Functional Properties of Rice Bran Proteins Extracted from Low-Heat-Treated Defatted Rice Bran.

Rice bran is rich in proteins with high nutritional values. However, current protein extraction methods from rice bran are greatly limited by their low yield. Therefore, in this study, we aimed to develop a feasible method to extract rice bran protein (RBP) of high purity and quality. We prepared RBP using low-heat-treated defatted rice bran (LDRB) and analyzed its functional properties. The protein solubility of LDRB increased from 25.4% to 56% upon increasing the pH level and was more than double that of heat-stabilized defatted rice bran. RBP prepared from LDRB had good functional properties, comparable to those of soy proteins. The emulsifying capacities of RBP were 424 ± 14 mL/g at pH 4 and 530 ± 21 mL/g at pH 7.0. Under acidic conditions, RBP showed a better emulsifying capacity than soy proteins (262 ± 1 mL/g at pH 4). RPB showed water-binding and oil-absorption capacities of 270 ± 35 g/100 g and 268 ± 30 g/100 g, respectively. Moreover, RBP showed better foaming capacity (610% vs. 590%) and foam stability (83% vs. 4%) than soy proteins; however, it lacked gelling properties. This study demonstrated that RBP is a potential new protein source in the food industry.

Glycogen synthase kinase 3 promotes p53 mRNA translation via phosphorylation of RNPC1.

The RNPC1 RNA-binding protein, also called Rbm38, is a target of p53 and a repressor of p53 mRNA translation. Thus, the p53-RNPC1 loop is critical for modulating p53 tumor suppression, but it is not clear how the loop is regulated. Here, we showed that RNPC1 is phosphorylated at Ser195 by glycogen synthase kinase 3 (GSK3). We also showed that GSK3 promotes p53 mRNA translation through phosphorylation of RNPC1. Interestingly, we found that the phosphor-mimetic mutant S195D and the deletion mutant Δ189-204, which lacks the GSK3 phosphorylation site, are unable to repress p53 mRNA translation due to loss of interaction with eukaryotic translation factor eIF4E on p53 mRNA. Additionally, we found that phosphorylated RNPC1, RNPC1-S195D, and RNPC1(Δ189-204) promote p53 mRNA translation through interaction with eukaryotic translation factor eIF4G, which then facilitates the assembly of the eIF4F complex on p53 mRNA. Furthermore, we showed that upon inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, GSK3 is activated, leading to increased RNPC1 phosphorylation and increased p53 expression in a RNPC1-dependent manner. Together, we postulate that the p53-RNPC1 loop can be explored to increase or decrease p53 activity for cancer therapy.

Effect of Three Defatting Solvents on the Techno-Functional Properties of an Edible Insect (Gryllus bimaculatus) Protein Concentrate.

Edible insects have received global attention as an alternative protein-rich food. However, their structural characteristics make them difficult to digest. To overcome this obstacle, we assessed the techno-functional properties of three protein concentrates from the cricket Gryllus bimaculatus. Freeze-dried G. bimaculatus powder was defatted using ethanol, hexene, or acetone as solvents, and the techno-functional properties (protein solubility, water and oil holding capacity, foaming properties, emulsion capacity, and gel formation) of the protein concentrates were determined. Freeze-dried G. bimaculatus powder comprised approximately 17.3% crude fat and 51.3% crude protein based on dry weight. Ethanol was the most effective solvent for reducing the fat content (from 17.30% to 0.73%) and increasing the protein content (from 51.3% to 62.5%) of the concentrate. Techno-functionality properties drastically differed according to the defatting solvent used and foaming properties were most affected. Thus, the techno-functional and whole properties must be considered for proper application of edible insects to achieve global food sustainability.

Mushroom-Derived Bioactive Molecules as Immunotherapeutic Agents: A Review.

Mushrooms with enhanced medicinal properties focus on finding such compounds that could modulate the human body's immune systems. Mushrooms have antimicrobial, antidiabetic, antiviral, hepatoprotective, antitumor, and immunomodulatory properties due to the presence of various bioactive components. ß-glucans are the major constituent of the mushroom cell wall and play a significant role in their biological activity. This review described the techniques used in the extraction of the active ingredients from the mushroom. We highlighted the structure of the bioactive polysaccharides present in the mushrooms. Therapeutic applications of different mushrooms were also described. It is interesting to note that mushrooms have the potential sources of many bioactive products that can regulate immunity. Thus, the development of functional medicinal food based on the mushroom is vital for human welfare.

Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner.

WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Nerve injury-induced protein 1 (Ninj1) is a target of p53 and forms a feedback loop with p53 by repressing p53 mRNA translation. Here, we show that loss of Ninj1 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of Ninj1 inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of Ninj1-deficient mice and found that Ninj1+/- mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of Ninj1 altered the tumor susceptibility in both mutant p53 and p53-null background. Specifically, in a mutant p53(R270H) background, Ninj1 deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a p53-null background, Ninj1 deficiency significantly increased the incidence of T-lymphoblastic lymphoma. Taken together, our data suggest that depending on p53 genetic status, Ninj1 has two opposing functions in tumorigenesis and that the Ninj1-p53 loop may be targeted to manage inflammatory diseases and cancer.

Protaetia brevitarsis seulensis Derived Protein Isolate with Enhanced Osteomodulatory and Antioxidative Property.

The osteogenic differentiation of stem cells is profoundly affected by their microenvironmental conditions. The differentiation behavior of stem cells can be tuned by changing the niche environments. The proteins or peptides that are derived by living organisms facilitate the osteogenic differentiation of stem cells. Here, we have evaluated the osteoinductive and antioxidative potential of the Protaetia brevitarsis seulensis insect-derived protein for human bone marrow-derived mesenchymal stem cells (hBMSCs). The amino acid contents in the isolated protein were determined by an amino acid analyzer. Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) were used to analyze the extract's functional groups and surface morphology. The extracted protein exhibited 51.08% ß-sheet conformation. No adverse effects were observed in extract-treated cells, indicating their biocompatibility. The protein isolate showed an excellent antioxidative property. Besides this, an enhancement in the hBMSCs' mineralization has been observed in the presence of treated protein isolates. Notably, osteogenic marker genes and proteins were effectively expressed in the treated cells. These results indicated that the P. brevitarsis-derived protein isolate can be used as a potential antioxidative biomaterial for bone tissue engineering applications.

Effects of partial replacement of dietary fish meal by bioprocessed plant protein concentrates on growth performance, hematology, nutrient digestibility and digestive enzyme activities in juvenile Pacific white shrimp, Litopenaeus vannamei.

BACKGROUND: Bioprocessing of plant feedstuff can be a novel approach for reducing the overwhelming dependence on fish meal in aquaculture. The objective of this study was to evaluate the performance of Pacific white shrimp Litopenaeus vannamei fed solid-state fermented protein concentrates in order to replace fish meal in the diet. RESULTS: In the first trial, a group of 15 shrimp (average 3.88 g) were randomly distributed into aquaria in triplicate according to the experimental diets. Ten isonitrogenous (400 g kg-1 CP) and isolipidic (90 g kg-1 CL) diets were formulated to contain high-protein fish meal (HFM) and low-protein fish meal (LFM), and four types of bioprocessed protein concentrates (BPCs) as a replacement of fish meal (BPC-A, -B, -C and -D) each at 30% and 50% FM replacement levels. BPC-A was a solid-state fermented mixture of soybean and corn gluten meals; BPC-B was pre-treated acid-hydrolyzed BPC-A; BPC-C and BPC-D were BPC-A + 2% shrimp soluble extract (SSE) and BPC-B + 2% SSE, respectively. After 8 weeks, shrimp fed the HFM, BPC-B, BPC-C and BPC-D diets showed significantly higher growth performance at 30% FM replacement than those of shrimp fed the BPC diets at 50% FM replacement. Interestingly, shrimp fed the BPC-D diet could replace up to 50% FM replacement. In the second trial, the results show that apparent digestibility coefficients of feeds and apparent digestibility coefficients of ingredients for crude protein were significantly higher in fish fed the BPC-B, BPC-C and BPC-D diets. CONCLUSIONS: The results demonstrated successful partial replacement of high-protein fish meal using high-quality fermented protein concentrates from plant sources. © 2019 Society of Chemical Industry.

Translational repression of p53 by RNPC1, a p53 target overexpressed in lymphomas.

