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Abnormal proliferation, migration, and foam cell formation of Vascular smooth muscle cells (VSMCs) each play a role in the development of atherosclerosis (AS). Schisandrin (Sch) is the active lignan ingredient with broad-spectrum pharmacological effects. However, the role of Sch in the AS process is not clear. Therefore, this study was proposed to explore the therapeutic effect and potential mechanism of Sch on VSMCs. Ox-LDL was selected to create an atherosclerosis injury environment for VSMCs and macrophages. The MTT assay, Oil red O staining, wound healing, transwell experiments and ELISA were used to investigate the phenotype effects of Sch. Network pharmacology, molecular docking, flow cytometry, and western blot were used to investigate the underlying mechanisms of Sch on AS progression. Our findings implied that Sch treatment inhibited the proliferation and migration of VSMCs, and suppressed the ROS production and inflammatory cytokines up-regulation of VSMCs and macrophages. Moreover, Sch reduced lipid uptake and foam cell formation through downregulating LOX-1. Mechanistically, we found that Sch can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2, and arrest cell cycle in GO/G1 phase. In summary, Sch can inhibit VSMCs proliferation and migration by arresting cell cycle and targeting JAK2 to regulating the JAK2/STAT3 pathway. Sch may serve as a potential drug for patients with AS.
Assuntos
Movimento Celular , Proliferação de Células , Ciclo-Octanos , Janus Quinase 2 , Lignanas , Músculo Liso Vascular , Compostos Policíclicos , Fator de Transcrição STAT3 , Transdução de Sinais , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/citologia , Lignanas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Compostos Policíclicos/farmacologia , Humanos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Animais , Aterosclerose/patologia , Aterosclerose/metabolismo , Aterosclerose/tratamento farmacológicoRESUMO
(-)-Epicatechin gallate (ECG) is beneficial to the treatment of cardiovascular diseases (CVDs), especially atherosclerosis (AS) through antioxidant stress, but there is a lack of detailed mechanism research. In this study, the therapeutic target of ECG was determined by crossing the drug target and disease target of CVDs and AS. The combination ability of ECG with important targets was verified by Discovery Studio software. The abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by Ang-II and the oxidative damage of AML 12 induced by H2O2 were established to verify the reliability of ECG intervention on the target protein. A total of 120 ECG targets for the treatment of CVDs-AS were predicted by network pharmacology. The results of molecular docking showed that ECG has strong binding force with VEGFA, MMP-9, CASP3 and MMP-2 domains. In vitro experiments confirmed that ECG significantly reduced the expression of VEGFA, MMP-9, CASP3 and MMP-2 in Ang-II-induced VSMCs, and also blocked the abnormal proliferation, oxidative stress and inflammatory reaction of VSMCs by inhibiting the phosphorylation of PI3K signaling pathway. At the same time, ECG also interfered with H2O2-induced oxidative damage of AML 12 cells, decreased the expression of ROS and MDA and cell foaming, and increased the activities of antioxidant enzymes such as SOD, thus playing a protective role.
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Aterosclerose , Catequina , Proliferação de Células , Peróxido de Hidrogênio , Simulação de Acoplamento Molecular , Músculo Liso Vascular , Estresse Oxidativo , Estresse Oxidativo/efeitos dos fármacos , Catequina/análogos & derivados , Catequina/farmacologia , Proliferação de Células/efeitos dos fármacos , Aterosclerose/metabolismo , Aterosclerose/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/citologia , Peróxido de Hidrogênio/farmacologia , Humanos , Transdução de Sinais/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Linhagem Celular , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Angiotensina II/farmacologia , Metaloproteinase 9 da Matriz/metabolismo , Antioxidantes/farmacologiaRESUMO
Natural products have been widely recognized in clinical treatment because of their low toxicity and high activity. It is worth paying attention to modifying the biopolymer into nanostructures to give natural active ingredients additional targeting effects. In this study, based on the multifunctional modification of ß-cyclodextrin (ß-CD), a nanoplatform encapsulating the unstable drug (-)-epicatechin gallate (ECG) was designed to deliver to atherosclerotic plaques. Acetalization cyclodextrin (PH-CD), which responds to low-pH environments, and hyaluronic acid cyclodextrin, which targets the CD44 receptor on macrophage membranes, were synthesized from ß-CD and hyaluronic acid using acetalization and transesterification, respectively. The resulting dual-carrier nanoparticles (Double-NPs) loaded with ECG were prepared using a solvent evaporation method. The Double-NPs effectively scavenged reactive oxygen species, promoted macrophage migration, inhibited macrophage apoptosis, and suppressed abnormal proliferation and migration of vascular smooth muscle cells. Furthermore, the Double-NPs actively accumulated in atherosclerotic plaques in ApoE-/- mice fed with a high-fat diet, leading to a reduced plaque area, inflammatory infiltration, and plaque instability. Our findings demonstrate that the newly developed ECG nanopreparation represents an effective and safe nanotherapy for diseases such as atherosclerosis.
