpass fluorescent drawbacks in the detection of lysosomes dysfunction. An appropriate numerical procedure was developed for detecting and evaluate such cellular substructures from in vitro cells cultures. Results reported in this study are encouraging about the further development of the proposed QPI-DH approach for such type of investigations about LSDs.
Assuntos
Lisossomos , Lisossomos/metabolismo , Animais , Camundongos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Doenças por Armazenamento dos Lisossomos/metabolismo , Doenças por Armazenamento dos Lisossomos/patologia , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/diagnóstico , Mucopolissacaridose III/metabolismo , Mucopolissacaridose III/patologia , Mucopolissacaridose III/genética , Imageamento Quantitativo de FaseRESUMO
This paper aims to describe a case of trombiculosis in llamas from the Puna region of Argentina caused by Eutrombicula cochinocaensis. Trombiculosis is a parasitic infestation caused by the larval form of trombiculid mites, commonly known as chigger mites. Six adult llamas out of eighteen (33%) were infested and showed dermatitis, hyperemia, and crusts together with an orange-dotted pattern. The chigger mites were found mainly in the hind limbs and the abdomen. Microscopic identification of E. cochinocaensis was made by phase-contrast microscopy. Then, a histopathological study of the affected animals' skin was performed. Histological findings included dermatitis withmainly lymphocytic infiltrate, pustules, crusts, hyperkeratosis, and the mites' stylostomes in the dermis and epidermis. This is the first report of trombiculosis caused by E. cochinocaensis in llamas from Argentina. Mites of the family Trombiculidae are vectors of certain diseases to humans and animals and are therefore of sanitary and productive importance.
Assuntos
Camelídeos Americanos , Trombiculíase , Trombiculidae , Animais , Argentina , Camelídeos Americanos/parasitologia , Trombiculíase/veterinária , Trombiculíase/parasitologia , Trombiculíase/patologia , Trombiculidae/classificação , Trombiculidae/fisiologiaRESUMO
Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.
Assuntos
Calcineurina , Proteínas de Drosophila , Animais , Calcineurina/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Mitofagia/genética , Mitocôndrias/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina/metabolismo , Drosophila/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismoRESUMO
El interrogatorio sobre hábito tabáquico no debe obviarse jamás, pues el abanico de posibilidades diagnósticas inherentes es amplio. Es un gesto clínico fundamental frente a individuos que consultan por síntomas y/o hallazgos radiológicos casuales. Presentamos tres casos clínicos: síndrome de combinación de fibrosis pulmonar y enfisema, neumonitis intersticial descamativa e histiocitosis de células de Langerhans, como parte del abanico de las enfermedades pulmonares intersticiales difusas asociadas a tabaco (EPIDAT), donde la tomografía de alta resolución de tórax tiene un rol destacado. Palabras clave: tabaquismo; enfisema; enfermedades pulmonares intersticiales; histiocitosis de células de Langerhans
Questioning about smoking habits should never be ignored, since the range of inherent diagnostic possibilities is wide. It is a fundamental clinical step facing individuals who consult for symptoms and/or casual radiological findings. We present three clinical cases: the combined syndrome of pulmonary fibrosis and emphysema, desquamative interstitial pneumonitis, and Langerhans cell histiocytosis, as part of the range of tobacco-associated diffuse interstitial lung diseases (EPIDAT), where high-resolution chest tomography has a prominent role. Key words: smoking; emphysema; interstitial lung diseases; Langerhans cell histiocytosis
Assuntos
Humanos , Masculino , Adulto , Idoso , Histiocitose de Células de Langerhans , Doenças Pulmonares Intersticiais , Enfisema , TabagismoRESUMO
In the brain, microRNAs (miRNAs) are believed to play a role in orchestrating synaptic plasticity at a higher level by acting as an additional mechanism of translational regulation, alongside the mRNA/polysome system. Despite extensive research, our understanding of the specific contribution of individual miRNA to the function of dopaminergic neurons (DAn) remains limited. By performing a dopaminergic-specific miRNA screening, we have identified miR-218 as a critical regulator of DAn activity in male and female mice. We have found that miR-218 is specifically expressed in mesencephalic DAn and is able to promote dopaminergic differentiation of embryonic stem cells and functional maturation of transdifferentiated induced DA neurons. Midbrain-specific deletion of both genes encoding for miR-218 (referred to as miR-218-1 and mir218-2) affects the expression of a cluster of synaptic-related mRNAs and alters the intrinsic excitability of DAn, as it increases instantaneous frequencies of evoked action potentials, reduces rheobase current, affects the ionic current underlying the action potential after hyperpolarization phase, and reduces dopamine efflux in response to a single electrical stimulus. Our findings provide a comprehensive understanding of the involvement of miR-218 in the dopaminergic system and highlight its role as a modulator of dopaminergic transmission.SIGNIFICANCE STATEMENT In the past decade, several miRNAs have emerged as potential regulators of synapse activity through the modulation of specific gene expression. Among these, we have identified a dopaminergic-specific miRNA, miR-218, which is able to promote dopaminergic differentiation and regulates the translation of an entire cluster of synapse related mRNAs. Deletion of miR-218 has notable effects on dopamine release and alters the intrinsic excitability of dopaminergic neurons, indicating a direct control of dopaminergic activity by miR-218.
