Sorbin and SH3 Domain Containing 2 (SORBS2), a multifunctional scaffold protein harbouring Sorbin homology (SoHo) and Src homology 3 (SH3) domains, serves as a molecular hub in human diseases by integrating cytoskeletal remodelling, signal transduction and RNA metabolic regulation. This study systematically analyses SORBS2's molecular features, expression regulatory mechanism and disease associations. In oncology, it suppresses metastasis via enhancing the stability of certain mRNAs and immunomodulation yet exhibits oncogenic properties in triple-negative breast cancer. Cardiovascular manifestations demonstrate dose-sensitive pathology: deficiency causes arrhythmogenic cytoskeletal disorganization, while overexpression induces β-tubulin hyper polymerization and ventricular maldevelopment. Epigenetic silencing by miR-484 exacerbates metabolic liver disease, whereas defective interaction with the large-conductance Ca2+-activated K+ (BK) channel drives diabetic vasculopathy. Neurologically, it modulates synaptic remodelling and neuroinflammatory pathways. Functioning as a signalling nexus, SORBS2 interconnects chronic inflammation, oxidative stress and metabolic dysfunction, supporting 'one target for multiple diseases' strategy. Future research requires integration of single-cell omics, Artificial intelligence (AI)-based drug design and epigenetic editing for clinical translation.

BACKGROUND:Keloid formation is a chronic inflammatory skin disease, characterized by abnormal fibroproliferative scars. There are no effective treatments. Many factors are involved in keloid formation, primarily a highly active inflammatory response, wound tension and hereditary susceptibility. Collagen signalling plays important roles in various diseases, including fibrotic diseases and tumours, but its function in keloid inflammation remains unknown. OBJECTIVES:To study the roles and mechanisms of collagen signalling in inflammation development during keloid formation. METHODS:Normal and keloid keratinocytes along with fibroblasts were isolated from fresh normal skin and keloid tissues. Picrosirius red staining, Western blotting, quantitative polymerase chain reaction, co-immunoprecipitation, APEX2-mediated proximity biotinylation, enzyme-linked immunosorbent assay, immunohistochemistry and immunofluorescence were used to discover the roles of collagen I-discoidin domain receptor 1 (DDR1) signalling in the development of inflammation. Human keloid samples were subcutaneously transplanted onto nude mice to build a keloid xenograft model. The therapeutic potential of a DDR1 inhibitor (7rh) and an ADP-ribosylation factor 6 (ARF6) inhibitor (NAV-2729) was examined in keloid inflammation development. RESULTS:In keloid tissue, we found significant elevation of both phosphorylated nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3). In keloid tissue: (i) collagen I was upregulated and comprised the vast proportion of collagen types; (ii) collagen I signalling promoted activation of the keloid inflammation amplifier by DDR1; (iii) DDR1 and ARF6 were upregulated, and their levels positively correlated with each other; (iv) elevated DDR1 was mainly expressed in fibroblasts, in keloid dermal tissues; (v) collagen I-DDR1 signalling activated NFκB and STAT3 signalling; and (vi) in the keloid xenograft model, 7rh restrained keloid inflammation development and growth. Mechanistically, DDR1 interacted with ARF6, which promoted transport of DDR1 to the plasma membrane and amplified collagen I-induced DDR1 signalling, then facilitated binding of DDR1 to STAT3, leading to STAT3 phosphorylation. The combined inhibition of DDR1 and ARF6 synergistically inhibited the keloid inflammation amplifier. CONCLUSIONS:Collectively, these findings reveal the molecular basis of the activation of NFκB and STAT3 signalling via collagen I-DDR1 signalling, and expose the role of the ARF6-DDR1 axis in promoting keloid inflammation development, indicating that DDR1 and ARF6 may serve as innovative therapeutic targets in keloid scars.

Author’s reply to ‘Beyond physical proximity and “tool cells”: the missing catalytic evidence in the DDR1-STAT3 axis of keloids’ by Qu et al.

