RÉSUMÉ
Lung cancer is the leading cause of cancer-related deaths worldwide, with metastasis being the primary cause of mortality in lung cancer patients, and its prevention and control efficacy remain limited. In recent years, immunotherapy has emerged as a promising direction for overcoming the bottleneck of metastasis. Macrophages, as essential components of innate immunity, participate in the entire process of tumor initiation and progression. Tumor-associated macrophages (TAMs) represent the most abundant immune population in the tumor microenvironment (TME), displaying both anti-tumor M1-like and pro-tumor M2-like phenotypes. The latter promotes tumor invasion and metastasis, angiogenesis, lymphangiogenesis, immune suppression, and reactivation of dormant disseminated tumor cells (DTCs), thereby facilitating tumor metastasis. In recent years, traditional Chinese medicine (TCM) has shown significant efficacy in inhibiting tumor metastasis and has been extensively validated. It exerts anti-tumor effects by reducing the recruitment of TAMs, inhibiting M2-like polarization, and modulating cytokines and proteins in the TME. This paper reviews the relationship between TAMs and lung cancer metastasis, elucidates the targets and mechanisms of TCM in regulating TAMs to prevent and treat lung cancer metastasis, aiming to provide insights into lung cancer prevention and treatment.â©.
Sujet(s)
Tumeurs du poumon , Médecine traditionnelle chinoise , Métastase tumorale , Macrophages associés aux tumeurs , Humains , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Tumeurs du poumon/immunologie , Métastase tumorale/prévention et contrôle , Macrophages associés aux tumeurs/immunologie , Macrophages associés aux tumeurs/métabolisme , Macrophages associés aux tumeurs/effets des médicaments et des substances chimiques , Animaux , Microenvironnement tumoral/effets des médicaments et des substances chimiquesRÉSUMÉ
This study introduces a novel approach of repetitive modeling to simulate the pathological process of recurrent gout attacks in humans. This methodology addresses the instability issues present in rat models of gout, providing a more accurate representation of the damage recurrent gout episodes inflict on human skeletal systems. A soluble nanoneedle system encapsulating colchicine and iguratimod ethosomal formulations was developed. This system aims to modulate inflammatory cytokines and inhibit osteoclast activity, thereby treating inflammatory pain and bone damage associated with recurrent gout. Additionally, a comprehensive evaluation of the microneedles' appearance, morphology, mechanical properties, and penetration capability confirmed their effectiveness in penetrating the stratum corneum. Dissolution tests and skin irritation assessments demonstrated that these microneedles dissolve rapidly without irritating the skin. In vitro permeation studies indicated that transdermal drug delivery via these microneedles is more efficient and incurs lower drug loss compared to traditional topical applications. In vivo pharmacodynamic assessments conducted in animal models revealed significant analgesic and anti-inflammatory effects when both types of microneedles were used together. Further analyses, including X-ray imaging, hematoxylin and eosin (H&E) staining, Safranin-O/fast green staining, tartrate-resistant acid phosphatase staining, and quantification of osteoclasts, confirmed the bone-protective effects of the microneedle combination. In conclusion, the findings of this research underscore the potential of this novel therapeutic approach for clinical application in the treatment of recurrent gout.
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8-17 DNAzymes (8-17, 17E, Mg5, and 17EV1) are in vitro-selected catalytic DNA molecules that are capable of cleaving complementary RNAs. The conserved residues in their similar catalytic cores, together with the metal ions, were suggested to contribute to the catalytic reaction. Based on the contribution of the less conserved residues in the bulge loop residues (W12, A15, A15.0) and the internal stem, new catalytic cores of 8-17 DNAzymes were programmed. The internal stem CTC-GAG seems to be more favorable for the DNAzymes than CCG-GGC, while an extra W12.0 led to a significant loss of activity of DNAzymes, which is contrary to the positive effect of A15.0, by which a new active DNAzyme 17EM was derived. It conducts a faster reaction than 17E. It is most active in the presence of Pb2+, with the metal ion preference of Pb2+ >> Zn2+ > Mn2+ > Ca2+ ≈ Mg2+. In the Pb2+ and Zn2+-mediated reactions of 17EM and 17E, the same Na+- and pH dependence were also observed as what was observed for 17E and other 8-17 DNAzymes. Therefore, 17EM is another member of the 8-17 DNAzymes, and it could be applied as a potential biosensor for RNA and metal ions.
