RESUMO
INTRODUCTION: Cutaneous adverse reactions to epidermal growth factor receptor inhibitors (EGFRi) are some of the most common side effects that patients experience. However, cutaneous adverse reactions that cause dyspigmentation in patients have been rarely reported. Erythema dyschromicum perstans (EDP) is a rare pigmentary condition that causes ashy-grey hyperpigmented macules and patches, with a few cases reported from EGFRi in the literature. The disfiguration caused by this condition may negatively impact patients' quality of life. Our study aimed to describe the clinical characteristics of EDP induced by EGFRi to better recognize and manage the condition. METHODS: We conducted a multicenter retrospective review at three academic institutions to identify patients with EDP induced by EGFRi from 2017 to 2023 and included sixteen patients in our study. RESULTS: The median age of patients was 66 years old, with 63% female and 37% male (Table 1). The majority of our patients were Asian (88%). All patients had non-small cell lung cancer and most patients received osimertinib. Median time to EDP was 6 months. The most common areas of distribution were the head/neck region, lower extremities, and upper extremities. Various topical ointments were trialed; however, approximately less than half had improvement in their disease and most patients had persistent EDP with no resolution. All patients desired treatment except one with EDP on the tongue, and there was no cancer treatment discontinuation or interruption due to EDP. Table 1 Patient demographics and clinical characteristics of 16 patients with EDP induced by EGFRi Case no Demographics: age, race, and sex Fitzpatrick skin type Cancer type EGFR therapy Concomitant photosensitive drug(s) Time to EDP (months) Clinical features Distribution Symptoms Treatments and clinical course EDP status from most recent follow up 1 47 y/o Asian male III Stage IV NSCLC Erlotinib None Unknown Brown-blue-gray hyperpigmented patches Bilateral shins Left thigh Xerosis Pruritus Triamcinolone 0.1% ointment for 4 months, improvement of blue discoloration Tacrolimus 0.1% BID for 9 months, improvement but no resolution Ongoing 2 62 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown hyperpigmented patches Bilateral arms Back Forehead Neck Right shin None Tacrolimus 0.1% ointment for 1 year with minor improvement Ongoing 3 69 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown macules and patches Chest Face Forehead Bilateral legs None Tacrolimus 0.1% ointment for 10 months, no improvement Ongoing 4 79 y/o White male II Stage IV NSCLC Osimertinib None 15 Mottled grey-blue hyperpigmented patches and plaques with mild scaling Bilateral arms Back Forehead Neck None Photoprotection, no improvement Ongoing 5 69 y/o Asian female III Stage IV NSCLC Osimertinib Ibuprofen 4 Blue-grey hyperpigmented macules and patches Abdomen Bilateral arms None Tacrolimus 0.1% ointment for 7 months, no improvement Ongoing 6 65 y/o Asian male III Stage IV NSCLC Osimertinib None 20 Hyperpigmented blue gray macules and patches Helix Bilateral shins None Photoprotection, no improvement Ongoing 7 66 y/o Asian female IV Stage IV NSCLC Erlotinib TMP-SMX 6 Ashy grey-brown thin plaques Back Forehead None 2.5% hydrocortisone ointment for 8 months, resolved Resolved 8 82 y/o Asian male III Stage III NSCLC Erlotinib Simvastatin 20 Ash-grey hyperpigmented patches Dorsal feet Forehead Scalp None Photoprotection Ongoing 9 57 y/o Asian female III Stage II NSCLC Erlotinib None 1 Bue-grey discoloration Tongue None No intervention Ongoing 10 51 y/o Asian female III Stage IV NSCLC Osimertinib None 9 Blue-grey hyperpigmented macules and patches Bilateral arms Axillae Groin Neck Trunk None 2.5% hydrocortisone ointment, triamcinolone 0.1% ointment, photoprotection with mild improvement Ongoing 11 67 y/o Asian male III Stage IV NSCLC Osimertinib None 7 Gray-blue macules and patches with mild background erythema and scaling Bilateral arms Ears Face Bilateral shins None Triamcinolone 0.1% ointment, protection for 6 months with mild improvement Ongoing 12 75 y/o Asian female IV Stage III NSCLC Osimertinib TMP-SMX 3 Gray-blue hyperpigmented patches Bilateral arms Abdomen Back Face Bilateral shins Pruritus Triamcinolone 0.1% and betamethasone 0.01% with relief of pruritus, lesions unchanged Triluma cream 6 months, mild improvement Ongoing 13 42 y/o Asian male IV Stage IV NSCLC Afatinib TMP-SMX 24 Grey-brown hyperpigmented patches Back Face None Hydroquinone 4% cream