Assuntos
Dopamina , MicroRNAs , Camundongos , Masculino , Feminino , Animais , Dopamina/metabolismo , Diferenciação Celular , Neurônios Dopaminérgicos/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neurotransmissores/metabolismoRESUMO
Post-colonoscopy colorectal cancer (PCCRC) is a tumor that appears after a normal colonoscopy before the established time for the endoscopic follow up. Its origin reflects the quality of the colonoscopy and the different tumoral biologics between the CRC and the CRCPC. Our aim is to describe the characteristics of the PCCRC in our region, to identify risk factors, to discriminate the potential causes according to the World Endoscopý Organization (WEO) and to determine its impact in the patient's survival. We studied patients with colorectal cancer (CRC) attended at the gastro-oncology clinic of two institutions of Medellin-Colombia, between January 2012 and December 2021 that had been submitted to a colonoscopy between 6-36 months before the colonoscopy in which the CRC was diagnosed. 919 patients during 10 years for CRC, 68 cases of PCCRC (6.9%); It was more frequent in older patients (74 vs. 66 years; p=0.03), with background of adenomatous polyps (36.8% vs. 20.1%; p=0.01) and in right colon (57.4% vs. 40.6%; p=0.006), with a tendency in patients with diverticulosis (41.2% vs. 31.3%; p=0.05) and diabetes (25% vs. 14%; p=0.06); less survival at 5 and 10 years (58% and 55.2% vs. 67% and 63%; p < 0.001). According to the WEO, the PCCRC presents in 61.3% because of abnormal findings omitted in inadequate colonoscopies, 29% in a suitable colonoscopy and 9.7% incomplete resections of adenomas. In conclusion, the rate of PCCRC was 6.9% with more propension in older patients, a background of polyp resection, and proximal colon. According to the WEO, the abnormal findings omitted more frequently were related with inadequate colonoscopies. The patients with PCCRC had less survival.
Assuntos
Colonoscopia , Neoplasias Colorretais , Idoso , Humanos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease.
