Practice effects of personalized interventions with interdisciplinary teamwork in type 2 diabetes remission: a retrospective study.

Objectives: A retrospective analysis of the clinical outcomes of personalized interventions for type 2 diabetes mellitus (T2DM) in an interdisciplinary team. Methods: Under the guidance of an interdisciplinary team, 40 patients with T2DM underwent a systematic examination at the beginning of the intervention, 3 months after the intervention, and 3 months of follow-up at the end of the intervention (i.e., at 6 months). Key indicators such as fasting plasma glucose (FPG), 2-hour postprandial glucose (2hPG), fasting insulin level (FINS), glycated hemoglobin (HbA1c), blood lipids, and body mass index (BMI) were measured. Results: After the 3-month intervention, participants' BMI, FPG, 2hPG, FINS, and HbA1c improved significantly, with statistically significant differences (P<0.05).These metrics remained essentially stable at the 3-month follow-up. Of all the participants, 92.5% (37 cases in total) successfully discontinued their medication after 3 months of intervention, of which 80% (32 cases) remained stable during the 3-month follow-up after discontinuation, fulfilling the criteria for remission of T2DM; 2 cases successfully reduced the dose of their medication, and only 1 case was maintained on the original treatment. Conclusions: Through an interdisciplinary team intervention strategy, we significantly optimized the glucose metabolism, lipid metabolism, and BMI status of patients with T2DM, making diabetes remission an achievable goal, which provides valuable experience for further optimization of diabetes prevention and control protocols.

MYL3 protects chondrocytes from senescence by inhibiting clathrin-mediated endocytosis and activating of Notch signaling.

As the unique cell type in articular cartilage, chondrocyte senescence is a crucial cellular event contributing to osteoarthritis development. Here we show that clathrin-mediated endocytosis and activation of Notch signaling promotes chondrocyte senescence and osteoarthritis development, which is negatively regulated by myosin light chain 3. Myosin light chain 3 (MYL3) protein levels decline sharply in senescent chondrocytes of cartilages from model mice and osteoarthritis (OA) patients. Conditional deletion of Myl3 in chondrocytes significantly promoted, whereas intra-articular injection of adeno-associated virus overexpressing MYL3 delayed, OA progression in male mice. MYL3 deficiency led to enhanced clathrin-mediated endocytosis by promoting the interaction between myosin VI and clathrin, further inducing the internalization of Notch and resulting in activation of Notch signaling in chondrocytes. Pharmacologic blockade of clathrin-mediated endocytosis-Notch signaling prevented MYL3 loss-induced chondrocyte senescence and alleviated OA progression in male mice. Our results establish a previously unknown mechanism essential for cellular senescence and provide a potential therapeutic direction for OA.

PP2 alleviates the progression of osteoarthritis by inhibiting Wnt/ß-catenin and activating TGF-ß/Smad signaling.

OBJECTIVE: We aimed to explore the effect and mechanism of the Src inhibitor PP2 on osteoarthritis (OA) progression. METHODS: The protein expressions of Src, p-Src (y418) and p-FAK in normal and OA human chondrocytes were detected by immunofluorescence (IF) analysis. Chondrocytes from the femur and tibial plateau of 3-day-old mice were extracted and inoculated into 6-well plates. The chondrocytes were co-cultured with IL-1ß and different doses of PP2, and then the degeneration of extracellular matrix was analyzed. A mouse OA model was induced by destabilizing medial meniscectomy of the right knee. Two weeks after the operation, different doses of PP2 were injected intraperitoneally. The drug was given three times a week for 6 weeks, and then the mice were sacrificed. Histopathological, IF and immunoblotting analyses were used to detect key OA catabolic markers and protein expression and related signaling. RESULTS: The levels of Src, p-Src (y418) and p-FAK in the knee cartilage tissue of patients with OA were abnormally increased. After chondrocytes were co-treated with IL-1ß and different doses of PP2, the results showed that PP2 reduced the abnormal increase of ß-catenin, p-ß-catenin and other proteins induced by IL-1ß, and reversed the decrease of p-Smad3, aggrecan and collagen Ⅱ protein levels. Meanwhile, intraperitoneal injection of PP2 in vivo significantly reduced the degeneration of articular cartilage in the OA mouse model. CONCLUSION: Our data indicate that targeting Src with PP2 protected against cartilage destruction in an OA mouse model by inhibiting Wnt/ß-catenin and activating TGF-ß/Smad signaling, suggesting that Src may be a potential therapeutic target for OA treatment.

