Genetically proxied PCSK9 inhibition is associated with reduced psoriatic arthritis risk.

BACKGROUND: Lipid pathways play a crucial role in psoriatic arthritis development, and some lipid-lowering drugs are believed to have therapeutic benefits due to their anti-inflammatory properties. Traditional observational studies face issues with confounding factors, complicating the interpretation of causality. This study seeks to determine the genetic link between these medications and the risk of psoriatic arthritis. METHODS: This drug target study utilized the Mendelian randomization strategy. We harnessed high-quality data from population-level genome-wide association studies sourced from the UK Biobank and FinnGen databases. The inverse variance-weighted method, complemented by robust pleiotropy methods, was employed. We examined the causal relationships between three lipid-lowering agents and psoriatic arthritis to unveil the underlying mechanisms. RESULTS: A significant association was observed between genetically represented proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition and a decreased risk of psoriatic arthritis (odds ratio [OR]: 0.51; 95% CI 0.14-0.88; P < 0.01). This association was further corroborated in an independent dataset (OR 0.60; 95% CI 0.25-0.94; P = 0.03). Sensitivity analyses affirmed the absence of statistical evidence for pleiotropic or genetic confounding biases. However, no substantial associations were identified for either 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or Niemann-Pick C1-like 1 inhibitors. CONCLUSIONS: This Mendelian randomization analysis underscores the pivotal role of PCSK9 in the etiology of psoriatic arthritis. Inhibition of PCSK9 is associated with reduced psoriatic arthritis risk, highlighting the potential therapeutic benefits of existing PCSK9 inhibitors.

Repetitive strikes loading organ culture model to investigate the biological and biomechanical responses of the intervertebral disc.

Background: Disc degeneration is associated with repetitive violent injuries. This study aims to explore the impact of repetitive strikes loading on the biology and biomechanics of intervertebral discs (IVDs) using an organ culture model. Methods: IVDs from the bovine tail were isolated and cultured in a bioreactor, with exposure to various loading conditions. The control group was subjected to physiological loading, while the model group was exposed to either one strike loading (compression at 38% of IVD height) or repetitive one strike loading (compression at 38% of IVD height). Disc height and dynamic compressive stiffness were measured after overnight swelling and loading. Furthermore, histological morphology, cell viability, and gene expression were analyzed on Day 32. Glycosaminoglycan (GAG) and nitric oxide (NO) release in conditioned medium were also analyzed. Results: The repetitive one strike group exhibited early disc degeneration, characterized by decreased dynamic compression stiffness, the presence of annulus fibrosus clefts, and degradation of the extracellular matrix. Additionally, this group demonstrated significantly higher levels of cell death (p < 0.05) and glycosaminoglycan (GAG) release (p < 0.05) compared to the control group. Furthermore, upregulation of MMP1, MMP13, and ADAMTS5 was observed in both nucleus pulposus (NP) and annulus fibrosus (AF) tissues of the repetitive one strike group (p < 0.05). The one strike group exhibited annulus fibrosus clefts but showed no gene expression changes compared to the control group. Conclusions: This study shows that repetitive violent injuries lead to the degeneration of a healthy bovine IVDs, thereby providing new insights into early-stage disc degeneration.

The causal relationship between sarcopenic obesity factors and benign prostate hyperplasia.

Background: Both benign prostatic hyperplasia (BPH) and sarcopenic obesity (SO) are common conditions among older adult/adults males. The prevalent lifestyle associated with SO is a significant risk factor for the development of BPH. Therefore, we investigated the causal relationship between SO factors and BPH. Method: The instrumental variables for SO factors were selected using the inverse variance-weighted method, which served as the primary approach for Mendelian randomization analysis to assess the causal effect based on summary data derived from genome-wide association studies of BPH. Result: The increase in BMR (OR = 1.248; 95% CI = (1.087, 1.432); P = 0.002) and ALM (OR = 1.126; 95% CI = (1.032, 1.228); P = 0.008) was found to be associated with an elevated risk of BPH. However, no genetic causality between fat-free mass distribution, muscle mass distribution, and BPH was observed. Conclusion: Our findings indicate that a genetic causal association between BMR, ALM and BPH. BMR and ALM are risk factors for BPH. The decrease in BMR and ALM signified the onset and progression of SO, thus SO is a protective factor for BPH.