Sujet(s)
ADN catalytique , ADN catalytique/composition chimique , ADN catalytique/métabolisme , Conformation d'acide nucléique , Catalyse , Concentration en ions d'hydrogène , Domaine catalytique , Séquence nucléotidique , Métaux/composition chimiqueRÉSUMÉ
BACKGROUND: Breast cancer patients undergoing chemotherapy via peripherally inserted central catheter often experience serious behavioral and psychological challenges, with uncertainty and cancer-related fatigue being prevalent issues that profoundly impact prognosis. Therefore, this study aimed to investigate the relationship between uncertainty and cancer-related fatigue by employing a chain mediation model to examine the potential mediating roles of psychological resilience and self-care. METHODS: A cross-sectional study was conducted with 223 breast cancer patients receiving peripherally inserted central catheter chemotherapy at two tertiary affiliated hospitals of China Medical University in Liaoning, China, from February 2021 to December 2022. Participants completed self-reported questionnaires to assess uncertainty, psychological resilience, self-care, and cancer-related fatigue. The collected data were subsequently analyzed using Pearson's correlation analysis, hierarchical regression analysis, and mediation analysis. RESULTS: Uncertainty exhibited a significant positive correlation with cancer-related fatigue (p < 0.01) and a negative correlation with psychological resilience (p < 0.01) and self-care (p < 0.01). Uncertainty was found to impact cancer-related fatigue through three pathways: psychological resilience mediated the relationship between uncertainty and cancer-related fatigue (mediating effect = 0.240, 95% confidence interval: 0.188 to 0.298, effect ratio = 53.22%); self-care also mediated this relationship (mediating effect = 0.080, 95% confidence interval: 0.044 to 0.121, effect ratio = 17.74%); furthermore, there was a significant joint mediating effect of psychological resilience and self-care on the association between uncertainty and cancer-related fatigue (mediating effect = 0.042, 95% confidence interval: 0.021 to 0.068, effect ratio o = 9.31%). CONCLUSION: The findings of this study revealed that uncertainty not only directly influenced cancer-related fatigue, but also operated through the mediating effect of psychological resilience, self-care, and sequential mediation of psychological resilience and self-care. Interventions tailored for breast cancer patients receiving peripherally inserted central catheter chemotherapy should target these factors to help alleviate uncertainty, enhance psychological resilience, and improve self-care practices, thereby ameliorating cancer-related fatigue.
Sujet(s)
Tumeurs du sein , Fatigue , Résilience psychologique , Autosoins , Humains , Femelle , Tumeurs du sein/psychologie , Tumeurs du sein/complications , Tumeurs du sein/traitement médicamenteux , Fatigue/psychologie , Fatigue/étiologie , Incertitude , Adulte d'âge moyen , Autosoins/psychologie , Autosoins/méthodes , Études transversales , Adulte , Chine/épidémiologie , Enquêtes et questionnaires , Cathétérisme périphérique/psychologie , Cathétérisme périphérique/effets indésirables , Sujet âgé , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/effets indésirables , Antinéoplasiques/administration et posologieRÉSUMÉ
Mammary tumors are the most frequent type of neoplasms in intact female dogs. New therapies that target neoplastic cells without affecting normal cells are highly sought. The Bacillus anthracis toxin has been reengineered to target tumor cells that express urokinase plasminogen activators and metalloproteinases. In previous studies carried out in our laboratory, the reengineered anthrax toxin had inhibitory effects on canine oral mucosal melanoma and canine osteosarcoma cells. In this study, five canine neoplastic epithelial cell lines (four adenocarcinomas and one adenoma) and one non-neoplastic canine mammary epithelial cell line were treated with different concentrations of reengineered anthrax toxin components. Cell viability was quantified using an MTT assay and half-maximal inhibitory concentration (IC50) values. Cell lines were considered sensitive when the IC50 was lower than 5000 ng/ml. One canine mammary adenocarcinoma cell line and one mammary adenoma cell line showed significantly decreased viability after treatment, whereas the non-neoplastic cell line was resistant. We conclude that the reengineered anthrax toxin may be considered a targeted therapy for canine mammary neoplasms while preserving normal canine mammary epithelial cells.
