Contralateral Neck-shaft Angle Lower Than 130° Is Associated With Clinical Failure in Nongeriatric Individuals: Analysis of the National Femoral Neck Fracture Database of 1066 Patients.

BACKGROUND: Treatment of femoral neck fractures in patients who are nongeriatric (≤ 60 years) is challenging because of high failure rates. Anatomic parameters influence the biomechanical environment for fracture healing, but their associations with clinical prognosis remains unclear. QUESTIONS/PURPOSES: (1) Which anatomic parameter that is identifiable on pelvic radiographs shows a statistical correlation with a higher risk of clinical failure defined as nonunion, avascular necrosis (AVN), reoperation, and functional failure (decrease in Harris hip score reaching the minimum clinically important difference) in the screw fixation of femoral neck fractures among nongeriatric patients? (2) How does the influence of anatomic parameters on clinical prognosis manifest: directly or mediated by additional mechanisms? METHODS: This retrospective, multicenter study used a nationwide database in China. Between January 2014 and December 2020, we evaluated 1066 patients with femoral neck fractures with a median age of 53 years (interquartile range 46 to 56) and median follow-up period of 62 months. Anatomic parameters including femoral neck-shaft angle (NSA), femoral head radius, femoral neck width, femoral offset, acetabular center-edge angle, and acetabular sharp angle were variables of interest. The primary outcome was clinical failure including nonunion, AVN, reoperation, and functional failure (decrease in Harris hip score reaching the minimum clinically important difference). Risk factors for failure were first filtered using the Bayesian information criterion and then assessed with multiple regression adjusting for confounders. The mediation effect was further explored using model-based causal mediation analysis with a quasi-Bayesian Monte Carlo method. RESULTS: Of all anatomic parameters we assessed, the contralateral NSA was associated with clinical failure, after adjusting for all potential covariates and confounding variables (adjusted odds ratio 0.92 [95% confidence interval 0.89 to 0.95]; p < 0.001). The optimal threshold for the NSA was 130°, with the highest Youden index of 0.27. Patients with an NSA < 130° (41% [441 of 1066]) demonstrated an increased occurrence of nonunion (15% [68 of 441] versus 5% [33 of 625]; p < 0.001), AVN (32% [141 of 441] versus 22% [136 of 625]; p < 0.001), functional failure (25% [110 of 441] versus 15% [93 of 625]), and reoperations (28% [122 of 441] versus 13% [79 of 625]). The impact of an NSA less than 130° on clinical failure was direct and substantially mediated by the type of displaced fracture (mediation proportion: 18.7%). CONCLUSION: In our study of screw fixations for femoral neck fractures among nongeriatric patients, we identified that a contralateral NSA < 130° correlates with an increased risk of clinical failure including nonunion, AVN, functional failure, and reoperation. The effect is either direct or mediated through displaced fracture types. This is important for surgeons in order to recognize the elevated rate of clinical failure and nature of the challenging biomechanical environment, which should guide them in refining surgical details and selecting appropriate fixation and rehabilitation plans. Approaches to managing these fractures require further validation with large-scale clinical trials. LEVEL OF EVIDENCE: Level III, prognostic study.

Sociodemographic characteristics of healthy volunteers along with their experience, attitude and concerns of clinical trials in Wuhan, China.

China has became the world's second largest pharmaceutical market, and the number of her registered clinical trials exceeded 3000 in 2021. Although thousands of healthy volunteers are participating in a large number of clinical trials in this country, there is no report about the characteristics, recognition, attitude of Chinese healthy volunteers and their concerns of clinical trials. A questionnaire survey was designed and given to 324 healthy volunteers participating in clinical trials in Wuhan, China. Four important findings emerged from our data. First, young, single and less educated men constituted the majority of Chinese healthy volunteers. Second, differences between the male and female healthy volunteers were observed. Female healthy volunteers are supposed to face more challenges and pressure in life, be more cautious about the clinical trials and more concerned about their health and feelings than the male. Third, no sociodemographic characteristic was associated with poorly understanding of the protocol research content, which was subjectively evaluated. Fourth, more support from society/family and more positive media reports about the participation of healthy volunteers in clinical trials are badly needed. These findings would help us to get a better understanding of Chinese healthy volunteers as a group for protecting them and promoting drug development.

