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Tumor Treating Fields (TTFields) therapy is an anti-cancer treatment modality that is delivered noninvasively to the tumor site via skin-placed arrays. The therapy is US Food and Drug Administration (FDA) approved and Conformité Européenne (CE) marked for adults with newly diagnosed and recurrent glioblastoma (GBM) (grade 4 glioma in the European Union). To date, there are limited data on the safety and efficacy of TTFields therapy in patients with implanted cardiac pacemakers. Herein, we report a case of a 79-year-old male patient with GBM receiving TTFields therapy with a prior medical history of cardiac events necessitating a cardiac pacemaker. The patient presented to the emergency department in May 2021 with newly onset left-sided weakness along with seizures. Based on an initial evaluation and results of the initial computed tomography (CT) scans (May 2021), the patient was clinically diagnosed with a high-grade glioma which was later confirmed as IDH wildtype following a biopsy. He was treated with radiotherapy (40 Gy in 15 fractions), followed by adjuvant temozolomide (TMZ) (75 mg/m2). TTFields therapy was initiated alongside maintenance TMZ (150 mg/m2). Average TTFields therapy usage was 67% throughout the duration of treatment. Follow-up CT scans (February and May of 2022) indicated stable disease. CT scans in August 2022 showed an increase in size of a mass with heterogeneous contrast enhancement and the patient subsequently passed away in October 2022. The patient's last cardiac tests demonstrated that the pacemaker was operational with adequate cardiac function. This report suggests that TTFields therapy concomitant with an implanted electronic device may be safe in patients with GBM.
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The µ-opioid receptor-biased agonist theory holds that Gio protein signaling mediates the analgesic effect of opioids and the related side effects via the ß-arrestin2 signaling pathway. A series of µ-opioid-biased agonists have been developed in accordance with this theory, and the FDA has approved TRV130 (as a representative of biased agonists) for marketing. However, several reports have raised the issue of opioid side effects associated with the use of agonists. In this study, five permeable peptides were designed to emulate 11 S/T phosphorylation sites at the µ-opioid receptor (MOR) carboxyl-terminal. In vitro experiments were performed to detect the activation level of G proteins from the cAMP inhibition assay and the ß-arrestin2 recruitment by the BRET assay. Designed peptides might effectively interfere with the activation of the Gio and ß-arrestin2 pathways when combined with morphine. The resulting morphine-induced tolerance, respiratory inhibition, and constipation in mice showed that the ß-arrestin2 pathway was responsible for morphine tolerance while the Gio signaling pathway was involved with respiratory depression and constipation and that these side effects were significantly related to phosphorylation sites S363 and T370. This study may provide new directions for the development of safer and more effective opioid analgesics, and the designed peptides may be an effective tool for exploring the mechanism by which µ-opioid receptors function, with the potential of reducing the side effects that are associated with clinical opioid treatment.
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Analgésicos Opioides , Morfina , Ratones , Animales , Morfina/efectos adversos , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/metabolismo , Receptores Opioides mu/metabolismo , Transducción de Señal , Estreñimiento/inducido químicamente , Péptidos/metabolismo , Arrestina beta 2/metabolismoRESUMEN
In this potential - study, the non - thermal atmospheric pressure plasma is utilized for the neutral - eradication of water contaminants. In the air ambient region, plasma induced reactive species, like as OHâ¢, O (O2-), H2O2 (OHâ¢+OHâ¢) & NOx are performed for the oxidative and reductive transformation of AsIII (H3AsO3) to AsV (H2As O4-) & Fe3O4 (Fe3+) (C-GIO) to Fe2O3 (Fe2+). Whereas, the H2O2 & NOx are quantified maximum (max.) in water, which is 144.24 & 111.82 µM, respectively. In the absence of plasma and plasma with C-GIO, the AsIII was more eradicated, which is 64.01 and 100.00%. While, the C - GIO (catalyst) synergistic enhancement was performed and proved by the neutral - degradation of CR. Also, the AsV adsorbed on C-GIO adsorption capacity qmax and redox-adsorption yield were evaluated, which are 1.36 mg/g and 20.80 g/kWh, respectively. In this research, the waste material (GIO) was recycled, modified, and utilized for the neutral - eradication of water contaminates, which are organic (CR) and inorganic (AsIII) toxicants by the controlling of H and OH⢠under the interaction of plasma with catalyst (C-GIO). However, in this research, plasma can't adopt the acidic, which is controlled by the C-GIO via RONS. Moreover, in this eradicative study, various water pH alignments were performed, from neutral to acidic & neutral & base for toxicants removal. Furthermore, according to WHO norms, the arsenic level was reduced to 0.01 mg/l for environmental safety. The kinetic and isotherm studies were followed by the mono and multi-layer adsorption was performed on the surface of C - GIO beads, which is estimated by the fitting of rate limiting constant R2 ≈ 1. Furthermore, the C-GIO was examined several characterizations alignments, such as crystal, surface, functional, elemental composition, retention time, mass spectrum, and elemental oriented properties. Overall, the suggested hybrid system is an eco-friendly pathway for the natural - eradication of contaminants, such as organic and inorganic compounds via waste material (GIO) recycling, modification, oxidation, reduction, adsorption, degradation, and neutralization phenomenon.