Assuntos
Aterosclerose , Ácido Hialurônico , Nanopartículas , beta-Ciclodextrinas , Ácido Hialurônico/química , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Camundongos , beta-Ciclodextrinas/química , Nanopartículas/química , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Células RAW 264.7 , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Portadores de Fármacos/química , Movimento Celular/efeitos dos fármacos , Humanos , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/prevenção & controle , Proliferação de Células/efeitos dos fármacosRESUMO
BACKGROUND: Systemic inflammatory response syndrome (SIRS) is an uncontrolled systemic inflammatory response. Proanthocyanidins (PC) is a general term of polyphenol compounds widely existed in blueberry fruits and can treat inflammation-related diseases. This study aimed to explore the regulatory effect of PC on lipopolysaccharide (LPS)-induced systemic inflammation and its potential mechanism, providing effective strategies for the further development of PC. METHODS: Here, RAW264.7 macrophages were stimulated with LPS to establish an inflammation model in vitro, while endotoxin shock mouse models were constructed by LPS in vivo. The function of PC was investigated by MTT, ELISA kits, H&E staining, immunohistochemistry, and Western blot analysis. RESULTS: Functionally, PC could demonstrate the potential to mitigate mortality in mice with endotoxin shock, as well as attenuated the levels of inflammatory cytokines (IL-6, TNF-α) and biochemical indicators (AST, ALT, CRE and BUN). Moreover, it had a significant protective effect on lung and kidney tissues damage. Mechanistically, PC exerted anti-inflammatory effects by inhibiting the activation of the NF-κB/NLRP3 signaling pathway. CONCLUSION: PC might have the potential ability of anti-inflammatory effects via modulation of the NF-κB/NLRP3 signaling pathway.
Assuntos
Anti-Inflamatórios , Mirtilos Azuis (Planta) , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proantocianidinas , Transdução de Sinais , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proantocianidinas/farmacologia , Camundongos , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Mirtilos Azuis (Planta)/química , Células RAW 264.7 , Anti-Inflamatórios/farmacologia , Masculino , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/farmacologia , Choque Séptico/tratamento farmacológico , Choque Séptico/metabolismo , Choque Séptico/induzido quimicamenteRESUMO
Inflammation and oxidative stress (OS) are the major pathogenic characteristics of acute kidney injury (AKI). Studies have shown that Schisandrin (Sch) could regulate inflammatory disease. However, the function and mechanism of Sch in AKI progression are still unknown. Here, we investigated Sch's potential effects and mechanism on mice's renal damage and macrophages induced by lipopolysaccharide (LPS). Sch decreased LPS-induced inflammatory factor production while increasing the activity of related antioxidant enzymes in macrophages and mouse kidney tissues. Hematoxylin and eosin staining revealed that Sch may have the ability to profoundly inhibit inflammatory cell invasion and tissue damage caused by LPS in renal tissue. Furthermore, Western blot and immunohistochemical studies showed that Sch exerted its effects mainly through up-regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 and inhibition of Toll-like receptor 4âmitogen-activated protein kinases/nuclear factor-kappa B pathways. Collectively, this study illustrates that Sch suppresses LPS-stimulated AKI by descending inflammation and OS, illuminating prospective AKI treatment options.
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Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.
