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Castration-resistant prostate cancer (CRPC) nearly inevitably develops after long-term treatment with androgen deprivation therapy (ADT), leading to significant mortality. Investigating the mechanisms driving CRPC development is imperative. Here, we determined that the pioneer transcription factor GATA2, which is frequently amplified in CRPC patients, inhibits interferon (IFN)-ß-mediated antitumor immunity, thereby promoting CRPC progression. Employing a genetically engineered mouse model (GEMM), we demonstrated that GATA2 overexpression hindered castration-induced cell apoptosis and tumor shrinkage, facilitating tumor metastasis and CRPC development. Notably, GATA2 drives castration resistance predominantly via repressing castration-induced activation of IFN-ß signaling and CD8+ T-cell infiltration. This finding aligns with the negative correlation between GATA2 expression and IFNB1 expression, as well as CD8+ T-cell infiltration in CRPC patients. Mechanistically, GATA2 recruited PIAS1 as corepressor, and reprogramed the cistrome of IRF3, a key transcription factor of the IFN-ß axis, in an androgen-independent manner. Furthermore, we identified a novel silencer element that facilitated the function of GATA2 and PIAS1 through looping to the IFNB1 promoter. Importantly, depletion of GATA2 augmented antitumor immunity and attenuated CRPC development. Consequently, our findings elucidate a novel mechanism wherein GATA2 promotes CRPC progression by suppressing IFN-ß axis-mediated antitumor immunity, underscoring GATA2 as a promising therapeutic target for CRPC.
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Fator de Transcrição GATA2 , Interferon beta , Neoplasias de Próstata Resistentes à Castração , Animais , Humanos , Masculino , Camundongos , Linhagem Celular Tumoral , Fator de Transcrição GATA2/genética , Fator de Transcrição GATA2/metabolismo , Regulação Neoplásica da Expressão Gênica , Interferon beta/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Transdução de SinaisRESUMO
Panax ginseng (C.A. Mey.) has been traditionally employed in Korea and China to alleviate fatigue and digestive disorders. In particular, Korean red ginseng (KRG), derived from streamed and dried P. ginseng, is known for its anti-aging and anti-inflammatory properties. However, its effects on benign prostatic hyperplasia (BPH), a representative aging-related disease, and the underlying mechanisms remain unclear. This study aims to elucidate the therapeutic effects of KRG on BPH, with a particular focus on mitochondrial dynamics, including fission and fusion processes. The effects of KRG on cell proliferation, apoptosis, and mitochondrial dynamics and morphology were evaluated in a rat model of testosterone propionate (TP)-induced BPH and TP-treated LNCaP cells, with mdivi-1 as a control. The results revealed that KRG treatment reduced the levels of androgen receptors (AR) and prostate-specific antigens in the BPH group. KRG inhibited cell proliferation by downregulating cyclin D and proliferating cell nuclear antigen (PCNA) levels, and it promoted apoptosis by increasing the ratio of B-cell lymphoma protein 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 expression. Notably, KRG treatment enhanced the phosphorylation of dynamin-related protein 1 (DRP-1, serine 637) compared with that in the BPH group, which inhibited mitochondrial fission and led to mitochondrial elongation. This modulation of mitochondrial dynamics was associated with decreased cell proliferation and increased apoptosis. By dysregulating AR signaling and inhibiting mitochondrial fission through enhanced DRP-1 (ser637) phosphorylation, KRG effectively reduced cell proliferation and induced apoptosis. These findings suggest that KRG's regulation of mitochondrial dynamics offers a promising clinical approach for the treatment of BPH.
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Apoptose , Proliferação de Células , Dinaminas , Dinâmica Mitocondrial , Panax , Hiperplasia Prostática , Receptores Androgênicos , Transdução de Sinais , Animais , Humanos , Masculino , Ratos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dinaminas/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Panax/química , Extratos Vegetais/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Prostate cancer (PCa) is the second leading disease of cancer-related death in men around the world, and it is almost impossible to treat advanced PCa. OTUD7B is a member of the deubiquitinase family that undergoes a post-translational transformation process, which is essential for cell stability and signaling and is known to play a critical role in cancer. However, its role in PCa has not been discovered. The aim of the study was to investigate the expression and mechanism of OTUD7B in PCa cells. According to the database, high OTUD7B expression showed a poor prognosis. Therefore, we downregulated OTUD7B using siRNA and confirmed the role of OTUD7B in PC3 prostate cancer cells. OTUD7B knockdown effectively induced apoptosis and inhibited the proliferation in PC3 cells. OTUD7B knockdown inhibited autophagy through AKT/mTOR signaling. We also confirmed the relationship between AKT/mTOR signaling and autophagy through rapamycin, an mTOR inhibitor. Taken together, OTUD7B promotes the proliferation, and autophagy, and inhibits apoptosis of prostate cancer cells via the AKT/mTOR signaling pathway.
