CXCL10 upregulation in radiation-exposed human peripheral blood mononuclear cells as a candidate biomarker for rapid triage after radiation exposure.

PURPOSE: In case of a nuclear accident, individuals with high-dose radiation exposure (>1-2 Gy) should be rapidly identified. While ferredoxin reductase (FDXR) was recently suggested as a radiation-responsive gene, the use of a single gene biomarker limits radiation dose assessment. To overcome this limitation, we sought to identify reliable radiation-responsive gene biomarkers. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from mice after total body irradiation, and gene expression was analyzed using a microarray approach to identify radiation-responsive genes. RESULTS: In light of the essential role of the immune response following radiation exposure, we selected several immune-related candidate genes upregulated by radiation exposure in both mouse and human PBMCs. In particular, the expression of ACOD1 and CXCL10 increased in a radiation dose-dependent manner, while remaining unchanged following lipopolysaccharide (LPS) stimulation in human PBMCs. The expression of both genes was further evaluated in the blood of cancer patients before and after radiotherapy. CXCL10 expression exhibited a distinct increase after radiotherapy and was positively correlated with FDXR expression. CONCLUSIONS: CXCL10 expression in irradiated PBMCs represents a potential biomarker for radiation exposure.

StemRegenin 1 Mitigates Radiation-Mediated Hematopoietic Injury by Modulating Radioresponse of Hematopoietic Stem/Progenitor Cells.

Hematopoietic injury resulting from the damage of hematopoietic stem/progenitor cells (HSPCs) can be induced by either nuclear accident or radiotherapy. Radiomitigation of HSPCs is critical for the development of medical countermeasure agents. StemRegenin 1 (SR1) modulates the maintenance and function of HSPCs under non-stress conditions. However, the impact of SR1 in radiation-induced hematopoietic injury both in vivo and in vitro remains unknown. In this study, we found that treatment with SR1 after irradiation of C57BL/6 mice significantly mitigates TBI-induced death (80% of SR1-treated mice survival vs. 30% of saline-treated mice survival) with enhanced recovery of peripheral blood cell counts, with the density and cell proliferation of bone marrow components as observed by Hematoxylin and Eosin (H&E) and Ki-67 staining. Interestingly, in vitro analysis of human HSPCs showed that SR1 enhanced the population of human HSPCs (CD34+) under both non-irradiating and irradiating conditions, and reduced radiation-induced DNA damage and apoptosis. Furthermore, SR1 attenuated the radiation-induced expression of a member of the pro-apoptotic BCL-2 family and activity of caspase-3. Overall, these results suggested that SR1 modulates the radioresponse of HSPCs and might provide a potential radiomitigator of hematopoietic injury, which contributes to increase the survival of patients upon irradiation.

ABCA1-Mediated EMT Promotes Papillary Thyroid Cancer Malignancy through the ERK/Fra-1/ZEB1 Pathway.

Papillary thyroid cancer (PTC) is the most prevalent histological type of thyroid cancer (TC) worldwide. Although tumor metastasis occurs in regional lymph nodes, distant metastasis (DM) may also occur. Radioactive iodine (RAI) therapy is an effective treatment for TC; however, resistance to RAI occurs in patients with DM. Therefore, in this study, we investigated the efficacy of DM-related biomarkers as therapeutic targets for PTC therapy. ABCA1 expression was higher in aggressive BCPAP cells than in other PTC cells in terms of migration and invasion capacity. The knockdown of ABCA1 substantially decreased the expression of the epithelial-mesenchymal transition (EMT) marker, N-cadherin, and EMT regulator (ZEB1), resulting in suppressed migration and invasion of BCPAP cells. ABCA1 knockdown also reduced ERK activity and Fra-1 expression, which correlated with the effects of an ERK inhibitor or siRNA-mediated inhibition of ERK or Fra-1 expression. Furthermore, ABCA1-knocked-down BCPAP cells suppressed cell migration and invasion by reducing Fra-1 recruitment to Zeb1 promoter; lung metastasis was not observed in mice injected with ABCA1-knocked-down cells. Overall, our findings suggest that ABCA1 regulates lung metastasis in TC cells.