Dynamic measurement of 3D displacements using dual-camera lensless Fourier transform digital holography.

Dynamic 3D displacement field measurement is an effective means to characterize the electrical performance stability and structural soundness of microsystems. Combining off-axis lensless Fourier transform multiplexed digital holography and multi-illumination profilometry, a dual-wavelength dual-camera optical setup with a multi-illumination system is developed to simultaneously acquire four phase images with different sensitivity vectors, as well as the object shapes. Meanwhile, the shared reference wave in off-axis lensless Fourier holography gives a convenient way for sensitivity vector modification and phase image registration, which are based on the stereo checkerboard calibration method. The dynamic 3D displacement fields and the strain maps of an energized integrated circuit board reveal that the inhomogeneous thermal expansion may cause some damage to chips, such as pin desoldering and microstructure fracture.

Factors associated with increased risk of lurasidone-induced somnolence: Two case-control studies based on one bioequivalence trial in healthy volunteers.

Somnolence is a common adverse effect of antipsychotic drugs used to treat psychotic disorders. It causes problems in many areas of life, such as gainful employment, driving, childcare, and social interactions. Somnolence is a major problem for a relatively new antipsychotic drug, lurasidone, whose dose-effect relationship remains unclear. Based on data from a bioequivalence study of two 40 mg lurasidone hydrochloride tablets, we designed two case-control studies to explore the correlation between somnolence and exposure to lurasidone and determine the factors associated with lurasidone-induced somnolence. In the first case-control study, lurasidone was administered to healthy volunteers; 30 experienced somnolence (as pre-defined) but 29 did not. Moreover, plasma concentration at 1 h was significantly associated with somnolence (OR = 1.124; p = 0.001). In the second case-control study, 48 volunteers administered lurasidone were classified into somnolence and no-somnolence groups based on different time-related criteria. We observed a positive association between plasma concentration at 0.75 h and somnolence (OR = 1.024; p = 0.002). Receiver operating characteristic analysis revealed that a plasma lurasidone concentration >21.65 ng/mL 1 h after administration strongly predicted somnolence. Our findings in healthy volunteers need to be further validated in patients in clinical settings to determine the optimal dose and duration of lurasidone administration.

Facilitative role of circPVT1 in osteogenic differentiation potentials of bone marrow mesenchymal stem cells from patients with osteoporosis through the miR-30d-5p/ITGB3 axis.

OBJECTIVE: The critical role of circular RNAs (circRNAs) in osteoporosis (OP) has been highlighted. We tried to explore the role of circPVT1 in OP in relation to microRNA-30d-5p (miR-30d-5p) and ITGB3. METHODS: After bone marrow collection, bone marrow mesenchymal stem cells (BMSCs) were isolated and identified. Then, Pearson coefficient was used to analyze the correlation among circPVT1, miR-30d-5p and ITGB3, and the binding sites were predicted and verified. Gain- and loss-of function assays in circPVT1, miR-30d-5p and ITGB3 were performed to analyze their effect on osteogenic differentiation of BMSCs. RESULTS: The osteogenic differentiation of BMSCs from OP patients was significantly decreased, and reduced circPVT1 expression was found in the BMSCs from OP patients. Overexpression of circPVT1 stimulated the formation of calcified nodules, increased alkaline phosphatase activity, and enhanced the expression of osteogenic marker genes in the BMSCs from OP patients. Additionally, circPVT1 expression was negatively correlated with miR-30d-5p, and miR-30d-5p was negatively correlated with ITGB3 in OP patients. Mechanically, circPVT1 regulated the osteogenic differentiation potential of BMSCs by relieving the inhibition of miR-30d-5p on ITGB3 through the competitive endogenous RNA mechanism. CONCLUSION: Our study highlighted a circPVT1/miR-30d-5p/ITGB3 axis in regulating osteogenic differentiation potential of BMSCs from OP patients.

Dynamic measurement of three-dimensional absolute displacements using dual-camera multiplexed digital holography.

