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1.
Contrast Media Mol Imaging ; 2022: 1892384, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35909589

RESUMO

Lung adenocarcinoma (LUAD) is one of the major causes of cancer death in the world. Studies show that the effective anticancer component in blister beetles is cantharidin, which can improve chemotherapy efficacy, median survival, and prognosis of LUAD. However, the antitumor mechanism of blister beetles has not been fully clarified. This study aimed to identify the key targets of the treatment of LUAD by blister beetles based on the principle of network pharmacology. An integrated approach including network pharmacology and a molecular docking technique was conducted, which mainly comprises target prediction, weighted gene correlation network analysis (WGCNA) analysis, network construction, gene ontology, and pathway enrichment analysis. 35 key targets were obtained and significantly associated with response to external stimuli, collagen binding, cyclin binding, organic acid binding, pyruvate metabolism, glycolysis, and amino acid biosynthesis pathways. Both LASSO regression and the RF model had a high predictive ability, and 9 candidate genes were screened, among which BIRC5 and PLK1 were the key targets for the treatment of LUAD by using blister beetles and showed significant survival significance. Cantharidin exerts its antitumor effects through 8 targets in 32 pathways, while BIRC5 and PLK1 have obvious survival significance.


Assuntos
Adenocarcinoma de Pulmão , Besouros , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Animais , Cantaridina/química , Cantaridina/farmacologia , Cantaridina/uso terapêutico , Besouros/genética , Besouros/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Simulação de Acoplamento Molecular , Farmacologia em Rede
2.
Biomed Pharmacother ; 153: 113328, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35785701

RESUMO

Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar concentrations of hydrophobic weak-base anticancer drugs. However, since lysosomal stress mediated by accumulation of weak-base drugs at such concentrations has never been proven and these drugs have diverse effects on malignant cells, we investigated whether the interpretation of the data was true. We found that lysosomal accumulation of the drugs daunorubicin, doxorubicin, mitoxantrone, symadex, chloroquine, clomipramine and sunitinib alone, was insufficient to induce lysosomal alkalization i.e., lysosomal stress-mediated biogenesis at nanomolar concentrations. Instead, we found that some of the drugs used induced G2 phase arrest and lysosomal biogenesis that is associated with activation of transcription factor EB (TFEB). Similarly, cantharidin, a control compound that does not belong to the weak base drugs, induced cell cycle arrest in the G2 phase associated with TFEB-driven lysosomal biogenesis. Overall none of the tested drugs caused stress-induced lysosomal biogenesis at nanomolar concentrations. However, daunorubicin, doxorubicin, mitoxantrone, symadex and cantharidin induced a massive block in the G2 phase of the cell cycle which is naturally associated with TFEB-driven lysosomal biogenesis.


Assuntos
Cantaridina , Mitoxantrona , Autofagia , Ciclo Celular , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Lisossomos/metabolismo , Mitoxantrona/farmacologia
3.
J Insect Sci ; 22(3)2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35762395

RESUMO

Cantharidin (CTD) is a defensive compound autogenously and exclusively produced by two phylogenetically related beetle families: Meloidae and Oedemeridae. Although this molecule usually acts as a strong deterrent against potential predators and parasites, some arthropod species, collectively named 'canthariphilous species', are attracted to CTD. Some species can sequester CTD from the CTD-producing species, using it as a chemical defense against enemies. The present paper focuses on the first-ever description of canthariphilous interactions between a checkered beetle species (Coleoptera: Cleridae) and a CTD -producing species. Field observations revealed individuals of the phytophagous beetle Tilloidea transversalis (Charpentier, 1825) (Coleoptera: Cleridae) biting individuals of the blister beetle Lydus trimaculatus (Fabricius, 1775) (Coleoptera: Meloidae). Laboratory behavioral experiments followed to verify if this peculiar behavior of T. transversalis also occurs on other co-occurring species. Moreover, chemical analyses were performed to assess whether T. transversalis can sequester CTD. Our results show that T. transversalis only attacks CTD-producing species. However, while chemical analyses prove that T. transversalis can sequester CTD from the hemolymph of L. trimaculatus, some clues (based on a CTD-baited traps sampling) suggest that this beetle, contrarily to other canthariphilous species, does not appear to show a high attraction to pure synthetic CTD. Thus, other unknown signals, alone or in combination with CTD, could be implicated in triggering the canthariphilous behaviors of T. transversalis.