The p53 pathway is critical for tumor suppression, as the majority of human cancer has a faulty p53. Here, we identified RNPC1, a p53 target and a RNA-binding protein, as a critical regulator of p53 translation. We showed that ectopic expression of RNPC1 inhibited, whereas knockdown of RNPC1 increased, p53 translation under normal and stress conditions. We also showed that RNPC1 prevented cap-binding protein eIF4E from binding p53 mRNA via its C-terminal domain for physical interaction with eIF4E, and its N-terminal domain for binding p53 mRNA. Consistent with this, we found that RNPC1 directly binds to p53 5' and 3'untranslated regions (UTRs). Importantly, we showed that RNPC1 inhibits ectopic expression of p53 in a dose-dependent manner via p53 5' or 3' UTR. Moreover, we showed that loss of RNPC1 in mouse embryonic fibroblasts increased the level of p53 protein, leading to enhanced premature senescence in a p53-dependent manner. Finally, to explore the clinical relevance of our finding, we showed that RNPC1 was frequently overexpressed in dog lymphomas, most of which were accompanied by decreased expression of wild-type p53. Together, we identified a novel p53-RNPC1 autoregulatory loop, and our findings suggest that RNPC1 plays a role in tumorigenesis by repressing p53 translation.

Ninjurin1, a target of p53, regulates p53 expression and p53-dependent cell survival, senescence, and radiation-induced mortality.

The tumor suppressor protein p53 plays a crucial role in coordinating cellular processes, such as cell cycle arrest, apoptosis, and senescence. The nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a homophilic adhesion molecule and involved in nerve regeneration. Interestingly, Ninj1 is found to be overexpressed in human cancer, but its role in tumorigenesis is not clear. Here, we found that Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage in a p53-dependent manner. We also found that knockout or knockdown of Ninj1 increases p53 expression potentially through enhanced p53 mRNA translation. In addition, we found that Ninj1 deficiency suppresses cell proliferation but enhances apoptosis and premature senescence in a p53-dependent manner. Consistent with this, we found that mice heterozygous in ninj1 are hypersensitive to ionizing radiation-induced lethality, along with increased expression of p53 in thymus. Taken together, we provided evidence that Ninj1 is a p53 target and modulates p53 mRNA translation and p53-dependent premature senescence, cell proliferation, apoptosis, and radiation-induced mortality in vitro and in vivo. Thus, we postulate that as a membrane adhesion molecule, Ninj1 is an ideal target to regulate p53 activity via the p53-Ninj1 loop.

DNA polymerase η is regulated by poly(rC)-binding protein 1 via mRNA stability.

POLH (DNA polymerase η), a target of p53 tumour suppressor, plays a key role in TLS (translesion DNA synthesis). Loss of POLH is responsible for the human cancer-prone syndrome XPV (xeroderma pigmentosum variant). Owing to its critical role in DNA repair and genome stability, POLH expression and activity are regulated by multiple pathways. In the present study, we found that the levels of both POLH transcript and protein were decreased upon knockdown of the transcript encoding PCBP1 [poly(rC)-binding protein 1]. We also found that the half-life of POLH mRNA was markedly decreased upon knockdown of PCBP1. Moreover, we found that PCBP1 directly bound to the POLH 3'-UTR and the PCBP1-binding site in POLH mRNA is an atypical AU-rich element. Finally, we showed that the AU-rich element in POLH 3'-UTR was responsive to PCBP1 and sufficient for PCBP1 to regulate POLH expression. Taken together, we uncovered a novel mechanism by which POLH expression is controlled by PCBP1 via mRNA stability.

RNPC1, an RNA-binding protein and a p53 target, regulates macrophage inhibitory cytokine-1 (MIC-1) expression through mRNA stability.

Macrophage inhibitory cytokine-1 (MIC-1), a secreted cytokine, is a direct target of p53 and known to play a role in cell proliferation, apoptosis, cell metastasis, and angiogenesis through autocrine and paracrine signaling. Previous studies have shown that serum levels of MIC-1 closely parallel cancer progression and are being explored as a diagnostic tool. MIC-1 has also shown potential as a therapeutic agent as it has exhibited several anti-carcinogenic activities. Thus, MIC-1 displays two opposing effects: tumor suppression versus promotion. However, it remains unclear whether MIC-1 is regulated by a mechanism other than transcription and how MIC-1 exerts its tumor suppression. In this study, we show that overexpression of RNA-binding protein RNPC1 can increase, whereas knockdown or knock-out of RNPC1 decreases, MIC-1 transcript and protein levels. Additionally, we demonstrate that RNPC1 can bind to MIC-1 mRNA via an AU-rich element within MIC-1 3'-UTR and then enhances MIC-1 mRNA stability. Finally, to explore the functional significance of MIC-1, we showed that knockdown of MIC-1 can decrease RNPC1-induced cell growth suppression. Altogether, we uncover a novel mechanism by which MIC-1 can be regulated through RNPC1 via mRNA stability.