Combined Administration of Pravastatin and Metformin Attenuates Acute Radiation-Induced Intestinal Injury in Mouse and Minipig Models.

Radiation-induced gastrointestinal (GI) damage is one of the critical factors that serve as basis for the lethality of nuclear accidents or terrorism. Further, there are no Food and Drug Administration-approved agents available to mitigate radiation-induced intestinal injury. Although pravastatin (PS) has been shown to exhibit anti-inflammatory and epithelial reconstructive effects following radiation exposure using mouse and minipig models, the treatment failed to improve the survival rate of high-dose irradiated intestinal injury. Moreover, we previously found that metformin (MF), a common drug used for treating type 2 diabetes mellitus, has a mitigating effect on radiation-induced enteropathy by promoting stem cell properties. In this study, we investigated whether the combined administration of PS and MF could achieve therapeutic effects on acute radiation-induced intestinal injury in mouse and minipig models. We found that the combined treatment markedly increased the survival rate and attenuated histological damage in a radiation-induced intestinal injury mouse model, in addition to epithelial barrier recovery, anti-inflammatory effects, and improved epithelial proliferation with stem cell properties. Furthermore, in minipig models, combined treatment with PS and MF ameliorates gross pathological damage in abdominal organs and attenuated radiation-induced intestinal histological damage. Therefore, the combination of PS and MF effectively alleviated radiation-induced intestinal injury in the mouse and minipig models. We believe that the combined use of PS and MF is a promising therapeutic approach for treating radiation-induced intestinal injury.

Centella asiatica-Derived Endothelial Paracrine Restores Epithelial Barrier Dysfunction in Radiation-Induced Enteritis.

Radiation-induced enteritis is frequently observed following radiotherapy for cancer or occurs due to radiation exposure in a nuclear accident. The loss of the epithelial integrity leads to 'leaky gut', so recovery of damaged epithelium is an important strategy in therapeutic trials. Centella asiatica (CA), a traditional herbal medicine, is widely used for wound healing by protecting against endothelial damage. In this study, we investigated the radio-mitigating effect of CA, focusing on the crosstalk between endothelial and epithelial cells. CA treatment relieved radiation-induced endothelial dysfunction and mitigated radiation-induced enteritis. In particular, treatment of the conditioned media from CA-treated irradiated endothelial cells recovered radiation-induced epithelial barrier damage. We also determined that epidermal growth factor (EGF) is a critical factor secreted by CA-treated irradiated endothelial cells. Treatment with EGF effectively improved the radiation-induced epithelial barrier dysfunction. We also identified the therapeutic effects of CA-induced endothelial paracrine in a radiation-induced enteritis mouse model with epithelial barrier restoration. Otherwise, CA treatment did not show radioprotective effects on colorectal tumors in vivo. We showed therapeutic effects of CA on radiation-induced enteritis, with the recovery of endothelial and epithelial dysfunction. Thus, our findings suggest that CA is an effective radio-mitigator against radiation-induced enteritis.

Zileuton Alleviates Radiation-Induced Cutaneous Ulcers via Inhibition of Senescence-Associated Secretory Phenotype in Rodents.

Radiation-induced cutaneous ulcers are a challenging medical problem for patients receiving radiation therapy. The inhibition of cell senescence has been suggested as a prospective strategy to prevent radiation ulcers. However, there is no effective treatment for senescent cells in radiation ulcers. In this study, we investigated whether zileuton alleviated radiation-induced cutaneous ulcer by focusing on cell senescence. We demonstrate increased cell senescence and senescence-associated secretory phenotype (SASP) in irradiated dermal fibroblasts and skin tissue. The SASP secreted from senescent cells induces senescence in adjacent cells. In addition, 5-lipoxygenase (5-LO) expression increased in irradiated dermal fibroblasts and skin tissue, and SASP and cell senescence were regulated by 5-LO through p38 phosphorylation. Finally, the inhibition of 5-LO following treatment with zileuton inhibited SASP and mitigated radiation ulcers in animal models. Our results demonstrate that inhibition of SASP from senescent cells by zileuton can effectively mitigate radiation-induced cutaneous ulcers, indicating that inhibition of 5-LO might be a viable strategy for patients with this condition.