Assuntos
Cantaridina , Besouros , Animais , Besouros/química , Hemolinfa
4.
Food Chem Toxicol ; 163: 112986, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35398186

RESUMO

Mylabris, as a natural product of traditional Chinese medicine (TCM), exhibiting typical antitumor activity, and cantharidin (CTD) is the major bioactive component. However, drug-induced nephrotoxicity (DIN) extremely limited its clinical application. In this study, we proved that activation of the endoplasmic reticulum (ER) stress-dependent PERK/CHOP pathway exerts a toxic role in rats and HK-2 cells through inducing autophagy and apoptosis. Results showed that CTD could cause renal function damage, cytotoxicity, and apoptosis. The ER dilatation and autolysosomes were observed after CTD treatment. Furthermore, the distribution of LC3, ATF4, and CHOP proteins was observed in the nucleus and cytoplasm. In addition, the mRNA levels of ER stress-regulated genes (PERK, eIF2α, CHOP, and ATF4) were increased, and the expression levels of GRP78, ATF4, CHOP, LC3, Beclin-1, Atg3, Atg7, Caspase 3, and Bax/Bcl-2 proteins were increased both in vitro and in vivo. Consistently, this upregulation could be inhibited by an ER stress inhibitor 4-Phenylbutyric acid (4-PBA), indicating that ER stress is partly responsible for activation of autophagy and apoptosis in CTD-induced DIN. In conclusion, CTD could induce DIN by triggering ER stress, further activating autophagy and apoptosis both in vivo and in vitro.


Assuntos
Cantaridina , Estresse do Retículo Endoplasmático , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Animais , Apoptose , Autofagia , Cantaridina/efeitos adversos , Ratos , Transdução de Sinais , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/metabolismo
5.
Fish Shellfish Immunol ; 123: 20-35, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35218974

RESUMO

Cantharidin is a toxic vesicant terpene used in folk and traditional medicine due to its various therapeutic effects. Since there are no previous data on the effect of cantharidin in fish, this study aimed to investigate the in vitro related-inflammatory effects of cantharidin in gilthead seabream (Sparus aurata L.) head-kidney leucocytes (HKLs). In the first experiment, the HKLs were incubated with 0, 5 and 10 µg mL-1 of cantharidin for 24 h to delimit its possible toxic effects. In a second experiment, leucocytes were incubated with ranging concentrations from 0 to 10 µg mL-1 for 3, 6, or 12 h. Cell viability was higher in acidophilic granulocytes than in monocytes/macrophages and lymphocytes. Cantharidin caused apoptosis as was evidenced by transmission electron microscopy. In addition, cantharidin produced a time- and dose-dependent decrease of respiratory burst and phagocytic activities in HKLs, while their peroxidase activity was increased at 24 h of incubation with 5 and 10 µg mL-1 of cantharidin. Different changes in the gene expression were observed after incubation with cantharidin. While the gene expression of tnfa, il1b and crel was up-regulated in HKLs, the nfkb1 and igmh genes were down-regulated in comparison to the expression found in control HKLs. Present results offer a first view of the possible effects and action mechanisms of cantharidin in HKLs, as well as its implication in the inflammatory process, which could be of interest not only for basic research but also in the aquaculture sector.


