Mediterranean diet in the targeted prevention and personalized treatment of chronic diseases: evidence, potential mechanisms, and prospects.

The prevalence of chronic diseases is currently a major public health issue worldwide and is exploding with the population growth and aging. Dietary patterns are well known to play a important role in our overall health and well-being, and therefore, poor diet and malnutrition are among the most critical risk factors for chronic disease. Thus, dietary recommendation and nutritional supplementation have significant clinical implications for the targeted treatment of some of these diseases. Multiple dietary patterns have been proposed to prevent chronic disease incidence, like Dietary Approaches to Stop Hypertension (DASH) and Diabetes Risk Reduction Diet (DRRD). Among them, the MedDiet, which is one of the most well-known and studied dietary patterns in the world, has been related to a wide extent of health benefits. Substantial evidence has supported an important reverse association between higher compliance to MedDiet and the risk of chronic disease. Innovative strategies within the healthcare framework of predictive, preventive, and personalized medicine (PPPM/3PM) view personalized dietary customization as a predictive medical approach, cost-effective preventive measures, and the optimal dietary treatment tailored to the characteristics of patients with chronic diseases in primary and secondary care. Through a comprehensive collection and review of available evidence, this review summarizes health benefits of MedDiet in the context of PPPM/3PM for chronic diseases, including cardiovascular disease, hypertension, type 2 diabetes, obesity, metabolic syndrome, osteoporosis, and cancer, thereby a working hypothesis that MedDiet can personalize the prevention and treatment of chronic diseases was derived.

The mir-199b-5p encapsulated in adipocyte-derived exosomes mediates radioresistance of colorectal cancer cells by targeting JAG1.

Radiotherapy is a key treatment option for colorectal cancer, but its efficacy varies among patients. Our previous studies suggested that adipose tissue may confer the radioresistance of several abdominal tumors, such as pancreatic cancer, biliary cancer, and others. In the present work, the effects of adipocytes in regulating the radiosensitivity of colorectal cancer are explored for the first time. It was found that colony formation was increased and radiation-induced apoptosis decreased in colorectal cancer cells HCT8 and HCT116 co-cultured with adipocytes, which verified the mediation of adipocyte-driven radioresistance in colorectal cancer in vitro. Next, the colorectal cancer cells were incubated with adipocyte-derived exosomes, and a perceptible reduction in radiosensitivity was detected. Furthermore, to investigate the possible mechanisms involved, the exosomes were isolated, the encapsulated microRNAs were extracted and analyzed by small RNA sequencing. Based on bioinformatics analysis and qRT-PCR verification, miR-199b-5p was chosen for functional annotation. It was shown that miR-199b-5p expression was significantly upregulated after 6 Gy irradiation, and overexpressed miR-199b-5p significantly suppressed the radiosensitivity of HCT8 and HCT116 cells. In addition, jagged canonical Notch ligand 1(JAG1) was identified as the target gene of miR-199b-5p by using bioinformatics prediction and dual luciferase reporter gene assay. It was demonstrated that JAG1 conferred the radioresistance of colorectal cancer cells both in vivo and in vitro. Taken together, the present study demonstrates that adipocytes trigger the radioresistance of colorectal cancer cells, probably by targeting JAG1 through an adipocyte-derived exosomal miR-199b-5p.

Mediterranean diet affects the metabolic outcome of metabolic dysfunction-associated fatty liver disease.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is on the rise globally. It is currently one of the most prevalent liver diseases and one of the world's important public health problems. At present, there is no consensus on a pharmacological treatment for MAFLD. By contrast, lifestyle interventions based on exercise and a balanced diet are considered to be the cornerstone of MAFLD management. Mediterranean diet (MD) have a large content of polyphenols, polyunsaturated fatty acids, oleic acid, carotenoids and fiber, which carry out antioxidant, anti-inflammatory and antibacterial benefits. It has been considered to reduce the incidence rate of cardiovascular disease and type 2 diabetes. The purpose of this narrative review is therefore to summarize and analyze the evidence for the effect of MD on metabolic outcomes in MAFLD patients.

