Construction and structure-activity mechanism of polysaccharide nano-selenium carrier.
Hu Shuqian,Hu Weicheng,Li Yanru,Li Shujing,Tian Huafeng,Lu Ang,Wang Jianguo
Carbohydrate polymers
In this study, a series water soluble sulfate polysaccharides (SPS) with different degrees of substitutions (DS = 0.02∼0.28) were prepared using a linear water-insoluble β-d-(1→3)-glucan. SPS-1, SPS-3 and SPS-7 with substitution degrees of 0.02, 0.06 and 0.25 were used as templates to prepare stable and size controlled selenium nanoparticles (SeNPs) with diameter from 54.35 to 123.04 nm using one-step method. The selenium contents of SPS-SeNPs with large, medium and small sizes were 0.172 %, 0.274 % and 0.305 %, respectively. SPS-SeNPs was confirmed to inhibit the production of nitric oxide (NO) in RAW 264.7 inflammatory macrophages induced by lipopolysaccharide (LPS), and downregulated the mRNA expression of TNF-α, IL-1β and iNOS. The results indicated that SPS-SeNPs had significant anti-inflammatory activity. Moreover, SPS-SeNPs with smaller size showed higher anti-inflammatory effects. All of these results suggest that SeNPs-SPS carriers have anti-inflammatory in concentration-dependent and size-dependent model.
10.1016/j.carbpol.2020.116052
Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke.
Alim Ishraq,Caulfield Joseph T,Chen Yingxin,Swarup Vivek,Geschwind Daniel H,Ivanova Elena,Seravalli Javier,Ai Youxi,Sansing Lauren H,Ste Marie Emma J,Hondal Robert J,Mukherjee Sushmita,Cave John W,Sagdullaev Botir T,Karuppagounder Saravanan S,Ratan Rajiv R
Cell
Ferroptosis, a non-apoptotic form of programmed cell death, is triggered by oxidative stress in cancer, heat stress in plants, and hemorrhagic stroke. A homeostatic transcriptional response to ferroptotic stimuli is unknown. We show that neurons respond to ferroptotic stimuli by induction of selenoproteins, including antioxidant glutathione peroxidase 4 (GPX4). Pharmacological selenium (Se) augments GPX4 and other genes in this transcriptional program, the selenome, via coordinated activation of the transcription factors TFAP2c and Sp1 to protect neurons. Remarkably, a single dose of Se delivered into the brain drives antioxidant GPX4 expression, protects neurons, and improves behavior in a hemorrhagic stroke model. Altogether, we show that pharmacological Se supplementation effectively inhibits GPX4-dependent ferroptotic death as well as cell death induced by excitotoxicity or ER stress, which are GPX4 independent. Systemic administration of a brain-penetrant selenopeptide activates homeostatic transcription to inhibit cell death and improves function when delivered after hemorrhagic or ischemic stroke.
10.1016/j.cell.2019.03.032
Selenium-GPX4 axis protects follicular helper T cells from ferroptosis.
Nature immunology
Follicular helper T (T) cells are a specialized subset of CD4 T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of T cell survival remains unclear. Here we report that T cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for T cell survival. The deletion of GPX4 in T cells selectively abrogated T cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased T cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating T homeostasis, which can be targeted to enhance T cell function in infection and following vaccination.
10.1038/s41590-021-00996-0
Boosting Natural Killer Cell-Based Cancer Immunotherapy with Selenocystine/Transforming Growth Factor-Beta Inhibitor-Encapsulated Nanoemulsion.
Liu Chang,Lai Haoqiang,Chen Tianfeng
ACS nano
Natural killer (NK) cell-based immunotherapy represents a promising strategy to overcome the bottlenecks of cancer treatment. However, the therapeutic efficacy is greatly limited by downregulation of recognition ligands on the tumor cell surface, and the immunosuppressive effects can be thwarted by the tumor microenvironment such as secretion of transforming growth factor-beta (TGF-β), which could stunt the NK cell-mediated immune response. To overcome these limitations, herein we developed a nanoemulsion system (SSB NMs) to co-deliver TGF-β inhibitor and selenocysteine (SeC) to achieve amplified anticancer efficacy. SSB NMs significantly enhanced the lytic potency of NK92 cells by 2.1-fold. Moreover, a subtoxic dose of SSB NMs effectively sensitized MDA-MB-231 triple-negative breast cancer (TNBC) cells to NK cells derived from seven clinical patients, resulting in an up to 13.8-fold increase in cancer lysis. Mechanistic studies reveal that the sensitizing effects relied on natural killer group 2, member D (NKG2D)/NKG2D ligands (NKG2DLs) signaling with the involvement of DNA damage response. SSB NMs also effectively restrained TGF-β/TGF-β RI/Smad2/3 signaling, which thus enhanced NKG2DL expression on tumor cells and stimulated NKG2D surface expression on NK92 cells, ultimately contributing to the enhanced immune response. Furthermore, SSB NMs sustained release of SeC and TGF-β inhibitor and synergized with NK92 cells to induce significant anticancer effects . Together, this study not only demonstrates a simple strategy for the design of a nanoemulsion to co-deliver synergistic drugs but also sheds light on the application and action mechanisms in NK cell adaptive therapy against breast cancer, especially TNBCs.
10.1021/acsnano.9b10103
Selenium and Selenocysteine in Protein Chemistry.
Mousa Reem,Notis Dardashti Rebecca,Metanis Norman
Angewandte Chemie (International ed. in English)
Selenocysteine, the selenium-containing analogue of cysteine, is the twenty-first proteinogenic amino acid. Since its discovery almost fifty years ago, it has been exploited in unnatural systems even more often than in natural systems. Selenocysteine chemistry has attracted the attention of many chemists in the field of chemical biology owing to its high reactivity and resulting potential for various applications such as chemical modification, chemical protein (semi)synthesis, and protein folding, to name a few. In this Minireview, we will focus on the chemistry of selenium and selenocysteine and their utility in protein chemistry.
