Low bone turnover is associated with advanced glycation end-products, oxidative stress, and inflammation induced by type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) can lead to multiple complications. T2DM-related bone damage has been linked to abnormal bone turnover, but it cannot fully explain the mechanisms of T2DM bone disease. This study attempts to elucidate the underlying mechanisms of poor bone quality in T2DM. Hence, T2DM model was induced by a high-fat diet combined with a single streptozotocin injection in 7-week-old male SD rats. Osteoblasts derived from SD rats were cultured in high glucose to mimic hyperglycemia. Low bone turnover was observed in T2DM bone with elevated levels of advanced glycation end-products (AGEs) and receptor for AGEs (RAGE). Additionally, higher levels of oxidative stress and inflammatory factors were found in T2DM bone. AGEs content in bone was pairwise correlated with RAGE, hydrogen peroxide, and inflammatory factors. Serum levels of RAGE, oxidative stress, and inflammatory factors were higher in T2DM, while AGEs content tended to be lower. Besides, 35 differentially expressed metabolites were screened in T2DM serum. Osteoblasts exposed to high glucose displayed analogous abnormal changes in these biomarkers. Thus, low bone turnover in T2DM might be partially due to excess oxidative stress and inflammation induced by AGE-RAGE signaling. Furthermore, these biomarker levels in serum were mostly consistent with bone, demonstrating their possibility for predicting bone quality in T2DM.

A dual computational and experimental strategy to enhance TSLP antibody affinity for improved asthma treatment.

Thymic stromal lymphopoietin is a key cytokine involved in the pathogenesis of asthma and other allergic diseases. Targeting TSLP and its signaling pathways is increasingly recognized as an effective strategy for asthma treatment. This study focused on enhancing the affinity of the T6 antibody, which specifically targets TSLP, by integrating computational and experimental methods. The initial affinity of the T6 antibody for TSLP was lower than the benchmark antibody AMG157. To improve this, we utilized alanine scanning, molecular docking, and computational tools including mCSM-PPI2 and GEO-PPI to identify critical amino acid residues for site-directed mutagenesis. Subsequent mutations and experimental validations resulted in an antibody with significantly enhanced blocking capacity against TSLP. Our findings demonstrate the potential of computer-assisted techniques in expediting antibody affinity maturation, thereby reducing both the time and cost of experiments. The integration of computational methods with experimental approaches holds great promise for the development of targeted therapeutic antibodies for TSLP-related diseases.

Hippocampal Glutamate Levels and Their Correlation With Subregion Volume in School-Aged Children With MRI-Negative Epilepsy: A Preliminary Study.

BACKGROUND: Abnormal levels of glutamate constitute a key pathophysiologic mechanism in epilepsy. The use of glutamate chemical exchange saturation transfer (GluCEST) imaging to measure glutamate levels in pediatric epilepsy is rarely reported in research. PURPOSE: To investigate hippocampal glutamate level variations in pediatric epilepsy and the correlation between glutamate and hippocampal subregional volumes. STUDY TYPE: Cross-sectional, prospective. SUBJECTS: A total of 38 school-aged pediatric epilepsy patients with structurally normal MRI as determined by at least two independent radiologists (60% males; 8.7 ± 2.5 years; including 20 cases of focal pediatric epilepsy [FE] and 18 cases of generalized pediatric epilepsy [GE]) and 17 healthy controls (HC) (41% males; 9.0 ± 2.5 years). FIELD STRENGTH/SEQUENCE: 3.0 T; 3D magnetization prepared rapid gradient echo (MPRAGE) and 2D turbo spin echo GluCEST sequences. ASSESSMENT: The relative concentration of glutamate was calculated through pixel-wise magnetization transfer ratio asymmetry (MTRasym) analysis of the GluCEST data. Hippocampal subfield volumes were computed from MPRAGE data using FreeSurfer. STATISTICAL TESTS: This study used t tests, one-way analysis of variance, Kruskal-Wallis tests, and Pearson correlation analysis. P < 0.05 was considered statistically significant. RESULTS: The MTRasym values of both the left and right hippocampi were significantly elevated in GE (left: 2.51 ± 0.23 [GE] vs. 2.31 ± 0.12 [HCs], right: 2.50 ± 0.22 [GE] vs. 2.27 ± 0.22 [HCs]). The MTRasym values of the ipsilateral hippocampus were significantly elevated in FE (2.49 ± 0.28 [ipsilateral] vs. 2.29 ± 0.16 [HCs]). The MTRasym values of the ipsilateral hippocampus were significantly increased compared to the contralateral hippocampus in FE (2.49 ± 0.28 [ipsilateral] vs. 2.35 ± 0.34 [contralateral]). No significant differences in hippocampal volume were found between different groups (left hippocampus, P = 0.87; right hippocampus, P = 0.87). DATA CONCLUSION: GluCEST imaging have potential for the noninvasive measurement of glutamate levels in the brains of children with epilepsy. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Fluid-solid coupling numerical simulation of the effects of different doses of verapamil on cancellous bone in type 2 diabetic rats.

