Therapeutic trends of priming mesenchymal stem cells: A bibliometric analysis.

Mesenchymal stem cells (MSCs) have gained substantial attention in regenerative medicine due to their multilineage differentiation potential and immunomodulatory capabilities. MSCs have demonstrated therapeutic promise in numerous preclinical and clinical studies across a variety of diseases, including neurodegenerative disorders, cardiovascular diseases, and autoimmune conditions. Recently, priming MSCs has emerged as a novel strategy to enhance their therapeutic efficacy by preconditioning them for optimal survival and function in challenging in vivo environments. This study presented a comprehensive bibliometric analysis of research activity in the field of priming mesenchymal stem cells (MSCs) from 2003 to 2023. Utilizing a dataset of 585 documents, we explored research trends, leading authors and countries, productive journals, and frequently used keywords. We also explored priming strategies to augment the therapeutic efficacy of MSCs. Our findings show increasing research productivity with a peak in 2019, identified the United States as the leading contributor, and highlighted WANG JA as the most prolific author. The most published journal was Stem Cell Research & Therapy. Keyword analysis revealed core research areas emerging hotspots, while coword and cited sources visualizations elucidated the conceptual framework and key information sources. Further studies are crucial to advance the translation of primed MSCs from bench to bedside, potentially revolutionizing the landscape of regenerative medicine.

Molecular insight into the initial hydration of tricalcium aluminate.

Portland cement (PC) is ubiquitously used in construction for centuries, yet the elucidation of its early-age hydration remains a challenge. Understanding the initial hydration progress of tricalcium aluminate (C3A) at molecular scale is thus crucial for tackling this challenge as it exhibits a proclivity for early-stage hydration and plays a pivotal role in structural build-up of cement colloids. Herein, we implement a series of ab-initio calculations to probe the intricate molecular interactions of C3A during its initial hydration process. The C3A surface exhibits remarkable chemical activity in promoting water dissociation, which in turn facilitates the gradual desorption of Ca ions through a metal-proton exchange reaction. The dissolution pathways and free energies of these Ca ions follow the ligand-exchange mechanism with multiple sequential reactions to form the ultimate products where Ca ions adopt fivefold or sixfold coordination. Finally, these Ca complexes reprecipitate on the remaining Al-rich layer through the interface-coupled dissolution-reprecipitation mechanism, demonstrating dynamically stable inner-sphere adsorption states. The above results are helpful in unmasking the early-age hydration of PC and advancing the rational design of cement-based materials through the bottom-up approach.

In vivo tracking of mesenchymal stem cell dynamics and therapeutics in LPS-induced acute lung injury models.

Mesenchymal stem cells (MSCs) have been widely used to treat various inflammatory and immune-related diseases in preclinical and clinical settings. Intravital microscopy (IVM) is considered the gold standard for investigating pathophysiological conditions in living animals. However, the potential for real-time monitoring of MSCs in the pulmonary microenvironment remains underexplored. In this study, we first constructed a lung window and captured changes in the lung at the cellular level under both inflammatory and noninflammatory conditions with a microscope. We further investigated the dynamics and effects of MSCs under two different conditions. Meanwhile, we assessed the alterations in the adhesive capacity of vascular endothelial cells in vitro to investigate the underlying mechanisms of MSC retention in an inflammatory environment. This study emphasizes the importance of the "lung window" for live imaging of the cellular behavior of MSCs by vein injection. Moreover, our results revealed that the upregulation of vascular cell adhesion molecule 1 (VCAM1) in endothelial cells post-inflammatory injury could enhance MSC retention in the lung, further ameliorating acute lung injury. In summary, intravital microscopy imaging provides a practical method to investigate the therapeutic effects of MSCs in acute lung injury.

STW-MD: a novel spatio-temporal weighting and multi-step decision tree method for considering spatial heterogeneity in brain gene expression data.

Gene expression during brain development or abnormal development is a biological process that is highly dynamic in spatio and temporal. Previous studies have mainly focused on individual brain regions or a certain developmental stage. Our motivation is to address this gap by incorporating spatio-temporal information to gain a more complete understanding of brain development or abnormal brain development, such as Alzheimer's disease (AD), and to identify potential determinants of response. In this study, we propose a novel two-step framework based on spatial-temporal information weighting and multi-step decision trees. This framework can effectively exploit the spatial similarity and temporal dependence between different stages and different brain regions, and facilitate differential gene analysis in brain regions with high heterogeneity. We focus on two datasets: the AD dataset, which includes gene expression data from early, middle and late stages, and the brain development dataset, spanning fetal development to adulthood. Our findings highlight the advantages of the proposed framework in discovering gene classes and elucidating their impact on brain development and AD progression across diverse brain regions and stages. These findings align with existing studies and provide insights into the processes of normal and abnormal brain development.

