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1.
Artigo em Inglês | MEDLINE | ID: mdl-36116673

RESUMO

Exposure to stressful stimuli induces various physiological and behavioral responses, affects pain perception, and alters gene expression. Stress elicits an analgesic effect in laboratory animals, termed the "stress-induced analgesia" (SIA). Orexin neuropeptides, processed from pre-pro-orexin in the hypothalamus, release during stress and are known to be antinociceptive. The current study examined the modulatory role of the ventral tegmental area (VTA) orexinergic system in the restraint SIA and extracellular signal-regulated kinase (ERK) activation in the nucleus accumbens (NAc). Adult male Wistar rats were subjected to intra-VTA injection of orexin-1 and -2 receptor antagonists (SB334867 and TCS OX2 29; 1, 3, 10, and 30 nmol/0.3 µl, respectively) five min before a 3-h period of exposure to restraint stress (RS). Western blot analysis was also used to assess the levels of ERK and phosphorylated ERK (p-ERK) in the NAc tissues. RS exposure produced an analgesic response to the thermal pain model (Tail-flick test). RS-induced antinociception was inhibited by intra-VTA administration of SB334867 and TCS OX2 29. Moreover, in the molecular study, exposure to forced swim stress (FSS) and RS significantly enhanced the p-ERK/ERK ratio. Blockade of both orexin receptors diminished the p-ERK/ERK ratio, but this decrease was significant only in the FSS group of animals that received TCS OX2 29. Collectively, the present findings suggested the functional roles of intra-VTA orexin receptors and ERK signaling in the SIA.


Assuntos
Analgesia , Neuropeptídeos , Animais , Masculino , Ratos , Analgésicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neuropeptídeos/metabolismo , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Dor/tratamento farmacológico , Ratos Wistar , Área Tegmentar Ventral/metabolismo , Comportamento Animal
2.
Int J Mol Sci ; 23(21)2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36362318

RESUMO

Bone absorption is necessary for the maintenance of bone homeostasis. An osteoclast (OC) is a monocyte-macrophage lineage cell that absorbs bone tissue. Extracellular signal-regulated kinases (ERKs) are known to play important roles in regulating OC growth and differentiation. In this study, we examined specific downstream signal pathways affected by ERK inhibition during OC differentiation. Our results showed that the ERK inhibitors PD98059 and U0126 increased receptor activator of NF-κB ligand (RANKL)-induced OC differentiation in RAW 264.7 cells, implying a negative role in OC differentiation. This is supported by the effect of ERK2-specific small interfering RNA on increasing OC differentiation. In contrast to our findings regarding the RAW 264.7 cells, the ERK inhibitors attenuated the differentiation of bone marrow-derived cells into OCs. The ERK inhibitors significantly increased the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) but not the activation of p38 MAPK, Lyn, and mTOR. In addition, while the ERK inhibition increased the expression of the RANKL receptor RANK, it decreased the expression of negative mediators of OC differentiation, such as interferon regulatory factor-8, B-cell lymphoma 6, and interferon-γ. These dichotomous effects of ERK inhibition suggest that while ERKs may play positive roles in bone marrow-derived cells, ERKs may also play negative regulatory roles in RAW 264.7 cells. These data provide important information for drug development utilizing ERK inhibitors in OC-related disease treatment.


Assuntos
Proteínas Quinases Ativadas por AMP , Reabsorção Óssea , Camundongos , Animais , Proteínas Quinases Ativadas por AMP/metabolismo , Células RAW 264.7 , Ligante RANK/farmacologia , Ligante RANK/metabolismo , Osteoclastos/metabolismo , Osteogênese , Diferenciação Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Reabsorção Óssea/metabolismo
3.
Molecules ; 27(21)2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36364267

RESUMO

Skin hyperpigmentation is an aesthetic problem that leads to psychosocial issues. Thus, skin whitening agents from agro- and poultry-industrial co-products are considered high economic value ingredients of interest for sustainable application. Therefore, this study aimed to determine the cosmeceutical potential of anserine/carnosine-rich chicken extract (ACCE) from the Thai native chicken Pradu Hang Dam Mor Kor 55 (PD) meat. The chemical composition was identified and quantified using the HPLC-UV method. Then, the antioxidation potential of the extract was compared to that of L-anserine and L-carnosine, using 1,1-diphenyl-2-picrylhydrazyl assay and shikonin-induced production of reactive oxygen species in CCD-986Sk cell models, and the anti-melanogenesis effect in the MNT-1 melanoma cell line model was investigated. Furthermore, related mechanisms were identified using colorimetric tyrosinase assay and the Western blot technique. The ACCE was composed of L-anserine and L-carnosine as two major constituents. In a dose-dependent manner, ACCE, L-anserine, and L-carnosine manifested significant antioxidation potential and significant reduction of melanin production. Activation of the extracellular signal-regulated kinase (ERK) signaling pathway and inhibition of tyrosinase activity of ACCE were demonstrated as the mechanisms of the anti-melanogenesis effect. In conclusion, ACCE has been revealed as a potential cosmeceutical agent due to its antioxidation and anti-melanogenic activity in association with L-anserine and L-carnosine composition and biomolecular regulating ability. Therefore, further studies and development should be considered to support the utilization of anserine/carnosine-rich chicken extract in the cosmetic industry for economic value creation and sustainability.


