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Oxidative stress and diabetes: antioxidative strategies

Pengju Zhang, Tao Li, Xingyun Wu, Edouard C. Nice, Canhua Huang, Yuanyuan Zhang

《医学前沿（英文）》 2020年第14卷第5期页码 583-600 doi: 10.1007/s11684-019-0729-1

摘要： Diabetes mellitus is one of the major public health problems worldwide. Considerable recent evidence suggests that the cellular reduction–oxidation (redox) imbalance leads to oxidative stress and subsequent occurrence and development of diabetes and related complications by regulating certain signaling pathways involved in β-cell dysfunction and insulin resistance. Reactive oxide species (ROS) can also directly oxidize certain proteins (defined as redox modification) involved in the diabetes process. There are a number of potential problems in the clinical application of antioxidant therapies including poor solubility, storage instability and non-selectivity of antioxidants. Novel antioxidant delivery systems may overcome pharmacokinetic and stability problem and improve the selectivity of scavenging ROS. We have therefore focused on the role of oxidative stress and antioxidative therapies in the pathogenesis of diabetes mellitus. Precise therapeutic interventions against ROS and downstream targets are now possible and provide important new insights into the treatment of diabetes.

关键词： diabetes oxidative stress redox modification antioxidative therapy novel antioxidant delivery

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Antioxidative potential of metformin: Possible protective mechanism against generating OH radicals

Huibin Guo, Ning Wang, Xiang Li

《环境科学与工程前沿（英文）》 2021年第15卷第2期 doi: 10.1007/s11783-020-1313-2

摘要： Abstract • Metformin consumes O2−• and OH• induced by PM are proposed. • OH• dominated the oxidation of metformin compared with O2−• • Metformin can prevent the harm of ROS induced by PM to human health. • Antioxidative potential of metformin was first proposed to provide measures. Exposure to particulate matter (PM) can lead to the excessive accumulation of reactive oxygen species (ROS), which causes oxidative stress and endangers human health. In this study, the effects of metformin on PM-induced radicals were investigated, and the antioxidation reaction mechanism of metformin was analyzed by the density functional theory (DFT) method. The corresponding results revealed that the consumption rate of dithiothreitol (DTT) increased as the metformin concentration (0–40 mmol/L) increased under exposure to PM active components. Moreover, the OH radical content decreased as the metformin concentration increased. This result may be related to the consumption of PM-induced OH radicals by metformin, which promotes the DTT consumption rate. Additionally, because the initiation reaction has a high barrier, the oxidation reaction rate between metformin and •O2− is not very fast, although various catalysts may be present in the human environment. Importantly, we found that the barrier of metformin induced by OH radicals is only 9.6 kcal/mol while the barrier of metformin induced by oxygen is 57.9 kcal/mol, which shows that the rate of the •OH-initiated oxidative reaction of metformin is much faster and that this reaction path occurs more easily. By sample analysis, the mean OH radical generation was 55 nmol/min/g (ranging from 5 to 105 nmol/min/g) on haze days and 30 nmol/min/g (ranging from 10 to 50 nmol/min/g) on non-haze days. Moreover, OH radical generation was higher on haze days than on neighboring non-haze days. Taken together, all data suggest that metformin could consume the PM-induced radicals, such as OH radicals and •O2−, thereby providing health protection.

关键词： Antioxidative potential Metformin Mechanism OH radical Health protection.

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Protective effects of lignin fractions obtained from grape seeds against bisphenol AF neurotoxicity via antioxidative

