Development of antifibrotic therapy for stricturing Crohn's disease: lessons from randomized trials in other fibrotic diseases.

Intestinal fibrosis is considered an inevitable complication of Crohn's disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

The optimal antithrombotic strategy for post-stroke patients with atrial fibrillation and extracranial artery stenosis-a nationwide cohort study.

BACKGROUND: In post-stroke atrial fibrillation (AF) patients who have indications for both oral anticoagulant (OAC) and antiplatelet agent (AP), e.g., those with carotid artery stenosis, there is debate over the best antithrombotic strategy. We aimed to compare the risks of ischemic stroke, composite of ischemic stroke/major bleeding and composite of ischemic stroke/intracranial hemorrhage (ICH) between different antithrombotic strategies. METHODS: This study included post-stroke AF patients with and without extracranial artery stenosis (ECAS) (n = 6390 and 28,093, respectively) identified from the Taiwan National Health Insurance Research Database. Risks of clinical outcomes and net clinical benefit (NCB) with different antithrombotic strategies were compared to AP alone. RESULTS: The risk of recurrent ischemic stroke was higher for patients with ECAS than those without (12.72%/yr versus 10.60/yr; adjusted hazard ratio [aHR] 1.104, 95% confidence interval [CI] 1.052-1.158, p < 0.001). For patients with ECAS, when compared to AP only, non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy was associated with lower risks for ischaemic stroke (aHR 0.551, 95% CI 0.454-0.669), the composite of ischaemic stroke/major bleeding (aHR 0.626, 95% CI 0.529-0.741) and the composite of ischaemic stroke/ICH (aHR 0.577, 95% CI 0.478-0.697), with non-significant difference for major bleeding and ICH. When compared to AP only, warfarin monotherapy was associated with higher risks of major bleeding (aHR 1.521, 95% CI 1.231-1.880), ICH (aHR 2.045, 95% CI 1.329-3.148), and the composite of ischaemic stroke and major bleeding. With combination of AP plus warfarin, there was an increase in ischaemic stroke, major bleeding, and the composite outcomes, when compared to AP only. NOAC monotherapy was the only approach associated with a positive NCB, while all other options (warfarin, combination of AP-OAC) were associated with negative NCB. CONCLUSIONS: For post-stroke AF patients with ECAS, NOAC monotherapy was associated with lower risks of adverse outcomes and a positive NCB. Combination of AP with NOAC or warfarin did not offer any benefit, but more bleeding especially with AP-warfarin combination therapy.

Efficacy of ultrasound guided caudal epidural steroid injection with or without ozone in patients with lumbosacral canal stenosis; a randomized clinical controlled trial.

BACKGROUND: Lumbosacral canal stenosis is known as the most common cause of back surgery with several complications. Selecting a minimally invasive treatment with high efficacy in such patients is necessary. This study was designed to evaluate the effectiveness of ozone therapy in combination with caudal epidural steroid in patients with lumbar spinal stenosis. METHODS: A double-blind randomized clinical trial was conducted on 50 patients with lumbar spinal stenosis allocated into two study groups. Under ultrasound guidance, the first group received 80 mg of triamcinolone hexavalent with 4 mL of Marcaine 0.5% and 6 mL of distilled water to the caudal epidural space. The second group received an injection similar to the first group, combined with 10 mL of ozone (O2-O3) gas at a concentration of 10 µg/cc. The patients were followed at baseline, one, and six months after injection with clinical outcomes measures using Visual Analog Scale (VAS), Walking Distance (WD) and Oswestry Disability Index (ODI). RESULTS: The mean age of subjects, 30 males (60%) and 20 females (40%), was reported as 64.51 ± 7.19 years old. Reduction of pain intensity based on VAS score was statistically significant in both groups at follow-up periods (P < 0.001). The VAS changes in the first month and sixth months showed no significant difference between the two groups (P = 0.28 and P = 0.33, respectively). The improvement in disability index (ODI) in both types of treatment during follow-up was significant (P < 0.0001), and there was no difference between the two treatment groups in one month and six months (P = 0.48 and P = 0.88, respectively). As for walking distance, the improvement process with both types of treatment during follow-up periods was significant (P < 0.001). However, after one and six months of treatment, the rate of improvement in patients' walking distance in the caudal epidural steroid injection plus ozone group was significantly higher than in the epidural steroid group (p = 0.026 and p = 0.017, respectively). CONCLUSIONS: In this study, the results of VAS and ODI outcomes showed that caudal epidural steroid injection combined with ozone has no advantage over caudal epidural steroid injection alone. Interestingly, our results demonstrated that the group receiving caudal epidural steroid injection plus ozone scored significantly higher on the walking distance index than the group receiving caudal epidural steroid alone. TRIAL REGISTRATION: IRCT IRCT20090704002117N2 (registration date: 07/08/2019).

