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1.
Int J Mol Sci ; 22(21)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34769159

RESUMO

Mori Ramulus, the dried twigs of Morus alba L., has been attracting attention for its potent antioxidant activity, but its role in muscle cells has not yet been elucidated. The purpose of this study was to evaluate the protective effect of aqueous extracts of Mori Ramulus (AEMR) against oxidative stress caused by hydrogen peroxide (H2O2) in C2C12 mouse myoblasts, and in dexamethasone (DEX)-induced muscle atrophied models. Our results showed that AEMR rescued H2O2-induced cell viability loss and the collapse of the mitochondria membrane potential. AEMR was also able to activate AMP-activated protein kinase (AMPK) in H2O2-treated C2C12 cells, whereas compound C, a pharmacological inhibitor of AMPK, blocked the protective effects of AEMR. In addition, H2O2-triggered DNA damage was markedly attenuated in the presence of AEMR, which was associated with the inhibition of reactive oxygen species (ROS) generation. Further studies showed that AEMR inhibited cytochrome c release from mitochondria into the cytoplasm, and Bcl-2 suppression and Bax activation induced by H2O2. Furthermore, AEMR diminished H2O2-induced activation of caspase-3, which was associated with the ability of AEMR to block the degradation of poly (ADP-ribose) polymerase, thereby attenuating H2O2-induced apoptosis. However, compound C greatly abolished the protective effect of AEMR against H2O2-induced C2C12 cell apoptosis, including the restoration of mitochondrial dysfunction. Taken together, these results demonstrate that AEMR could protect C2C12 myoblasts from oxidative damage by maintaining mitochondrial function while eliminating ROS, at least with activation of the AMPK signaling pathway. In addition, oral administration of AEMR alleviated gastrocnemius and soleus muscle loss in DEX-induced muscle atrophied rats. Our findings support that AEMR might be a promising therapeutic candidate for treating oxidative stress-mediated myoblast injury and muscle atrophy.

2.
Int J Mol Sci ; 22(20)2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34681914

RESUMO

Insulin-like growth factor-1 (IGF-1) primarily increases the release of gamma-aminobutyric acid (GABA) in neurons; moreover, it is responsible for the promotion of longitudinal growth in children and adolescents. Therefore, in this study, we investigated whether exogenous GABA supplementation activates IGF-mediated growth performance. Zebrafish larvae treated with GABA at three days post fertilization (dpf) showed a significant increase in the total body length from 6 to 12 dpf through upregulation of growth-stimulating genes, including IGF-1, growth hormone-1 (GH-1), growth hormone receptor-1 (GHR-1), and cholecystokinin A (CCKA). In particular, at 9 dpf, GABA increased total body length from 3.60 ± 0.02 to 3.79 ± 0.03, 3.89 ± 0.02, and 3.92 ± 0.04 mm at concentrations of 6.25, 12.5, and 25 mM, and the effect of GABA at 25 mM was comparable to 4 mM ß-glycerophosphate (GP)-treated larvae (3.98 ± 0.02 mm). Additionally, the highest concentration of GABA (50 mM) -induced death in 50% zebrafish larvae at 12 dpf. GABA also enhanced IGF-1 expression and secretion in preosteoblast MC3T3-E1 cells, concomitant with high levels of the IGF-1 receptor gene (IGF-1R). In zebrafish larvae, the GABA-induced growth rate was remarkably decreased in the presence of an IGF-1R inhibitor, picropodophyllin (PPP), which indicates that GABA-induced IGF-1 enhances growth rate via IGF-1R. Furthermore, we investigated the effect of GABA receptors on growth performance along with IGF-1 activation. Inhibitors of GABAA and GABAB receptors, namely bicuculline and CGP 46381, respectively, considerably inhibited GABA-induced growth rate in zebrafish larvae accompanied by a marked decrease in the expression of growth-stimulating genes, including IGF-1, GH-1, GHR-1, and CCKA, but not with an inhibitor of GABAC receptor, TPMPA. Additionally, IGF-1 and IGF-1R expression was impaired in bicuculline and CGP 46381-treated MC3T3-E1 cells, but not in the cells treated with TPMPA. Furthermore, treatment with bicuculline and CGP 46381 significantly downregulated GABA-induced IGF-1 release in MC3T3-E1 cells. These data indicate that GABA stimulates IGF-1 release via GABAA and GABAB receptors and leads to growth promotion performance via IGF-1R.