Framework Nucleic Acid-Based Multifunctional Tumor Theranostic Nanosystem for miRNA Fluorescence Imaging and Chemo/Gene Therapy.

Intelligent stimulus-responsive theranostic systems capable of specifically sensing low-abundance tumor-related biomarkers and efficiently killing tumors remain a pressing endeavor. Here, we report a multifunctional framework nucleic acid (FNA) nanosystem for simultaneous imaging of microRNA-21 (miR-21) and combined chemo/gene therapy. To achieve this, two FNA nanoarchitectures labeled with Cy5/BHQ2 signal tags were designed, each of which contained an AS1411 aptamer, two pairs of DNA/RNA hybrids, a pH-sensitive DNA catcher, and doxorubicin (DOX) intercalating between cytosine and guanine in the tetrahedral DNA nanostructure (TDN). In the acidic tumor microenvironment, the DNA catchers spontaneously triggered to form an i-motif and create an FNA dimer (dFNA) while releasing DOX molecules to exert a cytotoxic effect. In addition, the overexpressed miR-21 in tumor cells dismantled the DNA/RNA hybrids to produce vascular endothelial growth factor-associated siRNA via a toehold-mediated strand displacement reaction, thus enabling a potent RNA interfering. Also importantly, the liberated miR-21 could initiate cascade-reaction amplification to efficiently activate the Cy5 signal reporters, thereby realizing on-site fluorescence imaging of miR-21 in living cells. The exquisitely designed FNA-based nanosystem showed favorable biocompatibility and stability as well as acid-driven DOX release characteristics. Owing to the aptamer-guided targeting delivery, specific uptake of the FNA-based theranostic nanosystem by HepG2 cells was verified with confocal laser scanning microscopy and flow cytometry analyses, which therefore resulted in apoptosis of HepG2 cells while doing minimal damage to normal H9c2 and HL-7702 cells. Strikingly, both in vitro and in vivo experiments demonstrated the achievements of the FNA-enabled miR-21 imaging and synergistically enhanced chemo/gene therapy. This work thus represents a noteworthy advance on the FNA-based theranostic strategy that can effectively avoid the undesirable premature leakage of anticarcinogen and off-target of siRNA, and achieve on-demand reagents release for tumor diagnostics and treatment.

Three-dimensional printing of microfiber- reinforced hydrogel loaded with oxymatrine for treating spinal cord injury.

Spinal cord injury (SCI) causes severe neural tissue damage and motor/sensory dysfunction. Since the injured spinal cord tissue has limited self-regeneration ability, several strategies, including cell therapy, drug delivery, and tissue engineering scaffold implantation, have been employed to treat SCI. However, each of these strategies fails to obtain desirable outcomes due to their respective limitations. In comparison, advanced tissue engineering scaffolds with appropriate topographical features, favorable composition, and sustained drug delivery capability can be employed to recruit endogenous neural stem cells (NSCs), induce neuronal differentiation, and facilitate neuron maturation. This can lead to the regeneration of injured spinal cord tissue and the recovery of motor function. In this study, fiber bundle-reinforced spinal cord extracellular matrix hydrogel scaffolds loaded with oxymatrine (OMT) were produced through nearfield direct write electrospinning. The spinal cord extracellular matrix-based hydrogel was then coated with OMT. The physical/chemical properties and in vitro degradation behavior of the composite scaffolds were investigated. The in vitro cell culture results showed that composite scaffolds loaded with OMT promoted the differentiation of NSCs into neurons and inhibited differentiation into astrocytes. The in vivo results showed that the composite scaffolds loaded with OMT recruited NSCs from the host tissue, promoted neuronal differentiation and axon extension at the lesion site, inhibited glial scar formation at/around the lesion site, and improved the recovery of motor function in rats with SCI. To sum up, 3D-printed microfiber-reinforced spinal cord extracellular matrix hydrogel scaffolds loaded with OMT are promising biomaterials for the treatment of SCI.

