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Background: Cynanchum paniculatum (Bunge) Kitag. ex H.Hara, a member of the Asclepiadaceae family, has a rich history as a traditional Chinese medicinal plant used to treat digestive disorders. However, its potential anti-cancer effects in pancreatic cancer remain largely unexplored. Aim: This study delves into the intricate anti-pancreatic cancer mechanisms of C. paniculatum (Bunge) Kitag. ex H.Hara aqueous extract (CPAE) by elucidating its role in apoptosis induction and the inhibition of invasion and migration. Methods: A comprehensive set of methodologies was employed to assess CPAE's impact, including cell viability analyses using MTT and colony formation assays, flow cytometry for cell cycle distribution and apoptosis assessment, scratch-wound and Matrigel invasion assays for migration and invasion capabilities, and immunoblotting to measure the expression levels of key proteins involved in apoptosis and metastasis. Additionally, a murine xenograft model was established to investigate CPAE's in vivo anti-cancer potential. Results: CPAE exhibited time- and dose-dependent suppression of proliferation and colony formation in pancreatic cancer cells. Notably, CPAE induced apoptosis and G2/M phase arrest, effectively activating the caspase-dependent PARP pathway. At non-cytotoxic doses, CPAE significantly curtailed the metastatic abilities of pancreatic cells, effectively suppressing epithelial-mesenchymal transition (EMT) and downregulating the TGF-ß1/Smad2/3 pathway. In vivo experiments underscored CPAE's ability to inhibit tumor proliferation. Conclusion: This study illuminates the multifaceted anti-proliferative, pro-apoptotic, anti-invasive, and anti-migratory effects of CPAE, both in vitro and in vivo. CPAE emerges as a promising herbal medicine for pancreatic cancer treatment, with its potential mediated through apoptosis induction via the caspase-dependent PARP pathway and MET suppression via the TGF-ß1/Smad2/3 signaling pathway at non-cytotoxic doses. These findings advocate for further exploration of CPAE's therapeutic potential in pancreatic cancer.
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The U6 promoter is an important element driving sgRNA transcription in the CRISPR/Cas9 system. Seven PqU6 promo-ter sequences were cloned from the gDNA of Panax quinquefolium, and the transcriptional activation ability of the seven promoters was studied. In this study, seven PqU6 promoter sequences with a length of about 1 300 bp were cloned from the adventitious roots of P. quinquefolium cultivated for 5 weeks. Bioinformatics tools were used to analyze the sequence characteristics of PqU6 promoters, and the fusion expression vectors of GUS gene driven by PqU6-P were constructed. Tobacco leaves were transformed by Agrobacterium tumefaciens-mediated method for activity detection. The seven PqU6 promoters were truncated from the 5'-end to reach 283, 287, 279, 289, 295, 289, and 283 bp, respectively. The vectors for detection of promoter activity were constructed with GUS as a reported gene and used to transform P. quinquefolium callus and tobacco leaves. The results showed that seven PqU6 promoter sequences(PqU6-1P to PqU6-7P) were cloned from the gDNA of P. quinquefolium, with the length ranged from 1 246 bp to 1 308 bp. Sequence comparison results showed that the seven PqU6 promoter sequences and the AtU6-P promoter all had USE and TATA boxes, which are essential elements affecting the transcriptional activity of the U6 promoter. The results of GUS staining and enzyme activity test showed that all the seven PqU6 promoters had transcriptional activity. The PqU6-7P with a length of 1 269 bp had the highest transcriptional activity, 1.31 times that of the positive control P-35S. When the seven PqU6 promoters were truncated from the 5'-end(PqU6-1PA to PqU6-7PA), their transcriptional activities were different in tobacco leaves and P. quinquefolium callus. The transcriptional activity of PqU6-7PA promoter(283 bp) was 1.59 times that of AtU6-P promoter(292 bp) when the recipient material was P. quinquefolium callus. The findings provide more ideal endogenous U6 promoters for CRISPR/Cas9 technology in ginseng and other medicinal plants.