Assuntos
Dourada , Animais , Cantaridina/metabolismo , Cantaridina/toxicidade , Rim Cefálico , Rim , Leucócitos , Dourada/metabolismo
6.
Br J Pharmacol ; 179(7): 1450-1469, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34755897

RESUMO

BACKGROUND AND PURPOSE: Transient receptor potential cation channel subfamily V member 1 (TRPV1) is localized to sensory C-fibres and its opening leads to membrane depolarization, resulting in neuropeptide release and neurogenic inflammation. However, the identity of the endogenous activator of TRPV1 in this setting is unknown. The arachidonic acid metabolites 12-hydroperoxyeicosatetraenoyl acid (12-HpETE) and 20-hydroxyeicosatetraenoic acid (20-HETE) have emerged as potential endogenous activators of TRPV1. However, whether these lipids underlie TRPV1-mediated neurogenic inflammation remains unknown. EXPERIMENTAL APPROACH: We analysed human cantharidin-induced blister samples and inflammatory responses in TRPV1 transgenic mice. KEY RESULTS: In a human cantharidin-blister model, the potent TRPV1 activators 20-HETE but not 12-HETE (stable metabolite of 12-HpETE) correlated with arachidonic acid levels. Similarly, in mice, levels of 20-HETE (but not 12-HETE) and arachidonic acid were strongly positively correlated within the inflammatory milieu. Furthermore, LPS-induced oedema formation and neutrophil recruitment were substantially and significantly attenuated by pharmacological block or genetic deletion of TRPV1 channels, inhibition of 20-HETE formation or SP receptor neurokinin 1 (NK1 ) blockade. LPS treatment also increased cytochrome P450 ω-hydroxylase gene expression, the enzyme responsible for 20-HETE production. CONCLUSION AND IMPLICATIONS: Taken together, our findings suggest that endogenously generated 20-HETE activates TRPV1 causing C-fibre activation and consequent oedema formation. These findings identify a novel pathway that may be useful in the therapeutics of diseases/conditions characterized by a prominent neurogenic inflammation, as in several skin diseases.


Assuntos
Ácidos Hidroxieicosatetraenoicos , Inflamação Neurogênica , Canais de Cátion TRPV , Animais , Ácido Araquidônico/química , Ácido Araquidônico/metabolismo , Vesícula , Cantaridina , Edema , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Ácidos Hidroxieicosatetraenoicos/farmacologia , Ligantes , Lipopolissacarídeos , Camundongos , Inflamação Neurogênica/induzido quimicamente , Inflamação Neurogênica/metabolismo , Canais de Cátion TRPV/metabolismo
7.
J Appl Toxicol ; 42(6): 970-980, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34866203

RESUMO

Cantharidin (CTD) is an effective antitumor agent. However, it exhibits significant hepatotoxicity, the mechanism of which remains unclear. In this study, biochemical and histopathological analyses complemented with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabolomic analysis of bile acids (BAs) were employed to investigate CTD-induced hepatotoxicity in rats. Sixteen male and female Sprague-Dawley rats were randomly divided into two groups: control and CTD (1.0 mg/kg) groups. Serum and liver samples were collected after 28 days of intervention. Biochemical, histopathological, and BA metabolomic analyses were performed for all samples. Further, the key biomarkers of CTD-induced hepatotoxicity were identified via multivariate and metabolic pathway analyses. In addition, metabolite-gene-enzyme network and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to identify the signaling pathways related to CTD-induced hepatotoxicity. The results revealed significantly increased levels of biochemical indices (alanine aminotransferase, aspartate aminotransferase, and total bile acid). Histopathological analysis revealed that the hepatocytes were damaged. Further, 20 endogenous BAs were quantitated via UHPLC-MS/MS, and multivariate and metabolic pathway analyses of BAs revealed that hyocholic acid, cholic acid, and chenodeoxycholic acid were the key biomarkers of CTD-induced hepatotoxicity. Meanwhile, primary and secondary BA biosynthesis and taurine and hypotaurine metabolism were found to be associated with the mechanism by which CTD induced hepatotoxicity in rats. This study provides useful insights for research on the mechanism of CTD-induced hepatotoxicity.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Animais , Ácidos e Sais Biliares/metabolismo , Biomarcadores , Cantaridina/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cromatografia Líquida de Alta Pressão/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Feminino , Fígado , Masculino , Metabolômica/métodos , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
8.
FEBS Open Bio ; 12(5): 1017-1035, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-33999504

