Primary Pathological Mechanism Research Articles

Role of HDAC3 in the epithelial-mesenchymal transition of retinal pigment epithelium cells: Implications for proliferative vitreoretinopathy

Proliferative vitreoretinopathy(PVR) is a type of fibrotic eye disease with a poor clinical prognosis. Increasing evidence has shown that the primary pathological mechanism of PVR is the epithelial-mesenchymal transition(EMT) of retinal pigment epithelium(RPE) cells. Histone deacetylase 3(HDAC3) is a crucial enzyme involved in regulating the acetylation level of proteins. Several studies have reported associations between HDAC3 levels and EMT in various tumors; however, the specific effect of HDAC3 on PVR remains largely unknown. The current study found that HDAC3 was highly expressed in both human PVR membranes and experimental PVR. In vivo, silencing HDAC3 in RPE cells reduced their ability to develop experimental PVR through suppression of EMT. In vitro, inhibition of HDAC3 in RPE cells suppressed EGF-mediated cell proliferation, migration, and EMT. Additionally, overexpression of HDAC3 in RPE cells promoted cell proliferation, migration, and EMT. Mechanistically, the results of chromatin immunoprecipitation(ChIP) and luciferase assays revealed a direct binding of the transcription factor MAZ to the promoter region of HDAC3, thereby promoting its transcription. Furthermore, It was demonstrated that HDAC3 facilitated EMT by interacting with AKT and contributing to its deacetylation. In summary, our findings indicated the involvement of HDAC3 in the EMT of RPE cells, as well as its role in PVR through the regulation of the AKT pathway. These results suggested that targeting HDAC3 could be a potential strategy for preventing and treating PVR.

Polysialic acid driving cardiovascular targeting co-delivery 1,8-cineole and miR-126 to synergistically alleviate lipopolysaccharide-induced acute cardiovascular injury

Infection-induced cardiovascular damage is the primary pathological mechanism underlying septic cardiac dysfunction. This condition affects the majority of patients in intensive care unit and has an unfavorable prognosis due to the lack of effective therapies available. Vascular cell adhesion molecule-1 (VCAM-1) plays a vital role in coordinating the inflammatory response and recruitment of leukocytes in cardiac tissue, making it a potential target for developing novel therapies. MicroRNA-126 (miR-126) has been shown to downregulate VCAM-1 expression in endothelial cells, reducing leukocyte adhesion and exerting anti-inflammatory effects. Therefore, this work described a polysialic acid (PSA) modified ROS-responsive nanosystem to targeted co-delivery 1,8-Cineole and miR-126 for mitigating septic cardiac dysfunction. The nanosystem consists of 1,8-Cineole nanoemulsion (CNE) conjugated with PEI/miR126 complex by a ROS-sensitive linker, with PSA on its surface to facilitate targeted delivery via specific interactions with selectins on endothelial cells. CNE has demonstrated protective effects against inflammation in the cardiovascular system and synergistic anti-inflammatory effects when combined with miR-126. The targeted nanosystem successfully delivered miR-126 and 1,8-Cineole to the injured heart tissues and vessels, reducing inflammatory responses and improving cardiac function. In summary, this work provides a promising therapy for alleviating the inflammatory response in sepsis while boosting cardiovascular protection.

A cross-sectional study comparing the expression of DNA repair molecules in subjects with and without atherosclerotic plaques.

Atherosclerosis, serving as the primary pathological mechanism at the core of cardiovascular disease, is now widely acknowledged to be associated with DNA damage and repair, contributing to atherosclerotic plaque formation. Therefore, molecules involved in the DNA repair process may play an important role in the progression of atherosclerosis. Our research endeavors to explore the contributions of specific and interrelated molecules involved in DNA repair (APE1, BRCA1, ERCC2, miR-221-3p, miR-145-5p, and miR-155-5p) to the development of atherosclerotic plaque and their interactions with each other. Gene expression study was conducted using the real-time polymerase chain reaction (qRT-PCR) method on samples from carotid artery atherosclerotic plaques and nonatherosclerotic internal mammary arteries obtained from 50 patients diagnosed with coronary artery disease and carotid artery disease. Additionally, 50 healthy controls were included for the determination of 8-hydroxy-2'-deoxyguanosine (8-OHdG). Although no difference was observed in mRNA gene expressions, we noted a decrease in miR-155-5p gene expression (p = 0.003) and an increase in miR-221-3p gene expression (p = 0.015) in plaque samples, while miR-145-5p gene expression remained unchanged (p = 0.57). Regarding serum 8-OHdG levels, patients exhibited significantly higher levels (1111.82 ± 28.64) compared to controls (636.23 ± 24.23) (p < 0.0001). In our study demonstrating the role of miR-155-5p and miR-221-3p in atherosclerosis, we propose that these molecules are potential biomarkers and therapeutic targets for coronary artery diseases and carotid artery disease.

