- Discovery of fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one as VDR signaling regulators. [Journal Article]
- BMBioorg Med Chem 2019 Jul 12
- The modulation of VDR signaling is important in regulating tumor-related signal transduction and protecting from microorganismal infection. In this study we discovered by luciferase reporter assay th…
The modulation of VDR signaling is important in regulating tumor-related signal transduction and protecting from microorganismal infection. In this study we discovered by luciferase reporter assay that several fused bicyclic derivatives of 1H-pyrrolo[1,2-c]imidazol-1-one with the assistance of calcitriol result in up to three-fold increases of VDR promoter activity. Preliminary SAR results from 20 compounds disclose that ideal VDR signaling regulators of these compounds are built up by the optimal combination of multiple factors. Western blot analysis indicates that compounds of ZD-3, ZD-4 and ZD-5 not only significantly upregulate p62 and LC3-II but also elevate the ratio of LC3-II/LC3-I, which possibly leads to activated autophagy. All of five compounds also significantly downregulate p65 and upregulate p-p65 and ZD-3 is the most active one to NF-κB signaling, suggesting a possible induction of apoptosis through the regulation of NF-κB signal transduction mediated by VDR signaling. Compounds of ZD-3, ZD-4 and ZD-5 significantly counteract the interference by VDR shRNA, in which ZD-3 gets the highest compensation of VDR expression and the highest ratio of LC3-II/LC3-I, indicating that ZD-3 very likely activates VDR-mediated autophagy. Taken together, these 1H-pyrrolo[1,2-c]imidazol-1-one derivatives can modulate VDR signaling, possibly resulting in the regulation of some signal pathways to induce autophagy and apoptosis.
- Hedyotis diffusa Willd. inhibits VEGF‑C‑mediated lymphangiogenesis in colorectal cancer via multiple signaling pathways. [Journal Article]
- OROncol Rep 2019 Jul 05
- Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. For patients diagnosed with the presence of metastatic disease, surgery is not suitable for the majority of them.…
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. For patients diagnosed with the presence of metastatic disease, surgery is not suitable for the majority of them. Lymphangiogenesis is a key factor during cancer metastasis and is regulated by vascular endothelial growth factor C (VEGF‑C). Hedyotis diffusa Willd. (HDW) is a Chinese herb of the Rubiaceae family that reportedly inhibits tumor metastasis. However, its underlying anticancer mechanisms have not yet been elucidated. In the present study, we investigated the effects of an ethanol extract of HDW (EEHDW) on the migration capacity by wound healing and Transwell assays, and the effect on the VEGF‑C expression in different CRC cell lines by western blot analysis and ELISA assays. A model of VEGF‑C‑stimulated human lymphatic endothelial cells (HLECs) was constructed. It was found that EEHDW suppressed lymphangiogenesis via the mediation of multiple pathways, which attenuated the migration of cells and their tube formation abilities. Multiple signaling pathways were found to be involved in the VEGF‑C‑mediated lymphangiogenesis. After EEHDW treatment in VEGF‑C‑stimulated HLECs, EEHDW was found to downregulate the expression levels of multiple signaling pathways. Taken together, these results indicate that EEHDW possesses significant anti‑metastatic activities. Moreover, the suppressive effect of EEHDW on lymphangiogenesis, particularly via downregulation of VEGF‑C, partly explains the potential molecular mechanism underlying the inhibitory effect of EEHDW on CRC metastasis.