RESUMO

Cantharidin is a terpenoid compound of insect origin, naturally produced by male blister beetles as an antipredatory mechanism. Cantharidin has anticancer properties, which are attributed to its ability to induce cell cycle arrest, DNA damage, MAPK signaling pathway, and apoptosis. Cantharidin has been reported to induce apoptosis in triple-negative breast cancer cells by suppressing autophagy via downregulation of Beclin 1 expression and autophagosome formation. However, it remains unclear which stage of the autophagic pathway is targeted by cantharidin. Herein, we report that yeast cells are sensitive to cantharidin, and external supplementation of ethanolamine (ETA) ameliorates the cytotoxicity. In addition, cantharidin downregulates phosphatidylserine decarboxylase 1 (PSD1) expression. We also report that cantharidin inhibits autophagic flux, and external administration of ETA could rescue this inhibition. Additionally, cotreatment with chloroquine sensitized the autophagy inhibitory effects of cantharidin. We conclude that yeast cells are sensitive to cantharidin due to inhibition of autophagic flux.


Assuntos
Cantaridina , Carboxiliases , Autofagia , Cantaridina/farmacologia , Carboxiliases/farmacologia , Humanos , Masculino , Proteínas Mitocondriais , Saccharomyces cerevisiae
9.
J Drugs Dermatol ; 20(11): 1185-1190, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34784125

RESUMO

Molluscum contagiosum (molluscum) is a common skin condition, especially in children, yet treatment approaches by US health care practitioners vary widely. A dearth of clinical data from large, well-controlled studies has resulted in significant gaps in knowledge, including treatment guidelines and algorithms. As of this writing, there are no FDA-approved treatments for molluscum. The objective of this review is to provide practitioners with expert, evidence-based information and guidance about treatment approaches for, and the special circumstances faced by, patients with molluscum. To this end, a group of five pediatric and adult dermatologists collectively identified treatments and special considerations they felt were most commonly used to treat molluscum. Hence, in the first part of the review, seven treatment approaches identified as the most important to review (e.g., curettage, cantharidin) are discussed in terms of their mechanisms of action, supporting clinical data, and rationale for use. Each treatment approach concludes with a “clinical pearls” section, which summarizes the group’s experiences with the treatment. In the second part, five special considerations (e.g., atopic dermatitis, skin of color) are discussed with supporting clinical data and are also followed by a “clinical pearls” summary. J Drugs Dermatol. 2021;20(11): 1185-1190. doi:10.36849/JDD.6383.


Assuntos
Dermatite Atópica , Molusco Contagioso , Adulto , Cantaridina , Criança , Curetagem , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Humanos , Molusco Contagioso/diagnóstico , Molusco Contagioso/tratamento farmacológico , Pele
10.
BMC Genomics ; 22(1): 808, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749651

RESUMO

BACKGROUND: Meloidae (blister beetles) are known to synthetize cantharidin (CA), a toxic and defensive terpene mainly stored in male accessory glands (MAG) and emitted outward through reflex-bleeding. Recent progresses in understanding CA biosynthesis and production organ(s) in Meloidae have been made, but the way in which self-protection is achieved from the hazardous accumulation and release of CA in blister beetles has been experimentally neglected. To provide hints on this pending question, a comparative de novo assembly transcriptomic approach was performed by targeting two tissues where CA is largely accumulated and regularly circulates in Meloidae: the male reproductive tract (MRT) and the haemolymph. Differential gene expression profiles in these tissues were examined in two blister beetle species, Lydus trimaculatus (Fabricius, 1775) (tribe Lyttini) and Mylabris variabilis (Pallas, 1781) (tribe Mylabrini). Upregulated transcripts were compared between the two species to identify conserved genes possibly involved in CA detoxification and transport. RESULTS: Based on our results, we hypothesize that, to avoid auto-intoxication, ABC, MFS or other solute transporters might sequester purported glycosylated CA precursors into MAG, and lipocalins could bind CA and mitigate its reactivity when released into the haemolymph during the autohaemorrhaging response. We also found an over-representation in haemolymph of protein-domains related to coagulation and integument repairing mechanisms that likely reflects the need to limit fluid loss during reflex-bleeding. CONCLUSIONS: The de novo assembled transcriptomes of L. trimaculatus and M. variabilis here provided represent valuable genetic resources to further explore the mechanisms employed to cope with toxicity of CA in blister beetle tissues. These, if revealed, might help conceiving safe and effective drug-delivery approaches to enhance the use of CA in medicine.


