ABSTRACT
The low-birth-weight of piglets is an important factor affecting pig enterprises. The placenta, as a key organ for material exchange between mother and foetus, directly influences the growth and development of the foetus. Allicin exhibits various biological activities, including anti-inflammatory and antioxidant properties. It may also play a crucial role in enhancing sow reproductive performance and placental angiogenesis. In this study, we used 70 lactating Landrace × Yorkshire binary heterozygous sows to explore the effect of allicin on the reproductive performance of sows and placental development. The sows were randomly assigned into the Allicin group (Allicin), which was fed with a diet containing 0.25% allicin, and the negative control group, which was fed with basal feed. The experimental period lasted for 114 d from the date of mating to the end of farrowing. The results showed that the addition of allicin to the gestation diets increased the number of total born piglets, born alive piglets, and high-birth-weight piglets, reduced peripartum oxidative stress, alleviated dysregulation of glucose-lipid metabolism in sows, and increased the levels of antioxidant markers in the placenta. Differential analysis of metabolites in maternal plasma and placenta samples by non-targeted metabolomics revealed that allicin improved cholesterol metabolism, steroid biosynthesis, and increased plasma progesterone levels in sows. Allicin promoted sulphur metabolism, cysteine and methionine metabolism in placental samples and increased the hydrogen sulphide (H2S) content in the placenta. In addition, Quantitative Real-time PCR, Western blot and immunofluorescence results showed that allicin upregulated the expression of angiogenesis-related genes, VEGF-A, FLK 1 and Ang 1, in the placenta, implying that it promoted placental angiogenesis. These results indicate that supplementing the diet of pregnant sows with allicin reduces oxidative stress, alleviates dysregulation of glucose-lipid metabolism during the periparturient period, and promotes placental angiogenesis and foetal development by increasing plasma progesterone level and placental H2S content.
Subject(s)
Angiogenesis , Animal Feed , Disulfides , Fetal Development , Neovascularization, Physiologic , Placenta , Sulfinic Acids , Animals , Female , Pregnancy , Angiogenesis/drug effects , Animal Feed/analysis , Antioxidants/metabolism , Dietary Supplements , Disulfides/administration & dosage , Fetal Development/drug effects , Neovascularization, Physiologic/drug effects , Oxidative Stress/drug effects , Placenta/metabolism , Placenta/drug effects , Placentation/drug effects , Steroids/metabolism , Sulfates , Sulfinic Acids/administration & dosage , Swine/growth & developmentABSTRACT
We investigated whether diallyl disulfide (DADS) has protective effects against 1,3-dichloro-2-propanol (1,3-DCP)-induced hepatotoxicity and oxidative damage in rats and HepG2 cells. DADS was administered to rats once daily for 7 days at doses of 30 and 60 mg/kg/day. One hour after the final DADS treatment, the rats were administered 90 mg/kg 1,3-DCP to induce acute hepatotoxicity. DADS treatment significantly suppressed the increase in serum aminotransferase levels induced by 1,3-DCP administration, and reduced histopathological alterations in the liver. DADS treatment reduced 1-3-DCP-induced apoptotic changes in the liver, as revealed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining and immunohistochemistry for caspase-3. DADS treatment competitively inhibited or reduced cytochrome p450 2E1 (CYP2E1) expression, which is involved in the metabolic activation of 1,3-DCP, and enhanced antioxidant properties. Furthermore, DADS treatment inhibited phosphorylation of mitogen-activated protein kinases (MAPKs) and apoptotic signaling. In in vitro experiments, MAPKs inhibitors reduced the expression of Bax/Bcl-2/Caspase 3 signaling, which effects were more significant in co-treated cells with DADS and MAPKs inhibitors. In conclusion, the protective effect of DADS against 1,3-DCP-induced hepatotoxicity may be related to blocking the metabolic activation of 1,3-DCP by suppressing CYP2E1 expression, inducing antioxidant enzyme activity, and reducing apoptotic activity by inhibiting phosphorylation of MAPKs.
Subject(s)
Allyl Compounds/administration & dosage , Disulfides/administration & dosage , Liver Diseases/prevention & control , Mitogen-Activated Protein Kinases/metabolism , Protective Agents/pharmacology , alpha-Chlorohydrin/analogs & derivatives , Animals , Apoptosis/drug effects , Caspase 3/genetics , Caspase 3/metabolism , Cytochrome P-450 CYP2E1/genetics , Cytochrome P-450 CYP2E1/metabolism , Hep G2 Cells , Humans , Liver Diseases/etiology , Liver Diseases/metabolism , Liver Diseases/physiopathology , Male , Mitogen-Activated Protein Kinases/genetics , Oxidative Stress/drug effects , Phosphorylation , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , alpha-Chlorohydrin/toxicityABSTRACT
In recent years, nanozymes based on two-dimensional (2D) nanomaterials have been receiving great interest for cancer photothermal therapy. 2D materials decorated with nanoparticles (NPs) on their surface are advantageous over conventional NPs and 2D material based systems because of their ability to synergistically improve the unique properties of both NPs and 2D materials. In this work, we report a nanozyme based on flower-like MoS2nanoflakes (NFs) by decorating their flower petals with NCeO2using polyethylenimine (PEI) as a linker molecule. A detailed investigation on toxicity, biocompatibility and degradation behavior of fabricated nanozymes in wild-typeDrosophila melanogastermodel revealed that there were no significant effects on the larval size, morphology, larval length, breadth and no time delay in changing larvae to the third instar stage at 7-10 d for MoS2NFs before and after NCeO2decoration. The muscle contraction and locomotion behavior of third instar larvae exhibited high distance coverage for NCeO2decorated MoS2NFs when compared to bare MoS2NFs and control groups. Notably, the MoS2and NCeO2-PEI-MoS2NFs treated groups at 100µg ml-1covered a distance of 38.2 mm (19.4% increase when compared with control) and 49.88 mm (no change when compared with control), respectively. High-resolution transmission electron microscopy investigations on the new born fly gut showed that the NCeO2decoration improved the degradation rate of MoS2NFs. Hence, nanozymes reported here have huge potential in various fields ranging from biosensing, cancer therapy and theranostics to tissue engineering and the treatment of Alzheimer's disease and retinal therapy.