Modulation of the Nogo signaling pathway to overcome amyloid-β-mediated neurite inhibition in human pluripotent stem cell-derived neurites.

Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer's disease. The accumulation of amyloid-β peptides, a key hallmark of Alzheimer's disease, is believed to induce neuritic abnormalities, including reduced growth, extension, and abnormal growth cone morphology, all of which contribute to decreased connectivity. However, the precise cellular and molecular mechanisms governing this response remain unknown. In this study, we used an innovative approach to demonstrate the effect of amyloid-β on neurite dynamics in both two-dimensional and three-dimensional culture systems, in order to provide more physiologically relevant culture geometry. We utilized various methodologies, including the addition of exogenous amyloid-β peptides to the culture medium, growth substrate coating, and the utilization of human-induced pluripotent stem cell technology, to investigate the effect of endogenous amyloid-β secretion on neurite outgrowth, thus paving the way for potential future applications in personalized medicine. Additionally, we also explore the involvement of the Nogo signaling cascade in amyloid-β-induced neurite inhibition. We demonstrate that inhibition of downstream ROCK and RhoA components of the Nogo signaling pathway, achieved through modulation with Y-27632 (a ROCK inhibitor) and Ibuprofen (a Rho A inhibitor), respectively, can restore and even enhance neuronal connectivity in the presence of amyloid-β. In summary, this study not only presents a novel culture approach that offers insights into the biological process of neurite growth and inhibition, but also proposes a specific mechanism for reduced neural connectivity in the presence of amyloid-β peptides, along with potential intervention points to restore neurite growth. Thereby, we aim to establish a culture system that has the potential to serve as an assay for measuring preclinical, predictive outcomes of drugs and their ability to promote neurite outgrowth, both generally and in a patient-specific manner.

Inflammation and coronary microvascular disease: relationship, mechanism and treatment.

Coronary microvascular disease (CMVD) is common in patients with cardiovascular risk factors and is linked to an elevated risk of adverse cardiovascular events. Although modern medicine has made significant strides in researching CMVD, we still lack a comprehensive understanding of its pathophysiological mechanisms due to its complex and somewhat cryptic etiology. This greatly impedes the clinical diagnosis and treatment of CMVD. The primary pathological mechanisms of CMVD are structural abnormalities and/or dysfunction of coronary microvascular endothelial cells. The development of CMVD may also involve a variety of inflammatory factors through the endothelial cell injury pathway. This paper first reviews the correlation between the inflammatory response and CMVD, then summarizes the possible mechanisms of inflammatory response in CMVD, and finally categorizes the drugs used to treat CMVD based on their effect on the inflammatory response. We hope that this paper draws attention to CMVD and provides novel ideas for potential therapeutic strategies based on the inflammatory response.

Engineering Nanoplatforms for Theranostics of Atherosclerotic Plaques.

Atherosclerotic plaque formation is considered the primary pathological mechanism underlying atherosclerotic cardiovascular diseases, leading to severe cardiovascular events such as stroke, acute coronary syndromes, and even sudden cardiac death. Early detection and timely intervention of plaques are challenging due to the lack of typical symptoms in the initial stages. Therefore, precise early detection and intervention play a crucial role in risk stratification of atherosclerotic plaques and achieving favorable post-interventional outcomes. The continuously advancing nanoplatforms have demonstrated numerous advantages including high signal-to-noise ratio, enhanced bioavailability, and specific targeting capabilities for imaging agents and therapeutic drugs, enabling effective visualization and management of atherosclerotic plaques. Motivated by these superior properties, various noninvasive imaging modalities for early recognition of plaques in the preliminary stage of atherosclerosis are comprehensively summarized. Additionally, several therapeutic strategies are proposed to enhance the efficacy of treating atherosclerotic plaques. Finally, existing challenges and promising prospects for accelerating clinical translation of nanoplatform-based molecular imaging and therapy for atherosclerotic plaques are discussed. In conclusion, this review provides an insightful perspective on the diagnosis and therapy of atherosclerotic plaques.