Effect of mechanical stimulation on tissue heterotopic ossification: an in vivo experimental study.

Background: Heterotopic ossification of tendons and ligaments (HOTL) is a common clinical condition characterized by the absence of discernible features and a lack of effective treatment. In vitro experiments have demonstrated that mechanical stimulation can induce cell differentiation toward osteogenesis, thereby promoting heterotopic ossification. Currently, there are few experimental designs aimed at inducing ligament stretching in mice, and the mechanism of heterotopic ossification may not entirely mirror that observed in clinical cases. Therefore, there is an urgent imperative to develop a novel and feasible animal model. Methods: In this study, all the Enpp1 gene deficiency mice (a mouse model with heterotopic ossification of multiple ligaments) were divided into three groups: the control group, the spinal brake group, and the hyperactive group (treadmill training group). An external spinal fixation device was designed to restrict mice's spinal flexion and extension at 6 weeks of age. The brace was adjusted weekly according to the changes in the size of the mice. Additionally, treadmill training was used to increase activity in the spinal ligaments and Achilles tendons of the mice. Micro-CT scanning and HE staining were performed at 12, 20, and 28 W to evaluate the degree of ossification in the spinal ligament and Achilles tendon. What's more, As one of the mechanical stimulation transduction signals, YAP plays a crucial role in promoting osteogenic differentiation of cells. Immunofluorescence was utilized to assess YAP expression levels for the purpose of determining the extent of mechanical stimulation in tissues. Results: Our findings showed that a few ossification lesions were detected behind the vertebral space of mice at 8 weeks of age. Spinal immobilization effectively restricts the flexion and extension of cervical and thoracic vertebrae in mice, delaying spinal ligament ossification and reducing chronic secondary spinal cord injury. Running exercises not only enhance the ossification area of the posterior longitudinal ligament (PLL) and Achilles tendons but also exacerbate secondary spinal cord injury. Further immunofluorescence results revealed a notable increase in YAP expression levels in tissues with severe ossification, suggesting that these tissues may be subjected to higher mechanical stimulation. Conclusion: Mechanical stimulation plays a pivotal role in the process of heterotopic ossification in tissues. Our study provided valid animal models to further explore the pathological mechanism of mechanical stimulation in HOTL development.

Identification of novel gene signatures and immune cell infiltration in intervertebral disc degeneration using bioinformatics analysis.

Background: Intervertebral disc degeneration (IDD) is the leading cause of lower back pain, and an overall understanding of the molecular mechanisms related to IDD is still lacking. The purpose of this study was to explore gene signatures and immune cell infiltration related to IDD via bioinformatics analysis. Methods: A total of five expression profiles of mRNA and non-coding RNA were downloaded from the Gene Expression Omnibus (GEO) database. The potentially involved lncRNA/circRNA-miRNA-mRNA networks and protein-protein interaction networks were constructed by miRNet, circBank, STRING, and the Cytoscape database. Gene ontology, Kyoto Encyclopaedia of Genes and Genomes Analysis, Gene Set Enrichment Analysis, Gene Set Variation Analysis, Immune Infiltration Analysis, and Drug-Gene Interaction were used to analyse the top 20 hub genes. RT-qPCR was conducted to confirm the 12 differential expressions of genes both in the nucleus pulposus and annulus fibrosus tissues Results: There were 346 differentially expressed mRNAs, 12 differentially expressed miRNAs, 883 differentially expressed lncRNAs, and 916 differentially expressed circRNAs in the GEO database. Functional and enrichment analyses revealed hub genes associated with platelet activation, immune responses, focal adhesion, and PI3K-Akt signalling. The apoptotic pathway, the reactive oxygen species pathway, and oxidative phosphorylation play an essential role in IDD. Immune infiltration analysis demonstrated that the Treg cells had significant infiltration, and three levels of immune cells, including dendritic cells, Th2 cells, and tumour-infiltrating lymphocytes, were inhibited in IDD. Drug-gene interaction analysis showed that COL1A1 and COL1A2 were targeted by collagenase clostridium histolyticum, ocriplasmin, and PDGFRA was targeted by 66 drugs or molecular compounds. Finally, 24 cases of IDD tissues and 12 cases of normal disc tissues were collected, and the results of RT-qPCR were consistent with the bioinformatics results. Conclusion: Our data indicated that the 20 hub genes and immune cell infiltration were involved in the pathological process of IDD. In addition, the PDGFRA and two potential drugs were found to be significant in IDD development.