To evaluate whether transcatheter patent foramen ovale (PFO) closure is associated with higher rates of complete migraine remission in children with migraine and a concomitant right-to-left shunt. We conducted a single-center retrospective cohort study of children with migraine and PFO-mediated right-to-left shunting. The primary exposure was transcatheter PFO closure; the primary outcome was complete migraine remission (no attacks for ≥ 3 consecutive months) assessed at 1, 3, 6, and 12 months post-discharge. Kaplan–Meier and multivariable Cox regression with a 3-month landmark were adjusted for right-to-left shunt (RLS) grade, age, sex, duration of the current headache episode, body mass index, and concomitant flunarizine prophylaxis. Among 66 children (mean age 10.3 years; 67

Patent ductus arteriosus (PDA) is one of the most common forms of congenital heart disease (CHD). Infectious endocarditis (IE) is a rare but serious complication of PDA. PDA combined with pulmonary artery aneurysm (PAA) due to IE is rare in children. In this report, we report a rare pediatric PDA case, complicated with PAA due to IE. Transcatheter closure of PDA without the surgical intervention of PAA was performed, with a favorable prognosis.

BACKGROUND:Hyperhomocysteinemia (HHcy) and type 2 diabetes (T2D) are recognized risk factors for non-healing wounds, yet their combined effects and underlying mechanisms remain unclear. METHODS:In this study of 8406 National Health and Nutrition Examination Survey participants (1999-2004), weighted logistic regression was used to estimate odds ratios for non-healing wounds and Cox proportional hazards models were employed to assess hazard ratios for all-cause mortality. Additive and multiplicative interactions were evaluated. Nonlinear relationships used restricted cubic splines. Mediation analyses explored inflammatory marker contributions. Bulk transcriptomic and single-cell sequencing data were integrated to identify homocysteine (Hcy)-diabetic foot ulcers (DFU) hub genes, construct an Hcy risk gene scoring system, and elucidate key mechanisms by which Hcy remodels the DFU microenvironment. RESULTS:Both T2D [odds ratio (OR): 2.42, 95% confidence interval (CI): 1.69-3.47] and HHcy (OR: 1.67, 95% CI: 1.10-2.54) independently elevated non-healing wound risk. Participants with both conditions exhibited higher odds (OR: 5.28, 95% CI: 3.20-8.70), with additive interaction (relative excess risk due to interaction: 2.83, AP: 0.54, SI: 2.95). In diabetic men, Hcy displayed a J-shaped relationship with non-healing wounds ( P for nonlinearity = 0.027), with the lowest risk around 8.9 µmol/L. In diabetic patients, inflammatory markers mediated the link, with proportions of 11.1% for red cell distribution width, 9.16% for monocyte/lymphocyte ratio, 5.28% for systemic inflammation response index, and 4.03% for neutrophil/lymphocyte ratio. Hcy drove immune-metabolic reprogramming in the DFU microenvironment by regulating key gene networks such as IL1B and MMP9, activating the MIF-CD74/CXCR4 axis to form a B cell-centric inflammatory cascade network. Both T2D and HHcy were associated with higher all-cause mortality, without joint interaction observed. Participants with a history of non-healing wounds had a higher all-cause mortality risk. CONCLUSIONS:T2D and HHcy synergistically worsen non-healing wounds, but not all-cause mortality. In diabetic males, Hcy levels displayed a J-shaped relationship with non-healing wound risk. Mechanistically, Hcy amplified systemic inflammation and drove stromal-immune crosstalk via the MIF-CD74/CXCR4 axis, reshaping the diabetic wound microenvironment.

BACKGROUND:Condyloma acuminatum (CA) is caused by low-risk HPV infection and characterized by benign epithelial proliferation. NELL2, as a secreted glycoprotein, is strongly linked to dermatosis, but its function in CA remains unknown. OBJECTIVE:To investigate the expression, function and mechanism of NELL2 in CA. METHODS:The expression of NELL2 was detected in CA and normal skin tissues. HaCaT cells stably expressing HPV11-E7 (HPV11-E7-HaCaT) and control group (Vector-HaCaT) were constructed to explore the relationship between HPV infection and NELL2 expression. We downregulated NELL2 expression in HPV11-E7-HaCaT cells and added recombinant human NELL2 to medium of Vector-HaCaT and HPV11-E7-HaCaT cells to examine the effects of NELL2 on cell proliferation and apoptosis. The activation of MAPK pathway and the role of Robo3 were evaluated to explore the mechanisms underlying these effects. RESULTS:NELL2 was overexpressed in CA, and increased NELL2 expression was positively associated with high HPV copy number and high Ki67 expression. HPV11-E7 induced the expression of NELL2 in HaCaT cells. In addition, NELL2 promoted proliferation and inhibited apoptosis in HPV11-E7-HaCaT and Vector-HaCaT cells through autocrine and paracrine mechanisms. NELL2 treatment activated the ERK pathway, and ERK inhibition by U0126 confirmed that ERK pathway was essential for the function of NELL2 in CA. Moreover, Robo3 acts as the NELL2 receptor in CA. CONCLUSION:NELL2 binds Robo3 to promote keratinocyte proliferation and inhibit keratinocyte apoptosis in CA through autocrine and paracrine mechanisms. NELL2-Robo3 signaling may be regarded as a potential target for CA treatment in the future.