3.
Pharmaceutics ; 13(10)2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34683920

RESUMO

Isoalantolactone (IALT) is one of the isomeric sesquiterpene lactones isolated from the roots of Inula helenium L. IALT is known to possess various biological and pharmacological activities, but its anti-cancer mechanisms are not well understood. The aim of the present study was to investigate the anti-proliferative effects of IALT in human hepatocellular carcinoma (HCC) cells and to evaluate the potential anti-cancer mechanisms. Our results demonstrated that IALT treatment concentration-dependently suppressed the cell survival of HCC Hep3B cells, which was associated with the induction of apoptosis. IALT increased the expression of death-receptor-related proteins, activated caspases, and induced Bid truncation, subsequently leading to cleavage of poly (ADP-ribose) polymerase. In addition, IALT contributed to the cytosolic release of cytochrome c by destroying mitochondrial integrity, following an increase in the Bax/Bcl-2 expression ratio. However, IALT-mediated growth inhibition and apoptosis were significantly attenuated in the presence of a pan-caspase inhibitor, suggesting that IALT induced caspase-dependent apoptosis in Hep3B cells. Moreover, IALT activated the mitogen-activated protein kinases signaling pathway, and the anti-cancer effect of IALT was significantly diminished in the presence of a potent c-Jun N-terminal kinase (JNK) inhibitor. IALT also improved the generation of intracellular reactive oxygen species (ROS), whereas the ROS inhibitor significantly abrogated IALT-induced growth reduction, apoptosis, and JNK activation. Furthermore, ROS-dependent apoptosis was revealed as a mechanism involved in the anti-cancer activity of IALT in a 3D multicellular tumor spheroid model of Hep3B cells. Taken together, our findings indicate that IALT exhibited anti-cancer activity in HCC Hep3B cells by inducing ROS-dependent activation of the JNK signaling pathway.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34639412

RESUMO

Nurses are vulnerable to mental health challenges, including burnout, as they are exposed to adverse job conditions such as high workload. The mental health of this population can relate not only to individual well-being but also to patient safety outcomes. Therefore, there is a need for a mental health improvement strategy that targets this population. This cross-sectional survey study investigates emotional labor, burnout, turnover intention, and medical error levels among 117 nursing staff members in a South Korean university hospital; it also analyzes correlations among outcomes and conduct correlation analysis and multiple regression analysis to determine relationships among these factors. The participants had moderate to high levels of emotional labor and burnout, and 23% had experienced medical errors within the last six months. Save for medical errors, all outcomes significantly and positively correlated with each other. These results can be used to improve the mental health outcomes of nurses working in the hospital and their consequences. Specifically, the job positions of nursing personnel may be a major consideration in such a strategy, and job-focused emotional labor and employee-focused emotional labor may be promising targets in ameliorating turnover intention and client-related burnout, respectively.


Assuntos
Esgotamento Profissional , Recursos Humanos de Enfermagem no Hospital , Esgotamento Profissional/epidemiologia , Estudos Transversais , Hospitais Universitários , Humanos , Intenção , Satisfação no Emprego , Erros Médicos , República da Coreia , Inquéritos e Questionários , Local de Trabalho
5.
Antioxidants (Basel) ; 10(9)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34573124

RESUMO

Fine particulate matter (PM2.5) originates from the combustion of coal and is found in the exhaust of fumes of diesel vehicles. PM2.5 readily penetrates the skin via the aryl hydrocarbon receptor, causing skin senescence, inflammatory skin diseases, DNA damage, and carcinogenesis. In this study, we investigated whether fisetin, a bioactive flavonoid, prevents PM2.5-induced apoptosis in HaCaT human keratinocytes. The results demonstrated that fisetin significantly downregulated PM2.5-induced apoptosis at concentrations below 10 µM. Fisetin strongly inhibited the production of reactive oxygen species (ROS) and the expression of pro-apoptotic proteins. The PM2.5-induced apoptosis was associated with the induction of the endoplasmic reticulum (ER) stress response, mediated via the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4)-CCAAT-enhancer-binding protein (C/EBP) homologous protein (CHOP) axis. Additionally, the cytosolic Ca2+ levels were markedly increased following exposure to PM2.5. However, fisetin inhibited the expression of ER stress-related proteins, including 78 kDa glucose-regulated protein (GRP78), phospho-eIF2α, ATF4, and CHOP, and reduced the cytosolic Ca2+ levels. These data suggest that fisetin inhibits PM2.5-induced apoptosis by inhibiting the ER stress response and production of ROS.

