Single-Dose Radial Extracorporeal Shock Wave Therapy Modulates Inflammation During Meniscal Tear Healing in the Avascular Zone.

BACKGROUND: Extracorporeal shock wave therapy (ESWT) promotes tissue healing by modulating inflammation, which has implications for meniscal tear healing in the avascular zone. PURPOSE: To evaluate the effects of a single dose of radial ESWT on the healing process and inflammation of the meniscus and knee joints after meniscal tears in the avascular zone. STUDY DESIGN: Controlled laboratory study. METHODS: Avascular tears were induced in the medial meniscus (MM) of 72 Sprague-Dawley rats. One week postoperatively, the rats received a single session of radial ESWT with a Power+ handpiece (ESWT group; n = 36) or with a fake handpiece (sham-ESWT group; n = 36). The rats were then euthanized at 2, 4, or 8 weeks postoperatively. The MMs were harvested for analysis of healing (hematoxylin-eosin, safranin O-Fast Green, and collagen type 2 staining) and inflammation (interleukin [IL]-1ß and IL-6 staining). Lateral menisci and synovia were obtained to evaluate knee joint inflammation (enzyme-linked immunosorbent assay of IL-1ß and IL-6). Cartilage degeneration was assessed in the femurs and tibial plateaus using safranin O-Fast Green staining. RESULTS: The ESWT group showed significantly better meniscal healing scores than the sham-ESWT group at 4 (P = .0066) and 8 (P = .0050) weeks postoperatively. The IL-1ß level was significantly higher in the sham-ESWT group than in the ESWT group at 2 (MM: P = .0009; knee joint: P = .0160) and 8 (MM: P = .0399; knee joint: P = .0001) weeks. The IL-6 level was significantly lower in the sham-ESWT group than in the ESWT group at 2 (knee joint: P = .0184) and 4 (knee joint: P = .0247) weeks but higher at 8 weeks (MM: P = .0169; knee joint: P = .0038). The sham group had significantly higher osteoarthritis scores than the ESWT group at 4 (tibial plateau: P = .0157) and 8 (femur: P = .0048; tibial plateau: P = .0359) weeks. CONCLUSION: A single dose of radial ESWT promoted meniscal tear healing in the avascular zone, modulated inflammatory factors in the menisci and knee joints in rats, and alleviated cartilage degeneration. CLINICAL RELEVANCE: Radial ESWT can be considered a potential option for improving meniscal tear healing in the avascular zone because of its ability to modulate inflammation.

Probiotics for the management of irritable bowel syndrome: a systematic review and three-level meta-analysis.

OBJECTIVE: Previous systematic reviews demonstrated a potentially beneficial effect of probiotics on irritable bowel syndrome (IBS). However, these studies are either affected by the inclusion of insufficient trials or by the problem of dependent data across multiple outcomes, and an overall effect size has not been provided. We aimed to determine the effect of probiotics on IBS through a three-level meta-analysis and clarify potential effect moderators. METHODS: We searched MEDLINE, Embase, and Web of Science, screening for randomized controlled trials (RCTs) that examine the effect of probiotics on IBS. The primary outcome was the improvement in the severity of global IBS symptoms at the end of treatment. The secondary outcomes were the improvement in abdominal pain and the quality of life. The effect sizes of the probiotics were measured by using the standardized mean difference (SMD) and pooled by a three-level meta-analysis model. RESULTS: We included 72 RCTs in the analysis. The meta-analysis showed significantly better overall effect of probiotics than placebo on the global IBS symptoms (SMD -0.55, 95% CI -0.76 to -0.34, P <0.001), abdominal pain (SMD -0.89, 95% CI -1.29 to -0.5, P <0.001) and quality of life (SMD 0.99, 95% CI 0.45 to 1.54, P <0.001), respectively. Moderator analysis found that a treatment duration shorter than 4 weeks was associated with a larger effect size in all the outcomes, and Bacillus probiotics had better improvement on the abdominal pain. CONCLUSIONS: Probiotics had a short-term effect and a medium effect size on the global IBS symptoms. Treatment duration and types of probiotics affected the effect size of probiotics, and shorter durations and Bacillus probiotics were associated with better treatment effects. REGISTRATION: Open Science Framework.