Assuntos
Cantaridina , Besouros , Animais , Cantaridina/toxicidade , Besouros/genética , Genitália Masculina , Hemolinfa , Masculino , Transcriptoma
11.
Pediatr Dermatol ; 38(6): 1583-1585, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34647338

RESUMO

Common skin warts frequently appear on the fingers of children, a patient population in whom finger-sucking is a prevalent habit. Despite overlap between these two pediatric conditions, there are no well-reported specific precautions against the use of topical blistering wart treatments, such as trichloroacetic acid and cantharidin, in finger-sucking children with warts. We report the case of oral ulcers in a pediatric patient secondary to thumb-sucking after receiving treatment for multiple finger warts with combination cryotherapy, trichloroacetic acid, and cantharidin.


Assuntos
Úlceras Orais , Verrugas , Cantaridina , Criança , Família , Humanos , Ácido Tricloroacético/efeitos adversos , Verrugas/tratamento farmacológico
12.
Biomater Sci ; 9(23): 7862-7875, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34676840

RESUMO

The treatment efficiency of the Fenton reaction is expected to be greatly restricted due to problems such as inefficient delivery of Fenton catalysis, limited H2O2 concentration and uneven tumour tissue. Accurate photothermal therapy (PTT) could improve the efficiency of Fenton catalysis to some extent by raising the temperature. However, the heat shock response (HSR) of tumour cells caused by PTT and Fenton reaction would attenuate the treatment effect. In this study, we developed an iron ions-mediated Fenton reaction combined with a PTT treatment platform based on a metal-organic framework, i.e., PPy-CTD@MIL-100@MPCM nanoparticles (PCMM NPs), and further explored the inhibitory effect of PCMM NPs on the heat shock response (HSR). PCMM NPs could accumulate in tumour tissue via the coated macrophage cell membranes (MPCMs) to target inflammatory tissues. The photothermal effect of polypyrrole (PPy) accelerated the release of cantharidin (CTD) and iron ions loaded in the PCMM NPs. CTD, as an HSR inhibitor, could inhibit this response of tumour cells and improve the effect of PTT. Meanwhile, the heat generated during the PTT process could improve the efficiency of the Fenton reaction. This study suggested that PCMM NPs could serve as a combined treatment platform to enhance the Fenton reaction based on amplified photothermal therapy.


Assuntos
Cantaridina , Nanopartículas , Biomimética , Peróxido de Hidrogênio , Fototerapia , Terapia Fototérmica , Polímeros , Pirróis
13.
Toxicol Appl Pharmacol ; 430: 115726, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34537213

RESUMO

Breast cancer is the leading cause of cancer-related death in women worldwide, and despite multiple chemotherapeutic approaches, effective treatment strategies for advanced metastatic breast cancer are still lacking. Metabolic reprogramming is essential for tumor cell growth and propagation, and most cancers, including breast cancer, are accompanied by abnormalities in energy metabolism. Here, we confirmed that sodium cantharidate inhibited cell viability using the Cell Counting Kit-8, clonogenic assay, and Transwell assay. The cell cycle and apoptosis assays indicated that sodium cantharidate induced apoptosis and cell cycle arrest in breast cancer cells. Additionally, proteomic assays, western blots, and metabolic assays revealed that sodium cantharidate converted the metabolic phenotype of breast cancer cells from glycolysis to oxidative phosphorylation. Furthermore, bioinformatics analysis identified possible roles for p53 with respect to the effects of sodium cantharidate on breast cancer cells. Western blot, docking, and phosphatase assays revealed that the regulation of p53 activity by sodium cantharidate was related to its inhibition of protein phosphatase 5 activity. Moreover, sodium cantharidate significantly inhibited tumor growth in tumor-bearing nude mice. In summary, our study provides evidence for the use of sodium cantharidate as an effective and new therapeutic candidate for the treatment of human breast cancer in clinical trials.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Cantaridina/análogos & derivados , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fosfoproteínas Fosfatases/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Cantaridina/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Am J Clin Dermatol ; 22(6): 867-875, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34515985