6.
Nutrients ; 13(9)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34578864

RESUMO

Particulate matter 2.5 (PM2.5) may aggravate dry eye disease (DED). Corni Fructus (CF), which is fruit of Cornus officinalis Sieb. et Zucc., has been reported to have various beneficial pharmacological effects, whereas the effect of CF on the eye is still unknown. Therefore, in this study, we investigated the effect of oral administration of water extract of CF (CFW) on the eye, hematology, and biochemistry in a DED model induced by topical exposure to PM2.5. Furthermore, the efficacy of CFW compared with cyclosporine (CsA), an anti-inflammatory agent, and lutein, the posterior eye-protective agent. Sprague-Dawley rats were topically administered 5 mg/mL PM2.5 in both eyes four times daily for 14 days. During the same period, CFW (200 mg/kg and 400 mg/kg) and lutein (4.1 mg/kg) were orally administered once a day. All eyes of rats in the 0.05% cyclosporine A (CsA)-treated group were topically exposed to 20 µL of CsA, twice daily for 14 days. Oral administration of CFW attenuated the PM2.5-induced reduction of tear secretion and corneal epithelial damage. In addition, CFW protected against goblet cell loss in conjunctiva and overexpression of inflammatory factors in the lacrimal gland following topical exposure to PM2.5. Furthermore, CFW markedly prevented PM2.5-induced ganglion cell loss and recovered the thickness of inner plexiform layer. Meanwhile, CFW treatment decreased the levels of total cholesterol and low-density lipoprotein cholesterol in serum induced by PM2.5. Importantly, the efficacy of CFW was superior or similar to that of CsA and lutein. Taken together, oral administration of CFW may have protective effects against PM2.5-induced DED symptoms via stabilization of the tear film and suppression of inflammation. Furthermore, CFW may in part contribute to improving retinal function and lipid metabolism disorder.

7.
Pharmaceutics ; 13(9)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575516

RESUMO

Air pollutants, especially ambient fine particulate matter2.5, may contribute to various ocular surface disorders, including dry eye disease, keratitis and conjunctivitis. A natural polyamine spermidine has a protective effect on the retina and optic nerve; however, no study has been conducted on the application of spermidine in particulate matter2.5-induced dry eye disease. In the present study, we investigated the effect of spermidine eye drops in topically exposed particulate matter2.5-induced dry eye models of Sprague-Dawley rats, by hematological, biochemical and histological evaluation. Spermidine eye drops attenuated the particulate matter2.5 exposure-induced reduction of tear secretion and corneal epithelial damage. Furthermore, spermidine protected against conjunctival goblet cell loss and retinal ganglion cell loss induced by particulate matter2.5. Additionally, spermidine markedly prevented particulate matter2.5-induced infiltration of cluster of differentiation3+ and cluster of differentiation4+ T lymphocytes and F4/80+ macrophages on lacrimal gland. Moreover, over expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6 and interleukin-17 in the lacrimal gland and cornea. Meanwhile, the levels of serum total cholesterol and low-density lipoprotein cholesterol were markedly increased by topical exposure to particulate matter2.5, but this change in the lipid profile was decreased by spermidine. Taken together, spermidine may have protective effects against particulate matter2.5-induced dry eye symptoms via stabilization of the tear film and suppression of inflammation and may in part contribute to improving retinal function and lipid metabolism disorder.

8.
Genes Genomics ; 43(11): 1259-1268, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34427872

RESUMO

BACKGROUND: Rock bream iridovirus (RBIV) is one of the most dangerous pathogens that causes the highest mortality in the aquaculture of rock bream (Oplegnathus fasciatus). Even though RBIV infection leads to huge economic loss, proteome studies on RBIV-infected rock bream have not been conducted to provide information about the differential protein expression pattern by the host protection system. OBJECTIVE: The purpose of this study was to investigate the protein expression patterns in spleens of rock bream olive after infection by RBIV or mixed infection by RBIV and bacteria. METHODS: Depending on the infection intensity and sampling time point, fish were divided into five groups: uninfected healthy fish at week 0 as the control (0C), heavily infected fish at week 0 (0H), heavily mixed RBIV and bacterial infected fish at week 0 (0MH), uninfected healthy fish at week 3 (3C), and lightly infected fish at week 3 (3L). Proteins were extracted from the spleens of infected rock bream. We used 2-DE analysis with LC-MS/MS to investigate proteome changes in infected rock bream. RESULTS: The results of the LC-MS/MS analyses showed different protein expression profiles after infection. Proteins related to oxygen transport and energy generation, such as hemoglobin, beta-globin, and ATP synthase, were mostly expressed in the infected spleen. Whereas proteins involved in structure and cell movement, such as tubulin, myosin, actin binding proteins, and intermediate filament proteins, were down-regulated in the infected spleens. The protein expression profiles between infection by RBIV and mixed infection by RBIV and bacteria showed similar patterns. CONCLUSIONS: Our results indicated that infection by RBIV or mixed infection by RBIV and bacteria triggered energy generation and oxygen-transport, but cell migration and constructional changes in the spleen were extremely decreased.