Does the clopidogrel CYP2C19 genotype assay predict postprocedure stenosis in cerebral aneurysms treated with a flow diverter?

OBJECTIVE: Flow diverters have emerged as a popular modality for treating cerebral aneurysms but require dual antiplatelet therapy (DAPT) after placement. Clopidogrel is a common choice but is a prodrug that some patients may not convert into an active metabolite. The CYP2C19 genotype assay is used to predict activation speed; however, limited data exist showcasing whether this genotype accurately predicts postprocedure complications after flow diversion treatment of cerebral aneurysms. Therefore, the authors sought to characterize whether CYP2C19 genotype correlated with the development of postprocedure intimal hyperplasia (stenosis) after flow diverter placement. METHODS: Medical records were reviewed for patients who underwent flow diverter treatment of cerebral aneurysm at a single academic institution between January 1, 2012, and May 31, 2020. Patient demographics and comorbidities were reviewed alongside CYP2C19 genotype assay, DAPT regimen, and postprocedure angiogram data. Stenosis was defined based on review of angiogram data by two independent physicians. RESULTS: In this review of 120 unique cerebral aneurysms, 102 received DAPT with clopidogrel and 18 received DAPT with an alternative agent. Stenosis was present on 3-month follow-up angiogram for 35/102 (34.3%) aneurysms receiving DAPT with clopidogrel and in 11/18 (61.1%) aneurysms receiving an alternative DAPT regimen (p = 0.031). The CYP2C19 genotype did not correlate with postprocedure stenosis (p = 0.35). CONCLUSIONS: Clopidogrel was a significantly more effective DAPT agent for preventing stenosis when compared to nonclopidogrel DAPT regimens. The clopidogrel CYP2C19 genotype did not predict postprocedure stenosis in this cohort of 120 cerebral aneurysms treated with a flow diverter.

Vascular imaging of patients with refractory Takayasu arteritis treated with tocilizumab: post hoc analysis of a randomized controlled trial.

OBJECTIVES: Tocilizumab, an anti-IL-6 receptor antibody, was investigated in patients with refractory Takayasu arteritis (TAK) in a phase 3 randomized controlled trial. In this post hoc analysis, we investigated whether tocilizumab treatment inhibited the progression of vascular lesions caused by TAK in these patients. METHODS: Included patients received at least one dose of tocilizumab and underwent CT at baseline and at week 48 after tocilizumab initiation. Three radiologists not involved in the original trial independently evaluated the CT images. Twenty-two arteries from each patient were assessed for change from baseline in wall thickness (primary endpoint), dilatation/aneurysm, stenosis/occlusion or wall enhancement for at least 96 weeks after tocilizumab initiation. Patient-level assessments were also conducted. RESULTS: In 28 patients, 86.7% of 22 arteries had improved or stable wall thickness at week 96. Proportions of patients with improved or stable, partially progressed or newly progressed lesions were 57.1%, 10.7% and 28.6%, respectively, for wall thickness; proportions with improved or stable lesions were 92.9% for dilatation/aneurysm, and 85.7% for stenosis/occlusion. Patients with newly progressed lesions, reflecting more refractory disease, were prescribed glucocorticoids at dosages that could not be reduced below 0.1 mg/kg/day at week 96. CONCLUSIONS: Approximately 60% of patients with TAK did not experience progression in wall thickness within 96 weeks after initiation of tocilizumab treatment. Few patients experienced progressed dilatation/aneurysm, or stenosis/occlusion. Wall thickness progression likely resulted from refractory TAK. Patients who experience this should be monitored regularly by imaging, and additional glucocorticoid or immunosuppressive treatment should be considered to avoid vascular progression. TRIAL REGISTRATION: Japan Pharmaceutical Information Centre number, JapicCTI-142616.

