[Phagocytosis of microglia in neurodegenerative diseases].

With the acceleration of the aging society, neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), have become a rapidly growing global health crisis. Recent studies have indicated that microglia-neuron interactions are critical for maintaining homeostasis of the central nervous system. Genome-Wide Association Studies and brain imaging studies have suggested that microglia are activated in early stage of neurodegenerative diseases. Microglia are specialized phagocytes in the brain. The discovery of a new phagocytic pathway, trogocytosis, suggests that there is a close interaction between microglia and surviving neurons. In this review, we summarize the important roles of microglia in neurodegenerative diseases, and further analyze the functions and molecular mechanisms of microglia phagocytosis and trogocytosis.

CD200 maintains the region-specific phenotype of microglia in the midbrain and its role in Parkinson's disease.

Microglia are a specialized population of tissue macrophages in the mammalian brain. Microglial phenotype is tightly regulated by local environmental factors, although little is known about these factors and their region-preferred roles in regulating local neuroinflammatory responses. We hypothesized that microglia in different brain regions respond differently to neuroinflammatory stimulation and that CD200, an anti-inflammatory protein mainly originated from neurons, acts as a local cue inhibiting microglia activation in the midbrain. We utilized a CD200-deficient mouse line to analyze the phenotypic role of CD200 in the regulation of normal neuron-microglia homeostasis in the midbrain and in the dopaminergic degeneration in an α-synuclein overexpression model of PD. We found that systemic administration of an endotoxin lipopolysaccharide induced a region-preferred change in CD200 expression in the midbrain. Similarly, CD200-/- mice showed a regional preference in an enhancement of microglia activation and baseline inflammatory levels in the midbrain and dopamine neuron loss in the substantia nigra (SN). In a mouse model of Parkinson's disease (PD) induced by rAAV-hSYN injection into the SN, CD200-/- mice showed more dopamine neuron loss in the SN than wild type mice. Activation of CD200 receptors with a CD200 fusion protein alleviated the neuroinflammation and neuronal death in the SN of PD mice. These findings demonstrate that CD200 is essential for the midbrain homeostasis and acts as a critical local regulator in controlling microglial properties related to the PD pathogenesis.

MOTS-c inhibits Osteolysis in the Mouse Calvaria by affecting osteocyte-osteoclast crosstalk and inhibiting inflammation.

The Mitochondrial-derived peptide MOTS-c has recently been reported as a 16-amino acid peptide regulating metabolism and homeostasis in different cells. However, its effects on immune cells and bone metabolism are rarely reported. Here we demonstrate that MOTS-c treatment in ultra-high molecular weight polyethylene (UHMWPE) particle-induced osteolysis mouse model alleviated bone erosion and inflammation. MOTS-c increased osteoprotegerin (OPG)/ receptor activator of nuclear factor kappa-B ligand (RANKL) ratio in osteocytes, leading to inhibition of osteoclastogenesis. In primary bone marrow macrophages (BMMs) MOTS-c alleviated STAT1 and NF-κB phosphorylation triggered by UHMWPE particles. Promoting ROS production or suppressing peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) by adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) repression blocked these anti-inflammatory effects of MOTS-c treatment. Taken together, these findings provide evidence that the small peptide inhibits osteoclastogenesis by regulating osteocyte OPG/RANKL secretion and suppressing inflammation via restraining NF-κB and STAT1 pathway. Moreover, its effects on NF-κB activation is dependent on the AMPK-PGC-1α-ROS axis, suggesting its potential use in osteolysis and other inflammation disorders.

A Systematic Review of Anterior Cruciate Ligament Femoral Footprint Location Evaluated by Quadrant Method for Single-Bundle and Double-Bundle Anatomic Reconstruction.

