Platelet-rich plasma alleviates neuropathic pain in osteoarthritis by downregulating microglial activation.

BACKGROUND: The development of neuropathic pain (NP) is one of the reasons why the pain is difficult to treat, and microglial activation plays an important role in NP. Recently, platelet-rich plasma (PRP) has emerged as a novel therapeutic method for knee osteoarthritis (KOA). However, it's unclarified whether PRP has analgesic effects on NP induced by KOA and the underlying mechanisms unknown. PURPOSE: To observe the analgesic effects of PRP on NP induced by KOA and explore the potential mechanisms of PRP in alleviating NP. METHODS: KOA was induced in male rats with intra-articular injections of monosodium iodoacetate (MIA) on day 0. The rats received PRP or NS (normal saline) treatment at days 15, 17, and 19 after modeling. The Von Frey and Hargreaves tests were applied to assess the pain-related behaviors at different time points. After euthanizing the rats with deep anesthesia at days 28 and 42, the corresponding tissues were taken for subsequent experiments. The expression of activating transcription factor 3 (ATF3) in dorsal root ganglia (DRG) and ionized-calcium-binding adapter molecule-1(Iba-1) in the spinal dorsal horn (SDH) was detected by immunohistochemical staining. In addition, the knee histological assessment was performed by hematoxylin-eosin (HE) staining. RESULTS: The results indicated that injection of MIA induced mechanical allodynia and thermal hyperalgesia, which could be reversed by PRP treatment. PRP downregulated the expression of ATF3 within the DRG and Iba-1 within the SDH. Furthermore, an inhibitory effect on cartilage degeneration was observed in the MIA + PRP group only on day 28. CONCLUSION: These results indicate that PRP intra-articular injection therapy may be a potential therapeutic agent for relieving NP induced by KOA. This effect could be attributed to downregulation of microglial activation and reduction in nerve injury.

Balanced Thermal Insulation, Flame-Retardant and Mechanical Properties of PU Foam Constructed via Cost-Effective EG/APP/SA Ternary Synergistic Modification.

To address the challenge of balancing the mechanical, thermal insulation, and flame-retardant properties of building insulation materials, this study presented a facile approach to modify the rigid polyurethane foam composites (RPUFs) via commercial expandable graphite (EG), ammonium polyphosphate (APP), and silica aerogel (SA). The resulting EG/APP/SA/RPUFs exhibited low thermal conductivity close to neat RPUF. However, the compressive strength of the 6EG/2APP/SA/RPUF increased by 49% along with achieving a V-0 flame retardant rating. The residual weight at 700 °C increased from 19.2 wt.% to 30.9 wt.%. Results from cone calorimetry test (CCT) revealed a 9.2% reduction in total heat release (THR) and a 17.5% decrease in total smoke production (TSP). The synergistic flame-retardant mechanism of APP/EG made significant contribution to the excellent flame retardant properties of EG/APP/SA/RPUFs. The addition of SA played a vital role in reducing thermal conductivity and enhancing mechanical performance, effectively compensating for the shortcomings of APP/EG. The cost-effective EG/APP/SA system demonstrates a positive ternary synergistic effect in achieving a balance in RPUFs properties. This study provides a novel strategy aimed at developing affordable building wall insulation material with enhanced safety features.

GSDME in Endothelial Cells: Inducing Vascular Inflammation and Atherosclerosis via Mitochondrial Damage and STING Pathway Activation.

The initiation of atherosclerotic plaque is characterized by endothelial cell inflammation. In light of gasdermin E's (GSDME) role in pyroptosis and inflammation, this study elucidates its function in atherosclerosis onset. Employing Gsdme- and apolipoprotein E-deficient (Gsdme-/-/ApoE-/-) and ApoE-/- mice, an atherosclerosis model was created on a Western diet (WD). In vitro examinations with human umbilical vein endothelial cells (HUVECs) included oxidized low-density lipoprotein (ox-LDL) exposure. To explore the downstream mechanisms linked to GSDME, we utilized an agonist targeting the stimulator of the interferon genes (STING) pathway. The results showed significant GSDME activation in ApoE-/- mice arterial tissues, corresponding with atherogenesis. Gsdme-/-/ApoE-/- mice displayed fewer plaques and decreased vascular inflammation. Meanwhile, GSDME's presence was confirmed in endothelial cells. GSDME inhibition reduced the endothelial inflammation induced by ox-LDL. GSDME was linked to mitochondrial damage in endothelial cells, leading to an increase in cytoplasmic double-stranded DNA (dsDNA). Notably, STING activation partially offset the effects of GSDME inhibition in both in vivo and in vitro settings. Our findings underscore the pivotal role of GSDME in endothelial cells during atherogenesis and vascular inflammation, highlighting its influence on mitochondrial damage and the STING pathway, suggesting a potential therapeutic target for vascular pathologies.