for 2 years with mild improvement Ongoing 14 74 y/o White female III Stage II NSCLC Osimertinib Atorvastatin 4 Grey-brown hyperpigmented patches Bilateral legs Trunk None Photoprotection Ongoing 15 64 y/o Asian female IV Stage IV NSCLC Osimertinib None 3 Gray-brown hyperpigmentation Abdomen Bilateral arms Back Bilateral legs Pruritus Triamcinolone 0.1% cream; No change, minimal concern to patient Ongoing 16 52 y/o Asian female IV Stage IV NSCLC Osimertinib None 42 Gray hyperpigmented patches with digitate shape Abdomen Bilateral flanks None Triamcinolone 0.1% cream Ongoing NSCLC, non-small cell lung cancer, TMP-SMX, Trimethoprim/Sulfamethoxazole CONCLUSIONS: We highlight the largest case series describing EDP from EGFR inhibitors, which mostly affected Asian patients with lung malignancy and on EGFR tyrosine kinase inhibitors. Clinicians should be able to recognize this condition in their patients and assess how it is affecting their quality of life, and refer to dermatology to help with management.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Humanos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Eritema/induzido quimicamente , Eritema/etiologia , Acrilamidas/efeitos adversos , Acrilamidas/administração & dosagem , Toxidermias/etiologia , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Qualidade de VidaRESUMO
Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants (POPs) that pose serious challenges to aquatic animals and environments. Compared with BDE-47 which was one of the most toxic congeners known to date, BDE-209 is less toxic with higher abundance in biotic and abiotic samples. In this study, we have explored the effects of BDE-47 and BDE-209 at different concentrations on the radical oxygen species (ROS) levels and the antioxidant defense system of Brachionus plicatilis. Antioxidant indexes were measured, including total protein content (TSP), the activities of antioxidant enzymes, lipid peroxidation and DNA damage. The results indicated that while low concentrations of PBDEs could activate the antioxidant defense mechanisms, prolonged exposure to higher concentrations of PBDEs could impair the antioxidative capacity of B.plicatilis (P < 0.05). The overwhelming of the B.plicatilis antioxidant defense mechanism led to an accumulation of free radicals, resulting in the overactivation of lipid peroxidation and the increased frequency of DNA damage (P < 0.05). By studying the toxicity of PBDEs and the detoxification mechanism of B.plicatilis, our research has revealed useful indexes for detecting and monitoring the level of BDE-47 and BDE-209 in the future. Altogether, this study holds immense value in the field of ecotoxicology and environmental safety and will aid in the proper management of PBDEs pollution.
Assuntos
Éteres Difenil Halogenados , Rotíferos , Animais , Antioxidantes/metabolismo , Mecanismos de Defesa , Monitoramento Ambiental , Éteres Difenil Halogenados/metabolismoRESUMO
As a new form of nicotine introduction for novel tobacco products, the interaction of nicotine salt with biological macromolecules may differ from that of free nicotine and thus affect its transport and distribution in vivo. Hence, the mechanism underlying the interaction between 2,6-dihydroxybenzoic acid nicotine salt (DBN) and human serum albumin (HSA) was investigated by multi-spectroscopy, molecular docking, and dynamic simulation. Experiments on steady-state fluorescence and fluorescence lifetime revealed that the quenching mechanism of DBN and HSA was dynamic quenching, and binding constant was in the order of 10^4 L mol-1. Thermodynamic parameters exhibited that the binding was a spontaneous process with hydrophobic forces as the main driving force. Fluorescence competition experiments revealed that DBN bound to site I of HSA IIA subdomain. According to the results of synchronous fluorescence, 3D fluorescence, FT-IR spectroscopy, circular dichroism (CD) spectroscopy, and molecular dynamics (MD) simulation, DBN did not affect the basic skeleton structure of HSA but changed the microenvironment around the amino acid residues. Computer simulations positively corroborated the experimental results. Moreover, DBN decreased the surface hydrophobicity and weakened the esterase-like activity of HSA, leading to the impaired function of the latter. This work provides important information for studying the interaction between DBN as a nicotine substitute and biological macromolecules and contributes to the further development and application of DBN.
