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1.
Nanoscale ; 15(4): 1914-1924, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36617999

RESUMO

The anti-apoptotic B-cell lymphoma-2 (Bcl-2) family of proteins are critical regulators of cell death that are overexpressed in many cancer cells, especially in multi-drug resistant cancer cells. Combinatorial gene- and chemotherapies using antisense oligonucleotides (ASOs) to suppress the expression of Bcl-2-family mRNA and restore the sensitivity of the cell to chemodrugs provide a promising pathway for anticancer treatment. However, intrinsic differences between macromolecular ASOs and small molecular chemodrugs make their co-delivery challenging. Moreover, extraneous carriers may induce immunogenicity and inflammation problems. Herein, we develop a targeted nanodrug delivery system using the cationic amphiphilic chemodrug mitoxantrone (Mito), which interacts with Bcl-2 ASO through electrostatic interaction and self-assembles into nanoparticles (NP[Bcl-2/Mito]), whose size can be controlled by regulating the ratio of ASO and Mito. NP[Bcl-2/Mito] can protect the ASO from degradation during delivery and combine gene- and chemotherapies to improve the anticancer effect. Furthermore, cancer cell membranes (CCMs) derived from homologous tumors were used to camouflage NP[Bcl-2/Mito] (NP[Bcl-2/Mito]@CCM) to achieve immune escape and tumor targeting. Both in vitro and in vivo assessments demonstrate the excellent performance of NP[Bcl-2/Mito]@CCM for drug-resistant breast tumor therapy. This CCM-camouflaged ASO/chemodrug nanoplatform provides a promising pathway for the targeted delivery of ASOs and chemodrugs for tumor combination therapy.


Assuntos
Neoplasias , Oligonucleotídeos Antissenso , Humanos , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/genética , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Oligonucleotídeos , Neoplasias/metabolismo , Mitoxantrona/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
2.
Biomaterials ; 293: 121954, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36538847

RESUMO

Reactive oxygen species (ROS) as well-known endogenous stimuli has been widely used to activate drug delivery systems (DDSs) for tumor-specific therapy. Unfortunately, endogenous ROS in the tumor microenvironment (TME) is not enough to achieve effective therapeutic efficacy and cancer cells have adapted to high oxidative stress by upregulating glutathione (GSH) level. Herein, we devised a novel ROS-activable self-immolative prodrug CASDB with both GSH-depletion ability and ROS self-supply competence. Then, an stimuli-responsive nanoplatform integrating CASDB with clinical chemotherapeutics mitoxantrone (MTO) and PLGA was fabricated (denoted as CMPs) through nanoprecipitation method. The CMPs could achieve desired accumulation at tumor tissues through enhanced permeability and retention (EPR) effects. Then the accumulated CMPs could induce tumor cell apoptosis efficiently. Especially, ROS in tumor sites could trigger the immolation of CASDB to generate CA and quinone methide (QM). Then CA and QM cooperatively promoted damage of mitochondria due to oxidative stress and led to cancer cells more sensitive to MTO. Accordingly, MTO could perturb cellular microenvironment of cancer cells then promote the degradation of CASDB. The experiment results demonstrated that CMPs were ideal for desirable synergetic tumor-specific anticancer therapy with negligible systemic toxicity. The half-maximal inhibitory concentrations (IC50) value of CMPs was 6.53 µM, while the IC50 values of MTO was 14.76 µM. And the CMPs group showed the strongest tumor suppressor effect with the tumor sizes increased to 1.2-fold (Control group: 20.6-fold, MTO only: 3.0-fold). This study should be inspirational for designing efficient prodrugs to overcome the handicaps of traditional chemotherapy.


Assuntos
Nanopartículas , Pró-Fármacos , Mitoxantrona/farmacologia , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Estresse Oxidativo
3.
Front Public Health ; 10: 1005721, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36388340

RESUMO

Background: Coal dust is a major risk factor for the occupational health of coal miners, and underground workers with coal mine dust lung disease (Coal miners with coal mine dust lung disease (CMDLD) may have a higher risk of developing Nodular thyroid disease (NTD). The aim of this study was to investigate the relationship between coal mine dust lung disease and the development of Nodular thyroid disease in coal miners. Methods: This was a clinical retrospective observational study that included 955 male coal miners from 31 different coal mining companies in Huainan, Anhui Province, China, who were examined in April 2021 at the Huainan Occupational Disease Prevention and Control Hospital to collect all their clinical physical examination data, including general conditions, laboratory test indices and imaging indices. Based on the presence or absence of Nodular thyroid disease, 429 cases with Nodular thyroid disease were classified as the diseased group and 526 cases without Nodular thyroid disease were classified as the control group. Logistic regression was used to analyse the correlation between the occurrence of Nodular thyroid disease in coal miners, and further single- and multi-factor logistic regression was used to screen the risk exposure factors for Nodular thyroid disease in coal miners. Results: Age, coal mine dust lung disease (CMDLD), red blood cells (RBC), mean red blood cell volume (MCV), albumin (ALB), albumin/globulin (A/G), indirect bilirubin (IBIL), globulin (GLOB), total bilirubin (TBil) and myeloperoxidase (MPO) were associated with the development of Nodular thyroid disease in coal miners (p < 0.05) The results of univariate and multifactorial logistic regression analysis showed that CMDLD (OR:4.5,95%CI:2.79-7.51) had the highest OR and CMDLD was the strongest independent risk exposure factor for the development of Nodular thyroid disease in coal miners. Conclusions: There is a strong correlation between coal mine dust lung disease and Nodular thyroid disease in underground coal miners, and clinicians need to be highly aware of the high risk of NTD in coal miners with CMDLD and adopt individualized clinical prevention strategies.