Effect of pH-shifting on the water holding capacity and gelation properties of mung bean protein isolate.

In this study, alkaline pH-shifting modified the globular structure of mung bean protein isolate (MBPI) to form flexible and stretched structures. In contrast, acidic pH-shifting increased the rigidity of MBPI. The increased flexibility (at the level of the secondary structure) and newly exposed intermolecular amino acid groups induced by alkaline pH-shifting improved the water holding capacity and gelation properties of proteins. Specifically, MBPI treated at pH 12 (MP12) showed the most flexible structure and highest water holding capacity and gel formation properties (least gelation concentration). The water-holding capacity of native MBPI increased from 1.56 g/g to 4.81 g/g, and its least gelation concentration decreased from 22 % to 15 % by pH-shifting at pH 12. Furthermore, MP12 formed stronger and more elastic heat-induced gels than native MBPI. We identified significant differences in the structural properties and water holding capacity, and gelation properties of acidic and alkaline pH-shifted MBPI and investigated the gelation properties of MP12 including rheological and morphological analyses. Our findings can facilitate the use of mung beans as a protein source in a wide range of food applications, including plant-based and processed meats.

Preventive and therapeutic effects of low-dose whole-body irradiation on collagen-induced rheumatoid arthritis in mice.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive joint inflammation, resulting in cartilage destruction and bone erosion. It was reported that low-dose radiation modulates immune disease. Here, we investigated whether low-dose whole-body irradiation has preventive and therapeutic effects in collagen-induced RA (CIA) mouse models. Fractionated low-dose irradiation (0.05 Gy/fraction, total doses of 0.1, 0.5 or 0.8 Gy) was administered either concurrently with CIA induction by Type II collagen immunization (preventive) or after CIA development (therapeutic). The severity of CIA was monitored using two clinical parameters, paw swelling and redness. We also measured total Immunoglobulin G (IgG) and inflammatory cytokines (interleukine (IL)-6, IL-1ß and tumor necrosis factor-alpha (TNF-α)) in the serum by enzyme-linked immunosorbent assay, and we evaluated histological changes in the ankle joints by immunohistochemistry and hematoxylin and eosin staining. Low-dose irradiation reduced CIA clinical scores by up to 41% in the preventive model and by 28% in the therapeutic model, while irradiation in the preventive model reduced the typical CIA incidence rate from 82 to 56%. In addition, low-dose irradiation in the preventive model decreased total IgG by up to 23% and decreased IL-1ß and TNF-α by 69 and 67%, and in the therapeutic model, decreased total IgG by up to 35% and decreased IL-1ß and IL-6 by 59 and 42% with statistical significance (P < 0.01, 0.05 and 0.001). Our findings demonstrate that low-dose radiation has preventive and therapeutic anti-inflammatory effects against CIA by controlling the immune response, suggesting that low-dose radiation may represent an alternative therapy for RA, a chronic degenerative immune disease.

The RNA-binding protein RNPC1 stabilizes the mRNA encoding the RNA-binding protein HuR and cooperates with HuR to suppress cell proliferation.

The RNA-binding protein HuR, a member of the embryonic lethal abnormal vision/Hu protein family, plays a critical role in many cellular processes, including cell proliferation, angiogenesis, and inflammatory response. Despite significant progresses in understanding how HuR functions, the mechanism by which HuR expression is controlled is still poorly understood. Here, we showed that RNA-binding protein RNPC1 post-transcriptionally regulates HuR expression via mRNA stability. Specifically, we showed that overexpression of RNPC1 increases, whereas knockdown or knock-out of RNPC1 decreases, the level of HuR transcript and protein. Moreover, we showed that RNPC1, but not mutant RNPC1 deficient in RNA binding, stabilizes HuR transcript via binding to its 3'-untranslated region. Furthermore, to determine the biological significance of RNPC1-enhanced HuR expression, we showed that HuR, by repressing c-Myc expression, facilitates RNPC1-mediated growth suppression. Together, we have uncovered a novel mechanism by which HuR is regulated by RNPC1 via mRNA stability and HuR is a mediator of RNPC1-induced growth suppression.