Sujet(s)
Antigènes bactériens , Toxines bactériennes , Maladies des chiens , Tumeurs mammaires de l'animal , Animaux , Chiens , Tumeurs mammaires de l'animal/traitement médicamenteux , Toxines bactériennes/pharmacologie , Femelle , Antigènes bactériens/pharmacologie , Lignée cellulaire tumorale , Maladies des chiens/traitement médicamenteux , Cellules épithéliales/effets des médicaments et des substances chimiques , Adénocarcinome/médecine vétérinaire , Adénocarcinome/traitement médicamenteux , Adénocarcinome/anatomopathologie , Survie cellulaire/effets des médicaments et des substances chimiques , Adénomes/médecine vétérinaire , Adénomes/traitement médicamenteux , Adénomes/anatomopathologieRÉSUMÉ
Here, we describe an iron-catalyzed benzylic C-H thiolation of alkylarenes via photoinduced ligand-to-metal charge-transfer. The protocol features operational simplicity, mild reaction conditions, and the use of FeCl3 as catalyst and thiols/disulfides as sulfur sources, which enables the transformation of diverse benzylic C-H bonds into C-S bonds with a high efficiency.
RÉSUMÉ
OBJECTIVES: This study aimed to isolate a phage capable of lysing carbapenem-resistant Klebsiella pneumoniae (CRKP) and to analyse its biological characteristics and whole-genome sequence. METHODS: The phage was isolated and purified from the sewage. Transmission electron microscopy (TEM) was employed to observe the bacteriophage's morphology. Phenotypic characterization of the bacteriophages was determined. The genomic information was analysed. Evolutionary relationships were established through comparative genomics, proteomics, and phylogenetic analysis. RESULTS: The isolation of a virulent phage, named Klebsiella phage vB_KpnM_KpVB3, was notable for forming 6-7 mm transparent circular zones, each surrounded by a distinct halo. The phage had a head diameter of ca. 30 nm and a tail length of ca. 20 nm, being identified as a member of the Myoviridae family and the Caudovirales order. The optimal multiplicity of infection (MOI) was 0.00001, with an incubation period of 20 minutes and a lysis period of 60 minutes, and the number of released phages after lysis was 133±35 PFU/cell. The phage was relatively stable at temperatures ranging from 10°C to 40°C and at pH values ranging from 3 to 11. Its lytic efficiency against CRKP was 30.30%. It has been shown to be able to destroy the biofilm of host bacteria. The bacteriophage genome consists of double-stranded DNA (dsDNA) with a total length of 48,394 base pairs, a GC content of 48.99%, and 78 open reading frames (ORFs). CONCLUSION: The study resulted in the isolation vB_KpnM_KpVB3, a phage demonstrating potential therapeutic efficacy against infections caused by CRKP.
Sujet(s)
Bactériophages , Génome viral , Klebsiella pneumoniae , Phylogenèse , Klebsiella pneumoniae/virologie , Klebsiella pneumoniae/effets des médicaments et des substances chimiques , Bactériophages/isolement et purification , Bactériophages/génétique , Bactériophages/physiologie , Bactériophages/classification , Carbapénèmes/pharmacologie , Myoviridae/génétique , Myoviridae/isolement et purification , Myoviridae/classification , Myoviridae/physiologie , Enterobacteriaceae résistantes aux carbapénèmes/isolement et purification , Enterobacteriaceae résistantes aux carbapénèmes/virologie , Enterobacteriaceae résistantes aux carbapénèmes/génétique , Séquençage du génome entier , Eaux d'égout/virologie , Eaux d'égout/microbiologie , Microscopie électronique à transmission , Antibactériens/pharmacologie , Infections à Klebsiella/microbiologie , Caudovirales/génétique , Caudovirales/isolement et purification , Caudovirales/classification , Caudovirales/physiologie , HumainsRÉSUMÉ
The Dph1â¢Dph2 heterodimer from yeast is a radical SAM (RS) enzyme that generates the 3-amino-3-carboxy-propyl (ACP) precursor for diphthamide, a clinically relevant modification on eukaryotic elongation factor 2 (eEF2). ACP formation requires SAM cleavage and atypical Cys-bound Fe-S clusters in each Dph1 and Dph2 subunit. Intriguingly, the first Cys residue in each motif is found next to another ill-defined cysteine that we show is conserved across eukaryotes. As judged from structural modeling, the orientation of these tandem cysteine motifs (TCMs) suggests a candidate Fe-S cluster ligand role. Hence, we generated, by site-directed DPH1 and DPH2 mutagenesis, Dph1â¢Dph2 variants with cysteines from each TCM replaced individually or in combination by serines. Assays diagnostic for diphthamide formation in vivo reveal that while single substitutions in the TCM of Dph2 cause mild defects, double mutations almost entirely inactivate the RS enzyme. Based on enhanced Dph1 and Dph2 subunit instability in response to cycloheximide chases, the variants with Cys substitutions in their cofactor motifs are particularly prone to protein degradation. In sum, we identify a fourth functionally cooperative Cys residue within the Fe-S motif of Dph2 and show that the Cys-based cofactor binding motifs in Dph1 and Dph2 are critical for the structural integrity of the dimeric RS enzyme in vivo.