- The role of Zeb1 in the pathogenesis of morbidly adherent placenta. [Journal Article]
- MMMol Med Rep 2019 Jul 12
- Zinc finger E‑box‑binding homeobox 1 (Zeb1) is a promoter of epithelial‑mesenchymal transformation, which may serve an important role in morbidly adherent placenta (MAP). In the present study, the pr…
Zinc finger E‑box‑binding homeobox 1 (Zeb1) is a promoter of epithelial‑mesenchymal transformation, which may serve an important role in morbidly adherent placenta (MAP). In the present study, the protein expression levels of Zeb1 were examined in the placenta tissues of 60 patients, including 20 patients with placenta accreta (PA) and 20 patients with placenta previa without PA (UPA) and 20 patients in late pregnancy that delivered by cesarean section (normal). The expression levels of Zeb1, N‑cadherin, vascular endothelial growth factor (VEGF), Tumor necrosis factor‑related apoptosis‑inducing ligand‑receptor 2 (TRAIL‑R2), and tumor necrosis factor‑related apoptosis‑inducing ligand‑receptor 3 (TRAIL‑R3) were higher in PA tissues compared with in normal control tissues. The expression levels of E‑cadherin and TRAIL‑R2 were decreased in PA tissues compared with in normal control tissues. These findings indicated that Zeb1 may serve an important role in placental attachment, thus promoting the development of dangerous PA. Overexpression of Zeb1 may upregulate the expression levels of N‑cadherin, VEGF, TRAIL‑R3, cyclin D1 and Bcl‑2, and downregulate the expression levels of E‑cadherin and TRAIL‑R2. In addition, Zeb1 regulated the viability, apoptosis and migration of HTR‑8/SV neo cells and human umbilical vein endothelial cells by regulating the Akt pathway. In conclusion, these findings indicated that Zeb1 may promote placental implantation by activating the Akt signaling pathway, thus providing a theoretical basis for investigating the causes of MAP.
- ATRA protects skin fibroblasts against UV‑induced oxidative damage through inhibition of E3 ligase Hrd1. [Journal Article]
- MMMol Med Rep 2019 Jul 01
- All‑trans retinoic acid (ATRA) can protect fibroblasts against ultraviolet (UV)‑induced oxidative damage, however, its underlying molecular mechanism is still unclear. The present study aimed to inve…
All‑trans retinoic acid (ATRA) can protect fibroblasts against ultraviolet (UV)‑induced oxidative damage, however, its underlying molecular mechanism is still unclear. The present study aimed to investigate the role of 3‑hydroxy‑3‑methylglutaryl reductase degradation (Hrd1) in the protective effect of ATRA on human skin fibroblasts exposed to UV. The expression of Hrd1 in human or mice skin was assessed by immunohistochemistry (IHC) staining and western blot analysis. Hrd1 siRNA (si‑Hrd1) and Hrd1 recombinant adenoviruses (Ad‑Hrd1) were used to downregulate and upregulate Hrd1 expression in fibroblasts, respectively. The interaction between Hrd1 and NF‑E2‑related factor 2 (Nrf2) was assessed by co‑immunoprecipitation (co‑IP) and immunofluorescence analysis. The results revealed that Hrd1 expression was increased but Nrf2 expression was decreased in UV‑exposed human skin fibroblasts. In addition, ATRA could reverse the increase of Hrd1 expression induced by UV radiation in vivo and in vitro. ATRA or knockdown of Hrd1 could increase Nrf2 expression in fibroblasts exposed to UV radiation, and Hrd1 could directly interact with Nrf2 in skin fibroblasts. Notably, overexpression of Hrd1 abolished the protective effect of ATRA on the UV‑induced decrease of Nrf2 expression, the production of reactive oxygen species (ROS) and the decrease of cell viability. In conclusion, the present data demonstrated that ATRA protected skin fibroblasts against UV‑induced oxidative damage through inhibition of E3 ligase Hrd1.