PURPOSE: To unravel the standard position of anterior cruciate ligament (ACL) femoral origin and deduce practical arthroscopic localization and postsurgical evaluation method. METHODS: Two independent reviewers searched PubMed using the terms ACL, footprint, femur, etc. We included studies published since January 1, 2000, in which the results were measured by Bernard's quadrant method. This method consists of 4 distances, including total diameter of lateral condyle along Blumensaat's line (distance t), maximum intercondylar notch height (distance h), distance from center of footprint to proximal border (distance x), and distance from center of footprint to Blumensaat's line (distance y). The data of included studies were combined to calculate theoretical centers and standard area for both ACL as a whole bundle and as anteromedial (AM) and posterolateral (PL) bundles individually. Finally, we translated the combined data to arthroscopic localization and postsurgical evaluation. RESULTS: A total of 13 studies were included. The theoretical centers of ACL as a whole bundle is 28.4% ± 5.1% (x) of distance t and 35.7% ± 6.9% (y) of distance h, whereas AM bundle is 24.2% ± 4%, 21.6% ± 5.2% (x, y) and PL bundle is 32.8% ± 4.7%, 46.7% ± 4.9% (x, y), respectively. The standard area of ACL footprint is a circle with a center of 27.53%, 35.85% (x, y), and a radius of 4.58%, 9.2% (x, y), respectively. Translation of combined data shows that under arthroscopy, for single-bundle ACL reconstruction, the midpoint of distance from border of proximal to distal articular cartilage is the center of anatomic femoral socket. CONCLUSIONS: Combined data unravel the standard position of ACL femoral origin. It can be used by clinicians to localize anatomic tunnel both in surgery and postsurgical evaluation. For single-bundle ACL reconstruction, the midpoint of lateral femoral condyle corresponds to anatomic socket. LEVEL OF EVIDENCE: Level V, systematic review of anatomic studies.

RNA-binding Protein QKI Inhibits Osteogenic Differentiation Via Suppressing Wnt Pathway.

BACKGROUND: Dysregulation of MSCs differentiation is associated with many pathophysiological processes. Genetically modified MSCs transplantation helps restore bone loss efficiently. METHODS: BMSCs-specific QKI overexpressing and knockdown mice were built to explore QKI's role in bone formation and fat accumulation. Primary BMSCs with QKI overexpression and knockout were subjected to osteogenic and adipogenic differentiation. ALP staining and oil red O staining were performed to evaluate the differences between the groups. RNA immunoprecipitation was performed to identify the QKI-related pathway. QKI deficient BMSCs were transplanted into mice with glucocorticoid-induced osteoporosis to evaluate its therapeutic potential. RESULTS: Mice harboring BMSC-specific transgenic QKI exhibited reduced bone mass, while BMSC-specific QKI-deficient mice showed an increase in bone mass. Osteogenic differentiation of QKI deficient BMSCs was promoted and adipogenic differentiation was inhibited, while QKI overexpression in BMSCs displayed the opposite effects. To define the underlying mechanisms, RIP sequencing was performed. Wnt pathway-related genes were the putative direct target mRNAs of QKI, Canonical Wnt pathway activation was involved in QKI's effects on osteogenic differentiation. RNA immunoprecipitation quantitative real-time Polymerase Chain Reaction (PCR) and RNA fluorescence in situ hybridization experiments further validated that QKI repressed the expressions of Wnt5b, Fzd7, Dvl3 and ß-catenin via direct binding to their putative mRNA specific sites. Glucocorticoid-induced osteoporotic mice transplanted with QKI deficient BMSCs exhibited less bone loss compared with mice transplanted with control BMSCs. CONCLUSIONS: QKI suppressed BMSCs osteogenic differentiation by downregulating the expressions of Wnt5b, Fzd7, Dvl3 and ß-catenin. Loss of QKI in BMSCs transplantation may provide a new strategy for the treatment of orthopedic diseases such as osteoporosis.

Current study on the influence of psychological factors on returning to sports after ACLR.

It is considered that psychological factors are important in determining exercise regression outcomes of patients with anterior cruciate ligament reconstruction (ACLR). This review summarizes the definition and research progress of current undefined psychological factors related to returning to sports (RTS) after ACLR, as well as the application of corresponding measuring scales, and common psychological interventions in the field. The aim is to understand and clarify the impact of psychological factors in the ACL injury and rehabilitation, and to provide a theoretical basis for the application of psychological evaluation and intervention in the later stage. It is believed that there are still many prospects for the research in this field.

AQP5 Is a Novel Prognostic Biomarker in Pancreatic Adenocarcinoma.

