RESUMO
Tobacco smoking is a serious health problem in society. While smoking rates are declining, smoking remains a serious risk to national health. Currently, there are several medications available to aid in smoking cessation. However, these medications have the disadvantages of low success rates in smoking cessation and various side effects. Therefore, natural-based smoking cessation aids are being suggested as a good alternative due to their accessibility and minimal side effects. The roots and stems of Acanthopanax koreanum (AK) Nakai, a plant that is native to Jeju Island, South Korea, have traditionally been used as tonic and sedatives. Moreover, eleutheroside B and chlorogenic acid are the main components of AK stem extract. In the present study, we investigated the effect of 70% ethanol AK extract and its components on ameliorating nicotine dependence and withdrawal symptoms by using behavioural tests in mice. In addition, alterations in the dopaminergic and DRD1-EPAC-ERK-CREB pathways were observed using dopamine ELISA and western blotting using mouse brains. Our findings demonstrate that the AK extract and its components effectively mitigated the effects of nicotine treatment in behavioural tests. Furthermore, it normalized the dopamine concentration and the expression level of nicotine acetylcholine receptor α7. Additionally, it was observed that AK extract and its components led to the normalization of DRD1, ERK and CREB expression levels. These results indicate that AK extract exhibits effects in ameliorating nicotine dependence behaviour and alleviating withdrawal symptoms. Moreover, EB and CGA are considered potential marker components of AK extract.
Assuntos
Eleutherococcus , Síndrome de Abstinência a Substâncias , Tabagismo , Animais , Camundongos , Tabagismo/tratamento farmacológico , Nicotina/efeitos adversos , Dopamina , Síndrome de Abstinência a Substâncias/tratamento farmacológico , EtanolRESUMO
The increasing prevalence of sleep dysregulation cases has prompted the search for effective and safe sleep-enhancing agents. Numerous medications used in the treatment of sleep disorders function by enhancing γ-aminobutyric acid neurotransmitter activity. Unfortunately, these substances may induce significant adverse effects in chronic users, such as dependence and motor behavior impairments. Consequently, there is a growing interest in exploring therapeutic sleep-enhancing agents derived from natural sources, with the anticipation of causing less severe side effects. Prunella vulgaris (PV), a perennial plant indigenous to South Korea, exhibits various pharmacological effects, likely attributed to its chemical composition. Rosmarinic acid, one of its components, has previously demonstrated sleep-potentiating properties, suggesting the potential for PV to exhibit similar pharmacological effects. This study aims to investigate the potential effects of repeated administration of PV extract on the sleep behavior, brainwave activity, sleep-wake cycle, and physiological behavior of mice. Findings indicate that PV extracts exhibit sleep-enhancing effects in mice, characterized by prolonged sleep duration and a reduced onset time of pentobarbital-induced sleep. However, PV extracts only reduced alpha wave powers, with minor alterations in wakefulness and rapid-eye-movement sleep duration. In contrast to diazepam, PV extracts lack adverse effects on locomotor activity, motor coordination, or anxiety in mice. Receptor-binding assay and caffeine treatment support the potential involvement of adenosine A2A receptors in the effects of PV, suggesting distinct mechanisms of action compared to diazepam, despite both exhibiting sleep-altering effects. Overall, our results suggest that PV holds promise as a potential source of sleep-aiding agents.
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Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there are two approved drugs for IPF, they were not able to completely cure the disease. Therefore, the development of new drugs is required for the effective treatment of IPF. In this study, we investigated the effect of theophylline, which has long been used for the treatment of asthma, on pulmonary fibrosis. The administration of theophylline attenuated the fibrotic changes of lung tissues and improved mechanical pulmonary functions in bleomycin (BLM)-induced pulmonary fibrosis. Theophylline treatment suppressed IL-17 production through inhibiting cytokines controlling Th17 differentiation; TGF-ß, IL-6, IL-1ß, and IL-23. The inhibition of IL-6 and IL-1ß by theophylline is mediated by suppressing BLM-induced ROS production and NF-κB activation in epithelial cells. We further demonstrated that theophylline inhibited TGF-ß-induced epithelial-to-mesenchymal transition in epithelial cells through suppressing the phosphorylation of Smad2/3 and AKT. The inhibitory effects of theophylline on the phosphorylation of Smad2/3 and AKT were recapitulated in BLM-treated lung tissues. Taken together, these results demonstrated that theophylline prevents pulmonary fibrosis by inhibiting Th17 differentiation and TGF-ß signaling.