Assuntos
Simulação de Dinâmica Molecular , Albumina Sérica Humana , Sítios de Ligação , Dicroísmo Circular , Humanos , Hidroxibenzoatos , Simulação de Acoplamento Molecular , Nicotina , Ligação Proteica , Albumina Sérica Humana/metabolismo , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , TermodinâmicaRESUMO
HER2+ breast cancer is highly aggressive and proliferative even after multiple chemotherapy regimens. At present, the available clinical treatment duration of chemotherapeutic agents is limited by severe toxicity to noncancerous tissues, which are attributed to insufficient targeting. Here, we designed an active-targeted and pH-responsive liposome to improve the treatment. The ideas were as follows: (1) using liposome as a nano-delivery system for HER2 inhibitor (lapatinib; LAP) to reduce the toxicity; (2) modifying the capsule with T7 peptide for specific targeted delivery to the tumor cells, and (3) enabling the capsule with the pH-sensitive ability and triggering sustained drug release at extracellular weakly acidic microenvironment to emerge toxicity in tumors and to improve curative effects. It was found that T7 peptide-modified pH-sensitive liposome (T7-LP) was more effective and safer than free drug and unmodified liposome, and reduced drug-induced side effects and noncancerous toxicity. These results support the application potential of T7-LP in improving the efficacy of LAP in HER2+ breast cancer treatment. It might be a novel LAP formulation as a clinical agent.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Colágeno Tipo IV/química , Lapatinib/farmacologia , Fragmentos de Peptídeos/química , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Animais , Antineoplásicos/química , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Lapatinib/química , Lipossomos/química , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Imagem Óptica , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Receptor ErbB-2/metabolismoRESUMO
Lentinan is a natural ß-glucan with various bioactivities and is combined with chemotherapy drugs for cancer treatment. Regorafenib is an oral multi-kinase inhibitor approved by FDA for treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors. Regorafenib has poor water solubility and multiple toxicities. We report drug-drug nanosuspensions of regorafenib and lentinan. Results of dynamic light scattering and scanning electron microscopy showed that the mean particle size of the regorafenib-lentinan nanosuspensions was approximately 200 nm and was uniformly distributed. Transmission electron microscopy findings indicated that lentinan stabilized the nanosuspensions by steric manner. Hydrogen bonds and hydrophobic interactions were found between regorafenib and lentinan by molecular dynamics simulation. The results of cytotoxicity assay and pharmacokinetics study in rats showed that the regorafenib-lentinan nanosuspensions reduced the toxicity and enhanced the in vitro anticancer activity and oral bioavailability of regorafenib. Lentinan as a natural stabilizer has the potential using for drug nanosuspensions. Drug-drug nanosuspensions are a new form of combination therapies that can reduce the number of drugs taken by patients and improve their compliance.
Assuntos
Antineoplásicos/administração & dosagem , Lentinano/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Administração Oral , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidade Biológica , Composição de Medicamentos , Células HCT116 , Células HEK293 , Humanos , Lentinano/química , Lentinano/farmacocinética , Simulação de Dinâmica Molecular , Nanopartículas , Tamanho da Partícula , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacocinética , Piridinas/química , Piridinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Solubilidade , SuspensõesRESUMO
Hemoperfusion has become the third-generation treatment strategy for patients suffering from hyperbilirubinemia, but adsorbents used for bilirubin removal mostly face intractable problems, such as unsatisfactory adsorption performance and poor hemocompatibility. Metal-organic frameworks (MOFs) are promising adsorbents for hemoperfusion due to their high specific surface areas and easily modified organic ligands. However, their microporous properties and separation have hampered their application. Here, a novel hierarchical core-shell nanoplatform (named Double-PEG) with tailored binding sites and pore sizes based on Fe3O4@C and Uio66-NH2 was constructed. Notably, Double-PEG showed excellent bilirubin uptake of up to 1738.30 mg g-1 and maintained excellent bilirubin removal efficiency in simulated biological solutions. A study on the adsorption mechanism showed that the adsorption of Double-PEG towards bilirubin tended to be chemical adsorption and in accordance with the Langmuir model. Besides, the good separability, recyclability, cytotoxicity and hemocompatibility of Double-PEG show great potential in hemoperfusion therapy. The finding of this study may provide a novel insight into the application of MOF materials in the field of hemoperfusion.