VviKFB07 F-box E3 ubiquitin ligase promotes stilbene accumulation by ubiquitinating and degrading VviCHSs protein in grape.

Stilbene and flavonoid are phytochemicals in plants and play an important role in plant disease resistance and human health. The regulation of stilbene and flavonoid synthesis in plants has been extensively studied at the transcriptional level, but translational and post-translational controls of stilbene and flavonoid biosynthesis are still poorly understood. In this study, a grape F-box E3 ubiquitin ligase VviKFB07 associated with the metabolism of stilbene and flavonoid was screened out with transcriptome. Overexpression of VviKFB07 in the Nicotiana tabacum resulted in a decrease in flavonol and anthocyanin content in corolla, and stable overexpression assays of VviKFB07 in grape callus promoted the accumulation of resveratrol. Subsequently, Yeast two-hybrid and bimolecular fluorescence complementation assays identified the physical interaction between VviKFB07 and VviCHSs proteins. In vivo experiments verified that VviKFB07 was involved in the ubiquitination and degradation of VviCHSs protein. Taken together, our findings clarify the role of ubiquitin ligase VviKFB07 in the synthesis of stilbene and flavonoid in grapes.

The putative ABCG transporter VviABCG20 from grapevine (Vitis vinifera) is strongly expressed in the seed coat of developing seeds and may participate in suberin biosynthesis.

Half-size ATP binding cassette G (ABCG) transporters participate in many biological processes by transporting specific substrates. Our previous study showed that VviABCG20 was strongly expressed in the seeds of seeded grape and the silencing of VviABCG20 homolog gene in tomato led to a reduction in seed number. To reveal the molecular mechanism of VviABCG20 gene involved in grape seed development/abortion, the gene expression and functional analysis of VviABCG20 were further carried out in the grapevine. It was shown that the gene expression of VviABCG20 was higher in seeds of seeded grapes compared with seedless. Further the expression of VviABCG20 in the seed coat was significantly higher than in ovules (young seeds) and endosperm. VviABCG20 was also induced by exogenous hormones (especially MeJA) in grape leaves. Subcellular localization analysis showed that VviABCG20 is a membrane protein. In overexpressed VviABCG20 transgenic callus of Thompson seedless, expression of genes GPAT5, FAR1 and FAR5 was increased significantly. After treatment with suberin precursors, the transgenic callus reduced the sensitivity to three cinnamic acid derivatives (cis-ferulic acid, caffeic acid, coumaric acid), succinic acid, and glycerol. In suspension cells, expression of VviABCG20 was increased significantly after treatment with suberin precursors. Our research suggested that VviABCG20 may function in seed development in grapevine, at least in part by participating in suberin biosynthesis in the seed coat.

Retraction: Acellularized spinal cord scaffolds incorporating bpV(pic)/PLGA microspheres promote axonal regeneration and functional recovery after spinal cord injury.

[This retracts the article DOI: 10.1039/D0RA02661A.].

Error assessment and correction for extrusion-based bioprinting using computer vision method.

299Bioprinting offers a new approach to addressing the organ shortage crisis. Despite recent technological advances, insufficient printing resolution continues to be one of the reasons that impede the development of bioprinting. Normally, machine axes movement cannot be reliably used to predict material placement, and the printing path tends to deviate from the predetermined designed reference trajectory in varying degrees. Therefore, a computer vision-based method was proposed in this study to correct trajectory deviation and improve printing accuracy. The image algorithm calculated the deviation between the printed trajectory and the reference trajectory to generate an error vector. Furthermore, the axes trajectory was modified according to the normal vector approach in the second printing to compensate for the deviation error. The highest correction efficiency that could be achieved was 91%. More significantly, we discovered that the correction results, for the first time, were in a normal distribution instead of a random distribution.

Double crosslinked biomimetic composite hydrogels containing topographical cues and WAY-316606 induce neural tissue regeneration and functional recovery after spinal cord injury.