Subject(s)
Biocompatible Materials/toxicity , Cerium/toxicity , Disulfides/toxicity , Molybdenum/toxicity , Nanostructures/toxicity , Animals , Biocompatible Materials/administration & dosage , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacokinetics , Cerium/administration & dosage , Cerium/chemistry , Cerium/pharmacokinetics , Disulfides/administration & dosage , Disulfides/chemistry , Disulfides/pharmacokinetics , Drosophila melanogaster , Gastrointestinal Tract/metabolism , Larva/drug effects , Larva/growth & development , Larva/metabolism , Locomotion/drug effects , Materials Testing , Metabolic Clearance Rate , Molybdenum/administration & dosage , Molybdenum/chemistry , Molybdenum/pharmacokinetics , Muscle Contraction/drug effects , Nanostructures/administration & dosage , Nanostructures/chemistry , Polyethyleneimine/administration & dosage , Polyethyleneimine/chemistry , Polyethyleneimine/pharmacokinetics , Polyethyleneimine/toxicity , Reactive Oxygen Species/metabolismABSTRACT
Systemic hypertension is the leading cause of death and disability worldwide. The management of hypertension is challenging in the high-risk patient population with high salt-sensitivity and low serum renin levels. The renin-angiotensin system (RAS) plays a central role in blood pressure (BP) regulation. While we have effective medications to act on peripheral RAS, our understanding of brain RAS and its effect on BP regulation is still in an evolving stage. Brain RAS hyperactivity is associated with the development and maintenance of hypertension. In comparison to peripheral RAS, where angiotensin II is the most crucial component responsible for BP regulation, angiotensin III is likely the main active peptide in the brain RAS. Angiotensin II is metabolized by aminopeptidase A into angiotensin III in the brain. EC33 is a potent inhibitor of brain aminopeptidase A tested in animal models. The use of EC33 in conscious spontaneously hypertensive rats, hypertensive deoxycorticosterone acetate-salt rats, and conscious normotensive rat models leads to a reduction in BP. In order to facilitate the passage of EC33 through the blood-brain barrier, the 2 molecules of EC33 were linked by a disulfide bridge to form a prodrug called RB150. RB150, later renamed as QGC001 or firibastat, was found to be effective in animal models and well-tolerated when used in healthy participants. Firibastat was found to be safe and effective in phase 2 trials, and is now planned to undergo a phase 3 trial. Firibastat has the potential to be groundbreaking in the management of resistant hypertension.
Subject(s)
Disulfides , Hypertension , Sulfonic Acids , Administration, Oral , Animals , Antihypertensive Agents/administration & dosage , Brain/metabolism , Clinical Trials, Phase II as Topic , Disulfides/administration & dosage , Glutamyl Aminopeptidase/antagonists & inhibitors , Humans , Hypertension/drug therapy , Rats , Sulfonic Acids/administration & dosageABSTRACT
INTRODUCTION: Treating hair loss of Alopecia areata is a quite challenge. The treatment not only needs to be effective but must meet specific requirements in terms of accurate dose, sustain release, comfortable application with aesthetic appearance. Thus, the study was designed to develop sustained release topical patches releasing allicin using different sources, including the extract from fresh and aged garlic, and commercially pure one. METHODS: Patches were formulated by solvent casting method using ethylene-vinyl acetate as backing layer and Carbopol® 971P NF (CP) as mucoadhesive polymer. Physicochemical properties were evaluated including weight, thickness, drug content, surface pH, moisture content, folding endurance, and swelling. In addition to in vitro diffusion study across the cellulose and Strat-M® membranes. RESULTS: Patches showed good physicochemical properties. No significant difference (p > 0.05) was obvious in the percentage of allicin diffused across cellulose membrane between patch A (loaded with commercial allicin), patch B1 (loaded with fresh garlic extract), and patch C (loaded with aged garlic extract). However, ethanol enhanced the diffusion of allicin. The percentage of allicin diffused across cellulose membrane over 20 h from patch E (45 mg CP, 2 mL fresh garlic extract-equivalent to 60 mg allicin-and 1 mL of ethanol) was 79.94%. The flux and permeability coefficients were 2.62 mg/cm2 /h and 0.52 cm/h, respectively, with an enhancement ratio of 2.60 times the reference patch M (mashed garlic). CONCLUSION: Promising development of topical patches of allicin using garlic extract as natural source with lower cost than the commercial pure allicin and higher aesthetic acceptance than the used mashed garlic.