Effects of PCSK9 Inhibition on Coronary Atherosclerosis Regression of Nontarget Lesions after Primary Percutaneous Coronary Intervention in Acute Coronary Syndrome Patients.

Aims: To evaluate the regression of coronary atherosclerosis with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in acute coronary syndrome (ACS) patients following primary percutaneous coronary intervention (PPCI). Methods and Result. We examined 40 nontarget lesions in 17 ACS patients who underwent PPCI and were treated with PCSK9 inhibitors. At 1 year, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and atherogenic index (AI) decreased significantly by 2.5 mmol/L, 2.01 mmol/L, and 1.86, respectively. On quantitative coronary angiography, treatment with PCSK9 inhibitors reduced significantly the atherosclerotic area stenosis in nontarget lesions (61.18 ± 14.55 at baseline vs. 52.85 ± 15.51 at 1 year, P < 0.001). Conclusions: After 1 year of PCSK9 inhibition treatment for ACS patients, the area stenosis of non-TLR was considerably reduced.

Safety and efficacy comparison between OACs plus single antiplatelet and dual antiplatelet therapy in patients with cerebral venous sinus stenosis poststenting.

BACKGROUND AND PURPOSE: The present strategies regarding poststent management for cerebral venous sinus stenosis (CVSS) are inconsistent. Herein, we compared the safety and efficacy of oral anticoagulants (OACs) plus single antiplatelet therapy and dual antiplatelet therapy for CVSS poststenting. METHODS: A real-world observational study conducted from January 2009 through October 2019 enrolled patients who were diagnosed with CVSS and received stenting. Patients were divided into two groups according to the management they received poststenting. Group 1: OACs plus a single antiplatelet agent (clopidogrel 75 mg or aspirin 100 mg) and Group 2: dual antiplatelet therapy (clopidogrel 75 mg plus aspirin 100 mg). The safety (such as major or minor bleeding or venous thrombosis) and efficacy (the incidences of cerebral venous sinus restenosis, intrastent thrombosis, or stent displacement) of the two groups were compared. RESULTS: There were a total of 110 eligible patients in the final analysis, including 79 females and 31 males with a mean age of 43.42 ± 13.23 years. No major bleeding or venous thrombosis occurred in either of the two groups. Two minor bleeding events occurred in group 2 (one with subcutaneous bleeding points in both lower limbs, another with submucosal bleeding in the mouth), whereas no bleeding events occurred in Group 1. In addition, at the 1-year follow-up, one case of intraluminal restenosis and two cases of in-stent thrombi occurred in Group 2, while none occurred in Group 1. Neither stenosis at stent-adjacent segments nor stent migration was detected in either group during the 1-year following stent placement. CONCLUSION: OACs plus single antiplatelet therapy and dual antiplatelet therapy alone are both safe and efficacious management strategies after CVSS stent placement. The former may have more advantages than the latter for inhibiting intrastent thrombosis. However, further research by larger, multicenter clinical trials is needed.

Analysis of Inhibitory Effect of the Double-layer Nano-infusion on Vascular Restenosis in Animal Models of Coronary Atherosclerosis.

This study aimed to investigate the effect of double-layer nano-infusion on restenosis in animal models of coronary atherosclerosis (CAD). For this purpose, forty Apolipoprotein E (APOE) gene mice (ApoE -/ -) were fed with 1.25% cholesterol, 10% fat, and 88.75% standard diet to establish CAD models. They were classified into the control group with paclitaxel nanoparticles (PTX-NPs) and the observation group with balloon infusion of PTX combined with vascular endothelial growth factor (VEGF) double-layer nanoparticles (V-P-NPs). The vascular endothelial healing and the occurrence of vascular restenosis were assessed. Results showed no significant differences in the particle size, distribution, and Zeta-potential between PTX-NPs and V-P-NPs (P>0.05). According to the transmission electron microscope (TEM), the nanoparticles had good dispersity, and the structure of the inner and outer layers of V-P-NPs was obvious. There were insignificant differences between the entrapment efficiency of PTX in PTX-PNS and the PTX and VEGF in V-P-NPs (94.32%, 95.66%, 97.89%) and drug-loading rate (28.91%, 30.12%, 29.91%) (P>0.05). The vascular endothelial healing degree of the observation group was better than that of the control group under optical coherence tomography (OCT). The restenosis, including the stenosis (6.91±7.59)%, proliferation (0.12±0.02), and the maximum intima thickness (0.07±0.09)mm of the observation group was decreased compared with the control group ((24.01±12.78)%, (0.28±0.01), (0.19±0.08)mm) (P<0.05). Then the double-layer nano-infusion therapy was conducive to healing vascular endothelial tissue and could effectively inhibit vascular restenosis, with clinical adoption value.

