Exposure to Progestin 17-OHPC Induces Gastrointestinal Dysfunction through Claudin 1 Suppression in Female Mice with Increased Anxiety-Like Behaviors.

INTRODUCTION: Progestin, commonly used in oral contraception and preventing preterm birth, elicits various off-target side effects on brain and gastrointestinal (GI) functions, yet the precise mechanisms remain elusive. This study aims to probe progestin's impact on GI function and anxiety-like behaviors in female mice. METHODS: Colon stem cells were utilized to explore the mechanism underlying progestin 17-hydroxyprogesterone caproate (17-OHPC)-mediated suppression of claudin-1 (CLDN1), crucial for epithelial integrity. Chromatin immunoprecipitation and luciferase assays identified potential progestin-response elements on the CLDN1 promoter, with subsequent assessment of oxidative stress and pro-inflammatory cytokine release. Manipulation of vitamin D receptor (VDR) or estrogen receptor ß (ERß) expression elucidated their roles in 17-OHPC-mediated effects. Intestine-specific VDR deficient mice were generated to evaluate 17-OHPC's impact on GI dysfunction and anxiety-like behaviors in female mice. Additionally, gene expression was analyzed in various brain regions, including the amygdala, hypothalamus, and hippocampus. RESULTS: Exposure to 17-OHPC suppressed CLDN1 expression via epigenetic modifications and VDR dissociation from the CLDN1 promoter. Furthermore, 17-OHPC intensified oxidative stress and proinflammatory cytokine release. VDR knockdown partly mimicked, while overexpression of either VDR or ERß partly restored 17-OHPC-mediated effects. Intestinal VDR deficiency partly mirrored 17-OHPC-induced GI dysfunction, with minimal impact on 17-OHPC-mediated anxiety-like behaviors. CONCLUSIONS: 17-OHPC suppresses CLDN1 expression through VDR, contributing to GI dysfunction in female mice, distinct from 17-OHPC-induced anxiety-like behaviors. This study reveals a new mechanism and potential negative impact of progestin exposure on the gastrointestinal tract, alongside inducing anxiety-like behaviors in female mice.

Prenatal exposure of diabetes and progestin-mediated autistic biomarker in peripheral blood mononuclear cells.

Despite the importance of early diagnosis and intervention, the diagnosis of autism spectrum disorders (ASDs) remains delayed as it is mostly based on clinical symptoms and abnormal behaviours appearing after 2 years of age. Identification of autistic markers remains a top priority in achieving an early and effective ASD diagnosis. We have previously reported that prenatal exposure of hormones or diabetes triggers epigenetic changes and oxidative stress, resulting in gene suppression with autism-like behaviours in offspring. Here, a potential biomarker for ASD diagnosis was established through gene analysis in peripheral blood mononuclear cells (PBMCs). The study from in vivo mouse showed that prenatal hormone exposure or maternal diabetes suppresses mRNA expression of estrogen-related receptor α (ERRα), superoxide dismutase 2 (SOD2), G protein-coupled estrogen receptor (GPER) and retinoic acid-related orphan receptor α (RORA) in the brain as well as oxidative stress and mitochondrial dysfunction, subsequently triggering autism-like behaviour in mouse offspring. Also, similar gene suppression was found in hematopoietic stem cells (HSCs) and PBMC, with inherited epigenetic changes being identified on the related promoters. The human case-control study found that mRNA levels of ERRα, SOD2, GPER and RORA were significantly reduced in PBMC from ASD subjects (n = 132) compared with typically developing (n = 135) group. The receiver operating characteristic curve showed a .869 ± .021 of area under the curve for ASD subjects with 95% confidence interval of .829-.909, together with 1.000 of sensitivity and .856 of specificity. In conclusion, the combined mRNA expression in PBMC based on prenatal factor exposure-mediated gene suppression could be a potential biomarker for ASD diagnosis.

Transcript levels of 4 genes in umbilical cord blood are predictive of later autism development: a longitudinal follow-up study.

