RESUMO
Osteoarthritis (OA) is a chronic degenerative joint disease that affects worldwide. Oxidative stress plays a critical role in the chronic inflammation and OA progression. Scavenging overproduced reactive oxygen species (ROS) could be rational strategy for OA treatment. Bilirubin (BR) is a potent endogenous antioxidant that can scavenge various ROS and also exhibit anti-inflammatory effects. However, whether BR could exert protection on chondrocytes for OA treatment has not yet been elucidated. Here, chondrocytes were exposed to hydrogen peroxide with or without BR treatment. The cell viability was assessed, and the intracellular ROS, inflammation cytokines were monitored to indicate the state of chondrocytes. In addition, BR was also tested on LPS-treated Raw264.7 cells to test the anti-inflammation property. An in vitro bimimic OA microenvironment was constructed by LPS-treated Raw264.7 and chondrocytes, and BR also exert certain protection for chondrocytes by activating Nrf2/HO-1 pathway and suppressing NF-κB signalling. An ACLT-induced OA model was constructed to test the in vivo therapeutic efficacy of BR. Compared to the clinical used HA, BR significantly reduced cartilage degeneration and delayed OA progression. Overall, our data shows that BR has a protective effect on chondrocytes and can delay OA progression caused by oxidative stress.
Assuntos
NF-kappa B , Osteoartrite , Humanos , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Bilirrubina/farmacologia , Lipopolissacarídeos/farmacologia , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Inflamação/tratamento farmacológico , Condrócitos/metabolismo , Interleucina-1beta/farmacologiaRESUMO
Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson's disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.
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Neoplasias da Mama , Doença de Parkinson , Humanos , Camundongos , Animais , Feminino , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Carbidopa/farmacologia , Carbidopa/uso terapêutico , Estrogênios , Linhagem Celular TumoralRESUMO
Triptolide (TP) is a diterpene epoxide component extracted from Tripterygium wilfordii and has been shown to possess an impressive anticancer effect. However, TP has not yet entered any clinic trials due to the severe adverse effects that resulted from the off-target absorption and distribution found in animal studies. In this study, we designed and synthesized three amino acids (tryptophan, valine, and lysine) based TP prodrugs to target ATB0,+ which are highly expressed in pancreatic cancer cells for more effective pancreatic cancer therapy. The stability, uptake profiles, uptake mechanism, and cancer-killing ability were studied in vitro. All three prodrugs showed increased uptake and enhanced cytotoxicity in pancreatic cancer cells, but not in normal pancreatic cells. The difference in killing effect on normal and cancer cells was attributed to pancreatic cancer over-expressed ATB0,+-mediated uptake. Specifically, tryptophan-conjugated TP prodrug (TP-Trp) showed the highest uptake and the best cancer cell killing effect, considered as the best candidate. The present study provided the proof-of-concept of exploiting TP prodrug to target ATB0,+ for pancreatic cancer-selective delivery and treatment.
Assuntos
Sistemas de Transporte de Aminoácidos/antagonistas & inibidores , Antineoplásicos/farmacologia , Diterpenos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Fenantrenos/farmacologia , Pró-Fármacos/farmacologia , Sistemas de Transporte de Aminoácidos/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diterpenos/síntese química , Diterpenos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Compostos de Epóxi/farmacologia , Humanos , Conformação Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fenantrenos/síntese química , Fenantrenos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-AtividadeRESUMO
Gemcitabine is the first-line chemotherapy for pancreatic cancer. To overcome the often-acquired gemcitabine resistance, other drugs are used in combination with gemcitabine. It is well-known that cancer cells reprogram cellular metabolism, coupled with the up-regulation of selective nutrient transporters to feed into the altered metabolic pathways. Our previous studies have demonstrated that the amino acid transporter SLC6A14 is markedly up-regulated in pancreatic cancer and that it is a viable therapeutic target. α-Methyltryptophan (α-MT) is a blocker of SLC6A14 and is effective against pancreatic cancer in vitro and in vivo. In the present study, we tested the hypothesis that α-MT could synergize with gemcitabine in the treatment of pancreatic cancer. We investigated the effects of combination of α-MT and gemcitabine on proliferation, migration, and apoptosis in a human pancreatic cancer cell line, and examined the underlying mechanisms using 1H-NMR-based metabolomic analysis. These studies examined the intracellular metabolite profile and the extracellular metabolite profile separately. Combination of α-MT with gemcitabine elicited marked changes in a wide variety of metabolic pathways, particularly amino acid metabolism with notable alterations in pathways involving tryptophan, branched-chain amino acids, ketone bodies, and membrane phospholipids. The metabolomic profiles of untreated control cells and cells treated with gemcitabine or α-MT were distinctly separable, and the combination regimen showed a certain extent of overlap with the individual α-MT and gemcitabine groups. This represents the first study detailing the metabolomic basis of the anticancer efficacy of gemcitabine, α-MT and their combination.