The efficacy and safety of intravenous tranexamic acid in patients with posterior operation of multilevel thoracic spine stenosis: a prospective randomized controlled trial.

BACKGROUND: This study was a randomized controlled trial to evaluate efficacy and safety of the usage of intravenous tranexamic acid during posterior operation of multilevel thoracic spine stenosis for controlling perioperative blood loss. METHODS: Sixty eight patients with multilevel thoracic spine stenosis were randomized into the tranexamic acid group receiving 15 mg/kg body weight before the skin incision was made and 1 mg/kg body weight per hour during operation or the control group receiving the same dose of placebo (0.9% sodium chloride solution) intravenously. Pedicle screw fixation, laminectomy and selective discectomy were performed. Intraoperative and perioperative total blood loss were compared. The necessity and amount for blood transfusion, blood coagulation function, durations of postoperative hospital stays were compared. The complications of tranexamic acid were also investigated such as cardiovascular and cerebrovascular events, lower limb venous thrombosis. RESULTS: There were no statistically significant differences in age, gender, body mass index, ASA status, pathology required surgery, preoperative hemoglobin, operation time, laminectomy segments and discectomy segments between the tranexamic acid and control groups. The intraoperative blood loss (455.9 ± 206.6 ml vs 580.6 ± 224.3 ml, p < 0.05) and total blood loss (675.3 ± 170.3 ml vs 936.8 ± 306.4 ml, p < 0.01) in tranexamic acid group were significant lower than those in control group. The means of blood unit transfused (2.5 ± 1.0 vs 4.7 ± 2.4, p < 0.05) and Hb reduction in 48 h (22.5 ± 3.4 g/L vs 25.3 ± 3.9 g/L, p < 0.01) were significantly lower in tranexamic acid group than that in control group. There were no statistically significant differences in blood coagulation function pre-operation or 48 h post-operation between the tranexamic acid and the control groups. The requirements for patients to receive blood transfusion were fewer and durations of post-operational hospital stays were shorter in the tranexamic acid group, however, the difference did not achieve statistical significance. There was no significant difference in superficial or deep venous thrombosis of lower limbs or deterioration of neurological function between tranexamic acid group and control group. CONCLUSIONS: Application of intravenous tranexamic acid significantly reduces intraoperative and perioperative total blood loss without significant side effects in posterior operation of multilevel thoracic spine stenosis. TRIAL REGISTRATION: At Chinese Clinal Trial Registry. http://www.chictr.org.cn/ , ChiCTR2100054221. Registered on 11/12/2021.

Effect of Stenting Plus Medical Therapy vs Medical Therapy Alone on Risk of Stroke and Death in Patients With Symptomatic Intracranial Stenosis: The CASSISS Randomized Clinical Trial.