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Panax , Panax/genética , Regiones Promotoras Genéticas , Agrobacterium tumefaciens/genética , Biología Computacional , Clonación MolecularRESUMEN
PANoptosis, a new research hotspot at the moment, is a cell death pattern in which pyroptosis, apoptosis, and necroptosis all occur in the same cell population. In essence, PANoptosis is a highly coordinated and dynamically balanced programmed inflammatory cell death pathway that combines the main features of pyroptosis, apoptosis, and necroptosis. Many variables, such as infection, injury, or self-defect, may be involved in the occurrence of PANoptosis, with the assembly and activation of the PANoptosome being the most critical. PANoptosis has been linked to the development of multiple systemic diseases in the human body, including infectious diseases, cancer, neurodegenerative diseases, and inflammatory diseases. Therefore, it is necessary to clarify the process of occurrence, the regulatory mechanism of PANoptosis, and its relation to diseases. In this paper, we summarized the differences and relations between PANoptosis and the three types of programmed cell death, and emphatically expounded molecular mechanism and regulatory patterns of PANoptosis, with the expectation of facilitating the application of PANoptosis regulation in disease treatment.
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Apoptosis , Enfermedades Neurodegenerativas , Humanos , Apoptosis/fisiología , Piroptosis , Muerte Celular , Necroptosis , Enfermedades Neurodegenerativas/terapiaRESUMEN
BACKGROUND: Breast cancer is one of the most common cancers in women, affecting more than 2 million women worldwide annually. However, effective treatments for breast cancer are limited. Nobiletin is a flavonoid present in the dried mature pericarp of mandarin orange (Citrus reticulata Blanco), which is used to prepare Citri Renetulatae Pericarpium and can inhibit tumour growth and progression according to modern pharmacological studies. However, whether nobiletin exhibits an antimetastatic role in breast cancer and its potential mechanism need to be further investigated. PURPOSE: This study aims to evaluate the inhibitory effect of nobiletin on breast cancer and to elucidate potential mechanisms against invasion and migration. METHODS: Cell viability was determined by cell counting kit-8 and colony formation assays. Wound healing and Boyden chamber assays detected cancer cell migration and invasion capabilities. Immunoblotting and qPCR were applied to determine the protein and mRNA expression levels of extracellular signal-regulated kinases (ERK) and the c-Jun N-terminal kinase (JNK) signalling pathways. Molecular docking was used to assess the degree of nobiletin binding to phosphatidylinositol 3-kinase (PI3K). Xenografts and liver metastases were constructed in BALB/c nude mice to evaluate the anticancer effect of nobiletin in vivo. H&E staining and immunohistochemistry were used to detect proliferation and the expression of related proteins. RESULTS: Nobiletin induced cell death in a concentration- and time-dependent manner and possessed anti-invasion and anti-migration effects on MCF-7 and T47D cells by suppressing the interleukin-6-induced ERK and JNK signalling pathways. In addition, nobiletin docked with the binding site of PI3K, and the binding score was -8.0 kcal/mol. Furthermore, the inhibition of breast cancer growth and metastasis by nobiletin was demonstrated by constructing xenografts and liver metastases in vivo. CONCLUSION: Nobiletin inhibited liver metastasis of breast cancer by downregulating the ERK-STAT and JNK-c-JUN pathways, and its safety and efficacy were verified, indicating the potential of nobiletin as an anticancer agent.
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Quinasas MAP Reguladas por Señal Extracelular , Neoplasias Hepáticas , Animales , Femenino , Humanos , Ratones , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Interleucina-6/farmacología , Ratones Desnudos , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
An in-house-developed target amplicon sequencing by next-generation sequencing technology (TB-NGS) enables simultaneous detection of resistance-related mutations in Mycobacterium tuberculosis (MTB) against 8 anti-tuberculosis drug classes. In this multi-center study, we investigated the clinical utility of incorporating TB-NGS for rapid drug-resistant MTB detection in high endemic regions in southeast China. From January 2018 to November 2019, 4,047 respiratory specimens were available from patients suffering lower respiratory tract infections in Hong Kong and Guangzhou, among which 501 were TB-positive as detected by in-house IS6110-qPCR assay with diagnostic sensitivity and specificity of 97.9 and 99.2%, respectively. Preliminary resistance screening by GenoType MTBDRplus and MTBDRsl identified 25 drug-resistant specimens including 10 multidrug-resistant TB. TB-NGS was performed using MiSeq on all drug-resistant specimens alongside 67 pan-susceptible specimens, and demonstrated 100% concordance to phenotypic drug susceptibility test. All phenotypically resistant specimens with dominating resistance-related mutations exhibited a mutation frequency of over 60%. Three quasispecies were identified with mutation frequency of less than 35% among phenotypically susceptible specimens. They were well distinguished from phenotypically resistant cases and thus would not complicate TB-NGS results interpretations. This is the first large-scale study that explored the use of laboratory-developed NGS platforms for rapid TB diagnosis. By incorporating TB-NGS with our proposed diagnostic algorithm, the workflow would provide a user-friendly, cost-effective routine diagnostic solution for complicated TB cases with an average turnaround time of 6 working days. This is critical for timely management of drug resistant TB patients and expediting public health control on the emergence of drug-resistant TB.