9.
Phytomedicine ; 91: 153721, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34461423

RESUMO

BACKGROUND: The bark and petal of Hibiscus syriacus L. (Malvaceae) have been used to relieve pain in traditional Korean medicine. Recently, we identified anthocyanin-enriched polyphenols from the petal of H. syriacus L. (AHs) and determined its anti-melanogenic, anti-inflammatory, and anti-oxidative properties. Nevertheless, the osteogenic potential of AHs remains unknown. PURPOSE: This study was aimed to investigating the effect of AHs on osteoblast differentiation and osteogenesis in osteoblastic cell lines and zebrafish larvae. Furthermore, we investigated whether AHs ameliorates prednisolone (PDS)-induced osteoporosis. STUDY DESIGN AND METHODS: Cell viability was assessed by cellular morphology, MTT assay, and flow cytometry analysis, and osteoblast differentiation was measured alizarin red staining, alkaline phosphatase (ALP) activity, and osteoblast-specific marker expression. Osteogenic and anti-osteoporotic effects of AHs were determined in zebrafish larvae. RESULTS: AHs enhanced calcification and ALP activity concomitant with the increased expression of osterix (OSX), runt-related transcription factor 2 (RUNX2), and ALP in MC3T3-E1 preosteoblast and MG-63 osteosarcoma cells. Additionally, AHs accelerated vertebral formation and mineralization in zebrafish larvae, concurrent with the increased expression of OSX, RUNX2a, and ALP. Furthermore, PDS-induced loss of osteogenic activity and vertebral formation were restored by treatment with AHs, accompanied by a significant recovery of calcification, ALP activity, and osteogenic marker expression. Molecular docking studies showed that 16 components in AHs fit to glucagon synthase kinase-3ß (GSK-3ß); particularly, isovitexin-4'-O-glucoside most strongly binds to the peptide backbone of GSK-3ß at GLY47(O), GLY47(N), and ASN361(O), with a binding score of -7.3. Subsequently, AHs phosphorylated GSK-3ß at SER9 (an inactive form) and released ß-catenin into the nucleus. Pretreatment with FH535, a Wnt/ß-catenin inhibitor, significantly inhibited AH-induced vertebral formation in zebrafish larvae. CONCLUSION: AHs stimulate osteogenic activities through the inhibition of GSK-3ß and subsequent activation of ß-catenin, leading to anti-osteoporosis effects.


Assuntos
Antocianinas , Hibiscus , Osteogênese/efeitos dos fármacos , Osteoporose , Polifenóis , Animais , Antocianinas/farmacologia , Glicogênio Sintase Quinase 3 beta , Hibiscus/química , Simulação de Acoplamento Molecular , Osteoblastos/metabolismo , Osteoporose/tratamento farmacológico , Polifenóis/farmacologia , Via de Sinalização Wnt , Peixe-Zebra/metabolismo , beta Catenina/metabolismo
10.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361022