《化学科学与工程前沿（英文）》 2023年第17卷第7期页码 976-989 doi: 10.1007/s11705-022-2237-0

摘要： Lignin exhibits antioxidative and various other biological properties. However, its neuroprotection capability has rarely been studied. In this study, three types of lignin with different structures were prepared from grape seeds by using different isolation techniques. The antioxidative and neuroprotective effects of the lignin fractions were evaluated with the apoptosis model of murine neuroectodermal (NE-4C) neural stem cells stimulated with bisphenol AF. The results demonstrated that the half maximal inhibitory concentration for scavenging 2,2-diphenyl-1-picrylhydrazyl with water-soluble lignin (L-W, 58.19 μg·mL^–1) was lower than those of lignin in the autohydrolyzed residue of grape seeds (84.27 μg·mL^–1) and original lignin in grape seeds (99.44 μg·mL^–1). BPAF exposure had negative effects on the reactive oxygen species, malondialdehyde content, and superoxide dismutase and glutathione peroxidase activities in NE-4C cells, which can be reversed by using the prepared lignin to reduce oxidative stress. An immunofluorescence assay demonstrated that grape seed lignin induced protective effects on BPAF-injured NE-4C cells via the nuclear factor erythroid 2-related Factor 2 pathway. In addition, correlational analyses showed that lignin (L-W) with lower molecular weights and noncondensed phenolic hydroxyl group content and higher contents of COOH groups effectively prevented cell apoptosis, scavenged reactive oxygen species, and ensured protection from nerve injury. This study demonstrated that grape seed lignin can be used as a neuroprotective agent and serves as a demonstration of active lignin production from grape seed waste.

关键词： grape seed lignin structure antioxidant NE-4C cells neuroprotection

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How to judge the association of postmenopausal hormone therapy and the risk of breast cancer

Ling XU

《医学前沿（英文）》 2010年第4卷第3期页码 290-293 doi: 10.1007/s11684-010-0093-7

摘要： The relevance of postmenopausal hormone therapy (HT) for breast cancer risk has been long debated, although it is one of the most important barriers for women to accept HT. Various opinions have been reported from recent randomized clinical trials and epidemiological studies. These unanswered questions include: whether HT has a positive impact on breast cancer; whether risks of therapy with unopposed estrogen and combined estrogen-progestin are different; and whether different types and routes of estrogen and progestogens, as well as the duration and cessation of HT use, have different impacts on this disorder. Recently, there has been some good news such as the following: the currently available data do not provide sufficient evidence to prove a causal relationship between postmenopausal HT and breast cancer; breast cancer in postmenopausal women using HT usually has better prognosis than that of nonusers. In conclusion, HT is still the most effective method of relieving climacteric symptoms for many postmenopausal women. However, a possible risk of breast cancer associated with long-term HT usage should not be ignored. With respect to prevention of breast cancer, regular evaluation of individual breast cancer susceptibility and close follow-up through mammography and/or breast sonography are necessary strategies for the safety of HT use.

关键词： breast cancer postmenopausal hormone therapy unopposed estrogen therapy combined estrogen-progestin therapy

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Particle therapy for cancers: a new weapon in radiation therapy

null

《医学前沿（英文）》 2012年第6卷第2期页码 165-172 doi: 10.1007/s11684-012-0196-4

摘要：

Particle irradiation started to draw attention in the past decade and has now become a hotspot in the radiation oncology community. This article reviews the most advanced developments in particle irradiation, focusing on the characteristics of proton and carbon ions in radiation physics and radiobiology. The Bragg peak of physical dose distribution causes proton and carbon beams to optimally meet the requirement for cancer irradiation because the Bragg peak permits the accurate concentration of the dose on the tumor, thus sparing the adjacent normal tissues. Moreover, carbon ion has more radiobiological benefits than photon and proton beams. These benefits include stronger sterilization effects on intrinsic radio-resistant tumors and more effective killing of hypoxic, G₀, and S phase cells. Compared with the most advanced radiation techniques using photon, such as three-dimensional conformal radiation therapy and intensity-modulated radiation therapy, proton therapy has yielded more promising outcomes in local control and survival for head and neck cancers, prostate carcinoma, and pediatric cancers. Carbon therapy in Japan showed even more promising results than proton therapy. The local controls and overall survivals were as good as that treated by surgery in early stages of non-small cell lung cancer, hepatocellular carcinoma, prostate carcinoma, and head and neck cancers, especially for such highly resistant tumors as melanoma. The non-invasive nature of particle therapy affords more patients with chances to receive and benefit from treatment. Particle therapy is gradually getting attention from the oncology community. However, the cost of particle therapy facilities has limited the worldwide use of this technology.

