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1.
Molecules ; 26(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207340

RESUMO

Mass spectrometry (MS) used in proteomic approaches is able to detect hundreds of proteins in a single assay. Although undeniable high analytical power of MS, data acquired sometimes lead to confusing results, especially during a search of very selective, unique interactions in complex biological matrices. Here, we would like to show an example of such confusing data, providing an extensive discussion on the observed phenomenon. Our investigations focus on the interaction between the Zika virus NS3 protease, which is essential for virus replication. This enzyme is known for helping to remodel the microenvironment of the infected cells. Several reports show that this protease can process cellular substrates and thereby modify cellular pathways that are important for the virus. Herein, we explored some of the targets of NS3, clearly shown by proteomic techniques, as processed during infection. Unfortunately, we could not confirm the biological relevance of protein targets for viral infections detected by MS. Thus, although mass spectrometry is highly sensitive and useful in many instances, also being able to show directions where cell/virus interaction occurs, we believe that deep recognition of their biological role is essential to receive complete insight into the investigated process.


Assuntos
Espectrometria de Massas/métodos , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/metabolismo , Proteínas Virais/metabolismo , Infecção por Zika virus/virologia , Zika virus/metabolismo , Células A549 , Animais , Linhagem Celular , Linhagem Celular Tumoral , Microambiente Celular/fisiologia , Chlorocebus aethiops , Células HEK293 , Humanos , Proteômica/métodos , Transdução de Sinais/fisiologia , Células Vero
2.
Nutrients ; 13(5)2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-34065733

RESUMO

Skin photoaging is mainly induced by ultraviolet (UV) irradiation and its manifestations include dry skin, coarse wrinkle, irregular pigmentation, and loss of skin elasticity. Dietary supplementation of nutraceuticals with therapeutic and preventive effects against skin photoaging has recently received increasing attention. This article aims to review the research progress in the cellular and molecular mechanisms of UV-induced skin photoaging. Subsequently, the beneficial effects of dietary components on skin photoaging are discussed. The photoaging process and the underlying mechanisms are complex. Matrix metalloproteinases, transforming growth factors, skin adipose tissue, inflammation, oxidative stress, nuclear and mitochondrial DNA, telomeres, microRNA, advanced glycation end products, the hypothalamic-pituitary-adrenal axis, and transient receptor potential cation channel V are key regulators that drive the photoaging-associated changes in skin. Meanwhile, mounting evidence from animal models and clinical trials suggests that various food-derived components attenuate the development and symptoms of skin photoaging. The major mechanisms of these dietary components to alleviate skin photoaging include the maintenance of skin moisture and extracellular matrix content, regulation of specific signaling pathways involved in the synthesis and degradation of the extracellular matrix, and antioxidant capacity. Taken together, the ingestion of food-derived functional components could be an attractive strategy to prevent skin photoaging damage.


Assuntos
Dieta Saudável/métodos , Suplementos Nutricionais , Ingestão de Alimentos/fisiologia , Alimento Funcional , Envelhecimento da Pele/fisiologia , Animais , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Transdução de Sinais/fisiologia , Pele/metabolismo , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos
3.
Nat Commun ; 12(1): 3386, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099644

RESUMO

During early pregnancy in the mouse, nidatory estrogen (E2) stimulates endometrial receptivity by activating a network of signaling pathways that is not yet fully characterized. Here, we report that bone morphogenetic proteins (BMPs) control endometrial receptivity via a conserved activin receptor type 2 A (ACVR2A) and SMAD1/5 signaling pathway. Mice were generated to contain single or double conditional deletion of SMAD1/5 and ACVR2A/ACVR2B receptors using progesterone receptor (PR)-cre. Female mice with SMAD1/5 deletion display endometrial defects that result in the development of cystic endometrial glands, a hyperproliferative endometrial epithelium during the window of implantation, and impaired apicobasal transformation that prevents embryo implantation and leads to infertility. Analysis of Acvr2a-PRcre and Acvr2b-PRcre pregnant mice determined that BMP signaling occurs via ACVR2A and that ACVR2B is dispensable during embryo implantation. Therefore, BMPs signal through a conserved endometrial ACVR2A/SMAD1/5 pathway that promotes endometrial receptivity during embryo implantation.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Implantação do Embrião , Infertilidade Feminina/genética , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/metabolismo , Animais , Biópsia , Modelos Animais de Doenças , Endométrio/metabolismo , Endométrio/patologia , Estrogênios/metabolismo , Feminino , Humanos , Camundongos , Camundongos Knockout , Gravidez , Transdução de Sinais/fisiologia , Proteína Smad1/análise , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad5/análise , Proteína Smad5/genética , Proteína Smad5/metabolismo
4.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065396