The clinical validity of atlantoaxial joint inclination angle and reduction index for atlantoaxial dislocation.

Objective: Atlantoaxial dislocation patients with neurological defects require surgery. Sometimes, release surgery is necessary for irreducible atlantoaxial dislocation to further achieve reduction. Whether release surgery is essential relies on the surgeon's experience and lacks objective reference criteria. To evaluate the value of atlantoaxial joint inclination angle (AAJI) in sagittal and coronal planes and reduction index (RI) in the surgical approach selection for atlantoaxial dislocation. Methods: Retrospectively analyzed 87 cases (42 males and 45 females, 9-89 years) of atlantoaxial dislocation from January 2011 to November 2020. In addition, 40 individuals without atlantoaxial dislocation were selected as the control group. Imaging parameters were compared between the two groups. According to surgical methods, the experiment group was divided into two groups including Group A(release surgery group) and Group B (conventional operation group). The parameters were measured based on CT and x-ray. The relevant imaging parameters and clinical scores, including the AAJI in sagittal and coronal planes, the atlas-dens interval (ADI) before and after traction, the RI, and JOA scores were measured and analyzed. Results: The sagittal and coronal atlantoaxial joint inclination angles(SAAJI and CAAJI) in the control group were 7.91 ± 0.42(L), 7.99 ± 0.39°(R), 12.92 ± 0.41°(L), 12.97 ± 0.37°(R), in A were 28.94 ± 1.46°(L), 28.57 ± 1.55°(R), 27.41 ± 1.29°(L), 27.84 ± 1.55°(R), and in B were 16.16 ± 0.95°(L), 16.80 ± 1.00°(R), 24.60 ± 0.84°(L), 24.92 ± 0.93°(R) respectively. Statistical analysis showed that there was a statistical difference in the SAAJI between the control group and the experiment group (P < 0.01), as well as between groups A and B (P < 0.01). The RI in groups A and B was 27.78 ± 1.46% and 48.60 ± 1.22% respectively, and there was also a significant difference between the two groups (P < 0.01). There was negative correlation between SAAJI and RI. Conclusions: The SAAJI and RI can be used as objective imaging indexes to evaluate the reducibility of atlantoaxial dislocation. And these parameters could further guide the selection of surgery methods. When the RI is smaller than 48.60% and SAAJI is bigger than 28.94°, anterior release may be required.

Epoxy functionalised poly(epsilon-caprolactone): synthesis and application.

Glycidol is used as an initiator for ring-opening polymerisation of epsilon-caprolactone (epsilon-CL) to synthesise epoxy-functionalised poly(epsilon-caprolactone) (PCL) in a reaction catalysed by lipase, and the epoxy-functionalised PCL was further copolymerised with carbon dioxide or anhydride to produce novel graft or hyperbranched copolymers.

Simultaneous enzymatic ring opening polymerisation and RAFT-mediated polymerisation in supercritical CO2.

This report presents the first simultaneous, metal-free synthesis of block copolymers through combination of enzymatic ring-opening polymerisation of epsilon-caprolactone with RAFT-mediated controlled radical polymerisation of styrene.

PLGA microspheres with high drug loading and high encapsulation efficiency prepared by a novel solvent evaporation technique.

PLGA microspheres with high drug loading and high encapsulation efficiency were fabricated by a novel solvent evaporation process-in-situ S/O/W process. Insulin was dissolved in DMSO and dispersed into DCM to form fine particles due to an anti-solvent effect. The in-situ formed suspension was then added into an aqueous phase and emulsified. Microspheres were formed following the evaporation of organic solvents. The experimental results showed that the modified S/O/W process could encapsulate more than 90%(w/w) insulin in the microspheres with a drug loading of over 15% and the initial burst was much less than microspheres made by a W1/O/W2 process. Compared with a traditional water-in-oil-in-water (W1/O/W2) process, the in-situ S/O/W process does not require high solubility of the encapsulated drug in water and, because no special pre-treatment is needed to reduce the particle size of the drug, it is superior to an ordinary S/O/W process. The in-situ S/O/W process is particularly applicable to encapsulate peptides and low molecular weight proteins.