Background and Objective: Predicting potential risk factors for the occurrence of coronary artery lesions (CAL) in children with Kawasaki disease (KD) is critical for subsequent treatment. The aim of our study was to establish and validate a nomograph-based model for identifying children with KD at risk for CAL. Methods: Hospitalized children with KD attending Wuhan Children's Hospital from Jan 2011 to Dec 2023 were included in the study and were grouped into a training set (4793 cases) and a validation set (2054 cases) using a simple random sampling method in a 7:3 ratio. The analysis was performed using RStudio software, which first used LASSO regression analysis to screen for the best predictors, and then analyzed the screened predictors using logistic regression analysis to derive independent predictors and construct a nomogram model to predict CAL risk. The receiver operating characteristic (ROC) and calibration curves were employed to evaluate the discrimination and calibration of the model. Finally, decision curve analysis (DCA) was utilized to validate the clinical applicability of the models assessed in the data. Results: Of the 6847 eligible children with KD included, 845 (12 %) were ultimately diagnosed with CAL, of whom 619 were boys (73 %) with a median age of 1.81 (0.74, 3.51) years. Six significant independent predictors were identified, including sex, intravenous immunoglobulin nonresponse, peripheral blood hemoglobin, platelet distribution width, platelet count, and serum albumin. Our model has acceptable discriminative power, with areas under the curve at 0.671 and 0.703 in the training and validation sets, respectively. DCA analysis showed that the prediction model had great clinical utility when the threshold probability interval was between 0.1 and 0.5. Conclusions: We constructed and internally validated a nomograph-based predictive model based on six variables consisting of sex, intravenous immunoglobulin nonresponse, peripheral blood hemoglobin, platelet distribution width, platelet count, and serum albumin, which may be useful for earlier identification of children with KD who may have CAL.

Background Atrial tachycardia (AT) originating from the left atrial appendage (LAA) is uncommon and the most difficult arrhythmia to eliminate. Therefore, we present the case of a 5-year-old girl with tachycardia-induced cardiomyopathy (TIC) caused by AT originating from the LAA and successfully treated with RFCA associated to left atrial appendectomy. With resolution of AT, we observed a progressive improvement of LV function. The effectiveness and safety of this combination therapy were evaluated over a one-month follow-up period.Case presentation A 5 -year-old female was evaluated for three days of incessant cough and a syncopal episode. Surface echocardiography and 24-hour monitoring showed that the infant had persistent atrial tachycardia. Echocardiography revealed an enlarged tele diastolic diameter (46.1 mm) and malfunctioning (EF 28.53%) left ventricle. The location of the lesion at the apex of the LAA was further confirmed by electrophysiological study and RFCA. After RFCA, the infant's ECG monitor showed that sinus rhythm was maintained for up to 22 h. Subsequently, atrial tachycardia recurred and sinus rhythm disappeared. Finally, atrial appendectomy was performed and sinus rhythm returned to normal.Conclusions The heart function of the infant improved and sinus rhythm was maintained, further demonstrating the safety and effectiveness of combined treatment with RFCA and atrial appendectomy after electrophysiological localization of AT from LAA to TIC.