Assuntos
Doenças Transmissíveis , Pneumopatias , Doenças da Glândula Tireoide , Masculino , Humanos , Poeira , Carvão Mineral , Pneumopatias/epidemiologia , Doenças da Glândula Tireoide/epidemiologia , Mitoxantrona , Bilirrubina , Albuminas
4.
J Exp Clin Cancer Res ; 41(1): 326, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36397148

RESUMO

BACKGROUND: Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we identified a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitize poorly T-cell-infiltrated neuroblastoma (NB) to the host antitumor immune response. METHODS: 975A2 and 9464D NB cell lines derived from spontaneous tumors of TH-MYCN transgenic mice were employed to study drug combinations able of enhancing the antitumor immune response using in vivo and ex vivo approaches. Migration of immune cells towards drug-treated murine-derived organotypic tumor spheroids (MDOTS) were assessed by microfluidic devices. Activation status of immune cells co-cultured with drug-treated MDOTS was evaluated by flow cytometry analysis. The effect of drug treatment on the immune content of subcutaneous or orthotopic tumors was comprehensively analyzed by flow-cytometry, immunohistochemistry and multiplex immunofluorescence. The chemokine array assay was used to detect soluble factors released into the tumor microenvironment. Patient-derived organotypic tumor spheroids (PDOTS) were generated from human NB specimens. Migration and activation status of autologous immune cells to drug-treated PDOTS were performed. RESULTS: We found that treatment with low-doses of mitoxantrone (MTX) recalled immune cells and promoted CD8+ T and NK cell activation in MDOTS when combined with TGFß and PD-1 blockade. This combined immunotherapy strategy curbed NB growth resulting in the enrichment of a variety of both lymphoid and myeloid immune cells, especially intratumoral dendritic cells (DC) and IFNγ- and granzyme B-expressing CD8+ T cells and NK cells. A concomitant production of inflammatory chemokines involved in remodelling the tumor immune landscape was also detected. Interestingly, this treatment induced immune cell recruitment against PDOTS and activation of CD8+ T cells and NK cells. CONCLUSIONS: Combined treatment with low-dose of MTX and anti-TGFß treatment with PD-1 blockade improves antitumor immunity by remodelling the tumor immune landscape and overcoming the immunosuppressive microenvironment of aggressive NB.


Assuntos
Neuroblastoma , Receptor de Morte Celular Programada 1 , Humanos , Camundongos , Animais , Mitoxantrona/farmacologia , Linfócitos T CD8-Positivos , Fator de Crescimento Transformador beta , Linhagem Celular Tumoral , Neuroblastoma/tratamento farmacológico , Camundongos Transgênicos , Microambiente Tumoral
5.
Int J Mol Sci ; 23(22)2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36430670

RESUMO

Due to the unique structures of arvanil and olvanil, the drugs combine certain properties of both cannabinoids and vanilloids, which makes them able to stimulate both TPRV1 and CB1 receptors and causes them to be interesting agents in the setting of carcinoma treatment. The aim of this study was to investigate the cytotoxic and anti-proliferative effects of arvanil and olvanil when administered alone and in combination with cisplatin (CDDP) and mitoxantrone (MTX), using various primary (A375, FM55P) and metastatic (SK-MEL 28, FM55M2) human malignant melanoma cell lines. The results indicate that both arvanil and olvanil inhibited (dose-dependently) the viability and proliferation of various malignant melanoma cells, as demonstrated by MTT and BrdU assays. The safety profile of both arvanil and olvanil tested in human keratinocytes (HaCaT) and normal human melanocytes (HEMa-LP) revealed that neither arvanil nor olvanil caused significant cytotoxicity in HaCaT and HEMa-LP cell lines in LDH and MTT assays. Isobolographically, it was found that both arvanil and olvanil exerted additive interactions with MTX and antagonistic interactions with CDDP in the studied malignant melanoma cell lines. In conclusion, the combinations of arvanil or olvanil with MTX may be considered as a part of melanoma multi-drug therapy; however, the combination of these compounds with CDDP should be carefully considered due to the antagonistic interactions observed in the studied malignant melanoma cell lines.


