Abnormal Stress Research Articles

Comprehensive analysis of scRNA-Seq and bulk RNA-Seq reveals ubiquitin promotes pulmonary fibrosis in chronic pulmonary diseases

It is estimated that there are 544.9 million people suffering from chronic respiratory diseases in the world, which is the third largest chronic disease. Although there are various clinical treatment methods, there is no specific drug for chronic pulmonary diseases, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). Therefore, it is urgent to clarify the pathological mechanism and medication development. Single-cell transcriptome data of human and mouse from GEO database were integrated by “Harmony” algorithm. The data was standardized and normalized by using “Seurat” package, and “SingleR” algorithm was used for cell grouping annotation. The “Findmarker” function is used to find differentially expressed genes (DEGs), which were enriched and analyzed by using "clusterProfiler", and a protein interaction network was constructed for DEGs, and four algorithms are used to find the hub genes. The expression of hub genes were analyzed in independent human and mouse single-cell transcriptome data. Bulk RNA data were used to integrate by the "SVA" function, verify the expression levels of hub genes and build a diagnostic model. The L1000FWD platform was used to screen potential drugs. Through exploring the similarities and differences by integrated single-cell atlas, we found that the lung parenchymal cells showed abnormal oxidative stress, cell matrix adhesion and ubiquitination in COPD, corona virus disease 2019 (COVID-19), ILD and IPF. Meanwhile, the lung resident immune cells showed abnormal Toll-like receptor signals, interferon signals and ubiquitination. However, unlike acute pneumonia (COVID-19), chronic pulmonary disease shows enhanced ubiquitination. This phenomenon was confirmed in independent external human single-cell atlas, but unfortunately, it was not confirmed in mouse single-cell atlas of bleomycin-induced pulmonary fibrosis model and influenza virus-infected mouse model, which means that the model needs to be optimized. In addition, the bulk RNA-Seq data of COVID-19, ILD and IPF was integrated, and we found that the immune infiltration of lung tissue was enhanced, consistent with the single-cell level, UBA52, UBB and UBC were low expressed in COVID-19 and high expressed in ILD, and had a strong correlation with the expression of cell matrix adhesion genes. UBA52 and UBB have good diagnostic efficacy, and salermide and SSR-69071 can be used as their candidate drugs. Our study found that the disorder of protein ubiquitination in chronic pulmonary diseases is an important cause of pathological phenotype of pulmonary fibrosis by integrating scRNA-Seq and bulk RNA-Seq, which provides a new horizons for clinicopathology, diagnosis and treatment.

Evaluation under loading detects medial meniscus extrusion in patients with reconstructed anterior cruciate ligament and restricted knee extension.

Some patients who undergo anterior cruciate ligament (ACL) reconstruction experience abnormal mechanical stress in the meniscus. Medial meniscal extrusion (MME) is reflected in the pathological condition of the meniscus, which expands owing to repetitive mechanical stress. Thus, the effect of the reconstructed ACL on increasing MME under weight-bearing conditions remains unclear. This study investigated the effect of ACL reconstruction on meniscal extrusion under non-weight-bearing and weight-bearing conditions. Seventeen patients who underwent unilateral ACL reconstruction (ACL group) and 20 age-matched healthy volunteers (control group) were enrolled. Ultrasonography was performed in the supine, standing, and walking positions in preoperative and postoperative ACL patients. MME during walking was evaluated based on the dynamic behavior of extrusion, and kinetic and kinematic data were synchronously obtained. Moreover, the ACL group underwent magnetic resonance imaging (MRI) evaluation at two points: preoperatively and 12months postoperatively, and the ultrasound findings were compared. MME in the supine position measured using both ultrasonography and MRI was not significantly different preoperatively and postoperatively in the ACL group. However, postoperative MME and dynamic behavior of extrusion under standing and walking conditions were significantly higher than those in the preoperative state (dynamic behavior: 0.9 ± 0.4mm preoperatively, 1.2 ± 0.4mm postoperatively). Moreover, the deficits in knee extension during walking persisted postoperatively and were significantly higher than those in the control group. MME in patients with ACL reconstruction including meniscus repair was different under mechanical stress compared to the non-weight bearing condition.