BACKGROUND: The purpose of this study was to investigate the effects of four different doses of verapamil on the mechanical behaviors of solid and the characteristics of fluid flow in cancellous bone of distal femur of type 2 diabetes rats under dynamic external load. METHODS: Based on the micro-CT images, the finite element models of cancellous bones and fluids at distal femurs of rats in control group, diabetes group, treatment groups VER 4, VER 12, VER 24, and VER 48 (verapamil doses of 4, 12, 24, and 48 mg/kg/day, respectively) were constructed. A sinusoidal time-varying displacement load with an amplitude of 0.8 µm and a period of 1s was applied to the upper surface of the solid region. Then, fluid-solid coupling numerical simulation method was used to analyze the magnitudes and distributions of von Mises stress, flow velocity, and fluid shear stress of cancellous bone models in each group. RESULTS: The results for mean values of von Mises stress, flow velocity and FSS (t = 0.25s) were as follows: their values in control group were lower than those in diabetes group; the three parameters varied with the dose of verapamil; in the four treatment groups, the values of VER 48 group were the lowest, they were the closest to control group, and they were smaller than diabetes group. Among the four treatment groups, VER 48 group had the highest proportion of the nodes with FSS = 1-3 Pa on the surface of cancellous bone, and more areas in VER 48 group were subjected to fluid shear stress of 1-3 Pa for more than half of the time. CONCLUSION: It could be seen that among the four treatment groups, osteoblasts on the cancellous bone surface in the highest dose group (VER 48 group) were more easily activated by mechanical loading, and the treatment effect was the best. This study might help in understanding the mechanism of verapamil's effect on the bone of type 2 diabetes mellitus, and provide theoretical guidance for the selection of verapamil dose in the clinical treatment of type 2 diabetes mellitus.

Glutamate alterations in the premature infant brain during different gestational ages with glutamate chemical exchange saturation transfer imaging: a pilot study.

OBJECTIVES: To elucidate the change in glutamate levels in preterm infants at different gestational ages by glutamate chemical exchange saturated transfer (GluCEST) magnetic resonance imaging and to compare the difference in glutamate levels among different brain regions between very early preterm infants and middle and late preterm infants. METHODS: Fifty-three preterm infants (59% males; median gestational age = 33.6 weeks) underwent MRI, including conventional MRI and GluCEST. The original data were postprocessed in MATLAB. Correlation analysis was used to determine the relationship between the MTRasym and gestational age. The differences in MTRasym signals among different ROIs were statistically analysed by one-way analysis of variance (ANOVA). The MTRasym difference of the bilateral hemispherical ROI was compared by a paired T test. RESULTS: In all ROIs, glutamate concentration was positively correlated with gestational age. The glutamate concentration in the thalamus was higher than that in the frontal lobe in very early, middle and late preterm infants. A difference in glutamate concentration was not found in the bilateral ROIs. CONCLUSIONS: The concentration of glutamate in the brains of preterm infants of different gestational ages increased with gestational age, which may be one of the factors contributing to the higher incidence of neurodevelopmental dysfunction in very early preterm infants compared to that in middle and late preterm infants. Meanwhile, the glutamate concentrations among different brain regions were also diverse. KEY POINTS: • The glutamate concentration was positively correlated with gestational age in preterm infants of the brain. • Glutamate concentrations were dissimilar in different brain regions of preterm infants. • Glutamate concentration during the process of brain development in premature infants was not found to be asymmetric.