Assuntos
Antineoplásicos , Melanoma , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Mitoxantrona/farmacologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral
6.
Int J Mol Sci ; 23(22)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36430762

RESUMO

Monkeypox is caused by a DNA virus known as the monkeypox virus (MPXV) belonging to the Orthopoxvirus genus of the Poxviridae family. Monkeypox is a zoonotic disease where the primary significant hosts are rodents and non-human primates. There is an increasing global incidence with a 2022 outbreak that has spread to Europe in the middle of the COVID-19 pandemic. The new outbreak has novel, previously undiscovered mutations and variants. Currently, the US Food and Drug Administration (FDA) approved poxvirus treatment involving the use of tecovirimat. However, there has otherwise been limited research interest in monkeypox. Mitoxantrone (MXN), an anthracycline derivative, an FDA-approved therapeutic for treating cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against the vaccinia virus and monkeypox virus. In this study, virtual screening, molecular docking analysis, and pharmacophore ligand-based modelling were employed on anthracene structures (1-13) closely related to MXN to explore the potential repurposing of multiple compounds from the PubChem library. Four chemical structures (2), (7), (10) and (12) show a predicted high binding potential to suppress viral replication.


Assuntos
COVID-19 , Varíola dos Macacos , Animais , Humanos , Vírus da Varíola dos Macacos , Varíola dos Macacos/diagnóstico , Varíola dos Macacos/tratamento farmacológico , Simulação de Acoplamento Molecular , Mitoxantrona/farmacologia , Reposicionamento de Medicamentos , Pandemias , Receptores de Droga , Primatas , Roedores
7.
Front Immunol ; 13: 977265, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36248913

RESUMO

Background: We aim to evaluate the efficacy and tolerability of Janus kinase inhibitors (JAKi) as monotherapy and in combination with methotrexate (MTX) in active rheumatoid arthritis (RA). Methods: Medline, EMBASE, and Cochrane Library were systematically searched to identify relevant randomized controlled trials (RCTs). Pooled analysis was conducted using random-effects model, along with the risk difference (RD) and 95% confidence intervals (CIs). Results: Three RCTs, including 2,290 patients, were included. JAKi (tofacitinib, baricitinib, and filgotinib) plus MTX displayed a higher proportion of patients meeting the American College of Rheumatology (ACR) criteria than JAKi alone at week 52 (ACR20 RD 0.032; 95% CI -0.027 to 0.091; ACR50 RD 0.050; 95% CI 0.003 to 0.097; ACR70 RD 0.056; 95% CI 0.012 to 0.100). Similar results were observed for ACR20/50/70 at week 24. No significant difference was found between two regimens for the proportion of patients achieving Health Assessment Questionnaire disability index (HAQ-DI) improvement ≥ 0.22 at weeks 24 and 52. Regarding low disease activity and remission achievement, JAKi in combination with MTX, contributed higher response rates than JAKi alone at weeks 24 and 52. Compared with JAKi monotherapy, combination therapy had a higher risks of treatment-emergent adverse events (TEAEs) and adverse events (AEs) leading to study discontinuation. Conclusion: JAKi combined with MTX demonstrated superiority to JAKi monotherapy in terms of ACR responses, low disease activity and remission achievement. The two regimens presented comparable physical functioning measured by HAQ-DI improvement and similar tolerability, except for high risks of TEAEs and AEs leading to study discontinuation in combination therapy. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021288907.


Assuntos
Antirreumáticos , Artrite Reumatoide , Inibidores de Janus Quinases , Antirreumáticos/efeitos adversos , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Humanos , Inibidores de Janus Quinases/efeitos adversos , Metotrexato/efeitos adversos , Mitoxantrona/análogos & derivados
8.
J Environ Manage ; 323: 116186, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36103793

RESUMO

The synergistic piezo-photocatalysis with enhanced efficiency for degrading obstinate pollutants in wastewater is considered as an advanced way to ameliorate the global water contamination. In this work, we report a facile route to construct the Bi0.5Na0.5TiO3@Ag composite by photoreduction of AgNO3 to obtain Ag on Bi0.5Na0.5TiO3 nanoparticles. And the composite was used to degrade three representative pollutants, i.e. ciprofloxacin, methyl orange and mitoxantrone hydrochloride. Remarkably, for methyl orange solution with the initial concentration of 10 mg/L, the degradation rate constant of the composite reached 0.051 min-1. H+ and •O2- play a major role in this degradation process, verified by the radical quenching experiments. The absorption platform of Bi0.5Na0.5TiO3 was located in the UV region, after introducing Ag in the composite, the absorption region broadened to both UV and visible light, greatly promoting the response to light. Simultaneously, the induced piezo-potential by mechanical energy in Bi0.5Na0.5TiO3 hindered the carrier recombination, resulting in high-efficiency synergistic piezo-photocatalytic process. This work provides a paradigm to innovate both material and catalytic way for degrading multiple organic pollutants.