Ferroptosis: a promising candidate for exosome-mediated regulation in different diseases.

Ferroptosis is a newly discovered form of cell death that is featured in a wide range of diseases. Exosome therapy is a promising therapeutic option that has attracted much attention due to its low immunogenicity, low toxicity, and ability to penetrate biological barriers. In addition, emerging evidence indicates that exosomes possess the ability to modulate the progression of diverse diseases by regulating ferroptosis in damaged cells. Hence, the mechanism by which cell-derived and noncellular-derived exosomes target ferroptosis in different diseases through the system Xc-/GSH/GPX4 axis, NAD(P)H/FSP1/CoQ10 axis, iron metabolism pathway and lipid metabolism pathway associated with ferroptosis, as well as its applications in liver disease, neurological diseases, lung injury, heart injury, cancer and other diseases, are summarized here. Additionally, the role of exosome-regulated ferroptosis as an emerging repair mechanism for damaged tissues and cells is also discussed, and this is expected to be a promising treatment direction for various diseases in the future. Video Abstract.

PAFAH2 suppresses synchronized ferroptosis to ameliorate acute kidney injury.

Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and contributed to AKI. The emergence of PAF and PAF-LPLs in ferroptosis caused the instability of biomembranes and signaled the cell death of neighboring cells. This cascade could be suppressed by PAF-acetylhydrolase (II) (PAFAH2) or by addition of antibodies against PAF. Genetic knockout or pharmacological inhibition of PAFAH2 increased PAF production, augmented synchronized ferroptosis and exacerbated ischemia/reperfusion (I/R)-induced AKI. Notably, intravenous administration of wild-type PAFAH2 protein, but not its enzymatically inactive mutants, prevented synchronized tubular cell death, nephron loss and AKI. Our findings offer an insight into the mechanisms of synchronized ferroptosis and suggest a possibility for the preventive intervention of AKI.

Critical Review of Emerging Pre-metallization Technologies for Rechargeable Metal-Ion Batteries.

Low Coulombic efficiency, low-capacity retention, and short cycle life are the primary challenges faced by various metal-ion batteries due to the loss of corresponding active metal. Practically, these issues can be significantly ameliorated by compensating for the loss of active metals using pre-metallization techniques. Herein, the state-of-the-art development in various pr-emetallization techniques is summarized. First, the origin of pre-metallization is elaborated and the Coulombic efficiency of different battery materials is compared. Second, different pre-metallization strategies, including direct physical contact, chemical strategies, electrochemical method, overmetallized approach, and the use of electrode additives are summarized. Third, the impact of pre-metallization on batteries, along with its role in improving Coulombic efficiency is discussed. Fourth, the various characterization techniques required for mechanistic studies in this field are outlined, from laboratory-level experiments to large scientific device. Finally, the current challenges and future opportunities of pre-metallization technology in improving Coulombic efficiency and cycle stability for various metal-ion batteries are discussed. In particular, the positive influence of pre-metallization reagents is emphasized in the anode-free battery systems. It is envisioned that this review will inspire the development of high-performance energy storage systems via the effective pre-metallization technologies.

Intracellular delivery of nitric oxide enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.

Cell therapy by autologous mesenchymal stem cells (MSCs) is a clinically acceptable strategy for treating various diseases. Unfortunately, the therapeutic efficacy is largely affected by the low quality of MSCs collected from patients. Here, we showed that the gene expression of MSCs from patients with diabetes was differentially regulated compared to that of MSCs from healthy controls. Then, MSCs were genetically engineered to catalyze an NO prodrug to release NO intracellularly. Compared to extracellular NO conversion, intracellular NO delivery effectively prolonged survival and enhanced the paracrine function of MSCs, as demonstrated by in vitro and in vivo assays. The enhanced therapeutic efficacy of engineered MSCs combined with intracellular NO delivery was further confirmed in mouse and rat models of myocardial infarction, and a clinically relevant cell administration paradigm through secondary thoracotomy has been attempted.

Surface Engineering of Migratory Corrosion Inhibitors: Controlling the Wettability of Calcium Silicate Hydrate in the Nanoscale.