Subject(s)
Disulfides/administration & dosage , Garlic , Sulfinic Acids/administration & dosage , Transdermal Patch , Humans , Plant ExtractsABSTRACT
2D MoS2 has shown a great potential in biomedical applications, due to its superior loading capacity, photothermal property, and biodegradation. In this work, polyglycerol functionalized MoS2 nanosheets with photothermal and pH dual-stimuli responsive properties are used for the co-delivery of doxorubicin and chloroquine and treatment of multidrug-resistant HeLa (HeLa-R) cells. The polyglycerol functionalized MoS2 nanosheets with 80 nm average size show a high biocompatibility and loading efficiency (≈90%) for both drugs. The release of drugs from the nanosheets at pH 5.5 is significantly promoted by laser irradiation leading to efficient destruction of incubated HeLa-R cells. In vitro evaluation shows that the designed nanoplatform has a high ability to kill HeLa-R cells. Confocal experiments demonstrate that the synthesized drug delivery system enhances the cellular uptake of DOX via folic acid targeting ligand. Taking advantage of the combined properties including biocompatibility and targeting ability as well as high loading capacity and photothermal release, this multifunctional nanosystem is a promising candidate for anticancer therapy.
Subject(s)
Chloroquine/administration & dosage , Disulfides/administration & dosage , Doxorubicin/administration & dosage , Drug Resistance, Neoplasm/drug effects , Glycerol/administration & dosage , Molybdenum/administration & dosage , Nanostructures/administration & dosage , Neoplasms/drug therapy , Polymers/administration & dosage , HeLa Cells , Humans , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Spectrophotometry, UltravioletABSTRACT
Design of new nanoplatforms that integrates multiple imaging and therapeutic components for precision cancer nanomedicine remains to be challenging. Here, a facile strategy is reported to prepare polydopamine (PDA)-coated molybdenum disulfide (MoS2 ) nanoflakes as a nanocarrier to load dual drug cisplatin (Pt) and 1-methyl-tryptophan (1-MT) for precision tumor theranostics. Preformed MoS2 nanoflakes are coated with PDA, modified with methoxy-polyethylene glycol (PEG)-amine, and loaded with 1-MT and Pt. The formed functional 1-MT-Pt-PPDA@MoS2 (the second P stands for PEG) complexes exhibit good colloidal stability and photothermal conversion efficiency (47.9%), dual pH-, and photothermal-sensitive drug release profile, and multimodal thermal, computed tomography and photoacoustic imaging capability. Due to the respective components of Pt, MoS2 , and 1-MT that can block the immune checkpoint associated to tumoral indoleamine 2,3-dioxygenase-induced tryptophan metabolism, tri-mode chemo-photothermo-immunotherapy of tumors can be realized. In particular, under the near infrared laser irradiation, fast release of both drugs can be facilitated to achieve cooperative tumor therapy effect, and the combined immunogenic cell death induced by the dual-mode chemo-photothermo treatment and the 1-MT-induced immune checkpoint blockade can boost enhanced antitumor immune response to generate significant cytotoxic T cells for tumor killing. The developed 1-MT-Pt-PPDA@MoS2 complexes may be used as an intelligent nanoplatform for cooperative precision imaging-guided combinational tumor therapy.
Subject(s)
Antineoplastic Agents/administration & dosage , Disulfides/administration & dosage , Immunotherapy/methods , Molybdenum/administration & dosage , Neoplasms/therapy , Phototherapy/methods , Radiography, Interventional/methods , Animals , Cell Line, Tumor , Combined Modality Therapy , Disease Models, Animal , Mice , Nanoparticle Drug Delivery System , Photoacoustic Techniques , Tomography, X-Ray ComputedABSTRACT
MoS2 nanosheets were developed by undertaking the liquid-phase exfoliation of bulk counterparts. In order to enhance its photocatalytic properties, the host material was doped with p-type transition metals (i.e., Ag, Co, Bi, and Zr). The hydrothermal technique was used to produce samples doped with 7.5 wt% transition metals (TM). X-ray diffraction detected the existence of 2H-phase by mirroring its reflection at 2θ â¼ 14°, while the peak distribution revealed the degree of exfoliation in samples. Low PL intensities indicated a lower recombination of electron-hole pairs, as corroborated by a high degree of photocatalytic action. Raman analysis was undertaken to identify molecular vibrations. The A1g mode in Raman spectra consistently showed a blueshift in all samples and the E12g mode was only slightly affected, which is evidence of the p-type doping in the MoS2 nanosheets. In the XPS spectrum, two characteristic peaks of Mo 3d appeared at 229.87 and 233.03 eV assigned to Mo-3d5/2 and Mo-3d3/2, respectively. Furthermore, a microstructural examination with HR-TEM and FESEM divulged a thin-layered structure of MoS2 consisting of flat, gently curved or twisted nanosheets. Diverse morphologies were observed with a non-uniform distribution of the dopant. Photocatalytic action of the TM-doped products effectively degraded methylene blue (MB) concentrations of up to 94 percent (for Ag-MoS2). The synergistic effect of doped MoS2 nanosheets against S. aureus in comparison to E. coli bacteria was also evaluated. The efficacy % age improved from (0-31.7%) and (23.5-55.2%) against E. coli, and (0-34.2%) and (8.3-69.23%) against S. aureus. Moreover, results from first principles calculations indicate that substitutional doping of TM atoms is indeed advantageous. Theoretical calculations confirmed that doping with Ag, Co, Bi, and Zr leads to a decrease in the band gap to a certain degree, in which the conduction band edge shifts toward lower energy, while the valence band shifts closer to the high energy end. It can be concluded that Ag, Co, and Bi impurities can lead to beneficial p-type doping in MoS2 monolayered structures. With regards to doping with Zr, the acceptor levels are formed above the edge of the valence band, revealing an introduction of the p-type character.