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Quitosano , Gases em Plasma , Contaminantes Químicos del Agua , Rojo Congo , Peróxido de Hidrógeno/química , Agua , Adsorción , Concentración de Iones de HidrógenoRESUMEN
Recent evidence has shown that G protein-coupled receptors (GPCRs) are direct sensors of the autophagic machinery and opioid receptors regulate neuronal plasticity and neurotransmission with an as yet unclarified mechanism. Using in vitro and in vivo experimental approaches, this study aims to clarify the potential role of autophagy and κ-opioid receptor (κ-OR) signaling in synaptic alterations. We hereby demonstrate that the selective κ-OR agonist U50,488H, induces autophagy in a time-and dose-dependent manner in Neuro-2A cells stably expressing the human κ-OR by upregulating microtubule-associated protein Light Chain 3-II (LC3-II), Beclin 1 and Autophagy Related Gene 5 (ATG5). Pretreatment of neuronal cells with pertussis toxin blocked the above κ-OR-mediated cellular responses. Our molecular analysis also revealed a κ-OR-driven upregulation of becn1 gene through ERK1,2-dependent activation of the transcription factor CREB in Neuro-2A cells. Moreover, our studies demonstrated that sub-chronic U50,488H administration in mice causes profound increases of specific autophagic markers in the hippocampus with a concomitant decrease of several pre-and post-synaptic proteins, such as spinophilin, postsynaptic density protein 95 (PSD-95) and synaptosomal associated protein 25 (SNAP25). Finally, using acute stress, a stimulus known to increase the levels of the endogenous κ-OR ligand dynorphin, we are demonstrating that administration of the κ-ΟR selective antagonist, nor-binaltorphimine (norBNI), blocks the induction of autophagy and the stress-evoked reduction of synaptic proteins in the hippocampus. These findings provide novel insights about the essential role of autophagic machinery into the mechanisms through which κ-OR signaling regulates brain plasticity.
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The present study describes a detailed neuroanatomical distribution map of the cannabinoid type 1 (CB1) receptor, along with the biochemical characterization of the expression and functional coupling to their cognate G i/o proteins in the medial prefrontal cortex (mPCx) of the obese Zucker rats. The CB1 receptor density was higher in the prelimbic (PL) and infralimbic (IL) subregions of the mPCx of obese Zucker rats relative to their lean littermates which was associated with a higher percentage of CB1 receptor immunopositive excitatory presynaptic terminals in PL and IL. Also, a higher expression of CB1 receptors and WIN55,212-2-stimulated [35S]GTPγS binding was observed in the mPCx but not in the neocortex (NCx) and hippocampus of obese rats. Low-frequency stimulation in layers II/III of the mPCx induced CB1 receptor-dependent long-term synaptic plasticity in IL of area obese Zucker but not lean rats. Overall, the elevated 2-AG levels, up-regulation of CB1 receptors, and increased agonist-stimulated [35S]GTPγS binding strongly suggest that hyperactivity of the endocannabinoid signaling takes place at the glutamatergic terminals of the mPCx in the obese Zucker rat. These findings could endorse the importance of the CB1 receptors located in the mPCx in the development of obesity in Zucker rats.
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Chronic glucocorticoid (GC) therapy is the most common cause of iatrogenic osteoporosis and represents an important risk factor for osteoporosis and bone fractures. New therapeutic approaches are required in order to treat osteoporosis and reduce the side effects related to the use of anti-osteoporotic drugs. In this context, previous studies reported the efficacy of some isoflavones and carotenoids, such as lycopene and genistein, on the reduction of the risk of fracture related to osteoporosis. The aim of this study was to investigate the effects of a combined oral treatment, consisting of genistein and lycopene, in an experimental model of glucocorticoid-induced osteoporosis (GIO). GIO was induced by subcutaneous injection of methylprednisolone (MP, 30 mg/kg) for 60 days, whereas the control group (Sham) received saline solution only. Following induction, MP animals randomly were assigned to receive alendronate, genistein, lycopene, or the association of genistein and lycopene or saline solution for additional 60 days together with MP. Femurs obtained from the Sham group were used for osteoblasts extraction; they were then incubated with dexamethasone (DEX) for 24 h to be then treated with lycopene or genistein or the association of lycopene and genistein for an additional 24 h. Treatments with lycopene and genistein restored the impaired mineralization of cells observed following DEX treatment and stimulated osteoblast differentiation by increasing the depressed expression of bALP and RUNX2 (p < 0.0001). Wnt5a, ß-catenin, and Nrf-2 expression were significantly increased following genistein and lycopene treatment (p < 0.0001), thus confirming their antioxidant activity as well as their ability in stimulating osteoblast function, mostly when genistein and lycopene were used in association. The combined treatment of genistein and lycopene improved the bone damage induced by glucocorticoids and significantly restored the normal architecture of bones as well as adequate interconnectivity of bone trabeculae, thus increasing bone mineral density parameters. The obtained data demonstrated that genistein and lycopene but in particular their association might prevent GC's adverse effects, thus stimulating bone formation and reducing bone resorption, improving bone structure and microarchitecture, through different molecular pathways, such as the Wnt/ß-catenin and the Nrf-2 signaling.