- Autoimmune Bell's Palsy Following Immunotherapy For Metastatic Melanoma: A Report of 2 Cases. [Journal Article]
- JIJ Immunother 2019 Jul 16
- By targeting receptors that serve to downregulate the cellular immune system, monoclonal antibodies such as ipilimumab and nivolumab have transformed the management of metastatic melanoma, and their …
By targeting receptors that serve to downregulate the cellular immune system, monoclonal antibodies such as ipilimumab and nivolumab have transformed the management of metastatic melanoma, and their use is referred to as immune checkpoint therapy (ICT). However, because the antitumoral activity of these agents is achieved through the reversal of mechanisms that naturally serve to temper the immune response, the potential for adverse reactions secondary to autoimmunity is of clinical significance. Neurological immune-related adverse events (irAEs) may occur consequent to ICT, and the development of autoimmune Bell's palsy is a specific, uncommon manifestation of the body's immune response against the seventh cranial nerve, resulting in acute paresis of facial muscles. We describe 2 cases of autoimmune Bell's palsy following the administration of combination ICT using ipilimumab and nivolumab in 2 patients with metastatic melanoma. The use of a steroid taper in addition to the cessation of combination immunotherapy resulted in resolution of symptoms for both patients. In the first case, the patient was subsequently started on nivolumab monotherapy but developed autoimmune polyneuropathy, and immunotherapy was discontinued indefinitely. In the second case, the initiation of nivolumab monotherapy following resolution of symptoms resulted in an inadequate antitumoral response. Subsequent transition to treatment with encorafenib/binimetinib initially provided a positive response but also required discontinuation secondary to irAEs. Both of these cases demonstrate the potential for autoimmune Bell's palsy as a consequence of combination ICT and provide evidence of successful treatment of this irAE through temporary discontinuation of immunotherapy and administration of steroids.
- Src and Fyn define a new signaling cascade activated by canonical and non-canonical Wnt ligands and required for gene transcription and cell invasion. [Journal Article]
- CMCell Mol Life Sci 2019 Jul 16
- Wnt ligands signal through canonical or non-canonical signaling pathways. Although both routes share common elements, such as the Fz2 receptor, they differ in the co-receptor and in many of the final…
Wnt ligands signal through canonical or non-canonical signaling pathways. Although both routes share common elements, such as the Fz2 receptor, they differ in the co-receptor and in many of the final responses; for instance, whereas canonical Wnts increase β-catenin stability, non-canonical ligands downregulate it. However, both types of ligands stimulate tumor cell invasion. We show here that both the canonical Wnt3a and the non-canonical Wnt5a stimulate Fz2 tyrosine phosphorylation, Fyn binding to Fz2, Fyn activation and Fyn-dependent Stat3 phosphorylation. Wnt3a and Wnt5a require Src for Fz2 tyrosine phosphorylation; Src binds to canonical and non-canonical co-receptors (LRP5/6 and Ror2, respectively) and is activated by Wnt3a and Wnt5a. This Fz2/Fyn/Stat3 branch is incompatible with the classical Fz2/Dvl2 pathway as shown by experiments of over-expression or depletion. Fyn is necessary for transcription of genes associated with invasiveness, such as Snail1, and for activation of cell invasion by both Wnt ligands. Our results extend the knowledge about canonical Wnt pathways, demonstrating additional roles for Fyn in this pathway and describing how this protein kinase is activated by both canonical and non-canonical Wnts.