Assuntos
Carnosina , Cosmecêuticos , Animais , Anserina/química , Carnosina/química , Galinhas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Tailândia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Transdução de Sinais
4.
J Pathol ; 258(4): 339-352, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36181299

RESUMO

Hepatocellular carcinoma (HCC) is among the most prevalent visceral neoplasms. So far, reliable biomarkers for predicting HCC recurrence in patients undergoing surgery are far from adequate. In the aim of searching for genetic biomarkers involved in HCC development, we performed analyses of cDNA microarrays and found that the DNA repair gene NEIL3 was remarkably overexpressed in tumors. NEIL3 belongs to the Fpg/Nei protein superfamily, which contains DNA glycosylase activity required for the base excision repair for DNA lesions. Notably, the other Fpg/Nei family proteins NEIL1 and NEIL2, which have the same glycosylase activity as NEIL3, were not elevated in HCC; NEIL3 was specifically induced to participate in HCC development independently of its glycosylase activity. Using RNA-seq and invasion/migration assays, we found that NEIL3 elevated the expression of epithelial-mesenchymal transition (EMT) factors, including the E/N-cadherin switch and the transcription of MMP genes, and promoted the invasion, migration, and stemness phenotypes of HCC cells. Moreover, NEIL3 directly interacted with the key EMT player TWIST1 to enhance invasion and migration activities. In mouse orthotopic HCC studies, NEIL3 overexpression also caused a prominent E-cadherin decrease, tumor volume increase, and lung metastasis, indicating that NEIL3 led to EMT and tumor metastasis in mice. We further found that NEIL3 induced the transcription of MDR1 (ABCB1) and BRAF genes through the canonical E-box (CANNTG) promoter region, which the TWIST1 transcription factor recognizes and binds to, leading to the BRAF/MEK/ERK pathway-mediated cell proliferation as well as anti-cancer drug resistance, respectively. In the HCC cohort, the tumor NEIL3 level demonstrated a high positive correlation with disease-free and overall survival after surgery. In conclusion, NEIL3 activated the BRAF/MEK/ERK/TWIST pathway-mediated EMT and therapeutic resistances, leading to HCC progression. Targeted inhibition of NEIL3 in HCC individuals with NEIL3 induction is a promising therapeutic approach. © 2022 The Pathological Society of Great Britain and Ireland.


Assuntos
Carcinoma Hepatocelular , DNA Glicosilases , Neoplasias Hepáticas , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , DNA Glicosilases/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Transcrição Twist/metabolismo
5.
Biochem Soc Trans ; 50(5): 1341-1352, 2022 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-36281999

RESUMO

Extracellular signal-related kinases 1 and 2 (ERK1/2) are the final components of the mitogen-activated protein kinase (MAPK) phosphorylation cascade, an integral module in a diverse array of signalling pathways for shaping cell behaviour and fate. More recently, studies have shown that ERK1/2 plays an essential role downstream of immune receptors to elicit inflammatory gene expression in response to infection and cell or tissue damage. Much of this work has studied ERK1/2 activation in Toll-like receptor (TLR) pathways, providing mechanistic insights into its recruitment, compartmentalisation and activation in cells of the innate immune system. In this review, we summarise the typical activation of ERK1/2 in growth factor receptor pathways before discussing its known roles in immune cell signalling with a focus downstream of TLRs. We examine emerging research uncovering evidence of dysfunctional ERK1/2 signalling in inflammatory diseases and discuss the potential therapeutic benefit of targeting ERK1/2 pathways in inflammation.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular , Sistema de Sinalização das MAP Quinases , Humanos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Transdução de Sinais , Fosforilação , Inflamação
6.
Can J Vet Res ; 86(4): 254-260, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36211213