RESUMO

BACKGROUND: External genital warts are caused by various subtypes of the human papilloma virus and spread through direct skin-to-skin contact. Approximately 1% of the US population have external genital warts. Although cantharidin has been used to treat external genital warts for decades, there are no US Food and Drug Administration-approved cantharidin products and no reliable or controlled sources of cantharidin available. VP-102 is a drug-device combination product containing cantharidin (0.7% w/v) in a single-use shelf-stable applicator. OBJECTIVE: The objective of this randomized, double-blind, vehicle-controlled, phase II clinical trial was to determine the optimal regimen for the treatment, safety, and efficacy of VP-102 in external genital warts. METHODS: The study was conducted in two parts. Part A was dose finding and Part B was performed following the completion of Part A for a safety and efficacy evaluation. Following completion of Part A, 6-h and 24-h VP-102 regimens under occlusion were selected to be evaluated in Part B. RESULTS: Pooled results from Part B and Part A of the 6-h and 24-h VP-102 treatment regimens showed that 36.7% and 33.3% of participants achieved complete clearance of all treatable external genital warts at the end of treatment vs 4.2% (p < 0.0048) and 0% (p < 0.0075) with the vehicle. Adverse events experienced by the VP-102-treated participants were consistent with the pharmacodynamic action of cantharidin as a vesicant and were primarily mild to moderate in severity. The most common adverse events included application-site vesicles, pain, and erythema. No participants discontinued the study because of adverse events and no serious adverse events were deemed treatment related. CONCLUSIONS: The adverse event profile and efficacy of VP-102 under occlusion demonstrated in this study support the conclusion that a 6-h or up to 24-h exposure regimen represents an acceptable risk:benefit profile and justifies the conduct of a larger vehicle-controlled phase III study in external genital warts. CLINICAL TRIAL REGISTRATION: NCT03981822, actual study start date: 25 June, 2019; actual primary completion date: 21 May, 2020; actual study completion date: 8 July, 2020.


Assuntos
Cantaridina/administração & dosagem , Condiloma Acuminado/tratamento farmacológico , Administração Cutânea , Adulto , Cantaridina/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Fitoterapia ; 155: 105033, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34517057

RESUMO

AIM: Cantharidin (CTD), the major component of the anti-cancer medicine obtained from Mylabris cichorii, exerts good inhibitory effects on several cancers, such as liver and breast cancer. However, owing to its toxicity, its oral administration can cause various adverse effects, limiting its clinical applications. Therefore, the development of a novel nano-drug delivery system for CTD would be highly beneficial. METHODS: A nanostructured lipid carrier (NLC) was designed to actively target CTD to tumor cells using a hyaluronic acid (HA)-decorated copolymer (mPEG-NH2); the NLCs were called HA-mPEG-CTD-NLC. HA-mPEG was synthesized using amidation, and HA-mPEG-CTD-NLC was generated through ultrasonic emulsification in water. The mean hydrodynamic diameter of the particles was approximately 119.3 nm. RESULTS: Pharmacokinetic studies revealed that the half-life of HA-mPEG-CTD-NLC and its area under the curve were higher than those of a CTD solution. Further, the plasma clearance rate of HA-mPEG-CTD-NLC was 0.41 times that of the CTD solution, implying a significantly prolonged drug retention time in vivo. Fluorescence in vivo endo-microscopy and optical in vivo imaging revealed that HA-mPEG-CTD-NLC had superior cytotoxicity and targeting efficacy against SMMC-7721 cells. An evaluation of the in vivo anti-tumor activity showed that HA-mPEG-CTD-NLC significantly inhibited tumor growth and prolonged survival in tumor-bearing mice, with a tumor inhibition rate of 65.96%. CONCLUSIONS: Our results indicate that HA-mPEG-CTD-NLC may have great potential in liver cancer-targeted therapy.


