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1.
Small ; 17(40): e2102470, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34480417

RESUMO

Tumor cells adapt to excessive oxidative stress by actuating reactive oxygen species (ROS)-defensing system, leading to a resistance to oxidation therapy. In this work, self-delivery photodynamic synergists (designated as PhotoSyn) are developed for oxidative damage amplified tumor therapy. Specifically, PhotoSyn are fabricated by the self-assembly of chlorine e6 (Ce6) and TH588 through π-π stacking and hydrophobic interactions. Without additional carriers, nanoscale PhotoSyn possess an extremely high drug loading rate (up to 100%) and they are found to be fairly stable in aqueous phase with a uniform size distribution. Intravenously injected PhotoSyn prefer to accumulate at tumor sites for effective cellular uptake. More importantly, TH588-mediated MTH1 inhibition could destroy the ROS-defensing system of tumor cells by preventing the elimination of 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dG), thereby exacerbating the oxidative DNA damage induced by the photodynamic therapy (PDT) of Ce6 under light irradiation. As a consequence, PhotoSyn exhibit enhanced photo toxicity and a significant antitumor effect. This amplified oxidative damage strategy improves the PDT efficiency with a reduced side effect by increasing the lethality of ROS without generating superabundant ROS, which would provide a new insight for developing self-delivery nanoplatforms in photodynamic tumor therapy in clinic.

2.
Cell Prolif ; 54(9): e13100, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34347352

RESUMO

OBJECTIVES: To evaluate the long-term biosafety and efficacy of transplantation of human embryonic stem cells-derived retinal pigment epithelial (hESC-RPE) cells in early-stage of Stargardt macular degeneration (STGD1). MATERIALS AND METHODS: Seven patients participated in this prospective clinical study, where they underwent a single subretinal transplantation of 1 × 105 hESC-RPE cells in one eye, whereas the fellow eye served as control. These patients were reassessed for a 60-month follow-up through systemic and ophthalmic examinations. RESULTS: None of the patients experienced adverse reactions systemically or locally, except for two who had transiently high intraocular pressure post-operation. Functional assessments demonstrated that all of the seven operated eyes had transiently increased or stable visual function 1-4 months after transplantation. At the last follow-up visit, two of the seven eyes showed visual function loss than the baseline; however, one of them showed a stable visual acuity when compared with the change of fellow eye. Obvious small high reflective foci in the RPE layer were displayed after the transplantation, and maintained until the last visit. Interestingly, three categories of patients who were classified based on autofluorescence, exhibited distinctive patterns of morphological and functional change. CONCLUSIONS: Subretinal transplantation of hESC-RPE in early-stage STGD1 is safe and tolerated in the long term. Further investigation is needed for choosing proper subjects according to the multi-model image and function assessments.


Assuntos
Células Epiteliais/citologia , Células-Tronco Embrionárias Humanas/citologia , Degeneração Macular/patologia , Epitélio Pigmentado da Retina/citologia , Pigmentos da Retina/fisiologia , Doença de Stargardt/patologia , Adulto , Diferenciação Celular/fisiologia , Linhagem Celular , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Transplante de Células-Tronco/métodos , Acuidade Visual/fisiologia , Adulto Jovem
3.
Biomater Sci ; 9(9): 3445-3452, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33949456

RESUMO

Multidrug resistance (MDR) is one of the prime reasons for the failure of cancer chemotherapy, which continues to be a great challenge to be solved. In this work, α-tocopherol succinate (α-TOS) and doxorubicin (DOX)-based self-delivery nanomedicine (designated as α-TD) is prepared to combat drug resistance for cancer synergistic chemotherapy. Carrier-free α-TD possesses a fairly high drug loading rate and improves the cellular uptake via the endocytosis pathway. More importantly, the apoptotic inducer α-TOS could elevate the reactive oxygen species (ROS) generation, disrupt mitochondrial function and reduce adenosine 5'-triphosphate (ATP) production, which facilitate the intracellular drug retention while decreasing its efflux. As a result, α-TD achieves a considerable synergistic chemotherapeutic effect against drug resistant cancer cells. Moreover, it also exhibits a preferable inhibitory effect on tumor growth with a low system toxicity in vivo. This synergistic drug self-delivery strategy would open a new window for developing carrier-free nanomedicine for overcoming drug resistance in cancer therapy.


