Histone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression.Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography.HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo.Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked. Conceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress-activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination. • Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling. • HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. • Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination.
Abstract Background The study aim was to reevaluate the learning curve of laparoscopic Roux-en Y gastric bypass (LRYGB) in the modern era considering a single surgeon’s experience. Methods Except those with body mass index (BMI) >50 kg/m 2 needs further discussion; all other patients who met the regional criteria and underwent primary LRYGB were retrospectively enrolled. Those who underwent surgery in 2016-17, 2018 and 2019 by a single surgeon with 10+ years of laparoscopic experience were assigned to groups A, B and C, respectively. Patient demographics and 30-day outcome data, including operation time, length of stay (LOS), emergency room visits, readmission, and reoperation, were compared between groups. Results One hundred and eight patients met the inclusion criteria; 36, 38, and 34 patients were assigned to groups A, B and C, respectively. There were no differences in age, sex distribution or common comorbidities between groups, except group B had a lower BMI (35.1 kg/m 2 vs. 37.0 kg/m 2 ) and a higher rate of hypertension (44.7% vs. 22.2%) than group A. The operation time was markedly reduced (96.1 min and 114.9 min, respectively), and the LOS was shortened (2.2 days and 2.9 days, respectively) in group B compared to group A and remained stationary in group C, with no further reduction in 30-day complications. Conclusion The learning process for LRYGB can be shortened to approximately 30 cases if conducted selectively and by experienced laparoscopic surgeons. Further follow-up is required to verify the long-term safety and its applicability to other patient subgroups.
Acute abdominal pain during pregnancy is challenging, both from a diagnostic and management perspective. A non-localized, persistent pain out of proportion to physical examination is a sign that advanced imaging may be necessary. Mesenteric venous thrombosis in a pregnant patient is extremely rare, but if diagnosis is delayed, can be potentially fatal to both the mother and the fetus. We present here a pregnant patient in the tenth week of gestation with classic clinical manifestations of mesenteric vein thrombosis and the corresponding findings on magnetic resonance imaging (MRI) and computed tomography (CT).
Abstract Background: Activated microglia-mediated neuro-inflammation plays a vital aspect in regulating the micromilieu of the central nervous system. Neuro-inflammation involves distinct alterations of microglial phenotypes, containing nocuous pro-inflammatory (M1) phenotype and neuroprotective anti-inflammatory (M2) phenotype. Currently, there is no effective treatment for modulating such alterations. Little evidence shows that melatonin prevents the detrimental cascade of activated microglia-mediated neuro-inflammation. Methods: The expression levels of M1/M2 marker of primary microglia influenced by Melatonin were detected via qPCR. Functional activities were explored by western blotting, luciferase activity, EMSA, and ChIP assay. Structure interaction was assessed by molecular docking and LIGPLOT analysis. ER stress detection was examined by ultrastructure TEM, calapin activity, and ERSE assay. The neurobehavioral evaluations and immunofluorescence staining in animals were used for investigation of Melatonin on the neuroinflammation in vivo . Results: Melatonin had targeted on Peroxisome Proliferator Activated Receptor Delta (PPARd) activity, boosted LPS-stimulated alterations in polarization from the M1 to the M2 phenotype, and thereby inhibited NFkB–IKKb activation in primary microglia. The PPARd agonist L-165041 or over-expression of PPARd plasmid (ov-PPARd) showed similar results. Molecular docking screening, dynamic simulation approaches, and biological studies of melatonin showed that the activated site was located at PPARd (phospho-Thr256-PPARd). Furthermore, we found that activated microglia had lowered PPARd activity as well as the downstream SIRT1 formation via enhancing ER stress. Melatonin, PPARd agonist and ov-PPARd all effectively reversed the above-mentioned effects. Melatonin blocked ER stress by regulating calapin activity and expression in LPS-activated microglia. Additionally, melatonin or L-165041 ameliorated the neurobehavioral deficits in LPS-aggravated neuroinflammatory mice through blocking microglia activities, and also promoted phenotype changes to M2-predominant microglia. Conclusions Melatonin suppressed neuro-inflammation in vitro and in vivo by tuning microglial activation through the ER stress-dependent PPARd/SIRT1 signaling cascade. We proposed that this treatment strategy is an encouraging pharmacological approach for the remedy of neuro-inflammation associated disorders.
Abstract Bleeding is a major and potentially life-threatening complication of peptic ulcer. Despite endoscopic hemostatic therapy advance, conventional endoscopic hemostatic modalities remain refractory for peptic ulcer bleeding with big size, fibrous base or in difficult-to-access anatomical locations. In this study, we attempted to evaluate the efficacy and safety of endoscopic cyanoacrylate injection treatment (ECIT) for refractory high-risk peptic ulcer bleeding by conventional endoscopic therapy. The patients with refractory high-risk peptic ulcer bleeding by conventional endoscopic therapy were carried out ECIT. The data were retrospectively collected. A total of 119 patients accepted ECIT. 74 patients (62.18%) obtained successful intravascular injection and perivascular injection was performed in 45 patients (37.82%). Immediate hemostatic rate for active bleeding achieved 90.91%. Rebleeding rate within 30 days was 12.07%. Overall successful hemostasis rate achieved 87.93%. Immediate hemostatic rate and overall successful hemostasis rate in intravascular injection patients were markedly superior over perivascular injection. Rebleeding rate in intravascular injection patients was markedly lower than that in perivascular injection patients. 11 patients complicated abdominal pain and no other complication occurred. In conclusion, ECIT, especial intravascular injection, was effective and safe, with high successful hemostasis rate for refractory high-risk peptic ulcer bleeding by conventional endoscopic therapy.