RESUMO

Glässer's disease in pigs is associated with infection by Glaesserella parasuis and is characterized by pneumonia-like symptoms, fibrinous polyserositis, polyarthritis, and meningitis. Macleaya cordata, a commonly used traditional Chinese medication, has been shown to have anti-inflammatory, antiviral, antioxidative, antimicrobial, insecticidal, and antitumor properties. However, the anti-inflammatory effects of M. cordata on G. parasuis stimulation are still poorly understood. This study explored the anti-inflammatory effects and mechanisms of M. cordata extract on G. parasuis-induced inflammatory responses, via the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, in porcine alveolar macrophages (PAMs). Porcine alveolar macrophages, when stimulated with G. parasuis, initiated transcription of interleukin (IL)-1α, IL-1ß, IL-6, IL-8, and tumor necrosis factor alpha (TNF-α). Furthermore, p65, IκBα, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) phosphorylation were upregulated via the NF-κB and MAPK signaling pathways. However, treatment with M. cordata extract inhibited transcription of IL-1α, IL-1ß, IL-6, IL-8, and TNF-α and reduced p65, IκBα, p38, ERK, and JNK phosphorylation, by inhibiting activation of the NF-κB and MAPK signaling pathways in PAMs induced by G. parasuis. These findings reveal that M. cordata extract can reverse the inflammatory effect initiated by G. parasuis in vitro and that it possesses significant immunosuppression activity; thus, it may offer a novel strategy for controlling and treating G. parasuis infection.


La maladie de Glässer chez les porcs est associée avec une infection par Glaesserella parasuis et est caractérisée par des symptômes similaires à une pneumonie, une polysérosite fibrineuse, une polyarthrite et une méningite. Macleaya cordata, un médicament utilisé couramment en médecine traditionnelle chinoise, a été montré comme ayant des propriétés anti-inflammatoire, antivirale, anti-oxydative, antimicrobienne, insecticide et anti-tumeur. Toutefois, les effets anti-inflammatoires de M. cordata sur une stimulation par G. parasuis sont toujours peu compris. La présente étude explore les effets et mécanismes anti-inflammatoires d'un extrait de M. cordata sur les réponses inflammatoires induites par G. parasuis, via le facteur nucléaire-kappa B (NF-κB) et la voie de signalisation de la protéine kinase activée par les mitogènes (MAPK), dans les macrophages alvéolaires porcins (PAMs). Les PAMs, lorsque stimulés par G. parasuis, ont initié la transcription des interleukines (IL)-1α, IL-1ß, IL-6, IL-8, et le facteur de nécrose des tumeurs alpha (TNF-α). Également, la phosphorylation de p65, IκBα, p38, de la kinase régulée par signal extracellulaire (ERK), et de la kinase c-Jun N-terminal (JNK) était régulée à la hausse via les voies de signalisation NF-κB and MAPK. Toutefois, le traitement avec l'extrait de M. cordata a inhibé la transcription d'IL-1α, IL-1ß, IL-6, IL-8, et TNF-α et a diminué la phosphorylation de p65, IκBα, p38, ERK, et JNK, en inhibant les voies de signalisation de NF-κB et MAPK dans les PAMs induits par G. parasuis. Ces trouvailles révèlent qu'un extrait de M. cordata peut renverser l'effet inflammatoire initié par G. parasuis in vitro et qu'il possède une activité immunosuppressive significative; ainsi, ceci pourrait offrir une nouvelle stratégie pour limiter et traiter l'infection par G. parasuis.(Traduit par Docteur Serge Messier).


Assuntos
Haemophilus parasuis , Doenças dos Suínos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/metabolismo , Antivirais/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/veterinária , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/farmacologia , Lipopolissacarídeos , Macrófagos Alveolares/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Transdução de Sinais , Suínos , Doenças dos Suínos/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
7.
Neurosci Lett ; 790: 136890, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36181963

RESUMO

Neuropathic pain is a serious health problem, but optimal drug treatments remain lacking. It has been known that the compound NS5806 is a Kv4.3 activator, which increases Kv4.3-mediated K+ current to reduce neuronal excitability. In this study, we investigated the molecular and cellular mechanisms underlying the analgesic effect of NS5806 in neuropathic pain induced by peripheral nerve injury. Using lumbar (L)5/L6 spinal nerve ligation (SNL) in rats, we found that, without changing the basal nociception, the analgesic effect of NS5806 (220 µg/kg) peaked at 4 h and lasted for 8 h after intraperitoneal injection. Multiple doses of NS5806 reduced not only SNL-upregulated proinflammatory mediators in the DRG and spinal cord on day 1 and day 4 after L5/L6 SNL, but also SNL-evoked expansion of DRG macrophages and spinal microglia on day 4. Furthermore, at 10 min after L5 SNL, NS5806 pretreatment for 4 h suppressed SNL-induced phosphorylated extracellular signal-regulated kinase (pERK) in both Kv4.3+ and Kv4.3- neurons in the dorsal root ganglion (DRG) and superficial spinal dorsal horn, indicating that the action of NS5806 is not restricted to Kv4.3+ neurons. In vitro kinase activity assays revealed that NS5806 weakly inhibited ERK2, MEK1, MEK2, and c-Raf in the ERK pathway. Since NS5806 and the ERK pathway inhibitors have similar antinociceptive characteristics, this study suggests that NS5806 also acts as an ERK pathway inhibitor to attenuate neuropathic pain.