A novel diabetic foot ulcer diagnostic model: identification and analysis of genes related to glutamine metabolism and immune infiltration

BackgroundDiabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes, with vascular changes, neuropathy, and infections being the primary pathological mechanisms. Glutamine (Gln) metabolism has been found to play a crucial role in diabetes complications. This study aims to identify and validate potential Gln metabolism biomarkers associated with DFU through bioinformatics and machine learning analysis.MethodsWe downloaded two microarray datasets related to DFU patients from the Gene Expression Omnibus (GEO) database, namely GSE134431, GSE68183, and GSE80178. From the GSE134431 dataset, we obtained differentially expressed Gln-metabolism related genes (deGlnMRGs) between DFU and normal controls. We analyzed the correlation between deGlnMRGs and immune cell infiltration status. We also explored the relationship between GlnMRGs molecular clusters and immune cell infiltration status. Notably, WGCNA to identify differentially expressed genes (DEGs) within specific clusters. Additionally, we conducted GSVA to annotate enriched genes. Subsequently, we constructed and screened the best machine learning model. Finally, we validated the predictions' accuracy using a nomogram, calibration curves, decision curve analysis (DCA), and the GSE134431, GSE68183, and GSE80178 dataset.ResultsIn both the DFU and normal control groups, we confirmed the presence of deGlnMRGs and an activated immune response. From the GSE134431 dataset, we obtained 20 deGlnMRGs, including CTPS1, NAGS, SLC7A11, GGT1, GCLM, RIMKLA, ARG2, ASL, ASNS, ASNSD1, PPAT, GLS2, GLUD1, MECP2, ASS1, PRODH, CTPS2, ALDH5A1, DGLUCY, and SLC25A12. Furthermore, two clusters were identified in DFU. Immune infiltration analysis indicated the presence of immune heterogeneity in these two clusters. Additionally, we established a Support Vector Machine (SVM) model based on 5 genes (R3HCC1, ZNF562, MFN1, DRAM1, and PTGDS), which exhibited excellent performance on the external validation datasetGSE134431, GSE68183, and GSE80178 (AUC = 0.929).ConclusionThis study has identified five Gln metabolism genes associated with DFU, revealing potential novel biomarkers and therapeutic targets for DFU. Additionally, the infiltration of immune-inflammatory cells plays a crucial role in the progression of DFU.

BMP4 inhibits corneal neovascularization by interfering with tip cells in angiogenesis

Corneal neovascularization (CNV) can lead to impaired corneal transparency, resulting in vision loss or blindness. The primary pathological mechanism underlying CNV is an imbalance between pro-angiogenic and anti-angiogenic factors, with inflammation playing a crucial role. Notably, a vascular endothelial growth factor（VEGF）-A gradient triggers the selection of single endothelial cells（ECs） into primary tip cells that guide sprouting, while a dynamic balance between tip and stalk cells maintains a specific ratio to promote CNV. Despite the central importance of tip-stalk cell selection and shuffling, the underlying mechanisms remain poorly understood. In this study, we examined the effects of bone morphogenetic protein 4 (BMP4) on VEGF-A-induced lumen formation in human umbilical vein endothelial cells (HUVECs) and CD34-stained tip cell formation. In vivo, BMP4 inhibited CNV caused by corneal sutures. This process was achieved by BMP4 decreasing the protein expression of VEGF-A and VEGFR2 in corneal tissue after corneal suture injury. By observing the ultrastructure of the cornea, BMP4 inhibited the sprouting of tip cells and brought forward the appearance of intussusception. Meanwhile, BMP4 attenuated the inflammatory response by inhibiting neutrophil extracellular traps （NETs）formation through the NADPH oxidase-2（NOX-2）pathway. Our results indicate that BMP4 inhibits the formation of tip cells by reducing the generation of NETs, disrupting the dynamic balance of tip and stalk cells and thereby inhibiting CNV, suggesting that BMP4 may be a potential therapeutic target for CNV.