Assessment of abnormal transvalvular flow and wall shear stress direction for pediatric/young adults with bicuspid aortic valve: a cross-sectional 4D flow study

BackgroundAortic dilation is seen in pediatric/young adult patients with bicuspid aortic valve (BAV), and hemodynamic markers to predict aortic dilation are necessary for monitoring. Although promising hemodynamic metrics, such as abnormal wall shear stress (WSS) magnitude, have been proposed for adult BAV patients using 4D flow cardiovascular magnetic resonance, those for pediatric BAV patients have less frequently been reported, partly due to scarcity of data to define normal WSS range. To circumvent this challenge, this study aims to investigate if a recently proposed 4D flow-based hemodynamic measurement, abnormal flow directionality, is associated with aortic dilation in pediatric/young adult BAV patients. Methods4D flow scans for BAV patients (<20 years old) and age-matched controls were retrospectively enrolled. Static segmentation for the aorta and pulmonary arteries was obtained to quantify peak systolic hemodynamics and diameters in the proximal aorta. In addition to peak velocity, wall shear stress (WSS), vorticity, helicity, and viscous energy loss, direction of aortic velocity and WSS in BAV patients was compared with that of control atlas using registration technique; angle differences of >60deg and >120deg were defined as moderately and severely abnormal, respectively. Association between the obtained metrics and normalized diameters (Z-scores) were evaluated at the sinotubular junction, mid ascending aorta, and distal ascending aorta. ResultsFifty-three BAV patients, including eighteen with history of repaired aortic coarctation, and seventeen controls were enrolled. Correlation between moderately abnormal velocity/WSS direction and aortic Z-scores was moderate to strong at the sinotubular junction and mid ascending aorta (R=0.62-0.81; p<0.001) while conventional measurements exhibited weaker correlation (|R|=0.003-0.47, p=0.009-0.99) in all subdomains. Multivariable regression analysis found moderately abnormal velocity direction and existence of aortic regurgitation (only for isolated BAV group) were independently associated with mid ascending aortic Z-scores. ConclusionAbnormal velocity and WSS directionality in the proximal aorta was strongly associated with aortic Z-scores in pediatric/young adult BAV patients.

Biomechanical effects of mandibular deviation on the temporomandibular joint in patients with mandibular prognathism under incisal occlusion

PurposeThe aim of this study was to investigate the biomechanical effects of mandibular deviation on the TMJ in patients with mandibular prognathism before and after orthognathic surgery using three-dimensional finite element analysis. MethodsEight patients with mandibular prognathism without deviation, eight patients with mandibular prognathism with deviation and sixteen normal subjects were recruited. Three-dimensional models of the maxillofacial were reconstructed using MIMICS. Nine muscle forces were used to simulate incisal occlusion and contact was used to simulate fossa-disc-condyle interactions. ResultsBefore surgery, the stress in the TMJ was generally greater in the Pre-MD&MP group than in the Pre-MD group; it was much greater in both groups than in the control group, ranging from about 2 to 12 times as great in the Pre-MD group and from about 5 to 64 times as great in the Pre-MD&MP group. After orthognathic surgeries, the stresses in the Post-MP&MD were significantly reduced by approximately 21.7 % to 93.4 %. And in the Post-MP group, the stresses were reduced by approximately 1.4 % to 51.1 %. ConclusionMandibular deviation exacerbated the abnormal stress distribution in the TMJ of patients with mandibular prognathism. Orthognathic surgeries could improve the stress distribution in patients with mandibular prognathism (with and without deviation). TMD was closely related to the stress levels of the TMJ.

Deeply trapped electrons induced long-time sustainable mechanoluminescence of X-ray irradiated La2Ti2O7:Pr3+ for detection of stress burst

X-ray irradiated La2Ti2O7:Pr3+ was found to show long-time sustainable mechanoluminescence (ML), which can realize the high sensitivity and real time detection of stress burst for more than 72 h. Under the excitation of X-ray, La2Ti2O7:Pr3+ shows red ML emissions located at 610, 624 and 638 nm, which are similar to the afterglow emission spectrum and can be ascribed to1D2-3H4, 3P0-3H4 and 3P0-3H2 of Pr3+. And the linear increases of compressive load can induce the linear increases of ML intensity of the sample, indicating that the X-ray induced ML emission can be utilized to accurately detect the stress applied on the object. Furthermore, X-ray irradiated La2Ti2O7:Pr3+ possesses excellent stability and the repeatability of ML emission and the ML signals can keep stable even 50 load cycles after 1 h decay. The thermoluminescence results suggest that abundant electrons are trapped in shallow and deep answered for stable ML emission. More importantly, the deeply trapped electrons induced ML emissions from X-ray irradiated La2Ti2O7:Pr3+ can be utilized to detect the stress bursts for a long time. When the sample is recharged by 5 min X-ray irradiation once, within 24 h decay, the 1500 N burst among many 1000 N cycles can be clearly detected, and the signal to noise ratio (S/N) reaches 1.32 and 1.26 after 12 and 24 h decay, respectively. And even after 72 h decay, the S/N of 2500 N still arrives at 1.23 and that of 4000 N reaches 1.97, indicative of long-time high sensitivity detection of abnormal stress. All these results suggest that the X-ray-irradiated La1.97Ti2O7:0.03Pr3+/resin sample can realize the high sensitivity and real time detection of stress burst for more than 72 h, which thus possesses great potential application in early warning of the emergency disasters such as bridge fracture, tunnel collapse and so on.