Assuntos
Bleomicina , Fibrose Pulmonar Idiopática , Animais , Camundongos , Bleomicina/toxicidade , Teofilina/farmacologia , Interleucina-6/farmacologia , Proteínas Proto-Oncogênicas c-akt , Pulmão , Diferenciação Celular , Fator de Crescimento Transformador beta/farmacologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Camundongos Endogâmicos C57BLRESUMO
Novel psychoactive substances remain the popular recreational drugs of use over the years. They continue to bypass government restrictions due to their synthesis and modifications. Recent additions to the lists are the 4-F-PCP and 4-Keto-PCP, analogs of the drug phencyclidine (PCP) known to induce adverse effects and abuse potential. However, studies on the abuse potential of 4-F-PCP and 4-Keto-PCP remain scarce. The rewarding and reinforcing effects of the drugs were assessed using conditioned place preference (CPP), self-administration, and locomotor sensitization tests. Dopamine (DA) receptor antagonists (SCH23390 and haloperidol) were administered during CPP to evaluate the involvement of the mesolimbic dopaminergic system. DA-related protein expression in the nucleus accumbens (NAcc) and ventral tegmental area (VTA) was measured. Additionally, phosphorylated cyclic-adenosine monophosphate-activated protein (AMP) response element-binding (p-CREB) protein, deltaFosB (∆FosB), and brain-derived neurotrophic factor (BDNF) protein levels in the NAcc were measured to assess the addiction neural plasticity effect of the drugs. Both 4-F-PCP and 4-Keto-PCP-induced CPP and self-administration; however, only 4-F-PCP elicited locomotor sensitization. Treatment with DA receptor antagonists (SH23390 and haloperidol) inhibited the 4-F- and 4-Keto-induced CPP. Both substances altered the levels of DA receptor D1 (DRD1), thyroxine hydroxylase (TH), DA receptor D2 (DRD2), p-CREB, ∆FosB, and BDNF. The results suggest that 4-F-PCP and 4-Keto-PCP may induce abuse potential in rodents via alterations in dopaminergic system accompanied by addiction neural plasticity.
Assuntos
Condicionamento Operante/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Dopamina/metabolismo , Drogas Ilícitas/metabolismo , Medicamentos Sintéticos/metabolismo , Animais , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ratos , Reforço Psicológico , Recompensa , Autoadministração , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
Idiopathic pulmonary fibrosis (IPF) is a refractory interstitial lung disease for which there is no effective treatment. Although the pathogenesis of IPF is not fully understood, TGF-ß and epithelial-mesenchymal transition (EMT) have been shown to be involved in the fibrotic changes of lung tissues. Kurarinone is a prenylated flavonoid isolated from Sophora Flavescens with antioxidant and anti-inflammatory properties. In this study, we investigated the effect of kurarinone on pulmonary fibrosis. Kurarinone suppressed the TGF-ß-induced EMT of lung epithelial cells. To assess the therapeutic effects of kurarinone in bleomycin (BLM)-induced pulmonary fibrosis, mice were treated with kurarinone daily for 2 weeks starting 7 days after BLM instillation. Oral administration of kurarinone attenuated the fibrotic changes of lung tissues, including accumulation of collagen and improved mechanical pulmonary functions. Mechanistically, kurarinone suppressed phosphorylation of Smad2/3 and AKT induced by TGF-ß1 in lung epithelial cells, as well as in lung tissues treated with BLM. Taken together, these results suggest that kurarinone has a therapeutic effect on pulmonary fibrosis via suppressing TGF-ß signaling pathways and may be a novel drug candidate for pulmonary fibrosis.