Non-coding RNAs in lung cancer: molecular mechanisms and clinical applications.

Lung cancer (LC) is a heterogeneous disease with high malignant degree, rapid growth, and early metastasis. The clinical outcomes of LC patients are generally poor due to the insufficient elucidation of pathological mechanisms, low efficiency of detection and assessment methods, and lack of individualized therapeutic strategies. Non-coding RNAs (ncRNAs), including microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA), are endogenous regulators that are widely involved in the modulation of almost all aspects of life activities, from organogenesis and aging to immunity and cancer. They commonly play vital roles in various biological processes by regulating gene expression via their interactions with DNA, RNA, or protein. An increasing amount of studies have demonstrated that ncRNAs are closely correlated with the initiation and development of LC. Their dysregulation promotes the progression of LC via distinct mechanisms, such as influencing protein activity, activating oncogenic signaling pathways, or altering specific gene expression. Furthermore, some ncRNAs present certain clinical values as biomarker candidates and therapeutic targets for LC patients. A complete understanding of their mechanisms in LC progression may be highly beneficial to developing ncRNA-based therapeutics for LC patients. This review mainly focuses on the intricate mechanisms of miRNA, lncRNA, and circRNA involved in LC progression and discuss their underlying applications in LC treatment.

TMEM11 regulates cardiomyocyte proliferation and cardiac repair via METTL1-mediated m7G methylation of ATF5 mRNA.

The mitochondrial transmembrane (TMEM) protein family has several essential physiological functions. However, its roles in cardiomyocyte proliferation and cardiac regeneration remain unclear. Here, we detected that TMEM11 inhibits cardiomyocyte proliferation and cardiac regeneration in vitro. TMEM11 deletion enhanced cardiomyocyte proliferation and restored heart function after myocardial injury. In contrast, TMEM11-overexpression inhibited neonatal cardiomyocyte proliferation and regeneration in mouse hearts. TMEM11 directly interacted with METTL1 and enhanced m7G methylation of Atf5 mRNA, thereby increasing ATF5 expression. A TMEM11-dependent increase in ATF5 promoted the transcription of Inca1, an inhibitor of cyclin-dependent kinase interacting with cyclin A1, which suppressed cardiomyocyte proliferation. Hence, our findings revealed that TMEM11-mediated m7G methylation is involved in the regulation of cardiomyocyte proliferation, and targeting the TMEM11-METTL1-ATF5-INCA1 axis may serve as a novel therapeutic strategy for promoting cardiac repair and regeneration.

Non-coding RNA-mediated modulation of ferroptosis in cardiovascular diseases.

Cardiovascular disease (CVD) is a major contributor to increasing morbidity and mortality worldwide and seriously threatens human health and life. Cardiomyocyte death is considered the pathological basis of various CVDs, including myocardial infarction, heart failure, and aortic dissection. Multiple mechanisms, such as ferroptosis, necrosis, and apoptosis, contribute to cardiomyocyte death. Among them, ferroptosis is an iron-dependent form of programmed cell death that plays a vital role in various physiological and pathological processes, from development and aging to immunity and CVD. The dysregulation of ferroptosis has been shown to be closely associated with CVD progression, yet its underlying mechanisms are still not fully understood. In recent years, a growing amount of evidence suggests that non-coding RNAs (ncRNAs), particularly microRNAs, long non-coding RNAs, and circular RNAs, are involved in the regulation of ferroptosis, thus affecting CVD progression. Some ncRNAs also exhibit potential value as biomarker and/or therapeutic target for patients with CVD. In this review, we systematically summarize recent findings on the underlying mechanisms of ncRNAs involved in ferroptosis regulation and their role in CVD progression. We also focus on their clinical applications as diagnostic and prognostic biomarkers as well as therapeutic targets in CVD treatment. DATA AVAILABILITY: No new data were created or analyzed in this study. Data sharing is not applicable to this article.

TNC Accelerates Hypoxia-Induced Cardiac Injury in a METTL3-Dependent Manner.