Spinal cord injury (SCI) is an overwhelming and incurable disabling condition, for which increasing forms of multifunctional biomaterials are being tested, but with limited progression. The promising material should be able to fill SCI-induced cavities and direct the growth of new neurons, with effective drug loading to improve the local micro-organism environment and promote neural tissue regeneration. In this study, a double crosslinked biomimetic composite hydrogel comprised of acellularized spinal cord matrix (ASCM) and gelatin-acrylated-ß-cyclodextrin-polyethene glycol diacrylate (designated G-CD-PEGDA) hydrogel, loaded with WAY-316606 to activate canonical Wnt/ß-catenin signaling, and reinforced by a bundle of three-dimensionally printed aligned polycaprolactone (PCL) microfibers, was constructed. The G-CD-PEGDA component endowed the composite hydrogel with a dynamic structure with a self-healing capability which enabled cell migration, while the ASCM component promoted neural cell affinity and proliferation. The diffusion of WAY-316606 could recruit endogenous neural stem cells and improve neuronal differentiation. The aligned PCL microfibers guided neurite elongation in the longitudinal direction. Animal behavior studies further showed that the composite hydrogel could significantly recover the motor function of rats after SCI. This study provides a proficient approach to produce a multifunctional system with desirable physiological, chemical, and topographical cues for treating patients with SCI.

Metformin use and associated risk of total joint replacement in patients with type 2 diabetes: a population-based matched cohort study.

BACKGROUND: It is uncertain whether metformin use is associated with reduced risk of joint replacement in patients with type 2 diabetes mellitus. We aimed to establish whether metformin use was associated with a reduced risk of total knee replacement (TKR) or total hip replacement (THR) among these patients. METHODS: We selected patients with type 2 diabetes mellitus that was diagnosed between 2000 and 2012 from the Taiwan National Health Insurance Research Database. We used prescription time-distribution matching and propensity-score matching to balance potential confounders between metformin users and nonusers. We assessed the risks of TKR or THR using Cox proportional hazards regression. RESULTS: We included 20 347 participants who were not treated with metformin and 20 347 who were treated with metformin, for a total of 40 694 participants (mean age 63 yr, standard deviation 11 yr; 49.8% were women) after prescription time-distribution matching. Compared with participants who did not use metformin, those who used metformin had lower risks of TKR or THR (adjusted hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.60-0.81 for TKR or THR; adjusted HR 0.71, 95% CI 0.61-0.84 for TKR; adjusted HR 0.61, 95% CI 0.41-0.92 for THR) after adjustment for covariates. Propensity-score matching analyses (10 163 participants not treated with metformin v. 10 163 treated with metformin) and sensitivity analyses using inverse probability of treatment weighting and competing risk regression showed similar results. INTERPRETATION: Metformin use in patients with type 2 diabetes mellitus was associated with a significantly reduced risk of total joint replacement. Randomized controlled clinical trials in patients with osteoarthritis are warranted to determine whether metformin is effective in decreasing the need for joint replacement.

Corrigendum: Bio-high entropy alloys: Progress, challenges, and opportunities.

[This corrects the article DOI: 10.3389/fbioe.2022.977282.].

A review on magnesium alloys for biomedical applications.

Magnesium (Mg) and Mg alloys are considered as potential candidates for biomedical applications because of their high specific strength, low density, and elastic modulus, degradability, good biocompatibility and biomechanical compatibility. However, the rapid corrosion rate of Mg alloys results in premature loss of mechanical integrity, limiting their clinical application in load-bearing parts. Besides, the low strength of Mg alloys restricts their further application. Thus, it is essential to understand the characteristics and influencing factors of mechanical and corrosion behavior, as well as the methods to improve the mechanical performances and corrosion resistance of Mg alloys. This paper reviews the recent progress in elucidating the corrosion mechanism, optimizing the composition, and microstructure, enhancing the mechanical performances, and controlling the degradation rate of Mg alloys. In particular, the research progress of surface modification technology of Mg alloys is emphasized. Finally, the development direction of biomedical Mg alloys in the future is prospected.