Activated Beta-Catenin Signaling Ameliorates Radiation-Induced Skin Injury by Suppressing Marvel D3 Expression.

Radiation-induced skin injury remains a serious concern for cancer radiotherapy, radiation accidents and occupational exposure, and the damage mainly occurs due to apoptosis and reactive oxygen species (ROS) generation. There is currently no effective treatment for this disorder. The ß-catenin signaling pathway is involved in the repair and regeneration of injured tissues. However, the role of the ß-catenin signaling pathway in radiation-induced skin injury has not been reported. In this study, we demonstrated that the ß-catenin signaling pathway was activated in response to radiation and that its activation by Wnt3a, a ligand-protein involved in the ß-catenin signaling pathway, inhibited apoptosis and the production of ROS in irradiated human keratinocyte HaCaT cells and skin fibroblast WS1 cells. Additionally, Wnt3a promoted cell migration after irradiation. In a mouse model of full-thickness skin wounds combined with total-body irradiation, Wnt3a was shown to facilitate skin wound healing. The results from RNA-Seq revealed that 24 genes were upregulated and 154 were downregulated in Wnt3a-treated irradiated skin cells, and these dysregulated genes were mainly enriched in the tight junction pathway. Among them, Marvel D3 showed the most obvious difference. We further found that the activated ß-catenin signaling pathway stimulated the phosphorylation of JNK by silencing Marvel D3. Treatment of irradiated cells with SP600125, a JNK inhibitor, augmented ROS production and impeded cell migration. Furthermore, treatment with Wnt3a or transfection with Marvel D3-specific siRNAs could reverse the above effects. Taken together, these findings illustrate that activated ß-catenin signaling stimulates the activation of JNK by negatively regulating Marvel D3 to ameliorate radiation-induced skin injury.

Alteration of Metal Elements in Radiation Injury: Radiation-Induced Copper Accumulation Aggravates Intestinal Damage.

Ionizing radiation causes damage to a variety of tissues, especially radiation-sensitive tissues, such as the small intestine. Radiation-induced damage is caused primarily by increased oxidative stress in the body. Studies have shown that trace metal elements play an irreplaceable role in oxidative stress in humans, which may be associated with radiation-induced tissue damage. However, the alteration and functional significance of trace metal elements in radiation-induced injury is not clear. In this study, we explored the association between radiation-induced damage and 7 trace metal elements in mouse models. We found that the concentration of zinc and copper in mice serum was decreased significantly after irradiation, whereas that of nickel, manganese, vanadium, cobalt, and stannum was not changed by inductively coupled plasma mass spectrometry. The role of copper in radiation-induced intestines was characterized in detail. The concentration of copper was increased in irradiated intestine but reduced in irradiated heart. Immunohistochemistry staining showed that copper transporter protein copper transport 1 expression was upregulated in irradiated mouse intestine, suggesting its potential involvement in radiation-induced copper accumulation. At the cellular level, the addition of CuCl2 potentiated radiation-induced reactive oxygen species in intestine-derived human intestinal epithelial cell and IEC-6 cells. Moreover, the level of copper in damaged cells may be related to the severity of radiation-induced damage as evidenced by a cell viability assay. These results indicate that copper may be involved in the progression of radiation-induced tissue damage and may be a potential therapeutic target.

Ionizing radiation induces cutaneous lipid remolding and skin adipocytes confer protection against radiation-induced skin injury.