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Glucocorticoides , Osteoporosis , Animales , Alendronato/farmacología , Antioxidantes/metabolismo , beta Catenina/metabolismo , Densidad Ósea , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Dexametasona/farmacología , Suplementos Dietéticos , Genisteína/farmacología , Glucocorticoides/farmacología , Licopeno/farmacología , Metilprednisolona/efectos adversos , Osteoblastos , Osteogénesis , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológicoRESUMEN
In this study, total phosphorus (P) and P released forms were measured in core sediments from the areas affected by human settlement and shrimp farming activities and the core zone of the Can Gio Biosphere Reserve, a coastal district in south Vietnam. Furthermore, ecological risk assessment and parameters controlling P release from sediments were investigated, including pH, major elements (Al-Ca-Mg-Fe), and fine fraction. The average total amount of P in the sediments varied from 287 to 669 mg/kg, with significantly lower values being observed in the mangrove biosphere reserve area. According to the results of the correlation analysis, organic matter was the primary source of P in the sediments, but the majority of the P released was inorganic. Positive correlations were found between Fe and non-apatite inorganic P (NAIP) and apatite P (AP), as well as intercorrelations between P fractions (r = 0.40-0.79, p < 0.05), suggesting that Fe might be the controlling factor of P release in the investigated sediments. The rank orders of concentrations of P forms were significantly different between the areas. The range of P forms was AP (35-248 mg/kg) > NAIP (63-201 mg/kg) > LP (labile P) (4-25 mg/kg) in the human settlement and aquaculture areas and NAIP (84-99 mg/kg) > AP (20-38 mg/kg) > LP (7-12 mg/kg) in the mangrove biosphere reserve area. Risk assessment based on the total concentration of P and the availability of P from a single extraction suggested a relatively low risk of P from sediment as an internal load in the studied areas.
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Fósforo , Contaminantes Químicos del Agua , China , Monitoreo del Ambiente , Sedimentos Geológicos/análisis , Humanos , Fósforo/análisis , Medición de Riesgo , Vietnam , Contaminantes Químicos del Agua/análisisRESUMEN
Background: Glucocorticoids are used in different conditions such as autoimmune disorders and organ transplantation and their administration is the most common cause of secondary osteoporosis. Rutin is a flavonoid found in many plants. Flavonoids are natural products with various therapeutic and biological effects. Objective: Is to investigate the effect of Rutin Hydrate as a form of Rutin on glucocorticoid induced osteoporosis in mandibular alveolar bone radiologically, histologically and histochemically. Methods: Twenty-one adult male Albino rats were randomly divided into three groups. Group I (control), group II (osteoporotic) and group III (Rutin Hydrate treated). In both group II and III rats received 21 mg/kg of methylprednisolone daily for four weeks. Then group III received 50 mg/kg of rutin hydrate in distilled water daily for another four weeks. At the end of the experiment, mandibles were dissected for radiographic assessment, then processed for histological and histochemical examination and statistical analysis. Results: Radiologically, administration of Rutin Hydrate was able to enhance bone density than osteoporotic group. Histological examination revealed preserved cortical bone thickness that had been statistically proved. Apparently normal sized marrow cavities, some plump osteoblasts and normal osteocytes were seen in group III. Histochemical examination showed statistical increase in the area percentage of newly formed collagen in group III than group II. Conclusions: Rutin Hydrate was able to modify the radiological and histological picture of osteoporotic alveolar bone. This was achieved by the ability of Rutin Hydrate to increase bone density, preserve cortical plates thickness and enhance new collagen formation that was proved histochemically.