Digital holography has been frequently used to measure the micro-deformation in mechanical tests due to its full-field measurement with high resolution and accuracy. To measure dynamic three-dimensional absolute displacements without a known reference displacement, a new technique based on the combination of off-axis multiplexed digital holography and stereo photogrammetry is proposed. Under the illumination of two different wavelength lasers along various directions, two off-axis multiplexed holograms recorded by the dual-camera system are used to extract four phase maps with different sensitivity vectors simultaneously. Meanwhile, the variation of sensitivity vectors and registration of phase maps are carried out by the object shape measured by the dual-camera system. By the four registered phases with four varying sensitivity vectors, three-dimensional absolute displacements can be determined. The feasibility of our method is well demonstrated by a quantitative experiment and finite element analysis, and the dynamic measurement of a resistor undergoing thermal expansion is presented.

Berberine Ameliorates Glucose Metabolism in Diabetic Rats through the alpha7 Nicotinic Acetylcholine Receptor-Related Cholinergic Anti-Inflammatory Pathway.

Berberine is an isoquinoline derivative alkaloid extracted from Chinese herbs. Recent studies have demonstrated the therapeutic effect of berberine on glucose metabolic disorders. However, its specific mechanism is still unclear. Our study aimed to research the glucose-lowering effect of berberine in diabetic rats and to reveal the possible role of the cholinergic anti-inflammatory pathway. Diabetic rats induced by administration of a high-calorie diet and streptozocin tail vein injection were assessed by the oral glucose tolerance test. Then, the diabetic rats were divided into two groups, those with or without the alpha7 nicotinic acetylcholine receptor gene downregulated, respectively, followed by treatment including berberine for 6 weeks. Results of this study show that the administration of berberine downregulated levels of fasting blood glucose and fasting insulin, and ameliorated insulin resistance in diabetic rats. Treatment with berberine inhibited acetylcholinesterase activity, and upregulated acetylcholine levels in the serum and alpha7 nicotinic acetylcholine receptor gene expression in the liver tissue. Meanwhile, berberine reversed elevated expression of cytokines interleukin-1ß and TNF-α in the serum and downregulated nuclear factor κB expression. However, berberine administration showed no glucose-lowering or anti-inflammatory effect in diabetic rats in which alpha7 nicotinic acetylcholine receptor gene expression was downregulated, and acetylcholinesterase activity was also significantly inhibited. In conclusion, berberine may ameliorate glucose metabolism by activating the alpha7 nicotinic acetylcholine receptor-mediated cholinergic anti-inflammatory pathway.

Atomically Dispersed and O, N-Coordinated Mn-Based Catalyst for Promoting the Conversion of Polysulfides in Li2S-Based Li-S Battery.

Nowadays, Li-S batteries are facing many thorny challenges like volume expansion and lithium dendrites on the road to commercialization. Due to the peculiarity of complete lithiation and the capability to match non-lithium anodes, Li2S-based Li-S batteries have attracted more and more attention. Nevertheless, the same notorious shuttle effect of polysulfides as in traditional Li-S batteries and the poor conductivity of Li2S lead to sluggish conversion reaction kinetics, poor Coulombic efficiency, and cycling performance. Herein, we propose the interconnected porous carbon skeleton as the host, which is modified by an atomically dispersed Mn catalyst as well as O, N atoms (named as ON-MnPC) via the melt salt method, and introduce the Li2S nanosheet into the carbon host with poly(vinyl pyrrolidone) ethanol solution. It has been found that the introduction of O, N to bind with Mn atoms can endow the nonpolar carbon surface with ample unsaturated coordination active sites, restrain the shuttle effect, and enhance the diffusion of Li+ and accelerate the conversion reaction kinetics. Besides, due to the ultra-high catalyst activity of atomically dispersed Mn catalysts, the Li2S/ON-MnPC cathode shows good electrochemical performance, e.g., an initial capacity of 534 mAh g-1, a capacity of 514.18 mAh g-1 after 100 cycles, a high retention rate of 96.23%, and a decay rate of 0.04% per cycle. Hence, use of atomically dispersed Mn catalysts to catalyze the chemical conversion reactions of polysulfides from multiple dimensions is a significant exploration, and it can provide a brand-new train of thought for the development and commercialization of the economical, high-performance Li2S-based Li-S batteries.