Assuntos
Antineoplásicos , Nanopartículas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Portadores de Fármacos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Células MCF-7 , Nanomedicina
4.
Biomaterials ; 273: 120854, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33932703

RESUMO

The development of photodynamic therapy (PDT) is severely limited by short half-life of singlet oxygen (1O2) and the hypoxic microenvironment. In this work, a plasma membrane targeted photodynamic O2 economizer (designated as P-POE) is developed to improve the subcellular delivery of photosensitizers and alleviate the tumor hypoxia for enhanced PDT effect. After self-assembly into nanomicelles, P-POE has a relatively high stability and a favorable photochemical performance, which are conducive to boosting the 1O2 production. Besides, the plasma membrane anchoring of P-POE contributes to enhancing the preferential retention and cellular accumulation of photosensitizers on tumor tissues and cells. More importantly, P-POE-induced mitochondrial respiratory depression is demonstrated to reduce the O2 consumption of tumor cells to relieve the hypoxia. Consequently, P-POE still exhibits a robust PDT effect against hypoxic tumors, which greatly inhibits the proliferation of breast cancer with low adverse reactions. This innovative combination of subcellular targeting and hypoxic alleviation would advance the development of individualized drug delivery systems for photodynamic therapy against hypoxic tumors.


Assuntos
Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Membrana Celular , Humanos , Hipóxia/tratamento farmacológico , Oxigênio , Fármacos Fotossensibilizantes/uso terapêutico
5.
Adv Healthc Mater ; 10(12): e2100198, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33938637

RESUMO

Photodynamic therapy (PDT) often suffers from the exacerbated tumor hypoxia and the heterogeneous distribution of photosensitizers, leading to an inefficient ROS productivity and availability. In this work, a mitochondria targeted O2 economizer (designated as Mito-OxE) is developed to improve PDT efficiency by alleviating tumor hypoxia and enhancing the subcellular localization of photosensitizers. Specifically, the photosensitizer of protoporphyrin IX (PpIX) is modified with the hydrophilic polyethylene glycol and the lipophilic cation of triphenylphosphine (TPP) to fabricate the biocompatible mitochondria targeted photosensitizers (designated as Mito-PSs). And Mito-OxE is prepared by using Mito-PSs to load the mitochondrial oxidative phosphorylation inhibitors of atovaquone (ATO). Benefiting from the targeting capability of TPP, Mito-OxE can selectively accumulate in mitochondria after cellular uptake. Subsequently, the mitochondrial respiration would be suppressed to with the participation of ATO, resulting in a local hypoxia mitigation for enhanced PDT. Compared with Mito-PSs, Mito-OxE maximizes the therapeutic effect against hypoxic tumors under light irradiation. This design of mitochondria targeted O2 economizer would advance the development of targeted drug delivery system for effective PDT regardless of hypoxic microenvironment.


Assuntos
Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Hipóxia/metabolismo , Mitocôndrias/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Hipóxia Tumoral
6.
Arch Oral Biol ; 125: 105105, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33713982