Assuntos
Desoxicitidina/análogos & derivados , Sinergismo Farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Triptofano/análogos & derivados , Sistemas de Transporte de Aminoácidos/antagonistas & inibidores , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/efeitos dos fármacos , Aminoácidos/metabolismo , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/uso terapêutico , Humanos , Metabolômica , Neoplasias Pancreáticas/patologia , Triptofano/metabolismo , Triptofano/uso terapêutico , GencitabinaRESUMO
CONTEXT: Chronic non-healing diabetic wound therapy is an important clinical challenge. Manipulating the release of bioactive factors from an adhesive hydrogel is an effective approach to repair chronic wounds. As an endogenous antioxidant, bilirubin (BR) has been shown to promote wound healing. Nonetheless, its application is limited by its low water solubility and oxidative degradation. OBJECTIVE: This study developed a bilirubin-based formulation for diabetic wound healing. MATERIALS AND METHODS: Bilirubin was incorporated into ß-CD-based inclusion complex (BR/ß-CD) which was then loaded into a bioadhesive hydrogel matrix (BR/ß-CD/SGP). Scratch wound assays were performed to examine the in vitro pro-healing activity of BR/ß-CD/SGP (25 µg/mL of BR). Wounds of diabetic or non-diabetic rats were covered with BR or BR/ß-CD/SGP hydrogels (1 mg/mL of BR) and changed every day for a period of 7 or 21 days. Histological assays were conducted to evaluate the in vivo effect of BR/ß-CD/SGP. RESULTS: Compared to untreated (18.7%) and BR (55.2%) groups, wound closure was more pronounced (65.0%) in BR/ß-CD/SGP group. In diabetic rats, the wound length in BR/ß-CD/SGP group was smaller throughout the experimental period than untreated groups. Moreover, BR/ß-CD/SGP decreased TNF-α levels to 7.7% on day 3, and elevated collagen deposition and VEGF expression to 11.9- and 8.2-fold on day 14. The therapeutic effects of BR/ß-CD/SGP were much better than those of the BR group. Similar observations were made in the non-diabetic model. DISCUSSION AND CONCLUSION: BR/ß-CD/SGP promotes wound healing and tissue remodelling in both diabetic and non-diabetic rats, indicating an ideal wound-dressing agent.