Potential Method to Distinguish Copper Molten Marks Using Boundary and Grain Characteristics.

The microstructure of molten marks changes according to ambient temperatures, when a short circuit occurs. Investigation of microstructural changes is important for understanding the properties of copper and examining the cause of a fire. In this study, the boundary characteristics and grain-size distribution of molten marks-primary-arc beads (PABs), which short-circuited at room temperature (25 °C), and secondary-arc beads (SABs), which short-circuited at high temperatures (600 °C, 900 °C)-were compared using electron backscatter diffraction. The distribution of Σ3 boundaries was compared, and it was found that SABs have a higher fraction of Σ3 boundaries than PABs. Moreover, it was confirmed that the ratio of maximum grain size (area) to the total area of the molten mark in SABs is larger than that in PABs. Thus, reliable discriminant factors were suggested, such as the fraction of Σ3 boundaries and normalized maximum grain size, which can distinguish PABs and SABs. The four discriminant factors, such as the (001)//LD, GAR, fraction of Σ3 boundaries, and fraction of maximum grain size to the total molten-mark area, were verified using the machine learning of t-SNE and Pearson correlation analyses.

Metformin Protects the Intestinal Barrier by Activating Goblet Cell Maturation and Epithelial Proliferation in Radiation-Induced Enteropathy.

Radiotherapy or accidental exposure to high-dose radiation can cause severe damage to healthy organs. The gastrointestinal (GI) tract is a radiation-sensitive organ of the body. The intestinal barrier is the first line of defense in the GI tract, and consists of mucus secreted by goblet cells and a monolayer of epithelium. Intestinal stem cells (ISCs) help in barrier maintenance and intestinal function after injury by regulating efficient regeneration of the epithelium. The Wnt/ß-catenin pathway plays a critical role in maintaining the intestinal epithelium and regulates ISC self-renewal. Metformin is the most widely used antidiabetic drug in clinical practice, and its anti-inflammatory, antioxidative, and antiapoptotic effects have also been widely studied. In this study, we investigated whether metformin alleviated radiation-induced enteropathy by focusing on its role in protecting the epithelial barrier. We found that metformin alleviated radiation-induced enteropathy, with increased villi length and crypt numbers, and restored the intestinal barrier function in the irradiated intestine. In a radiation-induced enteropathy mouse model, metformin treatment increased tight-junction expression in the epithelium and inhibited bacterial translocation to mesenteric lymph nodes. Metformin increased the number of ISCs from radiation toxicity and enhanced epithelial repair by activating Wnt/ß-catenin signaling. These data suggested that metformin may be a potential therapeutic agent for radiation-induced enteropathy.

Elimination of Reprogramming Transgenes Facilitates the Differentiation of Induced Pluripotent Stem Cells into Hepatocyte-like Cells and Hepatic Organoids.

Hepatocytes and hepatic organoids (HOs) derived from human induced pluripotent stem cells (hiPSCs) are promising cell-based therapies for liver diseases. The removal of reprogramming transgenes can affect hiPSC differentiation potential into the three germ layers but not into hepatocytes and hepatic organoids in the late developmental stage. Herein, we generated hiPSCs from normal human fibroblasts using an excisable polycistronic lentiviral vector based on the Cre recombinase-mediated removal of the loxP-flanked reprogramming cassette. Comparing the properties of transgene-carrying and transgene-free hiPSCs with the same genetic background, the pluripotent states of all hiPSCs were quite similar, as indicated by the expression of pluripotent markers, embryonic body formation, and tri-lineage differentiation in vitro. However, after in vitro differentiation into hepatocytes, transgene-free hiPSCs were superior to the transgene-residual hiPSCs. Interestingly, the generation and hepatic differentiation of human hepatic organoids (hHOs) were significantly enhanced by transgene elimination from hiPSCs, as observed by the upregulated fetal liver (CK19, SOX9, and ITGA6) and functional hepatocyte (albumin, ASGR1, HNF4α, CYP1A2, CYP3A4, and AAT) markers upon culture in differentiation media. Thus, the elimination of reprogramming transgenes facilitates hiPSC differentiation into hepatocyte-like cells and hepatic organoids with properties of liver progenitor cells. Our findings thus provide significant insights into the characteristics of iPSC-derived hepatic organoids.