Current Status and Analysis of Machine Learning in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common tumor. Although the diagnosis and treatment of HCC have made great progress, the overall prognosis remains poor. As the core component of artificial intelligence, machine learning (ML) has developed rapidly in the past decade. In particular, ML has become widely used in the medical field, and it has helped in the diagnosis and treatment of cancer. Different algorithms of ML have different roles in diagnosis, treatment, and prognosis. This article reviews recent research, explains the application of different ML models in HCC, and provides suggestions for follow-up research.

Functional and Structural Outcomes After Arthroscopic Rotator Cuff Repair With or Without Preoperative Corticosteroid Injections.

BACKGROUND: Corticosteroid injections (CSIs) are effective in alleviating pain in patients with rotator cuff tears, but controversy still exists regarding their potential adverse effects on clinical outcomes after rotator cuff repair. PURPOSE: To compare both the functional and the structural outcomes in patients who underwent arthroscopic rotator cuff repair with or without preoperative CSIs. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective cohort study was carried out among patients who underwent arthroscopic rotator cuff repair for partial- and full-thickness tears between 2015 and 2019. The patients who received preoperative CSIs were included in the CSI group and compared with a group without preoperative CSIs (non-CSI group), matched at a ratio of 1:2 based on tear size, age, and follow-up time. Both functional evaluation and structural assessments using magnetic resonance imaging (MRI) were performed at the final follow-up. Clinical outcomes-including retear rate as the primary outcome; pain; functional scores including the Constant-Murley score, American Shoulder and Elbow Surgeons score, and Fudan University Shoulder Score; range of motion (ROM); tendon integrity; tendon healing type; and cartilage thickness-were compared between the 2 groups with a statistical significance of P < .05 and power of 0.9. RESULTS: Thirty-one patients were included in the CSI group, and 62 were included in the non-CSI group. After a mean 3-year follow-up, the 2 groups demonstrated no significant differences in retear rate; visual analog scale for pain; shoulder functional scores; and active ROM including forward flexion, abduction, external rotation, and internal rotation. No significant differences were observed on postoperative MRI scans of the rotator cuff tendon (tendon integrity, healing type, residual tendon attachment area, etc), cartilage thickness, and muscle atrophy. CONCLUSION: No significant differences were found at a mean 3-year follow-up in the retear rates, pain, ROM, and glenohumeral structure on postoperative MRI scans after arthroscopic rotator cuff repair with or without preoperative CSIs.

Bankart Repair With Remplissage Restores Better Shoulder Stability Than Bankart Repair Alone, and Medial or Two Remplissage Anchors Increase Stability but Decrease Range of Motion: A Finite Element Analysis.

PURPOSE: To investigate the effects of the number and location of anchors for remplissage on postoperative glenohumeral biomechanics. METHODS: A biomechanical study was conducted involving finite element model constructed based on data from the intact glenohumeral joint. Seven models were established, including a normal model, a model of Bankart lesion combined with "off-track" Hill-Sachs lesion, a model of Bankart repair alone, and 4 models of Bankart repair with remplissage based on different remplissage anchor numbers and locations. The effects of the number and location of the remplissage anchors on glenohumeral stability were studied through calculation and comparison of (1) the stress and its distribution on the joint capsule, cartilage, labrum and anchors as well as (2) the displacement of the humeral head. RESULTS: Finite element analysis demonstrated that contact stress on the glenohumeral cartilage decreased when medial or 2 anchors were used and was minimized in the combined repair model with 2 medial anchors. The stress on remplissage anchors was greater when the anchors were placed medially. The humeral head displacement was maximized in the combined lesion model. The combined repair models with 2 medially placed anchors showed the largest slope on the force-displacement curve, indicating the largest strain on the humeral head. CONCLUSIONS: Based on a finite element analysis, Bankart repair with remplissage restored better shoulder stability compared with Bankart repair alone in the treatment of anterior shoulder instability involving Bankart lesion combined with "off-track" Hill-Sachs lesion. When the anchor for remplissage was medially placed or 2 anchors were used, the stability of the glenohumeral joint increased but with a loss of range of motion. CLINICAL RELEVANCE: The results of this study will assist in choosing the number and location of anchors for remplissage during shoulder stabilization surgery although with some limitations.