Assuntos
Bilirrubina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Cicatrização/efeitos dos fármacos , beta-Ciclodextrinas/química , Adesivos , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/farmacologia , Bilirrubina/administração & dosagem , Bilirrubina/química , Colágeno/metabolismo , Diabetes Mellitus Experimental/complicações , Células Endoteliais da Veia Umbilical Humana , Humanos , Hidrogéis , Ratos , Solubilidade , Fatores de Tempo , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/etiologiaRESUMO
Disulfiram (DSF) is an FDA-approved anti-alcoholic drug that has recently proven to be effective in cancer treatment. However, the short half-life in the bloodstream and the metal ion-dependent antitumor activity significantly limited the further application of DSF in the clinical field. To this end, we constructed a silk fibroin modified disulfiram/zinc oxide nanocomposites (SF/DSF@ZnO) to solubilize and stabilize DSF, and, more importantly, achieve pH triggered Zn2+ release and subsequent synergistic antitumor activity. The prepared SF/DSF@ZnO nanocomposites were spherical and had a high drug loading. Triggered by the lysosomal pH, SF/DSF@ZnO could induce the rapid release of Zn2+ under the acidic conditions and caused nanoparticulate disassembly along with DSF release. In vitro experiments showed that cytotoxicity of DSF could be enhanced by the presence of Zn2+, and further amplified when encapsulated into SF/DSF@ZnO nanocomposites. It was confirmed that the significantly amplified cytotoxicity of SF/DSF@ZnO was resulted from pH-triggered Zn2+ release, inhibited cell migration, and increased ROS production. In vivo study showed that SF/DSF@ZnO nanocomposites significantly increased the tumor accumulation and prolonged the retention time. In vivo antitumor experiments in the xenograft model showed that SF/DSF@ZnO exerted the highest tumor-inhibition rate among all the drug treatments. Therefore, this exquisite study established silk fibroin-modified disulfiram/zinc oxide nanocomposites, SF/DSF@ZnO, where ZnO not only acted as a delivery carrier but also served as a metal ion reservoir to achieve synergistic antitumor efficacy. The established DSF nanoformulation displayed excellent therapeutic potential in future cancer treatment.
Assuntos
Antineoplásicos/farmacocinética , Nanocompostos/administração & dosagem , Neoplasias/tratamento farmacológico , Zinco/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Bombyx/química , Cátions Bivalentes/farmacocinética , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Dissulfiram/administração & dosagem , Dissulfiram/química , Dissulfiram/farmacocinética , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Fibroínas/química , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Neoplasias/patologia , Óxido de Zinco/administração & dosagem , Óxido de Zinco/química , Óxido de Zinco/farmacocinéticaRESUMO
Islet transplantation is the experimental strategy to treat type 1 diabetes by transplanting isolated islets from a donor pancreas into the recipient. While significant progress has been made in the islet transplantation field, islet loss before and after transplantation is still the major obstacle that currently precludes its widespread application. Islet must survive from possible cellular damages during the isolation procedure, storage time, islet injection process and post-transplantation immune rejection, only then the survived islets could produce insulin, actively regulating the blood glucose level. Therefore, islet protection needs to be addressed, especially regarding oxidative stress and immune response induced islet cell damages in diabetic patients. Many clinical data have shown that mildly elevated bilirubin levels in the body negatively correlate to the occurrence of an array of diseases that are related to increased oxidative stress, especially diabetes, and its complications. Recent studies confirmed that bilirubin helps receivers to suppress immune reaction and enable prolonged tolerance to islet transplantation. In this paper, we will review the pharmacological mechanism of bilirubin to modulate oxidative cellular damage and chronic inflammatory reaction in both diabetes and islet transplantation process. Also, we will present the clinical evidence of a strong correlation in bilirubin and diabetes. More importantly, we will summarize undergoing therapeutic applications of bilirubin in islet transplantation and discuss formulation approaches designed to overcome bilirubin delivery issues for future use.
Assuntos
Bilirrubina/uso terapêutico , Diabetes Mellitus Tipo 1/terapia , Transplante das Ilhotas Pancreáticas , Animais , Bilirrubina/farmacologia , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Low tumor specificity and multidrug resistance (MDR) remain challenging for many anticancer drugs. In this study, the micelles assembled by a matrix metalloproteinase 2 (MMP2)-sensitive self-assembling efflux inhibitor (PEG2k-pp-PE) were developed and evaluated in various cancer models. In vitro, the PEG2k-pp-PE micelles enhanced the cellular uptake and tissue penetration and sensitized the cancers to drug treatments in MDR cancer cells and their three-dimensional multicellular spheroids. Their efflux inhibitory capability was comparable to those of the well-known small-molecule P-glycoprotein (P-gp) inhibitor and polymeric P-gp inhibitor. In vivo, the PEG2k-pp-PE micelles could specifically and effectively deliver the loaded cargoes to the tumor, as evidenced by the enhanced drug accumulation and prolonged drug retention in the tumor tissue, resulting in the improved anticancer activity. Our results suggest that the PEG2k-pp-PE micelles may have great potential to be a simple but multifunctional nanocarrier for concurrent tumor-targeted drug delivery and sensitization of resistant cancers.