RESUMO

OBJECTIVE: The present study aimed to investigate the clinical significance and prognostic value of LINC01793 in OSCC patients, and to explore its role in the modulation of OSCC development. METHODS: LINC01793 expression was analyzed in 80 cases of OSCC patients and SCC9, SCC25, Cal27, and HN6 cell lines by qRT-PCR. The association of LINC01793 expression with clinicopathological features and prognosis in OSCC patients was analyzed. The effects of LINC01793 on cell proliferation, cell cycle, migration, and invasion of SCC9 and Cal27 cells were detected by MTT, flow cytometry, and Transwell assays in vitro, respectively. RESULTS: LINC01793 level was upregulated in cancer tissues and cell lines of OSCC, and its expression was increased in cancer tissues from patients with lymph node metastasis. ROC curve for LINC01793 expression and lymph node metastasis revealed a significant AUC of 0.84 (95 % CI: 0.75-0.93), with 76.51 % sensitivity and 83.69 % specificity. Moreover, high LINC01793 level was positively correlated with T category, TNM stage, lymph node metastasis, and local recurrence. OSCC patients with high level of LINC01793 was followed by low overall survival rate, and LINC01793 expression was an independent prognostic indicator for overall survival in patients with OSCC. Functionally, cell proliferation, invasion and migration of SCC9 and Cal27 cells were decreased after knockdown of LINC01793. Consistently, silence of LINC01793 induced G0/G1 cell cycle arrest in OSCC cells. CONCLUSION: High LINC01793 level is correlated with adverse clinicopathological features and poor prognosis of patients with OSCC. LINC01793 act as an oncogenic role in the development of OSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , RNA Longo não Codificante , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Bucais/genética , Recidiva Local de Neoplasia , Prognóstico , RNA Longo não Codificante/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
7.
ACS Nano ; 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33236625

RESUMO

Self-delivery of photosensitizer and immune modulator to tumor site is highly recommendable to improve the photodynamic immunotherapy yet remains challenging. Herein, self-delivery photoimmune stimulators (designated as iPSs) are developed for photodynamic sensitized tumor immunotherapy. Carrier-free iPSs are constructed by optimizing the noncovalent interactions between the pure drugs of chlorine e6 (Ce6) and NLG919, which avoid the excipients-raised toxicity and immunogenicity. Intravenously administrated iPSs prefer to passively accumulate on tumor tissues for a robust photodynamic therapy (PDT) with the induction of immunogenetic cell death (ICD) cascade to activate cytotoxic T lymphocytes (CTLs) and initiate antitumor immune response. Meanwhile, the concomitant delivery of NLG919 inhibits the activation of indoleamine 2,3-dioxygenase 1 (IDO-1) to reverse the immunosuppressive tumor microenvironment. Ultimately, the photodynamic sensitized immunotherapy with iPSs efficiently inhibit the primary and distant tumor growth with a low system toxicity, which would shed light on the development of self-delivery nanomedicine for clinical transformation in tumor precision therapy.

8.
Acta Biomater ; 117: 349-360, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33010514

RESUMO

Development of antitumor agents with high efficiency and low toxicity is one of the most important goals for biomedical research. However, most traditional therapeutic strategies were limited due to their non-specificity and abnormal tumor microenvironments, causing a poor therapeutic efficiency and severe side effects. In this paper, a tumor targeted self-synergistic nanoplatform (designated as PAO@PCN@HA) was developed for chemotherapy sensitized photodynamic therapy (PDT) against hypoxic tumors. The efficient drug loading of phenylarsine oxide (PAO) in porphyrinic metal organic framework of PCN-224 as well as the surface modification of hyaluronic acid (HA) improved the targeted drug delivery and reduced the side effects of PAO at the therapeutic dose. Particularly, PAO as an arsenical-based chemotherapeutic agent could not only induce cell apoptosis by generating reactive oxygen species (ROS), but also regulate tumor microenvironments to improve the PDT effect of PCN-224 by mitigating hypoxia and consuming cellular GSH. Both in vitro and in vivo investigations confirmed an effective self-synergy of PAO@PCN@HA in hypoxic tumor therapy with a low systemic toxicity. This integration of microenvironment adjustment with tumor targeted self-synergistic mechanism might provide a new insight for the development of arsenic-based antitumor strategy for clinical applications.


