CXCL13 promotes TNF-α synthesis in rheumatoid arthritis through activating ERK/p38 pathway and inhibiting miR-330-3p generation.

Rheumatoid arthritis (RA) is a well-known autoimmune disorder associated with joint pain, joint swelling, cartilage and bone degradation as well as deformity. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a crucial role in multiple cellular pathogenesis processes, including RA. TNF-α is a vital proinflammatory factor in the progression of RA. However, the role of CXCL13 in TNF-α production in RA has not been fully explored. Our analysis of both database and clinical samples revealed higher levels of CXCL13 and TNF-α in RA samples compared to healthy controls. CXCL13 concentration-dependently induces TNF-α synthesis in RA synovial fibroblasts. CXCL13 enhances TNF-α expression by interacting with the CXCR5 receptor, activating the ERK/p38 pathways, and inhibiting miR-330-3p generation. Importantly, treatment with CXCL13 shRNA counteracted the upregulation of TNF-α production induced by collagen-induced arthritis. Our findings support the notion that CXCL13 is a promising target in the treatment of RA.

High-mobility group box-1 impedes skeletal muscle regeneration via downregulation of Pax-7 synthesis by increasing miR-342-5p expression.

High mobility group box-1 (HMGB1) is a driver of inflammation in various muscular diseases. In a previous study, we determined that HMGB1 induced the atrophy of skeletal muscle by impairing myogenesis. Skeletal muscle regeneration after injury is dependent on pair box 7 (Pax-7)-mediated myogenic differentiation. In the current study, we determined that the HMGB1-induced downregulation of Pax-7 expression in myoblasts inhibited the regeneration of skeletal muscle. We also determined that HMGB1 inhibits Pax-7 and muscle differentiation by increasing miR-342-5p synthesis via receptors for advanced glycation end-products (RAGE), toll-like receptor (TLR) 2, TLR4, and c-Src signaling pathways. In a mouse model involving glycerol-induced muscle injury, the therapeutic inhibition of HMGB1 was shown to rescue Pax-7 expression and muscle regeneration. The HMGB1/Pax-7 axis is a promising therapeutic target to promote muscular regeneration.

Heparin-Loaded Composite Coatings on Porous Stent from Pure Magnesium for Biomedical Applications.

Challenges associated with drug-releasing stents used in percutaneous transluminal coronary angioplasty (PTCA) encompass allergic reactions, prolonged endothelial dysfunction, and delayed stent clotting. Although absorbable stents made from magnesium alloys seem promising, fast in vivo degradation and poor biocompatibility remain major challenges. In this study, zirconia (ZrO2) layers were used as the foundational coat, while calcium phosphate (CaP) served as the surface layer on unalloyed magnesium specimens. Consequently, the corrosion current density was decreased to 3.86, from 13.3 µA/cm2. Moreover, a heparin-controlled release mechanism was created by co-depositing CaP, gelatin (Gel), and heparin (Hep) on the specimens coated with CaP/ZrO2, thereby boosting magnesium's blood compatibility and prolonging the heparin-releasing time. Techniques like X-ray diffractometry (XRD), focused ion beam (FIB) system, toluidine blue testing, UV-visible spectrometry, field emission scanning electron microscopy (FESEM), and surrogate tests for endothelial cell viability were employed to examine the heparin-infused coatings. The drug content rose to 484.19 ± 19.26 µg/cm2 in multi-layered coatings (CaP-Gel-Hep/CaP-Hep/CaP/ZrO2) from 243.56 ± 55.18 µg/cm2 in a single layer (CaP-Hep), with the controlled release spanning beyond 28 days. Also, cellular viability assessments indicated enhanced biocompatibility of the coated samples relative to those without coatings. This suggests the potential of magnesium samples after coating ZrO2 and CaP with Gel as candidates for porous biodegradable stents or even scaffolds in biomedical applications.

Using convolutional neural network to analyze brain MRI images for predicting functional outcomes of stroke.