The cyclin-dependent kinase inhibitor p21 is regulated by RNA-binding protein PCBP4 via mRNA stability.

RNA-binding proteins (RBPs) play a major role in many post-transcriptional processes, including mRNA stability, alternative splicing and translation. PCBP4, also called MCG10, is an RBP belonging to the poly(C)-binding protein family and a target of p53 tumor suppressor. Ectopic expression of PCBP4 induces cell-cycle arrest in G2 and apoptosis. To identify RNA targets regulated by PCBP4 and further decipher its function, we generated multiple cell lines in which PCBP4 is either inducibly over-expressed or knocked down. We found that PCBP4 expression decreases cyclin-dependent kinase inhibitor p21 induction in response to DNA damage. We also provided evidence that PCBP4 regulates p21 expression independently of p53. In addition, we showed that a deficiency in PCBP4 enhances p21 induction upon DNA damage. To validate PCBP4 regulation of p21, we made PCBP4-deficient mice and showed that p21 expression is markedly increased in PCBP4-deficient primary mouse embryo fibroblasts compared to that in wild-type counterparts. Finally, we uncovered that PCBP4 binds to the 3'-UTR of p21 transcript in vitro and in vivo to regulate p21 mRNA stability. Taken together, we revealed that PCBP4 regulates both basal and stress-induced p21 expression through binding p21 3'-UTR and modulating p21 mRNA stability.

Effect of Microbial Transglutaminase Treatment on the Techno-Functional Properties of Mung Bean Protein Isolate.

The purpose of this study was to investigate the improvement in techno-functional properties of mung bean protein isolate (MBPI) treated with microbial transglutaminase (MTG), including water- and oil-holding capacity, gelling properties, and emulsifying capacity. MBPI dispersions were incubated with MTG (5 U/g of protein substrate) at 45 °C with constant stirring for 4 h (MTM4) or 8 h (MTM8). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that MTG treatment for different durations increased the amount of high-molecular-weight proteins in MBPI, and most of the cross-linking by MTG was terminated at 8 h. Improved water-holding capacity, gelling properties, emulsifying capacity, and stability were observed after MTG treatment, and decreased protein solubility and surface hydrophobicity were observed. Furthermore, the texture of the heat-induced gels made from MTG-treated MBPI was evaluated using a texture analyzer. MTG treatment increased the hardness, gumminess, chewiness, and adhesiveness of the heat-induced gels. Field-emission scanning electron microscopy demonstrated the enhanced hardness of the gels. This research reveals that MTG-catalyzed cross-linking may adjust the techno-functional properties of MBPI, allowing it to be used as a soy protein alternative in food products, such as plant-based and processed meats.

Physicochemical and functional properties of capsaicin loaded cricket protein isolate and alginate complexes.

As people become more aware of the health benefits of foods and their nutritional benefits for preventing diseases and promoting health, the demand for functional foods rich in proteins, fiber, and bioactives like capsaicin (CAP) is constantly rising. This study hypothesized that the electrostatic complexes developed by cricket protein isolate (CPI) and alginate (AL) could be utilized to encapsulate CAP, making it more water-soluble and protecting it at acidic pHs. Quantitative analysis revealed that CAP was efficiently encapsulated into the CPI-AL complexes with a maximum encapsulation efficiency of 91%, improving its aqueous solubility 45-fold. In vitro release tests showed that CAP was retained at acidic pHs (3.0 and 5.0) in CPI-AL complexes but released steadily at neutral pH (7.4), which will protect CAP in the stomach while enabling its release in the small intestine. Moreover, the antioxidant activity of CAP-CPI-AL complexes was superior to that of their individual bare equivalents. The complexes also demonstrated enhanced emulsifying capabilities and stability at acidic pHs (2.0-5.0) as the CPI fraction in the complexes increased. Our findings thus contribute to the growing body of knowledge that validates protein-polysaccharide complexation as a promising strategy for developing edible delivery systems.

Low-dose RaDiation therapy for patients with KNee osteoArthritis (LoRD-KNeA): a protocol for a sham-controlled randomised trial.

