Exploration of the miR-187-3p/CNR2 pathway in modulating osteoblast differentiation and treating postmenopausal osteoporosis through mechanical stress.

This study aimed to explore how mechanical stress affects osteogenic differentiation via the miR-187-3p/CNR2 pathway. To conduct this study, 24 female C57BL/6 mice, aged 8 weeks, were used and divided into four groups. The Sham and OVX groups did not undergo treadmill exercise, while the Sham + EX and OVX + EX groups received a 8-week treadmill exercise. Post-training, bone marrow and fresh femur samples were collected for further analysis. Molecular biology analysis, histomorphology analysis, and micro-CT analysis were conducted on these samples. Moreover, primary osteoblasts were cultured under osteogenic conditions and divided into GM group and CTS group. The cells in the CTS group underwent a sinusoidal stretching regimen for either 3 or 7 days. The expression of early osteoblast markers (Runx2, OPN, and ALP) was measured to assess differentiation. The study findings revealed that mechanical stress has a regulatory impact on osteoblast differentiation. The expression of miR-187-3p was observed to decrease, facilitating osteogenic differentiation, while the expression of CNR2 increased significantly. These observations suggest that mechanical stress, miR-187-3p, and CNR2 play crucial roles in regulating osteogenic differentiation. Both in vivo and in vitro experiments have confirmed that mechanical stress downregulates miR-187-3p and upregulates CNR2, which leads to the restoration of distal femoral bone mass and enhancement of osteoblast differentiation. Therefore, mechanical stress promotes osteoblasts, resulting in improved osteoporosis through the miR-187-3p/CNR2 signaling pathway. These findings have broad prospect and provide molecular biology guidance for the basic research and clinical application of exercise in the prevention and treatment of PMOP.

Chiral ligands and photothermal synergistic effects of inorganic nanoparticles for bacteria-killing.

As the drawbacks of antibiotics in treating bacterial infections emerged, physical methods such as near-infrared-activated (NIR-activated) bacterial killing, have attracted great interests for their advantages of no resistance, short action time and few side effects. In this manuscript, NIR-activated bacteria-killing performance of chiral copper sulphide nanoparticles (L-/d-CuS NPs) was investigated using linearly polarized light (LPL) and circularly polarized light (CPL) as illumination sources, respectively. Chiral CuS NPs showed enhanced NIR-activated bacteria-killing effect compared with achiral CuS NPs under the same conditions. Moreover, these chiral CuS NPs showed obvious chirality-related antibacterial effect: the bacterial killing was more efficient under CPL activation, and L- and d-CuS NPs had higher antibacterial efficiency under left circularly polarized light (LCPL) and right circularly polarized light (RCPL), respectively. The possible mechanism of bacteria-killing performance for chiral CuS NPs was discussed in detailed. Photothermal bacteria-killing tests of chiral CuS NPs "sealed" in polydimethylsiloxane (PDMS) demonstrated the individual influence of photothermal effect. These observations in this paper could provide ideas for the potential applications of chiral nanostructures with enhanced photothermal effect in efficient bacterial killing.

Feasibility of Amide Proton Transfer-Weighted Imaging at 3T for Renal Masses: A Preliminary Study.

BACKGROUND: To investigate the optimal B1,rms value of renal amide proton transfer-weighted (APTw) images and the reproducibility of this value, and to explore the utility of APT imaging of renal masses and kidney tissues. METHODS: APTw images with different B1,rms values were repeatedly recorded in 15 healthy volunteers to determine the optimal value. Two 4-point Likert scales (poor [1] to excellent [4]) were used to evaluate contour clarity and artifacts in masses and normal tissues. The APTw values of masses and normal tissues were then compared in evaluable images (contour clarity score > 1, artifacts score > 1). The APTw of malignant masses, normal tissues, and benign masses were calculated and compared with the Mann-Whitney U test. RESULTS: The optimal scanning parameter of B1,rms was 2 µT, and the APTw images had good agreement in the volunteers. Our study of APTw imaging examined 70 renal masses (13 benign, 57 malignant) and 49 normal kidneys (including those from 15 healthy volunteers). The mean APTw value for renal malignant masses (2.28(1.55)) was different from that for benign masses (0.91(1.30)) (P<0.001), renal cortex (1.30 (1.25)) (P<0.001), renal medulla (1.64 (1.33)) (P<0.05), and renal pelvis (5.49 (2.65)) (P<0.001). CONCLUSION: These preliminary data demonstrate that APTw imaging of the kidneys has potential use as an imaging biomarker for the differentiation of normal tissues, malignant masses, and benign masses.

