Neutrophils have been found to play an important role in the pathogenesis of inflammatory bowel disease (IBD), and anti-TNF-α mAb (i.e., infliximab) therapy is demonstrated to be effective in the induction of clinical remission and mucosal healing in these patients. However, how anti-TNF-α mAb regulates the functions of neutrophils is still unknown. Herein, we found that anti-TNF-α therapy significantly downregulated infiltration of neutrophils in inflamed mucosa of IBD patients. Importantly, anti-TNF-α mAb could inhibit neutrophils to produce proinflammatory mediators, such as ROS, calprotectin, IL-8, IL-6, and TNF-α. These data indicate that TNF-α plays a critical role in the induction of mucosal inflammatory response, and that blockade of TNF-α modulates intestinal homeostasis through balancing immune responses of neutrophils.
Background: Circular RNA (circRNA) is increasingly attracting attention in gastric cancer (GC). Hsa_circ_0032821 (circ_0032821) has been declared to be upregulated in human GC tissues. However, the biological role of circ_0032821 remains undisclosed in GC cells. Methods: Expression of circ_0032821 was measured by real-time quantitative PCR. Cell proliferation, autophagy, Epithelial-mesenchymal transition (EMT), migration, and invasion were evaluated by Cell counting kit-8 assay, western blotting or transwell assays. Expression of proliferating cell nuclear antigen (PCNA), Matrix metalloproteinase 2 (MMP2), MMP9, Light chain 3 (LC3), p62, total and phosphorylated Extracellular signal-regulated kinase 1/2 (ERK1/2) and Mitogen-activated protein kinase's kinase 1 (MEK1) was evaluated by western blotting. Xenograft tumor model was established to measure tumor growth in vivo. Results: Circ_0032821 was significantly upregulated in human GC tumors and cells. Moreover, circ_0032821 might be a biomarker for the advanced Tumor node metastasis (TNM) stage, lymphoid node metastasis and poor prognosis in gastric cancer. Knockdown of circ_0032821 by transfection induced decrease of cell proliferation, EMT, migration and invasion, but increase of autophagy of AGS and HGC-27 cells in vitro, as well as induced tumor growth inhibition in vivo. Besides, overexpression of circ_0032821 by transfection functioned the opposite effects in human GC cells. Mechanically, the MEK1/ERK1/2 signaling pathway was activated when circ_0032821 upregulation, whereas inhibited when circ_0032821 silencing. Conclusion: Circ_0032821 expression induced cell proliferation, EMT, migration, invasion, and autophagy inhibition in human GC cells in vitro and in vivo through activating MEK1/ERK1/2 signaling pathway, suggesting circ_0032821 as an oncogenic role in GC.
Background Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. Increasing evidence showed that circular RNAs (circRNAs) played critical roles in the progression of CRC. However, the effects and underlying mechanisms of circ_0000512 in CRC progression remain unclear. Methods The expression levels of circ_0000512, microRNA-296-5p (miR-296-5p) and runt-related transcription factor 1 (RUNX1) were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability, colony formation, cell cycle distribution and cell apoptosis were detected by Cell Counting Kit-8 (CCK-8) assay, colony formation assay and flow cytometry analysis, respectively. Western blot assay was utilized to measure the protein expression of Cyclin D1, Cleaved Caspase-3 and RUNX1. The interaction between miR-296-5p and circ_0000512 or RUNX1 was predicted by starBase and verified by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull-down assay. The mice xenograft model was established to explore the function of circ_0000512 in vivo. Results The expression of circ_0000512 was increased in CRC tissues and cells. Knockdown of circ_0000512 suppressed cell viability and colony formation and arrested the cells at the G0/G1 phase while it accelerated apoptosis in CRC cells. Mechanistically, circ_0000512 could increase RUNX1 expression by acting as a molecular sponge of miR-296-5p in CRC cells. Furthermore, miR-296-5p downregulation or RUNX1 overexpression reversed the anti-proliferation and pro-apoptosis effects caused by circ_0000512 knockdown in CRC cells. In addition, circ_0000512 interference inhibited tumor growth by upregulating miR-296-5p and downregulating RUNX1 in vivo. Conclusion Knockdown of circ_0000512 inhibited cell proliferation and induced apoptosis in CRC cell by regulating miR-296-5p/RUNX1 axis, which might provide a potential therapeutic target for CRC treatment.