Metallothionein 2 activation by pravastatin reinforces epithelial integrity and ameliorates radiation-induced enteropathy.

BACKGROUND: Radiotherapy or accidental exposure to ionizing radiation causes severe damage of healthy intestinal tissues. Intestinal barrier function is highly sensitive to ionizing radiation, and loss of epithelial integrity results in mucosal inflammation, bacterial translocation, and endotoxemia. Few studies have of epithelial integrity as a therapeutic target to treat radiation toxicity. Here, we examined the effects of pravastatin (PS) and the molecular mechanisms underlying epithelial integrity on radiation-induced enteropathy. METHODS: The radio-mitigative effects of PS were evaluated in a minipig model by quantifying clinical symptoms, and performing histological and serological analyses and mRNA sequencing in intestinal tissues. To evaluate the role of intercellular junctions on radiation damage, we used tight junction regulator and metallothionein 2 (MT2) as treatments in a mouse model of radiation-induced enteropathy. Caco-2 monolayers were used to examine functional epithelial integrityand intercellular junction expression. FINDING: Using a minipig model of pharmaceutical oral bioavailability, we found that PS mitigated acute radiation-induced enteropathy. PS-treated irradiated minipigs had mild clinical symptoms, lower intestinal inflammation and endotoxin levels, and improved gastrointestinal integrity, compared with control group animals. The results of mRNA sequencing analysis indicated that PS treatment markedly influenced intercellular junctions by inhibiting p38 MAPK signaling in the irradiated intestinal epithelium. The PS-regulated gene MT2 improved the epithelial barrier via enhancement of intercellular junctions in radiation-induced enteropathy. INTERPRETATION: PS regulated epithelial integrity by modulating MT2 in radiation-damaged epithelial cells. These findings suggested that maintenance of epithelial integrity is a novel therapeutic target for treatment of radiation-induced gastrointestinal damage. FUNDING: As stated in the Acknowledgments.

Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy.

Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.

Radiation-Activated PI3K/AKT Pathway Promotes the Induction of Cancer Stem-Like Cells via the Upregulation of SOX2 in Colorectal Cancer.

The current treatment strategy for patients with aggressive colorectal cancer has been hampered by resistance to radiotherapy and chemotherapy due to the existence of cancer stem-like cells (CSCs). Recent studies have shown that SOX2 expression plays an important role in the maintenance of CSC properties in colorectal cancer. In this study, we investigated the induction and regulatory role of SOX2 following the irradiation of radioresistant and radiosensitive colorectal cancer cells. We used FACS and western blotting to analyze SOX2 expression in cells. Among the markers of colorectal CSCs, the expression of CD44 increased upon irradiation in radioresistant cells. Further analysis revealed the retention of CSC properties with an upregulation of SOX2 as shown by enhanced resistance to radiation and metastatic potential in vitro. Interestingly, both the knockdown and overexpression of SOX2 led to increase in CD44+ population and induction of CSC properties in colorectal cancer following irradiation. Furthermore, selective genetic and pharmacological inhibition of the PI3K/AKT pathway, but not the MAPK pathway, attenuated SOX2-dependent CD44 expression and metastatic potential upon irradiation in vitro. Our findings suggested that SOX2 regulated by radiation-induced activation of PI3K/AKT pathway contributes to the induction of colorectal CSCs, thereby highlighting its potential as a therapeutic target.

Ghrelin reverts intestinal stem cell loss associated with radiation-induced enteropathy by activating Notch signaling.