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Periprosthetic osteolysis is a major long-term complication of total joint replacement. A series of biological reactions caused by the interaction of wear particles at the prosthesis bone interface and surrounding bone tissue cells after artificial joint replacement are vital reasons for aseptic loosening. Disorder of bone metabolism and aseptic inflammation induced by wear particles are involved in the occurrence and development of aseptic loosening of the prosthesis. Promoting osteogenesis and angiogenesis and mediating osteoclasts and inflammation may be beneficial in preventing the aseptic loosening of the prosthesis. Current research about the prevention and treatment of aseptic loosening of the prosthesis focuses on drug, gene, and stem cell therapy and has not yet achieved satisfactory clinical efficacy or has not been used in clinical practice. Exosomes are a kind of typical extracellular vehicle. In recent years, stem cell exosomes (Exos) have been widely used to regulate bone metabolism, block inflammation, and have broad application prospects in tissue repair and cell therapy.
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Ferroptosis is a kind of iron-dependent regulatory necrosis characterized by the fatal accumulation of iron-dependent lipid peroxides in the plasma membrane and the final oxidative damage of the cell membrane. Morphologically, ferroptosis features high membrane density, decreased or disappeared cristae, rupture of the mitochondrial outer membrane, plasma membrane integrity loss, cytoplasmic swelling, and organelle swelling. Under physiological conditions, ferroptosis occurs through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway, triggered by a series of small molecules inside and outside the cell. At present, it is assumed that ferroptosis is mainly related to abnormal toxicity of iron, lipid peroxidation, and mitochondrial dysfunction. With more detailed studies, ferroptosis plays potential pathogenic roles in multisystem diseases as a pathological response, and targeted regulation of ferroptosis in treating ferroptosis-related diseases has broad prospects. In conclusion, it is of great clinical significance to further clarify the specific mechanism of ferroptosis and explore new strategies for ferroptosis regulation. The present review emphatically summarizes the latest mechanism of ferroptosis, focusing on the regulation mechanism and clinical application of ferroptosis inducers and inhibitors. We are devoted to providing new ideas for the further study of ferroptosis and the diagnosis and treatment of ferroptosis-related multisystem diseases.
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Ferroptosis , Hierro/metabolismo , Peroxidación de Lípido , Peróxidos Lipídicos , Estrés OxidativoRESUMEN
Osteoporosis is a bone metabolic disorder characterized by decreased bone density and deteriorated microstructure, which increases the risk of fractures. The imbalance between bone formation and bone resorption results in the occurrence and progression of osteoporosis. Osteoblast-mediated bone formation, osteoclast-mediated bone resorption and macrophage-regulated inflammatory response play a central role in the process of bone remodeling, which together maintain the balance of the osteoblast-osteoclast-macrophage (OB-OC-MΦ) axis under physiological conditions. Bone formation and bone resorption disorders caused by the imbalance of OB-OC-MΦ axis contribute to osteoporosis. Many microRNAs are involved in the regulation of OB-OC-MΦ axis homeostasis, with microRNA-23a (miR-23a) being particularly crucial. MiR-23a is highly expressed in the pathological process of osteoporosis, which eventually leads to the occurrence and further progression of osteoporosis by inhibiting osteogenesis, promoting bone resorption and inflammatory polarization of macrophages. This review focuses on the role and mechanism of miR-23a in regulating the OB-OC-MΦ axis to provide new clinical strategies for the prevention and treatment of osteoporosis.