Subject(s)
Anti-Bacterial Agents , Disulfides , Nanostructures , Transition Elements , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/radiation effects , Catalysis , Disulfides/administration & dosage , Disulfides/chemistry , Disulfides/radiation effects , Escherichia coli/drug effects , Escherichia coli/growth & development , Light , Methylene Blue/chemistry , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Nanostructures/administration & dosage , Nanostructures/chemistry , Nanostructures/radiation effects , Nanostructures/ultrastructure , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , Transition Elements/administration & dosage , Transition Elements/chemistry , Transition Elements/radiation effectsABSTRACT
Neuroinflammation and oxidative stress play critical roles in pathogenesis of depression. Diallyl disulfide (DADS), an active compound in garlic oil, has been shown to exhibit obvious anti-inflammatory and anti-oxidative activities. Preliminary evidence indicates that depression is associated with high levels of pro-inflammatory cytokines and oxidative markers, suggesting that inhibition of neuroinflammatory response and oxidative stress may be beneficial for depression interruption. Here, we investigated the antidepressant effect of DADS as well as it mechanisms in a depression-like model induced by lipopolysaccharide (LPS). Similarly to imipramine (10 mg/kg), a clinical antidepressant, DADS (40 or 80 mg/kg), which was administered 1 h before LPS treatment (pre-LPS) or 1.5 h and 23.5 h after LPS treatment (post-LPS), prevented and reversed LPS (100 µg/kg)-induced increase in immobility time in the tail suspension test (TST) and forced swim test (FST) in mice. Mechanistic studies revealed that DADS pre-treatment or post-treatment at the dose of 40 and 80 mg/kg prevented and reversed (i) LPS-induced increases in interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) levels in the hippocampus and prefrontal cortex, (ii) LPS-induced increases in contents of malondialdehyde (MDA), a parameter reflecting high levels of oxidative stress, and (iii) LPS-induced decreases in contents of GSH, a marker reflecting weakened anti-oxidative ability, in the hippocampus and prefrontal cortex in mice. These results indicate that DADS is comparable to imipramine in effectively ameliorating LPS-induced depression-like behaviors in mice, providing a potential value for DADS in prevention and/or therapy of depression.
Subject(s)
Allyl Compounds/administration & dosage , Depression/metabolism , Disulfides/administration & dosage , Lipopolysaccharides/toxicity , Neuroinflammatory Diseases/metabolism , Nitrosative Stress/drug effects , Oxidative Stress/drug effects , Animals , Antihypertensive Agents/administration & dosage , Brain/drug effects , Brain/metabolism , Depression/chemically induced , Depression/drug therapy , Dose-Response Relationship, Drug , Drug Administration Schedule , Male , Mice , Mice, Inbred C57BL , Neuroinflammatory Diseases/chemically induced , Neuroinflammatory Diseases/drug therapy , Nitrosative Stress/physiology , Oxidative Stress/physiologyABSTRACT
Significance of MoS2 nanoparticles as a lubricant or drug carriers indicates the need to assess their safety. In the study we analyzed the effects of MoS2 nano- and microparticles and their internalization in vitro, using 2D and 3D culture models of human hepatoma HepG2 cell line. MoS2 micro- and nanoparticles were characterized with high resolution electron microscopy (HR-SEM), X-ray diffraction (XRD) and Energy Dispersive X-Ray Spectroscopy (EDS). The cells were exposed to a range of concentrations of the nano-and microparticles suspensions (maximum of 250⯵g/mL) for 72â¯h. Cell viability was assessed using WST-1 reduction test and LDH release assay. Particle internalization was analyzed using scanning transmission electron microscopy (STEM). The nanoparticles were internalized into the 2D and 3D cultured cells, in spheroids more efficiently into the outer layer. For microparticles mainly particles of less than 1⯵m in diameter underwent internalization. This process, however, did not affect cell viability as measured with the WST-1 and LDH assays. STEM observation showed well preserved integrity of the cell membrane and no apparent cytotoxic effect. Although the particles seemed to be safely sequestered in vacuoles or the cytoplasm, their fate and eventual biological effects are not certain and deserve further studies.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Disulfides/administration & dosage , Drug Carriers/administration & dosage , Liver Neoplasms/drug therapy , Molybdenum/administration & dosage , Nanoparticles/administration & dosage , Cell Survival/drug effects , Hep G2 Cells , Humans , Models, Biological , Particle SizeABSTRACT
Constructing biocompatible soft materials via supramolecular approaches remains an important challenge for in vivo applications. Substantial efforts have been made to develop biocompatible non-polymeric materials allowing sustained release of biomolecules and/or drugs in vivo. Herein, we introduce disulfide based low molecular weight gels (LMWGs) allowing the in vitro selective sustained release of proteins containing thiol residues. The novel glycosylated nucleoside based bola-amphiphile (GNBA), which features a disulfide bond inserted in the hydrophobic segment, self-assembles to stabilize the resulting hydrogel. Rheological studies show the dominant elastic character and thixotropic properties of the disulfide LMWG demonstrating its injectability. In vitro and in vivo biodegradation investigations reveal that the disulfide LMWG is stable for several weeks. Importantly, disulfide bonds can be cleaved through the thiol-disulfide exchange reactions with small redox molecules such as dithiothreitol (DTT). The disulfide LMWG loaded with a thiol-containing protein (bovine serum albumin) features sustained release in vitro, whereas a dextran of the same molecular weight, lacking a thiol biomolecule, shows quick release. The disulfide GNBA is the first example of a LMWG allowing selective long term sustained release in vitro via a disulfide reshuffling mechanism.