Importance: Prior randomized trials have generally shown harm or no benefit of stenting added to medical therapy for patients with symptomatic severe intracranial atherosclerotic stenosis, but it remains uncertain as to whether refined patient selection and more experienced surgeons might result in improved outcomes. Objective: To compare stenting plus medical therapy vs medical therapy alone in patients with symptomatic severe intracranial atherosclerotic stenosis. Design, Setting, and Participants: Multicenter, open-label, randomized, outcome assessor-blinded trial conducted at 8 centers in China. A total of 380 patients with transient ischemic attack or nondisabling, nonperforator (defined as nonbrainstem or non-basal ganglia end artery) territory ischemic stroke attributed to severe intracranial stenosis (70%-99%) and beyond a duration of 3 weeks from the latest ischemic symptom onset were recruited between March 5, 2014, and November 10, 2016, and followed up for 3 years (final follow-up: November 10, 2019). Interventions: Medical therapy plus stenting (n = 176) or medical therapy alone (n = 182). Medical therapy included dual-antiplatelet therapy for 90 days (single antiplatelet therapy thereafter) and stroke risk factor control. Main Outcomes and Measures: The primary outcome was a composite of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. There were 5 secondary outcomes, including stroke in the qualifying artery territory at 2 years and 3 years as well as mortality at 3 years. Results: Among 380 patients who were randomized, 358 were confirmed eligible (mean age, 56.3 years; 263 male [73.5%]) and 343 (95.8%) completed the trial. For the stenting plus medical therapy group vs medical therapy alone, no significant difference was found for the primary outcome of risk of stroke or death (8.0% [14/176] vs 7.2% [13/181]; difference, 0.4% [95% CI, -5.0% to 5.9%]; hazard ratio, 1.10 [95% CI, 0.52-2.35]; P = .82). Of the 5 prespecified secondary end points, none showed a significant difference including stroke in the qualifying artery territory at 2 years (9.9% [17/171] vs 9.0% [16/178]; difference, 0.7% [95% CI, -5.4% to 6.7%]; hazard ratio, 1.10 [95% CI, 0.56-2.16]; P = .80) and 3 years (11.3% [19/168] vs 11.2% [19/170]; difference, -0.2% [95% CI, -7.0% to 6.5%]; hazard ratio, 1.00 [95% CI, 0.53-1.90]; P > .99). Mortality at 3 years was 4.4% (7/160) in the stenting plus medical therapy group vs 1.3% (2/159) in the medical therapy alone group (difference, 3.2% [95% CI, -0.5% to 6.9%]; hazard ratio, 3.75 [95% CI, 0.77-18.13]; P = .08). Conclusions and Relevance: Among patients with transient ischemic attack or ischemic stroke due to symptomatic severe intracranial atherosclerotic stenosis, the addition of percutaneous transluminal angioplasty and stenting to medical therapy, compared with medical therapy alone, resulted in no significant difference in the risk of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. The findings do not support the addition of percutaneous transluminal angioplasty and stenting to medical therapy for the treatment of patients with symptomatic severe intracranial atherosclerotic stenosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01763320.

[The effective analysis of refractory esophageal stricture after endoscopic mucosal dissection of early esophageal cancer treated by endoscopic radiotomy combined with local injection of triamcinolone acetonide].

Refractor esophageal stenosis after endoscopic submucosal dissection of early esophageal carcinoma is a difficult clinical problem. To verify the effect of endoscopic radial incision combined local triamcinolone injection to treat refractory esophageal stenosis, we retrospectively analyzed 7 patients diagnosed with refractory esophageal stricture after endoscopic mucosal dissection of early esophageal cancer in this study, of whom 4 male and 3 female patients, aged 50-76 years, with the mean age of 63 years. We performed the endoscopic radial incision in the thickness point of the scar stricture and injected the triamcinolone locally. The results showed it was safe and effective. The follow-up showed no esophageal stenosis occured and no adverse reaction such as hemorrhage, perforation, tumor-recurrence and triamcinolone-allergy occured.

All-Trans Retinoic Acid Prevented Vein Grafts Stenosis by Inhibiting Rb-E2F Mediated Cell Cycle Progression and KLF5-RARα Interaction in Human Vein Smooth Muscle Cells.

PURPOSE: Vein graft failure (VGF) is an important limitation for coronary artery bypass graft (CABG) surgery. Inhibition of the excessive proliferation and migration of venous smooth muscle cells (SMCs) is an effective strategy to alleviate VGF during the CABG perioperative period. In the present study, we aimed to explore the role and potential mechanism of all-trans retinoic acid (ATRA) on preventing vein grafts stenosis. METHODS: The autogenous vein grafts model was established in the right jugular artery of rabbits. Immunohistochemistry staining and western blot assays were used to detected the protein expression, while real-time PCR assay was applied for mRNAs expression detection. The interaction between proteins was identified by co-immunoprecipitation assay. The Cell Counting Kit-8 and wound-healing assays were used to investigate the role of ATRA on human umbilical vein smooth muscle cells (HUVSMCs) function. Cell cycle progression was identified by flow cytometry assay. RESULTS: Vein graft stenosis and SMCs hyperproliferation were confirmed in vein grafts by histological and Ki-67 immunohistochemistry assays. Treatment of ATRA (10 mg/kg/day) significantly mitigated the stenosis extent of vein grafts, demonstrated by the decreased thickness of intima-media, and decreased Ki-67 expression. ATRA could repress the PDGF-bb-induced excessive proliferation and migration of HUVSMCs, which was mediated by Rb-E2F dependent cell cycle inhibition. Meanwhile, ATRA could reduce the interaction between KLF5 and RARα, thereby inhibiting the function of cis-elements of KLF5. KLF5-induced inducible nitric oxide synthase (iNOS) expression activation could be significantly inhibited by ATRA. CONCLUSIONS: These results suggested that ATRA treatment may represent an effective prevention and therapy avenue for VGF.