BACKGROUND: Over recent decades, autism spectrum disorder (ASD) has been of increasing epidemiological importance, given the substantial increase in its prevalence; at present, clinical diagnosis is possible only after 2 years of age. In this study, we sought to develop a potential predictive model for ASD screening. METHODS: We conducted a longitudinal follow-up study of newborns over 3 years. We measured transcript levels of 4 genes (superoxide dismutase-2 [SOD2], retinoic acid-related orphan receptor-α [RORA], G protein-coupled estrogen receptor-1 [GPER], progesterone receptor [PGR]), 2 oxidative stress markers and epigenetic marks at the RORA promoter in case-control umbilical cord blood mononuclear cell (UCBMC) samples. RESULTS: We followed 2623 newborns; we identified 41 children with ASD, 63 with delayed development and 2519 typically developing children. We matched the 41 children with ASD to 41 typically developing children for UCBMC measurements. Our results showed that children with ASD had significantly higher levels of H3K9me3 histone modifications at the RORA promoter and oxidative stress in UCBMC than typically developing children; children with delayed development showed no significant differences. Children with ASD had significantly lower expression of SOD2, RORA and GPER, but higher PGR expression than typically developing children. We established a model based on these 4 candidate genes, and achieved an area under the curve of 87.0% (standard deviation 3.9%) with a sensitivity of 1.000 and specificity of 0.854 to predict ASD in UCBMC. LIMITATIONS: Although the gene combinations produced a good pass/fail cut-off value for ASD evaluation, relatively few children in our study sample had ASD. CONCLUSION: The altered gene expression in UCBMC can predict later autism development, possibly providing a predictive model for ASD screening immediately after birth.

Maternal diabetes-mediated RORA suppression contributes to gastrointestinal symptoms in autism-like mouse offspring.

BACKGROUND: Retinoic acid-related orphan receptor alpha (RORA) has been reported to be suppressed in autistic patients and is associated with autism spectrum disorders (ASD), although the potential role and mechanism of RORA on gastrointestinal (GI) symptoms in ASD patients is still not reported. In this study, we aim to investigate the contribution of RORA to GI symptoms through a maternal diabetes-mediated autism-like mouse model. RESULTS: Male offspring of diabetic dams were treated with either superoxide dismutase (SOD) mimetic MnTBAP or RORA agonist SR1078, or were crossbred with intestine epithelial cells (IEC)-specific RORA knockout (RORA-/-) mouse. Gene expression, oxidative stress and inflammation were measured in brain tissues, peripheral blood mononuclear cells (PBMC) and IEC, and GI symptoms were evaluated. Our results showed that SOD mimetic MnTBAP completely, while RORA agonist SR1078 partly, reversed maternal diabetes-mediated oxidative stress and inflammation in the brain, PBMC and IEC, as well as GI symptoms, including intestine permeability and altered gut microbiota compositions. IEC-specific RORA deficiency either mimicked or worsened maternal diabetes-mediated GI symptoms as well as oxidative stress and inflammation in IEC, while there was little effect on maternal diabetes-mediated autism-like behaviors. CONCLUSIONS: We conclude that RORA suppression contributes to maternal diabetes-mediated GI symptoms in autism-like mouse offspring, this study provides a potential therapeutical target for maternal diabetes-mediated GI symptoms in offspring through RORA activation.

Maternal diabetes induces autism-like behavior by hyperglycemia-mediated persistent oxidative stress and suppression of superoxide dismutase 2.