Assuntos
Cantaridina/administração & dosagem , Ácido Hialurônico/química , Polietilenoglicóis/química , Animais , Cantaridina/farmacocinética , Linhagem Celular Tumoral , Feminino , Ácido Hialurônico/farmacocinética , Lipídeos/química , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Polietilenoglicóis/farmacocinética , Ratos Sprague-Dawley
16.
Toxins (Basel) ; 13(7)2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34357960

RESUMO

Arthropods and specifically beetles can synthesize and/or sequester metabolites from dietary sources. In beetle families such as Tenebrionidae and Meloidae, a few studies have reported species with toxic defensive substances and antiparasitic properties that are consumed by birds. Here we have studied the antiparasitic activity of extracts from beetle species present in the habitat of the Great Bustard (Otis tarda) against four pathogen models (Aspergillus niger, Meloidogyne javanica, Hyalomma lusitanicum, and Trichomonas gallinae). The insect species extracted were Tentyria peiroleri, Scaurus uncinus, Blaps lethifera (Tenebrionidae), and Mylabris quadripunctata (Meloidae). M. quadripunctata exhibited potent activity against M. javanica and T. gallinae, while T. peiroleri exhibited moderate antiprotozoal activity. The chemical composition of the insect extracts was studied by gas chromatography coupled with mass spectrometry (GC-MS) analysis. The most abundant compounds in the four beetle extracts were hydrocarbons and fatty acids such as palmitic acid, myristic acid and methyl linoleate, which are characteristic of insect cuticles. The presence of cantharidin (CTD) in the M. quadripunctata meloid and ethyl oleate (EO) in T. peiroleri accounted for the bioactivity of their extracts.


Assuntos
Antiparasitários/toxicidade , Besouros , Toxinas Biológicas , Animais , Anti-Infecciosos , Aves , Cantaridina
17.
Int J Biol Sci ; 17(10): 2504-2522, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326690

RESUMO

Background: As the leading primary bone cancer in adolescents and children, osteosarcoma patients with metastasis show a five-year-survival-rate of 20-30%, without improvement over the past 30 years. Wnt/ß-catenin is important in promoting osteosarcoma development. DKK3 is a Wnt/ß-catenin antagonist and predicted to have the specific binding site in 3'-UTR with miR-214-3p. Methods: miR-214-3p and DKK3 levels were investigated in human osteosarcoma tissues and cells by RT-qPCR; the prognostic importance of DKK3 level in osteosarcoma patients was determined with Log-rank test; direct binding between DKK3 with miR-214-3p was identified with targetscan; anti-osteosarcoma mechanism of cantharidin was investigated by miR-214-3p silence/over-expression with or without cantharidin treatment, and nuclear/cytoplasmic protein assay in osteosarcoma cells. Results: Down-regulated DKK3 indicated poor prognosis of osteosarcoma patients. Up-regulated miR-214-3p promoted proliferation and migration, while suppressed apoptosis of osteosarcoma cells by increasing ß-catenin nuclear translocation and LEF1 translation via degradation of DKK3. Cantharidin suppressed viabilities, migration and invasion, while promoted cell cycle arrest and apoptosis in 143B and U-2 OS cells via down-regulating miR-214-3p to up-regulate DKK3, thus inhibited p-GSK-3ß expression, ß-catenin nuclear translocation and LEF1 translation. Meanwhile, cantharidin inhibited tumor growth in xenograft-bearing mice with 143B cell injection in tibia. Conclusion: miR-214-3p mediated Wnt/ß-catenin/LEF1 signaling activation by targeting DKK3 to promote oncogenesis of osteosarcoma; cantharidin inhibited proliferation and metastasis of osteosarcoma cells via down-regulating miR-214-3p to up-regulate DKK3 and decrease ß-catenin nuclear translocation, indicating that cantharidin may be a prospective candidate for osteosarcoma treatment by targeting miR-214-3p/DKK3/ß-catenin signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Cantaridina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , MicroRNAs/metabolismo , Osteossarcoma/tratamento farmacológico , Regiões 3' não Traduzidas , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/metabolismo , Via de Sinalização Wnt , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
18.
Angew Chem Int Ed Engl ; 60(35): 19355-19363, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34105217

