Background/Aims: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. Methods: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. Results: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1α in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1α. Conclusions: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1α, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1α/VEGF signaling pathway.
BackgroundChromoblastomycosis is a chronic skin and subcutaneous fungal infection caused by dematiaceous fungi and is associated with low cure and high relapse rates. In southern China, Fonsecaea monophora and Fonsecaea pedrosoi are the main causative agents.Principal findingsWe treated 5 refractory and complex cases of chromoblastomycosis with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with oral antifungal drugs. The lesions improved after 4 to 9 sessions of ALA-PDT treatment at an interval of one or two weeks, and in some cases, mycological testing results became negative. The isolates were assayed for susceptibility to antifungal drugs and ALA-PDT in vitro, revealing sensitivity to terbinafine, itraconazole and voriconazole, with ALA-PDT altering the cell wall and increasing reactive oxygen species production.ConclusionsThese results provide the basis for the development of a new therapeutic approach, and ALA-PDT combined with oral antifungal drugs constitutes a promising alternative method for the treatment of refractory and complex cases of chromoblastomycosis.
The IjB kinase (IKK)/NF-jB pathway has been shown to be a major regulator in cell survival. However, the mechanisms through which IKK mediates cell death are not clear. In this study, we showed that IKK-b contributed to hydrogen peroxide (H 2 O 2 )-induced cell death independent of the NF-jB pathway. Our results demonstrated that the pro-death function of IKK-b under oxidative stress was mediated by p85 S6K1 (S6 kinase 1), but not p70 S6K1 through a rapamycin-insensitive and mammalian target of rapamycin complex 1 kinase-independent mechanism. We found that IKK-b associated with p85, but not p70 S6K1, which was required for H 2 O 2 -induced activation of p85 S6K1. IKK-b and p85 S6K1 contributed to H 2 O 2 -induced phosphorylation of Mdm2 (S166) and p53 accumulation. p85 S6K1 is critical for IKK-b-mediated cell death. Thus, these findings established a novel oxidative stress-responsive pathway that involves IKK-b, p85 S6K1 and Mdm2, which is response for H 2 O 2 -induced cell death. Our results have important implications for IKK-b and p85 S6K1 as potential targets for the prevention of diseases involved in oxidative stress-induced aberrant cell death. Reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ), are generated in cells as a consequence of oxidative metabolism. Although low levels of ROS are usually detoxified quickly by antioxidant enzymes, an excessive accumulation of ROS may result in oxidative stress. High and/or persistent levels of oxidative stress represent a major cause of cellular damage and aberrant death in a plethora of pathological conditions during the initiation and progression of a plethora of pathological conditions, including neurodegenerative diseases, cancer, autoimmune and the ageing process.1 While ROS may trigger cell death through multiple mechanisms, 2 recent studies have established the nuclear factor-kB (NF-kB) pathway as a critical signaling pathway in mediating the action of ROS in cell survival/cell death.
BackgroundMyiasis due to Old World screw-worm fly, Chrysomya bezziana, is an important obligate zoonotic disease in the OIE-list of diseases and is found throughout much of Africa, the Indian subcontinent, southeast and east Asia. C. bezziana myiasis causes not only morbidity and death to animals and humans, but also economic losses in the livestock industries. Because of the aggressive and destructive nature of this disease in hosts, we initiated this study to provide a comprehensive understanding of human myiasis caused by C. bezziana.MethodsWe searched the databases in English (PubMed, Embase and African Index Medicus) and Chinese (CNKI, Wanfang, and Duxiu), and international government online reports to 6th February, 2019, to identify studies concerning C. bezziana. Another ten human cases in China and Papua New Guinea that our team had recorded were also included.ResultsWe retrieved 1,048 reports from which 202 studies were ultimately eligible for inclusion in the present descriptive analyses. Since the first human case due to C. bezziana was reported in 1909, we have summarized 291 cases and found that these cases often occurred in patients with poor hygiene, low socio-economic conditions, old age, and underlying diseases including infections, age-related diseases, and noninfectious chronic diseases. But C. bezziana myiasis appears largely neglected as a serious medical or veterinary condition, with human and animal cases only reported in 16 and 24 countries respectively, despite this fly species being recorded in 44 countries worldwide.ConclusionOur findings indicate that cryptic myiasis cases due to the obligate parasite, C. bezziana, are under-recognized. Through this study on C. bezziana etiology, clinical features, diagnosis, treatment, epidemiology, prevention and control, we call for more vigilance and awareness of the disease from governments, health authorities, clinicians, veterinary workers, nursing homes, and also the general public.
Postherpetic neuralgia (PHN) is a debilitating disease characterized by continuous, intense pain following an outbreak of herpes zoster. The pain associated with PHN can severely affect a patient's quality of life, quality of sleep, and ability to participate in activities of daily living. The aim of this study was to explore the clinical efficacy of the subcutaneous injection of botulinum toxin-A (BTX-A) for the treatment of PHN. Thirteen patients with PHN were enrolled in this study and treated once with BTX-A. The effects of BTX-A on pain were measured with the visual analogue scale (VAS) 1, 2, 4, 8, 12, and 16 weeks after administration. Compared with pretreatment scores, VAS pain scores decreased at 2 weeks post-treatment in all patients. All patients felt varying degrees of pain relief but remained comfortable. Compared with oral analgesic drugs, VAS scores were significantly different at 2, 4, 8, 12, and 16 weeks posttreatment (p < .05). These results demonstrated that subcutaneous administration of BTX-A can decrease pain in patients with PHN.
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