Cardiac fibrosis and cardiomyocyte apoptosis are reparative processes after myocardial infarction (MI), which results in cardiac remodeling and heart failure at last. Tenascin-C (TNC) consists of four distinct domains, which is a large multimodular glycoprotein of the extracellular matrix. It is also a key regulator of proliferation and apoptosis in cardiomyocytes. As a significant m6A regulator, METTL3 binds m6A sites in mRNA to control its degradation, maturation, stabilization, and translation. Whether METTL3 regulates the occurrence and development of myocardial infarction through the m6A modification of TNC mRNA deserves our study. Here, we have demonstrated that overexpression of METTL3 aggravated cardiac dysfunction and cardiac fibrosis after 4 weeks after MI. Moreover, we also demonstrated that TNC resulted in cardiac fibrosis and cardiomyocyte apoptosis after MI. Mechanistically, METTL3 led to enhanced m6A levels of TNC mRNA and promoted TNC mRNA stability. Then, we mutated one m6A site "A" to "T", and the binding ability of METTL3 was reduced. In conclusion, METTL3 is involved in cardiac fibrosis and cardiomyocyte apoptosis by increasing m6A levels of TNC mRNA and may be a promising target for the therapy of cardiac fibrosis after MI.

Burden, Trends, and Inequalities of Heart Failure Globally, 1990 to 2019: A Secondary Analysis Based on the Global Burden of Disease 2019 Study.

Background Heart failure is a public health issue worldwide. However, no comprehensive study on the global burden of heart failure and its contributing causes has been reported. The present study aimed to quantify the burden, trends, and inequalities of heart failure globally. Methods and Results Heart failure data were extracted from the Global Burden of Diseases 2019 study. The number of cases, age-standardized prevalence, and years lived with disability in different locations from 1990 to 2019 were presented and compared. Joinpoint regression analysis was performed to assess trends in heart failure from 1990 to 2019. In 2019, the global age-standardized prevalence and years lived with disability rates for heart failure were 711.90 (95% uncertainty interval [UI], 591.15-858.29) and 63.92 (95% UI, 41.49-91.95) per 100 000 population, respectively. In general, the age-standardized rate decreased globally at an average annual percentage change of 0.3% (95% UI, 0.2-0.3). However, the rate increased at an average annual percentage change of 0.6% (95% UI, 0.4-0.8) from 2017 to 2019. Several nations and territories demonstrated an increased trend from 1990 to 2019, especially in less-developed countries. Ischemic heart disease and hypertensive heart disease accounted for the highest proportion of heart failure in 2019. Conclusions Heart failure remains a major health problem, with increased trends possible in the future. Efforts for prevention and control of heart failure should focus more on less-developed regions. It is essential to prevent and treat primary diseases such as ischemic heart disease and hypertensive heart disease for the control of heart failure.

Genome-wide analysis for nanofiber induced global gene expression profile: A study in MC3T3-E1 cells by RNA-Seq.

Nanofibers are one of the attractive biomaterials that can provide unique environments to direct cell behaviors. However, how nanofiber structure affects the global gene expression of laden cells remains unclear. Herein, high-throughput mRNA sequencing (RNA-seq) is applied to analyze the transcriptome of the MC3T3-E1 cells (a model osteoblast cell line) cultured on electrospun nanofibers. The cell-adhesive poly(L-lactide) nanofibers and membranes are developed by the mussel-inspired coating of gelatin-dopamine conjugate under H2O2-mediated oxidation. The MC3T3-E1 cells cultured on nanofibers exhibit elongated morphology and increased proliferation compared with those on membranes. The differences in global gene expression profiles are determined by RNA-seq, in which 905 differentially expressed genes (DEGs) are identified. Significantly, the DEGs related to cytoskeleton, promotion of cell cycle progression, cell adhesion, and cell proliferation, are higher expressed in the cells on nanofibers, while the DEGs involved in cell-cycle arrest and osteoblast mineralization are up-regulated in the cells on membranes. This study elucidates the roles of nanofiber structure in affecting gene expression of laden cells at the whole transcriptome level, and it will lay the foundation for understanding nanofiber-guided cell behaviors.

A transcriptome sequencing study on the effect of macro-pores in hydrogel scaffolds on global gene expression of laden human cartilage chondrocytes.

The macro-porous hydrogel scaffolds can not only enhance the proliferation of laden chondrocytes but also favor the deposition of hyaline cartilaginous extracellular matrix, however, the underlying molecular mechanism is still unclear. Herein, the global gene expression of human cartilage chondrocytes (HCCs) encapsulated in traditional hydrogel (Gel) constructs and micro-cavitary gel (MCG) constructs are investigated by using high-throughput RNA sequencing (RNA-seq). The differentially expressed genes (DEGs) between the HCCs cultured in Gel and MCG constructs have been identified via bioinformatics analysis. Significantly, the DEGs that promote cell proliferation (e.g. POSTN, MKI67, KIF20A) or neo-cartilage formation (e.g. COL2, ASPN, COMP, FMOD, FN1), are more highly expressed in MCG constructs than in Gel constructs, while the expressions of the DEGs associated with chondrocyte hypertrophy (e.g. EGR1, IBSP) are upregulated in Gel constructs. The expression of representative DEGs is verified at both mRNA and protein levels. Besides, cellular viability and morphology as well as the enriched signaling pathway of DEGs are studied in detail. These results of this work may provide data for functional tissue engineering of cartilage.