10.1002/anie.201706876
Biogenic selenium nanoparticles induce ROS-mediated necroptosis in PC-3 cancer cells through TNF activation.
Journal of nanobiotechnology
BACKGROUND:Selenium is well documented to inhibit cancer at higher doses; however, the mechanism behind this inhibition varies widely depending on the cell type and selenium species. Previously, we have demonstrated that Bacillus licheniformis JS2 derived biogenic selenium nanoparticles (SeNPs) induce non-apoptotic cell death in prostate adenocarcinoma cell line, PC-3, at a minimal concentration of 2 µg Se/ml, without causing toxicity to the primary cells. However, the mechanism behind its anticancer activity was elusive. RESULTS:Our results have shown that these SeNPs at a concentration of 2 µg Se/ml were able to induce reactive oxygen species (ROS) mediated necroptosis in PC-3 cells by gaining cellular internalization. Real-time qPCR analysis showed increased expression of necroptosis associated tumor necrotic factor (TNF) and interferon regulatory factor 1 (IRF1). An increased expression of RIP1 protein was also observed at the translational level upon SeNP treatment. Moreover, the cell viability was significantly increased in the presence of necroptosis inhibitor, Necrostatin-1. CONCLUSION:Data suggest that our biogenic SeNPs induce cell death in PC-3 cells by the ROS-mediated activation of necroptosis, independent to RIP3 and MLKL, regulated by a RIP1 kinase.
10.1186/s12951-017-0276-3
BSA-stabilized selenium nanoparticles ameliorate intracerebral hemorrhage's-like pathology by inhibiting ferroptosis-mediated neurotoxicology via Nrf2/GPX4 axis activation.
Redox biology
Intracerebral hemorrhage (ICH) is a prevalent hemorrhagic cerebrovascular emergency. Alleviating neurological damage in the early stages of ICH is critical for enhancing patient prognosis and survival rate. A novel form of cell death called ferroptosis is intimately linked to hemorrhage-induced brain tissue injury. Although studies have demonstrated the significant preventive impact of bovine serum albumin-stabilized selenium nanoparticles (BSA-SeNPs) against disorders connected to the neurological system, the neuroprotective effect on the hemorrhage stroke and the mechanism remain unknown. Therefore, based on the favorable biocompatibility of BSA-SeNPs, h-ICH (hippocampus-intracerebral hemorrhage) model was constructed to perform BSA-SeNPs therapy. As expected, these BSA-SeNPs could effectively improve the cognitive deficits and ameliorate the damage of hippocampal neuron. Furthermore, BSA-SeNPs reverse the morphology of mitochondria and enhanced the mitochondrial function, evidenced by mitochondrial respiration function (OCR) and mitochondrial membrane potential (MMP). Mechanistically, BSA-SeNPs could efficiently activate the Nrf2 to enhance the expression of antioxidant GPX4 at mRNA and protein levels, and further inhibit lipid peroxidation production in erastin-induced ferroptotic damages. Taken together, this study not only sheds light on the clinical application of BSA-SeNPs, but also provides its newly theoretical support for the strategy of the intervention and treatment of neurological impairment following ICH.
10.1016/j.redox.2024.103268
Translational selenium nanoparticles boost GPx1 activation to reverse HAdV-14 virus-induced oxidative damage.
Bioactive materials
Human adenovirus (HAdV) can cause severe respiratory infections in immunocompromised patients, but its clinical treatment is seriously limited by side effects of drugs such as poor efficacy, low bioavailability and severe nephrotoxicity. Trace element selenium (Se) has been found will affect the disease progression of pneumonia, but its antivirus efficacy could be improved by speciation optimization. Therefore, herein we performed -HAdV effects of different Se speciation and found that lentinan (LNT)-decorated selenium nanoparticles (SeNPs) exhibited low cytotoxicity and excellent -HAdV antiviral activity. Furthermore, SeNPs@LNT reduced the HAdV infection-induced mitochondrial damage and excessive production of reactive oxygen species (ROS). It was also involved in the repair of host cell DNA damage and inhibition of viral DNA replication. SeNPs@LNT inhibited HAdV-induced apoptosis mainly by modulating the p53/Bcl-2 apoptosis signaling pathway. , SeNPs@LNT replenished Se by targeting the infected site through the circulatory system and was involved in the synthesis of Glutathione peroxidase 1 (GPx1). More importantly, GPx1 played an antioxidant and immunomodulatory role in alleviating HAdV-induced inflammatory cytokine storm and alleviating adenovirus pneumonia in Se-deficient mice. Collectively, this study provides a Se speciation of SeNPs@LNT with -HAdV activity, and demonstrate that SeNPs@LNT is a promising pharmaceutical candidate for the treatment of HAdV.
10.1016/j.bioactmat.2024.04.034
Traditional Chinese medicine active ingredients-based selenium nanoparticles regulate antioxidant selenoproteins for spinal cord injury treatment.