Clinical severity in Parkinson's disease is determined by decline in cortical compensation.

Dopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e. bradykinesia) in Parkinson's disease. However, striatal dopamine loss fails to account for interindividual differences in motor phenotype and rate of decline, implying that the expression of motor symptoms depends on additional mechanisms, some of which may be compensatory in nature. Building on observations of increased motor-related activity in the parieto-premotor cortex of Parkinson patients, we tested the hypothesis that interindividual differences in clinical severity are determined by compensatory cortical mechanisms and not just by basal ganglia dysfunction. Using functional MRI, we measured variability in motor- and selection-related brain activity during a visuomotor task in 353 patients with Parkinson's disease (≤5 years disease duration) and 60 healthy controls. In this task, we manipulated action selection demand by varying the number of possible actions that individuals could choose from. Clinical variability was characterized in two ways. First, patients were categorized into three previously validated, discrete clinical subtypes that are hypothesized to reflect distinct routes of α-synuclein propagation: diffuse-malignant (n = 42), intermediate (n = 128) or mild motor-predominant (n = 150). Second, we used the scores of bradykinesia severity and cognitive performance across the entire sample as continuous measures. Patients showed motor slowing (longer response times) and reduced motor-related activity in the basal ganglia compared with controls. However, basal ganglia activity did not differ between clinical subtypes and was not associated with clinical scores. This indicates a limited role for striatal dysfunction in shaping interindividual differences in clinical severity. Consistent with our hypothesis, we observed enhanced action selection-related activity in the parieto-premotor cortex of patients with a mild-motor predominant subtype, both compared to patients with a diffuse-malignant subtype and controls. Furthermore, increased parieto-premotor activity was related to lower bradykinesia severity and better cognitive performance, which points to a compensatory role. We conclude that parieto-premotor compensation, rather than basal ganglia dysfunction, shapes interindividual variability in symptom severity in Parkinson's disease. Future interventions may focus on maintaining and enhancing compensatory cortical mechanisms, rather than only attempting to normalize basal ganglia dysfunction.

Tanshinone IIA alleviates chondrocyte apoptosis and extracellular matrix degeneration by inhibiting ferroptosis.

Articular cartilage degeneration caused by chondrocyte damage is the primary pathological mechanism of osteoarthritis (OA). Oxidative stress is correlated with chondrocyte injury by potentiating ferroptosis, a newly identified form of cell death. Given the effects of Tanshinone IIA (Tan IIA) on alleviating oxidative stress, we further explored whether Tan IIA inhibited chondrocyte death and cartilage degeneration by decreasing ferroptosis. ATDC5 chondrocytes were treated with lipopolysaccharides (LPS) and Tan IIA, and cell viability was assessed using cell counting kit-8 (CCK-8) assays. Matrix metalloproteinase-13 (MMP13), a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS5), and type II collagen (Col II) levels were measured using quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, and immunofluorescence (IF) analysis. We demonstrated that Tan IIA treatment prominently increased ATDC5 cell viability and decreased cell apoptosis in the presence of LPS-induced stress. MMP13 and ADAMTS5 expression was increased, and Col II expression was decreased in ATDC5 cells after LPS stimulation, whereas these changes were reversed by Tan IIA. Mechanistically, Tan IIA inhibited LPS-induced ferroptosis in ATDC5 cells, as indicated by decreased levels of iron, reactive oxygen species, and malondialdehyde and increased GSH levels. Importantly, a ferroptosis agonist partially abrogated the effect of Tan IIA on alleviating chondrocyte damage and death. Taken together, these results suggest that Tan IIA ameliorates chondrocyte apoptosis and cartilage degeneration by inhibiting ferroptosis and may be a potential therapeutic agent for OA.

Dual Efficacy of a Catalytic Anti-Oligomeric Aβ42 scFv Antibody in Clearing Aβ42 Aggregates and Reducing Aβ Burden in the Brains of Alzheimer's Disease Mice.

