Recombinant fibroblast growth factor 4 ameliorates axonal regeneration and functional recovery in acute spinal cord injury through altering microglia/macrophage phenotype.

Neuroinflammation is one of the extensive secondary injury processes that aggravate metabolic and cellular dysfunction and tissue loss following spinal cord injury (SCI). Thus, an anti-inflammatory strategy is crucial for modulating structural and functional restoration during the stage of acute and chronic SCI. Recombinant fibroblast growth factor 4 (rFGF4) has eliminated its mitogenic activity and demonstrated a metabolic regulator for alleviating hyperglycemia in type 2 diabetes and liver injury in non-alcoholic steatohepatitis. However, it remains to be explored whether or not rFGF4 has a neuroprotective effect for restoring neurological disorders, such as SCI. Here, we identified that rFGF4 could polarize microglia/macrophages into the restorative M2 subtype, thus exerting an anti-inflammatory effect to promote neurological functional recovery and nerve fiber regeneration after SCI. Importantly, these effects by rFGF4 were related to triggering PI3K/AKT/GSK3ß and attenuating TLR4/NF-κB signaling axes. Conversely, gene silencing of the PI3K/AKT/GSK3ß signaling or pharmacological reactivation of the TLR4/NF-κB axis aggravated inflammatory reaction. Thus, our findings highlight rFGF4 as a potentially therapeutic regulator for repairing SCI, and its outstanding effect is associated with regulating macrophage/microglial polarization.

An Efficient Electrochemical Biosensor to Determine 1,5-Anhydroglucitol with Persimmon-Tannin-Reduced Graphene Oxide-PtPd Nanocomposites.

1,5-Anhydroglucitol (1,5-AG) is a sensitive biomarker for real-time detection of diabetes mellitus. In this study, an electrochemical biosensor to specifically detect 1,5-AG levels based on persimmon-tannin-reduced graphene oxide-PtPd nanocomposites (PT-rGO-PtPd NCs), which were modified onto the surface of a screen-printed carbon electrode (SPCE), was designed. The PT-rGO-PtPd NCs were prepared by using PT as the film-forming material and ascorbic acid as the reducing agent. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), ultraviolet-visible spectroscopy (UV-vis), and X-ray diffraction (XRD) spectroscopy analysis were used to characterise the newly synthesised materials. PT-rGO-PtPd NCs present a synergistic effect not only to increase the active surface area to bio-capture more targets, but also to exhibit electrocatalytic efficiency to catalyze the decomposition of hydrogen peroxide (H2O2). A sensitive layer is formed by pyranose oxidase (PROD) attached to the surface of PT-rGO-PtPd NC/SPCE. In the presence of 1,5-AG, PROD catalyzes the oxidization of 1,5-AG to generate 1,5-anhydrofuctose (1,5-AF) and H2O2 which can be decomposed into H2O under the synergistic catalysis of PT-rGO-PtPd NCs. The redox reaction between PT and its oxidative product (quinones, PTox) can be enhanced simultaneously by PT-rGO-PtPd NCs, and the current signal was recorded by the differential pulse voltammetry (DPV) method. Under optimal conditions, our biosensor shows a wide range (0.1-2.0 mg/mL) for 1,5-AG detection with a detection limit of 30 µg/mL (S/N = 3). Moreover, our electrochemical biosensor exhibits acceptable applicability with recoveries from 99.80 to 106.80%. In summary, our study provides an electrochemical method for the determination of 1,5-AG with simple procedures, lower costs, good reproducibility, and acceptable stability.

H-rGO-Pd NPs Nanozyme Enhanced Silver Deposition Strategy for Electrochemical Detection of Glypican-3.