Journal of nanobiotechnology
BACKGROUND:As Traditional Chinese Medicine (TCM) drugs, Huangqi and Danshen are always applied in combination for spinal cord injury (SCI) treatment based on the compatibility theory of TCM. Astragalus Polysaccharidesis (APS) and Tanshinone IIA (TSIIA) are the main active ingredients of Huangqi and Danshen, and they both possess neuroprotective effects through antioxidant activities. However, low solubility and poor bioavailability have greatly limited their application. In recent years, selenium nanoparticles (SeNPs) have drawn enormous attention as potential delivery carrier for antioxidant drugs. RESULTS:In this study, TCM active ingredients-based SeNPs surface decorated with APS and loaded with TSIIA (TSIIA@SeNPs-APS) were successfully synthesized under the guidance of the compatibility theory of TCM. Such design improved the bioavailability of APS and TSIIA with the benefits of high stability, efficient delivery and highly therapeutic efficacy for SCI treatment illustrated by an improvement of the antioxidant protective effects of APS and TSIIA. The in vivo experiments indicated that TSIIA@SeNPs-APS displayed high efficiency of cellular uptake and long retention time in PC12 cells. Furthermore, TSIIA@SeNPs-APS had a satisfactory protective effect against oxidative stress-induced cytotoxicity in PC12 cells by inhibiting excessive reactive oxygen species (ROS) production, so as to alleviate mitochondrial dysfunction to reduce cell apoptosis and S phase cell cycle arrest, and finally promote cell survival. The in vivo experiments indicated that TSIIA@SeNPs-APS can protect spinal cord neurons of SCI rats by enhancing GSH-Px activity and decreasing MDA content, which was possibly via the metabolism of TSIIA@SeNPs-APS to SeCys and regulating antioxidant selenoproteins to resist oxidative stress-induced damage. CONCLUSIONS:TSIIA@SeNPs-APS exhibited promising therapeutic effects in the anti-oxidation therapy of SCI, which paved the way for developing the synergistic effect of TCM active ingredients by nanotechnology to improve the efficacy as well as establishing novel treatments for oxidative stress-related diseases associated with Se metabolism and selenoproteins regulation.
10.1186/s12951-022-01490-x
Selenium-Doped Nanoheterojunctions for Highly Efficient Cancer Radiosensitization.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Exploring efficient and low-toxicity radiosensitizers to break through the bottleneck of radiation tolerance, immunosuppression and poor prognosis remains one of the critical developmental challenges in radiotherapy. Nanoheterojunctions, due to their unique physicochemical properties, have demonstrated excellent radiosensitization effects in radiation energy deposition and in lifting tumor radiotherapy inhibition. Herein, they doped selenium (Se) into prussian blue (PB) to construct a nano-heterojunction (Se@PB), which could promote the increase of Fe/Fe ratio and conversion of Se to a high valence state with Se introduction. The Fe-Se-Fe electron transfer chain accelerates the rate of electron transfer on the surface of the nanoparticles, which in turn endows it with efficient X-ray energy transfer and electron transport capability, and enhances radiotherapy physical sensitivity. Furthermore, Se@PB induces glutathione (GSH) depletion and Fe accumulation through pro-Fenton reaction, thereby disturbs the redox balance in tumor cells and enhances biochemical sensitivity of radiotherapy. As an excellent radiosensitizer, Se@PB effectively enhances X-ray induced mitochondrial dysfunction and DNA damage, thereby promotes cell apoptosis and synergistic cervical cancer radiotherapy. This study elucidates the radiosensitization mechanism of Se-doped nanoheterojunction from the perspective of the electron transfer chain and biochemistry reaction, which provides an efficient and low-toxic strategy in radiotherapy.
10.1002/advs.202402039
The selenoprotein P-LRP5/6-WNT3A complex promotes tumorigenesis in sporadic colorectal cancer.
The Journal of clinical investigation
Some studies suggest that the trace element selenium protects against colorectal cancer (CRC). However, the contribution of selenoprotein P (SELENOP), a unique selenocysteine-containing protein, to sporadic colorectal carcinogenesis challenges this paradigm. SELENOP is predominately secreted by the liver but is also expressed in various cells of the small intestine and colon in mice and humans. In this issue of the JCI, Pilat et al. demonstrate that increased SELENOP expression promoted the progression of conventional adenomas to carcinoma. SELENOP functioned as a modulator of canonical WNT signaling activity through interactions with WNT3A and its coreceptor LDL receptor-related protein 5/6 (LRP5/6). Secreted SELENOP formed a concentration gradient along the gut crypt axis, which might amplify WNT signaling activity by binding to LRPL5/6. The mechanism for WNT control via SELENOP may affect colorectal tumorigenesis and provide therapeutic targets for CRC.
10.1172/JCI171885
TRAIL-driven targeting and reversing cervical cancer radioresistance by seleno-nanotherapeutics through regulating cell metabolism.
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
Recently, radioresistance has become a major obstacle in the radiotherapy of cervical cancer. To demonstrate enhanced radiosensitization against radioresistant cervical cancer, radioresistant cervical cancer cell line was developed and the mechanism of radioresistance was explored. Due to the overexpression of (death receptor 5, DR5) in cervical cancer, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-overexpressed cervical cancer cell membrane-camouflaged CuSe nanomedicine (CCMT) was designed. Since the CCMT was encapsulated with TRAIL-modified cell membrane, it represented high target to cervical cancer cell and immune evasion. Furthermore, CuSe had the ability to scavenge glutathione (GSH) and produce ·OH with excess HO in the tumor microenvironment. The presence of CCMT combined with radiation therapy could effectively increase the O produced by X-rays. In vitro and in vivo studies elaborated that CCMT exhibited excellent radiosensitization properties to reverse radiotolerance by scavenging GSH and promoting DNA damage, apoptosis, mitochondrial membrane potential damage and metabolic disruption. Collectively, this study suggested that the development of TRAIL-overexpressed cell membrane-camouflaged CuSe nanomedicine could advance future cervical cancer treatment and minimize the disadvantages associated with radiation treatment.
10.1016/j.drup.2023.101033
Selenium-containing ruthenium complex synergizes with natural killer cells to enhance immunotherapy against prostate cancer via activating TRAIL/FasL signaling.