RESUMO

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has long been implicated in modeling antitumor immunity; PD-1/PD-L1 axis inhibitors exert their antitumor effects by relieving PD-L1-mediated suppression on tumor-infiltrating T lymphocytes. However, recent studies have unveiled a distinct, tumor-intrinsic, potential role for PD-L1. In this review, we focus on tumor-intrinsic PD-L1 signaling and delve into preclinical evidence linking PD-L1 protein expression with features of epithelial-to-mesenchymal transition program, cancer stemness and known oncogenic pathways. We further summarize data from studies supporting the prognostic significance of PD-L1 in different tumor types. We show that PD-L1 may indeed have oncogenic potential and act as a regulator of tumor progression and metastasis.


Assuntos
Antígeno B7-H1/metabolismo , Metástase Neoplásica/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Progressão da Doença , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Prognóstico , Transdução de Sinais/fisiologia
5.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065591

RESUMO

Central and peripheral serotonin (5HT) have opposing functions in the regulation of energy homeostasis. Both increasing 5HT signaling in the brain and decreasing 5HT signaling in the periphery have been proposed as potential treatments for obesity. This study investigates the relationship between constitutionally high or low 5HT activity and systemic net energy balance. Two sublines of rats with high and low whole-body 5HT tone, obtained by selective breeding for platelet 5HT parameters, were examined for fat accumulation in different white adipose tissue (WAT) depots, glucose/insulin tolerance, blood metabolic parameters, and expression of various metabolic genes. High-5HT animals, unlike their low-5HT counterparts, developed widespread intra-abdominal obesity associated with glucose and insulin intolerance, which worsened with age. They also had elevated blood glucose and lipid parameters but showed no significant changes in circulating leptin, resistin, and adipsin levels. Surprisingly, adiponectin levels were increased in plasma but reduced in the WAT of high-5HT rats. A limited number of metabolic genes belonging to different functional classes showed differential expression in WAT of high-5HT compared to low-5HT rats. Overall, a constitutive increase in 5HT tone is associated with a positive energy balance acting through subtle dysregulation of a broad spectrum of metabolic pathways.


Assuntos
Homeostase/fisiologia , Serotonina/metabolismo , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Feminino , Insulina/metabolismo , Leptina/metabolismo , Lipídeos/fisiologia , Masculino , Obesidade/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia
6.
Nat Commun ; 12(1): 3754, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145241

RESUMO

Atherosclerosis is a major underlying cause of cardiovascular disease. Previous studies showed that inhibition of the co-stimulatory CD40 ligand (CD40L)-CD40 signaling axis profoundly attenuates atherosclerosis. As CD40L exerts multiple functions depending on the cell-cell interactions involved, we sought to investigate the function of the most relevant CD40L-expressing cell types in atherosclerosis: T cells and platelets. Atherosclerosis-prone mice with a CD40L-deficiency in CD4+ T cells display impaired Th1 polarization, as reflected by reduced interferon-γ production, and smaller atherosclerotic plaques containing fewer T-cells, smaller necrotic cores, an increased number of smooth muscle cells and thicker fibrous caps. Mice with a corresponding CD40-deficiency in CD11c+ dendritic cells phenocopy these findings, suggesting that the T cell-dendritic cell CD40L-CD40 axis is crucial in atherogenesis. Accordingly, sCD40L/sCD40 and interferon-γ concentrations in carotid plaques and plasma are positively correlated in patients with cerebrovascular disease. Platelet-specific deficiency of CD40L does not affect atherogenesis but ameliorates atherothrombosis. Our results establish divergent and cell-specific roles of CD40L-CD40 in atherosclerosis, which has implications for therapeutic strategies targeting this pathway.