Assuntos
Bilirrubina/isolamento & purificação , Materiais Biocompatíveis/química , Carbono/química , Óxido Ferroso-Férrico/química , Estruturas Metalorgânicas/química , Nanopartículas/química , Adsorção , Bilirrubina/química , Materiais Biocompatíveis/síntese química , Linhagem Celular , Humanos , Cinética , Estruturas Metalorgânicas/síntese química , Estrutura Molecular , Tamanho da Partícula , Propriedades de Superfície , Purificação da ÁguaRESUMO
Introduction of hydrophilic groups can improve the solubility of leading drugs but inevitably affect their interaction with proteins. This study selected sirtuin inhibitors Tenovin-1 (T1) and Tenovin-6 (T6) as drug models to determine differences in binding mode to human serum albumin (HSA). T1 and T6 quenched the endogenous fluorescence of HSA via static quenching mechanism. Introduction of hydrophilic groups greatly reduced the binding constant, i.e., from 1.302â¯×â¯104 L mol-1 for the HSA-T6 system to 0.128â¯×â¯104 L mol-1 for the HSA-T1 system. HSA-T1 system was mainly driven by electrostatic interactions while that of HSA-T6 system was hydrophobic interaction and both systems were spontaneous reactions. Site marker experiments and molecular docking indicated that both systems mainly bound to the hydrophobic site I of HSA. Molecular dynamics (MD) simulation analysis further revealed that Tyr148, Tyr150 and Arg257 residues played a key role in this recognition process for both systems. In particular, T6 maintained additional several hydrogen bonds with the surrounding residues. T1 had almost no effect on the esterase-like activity of HSA, but T6 inhibited the hydrolysis of p-NPA. Furthermore, differential scanning calorimetry (VP-DSC), circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopy confirmed that HSA in the T6 system undergone a more significant conformational transition than that in the T1 system.
Assuntos
Preparações Farmacêuticas , Sirtuínas , Acetanilidas , Benzamidas , Sítios de Ligação , Dicroísmo Circular , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Ligação Proteica , Albumina Sérica Humana/metabolismo , Espectrometria de Fluorescência , Termodinâmica , Tioureia/análogos & derivadosRESUMO
The clinical efficacy of lenvatinib (LFT) is limited by its poor aqueous solubility and low bioavailability. In this work, LFT-loaded soy phospholipid and sodium glycocholate mixed micelles (LFT-MMs) were prepared through classical co-precipitation. And it was served as an oral administration to address these shortcomings. The preparation conditions were optimized by single-factor experiments. The mass ratio of PC, SGC and LFT, and the species of dispersing media were proved to be decisive factors in controlling the properties of LFT-MMs. The optimal LFT-MMs presented prominent enhancement (500-fold) in LFT solubility, high encapsulation efficiency (87.6 %) as well as suitable stability (>1 month at 4 °C). The biocompatibility of LFT-MMs was estimated by in vitro serum stability measurement and hemolysis test. It showed that serum proteins hardly adhered to the surface of LFT-MMs, and insignificant hemolytic rate (<0.5 %) was observed at the micelles concentration below 1 mg/mL. Cytotoxicity test (MTT assay) was carried out to judge the in vitro antitumor activity. LFT-MMs showed an enhanced inhibitory activity against two main kinds of differentiated thyroid cancer cells over LFT and LFT Mesylate. To estimate the in vivo oral bioavailability of LFT-MMs, SD rats were used as animal model. Notably, the relative bioavailability of LFT-MMs compared with the original form of LFT was 176.7 %. These superior characteristics indicated that the mixed micelles are promising water-soluble formulations suitable for LFT oral delivery.
