Radial extracorporeal shockwave promotes osteogenesis-angiogenesis coupling of bone marrow stromal cells from senile osteoporosis via activating the Piezo1/CaMKII/CREB axis.

Radial extracorporeal shockwave (r-ESW) and bone marrow stromal cells (BMSCs) have been reported to alleviate senile osteoporosis (SOP), but its regulatory mechanism remains unclear. In this study, we firstly isolated human BMSCs from bone marrow samples and treated with varying r-ESW doses. And we found that r-ESW could enhance the proliferation of SOP-BMSCs in a dose-dependent manner by EdU assay. Subsequently, the impact of r-ESW on the proliferation, apoptosis and multipotency of BMSCs was assessed. And the outcomes of flow cytometry, Alizarin red S (ARS), and tube formation test demonstrated that the optimal shockwave obviously boosted SOP-BMSCs osteogenesis and angiogenesis but exhibited no significant impact on cell apoptosis. Additionally, the signaling of Piezo1 and CaMKII/CREB was examined by Western blotting, qPCR and immunofluorescence. And the results showed that r-ESW promoted the expression of Piezo1, increased intracellular Ca2+ and activated the CaMKII/CREB signaling pathway. Then, the application of Piezo1 siRNA hindered the r-ESW-induced enhancement ability of osteogenesis coupling with angiogenesis of SOP-BMSCs. The use of the CaMKII/CREB signaling pathway inhibitor KN93 suppressed the Piezo1-induced increase in osteogenesis and angiogenesis in SOP-BMSCs. Finally, we also found that r-ESW might alleviate SOP in the senescence-accelerated mouse prone 6 (SAMP6) model by activating Piezo1. In conclusion, our research offers experimental evidence and an elucidated underlying molecular mechanism to support the use of r-ESW as a credible rehabilitative treatment for senile osteoporosis.

Identification of PKM2 as a pyroptosis-related key gene aggravates senile osteoporosis via the NLRP3/Caspase-1/GSDMD signaling pathway.

BACKGROUNDS: Senile osteoporosis-alternatively labeled as skeletal aging-encompasses age-induced bone deterioration and loss of bone microarchitecture. Recent studies have indicated a potential association between senile osteoporosis and chronic systemic inflammation, and pyroptosis in bone marrow-derived mesenchymal stem cells is speculated to contribute to bone loss and osteoporosis. Therefore, targeting pyroptosis in stem cells may be a potential therapeutic strategy for treating osteoporosis. METHODS: Initially, we conducted bioinformatics analysis to screen the GEO databases to identify the key gene associated with pyroptosis in senile osteoporosis. Next, we analyzed the relationship between altered proteins and clinical data. In vitro experiments were then performed to explore whether the downregulation of PKM2 expression could inhibit pyroptosis. Additionally, an aging-related mouse model of osteoporosis was established to validate the efficacy of a PKM2 inhibitor in alleviating osteoporosis progression. RESULTS: We identified PKM2 as a key gene implicated in pyroptosis in senile osteoporosis patients through bioinformatics analysis. Further analyses of bone marrow and stem cells demonstrated significant PKM2 overexpression in senile osteoporosis patients. Silencing PKM2 expression inhibited pyroptosis in senile stem cells, of which the osteogenesis potential and angiogenic function were also primarily promoted. Moreover, the results in vivo demonstrated that administering PKM2 inhibitors suppressed pyroptosis in senile osteoporosis mice and mitigated senile osteoporosis progression. CONCLUSION: Our study uncovered PKM2, a key pyroptosis marker of bone marrow mesenchymal stem cells in senile osteoporosis. Shikonin, a PKM2 inhibitor, was then identified as a potential drug candidate for the treatment of osteoporosis.

Injectable Temperature-Sensitive Hydrogel Loaded with IL-36Ra for the Relief of Osteoarthritis.