Epidemiological studies show that maternal diabetes is associated with an increased risk of autism spectrum disorders (ASDs), although the detailed mechanisms remain unclear. The present study aims to investigate the potential effect of maternal diabetes on autism-like behavior in offspring. The results of in vitro study showed that transient hyperglycemia induces persistent reactive oxygen species (ROS) generation with suppressed superoxide dismutase 2 (SOD2) expression. Additionally, we found that SOD2 suppression is due to oxidative stress-mediated histone methylation and the subsequent dissociation of early growth response 1 (Egr1) on the SOD2 promoter. Furthermore, in vivo rat experiments showed that maternal diabetes induces SOD2 suppression in the amygdala, resulting in autism-like behavior in offspring. SOD2 overexpression restores, while SOD2 knockdown mimics, this effect, indicating that oxidative stress and SOD2 expression play important roles in maternal diabetes-induced autism-like behavior in offspring, while prenatal and postnatal treatment using antioxidants permeable to the blood-brain barrier partly ameliorated this effect. We conclude that maternal diabetes induces autism-like behavior through hyperglycemia-mediated persistent oxidative stress and SOD2 suppression. Here we report a potential mechanism for maternal diabetes-induced ASD.

Evaluation of the contamination by bacteria of the Bacillus cereus group and the determination of some physico-chemical parameters of Attiéké garba sold in Daloa (Central West, Côte d'Ivoire).

In Côte d'Ivoire as elsewhere in Africa, attiéké plays an important role in feeding the population. The objective of the work is to conduct a study on the sanitary quality of the attiéké garba sold in Daloa. Fifty (50) samples of attiéké garba were collected by purchase from various high-traffic outlets in different districts of Daloa town. Samples are collected in the morning around 10 a.m. every 2 days at a rate of 10 per site. Microbiological analyzes and the determination of some physico-chemical parameters of attiéké garba were carried out. The bacterial load of Bacillus cereus present in the samples tested in the majority of districts is greater than or equal to 105 CFU/g of food. About 60% of the samples tested was contaminated with B. cereus spores against 72% contaminated with the vegetative form of B. cereus. However, physicochemical analyzes showed that attiéké garba was acidic and the humidity was between 37.36 ± 15.9 and 55.26 ± 20.5%. Attiéké garba could pose a danger to consumers.

Urinary Metabonomic Profiling Discriminates Between Children with Autism and Their Healthy Siblings.

BACKGROUND Autism spectrum disorder (ASD) is a complicated neuropsychiatric disease that displays significant heterogeneity. The diagnosis of ASD is currently primarily dependent upon descriptions of clinical symptoms, and it remains urgent to find biological markers for the detection and diagnosis of autism. The current study applied the urinary metabolic profiling approach to characterize metabolic phenotypes in ASD. MATERIAL AND METHODS Urine was obtained from children with ASD and their matched healthy siblings. Samples were analyzed using 1H NMR-based methods designed to measure a broad range of metabolites. Partial least-square-discriminant analysis (PLS-DA) was used to develop models to identify metabonomic variations that can be used to distinguish between individuals with ASD and their unaffected siblings. RESULTS A significant difference was observed between the metabolomic profiles of children with ASD and that of their healthy siblings. An increase in the levels of tryptophan, hippurate, glycine, and creatine, and a decrease in trigonelline, melatonin, pantothenate, serotonin, and taurine were observed compared to the control group. We conclude that several metabolic pathways are affected by autism, which suggests that a gut-brain link may be important in the pathophysiology of ASD. CONCLUSIONS 1H NMR-based metabonomic analysis of the urine can determine perturbations of specific metabolic pathways related to ASD and help identify a characteristic metabolic fingerprint to better understand the disease and its causes.

EBNA2 mediates lipid metabolism and tumorigenesis through activation of ATF4 pathway.