The Identification and Validation of Hub Genes Associated with Acute Myocardial Infarction Using Weighted Gene Co-Expression Network Analysis.

Acute myocardial infarction (AMI), one of the most severe and fatal cardiovascular diseases, remains the main cause of mortality and morbidity worldwide. The objective of this study is to investigate the potential biomarkers for AMI based on bioinformatics analysis. A total of 2102 differentially expressed genes (DEGs) were screened out from the data obtained from the gene expression omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) explored the co-expression network of DEGs and determined the key module. The brown module was selected as the key one correlated with AMI. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses demonstrated that genes in the brown module were mainly enriched in 'ribosomal subunit' and 'Ribosome'. Gene Set Enrichment Analysis revealed that 'TNFA_SIGNALING_VIA_NFKB' was remarkably enriched in AMI. Based on the protein-protein interaction network, ribosomal protein L9 (RPL9) and ribosomal protein L26 (RPL26) were identified as the hub genes. Additionally, the polymerase chain reaction (PCR) results indicated that the expression levels of RPL9 and RPL26 were both downregulated in AMI patients compared with controls, in accordance with the bioinformatics analysis. In summary, the identified DEGs, modules, pathways, and hub genes provide clues and shed light on the potential molecular mechanisms of AMI.

A novel cell encapsulatable cryogel (CECG) with macro-porous structures and high permeability: a three-dimensional cell culture scaffold for enhanced cell adhesion and proliferation.

Hydrogel scaffold is a popular cell delivery vehicle in tissue engineering and regenerative medicine due to its capability to encapsulate cells as well as its modifiable properties. However, the inherent submicron- or nano-sized polymer networks of conventional hydrogel will produce spatial constraints on cellular activities of encapsulated cells. In this study, we endeavor to develop an innovative cell encapsulatable cryogel (CECG) platform with interconnected macro-pores, by combining cell cryopreservation technique with cryogel preparation process. The hyaluronan (HA) CECG constructs are fabricated under the freezing conditions via UV photo-crosslinking of the HA methacrylate (HA-MA) that are dissolved in the 'freezing solvent', namely the phosphate buffered saline supplemented with dimethyl sulphoxide and fetal bovine serum. Two model cell types, chondrocytes and human mesenchymal stem cells (hMSCs), can be uniformly three-dimensionally encapsulated into HA CECG constructs with high cell viability, respectively. The macro-porous structures, generated from phase separation under freezing, endow HA CECG constructs with higher permeability and more living space for cell growth. The chondrocytes encapsulated in HA CECG possess enhanced proliferation and extracellular matrix secretion than those in conventional HA hydrogels. In addition, the HA-Gel CECG constructs, fabricated with HA-MA and gelatin methacrylate precursors, provide cell-adhesive interfaces to facilitate hMSCs attachment and proliferation. The results of this work may lay the foundation for us to explore the applications of the CECG-based scaffolds in the field of tissue engineering and regenerative medicine.

A novel classification of the anatomical variations of the first extensor compartment.

The presence of a septum in the first extensor compartment is closely associated with the pathophysiology of de Quervain disease, and affects the efficacy of corticosteroid injection and surgical release. This study aimed to examine the incidence and length of the first extensor compartment septum.Forty sides of the wrists in 20 cadavers were used. The presence of a septum in the first extensor compartment was examined. The septum length was recorded with the radial styloid process as the reference point.The anatomical variations of the first extensor compartment were classified into 3 types. Type I compartment was found in 7 sides in males (29.2%) versus 6 sides in females (37.5%, P = .733), type II was found in 6 sides in males (25%) versus 1 side in females (6.25%, P = .21), and type III was found in 11 sides in males (45.8%) versus 9 sides in females (56.25%, P = .56). There was no significant difference in the septum length between males and females (5.3 ±â€Š2.3 vs 4.8 ±â€Š1.1 mm, P = .54).The incidence of a septum in the first extensor compartment is approximately 50%. The mean septum length is 5 mm. Injection at 5 mm proximal to the radial styloid process has a great chance of delivering the steroids into both subcompartments. Exposure to 5 mm proximal to the radial styloid process can avoid the overlook of subcompartment and achieve adequate decompression of the first extensor compartment.