Lai Haoqiang,Zeng Delong,Liu Chang,Zhang Qi,Wang Xuan,Chen Tianfeng
Biomaterials
Natural killer (NK) cells-based therapy has been used widely for cancer treatment in clinic trails. However, the immunotherapeutic efficacy of this method has been greatly hindered by tumor evasion and diminished activities of NK cells. In the present study, a selenium (Se)-bearing ruthenium (Ru) complex (RuSe) was designed that could synergistically potentiate NK cell-mediated killing against prostate cancer cells. As expected, pretreatment of cancer cells with subtoxic doses of RuSe effectively augmented the lysis potency of NK cells, with up to 2.46-fold enhancement than NK cells alone, against PC3 cells. More importantly, low concentrations of RuSe could augment the tumor destroying potency of NK cells derived from 10 clinical patients, with the enhancement range from 0.78- to 11.9-fold against PC3 cells and 0.67- to 3.8-fold against LNCAP cells. Mechanistic studies revealed that the sensitizing effect of RuSe primarily depended on TRAIL/TRAIL-R and Fas/FasL-mediated signaling. Furthermore, the increased expression level of these ligands highly relied on ROS overproduction-triggered DNA damage and the downstream ATM and ATR pathways. Furthermore, RuSe potently activated and synergized with NK cells to restrain tumor growth in vivo without causing toxic side effects on major organs. Taken together, the current study not only provides a strategy for application of metal complexes in chemo-immunotherapy but also sheds light on the potential roles and mechanisms of action on such Se-containing drugs as efficient immune-sensitizing agents for NK cell-based immunotherapy.
10.1016/j.biomaterials.2019.119377
Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins.
ACS nano
Easy recurrence and strong treatment side effects significantly limit the clinical treatment of allergic dermatitis. The human trace element selenium (Se) plays essential roles in redox regulation through incorporation into selenoproteins in the form of 21st necessary amino acid selenocysteine, to participates in the pathogenesis and intervention of chronic inflammatory diseases. Therefore, based on the safe and elemental properties of Se, we construct a facile-synthesis strategy for antiallergic selenium nanoparticles (LET-SeNPs), and scale up the production by employing a spray drying method with lactose (Lac-LET-SeNPs) or maltodextrin (Mal-LET-SeNPs) as encapsulation agents realizing larger scale production and a longer storage time. As expected, these as-prepared LET-SeNPs could effectively activate the Nrf2-Keap1 signaling pathway to enhance the expression of antioxidative selenoprotein at mRNA and protein levels, then inhibit mast cell activation to achieve efficient antiallergic activity. Interestingly, LET-SeNPs undergo metabolism to seleno-amino acids to promote biosynthesis of selenoproteins, which could suppress ROS-induced cyclooxygenase-2 (COX-2) and MAPKs activation to suppress the release of histamine and inflammatory cytokines. Allergic mouse and models further confirm that LET-SeNPs could increase the Se content and selenoprotein expression in the skin, decrease mast cells activation and inflammatory cells infiltration, and finally exhibit the high therapeutic effects on allergic dermatitis. Taken together, this study not only constructs facile large-scale synthesis of translational Se nanomedicine to break through the bottleneck problem of nanomaterials but also sheds light on its application in the intervention and treatment of allergies.
10.1021/acsnano.3c04344
The mechanism of selenium regulating the permeability of vascular endothelial cells through selenoprotein O.
Redox biology
Vascular diseases, a leading cause of death in human, are strongly associated with pathological damage to blood vessels. The selenoprotein (Sel) have been reported to play important roles in vascular disease. However, the role of SelO in vascular disease has not been conclusively investigated. The present experiment was to investigate the regulatory mechanism of the effect of SelO on the permeability of vascular endothelial. The H.E staining, FITC-Dextran staining, Dil-AC-LDL staining and FITC-WGA staining showed that vascular structure was damaged, and intercellular junctions were disrupted with selenium (Se)-deficient. Immunohistochemistry, qPCR and Western blot revealed decreased expression of the adhesion plaque proteins vinculin, talin and paxillin, decreased expression of the vascular connectivity effector molecules connexin, claudin-1 and E-cadherin and increased expression of JAM-A and N-cadherin, as well as decreased expression of the ZO-1 signaling pathways ZO-1, Rock, rhoGEF, cingulin and MLC-2. In a screening of 24 Sel present in mice, SelO showed the most pronounced changes in vascular tissues, and a possible association between SelO and vascular intercellular junction effectors was determined using IBM SPSS Statistics 25. Silencing of SelO, vascular endothelial intercellular junction adverse effects present. The regulatory relationship between SelO and vascular endothelial intercellular junctions was determined. The results showed that Se deficiency lead to increased vascular endothelial permeability and vascular tissue damage by decreasing SelO expression, suggesting a possible role for SelO in regulating vascular endothelial permeability.
10.1016/j.redox.2024.103063
SELENOP modifies sporadic colorectal carcinogenesis and WNT signaling activity through LRP5/6 interactions.
The Journal of clinical investigation
Although selenium deficiency correlates with colorectal cancer (CRC) risk, the roles of the selenium-rich antioxidant selenoprotein P (SELENOP) in CRC remain unclear. In this study, we defined SELENOP's contributions to sporadic CRC. In human single-cell cRNA-Seq (scRNA-Seq) data sets, we discovered that SELENOP expression rose as normal colon stem cells transformed into adenomas that progressed into carcinomas. We next examined the effects of Selenop KO in a mouse adenoma model that involved conditional, intestinal epithelium-specific deletion of the tumor suppressor adenomatous polyposis coli (Apc) and found that Selenop KO decreased colon tumor incidence and size. We mechanistically interrogated SELENOP-driven phenotypes in tumor organoids as well as in CRC and noncancer cell lines. Selenop-KO tumor organoids demonstrated defects in organoid formation and decreases in WNT target gene expression, which could be reversed by SELENOP restoration. Moreover, SELENOP increased canonical WNT signaling activity in noncancer and CRC cell lines. In defining the mechanism of action of SELENOP, we mapped protein-protein interactions between SELENOP and the WNT coreceptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6). Last, we confirmed that SELENOP-LRP5/6 interactions contributed to the effects of SELENOP on WNT activity. Overall, our results position SELENOP as a modulator of the WNT signaling pathway in sporadic CRC.