Assuntos
Glicoproteínas de Membrana , Lipofuscinoses Ceroides Neuronais , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/metabolismo , Receptor IGF Tipo 2/genética , Receptor IGF Tipo 2/metabolismo , Proteômica , Chaperonas Moleculares/metabolismo , Lisossomos/metabolismo , Hidrolases/metabolismo , AutofagiaRESUMO
Cáncer colorrectal post-colonoscopia (CCRP) es el tumor que aparece posterior a una colonoscopia normal antes de cumplirse el tiempo establecido para seguimiento endoscópico. Origen multifactorial, refleja la calidad de la colonoscopia y las diferentes biologías tumorales entre los cánceres colorrectales detectados (CCRD) y el CCRP. Nuestro objetivo es describir las características del CCRP en nuestro medio, identificar factores de riesgo, discriminar sus causas según la Organización Mundial de Endoscopia (OME) y determinar el efecto en la sobrevida del paciente. El estudio se realizó en pacientes con cáncer-colorrectal (CCR) atendidos en consulta de gastro-oncología de dos instituciones en Medellín-Colombia, entre enero de 2012 y diciembre de 2021 que se habían sometido a una colonoscopia en los 6 a 36 meses anteriores a la colonoscopia en la que se diagnosticó el CCR. 919 pacientes durante 10 años por CCR, 68 casos de CCRP (6,9%), se encontró que se presenta con más frecuencia en pacientes mayores (74 vs. 66 años; p=0,03), con antecedentes de pólipos adenomatosos (36,8% vs. 20,1%; p=0,01) y en colon derecho (57,4% vs. 40,6%; p=0,006), con una tendencia en pacientes con diverticulosis (41,2% vs. 31,3%; p=0,05) y diabetes (25% vs. 14%; p=0,06); menor sobrevida a 5 y 10 años (58%-55,2% vs. 67%-63%; p<0,001). Según la OME, los CCRP se presentaron en 61,3% por lesiones omitidas en colonoscopias inadecuadas, 29% colonoscopias adecuadas y 9,7% resecciones incompletas de adenomas. En conclusión, la tasa de CCRP fue de 6,9%, con mayor propensión en pacientes de mayores, antecedente de resección de pólipos, y en colon derecho. Acorde a la OME, las lesiones omitidas más frecuentemente se relacionaron con colonoscopias inadecuadas. Los pacientes con CCRP tienen menor sobrevida.
Post-colonoscopy colorectal cancer (PCCRC) is a tumor that appears after a normal colonoscopy before the established time for the endoscopic follow up. Its origin reflects the quality of the colonoscopy and the different tumoral biologics between the CRC and the CRCPC. Our aim is to describe the characteristics of the PCCRC in our region, to identify risk factors, to discriminate the potential causes according to the World Endoscopý Organization (WEO) and to determine its impact in the patient's survival. We studied patients with colorectal cancer (CRC) attended at the gastro-oncology clinic of two institutions of Medellin-Colombia, between January 2012 and December 2021 that had been submitted to a colonoscopy between 6-36 months before the colonoscopy in which the CRC was diagnosed. 919 patients during 10 years for CRC, 68 cases of PCCRC (6.9%); It was more frequent in older patients (74 vs. 66 years; p=0.03), with background of adenomatous polyps (36.8% vs. 20.1%; p=0.01) and in right colon (57.4% vs. 40.6%; p=0.006), with a tendency in patients with diverticulosis (41.2% vs. 31.3%; p=0.05) and diabetes (25% vs. 14%; p=0.06); less survival at 5 and 10 years (58% and 55.2% vs. 67% and 63%; p<0.001). According to the WEO, the PCCRC presents in 61.3% because of abnormal findings omitted in inadequate colonoscopies, 29% in a suitable colonoscopy and 9.7% incomplete resections of adenomas. In conclusion, the rate of PCCRC was 6.9% with more propension in older patients, a background of polyp resection, and proximal colon. According to the WEO, the abnormal findings omitted more frequently were related with inadequate colonoscopies. The patients with PCCRC had less survival.
RESUMO
The stress-responsive transcription factor EB (TFEB) is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. TFEB is regulated at the posttranslational level by the nutrient-sensitive kinase complex mTORC1. However, little is known about the regulation of TFEB transcription. Here, through integrative genomic approaches, we identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression in human cells and demonstrate that, in the absence of EGR1, TFEB-mediated transcriptional response to starvation is impaired. Remarkably, both genetic and pharmacological inhibition of EGR1, using the MEK1/2 inhibitor Trametinib, significantly reduced the proliferation of 2D and 3D cultures of cells displaying constitutive activation of TFEB, including those from a patient with Birt-Hogg-Dubé (BHD) syndrome, a TFEB-driven inherited cancer condition. Overall, we uncover an additional layer of TFEB regulation consisting in modulating its transcription via EGR1 and propose that interfering with the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.