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PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.
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Autofagia , Transição Epitelial-Mesenquimal , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Autofagia/fisiologia , Autofagia/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Inativação Gênica , Camundongos Nus , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
First-line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti-CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody-drug conjugate, TE-1146, comprising six lenalidomide drug molecules site-specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE-1146 is prepared using the HighDAR platform, which employs i) a maleimide-containing "multi-arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+-binding cysteine at the C-termini of a reconfigured daratumumab for site-specific drug bundle conjugation. It is shown that TE-1146 remains intact and effectively enters CD38-expressing tumor cells, releasing lenalidomide, leading to enhanced cell-killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE-1146 precisely delivers lenalidomide to target CD38-overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc-dependent effector functions to kill tumor cells.
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Anticorpos Monoclonais , Imunoconjugados , Lenalidomida , Mieloma Múltiplo , Mieloma Múltiplo/tratamento farmacológico , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/química , Lenalidomida/farmacologia , Lenalidomida/uso terapêutico , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Camundongos , Animais , Modelos Animais de DoençasRESUMO
Purpose Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. Methods PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. Results In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. Conclusion Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.
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Cisplatin-induced acute kidney injury (AKI) is a clinical disease characterized by a sudden loss of renal function within a few hours or days, due to cisplatin uptake. Fulvestrant is an oestrogen receptor alpha (ERα) antagonist used for endocrine therapy. However, the role of fulvestrant in cisplatin-induced AKI remains unclear. In this study, we investigated the effects of fulvestrant on the regulation of apoptotic cell death and autophagic response in cisplatin-induced AKI. The human kidney proximal tubule epithelial cell line (HK-2) was co-treated with fulvestrant and cisplatin. C57BL/6 mice were subcutaneously injected with fulvestrant and cisplatin was administered via intraperitoneal injection. First, cisplatin treatment increased ERα expression, apoptosis, and autophagy in HK-2 cells. Fulvestrant treatment decreased apoptosis and autophagy, which were accompanied by cisplatin treatment in HK-2 cells. Consistent with in vitro results, cisplatin treatment significantly increased ERα expression in vivo. Additionally, cisplatin treatment increased renal injury, apoptosis, and autophagy. Surprisingly, compared to that in the cisplatin-treated mice group, reduced cisplatin-induced renal injury, apoptosis, and autophagy was observed in the cisplatin+fulvestrant-treated mice group. In summary, these results suggest that fulvestrant plays an important role in cisplatin-induced AKI by decreasing apoptosis and autophagy.
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BACKGROUND: An effective vaccine response is currently a critical issue in the control of COVID-19. Little is known about humoral and cellular immunity comparing protein-based vaccine with other types of vaccines. The relevance of basal immunity to antibody production is also unknown. METHODS: Seventy-eight individuals were enrolled in the study. The primary outcome were the level of spike-specific antibodies and neutralizing antibodies measured by ELISA. Secondary measures included memory T cells and basal immunity estimated by flow cytometry and ELISA. Correlations for all parameters were calculated using the nonparametric Spearman correlation method. RESULTS: We observed that two doses of mRNA-based Moderna mRNA-1273 (Moderna) vaccine produced the highest total spike-binding antibody and neutralizing ability against the wild-type (WT), Delta, and Omicron variants. The protein-based MVC-COV1901 (MVC) vaccine developed in Taiwan produced higher spike-binding antibodies against Delta and Omicron variants and neutralizing ability against the WT strain than the adenovirus-based AstraZeneca-Oxford AZD1222 (AZ) vaccine. Moderna and AZ vaccination produced more central memory T cells in PBMC than the MVC vaccine. However, the MVC vaccine had the lowest adverse effects compared to the Moderna and AZ vaccines. Surprisingly, the basal immunity represented by TNF-α, IFN-γ, and IL-2 prior to vaccination was negatively correlated with the production of spike-binding antibodies and neutralizing ability. CONCLUSION: This study compared memory T cells, total spike-binding antibody levels, and neutralizing capacity against WT, Delta, and Omicron variants between the MVC vaccine and the widely used Moderna and AZ vaccines, which provides valuable information for future vaccine development strategies.
