Combined antegrade femoral artery and retrograde popliteal artery recanalization for chronic occlusions of the superficial femoral artery.

PURPOSE: To evaluate the efficacy and safety of a dual femoral-popliteal approach in the supine position after failed antegrade recanalization attempts in chronic total occlusion (CTO) of the superficial femoral artery (SFA). MATERIALS AND METHODS: From May 2011 to October 2012, 21 patients underwent dual femoral-popliteal recanalization for CTO of the SFA, with a mean lesion length of 87.4 mm ± 5.8. When contralateral antegrade recanalization of SFA occlusions via the common femoral artery could not be achieved, the occlusions were intrainterventionally accessed by retrograde approach via the popliteal artery, which was punctured anteriorly with gently flexed knee and crus extorsion. When the SFA had been recanalized, further angioplasty and stent placement procedures were completed via the femoral artery. RESULTS: A technical success rate of 100% (entailing puncture of the popliteal artery and SFA recanalization) was achieved, and no hemorrhage, hematoma, pseudoaneurysm, arteriovenous fistula, or other complications developed. During a mean follow-up of 9.8 months ± 1.5, claudication severity, rest pain, and toe ulcers improved significantly. The pulse of the distal arteries, as well as the filling of the veins, could be distinctly felt. Ankle-brachial index changed from 0.48 ± 0.17 to 0.84 ± 0.11 at 1 year after intervention (P < .001), and patency rates at 1, 6, and 12 months after interventions were 100%, 80%, and 42%, respectively. CONCLUSIONS: A dual femoral-popliteal approach in the supine position is an alternative backup option after failed attempts at the antegrade approach for patients with proximal barriers in CTO or lesions with major extending collateral vessels.

GW9662 ameliorates nonalcoholic steatohepatitis by inhibiting the PPARγ/CD36 pathway and altering the gut microbiota.

BACKGROUND & AIMS: Peroxisome proliferator-activated receptors (PPARs) are currently among the most focused-on therapeutic targets for non-alcoholic steatohepatitis (NASH), although no clinical transformation has been achieved to date. In this study, we aimed to evaluate the effects of GW9662 on choline-deficient, L-amino acid-defined high-fat diet (CDAA-HFD)-induced NASH mice and reveal the mechanism underlying this effect. METHODS: GW9662 (1 mg/kg) was administered in CDAA-HFD mouse model of NASH. The effect of GW9662 on hepatic lipid metabolism was investigated using liver RNA-seq and HepG2 cells induced by oleic acid and palmitic acid. In addition, 16S rRNA gene sequencing was performed to analyze the effects of GW9662 on the composition and function of the fecal microbiota. RESULTS: GW9662 improved the CDAA-HFD caused elevation in the levels of ALT, AST, hepatic free fatty acids and triglycerides. The liver pathological analysis indicated that GW9662 alleviated the hepatic steatosis and fibrosis. The NAFLD activity score and RNA-Seq revealed that GW9662 mainly regulated the fatty acids transport and lipid synthesis by inhibiting PPARγ, CD36, FABP1, FASN, and SCD1, and through the up-regulation of PPARα. Moreover, GW9662 reduced the epididymal fat weight. GW9662 reversed the gut microbiota disorder by increasing the abundance of the beneficial bacteria Dubosiella and Lactobacillus and decreasing the abundance of harmful bacteria Lachnospiraceae_NK4A136_group, Helicobacteraceae, Desulfovibriaceae, and Rickenaceae. CONCLUSIONS: GW9662 ameliorated lipid metabolism by inhibiting the PPARγ/CD36 pathway and altering the composition of the gut microbiota in NASH mice. Therefore, the PPARγ antagonist GW9662 deserves more attention as a potential therapeutic agent for NASH.

The anti-fibrotic efficacy of adelmidrol depends on hepatic PPARγ levels.