Osteoarthritis (OA) is an inflammatory disease accompanied by synovial joint inflammation, and IL-36 plays an important role in this process. Local application of IL-36 receptor antagonist (IL-36Ra) can effectively control the inflammatory response, thereby protecting cartilage and slowing down the development of OA. However, its application is limited by the fact that it is rapidly metabolized locally. We designed and prepared a temperature-sensitive poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA) hydrogel (IL-36Ra@Gel) system carrying IL-36Ra and evaluated its basic physicochemical characteristics. The drug release curve of IL-36Ra@Gel indicated that this system could slowly release the drug over a longer period. Furthermore, degradation experiments showed that it could be largely degraded from the body within 1 month. The biocompatibility-related results showed that it had no significant effect on cell proliferation compared to the control group. In addition, the expression of MMP-13 and ADAMTS-5 was lower in IL-36Ra@Gel-treated chondrocytes than in the control group, and the opposite results appeared in aggrecan and collagen X. After 8 weeks of treatment with IL-36Ra@Gel by joint cavity injection, HE and Safranin O/Fast green staining showed that the degree of cartilage tissue destruction in the IL-36Ra@Gel-treated group was less than those in other groups. Meanwhile, the joints of mice in the IL-36Ra@Gel group had the most intact cartilage surface, the smallest thickness of cartilage erosion, and the lowest OARSI and Mankins score among all groups. Consequently, the combination of IL-36Ra and PLGA-PLEG-PLGA temperature-sensitive hydrogels can greatly improve the therapeutic effect and prolong the drug duration time, thus effectively delaying the progression of degenerative changes in OA, providing a new feasible nonsurgical treatment for OA.

Advances in experimental models of osteonecrosis of the femoral head.

Background: Osteonecrosis of the femoral head (ONFH) is a devastating disease affecting young adults, resulting in significant pain, articular surface collapse, and disabling dysfunction. ONFH can be divided into two broad categories: traumatic and non-traumatic. It has been established that ONFH results from an inadequate blood supply that causes the death of osteocytes and bone marrow cells. Nonetheless, the precise mechanism of ONFH remains to be elucidated. In this regard, preclinical animal and cell models to study ONFH have been established to assess the efficacy of various modalities for preventing and treating ONFH. Nevertheless, it should be borne in mind that many models do not share the same physiologic and metabolic characteristics as humans. Therefore, it is necessary to establish a reproducible model that better mimics human disease. Methods: We systematically reviewed the literatures in regard to ONFH experimental models over the past 30 years. The search was performed in PubMed and Web of Science. Original animal, cell studies with available full-text were included. This review summarizes different methods for developing animal and cell experimental models of ONFH. The advantages, disadvantages and success rates of ONFH models are also discussed. Finally, we provide experimental ONFH model schemes as a reference. Results: According to the recent literatures, animal models of ONFH include traumatic, non-traumatic and traumatic combined with non-traumatic models. Most researchers prefer to use small animals to establish non-traumatic ONFH models. Indeed, small animal-based non-traumatic ONFH modeling can more easily meet ethical requirements with large samples. Otherwise, gradient concentration or a particular concentration of steroids to induce MSCs or EPCs, through which researchers can develop cell models to study ONFH. Conclusions: Glucocorticoids in combination with LPS to induce ONFH animal models, which can guarantee a success rate of more than 60% in large samples. Traumatic vascular deprivation combines with non-traumatic steroids to induce ONFH, obtaining success rates ranging from 80% to 100%. However, animals that undergo vascular deprivation surgery may not survive the glucocorticoid induction process. As for cell models, 10-6mol/L Dexamethasone (Dex) to treat bone marrow stem cells, which is optimal for establishing cell models to study ONFH. The translational potential of this article: This review aims to summarize recent development in experimental models of ONFH and recommended the modeling schemes to verify new models, mechanisms, drugs, surgeries, and biomaterials of ONFH to contribute to the prevention and treatment of ONFH.

A comparison of radiological and clinical outcomes between robotic-assisted and conventional total hip arthroplasty: A meta-analysis.

