The association between different physical activity (PA) patterns and cardiometabolic index (CMI) in US adult population from NHANES (2007-2016).

Background: Physical activity (PA) is widely recommended for preventing and combating obesity, but the most effective PA pattern for treating obesity remains unclear. Cardiometabolic index (CMI), derived from waist height ratio and triglycerides to high-density lipoprotein-cholesterol ratio, is a novel indicator for evaluating obesity. However, the relationship between different PA patterns and CMI remains unelucidated. Objective: This study aimed to explore the association between different PA patterns and CMI in U.S. adults. Methods: Participants with complete information in CMI, PA patterns, and other covariates in the National Health and Nutrition Examination Survey database (2007-2016) were included in this study. Multivariate linear regression models were utilized to explore the relationship between PA patterns and CMI. Moreover, stratified analyses, interaction tests and restricted cubic spline (RCS) regression analysis were used to investigate the stability and nonlinearity of the association, respectively. Results: A total of 16,442 adults were included in this study. After adjusting for all potential covariates, only the regularly active group was significantly associated with CMI reduction (ß = -0.13, 95% CI: 0.19 to -0.07, P < 0.0001), while the weekend warriors group did not achieve equivalent CMI reduction (ß = -0.09, 95% CI: 0.32 to 0.14, P = 0.4204). Subgroup analyses and interaction tests revealed that the CMI-PA association was more pronounced in the subgroup with age≤45 or >60, with higher education level, and who are current drinkers. Furthermore, RCS analysis indicated that total PA in a week was significantly, nonlinearly associated with CMI in non-inactive adults, and that a total of PA more than 330 min can reap favorable CMI reduction. Conclusion: Being regularly active is associated with significant CMI reduction, while being weekend warriors and insufficiently active do not achieve equivalent benefits. For non-inactive individuals, engaging in PA for more than 330 min weekly helps to reduce CMI effectively.

PTP1B knockdown alleviates BMSCs senescence via activating AMPK-mediated mitophagy and promotes osteogenesis in senile osteoporosis.

The senescence of bone marrow mesenchymal stem cells (BMSCs) is the basis of senile osteoporosis (SOP). Targeting BMSCs senescence is of paramount importance for developing anti-osteoporotic strategy. In this study, we found that protein tyrosine phosphatase 1B (PTP1B), an enzyme responsible for tyrosine dephosphorylation, was significantly upregulated in BMSCs and femurs with advancing chronological age. Therefore, the potential role of PTP1B in BMSCs senescence and senile osteoporosis was studied. Firstly, significantly upregulated PTP1B expression along with impaired osteogenic differentiation capacity was observed in D-galactose (D-gal)-induced BMSCs and naturally-aged BMSCs. Furthermore, PTP1B silencing could effectively alleviate senescence, improve mitochondrial dysfunction, and restore osteogenic differentiation in aged BMSCs, which was attributable to enhanced mitophagy mediated by PKM2/AMPK pathway. In addition, hydroxychloroquine (HCQ), an autophagy inhibitor, significantly reversed the protective effects from PTP1B knockdown. In SOP animal model, transplantation of LVsh-PTP1B-transfected D-gal-induced BMSCs harvested double protective effects, including increased bone formation and reduced osteoclastogenesis. Similarly, HCQ treatment remarkably suppressed osteogenesis of LVsh-PTP1B-transfected D-gal-induced BMSCs in vivo. Taken together, our data demonstrated that PTP1B silencing protects against BMSCs senescence and mitigates SOP via activating AMPK-mediated mitophagy. Targeting PTP1B may represent a promising interventional strategy to attenuate SOP.

Glucocorticoid-loaded pH/ROS dual-responsive nanoparticles alleviate joint destruction by downregulating the NF-κB signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune disease causing severe symptoms that are difficult to treat. Nano-drug delivery system is recognized as a promising strategy for management of RA. However, how to thoroughly release payloads from nanoformulations and synergistic therapy of RA needs to be further investigated. To address this issue, a pH and reactive oxygen species (ROS) dual-responsive, methylprednisolone (MPS)-loaded and arginine-glycine-aspartic acid (RGD)-modified nanoparticles (NPs) was fabricated using phytochemical and ROS-responsive moiety co-modified α-cyclodextrin (α-CD) as a carrier. In vitro and in vivo experiments verified that the pH/ROS dual-responsive nanomedicine could be efficiently internalized by activated macrophages and synovial cells, and the released MPS could promote transformation of M1-type macrophages into M2 phenotype, thereby down-regulating pro-inflammatory cytokines. In vivo experiments demonstrated that the pH/ROS dual-responsive nanomedicine was remarkably accumulated in the inflamed joints of mice with collagen-induced arthritis (CIA). The accumulated nanomedicine could obviously relieve joint swelling and cartilage destruction without obvious adverse effects. Importantly, the expression of interleukin-6 and tumor necrosis factor-α in the joints of CIA mice were significantly inhibited by the pH/ROS dual-responsive nanomedicine in comparison with free drug and non-targeted counterparts. In addition, the expression of the NF-κB signaling pathway molecule P65 was also significantly decreased by nanomedicine-treatment. Our results reveal that MPS-loaded pH/ROS dual-responsive NPs can effectively alleviate joint destruction via down-regulation of the NF-κB signaling pathway. STATEMENT OF SIGNIFICANCE: Nanomedicine is recognized as an attractive method for the targeting treatment of rheumatoid arthritis (RA). To thorough release of payloads from nanoformulations and synergistic therapy of RA, herein, a phytochemical and ROS-responsive moiety co-modified α-cyclodextrin was used as a pH/ROS dual-responsive carrier to encapsulate methylprednisolone to manage RA. The fabricated nanomedicine can effectively release its payloads under pH and/or ROS microenvironment, and the released drugs dramatically promote transformation of M1-type macrophages into M2 phenotype to reduce the release of pro-inflammatory cytokines. The prepared nanomedicine also obviously decreased the NF-κB signaling pathway molecule P65 expression in the joints, thereby down-regulating pro-inflammatory cytokines expression to alleviate joint swelling and cartilage destruction. We provided a candidate for the targeting treatment of RA.