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Heterotrimeric guanine nucleotide-binding proteins (G proteins) are composed of α, ß, and γ subunits, and Gα has a GDP/GTP-binding pocket. When a guanine nucleotide exchange factor (GEF) interacts with Gα, GDP is released, and GTP interacts to Gα. The GTP-bound activated Gα dissociates from GEF and Gßγ, mediating the induction of various intracellular signaling pathways. Depending on the sequence similarity and cellular function, Gα subunits are subcategorized into four subfamilies: Gαi/o, Gαs, Gαq/11, and Gα12/13. Although the Gαi/o subtype family proteins, Gαi3 and GαoA, share similar sequences and functions, they differ in their GDP/GTP turnover profiles, with GαoA possessing faster rates than Gαi3. The structural factors responsible for these differences remain unknown. In this study, we employed hydrogen/deuterium exchange mass spectrometry and mutational studies to investigate the factors responsible for these functional differences. The Gα subunit consists of a Ras-like domain (RD) and an α-helical domain (AHD). The RD has GTPase activity and receptor-binding and effector-binding regions; however, the function of the AHD has not yet been extensively studied. In this study, the chimeric construct containing the RD of Gαi3 and the AHD of GαoA showed a GDP/GTP turnover profile similar to that of GαoA, suggesting that the AHD is the major regulator of the GDP/GTP turnover profile. Additionally, site-directed mutagenesis revealed the importance of the N-terminal part of αA and αA/αB loops in the AHD for the GDP/GTP exchange. These results suggest that the AHD regulates the nucleotide exchange rate within the Gα subfamily.
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Subunidades alfa de la Proteína de Unión al GTP Gi-Go , Proteínas de Unión al GTP Heterotriméricas , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Proteínas de Unión al GTP Heterotriméricas/metabolismoRESUMEN
Despite the continued development of specialized immunosuppressive therapies in the form of monoclonal antibodies, glucocorticoids remain a mainstay in the treatment of rheumatological and auto-inflammatory disorders. Therapeutic glucocorticoids are unmatched in the breadth of their immunosuppressive properties and deliver their anti-inflammatory effects at unparalleled speed. However, long-term exposure to therapeutic doses of glucocorticoids decreases bone mass and increases the risk of fractures - particularly in the spine - thus limiting their clinical use. Due to the abundant expression of glucocorticoid receptors across all skeletal cell populations and their respective progenitors, therapeutic glucocorticoids affect skeletal quality through a plethora of cellular targets and molecular mechanisms. However, recent evidence from rodent studies, supported by clinical data, highlights the considerable role of cells of the osteoblast lineage in the pathogenesis of glucocorticoid-induced osteoporosis: it is now appreciated that cells of the osteoblast lineage are key targets of therapeutic glucocorticoids and have an outsized role in mediating their undesirable skeletal effects. As part of this article, we review the molecular mechanisms underpinning the detrimental effects of supraphysiological levels of glucocorticoids on cells of the osteoblast lineage including osteocytes and highlight the clinical implications of recent discoveries in the field.
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Osteocitos , Osteoporosis , Huesos/metabolismo , Glucocorticoides/metabolismo , Humanos , Osteoblastos/metabolismo , Osteocitos/metabolismo , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismoRESUMEN
Anthropogenic fibres are an emerging pollutant worldwide. The Can Gio mangrove area is located downstream of the Saigon River, and is characterised by high level of anthropogenic fibres originating from domestic and industrial textile and apparel manufacturing. In this area, biota is thus subjected to a high potential risk of anthropogenic fibre contamination. This study aims to characterise the accumulation of anthropogenic fibres in different tissues, i.e. gills, digestive systems, and remaining tissues, of white clams (Meretrix lyrata) cultivated in the Can Gio beach sand, during a seven-month sampling period. The results showed an average concentration of 3.6 ± 2.1 fibres individual-1 or 2.7 ± 2.4 fibres g-1 ww. Higher fibre accumulation was observed in remaining tissues than in gills and digestive systems, and no temporal variation was observed in all clam tissues. The intake of fibres by humans consuming clams was estimated to be 324 fibres inhabitant-1 yr-1.
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Bivalvos , Animales , Ciudades , Humanos , Ríos , VietnamRESUMEN
Microplastics have become a global concern due to their persistent properties and impacts on the marine environment. This research investigates pollution sources and behaviors of microplastics at UNESCO Can Gio Mangrove Biosphere Reserve. Density flotation with sodium chloride is employed to extract microplastics from sand at Can Gio Beach, and a double-filtration procedure is developed to recover microplastics from seawater at the beach and Dong Tranh Cape. The microplastics' morphology and type are analyzed by micro-Raman spectroscopy. The results show that microplastics are accumulated at concentrations from 31.99 to 92.56 MPs g-1 at various sand layers. The seawater at Can Gio Beach and Dong Tranh Cape contains 6.44 and 3.75 MPs L-1 of microplastics, respectively. White polyethylene fragments predominate, and all the microplastics comprise small secondary microplastics with a minimum size of 25 µm and a maximum size of 260 µm for fragments and a length of 640 µm for fibers. The proportions of polyethylene, polypropylene, polystyrene, and polymethylmethacrylate are similar. The differing percentages of other compositions in sand and seawater are attributed to the morphology and density of the microplastics. The results indicate the extent of microplastic pollution and suggest appropriate strategies for tourism development at the Biosphere Reserve.