Adelmidrol, an anti-inflammatory small-molecule compound, can treat inflammatory diseases like arthritis and colitis in a PPARγ-dependent manner. Effective anti-inflammatory therapy is beneficial in delaying the progression of liver fibrosis. This study aimed to investigate the effect and underlying mechanisms of adelmidrol on hepatic fibrosis induced by CCl4 and CDAA-HFD. In the CCl4 model, adelmidrol (10 mg/kg) significantly reduced the incidence of liver cirrhosis from 76.5% to 38.9%, with a reduction of ALT, AST, and extracellular matrix deposition. RNA-seq revealed adelmidrol markedly inhibited the activation of hepatic scar-associated Trem2+ macrophages and PDGFRα+ stellate cells. Adelmidrol exhibited a limited anti-fibrotic effect in CDAA-HFD-induced fibrosis. Further, inconsistencies were observed in the expression trends in liver PPARγ in both models. CCl4 injury led to the continuous decrease in hepatic PPARγ levels, adelmidrol treatment up-regulated hepatic PPARγ expression and down-regulated the expression of pro-inflammatory factor NF-κB and pro-fibrotic factor TGF-ß1. Adelmidrol also inhibited the activation of macrophages and HSCs in a PPARγ-dependent manner in vitro. GW9662, a specific PPARγ antagonist, counteracted the anti-fibrotic effect of adelmidrol. In CDAA-HFD-induced model, hepatic PPARγ expression gradually increased with the progress of modeling. Adelmidrol enhanced steatosis in hepatocytes by the activation of the PPARγ/CD36 pathway in the CDAA-HFD model and FFA-treated HepG2, showing a limited anti-fibrotic effect. GW9662 reversed the pro-steatotic effect of adelmidrol and improved fibrosis. The anti-fibrotic outcomes of adelmidrol were related to hepatic PPARγ levels, which depends on the synergistic effect of PPARγ agonism caused by adelmidrol on hepatocytes, macrophages, and HSCs in different pathological states.

[Assessment of external methods of traditional Chinese medicine in patients with chronic ulcer of the lower extremities: study protocol of a multicenter, randomized, parallel-group, prospective trial].

BACKGROUND: Chronic ulcer of the lower extremities amounts for a grave and serious problem for public health. Western medicine focuses on controlling infection, improving blood circulation, surgical debridement, skin grafting, etc, but there are bottlenecks in the treatment. Traditional Chinese medicine (TCM) has a long history and a legacy of sound clinical efficacy in this area. TCM has developed a unique, effective external theory, and a large number of topical prescriptions and external technology. Through this research, a safe and effective treatment protocol of TCM for chronic ulcer of the lower extremities can be formed. To this end, during China's "Eleventh Five-Year" Plan, special research committees and projects on TCM external treatments and external technologies were established. This study on ulcer of the lower extremities constitutes one of the major research topics. METHODS AND DESIGN: Clinical information of patients with chronic ulcer of the lower extremities will be first collected in a large, multicenter, epidemiological survey. Concurrently, a large multicenter, randomized, parallel-group, prospective study will be launched based on evidence-based medical principles to evaluate the efficacy and safety of external methods for removing carrion, dissolving stasis, reinforcing deficiency and promoting tissue regeneration. The evaluated indexes will include the wound healing percentage for primary outcome, wound healing time, wound healing rate, time and rate of removal of necrotic tissue, and TCM syndromes for secondary outcomes and routine blood test, routine urine test, liver and kidney function, blood mercury content and finally urine mercury content for adverse events. DISCUSSION: In this trial, the authors will evaluate the efficacy and safety of external methods for removing carrion, dissolving stasis, reinforcing deficiency and promoting tissue regeneration in cases of chronic ulcer of the lower extremities for standardizing external therapy of TCM for treatment of this condition, and establishing the clinical assessment system for TCM. TRIAL REGISTRATION NUMBER: The research program was registered in the Chinese Clinical Trial Registry in both English and Chinese in June 2011. REGISTRATION NUMBER: ChiCTR-TRC-11001365.

Dynamics of the gut-liver axis in rats with varying fibrosis severity.

The classic carbon tetrachloride (CCl4)-induced liver injury model is widely used to study the pathogenesis of fibrosis and evaluate anti-fibrosis drugs. Here, we investigated the dynamic changes in the gut microbiota, bile acids (BAs) and the gut barrier over different fibrosis severities in a CCl4-based model. 16S rDNA sequencing demonstrated that the beneficial taxon Lactobacillus was always underrepresented, and pathogens including Escherichia_Shigella, Clostridium_sensu_stricto_1, Colidextribacter, and Lachnospiraceae_UCG_010 were significantly overrepresented across liver fibrosis severities. Gut dysbiosis was more severe at the early stage of liver injury and advanced stage of fibrosis. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis revealed that with the progress of fibrosis, unconjugated BAs in faeces were significantly decreased and conjugated BAs in serum were significantly increased. The FXR-SHP signalling pathway in the liver and ileum was statistically repressed in the fibrosis groups. Determination of lipopolysaccharide (LPS) and fluorescein isothiocyanate (FITC)-dextran levels in plasma showed that the intestinal barrier remained relatively intact in the advanced fibrosis stage. The advances in knowledge of the gut-liver axis provided by this study yield new insights for application in research and drug evaluation.