BACKGROUND: The purpose of this study was to investigate whether robotic-assisted total hip arthroplasty (RATHA) is superior to conventional total hip arthroplasty (CTHA) in terms of radiological and clinical outcomes. METHODS: Three databases (PubMed, Cochrane Library, and Embase) were searched for articles published before 11 May 2021. The comparison outcomes of interest included radiological and clinical outcomes. RESULTS: Eighteen studies involving 2845 hips that compared the radiological and clinical outcomes of RATHA and CTHA were included in this study. There was no significant difference between RATHA and CTHA in cup anteversion or complications. However, RATHA showed better outcomes in terms of leg-length discrepancy, stem alignment, cup inclination, the Lewinnek safe zone, Callanan safe zone, total complications, and intraoperative complications. Robotic-assisted total hip arthroplasty was inferior to CTHA in terms of operative time and dislocations (all p-values < 0.05). CONCLUSIONS: The radiological and clinical outcomes of RATHA were comparable and even better than those of CTHA, except for operative time and dislocation outcomes.

Outpatient total knee and hip arthroplasty present comparable and even better clinical outcomes than inpatient operation.

Background: The purpose of this study was to compare total complications, complications stratified by type, readmissions, and reoperations at 30 and 90 days after outpatient and standard inpatient total knee and total hip arthroplasty (TKA, THA). Methods: A literature search was conducted from the PubMed, Cochrane Library, and Embase databases for articles published before 20 August 2021. The types of studies included prospective randomized controlled trials, prospective cohort studies, retrospective comparative studies, retrospective reviews of THA and TKA registration databases, and observational case-control studies. Comparisons of interest included total complications, complications stratified by type, readmissions, and reoperations at 30 and 90 days. The statistical analysis was performed using Review Manager 5.3. Results: Twenty studies with 582,790 cases compared relevant postoperative indicators of outpatient and inpatient total joint arthroplasty (TJA) (TKA and THA). There was a significant difference in the total complications at 30 days between outpatient and inpatient THA (p = 0.001), readmissions following TJA (p = 0.03), readmissions following THA (p = 0.001), stroke/cerebrovascular incidents following TJA (p = 0.01), cardiac arrest following TJA (p = 0.007), and blood transfusions following TJA (p = 0.003). The outcomes showed an obvious difference in 90-day total complications between outpatient and inpatient TJA (p = 0.01), readmissions following THA (p = 0.002), and surgical-related pain following TJA (p < 0.001). We did not find significant differences in the remaining parameters. Conclusion: Outpatient procedures showed comparable and even better outcomes in total complications, complications stratified by type, readmissions, and reoperations at 30 and 90 days compared with inpatient TJA for selected patients.

Corrigendum: A Coronal Landmark for Tibial Component Positioning With Anatomical Alignment in Total Knee Arthroplasty: A Radiological and Clinical Study.

[This corrects the article DOI: 10.3389/fsurg.2022.847987.].

Correlation between Surface Area Ratio of Medial to Lateral Tibial Plateau and Knee Alignment in Adults.

OBJECTIVE: This study aimed to investigate the correlation between the surface area ratio of medial tibial plateau (MTP) to lateral tibial plateau (LTP) and the mechanical tibiofemoral angle (mTFA). METHODS: Lower limb computed tomography (CT) images were collected at our hospital. Then, the original CT data were analyzed and reconstructed using medical image processing software. The proximal and distal centres of the femur and tibia were marked. The surface areas of MTP and LTP were identified using image processing software. GraphPad Prism 8.0.2 was used to perform the statistical analysis. RESULTS: The surface area ratio of MTP to LTP was significantly correlated with the mTFA in all patients (P<0.0001), male group (P<0.0001), female group (P<0.0001), varus group (P<0.0001), and valgus group (P=0.002). Furthermore, the surface area of MTP and LTP was significantly greater in the male group than in the female group (P<0.0001). There was significant difference in the surface area of the MTP between the varus and valgus groups (P<0.0001). Significant difference was also observed in the surface area ratio of MTP to LTP between the varus and valgus groups (P<0.0001). CONCLUSION: The surface area ratio of MTP to LTP was correlated with the mTFA. Within a certain range, the smaller the mTFA, the greater the surface area ratio of MTP to LTP. For patients undergoing total knee arthroplasty, of whom the surface area of the MTP was basically equal to that of the LTP, it is recommended that the osteotomy should be performed in accordance with mechanical alignment standards, and that a symmetrical tibial plateau prosthesis should be used. For patients whose surface area of MTP is significantly greater than that of the LTP, it is recommended that the osteotomy should be performed in accordance with kinematic alignment standards, and that an anatomical tibial plateau prosthesis should be used.