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Impaired bone formation is the main characteristics of glucocorticoid (GC)-induced osteoporosis (GIO), which can be ameliorated by tanshinol, an aqueous polyphenol isolated from Salvia miltiorrhiza Bunge. However, the underlying mechanism is still not entirely clear. In the present study, we determined the parameters related to microstructure and function of bone tissue, bone microcirculation, and TXNIP signaling to investigate the beneficial effects of tanshinol on skeleton and its molecular mechanism in GIO rats. Male Sprague-Dawley rats aged 4 months were administrated orally with distilled water (Con), tanshinol (Tan, 25 mg kg-1 d-1), prednisone (GC, 5 mg kg-1 d-1) and GC plus tanshinol (GC + Tan) for 14 weeks. The results demonstrated that tanshinol played a significant preventive role in bone loss, impaired microstructure, dysfunction of bone metabolism and poor bone quality, based on analysis of correlative parameters acquired from the measurement by using Micro-CT, histomorphometry, ELISA and biomechanical assay. Tanshinol also showed a significant protective effect in bone microcirculation according to the evidence of microvascular perfusion imaging of cancellous bone in GIO rats, as well as the migration ability of human endothelial cells (EA.hy926, EA cells). Moreover, tanshinol also attenuated GC-elicited the activation of TXNIP signaling pathway, and simultaneously reversed the down-regulation of Wnt and VEGF pathway as manifested by using Western-blot method in GIO rats, EA cells, and human osteoblast-like MG63 cells (MG cells). Collectively, our data highlighted that tanshinol ameliorated poor bone health mediated by activation of TXNIP signaling via inhibiting microcirculation disturbance and the following impaired bone formation in GIO rats.
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KEY POINTS: Receptor-operated activation of TRPC4 cation channels requires Gi/o proteins and phospholipase-Cδ1 (PLCδ1) activation by intracellular Ca2+ . Concurrent stimulation of the Gq/11 pathway accelerates Gi/o activation of TRPC4, which is not mimicked by increasing cytosolic Ca2+ . The kinetic effect of Gq/11 was diminished by alkaline intracellular pH (pHi ) and increased pHi buffer capacity. Acidic pHi (6.75-6.25) together with the cytosolic Ca2+ rise accelerated Gi/o -mediated TRPC4 activation. Protons exert their facilitation effect through Ca2+ -dependent activation of PLCδ1. The data suggest that the Gq/11 -PLCß pathway facilitates Gi/o activation of TRPC4 through hydrolysing phosphatidylinositol 4,5-bisphosphate (PIP2 ) to produce the initial proton signal that triggers a self-propagating PLCδ1 activity supported by regenerative H+ and Ca2+ . The findings provide novel mechanistic insights into receptor-operated TRPC4 activation by coincident Gq/11 and Gi/o pathways and shed light on how aberrant activation of TRPC4 may occur under pathological conditions to cause cell damage. ABSTRACT: Transient Receptor Potential Canonical 4 (TRPC4) forms non-selective cation channels activated downstream from receptors that signal through G proteins. Our recent work suggests that TRPC4 channels are particularly coupled to pertussis toxin-sensitive Gi/o proteins, with a co-dependence on phospholipase-Cδ1 (PLCδ1). The Gi/o -mediated TRPC4 activation is dually dependent on and bimodally regulated by phosphatidylinositol 4,5-bisphosphate (PIP2 ), the substrate hydrolysed by PLC, and intracellular Ca2+ . As a byproduct of PLC-mediated PIP2 hydrolysis, protons have been shown to play an important role in the activation of Drosophila TRP channels. However, how intracellular pH affects mammalian TRPC channels remains obscure. Here, using patch-clamp recordings of HEK293 cells heterologously co-expressing mouse TRPC4ß and the Gi/o -coupled µ opioid receptor, we investigated the role of intracellular protons on Gi/o -mediated TRPC4 activation. We found that acidic cytosolic pH greatly accelerated the rate of TRPC4 activation without altering the maximal current density and this effect was dependent on intracellular Ca2+ elevation. However, protons did not accelerate channel activation by directly acting upon TRPC4. We additionally demonstrated that protons exert their effect through sensitization of PLCδ1 to Ca2+ , which in turn promotes PLCδ1 activity and further potentiates TRPC4 via a positive feedback mechanism. The mechanism elucidated here helps explain how Gi/o and Gq/11 co-stimulation induces a faster activation of TRPC4 than Gi/o activation alone and highlights again the critical role of PLCδ1 in TRPC4 gating.