CircNRIP1 Encapsulated by Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles Aggravates Osteosarcoma by Modulating the miR-532-3p/AKT3/PI3K/AKT Axis.

Emerging evidence indicates that extracellular vesicle (EV)-encapsulated circRNAs have the potential diagnostic and prognostic values for malignancies. However, the role of circNRIP1 in osteosarcoma remains unclear. We herein investigated the therapeutic potential of circNRIP1 delivered by bone marrow mesenchymal stem cell-derived EVs (BMSC-EVs) in osteosarcoma. The expression of circNRIP1 was examined in the clinical tissue samples of osteosarcoma patients, after which the downstream genes of circNRIP1 were bioinformatically predicted. Gain- and loss-of function assays were then performed in osteosarcoma cells with manipulation of circNRIP1 and miR-532-3p expression. EVs isolated from BMSCs were characterized and co-cultured with osteosarcoma cells to examine their effects on cell phenotypes, as reflected by CCK-8 and Transwell assays. Further, a mouse model of tumor xenografts was established for in vivo substantiation. circNRIP1 was upregulated in osteosarcoma tissues and cells. Overexpression of circNRIP1 promoted the proliferative, migratory, and invasive potential of osteosarcoma cells. Co-culture data showed that BMSC-EVs could transfer circNRIP1 into osteosarcoma cells where it competitively bound to miR-532-3p and weakened miR-532-3p's binding ability to AKT3. By this mechanism, the PI3K/AKT signaling pathway was activated and the malignant characteristics of osteosarcoma cells were stimulated. In vivo experimental results unveiled that circNRIP1-overexpressing BMSC-EVs in nude mice resulted in enhanced tumor growth. In conclusion, the BMSC-EV-enclosed circNRIP1 revealed a new molecular mechanism in the pathogenesis of osteosarcoma, which might provide a novel therapeutic target for osteosarcoma.

CircATRNL1 protects against osteoarthritis by targeting miR-153-3p and KLF5.

BACKGROUND: Osteoarthritis (OA) is characterized by chondrocyte injury. Circular RNAs (circRNAs) are involved in the pathogenesis of various diseases, including OA. The purpose of this study was to determine the potential role of circATRNL1 in OA pathology in vitro. METHODS: Human chondrocytes were isolated and treated with interleukin-1 beta (IL-1ß) to mimic OA in vitro. High-throughput RNA sequencing was performed to identify differentially expressed circRNAs, miRNAs and mRNAs between IL and 1ß-treated chondrocytes and normal chondrocytes. The expression of circATRNL1, miR-153-3p and KLF5 was measured using quantitative real-time polymerase chain reaction (qRT-PCR). For functional analyses, cell apoptosis was assessed using a flow cytometry assay. Extracellular matrix (ECM) degradation was monitored by measuring the levels of ECM-associated proteins by Western blot. The potential target miRNAs of circATRNL1 were screened by bioinformatics analysis and verified by dual-luciferase reporter assay. RESULTS: The expression of circATRNL1 was decreased in IL-1ß-treated chondrocytes. CircATRNL1 overexpression ameliorated cell apoptosis and ECM degradation, which were promoted by IL-1ß treatment. Mechanistic analysis revealed that circATRNL1 directly targeted miR-153-3p and that miR-153-3p could reverse the inhibitory effects of circATRNL1 overexpression on inflammatory responses, cell apoptosis and ECM degradation. KLF5 is a target of miR-153-3p. CONCLUSION: Taken together, the results in this study suggested that circATRNL1 might ameliorate the development and progression of OA through regulating miR-153-3p/KLF5 axis. Our study increased the understanding of circRNAs as therapeutic targets in the treatment of OA.

IL1RN promotes osteoblastic differentiation via interacting with ITGB3 in osteoporosis.

