CircPIAS1 promotes hepatocellular carcinoma progression by inhibiting ferroptosis via the miR-455-3p/NUPR1/FTH1 axis.

BACKGROUND: The role of circRNAs in hepatocellular carcinoma (HCC) progression remains unclear. CircPIAS1 (circBase ID: hsa_circ_0007088) was identified as overexpressed in HCC cases through bioinformatics analysis. This study aimed to investigate the oncogenic properties and mechanisms of circPIAS1 in HCC development. METHODS: Functional analyses were conducted to assess circPIAS1's impact on HCC cell proliferation, migration, and ferroptosis. Xenograft mouse models were employed to evaluate circPIAS1's effects on tumor growth and pulmonary metastasis in vivo. Bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays were utilized to elucidate the molecular pathways influenced by circPIAS1. Additional techniques, including RNA pulldown, fluorescence in situ hybridization (FISH), chromatin immunoprecipitation (ChIP), qPCR, and western blotting, were used to further explore the underlying mechanisms. RESULTS: CircPIAS1 expression was elevated in HCC tissues and cells. Silencing circPIAS1 suppressed HCC cell proliferation and migration both in vitro and in vivo. Mechanically, circPIAS1 overexpression inhibited ferroptosis by competitively binding to miR-455-3p, leading to upregulation of Nuclear Protein 1 (NUPR1). Furthermore, NUPR1 promoted FTH1 transcription, enhancing iron storage in HCC cells and conferring resistance to ferroptosis. Treatment with ZZW-115, an NUPR1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib. CONCLUSION: This study highlights the critical role of circPIAS1 in HCC progression through modulation of ferroptosis. Targeting the circPIAS1/miR-455-3p/NUPR1/FTH1 regulatory axis may represent a promising therapeutic strategy for HCC.

Efficacy and safety of perioperative therapy for locally resectable gastric cancer: A network meta-analysis of randomized clinical trials.

BACKGROUND: Gastric cancer (GC) is the fifth most commonly diagnosed malignancy worldwide, with over 1 million new cases per year, and the third leading cause of cancer-related death. AIM: To determine the optimal perioperative treatment regimen for patients with locally resectable GC. METHODS: A comprehensive literature search was conducted, focusing on phase II/III randomized controlled trials (RCTs) assessing perioperative chemotherapy and chemoradiotherapy in treating locally resectable GC. The R0 resection rate, overall survival (OS), disease-free survival (DFS), and incidence of grade 3 or higher nonsurgical severe adverse events (SAEs) associated with various perioperative regimens were analyzed. A Bayesian network meta-analysis was performed to compare treatment regimens and rank their efficacy. RESULTS: Thirty RCTs involving 8346 patients were included in this study. Neoadjuvant XELOX plus neoadjuvant radiotherapy and neoadjuvant CF were found to significantly improve the R0 resection rate compared with surgery alone, and the former had the highest probability of being the most effective option in this context. Neoadjuvant plus adjuvant FLOT was associated with the highest probability of being the best regimen for improving OS. Owing to limited data, no definitive ranking could be determined for DFS. Considering nonsurgical SAEs, FLO has emerged as the safest treatment regimen. CONCLUSION: This study provides valuable insights for clinicians when selecting perioperative treatment regimens for patients with locally resectable GC. Further studies are required to validate these findings.

Effect of paeoniflorin on distal survival of random flaps.

BACKGROUND: Distal ischemic necrosisis a common complication of orthopedic random skin flaps surgery. Paeoniflorin, a natural compound extracted from Paeonia lactiflora, can enhances angiogenesis and alleviates excessive inflammatory response. We investigated the changes of ischemic extra-long flaps with paeoniflorin and its possible mechanism. METHODS: We raised dorsal McFarlane flaps in 54 Sprague-Dawley rats. We designed three groups of rats: high-paeoniflorin group (HP, 50 mg/kg/d), low-paeoniflorin group (LP, 20 mg/kg/d), and control group. The flap survival rate was calculated, seven days after flap construction.Blood perfusion was detected by laser Doppler flow imaging, and angiogenesis wasdetected by Lead oxide/gelatin angiography.Oxidative stress levels of flaps were determined by detecting superoxide dismutase (SOD) and malondialdehyde (MDA). The histopathological status of flap was evaluated by hematoxylin and eosin (H&E) staining.Immunohistochemistry was used to determine the expression of high mobility group protein B1 (HMGB1), nuclear factor-kappa B (NF-κB), Toll-like receptor 4 (TLR4), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1ß, IL-18, vascular endothelial growth factor (VEGF), cysteine protease-1 (caspase-1) and NLPR3. RESULTS: The flap survival rates and SOD activity in the experimental groups were significantly higher, while MDA activity was lower. Experimental groups showed significantly improved microcirculatory blood flow to the flap and increased angiogenesis. Immunohistochemistry revealed that paeoniflorin was associated with significantly increased VEGF expression, and decreased level of HMGB1, TLR4, TNF-α, NF-κB, IL-6, IL-1ß, caspase-1, NLPR3, and IL-18. CONCLUSIONS: Paeoniflorin effectively enhanced the survival of rat random skin flaps by promoting vascular hyperplasia, inhibiting pyroptosis, and down-regulating inflammation.