Analysis of mutations in DNA damage repair pathway gene in Chinese patients with hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) has increased in these years. DNA damage repair (DDR) pathway is required in response to DNA damage Gene mutations in DDR pathway play an important role in different stages of tumorigenesis and development. Based on the importance of DDR pathway in precision therapy of multiple cancers, we analyzed DDR gene mutations in Chinese patients with HCC. The results showed that (tumor mutation burden) TMB was significantly higher in HCC patients who carried somatic mutations in DDR than in non-carriers, and TMB in patients with DS, MMR mutations and DDR genes mutations such as RAD50, MLH1, MSH2, CHEK2 was significantly higher than that in wild-type patients. Based on the results of next-generation sequencing (NGS) testing, we are trying to provide clues for targeted therapy and provide feasible basis for PD-1/PD-L1 immune checkpoint inhibitor therapy.

A new model based inflammatory index and tumor burden score (TBS) to predict the recurrence of hepatocellular carcinoma (HCC) after liver resection.

To establish a model based on inflammation index and tumor burden score (TBS) to predict recurrence of hepatocellular carcinoma (HCC) after liver resection. A retrospective study was performed on 217 patients who diagnosed HCC underwent liver resection at Xiangya Hospital Central South University from June 1, 2017 to June 1, 2019. According to the receiver operating characteristic (ROC) curve, the optimal cut-off value of inflammatory index and the TBS was determined by the Youden index. Prediction performance was compared by the area under the receiver operating characteristic curve (AUC). Cox regression analysis was used to determine the risk factors for the recurrence of HCC after liver resection. According to the independent risk factors of the patients, a prediction model for HCC was established based on inflammation index and tumor burden score (TBS).The prediction performance of the model was compared with single index (TBS group and NLR group) and traditional HCC stage models (TNM stage and BCLC stage). MLR = 0.39, NLR = 2.63, PLR = 134, SII = 428 and TBS = 8.06 are the optimal cut-off values. AUC of SII, PLR, NLR, MLR and TBS were 0.643, 0.642, 0.642, 0.618 and 0.724respectively. MVI (P = 0.005), satellite nodule (P = 0.017), BCLC B-C stage (P = 0.013), NLR > 2.63 (P = 0.013), TBS > 8.06 (P = 0.017) are independent risk factors for the recurrence of HCC after liver resection. According to this study, the optimal inflammatory index NLR combined with TBS was obtained. The AUC of NLR-TBS model was 0.762, not only better than NLR group (AUC = 0.630) and TBS group (AUC = 0.671), also better than traditional BCLC (AUC = 0.620) and TNM (AUC = 0.587) stage models. Interestingly, we found that NLR and TBS should be good prognostic factor for recurrence of HCC after liver resection. The NLR-TBS model based the best inflammatory index (NLR) and TBS have a better prediction performance and the prediction performance of NLR-TBS model not only better than NLR group and TBS group, but better than BCLC and TNM stage models.

[Research progress on the relationship between shoulder instability and superior labrum anterior posterior lesion].

OBJECTIVE: To summarize the relationship between shoulder instability and superior labrum anterior posterior (SLAP) lesion. METHODS: The characteristics of shoulder instability and SLAP lesion were analyzed, and the relationship between them in pathogenesis, clinical symptoms, and biomechanics was discussed by referring to relevant domestic and foreign literature. RESULTS: Shoulder instability and SLAP lesion can occur both spontaneously and respectively. SLAP lesion destroys the superior labrum integrity and the long head of biceps tendon (LHBT) insertion, causing excessive humeral head displacement against glenoid, and leading to shoulder instability. While chronic repetitive or acute high-energy traumatic shoulder instability can in turn aggravate SLAP lesion, resulting in expansion and increased degree of the original lesion. CONCLUSION: SLAP lesion destroys mechanisms of shoulder stability, while shoulder instability causes tears of the upper labrum and the LHBT, showing a connection between shoulder instability and SLAP lesion. However, the existing evidence can only demonstrate that shoulder instability and SLAP lesion induce and promote the development of each other, instead of a necessary and sufficient condition. Therefore, the specific causal relationship between the two remains unknown and needs to be further studied.

Azithromycin-loaded linolenic acid-modified methoxy poly(ethylene glycol) micelles for bacterial infection treatment.