A finite element analysis of patellofemoral joint biomechanics: Exploring potential causes of postoperative anterior knee pain following unicompartmental knee arthroplasty

PurposeAnterior knee pain is a common complication following unicompartmental knee arthroplasty (UKA). This study aimed to elucidate the mechanism of anterior knee pain after UKA by examining the biomechanical characteristics of the patellofemoral joint. MethodsThis study employs the finite element analysis method. A healthy model of the right lower limb was created using CT scans of an intact right lower limb from a healthy woman. Based on this model, a preoperative pathological model was generated by removing the meniscus and part of the articular cartilage. The UKA prosthesis was then applied to this model with five different bearing thicknesses: 5 mm, 7 mm, 10 mm, 11 mm, and 13 mm. To simulate various degrees of knee joint flexion, the femur was rotated relative to the knee joint's rotational axis, producing lower limb models at flexion angles of 0°, 30°, 60°, 90°, and 120°. We applied a constant force from the center of the femoral head to the center of the ankle joint to simulate lower limb loading during squatting. The simulations were conducted using Ansys 17.0. ResultsBoth overstuffing and understuffing increased the peak stress on the patellar cartilage, with overstuffing having a more pronounced effect. Compared to healthy and balanced models, overstuffed and understuffed models exhibited abnormal stress distribution and stress concentration in the patellar cartilage during knee flexion. ConclusionOverstuffing and understuffing lead to residual varus or valgus deformities after UKA, causing mechanical abnormalities in the patellofemoral joint. These abnormalities, characterized by irregular stress distribution and excessive stress, result in cartilage damage, exacerbate wear in the patellofemoral joint and consequently lead to the occurrence of anterior knee pain.

Effects of Panax notoginseng saponins on alleviating low shear induced endothelial inflammation and thrombosis via Piezo1 signalling

Ethnopharmacological relevancePanax notoginseng saponins (PNS) are the major effective components of Panax notoginseng (burk) F.H.Chen which is one of the classic promoting blood circulation herbs in traditional Chinese medicine. PNS is widely used in China for the treatment of cerebral ischemic stroke. Pathological low shear stress is a causal factor in endothelial inflammation and thrombosis. However, the mechanism of PNS against low shear related endothelial inflammation is still unclear. Aim to the studyThis study aims to investigate the effects of PNS against endothelial inflammation induced by low shear stress and to explore the underlying mechanical and biological mechanisms. Materials and methodsMouse model of carotid partial ligation for inducing low endothelial shear stress was established, the pharmacodynamic effect and mechanism of PNS against endothelial inflammation induced by low shear stress through Piezo1 were explored. Yoda1-evoked Piezo1 activation and expression in human umbilical vein endothelial cells (HUVECs) were determined at static condition. Microfluidic channel systems were used to apply shear stress on HUVECs and Piezo1 siRNA HUVECs to determine PECAM-1, p-YAP and VCAM-1 expression. And platelet rich plasma (PRP) was introduced to low shear treated endothelial cells surface to observe the adhesion and activation by fluorescence imaging and flowcytometry. ResultsPNS attenuated endothelial inflammation and improved blood flow in a reasonable dose response pattern in carotid partial ligation mouse model by influencing Piezo1 and PECAM-1 expression, while suppressing yes-associated protein (YAP) nuclear translocation. We found Piezo1 sensed abnormal shear stress and transduced these mechanical signals by different pathways in HUVECs, and PNS relieved endothelial inflammation induced by low shear stress through Piezo1. We also found Piezo1 signalling has interaction with PECAM-1 under low shear stress, which were involved in platelets adhesion to endothelial cells. Low shear stress increased YAP nuclear translocation and increased VCAM-1 expression in HUVECs which might activate platelets. PNS inhibited low shear induced Piezo1 and PECAM-1 expression and YAP nuclear translocation in HUVECs, furthermore inhibited platelet adhesion and activation on dysfunctional endothelial cells induced by low shear stress. ConclusionPNS ameliorated endothelial inflammation and thrombosis induced by low shear stress through modulation of the Piezo1 channel, PECAM-1 expression, and YAP nuclear translocation. PNS might serve as a potential therapeutic candidate for ameliorating endothelial inflammation induced by abnormal blood shear stress.