Glypican-3 (GPC3), as an emerging biomarker, has been shown to be beneficial for the early diagnosis and treatment of hepatocellular carcinoma (HCC). In this study, an ultrasensitive electrochemical biosensor for GPC3 detection has been constructed based on the hemin-reduced graphene oxide-palladium nanoparticles (H-rGO-Pd NPs) nanozyme-enhanced silver deposition signal amplification strategy. When GPC3 specifically interacted with GPC3 antibody (GPC3Ab) and GPC3 aptamer (GPC3Apt), an "H-rGO-Pd NPs-GPC3Apt/GPC3/GPC3Ab" sandwich complex was formed with peroxidase-like properties which enhanced H2O2 to reduce the silver (Ag) ions in solution to metallic Ag, resulting in the deposition of silver nanoparticles (Ag NPs) on the surface of the biosensor. The amount of deposited Ag, which was derived from the amount of GPC3, was quantified by the differential pulse voltammetry (DPV) method. Under ideal circumstances, the response value was linearly correlated with GPC3 concentration at 10.0-100.0 µg/mL with R2 of 0.9715. When the GPC3 concentration was in the range from 0.01 to 10.0 µg/mL, the response value was logarithmically linear with the GPC3 concentration with R2 of 0.9941. The limit of detection was 3.30 ng/mL at a signal-to-noise ratio of three and the sensitivity was 1.535 µAµM-1cm-2. Furthermore, the electrochemical biosensor detected the GPC3 level in actual serum samples with good recoveries (103.78-106.52%) and satisfactory relative standard deviations (RSDs) (1.89-8.81%), which confirmed the applicability of the sensor in practical applications. This study provides a new analytical method for measuring the level of GPC3 in the early diagnosis of HCC.

The androgen receptor-targeted proteolysis targeting chimera and other alternative therapeutic choices in overcoming the resistance to androgen deprivation treatment in prostate cancer

Androgen receptor (AR) plays a vital role in prostate cancer (PCa), including castration-resistant PCa, by retaining AR signalling. Androgen deprivation treatment (ADT) has been the standard treatment in the past decades. A great number of AR antagonists initially had been found effective in tumour remission; however, most PCa relapsed that caused by pre-translational resistance such as AR mutations to turn antagonist into agonist, and AR variants to bypass the androgen binding. Recently, several alternative therapeutic choices have been proposed. Among them, proteolysis targeting chimera (PROTAC) acts different from traditional drugs that usually function as inhibitors or antagonists, and it degrades oncogenic protein and does not disrupt the transcription of an oncogene. This review first discussed some essential mechanisms of ADT resistance, and then introduced the application of AR-targeted PROTAC in PCa cells, as well as other AR-targeted therapeutic choices (AU)

Biomechanics evaluation of sacroiliac joint pain after lumbosacral fusion: A finite element analysis.

The sacroiliac joint (SIJ) constitutes the predominant pain source following lumbar or lumbosacral fusion. Although studies have investigated the biomechanical patterns of SIJ behaviors after lumbosacral fusion, the relationship between ligament strain and SIJ pain following lumbosacral fusion remains unclear. The present study developed a three-dimensional finite element model including L4, L5, sacrum, ilium, SIJ, and seven mainly ligaments. After successful validation, the model was used to investigate the biomechanics of SIJ and ligaments in simulating lumbosacral fusion process. Our results showed that small motion in a stable SIJ may significantly increases the contact pressure and stress of the SIJ, which increase the maximum contact pressure by 171%, 676%, 199%, and 203% and stress by 130%, 424%, 168%, and 241% for flexion, extension, bending, and axial rotation, respectively. An increase in contact pressure and stress in SIJ possibly causes pain at the SIJ, especially in extension and axial rotation. A comparison between the lumbosacral and intact models exhibited the maximum strain increase in the iliosacral ligament (ISL) and the ileal ligament (IL) under all loading conditions. The present study suggests that after lumbosacral fusion process, the ligament sudden increase or decrease is likely to lead sprain or strain ligament, especially ISL and IL thereby causing SIJ pain. This study may contribute to understand the relationship between SIJ ligaments and SIJ pain.