In the study, new polymeric micelles loaded with azithromycin were prepared to enhance azithromycin's solubility and evaluate its in vitro/in vivo antibacterial activity against Staphylococcus aureus. Amphiphilic α-Linolenic acid-methoxy poly (ethylene glycol) polymer (MPEG-LNA) was synthesized through DCC-DMAP esterification procedure. Through thin-film hydration method, optimized azithromycin-loaded micelles (AZI-M) were prepared with 87.15% of encapsulation efficiency and 11.07% of drug loading capacity when the ratio of LNA to MPEG was 4. Azithromycin's water-solubility was obviously enhanced due to its loading into the polymeric micelles. The azithromycin-loaded micelles were characterized in terms of x-ray diffraction, Fourier transform infrared spectroscopy, in vitro release, and in vitro/in vivo antibacterial experiments. Although the drug-loaded micelles provided a slow and continuous azithromycin's release in comparison with free azithromycin, in vitro antibacterial activity results confirmed that its effect on the inhibition of bacterial growth and biofilm formation was similar to free azithromycin. It is more interesting that the azithromycin-loaded micelles achieved good in vivo antibacterial therapeutic effect like QiXian® (azithromycin lactobionate injection) in mouse model of intraperitoneal infection. AZI-M can be considered as a potential candidate for in vivo antibiotic therapy of Staphylococcus aureus infections.

Genetically proxied inhibition of tumor necrosis factor and the risk of colorectal cancer: A drug-target mendelian randomization study.

Background: Previous studies suggested that anti-TNF drugs might be repurposed as a preventive treatment for colorectal cancer. We aimed to examine whether genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) reduces the absolute risk of colorectal cancer through mendelian randomization (MR) analysis. Methods: We obtained 28 single nucleotide polymorphisms (SNPs) that were located within a ±15 kilobase window of the TNFRSF1A-the gene that encodes the TNFR1 protein, and we used genetic data from three GWAS studies of circulating levels of TNFR1, C-reactive protein (CRP), and white blood counts (WBC) to screen SNPs that proxied the inhibition of TNFR1. Positive control analyses were then performed by using another three GWAS data from the ulcerative colitis cohort (n = 45,975), Crohn's disease cohort (n = 40,266), and multiple sclerosis cohort (n = 115,803) to confirm the effect of the included SNPs. A two-sample mendelian randomization analysis was performed to examine the association between TNFR1 inhibition and the absolute risk reduction (ARR) of colorectal cancer. Results: We finally included seven SNPs to proxy the anti-TNF effect, and these SNPs caused lower levels of TNFR1, CRP, and white blood counts. In positive control analyses, the included SNPs caused lower odds ratio of ulcerative colitis and Crohn's disease but a higher odds ratio of multiple sclerosis, consistent with drug mechanistic actions and previous trial evidence. By using the inverse-variance weighted analyses to combine the effects of the seven SNPs, we found that the anti-TNF effect was associated with a 0.988 (95%CI 0.985-0.991) mg/L decrease in CRP levels and a reduction in the risk of colorectal cancer (absolute risk reduction -2.1%, 95%CI -3.8% to -0.4%, p = 0.01). Conclusion: Our study confirmed that anti-TNF drugs were associated with a risk reduction in colorectal cancer. Physicians could consider using anti-TNF drugs for the prevention of colorectal cancer, especially in patients with high risks of developing cancer.

Relationship Between Age at Initial Shoulder Instability and Overall Outcomes After Arthroscopic Bankart Repair: Mean 6-Year Follow-up.

BACKGROUND: Age at surgery plays a crucial role in the frequency of recurrent shoulder instability. However, there are few studies that evaluate the relationship between age at initial shoulder instability and overall outcomes after stabilization surgery. PURPOSE: To compare clinical outcomes and structural changes after arthroscopic Bankart repair in patients who experienced initial shoulder instability during adolescence versus those with later onset instability. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study included patients who underwent arthroscopic Bankart repair at a single institution between 2007 and 2017. Comparisons were made between patients who experienced initial shoulder instability during adolescence (age 13-19 years; group A) and those with later onset instability (age 20-35 years; group B). Clinical outcomes (recurrence rate, postoperative pain, functional scores, active range of motion, and return to sports) and structural changes demonstrated by magnetic resonance imaging (MRI) were evaluated at minimum 2-year follow-up. In addition, functional outcomes within each group were compared between the patients with and without postoperative recurrence. RESULTS: A total of 58 patients were included (24 patients in group A and 34 patients in group B). The mean follow-up was 72.1 months. Group A demonstrated a significantly higher recurrence rate than group B (41.7% vs 11.8%, respectively; P = .009; risk ratio, 5.36 [95% CI, 1.43-20.09]) as well as significantly lower Rowe (76.9 ± 20.1 vs 88.7 ± 13.2, respectively; P = .01) and Constant-Murley scores (92.2 ± 7.6 vs 96.3 ± 4.2, respectively; P = .01). Postoperative MRI revealed no significant structural differences between the groups regarding the glenoid labrum, glenohumeral cartilage, or osseous reaction around the implanted anchors. In group A, patients with recurrence had less satisfaction regarding postoperative sports level than those without recurrence, whereas in group B, patients with recurrence had more postoperative pain and functional impairment compared with those without recurrence. CONCLUSION: Initial shoulder instability during adolescence was associated with a higher recurrence rate and lower functional scores after arthroscopic Bankart repair compared with later onset instability, although no significant structural differences were found between the groups on MRI at a mean 6-year follow-up.