Sujet(s)
Motifs d'acides aminés , Cystéine , Histidine/analogues et dérivés , Protéines de répression , Protéines de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Cystéine/métabolisme , Cystéine/génétique , Cystéine/composition chimique , Protéines de Saccharomyces cerevisiae/métabolisme , Protéines de Saccharomyces cerevisiae/génétique , Protéines de Saccharomyces cerevisiae/composition chimique , Saccharomyces cerevisiae/génétique , Saccharomyces cerevisiae/métabolisme , Saccharomyces cerevisiae/enzymologie , Multimérisation de protéines , Carbon-sulfur lyases/métabolisme , Carbon-sulfur lyases/composition chimique , Carbon-sulfur lyases/génétique , Mutagenèse dirigéeRÉSUMÉ
Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis. Abnormal expression of H3-H4 histone chaperones has been identified in many cancers and holds promise as a biomarker for diagnosis and prognosis. However, systemic analysis of H3-H4 histone chaperones in HCC is still lacking. Here, we investigated the expression of 19 known H3-H4 histone chaperones in HCC. Integrated analysis of multiple public databases indicated that these chaperones are highly expressed in HCC tumor tissues, which was further verified by immunohistochemistry (IHC) staining in offline samples. Additionally, survival analysis suggested that HCC patients with upregulated H3-H4 histone chaperones have poor prognosis. Using LASSO and Cox regression, we constructed a two-gene model (ASF1A, HJURP) that accurately predicts prognosis in ICGC-LIRI and GEO HCC data, which was further validated in HCC tissue microarrays with follow-up information. GSEA revealed that HCCs in the high-risk group were associated with enhanced cell cycle progression and DNA replication. Intriguingly, HCCs in the high-risk group exhibited increased immune infiltration and sensitivity to immune checkpoint therapy (ICT). In summary, H3-H4 histone chaperones play a critical role in HCC progression, and the two-gene (ASF1A, HJURP) risk model is effective for predicting survival outcomes and sensitivity to immunotherapy for HCC patients.
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Carcinome hépatocellulaire , Tumeurs du foie , Humains , Carcinome hépatocellulaire/génétique , Protéines du cycle cellulaire/génétique , Protéines du cycle cellulaire/métabolisme , Chaperons d'histones/métabolisme , Histone/génétique , Histone/métabolisme , Tumeurs du foie/génétique , Chaperons moléculaires/génétique , Chaperons moléculaires/métabolisme , PronosticRÉSUMÉ
Sorafenib resistance is one of the main causes of poor prognosis in patients with advanced hepatocellular carcinoma (HCC). Long noncoding RNAs (lncRNAs) function as suppressors or oncogenic factors during tumor progression and drug resistance. Here, to identify therapeutic targets for HCC, the biological mechanisms of abnormally expressed lncRNAs were examined in sorafenib-resistant HCC cells. Specifically, we established sorafenib-resistant HCC cell lines (Huh7-S and SMMC7721-S), which displayed an epithelial-mesenchymal transition (EMT) phenotype. Transcriptome sequencing (RNA-Seq) was performed to established differential lncRNA expression profiles for sorafenib-resistant cells. Through this analysis, we identified LINC00540 as significantly up-regulated in sorafenib-resistant cells and a candidate lncRNA for further mechanistic investigation. Functionally, LINC00540 knockdown promoted sorafenib sensitivity and suppressed migration, invasion, EMT and the activation of PI3K/AKT signaling pathway in sorafenib-resistant HCC cells, whereas overexpression of LINC00540 resulted in the opposite effects in parental cells. LINC00540 functions as a competing endogenous RNA (ceRNA) by competitively binding to miR-4677-3p , thereby promoting AKR1C2 expression. This is the first study that demonstrates a role for LINC00540 in enhancing sorafenib resistance, migration and invasion of HCC cells through the LINC00540/miR-4677-3p/AKR1C2 axis, suggesting that LINC00540 may represent a potential therapeutic target and prognosis biomarker for HCC.