Assuntos
Autofagia , Lisossomos , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Autofagia/genética , Lisossomos/metabolismo , Proliferação de Células/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismoRESUMO
Given the ever-increasing prevalence of type 2 diabetes and obesity, the pressure on global healthcare is expected to be colossal, especially in terms of blindness. Electroretinogram (ERG) has long been perceived as a first-use technique for diagnosing eye diseases, and some studies suggested its use for preventable risk factors of type 2 diabetes and thereby diabetic retinopathy (DR). Here, we show that in a non-evoked mode, ERG signals contain spontaneous oscillations that predict disease cases in rodent models of obesity and in people with overweight, obesity, and metabolic syndrome but not yet diabetes, using one single random forest-based model. Classification performance was both internally and externally validated, and correlation analysis showed that the spontaneous oscillations of the non-evoked ERG are altered before oscillatory potentials, which are the current gold-standard for early DR. Principal component and discriminant analysis suggested that the slow frequency (0.4-0.7 Hz) components are the main discriminators for our predictive model. In addition, we established that the optimal conditions to record these informative signals, are 5-minute duration recordings under daylight conditions, using any ERG sensors, including ones working with portative, non-mydriatic devices. Our study provides an early warning system with promising applications for prevention, monitoring and even the development of new therapies against type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Eletrorretinografia/métodos , Fatores de Risco , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/prevenção & controle , ObesidadeRESUMO
Spinal and bulbar muscular atrophy is caused by polyglutamine (polyQ) expansions in androgen receptor (AR), generating gain-of-function toxicity that may involve phosphorylation. Using cellular and animal models, we investigated what kinases and phosphatases target polyQ-expanded AR, whether polyQ expansions modify AR phosphorylation, and how this contributes to neurodegeneration. Mass spectrometry showed that polyQ expansions preserve native phosphorylation and increase phosphorylation at conserved sites controlling AR stability and transactivation. In small-molecule screening, we identified that CDC25/CDK2 signaling could enhance AR phosphorylation, and the calcium-sensitive phosphatase calcineurin had opposite effects. Pharmacologic and genetic manipulation of these kinases and phosphatases modified polyQ-expanded AR function and toxicity in cells, flies, and mice. Ablation of CDK2 reduced AR phosphorylation in the brainstem and restored expression of Myc and other genes involved in DNA damage, senescence, and apoptosis, indicating that the cell cycle-regulated kinase plays more than a bystander role in SBMA-vulnerable postmitotic cells.
Assuntos
Cálcio , Receptores Androgênicos , Camundongos , Animais , Receptores Androgênicos/química , Mutação com Ganho de Função , Quinases Ciclina-Dependentes/genética , Monoéster Fosfórico Hidrolases/genéticaRESUMO
Ca2+ is a universal second messenger that plays a wide variety of fundamental roles in cellular physiology. Thus, to warrant selective responses and to allow rapid mobilization upon specific stimuli, Ca2+ is accumulated in organelles to keep it at very low levels in the cytoplasm during resting conditions. Major Ca2+ storage organelles include the endoplasmic reticulum (ER), the mitochondria, and as recently demonstrated, the lysosome (Xu and Ren, Annu Rev Physiol 77:57-80, 2015). The importance of Ca2+ signaling deregulation in human physiology is underscored by its involvement in several human diseases, including lysosomal storage disorders, neurodegenerative disease and cancer (Shen et al., Nat Commun 3:731, 2012; Bae et al., J Neurosci 34:11485-11503, 2014). Recent evidence strongly suggests that lysosomal Ca2+ plays a major role in the regulation of lysosomal adaptation to nutrient availability through a lysosomal signaling pathway involving the lysosomal Ca2+ channel TRPML1 and the transcription factor TFEB, a master regulator for lysosomal function and autophagy (Sardiello et al., Science 325:473-477, 2009; Settembre et al., Science 332:1429-1433, 2011; Medina et al., Nat Cell Biol 17:288-299, 2015; Di Paola et al., Cell Calcium 69:112-121, 2018). Due to the tight relationship of this lysosomal Ca2+ channel and TFEB, in this chapter, we will focus on the role of the TRPML1/TFEB pathway in the regulation of lysosomal function and autophagy.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Doenças Neurodegenerativas , Humanos , Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
