ABSTRACT
BACKGROUND: Theileria haneyi is one of the three known causative agents of equine piroplasmosis. While imidocarb is generally effective in the clearance of the highly pathogenic Theileria equi, it is ineffective in the treatment of T. haneyi. Moreover, co-infection with T. haneyi has been shown to impede the successful treatment of T. equi. Furthermore, tulathromycin and diclazuril have demonstrated inefficacy in eradicating T. haneyi. The absence of an effective therapeutic agent against this parasite represents a significant obstacle in managing equine piroplasmosis. METHODS: To address this issue, we evaluated the efficacy of buparvaquone in the treatment of T. haneyi in chronically infected horses. RESULTS: Our findings showed that treatment of horses with the recommended dose of 2.5 mg/kg of buparvaquone led to a rapid abatement of T. haneyi levels, to a level where the parasites were not detectable by nested PCR. Following treatment, the horses remained PCR negative for a minimum of seven weeks until recrudescence occurred. Subsequent re-administration of buparvaquone at an increased dosage of 6 mg/kg upon recrudescence failed to exert a theilericidal effect on T. haneyi. Throughout the treatment regimen, the hematological parameters of the horses and most components of the chemistry panel remained within the normal range, except for blood urea nitrogen levels, which fell below the normal range in certain instances. CONCLUSIONS: BPQ at 2.5 mg/kg and 6 mg/kg had a robust theilericidal effect but was ineffective in the clearance of the T. haneyi infection in persistently infected animals.
Subject(s)
Antiprotozoal Agents , Horse Diseases , Naphthoquinones , Theileria , Theileriasis , Animals , Theileriasis/drug therapy , Theileriasis/parasitology , Horses , Theileria/drug effects , Horse Diseases/drug therapy , Horse Diseases/parasitology , Naphthoquinones/therapeutic use , Naphthoquinones/pharmacology , Naphthoquinones/administration & dosage , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/administration & dosage , Treatment Outcome , Chronic Disease , MaleABSTRACT
Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC.
Subject(s)
Carcinoma, Hepatocellular , Doxorubicin , Drug Synergism , Liver Neoplasms , Naphthoquinones , Doxorubicin/administration & dosage , Doxorubicin/pharmacology , Doxorubicin/chemistry , Naphthoquinones/administration & dosage , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Animals , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/drug therapy , Humans , Polyethylene Glycols/chemistry , Polyethylene Glycols/administration & dosage , Mice, Inbred BALB C , Polylactic Acid-Polyglycolic Acid Copolymer/chemistry , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , Cell Line, Tumor , Mice , Nanoparticles/chemistry , Drug Resistance, Neoplasm/drug effects , Nanoparticle Drug Delivery System/chemistry , Mice, Nude , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacology , Male , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacologyABSTRACT
Nitric oxide (NO) / ß-Lapachone (Lap) combined therapy by causing oxidative stress is an effective tumor therapy strategy. Herein, a dual-responsive lipid nanoparticles (LNPs) LSNO for NO / Lap co-delivery were constructed from the zinc-coordinated lipid (DSNO(Zn)) and the hydrophobic drug Lap in the presence of helper lipids (DOPE and DSPE-PEG2000). The zinc-coordinated structure in LSNO might elevate the Zn2+ content in tumor cells, contributing to antioxidant imbalance. The fluorescent assays proved the light-triggered NO release and fluorescent self-reporting abilities of LSNO. In addition, the LNPs had good drug release behavior under high concentration of GSH, indicating the NO / drug co-delivery capacity. In vitro antitumor assays showed that the NO / Lap combination treatment group could induce more significant tumor cell growth inhibition and cell apoptosis than individual NO or Lap treatment. The following mechanism studies revealed that NO / Lap combination treatment led to distinct oxidative stress by producing reactive oxygen species (ROS) and peroxynitrite anion (ONOO-). On the other hand, the intracellular redox balance could be further disrupted by Lap-induced NADPH consumption and Zn2+ / NO-induced reductase activities downregulation, thus promoting the degree of cell damage. Besides, it was also found that NO and Lap could directly damage nuclear DNA and induce mitochondrial dysfunction, thereby leading to caspase-3 activation and tumor cell death. These results proved that LSNO could serve as a promising multifunctional tumor therapy platform.