Epstein-Barr virus (EBV) can infect the majority of the human population with no obvious symptoms and is associated with tumor development, although the mechanism is still largely unknown. In this study, we investigated the role and the underlying mechanism of EBV nuclear antigen 2 (EBNA2) in tumorigenesis. We found that the infection of EBNA2 in human B lymphocytes (HBL) upregulated the expression of activating transcription factor 4 (ATF4). Furthermore, we used gene expression or knockdown approach to demonstrate the effect of EBNA2 on redox balance, mitochondrial function, lipid metabolism, and cell proliferation in both HBL and EBV-transformed lymphocyte cell line (LCL). More importantly, we applied in vivo xenograft tumor mouse model to explore the contribution of EBNA2 and ATF4 in tumor growth and mouse survival. Mechanistically, we revealed that EBNA2 exposure caused persistent expression of ATF4 via EBNA2-mediated epigenetic changes, which increased the binding ability of upstream stimulating factor 1 (USF1) on the ATF4 promoter. ATF4 activation in HBL cells modulated the expression of lipid metabolism-related genes and potentiated fatty acid oxidation and lipogenesis. Conversely, knockdown of either EBNA2 or ATF4 in LCL suppressed lipid metabolism, modulated redox balance and mitochondrial function, as well as inhibited tumor cell proliferation. In consistent with these findings from in vitro study, an in vivo xenograft model confirmed that knockdown of either EBNA2 or ATF4 inhibited the gene expression of SREBP1, ChREBP, and FAS, as well as suppressed tumor growth and prolonged animal survival. Collectively, this study demonstrates that EBNA2 mediates tumorigenesis through ATF4 activation and the modulation of lipid metabolism; therefore, our findings provide a novel avenue for the clinical treatment of EBV-mediated cancer.

LMP1 mediates tumorigenesis through persistent epigenetic modifications and PGC1ß upregulation.

Latent membrane protein 1 (LMP1), which is encoded by the Epstein­Barr virus (EBV), has been considered as an oncogene, although the detailed mechanism behind its function remains unclear. It has been previously reported that LMP1 promotes tumorigenesis by upregulation of peroxisome proliferator­activated receptor­Î³ coactivator­1ß (PGC1ß). The present study aimed to investigate the potential mechanism for transient EBV/LMP1 exposure­mediated persistent PGC1ß expression and subsequent tumorigenesis through modification of mitochondrial function. Luciferase reporter assay, chromatin immunoprecipitation and DNA mutation techniques were used to evaluate the PGC1ß­mediated expression of dynamin­related protein 1 (DRP1). Tumorigenesis was evaluated by gene expression, oxidative stress, mitochondrial function and in vitro cellular proliferation assays. The potential effects of EBV, LMP1 and PGC1ß on tumor growth were evaluated in an in vivo xenograft mouse model. The present in vitro experiments showed that LMP1 knockdown did not affect PGC1ß expression or subsequent cell proliferation in EBV­positive tumor cells. PGC1ß regulated DRP1 expression by coactivation of GA­binding protein α and nuclear respiratory factor 1 located on the DRP1 promoter, subsequently modulating mitochondrial fission. Transient exposure of either EBV or LMP1 in human hematopoietic stem cells caused persistent epigenetic changes and PGC1ß upregulation after long­term cell culture even in the absence of EBV/LMP1, which decreased oxidative stress, and potentiated mitochondrial function and cell proliferation in vitro. Enhanced tumor growth and shortened survival were subsequently observed in vivo. It was concluded that PGC1ß expression and subsequent cell proliferation were independent from LMP1 in EBV­positive tumor cells. PGC1ß modulated mitochondria fission by regulation of DRP1 expression. Transient EBV/LMP1 exposure caused persistent PGC1ß expression, triggering tumor growth in the absence of LMP1. The present study proposes a novel mechanism for transient EBV/LMP1 exposure­mediated tumorigenesis through persistent epigenetic changes and PGC1ß upregulation, uncovering the reason why numerous forms of lymphoma exhibit upregulated PGC1ß expression, but are devoid of EBV/LMP1.

Autism-like behavior of murine offspring induced by prenatal exposure to progestin is associated with gastrointestinal dysfunction due to claudin-1 suppression.