RESUMEN: La soberanía alimentaria es el derecho colectivo a decidir sobre la producción, distribución y consumo de alimentos y promueve la generación de suministros alimenticios para el consumo local de tal forma que los consumidores queden resguardados de la volatilidad de los precios de mercados internacionales. En los pueblos indígenas esta tendencia resulta trascendental para hacer frente a condiciones de inequidad histórica que han impactado negativamente su salud pública. No obstante, es ignorada en algunos casos y en otros reemplazada por nociones centradas en la seguridad alimentaria, término alineado con políticas transnacionales derivadas del modelo económico dominante. OBJETIVO: analizar con tres comunidades indígenas de Colombia las perspectivas de soberanía alimentaria y su influencia en la salud. MÉTODO: investigación participativa basada en la comunidad, para recolectar datos mediante grupos de discusión, entrevistas y observación. La población de estudio fueron tres comunidades indígenas del sur de Colombia. La selección de participantes se realizó según su trayectoria en la comunidad. RESULTADOS: las comunidades entienden la soberanía alimentaria como la conservación de semillas nativas y alimentos propios, vista como oportunidad para el cuidado de la salud. Su debilitamiento se relaciona con el desarrollo de enfermedades de las personas y de la madre tierra. Para su fortalecimiento identificaron el tul, el yatul y la chagra (huerta) que reafirman la unión familiar, contribuyen a la recuperación de modos de producción desde la sabiduría ancestral y se posicionan como alternativa para la sostenibilidad económica. CONCLUSIÓN: la soberanía alimentaria conserva los saberes y prácticas tradicionales para una alimentación propia, debilitada por los sistemas agroindustriales. Es asumida como iniciativa local suscrita en un proyecto global de resistencia política y económica para la salud colectiva de los pueblos.
Assuntos
Estudos Retrospectivos , Humanos , ColômbiaRESUMO
Resumen La autonomía alimentaria permite a las comunidades determinar sus prácticas alimentarias, comenzando con la producción agrícola en sus territorios garantizando la economía propia y la armonía con la madre tierra, en este contexto, la pandemia por COVID-19 generó cambios en las practicas sociales en las comunidades indígenas, incluidas sus prácticas alimentarias. Objetivo: Describir prácticas de autonomía alimentaria revitalizadas a partir del confinamiento por COVID-19 en una comunidad indígena Nasa del sur de Colombia. Método: Estudio cualitativo orientado en investigación participativa basada en comunidad (CBPR) realizado en una comunidad indígena Nasa del sur de Colombia. La recolección e interpretación de información se efectuó con técnicas de la investigación cualitativa: codificación abierta y axial y hasta llegar a la descripción de categorías emergentes. Resultados: Se fortalecieron prácticas ancestrales del sistema alimentario para mejorar el acceso a los alimentos sanos producidos en sus territorios, dentro de las que se destacan: tul (huerta familiar), trueque, mano-cambio, mercado Nasa y recetas tradicionales. Conclusiones: El confinamiento representó una oportunidad para retomar y revitalizar las prácticas alimentarias ancestrales de la comunidad que respondieron a necesidades concretas de salud y de alimentación, fortaleciendo el tejido social y la identidad indígena, acciones que pueden trascender a políticas públicas, planes de vida y aspiraciones de buen vivir.
Abstract Food autonomy allows communities to determine their food practices, starting with agricultural production in their territories, guaranteeing their own economy and harmony with Mother Earth. In this context, the COVID-19 pandemic generated changes in social practices in the communities. indigenous communities, including their food practices. Objective: Describe food autonomy practices revitalized following the COVID-19 confinement in a Nasa indigenous community in southern Colombia. Method: Qualitative study oriented on community-based participatory research (CBPR) carried out in a Nasa indigenous community in southern Colombia. The collection and interpretation of information was carried out with qualitative research techniques: open and axial coding and until reaching the description of emerging categories. Results: Ancestral practices of the food system were strengthened to improve access to healthy foods produced in their territories, among which the following stand out: tul (family garden), barter, hand-exchange, Nasa market and traditional recipes. Conclusions: Confinement represented an opportunity to resume and revitalize the community's ancestral food practices that responded to specific health and food needs, strengthening the social fabric and indigenous identity, actions that can transcend public policies, life plans and aspirations for a good life.