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The worldwide incidence and mortality rates of esophageal squamous cell carcinoma (ESCC) have increased over the last decade. Moreover, molecular targets that may benefit the therapeutics of patients with ESCC have not been fully characterized. Our study discovered that thousand and one amino-acid protein kinase 1 (TAOK1) is highly expressed in ESCC tumor tissues and cell lines. Knock-down of TAOK1 suppresses ESCC cell proliferation in vitro and patient-derived xenograft or cell-derived xenograft tumors growth in vivo. Moreover, TAOK1 overexpression promotes ESCC growth in vitro and in vivo. Additionally, we identified that the natural small molecular compound resveratrol binds to TAOK1 directly and diminishes the kinase activity of TAOK1. Targeting TAOK1 directly with resveratrol significantly inhibits cell proliferation, induces cell cycle arrest and apoptosis, and suppresses tumor growth in ESCC. Furthermore, the silencing of TAOK1 or the application of resveratrol attenuated the activation of TAOK1 downstream signaling effectors. Interestingly, combining resveratrol with paclitaxel, cisplatin, or 5-fluorouracil synergistically enhanced their therapeutic effects against ESCC. In conclusion, this work illustrates the underlying oncogenic function of TAOK1 and provides a theoretical basis for the application of targeting TAOK1 therapy to the clinical treatment of ESCC.
Sujet(s)
Tumeurs de l'oesophage , Carcinome épidermoïde de l'oesophage , Protein-Serine-Threonine Kinases , Humains , Apoptose , Lignée cellulaire tumorale , Prolifération cellulaire , Tumeurs de l'oesophage/traitement médicamenteux , Tumeurs de l'oesophage/génétique , Tumeurs de l'oesophage/métabolisme , Carcinome épidermoïde de l'oesophage/traitement médicamenteux , Carcinome épidermoïde de l'oesophage/génétique , Carcinome épidermoïde de l'oesophage/métabolisme , Régulation de l'expression des gènes tumoraux , Protein-Serine-Threonine Kinases/effets des médicaments et des substances chimiques , Protein-Serine-Threonine Kinases/génétique , Protein-Serine-Threonine Kinases/métabolisme , Resvératrol/pharmacologie , Resvératrol/usage thérapeutiqueRÉSUMÉ
Regulatory complexities in lipogenesis hinder the harmonization of metabolic carbon precursors towards lipid synthesis. Exploring regulatory complexities in lipogenesis, this study identifies NADP+-dependent isocitrate dehydrogenase (IDH) in Tetradesmus obliquus as a key factor. Overexpression IDH in strains ToIDH-1 and ToIDH-2 resulted in a 1.69 and 1.64-fold increase in neutral lipids, respectively, compared to the wild type, with lipid yield reaching 234.56 and 227.17 mg/L. Notably, despite slower growth, the cellular biomass augmented to 790.67 mg/L. Metabolite analysis indicated a shift in carbon precursors from protein to lipid and carbohydrate synthesis. Morphological observations revealed increases in the volume and number of lipid droplets, alongside a change in the fatty acid profile favoring monounsaturated and saturated fatty acids. Furthermore, IDH overexpression enhanced NADPH production and antioxidant activity, thereby further boosting lipid accumulation when combined with salt stress. This study suggests a pathway for improved lipogenesis and algal growth via metabolic engineering.
Sujet(s)
Antioxydants , Isocitrate dehydrogenases , Isocitrate dehydrogenases/génétique , Isocitrate dehydrogenases/métabolisme , NADP/métabolisme , NADPH dehydrogenase , Acides gras , CarboneRÉSUMÉ
The potential of Ferrimagnetic vortex iron oxide nanoring-mediated mild magnetic hyperthermia (FVIO-MHT) in solid tumor therapy has been demonstrated. However, the impact of FVIO-MHT on the tumor microenvironment (TME) remains unclear. This study utilized single-cell transcriptome sequencing to examine the alterations in the TME in response to FVIO-MHT in breast cancer. The results revealed the cellular composition within the tumor microenvironment (TME) was primarily modified due to a decrease in tumor cells and an increased infiltration of myeloid cells. Subsequently, an enhancement in active oxygen (ROS) metabolism was observed, indicating oxidative damage to tumor cells. Interestingly, FVIO-MHT reprogrammed the macrophages' phenotypes, as evidenced by alterations in the transcriptome characteristics associated with both classic and alternative activated phenotypes. And an elevated level of ROS generation and oxidative phosphorylation suggested that activated phagocytosis and inflammation occurred in macrophages. Additionally, cell-cell communication analysis revealed that FVIO-MHT attenuated the suppression between tumor cells and macrophages by inhibiting phagocytic checkpoint and macrophage migration inhibitory factor signaling pathways. Inhibition of B2m, an anti-phagocytosis checkpoint, could promote macrophage-mediated phagocytosis and significantly inhibit tumor growth. These data emphasize FVIO-MHT may promote the antitumor capabilities of macrophages by alleviating the suppression between tumor cells and macrophages.
