Ovule and seed developments are crucial processes during plant growth, which are affected by different signaling pathways. In this paper, we demonstrate that the brassinosteroid (BR) signal is involved in ovule initiation and development. Ovule and seed numbers are significantly different when comparing BR-related mutants to wild-type controls. Detailed observation indicates that BR regulates the expression level of genes related to ovule development, including HLL, ANT, and AP2, either directly by targeting the promoter sequences or indirectly via regulation by BR-induced transcription factor BZR1. Also, Western blot demonstrates that the dephosphorylation level of BZR1 is consistent with ovule and seed number. The intragenic bzr1-1D suppressors bzs247 and bzs248 have much fewer ovules and seeds than bzr1-1D, which are similar to wild-type, suggesting that the phenotype can be rescued. The molecular and genetic experiments confirm that BZR1 and AP2 probably affect Arabidopsis ovule number determination antagonistically.

Background: Ca 2ϩ moves across the outer mitochondrial membrane (OMM) through the voltage-dependent anion channel (VDAC). Results: Disrupting the interaction between VDAC and the antiapoptotic protein Bcl-x L reduces mitochondrial Ca 2ϩ uptake. Conclusion: Bcl-x L /VDAC interactions promote Ca 2ϩ uptake by increasing transfer across the OMM. Significance: Mitochondrial matrix Ca 2ϩ is tightly regulated at the OMM by the modulation of VDAC.

Mcl-1 is an antiapoptotic member of the Bcl-2 family frequently upregulated in non-small cell lung carcinoma (NSCLC). We now report the physiological significance of an interaction between Mcl-1 and the mitochondrial outer membrane-localized voltage-dependent anion channel (VDAC) in NSCLC cell lines. Mcl-1 bound with high affinity to VDAC1 and 3 isoforms but only very weakly to VDAC2 and binding was disrupted by peptides based on the VDAC1 sequence. In A549 cells, reducing Mcl-1 expression levels or application of VDAC-based peptides limited Ca2+ uptake into the mitochondrial matrix, the consequence of which was to inhibit reactive oxygen species (ROS) generation. In A549, H1299 and H460 cells, both Mcl-1 knockdown and VDAC-based peptides attenuated cell migration without affecting cell proliferation. Migration was rescued in Mcl-1 knockdown cells by experimentally restoring ROS levels, consistent with a model in which ROS production drives increased migration. These data suggest that an interaction between Mcl-1 and VDAC promotes lung cancer cell migration by a mechanism that involves Ca2+-dependent ROS production.

Background/Aims: Diabetic non-healing skin ulcers represent a serious challenge in clinical practice, in which the hyperglycemia-induced disturbance of angiogenesis, and endothelial dysfunction play a crucial role. Resveratrol (RES), a silent information regulator 1 (SIRT1) agonist, can improve endothelial function and has strong proangiogenic properties, and has thus become a research focus for the treatment of diabetic non-healing skin ulcers; however, the underlying mechanism by which RES regulates these processes remains unclear. Therefore, the present study was intended to determine if RES exerts its observed protective role in diabetic wound healing by alleviating hyperglycemia-induced endothelial dysfunction and the disturbance of angiogenesis. Methods:We investigated the effects of RES on cell migration, cell proliferation, apoptosis, tube formation, and the underlying molecular mechanisms in 33 mM high glucose-stimulated human umbilical vein endothelial cells (HUVECs) by semiquantitative RT-PCR, western blot analysis, terminal deoxynucleotidyl transferasemediated dUTP nick end labeling (TUNEL) staining, and immunofluorescence in vitro. We further explored the role of RES on endothelial dysfunction and wound healing disturbance in db/db mice by TUNEL staining, immunofluorescence, and photography in vivo. Results:We observed an obvious inhibition of hyperglycemia-triggered endothelial dysfunction and a disturbance of angiogenesis, followed by the promotion of diabetic wound healing via RES, along with restoration of the activity of the hyperglycemiaimpaired SIRT1 signaling pathway. Pretreatment with EX-527, a SIRT1 inhibitor, abolished the RES-mediated endothelial protection and pro-angiogenesis action, and then delayed diabetic wound healing. Furthermore, examination of the overexpression of forkhead box O1 (FOXO1), a transcription factor substrate of SIRT1, in HUVECs Frontiers in Pharmacology | www.frontiersin.org April 2019 | Volume 10 | Article 421 Huang et al.Resveratrol Promotes Diabetic Wound Healing and db/db mice revealed that RES activated SIRT1 to restore hyperglycemia-triggered endothelial dysfunction and disturbance of angiogenesis, followed by the promotion of diabetic wound healing in a c-Myc-dependent manner. Pretreatment with 10058-F4, a c-Myc inhibitor, repressed RES-mediated endothelial protection, angiogenesis, and diabetic wound healing. Conclusion:Our findings indicate that the positive role of RES in diabetic wound healing via its SIRT1-dependent endothelial protection and pro-angiogenic effects involves the inhibition of FOXO1 and the de-repression of c-Myc expression.