Background: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor with a poor prognosis. The identification of effective molecular markers is of great significance for diagnosis and treatment. Aquaporins (AQPs) are a family of water channel proteins that exhibit several properties and play regulatory roles in human carcinogenesis. However, the association between Aquaporin-5 (AQP5) expression and prognosis and tumor-infiltrating lymphocytes in PAAD has not been reported. Methods: AQP5 mRNA expression, methylation, and protein expression data in PAAD were analyzed using GEPIA, UALCAN, HAP, METHSURV, and UCSC databases. AQP5 expression in PAAD patients and cell lines from our cohort was examined using immunohistochemistry and Western blotting. The LinkedOmics database was used to study signaling pathways related to AQP5 expression. TIMER and TISIDB were used to analyze correlations among AQP5, tumor-infiltrating immune cells, and immunomodulators. Survival was analyzed using TCGA and Kaplan-Meier Plotter databases. Results: In this study, we investigated AQP5 expression in PAAD and determined whether the expression of AQP5 is a strong prognostic biomarker for PAAD. We searched and analyzed public cancer databases (GEO, TCGA, HAP, UALCAN, GEPIA, etc.) to conclude that AQP5 expression levels were upregulated in PAAD. Kaplan-Meier curve analysis showed that high AQP5 expression positively correlated with poor prognosis. Using TIMER and TISIDB, we found that the expression of AQP5 was associated with different tumor-infiltrating immune cells, especially macrophages. We found that hypomethylation of the AQP5 promoter region was responsible for its high expression in PAAD. Conclusions: AQP5 can serve as a novel biomarker to predict prognosis and immune infiltration in PAAD.

Theoretical Study of O-CH3 Bond Dissociation Enthalpy in Anisole Systems.

Understanding ubiquitous methyl transfer reactions requires a systematic study of thermodynamical parameters that could reveal valuable information about the nature of the chemical bond and the feasibility of those processes. In the present study, the O-CH3 bond dissociation enthalpies (BDEs) of 67 compounds belonging to phenol/anisole systems were calculated employing the Gaussian-4 (G4) method. Those compounds contain different substituents including alkyl groups, electron-donating groups (EDGs), and electron-withdrawing groups (EWGs). The results show that the bigger branched alkyl groups and EDGs will destabilize the O-CH3 bond, while EWGs have the opposite effect. A combination of different effects including steric effects, hydrogen bonds, and substituents and their position can achieve around 20 kcal/mol difference compared to the basic phenyl frame. Also, the linear correlation between σp + and O-CH3 BDE can provide a reference for the O-CH3 BDE prediction. The present study represents a step forward to establish a comprehensive O-CH3 BDE database to understand the substituent effect and make its contribution to the rational design of inhibitors and drugs.

Association between the inclination angle of the proximal tibiofibular joint surface and medial compartment knee osteoarthritis.

BACKGROUND: Fibular support for the lateral tibial plateau through the proximal tibiofibular joint (PTFJ) results in nonuniform settlement of the tibial plateau in middle-aged and elderly persons and may lead to medial compartment knee osteoarthritis. However, the inclination angle of the PTFJ surface varies widely and may affect nonuniform settlement. The purpose of this case-control study was to assess the association between the inclination angle of the PTFJ surface and medial compartment knee osteoarthritis. METHODS: The fibular inclination angle (FIA) and tibial inclination angle (TIA) of the PTFJ surface were measured using radiographs. Differences of FIA and TIA among groups were assessed with t tests and the odds ratios (ORs) for risk factors of medial compartment knee osteoarthritis were calculated with binary logistic regression analysis. RESULTS: Forty patients and 40 control participants were included in this case-control study. Patients had both a lower FIA (P=0.005) and TIA (P=0.000) than the controls, and logistic regression analysis showed that FIA (OR =7.000) and TIA (OR =17.000) were risk factors for medial compartment knee osteoarthritis. CONCLUSIONS: A lower inclination angle of the PTFJ surface is associated with a risk of medial compartment knee osteoarthritis. Clinically, early prevention of medial compartment knee osteoarthritis should be considered for middle-aged and elderly persons with low PTFJ inclination angles.

Loss of QKI in macrophage aggravates inflammatory bowel disease through amplified ROS signaling and microbiota disproportion.