Location of the Suture Anchor in Hill-Sachs Lesion Could Influence Glenohumeral Cartilage Quality and Limit Range of Motion After Arthroscopic Bankart Repair and Remplissage.

BACKGROUND: No study has reported clinical evidence for cartilage change in the glenohumeral joint or the cause of loss in range of motion (ROM) after arthroscopic Bankart repair with remplissage technique (BR). PURPOSE: To investigate the postoperative features of glenohumeral joint cartilage, ROM, and anchor placement for remplissage at a minimum of 2 years of follow-up after BR and to analyze the correlations. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A total of 21 patients who underwent BR received follow-up for a minimum of 2 years. At both preoperative assessment and final follow-up, passive shoulder ROM, Oxford Shoulder Instability Score, Simple Shoulder Test score, and Single Assessment Numerical Evaluation score were assessed. All patients underwent 3.0-T magnetic resonance imaging (MRI) examination at final follow-up. The clinical outcomes, glenohumeral cartilage or Hill-Sachs lesion-related MRI parameters, and their potential correlations were analyzed. RESULTS: The mean follow-up was 55.0 months (range, 24-119 months). Compared with preoperative assessment, all functional scores significantly improved (P < .001). At the final follow-up, a significant ROM loss (>15°) of external rotation (ER) at the side (ER0) was found in 12 patients, among whom 8 patients had significant ROM loss of ER at 90° of abduction as well. Further, 12 patients with decreased ER had significantly higher signal intensity of cartilage on the anterior, middle, and posterior humeral head (anterior, P = .002; middle, P < .001; posterior, P < .001) than 9 patients with normal ER. The ratio of the width of the remplissage anchor to the diameter of the humeral head (w:d ratio) was significantly greater (P = .031) in the decreased ER group than in the normal ER group. Correlation analysis showed that signal intensity on the posterior humeral head and ER0 loss (ΔER0) had a significantly positive correlation (r = 0.516; P = .034), while the w:d ratio and ΔER0 had a significantly positive correlation (r = 0.519; P = .039). CONCLUSION: At a minimum of 2 years of follow-up, patients who underwent BR showed significant clinical improvement compared with preoperative assessment, except for limitations in ER. The glenohumeral cartilage degeneration (higher signal intensity) after BR had a significantly positive correlation with the postoperative ER loss, which was found to be associated with a relatively medial placement of the remplissage anchor.

Electrospun PCL/Gel-aligned scaffolds enhance the biomechanical strength in tendon repair.

Tendons can transmit mechanical force from muscles to bones for movement. However, the mechanical strength of tendons is compromised after surgery, thus causing a high rate of tendon retear. Hence, the design and preparation of biodegradable materials with excellent mechanical properties have become an urgent demand for sports medicine. In this study, biomimetic polycaprolactone (PCL)/gelatin (Gel)-aligned scaffolds were fabricated for the mechanical restoration of the injured tendon in a rabbit model. The diameter of nanofibers was about 427.82 ± 56.99 nm, which was approximate to that of the native collagen fibrils; the directional consistency of the nanofibers in PCL/Gel-aligned scaffolds reached 77.33 ± 3.22%, which were ultrastructurally biomimetic. Compared to the observations for the control group, the in vitro mechanical results showed that the PCL/Gel-aligned scaffolds (P/G-A) were anisotropic in terms of failure load, tensile strength, and Young's modulus. After verifying their good cytocompatibility, the scaffolds were implanted into the rabbit patellar tendon in situ. The biomechanical properties of the repaired tendon in P/G-A reached 343.97 ± 65.30 N in failure load, 85.99 ± 16.33 MPa in tensile strength, 590.84 ± 201.87 MPa in Young's modulus, and 171.29 ± 61.50 N mm-1 in stiffness in vivo at 8 weeks post operation. In a word, our results demonstrated that P/G-A could support the regenerated tissue of injured patellar tendons to restore the biomechanical strength in a rabbit model. This suggested that the PCL/Gel-aligned scaffolds can pave a promising way to improve the healing of injured tendons in the clinic in the future.