Knockdown of HDAC9 Inhibits Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells Partially by Suppressing the MAPK Signaling Pathway.

Background: Histone deacetylase 9 (HDAC9) is a member of the HDAC gene family that plays essential roles in the organization of transcriptional regulation by catalyzing deacetylation of histone proteins. However, the effects of HDAC9 on osteonecrosis of femoral head (ONFH) have not been investigated. The present study aimed to reveal whether histone deacetylase 9 (HDAC9) regulated osteogenic differentiation. Methods: A lentiviral knockdown HDAC9 model was established in hBMSCs. Osteoblast-specific gene expression, such as Runx2, OCN was examined by qRT-PCR and Western blot, respectively. Though transcriptome sequencing and enrichment analysis, related signal pathways caused by down-regulation of HDAC9 were screened. The effect of HDAC9 on MAPK signaling pathway was determined by Western blot. Eventually, tert-Butylhydroquinone (tBHQ) was used to examine the effect of MAPK activation on osteogenesis in HDAC9 knockdown hBMSCs. Results: A lentiviral knockdown HDAC9 model was successfully established in hBMSCs. HDAC9 knockdown significantly inhibited osteoblast-specific gene expression, such as runt-related transcription factor 2 (Runx2), osteocalcin (OCN) and mineral deposition in vitro. Moreover, a total of 950 DEGs were identified in HDAC9-knockdown hBMSCs. We discovered that the MAPK signaling pathway might be related to this process by pathway enrichment analysis. HDAC9 knockdown significantly reduced the expression level of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). Finally, the decreased osteogenesis due to HDAC9 knockdown was partly rescued by a MAPK signaling pathway activator. Conclusion: Taken together, these results suggest that HDAC9 knockdown inhibits osteogenic differentiation of hBMSCs, partially through the MAPK signaling pathway. HDAC9 may serve as a potential target for the treatment of ONFH.

A Coronal Landmark for Tibial Component Positioning With Anatomical Alignment in Total Knee Arthroplasty: A Radiological and Clinical Study.

Objective: The purpose of this study was to investigate the value of the lateral point of articular surface of distal tibia (LADT) for anatomical alignment in total knee arthroplasty. Methods: We reconstructed 148 three-dimensional pre-arthritic tibias and measured the tibial component inclination angle corresponding to the distal landmark of LADT. A retrospective study included 81 TKA recipients divided into the AA group and MA group. Clinical assessments including ROM, HSS, WOMAC, satisfaction for surgery, and radiological assessment were evaluated at one-year follow-up. Results: The tibial component varus angle corresponding to the distal landmark of LADT in the male and female groups were 3.4 ± 0.3° (2.6~4.2°) and 3.2 ± 0.3° (2.3~4.0°), respectively (P <0.05). Using LADT as the distal landmark for extramedullary tibial cutting guidance, the medial proximal tibia angle (MPTA) of the AA group was 87.0±1.2° (85.0~90.0°), and the AA and MA technique showed no difference in improvement in postoperative knee functional recovery at final follow-up. Conclusions: This study preliminarily indicated that LADT can be a reliable and economical landmark for coronal plane alignment of the tibial component.

Comprehensive analysis of pivotal biomarkers, immune cell infiltration and therapeutic drugs for steroid-induced osteonecrosis of the femoral head.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a progressive disease that leads to an increased disability rate. This study aimed to ascertain biomarkers, infiltrating immune cells, and therapeutic drugs for SONFH. The gene expression profile of the GSE123568 dataset was downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the NetworkAnalyst platform. Functional enrichment, protein-protein interaction network (PPI), and module analyses were performed using Metascape tools. An immune cell abundance identifier was used to explore immune cell infiltration. Furthermore, hub genes were identified based on maximal clique centrality (MCC) evaluation using cytoHubba application and confirmed by qRT-PCR using clinical samples. Finally, the L1000 platform was used to determine potential drugs for SONFH treatment. The SONFH mouse model was used to determine the therapeutic effects of aspirin. In total, 429 DEGs were identified in SONFH samples. Functional enrichment analysis showed that these DEGs were enriched in myeloid leukocyte activation and osteoclast differentiation processes. A set of nine immune cell types was confirmed to be markedly different between the SONFH and control samples. All 10 hub genes were significantly highly expressed in the serum of SONFH patients, as shown by qRT-PCR. Finally, the therapeutic effect of aspirin on SONFH was examined in animal experiments. Taken together, our data revealed the hub genes and infiltrating immune cells in SONFH, and we also screened potential drugs for use in SONFH treatment.