10.1172/JCI165988
Rapid Selenoprotein Activation by Selenium Nanoparticles to Suppresses Osteoclastogenesis and Pathological Bone Loss.
Advanced materials (Deerfield Beach, Fla.)
Osteoclast hyperactivation stands as a significant pathological factor contributing to the emergence of bone disorders driven by heightened oxidative stress levels. The modulation of the redox balance to scavenge reactive oxygen species emerges as a viable approach to addressing this concern. Selenoproteins, characterized by selenocysteine (SeCys) as the active center, are crucial for selenium-based antioxidative stress therapy for inflammatory diseases. This study reveals that surface-active elemental selenium (Se) nanoparticles, particularly lentinan-Se (LNT-Se), exhibit enhanced cellular accumulation and accelerated metabolism to SeCys, the primary active Se form in biological systems. Consequently, LNT-Se demonstrates significant inhibition of osteoclastogenesis. Furthermore, in vivo studies underscore the superior therapeutic efficacy of LNT-Se over SeCys, potentially attributable to the enhanced stability and safety profile of LNT-Se. Specifically, LNT-Se effectively modulates the expression of the selenoprotein GPx1, thereby exerting regulatory control over osteoclastogenesis inhibition, and the prevention of osteolysis. In summary, these results suggest that the prompt activation of selenoproteins by Se nanoparticles serves to suppress osteoclastogenesis and pathological bone loss by upregulating GPx1. Moreover, the utilization of bioactive Se species presents a promising avenue for effectively managing bone disorders.
10.1002/adma.202401620
Selenium nanoparticles produce a beneficial effect in psoriasis by reducing epidermal hyperproliferation and inflammation.
Gangadevi Vinod,Thatikonda Sowjanya,Pooladanda Venkatesh,Devabattula Geetanjali,Godugu Chandraiah
Journal of nanobiotechnology
BACKGROUND:Psoriasis is a chronic autoimmune skin disease characterized by hyperproliferation of keratinocytes. Wide treatment options used to treat psoriasis is associated with various adverse effects. To overcome this nanoformulation is prepared. Selenium is an essential trace element and plays major role in oxidation reduction system. Toxicity and stability limits the applications of selenium. Toxicity can be reduced and stabilized upon preparation into nanoparticles. RESULTS:Selenium nanoparticles (SeNPs) exhibit potent apoptosis through the generation of reactive oxygen species (ROS) with cell cycle arrest. SeNPs topical gel application produced significant attenuation of psoriatic severity with the abrogation of acanthosis and splenomegaly. SeNPs reduced the phosphorylation and expressions of MAPKs, STAT3, GSK-3β, Akt along with PCNA, Ki67, and cyclin-D1. CONCLUSION:SeNPs inhibit various inflammation and proliferation mediated pathways and could be an ideal candidate for psoriasis therapy. MATERIALS AND METHODS:SeNPs were characterized and various techniques were used to determine apoptosis and other molecular mechanisms. In vivo studies were performed by inducing psoriasis with imiquimod (IMQ). SeNPs were administered via topical route.
10.1186/s12951-021-00842-3
Selenium nanoparticles as new strategy to potentiate γδ T cell anti-tumor cytotoxicity through upregulation of tubulin-α acetylation.
Hu Yi,Liu Ting,Li Jingxia,Mai Fengyi,Li Jiawei,Chen Yan,Jing Yanyun,Dong Xin,Lin Li,He Junyi,Xu Yan,Shan Changliang,Hao Jianlei,Yin Zhinan,Chen Tianfeng,Wu Yangzhe
Biomaterials
Immune cell therapy presents a paradigm for the treatment of malignant tumors. Human Vγ9Vδ2 T cells, a subset of peripheral γδ T cells, have been shown to have promising anti-tumor activity. However, new methodology on how to achieve a stronger anti-tumor activity of Vγ9Vδ2 T cells is under continuous investigation. In this work, we used selenium nanoparticles (SeNPs) to strengthen the anti-tumor cytotoxicity of Vγ9Vδ2 T cells. We found SeNPs pretreated γδ T cells had significantly stronger cancer killing and tumor growth inhibition efficacy when compared with γδ T cells alone. Simultaneously, SeNPs pretreatment could significantly upregulate the expression of cytotoxicity related molecules including NKG2D, CD16, and IFN-γ, meanwhile, downregulate PD-1 expression of γδ T cells. Importantly, we observed that SeNPs promoted tubulin acetylation modification in γδ T cells through interaction between microtubule network and lysosomes since the latter is the primary resident station of SeNPs shown by confocal visualization. In conclusion, SeNPs could significantly potentiate anti-tumor cytotoxicity of Vγ9Vδ2 T cells, and both cytotoxicity related molecules and tubulin acetylation were involved in fine-tuning γδ T cell toxicity against cancer cells. Our present work demonstrated a new strategy for further enhancing anti-tumor cytotoxicity of human Vγ9Vδ2 T cells by using SeNPs-based nanotechnology, not gene modification, implicating SeNPs-based nanotechnology had a promising clinical perspective in the γδ T cell immunotherapy for malignant tumors.
10.1016/j.biomaterials.2019.119397
Autoimmunity to selenoprotein P predicts breast cancer recurrence.