The occurrence and progress of osteoporosis (OP) are partially caused by impaired osteoblast differentiation. Interleukin-I receptor antagonist (IL1RN) is an immune modulatory molecule that commonly functions by means of competing the binding site of IL-1R with IL-1. Although it was recently reported that IL1RN is involved in osteoblast differentiation, the role of IL1RN in osteogenesis remains unclear. In this work, we first investigated the expression pattern of IL1RN in ovariectomy mice and in vitro osteogenic induction of MC3T3-E1 and C3H10T1/2 cells. To verify the exact role of IL1RN in osteoblast differentiation, we established IL1RN-downregulated/upregulated cell lines. The results indicated that IL1RN was constantly expressed in MC3T3-E1 and C3H10T1/2 cells. Interestingly, an increase of IL1RN expression in osteoblasts occurred when osteoblasts were cultured in osteogenic medium (OM). As expected, silencing of IL1RN attenuated the osteogenic effect of OM, while IL1RN overexpression increased the osteogenic staining and promoted the expression of osteogenic markers, including alkaline phosphatase, osterix, and osteocalcin. In addition to evaluating the function of IL1RN in osteoblasts, we also investigated the molecular mechanism of the role of IL1RN in osteoblasts. We found that IL1RN interacts with integrin ß3 to activate ß-catenin signaling, which finally regulates osteoblast differentiation. Taken together, this study provides the framework that IL1RN, as a novel regulator of osteogenesis, may be a potential therapeutic target for the treatment of OP.

Research and application of dual-camera dynamic in-line digital holography using a two-step phase-shifting cepstrum technique.

Due to limits in the properties of digital cameras, in-line digital holography is commonly used to take full advantage of the sampling space of the camera. To realize the dynamic high-resolution measurement of in-line digital holography, dual-camera dynamic in-line digital holography is proposed. By means of a two-step phase-shifting cepstrum algorithm and a dual-camera parallel phase-shifting recording optical path, the complex amplitude of the object wave can be reconstructed without its zero-order and conjugate terms. Meanwhile, a novel spherical wave interference calibration method is also developed for the dual-camera recording system, and image correction is carried out via rotation, translation, and diffraction, with an average error of phase correction of 0.1107 rad. Finally, the feasibility and effectiveness of the proposed technique is well demonstrated by a practical application of dynamic temperature field measurement in a transparent medium.

Berberine Ameliorates Spatial Learning Memory Impairment and Modulates Cholinergic Anti-Inflammatory Pathway in Diabetic Rats.

Background: Cognitive impairment caused by diabetes has been recognized. Berberine is well known for its resistance to peripheral lesions, but it is rarely used for the treatment of spatial learning and memory caused by diabetes. This study explored the mechanism of berberine to alleviate cognitive impairment via the cholinergic anti-inflammatory and insulin signaling pathways. Methods: Morris water maze was used to appraise spatial learning and memory. Positron-emission tomography (PET) imaging was adopted to detect the transport of glucose, and blood/cerebrospinal fluid (CSF) glucose was checked using commercial blood glucose meter. Insulin level was measured by ELISA kit and ß-Amyloid (Aß) formation was observed by Congo red staining. Western-blot was performed to appraise protein expression. Results: We found that berberine rectified some aberrant changes in signal molecules concerning inflammation, and cholinergic and insulin signaling pathways in the hippocampus. Furthermore, CSF/blood glucose, inflammatory response or acetyl cholinesterase enzyme (AChE) activity were reduced by berberine. Additionally, acetylcholine levels were enhanced after berberine treatment in diabetic rats. Finally, Aß formation in diabetic hippocampus was inhibited and spatial learning memory was ameliorated by berberine. Discussion: In conclusion, berberine clears Aß deposit and consequently ameliorates spatial learning memory impairment via the activation of the cholinergic anti-inflammatory and insulin signaling pathways in diabetic rats.

Coptidis Rhizoma inhibits NLRP3 inflammasome activation and alleviates renal damage in early obesity-related glomerulopathy.