Assuntos
Adenina , Vírus da Febre Suína Clássica , Peste Suína Clássica , Animais , Vírus da Febre Suína Clássica/genética , Imunidade Inata , Suínos , Receptor 4 Toll-LikeRESUMO
The optical transfer function is crucial for imaging system design and characterization. However, practical optical systems often deviate from linear spatial invariance due to aberrations and field-of-view considerations, posing challenges for optical transfer function characterization and aberration compensation in non-paraxial region imaging. Partitioning the field-of-view into isoplanatic regions and measuring the optical transfer function for each region is a potential solution, but practical implementation is hindered by the lack of field-of-view information. This Letter introduces a compensation method for the phase modulation function based on spatial frequency domain division, specifically tailored for scenarios where high imaging quality is not essential. The proposed method addresses the challenge by filling the phase transfer function in an annular form corresponding to aberrations in different isoplanatic regions, offers a valuable solution for adaptive aberration compensation in non-paraxial region imaging, and presents a practical illustration of its effectiveness.
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For fringe projection profilometry (FPP), the gamma effect of the camera and projector will cause non-sinusoidal distortion of the fringe patterns, leading to periodic phase errors and ultimately affecting the reconstruction accuracy. This paper presents a gamma correction method based on mask information. Since the gamma effect will introduce higher-order harmonics into the fringe patterns, on top of projecting two sequences of phase-shifting fringe patterns having different frequencies, a mask image is projected to provide enough information to determine the coefficients of higher-order fringe harmonics using the least-squares method. The true phase is then calculated using Gaussian Newton iteration to compensate for the phase error due to the gamma effect. It does not require projecting a large number of images, and only 2 × 3 phase shift patterns and 1 mask pattern minimum are required. Simulation and experimental results demonstrate that the method can effectively correct the errors caused by the gamma effect.
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The study sought to investigate whether and how expectation violation can modulate attention using the exogenous spatial cueing paradigm, under the theoretical framework of the Memory Encoding Cost (MEC) model. The MEC proposes that exogenous spatial cueing effects are mainly driven by a combination of two distinct mechanisms: attentional facilitation triggered by the presence of an abrupt cue, and attentional suppression induced by memory encoding of the cue. In current experiments, participants needed to identify a target letter that was sometimes preceded by a peripheral onset cue. Various types of expectation violation were introduced by regulating the probability of cue presentation (Experiments 1 & 5), the probability of cue location (Experiments 2 & 4), and the probability of irrelevant sound presentation (Experiment 3). The results showed that expectation violation could enhance the cueing effect (valid vs. invalid cue) in some cases. More crucially, all experiments consistently observed asymmetrical modulation of expectation violation on the cost (invalid vs. neutral cue) and benefit (valid vs. neutral cue) effects: Expectation violation increased the cost effects while did not modulate or decreased (or even reversed) the benefit effects. Furthermore, Experiment 5 provided direct evidence that violation of expectations could enhance the memory encoding of a cue (e.g., color) and this memory advantage could manifest quickly in the early stages of the experiment. The MEC better explains these findings than some traditional models like the spotlight: Expectation violation can both enhance the attentional facilitation of the cue and memory encoding of irrelevant cue information. These findings suggest that expectation violation has a general adaptive function in modulating the attention selectivity.
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Sinais (Psicologia) , Motivação , Humanos , Tempo de Reação/fisiologia , Atenção/fisiologia , ProbabilidadeRESUMO
Green tea is popular worldwide, so its main active ingredients have attracted people's attention. (-)-Epicatechin gallate (ECG) is the main active component of green tea polyphenols, which has good antioxidant activity, but its cardiovascular intervention is unknown. This study established in vitro and in vivo models of ox-LDL-induced macrophages and HFD-induced ApoE-/- mice to study the effects of ECG on atherosclerotic lesions. Firstly, the study confirmed that ECG has a therapeutic effect in different stages of atherosclerotic plaques. Subsequently, the results showed that the ox-LDL-induced release of pro-inflammatory mediators and the expression of the related protein CD86 in macrophages were inhibited by ECG. ECG blocked the formation of cellular foam by downregulating the expression of CD36 and LOX-1 proteins, thereby increasing SOD activity and reducing MDA production in cells. ECG also prevented ox-LDL-induced apoptosis, promoted macrophage migration, and increased plaque stability. The results confirmed that ECG attenuated ox-LDL-induced green fluorescence of ROS in macrophages by inhibiting the expression of related proteins in the NF-κB signaling pathway and activating the HO-1/Nrf2 signaling pathway. These results indicated that ECG has anti-oxidative stress and anti-inflammatory potential, and its molecular mechanism may be related to the inhibition of intracellular NF-κB signaling pathway proteins and activation of the HO-1/Nrf2 signaling pathway.