Inflammatory bowel disease (IBD) is a refractory chronic inflammatory illness of the gastrointestinal (GI) tract. Macrophage exerts an important role in IBD development. QKI, as an RNA binding protein, was related with inflammatory responses in bacterial infections by regulating the polarization of macrophages. Therefore, we suspected that QKI-regulated macrophages have the potential to play a certain role in IBD and the underlying mechanism. Our results demonstrated that the mice with macrophage-specific deletion of QKI induced with dextran sodium sulfate (DSS) are more susceptible to IBD development, exhibited a severe leaky gut barrier phenotype and higher intense oxidative stress, which are rescued by treating with butylated hydroxyanisole (BHA), an agonist of NRF2. Mechanically, we observed that Keap1 mRNA in the nucleus was exported to the cytoplasm after LPS stimuli in parallel with QKI reductions, and the removal of QKI by shRNA facilitated Keap1 mRNA nuclear exporting and expression in cytoplasm, consequently NRF2 activation in nucleus was weakened, and led to the impaired antioxidant abilities. In addition, mice models of fecal microbiota transplant (FMT) and the co-culturing of mice epithelia cells with feces derived from the DSS-treated QKI-deficit mice revealed consistently aggravated colitis along with a severe oxidative stress; 16S sequencing analysis substantiated the altered compositions of commensal bacteria too. Overall, the current study represents the first effort to explore the anti-oxidant role of QKI in the intestinal macrophage via post-transcriptional regulation of Keap1 mRNA localization and the relevant NRF2 antioxidant signaling, and the disproportional changes in the microbiota were attributable to the mediation of pathogenic damage in the IBD development of QKI-deficit mice.

QKI deficiency leads to osteoporosis by promoting RANKL-induced osteoclastogenesis and disrupting bone metabolism.

Quaking (QKI), an RNA-binding protein, has been reported to exhibit numerous biological functions, such as mRNA regulation, cancer suppression, and anti-inflammation. However, little known about the effects of QKI on bone metabolism. In this study, we used a monocyte/macrophage-specific QKI knockout transgenic mouse model to investigate the effects of QKI deficiency on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. The loss of QKI promoted the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) from bone marrow macrophages, and upregulated the expression of OC-specific markers, including TRAP (Acp5) and cathepsin K (Ctsk). The pro-osteoclastogenesis effect of QKI deficiency was achieved by amplifying the signaling cascades of the NF-κB and mitogen-activated protein kinase (MAPK) pathways; then, signaling upregulated the activation of nuclear factor of activated T cells c1 (NFATc1), which is considered to be the core transcription factor that regulates OC differentiation. In addition, QKI deficiency could inhibit osteoblast (OB) formation through the inflammatory microenvironment. Taken together, our data suggest that QKI deficiency promoted OC differentiation and disrupted bone metabolic balance, and eventually led to osteopenia under physiological conditions and aggravated the degree of osteoporosis under pathological conditions.

Disease Progression-Dependent Expression of CD200R1 and CX3CR1 in Mouse Models of Parkinson's Disease.

Microglial activation is an important contributor to the pathogenesis of Parkinson's disease (PD). Microglia are tightly and efficiently regulated by immune checkpoints, including CD200-CD200R1 and CX3CL1-CX3CR1. Understanding the involvement of these checkpoints in disease progression provides important insights into how microglial activation contributes to PD pathology. However, so far, studies have produced seemingly conflicting results. In this study, we demonstrate that CD200R1 expression is down-regulated at both early and late stage of PD model, and CX3CR1 expression is down-regulated in early stage and recovered in late stage. In primary cultured microglia, CD200R1 and CX3CR1 expressions are both directly regulated by LPS or α-synuclein, and CD200R1 expression is more sensitively regulated than CX3CR1. In addition, CD200 knockout causes an increase in proinflammatory cytokine production and microglial activation in the midbrain. Remarkably, DA neurons in the substantial nigra are degenerated in CD200-/- mice. Finally, activation of the CD200R with CD200Fc alleviates the neuroinflammation in microglia. Together, these results suggest that immune checkpoints play distinct functional roles in different stage of PD pathology, and the CD200-CD200R1 axis plays a significant role in nigrostriatal neuron viability and function.