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Calcio , Canales Catiónicos TRPC , Animales , Calcio/metabolismo , Células HEK293 , Humanos , Concentración de Iones de Hidrógeno , Ratones , Fosfolipasa C delta , Fosfolipasa DRESUMEN
G protein-coupled receptors (GPCRs) transmit extracellular signals into cells by activating G protein- and ß-arrestin-dependent pathways. Extracellular signal-regulated kinases (ERKs) play a central role in integrating these different linear inputs coming from a variety of GPCRs to regulate cellular functions. Here, we investigated human melatonin MT1 and MT2 receptors signaling through the ERK1/2 cascade by employing different biochemical techniques together with pharmacological inhibitors and siRNA molecules. We show that ERK1/2 activation by both receptors is exclusively G protein-dependent, without any participation of ß-arrestin1/2 in HEK293 cells. ERK1/2 activation by MT1 is only mediated though Gi/o proteins, while MT2 is dependent on the cooperative activation of Gi/o and Gq/11 proteins. In the absence of Gq/11 proteins, however, MT2 -induced ERK1/2 activation switches to a ß-arrestin1/2-dependent mode. The signaling cascade downstream of G proteins is the same for both receptors and involves activation of the PI3K/PKCζ/c-Raf/MEK/ERK cascade. The differential G protein dependency of MT1 - and MT2 -mediated ERK activation was confirmed at the level of EGR1 and FOS gene expression, two ERK1/2 target genes. Gi/o /Gq/11 cooperativity was also observed in Neuroscreen-1 cells expressing endogenous MT2 , whereas in the mouse retina, where MT2 is engaged into MT1 /MT2 heterodimers, ERK1/2 signaling is exclusively Gi/o -dependent. Collectively, our data reveal differential signaling modes of MT1 and MT2 in terms of ERK1/2 activation, with an unexpected Gi/o /Gq/11 cooperativity exclusively for MT2 . The plasticity of ERK activation by MT2 is highlighted by the switch to a ß-arrestin1/2-dependent mode in the absence of Gq/11 proteins and by the switch to a Gi/o mode when engaged into MT1 /MT2 heterodimers, revealing a new mechanism underlying tissue-specific responses to melatonin.
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Proteínas de Unión al GTP/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/metabolismo , Animales , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Introduction: An outbreak of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affec-ting worldwide. The association between this virus and the upregulation of Angiotensin-Converting Enzyme 2 (ACE2) has been suggested as a potential as an important factor in the development of Coronavirus Disease- 19 (COVID-19). Objective: To describe the relationship between some antihypertensive treatments and COVID-19. Methods: A research was conducted with the components of the PIO (Population, Intervention, Outcomes) strate-gy, including the literature of the last 20 years available in central PubMed, Web of Science, Scopus, and Embase databases. All relevant articles that assessed the epidemiological relationship between SARS-CoV-2 and hyperten-sion, the treatment and outcomes of the patients who have this comorbidity, as well as the relationship between the RAA axis and COVID-19 were included in the analysis. Results: A total of 292 items were found in the databases. After a thorough analysis, 17 papers were selected, including in vitro and in vivo tests, clinical trials, and epidemiological studies related to the topic analyzed. Conclusion: Due to the systemic benefits of antihypertensive drugs targeting the RAA axis, and the lack of eviden-ce of these treatments being a risk factor, It is not recommended to withdraw these medications from hypertensive patients infected with SARS-CoV 2, unless there is a clinical indication.
Introducción: el surgimiento y diseminación del coronavirus tipo 2 del síndrome respiratorio agudo severo (SARS-CoV-2), actualmente, afecta a la mayoría de los del mundo. La asociación entre este virus y la regulación positiva de la enzima convertidora de angiotensina 2 (ACE2) se ha sugerido como un factor potencial en el desarrollo de la enfermedad por coronavirus-19 (COVID- 19). Objetivo: describir la relación entre algunos tratamientos antihipertensivos y la COVID-19. Métodos: se revisaron los componentes de la estrategia PIO (población, intervención, resultados). Se incluyeron todos los artículos relevantes de los últimos 20 años disponibles en las bases de datos centrales PubMed, Web of Science, Scopus y Embase, que describen la relación epidemiológica entre SARS-CoV-2 e hipertensión, el tratamiento y el desenlace de los pacientes quienes tienen esta comor-bilidad, así como la relación entre el eje renina-angiotensina-aldosterona y COVID-19. Resultados: se encontraron inicialmente 292 artículos en las bases de datos, para finalmente seleccio-nar 17 artículos, incluyendo exámenes in vivo e in vitro, ensayos clínicos y estudios epidemiológicos relacionados con el tema analizado. Conclusión: debido a los beneficiosos efectos sistémicos del tratamiento antihipertensivo, cuyo blanco es el sistema renina-angiotensina- aldosterona, y a la falta de evidencia acerca de estos me-dicamentos en cuanto a la inducción de SARS-CoV-2, no se recomienda suspender o contraindicar el tratamiento con estos fármacos en pacientes hipertensos positivos para COVID-19, a menos que haya una indicación clínica