Assuntos
Antineoplásicos , Arsênio , Neoplasias , Fotoquimioterapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Arsênio/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente Tumoral
9.
SAGE Open Med Case Rep ; 8: 2050313X20952974, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32974025

RESUMO

Macular hemorrhage can occur spontaneously and repeatedly without choroidal neovascularization or other known lesions associated with myopia. We report a case of repeated myopic macular hemorrhage following fish oil supplementation. A 32-year-old male was referred with newly acquired paracentral scotoma in the left eye. Serial retinal imaging, including fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were performed. Fundus photography and fluorescein angiography showed a subtle red-colored lesion nasal to the fovea. Optical coherence tomography showed a dome shaped elevation in the ellipsoid zone and interdigitation zone in the left eye. No known ocular risk factors for macular hemorrhage, such as choroidal neovascularization, lacquer cracks, Fuch's spot or choroid thinning or keratoconus were observed. After 2 months without any treatment, the left eye lesion disappeared. However 2 weeks later, another newly developed red-colored lesion close to the left fovea was observed. At that moment, the detailed medical history revealed that the patient had been regularly taking a high dose of commercially available fish oil supplement beginning one month before the first macular hemorrhage. After discontinuation of the fish oil, the second left hemorrhage resolved gradually over the following 8 weeks. No recurrent hemorrhages have been detected at the 12 months follow-up visits. Our observations suggest that the relative value of nutritional supplementation with high doses of fish oil should be cautioned in patients with repetitive retinal hemorrhage.

10.
Zhongguo Zhong Yao Za Zhi ; 45(15): 3719-3725, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32893564

RESUMO

The aim of this paper was to investigate the effect of Schizonepetae Herba and Saposhnikoviae Radix(wind medicine) on the expression of AQP4 and AQP8 in colonic mucosa in rats with ulcerative colitis(UC). A total of 35 healthy SD male rats were randomly divided into normal group(gavaged with normal saline), DSS model group, as well as low, middle, and high dose wind medicine groups(Schizonepeta and Saposhnikovia 1∶1, gavaged at dosages of 6, 12, and 24 g·kg~(-1)·d~(-1)), with 7 in each group. UC rat model was established by free drinking of 3% dextran sulphate sodium(DSS) solution for 10 days. At the end of the 10 th day after the treatment, mice were put to death to collect colonic mucosa. The length of colon was measured; the colonic mucosal injury index(CMDI) and pathological changes of colon were observed. ELISA method was used for measuring the content of serum IL-1, IL-8, and immunohistochemical method was used to measure AQP4, AQP8 protein expressions in colon mucosa. The expressions of AQP4, AQP8 mRNA were measured by Real-time PCR. As compared with the normal group, the length of colon tissue was significantly reduced(P<0.01), CMDI scores and pathological scores were significantly increased(P<0.01), the levels of serum IL-1 and IL-8 were significantly increased(P<0.05) in model group; the immunohistochemical results showed that the protein expressions of AQP4, AQP8 were lower; the color was light yellow or brown; AQP4, AQP8 mRNA expressions in colon mucosa were significantly decreased in model group(P<0.01). CMDI scores, pathological scores, and the levels of serum IL-1, IL-8 in high, middle, low dose wind medicine groups were obvious lower than those in the model group(P<0.01 or P<0.05); the protein expressions of AQP4, AQP8 were higher; the color was chocolate brown or dark brown; the length of colon tissue, and the expressions of AQP4, AQP8 mRNA were obvious higher in wind medicine groups(P<0.01 or P<0.05). Schizonepetae Herba and Saposhnikoviae Radix could significantly improve the symptoms and histopathology of UC model rats and accelerate the intestinal mucosal healing. The mechanism may be related with up-regulating the expression level of AQP4 and AQP8 in colonic mucosa.