Subject(s)
Disulfides/administration & dosage , Nucleosides/administration & dosage , Serum Albumin, Bovine/administration & dosage , Animals , Cell Line , Cell Survival/drug effects , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemistry , Dextrans/chemistry , Disulfides/chemistry , Drug Liberation , Gels , Mice , Molecular Weight , Nucleosides/chemistry , Rheology , Serum Albumin, Bovine/chemistry , Sulfhydryl Compounds/administration & dosage , Sulfhydryl Compounds/chemistryABSTRACT
Co-delivery of anti-tumor agents with outstanding stimulus-triggered drug release in tumor cells, especially with the aid of nanotechnology, provided the possibility to enhance delivery efficiency for targeting tumor cells and antitumor efficacy. In this paper, docetaxel-dihydroartemisinin nanoconjugates linked by disulfide bond were designed to increase co-delivery and anti-tumor efficacy. Docetaxel and dihydroartemisinin were synthesized using two-step reaction and furtherly assembled to nanoconjugates. Nanoprescription was optimized to evaluate its physicochemical properties. In vitro anti-tumor activities of nanoformulation were assessed by MTT. The flow cytometry was adopted to analyze cell apoptosis and cell cycle arrest. The wound healing assay was used to evaluate antimigratory-property. In vivo pharmacokinetic and pharmacodynamic studies were investigated in rats and 4T1 bearing Balb/c mice model after intravenous injection, respectively. The chemical structure of conjugate was confirmed. The prepared nanoparticles possessed uniform size distribution (172.10 ± 1.70 nm, PDI 0.05 ± 0.01), was stable during storage period, sustained release profiles and sensitive reduction responsiveness. MTT assay indicated that the toxicity of nanoconjugates was slightly weak. Flow cytometry studies showed that nanoconjugates could promote early apoptosis significantly and mainly arose from G0/G1 phase. The wound healing assay provided an obvious antimetastatic potential of nanoparticles in 4T1 cells. The result of pharmacokinetic study suggested that nanoconjugates exhibited higher exposure levels. In vivo pharmacodynamic research showed that mice treated with docetaxel-dihydroartemisinin nanoconjugates had lower systemic toxicity and higher survival ratio than those of control groups. This potential of nanoconjugates was developed as a novel nanoplateform to treat tumor.
Subject(s)
Antineoplastic Agents/pharmacology , Artemisinins/pharmacology , Disulfides/pharmacology , Docetaxel/pharmacology , Nanoparticles/chemistry , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Artemisinins/administration & dosage , Artemisinins/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Disulfides/administration & dosage , Disulfides/chemistry , Docetaxel/administration & dosage , Docetaxel/chemistry , Drug Screening Assays, Antitumor , Female , Injections, Subcutaneous , Male , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Particle Size , Rats , Rats, Sprague-Dawley , Surface Properties , Tumor Cells, CulturedABSTRACT
Sorafenib (SF) is an FDA-approved molecular-targeted drug for treating hepatocellular carcinoma (HCC). SF, however, suffers from poor water solubility, low bioavailability, dose-limiting side effects, and possible drug resistance. Here, we report on apolipoprotein E peptide-decorated disulfide-cross-linked micellar SF (ApoE-Ms-SF) as a targeted and intelligent formulation for HCC therapy. ApoE-Ms-SF was prepared with a good SF loading of 7.0 wt %, small size (37 nm), high stability, and reduction-triggered drug release from poly(ethylene glycol)-b-poly(ε-caprolactone-co-dithiolane trimethylene carbonate)-mefenamate (PEG-P(CL-DTC)-MA) and ApoE-modified ApoE-PEG-P(CL-DTC) block copolymers. MTT assays in low-density lipoprotein receptors (LDLRs) overexpressing SMMC-7721 human liver cancer cells showed ApoE density-dependent antitumor potency of ApoE-Ms-SF, in which 7.5% ApoE led to the best antitumor effect (IC50: 8.5 vs 23.3 µg/mL for free SF). Confocal studies, flow cytometry, western blot, and apoptotic assays illustrated clearly a more efficient uptake of ApoE-Ms than nontargeted Ms by SMMC-7721 cells as well as lower phosphorylated extracellular signal-regulated kinase protein level and better cell apoptosis caused by ApoE-Ms-SF compared with Ms-SF and free SF. ApoE-Ms-SF revealed a long circulation time (elimination half-life = 6.8 h). DiR-loaded ApoE-Ms showed a significantly higher accumulation in SMMC-7721 tumor than the nontargeted counterpart. The therapeutic outcomes in the orthotopic SMMC-7721 tumor models demonstrated that ApoE-Ms-SF reduced SF-associated side effects and brought about enhanced angiogenesis inhibition and tumor apoptosis compared to free SF and Ms-SF controls, leading to a better treatment of HCC.