Assuntos
Sistemas de Liberação de Medicamentos , Metaloproteinase 2 da Matriz/metabolismo , Micelas , Neoplasias/tratamento farmacológico , Polímeros/química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular , Linhagem Celular Tumoral , Proliferação de Células , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Concentração Inibidora 50 , Camundongos , Neoplasias/patologia , Esferoides Celulares/metabolismo , Distribuição TecidualRESUMO
To improve the bioavailability of orally administered drugs, we synthesized a pH-sensitive polymer (poly(ethylene glycol)-poly(2-methyl-2-carboxyl-propylene carbonate)-vitamin E, mPEG-PCC-VE) attempting to integrate the advantages of enteric coating and P-glycoprotein (P-gp) inhibition. The aliphatic polycarbonate chain was functionalized with carboxyl groups and vitamin E via postpolymerization modification. Optimized by comparison and central composite design, mPEG113-PCC32-VE4 exhibited low critical micelle concentration of 1.7 × 10(-6) mg/mL and high drug loading ability for tacrolimus (21.2% ± 2.7%, w/w). The pH-responsive profile was demonstrated by pH-dependent swelling and in vitro drug release. Less than 4.0% tacrolimus was released under simulated gastric fluid after 2.5 h, whereas an immediate release was observed under simulated intestinal fluid. The mPEG113-PCC32-VE4 micelles significantly increased the absorption of P-gp substrate tacrolimus in the whole intestine. The oral bioavailability of tacrolimus micelles was 6-fold higher than that of tacrolimus solution in rats. This enteric polymer therefore has the potential to become a useful nanoscale carrier for oral delivery of drugs.
Assuntos
Portadores de Fármacos/síntese química , Micelas , Cimento de Policarboxilato/química , Polietilenoglicóis/química , Tacrolimo/administração & dosagem , Vitamina E/química , Administração Oral , Animais , Portadores de Fármacos/farmacocinética , Concentração de Íons de Hidrogênio , Absorção Intestinal , Ratos , Ratos Sprague-Dawley , Tacrolimo/farmacocinética , Distribuição TecidualRESUMO
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious lung injuries caused by various factors, leading to increased permeability of the alveolar-capillary barrier, reduced stability of the alveoli, inflammatory response, and hypoxemia. Despite several decades of research since ARDS was first formally described in 1967, reliable clinical treatment options are still lacking. Currently, supportive therapy and mechanical ventilation are prioritized, and there is no medication that can be completely effective in clinical treatment. In recent years, nanomedicine has developed rapidly and has exciting preclinical treatment capabilities. Using a drug delivery system based on nanobiotechnology, local drugs can be continuously released in lung tissue at therapeutic levels, reducing the frequency of administration and improving patient compliance. Furthermore, this novel drug delivery system can target specific sites and reduce systemic side effects. Currently, many nanomedicine treatment options for ARDS have demonstrated efficacy. This review briefly introduces the pathophysiology of ARDS, discusses various research progress on using nanomedicine to treat ARDS, and anticipates future developments in related fields.
Assuntos
Nanomedicina , Síndrome do Desconforto Respiratório , Humanos , Síndrome do Desconforto Respiratório/tratamento farmacológico , Pulmão , Sistemas de Liberação de MedicamentosRESUMO
INTRODUCTION: Epilepsy, a prevalent neurodegenerative disorder, profoundly impacts the physical and mental well-being of millions globally. Historically, antiseizure drugs (ASDs) have been the primary treatment modality. However, despite the introduction of novel ASDs in recent decades, a significant proportion of patients still experiences uncontrolled seizures. AREAS COVERED: The rapid advancement of nanomedicine in recent years has enabled precise targeting of the brain, thereby enhancing therapeutic efficacy for brain diseases, including epilepsy. EXPERT OPINION: Nanomedicine holds immense promise in epilepsy treatment, including but not limited to enhancing drug solubility and stability, improving drug across blood-brain barrier, overcoming resistance, and reducing side effects, potentially revolutionizing clinical management. This paper provides a comprehensive overview of current epilepsy treatment modalities and highlights recent advancements in nanomedicine-based drug delivery systems for epilepsy control. We discuss the diverse strategies used in developing novel nanotherapies, their mechanisms of action, and the potential advantages they offer compared to traditional treatment methods.