The androgen receptor-targeted proteolysis targeting chimera and other alternative therapeutic choices in overcoming the resistance to androgen deprivation treatment in prostate cancer.

Androgen receptor (AR) plays a vital role in prostate cancer (PCa), including castration-resistant PCa, by retaining AR signalling. Androgen deprivation treatment (ADT) has been the standard treatment in the past decades. A great number of AR antagonists initially had been found effective in tumour remission; however, most PCa relapsed that caused by pre-translational resistance such as AR mutations to turn antagonist into agonist, and AR variants to bypass the androgen binding. Recently, several alternative therapeutic choices have been proposed. Among them, proteolysis targeting chimera (PROTAC) acts different from traditional drugs that usually function as inhibitors or antagonists, and it degrades oncogenic protein and does not disrupt the transcription of an oncogene. This review first discussed some essential mechanisms of ADT resistance, and then introduced the application of AR-targeted PROTAC in PCa cells, as well as other AR-targeted therapeutic choices.

Gene correlation network analysis to identify regulatory factors in sciatic nerve injury.

BACKGROUND: Sciatic nerve injury (SNI), which frequently occurs under the traumatic hip and hip fracture dislocation, induces serious complications such as motor and sensory loss, muscle atrophy, or even disabling. The present work aimed to determine the regulating factors and gene network related to the SNI pathology. METHODS: Sciatic nerve injury dataset GSE18803 with 24 samples was divided into adult group and neonate group. Weighted gene co-expression network analysis (WGCNA) was carried out to identify modules associated with SNI in the two groups. Moreover, differentially expressed genes (DEGs) were determined from every group, separately. Subsequently, co-expression network and protein-protein interaction (PPI) network were overlapped to identify hub genes, while functional enrichment and Reactome analysis were used for a comprehensive analysis of potential pathways. GSE30165 was used as the test set for investigating the hub gene involvement within SNI. Gene set enrichment analysis (GSEA) was performed separately using difference between samples and gene expression level as phenotype label to further prove SNI-related signaling pathways. In addition, immune infiltration analysis was accomplished by CIBERSORT. Finally, Drug-Gene Interaction database (DGIdb) was employed for predicting the possible therapeutic agents. RESULTS: 14 SNI status modules and 97 DEGs were identified in adult group, while 15 modules and 21 DEGs in neonate group. A total of 12 hub genes was overlapping from co-expression and PPI network. After the results from both test and training sets were overlapped, we verified that the ten real hub genes showed remarkably up-regulation within SNI. According to functional enrichment of hub genes, the above genes participated in the immune effector process, inflammatory responses, the antigen processing and presentation, and the phagocytosis. GSEA also supported that gene sets with the highest significance were mostly related to the cytokine-cytokine receptor interaction. Analysis of hub genes possible related signaling pathways using gene expression level as phenotype label revealed an enrichment involved in Lysosome, Chemokine signaling pathway, and Neurotrophin signaling pathway. Immune infiltration analysis showed that Macrophages M2 and Regulatory T cells may participate in the development of SNI. At last, 25 drugs were screened from DGIdb to improve SNI treatment. CONCLUSIONS: The gene expression network is determined in the present work based on the related regulating factors within SNI, which sheds more light on SNI pathology and offers the possible biomarkers and therapeutic targets in subsequent research.

COL3A1, COL6A3, and SERPINH1 Are Related to Glucocorticoid-Induced Osteoporosis Occurrence According to Integrated Bioinformatics Analysis.