Redox biology
BACKGROUND:Low concentrations of serum selenium (Se) and its main transporter selenoprotein P (SELENOP) are associated with a poor prognosis following breast cancer diagnosis. Recently, natural autoantibodies (aAb) with antagonistic properties to SELENOP uptake have been identified in healthy subjects, and in patients with thyroid disease. Given the potential transport disrupting properties, we hypothesized that breast cancer patients with SELENOP-aAb may have a poor prognosis. METHODS:SELENOP-aAb along with serum Se, SELENOP and GPX3 activity were determined in serum samples of 1988 patients with a new diagnosis of breast cancer enrolled in the multicentre SCAN-B study. Patients were followed for ∼9 years and multivariate Cox regression models were applied to assess hazard ratios. RESULTS:Applying a cut-off based on outlier detection, we identified 7.65% of patients with SELENOP-aAb. Autoantibody titres correlated positively to total Se and SELENOP concentrations, but not to GPX3 activity, supporting a negative role of SELENOP-aAb on Se transport. SELENOP-aAb were associated with age, but independent of tumor characteristics. After fully adjusting for potential confounders, SELENOP-aAb were associated with higher recurrence, HR(95%CI) = 1.87(1.17-2.99), particularly in patients with low Se concentrations, HR(95%CI) = 2.16(1.20-3.88). Associations of SELENOP-aAb with recurrence and mortality were linear and dose-dependent, with fully adjusted HR(95%CI) per log increase of 1.25(1.01-1.55) and 1.31(1.13-1.51), respectively. CONCLUSION:Our results indicate a prognostic and pathophysiological relevance of SELENOP-aAb in breast cancer, with potential relevance for other malignancies. Assessment of SELENOP-aAb at time of diagnosis identifies patients with a distinctly elevated risk for a poor prognosis, independent of established prognostic factors, who may respond favourably to Se supplementation.
10.1016/j.redox.2022.102346
Selenium-Containing Nanocomplexes Achieve Dual Immune Checkpoint Blockade for NK Cell Reinvigoration.
Small (Weinheim an der Bergstrasse, Germany)
The blockade of immune checkpoints has emerged as a promising strategy for cancer immunotherapy. However, most of the current approaches focus on T cells, leaving natural killer (NK) cell-mediated therapeutic strategies rarely explored. Here, a selenium-containing nanocomplex is developed that acts as a dual immune checkpoint inhibitor to reinvigorate NK cell-based cancer immunotherapy. The Se nanocomplex can deliver and release siRNA that targets programmed death ligand-1 (PD-L1) in tumor cells, thereby silencing the checkpoint receptor PD-L1. The intracellular reactive oxygen species generated by porphyrin derivatives in the nanocomplexes can oxidize the diselenide bond into seleninic acid, which blocks the expression of another checkpoint receptor, human leukocyte antigen E. The blockade of dual immune checkpoints shows synergistic effects on promoting NK cell-mediated antitumoral activity. This study provides a new strategy to reinvigorate NK cell immunity for the development of combined cancer immunotherapy.
10.1002/smll.202306225
SELENOI Functions as a Key Modulator of Ferroptosis Pathway in Colitis and Colorectal Cancer.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether-linked phosphatidylethanolamine (ePE) and a marked increase in ether-linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate-15-lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI-knockdown cells, while SELENOI overexpression can partially rescue GPX4-knockdown-induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.
10.1002/advs.202404073
Selenopeptide Nanomedicine Activates Natural Killer Cells for Enhanced Tumor Chemoimmunotherapy.
Advanced materials (Deerfield Beach, Fla.)
Chemoimmunotherapy using nanotechnology has shown great potential for cancer therapy in the clinic. However, uncontrolled transportation and synergistic responses remain challenges. Here, a self-assembled selenopeptide nanoparticle that strengthens tumor chemoimmunotherapy through the activation of natural killer (NK) cells by the oxidative metabolite of the selenopeptide is developed. With the advantages of the enzyme-induced size-reduction and the reactive-oxygen-species-driven deselenization, this selenopeptide is able to deliver therapeutics, e.g., doxorubicin (DOX), to solid tumors and further activate the NK cells in a programmed manner. Importantly, in vitro and in vivo results prove the mutual promotion between the DOX-induced chemotherapy and the selenopeptide-induced immunotherapy, which synergistically contribute to the improved antitumor efficacy. It is anticipated that the selenopeptide may provide a type of promising stimuli-responsive immune modulator for versatile biomedical applications.
10.1002/adma.202108167
Organic Selenium induces ferroptosis in pancreatic cancer cells.
Redox biology
Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant dishomeostasis of free radicals. While this is compensated by the upregulation of detoxification mechanisms, it also represents a potential vulnerability. Here we demonstrate that PDA cells are sensitive to the inhibition of the mevalonate pathway (MVP), which supports the biosynthesis of critical antioxidant intermediates and protect from ferroptosis. We attacked the susceptibility of PDA cells to ferroptotic death with selenorganic compounds, including dibenzyl diselenide (DBDS) that exhibits potent pro-oxidant properties and inhibits tumor growth in vitro and in vivo. DBDS treatment induces the mobilization of iron from mitochondria enabling uncontrolled lipid peroxidation. Finally, we showed that DBDS and statins act synergistically to promote ferroptosis and provide evidence that combined treatment is a viable strategy to combat PDA.
10.1016/j.redox.2023.102962
Selenium and tellurium in the development of novel small molecules and nanoparticles as cancer multidrug resistance reversal agents.
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
Selenium is an essential trace element that is crucial for cellular antioxidant defense against reactive oxygen species (ROS). Recently, many selenium-containing compounds have exhibited a wide spectrum of biological activities that make them promising scaffolds in Medicinal Chemistry, and, in particular, in the search for novel compounds with anticancer activity. Similarly, certain tellurium-containing compounds have also exhibited substantial biological activities. Here we provide an overview of the biological activities of seleno- and tellurocompounds including chemopreventive activity, antioxidant or pro-oxidant activity, modulation of the inflammatory processes, induction of apoptosis, modulation of autophagy, inhibition of multidrug efflux pumps such as P-gp, inhibition of cancer metastasis, selective targeting of tumors and enhancement of the cytotoxic activity of chemotherapeutic drugs, as well as overcoming tumor drug resistance. A review of the chemistry of the most relevant seleno- or tellurocompounds with activity against resistant cancers is also presented, paying attention to the synthesis of these compounds and to the preparation of bioactive selenium or tellurium nanoparticles. Based on these data, the use of these seleno- and tellurocompounds is a promising approach in the development of strategies that can drive forward the search for novel therapies or adjuvants of current therapies against drug-resistant cancers.