Comparison of Individual Tissue-Engineered Bones and Allogeneic Bone in Treating Bone Defects: A Long-Term Follow-Up Study.

The treatment of bone defects has always been a challenge for orthopedic surgeons. The development of tissue engineering technology provides a novel method for repairing bone defects and has been used in animal experiments and clinical trials. However, there are few clinical studies on comparing the long-term outcomes of tissue-engineered bones (TEBs) and other bone grafts in treating bone defects, and the long-term efficiency of TEBs remains controversial. Therefore, a study designed by us was aimed to compare the long-term efficacy and safety of individual tissue-engineered bones (iTEBs) and allogeneic bone granules (ABGs) in treating bone defects caused by curettage of benign bone tumors and tumor-like lesions. From September 2003 to November 2009, 48 patients who received tumor curettage and bone grafting were analyzed with a mean follow-up of 122 mo (range 60 to 173 mo). Based on implant style, patients were divided into groups of iTEBs (n = 23) and ABGs (n = 25). Postoperatively, the healing time, healing quality, incidence of complications, and functional scores were compared between the two groups. The Musculoskeletal Tumor Society functional evaluation system and Activities of Daily Living Scale scores were significantly improved in both groups with no significant difference. The average healing time of ABGs was longer than that of iTEBs (P < 0.05). At the final follow-up, iTEBs had a better performance in the bone healing quality evaluated by modified Neer classification (P < 0.05). In the group of iTEBs, the complication and reoperation rate was lower than that in the group of ABGs, with no tumorigenesis or immune rejection observed. In summary, for treating bone defects caused by tumor curettage, iTEBs were safe, effective, and tagged with more rapid healing speed, better healing outcome, and lower complication and reoperation rate, in comparison with ABGs.

Modification of PLGA Scaffold by MSC-Derived Extracellular Matrix Combats Macrophage Inflammation to Initiate Bone Regeneration via TGF-ß-Induced Protein.

The immunologic response toward chronic inflammation or bone regeneration via the accumulation of M1 or M2 macrophages after injury could determine the fate of biomaterial. Human umbilical cord mesenchymal stem cells (hUCMSCs) have a pivotal immunomodulatory property on directing macrophage behaviors. Herein, for the first time, 3D-printed poly(lactide-co-glycolide) (PLGA) scaffolds modified with hUCMSC-derived extracellular matrix (PLGA-ECM) are prepared by a facile tissue engineering technique with physical decellularization and 2.44 ± 0.29 mg cm-3 proteins immobilized on the PLGA-ECM contain multiple soluble cytokines with a sustainable release profile. The PLGA-ECM not only attenuates the foreign body response, but also improves bone regeneration by increasing the accumulation of M2 macrophages in an improved heterotopic transplantation model of SCID mice. Furthermore, the PLGA-ECM scaffolds with the knockdown of transforming growth factor-ß-induced protein (TGFßI/ßig-H3) demonstrate that M2 macrophage accumulation improved by the PLGA-ECM could be attributed to increasing the migration of M2 macrophages and the repolarization of M1 macrophages to M2 phenotype, which are mediated by multiple integrin signaling pathways involving in integrin ß7, integrin α9, and integrin ß1 in a TGFßI-dependent manner. This study presents an effective surface modification strategy of polymeric scaffolds to initiate tissue regeneration and combat inflammatory response by increasing M2 macrophage accumulation.

Electrostatic wrapping of doxorubicin with curdlan to construct an efficient pH-responsive drug delivery system.

The development of environmentally responsive drug delivery systems for the treatment of cancer has attracted particular interest in recent years. However, the enhancement of drug loading capacity and realization of pH-responsive drug delivery remain challenging. Herein, we employ carboxymethyl curdlan as a hydrophilic carrier to wrap doxorubicin (DOX) directly via electrostatic interaction. The sizes of the formed nanoparticles can be simply tuned by changing their feeding ratios. In particular, the nanoparticles are highly stable in aqueous solution without size variation. In vitro drug release and cytotoxicity assays illustrate that this delivery system can release DOX differentially under various environmental conditions and transport it into cell nuclei efficiently, with comparable therapeutic effect to the free drug. These results suggest that the carrying of antitumor drugs by polysaccharide via electrostatic interaction is a simple but effective way to construct a pH-dependent drug delivery platform.

A prodrug strategy based on chitosan for efficient intracellular anticancer drug delivery.

Doxorubicin (DOX), one of the most widely used anticancer drugs, is restricted in clinical application due to its severe side effects and inefficient cellular uptake. To overcome the drawbacks, herein, an endosomal pH-activated prodrug was designed and fabricated by conjugating DOX with chitosan via an acid-cleavable hydrazone bond. The resulting DOX conjugates can self-assemble into nano-sized particles, which were very stable and presented no burst release of DOX at a neutral pH condition. Notably, the nanoparticles exhibited excellent cell uptake properties and a remarkable drug accumulation in tumor cells. Once internalized into the cells, moreover, DOX can be fast released from the nanoparticles, and the release mechanism changed from the anomalous transport at pH 7.4 to the combination pattern of diffusion- and erosion-controlled release at pH 6.0 or 5.0. The prodrugs showed obvious cytotoxicity for HeLa cells with fairly low IC50 values, offering a new platform for targeted cancer therapy.