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Aterosclerose , Placa Aterosclerótica , Animais , Camundongos , NF-kappa B/genética , Fator 2 Relacionado a NF-E2 , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Placa Aterosclerótica/metabolismo , Lipoproteínas LDL/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêuticoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Panlongqi Tablet is prepared with the ancestral secret recipe provided by Mr. Wang Jiacheng, a famous specialist in orthopedics and traumatology of China. The efficacy and safety of PLQT have been supported by years of clinical practice in the treatment of joint-related conditions. Has remarkable effect for treating rheumatoid arthritis (RA) clinically. However, its mechanism is not entirely clear. AIM OF THE STUDY: We aim to evaluate the anti-inflammatory activity of PLQT and explore its mechanism in adjuvant-induced arthritis (AA) mice and LPS-induced Human fibroblast-like synovial (HFLS) cells. MATERIALS AND METHODS: To this end, we analyzed the active ingredients in PLQT by HPLC-MS/MS. Furthermore, the anti-RA effect of PLQT was studied through proliferation, apoptosis, foot swelling, cytokine levels, immune organ index, histopathology and related signal pathways in LPS-induced HFLS cells and AA-treated mice. RESULTS: HPLC-MS/MS results showed that PLQT contained a variety of active compounds, such as epicatechin, imperatorin, hydroxysafflor yellow A and so on. PLQT significantly inhibited the abnormal proliferation of HFLS cells induced by LPS, promoted cell apoptosis. In AA-treated mice, PLQT alleviated RA symptoms by alleviating paw swelling, synovial hyperplasia, pannus formation, inflammatory cell infiltration, and inhibiting abnormal immune responses. The results showed that PLQT significantly decreased the expression of inflammatory mediators (IL-1ß, IL-6, IL-17) in vivo and in vitro, which may be related to the regulation of PI3K/Akt, MAPK and JAK/STAT signaling pathways. CONCLUSION: Based on serum pharmacology and in vivo pharmacology studies, PLQT may regulate RA symptoms by regulating inflammatory and immune response-related pathways, which is an effective method for the treatment of RA.
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Artrite Experimental , Artrite Reumatoide , Humanos , Camundongos , Animais , Lipopolissacarídeos , Fosfatidilinositol 3-Quinases , Espectrometria de Massas em Tandem , Artrite Reumatoide/tratamento farmacológico , Artrite Experimental/tratamento farmacológicoRESUMO
Bletilla striata (Thunb.) Reichb.f., is a traditional Chinese medicine, and the Bletilla striata polysaccharide (BSP) is one of the principal components extracted from Bletilla striata with various biological activities. Previous studies have shown that many natural polysaccharides have significant immunomodulatory activities. However, as a plant polysaccharide, the research of BSP on immunomodulatory activities is limited. In this study, we aim to investigate the immunomodulatory effect of BSP in vivo and further explore its underlying mechanism in vitro. In vivo, a cyclophosphamide (CTX)-induced immunosuppression mice mode was established by intraperitoneal injection of CTX, and the immune-enhancing effect of BSP (25, 50 and 100 mg/kg) on immunosuppressed mice were evaluated. The result indicated that BSP could significantly improve the immune organ index and the content of immunoglobulin, TNF-α and IL-4 in serum. It was also found that BSP could clearly ameliorate the spleen damage induced by CTX. Meanwhile, the result showed that BSP could not only improve the proliferation of splenocytes, but also activate the lactate dehydrogenase (LDH) and acid phosphatase (ACP) in mouse spleen tissue. In vitro, potential mechanism was further revealed in macrophages. The result supported that BSP could activate macrophages with high phagocytic ability, and induce macrophages to secrete cytokines. Finally, it revealed that activation of NF-κB and MAPK signalling pathway should be the underlying mechanism of the immunoenhancment of BSP.