RESUMO

Gamma-aminobutyric acid (GABA) is considered the primary inhibitory neurotransmitter in the human cortex. However, whether GABA regulates melanogenesis has not been comprehensively elucidated. In this study, we reveal that GABA (20 mM) significantly inhibited α-melanocyte-stimulating hormone (α-MSH)-induced extracellular (from 354.9% ± 28.4% to 126.5% ± 16.0%) and intracellular melanin contents (from 236.7% ± 11.1% to 102.7% ± 23.1%) in B16F10 melanoma cells, without inducing cytotoxicity. In addition, α-MSH-induced hyperpigmentation in zebrafish larvae was inhibited from 246.3% ± 5.4% to 116.3% ± 3.1% at 40 mM GABA, displaying no apparent cardiotoxicity. We also clarify that the GABA-mediated antimelanogenic properties were related to the direct inhibition of microphthalmia-associated transcription factor (MITF) and tyrosinase expression by inhibiting cyclic adenosine monophosphate (cAMP) and cAMP response element-binding protein (CREB). Furthermore, under α-MSH stimulation, GABA-related antimelanogenic effects were mediated through the GABAA and GABAB receptors, with subsequent inhibition of Ca2+ accumulation. In B16F10 melanoma cells and zebrafish larvae, pretreatment with bicuculline, a GABAA receptor antagonist, and CGP 46381, a GABAB receptor antagonist, reversed the antimelanogenic effect of GABA following α-MSH treatment by upregulating Ca2+ accumulation. In conclusion, our results indicate that GABA inhibits α-MSH-induced melanogenesis. Hence, in addition to the health benefits of GABA in the central nervous system, it could ameliorate hyperpigmentation disorders.


Assuntos
Melaninas/biossíntese , Receptores de GABA-B/metabolismo , alfa-MSH/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Sinalização do Cálcio , Linhagem Celular Tumoral , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Humanos , Fator de Transcrição Associado à Microftalmia/metabolismo , Monofenol Mono-Oxigenase/metabolismo , Receptores de GABA-A/metabolismo , Peixe-Zebra
11.
Artigo em Inglês | MEDLINE | ID: mdl-34444604

RESUMO

The mental health of nurses including burnout is an important issue. The purpose of this systematic review was to evaluate whether mind-body modalities improve burnout and other mental health aspects of nurses. A comprehensive search was conducted using six electronic databases. Randomized controlled trials using mind-body modalities on the mental health of nurses, up to January 2021, were included. The methodological quality of the included studies was assessed using the Cochrane Risk of Bias tool. Seventeen studies were included in the review. Data on mindfulness-based interventions (MBIs) and yoga were available for burnout, and there was no evidence that multimodal resilience programs including MBIs statistically significantly improved burnout levels compared to no intervention or active control groups. However, one study reported that yoga could significantly improve emotional exhaustion and depersonalization, which are subscales of burnout, compared to usual care. In addition, the effects of MBIs, relaxation, yoga, and music on various mental health outcomes and stress-related symptoms have been reported. In conclusion, there was some evidence that yoga was helpful for improvement in burnout of nurses. However, due to the heterogeneity of interventions and outcomes of the studies included, further high-quality clinical trials are needed on this topic in the future.


Assuntos
Atenção Plena , Enfermeiras e Enfermeiros , Ioga , Hospitais , Humanos , Saúde Mental
12.
Antioxidants (Basel) ; 10(8)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34439462

RESUMO

Fisetin has numerous therapeutic properties, such as anti-inflammatory, antioxidative, and anticancer effects. However, the mechanism by which fisetin inhibits NLRP3 inflammasome remains unclear. In this study, we observed that fisetin bound to TLR4 and occluded the hydrophobic pocket of MD2, which in turn inhibited the binding of LPS to the TLR4/MD2 complex. This prevented the initiation of scaffold formation by the inhibition of MyD88/IRAK4 and subsequently downregulated the NF-κB signaling pathway. The result also demonstrated that fisetin downregulated the activation of the NLRP3 inflammasome induced by LPS and ATP (LPS/ATP) and the subsequent maturation of IL-1ß. Fisetin also activated mitophagy and prevented the accumulation of damaged mitochondria and the excessive production of mitochondrial reactive oxygen species. The transient knockdown of p62 reversed the inhibitory activity of fisetin on the LPS/ATP-induced formation of the NLRP3 inflammasome. This indicated that fisetin induces p62-mediated mitophagy for eliminating damaged mitochondria. Recently, the existence of inflammasomes in non-mammalian species including zebrafish have been identified. Treatment of an LPS/ATP-stimulated zebrafish model with fisetin aided the recovery of the impaired heart rate, decreased the recruitment of macrophage to the brain, and gradually downregulated the expression of inflammasome-related genes. These results indicated that fisetin inhibited the TLR4/MD2-mediated activation of NLRP3 inflammasome by eliminating damaged mitochondria in a p62-dependent manner.