Autism spectrum disorders (ASD) are associated with the contribution of many prenatal risk factors; in particular, the sex hormone progestin and vitamin D receptor (VDR) are associated with gastrointestinal (GI) symptoms in ASD development, although the related mechanism remains unclear. We investigated the possible role and mechanism of progestin 17-hydroxyprogesterone caproate (17-OHPC) exposure-induced GI dysfunction and autism-like behaviours (ALB) in mouse offspring. An intestine-specific VDR-deficient mouse model was established for prenatal treatment, while transplantation of haematopoietic stem cells (HSCT) with related gene manipulation was used for postnatal treatment for 17-OHPC exposure-induced GI dysfunction and ALB in mouse offspring. The in vivo mouse experiments found that VDR deficiency mimics prenatal 17-OHPC exposure-mediated GI dysfunction, but has no effect on 17-OHPC-mediated autism-like behaviours (ALB) in mouse offspring. Furthermore, prenatal 17-OHPC exposure induces CLDN1 suppression in intestine epithelial cells, and transplantation of HSCT with CLDN1 expression ameliorates prenatal 17-OHPC exposure-mediated GI dysfunction, but has no effect on 17-OHPC-mediated ALB in offspring. In conclusion, prenatal 17-OHPC exposure triggers GI dysfunction in autism-like mouse offspring via CLDN1 suppression, providing a possible explanation for the involvement of CLDN1 and VDR in prenatal 17-OHPC exposure-mediated GI dysfunction with ASD.

Rethinking autism: the impact of maternal risk factors on autism development.

Autism spectrum disorders (ASD) are a group of lifelong neurodevelopmental disorders characterized by cognitive deficits and impaired social and communicative development that have been rising in prevalence in recent decades. These disorders may be accompanied by disabling health issues and often lead to a substantial economic burden. The causes and mechanisms of ASD have not yet been fully elucidated, although it has been reported that genetic background, epigenetic modification, and environmental risk factors all contribute to the development of ASD. Environmental factors, which include prenatal circumstances or events, all play a very important role in the early development of autism, yet the exact mechanism remains largely undetermined. In this review, we promote a 'rethinking' of autism as a neurodevelopmental disease that originates from early life development. We focus on the impact of the prenatal and maternal risk factors such as maternal diabetes, prenatal chemical exposure, and hormone imbalances during pregnancy on the risk for ASD development in children and offspring, identifying important pathological bases and prevention measures for future decades. Further research focused on understanding the role of the environmental factors in the etiology of ASD will drive forward innovation strategies towards intervention and the prevention of the maternal risk factors for autism.

Prenatal Progestin Exposure-Mediated Oxytocin Suppression Contributes to Social Deficits in Mouse Offspring.

Epidemiological studies have shown that maternal hormone exposure is associated with autism spectrum disorders (ASD). The hormone oxytocin (OXT) is a central nervous neuropeptide that plays an important role in social behaviors as well as ASD etiology, although the detailed mechanism remains largely unknown. In this study, we aim to investigate the potential role and contribution of OXT to prenatal progestin exposure-mediated mouse offspring. Our in vitro study in the hypothalamic neurons that isolated from paraventricular nuclei area of mice showed that transient progestin exposure causes persistent epigenetic changes on the OXT promoter, resulting in dissociation of estrogen receptor ß (ERß) and retinoic acid-related orphan receptor α (RORA) from the OXT promoter with subsequent persistent OXT suppression. Our in vivo study showed that prenatal exposure of medroxyprogesterone acetate (MPA) triggers social deficits in mouse offspring; prenatal OXT deficiency in OXT knockdown mouse partly mimics, while postnatal ERß expression or postnatal OXT peptide injection partly ameliorates, prenatal MPA exposure-mediated social deficits, which include impaired social interaction and social abilities. On the other hand, OXT had no effect on prenatal MPA exposure-mediated anxiety-like behaviors. We conclude that prenatal MPA exposure-mediated oxytocin suppression contributes to social deficits in mouse offspring.

Betulinic acid accelerates diabetic wound healing by modulating hyperglycemia-induced oxidative stress, inflammation and glucose intolerance.