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Resorción Ósea , MicroARNs , Osteoporosis , Resorción Ósea/genética , Resorción Ósea/metabolismo , Humanos , Macrófagos/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteoporosis/etiología , Osteoporosis/genética , Osteoporosis/fisiopatología , Osteoporosis/terapiaRESUMEN
A total of 8 bHLH transcription factors were cloned from Panax quinquefolius and the response of them to methyl jasmonate(MeJA) was studied.To be specific, based on the preliminary transcriptome screening, 8 bHLH transcription factors were cloned with seedlings which had been cultured for 3 weeks.The content of ginsenosides Rg_1, Re, and Rb_1, and total saponins in the adventitious roots of P.quinquefolius was determined at different time of MeJA treatment by high performance liquid chromatography(HPLC) and spectrophotometry.Real-time quantitative polymerase chain reaction(PCR) was used to detect the relative expression of 8 transcription factors after MeJA treatment.The correlation between the relative expression of the 8 transcription factors and the saponin content after MeJA treatment was checked by Pearson's correlation analysis.The results showed that the PCR products(Pq-bHLH21-Pq-bHLH28) of the 8 bHLH transcription factors were 762-2 013 bp in length.They were submitted to NCBI to obtain the Genbank access numbers.The proteins yielded from Pq-bHLH21-Pq-bHLH28 showed amino acid sequence identity of 24.90%, and each amino acid sequence had the bHLH(Basic Helix-loop-helix) conserved domain and belonged to the bHLH family.The 5 amino acid sequences of Pq-bHLH22 and Pq-bHLH24-Pq-bHLH27 contained the bHLH-MYC N domain, which belonged to the MYC transcription factors.Pq-bHLH21-Pq-bHLH28 responded to MeJA within 48 h of treatment.At 72 h, the expression of Pq-bHLH24 reached 106.53 folds the highest in the treatment group.Pq-bHLH25, Pq-bHLH27, and Pq-bHLH28 showed synergic expression.Pq-bHLH21 may re-gulate the biosynthetic pathway of ginsenoside Rb_1, while Pq-bHLH22, Pq-bHLH25, and Pq-bHLH28 were in significantly positive correlation with the biosynthetic pathway of ginsenoside Re.The result lays a foundation for further verifying the regulation of ginsenoside biosynthesis by bHLH transcription factors.
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Ginsenósidos , Panax , Saponinas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Clonación Molecular , Panax/genética , Panax/metabolismo , Raíces de Plantas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The homeobox gene family encodes transcription factors that are essential for cell growth, proliferation, and differentiation, and its dysfunction is linked to tumor initiation and progression. Sine oculis homeobox (SIX) belongs to the homeobox gene family, with SIX3 being a core member. Recent studies indicate that SXI3 functions as a cancer suppressor or promoter, which is mainly dependent on SIX3's influence on the signal pathways that promote or inhibit cancer in cells. The low expression of SIX3 in most malignant tumors was confirmed by detailed studies, which could promote the cell cycle, proliferation, migration, and angiogenesis. The recovery or upregulation of SIX3 expression to suppress cancer is closely related to the direct or indirect inhibition of the Wnt pathway. However, in some malignancies, such as esophageal cancer and gastric cancer, SIX3 is a tumor-promoting factor, and repressing SIX3 improves patients' prognosis. This review introduces the research progress of SIX3 in tumors and gives a comprehensive analysis, intending to explain why SIX3 plays different roles in different cancers and provide new cancer therapy strategies.