Subject(s)
Nanoparticles , Naphthoquinones , Nitric Oxide , Oxidation-Reduction , Oxidative Stress , Reactive Oxygen Species , Naphthoquinones/administration & dosage , Naphthoquinones/pharmacology , Naphthoquinones/chemistry , Nitric Oxide/metabolism , Nitric Oxide/administration & dosage , Humans , Nanoparticles/chemistry , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Cell Line, Tumor , Apoptosis/drug effects , Drug Delivery Systems/methods , Drug Liberation , Zinc/chemistry , Zinc/administration & dosage , Neoplasms/drug therapy , Neoplasms/metabolism , Lipids/chemistry , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacologyABSTRACT
Herein, 5-fluorouracil and shikonin (extracted from Fusarium tricinctum) were loaded in chitosan/pectin nanoparticle (CS/PEC-NPs), prepared by blending (B-CS/PEC-NPs) and coating (C-CS/PEC-NPs) methods. The nanoparticles characterized by Fourier Transform Infrared (FTIR), X-ray diffraction (XRD), Energy-dispersive X-ray (EDX), Scanning Electron Microscope (SEM) and Differential Light Scattering (DLS). Then, some properties of the nanoparticles such as drug release rate and the nanoparticles cytotoxicity were studied. The FTIR, XRD, EDX, SEM and DLS results showed that the nanoparticles synthesized properly with an almost spherical morphology, an average size of 82-93 nm for B-CS/PEC-NPs, an average diameter of below 100 nm (mostly 66-89 nm) for C-CS/PEC-NPs, and hydrodynamic diameter of 310-817 nm. The drug release results indicated the lower release rate of drugs for B-CS/PEC-NPs relative to C-CS/PEC-NPs at different pHs, high release rate of drugs for the nanoparticles in the simulated large intestinal fluids containing pectinase, and Korsmeyer-Peppas model for release of the drugs. The results showed more cytotoxicity of B-CS/PEC-NPs containing drugs, especially B-CS/PEC-NPs containing both drugs (B-CS/PEC/5-FU/SHK-NPs) after treating with pectinase (IC50 of 18.6 µg/mL). In conclusion, despite the limitation of C-CS/PEC-NPs for simultaneous loading of hydrophilic and hydrophobic drugs, B-CS/PEC-NPs showed suitable potency for loading and targeted delivery of the drugs.
Subject(s)
Chitosan , Colonic Neoplasms , Drug Carriers , Drug Liberation , Fluorouracil , Nanoparticles , Naphthoquinones , Pectins , Fluorouracil/chemistry , Fluorouracil/pharmacology , Fluorouracil/administration & dosage , Chitosan/chemistry , Pectins/chemistry , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Naphthoquinones/administration & dosage , Nanoparticles/chemistry , Drug Carriers/chemistry , Humans , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Drug Delivery Systems , Cell Line, Tumor , Particle SizeABSTRACT
SUMMARY: The objective of this study was to investigate the therapeutic wound healing potential and molecular mechanisms of shikonin as small molecules in vitro. A mouse burn model was used to explore the potential therapeutic effect of shikonin; we traced proliferating cells in vivo to locate the active area of skin cell proliferation. Through the results of conventional pathological staining, we found that shikonin has a good effect on the treatment of burned skin and promoted the normal distribution of skin keratin at the damaged site. At the same time, shikonin also promoted the proliferation of skin cells at the damaged site; importantly, we found a significant increase in the number of fibroblasts at the damaged site treated with shikonin. Most importantly, shikonin promotes fibroblasts to repair skin wounds by regulating the PI3K/AKT signaling pathway. This study shows that shikonin can effectively promote the proliferation of skin cell, and local injection of fibroblasts in burned skin can play a certain therapeutic role.
El objetivo de este trabajo fue investigar el potencial terapéutico de cicatrización de heridas y los mecanismos moleculares de la shikonina como moléculas pequeñas in vitro. Se utilizó un modelo de quemaduras en ratones para explorar el posible efecto terapéutico de la shikonina; Rastreamos las células en proliferación in vivo para localizar el área activa de proliferación de células de la piel. A través de los resultados de la tinción para patología convencional, encontramos que la shikonina tiene un buen efecto en el tratamiento de la piel quemada y promueve la distribución normal de la queratina de la piel en el sitio dañado. Al mismo tiempo, la shikonina también promovió la proliferación de células de la piel en el sitio dañado. Es importante destacar que encontramos un aumento significativo en la cantidad de fibroblastos en el sitio dañado tratado con shikonina. Lo más importante es que la shikonina promueve la función reparadora de fibroblastos en las heridas de la piel regulando la vía de señalización PI3K/ AKT. Este estudio muestra que la shikonina puede promover eficazmente la proliferación de células de la piel y que la inyección local de fibroblastos en la piel quemada puede desempeñar un cierto papel terapéutico.