Assuntos
Aterosclerose/patologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Interferon gama/metabolismo , Placa Aterosclerótica/patologia , Animais , Plaquetas/metabolismo , Linfócitos T CD4-Positivos/citologia , Doenças Cardiovasculares/patologia , Células Dendríticas/imunologia , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/citologia , Transdução de Sinais/fisiologia , Trombose/patologia
7.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063979

RESUMO

The KDEL receptor retrieval pathway is essential for maintaining resident proteins in the endoplasmic reticulum (ER) lumen. ER resident proteins serve a variety of functions, including protein folding and maturation. Perturbations to the lumenal ER microenvironment, such as calcium depletion, can cause protein misfolding and activation of the unfolded protein response (UPR). Additionally, ER resident proteins are secreted from the cell by overwhelming the KDEL receptor retrieval pathway. Recent data show that KDEL receptors are also activated during the UPR through the IRE1/XBP1 signaling pathway as an adaptive response to cellular stress set forth to reduce the loss of ER resident proteins. This review will discuss the emerging connection between UPR activation and KDEL receptors as it pertains to ER proteostasis and disease states.


Assuntos
Receptores de Peptídeos/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Animais , Humanos , Proteostase/fisiologia , Transdução de Sinais/fisiologia
8.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064029

RESUMO

The enzyme soluble guanylate cyclase (sGC) is the prototypical nitric oxide (NO) receptor in humans and other higher eukaryotes and is responsible for transducing the initial NO signal to the secondary messenger cyclic guanosine monophosphate (cGMP). Generation of cGMP in turn leads to diverse physiological effects in the cardiopulmonary, vascular, and neurological systems. Given these important downstream effects, sGC has been biochemically characterized in great detail in the four decades since its discovery. Structures of full-length sGC, however, have proven elusive until very recently. In 2019, advances in single particle cryo-electron microscopy (cryo-EM) enabled visualization of full-length sGC for the first time. This review will summarize insights revealed by the structures of sGC in the unactivated and activated states and discuss their implications in the mechanism of sGC activation.


Assuntos
Guanilil Ciclase Solúvel/metabolismo , Animais , Microscopia Crioeletrônica/métodos , GMP Cíclico/metabolismo , Humanos , Óxido Nítrico/metabolismo , Transdução de Sinais/fisiologia
9.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064048

RESUMO

Aneurysmal subarachnoid hemorrhage (aSAH) remains a disease with high mortality and morbidity. Since treating vasospasm has not inevitably led to an improvement in outcome, the actual emphasis is on finding neuroprotective therapies in the early phase following aSAH to prevent secondary brain injury in the later phase of disease. Within the early phase, neuroinflammation, thromboinflammation, disturbances in brain metabolism and early neuroprotective therapies directed against delayed cerebral ischemia (DCI) came into focus. Herein, the role of neuroinflammation, thromboinflammation and metabolism in aSAH is depicted. Potential neuroprotective strategies regarding neuroinflammation target microglia activation, metalloproteases, autophagy and the pathway via Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), NF-κB and finally the release of cytokines like TNFα or IL-1. Following the link to thromboinflammation, potential neuroprotective therapies try to target microthrombus formation, platelets and platelet receptors as well as clot clearance and immune cell infiltration. Potential neuroprotective strategies regarding metabolism try to re-balance the mismatch of energy need and supply following aSAH, for example, in restoring fuel to the TCA cycle or bypassing distinct energy pathways. Overall, this review addresses current neuroprotective strategies in aSAH, hopefully leading to future translational therapy options to prevent secondary brain injury.


Assuntos
Neuroproteção/fisiologia , Animais , Lesões Encefálicas/metabolismo , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Transdução de Sinais/fisiologia , Hemorragia Subaracnóidea/metabolismo
10.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34064290

RESUMO

Inositol 1,4,5-triphosphate receptor-associated cGMP kinase substrate 1 (IRAG1) is a substrate protein of the NO/cGMP-signaling pathway and forms a ternary complex with the cGMP-dependent protein kinase Iß (PKGIß) and the inositol triphosphate receptor I (IP3R-I). Functional studies about IRAG1 exhibited that IRAG1 is specifically phosphorylated by the PKGIß, regulating cGMP-mediated IP3-dependent Ca2+-release. IRAG1 is widely distributed in murine tissues, e.g., in large amounts in smooth muscle-containing tissues and platelets, but also in lower amounts, e.g., in the spleen. The NO/cGMP/PKGI signaling pathway is important in several organ systems. A loss of PKGI causes gastrointestinal disorders, anemia and splenomegaly. Due to the similar tissue distribution of the PKGIß to IRAG1, we investigated the pathophysiological functions of IRAG1 in this context. Global IRAG1-KO mice developed gastrointestinal bleeding, anemia-associated splenomegaly and iron deficiency. Additionally, Irag1-deficiency altered the protein levels of some cGMP/PKGI signaling proteins-particularly a strong decrease in the PKGIß-in the colon, spleen and stomach but did not change mRNA-expression of the corresponding genes. The present work showed that a loss of IRAG1 and the PKGIß/IRAG1 signaling has a crucial function in the development of gastrointestinal disorders and anemia-associated splenomegaly. Furthermore, global Irag1-deficient mice are possible in vivo model to investigate PKGIß protein functions.