Assuntos
Apiaceae , Colite Ulcerativa , Animais , Aquaporina 4 , Colo , Mucosa Intestinal , Masculino , Camundongos , Raízes de Plantas , Ratos
11.
Arch Oral Biol ; 117: 104818, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619704

RESUMO

BACKGROUND: MiRNAs have been demonstrated to be important regulators during osteogenic differentiation in multiple types of stem cells. In the study, the interaction between miR-375 and TOB2 was analyzed to identify their functions on the proliferation and osteogenic differentiation of hPDLSCs. METHODS: hPDLSCs were isolated from human first premolars, and hPDLSCs stably expressing and silenced miR-375 were constructed using miR-375-ago and miR-375-antago, respectively. miR-375 and RUNX2 mRNA expression levels in hPDLSCs during osteogenic differentiation were investigated using qRT-PCR. The impact of miR-375 expression on hPDLSCs proliferation and osteogenic differentiation was determined using MTT assay, ALP assay, and alizarin red S staining. The protein expression levels of COL1A1, RUNX2 and OCN were detected using Western blot. The targeting of TOB2 by miR-375 was validated using dual luciferase reporter assay. RESULTS: The expression levels of miR-375 were increased in hPDLSCs during osteogenic differentiation in a time-dependant manner, and was positively correlated with RUNX2 mRNA expression. miR-375 facilitated the proliferation and osteogenic differentiation of hPDLSCs, and promoted the protein expression levels of COL1A1, RUNX2 and OCN. Moreover, TOB2 protein expression was reduced in hPDLSCs during osteogenic differentiation in a time-dependant manner, and miR-375 directly targeted TOB2 expression. In addition, targeting TOB2 expression in hPDLSCs could rescue the suppression of cell proliferation and osteogenic differentiation by miR-375-antago. CONCLUSION: In summary, miR-375 promotes proliferation and osteogenic differentiation of hPDLSCs by targeting TOB2, which reveals a new regulatory mechanism underlying osteogenic differentiation of hPDLSCs by miR-375/TOB2 axis.


Assuntos
Proteínas de Ciclo Celular/metabolismo , MicroRNAs/genética , Osteogênese , Ligamento Periodontal/citologia , Células-Tronco/citologia , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos
12.
Nano Lett ; 20(3): 2062-2071, 2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32096643

RESUMO

Tumor hypoxia is the Achilles heel of oxygen-dependent photodynamic therapy (PDT), and tremendous challenges are confronted to reverse the tumor hypoxia. In this work, an oxidative phosphorylation inhibitor of atovaquone (ATO) and a photosensitizer of chlorine e6 (Ce6)-based self-delivery nanomedicine (designated as ACSN) were prepared via π-π stacking and hydrophobic interaction for O2-economized PDT against hypoxic tumors. Specifically, carrier-free ACSN exhibited an extremely high drug loading rate and avoided the excipient-induced systemic toxicity. Moreover, ACSN not only dramatically improved the solubility and stability of ATO and Ce6 but also enhanced the cellular internalization and intratumoral permeability. Abundant investigations confirmed that ACSN effectively suppressed the oxygen consumption to reverse the tumor hypoxia by inhibiting mitochondrial respiration. Benefiting from the synergistic mechanism, an enhanced PDT effect of ACSN was observed on the inhibition of tumor growth. This self-delivery system for oxygen-economized PDT might be a potential appealing clinical strategy for tumor eradication.


Assuntos
Neoplasias Mamárias Experimentais , Nanomedicina , Nanopartículas , Fotoquimioterapia , Porfirinas , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Nanopartículas/química , Nanopartículas/uso terapêutico , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia
13.
Neural Regen Res ; 15(8): 1502-1509, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31997815