10.1016/j.drup.2022.100844
Selenium-containing nanoparticles synergistically enhance Pemetrexed&NK cell-based chemoimmunotherapy.
Pan Shuojiong,Li Tianyu,Tan Yizheng,Xu Huaping
Biomaterials
NK cell-based immunotherapy and pemetrexed (Pem)-based chemotherapy have broad application prospects in cancer treatment. However, the over-expressed NK cell inhibitory receptor on the surface of cancer cells and the low cell internalization efficiency of Pem greatly limit their clinical application. Herein, we construct a series of selenium-containing nanoparticles to synergistically enhance Pem-based chemotherapy and NK cell-based immunotherapy. The nanoparticles could deliver Pem to tumor sites and strengthen the chemotherapy efficiency of Pem by seleninic acid, which is produced by the oxidation of β-seleno ester. Moreover, seleninic acid can block the expression of inhibitory receptors against NK cells, thereby activating the immunocompetence of NK cells. The in vitro and in vivo experiments reveal the potential chemo-enhancing and immune-activating mechanism of seleninic acid, emphasizing the promising prospects of this strategy in effective chemoimmunotherapy.
10.1016/j.biomaterials.2021.121321
Selenium-Containing Nanoparticles Combine the NK Cells Mediated Immunotherapy with Radiotherapy and Chemotherapy.
Gao Shiqian,Li Tianyu,Guo Ye,Sun Chenxing,Xianyu Banruo,Xu Huaping
Advanced materials (Deerfield Beach, Fla.)
Considering the limited clinical benefits of individual approaches against malignancy, natural killer (NK) cell-mediated immunotherapy is increasingly utilized in combination with radiotherapy and target therapeutics. However, the interplay of targeted agents, immunotherapy, and radiotherapy is complex. An improved understanding of the effect of chemotherapy or radiotherapy on specific molecular pathways in immune cells would help to optimize the synergistic antitumor efficiency. In this study, the selenium-containing nanoparticles (NPs) could deliver the chemotherapeutic drug doxorubicin (DOX) to tumor sites by systemic administration. Radiation stimuli facilitate DOX release and enhance chemotherapy efficiency. Moreover, radiation could oxidize diselenide-containing NPs to seleninic acid, which have both synergistic antitumor effect and immunomodulatory activity through enhancing NK cells function. These results indicate that the selenium-containing NPs would be a potential approach to achieve simultaneous treatments of immunotherapy, chemotherapy, and radiotherapy by a simple but effective method.
10.1002/adma.201907568
Selenium Nanoparticles for Biomedical Applications: From Development and Characterization to Therapeutics.
Ferro Cláudio,Florindo Helena F,Santos Hélder A
Advanced healthcare materials
Selenium (Se) is an essential element to human health that can be obtained in nature through several sources. In the human body, it is incorporated into selenocysteine, an amino acid used to synthesize several selenoproteins, which have an active center usually dependent on the presence of Se. Although Se shows several beneficial properties in human health, it has also a narrow therapeutic window, and therefore the excessive intake of inorganic and organic Se-based compounds often leads to toxicity. Nanoparticles based on Se (SeNPs) are less toxic than inorganic and organic Se. They are both biocompatible and capable of effectively delivering combinations of payloads to specific cells following their functionalization with active targeting ligands. Herein, the main origin of Se intake, its role on the human body, and its primary biomedical applications are revised. Particular focus will be given to the main therapeutic targets that are explored for SeNPs in cancer therapies, discussing the different functionalization methodologies used to improve SeNPs stability, while enabling the extensive delivery of drug-loaded SeNP to tumor sites, thus avoiding off-target effects.
10.1002/adhm.202100598
Selenium promotes immunogenic radiotherapy against cervical cancer metastasis through evoking P53 activation.
Biomaterials
Radiotherapy is still the recommended treatment for cervical cancer. However, radioresistance and radiation-induced side effects remain one of the biggest clinical problems. Selenium (Se) has been confirmed to exhibit radiation-enhancing effects for cancer treatment. However, Se species dominate the biological activities and which form of Se possesses better radiosensitizing properties and radiation safety remains elusive. Here, different Se species (the valence state of Se ranged from - 2, 0, +4 to + 6) synergy screen was carried out to identify the potential radiosensitizing effects and radiation safety of Se against cervical cancer. We found that the therapeutic effects varied with the changes in the Se valence state. Sodium selenite (+4) displayed strong cancer-killing effects but also possessed severe cytotoxicity. Sodium selenate (+6) neither enhanced the killing effects of X-ray nor possessed anticancer activity by its alone treatment. Although nano-selenium (0), especially Let-SeNPs, has better radiosensitizing activity, the - 2 organic Se, such as selenadiazole derivative SeD (-2) exhibited more potent anticancer effects and possessed a higher safe index. Overall, the selected Se drugs were able to synergize with X-ray to inhibit cell growth, clone formation, and cell migration by triggering G2/M phase arrest and apoptosis, and SeD (-2) was found to exhibit more potent enhancing capacity. Further mechanism studies showed that SeD mediated p53 pathway activation by inducing DNA damage through promoting ROS production. Additionally, SeD combined with X-ray therapy can induce an anti-tumor immune response in vivo. More importantly, SeD combined with X-ray significantly inhibited the liver metastasis of tumor cells and alleviated the side effects caused by radiation therapy in tumor-bearing mice. Taken together, this study demonstrates the radiosensitization and radiation safety effects of different Se species, which may shed light on the application of such Se-containing drugs serving as side effects-reducing agents for cervical cancer radiation treatment.