Assuntos
Neuralgia , Traumatismos dos Nervos Periféricos , Ratos , Animais , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Traumatismos dos Nervos Periféricos/complicações , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Ratos Sprague-Dawley , Nervos Espinhais/lesões , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Gânglios Espinais/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ligadura , Analgésicos/farmacologia , Analgésicos/uso terapêutico
8.
Mol Immunol ; 151: 242-251, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36182788

RESUMO

BACKGROUND: Neutrophil extracellular trap (NET) has been demonstrated to play important roles in the pathogenesis and progression of rheumatoid arthritis (RA). Emerging evidence indicates that ligation of signal inhibitory receptor on leukocytes-1 (SIRL-1) can dampen Fc receptor-induced reactive oxygen species (ROS) production in primary human neutrophils by reducing extracellular signal-regulated kinase (ERK) activation. The current study aimed to determine the regulatory effects of SIRL-1 on the NET formation and ROS production by comparing RA patients and healthy controls (HC). METHODS: Multiple assays were employed to detect the expression level of SIRL-1, including immunohistochemical staining, quantitative reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. Peripheral blood neutrophils from both HC and RA patients were freshly isolated. The NET formation was assessed spontaneously before and after exposure to serum samples from HC and RA patients, respectively. The quantification of NET formation was determined by fluorescence microscopy and Spectra Max M5 fluorescent plate reader. The ROS production was examined by flow cytometry. RESULTS: The expression level of SIRL-1 in peripheral blood neutrophils was decreased in RA, comparing to HC. The RA-originated neutrophils showed higher levels of ROS production and NET formation. Ligation of SIRL-1 to neutrophils suppressed ROS production and NET formation. Stimulation of neutrophils with severe anti-cyclic citrullinated peptides (CCP) induced NET formation, which could be inhibited by application of SIRL-1 ligation. CONCLUSION: The current study identified SIRL-1 differentially expressed in neutrophils between RA and HC. Ligation of SIRL-1 inhibited ROS production and NET formation. Downregulation of SIRL-1 showed correlation with upregulation of NET formation in RA. These findings showed the regulation of SIRL-1 on NET formation and provided a potential therapeutic target for RA.


Assuntos
Artrite Reumatoide , Armadilhas Extracelulares , Artrite Reumatoide/metabolismo , Antígenos CD5/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Armadilhas Extracelulares/metabolismo , Humanos , Neutrófilos/metabolismo , Peptídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Fc/metabolismo
9.
Ecotoxicol Environ Saf ; 246: 114150, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36215883

RESUMO

Betulinic acid (BA), an occurring pentacyclic triterpenoid, has various biological activities, such as anti-inflammation and antioxidation. Previous studies found that BA attenuated cyclophosphamide (CYP)-induced intestinal mucosal damage by inhibiting intestinal mucosal barrier dysfunctions and cell apoptosis. However, the effects and regulation mechanisms of BA on CYP-induced renal damage has not been reported in literature. Here, we found that BA pretreatment alleviated the elevation of serum urea level and inhibited the increase in serum neutrophil gelatinase-associated lipocalin level induced by CYP. Meanwhile, BA ameliorated renal tubular epithelial cell edema, and vacuolization of renal cortical tubular and renal glomerulus. Moreover, pretreatment with BA inhibited the mRNA expressions of pro-inflammatory cytokines interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α, and increased mRNA expressions of anti-inflammatory cytokines such as IL-10 and transforming growth factor-ß by inactivation nuclear factor kappa-B. Simultaneously, BA decreased the accumulation of reactive oxygen species and malondialdehyde, and lowered the levels of superoxide dismutase and glutathione, while increased the activity of glutathione peroxidase in CYP-induced kidney damage mice. Besides, BA reduced the phosphorylation of extracellular signal-regulated kinases (ERK), inhibited the ratio of Bcl-2/Bax and cell apoptosis in CYP-triggered kidney damage. Furthermore, BA and/or PD98059 (an inhibitor of ERK) regulated mitigation of CYP-elicited renal injury and deactivation of the ERK pathway and mitochondrial apoptotic pathway, indicating that the protective effect of BA on CYP-induced renal damage may be associated with the down-regulation of ERK-mediated mitochondrial apoptotic pathway. Thus, BA could be a candidate agent against chemotherapy drug-induced nephrotoxicity by reducing inflammation and oxidative stress through suppression of ERK-mediated mitochondrial apoptotic pathway.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Estresse Oxidativo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim , Apoptose , Ciclofosfamida/toxicidade , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , RNA Mensageiro/metabolismo
10.
Biomed Pharmacother ; 155: 113775, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36271557