Diffusivity of Human Cartilage Endplates in Healthy and Degenerated Intervertebral Disks.

The cartilage endplates (CEPs) on the superior and inferior surfaces of the intervertebral disk (IVD), are the primary nutrient transport pathways between the disk and the vertebral body. Passive diffusion is responsible for transporting small nutrient and metabolite molecules through the avascular CEPs. The baseline solute diffusivities in healthy CEPs have been previously studied, however alterations in CEP diffusion associated with IVD degeneration remain unclear. This study aimed to quantitatively compare the solute diffusion in healthy and degenerated human CEPs using a fluorescence recovery after photobleaching (FRAP) approach. Seven healthy CEPs and 22 degenerated CEPs were collected from five fresh-frozen human cadaveric spines and 17 patients undergoing spine fusion surgery, respectively. The sodium fluorescein diffusivities in CEP radial and vertical directions were measured using the FRAP method. The CEP calcification level was evaluated by measuring the average X-ray attenuation. No difference was found in solute diffusivities between radial and axial directions in healthy and degenerated CEPs. Compared to healthy CEPs, the average solute diffusivity was 44% lower in degenerated CEPs (Healthy: 29.07 µm2/s (CI: 23.96-33.62 µm2/s); degenerated: 16.32 µm2/s (CI: 13.84-18.84 µm2/s), p < 0.001). The average solute diffusivity had an inverse relationship with the degree of CEP calcification as determined by the normalized X-ray attenuation values (ß = -22.19, R2 = 0.633; p < 0.001). This study suggests that solute diffusion through the disk and vertebral body interface is significantly hindered by CEP calcification, providing clues to help further understand the mechanism of IVD degeneration.

Linking Community OPR and Communication Infrastructure During a Public Health Crisis: A Study of Community Engagement in Shanghai, China.

Engaging the public and community organizations in local health actions greatly assists disease prevention and control. However, it remains unclear how organization-public relationships (OPR) and communication networks within communities contribute to community health actions. To fill this gap, a survey was conducted among community members in Shanghai, China, who were challenged by the Omicron wave of the COVID-19 pandemic. Results revealed that integrated connectedness to a storytelling network (ICSN) was a significant predictor of residents' community engagement. Trust, control mutuality, commitment, and ICSN were positively associated with community engagement intentions through the sense of community and organizational efficacy. This study is a step toward understanding how organizations and members collectively respond to health crises at the community level.

ent-Herqueidiketal and epi-Peniciherqueinone Isolated from a Mushroom Derived Fungus Penicillium herquei YNJ-35.

A new polyaromatic metabolite, ent-herqueidiketal (1), and a new phenalenone derivative, epi-peniciherqueinone (2), along with twelve known compounds 3-14, were isolated from the fungus Penicillium herquei YNJ-35, a symbiotic fungus of Pulveroboletus brunneopunctatus collected from Nangunhe Nature Reserve, Yunnan Province, China. The structures of 1-14 and the absolute configurations of 1 and 2 were determined by their spectroscopic data or by their single-crystal X-ray diffraction analysis or optical rotation values. Compound 1 showed strong antibacterial activity against Staphylococcus aureus (ATCC 29213) with minimum inhibitory concentration (MIC) of 8 µg/mL. In the cytotoxicity assays, compound 1 showed weak inhibitory activity against breast cancer MCF-7 and mice microglial BV2 cells with half maximal inhibitory concentration (IC50 ) of 17.58 and 29.56 µM; compound 14 showed stronger cytotoxicity against BV2 and MCF-7 cells with IC50 values of 6.57 and 10.26 µM.

Vacuum sealing drainage to treat Fournier's gangrene.