Assembly of tetra-nuclear YbIII-containing selenotungstate clusters: synthesis, structures, and magnetic properties.

Two tetra-nuclear YbIII-incorporated selenotungstate clusters, Keggin (C2H8N)6Na14[Yb4Se6W44O160(H2O)12]·40H2O (1) and Wells-Dawson (C2H8N)4Na14[Yb4Se6W45O159(OH)6(H2O)11]·38H2O (2), have been isolated through a pH-controlled assembly, which exhibit the first YbIII-containing polyoxotungstates with selenium heteroatoms. Their assemblies rely on the structure-directing effects of SeO32- anion templates to give rise to available Se-containing Keggin-/Wells-Dawson-type motifs. Both compounds were characterized by single-crystal X-ray diffraction, IR spectroscopy, power X-ray diffraction (XRD), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS) as well as electrospray ionization mass spectrometry (ESI-MS). Furthermore, systematic magnetic studies revealed that 1 exhibits field-induced single-molecule magnetic behavior with a pre-exponential factor of τ0 = 6.60(7) × 10-8 s and a relaxation energy barrier of ΔE/kB = 39.44(2) K, while 2 only displays antiferromagnetic interactions between the ytterbium centers.

Mechanochromic luminescence properties of fluoro-substituted pinene-containing cyclometalated platinum(II) complexes with multiple triplet excited states.

The structure-mechanochromism relationship is explored with respect to packing patterns and corresponding intermolecular interactions that are affected by the number and location of -F. The distinct and reversible mechanochormic luminescence (Δλem up to ca. 90 nm) of yellow solids (-)-1-Yg, (-)-2-Yg, and (-)-3-Yg was displayed with a simultaneous crystal-to-amorphous transformation. The change of multiple triplet excited states accounted for the mechanochormic luminescence, and a switch from the 3π,π* monomer to the excimer/3MMLCT occurred in the grinding process. The mechanical force led to perturbation in the molecular packing, and aggregates with effective PtPt and π-π interactions were formed in the amorphous phase, leading to the variation of excited states. The mechanochromic luminescence could be reverted by dropping in CH2Cl2 and could be cycled multiple times without perceivable performance degradation. This work gives a reference for designing mechanochromic luminescent materials toward multicolor and multicomponent responses.

Personalized Cup Positioning Guides Improved Cup Positioning and Hip Ranges of Motion in Robotic Assisted Total Hip Arthroplasty.

OBJECTIVE: Precise hip cup positioning is essential for the prevention of component impingement and dislocation in robotic assisted total hip arthroplasty (THA). Currently, the robotic system uses a mechanical alignment guide (MAG) for cup placement, which is one-size-fits-all, and the optimal cup positioning is controversial. Robotic assisted THA has not used any personalized cup positioning guides. The goal of this study was to identify an optimal guide for cup placement in robotic assisted THA to improve prognosis and life quality after THA. MATERIALS AND METHODS: Pelvis and femoral CT data of 47 participants were retrospectively collected for preoperative planning of robotic THA. The universal MAG guide and three personalized guides, including acetabular rim labrum guide (ARLG), transverse acetabular ligament guide (TALG), and ischiatic-pubis line guide (IPLG), were used to pose cups in the acetabulum of each participant. The position of cups was evaluated by inclination and anteversion; the function of hip joints was evaluated by hip ranges of motion, including abduction, adduction, extension, flexion, internal rotation, and external rotation. RESULTS: In terms of cup positioning, ARLG provided a bigger cup inclination (p < 0.0001), while IPLG and TALG provided smaller cup inclination (p < 0.001) than MAG; the three personalized guides provided larger cup anteversion (p < 0.0001) than MAG. In terms of HROMs, compared with the use of MAG, the use of three personalized guides significantly decreased abduction (p < 0.0001), extension (p < 0.0001), and external rotation (p < 0.0001), but increased significantly flexion (p < 0.0001) and internal rotation (p < 0.0001); the use of ARLG significantly reduced adduction (p < 0.0001), but the use of IPLG and TALG increased adduction (p < 0.0001). CONCLUSION: Compared with MAG, personalized guides provided greater flexion and internal rotation, which may reduce the risk of posterior dislocation. Among the three personalized guides, IPLG is the most reliable one for the preoperative planning of robotic assisted THA.