Subject(s)
Antineoplastic Agents/metabolism , Apolipoproteins E/metabolism , Carcinoma, Hepatocellular/metabolism , Drug Delivery Systems/methods , Liver Neoplasms/metabolism , Micelles , Sorafenib/metabolism , Animals , Antineoplastic Agents/administration & dosage , Apolipoproteins E/administration & dosage , Carcinoma, Hepatocellular/drug therapy , Cell Survival/drug effects , Cell Survival/physiology , Cross-Linking Reagents/administration & dosage , Cross-Linking Reagents/metabolism , Disulfides/administration & dosage , Disulfides/metabolism , Dose-Response Relationship, Drug , Female , Hep G2 Cells , Humans , Liver Neoplasms/drug therapy , Mice , Mice, Inbred BALB C , Mice, Nude , Sorafenib/administration & dosage , Xenograft Model Antitumor Assays/methodsABSTRACT
The novel clopidogrel conjugate, DT-678, is an effective inhibitor of platelets and thrombosis in preclinical studies. However, a comparison of the bleeding risk with DT-678 and currently approved P2Y12 antagonists has yet to be determined. The objective of this study was to evaluate the bleeding tendency of animals treated with clopidogrel, ticagrelor, and DT-678. Ninety-one New Zealand white rabbits were randomized to one of 13 treatment groups (n = 7). Platelet activation was assessed by flow cytometry and light transmission aggregometry before and after the administration of various doses of DT-678, clopidogrel, and ticagrelor. Tongue template bleeding times were also measured before and after drug treatment. Treatment with P2Y12 receptor antagonists caused a dose-dependent reduction in markers of platelet activation (P-selectin and integrin αIIbß3) and aggregation in response to adenosine diphosphate stimulation. At the same doses required for platelet inhibition, clopidogrel and ticagrelor significantly prolonged bleeding times, while DT-678 did not. DT-678 and the FDA-approved P2Y12 antagonists clopidogrel and ticagrelor are effective inhibitors of platelet activation and aggregation. However, unlike clopidogrel and ticagrelor, DT-678 did not prolong bleeding times at equally effective antiplatelet doses. The results suggest a more favorable benefit/risk ratio for DT-678 and potential utility as part of a dual antiplatelet therapy regimen.
Subject(s)
Disulfides/administration & dosage , Platelet Activation/drug effects , Purinergic P2Y Receptor Antagonists/administration & dosage , Animals , Bleeding Time , Clopidogrel/administration & dosage , Clopidogrel/chemistry , Clopidogrel/pharmacology , Disulfides/chemistry , Disulfides/pharmacology , Dose-Response Relationship, Drug , Purinergic P2Y Receptor Antagonists/pharmacology , Rabbits , Random Allocation , Ticagrelor/administration & dosage , Ticagrelor/pharmacologyABSTRACT
The purpose of this study was to design an injectable hydrogel with temperature-sensitive property for safe and high efficient in vivo colon cancer hyperthermia and chemotherapy. Chitosan (CS) solution was injected into the tumor at room temperature and automatically gelled after warming to body temperature in the present of ß-glycerophosphate (ß-GP). Combined localized tumor photothermal and chemotherapy were achieved by dissolving photothermal material MoS2/Bi2S3-PEG (MBP) nanosheets and drug molecule doxorubicin (DOX) into the hydrogel, and the gel system could encapsulate DOX and MBP nanosheets and prevent them from entering the blood circulation and damaging normal tissues and cells. More importantly, the CS/MBP/DOX (CMD) hydrogel exhibited a photothermal efficiency of 22.18% and 31.42% in the first and second near infrared light (NIR I and NIR II) biowindows respectively at a low MBP concentration (0.5â¯mg/mL). Besides, the release of the DOX from CMD hydrogel was controllable since the gel temperature could be governed by NIR laser irradiation. Moreover, the chitosan-based hydrogel had antibacterial effects. The designed composite hydrogel is anticipated to act as a platform for the high efficient treatment of tumors owing to the different penetration depths of NIR I and NIR II.