BACKGROUND: Vacuum sealing drainage (VSD) is widely applied in complex wound repair. We aimed to compare traditional debridement and drainage and VSD in treating Fournier's gangrene (FG). METHODS: Data of patients surgically treated for FG were retrospectively analyzed. RESULTS: Of the 36 patients (men: 31, women: 5; mean age: 53.5 ± 11.3 [range: 28-74] years) included in the study, no patients died. Between-group differences regarding sex, age, BMI, time from first debridement to wound healing, number of debridements, FGSI, and shock were not statistically significant (P > 0.05). However, lesion diameter, colostomy, VAS score, dressing changes, analgesic use, length of hospital stay, and wound reconstruction method (χ2 = 5.43, P = 0.04) exhibited statistically significant differences. Tension-relieving sutures (6 vs. 21) and flap transfer (4 vs. 2) were applied in Groups I and II, respectively. CONCLUSION: VSD can reduce postoperative dressing changes and analgesic use, and shrunk the wound area, thereby reducing flap transfer in wound reconstruction.

Effect of verapamil on bone mass, microstructure and mechanical properties in type 2 diabetes mellitus rats.

BACKGROUND: Verapamil was mainly used to treat hypertension, cardiovascular disease, inflammation and improve blood glucose in patients with diabetes, but its effects on bone mass, microstructure and mechanical properties were unclear. This study described the effects of verapamil on bone mass, microstructure, macro and nano mechanical properties in type 2 diabetic rats. METHODS: Rat models of type 2 diabetes were treated with verapamil at doses of 4, 12, 24 and 48 mg/kg/day by gavage respectively, twice a day. After 12 weeks, all rats were sacrificed under general anesthesia. Blood glucose, blood lipid, renal function and biochemical markers of bone metabolism were obtained by serum analysis, Micro-CT scanning was used to assess the microstructure parameters of cancellous bone of femoral head, three-point bending test was used to measure maximum load and elastic modulus of femoral shaft, and nano-indentation tests were used to measure indentation moduli and hardnesses of longitudinal cortical bone in femoral shaft, longitudinal and transverse cancellous bones in femoral head. RESULTS: Compared with T2DM group, transverse indentation moduli of cancellous bones in VER 24 group, longitudinal and transverse indentation moduli and hardnesses of cancellous bones in VER 48 group were significantly increased (p < 0.05). Furthermore, the effects of verapamil on blood glucoses, microstructures and mechanical properties in type 2 diabetic rats were dependent on drug dose. Starting from verapamil dose of 12 mg/kg/day, with dose increasing, the concentrations of P1NP, BMD, BV/TV, Tb. Th, Tb. N, maximum loads, elastic moduli, indentation moduli and hardnesses of femurs in rats in treatment group increased gradually, the concentrations of CTX-1 decreased gradually, but these parameters did not return to the level of the corresponding parameters of normal rats. Verapamil (48 mg/kg/day) had the best therapeutic effect. CONCLUSION: Verapamil treatment (24, 48 mg/kg/day) significantly affected nano mechanical properties of the femurs, and tended to improve bone microstructures and macro mechanical properties of the femurs, which provided guidance for the selection of verapamil dose in the treatment of type 2 diabetic patients.

Effects of continuous subcutaneous insulin infusion on the microstructures, mechanical properties and bone mineral compositions of lumbar spines in type 2 diabetic rats.

BACKGROUND: Continuous subcutaneous insulin infusion (CSII) for the treatment of type 2 diabetes (T2D) can improve the structure and strength of femur of rats, but the effect of CSII treatment on the lumbar spine of T2D rats is unknown. The purpose of this study is to investigate the effects of CSII on the microstructure, multi-scale mechanical properties and bone mineral composition of the lumbar spine in T2D rats. METHODS: Seventy 6-week-old male Sprague-Dawley (SD) rats were divided into two batches, each including Control, T2D, CSII and Placebo groups, and the duration of insulin treatment was 4-week and 8-week, respectively. At the end of the experiment, the rats were sacrificed to take their lumbar spine. Microstructure, bone mineral composition and nanoscopic-mesoscopic-apparentand-macroscopic mechanical properties were evaluated through micro-computed tomography (micro-CT), Raman spectroscopy, nanoindentation test, nonlinear finite element analysis and compression test. RESULTS: It was found that 4 weeks later, T2D significantly decreased trabecular thickness (Tb.Th), nanoscopic-apparent and partial mesoscopic mechanical parameters of lumbar spine (P < 0.05), and significantly increased bone mineral composition parameters of cortical bone (P < 0.05). It was shown that CSII significantly improved nanoscopic-apparent mechanical parameters (P < 0.05). In addition, 8 weeks later, T2D significantly decreased bone mineral density (BMD), bone volume fraction (BV/TV) and macroscopic mechanical parameters (P < 0.05), and significantly increased bone mineral composition parameters of cancellous bone (P < 0.05). CSII treatment significantly improved partial mesoscopic-macroscopic mechanical parameters and some cortical bone mineral composition parameters (P < 0.05). CONCLUSIONS: CSII treatment can significantly improve the nanoscopic-mesoscopic-apparent-macroscopic mechanical properties of the lumbar spine in T2D rats, as well as the bone structure and bone mineral composition of the lumbar vertebrae, but it will take longer treatment time to restore the normal level. In addition, T2D and CSII treatment affected bone mineral composition of cortical bone earlier than cancellous bone of lumbar spine in rat. Our study can provide evidence for clinical prevention and treatment of T2D-related bone diseases.