Assuntos
Anemia/metabolismo , Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo , Transdução de Sinais/fisiologia , Esplenomegalia/metabolismo , Animais , Cálcio/metabolismo , Colo/metabolismo , GMP Cíclico/metabolismo , Feminino , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Camundongos , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Fosforilação/fisiologia , RNA Mensageiro/metabolismo , Baço/metabolismo , Estômago
11.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067256

RESUMO

Tumor necrosis factor (TNF) is one of the main cytokines regulating a pro-inflammatory environment. It has been related to several cell functions, for instance, phagocytosis, apoptosis, proliferation, mitochondrial dynamic. Moreover, during mycobacterial infections, TNF plays an essential role to maintain granuloma formation. Several effector mechanisms have been implicated according to the interactions of the two active forms, soluble TNF (solTNF) and transmembrane TNF (tmTNF), with their receptors TNFR1 and TNFR2. We review the impact of these interactions in the context of mycobacterial infections. TNF is tightly regulated by binding to receptors, however, during mycobacterial infections, upstream activation signalling pathways may be influenced by key regulatory factors either at the membrane or cytosol level. Detailing the structure and activation pathways used by TNF and its receptors, such as its interaction with solTNF/TNFRs versus tmTNF/TNFRs, may bring a better understanding of the molecular mechanisms involved in activation pathways which can be helpful for the development of new therapies aimed at being more efficient against mycobacterial infections.


Assuntos
Proteínas de Membrana/metabolismo , Infecções por Mycobacterium/metabolismo , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Membrana Celular/metabolismo , Humanos , Transdução de Sinais/fisiologia
12.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067450

RESUMO

The endocannabinoid system (ECS) consists of endogenous cannabinoids, their receptors, and metabolic enzymes that play a critical homeostatic role in modulating polyunsaturated omega fatty acid (PUFA) signaling to maintain a balanced inflammatory and redox state. Whole food-based diets and dietary interventions linked to PUFAs of animal (fish, calamari, krill) or plant (hemp, flax, walnut, algae) origin, as well as full-spectrum hemp oils, are increasingly used to support the ECS tone, promote healthy metabolism, improve risk factors associated with cardiovascular disorders, encourage brain health and emotional well-being, and ameliorate inflammation. While hemp cannabinoids of THC and CBD groups show distinct but complementary actions through a variety of cannabinoid (CB1 and CB2), adenosine (A2A), and vanilloid (TRPV1) receptors, they also modulate PUFA metabolism within a wide variety of specialized lipid mediators that promote or resolve inflammation and oxidative stress. Clinical evidence reviewed in this study links PUFAs and cannabinoids to changes in ECS tone, immune function, metabolic and oxidative stress adaptation, and overall maintenance of a well-balanced systemic function of the body. Understanding how the body coordinates signals from the exogenous and endogenous ECS modulators is critical for discerning the underlying molecular mechanisms of the ECS tone in healthy and disease states. Nutritional and lifestyle interventions represent promising approaches to address chronic metabolic and inflammatory disorders that may overlap in the population at risk. Further investigation and validation of dietary interventions that modulate the ECS are required in order to devise clinically successful second-generation management strategies.