Assuntos
Flavonoides/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Bleomicina , Linhagem Celular , Transição Epitelial-Mesenquimal , Flavonoides/farmacologia , Humanos , Masculino , Camundongos Endogâmicos BALB C , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologiaRESUMO
An increasing number of N-2-methoxybenzyl-phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25B-NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B-NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self-administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD1 ), dopamine D2 (DRD2 ), and serotonin 2A (5-HT2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B-NBOMe-mediated effects. We also examined the effects of 25B-NBOMe on the expression of dopamine-related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p-CREB), deltaFosB (ΔFosB), and brain-derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5-HT2A receptors in the 25B-NBOMe-induced head twitch response (HTR). We also examined the effects of 25B-NBOMe on brain wave activity using electroencephalography. 25B-NBOMe elicited CPP and SA. SCH and HAL blocked 25B-NBOMe-induced CPP, whereas KS did not. Moreover, 25B-NBOMe altered the DRD1 , DRD2 , and dopamine transporter expression and increased dopamine levels. It also induced changes in p-CREB, ΔFosB, and BDNF expression. 25B-NBOMe induced HTR and increased 5-HT2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B-NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show that 25B-NBOMe may induce rewarding and reinforcing effects via a dopaminergic mechanism, suggesting its abuse potential.
Assuntos
Anisóis/efeitos adversos , Anisóis/química , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Fenetilaminas/efeitos adversos , Fenetilaminas/química , Reforço Psicológico , Recompensa , Transtornos Relacionados ao Uso de Substâncias/etiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismoRESUMO
BACKGROUND: Allergic asthma causes morbidity in many subjects, and novel precision-directed treatments would be valuable. OBJECTIVE: We sought to examine the role of a novel innate molecule, repulsive guidance molecule b (RGMb), in murine models of allergic asthma. METHODS: In models of allergic asthma using ovalbumin or cockroach allergen, mice were treated with anti-RGMb or control mAb and examined for airway inflammation and airway hyperreactivity (AHR), a cardinal feature of asthma. The mechanisms by which RGMb causes airways disease were also examined. RESULTS: We found that blockade of RGMb by treatment with anti-RGMb mAb effectively blocked the development of airway inflammation and AHR. Importantly, blockade of RGMb completely blocked the development of airway inflammation and AHR, even if treatment occurred only during the challenge (effector) phase. IL-25 played an important role in these models of asthma because IL-25 receptor-deficient mice did not develop disease after sensitization and challenge with allergen. RGMb was expressed primarily by innate cells in the lungs, including bronchial epithelial cells (known producers of IL-25), activated eosinophils, and interstitial macrophages, which in the inflamed lung expressed the IL-25 receptor and produced IL-5 and IL-13. We also found that neogenin, the canonical receptor for RGMb, was expressed by interstitial macrophages and bronchial epithelial cells in the inflamed lung, suggesting that an innate RGMb-neogenin axis might modulate allergic asthma. CONCLUSIONS: These results demonstrate an important role for a novel innate pathway in regulating type 2 inflammation in patients with allergic asthma involving RGMb and RGMb-expressing cells, such as interstitial macrophages and bronchial epithelial cells. Moreover, targeting this previously unappreciated innate pathway might provide an important treatment option for allergic asthma.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Asma/tratamento farmacológico , Hiper-Reatividade Brônquica/tratamento farmacológico , Moléculas de Adesão Celular Neuronais/antagonistas & inibidores , Alérgenos/imunologia , Animais , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Moléculas de Adesão Celular Neuronais/imunologia , Baratas/imunologia , Feminino , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Macrófagos/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/imunologia , Proteína 2 Ligante de Morte Celular Programada 1/genética , Receptores de Interleucina/genética , Receptores de Interleucina/imunologiaRESUMO
Collagen hydrolysate is a well-known nutritional supplement for the improvement of healthy skin. Here, collagen peptide NS (CPNS) from fish scale was prepared, and its physicochemical properties were investigated. Gly-Pro was revealed as a representative low molecular weight peptide of CPNS, by performing prep-HPLC and LC-MS/MS. CPNS treatment attenuated matrix metalloproteinase-1 production and increased the synthesis of type 1 procollagen in HDF cells. After orally administering CPNS to rats, the plasma concentrations of Gly-Pro and Pro-Hyp increased dramatically. To examine the protective effects of CPNS against ultraviolet B (UVB)-induced photoaging in vivo, the dorsal skins of hairless mice were exposed to UVB and supplemented with CPNS for 12 weeks. The CPNS consumption significantly attenuated UVB-induced wrinkle formation, transepidermal water loss, and epidermis thickness, and increased skin hydration. Collectively, these results suggest that bioactive peptides of CPNS, Gly-Pro and Pro-Hyp, exert beneficial effects on skin health.