Migratory corrosion inhibitors (MCIs) are regarded as effective additives to prevent harmful ion transmission and improve concrete durability, but their behavior in the porosity of concrete is still unclarified. This paper proposes a unique perspective to evaluate the effects of surfactant-like MCIs in calcium silicate hydrate (C-S-H) nanoporosity through molecular and electronic structural information. Advanced enhanced sampling methods and perturbation theory methods were applied to evaluate the role of different MCIs. The reduced density gradient of MCI molecules was obtained by using quantum chemical calculations. This calculation is instrumental in elucidating the intensity of interactions among distinct MCI molecule head groups and the C-S-H matrix. It is found that MCIs can effectively improve the interfacial tension (IFT) between C-S-H and water, which corresponds to the inhibitory ability of transmission. Free energy indicates that the MCI has the properties of strong adsorption and weak dissolution, facilitating the improvement of IFT. The relationship between the MCI functional group and the ability of adsorption and dissolution is revealed. This study suggests that MCIs work as surface controllers of C-S-H pores and that their properties can be assessed on the nanoscale.

Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy.

Nitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of these gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, human MSCs were genetically modified to produce mutant ß-galactosidase (ß-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can enter cells and selectively trigger NO release from genetically engineered MSCs (eMSCs) in the presence of ß-GALH363A. Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells.

Animals are made up of cells of different types, with each type of cell specializing on a specific role. But for the body to work properly, the different types of cells must be able to coordinate with each other to respond to internal and external stimuli. This can be achieved through signaling molecules, that is, molecules released by a cell that can elicit a specific response in other cells. There are many types of different molecules, including hormones and signaling proteins. Gases can also be potent signaling molecules, participating in various biological processes. Nitric oxide (NO) is a gas signaling molecule that can freely diffuse through the membranes of cells and has roles in blood vessel constriction and other disease processes, making it a promising therapeutic agent. Unfortunately, using artificial carriers to deliver nitric oxide to the organs and tissues where it is needed can lead to issues, including immune reactions to the carrier and long-term toxicity. One way to avoid these effects is by using cells to deliver nitric oxide to the right place. Huang, Qian, Liu et al. have used mesenchymal stem cells ­ which usually develop to form connective tissues such as bone and muscle ­ to develop a cell-based NO-delivery system. The researchers genetically modified the mesenchymal stem cells to produce a compound called ß-GAL^H363A. On its own ß-GAL^H363A does not do much, but in its presence, a non-toxic, non-reactive compound developed by Huang, Qian, Liu et al., called MGP, can drive the release of NO from cells. To confirm the usefulness of their cells as a delivery system, Huang, Qian, Liu et al. transplanted some of the genetically modified mesenchymal stem cells into the kidneys of mice, and then showed that when these mice were given MGP, the levels of NO increased in the kidneys but not in other organs. This result confirms that the cell-based delivery system provides spatial and temporal control of the production of NO. These findings demonstrate a new delivery system for therapies using gas molecules, which can be controlled spatiotemporally in mice. In the future, these types of systems could be used in the clinic for long-term treatment of conditions where artificial carriers could lead to complications.

Embryonic stem cell-derived extracellular vesicles rejuvenate senescent cells and antagonize aging in mice.

Aging is a degenerative process that leads to tissue dysfunction and death. Embryonic stem cells (ESCs) have great therapeutic potential for age-related diseases due to their capacity for self-renewal and plasticity. However, the use of ESCs in clinical treatment is limited by immune rejection, tumourigenicity and ethical issues. ESC-derived extracellular vesicles (EVs) may provide therapeutic effects that are comparable to those of ESCs while avoiding unwanted effects. Here, we fully evaluate the role of ESC-EVs in rejuvenation in vitro and in vivo. Using RNA sequencing (RNA-Seq) and microRNA sequencing (miRNA-Seq) screening, we found that miR-15b-5p and miR-290a-5p were highly enriched in ESC-EVs, and induced rejuvenation by silencing the Ccn2-mediated AKT/mTOR pathway. These results demonstrate that miR-15b-5p and miR-290a-5p function as potent activators of rejuvenation mediated by ESC-EVs. The rejuvenating effect of ESC-EVs was further investigated in vivo by injection into aged mice. The results showed that ESC-EVs successfully ameliorated the pathological age-related phenotypes and rescued the transcriptome profile of aged mice. Our findings demonstrate that ESC-EVs treatment can rejuvenate senescence both in vitro and in vivo and suggest the therapeutic potential of ESC-EVs as a novel cell-free alternative to ESCs for age-related diseases.