Non-professional Medical Interpreting as a Contextualized Practice: Chinese Volunteer Interpreters' Role-Spaces in Mediating Provider-Patient Conflicts Amid the Pandemic.

Non-professional medical interpreters are frequent participants of bilingual health communication. Yet, scholarly attention paid to this group's roles in less routinized medical encounters is insufficient. Adopting the concept of "role-space," this study explores volunteer medical interpreters' (VMIs) roles in mediating provider-patient conflicts at a designated hospital tasked to admit and treat foreign patients in City Y, China. In-depth interviews with eight VMIs, two doctors, two patients, and one Foreign Affairs officer indicate that VMIs took on the roles of provider proxy, patient advocates, information gatekeepers, and emotional supporters while navigating through challenges at the macro-, meso- and micro-level; Their practices led to four role-spaces that featured high presentation of VMIs' self-driven actions during dyadic communication with patients only and, in most cases, minimal interaction management and participant alignment in provider-patient encounters.

Biochemical and Morphological Abnormalities of Subchondral Bone and Their Association with Cartilage Degeneration in Spontaneous Osteoarthritis.

This study aims to investigate how biochemical composition in subchondral bone (SB) relates to the sulfated glycosaminoglycan (sGAG) content of articular cartilage (AC) in the knee joint of guinea pigs from the early to moderate osteoarthritis (OA). Male Dunkin Hartley strain guinea pigs were grouped according to age (1, 3, 6, and 9 months, with 10 guinea pigs in each group). The biochemical properties of the AC and SB in the tibial plateau of the guinea pigs were determined through histology and Raman spectroscopy, respectively. Furthermore, the microstructures of the SB were investigated using micro-computed tomography (micro-CT) and histology. Increased thickness and bone mineral density (BMD) and decreased porosity were observed in the subchondral plate (SP) with the progression of spontaneous OA, accompanied by a decreasing trend in sGAG integrated optical density (IOD) of AC. Compared with the changes in the microstructure of subchondral bone, the content of sGAG was more correlated to the changes in the mineral/matrix ratio of subchondral bone. The mineralization of the matrix was significantly correlated to the content of sGAG compared with crystallinity/maturity and Type B carbonate substitution. PO43- ν1/Amide III was more correlated to the content of sGAG than PO43- ν1/Amide I, PO43- ν1/CH2 wag during the progression of spontaneous osteoarthritis. This study demonstrated that the mineralization of subchondral bone plays a crucial role in the pathogenesis of OA. Future studies may access to the mineralization of subchondral bone in addition to its microstructure in the study for pathogenesis and early diagnosis of osteoarthritis.

Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases.

Bruton's tyrosine kinase (BTK) plays a crucial role in B-cell receptor and Fc receptor signaling pathways. BTK is also involved in the regulation of Toll-like receptors and chemokine receptors. Given the central role of BTK in immunity, BTK inhibition represents a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases. Great efforts have been made in developing BTK inhibitors for potential clinical applications in inflammatory and autoimmune diseases. This review covers the recent development of BTK inhibitors at preclinical and clinical stages in treating these diseases. Individual examples of three types of inhibitors, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors, are discussed with a focus on their structure, bioactivity and selectivity. Contrary to expectations, reversible BTK inhibitors have not yielded a significant breakthrough so far. The development of covalent, irreversible BTK inhibitors has progressed more rapidly. Many candidates entered different stages of clinical trials; tolebrutinib and evobrutinib are undergoing phase 3 clinical evaluation. Rilzabrutinib, a covalent reversible BTK inhibitor, is now in phase 3 clinical trials and also offers a promising future. An analysis of the protein-inhibitor interactions based on published co-crystal structures provides useful clues for the rational design of safe and effective small-molecule BTK inhibitors.