Assuntos
Colágeno Tipo I/química , Dipeptídeos/farmacologia , Hidroxiprolina/química , Prolina/química , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Raios Ultravioleta , Administração Oral , Animais , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Colágeno Tipo I/sangue , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Dipeptídeos/química , Feminino , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Camundongos Pelados , Peso Molecular , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodosRESUMO
Chronic obstructive pulmonary disease (COPD) is a major inflammatory lung disease characterized by irreversible and progressive airflow obstruction. Although corticosteroids are often used to reduce inflammation, steroid therapies are insufficient in patients with refractory COPD. Both serum amyloid A (SAA) and IL-33 have been implicated in the pathology of steroid-resistant lung inflammation. Picroside II isolated from Pseudolysimachion rotundum var. subintegrum (Plantaginaceae) is a major bioactive component of YPL-001, which has completed phase-2a clinical trials in chronic obstructive pulmonary disease patients. In this study, we investigated whether picroside II is effective in treating steroid refractory lung inflammation via the inhibition of the SAA-IL-33 axis. Picroside II inhibited LPS-induced SAA1 expression in human monocytes, which are resistant to steroids. SAA induced the secretion of IL-33 without involving cell necrosis. Picroside II, but not dexamethasone effectively inhibited SAA-induced IL-33 expression and secretion. The inhibitory effect by picroside II was mediated by suppressing the mitogen-activated protein kinase (MAPK) p38, ERK1/2, and nuclear factor-κB pathways. Our results suggest that picroside II negatively modulates the SAA-IL-33 axis that has been implicated in steroid-resistant lung inflammation. These findings provide valuable information for the development of picroside II as an alternative therapeutic agent against steroid refractory lung inflammation in COPD.
Assuntos
Cinamatos/isolamento & purificação , Cinamatos/farmacologia , Glucocorticoides/farmacologia , Interleucina-33/metabolismo , Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Plantaginaceae/química , Proteína Amiloide A Sérica/metabolismo , Cinamatos/química , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Glucosídeos Iridoides/química , Lipopolissacarídeos/farmacologia , Pulmão/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Células THP-1 , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Transcrição Gênica/efeitos dos fármacosRESUMO
Airway mucus secretion is an essential innate immune response for host protection. However, overproduction and hypersecretion of mucus, mainly composed of MUC5AC, are significant risk factors in asthma and chronic obstructive pulmonary disease (COPD) patients. Previously, we reported that verproside, a catalpol derivative iridoid glycoside isolated from Pseudolysimachion rotundum var. subintegrum, is a potent anti-asthmatic candidate drug in vivo. However, the molecular mechanisms underlying the pharmacological actions of verproside remain unknown. Here, we found that verproside significantly reduces the expression levels of tumor necrosis factor alpha (TNF-α)-induced MUC5AC mRNA and protein by inhibiting both nuclear factor kappa B (NF-κB) transcriptional activity and the phosphorylation of its upstream effectors such as IκB kinase (IKK)ß, IκBα, and TGF-ß-activated kinase 1 (TAK1) in NCI-H292 cells. Moreover, verproside attenuated TNF-α-induced MUC5AC transcription more effectively when combined with an IKK (BAY11-7082) or a TAK1 (5z-7-oxozeaenol) inhibitor than when administered alone. Importantly, we demonstrated that verproside negatively modulates the formation of the TNF-α-receptor (TNFR) 1 signaling complex [TNF-RSC; TNFR1-recruited TNFR1-associated death domain protein (TRADD), TNFR-associated factor 2 (TRAF2), receptor-interacting protein kinase 1 (RIP1), and TAK1], the most upstream signaling factor of NF-κB signaling. In silico molecular docking studies show that verproside binds between TRADD and TRAF2 subunits. Altogether, these results suggest that verproside could be a good therapeutic candidate for treatment of inflammatory airway diseases such as asthma and COPD by blocking the TNF-α/NF-κB signaling pathway.