Assuntos
Cannabis/metabolismo , Endocanabinoides/metabolismo , Ácidos Graxos Insaturados/metabolismo , Extratos Vegetais/metabolismo , Adenosina/metabolismo , Animais , Canabinoides/metabolismo , Dieta , Homeostase/fisiologia , Humanos , Inflamação/metabolismo , Metabolismo dos Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologia , Canais de Cátion TRPV/metabolismo
13.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071721

RESUMO

Changes in lifestyle in developed countries have triggered the prevalence of obesity and type 2 diabetes mellitus (T2DM) in the latest years. Consequently, these metabolic diseases associated to insulin resistance, and the morbidity associated with them, accounts for enormous costs for the health systems. The best way to face this problem is to identify potential therapeutic targets and/or early biomarkers to help in the treatment and in the early detection. In the insulin receptor signaling cascade, the activities of protein tyrosine kinases and phosphatases are coordinated, thus, protein tyrosine kinases amplify the insulin signaling response, whereas phosphatases are required for the regulation of the rate and duration of that response. The focus of this review is to summarize the impact of transmembrane receptor protein tyrosine phosphatase (RPTPs) in the insulin signaling cascade and secretion, and their implication in metabolic diseases such as obesity and T2DM.


Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Insulina/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Animais , Humanos , Resistência à Insulina , Obesidade , Prevalência , Proteínas Tirosina Fosfatases/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais/fisiologia
14.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070424

RESUMO

BACKGROUND: The extracellular matrix of the PNS/CNS is unusual in that it is dominated by glycosaminoglycans, especially hyaluronan, whose space filling and hydrating properties make essential contributions to the functional properties of this tissue. Hyaluronan has a relatively simple structure but its space-filling properties ensure micro-compartments are maintained in the brain ultrastructure, ensuring ionic niches and gradients are maintained for optimal cellular function. Hyaluronan has cell-instructive, anti-inflammatory properties and forms macro-molecular aggregates with the lectican CS-proteoglycans, forming dense protective perineuronal net structures that provide neural and synaptic plasticity and support cognitive learning. AIMS: To highlight the central nervous system/peripheral nervous system (CNS/PNS) and its diverse extracellular and cell-associated proteoglycans that have cell-instructive properties regulating neural repair processes and functional recovery through interactions with cell adhesive molecules, receptors and neuroregulatory proteins. Despite a general lack of stabilising fibrillar collagenous and elastic structures in the CNS/PNS, a sophisticated dynamic extracellular matrix is nevertheless important in tissue form and function. CONCLUSIONS: This review provides examples of the sophistication of the CNS/PNS extracellular matrix, showing how it maintains homeostasis and regulates neural repair and regeneration.


Assuntos
Sistema Nervoso Central/metabolismo , Matriz Extracelular/metabolismo , Rede Nervosa/metabolismo , Neurônios/metabolismo , Sistema Nervoso Periférico/metabolismo , Animais , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/fisiologia , Humanos , Ácido Hialurônico/metabolismo , Rede Nervosa/enzimologia , Rede Nervosa/fisiologia , Neurogênese/genética , Neurogênese/fisiologia , Sistema Nervoso Periférico/enzimologia , Sistema Nervoso Periférico/fisiologia , Proteoglicanas/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
15.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069759

RESUMO

Sexual dimorphism involves differences between biological sexes that go beyond sexual characteristics. In mammals, differences between sexes have been demonstrated regarding various biological processes, including blood pressure and predisposition to develop hypertension early in adulthood, which may rely on early events during development and in the neonatal period. Recent studies suggest that corticosteroid signaling pathways (comprising glucocorticoid and mineralocorticoid signaling pathways) have distinct tissue-specific expression and regulation during this specific temporal window in a sex-dependent manner, most notably in the kidney. This review outlines the evidence for a gender differential expression and activation of renal corticosteroid signaling pathways in the mammalian fetus and neonate, from mouse to human, that may favor mineralocorticoid signaling in females and glucocorticoid signaling in males. Determining the effects of such differences may shed light on short term and long term pathophysiological consequences, markedly for males.


Assuntos
Corticosteroides/metabolismo , Rim/embriologia , Aldosterona/metabolismo , Animais , Pressão Sanguínea/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Glucocorticoides/metabolismo , Humanos , Hipertensão/metabolismo , Rim/metabolismo , Mineralocorticoides/metabolismo , Organogênese , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Caracteres Sexuais , Transdução de Sinais/fisiologia
16.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069904

RESUMO

Biological signals are sensed by their respective receptors and are transduced and processed by a sophisticated intracellular signaling network leading to a signal-specific cellular response. Thereby, the response to the signal depends on the strength, the frequency, and the duration of the stimulus as well as on the subcellular signal progression. Optogenetic tools are based on genetically encoded light-sensing proteins facilitating the precise spatiotemporal control of signal transduction pathways and cell fate decisions in the absence of natural ligands. In this review, we provide an overview of optogenetic approaches connecting light-regulated protein-protein interaction or caging/uncaging events with steering the function of signaling proteins. We briefly discuss the most common optogenetic switches and their mode of action. The main part deals with the engineering and application of optogenetic tools for the control of transmembrane receptors including receptor tyrosine kinases, the T cell receptor and integrins, and their effector proteins. We also address the hallmarks of optogenetics, the spatial and temporal control of signaling events.