INTRODUCTION: Low-dose radiation therapy (LDRT) for osteoarthritis (OA) has been performed for several decades. However, supporting evidence from randomised studies using modern methodologies is lacking, and a recently published randomised study failed to show the significant benefit of LDRT. The presented trial aims to evaluate the efficacy and safety of LDRT for patients with knee OA. METHODS AND ANALYSIS: This prospective, multicentre, randomised trial will be conducted in the Republic of Korea. A total of 114 participants will be randomly assigned (1:1:1) to receive sham irradiation, 0.3 Gy/6 fractions of LDRT or 3 Gy/6 fractions of LDRT. Key inclusion criteria are primary knee OA with Kellgren-Lawrence grade 2-3 and visual analogue scale 50-90 when walking at the baseline. The primary endpoint is the rate of responders at 4 months after LDRT according to the OARSI-OMERACT criteria. Concomitant use of analgesics is prohibited until the primary efficacy evaluation is scheduled. ETHICS AND DISSEMINATION: Currently, approval from the Ministry of Food and Drug Safety of the Republic of Korea and the institutional review board of each participating hospital has been obtained. Patient enrolment began in October 2022 and is ongoing at three participating sites. The results will be disseminated to academic audiences and the public via publication in an international peer-reviewed journal and presentation at conferences. This trial will provide valuable information on the safety and efficacy of LDRT for patients with knee OA. TRIAL REGISTRATION NUMBER: NCT05562271.

Evaluation of Efficacy and Safety Using Low Dose Radiation Therapy with Alzheimer's Disease: A Protocol for Multicenter Phase II Clinical Trial.

BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disease resulting from extracellular and intracellular deposits of amyloid-ß (Aß) and neurofibrillary tangles in the brain. Although many clinical studies evaluating pharmacological approaches have been conducted, most have shown disappointing results; thus, innovative strategies other than drugs have been actively attempted. OBJECTIVE: This study aims to explore low-dose radiation therapy (LDRT) for the treatment of patients with AD based on preclinical evidence, case reports, and a small pilot trial in humans. METHODS: This study is a phase II, multicenter, prospective, single-blinded, randomized controlled trial that will evaluate the efficacy and safety of LDRT to the whole brain using a linear accelerator in patients with mild AD. Sixty participants will be randomly assigned to three groups: experimental I (24 cGy/6 fractions), experimental II (300 cGy/6 fractions), or sham RT group (0 cGy/6 fractions). During LDRT and follow-up visits after LDRT, possible adverse events will be assessed by the physician's interview and neurological examinations. Furthermore, the effectiveness of LDRT will be measured using neurocognitive function tests and imaging tools at 6 and 12 months after LDRT. We will also monitor the alterations in cytokines, Aß42/Aß40 ratio, and tau levels in plasma. Our primary endpoint is the change in cognitive function test scores estimated by the Alzheimer's Disease Assessment Scale-Korea compared to baseline after 6 months of LDRT. CONCLUSIONS: This study is registered at ClinicalTrials.gov [NCT05635968] and is currently recruiting patients. This study will provide evidence that LDRT is a new treatment strategy for AD.

Mutant p53 protein is targeted by arsenic for degradation and plays a role in arsenic-mediated growth suppression.

p53 is frequently mutated in tumor cells, and mutant p53 is often highly expressed due to its increased half-life. Thus, targeting mutant p53 for degradation might be explored as a therapeutic strategy to manage tumors that are addicted to mutant p53 for survival. Arsenic trioxide, a drug for patients with acute promyelocytic leukemia, is found to target and degrade a class of proteins with high levels of cysteine residues and vicinal thiol groups, such as promyelocytic leukemia protein (PML) and PML-retinoic acid receptor α fusion protein. Interestingly, wild type p53 is accumulated in cells treated with arsenic compounds, presumably due to arsenic-induced oxidative stresses. In this study, we found that wild type p53 is induced by arsenic trioxide in tumor cells, consistent with published studies. In contrast, we found that arsenic compounds degrade both endogenous and ectopically expressed mutant p53 in time- and dose-dependent manners. We also found that arsenic trioxide decreases the stability of mutant p53 protein through a proteasomal pathway, and blockage of mutant p53 nuclear export can alleviate the arsenic-induced mutant p53 degradation. Furthermore, we found that knockdown of endogenous mutant p53 sensitizes, whereas ectopic expression of mutant p53 desensitizes, tumor cells to arsenic treatment. Taken together, we found that mutant p53 is a target of arsenic compounds, which provides an insight into exploring arsenic compound-based therapy for tumors harboring a mutant p53.