Enhanced Circularly Polarized Luminescence Activity in Chiral Platinum(II) Complexes With Bis- or Triphenylphosphine Ligands.

Distinct circularly polarized luminescence (CPL) activity was observed in chiral (C∧N∧N)Pt(II) [(C∧N∧N) = 4,5-pinene-6'-phenyl-2,2'-bipyridine] complexes with bis- or triphenylphosphine ligands. Compared to the pseudo-square-planar geometry of chiral (C∧N∧N)Pt(II) complexes with chloride, phenylacetylene (PPV) and 2,6-dimethylphenyl isocyanide (Dmpi) ligands, the coordination configuration around the Pt(II) nucleus of chiral (C∧N∧N)Pt(II) complexes with bulk phosphine ligands is far more distorted. The geometry is straightforwardly confirmed by X-ray crystallography. The phosphines' participation enhanced the CPL signal of Pt(II) complexes profoundly, with the dissymmetry factor (g lum) up to 10-3. The distorted structures and enhanced chiroptical signals were further confirmed by time-dependent density functional theory (TD-DFT) calculations.

Knockdown of POSTN Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells From Patients With Steroid-Induced Osteonecrosis.

Steroid-induced osteonecrosis of femoral head (SONFH) is a common and serious complication caused by long-term and/or excessive use of glucocorticoids (GCs). The decreased activity and abnormal differentiation of bone marrow mesenchymal stem cells (BMSCs) are considered to be one of the major reasons for the onset and progression of this disease. Periostin (POSTN) is a matricellular protein which plays an important role in regulating osteoblast function and bone formation. Sclerostin (SOST) is a secreted antagonist of Wnt signaling that is mainly expressed in osteocytes to inhibit bone formation. However, the exact role of POSTN and SOST in SONFH has not been reported yet. Therefore, we detected the differential expression of POSTN and SOST in BMSCs of SONFH Group patients, and Control Group was patients with traumatic ONFH (TONFH) and developmental dysplasia of the hip (DDH). Furthermore, we used lentiviral transfection to knockdown POSTN expression in BMSCs of patients with SONFH to study the effect of POSTN knockdown on the SOST expression and osteogenic differentiation of BMSCs. The results indicated that the endogenous expression of POSTN and SOST in BMSCs of SONFH Group was upregulated, compared with Control Group. POSTN was upregulated gradually while SOST was downregulated gradually at days 0, 3, and 7 of osteogenic differentiation of BMSCs in Control Group. Contrarily, POSTN was gradually downregulated while SOST was gradually upregulated during osteogenic differentiation of BMSCs in SONFH Group. This could be due to increased expression of SOST in BMSCs, which was caused by excessive GCs. In turn, the increased expression of POSTN in BMSCs may play a role in antagonizing the continuous rising of SOST during the osteogenic differentiation of BMSCs in patients with SONFH. POSTN knockdown significantly attenuated osteo-specific gene expression, alkaline phosphatase activity, and calcium nodule formation in vitro; thus inhibiting the osteogenic differentiation of BMSCs in patients with SONFH. Besides, POSTN knockdown upregulated SOST expression, increased GSK-3ß activity, and downregulated ß-catenin. These findings suggest that POSTN have an essential role in regulating the expression of SOST and osteogenic differentiation of BMSCs in patients with SONFH, and POSTN knockdown suppresses osteogenic differentiation by upregulating SOST and partially inactivating Wnt/ß-catenin signaling pathway. Therefore, targeting POSTN and SOST may serve as a promising therapeutic target for the prevention and treatment of SONFH.