Dppa3 Improves the Germline Competence of Pluripotent Stem Cells.

BACKGROUND: Chimera formation and germline competence are critical features of mouse pluripotent stem cells (PSCs). However, the factors that contribute to germline competence in the chimeras remain to be understood. METHODS: To determine the role of Dppa3 in PSCs, we first constructed Dppa3 knockout (Dppa3 KO) and Dppa3 overexpression (Dppa3 OE) PSCs, respectively. Using Dppa3 KO and Dppa3 OE PSCs, we then investigated the role of Dppa3 in PSCs by evaluating the chimera generation, DNA methylation, and pluripotent state conversion. RESULTS: We show that Dppa3 plays an important role in chimera formation and germline competence of mouse PSCs. PSC lines with high expression of Dppa3 show high germline competence. In contrast, Dppa3 deficiency reduces chimera formation and abrogates the germline transmission capacity of PSCs. Molecularly, Dppa3 facilitates establishing global DNA hypomethylation in PSCs. High levels of Dppa3 in PSCs reduce the expression of Dnmt3a/b and impede Uhrf1-Dnmt1 complex binding to DNA replication forks, maintaining DNA hypomethylation. Additionally, Dppa3 facilitates two-cell-stage (2C) genes expression and promotes conversion to a 2C-like state. CONCLUSION: These data show that Dppa3 is involved in maintaining DNA hypomethylation homeostasis and is required for high chimera formation and germline competence of PSCs.

Subconjunctival Administration of Mesenchymal Stem Cells Alleviates Ocular Inflammation in a Murine Model of Corneal Alkali Burn.

Corneal alkali burns cause extensive damage not only to the cornea but also to the intraocular tissues. As an anti-inflammatory therapy, subconjunctival administration of mesenchymal stem cells (MSCs) for corneal protection after corneal alkali burn has been explored. Little evidence demonstrates the potential of subconjunctival MSCs delivery in protecting the post-burn intraocular tissues. This study aimed to evaluate the therapeutic efficacy of subconjunctival injection of human placental (hP)-MSCs in protecting against ocular destruction after the burn. hP-MSCs were subconjunctivally administered to C57/BL mice after corneal alkali burn. Western blot of iNOS and CD206 was performed to determine the M1 and M2 macrophage infiltration in the cornea. Infiltration of inflammatory cells in the anterior uvea and retina was analyzed by flow cytometry. The TUNEL assay or Western blot of Bax and Bcl2 was used to evaluate the anti-apoptotic effects of MSCs. MSCs could effectively facilitate cornea repair by suppressing inflammatory cytokines IL-1ß, MCP-1, and MMP9, and polarizing CD206 positive M2 macrophages. Anterior uveal and retinal inflammatory cytokines expression and inflammatory cell infiltration were inhibited in the MSC-treated group. Reduced TUNEL positive staining and Bax/Bcl2 ratio indicated the anti-apoptosis of MSCs. MSC-conditioned medium promoted human corneal epithelial cell proliferation and regulated LPS-stimulated inflammation in RAW 264.7 macrophages, confirming the trophic and immunoregulatory effects of MSCs. Our findings demonstrate that subconjunctival administration of MSCs exerted anti-inflammatory and anti-apoptotic effects in the cornea, anterior uvea, and retina after corneal alkali burn. This strategy may provide a new direction for preventing post-event complications after corneal alkali burn.

Superior protective effects of PGE2 priming mesenchymal stem cells against LPS-induced acute lung injury (ALI) through macrophage immunomodulation.

BACKGROUND: Mesenchymal stem cells (MSCs) have demonstrated remarkable therapeutic promise for acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS). MSC secretomes contain various immunoregulatory mediators that modulate both innate and adaptive immune responses. Priming MSCs has been widely considered to boost their therapeutic efficacy for a variety of diseases. Prostaglandin E2 (PGE2) plays a vital role in physiological processes that mediate the regeneration of injured organs. METHODS: This work utilized PGE2 to prime MSCs and investigated their therapeutic potential in ALI models. MSCs were obtained from human placental tissue. MSCs were transduced with firefly luciferase (Fluc)/eGFP fusion protein for real-time monitoring of MSC migration. Comprehensive genomic analyses explored the therapeutic effects and molecular mechanisms of PGE2-primed MSCs in LPS-induced ALI models. RESULTS: Our results demonstrated that PGE2-MSCs effectively ameliorated lung injury and decreased total cell numbers, neutrophils, macrophages, and protein levels in bronchoalveolar lavage fluid (BALF). Meanwhile, treating ALI mice with PGE2-MSCs dramatically reduced histopathological changes and proinflammatory cytokines while increasing anti-inflammatory cytokines. Furthermore, our findings supported that PGE2 priming improved the therapeutic efficacy of MSCs through M2 macrophage polarization. CONCLUSION: PGE2-MSC therapy significantly reduced the severity of LPS-induced ALI in mice by modulating macrophage polarization and cytokine production. This strategy boosts the therapeutic efficacy of MSCs in cell-based ALI therapy.