10.1016/j.biomaterials.2023.122452
Selenoxide elimination manipulate the oxidative stress to improve the antitumor efficacy.
Sun Chenxing,Wang Lu,Xianyu Banruo,Li Tianyu,Gao Shiqian,Xu Huaping
Biomaterials
Selenoxide elimination reaction has been widely used in the field of organic synthesis. However, few studies have been conducted to apply this reaction in biodegradable nanomedicine. In this work, the selenoxide elimination reaction was used for cancer treatment via producing excess cellular reactive oxygen species (ROS) for the first time. The β-seleno diesters and porphyrin derivates containing nanoparticle could be responsive to the intracellular ROS and produce acrylates through the elimination reaction. The acrylates would further deplete intracellular GSH in tumor cells and finally improved the anticancer activity in the mice tumor model. Different from traditional ROS-responsive nanomedicine, the elimination product of this reaction could regenerate cytotoxic ROS and specifically disturb the redox balance of tumor cells. This work would provide attractive avenues for the development of therapeutic strategies against cancer via synthesis of well-designed biodegradable polymers.
10.1016/j.biomaterials.2019.119514
Selenium Modulates Cancer Cell Response to Pharmacologic Ascorbate.
Cancer research
High-dose ascorbate (vitamin C) has shown promising anticancer activity. Two redox mechanisms have been proposed: hydrogen peroxide generation by ascorbate itself or glutathione depletion by dehydroascorbate (formed by ascorbate oxidation). Here we show that the metabolic effects and cytotoxicity of high-dose ascorbate in vitro result from hydrogen peroxide independently of dehydroascorbate. These effects were suppressed by selenium through antioxidant selenoenzymes including glutathione peroxidase 1 (GPX1) but not the classic ferroptosis-inhibiting selenoenzyme GPX4. Selenium-mediated protection from ascorbate was powered by NADPH from the pentose phosphate pathway. In vivo, dietary selenium deficiency resulted in significant enhancement of ascorbate activity against glioblastoma xenografts. These data establish selenoproteins as key mediators of cancer redox homeostasis. Cancer sensitivity to free radical-inducing therapies, including ascorbate, may depend on selenium, providing a dietary approach for improving their anticancer efficacy. SIGNIFICANCE:Selenium restriction augments ascorbate efficacy and extends lifespan in a mouse xenograft model of glioblastoma, suggesting that targeting selenium-mediated antioxidant defenses merits clinical evaluation in combination with ascorbate and other pro-oxidant therapies.
10.1158/0008-5472.CAN-22-0408
Theranostic applications of selenium nanomedicines against lung cancer.
Journal of nanobiotechnology
The incidence and mortality rates of lung cancer are among the highest in the world. Traditional treatment methods include surgery, chemotherapy, and radiotherapy. Although rapid progress has been achieved in the past decade, treatment limitations remain. It is therefore imperative to identify safer and more effective therapeutic methods, and research is currently being conducted to identify more efficient and less harmful drugs. In recent years, the discovery of antitumor drugs based on the essential trace element selenium (Se) has provided good prospects for lung cancer treatments. In particular, compared to inorganic Se (Inorg-Se) and organic Se (Org-Se), Se nanomedicine (Se nanoparticles; SeNPs) shows much higher bioavailability and antioxidant activity and lower toxicity. SeNPs can also be used as a drug delivery carrier to better regulate protein and DNA biosynthesis and protein kinase C activity, thus playing a role in inhibiting cancer cell proliferation. SeNPs can also effectively activate antigen-presenting cells to stimulate cell immunity, exert regulatory effects on innate and regulatory immunity, and enhance lung cancer immunotherapy. This review summarizes the application of Se-based species and materials in lung cancer diagnosis, including fluorescence, MR, CT, photoacoustic imaging and other diagnostic methods, as well as treatments, including direct killing, radiosensitization, chemotherapeutic sensitization, photothermodynamics, and enhanced immunotherapy. In addition, the application prospects and challenges of Se-based drugs in lung cancer are examined, as well as their forecasted future clinical applications and sustainable development.
10.1186/s12951-023-01825-2
Selenium detoxification is required for cancer-cell survival.
Carlisle Anne E,Lee Namgyu,Matthew-Onabanjo Asia N,Spears Meghan E,Park Sung Jin,Youkana Daniel,Doshi Mihir B,Peppers Austin,Li Rui,Joseph Alexander B,Smith Miles,Simin Karl,Zhu Lihua Julie,Greer Paul L,Shaw Leslie M,Kim Dohoon
Nature metabolism
The micronutrient selenium is incorporated via the selenocysteine biosynthesis pathway into the rare amino acid selenocysteine, which is required in selenoproteins such as glutathione peroxidases and thioredoxin reductases. Here, we show that selenophosphate synthetase 2 (SEPHS2), an enzyme in the selenocysteine biosynthesis pathway, is essential for survival of cancer, but not normal, cells. SEPHS2 is required in cancer cells to detoxify selenide, an intermediate that is formed during selenocysteine biosynthesis. Breast and other cancer cells are selenophilic, owing to a secondary function of the cystine/glutamate antiporter SLC7A11 that promotes selenium uptake and selenocysteine biosynthesis, which, by allowing production of selenoproteins such as GPX4, protects cells against ferroptosis. However, this activity also becomes a liability for cancer cells because selenide is poisonous and must be processed by SEPHS2. Accordingly, we find that SEPHS2 protein levels are elevated in samples from people with breast cancer, and that loss of SEPHS2 impairs growth of orthotopic mammary-tumour xenografts in mice. Collectively, our results identify a vulnerability of cancer cells and define the role of selenium metabolism in cancer.
10.1038/s42255-020-0224-7