Changes of bone and articular cartilage in broilers with femoral head necrosis

Femoral head necrosis (FHN) in broilers is a common leg disorder in intensive poultry farming, giving rise to poor animal health and welfare. Abnormal mechanical stress in the hip joint is a risk factor for FHN, and articular cartilage is attracting increasing attention as a cushion and lubrication structure for the joint. In the present study, broilers aged 3 to 4 wk with FHN were divided into femoral head separation (FHS) and femoral head separation with growth plate lacerations (FHSL) groups, with normal broilers as control. The features of the hip joint, bone, and cartilage were assessed in FHN progression using devices including computed tomography (CT), atomic force microscope (AFM), and transmission electron microscopy (TEM). Broilers with FHN demonstrated decreased bone mechanical properties, narrow joint space, and thickened femoral head stellate structures. Notably, abnormal cartilage morphology was observed in FHN-affected broilers, characterized by increased cartilage thickness and rough cartilage surfaces. In addition, as FHN developed, cartilage surface friction and friction coefficient dramatically increased, while cartilage modulus and stiffness decreased. The ultramicro-damage occurred in chondrocytes and the extracellular matrix (ECM) of cartilage. Cell disintegration, abnormal mitochondrial accumulation, and oxidative stress damage were observed in chondrocytes. A notable decline in cartilage collagen content was observed in ECM during the initial stages of FHN, accompanied by a pronounced reduction in collagen fiber diameter and proteoglycan content as FHN progressed. Furthermore, the noticeable loosening of the collagen fiber structure and the appearance of type I collagen were noted in cartilage. In conclusion, there was a progressive decrease in bone quality and multifaceted damage of cartilage in the femoral head, which was closely linked to the severity of FHN in broilers.

Nuclear receptor Rev-erbα alleviates intervertebral disc degeneration by recruiting NCoR-HDAC3 co-repressor and inhibiting NLRP3 inflammasome.

Intervertebral discs (IVDs) are rhythmic tissues that experience daily low-load recovery. Notably, aging and abnormal mechanical stress predispose IVDs to degeneration due to dysrhythmia-induced disordered metabolism. Meanwhile, Rev-erbα acts as a transcriptional repressor in maintaining biorhythms and homeostasis; however, its function in IVD homeostasis and degeneration remains unclear. This study assessed the relationship between low Rev-erbα expression levels and IVD degeneration. Rev-erbα deficiency accelerated needle puncture or aging-induced IVD degeneration, characterized by increased extracellular matrix (ECM) catabolism and nucleus pulposus (NP) cell apoptosis. Mechanistically, Rev-erbα knockdown in NP cells aggravated rhIL1β-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, exacerbating the imbalanced ECM and NP cell apoptosis. Meanwhile, blocking NLRP3 inflammasome activation mitigated Rev-erbα deficiency and needle puncture-induced IVD degeneration. Particularly, Rev-erbα mediated the transcriptional repression of the NLRP3 inflammasome via the ligand heme-binding of nuclear receptor co-repressor (NCoR) and histone deacetylase 3 (HDAC3) complex. Thus, the increased expression of Rev-erbα in NP cells following short-term rhIL1β treatment failed to inhibit NLRP3 transcription in vitro owing to heme depletion. Pharmacological activation of Rev-erbα in vivo and in vitro alleviated IVD degeneration by altering the NLRP3 inflammasome. Taken together, targeting Rev-erbα may be a potential therapeutic strategy for alleviating IVD degeneration and its related diseases.

Interplay of miRNAs and molecular pathways in spaceflight-induced depression: Insights from a rat model using simulated complex space environment.