Assuntos
Micelas , Fosfolipídeos , Administração Oral , Animais , Disponibilidade Biológica , Portadores de Fármacos , Tamanho da Partícula , Compostos de Fenilureia , Quinolinas , Ratos , Ratos Sprague-Dawley , SolubilidadeRESUMO
The interaction between a DPP-4 inhibitor, alogliptin benzoate (AB), and human serum albumin (HSA) was systematically investigated via spectroscopy, microcalorimetry and molecular simulations. Steady-state fluorescence and time-resolved fluorescence spectrometry illustrated that the fluorescence quenching type of AB to HSA was static and caused by the formation of ground state AB-HSA complex. Isothermal titration calorimetry (ITC) combined with fluorescence spectra revealed that the affinity of AB to the subdomain IIA of HSA was moderate with a binding constant in the order of 104. Molecular docking analysis and thermodynamic parameters demonstrated that this combination was maintained by hydrogen bonding along with van der Waals force and hydrophobic force. Circular dichroism and three-dimensional (3D) fluorescence showed that AB increased the hydrophobicity of Trp residue and the α-helix content of HSA by 1.99%. Microdifferential scanning calorimetry revealed that the addition of AB enhanced the thermal stability of HSA. The action forces, binding stability, binding sites, and protein structure of the AB-HSA system were evaluated via molecular dynamics analysis in the simulated environment. On the basis of molecular docking, MD simulation constructed a more reliable 3D model of the AB-HSA complex in terms of spatial structure.
Assuntos
Simulação de Dinâmica Molecular , Albumina Sérica Humana , Benzoatos , Sítios de Ligação , Calorimetria , Dicroísmo Circular , Humanos , Simulação de Acoplamento Molecular , Piperidinas , Ligação Proteica , Albumina Sérica Humana/metabolismo , Espectrometria de Fluorescência , Termodinâmica , Uracila/análogos & derivadosAssuntos
Adjuvantes Imunológicos/administração & dosagem , Ciclobutanos/administração & dosagem , Herpes Labial/tratamento farmacológico , Prevenção Secundária/métodos , Exacerbação dos Sintomas , Adjuvantes Imunológicos/efeitos adversos , Administração Tópica , Ciclobutanos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Herpes Labial/diagnóstico , Herpes Labial/imunologia , Herpes Labial/virologia , Herpesvirus Humano 1/imunologia , Humanos , Placebos/administração & dosagem , Placebos/efeitos adversos , Recidiva , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The objective of present study is to explore whether polysaccharide could be a crystal growth inhibitor in poorly soluble antitumor drug Ibrutinib (IBR) formulation. In this work, small molecular ligands (amino or organic acids) in co-amorphous system (CAS) were preliminarily screened. A polysaccharide, microcrystalline cellulose (MCC) was selected to stabilize amorphous drug and enhance pharmacokinetic properties. Fourier-transform infrared, Raman, and X-ray photoelectron spectroscopy confirmed the ionic interaction of the ternary IBR formulation. Moreover, the biosafety of the ternary formulation was the same as that of IBR while the in vitro performance advantage of the ternary formulation was converted into higher bioavailability in vivo experiments. Overall, MCC as an effective crystal growth inhibitor in the novel ternary IBR formulation is a promising approach to improve the dissolution rate of crystalline drugs and the stability of amorphous drugs, as well as providing a theoretical basis for clinical applications.
Assuntos
Celulose/química , Pirazóis/química , Pirimidinas/química , Adenina/análogos & derivados , Animais , Disponibilidade Biológica , Linhagem Celular Tumoral , Fenômenos Químicos , Cristalização , Composição de Medicamentos , Humanos , Masculino , Piperidinas , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , RatosRESUMO
In this study, a novel Bruton's tyrosine kinase inhibitor, ibrutinib, was loaded into chitosan/sulfobutylether-ß-cyclodextrin nanoparticles (NPs). NPs have gained high loading efficiency for the hydrophobic drug due to the inclusion of cyclodextrin. Ibrutinib-loaded NPs with an average diameter of 277.9 nm and ζ-potential of +19.1 mV were obtained after regulating several influencing factors. Electrostatic reaction between mucin and NPs indicated that the NPs had a mucoadhesive property. Kinase catalytic phosphorylation was monitored by capillary zone electrophoresis and found that chitosan/sulfobutylether-ß-cyclodextrin NPs did not weaken ibrutinib activity on the target kinase. In vitro drug release studies revealed that ibrutinib-loaded NPs exhibited a significantly slower gastric-release rate. This study applied a feasible nanocarrier for ibrutinib delivery, and the potential nanoformulation maintains drug activity and shows a sustained release property. These outcomes are helpful for the formulation exploitation of tyrosine kinase inhibitors.