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Vacinas contra COVID-19 , COVID-19 , Humanos , SARS-CoV-2 , ChAdOx1 nCoV-19 , Leucócitos Mononucleares , COVID-19/prevenção & controle , Vacinação , Anticorpos Neutralizantes , Imunidade Celular , Análise de Dados , Anticorpos AntiviraisRESUMO
The transport and ultimate fate of per- and polyfluoroalkyl substances (PFASs) are generally considered to be influenced by partitioning behavior between water, suspended particulate matters (SPM), and sediments. This study examined the distribution and partitioning of the PFASs in the water, SPM, and sediments in a densely populated urban river-coastal system. The total concentrations of eight PFASs (∑8 PFASs) in the water phase, SPM, and sediments varied from 0.59 to 7.40 ng/L, 0.54 to 9.08 ng/g, and 0.05 to 0.13 ng/g, respectively. The PFAS concentrations in the water and SPM phase decreased as the salinity increased, confirming contaminant inputs from the upstream of the river to the estuary zone. Notably, the positive correlation between SPM-bound PFASs and transparent exopolymer particles (TEPs) content, providing first evidence that TEPs may accumulate and concentrate more PFASs on the SPM. Collectively, this results offers useful information about roles of TEPs in determining environmental fate of PFASs.
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Fluorocarbonos , Poluentes Químicos da Água , Rios , Matriz Extracelular de Substâncias Poliméricas/química , Material Particulado/análise , Fluorocarbonos/análise , Poluentes Químicos da Água/análise , Monitoramento Ambiental , Água , China , Sedimentos GeológicosRESUMO
Benign prostatic hyperplasia (BPH) is an age-related disease, whose etiology largely remains unclear. The regulation of mitophagy plays a key role in aging and associated diseases, however, its function in BPH has not been studied. Although the expression of the androgen receptor is primarily implicated in BPH, the estrogen receptor (ER) has been reported to be involved in the development of BPH by mediating the proliferation of prostate cells. Here, we studied the involvement of mitophagy and ERs in spontaneous BPH in aging mice and investigated their functions. To identify the activation of mitophagy and expression of ERs, 8-week, 12-month, and 24-month-old mice were used. Mice were treated with mitochondrial division inhibitor mdivi-1, a dynamin-related protein 1 (Drp1) inhibitor, to examine the expression of mitophagy-related proteins and the development of BPH. In addition, prostate stromal cells were treated with an ER antagonist to investigate the regulation of mitophagy following the expression of ERs. With aging, the Drp1 and phosphorylation of parkin reduce. Electron microscopy revealed reduced mitochondrial fission and mitophagy. In addition, the expression of androgen receptor was decreased and that of ERα was increased in aged mice with BPH. Treatment with mdivi-1 exacerbated BPH and increased cell proliferation. In addition, blockade of ERα increased mitophagy and decreased cell proliferation. In conclusion, mitophagy is reduced with aging during the development of BPH. We speculate that spontaneous BPH progresses through the reduction in the expression of ERα in aged mice by downregulating mitophagy.
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Hiperplasia Prostática , Animais , Humanos , Masculino , Camundongos , Dinaminas/metabolismo , Receptor alfa de Estrogênio/metabolismo , Mitofagia , Hiperplasia Prostática/metabolismo , Receptores Androgênicos , Receptores de Estrogênio , Ubiquitina-Proteína LigasesRESUMO
Lethal giant larvae (Lgl) is an apical-basal polarity gene first identified in Drosophila. LLGL2 is one of the mammalian homologs of Lgl. However, little is known about its function in the prostate. In this study, to explore the new role of LLGL2 in the prostate, we examined the proliferative activity of a BPH-1 cell line, a well-established model for the human prostate biology of benign prostatic hyperplasia (BPH). The expression of LLGL2 was dose-dependently increased in BPH-1 cells after treatment with 17ß-estradiol (E2). Additionally, E2 treatment increased the proliferation of the BPH-1 cells. However, the knockdown of LLGL2 with siRNA significantly suppressed the proliferation of the E2-treated BPH-1 cells. Moreover, si-llgl2 treatment up-regulated the expression of LC-3B, ATG7, and p-beclin, which are known to play a pivotal role in autophagosome formation in E2-treated BPH-1 cells. Overexpression of LLGL2 was able to further prove these findings by showing the opposite results from the knockdown of LLGL2 in E2-treated BPH-1 cells. Collectively, our results suggest that LLGL2 is closely involved in the proliferation of prostate cells by regulating autophagosome formation. These results provide a better understanding of the mechanism involved in the effect of LLGL2 on prostate cell proliferation. LLGL2 might serve as a potential target in the diagnosis and/or treatment of human BPH.