Depression is a significant concern among astronauts, yet the molecular mechanisms underlying spaceflight-induced depression remain poorly understood. MicroRNAs (miRNAs) have emerged as potential regulators of neuropsychiatric disorders, including depression, but their specific role in space-induced depression remains unexplored. This study aimed to elucidate the involvement of candidate miRNAs (miR-455-3p, miR-206-3p, miR-132-3p, miR-16-5p, miR-124-3p, and miR-145-3p) and their interaction with differentially expressed genes (DEGs) in the neurobiology of spaceflight-induced depressive behavior. Using a simulated space environmental model (SCSE) for 21 days, depressive behavior was induced in rats, and candidate miRNA expressions and DEGs in the cortex region were analyzed through qRT-PCR and HPLC, respectively. Results showed that SCSE-exposed rats exhibited depressive behaviors, including anhedonia, increased immobility, and anxiousness compared to controls. Further analysis revealed increased hydrogen peroxide levels and decreased superoxide dismutase levels in the SCSE group, indicating abnormal oxidative stress in the cerebral cortex. Moreover, miRNA analysis demonstrated significant upregulation of miR-455-3p, miR-206-3p, miR-132-3p, and miR-16-5p expression. Among the DEGs identified, the in silico analysis highlighted their involvement in crucial pathways such as glutamatergic signaling, GABA synaptic pathway, and calcium signaling, implicating their role in spaceflight-induced depression. Protein-protein interaction analysis identified hub genes, including DLG4, DLG3, GRIN1, GRIN2B, GRIN2A, SYNGAP1, DLGAP1, GRIK2, and GRIN3A, impacting neuronal dysfunction functions in the cortex region of SCSE depressive rats. DLG4 emerged as a core gene regulated by miR-455-3p and miR-206-3p. Overall, this study underscores the potential of miRNAs as biomarkers for mood disorders and neurological abnormalities associated with spaceflight, advancing health sciences, and space health care.

Identifying Diagnostic Markers and Constructing Predictive Models for Oxidative Stress in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease characterized by inflammation and neurodegeneration of the central nervous system. Despite the significant role of oxidative stress in the pathogenesis of MS, its precise molecular mechanisms remain unclear. This study utilized microarray datasets from the GEO database to analyze differentially expressed oxidative-stress-related genes (DE-OSRGs), identifying 101 DE-OSRGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicate that these genes are primarily involved in oxidative stress and immune responses. Through protein-protein interaction (PPI) network, LASSO regression, and logistic regression analyses, four genes (MMP9, NFKBIA, NFKB1, and SRC) were identified as being closely related to MS. A diagnostic prediction model based on logistic regression demonstrated good predictive power, as shown by the nomogram curve index and DAC results. An immune-cell infiltration analysis using CIBERSORT revealed significant correlations between these genes and immune cell subpopulations. Abnormal oxidative stress and upregulated expression of key genes were observed in the blood and brain tissues of EAE mice. A molecular docking analysis suggested strong binding potentials between the proteins of these genes and several drug molecules, including isoquercitrin, decitabine, benztropine, and curcumin. In conclusion, this study identifies and validates potential diagnostic biomarkers for MS, establishes an effective prediction model, and provides new insights for the early diagnosis and personalized treatment of MS.

Reduced expression of NUPR1 alleviates epilepsy progression via attenuating ER stress

Epilepsy is a neurological disorder characterized by recurring seizures. It is necessary to further understand the mechanisms of epilepsy in order to develop novel strategies for its prevention and treatment. Abnormal endoplasmic reticulum stress (ERS) activation is related to the pathogenesis of epilepsy. Nuclear protein 1, transcriptional regulator (NUPR1) is involved in ERS and it might play a role in epilepsy progression. In the present study, we generated an epileptic mouse model using pilocarpine induction. After 72 h of pilocarpine treatment, the expression of NUPR1 was increased in epileptic mice. Furthermore, NUPR1 knockdown reduced the number of spontaneous recurrent seizures and alleviated hippocampal damage in these mice. Interestingly, NUPR1 knockdown also reduced the protein expression levels of LC3, PINK1, and Parkin in the mitochondria, and decreased the PINK1 expression in hippocampus. Additionally, the expression of ERS-related proteins—cleaved caspase-12, ATF4, and CHOP—decreased in epileptic mice following NUPR1 knockdown. In vitro experiments showed that the absence of NUPR1 reduced the expression of ATF4, CHOP, and cleaved caspase-12 in hippocampal neurons and inhibited the neuron apoptosis. In all, our study suggested that NUPR1 maybe a potential molecular target for epilepsy therapy.

Sur7 mediates a novel pathway for PI4,5P2 regulation in C. albicans that promotes stress resistance and cell wall morphogenesis.

The human fungal pathogen Candida albicans can cause lethal systemic infections due to its ability to resist stress from the host and to undergo invasive hyphal growth. Previous studies showed that plasma membrane MCC/eisosome domains were important for virulence by promoting the ability of Sur7 to mediate normal cell wall morphogenesis and stress resistance. The sur7Δ mutant displayed abnormal clusters of PI4,5P2, suggesting that misregulation of this lipid underlies the sur7Δ phenotype. To test this, we increased PI4,5P2 levels by deleting combinations of the three PI4,5P2 5' phosphatase genes (INP51, INP52, and INP54) and found that some combinations, such as inp51Δ inp52Δ, gave phenotypes similar the sur7Δ mutant. In contrast, deleting one copy of MSS4, the gene that encodes the 5' kinase needed to create PI4,5P2, reduced the abnormal PI4,5P2 clusters and also decreased the abnormal cell wall and stress sensitive phenotypes of the sur7Δ mutant. Additional studies support a model that the abnormal PI4,5P2 patches recruit septin proteins, which in turn promote aberrant cell wall growth. These results identify Sur7 as a novel regulator of PI4,5P2 and highlight the critical role of PI4,5P2 in the regulation of C. albicans virulence properties.