BACKGROUND: Obese subjects have been considered to be in a state of chronic, low-grade systemic inflammation. Excess fat accumulation and persistent inflammation may promote renal dysfunction, to cause chronic kidney disease (CKD) and even end-stage kidney failure. Coptidis Rhizoma is a classical traditional Chinese herb well known for its hypoglycemic and hypolipidemic properties. The mechanism is partially associated with its anti-inflammatory effect. However, this effect is rarely investigated in obesity and obesity-related glomerulopathy (ORG). PURPOSE: The current study was designed to evaluate the effect of Coptidis Rhizoma on ORG. It also aimed to determine whether this renal protection effect of Coptidis Rhizoma was related to the inhibition of NLRP3 inflammasome in ORG. METHODS: Coptidis Rhizoma concentrated granules were prepared and the main components were identified by 3D-High Performance Liquid Chromatography (3D-HPLC) assay. The animal model of early stage ORG was established in obesity-prone (OP) rats by high protein and high fat diet feeding for 12 weeks. The treatment with Coptidis Rhizoma at different dosages was administered by intragastric infusion simultaneously. Then body weight, kidney weight, plasma lipid profiles, 24 h urine protein/albumin content and kidney histology were measured. Inflammatory biomarkers were examined both in the rat plasma and renal cortex. The gene expressions of NLRP3 inflammasome complex and NF-κB in renal tissues were also measured. RESULTS: Coptidis Rhizoma alleviated dyslipidemia and reduced the renal weight of the rats with ORG. Meanwhile, urinary albumin to creatinine ratio and creatinine clearance rate were significantly improved. Coptidis Rhizoma also attenuated glomerular hypertrophy, mesangial hyperplasia, and effacement of podocyte foot in renal tissues of ORG rats. In addition, Coptidis Rhizoma intervention decreased the levels of proinflammatory cytokines (TNF-α, IL-1ß, IL-6, and IL-18) both in plasma and renal tissue. The gene expression of NLRP3 inflammasome was down-regulated and NF-κB activity was also inhibited by Coptidis Rhizoma in renal tissues of ORG rats. CONCLUSION: Coptidis Rhizoma can ameliorate early renal damage in ORG rats and the mechanisms appear to be related to the inhibition of NLRP3 inflammasome complex.

Jiao-tai-wan Up-regulates Hypothalamic and Peripheral Circadian Clock Gene Cryptochrome and Activates PI3K/AKT Signaling in Partially Sleep-deprived Rats.

This study aims to explore the effect and mechanism of Jiao-tai-wan (JTW) on systemic and tissue-specific inflammation and insulin resistance in obesity-resistant (OR) rats with chronic partial sleep deprivation (PSD). OR rats with PSD were orally given JTW and Estazolam for 4 weeks. The amount of food intake and metabolic parameters such as body weight increase rate, fasting plasma glucose (FPG), fasting insulin (FINS), homeostasis model assessment-insulin resistance (HOMA-IR) and plasma inflammatory markers were measured. The expression levels of circadian proteins cryptochrome 1 (Cryl) and cryptochrome 2 (Cry2) in hypothalamus, adipose and liver tissues were also determined. Meanwhile, the mRNA expression of inflammatory markers, activity of nuclear factor kappa B (NF-κB) p65 protein, as well as the expression levels of insulin signaling pathway proteins in hypothalamus, adipose and liver tissues were measured. Additionally, cyclic adenosine 3', 5'-monophosphate (cAMP) and activity of vasodilator-stimulated phosphoprotein (VASP) in hypothalamus tissue were measured. JTW significantly decreased the body weight increase rate and food intake, ameliorated systemic inflammation and insulin resistance. JTW effectively ameliorated inflammation and increased PI3K/AKT signaling activation in hypothalamus, adipose and liver. Interestingly, all these changes were associated with the up-regulation of circadian gene Cryl and Cry2 protein expression. We also found that in hypothalamus tissue of PSD rats, down-regulation of Cryl and Cry2 activated cAMP/PKA signaling and then led to inflammation, while JTW inhibited this signaling. These results suggested that JTW has the beneficial effect on ameliorating inflammation and insulin resistance in partially sleep-deprived rats by up-regulating Cry expression.

Comprehensive Effects of Suppression of MicroRNA-383 in Human Bone-Marrow-Derived Mesenchymal Stem Cells on Treating Spinal Cord Injury.