Assuntos
Células Epiteliais/efeitos dos fármacos , Glucosídeos Iridoides/farmacologia , Mucina-5AC/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Immunoblotting , Lactonas/farmacologia , Pulmão/metabolismo , Pulmão/patologia , MAP Quinase Quinase Quinases/metabolismo , Mucina-5AC/genética , Nitrilas/farmacologia , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Resorcinóis/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonas/farmacologia , Proteína de Domínio de Morte Associada a Receptor de TNF/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismoRESUMO
Diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step in triacylglycerol (TG) synthesis, is a key enzyme associated with hepatic steatosis and insulin resistance. Here, using an in vitro screen of 20000 molecules, we identified a class of compounds with a substituted 1H-pyrrolo[2,3-b]pyridine core which proved to be potent and selective inhibitors of human DGAT2. Of these compounds, H2-003 and -005 exhibited a considerable reduction in TG biosynthesis in HepG2 hepatic cells and 3T3-L1 preadipose cells. These compounds exert DGAT2-specific-inhibitory activity, which was further confirmed in DGAT2- or DGAT1-overexpressing HEK293 cells. In addition, these compounds almost completely abolished lipid droplet formation in 3T3-L1 cells when co-treated with a DGAT1 inhibitor, which was not attained using either a DGAT2 or DGAT1 inhibitor alone. Collectively, we identified two DGAT2 inhibitors, H2-003 and -005. These compounds will aid in DGAT2-related lipid metabolism research as well as in therapeutic development for the treatment of metabolic diseases associated with excessive TG.
Assuntos
Acetatos/química , Acetatos/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Descoberta de Drogas/métodos , Piridinas/química , Piridinas/farmacologia , Células 3T3-L1 , Animais , Diacilglicerol O-Aciltransferase/metabolismo , Células HEK293 , Células Hep G2 , Humanos , CamundongosRESUMO
Diffuse cutaneous mastocytosis, the most rare form of cutaneous mastocytosis, often manifests as bullous lesions. Although cutaneous mastocytosis should be included in a differential diagnosis for pruritic skin lesions in children, early diagnosis of the disease is not easy due to its rare occurrence. A 17-month-old boy presented with recurrent itchy bullous skin lesions. He had been treated as atopic dermatitis at other hospitals for about one year, however, he was eventually diagnosed with diffuse cutaneous mastocytosis through skin biopsy. Unlike adults, children with cutaneous mastocytosis usually improve with age and do not develop systemic mastocytosis. Therefore, early and accurate diagnosis of cutaneous mastocytosis in children is essential for appropriate care.
Assuntos
Mastocitose Cutânea/diagnóstico , Dermatite Atópica/diagnóstico , Diagnóstico Diferencial , Humanos , Lactente , Masculino , Pele/patologiaRESUMO
A significant proportion of the world's population suffers from insomnia, a disorder characterized by complications in initiating and maintaining sleep. Many medications used to treat insomnia target the γ-aminobutyric acid (GABA) neurotransmitter system. However, these substances, such as benzodiazepines, induce significant adverse consequences, including dependence and memory impairment, after prolonged use. Thus, current studies are aimed at developing therapeutic hypnotics derived from natural sources that may cause less severe side effects. Heukharang is a variety of lettuce from Korea that was discovered to contain sleep-promoting compounds. Therefore, we investigated the potential effects of sub-chronic administration of Heukharang extract (FSD-LS) on sleep behavior (pentobarbital-induced sleeping test), brain wave activity and sleep architecture (electroencephalography), and physiological behavior (open-field test and rota-rod) in mice, along with radioligand binding assays (GABAA, adenosine A1 and A2A receptors). We found that FSD-LS prolonged the total sleep duration and reduced the onset time of sleep, and enhanced delta wave power and non-rapid eye movement (NREM) sleep duration, all indicating persistent sleep-enhancing effects. FSD-LS lacked adverse effects on the spontaneous locomotor activity and motor coordination of mice, unlike diazepam. Pharmacological blocking using caffeine and bicuculline supported the possible involvement of adenosine receptors in the sleep-promoting effects of FSD-LS, with partial contribution from GABA receptor activity. Overall, our study recommends FSD-LS as a potential source for the development of sleep-aiding therapeutics.