BACKGROUD: Exposure to high-dose radiation, such as after a nuclear accident or radiotherapy, elicits severe intestinal damage and is associated with a high mortality rate. In treating patients exhibiting radiation-induced intestinal dysfunction, countermeasures to radiation are required. In principle, the cellular event underlying radiation-induced gastrointestinal syndrome is intestinal stem cell (ISC) apoptosis in the crypts. High-dose irradiation induces the loss of ISCs and impairs intestinal barrier function, including epithelial regeneration and integrity. Notch signaling plays a critical role in the maintenance of the intestinal epithelium and regulates ISC self-renewal. Ghrelin, a hormone produced mainly by enteroendocrine cells in the gastrointestinal tract, has diverse physiological and biological functions. PURPOSE: We investigate whether ghrelin mitigates radiation-induced enteropathy, focusing on its role in maintaining epithelial function. METHODS: To investigate the effect of ghrelin in radiation-induced epithelial damage, we analyzed proliferation and Notch signaling in human intestinal epithelial cell. And we performed histological analysis, inflammatory response, barrier functional assays, and expression of notch related gene and epithelial stem cell using a mouse model of radiation-induced enteritis. RESULTS: In this study, we found that ghrelin treatment accelerated the reversal of radiation-induced epithelial damage including barrier dysfunction and defective self-renewing property of ISCs by activating Notch signaling. Exogenous injection of ghrelin also attenuated the severity of radiation-induced intestinal injury in a mouse model. CONCLUSION: These data suggest that ghrelin may be used as a potential therapeutic agent for radiation-induced enteropathy.

Evaluation of the radiation response and regenerative effects of mesenchymal stem cell-conditioned medium in an intestinal organoid system.

Intestinal organoids have recently emerged as an in vitro model relevant to the gut system owing to their recapitulation of the native intestinal epithelium with crypt-villus architecture. However, it is unclear whether intestinal organoids reflect the physiology of the in vivo stress response. Here, we systemically investigated the radiation response in organoids and animal models using mesenchymal stem cell-conditioned medium (MSC-CM), which contains secreted paracrine factors. Irradiated organoids exhibited sequential induction of viability loss and regrowth after irradiation (within 12 days), similar to the response of the native intestinal epithelium. Notably, treatment with MSC-CM facilitated the reproliferation of intestinal stem cells (ISCs) and restoration of damaged crypt-villus structures in both models. Furthermore, Wnt/Notch signaling pathways were commonly upregulated by MSC-CM, but not radiation, and pharmacologically selective inhibition of Wnt or Notch signaling attenuated the enhanced recovery of irradiated organoids, with increases in ISCs, following MSC-CM treatment. Interestingly, the expression of Wnt4, Wnt7a, and active ß-catenin was increased, but not notch family members, in MSC-CM-treated organoid after irradiation. Treatment of recombinant mouse Wnt4 and Wnt7a after irradiation improved to some extent intestinal epithelial regeneration both in vitro and in vivo. Overall, these results suggested that intestinal organoids recapitulated the physiological stress response of the intestinal epithelium in vivo. Thus, our findings provided important insights into the physiology of intestinal organoids and may contribute to the development of strategies to enhance the functional maturation of engineered organoids.

Pravastatin Alleviates Radiation Proctitis by Regulating Thrombomodulin in Irradiated Endothelial Cells.

Although radiotherapy plays a crucial in the management of pelvic tumors, its toxicity on surrounding healthy tissues such as the small intestine, colon, and rectum is one of the major limitations associated with its use. In particular, proctitis is a major clinical complication of pelvic radiotherapy. Recent evidence suggests that endothelial injury significantly affects the initiation of radiation-induced inflammation. The damaged endothelial cells accelerate immune cell recruitment by activating the expression of endothelial adhesive molecules, which participate in the development of tissue damage. Pravastatin, a cholesterol lowering drug, exerts persistent anti-inflammatory and anti-thrombotic effects on irradiated endothelial cells and inhibits the interaction of leukocytes and damaged endothelial cells. Here, we aimed to investigate the effects of pravastatin on radiation-induced endothelial damage in human umbilical vein endothelial cell and a murine proctitis model. Pravastatin attenuated epithelial damage and inflammatory response in irradiated colorectal lesions. In particular, pravastatin improved radiation-induced endothelial damage by regulating thrombomodulin (TM) expression. In addition, exogenous TM inhibited leukocyte adhesion to the irradiated endothelial cells. Thus, pravastatin can inhibit endothelial damage by inducing TM, thereby alleviating radiation proctitis. Therefore, we suggest that pharmacological modulation of endothelial TM may limit intestinal inflammation after irradiation.