Lower Signal Intensity of the Anterior Talofibular Ligament is Associated with a Higher Rate of Return to Sport After ATFL Repair for Chronic Lateral Ankle Instability.

BACKGROUND: The treatment strategy for anterior talofibular ligament (ATFL) injury is usually determined by the ATFL remnant condition during surgery. Preoperative magnetic resonance imaging (MRI)-based signal intensity of the ATFL remnant, represented by the signal/noise ratio (SNR) value, can reveal the ATFL remnant condition. Thus far, there is a lack of evidence regarding the relationship between the ATFL remnant condition and functional outcomes. PURPOSE/HYPOTHESIS: The purpose was to quantitatively evaluate whether the MRI-based ATFL ligament SNR value is related to functional outcomes after ATFL repair for ankles with chronic lateral ankle instability. The hypothesis was that a lower preoperative SNR is related to a better clinical outcome, particularly a higher rate of return to sport. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: First, a preliminary study was performed to measure the ATFL SNR in preoperative MRI, the results of which suggested that a preoperative SNR >10.4 was indicative of a poor ATFL condition. Then, a cohort study was retrospectively performed with consecutive patients who underwent open repair of ATFL injuries between January 2009 and August 2014. Accordingly, the patients were divided into 2 groups: high SNR (HSNR; ≥10.4) and low SNR (LSNR; <10.4). Functional outcomes based on the American Orthopaedic Foot and Ankle Society (AOFAS) score, Karlsson Ankle Functional Score (KAFS), and Tegner Activity Scale were then compared between the HSNR group and the LSNR group. RESULTS: Ultimately, 70 patients were available for the final follow-up: 37 in the HSNR group and 33 in the LSNR group. No significant difference was detected between the HSNR group and the LSNR group in terms of the AOFAS score, KAFS, or Tegner Activity Scale (P > .05 for all) preoperatively. At the final follow-up, the mean ± SD AOFAS score in the LSNR group (92 ± 6) was higher than that in the HSNR group (87 ± 12), although no significant difference was detected postoperatively (P = .16). The mean KAFS in the LSNR group (94 ± 7) was significantly higher than that in the HSNR group (88 ± 11) postoperatively (P = .03). At follow-up, the mean Tegner score in the LSNR group (6; range, 3-7) was significantly higher than that in the HSNR group (5; range, 1-8) postoperatively (P = .03). Patients in the LSNR group had a significantly higher percentage of sports participation than those in the HSNR group (91% vs 65%, P = .02) postoperatively. CONCLUSION: A lower signal intensity in the ATFL ligament based on preoperative MRI is associated with a better clinical outcome, particularly a higher rate of return to sport.

Linolenic acid-modified methoxy poly (ethylene glycol)-oligochitosan conjugate micelles for encapsulation of amphotericin B.

Introduction of linolenic acid (LNA) and methoxy poly (ethylene glycol) (MPEG) to the backbone of oligochitosan (CS) afforded LNA-modified MPEG-CS conjugate (MPEG-CS-LNA). Amphotericin B-loaded MPEG-CS-LNA micelles (AmB-M) were prepared via dialysis method with 82.27 ± 1.96% of drug encapsulation efficiency and 10.52 ± 0.22% of drug loading capacity. The AmB-M enhanced AmB's water-solubility to 1.64 mg/mL, being 1640-folds higher than native AmB. The AmB-M obviously reduced hemolytic effect and renal toxicity of AmB when compared to marketed AmB injection (AmB-I). Its antifungal activity against Candida albicans was equivalent to AmB-I although AmB's release from AmB-M was significantly retarded. According to fluorescence microscopy test, the unchanged activity should be attributed to enhanced fungal cellular uptake of AmB-M caused by combined inducement of LNA and CS. The pharmacokinetic studies demonstrated that AmB-M also improved the pharmacokinetic parameters of AmB with AmB-I as control. Conclusively, developed LNA-modified MPEG-CS micellar system could be a viable alternative to the current toxic commercial AmB-I as a highly efficacious drug delivery system.