Assuntos
Quitosana , Nanopartículas , Adenina/análogos & derivados , Portadores de Fármacos , Tamanho da Partícula , Piperidinas , Inibidores de Proteínas Quinases , beta-CiclodextrinasRESUMO
Empagliflozin is an oral sodium glucose co-transporter-2 inhibitor for type 2 diabetes mellitus. The interaction between empagliflozin and human serum albumin (HSA) was investigated experimentally and theoretically. Fluorescence quenching and time-resolved fluorescence spectroscopy indicated that the quenching mechanism of empagliflozin and HSA was dynamic and that the effective binding constant at body temperature was 3.495 × 103 M-1. Thermodynamic parameters showed that hydrophobic forces were the major binding force in the interaction between empagliflozin and HSA. Circular dichroism, Fourier transform infrared, and 3 D fluorescence spectroscopy revealed that empagliflozin showed a slight change in secondary structure without changing the basic carbon framework of HSA. Site marker displacement experiments revealed that empagliflozin bound to site I of HSA, which was supported by molecular docking. Molecular dynamic simulations indicated that empagliflozin could bind to HSA stably. This study provided insights into the binding mechanism between empagliflozin and HSA.Communicated by Ramaswamy H. Sarma.
Assuntos
Compostos Benzidrílicos , Glucosídeos , Inibidores do Transportador 2 de Sódio-Glicose , Simportadores , Sítios de Ligação , Dicroísmo Circular , Diabetes Mellitus Tipo 2 , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Albumina Sérica Humana/metabolismo , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , TermodinâmicaRESUMO
The presence of dyes in a water system has potential adverse effects on the ecological environment. The conventional cyclodextrin (CD) polymer only has CD cavities as adsorption sites and exhibits slow adsorption for dye removal. In this study, we designed a novel carboxymethyl ß-CD polymer (ß-CDP-COOH). The structural properties of ß-CDP-COOH were characterized as an irregular cross-linked polymer with negative surface charge, and the introduction of carboxymethyl groups greatly enhanced the adsorption ability of the ß-CD polymer to basic fuchsin (BF). The maximum removal efficiency of ß-CDP-COOH (96%) could be achieved within 1 min, whereas that of conventional ß-CD polymer (70%) was achieved after 50 min. The adsorption mechanism revealed that the adsorption behavior of ß-CDP-COOH could be effectively fitted with the pseudo-second-order kinetic model and Langmuir isotherm. Both CD cavities and carboxymethyl groups were effective adsorption sites, so ß-CDP-COOH had an advantage in adsorption capacity over the conventional ß-CD polymer. This study indicated that ß-CDP-COOH is a potential highly efficient adsorbent for the removal of cationic dye contaminants.
RESUMO
The study mainly aimed to improve the aqueous solubility of Balofloxacin (BLFX) by preparing the inclusion complexes (ICs) of BLFX with cyclodextrins (CDs). In this study, ICs in solid state were obtained by using beta-CD (ß-CD), 2-hydroxypropyl-ß-CD (HP-ß-CD), 2, 6-dimethyl-ß-CD (DM-ß-CD) through a freeze-drying technique. The formation of ICs was confirmed through Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, nuclear magnetic resonance, and scanning electron microscopy. Results demonstrated that the water solubility and dissolution rates of three ICs were distinctly improved than that of parent BLFX. Bacteriostatic experiment manifested that the antibacterial effect of BLFX was not inhibited after encapsulation in CDs. The damage of BLFX to kidney and liver cells was reduced. Consequently, successful preparation of the ICs of BLFX with CDs provided possibility for devising new dosage form of BLFX, which held great promise for further applications in clinical fields.
Assuntos
Fluoroquinolonas/química , beta-Ciclodextrinas/química , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Liofilização/métodos , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Pós , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios XRESUMO
Nanoscale metal-organic frameworks (NMOFs) have attracted considerable attention for controlled drug delivery. However, the interaction between nanoparticles and the biological macromolecules of physiological system must be valued because the formed protein corona will endow NMOFs with new biorecognition properties. In this study, we carried out detailed protein adsorption studies in vitro and cell uptake tests of HeLa cells for nanospherical Uio66 and nanooctahedral Uio67. Uio67 with higher binding constants to human serum albumin needed to combine more protein molecules to achieve colloidal stability state than that needed by Uio66, and this phenomenon led Uio67 to aggregate under the same incubation condition due to the formation of a single-layer protein. Uio67 also induced an evident conformation change in protein to stabilize the combination. In particular, the cell uptake efficiencies of the two systems showed a significant thickness dependence on the protein corona. When samples incubated in 10% fetal bovine serum (FBS), the intracellular rate was the highest for both systems, but the rate was not proportional to the FBS concentration. Results of this work are important to the development of the considerable potential NMOFs-based medicals and also provide additional insight into protein corona.