Hypertrophic scar (HS) is characterized by fibroblast hyperproliferation and excessive matrix deposition. Aberrant keratinocyte differentiation and their abnormal cytokine secretion are said to contribute to HS by activating fibroblasts. However, the signalling pathway causing the aberrant keratinocytes in HS has remained unidentified thus far. Given that Notch signalling is crucial in initiating keratinocyte differentiation, we hypothesized that Notch signalling contributes to HS by modulating the phenotype of keratinocytes. We found that Notch1, Notch intracellular domain, Jagged1 and Hes-1 were overexpressed in the epidermis of patients with HS. Supernatants from recombinant-Jagged1-treated keratinocyte cultures could accelerate dermal fibroblast proliferation and collagen production. Furthermore, Jagged1 induced keratinocyte differentiation and upregulated the expression of fibrotic factors, including transforming growth factors β1 and β2 , insulin-like growth factor-1, connective tissue growth factor, vascular endothelial growth factor and epidermal growth factor, while DAPT (a Notch inhibitor) significantly suppressed these processes. In a rabbit ear model of HS, local application of DAPT downregulated the production of fibrotic factors in keratinocytes, together with ameliorated scar hyperplasia. Our findings suggest that Notch signalling contributes to HS by modulating keratinocyte phenotype. These results provide new insights into the pathogenesis of HS and indicate a potential therapeutic target.
Hypoxic microenvironment represents the hallmark of solid tumors including colorectal cancer (CRC) and facilitates angiogenesis and chemoresistance, leading to poor prognosis. lncRNA NORAD acts as an oncogenic gene to orchestrate cancer progression by regulating cell proliferation and migration. Notably, an emerging study corroborates the elevation of NORAD during hypoxic conditions in pancreatic cancer. Nevertheless, its biological role in hypoxia-evoked CRC remains unclear. Herein, enhanced expression of NORAD and hypoxia-inducible factor-1α (HIF-1α) was validated in CRC tissues. Furthermore, there was a positive association between NORAD and HIF-1α in CRC tissues. CRC cells exposed to hypoxia exhibited a stronger ability to form vasculogenic mimicry (VM) and resistance to 5-fluorouracil (5-FU), concomitant with higher expression of NORAD. NORAD knockdown restrained hypoxia-induced VM formation and VM marker VE-cadherin expression. Moreover, knockdown of NORAD counteracted CRC cell resistance to 5-FU by decreasing cell viability and increasing cell apoptosis. Additionally, NORAD loss reduced hypoxia-induced HIF-1α expression and subsequent epithelial-mesenchymal transition (EMT) by increasing E-cadherin and inhibiting N-cadherin expression. Intriguingly, HIF-1α overexpression reversed NORAD downregulation-mediated inhibition of VM formation and 5-FU resistance. There was a low expression of miR-495-3p in CRC tissues. Furthermore, NORAD could act as a competitive endogenous RNA of miR-495-3p to regulate HIF-1α. Importantly, inhibition of miR-495-3p muted the efficacy of NORAD loss in hypoxia-induced EMT, VM, and chemoresistance. Thus, the current data highlight that NORAD knockdown may antagonize hypoxia-triggered CRC malignancy by suppressing VM formation and chemoresistance by sponging miR-495-3p/HIF-1α to regulate EMT, supporting a promising therapeutic target for refractory hypoxia in CRC.
Background: Loss of beard in adult male caused by severe burn may cause cosmetic and psychological problems for these patients. Reconstruction of the beard with hair-bearing skin flaps in similar color and texture of the surrounding tissues remains a challenge. Methods: Eight male patients suffered from submental postburn scar and beard loss were treated by using the hair-bearing expanded scalp flap. A 1000 mL nephroid tissue expander was first implanted under the frontal and mid scalp. After a 3 to 4-month tissue expansion, the expanded hair-bearing scalp flap based on bilateral superficial temporal vessels were raised and transferred for beard reconstruction, and the cutaneous pedicles were curled into tubes. Delay and division of the pedicles were performed 3 to 4 weeks after flap transfer. Results: Eight male patients with postburn scar and beard loss were successfully treated with no major complication. One patient suffered from edge necrosis at distal end of the flap and healed after daily dressing change. Chin and submental areas were repaired by expanded scalp flap and total beard was reconstructed at the same time. All donor sites were closed directly without skin grafting. Conclusions: The modified expanded bipedicled scalp flap provides an easy and reliable way for total beard reconstruction and large-scale submental scars repairment.
BackgroundA technique for reconstructing facial units with matching colour, similar texture and sufficient contour is ideal for patients with various facial defects. The current report aimed to present the experience of the authors in facial reconstruction using pre-expanded scalp flaps combined with laser hair removal.MethodsFrom January 2014 to August 2021, 43 patients with different facial defects, such as post-burn scar and congenital nevus, were treated using this surgical technique that involved tissue expansion, scalp flap transfer and laser hair removal. Facial defects were artificially classified into three regions (forehead, n = 19; cheek, n = 15; and lips and chin, n = 9). Pedicle delaying and division were performed in patients who underwent reconstruction with pedicled flaps.ResultsOf the included patients, one presented with haematoma, one with infection and three had distal necrosis after expanded scalp flap transfer. The donor site was primarily closed in all patients. Further, all patients were successfully treated without major complications. The texture, colour and contour of the scalp flap after laser hair removal matched well with the surrounding skin tissues at 2–30-month follow-up.ConclusionReconstruction using pre-expanded scalp flaps combined with laser hair removal is an effective and reliable option for facial reconstruction with excellent colour and texture match.
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