Introdução: Um surto de Síndrome Respiratória Aguda Grave Coronavirus 2 (SARS-CoV-2) está afe-tando atualmente em todo o mundo. A associação entre esse vírus e a suprarregulação da Enzima Conversora da Angiotensina 2 (ACE2) tem sido sugerida como um fator potencial importante no de-senvolvimento da Doença do Coronavírus-19 (COVID-19). Objetivo: Descrever a relação entre al-guns tratamentos anti-hipertensivos e COVID-19. Métodos: Foi realizada uma pesquisa com os com-ponentes da estratégia Population, Intervention, Resultados (PIR), incluindo a literatura dos últimos 20 anos disponível nas bases de dados centrais PubMed, Web of Science, Scopus e Embase. Todos os artigos relevantes que avaliaram a relação epide-miológica entre SARS-CoV-2 e hipertensão, o trata-mento e resultados dos pacientes que apresentam essa comorbidade, bem como a relação entre o eixo RAA e COVID-19 foram incluídos na análise. Resultados: Foram encontrados 292 itens nas bases de dados. Após análise aprofundada, foram selecionados 17 artigos, entre testes in vitro e in vivo, en-saios clínicos e estudos epidemiológicos relacionados ao tema analisado. Conclusão: Devido aos be-nefícios sistêmicos dos medicamentos anti-hipertensivos direcionados ao eixo RAA e à falta de evi-dência desses tratamentos serem um fator de risco, não é recomendado retirar esses medicamentos de pacientes hipertensos infectados com SARS-CoV 2, a menos que haja um indicação clínica.
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Inhibidores de la Enzima Convertidora de Angiotensina , Coronavirus , Antagonistas de Receptores de Angiotensina , COVID-19 , HipertensiónRESUMEN
Adipose tissue is a primary site of obesity-induced inflammation, which has been emerging as an important contributor to obesity associated disorders. The factors influencing adipose tissue-induced inflammation and the resulting pathophysiological events remain poorly understood. However, dietary fiber consumptions appear to be protective. Short-chain fatty acids such as propionic acid (PA) are the principal products of the dietary fiber fermentation by microbiota. Therefore, we aim to investigate the influence of PA on inflammation, lipogenesis and glucose uptake markers from human subcutaneous adipose tissue (SAT). We showed that the treatment of SAT with PA resulted in a significant downregulation of inflammatory parameters (e.g. TNF-α and IP-10) and macrophage markers (e.g. CD163 and MMP-9). The expression levels of PA receptors (i.e. G protein coupled receptor-41 and -43) in human primary adipocytes were very low in comparison with SAT and macrophages. Upon PA treatment, no anti-inflammatory effect was observed in human adipocytes. PA significantly upregulated the expression of lipoprotein lipase (LPL), sterol regulatory-element-binding protein-1c (SREBP-1c) and glucose transporter 4 (GLUT-4), which are associated with lipogenesis and glucose uptake. We also showed that the observed anti-inflammatory effects of PA on SAT were partly mediated by Gi/o protein coupled receptor. Our data suggests that PA anti-inflammatory effects on SAT are mediated partly via Gi/o proteins, leading to the improved expression of factors associated with lipogenesis and glucose uptake. These responses appeared to be not mediated by adipocytes; but most probably by macrophages. The current study provides new knowledge, which can be used as a potential new avenue for drug development in preventing obesity-related inflammation and metabolic disorders in future. Graphical abstract Schematic presentation of study flow and the components of the investigation. In this study the effect of propionic acid (PA) on inflammation investigated in human subcutaneous adipose tissue (SAT), human primary adipocytes and the expression of a few hallmark inflammatory components produced by SAT and human adipocytes.
Asunto(s)
Antiinflamatorios/farmacología , Citocinas/genética , Propionatos/farmacología , Grasa Subcutánea/efectos de los fármacos , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Quimiocina CXCL10/genética , Regulación hacia Abajo , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Metaloproteinasa 9 de la Matriz/genética , Persona de Mediana Edad , Receptores de Superficie Celular/genética , Grasa Subcutánea/inmunología , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Cells translate extracellular signals to regulate processes such as differentiation, metabolism and proliferation, via transmembranar receptors. G protein-coupled receptors (GPCRs) belong to the largest family of transmembrane receptors, with over 800 members in the human species. Given the variety of key physiological functions regulated by GPCRs, these are main targets of existing drugs. During normal aging, alterations in the expression and activity of GPCRs have been observed. The central nervous system (CNS) is particularly affected by these alterations, which results in decreased brain functions, impaired neuroregeneration, and increased vulnerability to neuropathologies, such as Alzheimer's and Parkinson diseases. GPCRs signal via heterotrimeric G proteins, such as Go, the most abundant heterotrimeric G protein in CNS. We here review age-induced effects of GPCR signaling via the Gi/o subfamily at the CNS. During the aging process, a reduction in protein density is observed for almost half of the Gi/o-coupled GPCRs, particularly in age-vulnerable regions such as the frontal cortex, hippocampus, substantia nigra and striatum. Gi/o levels also tend to decrease with aging, particularly in regions such as the frontal cortex. Alterations in the expression and activity of GPCRs and coupled G proteins result from altered proteostasis, peroxidation of membranar lipids and age-associated neuronal degeneration and death, and have impact on aging hallmarks and age-related neuropathologies. Further, due to oligomerization of GPCRs at the membrane and their cooperative signaling, down-regulation of a specific Gi/o-coupled GPCR may affect signaling and drug targeting of other types/subtypes of GPCRs with which it dimerizes. Gi/o-coupled GPCRs receptorsomes are thus the focus of more effective therapeutic drugs aiming to prevent or revert the decline in brain functions and increased risk of neuropathologies at advanced ages.