RESUMO

The regenerative capacity of peripheral nerves is limited after nerve injury. A number of growth factors modulate many cellular behaviors, such as proliferation and migration, and may contribute to nerve repair and regeneration. Our previous study observed the dynamic changes of genes in L4-6 dorsal root ganglion after rat sciatic nerve crush using transcriptome sequencing. Our current study focused on upstream growth factors and found that a total of 19 upstream growth factors were dysregulated in dorsal root ganglions at 3, 9 hours, 1, 4, or 7 days after nerve crush, compared with the 0 hour control. Thirty-six rat models of sciatic nerve crush injury were prepared as described previously. Then, they were divided into six groups to measure the expression changes of representative genes at 0, 3, 9 hours, 1, 4 or 7 days post crush. Our current study measured the expression levels of representative upstream growth factors, including nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor 2 and amphiregulin genes, and explored critical signaling pathways and biological process through bioinformatic analysis. Our data revealed that many of these dysregulated upstream growth factors, including nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor 2 and amphiregulin, participated in tissue remodeling and axon growth-related biological processes Therefore, the experiment described the expression pattern of upstream growth factors in the dorsal root ganglia after peripheral nerve injury. Bioinformatic analysis revealed growth factors that may promote repair and regeneration of damaged peripheral nerves. All animal surgery procedures were performed in accordance with Institutional Animal Care Guidelines of Nantong University and ethically approved by the Administration Committee of Experimental Animals, China (approval No. 20170302-017) on March 2, 2017.

14.
Biosci Rep ; 40(1)2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-31904091

RESUMO

BACKGROUND: The USH2A gene encodes usherin, a basement membrane protein that is involved in the development and homeostasis of the inner ear and retina. Mutations in USH2A are linked to Usher syndrome type II (USH II) and non-syndromic retinitis pigmentosa (RP). Molecular diagnosis can provide insight into the pathogenesis of these diseases, facilitate clinical diagnosis, and identify individuals who can most benefit from gene or cell replacement therapy. Here, we report 21 pathogenic mutations in the USH2A gene identified in 11 Chinese families by using the targeted next-generation sequencing (NGS) technology. METHODS: In all, 11 unrelated Chinese families were enrolled, and NGS was performed to identify mutations in the USH2A gene. Variant analysis, Sanger validation, and segregation tests were utilized to validate the disease-causing mutations in these families. RESULTS: We identified 21 pathogenic mutations, of which 13, including 5 associated with non-syndromic RP and 8 with USH II, have not been previously reported. The novel variants segregated with disease phenotype in the affected families and were absent from the control subjects. In general, visual impairment and retinopathy were consistent between the USH II and non-syndromic RP patients with USH2A mutations. CONCLUSIONS: These findings provide a basis for investigating genotype-phenotype relationships in Chinese USH II and RP patients and for clarifying the pathophysiology and molecular mechanisms of the diseases associated with USH2A mutations.


Assuntos
Análise Mutacional de DNA , Proteínas da Matriz Extracelular/genética , Sequenciamento de Nucleotídeos em Larga Escala , Retinite Pigmentosa/genética , Síndromes de Usher/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/etnologia , Síndromes de Usher/diagnóstico , Síndromes de Usher/etnologia , Adulto Jovem
15.
Mol Vis ; 25: 654-662, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31741654

RESUMO

Purpose: To identify any novel mutations in CYP4V2 in 85 Chinese families with Bietti corneoretinal crystalline dystrophy (BCD) by using next-generation sequencing, and to summarize the mutation spectrum in this population, along with any genotype-phenotype correlations. Methods: A total of 90 patients with BCD from 85 unrelated Chinese families were recruited. All probands were analyzed by using gene chip-based next-generation sequencing, to capture and sequence all the exons of 57 known hereditary retinal degeneration-associated genes. The candidate variants were validated with PCR and Sanger sequencing. Results: Twenty-eight mutations were detected in all patients, including thirteen novel mutations (five missense, six deletions, one splicing and one frame-shift mutations) and 15 previously reported mutations. Mutations in 64 patients were inherited from their parents, while three patients had de novo mutations. c.802-8_810del17insGC was the most common mutation, accounting for 78% of the mutations. Although 16 patients were homozygous at this site, the clinical features of all 16 patients were highly heterogeneous. Conclusions: These results expand the spectrum of mutations in CYP4V2, and suggest that mutations in CYP4V2 may be common in the Chinese population. The phenotype of patients with the homozygous mutation (hom.c.802-8_810del17insGC) is highly heterogeneous.