BACKGROUND: Radiation-induced skin injury is a serious concern during radiotherapy and radiation accidents. Skin fat represents the dominant architectural component of the human skin. However, the interplay between skin fat and the progression of radiation-induced skin injury remains largely unexplored. OBJECTIVE: This study aims to elucidate the interplay between skin fat and the progression of radiation-induced skin injury. METHODS: SD rats were irradiated with an electron beam. mRNA profiles were determined by RNA-Seq. The skin lipid mass was monitored by magnetic resonance imaging (MRI) and lipid profiles were measured by liquid chromatography-mass spectrometry (LC-MS). Human mature adipocytes isolated from dermal and subcutaneous white adipose tissues (WATs) were co-cultured with human keratinocytes (HaCaT) and skin fibroblasts (WS1) in the transwell culture system. Cell migration ability was measured by migration assay. RESULTS: Radiation modulated cutaneous lipid metabolism by downregulating multiple pathways. Moreover, radiation decreased skin fat mass with altered lipid metabolite profiles. The rats fed with a high-fat diet showed resistance to radiogenic skin injury compared with that with a control diet, indicating that skin lipid plays a radioprotective role. Mature adipocytes promoted the migration but not the proliferation of co-cultured skin keratinocytes and fibroblasts. Palmitic acid, the most abundant fatty acid in skin tissues, facilitated the migration of WS1 cells. Moreover, fatty acid-binding protein 4 (FABP4) could be incorporated into skin cells and promote DNA damage repair in irradiated skin fibroblasts. CONCLUSION: Radiation induces cutaneous lipid remolding, and skin adipocytes confer a protective role against radiation-induced skin injury.

The Involvement of SDF-1α/CXCR4 Axis in Radiation-Induced Acute Injury and Fibrosis of Skin.

Radiation-induced acute skin injury and consequent fibrosis are common complications of cancer radiotherapy and radiation accidents. Stromal cell-derived factor-1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4) have been shown to be involved in multiple cellular events. However, the role of SDF-1α/CXCR4 axis in radiation-induced acute injury and fibrosis of skin has not been reported. In this study, we found that the expression of SDF-1α and CXCR4 was significantly increased in irradiated skin tissues of humans, monkeys and rats, compared to their nonirradiated counterparts. Mice with keratinocyte-specific ablation of CXCR4 showed less severe skin damage than wild-type mice after receiving a 35 Gy dose of radiation. Consistently, subcutaneous injection of AMD3100, an FDA approved SDF-1α/CXCR4 inhibitor, attenuated skin injury and fibrosis induced by exposure to radiation in a rat model. Mechanically, the SDF-1α/CXCR4 axis promotes pro-fibrotic TGF-b/Smad signaling through the PI3K-MAPK signaling cascade in human keratinocyte HaCaT cells and skin fibroblast WS1 cells. AMD3100 inhibited Smad2 nuclear translocation and transcriptional activity of Smad2/3 induced by radiation, which suppressed the pro-fibrotic TGF-b/Smad signaling pathway activated by exposure. Taken together, these findings demonstrate the involvement of SDF-1α/CXCR4 axis in radiation-induced acute injury and fibrosis of skin, and indicate that AMD3100 would be an effective countermeasure against these diseases.

Overexpression of Peroxiredoxin 6 (PRDX6) Promotes the Aggressive Phenotypes of Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. Peroxiredoxin 6 (PRDX6), a member of peroxidase superfamily, has a function of eliminating the reactive oxygen species (ROS), and participates in development of multiple diseases, including tumors. The purpose of this study was to investigate the expression of PRDX6 in normal and cancerous esophageal tissues and to characterize its role in ESCC progression. We found significantly higher expression of PRDX6 in ESCC tissues than in normal esophageal tissues or tumor-adjacent tissues and that the PRDX6 expression level was positively correlated with the proliferation-related markers. In ESCC cells, PRDX6 distribution was more pronounced in the nucleus region. PRDX6 overexpression by an adenovirus significantly promoted cell proliferation, migration and invasion in TE-1 and Eca-109 cells. Conversely, lentivirus-mediated knock-down of PRDX6 expression significantly reduced cell growth, colony formation and metastasis in ESCC cells. PRDX6 modulated the phosphorylation of Akt and Erk1/2, and the expression of MMP2. We also found that PRDX6 and Erk1/2 pathway were mutually regulated in ESCC cells. In addition, PRDX6 overexpression eliminated radiation-induced ROS and decreased consequent cell apoptosis, indicative of a role in radioresistance. Finally, the role of PRDX6 in promoting tumor growth was further confirmed in nude mice with ESCC xenografts. Taken together, we demonstrated that overexpression of PRDX6 promotes the progression of ESCC through Erk1/2, which provides a potential therapeutic target for human ESCC.