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Proteínas de Homeodominio , Neoplasias , Humanos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Regiones Promotoras Genéticas , Neoplasias/genética , Neoplasias/terapiaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng Xiaojijinzhan (FZXJJZF) decoction is an effective prescription for treating colorectal cancer liver metastasis (LMCRC). AIM OF THE STUDY: To elucidate the pharmacological mechanism of the FZXJJZF decoction therapy on LMCRC. MATERIALS AND METHODS: Firstly, a network pharmacological approach was used to characterize the underlying targets of FZXJJZF on LMCRC. Secondly, LMCRC-related genes are obtained from the public database TCGA, and those genes are further screened and clustered through Mfuzz, an R package tool. Then, targets of FZXJJZF predicted by network pharmacology were overlapped with LMCRC related genes screened by Mfuzz. Meanwhile, FZJZXJF intervened in LMCRC model,epithelial-to-mesenchymal transition (EMT), and migration and invasion of HCT-116 cells. Thirdly, the transcriptomics data of FZJZXJF inhibited HCT-116 cells of EMT cells were overlapped with EMT database data to narrow the possible range of targets. Based on this, the potential targets and signal pathways of FZJZXJF were speculated by combining the transcriptomics data with the targets from network pharmacology-TCGA. Finally, the anti-cancer mechanism of FZXJJZF on LMCRC was verified in vitro by Real-Time PCR and Western Blot in vitro. RESULTS: By network pharmacological analysis, 282 ingredients and 429 potential targets of FZXJJZF were predicted. The 9268 LMCRC-related genes in the TCGA database were classified into 10 clusters by the Mfuzz. The two clustering genes with the most similar clustering trends were overlapped with 429 potential targets, and 32 genes were found, such as CD34, TRPV3, PGR, VDR, etc. In vivo experiments, FZJZXJF inhibited the tumor size in LMCRC models, and the EMT, migration, and invasion of HCT-116 also be inhibited. Intersecting transcriptomics dates with 32 target genes, it is speculated that the VDR-TGF-ß signaling pathway may be an effective mechanism of FZXJJZF. Additionally, it is shown that FZXJJZF up-regulated the expression levels of VDR and E-cadherin and down-regulated the expression levels of TGF-ß and Snail1 in vitro. These results confirmed that FZXJJZF plays an effective role in LMCRC mainly by inhibiting EMT phenotype via the VDR-TGF-ß signaling pathway. CONCLUSIONS: Collectively, this study reveals the anti-LMCRC effect of FZXJJZF and its potential therapeutic mechanism from the perspective of potential targets and potential pathways.
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Antineoplásicos Fitogénicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Neoplasias Hepáticas/prevención & control , Animales , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Células HCT116 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Ratones , Ratones Desnudos , Invasividad Neoplásica/prevención & control , Farmacología en Red , Receptores de Calcitriol/metabolismo , Transducción de Señal/efectos de los fármacos , Factores de Transcripción de la Familia Snail/metabolismo , Transcriptoma , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Ferroptosis is an iron-dependent regulated necrosis characterized by the peroxidation damage of lipid molecular containing unsaturated fatty acid long chain on the cell membrane or organelle membrane after cellular deactivation restitution system, resulting in the cell membrane rupture. Ferroptosis is biochemically and morphologically distinct and disparate from other forms of regulated cell death. Recently, mounting studies have investigated the mechanism of ferroptosis, and numerous proteins play vital roles in regulating ferroptosis. With detailed studies, emerging evidence indicates that ferroptosis is found in multiple lung diseases, demonstrating that ferroptosis appears to be particularly important for lung diseases. The mounting interest in ferroptosis drugs specifically targeting the ferroptosis mechanism holds substantial therapeutic promise in lung diseases. The present review emphatically summarizes the functions and integrated molecular mechanisms of ferroptosis in various lung diseases, proposing that multiangle regulation of ferroptosis might be a promising strategy for the clinical treatment of lung diseases.
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Ferroptosis/efectos de los fármacos , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/metabolismo , Terapia Molecular Dirigida/métodos , Animales , Autofagia , Humanos , Hierro/metabolismo , Peroxidación de Lípido , Necrosis , Piroptosis , Especies Reactivas de Oxígeno/metabolismo , Resultado del TratamientoRESUMEN
Citrus folium and its main ingredient nobiletin (NOB) have received widespread attention in recent years due to their antitumor effects. The antitumor effect of Citrus folium is related to the traditional use, mainly in its Chinese medicinal properties of soothing the liver and promoting qi, resolving phlegm, and dispelling stagnation. Some studies have proved that Citrus folium and NOB are more effective for triple-negative breast cancer (TNBC), which is related to the syndrome of stagnation of liver qi. From the perspective of modern biomedical research, NOB has anticancer effects. Its potential molecular mechanisms include inhibition of the cell cycle, induction of apoptosis, and inhibition of angiogenesis, invasion, and migration. Citrus folium and NOB can also reduce the side effects of chemotherapy drugs and reverse multidrug resistance (MDR). However, more research studies are needed to clarify the underlying mechanisms. The modern evidence of Citrus folium and NOB in breast cancer treatment has a strong connection with the traditional concepts and laws of applying Citrus folium in Chinese medicine (CM). As a low-toxic anticancer drug candidate, NOB and its structural changes, Citrus folium, and compound prescriptions will attract scientists to use advanced technologies such as genomics, proteomics, and metabolomics to study its potential anticancer effects and mechanisms. On the contrary, there are relatively few studies on the anticancer effects of Citrus folium and NOB in vivo. The clinical application of Citrus folium and NOB as new cancer treatment drugs requires in vivo verification and further anticancer mechanism research. This review aims to provide reference for the treatment of breast cancer by Chinese medicine.