Assuntos
Anticonvulsivantes , Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Epilepsia , Nanomedicina , Humanos , Nanomedicina/métodos , Epilepsia/tratamento farmacológico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Animais , Barreira Hematoencefálica/metabolismo , Nanopartículas , Solubilidade , Estabilidade de MedicamentosRESUMO
[This corrects the article DOI: 10.1039/D4RA02811B.].
RESUMO
The purpose of the study is to investigate the effect of ternary systems consisting of meloxicam with cyclodextrins (HP-ß-CD or SBE-ß-CD) and different polymers (HA, HPMC and PVP) on the stability of meloxicam. The t 0.9 values of meloxicam were determined within all the aforementioned systems and the influence of various polymers on the alteration in meloxicam's stability was evaluated. All three polymers altered the stability of meloxicam to varying degrees, with the extent of the effect being related to hydrophilicity, concentration of components, and the interaction of the newly formed ternary system. Among them, meloxicam demonstrated its highest degree of stabilization within the ternary system formed by SBE-ß-CD&HPMC and HP-ß-CD&HA. We characterized the ternary system of meloxicam using differential scanning calorimetry (DSC), X-ray diffraction, and scanning electron microscopy analysis, which determined the presence of ternary system inclusions. In addition, we investigated the optimized prescription of eye drops of meloxicam using the ternary system and further determined that the ternary system improved the stability of the drug in liquid formulations.
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Islet transplantation holds significant promise as a curative approach for type 1 diabetes (T1D). However, the transition of islet transplantation from the experimental phase to widespread clinical implementation has not occurred yet. One major hurdle in this field is the challenge of insufficient vascularization and subsequent early loss of transplanted islets, especially in non-intraportal transplantation sites. The establishment of a fully functional vascular system following transplantation is crucial for the survival and secretion function of islet grafts. This vascular network not only ensures the delivery of oxygen and nutrients, but also plays a critical role in insulin release and the timely removal of metabolic waste from the grafts. This review summarizes recent advances in effective strategies to improve graft revascularization and enhance islet survival. These advancements include the local release and regulation of angiogenic factors (e.g., vascular endothelial growth factor, VEGF), co-transplantation of vascular fragments, and pre-vascularization of the graft site. These innovative approaches pave the way for the development of effective islet transplantation therapies for individuals with T1D.
Assuntos
Diabetes Mellitus Tipo 1 , Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas , Humanos , Ilhotas Pancreáticas/metabolismo , Diabetes Mellitus Tipo 1/cirurgia , Materiais Biocompatíveis , Fator A de Crescimento do Endotélio Vascular/metabolismo , Transplante das Ilhotas Pancreáticas/fisiologia , Neovascularização FisiológicaRESUMO
Disulfiram (DSF) is a second-line drug for the clinical treatment of alcoholism and has long been proven to be safe for use in clinical practice. In recent years, researchers have discovered the cancer-killing activity of DSF, which is highly dependent on the presence of metal ions, particularly copper ions. Additionally, free DSF is highly unstable and easily degraded within few minutes in blood circulation. Therefore, an ideal DSF formulation should facilitate the co-delivery of metal ions and safeguard the DSF throughout its biological journey before reaching the targeted site. Extensive research have proved that nanotechnology based formulations can effectively realize this goal by strategic encapsulation therapeutic agents within nanoparticle. To be more specific, this is accomplished through precise delivery, coordinated release of metal ions at the tumor site, thereby amplifying its cytotoxic potential. Beyond traditional co-loading techniques, innovative approaches such as DSF-metal complex and metal nanomaterials, have also demonstrated promising results at the animal model stage. This review aims to elucidate the anticancer mechanism associated with DSF and its reliance on metal ions, as well as to provide a comprehensive overview of recent advances in the arena of nanomedicine based co-delivery strategies for DSF and metal ion in the context of cancer therapy.