Augmented Cortisol and Antiglucocorticoid Therapy in Mood Disorders: the Hippocampus as a Potential Drug Target

The pathophysiology of many mood disorders is closely relatedto abnormal stress response associated with the dysfunction of thehypothalamic–pituitary–adrenal (HPA) axis and cortisol overproduction. Thehippocampus, a key structure of the limbic system responsible forboth cognitive and emotional spheres, is selectively vulnerableto excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration.The antiGC therapy of psychiatric diseases, in particular depressivedisorders, may be a useful additional treatment. Among other approaches,targeting glucocorticoid receptors, abounded in the hippocampus,is regarded as highly promising. However, though the preclinicaldata provide fairly firm evidence to the concept of antiGC therapyfor stress-related diseases, clinical studies still are at the proof-of-conceptstage. Noteworthy, chronic GC excess is associated not only withmood diseases, but also with cognitive decline, metabolic disorders,diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviateaffective symptoms, cognitive disturbances, GC and insulin resistanceand adverse side effects of conventional drugs through beneficialeffects on the hippocampus mitigating its dysfunction and neurodegeneration,neuroinflammation, and impairment of neurogenesis. Since stress/GC-associatedneuroinflammation-mediated pathology of the limbic system and, specifically,the hippocampus, is a general feature typical for many brain diseases,the concept of antiGC therapy may be extended, tested and validatedin a wider spectrum of cerebral pathologies.

Well-Being As a Component Of Subjective Health Assessment In Students

Introduction. The effectiveness of professional education in students largely depends on subjective health assessments such as well-being, which affects psychological resistance in stressful situations and unusual conditions; prevention of maladjustment, neurotic disorders, and abnormal stress responses, and adaptability. Identification of aspects indicating decline in well-being (sleep-wake disorders, weakness of volition; autonomic dysfunction, and emotional dysregulation; signs of addiction; physical fatigue and mental exhaustion; psychological fatigue and lack of energy; fears and anxiety) is aimed at being the basis for a new program on mental health promotion and mental disorder prevention. Purpose. The goal was to determine the main aspects of well-being as a component of subjective health assessment in students. Methods and materials. A total of 712 adult students from Moscow universities participated in the study on a voluntary basis. In order to identify sleep-wake disorders, autonomic dysfunction and emotional dysregulation, signs of addiction, psychological fatigue and lack of energy, anxiety, and fears, the participants were provided with two questionnaires: “Mood is health,” elaborated by G. S. Odinokov, and “Symptomatic questionnaire of well-being,” developed by A. Volkov and N. E. Vodopyanova. Then, the data were processed using the Pearson correlation coefficient and the Chaddock–Snedecor scale. Results. It was revealed that the level of well-being as a component of subjective health assessment in students was above-average. There was an average level of sleep-wake disorders, emotional dysregulation, psychological fatigue and lack of energy, anxiety and fears, as well as a below-average level of weakness of volition, autonomic dysfunction and signs of addiction. A strong correlation between the total and final results of well-being aspects and sleep-wake disorders, weakness of volition, autonomic dysfunction and emotional dysregulation, signs of addiction, psychological fatigue and lack of energy, fears and anxiety indicates that the lower these components, the higher the well-being.

Biomechanism of abnormal stress on promoting osteoarthritis of temporomandibular joint through Piezo1 ion channel.