Assuntos
Optogenética/métodos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Animais , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Humanos , Integrinas/metabolismo , Luz , Receptores Proteína Tirosina Quinases/metabolismo
17.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063911

RESUMO

The triad of obesity, metabolic syndrome (MetS), Type 2 diabetes mellitus (T2DM) and advancing age are currently global societal problems that are expected to grow over the coming decades. This triad is associated with multiple end-organ complications of diabetic vasculopathy (maco-microvessel disease), neuropathy, retinopathy, nephropathy, cardiomyopathy, cognopathy encephalopathy and/or late-onset Alzheimer's disease. Further, obesity, MetS, T2DM and their complications are associated with economical and individual family burdens. This review with original data focuses on the white adipose tissue-derived adipokine/hormone leptin and how its deficient signaling is associated with brain remodeling in hyperphagic, obese, or hyperglycemic female mice. Specifically, the ultrastructural remodeling of the capillary neurovascular unit, brain endothelial cells (BECs) and their endothelial glycocalyx (ecGCx), the blood-brain barrier (BBB), the ventricular ependymal cells, choroid plexus, blood-cerebrospinal fluid barrier (BCSFB), and tanycytes are examined in female mice with impaired leptin signaling from either dysfunction of the leptin receptor (DIO and db/db models) or the novel leptin deficiency (BTBR ob/ob model).


Assuntos
Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Transdução de Sinais/fisiologia , Animais , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos Obesos/metabolismo
18.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067660

RESUMO

G-protein-coupled receptors (GPCRs) are known to play central roles in the physiology of many organisms. Members of this seven α-helical transmembrane protein family transduce the extracellular signals and regulate intracellular second messengers through coupling to heterotrimeric G-proteins, adenylate cyclase, cAMPs, and protein kinases. As a result of the critical function of GPCRs in cell physiology and biochemistry, they not only play important roles in cell biology and the medicines used to treat a wide range of human diseases but also in insects' physiological functions. Recent studies have revealed the expression and function of GPCRs in insecticide resistance, improving our understanding of the molecular complexes governing the development of insecticide resistance. This article focuses on the review of G-protein coupled receptor (GPCR) signaling pathways in insect physiology, including insects' reproduction, growth and development, stress responses, feeding, behaviors, and other physiological processes. Hormones and polypeptides that are involved in insect GPCR regulatory pathways are reviewed. The review also gives a brief introduction of GPCR pathways in organisms in general. At the end of the review, it provides the recent studies on the function of GPCRs in the development of insecticide resistance, focusing in particular on our current knowledge of the expression and function of GPCRs and their downstream regulation pathways and their roles in insecticide resistance and the regulation of resistance P450 gene expression. The latest insights into the exciting technological advances and new techniques for gene expression and functional characterization of the GPCRs in insects are provided.


Assuntos
Resistência a Inseticidas/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Animais , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Insetos/genética , Insetos/metabolismo , Transdução de Sinais/fisiologia
19.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067904

RESUMO

Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.


Assuntos
Antígenos CD/metabolismo , Antígenos CD/fisiologia , Transdução de Sinais/fisiologia , Humanos , Imunoterapia , Ativação Linfocitária , Neoplasias/metabolismo , Receptores Imunológicos/metabolismo , Linfócitos T/imunologia
20.
Nat Commun ; 12(1): 3525, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112797

RESUMO

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4RdlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Metabolismo Energético/fisiologia , Hipotálamo/metabolismo , Condução Nervosa/fisiologia , Neurônios Serotoninérgicos/fisiologia , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Peso Corporal , Cromatografia Líquida , Ingestão de Alimentos/fisiologia , Metabolismo Energético/genética , Masculino , Camundongos , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/efeitos da radiação , Obesidade/metabolismo , Optogenética , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/efeitos da radiação , Serotonina/metabolismo , Serotonina/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Espectrometria de Massas em Tandem , Temperatura
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