RATIONALE:Long QT interval syndrome type 7 (LQT7) is a rare hereditary multisystem disorder characterized by a classic triad of ventricular arrhythmias with QT interval prolongation, periodic paralysis, and distinctive skeletal and facial features. The Kir2.1 protein is encoded by the KCNJ2 gene, which has been associated with LQT7. PATIENT CONCERNS:We report an 8-year-old boy who presented with frequent premature ventricular contraction with QRS electrical alternans, QT interval prolongation, bidirectional ventricular tachycardia, and learning disability with poor school performance. Gene sequencing revealed a novel missense mutation in the KCNJ2 gene (c.224 C>A, p.Thr75Lys). DIAGNOSES:The patient was diagnosed as LQT7 and a learning disability. INTERVENTIONS:During the follow-up period, the ventricular arrhythmias were difficult to treat with β-blocker. Due to the frequent premature ventricular contraction and bidirectional ventricular tachycardia, radiofrequency catheter ablation was tried but failed. OUTCOMES:An implantable cardioverter-defibrillator was recommended due to the recurrent syncope, but the boy's legal guardian rejected the recommendation, opting to continue his treatment in another hospital. LESSONS:Clinical management is mostly focused on reducing adverse cardiac events. As a first option, β-blockers are often chosen as treatments for LQT7 patients, but there is no clear evidence for their effectiveness in preventing fatal arrhythmias. If the drug treatment is not effective, radiofrequency catheter ablation can be considered. However, it may be difficult to target accurately the right spot, and the attempt of the radiofrequency catheter ablation failed. Therefore, after ineffective medical treatment, implantable cardioverter-defibrillator implantation could be an option for patients with life-threatening cardiac events.

SPRY4 is a protein encoding gene that belongs to the Spry family. It inhibits the mitogen-activated protein kinase (MAPK) signaling pathway and plays a role in various biological functions under normal and pathological conditions. The SPRY4 protein has a specific structure and interacts with other molecules to regulate cellular behavior. It serves as a negative feedback inhibitor of the receptor protein tyrosine kinases (RTK) signaling pathway and interferes with cell proliferation and migration. SPRY4 also influences inflammation, oxidative stress, and cell apoptosis. In different types of tumors, SPRY4 can act as a tumor suppressor or an oncogene. Its dysregulation is associated with the development and progression of various cancers, including colorectal cancer, glioblastoma, hepatocellular carcinoma, perihilar cholangiocarcinoma, gastric cancer, breast cancer, and lung cancer. SPRY4 is also involved in organ development and is associated with ischemic diseases. Further research is ongoing to understand the expression and function of SPRY4 in specific tumor microenvironments and its potential as a therapeutic target.

Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.

In the process of bone metabolism and bone remodeling, bone marrow mesenchymal stem cells (BM-MSCs) differentiate into osteoblasts (OBs) under certain conditions to enable the formation of new bone, and normal bone reconstruction and pathological bone alteration are closely related to the differentiation and proliferation functions of OBs. Osteogenic differentiation of BM-MSCs involves multiple signaling pathways, which function individually but interconnect intricately to form a complex signaling regulatory network. Natural compounds have fewer adverse effects than chemically synthesized drugs, optimize bone health, and are more suitable for long-term use. In this paper, we focus on OBs, summarize the current research progress of signaling pathways related to OBs differentiation, and review the molecular mechanisms by which chemically synthesized drugs with potential anti-osteoporosis properties regulate OBs-mediated bone formation.

Homeobox (HOX) C9, a member of the HOX family, is an important transcription factor, and it plays a significant role in various biological processes. This family of genes is highly valued for their essential roles in establishing and maintaining the body axis during embryonic development and adult tissues. Further, HOXC9 plays a central role in neuronal differentiation, angiogenesis, and adipose distribution, which are essential for the development of the nervous system, maturation of tissues and organs, and maintenance of energy balance and metabolic health. Recent research has found that abnormal HOXC9 expression is closely associated with the development and progression of various tumor types. The HOXC9 expression level can be an indicator of tumor prognosis. Therefore, elucidating the association between HOXC9 expression and its regulatory mechanisms and tumorigenesis can provide novel insights on the diagnosis and treatment of patients with cancer.

Nuclear receptors (NRs) are key regulators of multiple physiological functions and pathological changes in the liver in response to a variety of extracellular signaling changes. Retinoid X receptor (RXR) is a special member of the NRs, which not only responds to cellular signaling independently, but also regulates multiple signaling pathways by forming heterodimers with various other NR. Therefore, RXR is widely involved in hepatic glucose metabolism, lipid metabolism, cholesterol metabolism and bile acid homeostasis as well as hepatic fibrosis. Specific activation of particular dimers regulating physiological and pathological processes may serve as important pharmacological targets. So here we describe the basic information and structural features of the RXR protein and its heterodimers, focusing on the role of RXR heterodimers in a number of physiological processes and pathological imbalances in the liver, to provide a theoretical basis for RXR as a promising drug target.