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Activation of inflammasomes has been reported in human pancreatic adenocarcinoma (PAAD); however, the expression pattern and functional role of inflammasome-related proteins in PAAD have yet to be identified. In this study, we systemically examined the expression and role of different inflammasome proteins by retrieving human expression data. Several genes were found to be differentially expressed; however, only interferon-inducible protein 16 (IFI16) expression was found to be adversely correlated with the overall survival of PAAD patients. Overexpression of IFI16 significantly promoted tumor growth, increased tumor size and weight in the experimental PAAD model of mice, and specifically increased the population of tumor-associated macrophages (TAMs) in the tumor microenvironment. Depletion of TAMs by injection of liposome clodronate attenuated the IFI16 overexpression-induced tumor growth in PAAD. In vitro treatment of conditioned medium from IFI16-overexpressing PAAD cells induced maturation, proliferation, and migration of bone marrow-derived monocytes, suggesting that IFI16 overexpression resulted in cytokine secretion that favored the TAM population. Further analysis suggested that IFI16 overexpression activated inflammasomes, thereby increasing the release of IL-1ß. Neutralization of IL-1ß attenuated TAM maturation, proliferation, and migration induced by the conditioned medium from IFI16-overexpressing PAAD cells. Additionally, knockdown of IFI16 could significantly potentiate gemcitabine treatment in PAAD, which may be associated with the reduced infiltration of TAMs in the tumor microenvironment. The findings of our study shed light on the role of IFI16 as a potential therapeutic target for PAAD.
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Adenocarcinoma , Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Gástricas , Humanos , Pulmón , alfa-FetoproteínasRESUMEN
Cynanchum paniculatum Radix, known as Xuchangqing in Chinese, is commonly prescribed in Chinese Medicine (CM) for the treatment of various inflammatory diseases. The anti-inflammatory property of Cynanchum paniculatum can be traced from its wind-damp removing, collaterals' obstruction relieving, and toxins counteracting effects as folk medicine in CM. This paper systematically reviewed the research advancement of the pharmacological effects of Cynanchum paniculatum among a variety of human diseases, including diseases of the respiratory, circulatory, digestive, urogenital, hematopoietic, endocrine and metabolomic, neurological, skeletal, and rheumatological systems and malignant diseases. This review aims to link the long history of clinical applications of Cynanchum paniculatum in CM with recent biomedical investigations. The major bioactive chemical compositions of Cynanchum paniculatum and their associated action mechanism unveiled by biomedical investigations as well as the present clinical applications and future perspectives are discussed. The major focuses of this review are on the diverse mechanisms of Cynanchum paniculatum and the role of its active components in inflammatory diseases.
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PURPOSE: Paeonol, a natural product derived from the root of Cynanchum paniculatum (Bunge) K. Schum and the root of Paeonia suffruticosa Andr. (Ranunculaceae) has attracted extensive attention for its anti-cancer proliferation effect in recent years. The present study examined the role of paeonol in suppressing migration and invasion in pancreatic cancer cells by inhibiting TGF-ß1/Smad signaling. METHODS: Cell viability was evaluated by MTT and colonial formation assay. Migration and invasion capabilities were examined by cell scratch-wound healing assay and the Boyden chamber invasion assay. Western Blot and qRT-PCR were used to measure the protein and RNA levels of vimentin, E-cadherin, N-cadherin, and TGF-ß1/Smad signaling. RESULTS: At non-cytotoxic dose, 100 µΜ and 150 µΜ of paeonol showed significant anti-migration and anti-invasion effects on Panc-1 and Capan-1 cells (p<0.01). Paeonol inhibited epithelial-mesenchymal-transition by upregulating E-cadherin, and down regulating N-cadherin and vimentin expressions. Paeonol inhibited TGF-ß1/Smad signaling pathway by downregulating TGF-ß1, p-Smad2/Smad2 and p-Smad3/Smad3 expressions. Further, TGF-ß1 attenuated the anti-migration and anti-invasion capacities of paeonol in Panc-1 and Capan-1 cells. CONCLUSION: These findings revealed that paeonol could suppress proliferation and inhibit migration and invasion in Panc-1 and Capan-1 cells by inhibiting the TGF-ß1/Smad pathway and might be a promising novel anti-pancreatic cancer drug.
