BI1 alleviates cardiac microvascular ischemia-reperfusion injury via modifying mitochondrial fission and inhibiting XO/ROS/F-actin pathways

Pathogenesis of cardiac microvascular ischemia-reperfusion (IR) injury is associated with excessive mitochondrial fission. However, the upstream mediator of mitochondrial fission remains obscure. Bax inhibitor 1 (BI1) is linked to multiple mitochondrial functions, and there have been no studies investigating the contribution of BI1 on mitochondrial fission in the setting of cardiac microvascular IR injury. This study was undertaken to establish the action of BI1 on the cardiac microvascular reperfusion injury and figure out whether BI1 sustained endothelial viability via inhibiting mitochondrial fission. Our observation indicated that BI1 was downregulated in reperfused hearts and overexpression of BI1 attenuated microvascular IR injury. Mechanistically, reperfusion injury elevated the levels of xanthine oxidase (XO), an effect that was followed by increased reactive oxygen species (ROS) production. Subsequently, oxidative stress mediated F-actin depolymerization and the latter promoted mitochondrial fission. Aberrant fission caused mitochondrial dysfunction and ultimately activated mitochondrial apoptosis in cardiac microvascular endothelial cells. By comparison, BI1 overexpression repressed XO expression and thus neutralized ROS, interrupting F-actin-mediated mitochondrial fission. The inhibitory effect of BI1 on mitochondrial fission sustained endothelial viability, reversed endothelial barrier integrity, attenuated the microvascular inflammation response, and maintained microcirculation patency. Altogether, we conclude that BI1 is essential in maintaining mitochondrial homeostasis and alleviating cardiac microvascular IR injury. Deregulated BI1 via the XO/ROS/F-actin pathways plays a causative role in the development of cardiac microvascular reperfusion injury.     

AIM2 promotes non-small-cell lung cancer cell growth through inflammasome-dependent pathway

The human absent in melanoma 2 (AIM2) is considered as a DNA recognizer. AIM2 has been described as a tumor suppressor gene in the early years. But recent studies suggested that it functions as an oncogene in several cancers. However, its roles in non-small-cell lung cancer (NSCLC) remain unclear. Here we reported that AIM2 highly expressed in NSCLC cells and exhibited a tumor-promoting property both in vitro and in vivo. Besides, AIM2 short hairpin RNA (shRNA)-mediated suppression of cell proliferation was triggered by the accumulation of cells at the G2/M phase. Knockdown of AIM2 reduced the inflammasome formation, while overexpression of AIM2 or stimulation by poly(dA:dT) induced the inflammasome formation. Interestingly, blockade of the inflammasome by caspase-1 inhibitor VX-765 or ASC small interfering RNA (siRNA) abolished the effects brought by AIM2 shRNA and AIM2 plasmid. In summary, our results revealed that AIM2 functioned as an oncogene in NSCLC in an inflammasome-dependent way.     

Exosomal microRNA-155-5p from PDLSCs regulated Th17/Treg balance by targeting sirtuin-1 in chronic periodontitis

The mechanism of local inflammation and systemic injury in chronic periodontitis is complicated, in which and exosomes play an important role. In our study, we found that T helper cell 17 (Th17)/regulatory T cell (Treg) balance is destabilized in the peripheral blood of patients with periodontitis, with upregulated Th17 or downregulated Treg, respectively. Porphyromonas gingivalis lipopolysaccharide (LPS) was used to simulate the inflammatory microenvironment of chronic periodontitis. The exosomes were extracted from periodontal ligament stem cells (PDLSCs) in LPS-induced periodontitis environment, which inversely effected on CD4+ T cells under normal and inflammatory conditions. Furthermore, compared with exosomes from normal PDLSCs, lower expression of microRNA-155-5p (miR-155-5p) and higher expression of Sirtuin-1 (SIRT1) were observed in exosomes from LPS-stimulated PDLSCs. Exosomes from PDLSCs alleviated inflammatory microenvironment through Th17/Treg/miR-155-5p/SIRT1 regulatory network. This study aimed to find the “switching” factors that affected the further deterioration of periodontitis to maximally control the multiple downstream damage signal factors to further understand periodontitis and find new targets for its treatment.     

Retracted: Impaired Th17 cell proliferation and decreased pro-inflammatory cytokine production in CXCR3/CXCR4 double-deficient mice of vulvovaginal candidiasis

Vulvovaginal candidiasis (VVC) is a common observed infection, affecting approximately 75% of women of reproductive age. Drug resistance represents a troublesome stumbling block associated with VVC therapy. Thus the aim of the present study was to provide information regarding the selection of potential drug targets for VVC. CXCR3-, CXCR4-, or CXCR/CXCR4 double-deficient mouse models of VVC were subsequently established, with changes to the load of Candida Albicans evaluated accordingly. The biological behaviors of the vaginal epithelial cells were characterized in response to the CXCR3-, CXCR4-, or CXCR3/CXCR4 double-knockout in vivo. Our initial observations revealed that in mice with VVC, CXCR3-, CXCR4-, or CXCR3 - CXCR4 double-knockout resulted in a decreased load of C. Albicans as well as reduced levels and proportion of Th17 cells. Proinflammatory cytokine production was found to be inhibited by CXCR3-, CXCR4-, or CXCR3/CXCR4 double-knockout whereby the mRNA and protein expressions CXCR3, CXCR4, IL-17, IL-6, and TNF-α exhibited decreased levels. CXCR3-, CXCR4-, or CXCR3/CXCR4 double-knockout appeared to function as positive proliferation factors, while playing a negative role in the processes of apoptosis and the cell cycle of vaginal epithelial cells. Taken together, the key findings of the study suggested that CXCR3/CXCR4 double-knockout could act to hinder the progression of VVC, highlighting its promise as a novel therapeutic target in the treatment of VVC. CXCR3 and CXCR4 genes may regulate Th17/IL-17 immune inflammatory pathways to participate in antifungal immunity.     