Platelet-rich plasma improves the therapeutic efficacy of mesenchymal stem cells by enhancing their secretion of angiogenic factors in a combined radiation and wound injury model.

Delayed wound healing after radiation exposure can cause serious cutaneous damage, and its treatment is a major clinical challenge. Although mesenchymal stem cells (MSCs) have emerged as a promising therapeutic agent in regenerative medicine, they alone do not produce satisfactory effects in a combined radiation and wound injury (CRWI) model. Here, we investigated the therapeutic effect of combined umbilical cord blood-derived (UCB)-MSCs and platelet-rich plasma (PRP) treatment on wound healing in a CRWI mouse model. First, we assessed the release of cytokines from UCB-MSCs cultured with PRP and observed changes in the expression of angiogenic factors. The angiogenic paracrine factors from UCB-MSCs cultured with PRP were assessed in human umbilical vein endothelial cells (HUVECs). To assess therapeutic efficacy, UCB-MSCs and PRP were topically implanted into a CRWT mouse model. Vascular endothelial growth factor (VEGF), a pro-angiogenic growth factor, urokinase-type plasminogen activator and contributor to VEGF-induced signalling were more highly expressed in conditioned media of UCB-MSCs cultured with PRP than in that of UCB-MSCs alone. Furthermore, conditioned media of UCB-MSCs cultured with PRP increased the formation of tube-like structures in HUVECs. Co-treatment of UCB-MSCs and PRP in a CRWI mouse model increased the wound closure rate and angiogenesis compared with an untreated irradiated group. Moreover, increased expression of VEGF and CD31 were observed in the wound tissue of co-treated mice compared with untreated irradiated mice. PRP stimulates the release of angiogenic factors from UCB-MSCs, and combined therapy of UCB-MSCs and PRP improves regeneration efficacy by enhancing angiogenesis in a CRWI model.

Baicalein Mitigates Radiation-Induced Enteritis by Improving Endothelial Dysfunction.

Background and Aims: Radiation-induced intestinal injury occurred in application of radiotherapy for abdominal and pelvic cancers or in nuclear accidents. Radiation-induced enteritis may be considered an ideal model of gastrointestinal inflammation. The endothelium is a crucial component of inflammation, and the endothelial dysfunction following radiation exposure induces the intestinal proinflammatory response and progression of radiation enteritis. Baicalein (5,6,7-trihydroxyflavonoid) is a flavonoid from Scutellaria baicalensis used in oriental herbal medicine. Baicalein has been found to have multiple beneficial properties including antioxidant, anti-inflammatory, anti-allergic, and anti-cancer activities. Here, we investigated the therapeutic effects of baicalein on endothelial dysfunction in radiation-induced intestinal inflammation. Materials and Methods: We performed histological analysis, bacterial translocation, and intestinal permeability assays and also assessed infiltration of leukocytes and inflammatory cytokine expression using a mouse model of radiation-induced enteritis. In addition, to investigate the effect of baicalein in endothelial dysfunction, we analyzed endothelial-derived adherent molecules in human umbilical vein endothelial cells (HUVECs) and irradiated intestinal tissue. Results: Histological damage such as shortening of villi length and impaired intestinal crypt function was observed in the radiation-induced enteritis mouse model. Intestinal damage was attenuated in baicalein-treated groups with improvement of intestinal barrier function. Baicalein inhibited the expression of radiation-induced adherent molecules in HUVECs and intestine of irradiated mouse and decreased leukocyte infiltration in the radiation-induced enteritis. Conclusions: Baicalein could accelerate crypt regeneration via recovery of endothelial damage. Therefore, baicalein has a therapeutic effect on radiation-induced intestinal inflammation by attenuating endothelial damage.

Platelet-rich plasma activates AKT signaling to promote wound healing in a mouse model of radiation-induced skin injury.