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Tolllike receptor 3 (TLR3) can react with double stranded RNA and is involved in the inflammatory response to respiratory syncytial virus (RSV) infection. Also, oxidative stress has been reported to be involved in RSV infection. However, the correlation between oxidative stress and TLR3 activation during RSV infection is unclear. Therefore, the present study investigated the association between TLR3 expression and oxidative stress modulation during RSV infection in A549 cells. For comparison, seven treatment groups were established, including RSVtreated cells, NacetylLcysteine (NAC)+RSVtreated cells, oxidant hydrogen peroxide (H2O2)+RSVtreated cells, normal cell control, inactivated RSV control, NAC control and H2O2 control. The mRNA expression changes of TLR3, interferon regulatory factor3 (IRF3), nuclear factorκB (NFκB) and superoxide dismutase 1 (SOD1) were measured using semiquantitative reverse transcriptionpolymerase chain reaction, and the protein changes of TLR3 and phosphoNFκB p65 were determined using western blot in A549 cells from the different treatment groups. The present study also evaluated the differences in hydroxyl free radical (·OH), nitric oxide (NO) and total SOD activity in the different treatment groups. The results demonstrated that RSV infection of A549 cells increased the levels of ·OH and NO, while decreasing the activity of total SOD. Pretreatment of A549 cells with H2O2 prior to RSV infection upregulated the mRNA and protein expression of TLR3 and NFκB, and downregulated the mRNA expression of IRF3 and SOD1, as well as the total SOD activity. When the infected cells were pretreated with NAC, the mRNA and protein expression of these genes were reversed. These variations in the TLR3mediated signaling pathway molecules suggested that oxidative stress may be a key regulator for TLR3 activation during RSV infection. RSVinduced oxidative stress may potentially activate TLR3 and enhance TLR3mediated inflammation. These results may provide better understanding of the RSVinduced inflammatory and immune pathways, and may also contribute to the drug development and prevention of human RSV diseases.
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Estrés Oxidativo/genética , Infecciones por Virus Sincitial Respiratorio/genética , Virus Sincitiales Respiratorios/patogenicidad , Receptor Toll-Like 3/genética , Células A549 , Células Epiteliales/virología , Regulación de la Expresión Génica/genética , Humanos , Radical Hidroxilo/metabolismo , Pulmón/patología , Pulmón/virología , Óxido Nítrico/genética , Infecciones por Virus Sincitial Respiratorio/patología , Infecciones por Virus Sincitial Respiratorio/virología , Superóxido Dismutasa-1/genéticaRESUMEN
BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeted treatment has been a standard therapy for advanced non-small cell lung cancer (NSCLC), but it is not tolerated well by all patients. In China, some studies have reported that traditional Chinese medicinal herbs (TCMHs) may increase efficacy and reduce toxicity when combined with EGFR-TKI, but outside of China few studies of this kind have been attempted. OBJECTIVE: This study is intended to systematically review the existing clinical evidence on TCMHs combined with EGFR-TKI for treatment of advanced NSCLC. SEARCH STRATEGY: PubMed, the Cochrane Library, the Excerpta Medica Database (EMBASE), the China BioMedical Literature (CBM), and the China National Knowledge Infrastructure (CNKI) and web site of the American Society of Clinical Oncology (ASCO), the European Society for Medical Oncology (ESMO), the World Conference of Lung Cancer (WCLC) were searched; the search included all documents published in English or Chinese before October 2013. INCLUSION CRITERIA: We selected randomized controlled trials based on specific criteria, the most important of which was that a TCMH plus EGFR-TKI treatment group was compared with an EGFR-TKI control group in patients with advanced NSCLC. DATA EXTRACTION AND ANALYSIS: The modified Jadad scale was used to assess the quality of studies. For each included study, patient characteristics, treatment details, therapeutic approach and clinical