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In assisted reproduction techniques, oocytes encounter elevated levels of reactive oxygen species (ROS) during in vitro maturation (IVM). Oxidative stress adversely affects oocyte quality, hampering their maturation, growth, and subsequent development. Thus, mitigating excessive ROS to safeguard less viable oocytes during IVM stands as a viable strategy. Numerous antioxidants have been explored for oocyte IVM, yielding considerable effects; however, several aspects, including solubility, stability, and safety, demand attention and resolution. In this study, we developed nanoparticles by self-assembling endogenous bilirubin and melatonin hormone coated with bilirubin-conjugated glycol chitosan (MB@GBn) to alleviate oxidative stress and enhance oocyte maturation. The optimized MB@GBn exhibited a uniform spherical shape, measuring 128 nm in particle size, with a PDI value of 0.1807 and a surface potential of +11.35 mV. The positively charged potential facilitated nanoparticle adherence to the oocyte surface through electrostatic interaction, allowing for functional action. In vitro studies demonstrated that MB@GB significantly enhanced the maturation of compromised oocytes. Further investigation revealed MB@GB's effectiveness in scavenging ROS, reducing intracellular calcium levels, and suppressing mitochondrial polarization. This study not only offers a novel perspective on nano drug delivery systems for biomedical applications but also presents an innovative strategy for enhancing oocyte IVM.
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Triple negative breast cancer (TNBC) presents a formidable challenge due to its low sensitivity to many chemotherapeutic drugs and a relatively low overall survival rate in clinical practice. Photothermal therapy has recently garnered substantial interest in cancer treatment, owing to its swift therapeutic effectiveness and minimal impact on normal cells. Metal-polyphenol nanostructures have recently garnered significant attention as photothermal transduction agents due to their facile preparation and favorable photothermal properties. In this study, we employed a coordinated approach involving Fe3+ and apigenin, a polyphenol compound, to construct the nanostructure (nFeAPG), with the assistance of ß-CD and DSPE-PEG facilitating the formation of the complex nanostructure. In vitro research demonstrated that the formed nFeAPG could induce cell death by elevating intracellular oxidative stress, inhibiting antioxidative system, and promoting apoptosis and ferroptosis, and near infrared spectrum irradiation further strengthen the therapeutic outcome. In 4T1 tumor bearing mice, nFeAPG could effectively accumulate into tumor site and exhibit commendable control over tumor growth. Futher analysis demonstrated that nFeAPG ameliorated the suppressed immune microenvironment by augmenting the response of DC cells and T cells. This study underscores that nFeAPG encompasses a multifaceted capacity to combat TNBC, holding promise as a compelling therapeutic strategy for TNBC treatment.