One of the primary pathological mechanisms underlying Alzheimer's disease (AD) is the deposition of amyloid β-protein (Aβ42) aggregates in the brain. In this study, a catalytic anti-oligomeric Aβ42 scFv antibody, HS72, was identified by screening a human antibody library, its ability to degrade Aβ42 aggregates was defined, and its role in the reduction of Aβ burden in the AD mouse brain was evaluated. HS72 specifically targeted Aβ42 aggregates with an approximately 14-68kDa range. Based on molecular docking simulations, HS72 likely catalyzed the hydrolytic cleavage of the His13-His14 bond of Aβ42 chains in an Aβ42 aggregate unit, releasing N/C-terminal fragments and Aβ42 monomers. Degradation of Aβ42 aggregates by HS72 triggered a considerable disassembly or breakdown of the Aβ42 aggregates and greatly reduced their neurotoxicity. Aβ deposit/plaque load in the hippocampus of AD mice was reduced by approximately 27% after 7 days (once daily) of intravenous HS72 administration, while brain neural cells were greatly restored and their morphology was drastically improved. The above efficacies of HS72 were all greater than those of HT7, a simple anti-oligomeric Aβ42 scFv antibody. Although a catalytic anti-oligomeric Aβ42 antibody may have a slightly lower affinity for Aβ42 aggregates than a simple anti-oligomeric Aβ42 antibody, the former may display a stronger overall efficacy (dual efficacy of induction and catalysis) than the latter (induction alone) in clearing Aβ42 aggregates and improving histopathological changes in AD brain. Our findings on the catalytic antibody HS72 indicate the possibility of functional evolution of anti-oligomeric Aβ42 antibodies and provide novel insights into the immunotherapy of AD.

Clinical and Molecular Insights into Gastrointestinal Dysfunction in Myotonic Dystrophy Types 1 & 2.

Myotonic dystrophy (DM) is a highly variable, multisystemic disorder that clinically affects one in 8000 individuals. While research has predominantly focused on the symptoms and pathological mechanisms affecting striated muscle and brain, DM patient surveys have identified a high prevalence for gastrointestinal (GI) symptoms amongst affected individuals. Clinical studies have identified chronic and progressive dysfunction of the esophagus, stomach, liver and gallbladder, small and large intestine, and rectum and anal sphincters. Despite the high incidence of GI dysmotility in DM, little is known regarding the pathological mechanisms leading to GI dysfunction. In this review, we summarize results from clinical and molecular analyses of GI dysfunction in both genetic forms of DM, DM type 1 (DM1) and DM type 2 (DM2). Based on current knowledge of DM primary pathological mechanisms in other affected tissues and GI tissue studies, we suggest that misregulation of alternative splicing in smooth muscle resulting from the dysregulation of RNA binding proteins muscleblind-like and CUGBP-elav-like is likely to contribute to GI dysfunction in DM. We propose that a combinatorial approach using clinical and molecular analysis of DM GI tissues and model organisms that recapitulate DM GI manifestations will provide important insight into defects impacting DM GI motility.

Amniotic band syndrome: A case series

Introduction: Amniotic band sequence (ABS) is a constellation of congenital anomalies that can be seen in infants without any known genetic mutations. Amniotic band syndrome is thought to be responsible for 1/70 still births. There are two leading theories for proposed pathogenesis of ABS, commonly referred to as “extrinsic” and “intrinsic” models. Case Series: Our case series depicts four deliveries at two large military hospitals. Each of our patient case demonstrates the spectrum of ABS and supports the extrinsic theory as the primary mechanism. The first case resulting in lateral encephalocele with a complex facial cleft and subsequent intrauterine fetal demise. The second patient case resulting in fetal unilateral lower extremity limb reduction. The third patient case resulting in premature prelabor rupture of membranes and delivery at 29 weeks with pedal amputation. The fourth and final patient case resulted in a lethal limb-body-wall defect with extravasation of visceral organs and a sacral myelomeningocele. Conclusion: All four of our cases lend support to the extrinsic theory as the primary pathological mechanism. Each of our patients had risk factors for potential hypoxic injury and subsequent amniotic band formation.