关键词： radiation therapy particle therapy proton carbon cancer

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Passive antibody therapy in emerging infectious diseases

《医学前沿（英文）》 doi: 10.1007/s11684-023-1021-y

摘要： The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 and its variants of concern (VOCs) has been ongoing for over 3 years. Antibody therapies encompassing convalescent plasma, hyperimmunoglobulin, and neutralizing monoclonal antibodies (mAbs) applied in passive immunotherapy have yielded positive outcomes and played a crucial role in the early COVID-19 treatment. In this review, the development path, action mechanism, clinical research results, challenges, and safety profile associated with the use of COVID-19 convalescent plasma, hyperimmunoglobulin, and mAbs were summarized. In addition, the prospects of applying antibody therapy against VOCs was assessed, offering insights into the coping strategies for facing new infectious disease outbreaks.

关键词： SARS-CoV-2 COVID-19 convalescent plasma hyperimmunoglobulin neutralizing monoclonal antibodies

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mTOR-targeted cancer therapy: great target but disappointing clinical outcomes, why?

Shi-Yong Sun

《医学前沿（英文）》 2021年第15卷第2期页码 221-231 doi: 10.1007/s11684-020-0812-7

摘要： The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.

关键词： mTOR cancer therapy resistance GSK3 protein degradation E3 ubiquitin ligase PD-L1

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Targeted therapy of desmoid-type fibromatosis: mechanism, current situation, and future prospects

Zhen Wang, Jianhui Wu, Xiuyun Tian, Chunyi Hao

《医学前沿（英文）》 2019年第13卷第4期页码 427-437 doi: 10.1007/s11684-018-0672-6

摘要： Desmoid-type fibromatosis (DF) is a rare monoclonal fibroblastic proliferation that is characterized by locally infiltrative but rarely metastatic lesions. Tyrosine kinase and γ-secretase inhibitors are primarily used in the targeted therapy of DF. The use of these drugs, however, is mainly based on the recommendations of retrospective studies with small sample sizes. Previous studies that focused on the mechanism, efficacy, and safety of targeted therapy for DF were reviewed to provide references for clinical applications and research. The efficacy and safety of targeted therapy were compared with those of other systemic therapy options. Targeted therapy does not provide considerable advantages in efficacy and safety over other medical treatments and is usually applied after the failure of antihormonal therapies, nonsteroidal anti-inflammatory drugs, and chemotherapy. Further studies are required to explore the mechanism, indications, and appropriate drug dosage of the targeted therapy of DF.

关键词： targeted therapy desmoid-type fibromatosis tyrosine kinase inhibitor γ-secretase inhibitor

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Hydroxyl radical-involved cancer therapy via Fenton reactions

《化学科学与工程前沿（英文）》 2022年第16卷第3期页码 345-363 doi: 10.1007/s11705-021-2077-3

摘要： The tumor microenvironment features over-expressed hydrogen peroxide (H₂O₂). Thus, versatile therapeutic strategies based on H₂O₂ as a reaction substrate to generate hydroxyl radical (•OH) have been used as a prospective therapeutic method to boost anticancer efficiency. However, the limited Fenton catalysts and insufficient endogenous H₂O₂ content in tumor sites greatly hinder •OH production, failing to achieve the desired therapeutic effect. Therefore, supplying Fenton catalysts and elevating H₂O₂ levels into cancer cells are effective strategies to improve •OH generation. These therapeutic strategies are systematically discussed in this review. Furthermore, the challenges and future developments of hydroxyl radical-involved cancer therapy are discussed to improve therapeutic efficacy.

关键词： hydroxyl radical Fenton catalyst hydrogen peroxide cancer therapy

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Progress in systemic therapy for triple-negative breast cancer

Hongnan Mo, Binghe Xu

《医学前沿（英文）》 2021年第15卷第1期页码 1-10 doi: 10.1007/s11684-020-0741-5

摘要： Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a heterogeneous genetic profile. Chemotherapy exhibits substantial activity in a small subset of these patients. Drug resistance is inevitable. Major progress has been made in the genetic analysis of TNBC to identify novel targets and increase the precision of therapeutic intervention. Such progress has translated into major advances in treatment strategies, including modified chemotherapy approaches, immune checkpoint inhibitors, and targeted therapeutic drugs. All of these strategies have been evaluated in clinical trials. Nevertheless, patient selection remains a considerable challenge in clinical practice.