Assuntos
Distrofias Hereditárias da Córnea/genética , Família 4 do Citocromo P450/genética , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação/genética , Doenças Retinianas/genética , Adulto , Distrofias Hereditárias da Córnea/fisiopatologia , Análise Mutacional de DNA , Eletrorretinografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/fisiopatologia
16.
Cardiol Res Pract ; 2019: 6857232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31662902

RESUMO

Objectives: Chronic total occlusion (CTO) is prevalent in patients with prior coronary artery bypass grafting (CABG). However, data available concerning the prevalence of new-onset CTO of native vessels in patients with prior CABG is limited. Therefore, the objective of the study is to determine predictors for new native-vessel occlusion in patients with prior coronary bypass surgery. Methods: 354 patients with prior CABG receiving follow-up angiography are selected and analyzed in the present study, with clinical and angiographic variables being analyzed by logistic regression to determine the predictors of new native-vessel occlusion. Results: The overall new occlusion rate was 35.59%, with multiple CTOs (42.06%) being the most prevalent (LAD 24.60% and RCA 18.25%, respectively). Additionally, current smoking (OR: 2.67; 95% CI: 2.60 to 2.74; p=0.01), reduced ejection fraction (OR: 1.76; 95% CI: 1.04 to 2.97; p=0.04), severe stenosis (OR: 3.65; 95% CI: 2.55 to 5.24; p=0.01), and diabetes mellitus (OR: 1.86; 95% CI: 1.34 to 2.97; p=0.04) serve as the independent predictors for new native-vessel occlusion. Conclusion: As to high incidence of postoperative CTO, appropriate revascularization strategies and postoperative management should be taken into careful consideration.

17.
Biomaterials ; 224: 119497, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31541935

RESUMO

In recent years, epigenetics has attracted great attentions in the field of biomedicine, which is used to denote the heritable changes in gene expression without any variation in DNA sequence, including DNA methylation, histone modification and so on. Inspired by it, a simple and versatile amino acids modification strategy is proposed in this paper to regulate the subcellular distribution of photosensitizer for plasma membrane targeted photodynamic therapy (PDT). Particularly, the plasma membrane anchoring ability and photo toxicity of the photosensitizer against different cell lines could be effectively manipulated at a single amino acid level. Systematic researches indicate that the number and variety of amino acids have a significant influence on the plasma membrane targeting effect of the photosensitizer. Furthermore, after self-assembling into nanoparticles, the obtained nano photosensitizers (NPs) also exhibit a good biocompatibility and plasma membrane targeting ability, which are conducive to enhancing the PDT therapeutic effect under light irradiation. Both in vitro and in vivo investigations confirm a robust tumor inhibition effect of NPs with a good biocompatibility. This epigenetics-inspired photosensitizer modification strategy would contribute to the development of structure-based drug design for tumor precision therapy.


Assuntos
Membrana Celular/metabolismo , Epigênese Genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Células 3T3 , Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Camundongos , Nanopartículas/química , Nanopartículas/ultraestrutura , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/farmacologia , Protoporfirinas/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Distribuição Tecidual/efeitos dos fármacos
18.
Biomaterials ; 211: 14-24, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078049