Amide proton transfer-weighted MRI for renal tumors: Comparison with diffusion-weighted imaging.

OBJECTIVE: To investigate the potential of amide proton transfer-weighted (APTw) MRI in identifying benign and malignant renal tumors and to evaluate whether APTw MRI can add diagnostic value to diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Participants with renal tumor underwent preoperative multiparametric MRI, including APTw MRI and DWI. The APTw and apparent diffusion coefficient (ADC) of malignant tumors and benign tumors were calculated independently by two radiologists and compared. The value of the mean APTw and the mean ADC for differentiating malignant and benign tumors was evaluated by receiver operating characteristic analysis. RESULTS: In total, 65 participants (mean age, 59 years ±14; 41 men) were evaluated: 54 with malignant and 11 with benign renal tumors. Malignant renal tumors showed higher mean APTw values [2.03% (1.63) vs 1.00% (1.60); P < 0.01] and lower mean ADC values (1.22 × 10-3 mm2/s ± 0.37 vs 1.51 × 10-3 mm2/s ± 0.37; P < 0.05) than benign renal tumors. The area under the receiver operating characteristic curve (AUC) of APTw, ADC and the combination of them for the identification of benign and malignant renal tumors was 0.78(95% CI: 0.66, 0.87; P < 0.001),0.70(95% CI: 0.54, 0.86; P < 0.05) and 0.79 (95% CI: 0.67, 0.88; P < 0.001). The optimal cutoff value for mean APTw was 2.14% (sensitivity, 74%; specificity, 73%). There was no difference between these three parameters for differentiating malignant from benign renal tumors (P > 0.05). CONCLUSION: The APTw MRI has the potential use as an imaging biomarker for renal malignant and benign tumors.

Microglia Promote Lymphangiogenesis Around the Spinal Cord Through VEGF-C/VEGFR3-Dependent Autophagy and Polarization After Acute Spinal Cord Injury.

Reducing secondary injury is a key focus in the field of spinal cord injury (SCI). Recent studies have revealed the role of lymphangiogenesis in reducing secondary damage to central nerve. However, the mechanism of lymphangiogenesis is not yet clear. Macrophages have been shown to play an important role in peripheral tissue lymphangiogenesis. Microglia is believed to play a role similar to macrophages in the central nervous system (CNS); we hypothesized that there was a close relationship between microglia and central nerve system lymphangiogenesis. Herein, we used an in vivo model of SCI to explored the relationship between microglia and spinal cord lymphangiogenesis and further investigated the polarization of microglia and its role in promoting spinal cord lymphangiogenesis by a series of in vitro experiments. The current study elucidated for the first time the relationship between microglia and lymphangiogenesis around the spinal cord after SCI. Classical activated (M1) microglia can promote lymphangiogenesis by secreting VEGF-C which further increases polarization and secretion of lymphatic growth factor by activating VEGFR3. The VEGF-C/VEGFR3 pathway activation downregulates microglia autophagy, thereby regulating the microglia phenotype. These results indicate that M1 microglia promote lymphangiogenesis after SCI, and activated VEGF-C/VEGFR3 signaling promotes M1 microglia polarization by inhibiting autophagy, thereby facilitates lymphangiogenesis.

An Adaptable Nanoprobe Integrated with Quantitative T1 -Mapping MRI for Accurate Differential Diagnosis of Multidrug-Resistant Lung Cancer.