RESUMEN
Glucocorticoid-induced osteoporosis (GIO) is a secondary osteoporosis with extensive use of glucocorticoids (GCs). GCs can increase bone fragility and fracture via inhibiting osteoblastic proliferation and differentiation. Luteolin (LUT), a kind of plant flavonoid, has been reported to exhibit the antioxidant activity, but the effects of LUT on GIO still remain unclear. This study aimed to investigate the effects of LUT on GIO both in vivo and in vitro and elaborate the potential molecular mechanisms. LUT increased the superoxide dismutase activity, glutathione level and decreased reactive oxygen species (ROS) level and lactate dehydrogenase release in GIO. Meanwhile, LUT decreased caspase-3, caspase-9, and Bax protein expressions and increased Bcl-2 protein expression in GIO. LUT increased the ratio of osteoprotegerin (OPG)/receptor activator of nuclear factor-κB Ligand (RANKL) messenger RNA (mRNA) expression and mRNA expression levels of osteogenic markers, including runt-related transcription factor 2, osterix, collagen type I, and osteocalcin. LUT also enhanced the extracellular signal-regulated kinases (ERK) phosphorylation, glycogen synthase kinase 3ß (GSK-3ß) phosphorylation, mRNA expression levels of lipoprotein-receptor-related protein 5 (Lrp-5) and ß-catenin. Further study revealed that Lrp-5 small interfering RNA (siRNA )and ERK-siRNA reduced the effects of LUT on GSK-3ß phosphorylation, alkaline phosphatase (ALP) activity and the ratio of OPG/RANKL mRNA expression. Moreover, ERK-siRNA decreased Lrp-5 mRNA expression in vitro. These results indicated that LUT promoted proliferation by attenuating oxidative stress and promoted osteoblastic differentiation by regulating the ERK/Lrp-5/GSK-3ß pathway in GIO. This study may bring to light the possible mechanisms involved in the action of LUT in GIO treatment, and benefit for further research on GIO.
Asunto(s)
Dexametasona , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Fémur/efectos de los fármacos , Glucocorticoides , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Luteolina/farmacología , Osteoblastos/efectos de los fármacos , Osteoporosis/prevención & control , Transducción de Señal/efectos de los fármacos , Células 3T3 , Animales , Apoptosis/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Hueso Esponjoso/efectos de los fármacos , Hueso Esponjoso/enzimología , Hueso Esponjoso/patología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/genética , Femenino , Fémur/enzimología , Fémur/patología , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Ratones , Osteoblastos/enzimología , Osteoblastos/patología , Osteogénesis/efectos de los fármacos , Osteoporosis/inducido químicamente , Osteoporosis/enzimología , Osteoporosis/patología , Estrés Oxidativo/efectos de los fármacos , FosforilaciónRESUMEN
Dopamine (D2) receptors provide autoinhibitory feedback onto dopamine neurons through well-known interactions with voltage-gated calcium channels and G protein-coupled inwardly-rectifying potassium (GIRK) channels. Here, we reveal a third major effector involved in D2R modulation of dopaminergic neurons - the sodium leak channel, NALCN. We found that activation of D2 receptors robustly inhibits isolated sodium leak currents in wild-type mice but not in NALCN conditional knockout mice. Intracellular GDP-ßS abolished the inhibition, indicating a G protein-dependent signaling mechanism. The application of dopamine reliably slowed pacemaking even when GIRK channels were pharmacologically blocked. Furthermore, while spontaneous activity was observed in nearly all dopaminergic neurons in wild-type mice, neurons from NALCN knockouts were mainly silent. Both observations demonstrate the critical importance of NALCN for pacemaking in dopaminergic neurons. Finally, we show that GABA-B receptor activation also produces inhibition of NALCN-mediated currents. Therefore, we identify NALCN as a core effector of inhibitory G protein-coupled receptors.