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With the global increase in life expectancy, there has been a rise in the incidence of cognitive impairments attributed to diverse etiologies. Notably, approximately 50% of individuals diagnosed with mild cognitive impairment (MCI) progress to dementia within 3 years. However, the precise mechanisms underlying MCI remain elusive. Therefore, this study aimed to elucidate potential mechanisms implicated in MCI utilizing Per2 knockout (KO) mice, which have previously been shown to have cognitive deficits. Behavioral (Y-maze, Barnes maze) and molecular (electrophysiology, RNA sequencing, western blot, and immunofluorescence) experiments were conducted in Per2 KO and wild-type (WT) mice. Per2 KO mice exhibited impaired spatial working memory in the Y-maze and Barnes maze. However, there were no significant group differences in hippocampal long-term potentiation (LTP) between Per2 KO and WT mice, whereas striatal LTP in Per2 KO mice was lower compared to WT mice. In RNA sequencing analysis, 58 genes were downregulated and 64 genes were upregulated in the striatum of Per2 KO mice compared to WT mice. Among the differentially expressed genes, four genes (Chrm2, EphB2, Htr1b, Oprm1) were identified. Optimal expression levels of EPHB2 and OPRM1 were found to significantly enhance cognitive performance in mice. Additionally, Per2 KO mice exhibited reduced EPHB2-NMDAR-LTP and OPRM-mTOR signaling, along with elevated amyloid beta (Aß) levels, when compared to WT mice. However, these alterations were reversed upon administration of morphine treatment. Striatal OPRM1-mTOR signaling, EPHB2-NMDAR-LTP signaling, and Aß expression levels may exert a combined effect on MCI under the control of Per2 expression.
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BACKGROUND: Musculoskeletal symptoms, such as neck pain and low back pain (LBP) are common after a traffic accident (TA). While motion-style acupuncture treatment (MSAT) is effective in relieving pain, MSAT using traction (T-MSAT) has rarely been studied, and evidence for its efficacy and safety is lacking. To address this gap, this study aimed to assess the effectiveness and safety of T-MSAT for pain and functional disturbances in patients with acute LBP caused by a TA. METHODS: This two-armed, parallel, assessor blinded randomized controlled trial, conducted at Jaseng Hospital of Korean Medicine, included 100 patients with acute LBP occurring within 1 week of a TA. The participants were randomly allocated (1:1 ratio) to receive either combined T-MSAT and integrative Korean medicine treatment (IKMT) or only conventional IKMT, applied for 3 consecutive days after admission. The primary outcome was the difference between numerical rating scale (NRS) scores for LBP at baseline and after treatment completion on day 4 after admission. RESULTS: At the primary endpoint, the difference in NRS scores for LBP between the T-MSAT and control groups was 0.94 (95% confidence interval [CI] 0.40-1.48). The T-MSAT group showed a significantly lower NRS score for LBP than the control group. Differences in visual analogue scale (VAS) scores between the T-MSAT and control groups were significant at baseline and discharge. The area under the curve of the VAS score showed a significant difference (-46.86 [95% CI -85.13 to -8.59]), indicating faster pain reduction in the T-MSAT group than in the control group. Recovery (30% pain reduction) was achieved more rapidly in the T-MSAT group than in the control group (log-rank test Pâ =â .005). Meanwhile, the NRS, VAS, Oswestry disability index, and quality of life scores at discharge or at the 12-week follow-up showed no significant difference. The rates of mild adverse events (AEs) were comparable between the groups. No severe AEs were reported, and none of the AEs were associated with the clinical trial. CONCLUSIONS: T-MSAT combined with IKMT is a safe treatment that can effectively and quickly reduce initial pain in patients with LBP.
Assuntos
Acidentes de Trânsito , Terapia por Acupuntura , Dor Lombar , Tração , Humanos , Dor Lombar/terapia , Masculino , Feminino , Terapia por Acupuntura/métodos , Terapia por Acupuntura/efeitos adversos , Pessoa de Meia-Idade , Tração/métodos , Adulto , Resultado do Tratamento , Medição da Dor , Método Simples-CegoRESUMO
Improved out-coupling efficiency and low haze of organic light-emitting diode (OLED) lighting with an auxiliary electrode are demonstrated by selective microlens arrays (SMLAs). The microlens arrays, aligned with the auxiliary electrode, were selectively fabricated, since the fully packed microlens arrays lead to OLED lighting with high haze. The external quantum efficiency and power efficiency of the devices with the SMLAs increased by 32% when compared with the devices without these arrays. Using the SMLAs, dark grid lines in the emission region became brighter, with a low haze, and the spectra of the emitted light had no shift.