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NF-kappa B , Orchidaceae , Fosfatase Ácida/metabolismo , Animais , Ciclofosfamida/metabolismo , Citocinas/metabolismo , Interleucina-4/metabolismo , Lactato Desidrogenases/metabolismo , Camundongos , NF-kappa B/metabolismo , Orchidaceae/metabolismo , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammation infiltration of the synovial tissues and the fibroblast-like synoviocytes. Tectoridin is a botanical active ingredient with anti-inflammatory properties. In this study, the anti-arthritic effects of tectoridin and its mechanism of action are examined in TNF-α-induced human fibroblast-like synovial cells (HFLSs cells) and complete Freund's adjuvant (CFA)-stimulated arthritic mice. Arthritis progression was evaluated via bodyweight, hind paw swelling, organ index, and synovial pathology. IL-1ß, IL-6 and other pro-inflammatory factors concentrations, and the expression of MAPK pathway proteins in HFLSs cells and arthritic mice were measured using ELISA and western blotting. Results showed that tectoridin significantly decreased the swelling of the paws and joints as well as the increased immune organ index within CFA-induced arthritic mice. Histopathological analysis showed that tectoridin alleviated the lesions of ankle joints and synovial tissues induced by CFA. Secretion of pro-inflammatory cytokines in TNF-α-induced HFLSs cells and CFA-stimulated arthritic mice were also abated by tectoridin. Similarly, the presence of tectoridin significantly inhibited the abnormal phosphorylation levels of ERK, JNK, and p38 in vivo and in vitro. All those results highlighted that tectoridin exhibits anti-arthritis effects by inhibiting MAPK-mediated inflammatory responses.
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Artrite Experimental , Artrite Reumatoide , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/patologia , Adjuvante de Freund/efeitos adversos , Humanos , Isoflavonas , Camundongos , Fator de Necrose Tumoral alfa/efeitos adversosRESUMO
Tectoridin, isolated from the dry rhizome of iris, is a compound with multiple biological activities. However, its biological roles in rheumatoid arthritis (RA) have still not been clearly elucidated. The aim of this study was to focus on the effects of tectoridin on tumor necrosis factor (TNF)-α-induced human fibroblastlike synoviocyte rheumatoid arthritis (HFLSRA) cells, and its associated mechanisms. After TNF-α stimulation, CCK8 and MTT assays, TUNEL assay and flow cytometry, Western blotting and immunohistochemistry analysis were performed to check the cell proliferation, cell apoptosis and cycle analysis, and the expression of related proteins, respectively. Our results showed that tectoridin significantly hindered cell proliferation, S-to-G2/M phase transition and down-regulated Cyclind 1 and PCNA protein levels. Additionally, tectoridin markedly promoted apoptosis rates of HFSL-RA cells and elevated the expression levels of Cleaved Caspase-3 and Bax, while reduced the expression level of Bcl-2. Moreover, tectoridin reversed TNF-α-induced overexpression of MMPs and factors associated with the TLR4/NLRP3/NF-κB pathway. We conclude that tectoridin ameliorated TNF-α-induced proliferation and inflammation by inhibiting TLR4/NLRP3/NF-κB pathway. It might provide a new insight for the clinical application of RA.
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Artrite Reumatoide , NF-kappa B , Apoptose , Artrite Reumatoide/metabolismo , Proliferação de Células/fisiologia , Células Cultivadas , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Isoflavonas , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
BACKGROUND: Tectoridin, widely extracted and separated from the rhizome of Iris tectorum Maxim, is extensively reported to have affluent bioactivity, but rarely reported to have anti-inflammatory effects. In this study, we aim to investigate the anti-inflammatory effects and the underlying mechanisms of tectoridin. METHODS: Here, RAW264.7 macrophages were stimulated with Lipopolysaccharide (LPS) for the inflammation model in vitro. Experimental animals received tectoridin and Dexamethasone (DEX) before LPS injection for endotoxic shock mouse model in vivo. The pro-inflammatory mediators and cytokines in the cell supernatant and serum were detected by ELISA kits. The tissue damages were assessed by biochemical indexes and H&E staining. Immunohistochemistry and Western blot were performed for the detection of proteins. RESULTS: Our data showed that tectoridin attenuated the LPS-up-regulated nitric oxide (NO), interleukin-6 (IL-6), and interleukin-18 (IL-18) from macrophages and tumor necrosis factor-α (TNF-α); (IL-6) and (IL-1ß) in the serum levels. Besides, our histopathological study showed that the damages caused by LPS in the lung, liver, and kidney tissues were decreased. Furthermore, our results demonstrated that tectoridin inhibited the activation of TLR4-NF-κB/NLRP3 signaling proved by immunohistochemistry assay and Western blot. CONCLUSION: Taken all together, tectoridin might have the potential ability of anti-inflammatory effects and the possible mechanism may be relevant to its inhibition of TLR4-NF-κB/NLRP3 signaling.