Bio-high entropy alloys: Progress, challenges, and opportunities.

With the continuous progress and development in biomedicine, metallic biomedical materials have attracted significant attention from researchers. Due to the low compatibility of traditional metal implant materials with the human body, it is urgent to develop new biomaterials with excellent mechanical properties and appropriate biocompatibility to solve the adverse reactions caused by long-term implantation. High entropy alloys (HEAs) are nearly equimolar alloys of five or more elements, with huge compositional design space and excellent mechanical properties. In contrast, biological high-entropy alloys (Bio-HEAs) are expected to be a new bio-alloy for biomedicine due to their excellent biocompatibility and tunable mechanical properties. This review summarizes the composition system of Bio-HEAs in recent years, introduces their biocompatibility and mechanical properties of human bone adaptation, and finally puts forward the following suggestions for the development direction of Bio-HEAs: to improve the theory and simulation studies of Bio-HEAs composition design, to quantify the influence of composition, process, post-treatment on the performance of Bio-HEAs, to focus on the loss of Bio-HEAs under actual service conditions, and it is hoped that the clinical application of the new medical alloy Bio-HEAs can be realized as soon as possible.

Application of aptamers in regenerative medicine.

Regenerative medicine is a discipline that studies how to use biological and engineering principles and operation methods to repair and regenerate damaged tissues and organs. Until now, regenerative medicine has focused mainly on the in-depth study of the pathological mechanism of diseases, the further development and application of new drugs, and tissue engineering technology strategies. The emergence of aptamers has supplemented the development methods and types of new drugs and enriched the application elements of tissue engineering technology, injecting new vitality into regenerative medicine. The role and application status of aptamers screened in recent years in various tissue regeneration and repair are reviewed, and the prospects and challenges of aptamer technology are discussed, providing a basis for the design and application of aptamers in long-term transformation.

Salinomycin alleviates osteoarthritis progression via inhibiting Wnt/ß-catenin signaling.

Osteoarthritis (OA) is the most prevalent degenerative whole-joint disease characterized by cartilage degeneration, synovial hyperplasia, osteophyte formation, and subchondral bone sclerosis. Currently there are no disease-modifying treatments available for OA because its etiology and pathogenesis are largely unknown. Here we report that a natural carboxylic polyether ionophore that is used as an anti-tumor drug, salinomycin (SAL), may be a promising therapeutic drug for OA in the future. We found that SAL showed no cytotoxicity on mouse chondrocytes and displayed a protective effect against interleukin-1ß (IL-1ß), in cultured mouse chondrocytes and cartilage explants. Treatment with low SAL concentrations directly upregulated the anabolism factors collagen II and aggrecan, while it inhibited the catabolic factors matrix metalloproteinase-13 (MMP13) and metalloproteinase with thrombospondin motifs-5 (ADAMTS5) to protect against extracellular matrix (ECM) degradation, and also suppressed inflammatory responses in mouse chondrocytes. Furthermore, SAL reduced the severity of OA-associated changes and delayed cartilage destruction, subchondral bone sclerosis, and osteophyte formation in a destabilized medial meniscus (DMM) surgery-induced mouse OA model. Mechanistically, a low SAL concentration induced anabolism and inhibited catabolism in chondrocytes via inhibiting Lrp6 phosphorylation and Wnt/ß-catenin signaling. Our results suggested that SAL may serve as a potential disease-modifying therapeutic against OA pathogenesis.

Simultaneous detection of cancerous exosomal miRNA-21 and PD-L1 with a sensitive dual-cycling nanoprobe.