Assuntos
Comunicação Celular/fisiologia , Estruturas Metalorgânicas/química , Nanopartículas/química , Coroa de Proteína/química , Coroa de Proteína/metabolismo , Adsorção , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Células HeLa , Humanos , Tamanho da Partícula , Ligação Proteica , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismoRESUMO
In the liver, Wnt/ß-catenin signaling is involved in regulating zonation and hepatocyte proliferation during homeostasis. We examined Wnt gene expression and signaling after injury, and we show by in situ hybridization that Wnts are activated by acute carbon tetrachloride (CCl4 ) toxicity. Following injury, peri-injury hepatocytes become Wnt-responsive, expressing the Wnt target gene axis inhibition protein 2 (Axin2). Lineage tracing of peri-injury Axin2+ hepatocytes shows that during recovery the injured parenchyma becomes repopulated and repaired by Axin2+ descendants. Using single-cell RNA sequencing, we show that endothelial cells are the major source of Wnts following acute CCl4 toxicity. Induced loss of ß-catenin in peri-injury hepatocytes results in delayed repair and ultimately injury-induced lethality, while loss of Wnt production from endothelial cells leads to a delay in the proliferative response after injury. Conclusion: Our findings highlight the importance of the Wnt/ß-catenin signaling pathway in restoring tissue integrity following acute liver toxicity and establish a role of endothelial cells as an important Wnt-producing regulator of liver tissue repair following localized liver injury.
Assuntos
Proteína Axina/genética , Regeneração Hepática/genética , Fígado/lesões , Proteínas Wnt/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Biópsia por Agulha , Tetracloreto de Carbono/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Expressão Gênica/genética , Hepatócitos/citologia , Imuno-Histoquímica , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase/métodos , RNA/genética , Distribuição Aleatória , Valores de ReferênciaRESUMO
The binding properties between γ-lactone essences and HSA were investigated to explore interactional mechanism and influence of ligand side chains on binding via computer simulations, microscopy, and multiple-spectroscopies. Docking and molecular dynamics presented protein recognition mode with low fluctuations. NMR analysis revealed that the lactone ring of ligands was the main group bound to HSA. UV-vis and lifetime results revealed that the combination was static quenching mechanism with binding constants of 102-103â¯L/mol. FTIR and CD spectra showed conformational changes in the protein secondary structure induced by ligands. Side chains affect the binding process through steric hindrance and hydrophobicity. AFM images showed the four compounds caused different effects on molecular size of HSA. In conclusion, the binding ability and the protein secondary structure changes had a positive correlation with the length of side chain. These studies are beneficial for understanding the safety and biological action of γ-lactone essences.
Assuntos
Lactonas/química , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Sítios de Ligação , Dicroísmo Circular , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lactonas/metabolismo , Ligantes , Espectroscopia de Ressonância Magnética , Microscopia de Força Atômica , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The interaction mechanism and binding mode of capecitabine with ctDNA was extensively investigated using docking and molecular dynamics simulations, fluorescence and circular dichroism (CD) spectroscopy, DNA thermal denaturation studies, and viscosity measurements. The possible binding mode and acting forces on the combination between capecitabine and DNA had been predicted through molecular simulation. Results indicated that capecitabine could relatively locate stably in the G-C base-pairs-rich DNA minor groove by hydrogen bond and several weaker nonbonding forces. Fluorescence spectroscopy and fluorescence lifetime measurements confirmed that the quenching was static caused by ground state complex formation. This phenomenon indicated the formation of a complex between capecitabine and ctDNA. Fluorescence data showed that the binding constants of the complex were approximately 2 × 104 M-1. Calculated thermodynamic parameters suggested that hydrogen bond was the main force during binding, which were consistent with theoretical results. Moreover, CD spectroscopy, DNA melting studies, and viscosity measurements corroborated a groove binding mode of capecitabine with ctDNA. This binding had no effect on B-DNA conformation.