RESUMO

Atherosclerosis (AS) is a pathological basis of cardiovascular and cerebrovascular diseases. A severe global public health problem contributes to the growing burden of cardiovascular disease due to its high risk and limited therapeutic measures. AS treatment is challenging, and requires the doctors to integrate clinical manifestations such as the multiplicity of risk factors, the complexity of lesions, and individual variability. Signal transduction is involved in the formation and progression of AS. The transforming growth factor/extracellular regulated protein kinases (TGF/ERK) signaling pathway is involved in the pathophysiological regulation such as vascular smooth muscle cell proliferation and inflammatory response, which are central links related to the development of AS. Resveratrol can exert beneficial effects at various stages of AS development by regulating lipid metabolism, inhibiting inflammatory development, and alleviating oxidative stress. We hypothesize that its anti-AS effects mainly through modulating the TGF/ERK signaling pathways. This review summarizes the current research progress of resveratrol in the treatment of AS via inhibiting the TGF/ERK signaling pathway and presents the prospects.


Assuntos
Aterosclerose , Fator de Crescimento Transformador beta , Humanos , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Fator de Crescimento Transformador beta/metabolismo , Transdução de Sinais , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fatores de Crescimento Transformadores/uso terapêutico
11.
J Med Chem ; 65(20): 13561-13573, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36205714

RESUMO

Extracellular signal-regulated protein kinase 1/2 (ERK1/2), the only known substrate of MEK1/2, is located downstream of the RAS-RAF-MEK-ERK (MAPK) pathway and is associated with the abnormal activation and poor prognosis of cancer. To date, several small-molecule inhibitors of RAS, RAF, and MEK have been reported to make rapid advances in cancer therapy; however, acquired resistance still occurs, thereby weakening the therapeutic efficacy of these inhibitors. Recently, selective inhibition of ERK1/2 has been regarded as a potential cancer therapeutic strategy that can not only effectively block the MAPK pathway but also overcome drug resistance caused by upstream mutations in RAS, RAF, and MEK. Herein, we summarize the oncogenic roles, key signaling network, and the single- and dual-target inhibitors of ERK1/2 in preclinical and clinical trials. Together, these inspiring findings shed new light on the discovery of more small-molecule inhibitors of ERK1/2 as candidate drugs to improve cancer therapeutics.


Assuntos
Sistema de Sinalização das MAP Quinases , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Transdução de Sinais , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , MAP Quinases Reguladas por Sinal Extracelular/metabolismo
12.
Nature ; 611(7934): 173-179, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36289326

RESUMO

G-protein-coupled receptors (GPCRs), the largest family of signalling receptors, as well as important drug targets, are known to activate extracellular-signal-regulated kinase (ERK)-a master regulator of cell proliferation and survival1. However, the precise mechanisms that underlie GPCR-mediated ERK activation are not clearly understood2-4. Here we investigated how spatially organized ß2-adrenergic receptor (ß2AR) signalling controls ERK. Using subcellularly targeted ERK activity biosensors5, we show that ß2AR signalling induces ERK activity at endosomes, but not at the plasma membrane. This pool of ERK activity depends on active, endosome-localized Gαs and requires ligand-stimulated ß2AR endocytosis. We further identify an endosomally localized non-canonical signalling axis comprising Gαs, RAF and mitogen-activated protein kinase kinase, resulting in endosomal ERK activity that propagates into the nucleus. Selective inhibition of endosomal ß2AR and Gαs signalling blunted nuclear ERK activity, MYC gene expression and cell proliferation. These results reveal a non-canonical mechanism for the spatial regulation of ERK through GPCR signalling and identify a functionally important endosomal signalling axis.


Assuntos
Adrenérgicos , Endossomos , MAP Quinases Reguladas por Sinal Extracelular , Receptores Adrenérgicos beta 2 , Adrenérgicos/metabolismo , Adrenérgicos/farmacologia , Proliferação de Células , Endossomos/efeitos dos fármacos , Endossomos/enzimologia , Endossomos/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genes myc , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
Cell Mol Biol (Noisy-le-grand) ; 68(6): 92-97, 2022 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-36227671