Nowadays, the physicians usually predict functional outcomes of stroke based on clinical experiences and big data, so we wish to develop a model to accurately identify imaging features for predicting functional outcomes of stroke patients. Using magnetic resonance imaging of ischemic and hemorrhagic stroke patients, we developed and trained a VGG-16 convolutional neural network (CNN) to predict functional outcomes after 28-day hospitalization. A total of 44 individuals (24 men and 20 women) were recruited from Taoyuan General Hospital and China Medical University Hsinchu Hospital to enroll in the study. Based on "modified Rankin Scale (mRS)" and "National Institutes of Health Stroke Scale (NIHSS)" assessments, men, women, and mixed men and women were trained separately to evaluate the differences of the results, and we have shown that VGG-16 demonstrated high accuracy in predicting the functional outcomes of stroke patients. The new deep-learning approach has provided an automated decision support system for personalized recommendations and treatments, assisting the physicians to predict functional outcomes of stroke patients in clinical practice.

Hyperlipidemia and Statins Use for the Risk of New Diagnosed Sarcopenia in Patients with Chronic Kidney: A Population-Based Study.

Background: Previous research found that statins, in addition to its efficiency in treating hyperlipidemia, may also incur adverse drug reactions, which mainly include myopathies and abnormalities in liver function. Aim: This study aims to assess the risk for newly onset sarcopenia among patients with chronic kidney disease using statins. Material and Method: In a nationwide retrospective population-based cohort study, 75,637 clinically confirmed cases of chronic kidney disease between 1997 and 2011were selected from the National Health Insurance Research Database of Taiwan. The selection of the chronic kidney disease cohort included a discharge diagnosis with chronic kidney disease or more than 3 outpatient visits with the diagnosis of chronic kidney disease found within 1 year. After consideration of patient exclusions, we finally got a total number of 67,001 cases of chronic kidney disease in the study. The Cox proportional hazards model was used to perform preliminary analysis on the effect of statins usage on the occurrence of newly diagnosed sarcopenia; the Cox proportional hazards model with time-dependent covariates was conducted to take into consideration the individual temporal differences in medication usage, and calculated the hazard ratio (HR) and 95% confidence interval after controlling for gender, age, income, and urbanization. Results: Our main findings indicated that patients with chronic kidney disease who use statins seem to effectively prevent patients from occurrences of sarcopenia, high dosage of statins seem to show more significant protective effects, and the results are similar over long-term follow-up. In addition, the risk for newly diagnosed sarcopenia among patients with lipophilic statins treatment was lower than that among patients with hydrophilic statins treatment. Conclusion: It seems that patients with chronic kidney disease could receive statin treatment to reduce the occurrence of newly diagnosed sarcopenia. Additionally, a higher dosage of statins could reduce the incidence of newly diagnosed sarcopenia in patients with chronic kidney disease.

Doxorubicin - chitosan - hydroxyapatite composite coatings on titanium alloy for localized cancer therapy.

The doxorubicin-chitosan composite is deposited electrochemically on the Ti alloy post hydroxyapatite coated for reducing the side effects by sustaining release of drugs localized near the tumor to achieve the inhibition or apoptosis of cancer. The possibility of danger in case of exfoliation of medicine composite and HA agglomerates from the alloy surface due to the dynamic erosion of blood flow could be overcome with the additional surface modification by the electrochemical deposition way. The cathodic polarization tests coupled with electrochemical reactions were analyzed to speculate the deposition mechanism of doxorubicin, spectrophotometer (UV visible spectrometer) to measure doxorubicin loading and release, field emission scanning electron microscope (FESEM) to observe surface morphology, Fourier transform infrared (FTIR) spectroscopy for chemical bonding of composites, and X-ray diffractometry (XRD) for crystal structure. The cell culture was carried out to analyze the drug efficacy on cell viability. It is concluded that doxorubicin-chitosan composites can be successfully deposited on the uncoated and hydroxyapatite-coated titanium specimen alloy by electrochemical methods. Both have revealed the sustaining drug release for a month and the latter with high porosity can enhance the drug loading to 37.46 µg/cm2, revealing this electrochemical method is a practical way to load doxorubicin cancer drug releasing locally to significantly reduce the amount of medication needed for future clinical applications.

Paclitaxel/hydroxyapatite composite coatings on titanium alloy for biomedical applications.