This study aimed to investigate whether flow fluid shear stress (FFSS)-mediated signal transduction affects the function of Piezo1 ion channel in chondrocyte and to further explore the role of mechanical overloading in development of temporomandibular joint osteoarthritis (TMJ OA). Immunohistochemical staining was used to determine the expression of Piezo1 in TMJ OA tissue collected from rat unilateral anterior crossbite (UAC) models. Chondrocytes harvested from normal adult SD rats were treated with FFSS (0, 4, 8, 12 dyn/cm2) invitro. Immunofluorescent staining, real-time polymerase chain reaction, western blotting, flow cytometry and phalloidin assay were performed to detect the changes of cellular morphology as well as the expression of Piezo1 and certain pro-inflammatory and degradative factors in chondrocyte. Immunohistochemical analysis revealed that significantly increased Piezo1 expression was associated with UAC stimulation (p < .05). As applied FFSS escalated (4, 8 and 12 dyn/cm2), the expression levels of Piezo1, ADAMTS-5, MMP-13 and Col-X gradually increased, compared with the non-FFSS group (p < .05). Administering Piezo1 ion channel inhibitor to chondrocytes beforehand, it was observed that expression of ADAMTS-5, MMP-13 and Col-X was substantially decreased following FFSS treatment (p < .05) and the effect of cytoskeletal thinning was counteracted. The activated Piezo1 ion channel enhanced intracellular Ca2+ excess in chondrocytes during abnormal mechanical stimulation and the increased intracellular Ca2+ thinned the cytoskeleton of F-actin. Mechanical overloading activates Piezo1 ion channel to promote pro-inflammation and degradation and to increase Ca2+ concentration in chondrocyte, which may eventually result in TMJ OA.

Prognostic Value of Stress Perfusion Cardiac MRI in Cardiovascular Disease: A Systematic Review and Meta-Analysis of the Effects of the Scanner, Stress Agent, and Analysis Technique.

Purpose To perform a systematic review and meta-analysis to assess the prognostic value of stress perfusion cardiac MRI in predicting cardiovascular outcomes. Materials and Methods A systematic literature search from the inception of PubMed, Embase, Web of Science, and China National Knowledge Infrastructure until January 2023 was performed for articles that reported the prognosis of stress perfusion cardiac MRI in predicting cardiovascular outcomes. The quality of included studies was assessed using the Quality in Prognosis Studies tool. Reported hazard ratios (HRs) of univariable regression analyses with 95% CIs were pooled. Comparisons were performed across different analysis techniques (qualitative, semiquantitative, and fully quantitative), magnetic field strengths (1.5 T vs 3 T), and stress agents (dobutamine, adenosine, and dipyridamole). Results Thirty-eight studies with 58 774 patients with a mean follow-up time of 53 months were included. There were 1.9 all-cause deaths and 3.5 major adverse cardiovascular events (MACE) per 100 patient-years. Stress-inducible ischemia was associated with a higher risk of all-cause mortality (HR: 2.55 [95% CI: 1.89, 3.43]) and MACE (HR: 3.90 [95% CI: 2.69, 5.66]). For MACE, pooled HRs of qualitative, semiquantitative, and fully quantitative methods were 4.56 (95% CI: 2.88, 7.22), 3.22 (95% CI: 1.60, 6.48), and 1.78 (95% CI: 1.39, 2.28), respectively. For all-cause mortality, there was no evidence of a difference between qualitative and fully quantitative methods (P = .79). Abnormal stress perfusion cardiac MRI findings remained prognostic when subgrouped based on underlying disease, stress agent, and field strength, with HRs of 3.54, 2.20, and 3.38, respectively, for all-cause mortality and 3.98, 3.56, and 4.21, respectively, for MACE. There was no evidence of subgroup differences in prognosis between field strengths or stress agents. There was significant heterogeneity in effect size for MACE outcomes in the subgroups assessing qualitative versus quantitative stress perfusion analysis, underlying disease, and field strength. Conclusion Stress perfusion cardiac MRI is valuable for predicting cardiovascular outcomes, regardless of the analysis method, stress agent, or magnetic field strength used. Keywords: MR-Perfusion, MRI, Cardiac, Meta-Analysis, Stress Perfusion, Cardiac MR, Cardiovascular Disease, Prognosis, Quantitative © RSNA, 2024 Supplemental material is available for this article.

M1 macrophage-derived exosomes promote intervertebral disc degeneration by enhancing nucleus pulposus cell senescence through LCN2/NF-κB signaling axis