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Benign prostatic hyperplasia (BPH) is a chronic male disease characterized by the enlarged prostate. Celtis chosenianaNakai (C. choseniana) is medicinally used to alleviate pain, gastric disease, and lung abscess. In this study, the effect of C. choseniana extract on BPH was investigated using testosterone-induced rats. Sprague Dawley rats were divided into five groups: control, BPH (testosterone 5 mg·kg-1), Fina (finasteride 2 mg·kg-1), and C. choseniana (50 and 100 mg·kg-1). After four weeks of TP treatment with finasteride or C. choseniana, prostate weights and DHT levels were measured. In addition, the prostates were histopathologically examined and measured for protein kinase B (Akt)/nuclear factor-κB (NF-κB)/AR signaling, proliferation, apoptosis, and autophagy. Prostate weight and epithelial thickness were reduced in the C. choseniana groups compared with that in the BPH group. The extract of C. choseniana acted as a 5α reductase inhibitor, reducing DHT levels in the prostate. Furthermore, the extract of C. choseniana blocked the activation of p-Akt, nuclear NF-κB activation and reduced the expression of AR and PSA compared with BPH. Moreover, the expression of Bax, PARP-1, and p53 increased, while the expression of bcl-2 decreased. The present study demonstrated that C. choseniana extract alleviated testosterone-induced BPH by suppressing 5α reductase and Akt/NF-κB activation, reducing AR signaling and inducing apoptosis and autophagy in the prostate. These results suggested that C. choseniana probably contain potential herbal agents to alleviate BPH.
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Hiperplasia Prostática , Animais , Colestenona 5 alfa-Redutase/metabolismo , Finasterida/efeitos adversos , Masculino , NF-kappa B/genética , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Receptores Androgênicos/metabolismo , Testosterona , Ulmaceae/metabolismoRESUMO
The pervasiveness of microplastics (MPs) in global oceans is raising concerns about their adverse impacts on ecosystems. The mechanistic understanding of MP transport is critical for evaluating its fate, flux, and ecological risks specifically. Currently, bubble bursting is believed to represent an important route for MP transfer from sea surfaces to the atmosphere. However, the detailed mechanisms of the complex physico-chemical interactions between MPs, water composition, and gel particles in the air-sea interface remain unknown. Our results suggested three steps for MP transfer between air-sea phases: (1) MPs incorporating into gel aggregates in the water column; (2) further accumulation of plastic-gel aggregate in the surface layer phase; finally (3) ejection of aggregates from the sea when bubbles of trapped air rise to the surface and burst. The water composition (e.g., high salinity, gel concentration and viscosity) can modulate plastic-gel aggregation and subsequent transport from water to the atmosphere. The possible mechanism may be closely tied to the formation of plastic-gel via cation-linking bridges, thereby enhancing plastic-gel ejection into air. Collectively, this work offers unique insights into the role of marine plastic-gels in determining MP fate and transport, especially at air-sea interfaces. The data also provide a better understanding of the corresponding mechanism that may explain the fates of missing plastics in the ocean.