Abstract A autonomia alimentar permite que as comunidades determinem suas práticas alimentares, começando pela produção agrícola em seus territórios, garantindo sua própria economia e harmonia com a Mãe Terra. Nesse contexto, a pandemia da Covid-19 gerou mudanças nas práticas sociais nas comunidades indígenas, incluindo suas práticas alimentares. Objetivo: Descrever as práticas de autonomia alimentar revitalizadas após o confinamento da COVID-19 em uma comunidade indígena Nasa no sul da Colômbia. Método: Estudo qualitativo orientado à pesquisa participativa de base comunitária (CBPR) realizada em uma comunidade indígena Nasa no sul da Colômbia. A coleta e interpretação das informações foram realizadas com técnicas de pesquisa qualitativa: codificação aberta e axial e até chegar à descrição das categorias emergentes. Resultados: As práticas ancestrais do sistema alimentar foram fortalecidas para melhorar o acesso aos alimentos saudáveis produzidos em seus territórios, entre os quais se destacam: tul (horta familiar), escambo, troca de mãos, mercado Nasa e receitas tradicionais. Conclusões: O confinamento representou uma oportunidade para retomar e revitalizar as práticas alimentares ancestrais da comunidade que respondiam às necessidades específicas de saúde e alimentação, fortalecendo o tecido social e a identidade indígena, ações que podem transcender as políticas públicas, os planos de vida e as aspirações por uma vida boa.
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Partial Retraction of: The EMBO Journal (2010) 29: 3607-3620. DOI: 10.1038/emboj.2010.237 | Published online 24 September 2010 Journal statement The journal contacted the authors in February 2022 about potential image insertions and duplications in Fig 4A and 4E. In the absence of source data, the authors are retracting Fig 4A, the lower panel of Fig 4E (LAMP1 immunoblot), and the following statements in the text that rely on these data: "Quantitative analysis showed that the percentage of Flotillin-1 associated with DRMs was increased in LSD endolysosomal membranes (Figure 4A), indicating an increased amount of cholesterol-enriched regions in these membrane samples." "LAMP1 also displayed a similar distribution profile in WT and LSD cells (Figure 4E)". Author statement The authors could not verify the aberrations in panel A of Fig 4 and the lower immunoblot (LAMP1) of 4E because the original source data are no longer available (12 years after publication, which is beyond the institute's 10-year data retention policy). The authors wish to clarify that the main conclusions of the paper are not affected by the retraction of Figure panels 4A and 4E for the following reasons: Figure panel 4A supports the observation that there are increased cholesterol-enhanced regions in LSD samples. This finding is also supported by data provided in figs 4B, 4C and 4D. Figure panel 4E: The LAMP1 blot in Fig 4E shows that the distribution of protein normally excluded from DRMs is not altered between Wt and LSD samples. This result is also supported by the upper blot in this panel (Transferrin receptor). The authors apologize for these errors and agree with this corrigendum; no response could be obtained from AL.
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Lysosomes are cell organelles that degrade macromolecules to recycle their components. If lysosomal degradative function is impaired, e.g., due to mutations in lysosomal enzymes or membrane proteins, lysosomal storage diseases (LSDs) can develop. LSDs manifest often with neurodegenerative symptoms, typically starting in early childhood, and going along with a strongly reduced life expectancy and quality of life. We show here that small molecule activation of the Ca2+ -permeable endolysosomal two-pore channel 2 (TPC2) results in an amelioration of cellular phenotypes associated with LSDs such as cholesterol or lipofuscin accumulation, or the formation of abnormal vacuoles seen by electron microscopy. Rescue effects by TPC2 activation, which promotes lysosomal exocytosis and autophagy, were assessed in mucolipidosis type IV (MLIV), Niemann-Pick type C1, and Batten disease patient fibroblasts, and in neurons derived from newly generated isogenic human iPSC models for MLIV and Batten disease. For in vivo proof of concept, we tested TPC2 activation in the MLIV mouse model. In sum, our data suggest that TPC2 is a promising target for the treatment of different types of LSDs, both in vitro and in-vivo.