关键词： triple-negative breast cancer immunotherapy targeted therapy

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Translational medicine promising personalized therapy in oncology

Yi-Xin ZENG, Xiao-Shi ZHANG, Qiang LIU,

《医学前沿（英文）》 2010年第4卷第4期页码 351-355 doi: 10.1007/s11684-010-0320-2

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Silica-based nanoarchitecture for an optimal combination of photothermal and chemodynamic therapy functions

《化学科学与工程前沿（英文）》 2023年第17卷第12期页码 2144-2155 doi: 10.1007/s11705-023-2362-4

摘要： This study introduces multifunctional silica nanoparticles that exhibit both high photothermal and chemodynamic therapeutic activities, in addition to luminescence. The activity of the silica nanoparticles is derived from their plasmonic properties, which are a result of infusing the silica nanoparticles with multiple Cu_2–xS cores. This infusion process is facilitated by a recoating of the silica nanoparticles with a cationic surfactant. The key factors that enable the internal incorporation of the Cu_2–xS cores and the external deposition of red-emitting carbon dots are identified. The Cu_2–xS cores within the silica nanoparticles exhibit both self-boosting generation of reactive oxygen species and high photothermal conversion efficacy, which are essential for photothermal and chemodynamic activities. The silica nanoparticles’ small size (no more than 70 nm) and high colloidal stability are prerequisites for their cell internalization. The internalization of the red-emitting silica nanoparticles within cells is visualized using fluorescence microscopy techniques. The chemodynamic activity of the silica nanoparticles is associated with their dark cytotoxicity, and the mechanisms of cell death are evaluated using an apoptotic assay. The photothermal activity of the silica nanoparticles is demonstrated by significant cell death under near-infrared (1064 nm) irradiation.

关键词： copper sulfide nanoparticles chemodynamic therapy photothermal therapy carbon dots silica nanoparticles

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The effect of orbital radiation therapy on thyroid-associated orbitopathy complicated with dysthyroid

null

《医学前沿（英文）》 2017年第11卷第3期页码 359-364 doi: 10.1007/s11684-017-0528-5

摘要：

Thyroid-associated orbitopathy (TAO) is an inflammatory autoimmune disorder. The most serious complication of TAO is dysthyroid optic neuropathy (DON), which can lead to permanent vision loss because of volume expansion in the orbital apex. Orbital radiation therapy (ORT) is an anti-inflammatory treatment used in the treatment of active TAO. Clinical studies support radiotherapy as having a modest effect on DON, and early radiotherapy may protect against disease progression to DON. Current studies suggest that radiotherapy is generally safe. However, risks still exist in some cases. The possible effects of radiotherapy on TAO, especially complicated with DON, are reviewed. The effects of radiotherapy on DON are not completely known, and evidence from standardized, prospective, and multicenter clinical trials is still lacking.

关键词： thyroid-associated orbitopathy dysthyroid optic neuropathy orbital radiation therapy

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Stem cell gene therapy: the risks of insertional mutagenesis and approaches to minimize genotoxicity

Chuanfeng Wu, Cynthia E. Dunbar

《医学前沿（英文）》 2011年第5卷第4期页码 356-371 doi: 10.1007/s11684-011-0159-1

摘要： Virus-based vectors are widely used in hematopoietic stem cell (HSC) gene therapy, and have the ability to integrate permanently into genomic DNA, thus driving long-term expression of corrective genes in all hematopoietic lineages. To date, HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficiency (ADA-SCID), adrenoleukodystrophy (ALD), thalassemia, chronic granulomatous disease (CGD), and Wiskott-Aldrich syndrome (WAS). However, adverse events were observed during some of these HSC gene therapy clinical trials, linked to insertional activation of proto-oncogenes by integrated proviral vectors leading to clonal expansion and eventual development of leukemia. Numerous studies have been performed to understand the molecular basis of vector-mediated genotoxicity, with the aim of developing safer vectors and lower-risk gene therapy protocols. This review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors, discuss the available assays for predicting genotoxicity and mapping vector integration sites, and introduce newly-developed approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application.

关键词： gene therapy hematopoietic stem cells insertional mutagenesis genotoxicity induced pluripotent stem cell