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Tumeurs du sein , Hyperthermie provoquée , Humains , Femelle , Tumeurs du sein/génétique , Tumeurs du sein/thérapie , Espèces réactives de l'oxygène/pharmacologie , Macrophages , Phénomènes magnétiques , Analyse de profil d'expression de gènes , Microenvironnement tumoralRÉSUMÉ
Recently, PI3K and HDAC have been considered as promising targets for the cancer therapy. A couple of pan-PI3K/HDAC dual inhibitors have been developed as a new class of anticancer agents. Herein, we discovered a new series of (S)-N1-(thiazol-2-yl) pyrrolidine-1,2-dicarboxamide derivatives targeting PI3Kα/HDAC6. All the derivatives exerted dual-target inhibitory activities. Particularly, in the enzymatic selectivity assay, compound 21j was identified as a subtype-selective PI3Kα/HDAC6 dual inhibitor (IC50 = 2.9 and 26 nM against PI3Kα and HDAC6, respectively), which displayed high potency against L-363 cell line with IC50 value of 0.17 µM. In addition, 21j significantly inhibited phosphorylation of pAkt(Ser473) and induced accumulation of acetylated α-tubulin while having a negligible effect on the levels of acetylated Histone H3 and H4 at nanomolar level. Attributed to its favorable in vitro performance, 21j has the potential to alleviate the adverse effects resulted from pan-PI3K inhibition and pan-HDAC inhibition. It is valuable for further functional investigation as an anti-cancer agent.
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Tumeurs , Humains , Dosages enzymatiques , Histone deacetylase 6 , Inhibiteurs de désacétylase d'histone/pharmacologie , Histone , Tumeurs/traitement médicamenteux , Pyrrolidines , Phosphatidylinositol 3-kinase , Inhibiteurs des phosphoinositide-3 kinases/composition chimique , Inhibiteurs des phosphoinositide-3 kinases/pharmacologieRÉSUMÉ
Herein, we have designed and synthesized a novel type-I photosensitizer (PhPA) via Rh-catalyzed oxidative cyclization of diacetoxyterephthalamide with alkynes. The photoelectric properties, photosensitivity and photodegradation process of PhPA have been systematically investigated. The remarkable fluorescence quenching effect (ΦPL < 0.01) of PhPA suggests that the intersystem crossing from the singlet excited state to the reactive triplet state is enhanced by the enlarged conjugated backbone. Additionally, the ability of superoxide radical (O2-Ë) generation was confirmed by electron paramagnetic resonance spectroscopy. Finally, the mechanism of PhPA photo-oxidative degradation via the structure of two metabolites is proposed.
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Cationic polymeric materials and cell-penetrating peptides (CPPs) were often used as the delivery vectors in the evaluation of nucleic acid therapeutics. 10-23 DNAzyme is a kind of potential antisense therapeutics by catalytic cleavage of the disease-related RNAs. Here, lipofectamine 2000 and Tat peptide were evaluated for their effect on the catalytic activity of 10-23 DNAzyme, with the observed rate constant, thermal stability, CD spectra, and PAGE analysis, with a duplex DNA mimicking DNAzyme-substrate as a control. It was shown that the cationic carriers had a negative effect on the catalytic performance of the 10-23 DNAzyme. Significantly, the destabilizing effect of the cationic carriers on the duplex formation was noteworthy, as a duplex formation is an essential prerequisite in the silencing mechanisms of antisense and RNAi.