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Lipopolissacarídeos , NF-kappa B , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Dexametasona/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-18 , Interleucina-6 , Isoflavonas , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfaRESUMO
Acute lung injury (ALI) is characterized by an excessive inflammatory response, closely related to sepsis occurrence and development. It has been reported that Schisandrin (Sch) exhibits anti-inflammatory activity. However, whether the beneficial effects of Sch exists during ALI remains to be studied. In this study, the impact of Sch was evaluated by studying lung tissue damage, measuring the concentrations of pro-inflammatory factors, and the expression of apoptotic proteins in the LPS-induced ALI mice model. Protein expression of inflammation-related signaling pathway within the lung tissue and A549 cells were also measured. In addition, the effect of Sch on A549 cell apoptosis and inflammatory markers was also detected. Animal experiments demonstrated that pre-feeding Sch alleviated the production of inflammation mediators, abnormal pathological injuries, and blocked the progression of apoptotic events in the lung tissue. The in vitro experiments showed that Sch pretreatment reduced LPS upregulated interleukin-1ß (IL-1ß), IL-18, and IL-6 levels, and improved LPS-induced abnormal apoptosis. Sch and the pathway inhibitor AG490 also inhibited the expression levels of p-JAK2 and p-STAT3 in A549 cells. Moreover, pretreatment with Sch significantly inhibited the activation of NLRP3 inflammasomes, reduced inducible nitric oxide synthase, and cyclooxygenase 2 proteins expression during ALI in vitro and in vivo. Overall, Sch effectively alleviated ALI and provided a new mechanism to support the protective effect of Sch for sepsis-induced ALI. PRACTICAL IMPLICATIONS: ALI is characterized by inflammatory injury of the lungs, which is an important cause of high morbidity and mortality in severe patients. Sch is considered as a botanical active ingredient with various pharmacological activities, such as neuroprotective and vascular protective effects. However, the effect of Sch on ALI and its mechanism remains largely unknown. Research data indicate that Sch exerts an anti-inflammatory effect by reducing the production of inflammatory factors and abnormal apoptosis of cells, further alleviating lung damage. The protective effect of Sch was associated with inhibition of the activation of NLRP3 and the JAK2/STAT3 inflammatory pathways. The study, therefore, confirmed that Sch has a potential as an effective drug to prevent ALI diseases.
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Lesão Pulmonar Aguda , Sepse , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Ciclo-Octanos , Lignanas , Lipopolissacarídeos/efeitos adversos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Compostos Policíclicos , Sepse/tratamento farmacológicoRESUMO
Background: Mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is an extremely rare entity, consisting of neuroendocrine and non-neuroendocrine components. It can occur in various organs throughout the body, with a rising incidence. Its clinical management is a rapidly growing field of interest; however, large-scale patient cohorts are still missing to guide clinical practice. Patients and methods: The demographic, clinicopathological, and survival information of all patients diagnosed with MiNEN in the national Surveillance, Epidemiology, and End Results (SEER) program database (2000-2017) were extracted and further analyzed. The information of the patients before and after 2010 was compared to understand the epidemiological changes of MiNEN. The characteristics of MiNEN originating in different organs were compared. The clinical significance of surgical resection for metastatic MiNENs was also analyzed. Results: A total of 1081 patients were screened, and after applying the exclusion criteria, 767 patients were finally analyzed. There was no obvious sex preference (49.2% vs 50.8%, p>0.05) and the majority of the patients were Caucasians (n=627, 81.7%). A total of 88.3% of the patients were older than 50 years old, and the median age was 60 years. 79.3% of the tumors are located in the distal digestive tract, and 67.7% were grade 3/4. Distant metastasis was presented in 33.9% of the patients at diagnosis. A total of 88% of the patients underwent surgical treatments. The number of patients increased 10-fold between 2000 and 2017. There was no significant difference in sex, race, stage, or surgical treatments among the patients diagnosed before and after 2010. More patients older than 60 years were diagnosed after 2010 (p=0.009). The median survival was 61.0 ± 9.8 months for the whole cohort. After multivariate analysis, older age (>60 years, p<0.01), more advanced stage (p<0.01), grade 3/4 (p<0.01), and non-surgical treatment (p<0.01) were independent risk factors for poorer survival. The appendiceal MiNENs showed the best prognosis. A total of 260 metastatic MiNENs were further analyzed. Only patients with metastatic MiNENs originating from the appendix had a potential benefit from surgical resection, compared to other sites (p=0.05). Conclusion: This study provides the epidemiological, clinicopathological, and survival information of the largest number of MiNEN patients. Although MiNEN is an extremely rare malignant neoplasm, its incidence increases rapidly. The majority of the patients suffered from advanced-stage disease, which highlights the need for improvement of early detection in the future. The appendix is the most common primary site of MiNEN, and surgical resection for selected metastatic MiNEN originating in the appendix has favorable survival outcomes.