BACKGROUND: The skin is impacted by every form of external radiation therapy. However, effective therapeutic options for severe, acute radiation-induced skin reactions are limited. Although platelet-rich plasma (PRP) is known to improve cutaneous wound healing, its effects in the context of high-dose irradiation are still poorly understood. METHODS: We investigated the regenerative functions of PRP by subjecting the dorsal skin of mice to local irradiation (40 Gy) and exposing HaCaT cells to gamma rays (5 Gy). The cutaneous benefits of PRP were gauged by wound size, histologic features, immunostains, western blot, and transepithelial water loss (TEWL). To assess the molecular effects of PRP on keratinocytes of healing radiation-induced wounds, we evaluated AKT signaling. RESULTS: Heightened expression of keratin 14 (K14) was documented in irradiated HaCaT cells and skin tissue, although the healing capacity of injured HaCaT cells declined. By applying PRP, this capacity was restored via augmented AKT signaling. In our mouse model, PRP use achieved the following: (1) healing of desquamated skin, acutely injured by radiation; (2) activated AKT signaling, improving migration and proliferation of K14 cells; (3) greater expression of involucrin in keratin 10 cells and sebaceous glands; and (4) reduced TEWL, strengthening the cutaneous barrier function. CONCLUSIONS: Our findings indicate that PRP enhances the functions of K14 cells via AKT signaling, accelerating the regeneration of irradiated skin. These wound-healing benefits may have merit in a clinical setting.

Effects of metformin and phenformin on apoptosis and epithelial-mesenchymal transition in chemoresistant rectal cancer.

Recurrence and chemoresistance in colorectal cancer remain important issues for patients treated with conventional therapeutics. Metformin and phenformin, previously used in the treatment of diabetes, have been shown to have anticancer effects in various cancers, including breast, lung and prostate cancers. However, their molecular mechanisms are still unclear. In this study, we examined the effects of these drugs in chemoresistant rectal cancer cell lines. We found that SW837 and SW1463 rectal cancer cells were more resistant to ionizing radiation and 5-fluorouracil than HCT116 and LS513 colon cancer cells. In addition, metformin and phenformin increased the sensitivity of these cell lines by inhibiting cell proliferation, suppressing clonogenic ability and increasing apoptotic cell death in rectal cancer cells. Signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling pathways were more activated in rectal cancer cells, and inhibition of signal transducer and activator of transcription 3 expression using an inhibitor or siRNA sensitized rectal cancer cells to chemoresistant by inhibition of the expression of antiapoptotic proteins, such as X-linked inhibitor of apoptosis, survivin and cellular inhibitor of apoptosis protein 1. Moreover, metformin and phenformin inhibited cell migration and invasion by suppression of transforming growth factor ß receptor 2-mediated Snail and Twist expression in rectal cancer cells. Therefore, metformin and phenformin may represent a novel strategy for the treatment of chemoresistant rectal cancer by targeting signal transducer and activator of transcription 3 and transforming growth factor-ß/Smad signaling.

Photobiomodulation Enhances the Angiogenic Effect of Mesenchymal Stem Cells to Mitigate Radiation-Induced Enteropathy.

Radiation-induced enteropathy remains a major complication after accidental or therapeutic exposure to ionizing radiation. Recent evidence suggests that intestinal microvascular damage significantly affects the development of radiation enteropathy. Mesenchymal stem cell (MSC) therapy is a promising tool to regenerate various tissues, including skin and intestine. Further, photobiomodulation (PBM), or low-level light therapy, can accelerate wound healing, especially by stimulating angiogenesis, and stem cells are particularly susceptible to PBM. Here, we explored the effect of PBM on the therapeutic potential of MSCs for the management of radiation enteropathy. In vitro, using human umbilical cord blood-derived MSCs, PBM increased proliferation and self-renewal. Intriguingly, the conditioned medium from MSCs treated with PBM attenuated irradiation-induced apoptosis and impaired tube formation in vascular endothelial cells, and these protective effects were associated with the upregulation of several angiogenic factors. In a mouse model of radiation-induced enteropathy, treatment with PBM-preconditioned MSCs alleviated mucosal destruction, improved crypt cell proliferation and epithelial barrier functions, and significantly attenuated the loss of microvascular endothelial cells in the irradiated intestinal mucosa. This treatment also significantly increased angiogenesis in the lamina propria. Together, we suggest that PBM enhances the angiogenic potential of MSCs, leading to improved therapeutic efficacy for the treatment of radiation-induced enteropathy.