Renal Endothelial Cell-Targeted Extracellular Vesicles Protect the Kidney from Ischemic Injury.

Endothelial cell injury plays a critical part in ischemic acute kidney injury (AKI) and participates in the progression of AKI. Targeting renal endothelial cell therapy may ameliorate vascular injury and further improve the prognosis of ischemic AKI. Here, P-selectin as a biomarker of ischemic AKI in endothelial cells is identified and P-selectin binding peptide (PBP)-engineered extracellular vesicles (PBP-EVs) with imaging and therapeutic functions are developed. The results show that PBP-EVs exhibit a selective targeting tendency to injured kidneys, while providing spatiotemporal information for the early diagnosis of AKI by quantifying the expression of P-selectin in the kidneys by molecular imaging. Meanwhile, PBP-EVs reveal superior nephroprotective functions in the promotion of renal repair and inhibition of fibrosis by alleviating inflammatory infiltration, improving reparative angiogenesis, and ameliorating maladaptive repair of the renal parenchyma. In conclusion, PBP-EVs, as an ischemic AKI theranostic system that is designed in this study, provide a spatiotemporal diagnosis in the early stages of AKI to help guide personalized therapy and exhibit superior nephroprotective effects, offering proof-of-concept data to design EV-based theranostic strategies to promote renal recovery and further improve long-term outcomes following AKI.

Off-the-shelf GMP-grade UC-MSCs as therapeutic drugs for the amelioration of CCl4-induced acute-on-chronic liver failure in NOD-SCID mice.

BACKGROUND AND PURPOSE: Umbilical cord-derived mesenchymal stem/stromal cells (UC-MSCs) are advanced therapy medicinal products (ATMPs) and thus act as an alternative to liver transplantation for acute-on-chronic liver failure (ACLF). Therewith, we are aiming to evaluate the pharmacologyandpharmacokinetics of GMP-grade UC-MSCs products on carbon tetrachloride (CCl4)-induced ACLF mouse model and the concomitant therapeutic dose for intravenous administration. METHODS: For the purpose, the GMP-grade UC-MSCs products were transplanted intravenously into the aforementioned CCl4-induced ACLF NOD-SCID mouse model, and the therapeutic effect was evaluated with the aid of serological, biochemical and histological assessments. Meanwhile, the correlationshipbetween the treatment groups and other characteristics were determined by conducting principal component analysis (PCA). To further verify the spatio-temporal pharmacokinetics of UC-MSCs products on ACLF treatment, we took advantage of the bioluminescence imaging (BLI) technology with the dual-color fluorescence reporter construct (pLV-Fluc-eGFP). RESULTS: The biological characteristics of UC-MSCs products were in conformity with the International Society of Cell Therapy (ISCT) criteriaand the GMP requirements. ACLF mice with high dose of UC-MSCs treatment revealed significantly alleviated pathological manifestations with a dramatically improved survival rate, the alleviation of liver injury with reduced hepatic enzyme, inflammatory infiltration and inflammatory cytokines. Notably, UC-MSCs in ACLF mice displayed preferable homing and delayed attenuation in the damaged liver tissue. CONCLUSION: Collectively, our data indicated the feasibility of UC-MSC-based cytotherapy for ACLF model administration. Our findings have provided new references for pharmacologyandpharmacokinetics assessments, which will provide overwhelming evidence for pre-clinical study in vivo.

Enhancement of hair growth through stimulation of hair follicle stem cells by prostaglandin E2 collagen matrix.