Subject(s)
Animals , Mice , Wound Healing/drug effects , Burns/drug therapy , Naphthoquinones/administration & dosage , Skin , In Vitro Techniques , Naphthoquinones/pharmacology , Phosphatidylinositol 3-Kinases , Cell Proliferation/drug effects , Disease Models, Animal , Proto-Oncogene Proteins c-akt , Fibroblasts , Mice, Inbred C57BLABSTRACT
Estudos prévios com o lapachol, administrados durante o período de organogênese, indicaram que o fitofármaco é embriotóxico. A exposição de ratas prenhes a xenobióticos por longo período pode causar toxicidade materna responsável por alterações morfológicas do concepto. No presente trabalho avalia-se o efeito do lapachol, administrado no nono dia de prenhez, sobre o organismo materno e o sistema morfogenético do concepto. Ratas Wistar foram distribuídas em quatro grupos: controle (1 ml de água destilada), veículo (1 ml de solção hidroalcoólica), lapachol 100 (L - 100) e 200 (L - 200) mg/kg peso corporal. Tratamento por via gástrica em dose única. Mediu-se peso corporal e consumo de ração. No 21º dia os animais foram sacrificados por exsanguinação total sob anestesia. No soro foram dosadas TGP e uréia. Procedeu-se á autópsia e á remoção de fígado, rins (pesados e fixados para análise anatomopatológica) e trato reprodutor materno. O vários foram pesados e os corpos lúteos contados. Nos cornos uterinos contaram-se implantes, reabsorções, e fetos mortos. Fetos e placentas foram pesados. Ratas tratadas com L - 200 tiveram peso de fígado e de ovários menor que os demais grupos; aumento da concentração de TGP e de uréia e 83% de mortes de conceptos. Ratas tratadas com L - 100 tiveram 32% de mortes de conceptos. os resultados indicam possibilidade de toxicidade materna com a dose maior de lapachol. Pode-se concluir que o lapachol ou seus produtos biotransformados, agem diretamente sobre o sistema morfogenético do embrião e doses elevadas podem ter seu efeito potencializado por toxicidade materna leve.
Subject(s)
Animals , Rats , Naphthoquinones/administration & dosage , Naphthoquinones/toxicity , Rats, Wistar , Rats, Wistar/embryologyABSTRACT
ß-Lapachona prolonga la sobrevida de ratones con leucemia inducida por el virus de Friend y de pollos con sarcoma inducido por el virus de Rous y recientemente ha demostrado inhibir la proliferación in vitro de varias líneas tumorales humanas. La estructura química de esta droga y presumiblemente su modo de acción, son muy diferentes de la estructura y modo de acción de las drogas antitumorales comúnmente utilizadas en la terapia. Por tal motivo, y con el propósito de ampliar el conocimiento sobre nuevas drogas antineoplásicas intentamos determinar, en este trabajo, si ß-lapachona era capaz de inhibir in vivo el desarrollo de un tumor de ratón no inducido por virus que ha demostrado ser refractario al tratamiento con drogas antineoplásicas convencionales. Se mostró que la administración oral y diaria de ß-lapachona redujo la toma tumoral y prolongó la sobrevida en aquellos ratones donde el tumor LB había crecido. El mayor efecto se produjo cuando la droga fue administrada en la concentración de 125 mg/Kg/día simultáneamente con un inóculo tumoral de 10n ó 10 elevado a la 4, células LB. El efecto sobre un inóculo mayor (10 elevado a la 5, células) o sobre un tumor vascularizado y en activo crecimiento fue más tenue aunque igualmente perceptible. Estos resultados son, en principio, promisorios, pero más experimentos, con diferentes concentraciones de la droga y con diferentes modelos tumorales serán necesarios para determinar adecuadamente el valor terapéutico de ß-lapachona sobre tumores murinos.(AU)