RESUMO

The study aimed to investigate the influence of heme oxygenase-1 (HO-1) on rats with diabetic retinopathy (DR) through the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway. 40 rats were selected and divided into Control group (n=10), diabetes mellitus (DM) group (n=10), cobalt protoporphyrin (CoPP) group (n=10) and zinc protoporphyrin (ZnPP) group (n=10) according to weight. Streptozotocin (STZ) was intraperitoneally injected to establish the DM model in DM, CoPP and ZnPP groups, and CoPP and ZnPP solution was intraperitoneally injected in CoPP and ZnPP groups, respectively. Blood was drawn to determine fasting blood glucose. The changes in the protein and messenger ribonucleic acid (mRNA) levels were evaluated via Western blotting and polymerase chain reaction (qRT-PCR), respectively. Enzyme-linked immunosorbent assay (ELISA) was performed to measure antioxidant capacity and the levels of total reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and glutathione peroxidase (GPx). The weight of rats was notably higher in the CoPP group and lower inZnPP group than in the DM group (p<0.05). After induction of DM, compared with those in the DM group, the protein expression levels of Nrf2 and pERK were considerably elevated in the CoPP group (p<0.05) but declined remarkably in the ZnPP group (p<0.05). The levels of total ROS and MDA were notably elevated (p<0.05) in DM and ZnPP groups, with a lowered level of GPx and distinctly elevated levels of MDA and total ROS (p<0.05). Moreover, the mRNA expression level of HO-1 in the retinas of rats was remarkably raised in the DM group and CoPP group (p<0.05), but it declined markedly in the ZnPP group (p<0.05). The red fluorescent aggregation of Nrf2 and pERK proteins was overtly less in the ZnPP group than that in the DM group (p<0.05). HO-1 can affect the level of oxidative stress and intervene in retinopathy in DM rats through the Nrf2/ERK pathway.


Assuntos
Retinopatia Diabética , Heme Oxigenase-1 , Animais , Antioxidantes/metabolismo , Glicemia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Sistema de Sinalização das MAP Quinases , Malondialdeído , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Transdução de Sinais , Estreptozocina
14.
Saudi Med J ; 43(10): 1087-1095, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36261201

RESUMO

OBJECTIVES: To analyze the mechanism of testis-specific protein Y-encoded 1 (TSPY1) in male hepatocellular carcinoma (HCC). METHODS: This experimental study was carried out at Guangxi Medical University's First Affiliated Hospital, Guangxi, China, between January 2016 and December 2019. The expression of TSPY1, androgen receptor (AR), messenger ribonucleic acids (mRNAs), and proteins were detected by qRT-PCR and Western blotting. The co-localization and interaction of TSPY1 and AR were observed by immunofluorescence assay and co-immunoprecipitation. Hepatocellular carcinoma cells overexpressing and silencing TSPY1 were constructed, and the expression and phosphorylation levels of TSPY1, AR, and mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway-related key molecules ERK1/2, p38, and JNK were also detected. RESULTS: The expression levels of TSPY1, AR mRNAs, and proteins were highly positively correlated in HCC cells in different metastatic potentials with a high correlation coefficient of R=0.929 and R=0.884. Testis-specific protein Y-encoded 1 and AR were then co-localized in the nucleus of HCC cells, and TSPY1 and AR can interact with each other. In addition, the expression of AR and phosphorylation of ERK1/2 were enhanced in TSPY1 overexpressed Huh7 cells. They were reduced in HCCLM3 cells with TSPY1 knockdown expression. In addition, in response to blocking MAPK/ERK signaling activity, AR was reduced in expression. CONCLUSION: These findings suggested that there was a positive correlation between TSPY1 expression and AR in male HCC cells, and high TSPY1 expression stimulates AR expression, MAPK/ERK signaling pathway may be involved in its mechanism.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Androgênios , Testículo/metabolismo , Testículo/patologia , China , RNA Mensageiro/metabolismo , Proteínas de Ciclo Celular/metabolismo
15.
Molecules ; 27(19)2022 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-36235048

RESUMO

The present study investigated the melanogenic effects of imperatorin and isoimperatorin and the underlying mechanisms of imperatorin using a mouse melanoma B16F10 model. Interestingly, treatment with 25 µM of either imperatorin or isoimperatorin, despite their structural differences, did not produce differences in melanin content and intracellular tyrosinase activity. Imperatorin also activated the expression of melanogenic enzymes, such as tyrosinase (TYR) and tyrosinase-related proteins TYRP-1 and TYRP-2. Mechanistically, imperatorin increases melanin synthesis through the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA)/cAMP-responsive element-binding protein (CREB)-dependent upregulation of microphthalmia-associated transcription factor (MITF), which is a key transcription factor in melanogenesis. Furthermore, imperatorin exerted melanogenic effects by downregulating extracellular signal-regulated kinase (ERK) and upregulating phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/glycogen synthesis kinase-3ß (GSK-3ß). Moreover, imperatorin increased the content of ß-catenin in the cell cytoplasm and nucleus by reducing the content of phosphorylated ß-catenin (p-ß-catenin). Finally, we tested the potential of imperatorin in topical application through primary human skin irritation tests. These tests were performed on the normal skin (upper back) of 31 volunteers to determine whether 25 or 50 µM of imperatorin had irritation or sensitization potential. During these tests, imperatorin did not induce any adverse reactions. Taken together, these findings suggest that the regulation of melanogenesis by imperatorin can be mediated by signaling pathways involving PKA/CREB, ERK, AKT, and GSK3ß/ß-catenin and that imperatorin could prevent the pathogenesis of pigmentation diseases when used as a topical agent.