BACKGROUND:Hepatocellular Carcinoma (HCC) possesses the high mortality in cancers worldwide. Nevertheless, the concrete mechanism underlying HCC proliferation remains obscure. In this study, we show that high expression of ARF6 is associated with a poor clinical prognosis, which could boost the proliferation of HCC.METHODS:Immunohistochemistry and western blotting were used to detect the expression level of ARF6 in HCC tissues. We analyzed the clinical significance of ARF6 in primary HCC patients. We estimated the effect of ARF6 on tumor proliferation with in vitro CCK8, colony formation assay, and in vivo nude mouse xenograft models. Immunofluorescence was conducted to investigate the ARF6 localization. western blotting was used to detect the cell cycle-related proteins with. Additionally, we examined the correlation between ARF6 and STAT3 signaling in HCC with western blotting, immunohistochemistry and xenograft assay.RESULTS:ARF6 was upregulated in HCC tissues compared to adjacent normal liver tissues. The increased expression of ARF6 correlated with poor tumor differentiation, incomplete tumor encapsulation, advanced tumor TNM stage and poor prognosis. ARF6 obviously promoted HCC cell proliferation, colony formation, and cell cycle progression. In vivo nude mouse xenograft models showed that ARF6 enhanced tumor growth. Furthermore, ARF6 activated the STAT3 signaling and ARF6 expression was positively correlated with phosphorylated STAT3 level in HCC tissues. Furthermore, after intervening of STAT3, the effect of ARF6 on tumor-promoting was weakened, which demonstrated ARF6 functioned through STAT3 signaling in HCC.CONCLUSIONS:Our results indicate that ARF6 promotes HCC proliferation through activating STAT3 signaling, suggesting that ARF6 may serve as potential prognostic and therapeutic targets for HCC patients.

Mitochondria play a central role in cellular energy conversion, metabolism, and cell proliferation. The regulation of mitochondrial function by HIGD1A, which is located on the inner membrane of the mitochondria, is essential to maintain cell survival under hypoxic conditions. In recent years, there have been shown other cellular pathways and mechanisms involving HIGD1A diametrically or through its interaction. As a novel regulator, HIGD1A maintains mitochondrial integrity and enhances cell viability under hypoxic conditions, increasing cell resistance to hypoxia. HIGD1A mainly targets cytochrome c oxidase by regulating downstream signaling pathways, which affects the ATP generation system and subsequently alters mitochondrial respiratory function. In addition, HIGD1A plays a dual role in cell survival in distinct degree hypoxia regions of the tumor. Under mild and moderate anoxic areas, HIGD1A acts as a positive regulator to promote cell growth. However, HIGD1A plays a role in inhibiting cell growth but retaining cellular activity under severe anoxic areas. We speculate that HIGD1A engages in tumor recurrence and drug resistance mechanisms. This review will focus on data concerning how HIGD1A regulates cell viability under hypoxic conditions. Therefore, HIGD1A could be a potential therapeutic target for hypoxia-related diseases.

Background: IFN-& epsilon; is essential in combating viral infections, particularly in epithelial cells and protected mucosal tissues. Its protective effects have been demonstrated against HSV2, Zika virus, HIV and SARS-COV2. However, the specific expression and role of IFN-& epsilon; in skin keratinocytes and HPV infection are still not fully understood and require further investigation.Objective: In this study, we aimed to investigate the functions and expression mechanism of IFN-& epsilon; in keratinocytes during HPV infection and the progression of condyloma acuminata.Methods: Keratinocytes isolated from biopsied CA warts and normal skins samples were analyzed by MeRIP-seq analysis. IFN-& epsilon; and WTAP in CA warts and normal skins were analyzed by immunostaining and qPCR.Results: In this study, we identified IFN-e was markedly upregulated in CA warts and HPV-infected keratinocytes. IFN-e expression also showed negatively correlation with the size of CA warts (R=-0.4646, P = 0.009). IFN-e suppressed the susceptibility of HPV infection directly. m6A analysis reveals WTAP is a key m6A writer promoting the m6A modification of IFNE mRNA.Conclusion: Our research suggests that IFN-e is an important Type I IFN cytokine involved in the development of genital warts. Furthermore, we found that HPV infection affects the m6A modifications of IFNE through a mechanism dependent on WTAP. This study provides insights into the innate immune response of the host to HPV infection and may contribute to the development of future strategies for regulating innate immunity to treat genital warts. & COPY; 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

MicroRNA 484 (miR‐484) plays a pivotal role in the development and progression of different diseases and is typically described as a mitochondrial regulator. Whether miR‐484 is involved in lipid metabolism or exerts a role in nonalcoholic fatty liver disease remains unclear.