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Pancreatic cancer is an inflammatory malignancy, and tumor-associated macrophages (TAMs) are the predominant inflammatory cells in tumor tissue. TAMs have complicated interactions with pancreatic cancer cells, however, the details and mechanisms remain largely unknown. In this study, transcriptomics and proteomics analyses were performed to explore the interactions between murine pancreatic cancer cells and TAMs. Dopamine (DA) has been reported to suppress inflammations. However, its roles in TAMs of pancreatic cancer have not been reported. Herein, the roles and mechanisms of DA to affect the chemotherapeutic efficacy for pancreatic cancer were studied. Multi-omics results revealed that there was a tumor-promoting vicious cycle involving murine pancreatic cancer cells and TAMs. DA substantially improved the chemotherapeutic efficacy both in vitro study and in immunocompetent murine pancreatic cancer models by suppression of the M2 characters of TAMs. Further studies found that activation of DRD4 by DA led to the decrease of cAMP, and then inhibited the activation of PKA/p38 signal pathway, which suppressed the tumor-promoting inflammation of TAMs. This study uncovers the reciprocal interactions between TAMs and pancreatic cancer cells using multi-omics techniques and presents that DA has synergistic roles with chemotherapy for pancreatic cancer by suppressing of TAM-derived inflammations.
Assuntos
Dopamina/metabolismo , Inflamação/metabolismo , Macrófagos/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Receptores de Dopamina D4/metabolismo , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologiaRESUMO
Circular RNAs (circRNAs) are small non-coding RNAs with a unique ring structure and play important roles as gene regulators. Disturbed expressions of circRNAs is closely related to varieties of pathological processes. The roles of circRNAs in cancers have gained increasing concerns. The communications between the cancer cells and tumor microenvironment (TME) play complicated roles to affect the malignant behaviors of cancers, which potentially present new therapeutic targets. Herein, we reviewed the roles of circRNAs in the TME.
RESUMO
OBJECTIVE AND DESIGN: We aimed to investigate the alterations of microRNA (miRNA) genomics in peripheral blood lymphocytes in experimental autoimmune uveitis (EAU) rats versus control samples. MATERIALS/METHODS: Six Lewis rats received interphotoreceptor retinoid-binding protein (IRBP) emulsion to induce EAU. On day 12, peripheral blood lymphocytes were isolated, and total RNAs were extracted. Using microarray analysis, we analyzed the aberrant miRNAs, validated the relevant expression of differentially expressed miRNAs, and predicted the possible miRNA targets and signaling pathways. RESULTS: The results indicated that 36 miRNAs were upregulated and 31 miRNAs were downregulated in EAU rats versus normal samples. Real-time quantitative PCR substantiated a high degree of confidence for the differentially expressed miRNAs, and miRNA analyses showed the differentially expressed miRNA targets were involved not only in the multicellular organismal process and developmental process, but also in T cell receptor signaling pathway, B cell receptor signaling pathway and so on. CONCLUSIONS: Our findings show that the differentially expressed miRNAs in EAU rats were closely associated with immune signaling pathways and may be applied in early prevention, prognosis and possible therapy in uveitis, indicating that miRNAs play an important role in the development of uveitis.