BACKGROUND/AIMS: Transplantation of bone-marrow-derived mesenchymal stem cells (MSCs) promotes neural cell regeneration after spinal cord injury (SCI). Recently, we showed that suppression of microRNA-383 (miR-383) in MSCs increased the protein levels of glial cell line derived neurotrophic factor (GDNF), resulting in improved therapeutic effects on SCI. However, the overall effects of miR-383 suppression in MSCs on SCI therapy were not determined yet. Here, we addressed this question. METHODS: We used bioinformatics tools to predict all miR-383-targeting genes, confirmed the functional bindings in a dual luciferase reporter assay. The effects of alteration of candidate genes in MSCs on cell proliferation were analyzed by MTT assay and by Western blotting for PCNA. The effects on angiogenesis were assessed by HUVEC assay. The effects on SCI in vivo were analyzed by transplantation of the modified MSCs into nude rats that underwent SCI. RESULTS: Suppression of miR-383 in MSCs not only upregulated GDNF protein, but also increased vascular endothelial growth factor A (VEGF-A) and cyclin-dependent kinase 19 (CDK19), two other miR-383 targets. MiR-383-suppression-induced increases in CDK19 resulted in a slight but significant increase in MSC proliferation, while miR-383-suppression-induced increases in VEGF-A resulted in a slight but significant increase in MSC-mediated angiogenesis. CONCLUSIONS: Upregulation of CDK19 and VEGF-A by miR-383 suppression in MSCs further improve the therapeutic potential of MSCs in treating SCI in rats.

Promotion of cell growth and adhesion of a peptide hydrogel scaffold via mTOR/cadherin signaling.

Understanding neurite outgrowth, orientation, and migration is important for the design of biomaterials that interface with the neural tissue. However, the molecular signaling alternations have not been well elucidated to explain the impact of hydrogels on cell morphology. In our previous studies, a silk fibroin peptide (SF16) hydrogel was found to be an effective matrix for the viability, morphology, and proliferation of PC12 rat pheocrhomocytoma cells. We found that PC12 cells in the peptide hydrogel exhibited adhesive morphology compared to those cultured in agarose or collagen. Moreover, we identified that cell adhesion molecules (E- and N-cadherin) controlled by mTOR signaling were highly induced in PC12 cells cultured in the SF16 peptide hydrogel. Our findings suggest that the SF16 peptide might be suitable to be a cell-adhesion material in cell culture or tissue engineering, and mTOR/cadherin signaling is required for the cell adhesion in the SF16-peptide hydrogel.

Jia-Wei-Jiao-Tai-Wan ameliorates type 2 diabetes by improving ß cell function and reducing insulin resistance in diabetic rats.

BACKGROUND: Jia-Wei-Jiao-Tai-Wan (JWJTW), composed of Jiao-Tai-Wan (Cinnamomum cassia and Rhizoma coptidis) and other antidiabetic herbs, including Astragalus membranaceus, Herba Gynostemmatis, Radix Puerariae Lobatae, Folium Mori and Semen Trigonellae, is widely used to treat diabetes and has demonstrated a curative effect in the clinic, but the potential mechanism is unknown. This study aimed to explore the effects of JWJTW on diabetic rats and to clarify the underlying mechanism. METHODS: JWJTW was prepared, and the main components contained in the formula were identified by high-performance liquid chromatography (HPLC) fingerprint analysis. Diabetic rats induced by streptozotocin (STZ) and a high-sucrose-high-fat diet were treated with two concentrations of JWJTW (1.025 and 2.05 g/kg/d) for 100 days. The oral glucose tolerance test (OGTT), insulin release test (IRT) and insulin tolerance test (ITT) were performed to measure the glycometabolism of the diabetic rats at the end of the treatment period. Blood was collected to determine the serum lipid levels of the diabetic rats. Nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) were detected in pancreas homogenates to analyze the oxidative stress in the pancreata of diabetic rats, and the expression levels of pancreatic and duodenal homeobox 1 (PDX-1) and insulin in the pancreas were tested by Western blot to measure pancreatic islet function. In addition, Western blots were used to measure the expression of proteins related to the insulin signaling pathway in skeletal muscle of the diabetic rats. RESULTS: The results showed that the administration of JWJTW could ameliorate impairments in glucose tolerance, insulin release function and insulin tolerance in diabetic rats. JWJTW could also dose-dependently reduce serum lipid levels in diabetic rats. JWJTW restrained oxidative stress by decreasing the expression of NO and MDA and increasing the expression of SOD and GSH-px. JWJTW improved the function of pancreatic ß cells by increasing PDX-1 and insulin expression. In addition, JWJTW restored the impaired insulin signaling; upregulated phospho-insulin receptor (pInsR) expression, insulin receptor substrate (IRS) tyrosine phosphorylation, phosphatidylinositol 3-kinase (PI3K) (p85), and glucose transporter 4 (GLUT4) expression; and downregulated the serine phosphorylation of IRS. CONCLUSIONS: This study suggests that JWJTW can ameliorate type 2 diabetes by improving ß cell function and reducing insulin resistance in diabetic rats.