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Intervertebral disc degeneration (IDD) has been considered as the primary pathological mechanism that underlies low back pain. Understanding the molecular mechanisms underlying human IDD is imperative for making strategies to treat IDD-related diseases. Herein, we report the molecular programs, lineage progression patterns, and paths of cellular communications during the progression of IDD using single-cell RNA sequencing (scRNA-seq) on nucleus pulposus (NP) cells from patients with different grades of IDD undergoing discectomy. New subtypes of cells and cell-type-specific gene signatures of the metabolic homeostatic NP cells (Met NPC), adhesive NP cells (Adh NPC), inflammatory response NP cells (IR NPC), endoplasmic reticulum stress NP cells (ERS NPC), fibrocartilaginous NP cells (Fc NPC), and CD70 and CD82+ progenitor NP cells (Pro NPC) were identified. In the late stage of IDD, the IR NPC and Fc NPC account for a large proportion of NPC. Importantly, immune cells including macrophages, T cells, myeloid progenitors, and neutrophils were also identified, and further analysis showed that significant intercellular interaction between macrophages and Pro NPC occurred via MIF (macrophage migration inhibitory factor) and NF-kB signaling pathways during the progression of IDD. In addition, dynamic polarization of macrophage M1 and M2 cell subtypes was found in the progression of IDD, and gene set functional enrichment analysis suggested a significant role of the macrophage polarization in regulating cell metabolism, especially the Pro NPC. Finally, we found that the NP cells in the late degenerative stage were mainly composed of the cell types related to inflammatory and endoplasmic reticulum (ER) response, and fibrocartilaginous activity. Our results provided new insights into the identification of NP cell populations at single-cell resolution and at the relatively whole-transcriptome scale, accompanied by cellular communications between immune cells and NP cells, and discriminative markers in relation to specific cell subsets. These new findings present clues for effective and functional manipulation of human IDD-related bioremediation and healthcare.

Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin (FXN) gene. The most prevalent mutation is a GAA expansion in the first intron of the gene causing decreased frataxin expression. Some patients present the GAA expansion in one allele and a missense mutation in the other allele. One of these mutations, FXNI154F, was reported to result in decreased content of mature frataxin and increased presence of an insoluble intermediate proteoform in cellular models. By introducing this mutation into the murine Fxn gene (I151F, equivalent to human I154F) we have now analyzed the consequences of this pathological point mutation in vivo. We have observed that FXNI151F homozygous mice present low frataxin levels in all tissues, with no evidence of insoluble proteoforms. Moreover, they display neurological deficits resembling those observed in FA patients. Biochemical analysis of heart, cerebrum and cerebellum have revealed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in antioxidant defenses. These mitochondrial alterations are more marked in the nervous system than in heart, precede the appearance of neurological symptoms, and are similar to those observed in other FA models. We conclude that the primary pathological mechanism underlying the I151F mutation is frataxin deficiency, like in patients carrying GAA expansions. Therefore, patients carrying the I154F mutation would benefit from frataxin replacement therapies. Furthermore, our results also show that the FXNI151F mouse is an excellent tool for analyzing tissue-specific consequences of frataxin deficiency and for testing new therapies.

HIF1A Alleviates compression-induced apoptosis of nucleus pulposus derived stem cells via upregulating autophagy