Prostaglandin metabolism is involved in the regulation of the periodic process of hair follicles. Preliminary research data reported that prostaglandin E2 (PGE2) exhibits potential in hair growth. However, the relevant evidence is still insufficient. Herein, we prepared a PGE2 matrix by conjugating PGE2 with collagen via crosslinkers to avoid rapid degradation of PGE2 molecules in vivo. First, we measured the physical properties of the PGE2 matrix. A mouse model of hair loss was established, and PGE2 matrix subcutaneous injection was applied to evaluate hair growth. Under different treatments with the PGE2 matrix, the morphology of hair follicles, the dynamic expression of hair follicle stem cell markers and key regulators in the hair growth cycle were explored. Our data revealed that the PGE2 matrix increased the proportion of developing hair follicles at the early growth stage. Improvements in hair follicle stem cells, such as Sox9+ and Lgr5+ cells, have also been confirmed as therapeutic effects of PGE2 to stimulate hair follicle growth. Our study indicated that PGE2 exhibits effective roles in hair development during anagen. Furthermore, the results also highlight the potential of the PGE2 delivery system as a novel therapeutic strategy for the treatment of hair disorders in the future.

Changes in serum angiogenic factors among patients with acute pain and subacute pain.

Screening serum biomarkers for acute and subacute pain is important for precise pain management. This study aimed to examine serum levels of angiogenic factors in patients with acute and subacute pain as potential biomarkers. Serum samples were collected from 12 healthy controls, 20 patients with postherpetic neuralgia (PHN), 4 with low back pain (LBP), and 1 with trigeminal neuralgia (TN). Pain intensity in these patients was evaluated using the visual analog scale (VAS). The serum concentrations of 11 angiogenic biomarkers were examined by Milliplex Map Human Angiogenesis Magnetic Bead Panel 2. The pain assessment from VAS showed that all patients showed moderate and severe pain. Among 11 angiogenic factors, osteopontin (OPN), thrombospondin-2 (TSP-2), soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1), soluble urokinase-type plasminogen activator receptor (suPAR), and soluble epidermal growth factor receptors (sErbB2) were up-regulated and soluble interleukin-6 receptor α (sIL-6Rα) were down-regulated in patients with pain compared to the healthy participants (all P-values were < 0.005). Moreover, a linear regression model showed that the serum OPN concentration was correlated with pain intensity in patients with PHN (P = 0.03). There was no significant difference between the serum concentration of soluble epidermal growth factor receptors, sErbB3, soluble AXL, tenascin, and soluble neuropilin-1 in patients with acute and subacute pain and that of healthy controls. The results of this study provided new valuable insights into our understanding of angiogenic factors that may contribute to as mechanistic biomarkers of pain, and reveal the pathophysiological mechanism of pain. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2200061775.

Transient upregulation of EGR1 signaling enhances kidney repair by activating SOX9+ renal tubular cells.

Background: Acute kidney injury (AKI) is associated with damage to the nephrons and tubular epithelial cells (TECs), which can lead to chronic kidney disease and end-stage renal disease. Identifying new biomarkers before kidney dysfunction will offer crucial insight into preventive and therapeutic options for the treatment of AKI. Early growth response 1 (EGR1) has been found to be a pioneer transcription factor that can sequentially turn on/off key downstream genes to regulate whole-body regeneration processes in the leopard worm. Whether EGR1 modulates renal regeneration processes in AKI remains to be elucidated. Methods: AKI models of ischemia-reperfusion injury (IRI) and folic acid (FA) were developed to investigate the roles of EGR1 in kidney injury and regeneration. To further determine the function of EGR1, Egr1-/- mice were applied. Furthermore, RNA sequencing of renal TECs, Chromatin Immunoprecipitation (ChIP) assay, and Dual-luciferase reporter assay were carried out to investigate whether EGR1 affects the expression of SOX9. Results: EGR1 is highly expressed in the kidney after AKI both in humans and mice through analysis of the Gene Expression Omnibus (GEO) database. Furthermore, we verified that EGR1 rapidly up-regulates in the very early stage of IRI and nephrotoxic models of AKI, and validation studies confirmed the essential roles of EGR1 in renal tubular cell regeneration. Further experiments affirmed that genetic inhibition of Egr1 aggravates the severity of AKI in mouse models. Furthermore, our results revealed that EGR1 could increase SOX9 expression in renal TECs by directly binding to the promoter of the Sox9 gene, thus promoting SOX9+ cell proliferation by activating the Wnt/ß-catenin pathway. Conclusions: Together, our results demonstrated that rapid and transient induction of EGR1 plays a renoprotective role in AKI, which highlights the prospects of using EGR1 as a potential therapeutic target for the treatment of AKI.