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Microplásticos , Poluentes Químicos da Água , Atmosfera , Ecossistema , Monitoramento Ambiental , Géis , Plásticos/química , Água , Poluentes Químicos da Água/análiseRESUMO
BACKGROUND: Interferon-induced protein with tetratricopeptide repeat 2 (IFIT2) is a reported metastasis suppressor in oral squamous cell carcinoma (OSCC). Metastases and cachexia may coexist. The effect of cancer metastasis on cancer cachexia is largely unknown. We aimed to address this gap in knowledge by characterizing the cachectic phenotype of an IFIT2-depleted metastatic OSCC mouse model. METHODS: Genetically engineered and xenograft tumour models were used to explore the effect of IFIT2-depleted metastatic OSCC on cancer cachexia. Muscle and organ weight changes, tumour burden, inflammatory cytokine profiles, body composition, food intake, serum albumin and C-reactive protein (CRP) levels, and survival were assessed. The activation of the IL6/p38 pathway in atrophied muscle was measured. RESULTS: IFIT2-depleted metastatic tumours caused marked body weight loss (-18.2% vs. initial body weight, P < 0.001) and a poor survival rate (P < 0.01). Skeletal muscles were markedly smaller in IFIT2-depleted metastatic tumour-bearing mice (quadriceps: -28.7%, gastrocnemius: -29.4%, and tibialis: -24.3%, all P < 0.001). Tumour-derived circulating granulocyte-macrophage colony-stimulating factor (+772.2-fold, P < 0.05), GROα (+1283.7-fold, P < 0.05), IL6 (+245.8-fold, P < 0.001), IL8 (+616.9-fold, P < 0.001), IL18 (+24-fold, P < 0.05), IP10 (+18.8-fold, P < 0.001), CCL2 (+439.2-fold, P < 0.001), CCL22 (+9.1-fold, P < 0.01) and tumour necrosis factor α (+196.8-fold, P < 0.05) were elevated in IFIT2-depleted metastatic tumour-bearing mice. Murine granulocyte colony-stimulating factor (+61.4-fold, P < 0.001) and IL6 (+110.9-fold, P < 0.01) levels were significantly increased in IFIT2-depleted metastatic tumour-bearing mice. Serum CRP level (+82.1%, P < 0.05) was significantly increased in cachectic shIFIT2 mice. Serum albumin level (-26.7%, P < 0.01) was significantly decreased in cachectic shIFIT2 mice. An assessment of body composition revealed decreased fat (-81%, P < 0.001) and lean tissue (-21.7%, P < 0.01), which was consistent with the reduced food intake (-19.3%, P < 0.05). Muscle loss was accompanied by a smaller muscle cross-sectional area (-23.3%, P < 0.05). Muscle atrophy of cachectic IFIT2-depleted metastatic tumour-bearing mice (i.v.-shIFIT2 group) was associated with elevated IL6 (+2.7-fold, P < 0.05), phospho-p38 (+2.8-fold, P < 0.05), and atrogin-1 levels (+2.3-fold, P < 0.05) in the skeletal muscle. Neutralization of IL6 rescued shIFIT2 conditioned medium-induced myotube atrophy (+24.6%, P < 0.01). CONCLUSIONS: Our results suggest that the development of shIFIT2 metastatic OSCC lesions promotes IL6 production and is accompanied by the loss of fat and lean tissue, anorexia, and muscle atrophy. This model is appropriate for the study of OSCC cachexia, especially in linking metastasis with cachexia.
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Proteínas Reguladoras de Apoptose , Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Proteínas de Ligação a RNA , Animais , Proteínas Reguladoras de Apoptose/genética , Caquexia/patologia , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/complicações , Humanos , Camundongos , Neoplasias Bucais/complicações , Neoplasias Bucais/patologia , Atrofia Muscular/patologia , Proteínas de Ligação a RNA/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicaçõesRESUMO
Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease characterized by multifocal perivascular infiltration of immune cells in the central nervous system (CNS). Cordycepin (3'-deoxyadenosine), an adenosine analogue initially extracted from the fungus Cordyceps militarisa, is one of the candidates that has multiple actions. We investigated that cordycepin attenuated the activation of LPS-induced mouse bone marrow-derived dendritic cells (BMDCs) and human monocyte-derived dendritic cells (MoDCs) through the inhibition of the AKT, ERK, NFκB, and ROS pathways and impaired the migration of BMDCs through the downregulation of adhesion molecules and chemokine receptors in vitro. In experimental autoimmune encephalomyelitis (EAE) model, preventive treatment with cordycepin decreased the expression of trafficking factors in the CNS, inhibited the secretion of inflammatory cytokines (IFN-γ, IL-6, TNF-α, and IL-17), and attenuated disease symptoms. A chemokine array indicated that cordycepin treatment reversed the high levels of CCL6, PARRES2, IL-16, CXCL10, and CCL12 in the brain and spinal cord of EAE mice, consistent with the RNA-seq data. Moreover, cordycepin suppressed the release of neuroinflammatory cytokines by activated microglial cells, macrophages, Th17 cells, Tc1 cells, and Th1 cells in vitro. Furthermore, cordycepin treatment exerted therapeutic effects on attenuating the disease severity in the early disease onset stage and late disease progression stage. Our study suggests that cordycepin treatment may not only prevent the occurrence of MS by inhibiting DC activation and migration but also potentially ameliorates the progression of MS by reducing neuroinflammation, which may provide insights into the development of new approaches for the treatment of MS.