Assuntos
Nanopartículas , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Terapia Fototérmica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Apigenina , Ferro , Linhagem Celular Tumoral , Polifenóis , Microambiente TumoralRESUMO
Chronic diabetic wounds pose a serious threat to human health and safety because of their refractory nature and high recurrence rates. The formation of refractory wounds is associated with wound microenvironmental factors such as increased expression of proinflammatory factors and oxidative stress. Bilirubin is a potent endogenous antioxidant, and morin is a naturally active substance that possesses anti-inflammatory and antioxidant effects. Both hold the potential for diabetic wound treatment by intervening in pathological processes. In this study, we developed bilirubin/morin-based carrier-free nanoparticles (BMn) to treat chronic diabetic wounds. In vitro studies showed that BMn could effectively scavenge overproduced reactive oxygen species and suppress elevated inflammation, thereby exerting a protective effect. BMn was then loaded into a collagen/polyvinyl alcohol gel (BMn@G) for an in vivo study to maintain a moist environment for the skin and convenient biomedical applications. BMn@G exhibits excellent mechanical properties, water retention capabilities, and in vivo safety. In type I diabetic mice, BMn@G elevated the expression of the anti-inflammatory factor IL-10 and concurrently diminished the expression of the proinflammatory factor TNF-α in the tissues surrounding the wounds. Furthermore, BMn@G efficiently mediated macrophage polarization from the M1-type to the M2-type, thereby fostering anti-inflammatory effects. Additionally, BMn@G facilitated the conversion of type III collagen fiber bundles to type I collagen fiber bundles, resulting in a more mature collagen fiber structure. This study provides a promising therapeutic alternative for diabetic wound healing.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus , Flavonas , Nanopartículas , Camundongos , Humanos , Animais , Álcool de Polivinil/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Bilirrubina/metabolismo , Cicatrização , Colágeno/química , Inflamação/patologia , Anti-Inflamatórios/uso terapêutico , Flavonoides/uso terapêutico , Estresse Oxidativo , Hidrogéis/uso terapêutico , Diabetes Mellitus/tratamento farmacológicoRESUMO
Osteoarthritis (OA) is a chronic inflammatory disease characterized by cartilage destruction, synovitis, and osteophyte formation. Disease-modifying treatments for OA are currently lacking. Because inflammation mediated by an imbalance of M1/M2 macrophages in the synovial cavities contributes to OA progression, regulating the M1 to M2 polarization of macrophages can be a potential therapeutic strategy. Basing on the inherent immune mechanism and pathological environment of OA, an immunoglobulin G-conjugated bilirubin/JPH203 self-assembled nanoparticle (IgG/BRJ) is developed, and its therapeutic potential for OA is evaluated. After intra-articular administration, IgG conjugation facilitates the recognition and engulfment of nanoparticles by the M1 macrophages. The internalized nanoparticles disassemble in response to the increased oxidative stress, and the released bilirubin (BR) and JPH203 scavenge reactive oxygen species (ROS), inhibit the nuclear factor kappa-B pathway, and suppress the activated mammalian target of rapamycin pathway, result in the repolarization of macrophages and enhance M2/M1 ratios. Suppression of the inflammatory environment by IgG/BRJ promotes cartilage protection and repair in an OA rat model, thereby improving therapeutic outcomes. This strategy of opsonization involving M1 macrophages to engulf carrier-free BR/JPH203 nanoparticles to suppress inflammation for OA therapy holds great potential for OA intervention and treatment.
Assuntos
Bilirrubina , Modelos Animais de Doenças , Inflamação , Macrófagos , Nanopartículas , Osteoartrite , Animais , Osteoartrite/imunologia , Osteoartrite/tratamento farmacológico , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Ratos , Inflamação/imunologia , Bilirrubina/farmacologia , Bilirrubina/metabolismo , Masculino , Ratos Sprague-DawleyRESUMO
In addition to being a physiological protective barrier, the gastrointestinal mucosal membrane is also a primary obstacle that hinders the oral absorption of many therapeutic compounds, especially drugs with a poor permeability. In order to resolve this impasse, we have designed multifunctional nanomicelles based on the acetylcysteine functionalized chitosan-vitamin E succinate copolymer (CS-VES-NAC, CVN), which exhibit marked bioadhesion, possess the ability to penetrate mucus, and enhance the oral absorption of a hydrophobic drug with a poor penetrative profile, paclitaxel. The intestinal absorption (Ka = 0.38 ± 0.04 min(-1), Papp = 0.059 cm · min(-1)) of CVN nanomicelles was greatly improved (4.5-fold) in comparison with paclitaxel solution, and CLSM (confocal laser scanning microscope) pictures also showed not only enhanced adhesion to the intestinal surface but improved accumulation within intestinal villi. The in vivo pharmacokinetics indicated that the AUC0-t (586.37 ng/mL · h) of CVN nanomicelles was markedly enhanced compared with PTX solution. In summary, the novel multifunctional CVN nanomicelles appear to be a promising nanocarrier for insoluble and poorly permeable drugs due to their high bioadhesion and permeation-enhancing capability.