13.
Genes Genomics ; 43(12): 1381-1388, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34436741

RESUMO

BACKGROUND: Previously, we identified eight novel minisatellites in the MUC2, of which allelic variants in MUC2-MS6 were examined to influence susceptibility to gastric cancer. However, studies on the susceptibility to gastrointestinal cancer of other minisatellites in the MUC2 region still remain unprogressive. OBJECTIVE: In this study, we investigated whether polymorphic variations in the MUC2-MS8 region are related to susceptibility to gastrointestinal cancer. METHODS: We assessed the association between MUC2-MS8 and gastrointestinal cancers by a case-control study with 1229 controls, 486 gastric cancer cases, 220 colon cancer cases and 278 rectal cancer cases. To investigate whether intronic minisatellites affect gene expression, various minisatellites were inserted into the luciferase-reporter vector and their expression levels were examined. We also examined the length of MUC2-MS8 alleles in blood and cancer tissue matching samples of 107 gastric cancer patients, 125 colon cancer patients, and 85 rectal cancer patients, and investigated whether the repeat sequence affects genome instability. RESULTS: A statistically significant association was identified between rare MUC2-MS8 alleles and the occurrence of rectal cancer: odds ratio (OR), 6.66; 95% confidence interval (CI), 1.11-39.96; and P = 0.0165. In the younger group (age, < 55), rare alleles were significant associated with an increased risk of rectal cancer (odds ratio, 24.93 and P = 0.0001). Suppression of expression was found in the reporter vector inserted with minisatellites, and loss of heterozygosity (LOH) of the MUC2-MS8 region was confirmed in cancer tissues of gastrointestinal cancer patients (0.8-5.9%). CONCLUSION: Our results suggest that the rare alleles of MUC2-MS8 could be used to identify the risk of rectal cancer and that this repeat region is related to genomic instability.

14.
EXCLI J ; 20: 968-982, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267609

RESUMO

Inflammation caused by the excessive production of pro-inflammatory mediators and cytokines in abnormally activated macrophages promotes the initiation and progression of many diseases along with oxidative stress. Previous studies have suggested that nargenicin A1, an antibacterial macrolide isolated from Nocardia sp. may be a potential treatment for inflammatory responses and oxidative stress, but the detailed mechanisms are still not well studied. In this study, we investigated the inhibitory effect of nargenicin A1 on inflammatory and oxidative stress in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and zebrafish (Danio rerio) models. Our results indicated that nargenicin A1 treatment significantly inhibited LPS-induced release of pro-inflammatory mediators including nitric oxide (NO) and prostaglandin E2, which was associated with decreased inducible NO synthase and cyclooxygenase-2 expression. In addition, nargenicin A1 attenuated the LPS-induced expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and monocyte chemotactic protein-1, reducing their extracellular secretion. Nargenicin A1 also suppressed LPS-induced generation of reactive oxygen species. Moreover, nargenicin A1 abolished the LPS-mediated nuclear translocation of nuclear factor-kappa B (NF-κB) and the degradation of inhibitor IκB-α, indicating that nargenicin A1 exhibited anti-inflammatory effects by inhibiting the NF-κB signaling pathway. Furthermore, nargenicin A1 showed strong protective effects against NO and ROS production in LPS-injected zebrafish larvae. In conclusion, our findings suggest that nargenicin A1 ameliorates LPS-induced anti-inflammatory and antioxidant effects by downregulating the NF-κB signaling pathway, and that nargenicin A1 can be a potential functional agent to prevent inflammatory- and oxidative-mediated damage.

15.
Anim Cells Syst (Seoul) ; 25(2): 119-127, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234893

RESUMO

Although previous studies have shown anti-cancer activity of betulinic acid (BA), a pentacyclic triterpenoid, against various cancer lines, the underlying molecular mechanisms are not well elucidated. In this study, we evaluated the mechanisms involved in the anti-cancer efficacy of BA in U937 human myeloid leukemia cells. BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA. The down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA. In addition, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio. BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase. However, quenching of ROS by N-acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment. Taken together, our results provide a mechanistic rationale that BA exhibits anti-cancer properties in U937 leukemia cells through ROS-dependent induction of cell cycle arrest at G2/M phase and apoptosis.