Simultaneous detection of specific exosomal surface proteins and inner microRNAs are hampered by their heterogeneity, low abundance and spatial segregation in nanovesicles. Here, we design a dual-cycling nanoprobe (DCNP) to enable single-step simultaneous quantitation of cancerous exosomal surface programmed death-ligand 1 (PD-L1) (ExoPD-L1) and miRNA-21 (ExomiR-21) directly in exosome lysates, without resorting to either RNA extraction or time-consuming transmembrane penetration. In this design, DNA molecular machine-based dual-recognition probes co-assemble onto gold nanoparticle surface for engineering 'silent' DCNPs, which enable signal-amplified synchronous response to dual-targets as activated by ExomiR-21 and ExoPD-L1 within 20 min. Benefiting from cycling amplification of the molecular machine, DCNPs sensor achieves detection limits of tumor exosomes, ExoPD-L1 and ExomiR-21 down to 10 particles/µL, 0.17 pg/mL and 66 fM, respectively. Such a sensitive dual-response strategy allows simultaneous tracking the dynamic changes of ExoPD-L1 and ExomiR-21 expression regulated by signaling molecules or therapeutics. This approach further detects circulating ExoPD-L1 and ExomiR-21 in human plasma to differentiate breast cancer patients from healthy individuals with high accuracy, showing great potential of DCNPs for simultaneous profiling exosomal surface and inside biomarkers, and for clinical precision diagnosis.

Medical high-entropy alloy: Outstanding mechanical properties and superb biological compatibility.

Medical metal implants are required to have excellent mechanical properties and high biocompatibility to handle the complex human environment, which is a challenge that has always existed for traditional medical metal materials. Compared to traditional medical alloys, high entropy alloys (HEAs) have a higher design freedom to allow them to carry more medical abilities to suit the human service environment, such as low elastic modulus, high biocompatible elements, potential shape memory capability. In recent years, many studies have pointed out that bio-HEAs, as an emerging medical alloy, has reached or even surpassed traditional medical alloys in various medical properties. In this review, we summarized the recent reports on novel bio-HEAs for medical implants and divide them into two groups according the properties, namely mechanical properties and biocompatibility. These new bio-HEAs are considered hallmarks of a historic shift representative of a new medical revolution.

Computer Vision-Aided 2D Error Assessment and Correction for Helix Bioprinting.

Bioprinting is an emerging multidisciplinary technology for organ manufacturing, tissue repair, and drug screening. The manufacture of organs in a layer-by-layer manner is a characteristic of bioprinting technology, which can also determine the accuracy of constructs confined by the printing resolution. The lack of sufficient resolution will result in defect generation during the printing process and the inability to complete the manufacture of complex organs. A computer vision-based method is proposed in this study to detect the deviation of the printed helix from the reference trajectory and calculate the modified reference trajectory through error vector compensation. The new printing helix trajectory resulting from the modified reference trajectory error is significantly reduced compared with the original helix trajectory and the correction efficiency exceeded 90%.

BSISTER transcription factors directly binds to the promoter of IAA19 and IAA29 genes to up-regulate gene expression and promote the root development.

Roots play an important role in the growth and development of plants and auxin participates in regulating plant root development. Some studies have shown that BS (BSISTER) gene (the closest gene of class B gene) is involved in plant root development, but whether BS regulates root development via auxin signaling still not clear. To explore VviBS1 and VviBS2 roles in root development, VviBS1 and VviBS2 were overexpressedin Arabidopsis tt16 mutant and we found that they could restore the phenotype of shorter PR (primary roots) and high density of LR (lateral root) of tt16 compared with the wild type Ws Arabidopsis seedlings. However, the addition of exogenous NAA (naphthalene acetic acid) could not significantly promote the PR length of tt16 Arabidopsis, and the auxin signal transduction of tt16 may be blocked. The expression levels of auxin signal transduction pathway genes in Ws, tt16, p35s:VviBS1 in tt16 and p35s:VviBS2 in tt16 seedlings were detected. It was found that the expression of AtARF2, AtARF12, AtARF14, AtARF15, AtARF20, AtGH3, AtGH3-2 and AtSAUR51 genes in tt16 seedlings was higher than that in Ws, while the expression of AtIAA19 and AtIAA29 in Ws seedlings was higher than that of tt16. More importantly, BS may up regulate AtIAA19 and AtIAA29 expression directly by binding to their promoter. In addition, VviBS1 and VviBS2 also affect seed germination and may regulate leaf yellowing by regulating ethylene synthase. Therefore, our findings reveal a molecular mechanism that BS may modulate root system development via Aux/IAA-based auxin signaling, and provide insight into the BS function in regulation of leaf yellowing.