BACKGROUND Glucocorticoid-induced osteoporosis (GIOP) represents the most frequently seen type of secondary osteoporosis, a systemic skeleton disorder. Numerous factors are associated with GIOP occurrence, but there are no specific diagnostic and therapeutic biomarkers for GIOP so far. MATERIAL AND METHODS In this work, gene modules related to GIOP were screened through weighted gene coexpression network analysis. Moreover, protein-protein interaction (PPI) networks and gene set enrichment analysis (GSEA) were carried out for hub genes. In addition, microarray GSE30159 dataset was used as a training set to analyze gene expression within bone biopsy samples from patients with endogenous Cushing's syndrome with GIOP and from normal controls. GSE129228 was used as the test set for investigating the hub gene involvement within GIOP. RESULTS According to our results, the turquoise module showed clinical significance, and 10 genes (COL3A1, POSTN, COL6A3, COL14A1, SERPINH1, ASPN, OGN, THY1, NID2, and TNMD) were discovered to be the "real" hub genes within coexpression as well as PPI networks. GSEA showed that the interaction of extracellular matrix receptors together with the focal adhesion pathway had significant enrichment within samples with high COL3A1 and COL6A3 expression. After the results from both test and training sets were overlapped, SERPINH1 was also significantly altered between GIOP and normal control samples. CONCLUSIONS COL3A1, COL6A3, and SERPINH1 were identified to be the candidate biomarkers for GIOP.

MiR-27a promotes the autophagy and apoptosis of IL-1ß treated-articular chondrocytes in osteoarthritis through PI3K/AKT/mTOR signaling.

Osteoarthritis (OA) is a common degenerative joint disorder, which involves articular cartilage degeneration as well as joint inflammatory reactions. The recent studies have identified microRNA (miRNA) as one of the epigenetic mechanisms for the regulation of gene expression. Here we aim to reveal the role of miRNA in the regulation of gene expression in articular chondrocytes and its significance in the OA pathogenesis. In the present study, miRNA profiling was performed using OA cartilage and normal healthy cartilage tissues. As compared to their levels in normal cells and tissues, miR-27a expression was found to be upregulated in OA cartilage and IL-1ß-treated articular chondrocytes. TUNEL staining, as well as flow cytometry with Annexin V-FITC/PI double labeling indicated that miR-27a inhibition reduced the apoptosis of IL-1ß-treated articular chondrocytes. Bioinformatics prediction and the dual-luciferase reporter assay indicated that miR-27a targeted the 3'-UTR of the PI3K gene to silence it. The PI3K mRNA level in OA cartilage and IL-1ß-treated articular chondrocytes was also downregulated, comparing with normal cells and tissues. Transfection of chondrocytes transfected with the miR-27a inhibitor upregulated the PI3K expression. This study demonstrated miR-27a is a regulator of the PI3K-Akt-mTOR axis in human chondrocytes and could participate in OA pathogenesis.

The Influence of Age on Sensitivity to Dexmedetomidine Sedation During Spinal Anesthesia in Lower Limb Orthopedic Surgery.

To investigate the influence of age on sensitivity to dexmedetomidine sedation in adult patients, we selected 79 patients scheduled for lower limb orthopedic surgery under spinal anesthesia to identify the dexmedetomidine ED50 for adequate sedation among different age groups. After a spinal anesthetic was placed, a dose of dexmedetomidine determined by the Dixon up-and-down method was administered over 15 minutes. The ED50 in the elderly group was lower than in the other 2 groups (elderly: 0.88 ± 0.07; middle aged: 1.16 ± 0.08; young: 1.21 ± 0.06 µg/kg; both P < .001). There was no difference between the young and middle-aged groups (P = .160).

Rapid progression of mixed neuroendocrine carcinoma-acinar adenocarcinoma of the prostate: A case report.

The current study presents the case of a 78-year-old male with mixed neuroendocrine (NE) carcinoma-acinar adenocarcinoma of the prostate. The patient received endocrine therapy (maximal androgen blockade) after the initial diagnosis resulting in a significant decrease in serum prostate-specific antigen (PSA) level. The patient underwent transurethral resection of the prostate after 6 months of androgen-deprivation therapy for extraordinarily salient difficulty in urination, and histopathology demonstrated mixed NE carcinoma-acinar adenocarcinoma once again. The NE prostate cancer progressed rapidly even though the serum PSA was controlled at a low level on account of the endocrine therapy. Previous treatment protocols were replaced by combined chemotherapy and endocrine therapy, and the patient responded well. The patient's serum PSA remained at a low level, however, urethral dilatation for acute urinary retention was required again 5 months later and the lower urinary tract symptoms became increasingly evident. The patient eventually died of cachexia.. These findings indicate that mixed NE carcinoma-acinar adenocarcinoma has a higher degree of malignancy and that endocrine therapy for prostate cancer has a propensity to facilitate progression of this tumor.