16.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299326

RESUMO

Ziziphus jujuba extracts possess a broad spectrum of biological activities, such as antioxidant and anticancer activities in melanoma cancers. Nevertheless, the compounds contain high antioxidant capacities and anticancer activities in melanoma cells, shown to be effective in hyperpigmentation disorders, but whether flavonoid glycosides from Z. jujuba regulate anti-melanogenesis remains unclear. In this study, we evaluated the anti-melanogenic activity of five flavonoid glycosides from Z. jujuba var. inermis (Bunge) Rehder seeds, including jujuboside A (JUA), jujuboside B (JUB), epiceanothic acid (EPA), betulin (BTL), and 6'''-feruloylspinosin (FRS), in B16F10 melanoma cells and zebrafish larvae. According to our results, JUB, EPA, and FRS potently inhibited α-melanocyte-stimulating hormone (α-MSH)-induced melanogenesis and prevented hyperpigmentation in zebrafish larvae. In particular, under α-MSH-stimulated conditions, FRS most significantly inhibited α-MSH-induced intracellular and extracellular melanin content in B16F10 melanoma cells. Additionally, JUB, EPS, and FRS remarkably downregulated melanogenesis in α-MSH-treated zebrafish larvae, with no significant change in heart rate. Neither JUA nor BTA were effective in downregulating melanogenesis in B16F10 melanoma cells and zebrafish larvae. Furthermore, JUB, EPA, and FRS directly inhibited in vitro mushroom tyrosinase enzyme activity. JUB, EPA, and FRS also downregulated cyclic adenosine monophosphate (cAMP) levels and the phosphorylation of cAMP-response element-binding protein (CREB), and subsequent microphthalmia transcription factor (MITF) and tyrosinase expression. In conclusion, this study demonstrated that JUB, EPA, and FRS isolated from Z. jujuba var. inermis (Bunge) Rehder seeds exhibit potent anti-melanogenic properties by inhibition of the cAMP-CERB-MITF axis and consequent tyrosinase activity.


Assuntos
Flavonoides/farmacologia , Glicosídeos/farmacologia , Ziziphus/metabolismo , alfa-MSH/metabolismo , Animais , Antioxidantes/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Flavonoides/isolamento & purificação , Glicosídeos/isolamento & purificação , Larva , Melaninas/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma Experimental , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Sementes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra , alfa-MSH/antagonistas & inibidores
17.
Biochem Pharmacol ; 192: 114676, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256044

RESUMO

Fisetin is a bioactive flavonol that inhibits osteoclastogenesis and promotes osteoblastogenesis. However, the osteogenic activity of fisetin needs to be comprehensively elucidated. In the present study, we observed that fisetin significantly increased alkaline phosphatase (ALP) activity and bone mineralization in MC3T3-E1 preosteoblasts, accompanied by a significant increase in runt-related transcription factor 2 (RUNX2), ALP, collagen type Ⅰ alpha 1 (Col1α1), osterix (OSX), osteocalcin (OCN), and bone morphogenetic protein 4 (BMP4) expression. Furthermore, fisetin promoted vertebral formation in zebrafish larvae, with the highest fisetin concentration comparable with that observed in ß-glycerophosphate treatment. Fisetin also inhibited prednisolone (PDS)-induced anti-osteoblastic genes, including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), tartrate-resistant acid phosphatase-6 (ACP6), dendritic cell-specific transmembrane protein (DC-STAMP), and cathepsin K (CTSK). Fisetin potently mitigated the PDS-induced inhibition of ALP activity and bone mineralization, as well as vertebral resorption in zebrafish larvae. Moreover, we confirmed that fisetin-induced osteogenic effect was activated through phosphorylation of glycogen synthase kinase-3ß (GSK-3ß) at Ser9, consequently releasing ß-catenin from the destructive complex to promote its nuclear translocation. ß-Catenin inhibition by FH535 and the stabilization of GSK-3ß by DOI hydrochloride remarkably inhibited fisetin-induced osteogenic activities, indicating that the GSK-3ß/ß-catenin signaling pathway plays a vital role in fisetin-induced osteogenesis. Collectively, our findings suggest that fisetin stimulates osteogenic activity and could be used as an effective strategy to prevent bone resorption.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Flavonóis/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , beta Catenina/metabolismo , Animais , Animais Geneticamente Modificados , Diferenciação Celular/fisiologia , Linhagem Celular , Relação Dose-Resposta a Droga , Flavonóis/uso terapêutico , Camundongos , Osteogênese/fisiologia , Osteoporose/prevenção & controle , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Serina/metabolismo , Peixe-Zebra
18.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072916