Subject(s)
Antineoplastic Agents/therapeutic use , Chitosan/chemistry , Colonic Neoplasms/drug therapy , Doxorubicin/therapeutic use , Drug Carriers/chemistry , Hydrogels/chemistry , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/administration & dosage , Bismuth/administration & dosage , Cell Line , Chitosan/administration & dosage , Chitosan/pharmacology , Disulfides/administration & dosage , Disulfides/radiation effects , Doxorubicin/administration & dosage , Drug Carriers/administration & dosage , Drug Carriers/pharmacology , Drug Liberation , Escherichia coli/drug effects , Hydrogels/administration & dosage , Hydrogels/pharmacology , Hyperthermia, Induced/methods , Infrared Rays , Injections , Mice, Inbred BALB C , Molybdenum/administration & dosage , Molybdenum/radiation effects , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/chemistry , Sulfides/administration & dosage , Sulfides/radiation effects , Temperature , Xenograft Model Antitumor AssaysABSTRACT
Mutations in the tumor protein (TP53) and the mammalian target of rapamycin (mTOR) pathway have been elucidated as driver mutations in ovarian carcinomas that transform into an invasive phenotype under hypoxic conditions. Chetomin (CHE) targets the hypoxic pathway while Everolimus (EVR) acts on the mTOR pathway. Poor aqueous solubilities of both compounds limit their clinical applications. Diblock copolymer nanoplatforms of methoxy poly(ethylene glycol)2000-block-poly (lactic acid)1800 (mPEG2000-b-PLA1800) and (mPEG4000-b-PLA2200) were used to formulate individual and dual drug loaded micelles (DDM) using the solvent evaporation method. The CHE micelles (CHE-M) had a size of 21â¯nm with CHE loading of 0.5â¯mg/mL while the EVR micelles (EVR-M) and the DDM had a size around 35 and 39â¯nm, respectively, with EVR loading up to 2.3â¯mg/mL. The anti-proliferative effects of these micelles have been tested in vitro in three ovarian cell lines (ES2, OVCAR3 and TOV21G) with the DDM exhibiting a strong synergistic anti-proliferative effect in the ES2 and the TOV21G cells. The DDM were able to significantly induce tumor regression in ES2 ovarian xenograft mouse models by inhibiting angiogenesis and inducing apoptosis when compared to the individual micelles. The inhibition of hypoxia inducible factor (HIF) and the mTOR pathways has been elucidated using immunohistochemistry studies. In conclusion, we have developed a mPEG-b-PLA based micellar nanoplatform that could prevent drug resistance by delivering multiple drugs at therapeutically relevant concentrations for effectively treating ovarian carcinomas.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Disulfides/administration & dosage , Drug Carriers/administration & dosage , Everolimus/administration & dosage , Indole Alkaloids/administration & dosage , Micelles , Ovarian Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Combined Chemotherapy Protocols/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Disulfides/chemistry , Drug Carriers/chemistry , Drug Combinations , Drug Liberation , Drug Synergism , Everolimus/chemistry , Female , Humans , Hypoxia-Inducible Factor 1/antagonists & inhibitors , Indole Alkaloids/chemistry , Mice, Nude , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/pathology , Polyesters/administration & dosage , Polyesters/chemistry , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/chemistry , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/antagonists & inhibitorsABSTRACT
Nanoengineering has the potential to revolutionize medicine by designing drug delivery systems that are both efficacious and highly selective. Determination of the affinity between cell lines and nanoparticles is thus of central importance, both to enable comparison of particles and to facilitate prediction of in vivo response. Attempts to compare particle performance can be dominated by experimental artifacts (including settling effects) or variability in experimental protocol. Instead, qualitative methods are generally used, limiting the reusability of many studies. Herein, we introduce a mathematical model-based approach to quantify the affinity between a cell-particle pairing, independent of the aforementioned confounding artifacts. The analysis presented can serve as a quantitative metric of the stealth, fouling, and targeting performance of nanoengineered particles in vitro. We validate this approach using a newly created in vitro dataset, consisting of seven different disulfide-stabilized poly(methacrylic acid) particles ranging from ~100 to 1000â¯nm in diameter that were incubated with three different cell lines (HeLa, THP-1, and RAW 264.7). We further expanded this dataset through the inclusion of previously published data and use it to determine which of five mathematical models best describe cell-particle association. We subsequently use this model to perform a quantitative comparison of cell-particle association for cell-particle pairings in our dataset. This analysis reveals a more complex cell-particle association relationship than a simplistic interpretation of the data, which erroneously assigns high affinity for all cell lines examined to large particles. Finally, we provide an online tool (http://bionano.xyz/estimator), which allows other researchers to easily apply this modeling approach to their experimental results.
Subject(s)
Models, Theoretical , Nanoparticles/administration & dosage , Animals , Disulfides/administration & dosage , Disulfides/chemistry , Gold/administration & dosage , Gold/chemistry , HeLa Cells , Humans , Mice , Nanoparticles/chemistry , Particle Size , Polymethacrylic Acids/administration & dosage , Polymethacrylic Acids/chemistry , RAW 264.7 Cells , Silicon Dioxide/administration & dosage , Silicon Dioxide/chemistry , THP-1 CellsABSTRACT
Nano-MoS2 has been extensively investigated in materials science and biomedicine. However, the effects of different methods of exposure on their translocation, biosafety, and biotransformation-related degradability remain unclear. In this study, we combined the advantages of synchrotron radiation (SR) X-ray absorption near-edge structure (XANES) and high-resolution single-cell SR transmission X-ray microscopy (SR-TXM) with traditional analytical techniques to investigate translocation, precise degraded species/ratio, and correlation between the degradation and toxicity levels of polyvinylpyrrolidone-modified 2H-phase MoS2 nanosheets (MoS2-PVP NSs). These NSs demonstrated different biodegradability levels in biomicroenvironments with H2O2, catalase, and human myeloperoxidase (hMPO) (H2O2 < catalase < hMPO). The effects of NSs and their biodegraded byproducts on cell viability and 3D translocation at the single-cell level were also assessed. Toxicity and translocation in mice via intravenous (i.v.), intraperitoneal (i.p.), and intragastric (i.g.) administration routes guided by fluorescence (FL) imaging were investigated within the tested dosage. After i.g. administration, NSs accumulated in the gastrointestinal organs and were excreted from feces within 48 h. After i.v. injection, NSs showed noticeable clearance due to their decreased accumulation in the liver and spleen within 30 days when compared with that in the i.p. group, which exhibited slight accumulation in the spleen. This work paves the way for understanding the biological behaviors of nano-MoS2 using SR techniques that provide more opportunities for future applications.