[Design of new gradient scaffolds based on triply periodic minimal surfaces and study on its mechanical, permeability and tissue differentiation characteristics].

In order to establish a bone scaffold with good biological properties, two kinds of new gradient triply periodic minimal surfaces (TPMS) scaffolds, i.e., two-way linear gradient G scaffolds (L-G) and D, G fusion scaffold (N-G) were designed based on the gyroid (G) and diamond (D)-type TPMS in this study. The structural mechanical parameters of the two kinds of scaffolds were obtained through the compressive simulation. The flow property parameters were also obtained through the computational fluid dynamics (CFD) simulation in this study, and the permeability of the two kinds of scaffolds were calculated by Darcy's law. The tissue differentiation areas of the two kinds of scaffolds were calculated based on the tissue differentiation theory. The results show that L-G scaffold has a better mechanical property than the N-G scaffold. However, N-G scaffold is better than the L-G scaffold in biological properties such as permeability and cartilage differentiation areas. The modeling processes of L-G and N-G scaffolds provide a new insight for the design of bone scaffold. The simulation in this study can also give reference for the prediction of osseointegration after the implantation of scaffold in the human body.

An Active Biomechanical Model of Cell Adhesion Actuated by Intracellular Tensioning-Taxis.

Cell adhesion to the extracellular matrix (ECM) is highly active and plays a crucial role in various physiological functions. The active response of cells to physicochemical cues has been universally discovered in multiple microenvironments. However, the mechanisms to rule these active behaviors of cells are still poorly understood. Here, we establish an active model to probe the biomechanical mechanisms governing cell adhesion. The framework of cells is modeled as a tensional integrity that is maintained by cytoskeletons and extracellular matrices. Active movement of the cell model is self-driven by its intrinsic tendency to intracellular tensioning, defined as tensioning-taxis in this study. Tensioning-taxis is quantified as driving potential to actuate cell adhesion, and the traction forces are solved by our proposed numerical method of local free energy adaptation. The modeling results account for the active adhesion of cells with dynamic protruding of leading edge and power-law development of mechanical properties. Furthermore, the morphogenesis of cells evolves actively depending on actin filaments alignments by a predicted mechanism of scaling and directing traction forces. The proposed model provides a quantitative way to investigate the active mechanisms of cell adhesion and holds the potential to guide studies of more complex adhesion and motion of cells coupled with multiple external cues.

A comparative study on phenazone degradation by sulfate radicals based processes.

In this paper, a comparative study on removal of the emerging pollutant phenazone (PNZ) by two treatment processes UVA/Fe(II)/persulfate (PS) and UVA/Fe(II)/peroxymonosulfate (PMS) was conducted. The two processes showed high efficiency in PNZ degradation, followed by a reasonable mineralization. The treatment system with PMS was found to be more efficient for PNZ degradation than that with PS due to the larger amounts of radicals generated. While the treatment process UVA/Fe(II)/PS showed higher ΔTOC/ΔSMX (TOC removal per unit of PNZ decay) than UVA/Fe(II)/PMS process. The sulfate and hydroxyl radicals played dominant roles in PNZ degradation in the UVA/Fe(II)/PS and UVA/Fe(II)/PMS process, respectively. Six and seven intermediates during PNZ degradation by UVA/Fe(II)/PS and UVA/Fe(II)/PMS process were detected, respectively. Among the detected intermediates, six of them are found for the first time. It takes shorter time for toxicity elimination by UVA/Fe(II)/PS process than UVA/Fe(II)/PMS, possibly due to the lower Kow values of hydroxylated products. The results demonstrate that UVA/Fe(II)/PMS process is more efficient in PNZ degradation, while UVA/Fe(II)/PS is more efficient in detoxification of PNZ. The two sulfate radicals based processes have good potentials in degradation, mineralization and detoxification of the emerging contaminants such as PNZ.