ABSTRACT Intervertebral disc degeneration (IDD) is the primary pathological mechanism that underlies low back pain. Overloading-induced cell death, especially endogenous stem cell death, is the leading factor that undermines intrinsic repair and aggravates IDD. Previous research has separately studied the effect of oxygen concentration and mechanical loading in IDD. However, how these two factors synergistically influence endogenous repair remains unclear. Therefore, we established in vitro and in vivo models to study the mechanisms by which hypoxia interacted with overloading-induced cell death of the nucleus pulposus derived stem cells (NPSCs). We found the content of HIF1A (hypoxia inducible factor 1 subunit alpha) and the number of NPSCs decreased with disc degeneration in both rats and human discs. Hence, we isolated this subpopulation from rat discs and treated them simultaneously with hypoxia and excessive mechanical stress. Our results demonstrated that hypoxia exerted protective effect on NPSCs under compression, partially through elevating macroautophagy/autophagy. Proteomics and knockdown experiments further revealed HIF1A-BNIP3-ATG7 axis mediated the increase in autophagy flux, in which HMOX1 and SLC2A1 were also involved. Moreover, HIF1A-overexpressing NPSCs exhibited stronger resistance to over-loading induced apoptosis in vitro. They also showed higher survival rates, along with elevated autophagy after being intra-disc transplanted into over-loaded discs. Jointly, both in vivo and in vitro experiments proved the anti-apoptotic effect of HIF1A on NPSCs under the excessive mechanical loading, suggesting that restoring hypoxia and manipulating autophagy is crucial to maintain the intrinsic repair and to retard disc degeneration. Abbreviations: 3-MA: 3-methyladenine; ACAN: aggrecan; ATG7: autophagy related 7; BafA1: bafilomycin A1; BAX: BCL2 associated X, apoptosis regulator; BECN1: beclin 1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CASP3: caspase 3; CCK8: cell counting kit-8; CHT: chetomin; CMP: compression; CoCl2: cobalt chloride; COL2A1: collagen type II alpha 1 chain; Ctrl: control; DAPI: 4,6-diamidino-2-phenylindole; DEP: differentially expressed protein; DiR: 1,1-dioctadecyl-3,3,3,3-tetramethyl indotricarbocyanine; ECM: extracellular matrix; FCM: flow cytometry; GD2: disialoganglioside GD 2; GFP: green fluorescent protein; GO: gene ontology; GSEA: gene set enrichment analysis; H&E: hematoxylin-eosin; HIF1A: hypoxia inducible factor 1 subunit alpha; HK2: hexokinase 2; HMOX1: heme oxygenase 1; HX: hypoxia mimicry; IDD: intervertebral disc degeneration; IF: immunofluorescence; IHC: immunohistochemistry; IVD: intervertebral disc; KEGG: kyoto encyclopedia of genes and genomes; LBP: low back pain; Lv: lentivirus; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MMP: mitochondrial membrane potential; NC: negative control; NIR: near-infrared; NP: nucleus pulposus; NPC: nucleus pulposus cell; NPSC: nucleus pulposus derived stem cell; NX: normoxia; PPI: protein-protein interactions; RFP: red fluorescent protein; SLC2A1/GLUT1: solute carrier family 2 member 1; SQSTM1/p62: sequestosome 1; TEK/TIE2: TEK receptor tyrosine kinase; TEM: transmission electron microscopy; TUBB: tubulin beta class I.

The impact of delayed heart rate recovery on prevalent hypertension

ABSTRACT Objectives: Delayed heart rate recovery (HRR) is considered an indicator of autonomic nervous dysfunction, which is a primary pathological mechanism of hypertension. The present study aimed to explore the independent association between delayed HRR and prevalent hypertension. Methods: In this cross-sectional study, 314 inpatients were recruited between January 2018 and December 2019. HRR was defined as the peak heart rate during exercise minus the 2nd-minute heart rate after exercise in the treadmill exercise test. Results: The mean HRR in the hypertension group was lower than that in the non-hypertension group (41 bpm vs. 46 bpm; P < 0.001). After full adjustment, each standard deviation increase in HRR was associated with a 35% decrease in the risk of prevalent hypertension (OR: 0.65, 95% CI: 0.48–0.87; P = 0.004). When the HRR was divided into quartiles, the risk in the top quartile was 26% of that in the bottom quartile (OR: 0.26, 95% CI: 0.12–0.56; P = 0.001). Furthermore, smooth curve fitting showed that the risk of prevalent hypertension decreased linearly with the increase in HRR. Conclusion: Delayed HRR was independently associated with prevalent hypertension. The association was linear and robust over the entire range of HRR. The present study suggested that delayed HRR could be used to optimize hypertension risk stratification.

JAB1 promotes palmitate-induced insulin resistance via ERK pathway in hepatocytes.