Assuntos
Melanoma Experimental , Fator de Transcrição Associado à Microftalmia , Monofosfato de Adenosina/farmacologia , Animais , Linhagem Celular Tumoral , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Furocumarinas , Glicogênio/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Melaninas , Melanoma Experimental/patologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , beta Catenina/metabolismo
16.
Molecules ; 27(19)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36235070

RESUMO

Keratinocytes form the physical barrier of the skin and play an important role in the inflammatory process. Amauroderma rugosum is an edible mushroom; however, its pharmacological properties have seldom been studied. Although the anti-inflammatory effect of the organic solvent extract of Amauroderma rugosum has been previously reported, it is not known whether the aqueous extract has a similar effect. In addition, the effect of Amauorderma rugosum extract on skin has never been explored. Therefore, the objectives of the present study were to evaluate the anti-inflammatory effects of the aqueous extract of Amauroderma rugosum on HaCaT keratinocytes, to explore its mechanisms of action, and to study the possible active ingredients involved. The results showed that the aqueous extract of Amauroderm rugosum at a concentration of 1.5 mg/mL was non-toxic to HaCaT cells and inhibited the release of cytokine interleukin-1ß, and chemokines interleukin-8 and monocyte chemoattractant protein-1 in tumor necrosis factor (TNF)-α- and interferon (IFN)-γ-stimulated HaCaT cells. Amauroderma rugosum extract reduced the intracellular levels of reactive oxygen species. In addition, Amauroderma rugosum extract reduced the total protein expression of nuclear factor-kappa B (NF-κB) and B-cells inhibitor alpha in HaCaT keratinocytes and inhibited the phosphorylation of mitogen-activated protein kinase kinase (MEK) 1/2, extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (Akt), and mammalian target of rapamycin (mTOR) in TNF-α- and INF-γ-stimulated HaCaT keratinocytes. Chemical analysis revealed that the aqueous extract of Amauroderma rugosum contains polysaccharides, triterpenes, and phenolic compounds. Anti-inflammatory compounds, such as gallic acid, guanosine, and uridine, were also present. The anti-inflammatory effect of Amauroderma rugosum could be mimicked by a combination of gallic acid, guanosine, and uridine. In conclusion, our study suggests that the aqueous extract of Amauroderma rugosum exerts anti-inflammatory effects on keratinocytes through its antioxidant and inhibitory effects on MEK/ERK-, Akt/mTOR-, and NF-κB-dependent signaling pathways.


Assuntos
Triterpenos , Fator de Necrose Tumoral alfa , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Ácido Gálico/farmacologia , Guanosina/metabolismo , Interferon gama/metabolismo , Interferon gama/farmacologia , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Queratinócitos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Polyporaceae , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Solventes/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Uridina/farmacologia
17.
In Vivo ; 36(6): 2740-2750, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36309386

RESUMO

BACKGROUND/AIM: Sarcopenia is an age-related disease in which muscle mass and strength are markedly reduced. There are few effective treatments, but the angiotensin II receptor antagonist losartan has been reported to be effective. Our aim was to evaluate the therapeutic effectiveness of losartan for sarcopenia and explore the underlying mechanisms. MATERIALS AND METHODS: We investigated body weight, muscle mass (gastrocnemius, soleus, peroneus longus, and tibialis anterior muscles), and serum markers in an aged rat model population divided into four treatment groups: Control, exercise, losartan, and exercise plus losartan. The rats were sacrificed at 6, 12, or 18 months after the start of the experiment and autopsies were performed. RESULTS: Compared with the control group, average muscle mass and weight increased in the two groups treated with losartan. AKT serine/threonine kinase (AKT) and extracellular signal-regulated kinase (ERK) muscle growth factors increased in the peroneus longus. mechanistic target of rapamycin kinase (mTOR) increased in tibialis anterior, peroneus longus, and soleus. CONCLUSION: Losartan treatment slowed muscle degeneration and activated the PI3K-AKT-mTOR and ERK/mitogen-activated protein kinase signalling pathways required for production of muscle growth factors when combined with exercise.