Combinatorial effect of blueberry extracts and oxaliplatin in human colon cancer cells

The use of natural compounds to potentiate the effect of drugs and lower their adverse effects is an active area of research. The objective is to determine the effect of combined blueberry extracts (BE) and oxaliplatin (OX) in colon cancer cells. The results demonstrated that treatments of BE/OX showed inhibitory effects on HCT-116 cell and nontoxic effect on CCD-18Co normal colon cells. Flow cytometry analysis indicated that treatment with the BE, OX or in combination could induce G0/G1 cell cycle arrest, apoptosis, increase of reactive oxygen species, and induce loss of mitochondrial membrane potential in HCT-116 cells. Furthermore, after treatments, the expression of inflammatory cytokines was decreased, cyclin D1 and CDK4 were decreased; caspases-3 and 9 were activated; the Akt/Bad/Bcl-2 pathway was modulated. Moreover, the combination treatment had a considerably higher growth inhibitory effect on human colon cancer HCT-116 cells than that of BE or oxaliplatin alone. Our results showed that BE increased the anticolon cancer effect of OX making it an attractive strategy as adjuvant therapy to potentially reduce the adverse side effects associated with chemotherapeutic drugs.     

Scutellarin exerts protective effects against atherosclerosis in rats by regulating the Hippo–FOXO3A and PI3K/AKT signaling pathways

Atherosclerosis (AS), a progressive disorder, is one of the tough challenges in the clinic. Scutellarin, an extract from Herba Erigerontis, is found to have oxygen-free radicals scavenging effects and antioxidant effects. In this study, we aimed to investigate the anti-AS effects of scutellarin is related to controlling the Hippo–FOXO3A and PI3K/AKT signal pathway. To establish an AS model, the rats in the scutellarin and model groups were intraperitoneally injected with vitamin D ₃ and then fed a high-fat diet for 12 weeks. In addition, in vitro angiotensin II-induced apoptosis of human aortic endothelial cells (HAECs) were used to establish models. Scutellarin significantly reduced blood lipid levels and increased antioxidase levels in both models. Additionally, scutellarin inhibited reactive oxygen species generation and apoptosis in HAECs. The impaired vascular barrier function was restored by using scutellarin in AS rats and in HAECs cells characterized by inhibiting mammalian sterile-20-like kinases 1 (Mst1) phosphorylation, Yes-associated protein (YAP) phosphorylation, forkhead box O3A (FOXO3A) phosphorylation at serine 207, nuclear translocation of FOXO3A, and upregulating protein expression of AKT and FOXO3A phosphorylation at serine 253. Scutellarin significantly reduced Bcl-2 interacting mediator of cell death (Bim), caspase-3, APO-1, CD95 (Fas), and Bax: Bcl-2-associated X (Bax) levels and activated Bcl-2: B-cell lymphoma-2 (Bcl-2). Scutellarin also significantly inhibited the expression of Mst1, YAP, FOXO3A at the messenger RNA level. When Mst1 was overexpressed or phosphoinositide 3-kinases suppressed, the effects of scutellarin were significantly blocked. In conclusion, the results of the present study suggest that scutellarin exerts protective effects against AS by inhibiting endothelial cell injury and apoptosis by regulating the Hippo–FOXO3A and PI3K/AKT signal pathways.     

Role of bta-miR-204 in the regulation of adipocyte proliferation,differentiation, and apoptosis

Adipocyte growth and development are complex and precisely orchestrated processes. Several microRNAs have been identified as critical regulators of the adipocyte growth and development. Recently, bta-miR-204 was found to be involved in adipogenesis; however, the underlying molecular mechanism involved in bta-miR-204-mediated regulation of proliferation, differentiation, and apoptosis of adipocytes is not fully understood or elucidated. In this study, quantitative real-time polymerase chain reaction (qRT-PCR), Cell Counting Kit-8, EdU, flow cytometer, Oil Red O staining, and the western blot assays were used to assess the role of bta-miR-204 in adipocyte growth and development. Overexpression of bta-miR-204 had no significant effect on 3T3-L1 cell proliferation. The forced expression of bta-miR-204 promoted 3T3-L1 cell differentiation. Meanwhile, overexpression of bta-miR-204 upregulated the expression of Bax and downregulated the expression of Bcl-2 both at messenger RNA and protein levels, which suggested that bta-miR-204 can promote 3T3-L1 cell apoptosis. Using bioinformatic analysis, dual-luciferase reporter system and qRT-PCR, TGFBR2, and ELOVL6 were identified as the direct target genes of bta-miR-204. Therefore, our study provides a novel insight into the role of bta-miR-204 in the regulation of adipocyte growth and development, which may provide a novel therapeutic alternative against obesity.