Boosting the Theranostic Effect of Liposomal Probes toward Prominin-1 through Optimized Dual-Site Targeting.

Ligand-targeting specific liposomal probes are increasingly used as imaging and delivery vehicles for in vivo diagnosis. Thereinto, the ligand variety and density profoundly affect the binding behaviors toward the target. The synergetic effect of different ligands could be achieved only when the optimized molecular-recognition configuration occurred. In this study, we construct a dual-peptides-targeting liposomal probe named BTLS that could synergistically bind two different sites of prominin-1, a cancer stem cell marker. At the distance of 11 Å between the two new peptides, ligands could insert into the hollow pocket of prominin-1 and BTLS could achieve the appropriate spatial structure, showing the strong binding affinity in both cellular and in vivo levels. It is indicated that the design of density-optimized peptide-targeted liposomes could be promising to maximize the multifunctional targeting effects on the cancer theranostics.

Effects of treadmill with different intensities on bone quality and muscle properties in adult rats.

BACKGROUND: Bone is a dynamically hierarchical material that can be divided into length scales of several orders of magnitude. Exercise can cause bone deformation, which in turn affects bone mass and structure. This study aimed to study the effects of treadmill running with different intensities on the long bone integrity and muscle biomechanical properties of adult male rats. METHODS: Forty-eight 5-month-old male SD rats were randomly divided into 4 groups: i.e., sedentary group (SED), exercise with speed of 12 m/min group (EX12), 16 m/min group (EX16), and 20 m/min group (EX20). The exercise was carried out for 30 min every day, 5 days a week for 4 weeks. The femurs were examined using three-point bending test, microcomputer tomography scanning and nanoindentation test; the soleus muscle was dissected for tensile test; ALP and TRACP concentrations were measured by serum analysis. RESULTS: The failure load was significantly increased by the EX12 group, whereas the elastic modulus was not significantly changed. The microstructure and mineral densities of the trabecular and cortical bone were significantly improved by the EX12 group. The mechanical properties of the soleus muscle were significantly increased by treadmill exercise. Bone formation showed significant increase by the EX12 group. Statistically higher nanomechanical properties of cortical bone were detected in the EX12 group. CONCLUSION: The speed of 12 m/min resulted in significant changes in the microstructure and biomechanical properties of bone; besides, it significantly increased the ultimate load of the soleus muscle. The different intensities of treadmill running in this study provide an experimental basis for the selection of exercise intensity for adult male rats.

Multiscale experimental study on the effects of different weight-bearing levels during moderate treadmill exercise on bone quality in growing female rats.

BACKGROUND: Bone tissue displays a hierarchical organization. Mechanical environments influence bone mass and structure. This study aimed to explore the effects of different mechanical stimuli on growing bone properties at macro-micro-nano scales. METHODS: Sixty five-week-old female Wistar rats were treadmill exercised at moderate intensity with the speed of 12 m/min, and then randomly divided into five groups according to weight-bearing level. After 8 weeks of experiment, femurs were harvested to perform multiscale tests. RESULTS: Bone formation was significantly increased by weight-bearing exercise, whereas bone resorption was not significantly inhibited. Trabecular and cortical bone mineral densities showed no significant increase by weight-bearing exercise. The microstructure of trabecular bone was significantly improved by 12% weight-bearing exercise. However, similar positive effects were not observed with further increase in weight-bearing levels. The nanomechanical properties of trabecular bone were not significantly changed by weight-bearing exercise. The macrostrength of whole femur and the nanomechanical properties of cortical bone significantly decreased in the 19% and 26% weight-bearing exercise groups. CONCLUSION: When rats ran on the treadmill at moderate intensity during growth period, additional 12% weight-bearing level could significantly increase bone formation, improve microstructure of trabecular bone, as well as maintain the structure and mechanical properties of cortical bone. Excessive weight-bearing level caused no positive effects on the trabecular bone microstructure and properties of cortical bone at all scales. In addition, increased weight-bearing level exerted no significant influence on trabecular and cortical bone mineral densities.