RESUMO

Chronic inflammation, which is promoted by the production and secretion of inflammatory mediators and cytokines in activated macrophages, is responsible for the development of many diseases. Auranofin is a Food and Drug Administration-approved gold-based compound for the treatment of rheumatoid arthritis, and evidence suggests that auranofin could be a potential therapeutic agent for inflammation. In this study, to demonstrate the inhibitory effect of auranofin on chronic inflammation, a saturated fatty acid, palmitic acid (PA), and a low concentration of lipopolysaccharide (LPS) were used to activate RAW264.7 macrophages. The results show that PA amplified LPS signals to produce nitric oxide (NO) and various cytokines. However, auranofin significantly inhibited the levels of NO, monocyte chemoattractant protein-1, and pro-inflammatory cytokines, such as interleukin (IL)-1ß, tumor necrosis factor-α, and IL-6, which had been increased by co-treatment with PA and LPS. Moreover, the expression of inducible NO synthase, IL-1ß, and IL-6 mRNA and protein levels increased by PA and LPS were reduced by auranofin. In particular, the upregulation of NADPH oxidase (NOX) 4 and the translocation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) induced by PA and LPS were suppressed by auranofin. The binding between the toll-like receptor (TLR) 4 and auranofin was also predicted, and the release of NO and cytokines was reduced more by simultaneous treatment with auranofin and TLR4 inhibitor than by auranofin alone. In conclusion, all these findings suggested that auranofin had anti-inflammatory effects in PA and LPS-induced macrophages by interacting with TLR4 and downregulating the NOX4-mediated NF-κB signaling pathway.


Assuntos
Auranofina/farmacologia , Inflamação/tratamento farmacológico , NADPH Oxidase 4/genética , Receptor 4 Toll-Like/genética , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Camundongos , NF-kappa B/genética , Ácido Palmítico/toxicidade , Células RAW 264.7
19.
Biol Pharm Bull ; 44(6): 875-883, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34078820

RESUMO

Inflammation caused by the excessive secretion of inflammatory mediators in abnormally activated macrophages promotes many diseases along with oxidative stress. Loganin, a major iridoid glycoside isolated from Cornus officinalis, has recently been reported to exhibit anti-inflammatory and antioxidant effects, whereas the underlying mechanism has not yet been fully clarified. Therefore, the aim of the present study is to investigate the effect of loganin on inflammation and oxidative stress in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Our results indicated that loganin treatment markedly attenuated the LPS-mediated phagocytic activity and release of nitric oxide (NO) and prostaglandin E2, which was associated with decreased the expression of inducible NO synthase and cyclooxygenase-2. In addition, loganin suppressed the expression and their extracellular secretion of LPS-induced pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1ß. Furthermore, loganin abolished reactive oxygen species (ROS) generation, and promoted the activation of nuclear factor-E2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in LPS-stimulated macrophages. However, zinc protoporphyrin, a selective HO-1 inhibitor, reversed the loganin-mediated suppression of pro-inflammatory cytokines in LPS-treated macrophages. In conclusion, our findings suggest that the upregulation of the Nrf2/HO-1 signaling pathway is concerned at least in the protective effect of loganin against LPS-mediated inflammatory and oxidative stress, and that loganin can be a potential functional agent to prevent inflammatory and oxidative damage.

20.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068421

RESUMO

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) is a major obstacle in managing lung cancer. The root of Scutellaria baicalensis (SB) traditionally used for fever clearance and detoxification possesses various bioactivities including anticancer effects. The purpose of this study was to investigate whether SB exhibited anticancer activity in EGFR TKI-resistant lung cancer cells and to explore the underlying mechanism. We used four types of human lung cancer cell lines, including H1299 (EGFR wildtype; EGFR TKI-resistant), H1975 (acquired TKI-resistant), PC9/ER (acquired erlotinib-resistant), and PC9/GR (acquired gefitinib-resistant) cells. The ethanol extract of SB (ESB) decreased cell viability and suppressed colony formation in the four cell lines. ESB stimulated nuclear fragmentation and the cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3. Consistently, the proportion of sub-G1 phase cells and annexin V+ cells were significantly elevated by ESB, indicating that ESB induced apoptotic cell death in EGFR TKI-resistant cells. ESB dephosphorylated signal transducer and activator of transcription 3 (STAT3) and downregulated the target gene expression. The overexpression of constitutively active STAT3 reversed ESB-induced apoptosis, suggesting that ESB triggered apoptosis in EGFR TKI-resistant cells by inactivating STAT3. Taken together, we propose the potential use of SB as a novel therapeutic for lung cancer patients with EGFR TKI resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Extratos Vegetais/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Scutellaria baicalensis/química , Apoptose , Proliferação de Células , Receptores ErbB/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Raízes de Plantas/química , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas
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