outcomes were collected on a standardized form. When disagreements on study inclusion or data extracted from a study emerged, the consensus of all coauthors provided the resolution. The clinical outcome metrics consisted of objective response rate (ORR; complete response + partial response divided by the total number of patients), disease control rate (DCR; complete response + partial response + no change divided by the total number of patients), survival rate, improved or stabilized Karnofsky performance status (KPS), and severe toxicity. RevMan 5.0 software was used for data syntheses and analyses. Risk ratio (RR) and 95% confidence interval (CI) were calculated; if the hypothesis of homogeneity was not rejected (P>0.1, I(2)<50%), the fixed-effect model was used to calculate the summary RR and the 95% CI. Otherwise, a random-effect model was used. RESULTS: In this review, 19 studies were included based on the selection criteria. Of them, 13 studies were of high quality and 6 studies were of low quality, according to the modified Jadad scale. When the TCMH plus EGFR-TKI treatment groups were compared with the EGFR-TKI control groups the meta-analysis demonstrated a statistically significant higher ORR (RR 1.34; 95% CI 1.15 to 1.57; P=0.000 2), DCR (RR 1.18; 95% CI 1.09 to 1.27; P<0.000 1), one-year survival rate (RR 1.21; 95% CI 1.01 to 1.44; P=0.04), 2-year survival rate (RR 1.91; 95% CI 1.26 to 2.89; P=0.002) and improved or stable KPS (RR 1.38; 95% CI 1.26 to 1.51; P<0.000 01). Severe toxicity for rash was decreased (RR 0.55; 95% CI 0.32 to 0.94; P=0.03), as were nausea and vomiting (RR 0.17; 95% CI 0.04 to 0.72; P=0.02) and diarrhea (RR 0.46; 95% CI 0.24 to 0.89; P=0.02). Sensitivity analysis indicated that findings of the meta-analysis were robust to study quality. In the funnel plot analysis, asymmetry was observed, and publication bias was indicated by Egger's test (P=0.03). CONCLUSION: TCMH intervention can increase efficacy and reduce toxicity when combined with EGFR-TKI for advanced NSCLC, although this result requires further verification by more well designed studies.
Asunto(s)
Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Medicamentos Herbarios Chinos/administración & dosificación , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Quimioterapia Combinada , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimología , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: To observe effects of xuefu zhuyu Oral Liquid (XZOL) on the brain behavior and monoamine neurotransmitter 5-HT, and brain derived neurotrophic factor (BDNF) content on depression model rats. METHODS: Male SD rats were randomly divided into the control group, the model group, the XZOL group, and the Deanxit Tablet group, 12 in each group. The depressive rat model was established by chronic unpredictable mild stress method. XZOL was administered to rats in the XZOL group by gastro-gavage, while Deanxit Tablet was given to those in the Deanxit Tablet group by gastrogavage. The intervention lasted for two weeks. The behavioral changes were observed by sucrose water consumption test and open-field test. The 5-HT and BDNF contents were detected using ELISA. RESULTS: After chronic stress stimulus, experimental rats in the model group might have abnormal behavioral changes and lowered 5-HT content, showing statistical difference when compared with the control group (P <0.01). No obvious change in stimulated rats' behavior after intervention of XZOL and Deanxit Tablet. 5-HT content was not obviously reduced (P>0.05). Besides, XZOL was superior to Deanxit Tablet in increasing the 5-HT content (P<0.05). But the brain BDNF level of rats in the model group was not statistically different from that of rats in the model group (P >0.05), while the brain BDNF level of rats in the XZOL group and the Deanxit Tablet group was lower than that of rats in the model group (P <0.01). CONCLUSIONS: Stress can lead to behavioral changes and lowered 5-HT content of rats. The intervention of XZOL could fight against depression-induced behavioral changes and increase 5-HT content. But it did not significantly affect the brain BDNF level. We inferred that it might not effect through the BDNF pathway.