Assuntos
Poluentes Ambientais , Compostos Azo , Ciprofloxacina , Mitoxantrona , Poluentes da Água
9.
Int J Clin Pract ; 2022: 3406783, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36101813

RESUMO

Background: Infliximab (IFX) biosimilar was the first biosimilar approved in Jordan in 2014, with limited evidence of its safety and effectiveness from the Middle East and North Africa (MENA) region. Thus, this study aimed to evaluate the safety and effectiveness of IFX biosimilar in active rheumatoid arthritis (RA) patients over 34 weeks by investigating (1) the adverse events (AEs), serious adverse events (SAEs), and therapy discontinuation and (2) the score changes of the 28-Joint Disease Activity Score (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ-DI). Methods: This multicenter prospective cohort study collected clinical parameters within hospital settings every four weeks. The numbers and percentages of observed AEs and SAEs were informed. The DAS28 utilizing Erythrocyte Sedimentation Rate (ESR), HAQ-DI, and ESR were reported at baseline and 14th and 30th weeks; thus, they were reported as means (SD). Results: A total of 22 RA patients were enrolled and initiated IFX biosimilar, of which nine (41.0%) discontinued the study, but their data were analyzed up to the point of withdrawal. A total of 35 AEs were reported in 14 patients, including two (5.7%) SAEs. None of the participants discontinued treatment due to AEs. The mean (SD) score of DAS28-ESR significantly decreased from 6.55 (1.16) at baseline to 4.59 (1.45) at week 14 (p < 0.0001) and to 4.77 (1.09) at week 30 (p < 0.0001). Similarly, the mean (SD) HAQ-DI score significantly decreased from 0.95 (0.74) at baseline to 0.48 (0.62) at week 14 (p=0.008) and to 0.71 (0.78) at week 30 (p=0.483). The mean (SD) value of ESR decreased from 58.75 (26.94) at baseline to 47.92 (33.89) at week 14 (p=0.082) and to 39.83 (17.38) at week 30 (p=0.005). Conclusion: IFX biosimilar demonstrated safety and effectiveness in managing RA patients bringing real-world clinical support for biosimilars' role in rheumatology.


Assuntos
Antirreumáticos , Artrite Reumatoide , Medicamentos Biossimilares , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/efeitos adversos , Humanos , Infliximab/efeitos adversos , Jordânia , Mitoxantrona/análogos & derivados , Estudos Prospectivos
10.
RMD Open ; 8(2)2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36180102

RESUMO

OBJECTIVE: In rheumatoid arthritis (RA), chronic inflammation can enhance the development of sarcopenia with a depletion of muscle mass, strength and performance. Currently, a consensus definition for sarcopenia and solid results for the prevalence of sarcopenia in patients with RA are lacking. METHODS: In this cross-sectional study, 289 patients ≥18 years with RA were recruited. Dual X-ray absorptiometry was performed to measure appendicular lean mass. Assessment of muscle function included grip strength, gait speed and chair rise time. Prevalence of sarcopenia was defined using the updated European Working Group on Sarcopenia in Older People (EWGSOP2) and the Foundation for the National Institutes of Health (FNIH) definition. In addition, the RA study population was compared with existing data of healthy controls (n=280). RESULTS: 4.5% of patients (59.4±11.3 years) and 0.4% of controls (62.9±11.9 years) were affected by sarcopenia according to the EWGSOP2 definition. Body weight (OR 0.92, 95% CI 0.86 to 0.97), body mass index (BMI) (OR 0.70, 95% CI 0.57 to 0.87), C reactive protein (CRP) (OR 1.05, 95% CI 1.01 to 1.10), disease duration (OR 1.08, 95% CI 1.02 to 1.36), current medication with glucocorticoids (OR 5.25, 95% CI 2.14 to 24.18), cumulative dose of prednisone equivalent (OR 1.04, 95% CI 1.02 to 1.05) and Health Assessment Questionnaire (HAQ) (OR 2.50, 95% CI 1.27 to 4.86) were associated with sarcopenia in patients with RA. In contrast, the prevalence was 2.8% in patients compared with 0.7% in controls when applying the FNIH definition, and body height (OR 0.75, 95% CI 0.64 to 0.88), BMI (OR 1.20, 95% CI 1.02 to 1.41), CRP (OR 1.06, 95% CI 1.01 to 1.11) and HAQ (OR 2.77, 95% CI 1.17 to 6.59) were associated with sarcopenia. CONCLUSION: Sarcopenia is significantly more common in patients with RA compared with controls using the EWGSOP2 criteria. The FNIH definition revealed sarcopenia in individuals with high BMI and fat mass, regardless of the presence of RA. TRIAL REGISTRATION NUMBER: It was registered at the German Clinical Trials Registry (DRKS) as well as WHO Clinical Trials Registry (ICTRP) (DRKS00011873, registered on 16 March 2017).