Assuntos
Doenças Musculares , Sarcopenia , Ratos , Animais , Sarcopenia/tratamento farmacológico , Losartan/farmacologia , Losartan/metabolismo , Losartan/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Músculo Esquelético/patologia , Envelhecimento , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Serina-Treonina Quinases TOR/metabolismo
18.
Sci Rep ; 12(1): 18077, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36302844

RESUMO

Biochemical correlates of stochastic single-cell fates have been elusive, even for the well-studied mammalian cell cycle. We monitored single-cell dynamics of the ERK and Akt pathways, critical cell cycle progression hubs and anti-cancer drug targets, and paired them to division events in the same single cells using the non-transformed MCF10A epithelial line. Following growth factor treatment, in cells that divide both ERK and Akt activities are significantly higher within the S-G2 time window (~ 8.5-40 h). Such differences were much smaller in the pre-S-phase, restriction point window which is traditionally associated with ERK and Akt activity dependence, suggesting unappreciated roles for ERK and Akt in S through G2. Simple metrics of central tendency in this time window are associated with subsequent cell division fates. ERK activity was more strongly associated with division fates than Akt activity, suggesting Akt activity dynamics may contribute less to the decision driving cell division in this context. We also find that ERK and Akt activities are less correlated with each other in cells that divide. Network reconstruction experiments demonstrated that this correlation behavior was likely not due to crosstalk, as ERK and Akt do not interact in this context, in contrast to other transformed cell types. Overall, our findings support roles for ERK and Akt activity throughout the cell cycle as opposed to just before the restriction point, and suggest ERK activity dynamics may be more important than Akt activity dynamics for driving cell division in this non-transformed context.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular , Proteínas Proto-Oncogênicas c-akt , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Transdução de Sinais , Divisão Celular , Ciclo Celular , Mamíferos/metabolismo
19.
Biol Pharm Bull ; 45(10): 1553-1558, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36184515

RESUMO

9,10-Phenanthrenequinone (9,10-PQ), a polycyclic aromatic hydrocarbon that is present in air pollutants, such as diesel exhaust gas and PM2.5, causes the production of excess reactive oxygen species. 9,10-PQ was recently shown to induce the activation of epidermal growth factor receptor (EGFR) by inhibiting protein tyrosine phosphatase 1B. In the present study, we focused on the non-canonical regulation of EGFR, including negative feedback and internalization. In contrast to previous findings, 9,10-PQ inhibited the constitutive tyrosine phosphorylation of EGFR via the mitogen-activated protein extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Thr-669 in EGFR-overexpressing A431 and MDA-MB-468 cells. In addition, 9,10-PQ induced the clathrin-mediated endocytosis of EGFR via the p38 phosphorylation of Ser-1015 in HeLa and A549 cells. These results revealed that 9,10-PQ strongly induced the non-canonical regulation of EGFR by activating mitogen-activated protein kinase (MAPK).


Assuntos
Poluentes Atmosféricos , Fenantrenos , Poluentes Atmosféricos/toxicidade , Clatrina/metabolismo , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mitógenos , Material Particulado , Fenantrenos/farmacologia , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Espécies Reativas de Oxigênio/metabolismo , Tirosina/metabolismo , Emissões de Veículos
20.
Exp Cell Res ; 420(1): 113352, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36108712

RESUMO

Staphylococcus aureus causes subclinical mastitis; lipoteichoic acid (LTA) from S. aureus causes mastitis-like adverse effects on milk production by mammary epithelial cells (MECs). Here, we investigated the early effects of LTA from S. aureus on mouse MECs using a culture model, in which MECs produced milk components and formed less permeable tight junctions (TJs). In MECs of this model, Toll-like receptor 2 (receptor for LTA), was localized on the apical membrane, similar to MECs in lactating mammary glands. LTA weakened the TJ barrier within 1 h, concurrently with localization changes of claudin 4. LTA treatment for 24 h increased αS1-casein and decreased ß-casein levels. In MECs exposed to LTA, the activation level of signal transducer and activator of transcription 5 (major transcriptional factor for milk production) was low. LTA activated signaling pathways related to cell survival (extracellular signal-regulated kinase, heat shock protein 27, and Akt) and inflammation (p38, c-Jun N-terminal kinase, and nuclear factor κB). Thus, LTA caused abnormalities in casein production and weakened the TJs by affecting multiple signaling pathways in MECs. LTA-induced changes in signaling pathways were not uniform in all MECs. Such complex and semi-negative actions of LTA may contribute to subclinical mastitis caused by S. aureus.


Assuntos
Mastite , Staphylococcus aureus , Animais , Caseínas/metabolismo , Caseínas/farmacologia , Claudina-4/metabolismo , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP27/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lactação/metabolismo , Lipopolissacarídeos/farmacologia , Glândulas Mamárias Animais , Mastite/metabolismo , Camundongos , Leite/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Staphylococcus aureus/metabolismo , Ácidos Teicoicos/farmacologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo
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