MicroRNA302-367-PI3K-PTEN-AKT-mTORC1 pathway promotes the development of cardiac hypertrophy through controlling autophagy.

Cardiac hypertrophy at a decompensated state eventually leads to heart failure that mostly contributes to deaths globally. Dysregulated cardiac autophagy is a hallmark of a diseased heart, and a close contact between cardiac autophagy and cardiac hypertrophy is emerging. MicroRNAs (miRNAs) have been recently reported to be prominently implicated in cardiac hypertrophy through regulating cardiac autophagy. However, the role and function of miR302-367 clusters in cardiac autophagy and cardiac hypertrophy remain largely masked. Therefore, to investigate the performance of miR302-367 in cardiac hypertrophy, the specific in vitro hypertrophic model was established in H9c2 cells upon Ang II treatment. Consequently, we discovered a distinct inhibition on autophagy and a remarkable upregulation of miR302-367 expression in hypertrophic H9c2 cells. Besides, loss- and gain-of-function assays demonstrated miR302-367 inhibited autophagy and then aggravated cardiac hypertrophy. Mechanically, PTEN was predicted and confirmed as the shared target of miR302-367. Further, we recognized the apparent inactivation of PI3K/AKT/mTORC1 signaling in the face of miR302-367 suppression in Ang II-induced hypertrophic H9c2 cells. Moreover, co-treatment of PTEN inhibitor re-activated the PI3K/AKT/mTORC1 pathway, therefore counteracting the pro-autophagic and anti-hypertrophic effects of miR302-367 depletion on cardiomyocytes. These findings unveiled the pivotal role of the miR302-367 cluster in regulating cardiac autophagy and therefore modulating cardiac hypertrophy through PTEN/PI3K/AKT/mTORC1 signaling, indicating a promising therapeutic strategy for cardiac hypertrophy and even heart failure. Graphical abstract .

The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor.

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into several tissues, such as bone, cartilage, and fat. Glucocorticoids affect a variety of biological processes such as proliferation, differentiation, and apoptosis of various cell types, including osteoblasts, adipocytes, or chondrocytes. Glucocorticoids exert their function by binding to the glucocorticoid receptor (GR). Physiological concentrations of glucocorticoids stimulate osteoblast proliferation and promote osteogenic differentiation of MSCs. However, pharmacological concentrations of glucocorticoids can not only induce apoptosis of osteoblasts and osteocytes but can also reduce proliferation and inhibit the differentiation of osteoprogenitor cells. Several signaling pathways, including the Wnt, TGFß/BMP superfamily and Notch signaling pathways, transcription factors, post-transcriptional regulators, and other regulators, regulate osteoblastogenesis and adipogenesis of MSCs mediated by GR. These signaling pathways target key transcription factors, such as Runx2 and TAZ for osteogenesis and PPARγ and C/EBPs for adipogenesis. Glucocorticoid-induced osteonecrosis and osteoporosis are caused by various factors including dysfunction of bone marrow MSCs. Transplantation of MSCs is valuable in regenerative medicine for the treatment of osteonecrosis of the femoral head, osteoporosis, osteogenesis imperfecta, and other skeletal disorders. However, the mechanism of inducing MSCs to differentiate toward the osteogenic lineage is the key to an efficient treatment. Thus, a better understanding of the molecular mechanisms behind the imbalance between GR-mediated osteoblastogenesis and adipogenesis of MSCs would not only help us to identify the pathogenic causes of glucocorticoid-induced osteonecrosis and osteoporosis but also promote future clinical applications for stem cell-based tissue engineering and regenerative medicine. Here, we primarily review the signaling mechanisms involved in adipogenesis and osteogenesis mediated by GR and discuss the factors that control the adipo-osteogenic balance.

Prognostic and Clinicopathological Significance of Long Non-coding RNA PANDAR Expression in Cancer Patients: A Meta-Analysis.