In order to reduce the side effects of chemotherapy, target therapies have been spotlighted. In this study, paclitaxel, the drug for cancer treatment, is electrochemically deposited on Ti alloy as vascular stents for the tumor localized therapy by sustaining drug releasing to achieve the cancer cells apoptosis or the prevention of cancer metastasis. In the experiment, cathodic polarization tests coupled with electrochemical reactions were analyzed to speculate the deposition mechanism, and the field emission scanning electron microscope (FESEM), focused ion beam (FIB) system and Fourier transform infrared spectroscopy (FTIR) to observe the surface morphology and analyze constituent elements. A spectrophotometer (UV visible spectrometer) was used to measure drug loading and release. Finally, MTT Assay was carried out to analyze the cell viability for drug efficacy. It is concluded that paclitaxel can be successfully deposited on the titanium alloy by electrochemical method. Besides, the post-hydroxyapatite coated specimen with high porosity can enhance the drug loading from 395±95µg/cm2 to 572±99µg/cm2, a lower burst release in the first day, a higher sustaining release rate in a month, and the more complete drug release. All results indicate that the paclitaxel/hydroxyapatite composite coating by the electrochemical deposition method is much more effective and promising.

Significant association of caveolin-1 single nucleotide polymorphisms with childhood leukemia in Taiwan.

BACKGROUND: A growing body of evidence indicates that caveolin-1 (CAV1) may influence the development of human cancer. However, the exact role of CAV1 in childhood leukemia is still controversial. We investigated six novel polymorphic variants of CAV1, namely C521A (rs1997623), G14713A (rs3807987), G21985A (rs12672038), T28608A (rs3757733), T29107A (rs7804372), and G32124A (rs3807992), and analyzed the association of each specific genotype with susceptibility to childhood leukemia. MATERIALS AND METHODS: In total, 266 patients with childhood leukemia and 266 age-matched healthy controls, recruited from two major medical centers in Taiwan, were genotyped investigating the association of these polymorphisms with childhood leukemia. RESULTS: We found that there were significant differences between childhood leukemia and control groups in the distributions of their genotypes (p=4.1×10(-8) and 0.0167) and allelic frequencies (p=4.9×10(-10) and 3.7×10(-3)) in the CAV1 G14713A and T29107A polymorphisms, respectively. As for the haplotype analysis, those who had GG/AT or GG/AA at CAV1 G14713A/T29107A had a reduced risk of childhood leukemia compared to those with GG/TT, while those with any other combinations were at increased risk. CONCLUSION: The A allele of CAV1 G14713A is risky, while the A allele of CAV1 T29107A is protective for the development of childhood leukemia and these may be novel useful genomic markers for the early detection of childhood leukemia.

Synthesis and cytotoxicity of 9-alkoxy-1,5-dichloroanthracene derivatives in murine and human cultured tumor cells.

9-Alkoxy-1,5-dichloroanthracenes were successfully prepared. Their cytotoxicity was evaluated in vitro on rat glioma C6 cell lines and human hepatoma G2 cell lines, respectively. Alkylation of 1,5-dichloro-9(10H)-anthracenone with either the appropriate alcohols or alkyl chlorides in the presence of sulfuric acid or sodium hydride, respectively, furnished this structural class of anthracenes. Contrary to mitoxantrone, cytotoxic properties were observed as documented by the reactivity of the novel compounds and potent in vitro activity against C6 cells and hep G2 cells over a wide range of structural variants. Among these compounds, 5c, 5h, 5l and 5n are potent cytotoxins. They inhibit C6 cell growth in culture, indicated by using 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide sodium salt (XTT) colorimetric assay. By using this assay it was also shown that 5c, 5d and 5l possess potent cytotoxicity on hep G2 cells. The most active compound displaying in vitro cytotoxicity was the 9-butoxy derivative 5h with IC50 values 0.02 microM against C6 cells, as compared with mitoxantrone with IC50 values 0.07 microM. The most active compound displaying in vitro cytotoxicity against hep G2 cells was 5c with IC50 values 1.7 microM (mitoxantrone: 0.8 microM). Structure-activity relationships (SAR) of these compounds with respect to the nature of the alkoxy substitution in the 9 position are discussed for both cell lines.