Assuntos
Artrite Reumatoide , Sarcopenia , Idoso , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Proteína C-Reativa , Estudos Transversais , Glucocorticoides , Humanos , Mitoxantrona/análogos & derivados , National Institutes of Health (U.S.) , Prednisona , Prevalência , Sarcopenia/diagnóstico , Sarcopenia/epidemiologia , Sarcopenia/etiologia , Estados Unidos/epidemiologia
11.
Biomed Pharmacother ; 154: 113525, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36049314

RESUMO

The standard breast cancer therapy still faces major challenges due to non-specific tumor distribution and occurrence of dose-limiting adverse side-effects. Nanomedicine constitutes an appealing approach to improve the therapeutic index of different anti-cancer drugs. Given their biocompatibility, low-cost manufacture and easy surface modification, lipid nanoparticles, such as solid lipid nanoparticles (SLN), have a great potential for drug delivery in cancer therapy. In this work, SLN entrapping the antineoplastic drug Mitoxantrone (Mito) were developed and functionalized with Disteroylphosphatidylethanolamine-poly(ethylene glycol)-folic acid (DSPE-PEG-FA) ligand to improve blood circulation and tumor selectivity and limit the drug systemic side-effects. Nanoparticles presented adequate size and size distribution for intravenous injection and were stable for at least 6 months. Additionally, their hemocompatibility was demonstrated. Moreover, functionalized nanoparticles were able to improve the anti-cancer effect of the free drug, as assessed by the values of IC50 and the apoptotic effects in MCF-7 cells. Moreover, an enhanced cellular internalization of the functionalized SLN was demonstrated by confocal microscopy and flow cytometry studies. Finally, the cellular uptake of the SLN was found to occur via macropinocytosis and clathrin-mediated endocytosis, suggesting the involvement of (folate receptor) (FR)-mediated endocytosis. Overall these findings highlight that the developed SLN are efficient nanocarriers for the selective delivery of Mito to breast cancer cells.


Assuntos
Antineoplásicos , Neoplasias da Mama , Nanopartículas , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Ácido Fólico/farmacologia , Humanos , Lipossomos , Mitoxantrona/farmacologia , Polietilenoglicóis/farmacologia
12.
Biochem Biophys Res Commun ; 627: 52-59, 2022 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-36007336

RESUMO

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a common nutritional metabolic disease in poultry that seriously compromises the health of chickens and reduces the economic benefits of the industry. In this study, we investigated the therapeutic effect of mitoxantrone (MTX) on hepatic steatosis in broilers. We constructed a steatosis cell model in vitro by adding oleic acid and palmitic acid to chicken hepatocytes (LMH cells), to examine influence of MTX on fat deposition on LMH cells. To determine the effects of MTX on hepatic steatosis in broiler livers in vivo, broilers were fed a high-fat diet to establish a fatty liver model. Our data show that MTX reduced the triglyceride (TG) levels and total cholesterol levels in LMH cells. In the MAFLD chick model, MTX decreased mRNA abundance of hepatic-lipid-synthesis-related gene such as FASN and increased mRNA abundance of fatty-acid-ß-oxidation-related genes such as CPT1, PPARα, and reduced hepatic TG levels. MTX also reduced serum lipid and the percentage of abdominal fat. These results suggest that MTX improves hepatic steatosis in broilers as well as reduces circulating lipid levels and fat accumulation in broilers. Our work provides a promising therapeutic strategy for MAFLD and excessive fat accumulation in broiler chickens.


Assuntos
Galinhas , Fígado Gorduroso , Animais , Galinhas/genética , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Metabolismo dos Lipídeos , Lipídeos/farmacologia , Fígado/metabolismo , Mitoxantrona/farmacologia , Mitoxantrona/uso terapêutico , RNA Mensageiro/metabolismo
13.
Biomater Sci ; 10(19): 5596-5607, 2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-35979933

RESUMO

Tumor stroma plays an important role in the occurrence, development, and metastasis of colorectal cancer (CRC). The dense collagenous stroma forms a physical barrier for antitumor drugs and sustains a highly tumor immunosuppressive microenvironment. To address this issue, a spatiotemporal combination of antitumor stroma and nanoscale functional materials was used as an antitumor strategy for reprogramming the tumor immune microenvironment. In this combination, metformin hydrochloride (MET) was intraperitoneally injected to disrupt the dense tumor stroma for promoting drug delivery and remodeling the tumor immune microenvironment. Subsequently, intravenously injected multifunctional drug-delivery materials (MIL-100/mitoxantrone/hyaluronic acid nanoparticles, MMH NPs) were visualized by double imaging (photoacoustic (PA) and fluorescence imaging) and generated a robust immune response via immunogenic cell death (ICD). More importantly, the combination treatment also acted synergistically with the anti-OX40 agonist antibody (αOX40), which enhanced the treatment of orthotopic CRC. In summary, the combination strategy of MET/MMH NPs/αOX40 provides a novel and effective clinical option for CRC therapy.