The effect of immediate surgical bipolar plasmakinetic transurethral resection of the prostate on prostatic hyperplasia with acute urinary retention.

In the present study, we evaluated the safety and efficacy of immediate surgical bipolar plasmakinetic transurethral resection of the prostate (PK-TURP) for patients with benign prostatic hyperplasia (BPH) with acute urinary retention (AUR). We conducted a retrospective analysis of clinical data of BPH patients who received PK-TURP. A total of 1126 BPH patients were divided into AUR (n = 348) and non-AUR groups (n = 778). After the urethral catheters were removed, the urine white blood cell (WBC) count in the AUR group significantly increased compared with the non-AUR group (P < 0.01). However, there was no significant difference in international prostate symptom score, painful urination, and maximal urinary flow rate. The duration of hospitalization of the AUR group was longer than that of the non-AUR group (P < 0.001). A total of 87.1% (303/348) patients in the AUR group and 84.1% (654/778) patients in the non-AUR group completed all of the postoperative follow-up visits. The incidence of urinary tract infection in the AUR group within 3 months after surgery was significantly higher than that in the non-AUR group (P < 0.01). The incidence of temporary urinary incontinence in the AUR group did not exhibit significant difference. During 3-12 months after surgery, there were no significant differences in major complications between the two groups. Multivariate regression analyses showed that age, postvoid residual, maximal urinary flow rate, diabetes, and hypertension, but not the presence of AUR, were independent predictors of IPSS post-PK-TURP. In conclusion, immediate PK-TURP surgery on patients accompanied by AUR was safe and effective.

[A case of metastatic castration-resistant prostate cancer by abiraterone treatment].

We reviewed and analyzed the clinical data for a patient with metastatic castration-resistant prostate cancer (mCRPC) from September, 2009 to December, 2014. After the treatment with abiraterone, patient's performance status improved, pain relieved, total prostate specific antigen (tPSA) and free prostate specific antigen (fPSA) markedly decreased. tPSA or fPSA fluctuated between 30 and 50 ng/mL or between 10 and 20 ng/mL. MRI showed the left peripheral zone reduced. MRI and bone single photon emission computed tomography (SPECT) scan showed no new metastasis. These results indicated that application of abiraterone for patient with mCRPC not only decreased prostate specific antigen (PSA) levels and tumor volume, but also blocked bone metastasis progression and enhanced pain relief.

[Expression of perforin and granzyme-B in peripheral blood lymphocyte in patients with prostate cancer and the clinical significance].

OBJECTIVE: To explore the expression of perforin and granzyme-B in peripheral blood lymphocyte (PBL) in patients with prostate cancer (PCa) and the clinical significance. METHODS: The expressions of perforin and granzyme-B in PBL were detected by fluorescence quantitative reverse transcription polymerase chain reaction. The results of perforin and granzyme-B expression were compared among patients with PCa (n=60), patients with BPH (benign prostatic hyperplasia, n=40) and healthy controls (n=20). RESULTS: Th e expressions of perforin and granzyme-B in patients with PCa were significantly lower than that in patients with BPH or that in the healthy controls (P<0.05), respectively. Furthermore, in PCa patients with low pathological grade, the expressions of perforin and granzyme-B in PBL was statistically higher than that in patients with high pathological grade (P<0.05). The expressions of perforin and granzyme-B in PCa patients at high clinical stage was statistically lower than that in PCa patients at low clinical stage (P<0.05). CONCLUSION: The results of this study suggest that development and progression of PCa might be associated with poor immune status of patients.