Insulin resistance (IR) is the primary pathological mechanism underlying Type 2 diabetes mellitus (T2DM). Many researches have reported the relationship between chronic inflammation and IR, while the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is rapidly activated in inflammatory conditions. However, the functional role of ERK1/2 in IR remains to be identified. We here reported that C-Jun activation domain-binding protein-1 (JAB1) was upregulated in IR. In addition, we showed that depletion of JAB1 led to recovery of insulin sensitivity. Given the fact that JAB1 played as an activator of ERK1/2, we assumed JAB1 was involved in IR through ERK pathway. So we assessed the effects of JAB1 knockdown in palmitate acid (PA) treated HepG2 cells. Importantly, JAB1 siRNA blocked the effect of PA-induced activation of ERK1/2. Furthermore, silencing of JAB1 could reduce the release of inflammatory factors, facilitate hepatic glucose uptake and improve lipid metabolism. All these data implicated that JAB1 knockdown might alleviate PA-induced IR through ERK pathway in hepatocytes.

Embolization of the middle meningeal artery in patients with chronic subdural hematoma-a systematic review and meta-analysis.

Chronic subdural hematoma (CSDH) remains a neurosurgical condition with high recurrence rate after surgical treatment. The primary pathological mechanism is considered to be repeated microbleedings from fragile neo-vessels within the outer hematoma membrane. The neo-vessels are supplied from peripheral branches of the middle meningeal artery, and embolization of MMA (eMMA) has been performed to prevent re-bleeding episodes and thereby CSDH recurrence. To evaluate the published evidence for the effect of eMMA in patients with recurrent CSDH. Secondarily, to investigate the effect of eMMA as an alternative to surgery for primary treatment of CSDH. A systematic review of the literature on eMMA in patients with recurrent CSDH was conducted. PubMed, Embase, and Cochrane databases were reviewed using the search terms: Embolization, Medial Meningeal Artery, Chronic Subdural Haematoma, and Recurrence. Furthermore, the following mesh terms were used: Chronic Subdural Haematoma AND embolization AND medial meningeal artery AND recurrence. Eighteen papers were found and included. No papers were excluded. The number of patients with primary CSDH and the number of patients with recurrent CSDH treated with eMMA were listed. Furthermore, the number of recurrences in both categories was registered. Eighteen papers with a total of 191 included patients diagnosed with CSDH treated with eMMA for primary and recurrent CSDH were identified. Recurrence rate for patients treated with eMMA for recurrent CSDH was found to be 2.4%, 95% CI (0.5%; 11.0%), whereas the recurrence rate for patients treated with eMMA for primary CSDH was 4.1%, 95% CI (1.4%; 11.4%). eMMA is a minimally invasive procedure for treatment of CSDH. Although this study is limited by publication bias, it seems that this procedure may reduce recurrence rates compared with burr hole craniostomy for both primary and recurrent hematomas. A controlled study is warranted.

The Nrf2 activator MIND4-17 protects retinal ganglion cells from high glucose-induced oxidative injury.

Diabetic retinopathy (DR) is a leading cause of acquired blindness among adults. High glucose (HG) induces oxidative injury and apoptosis in retinal ganglion cells (RGCs), serving as a primary pathological mechanism of DR. MIND4-17 activates nuclear-factor-E2-related factor 2 (Nrf2) signaling via modifying one cysteine (C151) residue of Kelch-like ECH-associated protein 1 (Keap1). The current study tested its effect in HG-treated primary murine RGCs. We show that MIND4-17 disrupted Keap1-Nrf2 association, leading to Nrf2 protein stabilization and nuclear translocation, causing subsequent expression of key Nrf2 target genes, including heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. Functional studies showed that MIND4-17 pretreatment significantly inhibited HG-induced cytotoxicity and apoptosis in primary murine RGCs. Reactive oxygen species production and oxidative injury in HG-treated murine RGCs were attenuated by MIND4-17. Nrf2 silencing (by targeted small interfering RNA) or knockout (by CRISPR/Cas9 method) abolished MIND4-17-induced RGC cytoprotection against HG. Additionally, Keap1 knockout or silencing mimicked and abolished MIND4-17-induced activity in RGCs. In vivo, MIND4-17 intravitreal injection activated Nrf2 signaling and attenuated retinal dysfunction by light damage in mice. We conclude that MIND4-17 activates Nrf2 signaling to protect murine RGCs from HG-induced oxidative injury.