Assuntos
Antineoplásicos , Neoplasias Colorretais , Metformina , Nanopartículas , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Humanos , Ácido Hialurônico/farmacologia , Imunoterapia/métodos , Metformina/farmacologia , Metformina/uso terapêutico , Mitoxantrona , Nanopartículas/metabolismo , Microambiente Tumoral
14.
Int J Rheum Dis ; 25(10): 1123-1128, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35851993

RESUMO

BACKGROUND AND AIM: Concomitant fibromyalgia syndrome (FMS) has been known to be more frequent in patients with several rheumatic diseases. In this study, our aim was to investigate the prevalence of FMS in patients with familial Mediterranean fever (FMF), to analyze the possible factors related to this frequency, and to evaluate the impact of FMS on the functionality and quality of life (QoL) of the patients with FMF. PATIENTS AND METHODS: One hundred cases with FMF and 100 controls were included to this case-control study. FMS coincidence was investigated in all participants according to revised 2016 classification criteria. Demographic features, FMF disease duration, FMF gene mutations, drugs used, attack frequency per year, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum fibrinogen levels were recorded. FMF disease severity was assessed by International Severity Scoring System for Familial Mediterranean Fever (ISSF). For the assessments of QoL and functioning, FMF-QoL, Short form 36 (SF-36), and Health Assessment Questionnaire-Disability Index (HAQ-DI) were used, and for the assessment of FMS impact, the fibromyalgia impact questionnaire (FIQ) were used. RESULTS: We found an FMS frequency of 33% in patients with FMF in our study using the current FMS classification criteria. This result was significantly higher than in age- and gender-similar controls (6% FMS frequency; P < 0.05). The number of woman patients and FMF disease duration were significantly higher in patients with FMF + FMS than in patients with only FMF (P < 0.001). There was no significant difference in ISSF scores, ESR, CRP, and fibrinogen levels, management regimens, and FMF gene mutation distributions between FMF + FMS and FMF groups. FMF attack frequency was reported as significantly higher in FMF + FMS patients than in others (P < 0.000). In spite of similar FMF-QoL scores, there were significant differences in HAQ-DI and SF-36 scores between groups (P < 0.05). Higher impact of FMS presented negative correlation with functioning and general health, and positive correlation with QoL in FMF + FMS (P < 0.05). CONCLUSION: Concomitant FMS was a common clinical problem in patients with FMF regardless of the severity and characteristics of FMF. The FMS impact may affect function and QoL in patients of FMF. Considerations of the FMS component in the management of FMF may contribute to the holistic approach to FMF.


Assuntos
Febre Familiar do Mediterrâneo , Fibromialgia , Proteína C-Reativa/análise , Estudos de Casos e Controles , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/epidemiologia , Feminino , Fibrinogênio , Fibromialgia/complicações , Fibromialgia/diagnóstico , Fibromialgia/epidemiologia , Humanos , Mitoxantrona/análogos & derivados , Qualidade de Vida
15.
Biomater Sci ; 10(16): 4549-4560, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35790120

RESUMO

Immunological checkpoint inhibitors provide a revolutionary method for cancer treatment. However, due to low tumor mutations and insufficient infiltration of immune cells into the tumor microenvironment, 85% of colorectal cancer patients cannot respond to checkpoint blockade immunotherapy. In this study, tumor microenvironment-responsive deformable nanoparticles (DMP@NPs) were rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. DMP@NPs self-assemble from a newly synthesized tumor acidity responsive polypeptide checkpoint inhibitor polymer (PEG-DMA-DPPA-1) with immunogenic cell death (ICD) enhanced combination drugs containing a certain proportion of mitoxantrone (MITX) and proanthocyanidins (PC). Upon tumor acidity-triggered cleavage of PEG-DMA-DPPA-1, DMP@NPs undergo special "sphere-ring deformation" dissociation, gradually releasing polypeptide checkpoint inhibitor DPPA-1, MITX and PC. MITX/PC in vitro synergistically triggers higher ICD with the release of the high mobility group box-1 (HMGB-1) and calreticulin (CRT). After intravenous injection of DMP@NPs, the local tumor microenvironment of CT26 tumor-bearing mice was reprogrammed, and dendritic cell activation and T cell infiltration were significantly increased. Most importantly, the synergistic immune nanodrug DMP@NPs improved the efficacy of colorectal cancer immunotherapy and reduced toxicity and side effects for the immune organs.