A heparin-rosuvastatin-loaded P(LLA-CL) nanofiber-covered stent inhibits inflammatory smooth-muscle cell viability to reduce in-stent stenosis and thrombosis.

BACKGROUND: An endovascular covered-stent has unique advantages in treating complex intracranial aneurysms; however, in-stent stenosis and late thrombosis have become the main factors affecting the efficacy of covered-stent treatment. Smooth-muscle-cell phenotypic modulation plays an important role in late in-stent stenosis and thrombosis. Here, we determined the efficacy of using covered stents loaded with drugs to inhibit smooth-muscle-cell phenotypic modulation and potentially lower the incidence of long-term complications. METHODS: Nanofiber-covered stents were prepared using coaxial electrospinning, with the core solution prepared with 15% heparin and 20 µM rosuvastatin solution (400: 100 µL), and the shell solution prepared with 120 mg/mL hexafluoroisopropanol. We established a rabbit carotid-artery aneurysm model, which was treated with covered stents. Angiography and histology were performed to evaluate the therapeutic efficacy and incidence rate of in-stent stenosis and thrombosis. Phenotype, function, and inflammatory factors of smooth-muscle cells were studied to explore the mechanism of rosuvastatin action in smooth-muscle cells. RESULT: Heparin-rosuvastatin-loaded nanofiber scaffold mats inhibited the proliferation of synthetic smooth-muscle cells, and the nanofiber-covered stent effectively treated aneurysms in the absence of notable in-stent stenosis. Additionally, in vitro experiments showed that rosuvastatin inhibited the smooth-muscle-cell phenotypic modulation of platelet-derived growth factor-BB induction and decreased synthetic smooth-muscle-cell viability, as well as secretion of inflammatory cytokines. CONCLUSION: Rosuvastatin inhibited the abnormal proliferation of synthetic smooth-muscle cells, and heparin-rosuvastatin-loaded covered stents reduced the incidence of stenosis and late thrombosis, thereby improving the healing rates of stents used for aneurysm treatment.

ß-elemene alleviates airway stenosis via the ILK/Akt pathway modulated by MIR143HG sponging miR-1275.

BACKGROUND: We have previously found that ß-elemene could inhibit the viability of airway granulation fibroblasts and prevent airway hyperplastic stenosis. This study aimed to elucidate the underlying mechanism and protective efficacy of ß-elemene in vitro and in vivo. METHODS: Microarray and bioinformatic analysis were used to identify altered pathways related to cell viability in a ß-elemene-treated primary cell model and to construct a ß-elemene-altered ceRNA network modulating the target pathway. Loss of function and gain of function approaches were performed to examine the role of the ceRNA axis in ß-elemene's regulation of the target pathway and cell viability. Additionally, in a ß-elemene-treated rabbit model of airway stenosis, endoscopic and histological examinations were used to evaluate its therapeutic efficacy and further verify its mechanism of action. RESULTS: The hyperactive ILK/Akt pathway and dysregulated LncRNA-MIR143HG, which acted as a miR-1275 ceRNA to modulate ILK expression, were suppressed in ß-elemene-treated airway granulation fibroblasts; ß-elemene suppressed the ILK/Akt pathway via the MIR143HG/miR-1275/ILK axis. Additionally, the cell cycle and apoptotic phenotypes of granulation fibroblasts were altered, consistent with ILK/Akt pathway activity. In vivo application of ß-elemene attenuated airway granulation hyperplasia and alleviated scar stricture, and histological detections suggested that ß-elemene's effects on the MIR143HG/miR-1275/ILK axis and ILK/Akt pathway were in line with in vitro findings. CONCLUSIONS: MIR143HG and ILK may act as ceRNA to sponge miR-1275. The MIR143HG/miR-1275/ILK axis mediates ß-elemene-induced cell cycle arrest and apoptosis of airway granulation fibroblasts by modulating the ILK/Akt pathway, thereby inhibiting airway granulation proliferation and ultimately alleviating airway stenosis.