Background: Long non-coding RNA PANDAR is an emerging non-coding RNA mapping to 6p21.2. It underlies metastatic progression and chromosomal instability in a variety of cancers. Despite the fact that recent studies have revealed that lncRNA PANDAR may be a potential prognostic biomarker for patients with cancer, there has still been controversy on the prognostic value of PANDAR. Methods: Databases of PubMed, Embase, SinoMed, and Web of Science were carefully searched and the literature which investigated the prognostic value of PANDAR expression among human cancers was collected for further analysis. Odds ratios (ORs) or hazards ratios (HRs) with 95% confidence intervals (CIs) were pooled to estimate the relation between PANDAR expression and survival or clinicopathological characteristics of cancer patients. Results: There were 13 eligible studies in total, with 1,465 patients enlisted in this meta-analysis. All the eligible studies complied with the case-control study. The outcome showed that the elevated expression level of PANDAR was significantly related to poor overall survival (OS) (pooled HR 1.72, 95%CI 1.14-2.60). However, high or low expression of PANDAR did not differ in the prediction of event-free survival (EFS). Moreover, we discovered that high PANDAR expression was closely related to decreased OS in colorectal cancer (pooled HR 3.43, 95%CI 2.06-5.72) and reduced expression level of PANDAR was markedly related to poor OS (pooled HR 0.65, 95%CI 0.45-0.88) in non-small cell lung cancer. However, the expression level of PANDAR had no significant association with OS in renal cell carcinoma (pooled HR 1.19, 95%CI 0.56-2.50). Moreover, after analysis, we discovered that the high expression level of PANDAR was associated closely with the depth of invasion (pooled OR 3.95, 95%CI 2.36-6.63), lymph node metastasis (pooled OR 1.92, 95%CI 0.93-3.98), tumor stage (pooled OR 2.05, 95%CI 0.99-4.27), and distant metastasis (pooled OR 2.87, 95%CI 1.60-5.16). Conclusions: Our study revealed that increased PANDAR expression may serve as an adverse prognostic biomarker for cancer patients, thus helping the clinical decision-making process.

Synthesis and characterization of two isostructural 3d-4f coordination compounds based on pyridine-2,6-dicarboxylic acid and 4,4'-bipyridine.

The design and synthesis of 3d-4f heterometallic coordination polymers have attracted much interest due to the intriguing diversity of their architectures and topologies. Pyridine-2,6-dicarboxylic acid (H2pydc) has a versatile coordination mode and has been used to construct multinuclear and heterometallic compounds. Two isostructural centrosymmetric 3d-4f coordination compounds constructed from pyridine-2,6-dicarboxylic acid and 4,4'-bipyridine (bpy), namely 4,4'-bipyridine-1,1'-diium diaquabis(µ2-pyridine-2,6-dicarboxylato)tetrakis(pyridine-2,6-dicarboxylato)bis[4-(pyridin-4-yl)pyridinium]cobalt(II)dieuropium(III) octahydrate, (C10H10N2)[CoEu2(C10H9N2)2(C7H3NO4)6(H2O)2]·8H2O, (I), and 4,4'-bipyridine-1,1'-diium diaquabis(µ2-pyridine-2,6-dicarboxylato)tetrakis(pyridine-2,6-dicarboxylato)bis[4-(pyridin-4-yl)pyridinium]cobalt(II)diterbium(III) octahydrate, (C10H10N2)[CoTb2(C10H9N2)2(C7H3NO4)6(H2O)2]·8H2O, (II), were synthesized under hydrothermal conditions and characterized by IR and fluorescence spectroscopy, thermogravimetric analysis and powder X-ray diffraction. Both compounds crystallize in the triclinic space group P-1. The EuIII and TbIII cations adopt nine-coordinated distorted tricapped trigonal-prismatic geometries bridged by three pydc2- ligands. The CoII cation has a six-coordination environment formed by two pydc2- ligands, two bpy ligands and two coordinated water molecules. Adjacent molecules are connected by π-π stacking interactions to form a one-dimensional chain, which is further extended into a three-dimensional supramolecular network by multipoint hydrogen bonds.