IntroductionVegetarian diets have been shown to improve glucose metabolism and reduce risk for diabetes in Westerners but whether Chinese vegetarian diets have the same benefits is unknown.MethodsWe evaluated the association between diet and diabetes/impaired fasting glucose (IFG) among 4384 Taiwanese Buddhist volunteers and identified diabetes/IFG cases from a comprehensive review of medical history and fasting plasma glucose.ResultsVegetarians had higher intakes of carbohydrates, fiber, calcium, magnesium, total and non-heme iron, folate, vitamin A, and lower intakes of saturated fat, cholesterol, and vitamin B12. Besides avoiding meat and fish, vegetarians had higher intakes of soy products, vegetables, whole grains, but similar intakes of dairy and fruits, compared with omnivores. The crude prevalence of diabetes in vegetarians versus omnivores is 0.6% versus 2.3% in pre-menopausal women, 2.8% versus 10% in menopausal women, and 4.3% versus 8.1% in men. Polytomous logistic regression adjusting for age, body mass index, family history of diabetes, education, leisure time physical activity, smoking and alcohol, showed that this vegetarian diet was negatively associated with diabetes and IFG in men (OR for diabetes: 0.49, 95% CI: 0.28–0.89; OR for IFG: 0.66, 95% CI: 0.46–0.95); in pre-menopausal women (OR for diabetes: 0.26, 95% CI: 0.06–1.21; OR for IFG: 0.60, 95% CI: 0.35–1.04); and in menopausal women (OR for diabetes: 0.25, 95% CI: 0.15–0.42; OR for IFG: 0.73, 95% CI: 0.56–0.95).ConclusionWe found a strong protective association between Taiwanese vegetarian diet and diabetes/IFG, after controlling for various potential confounders and risk factors.

Improving efficacy of oncolytic virotherapy remains challenging due to difficulty increasing specificity and immune responses against cancer and limited understanding of its population dynamics. Here, we construct programmable and modular synthetic gene circuits to control adenoviral replication and release of immune effectors selectively in hepatocellular carcinoma cells in response to multiple promoter and microRNA inputs. By performing mouse model experiments and computational simulations, we find that replicable adenovirus has a superior tumor-killing efficacy than non-replicable adenovirus. We observe a synergistic effect on promoting local lymphocyte cytotoxicity and systematic vaccination in immunocompetent mouse models by combining tumor lysis and secretion of immunomodulators. Furthermore, our computational simulations show that oncolytic virus which encodes immunomodulators can exert a more robust therapeutic efficacy than combinatorial treatment with oncolytic virus and immune effector. Our results provide an effective strategy to engineer oncolytic adenovirus, which may lead to innovative immunotherapies for a variety of cancers.

The molecular signaling mechanisms of Coenzyme Q10 (CoQ10) in diabetic nephropathy (DN) remain poorly understood. We verified that mitochondrial abnormalities, like defective mitophagy, the generation of mitochondrial reactive oxygen species (mtROS) and the reduction of mitochondrial membrane potential, occurred in the glomerulus of db/db mice, accompanied by reduced PINK and parkin expression and increased apoptosis. These changes were partially reversed following oral administration of CoQ10. In inner fenestrated murine glomerular endothelial cells (mGECs), high glucose (HG) also resulted in deficient mitophagy, mitochondrial dysfunction and apoptosis, which were reversed by CoQ10. Mitophagy suppression mediated by Mdivi-1 or siPINK abrogated the renoprotective effects exerted by CoQ10, suggesting a beneficial role for CoQ10-restored mitophagy in DN. Mechanistically, CoQ10 restored the expression, activity and nuclear translocation of Nrf2 in HG-cultured mGECs. In addition, the reduced PINK and parkin expression observed in HG-cultured mGECs were partially elevated by CoQ10. CoQ10-mediated renoprotective effects were abrogated by the Nrf2 inhibitor ML385. When ML385 abolished mitophagy and the renoprotective effects exerted by CoQ10, mGECs could be rescued by treatment with mitoTEMPO, which is a mtROS-targeted antioxidant. These results suggest that CoQ10, as an effective antioxidant in mitochondria, exerts beneficial effects in DN via mitophagy by restoring Nrf2/ARE signaling. In summary, CoQ10-mediated mitophagy activation positively regulates DN through a mechanism involving mtROS, which influences the activation of the Nrf2/ARE pathway.

Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare, low-grade soft tissue neoplasm preferentially arising in the extremities of young to middle-aged adults that is characterized histologically by a variegated appearance and absence of a distinctive immunophenotype. Herein a series of 80 cases of MIFS has been evaluated to define potential features and markers that may facilitate diagnosis. An immunohistochemical study with a large panel of antibodies showed strong positivity of the tumor cells for bcl-1 (95%), FXIIIa (90%), CD10 (83%), and D2-40 (56%). FISH and array comparative genomic hybridization (aCGH) were performed in a large subset of cases to investigate the utility for detecting the TGFBR3 and OGA t(1;10) rearrangement and BRAF abnormalities. Using a combination of FISH and/or aCGH, t(1;10) was detected in 4 of 56 cases (7.1%). The aCGH study also demonstrated amplification of VGLL3 on chromosome 3 that was detected in 8 of 20 cases (40%). BRAF alterations were observed by FISH in 4 of 70 cases (5.7%) and correlated with gain of chromosome 3p12 (VGLL3). A novel fusion transcript involving exon 6 of ZNF335 and exon 10 of BRAF was identified in one case.Albeit not entirely specific, demonstration of amplification of VGLL3 on chromosome 3 in combination with expression of bcl-1 and FXIIIa may help support the diagnosis. Until a more robust genetic signature is identified, the diagnosis of MIFS rests on its characteristic clinicopathological features.