RESUMO

Nanomedicine can regulate the balance between cytotoxic T lymphocytes (CTLs) and suppressive regulatory T lymphocytes (Tregs), which however has been rarely exploited for cancer immunotherapy. We report a charge-reversal polymer nano-modulator (SPDMC N) activated by tumor microenvironment (TME) for photodynamic immunotherapy of cancer. SPDMC N is constructed by conjugating an immunomodulator (demethylcantharidin, DMC) to the side chains of a photodynamic polymer via an acid-liable linker. The negative charge of SPDMC N ensures its high stability in blood circulation and ideal tumor accumulation; exposure to acidic TME reverses its surface charge to positive, enhancing tumor penetration and locally releasing DMC. Upon near-infrared photoirradiation, SPDMC N generates singlet oxygen to ablate tumors and promote maturation of dendritic cells. Released DMC inhibits protein phosphatase 2 (PP2A) activity and decreases Tregs differentiation. Such combinational action induces a sharp increase in CTL/Treg ratio in TME and effectively inhibits both primary and distant tumors in living mice.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/terapia , Fatores Imunológicos/uso terapêutico , Imunoterapia , Nanopartículas/química , Fotoquimioterapia , Polímeros/química , Animais , Cantaridina/análogos & derivados , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Nanomedicina , Neoplasias Experimentais/terapia , Tamanho da Partícula , Polímeros/síntese química
19.
Biomed Chromatogr ; 35(10): e5172, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33982312

RESUMO

A sensitive gas chromatography-mass spectroscopy method was established for the determination of cantharidin (CTD) in rat plasma and liver homogenates. During the experiment, rats were randomly divided into two groups (low, high) and were administered aqueous extract of Mylabris compound for 7 days. Then, plasma and tissue samples were taken at different time points to study the pharmacokinetics and tissue distribution of CTD in rats. The selected reaction monitoring transitions for CTD and clofibrate (internal standard) were m/z 128 → 85 and m/z 169 → 141, respectively. The calibration curve ranged from 10.26 to 3,078 ng/ml for plasma and from 10.26 to 246.24 ng/ml for liver homogenates. The lower limits of quantification were 10.26 ng/ml for both plasma and liver. The intra- and inter-day precision and accuracy were <20% for both plasma and liver homogenates. Extraction recovery ranged from 89.21 to 103.61% for CTD in rat plasma and liver and from 83.79 to 102.74% for IS in rat plasma and liver. Matrix effects ranged from 93.06 to 110.44% for CTD and from 91.65 to 110.80% for IS.


Assuntos
Produtos Biológicos , Cantaridina , Besouros , Administração Oral , Animais , Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacocinética , Cantaridina/análise , Cantaridina/química , Cantaridina/farmacocinética , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Masculino , Medicina Tradicional Chinesa , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
20.
Appl Opt ; 60(12): 3365-3373, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33983241

RESUMO

The study focuses on a methodology providing noninvasive monitoring and evaluation of the antitumor effect of traditional Chinese medicine, cantharides complex (canth), on 4T1 breast tumor cells. Digital holographic tomography (DHT) and developed data post-processing algorithms were used for quantitative estimation of changes in optical and morphological parameters of cells. We calculated and compared data on the refractive index, thickness, and projected area of 4T1 breast tumor cells in control untreated specimens and those treated with doxorubicin hydrochloride (DOX), canth, and their combinations. Post-treatment changes in cellular morphology recorded by DHT demonstrated that the two drugs led to noticeably different morphological changes in cells that can be presumably associated with different pathways of their death, apoptosis, or necrosis. The effect of combined treatment with these two drugs strongly depended on their relative concentrations and could lead to changes characteristic either for DOX or for canth; however, being more profound than those obtained when using each drug solely. The results obtained by DHT are in a good correspondence with commonly used cell viability analysis and immunofluorescent analysis of changes in cellular cytoskeleton.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cantaridina/farmacologia , Holografia/métodos , Tomografia/métodos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Feminino , Imunofluorescência , Medicina Tradicional Chinesa , Camundongos , Refratometria/métodos
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