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Peptides de pénétration cellulaire , ADN catalytique , ADN catalytique/composition chimique , Peptides de pénétration cellulaire/pharmacologie , Peptides de pénétration cellulaire/composition chimique , Lipides , ADN , CationsRÉSUMÉ
Disulfiram (DSF), a drug for alcohol withdrawal, has attracted extensive scientific attention due to its potential to treat cancer. The metabolite of DSF, diethyl dithiocarbamate (DDTC), forms a Cu-DDTC complex in vivo with copper ions, which has been shown to be a proteasome inhibitor with high antitumor activity. However, the in vivo stability of Cu-DDTC complexes remains a challenge. In this study, the nanomedicine Cu-BTC@DDTC with high antitumor activity was prepared by using the nanoscale metal-organic framework (MOF) Cu-BTC as a carrier and loading diethyldithiocarbamate (DDTC) through coordination interaction. The results showed that Cu-BTC@DDTC had high drug loading and adequate stability, and exhibited DDTC-Cu(I) chemical valence characteristics and polycrystalline structure features. In vitro cytocompatibility investigation and animal xenograft tumor model evaluation demonstrated the anti-cancer potential of Cu-BTC@DDTC, especially the combination of Cu-BTC@DDTC with low-dose cisplatin showed significant antitumor effect and biosafety. This study provides a feasible protocol for developing antitumor drugs based on the drug repurposing strategy.
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Alcoolisme , Ferroptose , Mélanome , Réseaux organométalliques , Syndrome de sevrage , Animaux , Humains , Acide diéthyl-dithiocarbamique/pharmacologie , Réseaux organométalliques/pharmacologie , Réseaux organométalliques/métabolisme , Disulfirame/pharmacologie , Disulfirame/métabolisme , Mélanome/traitement médicamenteux , Cuivre/composition chimique , Lignée cellulaire tumorale , Système y+ de transport d'acides aminésRÉSUMÉ
NK-4 plays a key role in the treatment of various diseases, such as in hay fever to expect anti-allergic effects, in bacterial infections and gum abscesses to expect anti-inflammatory effects, in scratches, cuts, and mouth sores from bites inside the mouth for enhanced wound healing, in herpes simplex virus (HSV)-1 infections for antiviral effects, and in peripheral nerve disease that causes tingling pain and numbness in hands and feet, while NK-4 is used also to expect antioxidative and neuroprotective effects. We review all therapeutic directions for the cyanine dye NK-4, as well as the pharmacological mechanism of NK-4 in animal models of related diseases. Currently, NK-4, which is sold as an over-the-counter drug in drugstores, is approved for treating allergic diseases, loss of appetite, sleepiness, anemia, peripheral neuropathy, acute suppurative diseases, wounds, heat injuries, frostbite, and tinea pedis in Japan. The therapeutic effects of NK-4's antioxidative and neuroprotective properties in animal models are now under development, and we hope to apply these pharmacological effects of NK-4 to the treatment of more diseases. All experimental data suggest that different kinds of utility of NK-4 in the treatment of diseases can be developed based on the various pharmacological properties of NK-4. It is expected that NK-4 could be developed in more therapeutic strategies to treat many types of diseases, such as neurodegenerative and retinal degenerative diseases.
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Herpès , Infections à Herpesviridae , Animaux , Cellules tueuses naturelles , CarbocyaninesRÉSUMÉ
The limited efficacy of the current antitumor microenvironment strategies is due in part to the poor understanding of the roles and relative contributions of the various tumor stromal cells to tumor development. Here, we describe a versatile in vivo anthrax toxin protein delivery system allowing for the unambiguous genetic evaluation of individual tumor stromal elements in cancer. Our reengineered tumor-selective anthrax toxin exhibits potent antiproliferative activity by disrupting ERK signaling in sensitive cells. Since this activity requires the surface expression of the capillary morphogenesis protein-2 (CMG2) toxin receptor, genetic manipulation of CMG2 expression using our cell-type-specific CMG2 transgenic mice allows us to specifically define the role of individual tumor stromal cell types in tumor development. Here, we established mice with CMG2 only expressed in tumor endothelial cells (ECs) and determined the specific contribution of tumor stromal ECs to the toxin's antitumor activity. Our results demonstrate that disruption of ERK signaling only within tumor ECs is sufficient to halt tumor growth. We discovered that c-Myc is a downstream effector of ERK signaling and that the MEK-ERK-c-Myc central metabolic axis in tumor ECs is essential for tumor progression. As such, disruption of ERK-c-Myc signaling in host-derived tumor ECs by our tumor-selective anthrax toxins explains their high efficacy in solid tumor therapy.