Effect of Jiaotai Pill () on intestinal damage in partially sleep deprived rats.

OBJECTIVE: To explore the effect and mechanism of Jiaotai Pill (, JTW) on intestinal mucosal damage in rats with chronic partial sleep deprivation (PSD). METHODS: Obesity resistant (OR) rats were selected, and underwent 4 h PSD by being exposed to environmental noise for 4 weeks. During the whole PSD period, JTW and estazolam were orally given to the rats respectively in the treating groups. Plasma concentration of lipopolysaccharide (LPS) which is the marker of gut-origin endotoxemia was examined. Intestinal morphology changes were observed by optical microscopy. The protein expression of occludin (Ocln) in the intestine was measured by immunofluorescence technique and Western blot. The expressions of circadian proteins cryptochromes (Cry1 and Cry2) in the intestine were also determined. RESULTS: The treatment of JTW significantly decreased LPS level in OR rats with PSD (P<0.05). JTW also attenuated insomnia-induced intestinal injury like shorter, sparse and incomplete villus, wide gap between the villus, mucosal swelling and congesting (P<0.05). These changes were associated with the effect of JTW on up-regulating the expressions of Cry1 protein, Cry2 protein and Ocln protein in the intestine. CONCLUSIONS: JTW has the beneficial effect on improving intestinal mucosal damage caused by PSD. The mechanism appears to be related to the modulation of the expressions of circadian proteins and Ocln protein in the intestine, thereby attenuating inflammation and improving insulin resistance in insomnia rats.

Berberine Ameliorates Diabetes-Associated Cognitive Decline through Modulation of Aberrant Inflammation Response and Insulin Signaling Pathway in DM Rats.

Background: Memory-impairment was one of the common characteristics in patients with diabetes mellitus. The release of chronic inflammation mediators and insulin resistance in diabetic brain gave rise to the generation of toxic factor Aß42 which was the marker of Alzheimer's disease. In addition, the impairment of memory in diabetes mellitus was also correlated predominantly with uptake/metabolism of glucose in medial prefrontal cortex (mPFC). Previously, anti-inflammation and hypoglycemic effects of berberine (BBr) have been described in peripheral tissues. For better understanding the effects of BBr on cognitive action in diabetics, we investigated the functions of BBr involved in anti-inflammation and ameliorating insulin resistance in prefrontal cortex of diabetic rats. Methods: Intragastric administration of BBr (187.5 mg/Kg/d) was used in diabetic rats. Fear-condition assay was applied for cognitive assessment, and relative protein expressions were detected by western-blot. The glucose uptake in prefrontal cortex of diabetic rats was tested by Positron-Emission Tomography imaging. The levels of inflammation mediators were determined by commercial ELISA kits. Results: The inflammation mediator release and insulin resistance in the mPFC of diabetic rats was inhibited by BBr. The activation of PI3K/Akt/mTOR and MAPK signaling pathway, as well as two novel isoforms PKCη and PKC𝜀 and the translocation of NF-κB in neuron were also down-regulated by BBr; furthermore, the neuron specific glucose transporter GLUT3 was remarkably augmented by 2-3 times when compared with diabetic group; meanwhile, BBr also promoted glucose uptake in the brain. Additionally BBr decreased the expressions of amyloid precursor protein and BACE-1, and the production of oligomeric Aß42. Finally, it accelerates the reinforcement of the information and ameliorates cognitive impairment. Conclusion: BBr inhibited the activation of inflammation pathway and insulin resistance in the mPFC of diabetic rats. Finally, it improved the lesion of cognition in diabetic rats.