Exenatide inhibits necrosis by enhancing angiogenesis and ameliorating ischemia/reperfusion injury in a random skin flap rat model.

BACKGROUND: Random skin flaps are often used for plastic repair because they are convenient and flexible. However, necrosis of flaps is a common complication that may lead to disastrous consequences. Exenatide, a glucagon-like peptide 1 receptor agonist, can enhance angiogenesis and ameliorate ischemia/reperfusion injury. Our experiments explored random skin flap outcomes after its use. METHODS: We established modified dorsal McFarlane flaps on 54 Sprague-Dawley rats and divided the rats into three groups (control, Exe-I, and Exe-II). We intraperitoneally injected either 4 or 8 µg/kg/day exenatide into the rats of the Exe-I and Exe-II groups, respectively. On the seventh day after the operation, we measured the levels of superoxide dismutase (SOD) and malondialdehyde (MDA). Tissue sections were obtained for histopathological and immunohistochemical analyses, and we evaluated the expression of vascular endothelial growth factor (VEGF), interleukin (IL) 6, IL-1ß, nuclear factor kappa beta (NF-κB), Toll-like receptor 4 (TLR4), and tumor necrosis factor α (TNF-α). We measured blood flow reconstruction and angiogenesis using laser Doppler blood flowmetry and lead oxide/gelatin angiography, respectively. RESULTS: Exenatide increased the average survival area of the flap and improved microvascular density and blood flow intensity in a dose-dependent manner. Meanwhile, the SOD level was up-regulated and the MDA level down-regulated. Exenatide also enhanced the expression of VEGF and reduced the expression of inflammatory cytokines (IL-6, IL-1ß, NF-κB, TLR4, and TNF-α), thereby promoting angiogenesis and inhibiting inflammation. CONCLUSIONS: Exenatide potentially inhibits necrosis in our rat random skin flap model.

Angiogenic and anti-inflammatory properties of azadirachtin A improve random skin flap survival in rats.

Random skin flaps are widely used to repair tissue defects. However, the distal flap regions are prone to ischemic necrosis, limiting clinical applications. Azadirachtin A, a fruit extract from the neem, improves tissue blood supply and metabolism, reduces cell swelling, promotes tissue healing, and prevents venous thrombosis. We explored whether it enhances random skin flap survival. Fifty-four Sprague-Dawley rats were divided into control, low-dose, and high-dose Azadirachtin A-treated groups using a random number table. We used an improved version of the McFarlane technique to create flaps. On day 2, superoxide dismutase and malondialdehyde levels were measured. Tissue slices prepared on day 7 were stained with hematoxylin and eosin. The expression levels of vascular endothelial growth factor (VEGF), toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-kB), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were immunohistochemically assayed. Microcirculatory blood flow was measured via laser Doppler blood flowmetry. Flap angiography was performed using the lead-oxide gelatin injection technique. And the azadirachtin A groups exhibited a greater mean flap survival area, an improved mean blood vessel density, a greater blood flow, and higher superoxide dismutase and VEGF levels, especially at the high dose. Azadirachtin A markedly reduced the levels of TNF-α, IL-6, IL-1ß, TLR4, and NF-kB. These findings suggest that azadirachtin A promotes random skin flap survival by improving the blood supply, reducing tissue inflammation, and inhibiting flap ischemia reperfusion injury.

Overexpression of MMP-1 and VEGF-C is associated with a less favorable prognosis in esophageal squamous cell carcinoma.

BACKGROUND: This study addresses the association of matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor-C (VEGF-C) expression in esophageal squamous cell carcinoma (SCC) with clinicopathologic characteristics in the patients. MATERIAL AND METHODS: We profiled the expression of MMP-1 and VEGF-C by cDNA microarray in 4 cases and by reverse transcription-polymerase chain reaction (RT-PCR) in 14 cases of esophageal SCC. Another 90 cases were reviewed by immunohistochemical examination of paraffin-embedded sections. RESULTS: Expression of MMP-1 and VEGF-C mRNA in normal esophageal tissue and tumor tissue was compared. Data were fully consistent with the results of RT-PCR. Immunohistochemistry showed that compared to the normal mucosa MMP-1 and VEGF-C protein expression was upregulated in both esophageal atypical hyperplasia (n = 16) and esophageal SCC. Depth of tumor invasion, lymph node metastasis, and clinical stage were directly associated with prognosis in all cases. Furthermore, median overall survival and disease-free survival were significantly shorter in patients with a higher expression of MMP-1 and VEGF-C than in patients with lower expression levels. CONCLUSION: We demonstrated that the expression of both MMP-1 and VEGF-C mRNA and protein was upregulated in esophageal SCC tissues. Protein expression was associated with progressive tumor stage and poor prognosis in patients with esophageal SCC.