Revealing potential anti-fibrotic mechanism of Ganxianfang formula based on RNA sequence.

BACKGROUND: Ganxianfang (GXF) formula as a traditional Chinese medicine (TCM) is used for liver fibrosis in clinical practice while its mechanism is unclear. The aim of this study is to explore the molecular mechanism of GXF against CCl4-induced liver fibrosis rats. METHODS: Detected the main compounds of GXF by UPLC-MS/MS. Evaluated the efficacy of GXF (1.58, 3.15, 4.73 g/kg/day) and Fuzheng Huayu (FZHY, positive control, 0.47 g/kg/day) through serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels and histopathological changes. Explored the underlying mechanisms by integrating our total liver RNA sequencing (RNA-seq) data with recent liver single-cell sequencing (scRNA-seq) studies. Verified potential pharmacodynamic substances of GXF by hepatic stellate cell (HSC)-T6 line. RESULTS: Main compounds were identified in GXF by UPLC-MS/MS, including baicalin, wogonoside and matrine etc. With GXF-high dose treatment, the elevation of ALT and AST induced by CCl4 were significantly reduced, and the protective effect of GXF-high dose treatment was better than FZHY. Liver histopathological changes were alleviated by GXF-high dose treatment, the ISHAK scoring showed the incidence of liver cirrhosis (F5/F6) decreased from 76.5 to 55.6%. The results of liver hydroxyproline content were consistent with the histopathological changes. RNA-seq analysis revealed the differential genes (DEGs) were mainly enriched in ECM-receptor interaction and chemokine signaling pathway. GXF effectively inhibited collagen deposition and significantly downregulated CCL2 to inhibit the recruitment of macrophages in liver tissue. Integrating scRNA-seq data revealed that GXF effectively inhibited the expansion of scar-associated Trem2+CD9+ macrophages subpopulation and PDGFRα+PDGFRß+ scar-producing myofibroblasts in the damaged liver, and remodeled the fibrotic niche via regulation of ligand-receptor interactions including TGFß/EGFR, PDGFB/PDGFRα, and TNFSF12/TNFRSF12a signaling. In vitro experiments demonstrated that baicalin, matrine and hesperidin in GXF inhibited the activation of hepatic stellate cells. CONCLUSIONS: This study clarified the potential anti-fibrotic effects and molecular mechanism of GXF in CCl4-induced liver fibrosis rats, which deserves further promotion and application.

[Therapy mainly for strengthening healthy energy to promote blood circulation in treating 112 diabetic patients with gangrene].

OBJECTIVE: To evaluate the effects of the therapy mainly for strengthening healthy energy to promote blood circulation in treating diabetic patients with gangrene. METHODS: A series of 112 diabetic patients with gangrene were investigated before and after treatment in the changes of wounds, clinical symptoms and quality of life. RESULTS: Fifty-eight cases were cured, 12 cases showed response, 36 cases improved, and 6 cases failure of treatment. The total obvious effect rate was 62.5% (70/112) and the amputation rate was 8.9% (10/112). The 104 diabetic cases of three-stage gangrene were classified into grade I, II and III. The total effect rates of the diabetic cases of grade I, II and III were 83.3% (30/36), 55.6% (35/63) and 20% (1/5), and the amputation rates were 0%, 12.7% (8/63), and 40% (2/5) respectively. After the treatment, the clinical symptoms, gangrene number, gangrene area and gangrene depth were obviously improved (P<0.05), and the quality of life was obviously improved (P<0.01), especially in physical condition, emotional well-being and therapeutic effects on patients (P<0.05). CONCLUSION: Strengthening healthy energy to promote blood circulation is effective in treating diabetic patients with gangrene.