Multidrug resistance (MDR) is one of the major factors causing failure of non-small-cell lung cancer (NSCLC) chemotherapy. Real-time and accurate differentiation between drug-resistant and sensitive NSCLC is of primary importance for guiding the subsequent treatments and improving the therapeutic outcome. However, there is no effective method to provide such an accurate differentiation. This study creates an innovative strategy of integrating H2 O2 -responsive nanoprobes with the quantitative T1 -mapping magnetic resonance imaging (MRI) technique to achieve an accurate differential diagnosis between drug-resistant and sensitive NSCLC in light of differences in H2 O2 content in the tumor microenvironment (TME). The result demonstrates that the synthesized MIL-53(Fe)@MnO2 nanocomposites possess an excellent capability of shortening the cancer longitudinal relaxation time (T1 ) when meeting H2 O2 in TME. T1 -mapping MRI could sensitively detect this T1 variation (about 2.6-fold that of T1-weighted imaging (T1 WI)) to accurately differentiate the H2 O2 content between drug-resistant and sensitive NSCLC. In addition, the quantitative data provided by the T1 -mapping MRI dedicates correct comparison across imaging tests and is more reliable than T1 WI, thus giving it a chance for precise assessment of the anti-cancer effect. This innovative strategy of merging TME adaptable nanoprobes with the quantitative MRI technique provides a new approach for the precise diagnosis of multidrug-resistant NSCLC.

Bioactivity and pharmacokinetics of two human serum albumin-thymosin alpha1-fusion proteins, rHSA-Talpha1 and rHSA-L-Talpha1, expressed in recombinant Pichia pastoris.

Thymosin-alpha1 (Talpha1) is indicated for the treatment of certain viral infections, including hepatitis B and C, and cancers, such as melanoma. In this paper, the fusion genes encoding human serum albumin (HSA) and Talpha1 with (rHSA-L-Talpha1) and without a linker peptide (rHSA-Talpha1) were constructed and overexpressed in P. pastoris. Through the process of ion interaction chromatography (Q-Sepharose F.F), hydrophobic interaction chromatography (Phenyl Sepharose HP) and affinity chromatography (Blue Sepharose F.F), the purity of fusion proteins was greater than 97%. In contrast to the reactivity of normal spleen cells to Con A, the data of in vitro murine spleen lymphocytes proliferation experiment suggested that spleen cells achieved a higher degree of T cell maturation after rHSA-L-Talpha1, rHSA-Talpha1 and Talpha1 treatments, respectively. Moreover, rHSA-L-Talpha1, rHSA-Talpha1 and Talpha1 can also antagonize dexamethasone-induced apoptosis of thymocyte sub-populations. In hydrocortisone-induced immunosuppression mice (in vivo experiments), after subcutaneous injections with two fusion proteins and Talpha1 for seven consecutive days, the net increment of body weight, the spleen index and the thymus index were significantly improved. Simultaneously, the increase in SOD level and the decrease in MDA level in plasma were observed. The pharmacokinetic data of rHSA-L-Talpha1 and rHSA-Talpha1 administered in rats showed an improved pharmacokinetic profile with a conspicuous prolonged half life. The analysis of bioactivity and pharmacokinetics suggested that fusion proteins rHSA-L-Talpha1 and rHSA-Talpha1 were new drug candidates.

A charged aerosol detector/chemiluminescent nitrogen detector/liquid chromatography/mass spectrometry system for regular and fragment compound analysis in drug discovery.

In this paper, we introduce a high throughput LCMS/UV/CAD/CLND system that improves upon previously reported systems by increasing both the quantitation accuracy and the range of compounds amenable to testing, in particular, low molecular weight "fragment" compounds. This system consists of a charged aerosol detector (CAD) and chemiluminescent nitrogen detector (CLND) added to a LCMS/UV system. Our results show that the addition of CAD and CLND to LCMS/UV is more reliable for concentration determination for a wider range of compounds than either detector alone. Our setup also allows for the parallel analysis of each sample by all four detectors and so does not significantly increase run time per sample.