Suppression of miR-143-3p contributes to the anti-fibrosis effect of atorvastatin on myocardial tissues via the modulation of Smad2 activity.

Atorvastatin is a commonly prescribed statin drug for the control of lipid synthesis and recent studies have shown the cardiac protection potential of atorvastatin. Cardiac fibrosis is a critical process that impairs heart function. In the current study, the anti-fibrosis potential of atorvastatin was assessed and the mechanism associated with the treatment was explored. Fibrotic symptoms were induced using transverse aortic constriction (TAC) method in vivo and using TGF-ß1 in vitro. The effect of atorvastatin on the development of cardiac fibrosis was firstly measured. Moreover, the influence of miR-143-3p induction on the anti-fibrosis function of atorvastatin was determined. TAC administration induced cardiac fibrosis and heart weight increase, which was associated with the induced expressions of TGF-ß1, miR-143-3p, p-Smad2, and collagens. Atorvastatin restored the levels of TGF-ß1, miR-143-3p, p-Smad2, and collagens. The administration of TGF-ß1 induced the expressions of miR-143-3p, p-Smad2, and collagens in cardiac fibroblasts (CFs) and the effect was inhibited by atorvastatin. However, the function of atorvastatin was blocked by miR-143-3p mimics. The current study demonstrated that the suppression of miR-143-3p contributed to the anti-fibrosis effect of atorvastatin on myocardial tissues, which subsequently inhibited Smad2-mediated production of collagens.

Synthesis and evaluation of resveratrol derivatives as fetal hemoglobin inducers.

Resveratrol (RVT) derivatives (10a-i) were designed, synthesized, and evaluated for their potential as gamma-globin inducers in treating Sickle Cell Disease (SCD) symptoms. All compounds were able to release NO at different levels ranging from 0 to 26.3%, while RVT did not demonstrate this effect. In vivo, the antinociceptive effect was characterized using an acetic acid-induced abdominal contortion model. All compounds exhibited different levels of protection, ranging from 5.9 to 37.3%; the compound 10a was the most potent among the series. At concentrations between 3.13 and 12.5 µM, the derivative 10a resulted in a reduction of 41.1-64.3% in the TNF-α levels in the supernatants of macrophages that were previously LPS-stimulated. This inhibitory effect was higher than that of RVT used as the control. In addition, the compound 10a and RVT induced double the production of the gamma-globin chains (γG + Î³A), compared to the vehicle, using CD34+ cells. Compound 10a also did not induce membrane perturbation and it was not mutagenic in the in vivo assay. Thus, compound 10a emerged as a new prototype of the gamma-globin-inducer group with additional analgesic and anti-inflammatory activities and proving to be a useful alternative to treat SCD symptoms.

Systemic steroid application for treatment of edematous anastomotic stenosis following delta-shaped anastomosis in laparoscopic distal gastrectomy: a case report.

BACKGROUND: Delta-shaped anastomosis is a common method of intracorporeal gastroduodenostomy in totally laparoscopic distal gastrectomy. One common postoperative complication of this procedure is anastomotic stenosis, and endoscopic balloon dilatation is a major remedy for such complications. Other treatment strategies are necessary to manage unsuccessful endoscopic balloon dilatation. CASE PRESENTATION: We present a case where systemic steroid treatment was applied in sustained anastomotic stenosis after endoscopic balloon dilatation. We performed delta-shaped anastomosis in laparoscopic distal gastrectomy to treat early-stage gastric cancer in a patient. The patient experienced abdominal pain post-surgery; subsequent investigation revealed edematous anastomotic stenosis. The stenosis sustained even after endoscopic balloon dilatation and local steroid injection. Consequently, we applied systemic steroid treatment. CONCLUSION: Systemic steroid treatment improved the stenosis and no recurrence was observed. These results suggest that systemic steroid application could be useful to treat anastomotic stenosis.

Role of Muscarinic Receptors in Hypoalgesia Induced by Crocin in Neuropathic Pain Rats.