Itraconazole-loaded micelles based on linear-dendritic poly (ethylene glycol)-b-poly (ε-caprolactone).

A copolymeric micelle formulation of itraconazole (ITR-M) was prepared using linear-dendritic monoallyloxy poly (ethylene glycol)-b-poly (ε-caprolactone) (APEG-PCL) as drug carrier materials. DL and EE values of ITR-M were 5.70 ± 0.12% and 91.30 ± 1.90%, respectively. The micelle formulation enhanced the ITR solubility up to 30.42 µg/mL. In vitro release of ITR from the ITR-M was mainly drug diffusion process followed by the copolymer's degradation. ITR-M showed similar anti-Candida albicans activity to that of crude ITR although its release of ITR was slow and continuous. The in vivo pharmacokinetic study demonstrated that the ITR-M could improve tissue distribution of ITR. In conclusion, APEG-PCL could be a potential carrier in the development of antifungal drug delivery system.

The Effects of Angelica Sinensis Polysaccharide on Tumor Growth and Iron Metabolism by Regulating Hepcidin in Tumor-Bearing Mice.

BACKGROUND/AIMS: Iron plays a fundamental role in cell biology and its concentration must be precisely regulated. It is well documented that excess iron burden contributes to the occurrence and progression of cancer. Hepcidin secreted by liver plays an essential role in orchestrating iron metabolism. In the present study, we aimed to investigate the ability of angelica sinensis polysaccharide (ASP) to decrease iron burden in tumor-bearing mice and the mechanism of ASP regulation hepcidin expression. METHODS: Western blot, RT-PCR, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA) were used to detect the regulation of hepcidin and related cytokines by ASP. The role of ASP in tumor proliferation was investigated using in vivo assays. Iron depositions and iron concentrations in organs were determined by hematoxylin-eosin (H&E) staining and atomic absorption spectrophotometer. RESULTS: We found that ASP could inhibit tumor growth in mice xenografted with 4T1 and H22 cancer cells. In vivo experiments also showed that ASP could potently regulate hepcidin expression in liver and serum and decrease iron burden in liver, spleen and grafted tumors in mouse model. Treatment with ASP in hepatic cell lines reproduced comparable results in decreasing hepcidin as in mouse liver. Furthermore, we found that ASP markedly suppressed the expression of interleukin-6 (IL-6), JAK2, p-STAT3, and p-SMAD1/5/8 in liver, suggesting that JAK/STAT and BMP-SMAD pathways were involved in the regulation of hepcidin expression by ASP. We also found down-regulation of iron-related cytokines in ASP treated mice. CONCLUSION: The present study provides new evidence that ASP decreases hepcidin expression, which can reduce iron burden and inhibit tumor proliferation. These findings might aid ASP developed as a potential candidate for cancer treatment in patients with iron overload.

Arctigenin anti-tumor activity in bladder cancer T24 cell line through induction of cell-cycle arrest and apoptosis.

Bladder cancer is the most common neoplasm in the urinary system. This study assesses arctigenin anti-tumor activity in human bladder cancer T24 cells in vitro and the underlying molecular events. The flow cytometry analysis was used to detect cell-cycle distribution and apoptosis. Western blotting was used to detect changes in protein expression. The data showed that arctigenin treatment reduced viability of bladder cancer T24 cells in a dose- and time-dependent manner after treatment with arctigenin (10, 20, 40, 80, and 100 µmol/L) for 24 hr and 48 hr. Arctigenin treatment clearly arrested tumor cells in the G1 phase of the cell cycle. Apoptosis was detected by hoechst stain and flow cytometry after Annexin-V-FITC/PI double staining. Early and late apoptotic cells were accounted for 2.32-7.01% and 3.07-7.35%, respectively. At the molecular level, arctigenin treatment decreased cyclin D1 expression, whereas CDK4 and CDK6 expression levels were unaffected. Moreover, arctigenin selectively altered the phosphorylation of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 and activated phosphorylation of p38 significantly in a dose-dependent manner. These results suggest that arctigenin may inhibit cell viability and induce apoptosis by direct activation of the mitochondrial pathway, and the mitogen-activated protein kinase pathway may play an important role in the anti-tumor effect of arctigenin. The data from the current study demonstrate the usefulness of arctigenin in bladder cancer T24 cells, which should further be evaluated in vivo before translation into clinical trials for the chemoprevention of bladder cancer.