Background: Diabetes significantly delays wound healing through oxidative stress, inflammation and impaired re-epithelialization that lead to defective regulation of the healing process, although the related mechanism remains unclear. Here, we aim to investigate the potential role and mechanism for the beneficial effect of betulinic acid (BA) on diabetic wound healing. Methods: The molecular effect of BA on hyperglycemia-mediated gene expression, oxidative stress, inflammation and glucose uptake was evaluated in endothelial, fibroblast and muscle cells. Burn injury was introduced to streptozotocin-induced diabetic rats and BA administration through either an intraperitoneal (IP) or topical (TOP) technique was used for wound treatment. Glucose tolerance was evaluated in both muscle tissue and fibroblasts, while oxidative stress and inflammation were determined in both the circulatory system and in wound tissues. The effect of BA on the wound healing process was also evaluated. Results: BA treatment reversed hyperglycemia-induced glucose transporter type 4 (GLUT4) suppression in both muscle and fibroblast cells. This treatment also partly reversed hyperglycemia-mediated suppression of endothelial nitric oxide synthase (eNOS), nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and nuclear factor NFκB p65 subunit (NFκB p65) activation in endothelial cells. An in vivo rat study showed that BA administration ameliorated diabetes-mediated glucose intolerance and partly attenuated diabetes-mediated oxidative stress and inflammation in both the circulatory system and wound tissues. BA administration by both IP and TOP techniques significantly accelerated diabetic wound healing, while BA administration by either IP or TOP methods alone had a significantly lower effect. Conclusions: BA treatment ameliorates hyperglycemia-mediated glucose intolerance, endothelial dysfunction, oxidative stress and inflammation. Administration of BA by both IP and TOP techniques was found to significantly accelerate diabetic wound healing, indicating that BA could be a potential therapeutic candidate for diabetic wound healing.

Hematopoietic stem cell transplantation ameliorates maternal diabetes-mediated gastrointestinal symptoms and autism-like behavior in mouse offspring.

Epidemiological studies have shown that maternal diabetes is associated with autism spectrum disorder development, although the detailed mechanism remains unclear. We have previously found that maternal diabetes induces persistent epigenetic changes and gene suppression in neurons, subsequently triggering autism-like behavior (ALB). In this study, we investigated the potential role and effect of hematopoietic stem cells (HSCs) on maternal diabetes-mediated gastrointestinal (GI) dysfunction and ALB in a mouse model. We show in vitro that transient hyperglycemia induced persistent epigenetic changes and gene suppression of tight junction proteins. In vivo, maternal diabetes-mediated oxidative stress induced gene suppression and inflammation in both peripheral blood mononuclear cells and intestine epithelial cells, subsequently triggering GI dysfunction with increased intestinal permeability and altered microbiota compositions, as well as suppressed gene expression in neurons and subsequent ALB in offspring; HSC transplantation (HSCT) ameliorates this effect by systematically reversing maternal diabetes-mediated oxidative stress. We conclude that HSCT can ameliorate maternal diabetes-mediated GI symptoms and autism-like behavior in mouse offspring.

Topical administration of pterostilbene accelerates burn wound healing in diabetes through activation of the HIF1α signaling pathway.

Impaired wound healing is one of a variety of severe diabetic complications and involves many factors, including consistent oxidative stress, prolonged inflammation, impaired angiogenesis, and delayed re-epithelialization. Despite the severe negative impacts that impaired wound healing has on patients' lives, detailed mechanisms and effective therapies are still not fully developed. In this study, we aim to investigate the potential effects and mechanisms of topical administration of pterostilbene and resveratrol on burn wound healing in diabetes. Our in vitro experiments in human umbilical vein endothelial cells showed that long term exposure of hyperglycemia induces oxidative stress and suppression of hypoxia inducible factor1α (HIF1α) signaling pathway, and pterostilbene treatment completely, while resveratrol treatment partly, reversed this effect. Further in vivo experiments in diabetic rats showed that topical administration of pterostilbene exhibited stronger efficacy than resveratrol in normalizing oxidative stress, HIF1α activity, and accelerating burn wound healing in diabetes. We conclude that topical administration of pterostilbene accelerates burn wound healing in diabetes through activation of the HIF1α signaling pathway; thus, pterostilbene may be a potential candidate for clinical treatment of burn wound healing in diabetes.

Maternal diabetes-mediated RORA suppression in mice contributes to autism-like offspring through inhibition of aromatase.