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Desoxiadenosinas/uso terapêutico , Encefalomielite Autoimune Experimental/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Animais , Linhagem Celular Transformada , Células Cultivadas , Desoxiadenosinas/farmacologia , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/induzido quimicamente , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/prevenção & controle , Células RAW 264.7 , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Background: Stauntonia hexaphylla has been a traditional folk remedy for alleviating fever and providing anti-inflammatory properties. Androgenetic alopecia (AGA) is the most common form mediated by the presence of the dihydrotestosterone (DHT). Objectives: In this study, we evaluated the effects of an extract of S. hexaphylla on AGA models and its mechanisms of action. Methods: We studied S. hexaphylla extract to evaluate 5α-reductase and androgen receptor (AR) levels, apoptosis, and cell proliferation in vitro and in vivo. In addition, paracrine factors for androgenic alopecia, such as transforming growth factor beta-1 (TGF-ß1) and dickkopf-a (DKK-1), were examined. Apoptosis was investigated, and the evaluation of proliferation was examined with cytokeratin 14 (CK-14) and proliferating cell nuclear antigen (PCNA). Results: In human follicular dermal papilla cells, the 5α-reductase and AR were decreased following S. hexaphylla treatment, which reduced the Bax/Bcl-2 ratio. Histologically, the dermal thickness and follicle number were higher in the S. hexaphylla groups compared with the AGA group. In addition, the DHT concentration, 5α-reductase, and AR were decreased, thereby downregulating TGF-ß1 and DKK-1 expression and upregulating cyclin D in S. hexaphylla groups. The numbers of keratinocyte-positive and PCNA-positive cells were increased compared to those in the AGA group. Conclusions: The present study demonstrated that the S. hexaphylla extract ameliorated AGA by inhibiting 5α-reductase and androgen signaling, reducing AGA paracrine factors that induce keratinocyte (KC) proliferation, and inhibition apoptosis and catagen prematuration.
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Calocedrus formosana (Cupressaceae) is one of the five precious woods of Taiwan. In this study, we investigated the anti-melanogenic activity of C. formosana wood essential oil (CFEO) and its bioactive components in vitro. Initially, CFEO exhibited strong mushroom tyrosinase activity in the cell-free mushroom tyrosinase assay system with an IC50 value of 2.72 µg/mL. Next, treatment with CFEO significantly as well as dose-dependently reduced a combination of α-melanocyte-stimulating hormone and forskolin (α-MSH-FSK)-induced melanin synthesis in B16-F10 cells. Indeed, 80 µg/mL CFEO completely inhibited melanin production, which is similar to that of control cells. Further studies revealed that treatment with CFEO significantly inhibited melanogenesis regulatory proteins, including TRP-1, TRP-2, and MITF, whereas tyrosinase was unaffected by either α-MSH-FSK or CFEO. In addition, the composition of the CFEO was characterized. The major components of CFEO were α-terpineol (23.47%), shonanic acid (10.45%), terpinen-4-ol (12.23%), thymol (5.3%), piperitone (3.44%), berbenone (2.81%), thujic acid (1.65%), and chaminic acid (0.13%). Among them, shonanic acid (1), thujic acid (2), and chaminic acid (3) were uncommon constitutes in essential oils, which could be the index compounds of CFEO, and the structure of these compounds were confirmed by spectral analysis. Furthermore, we found that thymol is an active ingredient responsible for CFEO's anti-melanogenic activity. Based on these results, we suggest that CFEO or thymol could be a potential candidate for the development of skin whitening products for cosmetic purposes.