Assuntos
Neoplasias Colorretais , Nanopartículas , Proantocianidinas , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Morte Celular Imunogênica , Imunoterapia/métodos , Camundongos , Mitoxantrona/farmacologia , Proantocianidinas/farmacologia , Microambiente Tumoral
16.
Biomed Pharmacother ; 153: 113328, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35785701

RESUMO

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


Assuntos
Cantaridina , Mitoxantrona , Autofagia , Ciclo Celular , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Lisossomos/metabolismo , Mitoxantrona/farmacologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-35853752

RESUMO

BACKGROUND AND OBJECTIVES: To investigate the frequency and predictors of hypogammaglobulinemia during long-term rituximab (RTX) treatment in patients with neuromyelitis optica spectrum disorder (NMOSD) and its association with infections. METHODS: We retrospectively reviewed the data of patients with NMOSD who received RTX through the maintenance regimen based on memory B-cell detection for at least 1 year from 2006 to 2021 at an institutional referral center for NMOSD. RESULTS: A total of 169 patients received a median of 10 courses (range 1-27) of RTX reinfusion after induction over a median of 8 (range, 1-15) years. Their mean serum immunoglobulin (Ig)G level began to decline significantly after 2 years of treatment, steadily declined at a rate of 2%-8% per year for the following 8 years, and then plateaued after 10 years. The proportion of patients with hypo-IgG (<6 g/L) increased from 1.2% after 1 year of treatment to 41% after 14 years of treatment. While being treated with RTX, 58 (34%) patients had 114 infections, of whom 14 (8%) patients had 15 severe infections. Multivariable logistic regression analyses identified duration of RTX treatment in years (odds ratio [OR] 1.234, 95% confidence interval [CI] 1.015-1.502), mean annual RTX dose (OR 0.063, 95% CI 0.009-0.434), history of mitoxantrone (OR 3.318, 95% CI 1.109-9.93), hypo-IgG at baseline (OR 40.552, 95% CI 3.024-543.786), and body mass index >25 kg/m2 (OR 4.798, 95% CI 1.468-15.678) as independent predictors of hypo-IgG. The risk of infection during RTX treatment was independently associated with high Expanded Disability Status Scale scores (OR 1.427, 95% CI 1.2-1.697) and relapses during RTX treatment (OR 1.665, 95% CI 1.112-2.492), but not with hypogammaglobulinemia. DISCUSSION: Over 14 years of long-term RTX treatment, IgG levels gradually decreased, and the frequency of hypo-IgG increased to 41% of the patients. Patients with prolonged memory B-cell depletion after RTX, previous mitoxantrone history, hypo-IgG at baseline, or obesity were at risk of developing RTX-induced hypogammaglobulinemia. Nevertheless, infection rates remained low during treatment, and reduced immunoglobulin levels were not associated with an increased incidence of infections.


Assuntos
Agamaglobulinemia , Neuromielite Óptica , Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/epidemiologia , Humanos , Imunoglobulina G , Fatores Imunológicos/farmacologia , Mitoxantrona/efeitos adversos , Neuromielite Óptica/tratamento farmacológico , Estudos Retrospectivos , Rituximab
18.
Acta Biomater ; 149: 321-333, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35779772

RESUMO

B-cell lymphoma is one of the most common types of lymphoma, and chemotherapy is still the current first-line treatment. However, due to the systemic side effects caused by chemotherapy drugs, traditional regimens have limitations and are difficult to achieve ideal efficacy. Recent studies have found that CD22 (also known as Siglec-2), as a specific marker of B-cells, is significantly up-regulated on B-cell lymphomas. Inspired by the specific recognition and binding of sialic acid residues by CD22, a polysialic acid (PSA)-modified PLGA nanocarrier (SAPC NP) designed to target B-cell lymphoma was fabricated. Mitoxantrone (MTO) was further loaded into SAPC NP through hydrophobic interactions to obtain polysialylated immunogenic cell death (ICD) nanoinducer (MTO@SAPC NP). Cellular experiments confirmed that MTO@SAPC NP could be specifically taken up by two types of CD22+ B lymphoma cells including Raji and Ramos cells, unlike the poor endocytic performance in other lymphocytes or macrophages. MTO@SAPC NP was determined to enhance the ICD and show better apoptotic effect on CD22+ cells. In the mouse model of B-cell lymphoma, MTO@SAPC NP significantly reduced the systemic side effects of MTO through lymphoma targeting, then achieved enhanced anti-tumor immune response, better tumor suppressive effect, and improved survival rate. Therefore, the polysialylated ICD nanoinducer provides a new strategy for precise therapy of B-cell lymphoma. STATEMENT OF SIGNIFICANCE: • Polysialic acid functionalized nanocarrier (SAPC NP) was designed and prepared. • SAPC NP is specifically endocytosed by two CD22+ B lymphoma cells. • Mitoxantrone-loaded nanoinducer (MTO@SAPC NP) promote immunogenic cell death and anti-tumor immune response. • "Polysialylation" is a potential new approach for precision treatment of B-cell lymphoma.