Retinoic acid-related orphan receptor alpha (RORA) suppression is associated with autism spectrum disorder (ASD) development, although the mechanism remains unclear. In this study, we aim to investigate the potential effect and mechanisms of RORA suppression on autism-like behavior (ALB) through maternal diabetes-mediated mouse model. Our in vitro study in human neural progenitor cells shows that transient hyperglycemia induces persistent RORA suppression through oxidative stress-mediated epigenetic modifications and subsequent dissociation of octamer-binding transcription factor 3/4 from the RORA promoter, subsequently suppressing the expression of aromatase and superoxide dismutase 2. The in vivo mouse study shows that prenatal RORA deficiency in neuron-specific RORA null mice mimics maternal diabetes-mediated ALB; postnatal RORA expression in the amygdala ameliorates, while postnatal RORA knockdown mimics, maternal diabetes-mediated ALB in offspring. In addition, RORA mRNA levels in peripheral blood mononuclear cells decrease to 34.2% in ASD patients (n = 121) compared to the typically developing group (n = 118), and the related Receiver Operating Characteristic curve shows good sensitivity and specificity with a calculated 84.1% of Area Under the Curve for ASD diagnosis. We conclude that maternal diabetes contributes to ALB in offspring through suppression of RORA and aromatase, RORA expression in PBMC could be a potential marker for ASD screening.

Latent Membrane Protein 1 Promotes Tumorigenesis Through Upregulation of PGC1ß Signaling Pathway.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma with poor prognosis. In this study, we aimed to investigate the potential mechanism of latent membrane protein 1 (LMP1)-mediated tumorigenesis and provide a novel therapeutic strategy for targeting the EBV DNA genome. We found that LMP1 upregulated the expression of peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1ß (PGC1ß) through activation of nuclear factor-κB (NF-κB). Furthermore, the activated PGC1ß upregulated the expression of 8-oxoguanine DNA glycosylase (OGG1) through the coactivation of nuclear respiratory factor 1 (NRF1) and GA-binding protein α (GABPα), preventing reactive oxygen species (ROS)-mediated base incision in the EBV genome and favoring its survival. Interruption of hexokinase domain component 1 (HKDC1) by either shRNA or Tf-D-HKC8 peptide suppressed the interaction of HKDC1 with voltage-dependent anion channel 1 (VDAC1), triggering mitochondrial dysfunction and excessive generation of ROS, thus resulting in EBV suppression through ROS-mediated DNA damage. Suppression of the EBV genome inhibited the expression of the LMP1/PGC1ß/HKDC1/OGG1 signaling pathway, forming a positive feed forward loop for the generation of ROS, hence inhibiting the EBV genome and subsequent EBV-associated tumor development. We concluded that LMP1 triggers EBV-associated tumorigenesis through activation of the PGC1ß pathway. This study provided a novel therapeutic strategy for the treatment of EBV-associated tumors by targeting HKDC1.

Pterostilbene accelerates wound healing by modulating diabetes-induced estrogen receptor ß suppression in hematopoietic stem cells.

BACKGROUND: Delayed wound healing is one of the major complications of diabetes mellitus and is characterized by prolonged inflammation, delayed re-epithelialization and consistent oxidative stress, although the detailed mechanism remains unknown. In this study, we aimed to investigate the potential role and effect of pterostilbene (PTE) and hematopoietic stem cells (HSCs) on diabetic wound healing. METHODS: Diabetic rats were used to measure the epigenetic changes in both HSCs and peripheral blood mononuclear cells (PBMCs). A cutaneous burn injury was induced in the rats and PTE-treated diabetic HSCs were transplanted for evaluation of wound healing. In addition, several biomedical parameters, including gene expression, oxidative stress, mitochondrial function and inflammation in macrophages, were also measured. RESULTS: Our data showed that PTE had a much stronger effect than resveratrol on accelerating diabetic wound healing, likely because PTE can ameliorate diabetes-induced epigenetic changes to estrogen receptor ß promoter in HSCs, while resveratrol cannot. Further investigation showed that bone marrow transplantation of PTE-treated diabetic HSCs restores diabetes-induced suppression of estrogen receptor ß and its target genes, including nuclear respiratory factor-1 and superoxide dismutase 2, and protects against diabetes-induced oxidative stress, mitochondrial dysfunction and elevated pro-inflammatory cytokines in both PBMCs and macrophages, subsequently accelerating cutaneous wound healing. CONCLUSIONS: HSC may play an important role in wound healing through transferring epigenetic modifications to subsequent PBMCs and macrophages by differentiation, while PTE accelerates diabetic wound healing by modulating diabetes-induced epigenetic changes in HSCs. Thus, PTE may be a novel therapeutic strategy for diabetic wound healing.