RESUMO
The anti-melanogenic activity of essential oils of Alpinia nantoensis and their bioactive ingredients were investigated in vitro. Treatment with leaf (LEO) and rhizome (REO) essential oils of A. nantoensis, significantly reduced forskolin-induced melanin production followed by down-regulation of tyrosinase (TYR) and tyrosinase related protein-1 (TRP-1) expression at both transcriptional and translational levels. Further studies revealed that down-regulation TYR and TRP-1 were caused by LEO/REO-mediated suppression of Microphthalmia-associated transcription factor (MITF), as evidenced by reduced nuclear translocation of MITF. Also, we found that LEO/REO induce the sustained activation of ERK1/2, which facilitate subsequent proteasomal degradation of MITF, as confirmed by that LEO/REO failed to inhibits MITF activity in ERK1/2 inhibitor treated cells. In addition, a significant increase of ubiquitinated MITF was observed after treatment with LEO and REO. Furthermore, the chemical composition of LEO and REO were characterized by gas chromatography-mass spectrometry (GC-MS) resulted that camphor, camphene, α-pinene, ß-pinene, isoborneol and D-limonene were the major compounds in both LEO and REO. Further studies revealed that α-pinene and D-limonene were the active components responsible for the anti-melanogenic properties of LEO and REO. Based on the results, this study provided a strong evidence that LEO and REO could be promising natural sources for the development of novel skin-whitening agents for the cosmetic purposes.
RESUMO
Parkinson's disease (PD) is a neurodegenerative disorder featuring progressive loss of midbrain dopaminergic (DA) neurons that leads to motor symptoms. The etiology and pathogenesis of PD are not clear. We found that expression of COUP-TFII, an orphan nuclear receptor, in DA neurons is upregulated in PD patients through the analysis of public datasets. We show here that through epigenetic regulation, COUP-TFII contributes to oxidative stress, suggesting that COUP-TFII may play a role in PD pathogenesis. Elevated COUP-TFII expression specifically in DA neurons evokes DA neuronal loss in mice and accelerates the progression of phenotypes in a PD mouse model, MitoPark. Compared to control mice, those with elevated COUP-TFII expression displayed reduced cristae in mitochondria and enhanced cellular electron-dense vacuoles in the substantia nigra pars compacta. Mechanistically, we found that overexpression of COUP-TFII disturbs mitochondrial pathways, resulting in mitochondrial dysfunction. In particular, there is repressed expression of genes encoding cytosolic aldehyde dehydrogenases, which could enhance oxidative stress and interfere with mitochondrial function via 3,4-dihydroxyphenylacetaldehyde (DOPAL) buildup in DA neurons. Importantly, under-expression of COUP-TFII in DA neurons slowed the deterioration in motor functions of MitoPark mice. Taken together, our results suggest that COUP-TFII may be an important contributor to PD development and a potential therapeutic target.
Assuntos
Fator II de Transcrição COUP/metabolismo , Neurônios Dopaminérgicos/patologia , Mitocôndrias/patologia , Doença de Parkinson/genética , Ácido 3,4-Di-Hidroxifenilacético/análogos & derivados , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Aldeído Desidrogenase , Animais , Encéfalo/citologia , Encéfalo/patologia , Linhagem Celular , Linhagem Celular Tumoral , Estudos de Coortes , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Progressão da Doença , Neurônios Dopaminérgicos/citologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Estresse Oxidativo/genética , Doença de Parkinson/patologia , Cultura Primária de Células , RNA-Seq , Ratos , Regulação para CimaRESUMO
Viral infection is associated with many types of tumorigenesis, including human papillomavirus (HPV)-induced cervical cancer. The induction of a specific T-cell response against virus-infected cells is desired to develop an efficient therapeutic approach for virus-associated cancer. Chinese herbal medicine (CHM) has a long history in the treatment of cancer patients in Asian countries. Hedyotis diffusa Willd (Bai Hua She She Cao, BHSSC) is frequently used clinically and has been shown to inhibit tumor growth in vitro. However, in vivo data demonstrating the antitumor efficacy of BHSSC are still lacking. We showed that BHSSC induces murine and human antigen-presenting cell (APC) activation via the MAPK signaling pathway and enhances antigen presentation in bone marrow-derived dendritic cells (BMDCs) in vitro. Furthermore, we identified that treatment with BHSSC leads to improved specific effector and memory T-cell responses in vivo. Variant peptide-based vaccines combined with BHSSC improved antitumor activity in preventive, therapeutic, and recurrent HPV-related tumor models. Furthermore, we showed that rutin, one of the ingredients in BHSSC, induces a strong specific immune response against HPV-related tumors in vivo. In summary, we demonstrated that BHSSC extract and its active compound, rutin, can be used as adjuvants in peptide-based vaccines to increase immunogenicity and to bypass the requirement of a conditional adjuvant.