Subject(s)
Disulfides/pharmacokinetics , Disulfides/toxicity , Molybdenum/pharmacokinetics , Molybdenum/toxicity , Nanostructures/toxicity , Povidone/pharmacokinetics , Povidone/toxicity , Animals , Biotransformation , Cell Survival/drug effects , Disulfides/administration & dosage , Disulfides/chemistry , Drug Administration Routes , Male , Mice, Inbred BALB C , Molybdenum/administration & dosage , Molybdenum/chemistry , Nanomedicine , Nanostructures/administration & dosage , Nanostructures/chemistry , Povidone/administration & dosage , Povidone/chemistry , Tissue DistributionABSTRACT
AIMS: Inhibition of brain angiotensin III by central infusion of aminopeptidase A (APA) inhibitor firibastat (RB150) inhibits sympathetic hyperactivity and heart failure in rats after myocardial infarction (MI). This study evaluated effectiveness of systemic treatment with firibastat compared with AT1R blocker, losartan. METHODS AND RESULTS: MI was induced by ligation of left coronary artery in male Wistar rats. Rats were treated from 1 to 5 weeks after MI in protocol 1 with vehicle, or firibastat at 50 mg/kg/d subcutaneously (s.c.) or 150 mg/kg/d oral, once daily, and in protocol 2, with vehicle, firibastat 150 mg/kg or losartan 50 mg/kg oral twice daily. At 5 weeks, left ventricle function was evaluated by echocardiography and Millar catheter. After MI, rats developed moderate severe heart failure. Both s.c. and oral firibastat inhibited brain APA and attenuated left ventricle dysfunction. Oral firibastat and losartan similarly improved left ventricular end diastolic pressure. However, whereas firibastat improved dP/dtmax, losartan lowered dP/dtmax and left ventricular peak systolic pressure, and increased plasma creatinine by ~50%. On the other hand, losartan more effectively inhibited cardiac fibrosis. CONCLUSION: Inhibition of the brain renin-angiotensin system by oral APA inhibitor is at least as effective as oral AT1R blocker to inhibit cardiac dysfunction after MI but without hypotension or renal dysfunction.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/administration & dosage , Angiotensin III/metabolism , Brain/drug effects , Disulfides/administration & dosage , Enzyme Inhibitors/administration & dosage , Glutamyl Aminopeptidase/antagonists & inhibitors , Heart Failure/prevention & control , Losartan/administration & dosage , Myocardial Infarction/drug therapy , Sulfonic Acids/administration & dosage , Administration, Oral , Animals , Brain/enzymology , Brain/physiopathology , Disease Models, Animal , Fibrosis , Glutamyl Aminopeptidase/metabolism , Heart Failure/enzymology , Heart Failure/etiology , Heart Failure/physiopathology , Injections, Subcutaneous , Male , Myocardial Infarction/complications , Myocardial Infarction/enzymology , Myocardial Infarction/physiopathology , Rats, Wistar , Signal Transduction , Ventricular Function, Left/drug effects , Ventricular Pressure/drug effects , Ventricular Remodeling/drug effectsABSTRACT
Transforming growth factorß1 (TGFß1) has been demonstrated to promote epithelialmesenchymal transition (EMT), invasion and proliferation in tumors via the activation of Rac1 and ßcatenin signaling pathways. The present study investigated the effects of diallyl disulfide (DADS) on TGFß1induced EMT, invasion and growth of gastric cancer cells. TGFß1 treatment augmented EMT and invasion, concomitantly with increased expression of TGFß1, Rac1 and ßcatenin in gastric cancer cells. DADS downregulated the expression levels of TGFß1, Rac1 and ßcatenin. DADS, TGFß1 receptor inhibitor as well as Rac1 inhibitor antagonized the upregulation of the TGFß1induced expression of these genes, abolishing the enhanced effects of TGFß1 on EMT and invasion. Blocking the TGFß1 receptor through inhibition resulted in the decreased expression of Rac1 and ßcatenin. Rac1 inhibitor reduced the TGFß1induced ßcatenin expression. In addition, DADS and the aforementioned inhibitors attenuated the TGFß1induced tumor growth and the expression changes of Ecadherin, vimentin, Ki67 and CD34 in nude mice. These data indicated that the blockage of TGFß1/Rac1 signaling by DADS may be responsible for the suppression of EMT, invasion and tumor growth in gastric cancer.