Resveratrol accelerates wound healing by attenuating oxidative stress-induced impairment of cell proliferation and migration.

BACKGROUND: Impaired wound healing, which is due to various external and internal factors that are involved in wound pathophysiology, leads to high rates of morbidity and mortality worldwide. Oxidative stress injury is an important factor that affects wound healing by changing the whole healing process. So, resveratrol, a dietary fruits polyphenol, which is known for its antioxidant properties, maybe the candidate to accelerate the wound-healing process. METHODS: The Human Umbilical Vein Endothelial Cells (HUVECs) was used for in vitro experiments to evaluate the effect of resveratrol on hyperglycemia-induced gene expression, oxidative stress and cell proliferation. The diabetic rat model was used to evaluate the effect of resveratrol on cutaneous burn injury healing process. RESULTS: Increases in H2O2 decreased cell viability with the 0-800 µM concentration range, and resveratrol could protect HUVECs against H2O2-induced injury. The scratched wound closed rate in H2O2 group was significantly smaller than the Control group (p < 0.05) and Resveratrol + H2O2 group (p < 0.05). The fluorescence intensity of ROS was lower in Control and Resveratrol + H2O2 groups than H2O2 group. Correspondingly, compared to H2O2 group, the expressions of Mn-SOD and nuclear Nrf2 (N-Nrf2) was up-regulated in Resveratrol + H2O2 group (p < 0.05). In vivo, compared with the saline group, using resveratrol could significantly accelerate wound healing of rats on Day 14 (p < 0.05) and make the regenerated skin structure more complete and inflammatory response lower. Moreover, the expressions of Mn-SOD was significantly up-regulated after using resveratrol. CONCLUSIONS: Resveratrol has the positive effects on promoting the acceleration and quality of skin wound healing, which maybe at least in part caused by the up-regulation of nuclear Nrf2 and Mn-SOD that subsequently attenuated oxidative stress.

Maternal Diabetes-Induced Suppression of Oxytocin Receptor Contributes to Social Deficits in Offspring.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by impaired skills in social interaction and communication in addition to restricted and repetitive behaviors. Many different factors may contribute to ASD development; in particular, oxytocin receptor (OXTR) deficiency has been reported to be associated with ASD, although the detailed mechanism has remained largely unknown. Epidemiological study has shown that maternal diabetes is associated with ASD development. In this study, we aim to investigate the potential role of OXTR on maternal diabetes-mediated social deficits in offspring. Our in vitro study of human neuron progenitor cells showed that hyperglycemia induces OXTR suppression and that this suppression remains during subsequent normoglycemia. Further investigation showed that OXTR suppression is due to hyperglycemia-induced persistent oxidative stress and epigenetic methylation in addition to the subsequent dissociation of estrogen receptor ß (ERß) from the OXTR promoter. Furthermore, our in vivo mouse study showed that maternal diabetes induces OXTR suppression; prenatal OXTR deficiency mimics and potentiates maternal diabetes-mediated anxiety-like behaviors, while there is less of an effect on autism-like behaviors. Additionally, postnatal infusion of OXTR partly, while infusion of ERß completely, reverses maternal diabetes-induced social deficits. We conclude that OXTR may be an important factor for ASD development and that maternal diabetes-induced suppression of oxytocin receptor contributes to social deficits in offspring.