- Glutathione peroxidase 3 (GPX3) suppresses the growth of melanoma cells through reactive oxygen species (ROS)-dependent stabilization of hypoxia-inducible factor 1-α and 2-α. [Journal Article]
- JCJ Cell Biochem 2019 Jul 16
- In this study, we aimed to explore the mechanism of glutathione peroxidase 3 (GPX3) in the growth of malignant melanoma (MM) cells by hypoxia-inducible factor-1α (HIF1-α) and HIF2-α regulating the me…
In this study, we aimed to explore the mechanism of glutathione peroxidase 3 (GPX3) in the growth of malignant melanoma (MM) cells by hypoxia-inducible factor-1α (HIF1-α) and HIF2-α regulating the metabolism through reactive oxygen species (ROS). The messenger RNA and protein expression of GPX3, HIF1-α, HIF2-α in tissues, and cell lines were measured by reverse transcription-quantitative PCR and Western blot analysis. A375 cells were transfected with GPX3 overexpression plasmid, small interfering RNA (siRNA) targeting GPX3, or siRNA targeting HIF1-α/HIF2-α to upregulate or downregulate the expression of GPX3 or HIF1-α/HIF2-α. The effects of H2 O2 and N-acetylcysteine (NAC) on the levels of HIF1-α and HIF2-α after overexpression of GPX3 were studied. The cell viability was detected by Cell Counting Kit-8. The levels of ROS, glucose uptake and lactic acid production, oxidative phosphorylation, and glycolysis of cells were measured for assessment of cellular metabolism. The expression of GPX3 decreased, while ROS, HIF1-α, and HIF2-α increased in MM tissues and cells. Overexpression of GPX3 inhibited the viability of MM cells and the growth of melanoma xenografts. The overexpression of GPX3 reduced the glucose uptake, extracellular lactic acid content, and extracellular acidification rate and increased the oxygen consumption rate level. Overexpression of GPX3 could reduce the levels of HIF1-α and HIF2-α, which could regulate metabolic levels. GPX3 reduced ROS level in MM to inhibit HIF1-α and HIF2-α. The addition of H2 O2 increased while NAC reduced the protein levels of HIF1-α and HIF2-α in the cells overexpressing GPX3. Our study demonstrates that GPX3 inhibits the growth of MM cells through its inhibitory effect on cell metabolic disorder by inhibiting HIF1-α via regulating ROS.
- miR-4513 promotes gastric cancer cell proliferation and epithelial-mesenchymal transition through targeting KAT6B. [Journal Article]
- HGHum Gene Ther Clin Dev 2019 Jul 16
- The purpose of this study was to investigate the expression level of microRNA-4513 (miR-4513) in gastric cancer, and the underlying mechanisms of miR-4513 in regulating gastric cancer (GC) progressio…
The purpose of this study was to investigate the expression level of microRNA-4513 (miR-4513) in gastric cancer, and the underlying mechanisms of miR-4513 in regulating gastric cancer (GC) progression. Quantitative real time-polymerase chain reaction (qRT-PCR) was performed to measure the expression level of miR-4513 in GC cells. Transfection efficacy of synthetic miRNAs was examined by qRT-PCR. After synthetic miRNAs transfection, cell counting kit-8 assay and transwell invasion assay was conducted to measure biological changes in these groups. Key molecular expression level involved in epithelial-mesenchymal transition (EMT) was analyzed by western blot. Bioinformatic analysis and western blot were performed to investigate the connection between miR-4513 and lysine acetyltransferase 6B (KAT6B). qRT-PCR results showed miR-4513 expression level was upregulated in GC cell lines. Downregulate miR-4513 expression inhibited GC cell proliferation, invasion, and EMT. KAT6B was validated as a direct target of miR-4513. In addition, KAT6B expression level can be upregulated by miR-4513 inhibitor. Collectively, we showed miR-4513 involved in regulating the biological function of GC cells via KAT6B. In addition, miR-4513 may serve as a potential target for the molecular therapy of GC.
- Differential Patterns of Visual Sensory Alteration Underlying Face Emotion Recognition Impairment and Motion Perception Deficits in Schizophrenia and Autism Spectrum Disorder. [Journal Article]
- BPBiol Psychiatry 2019 May 29
- CONCLUSIONS: SZ and ASD participants showed equivalent deficits in FER and motion sensitivity but markedly different profiles of physiological dysfunction. The specific pattern of deficits observed in each group may help guide development of treatments designed to downregulate versus upregulate visual processing within the respective clinical groups.
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- (5R)-5-hydroxytriptolide ameliorates liver lipid accumulation by suppressing lipid synthesis and promoting lipid oxidation in mice. [Journal Article]
- LSLife Sci 2019 Jul 10; :116644
- CONCLUSIONS: Our results provide a novel application of LLDT-8 in improving NAFLD.