Intervertebral disc degeneration (IVDD) is the primary factor contributing to low back pain (LBP). Unlike elderly patients, many young IVDD patients usually have a history of trauma or long-term abnormal stress, which may lead to local inflammatory reaction causing by immune cells, and ultimately accelerates degeneration. Research has shown the significance of M1-type macrophages in IVDD; nevertheless, the precise mechanism and the route by which it influences the function of nucleus pulposus cell (NPC) remain unknown. Utilizing a rat acupuncture IVDD model and an NPC degeneration model induced by lipopolysaccharide (LPS), we investigated the function of M1 macrophage-derived exosomes (M1-Exos) in IVDD both in vivo and in vitro in this study. We found that M1-Exos enhanced LPS-induced NPC senescence, increased the number of SA-β-gal-positive cells, blocked the cell cycle, and promoted the activation of P21 and P53. M1-Exos derived from supernatant pretreated with the exosome inhibitor GW4869 reversed this result in vivo and in vitro. RNA-seq showed that Lipocalin2 (LCN2) was enriched in M1-Exos and targeted the NF-κB pathway. The quantity of SA-β-gal-positive cells was significantly reduced with the inhibition of LCN2, and the expression of P21 and P53 in NPCs was decreased. The same results were obtained in the acupuncture-induced IVDD model. In addition, inhibition of LCN2 promotes the expression of type II collagen (Col-2) and inhibits the expression of matrix metalloproteinase 13 (MMP13), thereby restoring the equilibrium of metabolism inside the extracellular matrix (ECM) in vitro and in vivo. In addition, the NF-κB pathway is crucial for regulating M1-Exo-mediated NPC senescence. After the addition of M1-Exos to LPS-treated NPCs, p-p65 activity was significantly activated, while si-LCN2 treatment significantly inhibited p-p65 activity. Therefore, this paper demonstrates that M1 macrophage-derived exosomes have the ability to deliver LCN2, which activates the NF-κB signaling pathway, and exacerbates IVDD by accelerating NPC senescence. This may shed new light on the mechanism of IVDD and bring a fresh approach to IVDD therapy.Graphical

Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling

Degenerated endplate appears with cheese-like morphology and sensory innervation, contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.1 However, the origin and development mechanism of the cheese-like morphology remain unclear. Here in this study, we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change. Transcriptome sequencing of the endplate chondrocytes under abnormal stress revealed that the Hippo signaling was key for this process. Activation of Hippo signaling or knockout of the key gene Yap1 in the cartilage endplate severed the cheese-like morphological change and disc degeneration after lumbar spine instability (LSI) surgery, while blocking the Hippo signaling reversed this process. Meanwhile, transcriptome sequencing data also showed osteoclast differentiation related gene set expression was up regulated in the endplate chondrocytes under abnormal mechanical stress, which was activated after the Hippo signaling. Among the discovered osteoclast differentiation gene set, CCL3 was found to be largely released from the chondrocytes under abnormal stress, which functioned to recruit and promote osteoclasts formation for cartilage endplate remodeling. Over-expression of Yap1 inhibited CCL3 transcription by blocking its promoter, which then reversed the endplate from remodeling to the cheese-like morphology. Finally, LSI-induced cartilage endplate remodeling was successfully rescued by local injection of an AAV5 wrapped Yap1 over-expression plasmid at the site. These findings suggest that the Hippo signaling induced osteoclast gene set activation in the cartilage endplate is a potential new target for the management of instability induced low back pain and lumbar degeneration.

Picein alleviates oxidative stress and promotes bone regeneration in osteoporotic bone defect by inhibiting ferroptosis via Nrf2/HO-1/GPX4 pathway.

Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to abnormal oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation, making the OP-related bone healing a significant clinical challenge. As the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) is closely related to bone regeneration; currently, this study assessed the effects of Picein on BMSCs in vitro and bone regeneration in osteoporotic bone defect in vivo. Cell viability was determined by CCK-8 assay. The production of (ROS), malonaldehyde, superoxide dismutase activities, and glutathione was evaluated by using commercially available kits, and a flow cytometry analysis was adopted to detect macrophage polarization. Osteogenic capacity of BMSCs was evaluated by alkaline phosphatase (ALP) activity, ALP staining, and Alizarin red S staining. The expression of osteogenic-related proteins (OPN, Runx-2, OCN) and osteogenic-related genes (ALP, BMP-4, COL-1, and Osterix) were evaluated by Western blotting and real-time PCR (RT-PCR). In addition, proliferation, migration ability, and angiogenic capacity of human umbilical vein endothelial cells (HUVECs) were evaluated by EdU staining, scratch test, transwell assay, and tube formation assay, respectively. Angiogenic-related genes (VEGF, vWF, CD31) were also evaluated by RT-PCR. Results showed that Picein alleviated erastin-induced oxidative stress, enhanced osteogenic differentiation capacity of BMSCs, angiogenesis of HUVECs, and protects cells against ferroptosis through Nrf2/HO-1/GPX4 axis. Moreover, Picein regulate immune microenvironment by promoting the polarization of M2 macrophages in vitro. In addition, Picein also reduce the inflammation levels and promotes bone regeneration in osteoporotic bone defect in OP rat models in vivo. Altogether, these results suggested that Picein can promote bone regeneration and alleviate oxidative stress via Nrf2/HO-1/GPX4 pathway, offering Picein as a novel antioxidant agent for treating osteoporotic bone defect.