Assuntos
Linfoma de Células B , Linfoma , Animais , Apoptose , Imunidade , Linfoma de Células B/tratamento farmacológico , Camundongos , Mitoxantrona/farmacologia , Mitoxantrona/uso terapêutico
19.
Acta Biomater ; 150: 353-366, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35843594

RESUMO

Immunosuppressive tumor microenvironment (ITM), poor immunogenicity, and low tumor penetration markedly reduce the capability of tumor immunotherapy. To address these challenges, we successfully engineered acidity-triggered nanoparticles (NPs) with size reduction and charge switchable features to boost tumor immunotherapy based on indoleamine 2,3-dioxygenase 1 siRNA (IDO1 siRNA) and immunogenic cell death (ICD). The NPs significantly augmented tumor penetrating ability and improved cellular uptake via the detachment of 2,3-dimethylmaleic anhydride-grafted poly(ethylene glycol)-poly(L-lysine) copolymer (mPEG-PLL-DMA, PLM) from large-sized NPs with a negative charge. Subsequently, the NPs with a positive charge and small size rapidly escaped from the lysosomes and released mitoxantrone (MIT) and IDO1 siRNA. The antitumor immune response of IDO1 siRNA and MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in tumor tissues. In summary, the results demonstrated that charge-switchable NPs based on the blockage of the IDO1 pathway and ICD activation induce an efficient antitumor immune response, thus showing high potential for treating primary/distant tumors and reducing metastasis. STATEMENT OF SIGNIFICANCE: Acidity-triggered nanoparticles (NPs) with size reduction and charge reversal to boost tumor immunotherapy based on indoleamine 2,3-dioxygenase 1 siRNA (IDO1 siRNA) and immunogenic cell death (ICD) were engineered. NPs augmented tumor penetrating ability and improved cellular uptake through the detachment of mPEG-PLL-DMA (PLM) from the large-sized MIT/siR-PLM/PPA NPs with negative charge to expose miniature and positively charged MIT/siR-PPA NPs. The NPs rapidly escaped from the lysosome and sequentially released mitoxantrone (MIT) and IDO1 siRNA. The antitumor synergistic effect of inhibiting the IDO1 pathway by IDO1 siRNA and inducing ICD by MIT provided good antitumor capability by enhancing DC maturation, improving the number of CTLs, and downregulating the level of Tregs in tumor tissues. Thus, the NPs showed a promising pathway against aggressive and difficult-to-treat cancers.


Assuntos
Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Morte Celular Imunogênica , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Mitoxantrona , Neoplasias/terapia , RNA Interferente Pequeno/genética , Microambiente Tumoral
20.
Int J Biol Macromol ; 216: 558-570, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35809672

RESUMO

Chemo-photothermal therapy is one of the emerging therapies for treating triple-negative breast cancer. In this study, we have used ionotropic gelation method to fabricate chitosan and IR806 dye-based polyelectrolyte complex (CIR-PEx) nanoparticles. These nano-complexes were in size range of 125 ± 20 nm. The complexation of IR 806 dye with chitosan improved photostability, photothermal transduction, and showed excellent biocompatibility. Cancer cells treated with CIR-PEx NPs enhanced intracellular uptake within 5 h of incubation and also displayed mitochondrial localization. With the combination of CIR-PEx NPs and a chemotherapeutic agent (i.e., mitoxantrone, MTX), a significant decline in cancer cell viability was observed in both 2D and 3D cell culture models. The chemo-photothermal effect of CIR-PEx NPs + MTX augmented apoptosis in cancer cells when irradiated with NIR light. Furthermore, when tested in the 4 T1-tumor model, the chemo-photothermal therapy showed a drastic decline in tumor volume and inhibited metastatic lung nodules. The localized hyperthermia caused by photothermal therapy reduced the primary tumor burden, and the chemotherapeutic activity of mitoxantrone further complemented by inhibiting the spread of cancer cells. The proposed chemo-photothermal therapy combination could be a promising strategy for treating triple-negative metastatic breast cancer.


Assuntos
Quitosana , Hipertermia Induzida , Nanopartículas , Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Humanos , Hipertermia Induzida/métodos , Mitoxantrona/farmacologia , Fototerapia/métodos , Terapia Fototérmica , Polieletrólitos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
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