Peritoneal dissemination of tumor has high mortality and is associated with the loss of epithelial features, acquisition of motile mesenchymal morphology characteristics, and invasive properties by tumor cells. Melatonin is an endogenously produced molecule in all plant species that is known to exert antitumor activity, but to date, its underlying mechanisms and antiperitoneal metastasis efficacy is not well defined. This study determined the antiperitoneal dissemination potential of melatonin in vivo and assessed its association with the inhibition of epithelial-to-mesenchymal transition (EMT) signaling mechanism by endoplasmic reticulum (ER) stress, which may be a major molecular mechanism of melatonin against cancer. The results demonstrate that melatonin inhibited peritoneal metastasis in vivo and activated ER stress in Cignal ERSE Reporter Assay, organelle structure in transmission electron microscopy images, calpain activity, and protein biomarkers like p-elf2α. Moreover, the overexpression of transcription factor C/EBPβ in gastric cancer interacted with NFκB and further regulates COX-2 expression. These were dissociated and downregulated by melatonin, as proven by immunofluorescence imaging, immunoprecipitation, EMSA, and ChIP assay. Melatonin or gene silencing of C/EBPβ decreased the EMT protein markers (E-cadherin, Snail, and Slug) and Wnt/beta-catenin activity by Topflash activity, and increased ER stress markers. In an animal study, the results of melatonin therapy were consistent with those of in vitro findings and attenuated systemic proangiogenesis factor production. In conclusion, C/EBPβ and NFκB inhibition by melatonin may impede both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT.
Idiopathic pulmonary fibrosis is a devastating disease with multiple contributing factors. Insulin-like growth factor 1 receptor (IGF1R), with a reciprocal function to aryl hydrocarbon receptor (AhR), is involved in airway inflammation. The exact relationship between IGF1R and AhR in lung fibrogenesis is unclear. This study aimed to investigate the cascade pathway involving IGF1R and AhR in idiopathic pulmonary fibrosis.The AhR and IGF1R expressions were determined in the lungs of idiopathic pulmonary fibrosis patients and in a rodent fibrosis model. Pulmonary fibrosis was evaluated in bleomycin (BLM)-induced lung injury in wild type and AhR knockout (Ahr-/- ) mice. The effects of IGF1R inhibition and AhR activation in vitro on TGF-β1-induced epithelial-mesenchymal transition (EMT) in Beas2B cells and in vivo on BLM-exposed mice were also examined.There were increased IGF1R levels but AhR expression decreased in the lung of idiopathic pulmonary fibrosis patients and BLM-induced mice. Knockout of AhR aggravated lung fibrosis, while the use of IGF1R inhibitor and AhR agonist significantly attenuated such effects and inhibited TGF-β1-induced epithelial-mesenchymal transition in Beas2B cells. Both TGF-β1 and BLM markedly suppressed AhR expression through endoplasmic reticulum stress and consequently, IGF1R activation. The IGF1R inhibitor and specific knockdown of IGF1R reversed the activation of the TGF-β1 signal pathway.In the development of idiopathic pulmonary fibrosis, AhR and IGF1R play opposite roles via the TGF-β/Smad/STAT signalling cascade. The AhR/IGF1R axis is a potential target for the treatment of lung injury and fibrosis.
In this study, we studied the therapeutic effectiveness of percutaneous drainage with antibiotics and the need for an interval appendectomy for treating appendiceal abscess in children with a research-oriented dataset released by the Bureau of National Health Insurance in Taiwan through the Collaboration Center for Health Information Application (CCHIA).We identified 1225 patients under 18 years of age who had non-surgical treatment for an appendiceal abscess between 2007 and 2012 in a Taiwan CCHIA dataset. The treatment included percutaneous drainage with antibiotics or antibiotics alone. We also analyzed data of patient's baseline characteristics, outcomes of percutaneous drainage, and indicating factors for performing an interval appendectomy.Totally, 6190 children had an appendiceal abscess, an 1225 patients received non-operative treatment. Of 1225 patients, 150 patients received treatment with percutaneous drainage and antibiotics, 78 had recurrent appendicitis, 185 went on to receive an interval appendectomy, and 10 had postoperative complications after the interval appendectomy. We found that patients treated with percutaneous drainage and antibiotics had a significantly lower rate of recurrent appendicitis (p < 0.05), a significantly smaller chance of receiving an interval appendectomy (p < 0.05), and significantly fewer postoperative complications after the interval appendectomy (p < 0.05) than those without percutaneous drainage treatment. Older children (13 ~ 18 years) patients were found to have a significantly smaller need to receive an interval appendectomy than those who were ≤ 6 years of age (odd ratio (OR) = 2.071, 95 % confidence interval (CI) = 1.34-3.19, p < 0.01), and those who were 7 ~ 12 years old (OR = 1.662, 95 % CI = 1.15-2.41, p < 0.01). In addition, those treated with percutaneous drainage were significantly less indicated to receive an interval appendectomy later (OR = 2.249, 95 % CI = 1.19 ~ 4.26, p < 0.05). In addition, those with recurrent appendicitis had a significantly increased incidence of receiving an interval appendectomy later (OR = 3.231, 95 % CI = 1.95 ~ 5.35, p < 0.001).In this study, we used nationwide data to demonstrate therapeutic effectiveness of percutaneous drainage and antibiotics was more beneficial than only antibiotics in treating patients with an appendiceal abscess. We also found three factors that were significantly associated with receiving an interval appendectomy: recurrent appendicitis, being aged ≤ 13 years, and treatment with antibiotics only.
'/%3e%3cuse xlink:href='%23a' transform='rotate(60)'/%3e%3ccircle r='17' fill='%23000095'/%3e%3ccircle r='15' fill='%23fff'/%3e%3c/svg%3e)