RESUMO

Targeted delivery of the drug to its therapeutically active site with low immunogenicity and system toxicity is critical for optimal tumor therapy. In this paper, exosomes as naturally-derived nano-sized membrane vesicles are engineered by chimeric peptide for plasma membrane and nucleus targeted photosensitizer delivery and synergistic photodynamic therapy (PDT). Importantly, a dual-stage light strategy is adopted for precise PDT by selectively and sequentially destroying the plasma membrane and nucleus of tumor cells. Briefly, plasma membrane-targeted PDT of chimeric peptide engineered exosomes (ChiP-Exo) could directly disrupt the membrane integrity and cause cell death to some extent. More interestingly, the photochemical internalization (PCI) and lysosomal escape triggered by the first-stage light significantly improve the cytosolic delivery of ChiP-Exo, which could enhance its nuclear delivery due to the presence of nuclear localization signals (NLS) peptide. Upon the second-stage light irradiation, the intranuclear ChiP-Exo would activate reactive oxygen species (ROS) in situ to disrupt nuclei for robust and synergistic PDT. Based on exosomes, this dual-stage light guided subcellular dual-targeted PDT strategy exhibits a greatly enhanced therapeutic effect on the inhibition of tumor growth with minimized system toxicity, which also provides a new insight for the development of individualized biomedicine for precise tumor therapy.


Assuntos
Exossomos/transplante , Neoplasias/terapia , Peptídeos/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/patologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos/administração & dosagem , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem
19.
Br J Nutr ; 121(12): 1431-1440, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30975227

RESUMO

Residents of Hong Kong have undergone a dietary transition from a traditional Chinese diet that is high in seafood to a more Western diet. This may have affected the nutritional composition of breast milk of Hong Kong mothers. The present study aims to investigate the relationship between the dietary pattern and the fatty acid profile of the breast milk of lactating women in Hong Kong. Seventy-three volunteering healthy Hong Kong lactating mothers participated in the study. Their dietary intakes were assessed by using a 3-d dietary record and FFQ. The mean n-3 fatty acid levels were approximately 0·4 % (EPA) and 0·9 % (DHA) of total fatty acids in the breast milk of lactating mothers who had exclusively breastfed their infants aged 2-6 months. Maternal dietary intakes of n-3 fatty acids were positively associated with their levels in the breast milk. The levels of maternal intakes of freshwater and saltwater fish, especially the consumption of salmon, croaker and mandarin, were significantly correlated with the content of DHA in breast milk. The present study is among the very few in the literature to determine the fatty acid profile of breast milk in Hong Kong populations and verify certain dietary factors that influence this profile. High levels of n-3 PUFA, especially DHA, were observed in the breast milk of Hong Kong lactating women. The findings may serve as a dietary reference for lactating mothers to optimise the fatty acid profile of their breast milk.


Assuntos
Dieta/métodos , Ácidos Graxos Ômega-3/análise , Peixes , Lactação , Leite Humano/química , Alimentos Marinhos/análise , Adulto , Animais , Registros de Dieta , Feminino , Hong Kong , Humanos , Fenômenos Fisiológicos da Nutrição Materna , Adulto Jovem
20.
Nanoscale ; 11(18): 9008-9014, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31020984

RESUMO

An abnormal pH microenvironment results from the development of tumors, and also affects the therapeutic efficiency of anti-tumor drugs. In this work, a Förster resonance energy transfer (FRET)-based theranostic fluorescent nanoprobe was constructed for simultaneous ratiometric pH sensing and tumor-targeted photodynamic therapy. Based on the FRET process between rhodamine B and protoporphyrin IX (PpIX), the fabricated nanoprobe exhibited excellent pH responsiveness in both solutions and live cells with the ratiometric fluorescence changes. Moreover, this ratiometric pH fluorescent nanoprobe also possessed the capability for pH-responsive singlet oxygen (1O2) generation under light irradiation, guiding robust photodynamic therapy in a pH-dependent manner. Benefiting from the enhanced permeability and retention (EPR) effect, the nanoprobe could significantly inhibit tumor growth and metastasis via targeted photodynamic therapy in vivo. This work presents a novel paradigm for precise tumor theranostics by ratiometric pH fluorescence imaging-guided photodynamic therapy.


Assuntos
Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Microscopia Confocal , Neoplasias/diagnóstico por imagem , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Rodaminas/química , Oxigênio Singlete/metabolismo , Transplante Heterólogo
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