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G-protein coupled receptor 43 (GPR43) serves as a receptor for short-chain fatty acids (SCFAs), implicated in neutrophil migration and inflammatory cytokine production. However, the intracellular signaling pathway mediating GPR43 signaling remains unclear. Here, we show that ß-arrestin 2 mediates the internalization of GPR43 by agonist. Agonism of GPR43 reduced the phosphorylation and nuclear translocation of nuclear factor-κB (NF-κB), which was relieved by short interfering RNA (siRNA) of ß-arrestin 2. Subsequently, mRNA expression of proinflammatory cytokines, interleukin (IL)-6 and IL-1ß, was downregulated by activation of GPR43 and knockdown of ß-arrestin 2 recovered the expression of the cytokines. Taken together, these results suggest that GPR43 may be a plausible target for a variety of inflammatory diseases.
Assuntos
Arrestinas/metabolismo , NF-kappa B/metabolismo , Receptores de Superfície Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , beta-Arrestina 2 , beta-ArrestinasRESUMO
Diacylglycerol acyltransferase 2 (DGAT2) is one of two distinct DGAT enzymes that catalyze the last step in triacylglycerol (TG) synthesis. Findings from previous studies suggest that inhibition of DGAT2 is a promising strategy for the treatment of hepatic steatosis and insulin resistance. Here, we identified compound 122 as a potent and selective inhibitor of human DGAT2, which appeared to act competitively against oleoyl-CoA in vitro. The selective inhibition of DGAT2 was also confirmed by the reductions in enzymatic activity and de novo TG synthesis in DGAT2-overexpressing HEK293 cells and hepatic cells HepG2. Compound 122, as a newly identified inhibitor of DGAT2, will be useful for the research on DGAT2-related lipid metabolism as well as the development of therapeutic drug for several metabolic diseases.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Diacilglicerol O-Aciltransferase/genética , Inibidores Enzimáticos/química , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Células Sf9 , Bibliotecas de Moléculas Pequenas/química , Spodoptera , Relação Estrutura-Atividade , TransfecçãoRESUMO
Background: Alcohol is one of the most commonly used psychoactive drugs. Due to its addictive characteristics, many people struggle with the side effects of alcohol. Korean Red Ginseng (KRG) is a traditional herbal medicine that is widely used to treat various health problems. However, the effects and mechanisms of KRG in alcohol-induced responses remain unclear. Therefore, the purpose of this study was to investigate the effects of KRG in alcohol-induced responses. Methods: We investigated two aspects: alcohol-induced addictive responses and spatial working memory impairments. To determine the effects of KRG in alcohol-induced addictive responses, we performed conditioned place preference tests and withdrawal symptom observations. To assess the effects of KRG in alcohol-induced spatial working memory impairment, Y-maze, Barnes maze, and novel object recognition tests were performed using mice after repeated alcohol and KRG exposure. To investigate the potential mechanism of KRG activity, gas chromatography-mass spectrometry and western blot analysis were performed. Results: KRG-treated mice showed dose-dependent restoration of impaired spatial working memory following repeated alcohol exposure. Furthermore, withdrawal symptoms to alcohol were reduced in mice treated with KRG and alcohol. The PKA-CREB signaling pathway was activated after alcohol administration, which was reduced by KRG. However, the levels of inflammatory cytokines were increased by alcohol and decreased by KRG. Conclusion: Taken together, KRG may alleviate alcohol-induced spatial working memory impairments and addictive responses through anti-neuroinflammatory activity rather than through the PKA-CREB signaling pathway.
RESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there is no cure for IPF, the development of drugs with improved efficacy in the treatment of IPF is required. Daphnetin, a natural coumarin derivative, has immunosuppressive, anti-inflammatory, and antioxidant activities. However, its antifibrotic effects have not yet been elucidated. In this study, we investigated the antifibrotic effects of daphnetin on pulmonary fibrosis and the associated molecular mechanism. We examined the effects of daphnetin on splenocytes cultured in Th17 conditions, lung epithelial cells, and a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. We identified that daphnetin inhibited IL-17A production in developing Th17 cells. We also found that daphnetin suppressed epithelial-to-mesenchymal transition (EMT) in TGF-ß-treated BEAS2B cells through the regulation of AKT phosphorylation. In BLM-treated mice, the oral administration of daphnetin attenuated lung histopathology and improved lung mechanical functions. Our findings clearly demonstrated that daphnetin inhibited IL-17A and EMT both in vitro and in vivo, thereby protecting against BLM-induced pulmonary fibrosis. Taken together, these results suggest that daphnetin has potent therapeutic effects on lung fibrosis by modulating both Th17 differentiation and the TGF-ß signaling pathway, and we thus expect daphnetin to be a drug candidate for the treatment of IPF.