OBJECTIVE: Crocin as an important constituent of saffron has antineuropathic pain properties; however, the exact mechanism of this effect is not known. The aim of this study was whether the hypoalgesic effect of crocin can be exerted through muscarinic receptors. MATERIALS AND METHODS: In the present project, 36 male Wistar rats (200 ± 20 g) were used. Animals randomly divided into six groups (sham, neuropathy, neuropathy + crocin, neuropathy + atropine 0.5 mg/kg, neuropathy + atropine 1 mg/kg, and neuropathy + atropine 1 mg/kg + crocin). Neuropathy was induced by the chronic constriction injury (CCI) method on the sciatic nerve. Crocin and atropine was administered intraperitoneally during 14 days following the 14th day after surgery. Pain response was detected every three days, two hours after each injection and 3 days following last injection. Mechanical allodynia and thermal hyperalgesia were detected using the Von Frey filaments and plantar test device, respectively. RESULTS: CCI significantly reduced the paw withdrawal response to mechanical and thermal stimulus (P < 0.01 and P < 0.05, respectively). Crocin therapy significantly reduced mechanical allodynia and thermal hyperalgesia induced by CCI (P < 0.05). Atropine pretreatment significantly blocked the hypoalgesic effect of crocin (P < 0.05 in mechanical allodynia and P < 0.01 in thermal hyperalgesia). Fourteen days administration of atropine alone at a dose of 0.5 mg/kg but not 1 mg/kg significantly reduced CCI-induced mechanical allodynia at day 30 after surgery. CONCLUSION: Crocin significantly decreased CCI-induced neuropathic pain. The hypoalgesic effect of crocin was blocked by atropine pretreatment, which indicates an important role for muscarinic receptors in the effect of crocin.

[Antithrombotic therapy after iliac vein stenting].

Stenting for iliac vein stenosis or compression has become a common therapeutic approach in recent years. The antithrombotic therapy after the stent deployment, however, reaches no consensus. Medications strategies and patients' prognoses differ in non-thrombotic, acute thrombotic and chronic thrombotic these three circumstances. Non-thrombotic patients usually possess satisfactory stent patency whatever antithrombotic therapy is used. Anticoagulant is the basic medication for acute thrombotic patients, benefits from additional antiplatelet drug remains to be clarified. In terms of chronic thrombotic patients, their prognoses are unsatisfactory under all antithrombotic therapies. In this review, we outlined the recent progress of antithrombotic therapy after iliac vein stenting, aiming to provide feasible medication plans for each circumstance.

Prophylactic steroid administration against strictures is not enough for mucosal defects involving the entire circumference of the esophageal lumen after esophageal endoscopic submucosal dissection (ESD).

BACKGROUNDS: The width of mucosal defects after endoscopic submucosal dissection (ESD) of esophageal squamous cell carcinoma (ESCC) is known to be a risk factor for esophageal strictures. Although steroid injection and oral steroid have recently been reported as prophylactic treatments, these were shown to be ineffective in a subset of patients with post-ESD mucosal defects involving the entire circumference of the esophagus. The aim of this study was to demonstrate outcome with prophylactic steroid administration for post-ESD mucosal defects involving the entire circumference, and to explore risk factors for esophageal strictures except for circumference of the esophagus. METHODS: Between November 2012 and August 2018, we enrolled patients with post-ESD mucosal defects involving the entire circumference of the esophagus who had received steroid injection (triamcinolone acetonide 50-100 mg, given immediately after ESD) followed by oral steroid (prednisolone 30 mg/day, tapered gradually over 8 weeks) as prophylactic treatment. Esophageal stricture was defined as case where ordinary-sized endoscope could not pass through post-ESD site, thus requiring endoscopic balloon dilation (EBD) repeatedly until relief of stricture was achieved. We retrospectively evaluated the rates of strictures, refractory strictures (requiring ≥ 6 EBD procedures) and unimproved strictures (not improvable by repeated EBD alone) and explored risk factors for strictures. RESULTS: A total of 26 patients met the including criteria. The rates of strictures, refractory strictures, and unimproved strictures were 62%, 38%, and 12%, respectively. The pre-ESD longitudinal extension of the lesion > 5 cm was identified as a risk factor for refractory strictures, suggesting that lesions with this factor had a shorter time to stricture development, required more EBD procedures, and longer EBD durations. CONCLUSION: Although additional study is required in a larger number of patients, careful consideration needs to be given to ESD as an indication for large spreading ESCC involving the entire circumference of esophagus given its high stricture risk.