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Volume 12 ， Issue 2 ， 2025
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Endophilin A2 controls touch and mechanical allodynia
via kinesin-mediated Piezo2 trafficking AI Introduction“In the field of mechanical pain research, the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and sustaining transmission of touch and mechanical hypersensitivity signals. Expert EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons, which provides a potential new target for the treatment of mechanical pain.”
Abstract：Background:Tactile and mechanical pain are crucial to our interaction with the environment, yet the underpinning molecular mechanism is still elusive. Endophilin A2 (EndoA2) is an evolutionarily conserved protein that is documented in the endocytosis pathway. However, the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear.Methods:Male and female C57BL/6 mice (8–12 weeks) and male cynomolgus monkeys (7–10 years old) were used in our experiments. Nerve injury-, inflammatory-, and chemotherapy-induced pathological pain models were established for this study. Behavioral tests of touch, mechanical pain, heat pain, and cold pain were performed in mice and nonhuman primates. Western blotting, immunostaining, co-immunoprecipitation, proximity ligation and patchclamp recordings were performed to gain insight into the mechanisms.Results:The results showed that EndoA2 was primarily distributed in neurofilament-200-positive (NF200+) mediumto-large diameter dorsal root ganglion (DRG) neurons of mice and humans. Loss of EndoA2 in mouse NF200+ DRG neurons selectively impaired the tactile and mechanical allodynia. Furthermore, EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons. Moreover, as an adaptor protein, EndoA2 also bound to kinesin family member 5B (KIF5B), which was involved in the EndoA2-mediated membrane trafficking process of Piezo2. Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents, and re-expression of EndoA2 rescued the MA currents. In addition, interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates.Conclusions:Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals. EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons. Our findings identify a potential new target for the treatment of mechanical pain.Keywords：Endophilin A2;Touch;Mechanical allodynia;Piezo2;kinesin family member 5B (KIF5B)65|4|0Updated：2025-12-13 - “In the field of liver ischemia/reperfusion injury, this study introduces its research progress. Expert xx verified the conjecture that interferon-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, which provides solutions to prevent hepatic ferroptosis during liver I/R injury.”
Abstract：Background:Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family.Methods:The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep−/−. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS).Results:Excessive production of reactive oxygen species (ROS) decreased the expression of the interferon (IFN)-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the N6-methyladenosine (m6A) reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis.Conclusions:This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.Keywords：Ischemia/reperfusion (I/R);DExH-box helicase 58 (DHX58);Glutathione peroxidase 4 (GPX4);N6-methyladenosine (m6A) modification;YT521-B homology domain containing 2 (YTHDC2)38|0|0Updated：2025-12-13 -
Neuronal Panx1 drives peripheral sensitization in experimental plantar inflammatory pain AI Introduction
Abstract：Background:The channel-forming protein Pannexin1 (Panx1) has been implicated in both human studies and animal models of chronic pain, but the underlying mechanisms remain incompletely understood.Methods:Wild-type (WT, n=24), global Panx1 KO (n=24), neuron-specific Panx1 KO (n=20), and glia-specific Panx1 KO (n=20) mice were used in this study at Albert Einstein College of Medicine. The von Frey test was used to quantify pain sensitivity in these mice following complete Freund’s adjuvant (CFA) injection (7, 14, and 21 d). The qRT-PCR was employed to measure mRNA levels of Panx1, Panx2, Panx3, Cx43, Calhm1, and β-catenin. Laser scanning confocal microscopy imaging, Sholl analysis, and electrophysiology were utilized to evaluate the impact of Panx1 on neuronal excitability and morphology in Neuro2a and dorsal root ganglion neurons (DRGNs) in which Panx1 expression or function was manipulated. Ethidium bromide (EtBr) dye uptake assay and calcium imaging were employed to investigate the role of Panx1 in adenosine triphosphate (ATP) sensitivity. β-galactosidase (β-gal) staining was applied to determine the relative cellular expression levels of Panx1 in trigeminal ganglia (TG) and DRG of transgenic mice.Results:Global or neuron-specific Panx1 deletion markedly decreased pain thresholds after CFA stimuli (7, 14, and 21 d; P<0.01 vs. WT group), indicating that Panx1 was positively correlated with pain sensitivity. In Neuro2a, global Panx1 deletion dramatically reduced neurite extension and inward currents compared to the WT group (P<0.05), revealing that Panx1 enhanced neurogenesis and excitability. Similarly, global Panx1 deletion significantly suppressed Wnt/β-catenin dependent DRG neurogenesis following 5 d of nerve growth factor (NGF) treatment (P<0.01 vs. WT group). Moreover, Panx1 channels enhanced DRG neuron response to ATP after CFA injection (P<0.01 vs. Panx1 KO group). Furthermore, ATP release increased Ca2+ responses in DRGNs and satellite glial cells surrounding them following 7 d of CFA treatment (P<0.01 vs. Panx1 KO group), suggesting that Panx1 in glia also impacts exaggerated neuronal excitability. Interestingly, neuron-specific Panx1 deletion was found to markedly reduce differentiation in cultured DRGNs, as evidenced by stunted neurite outgrowth (P<0.05 vs. Panx1 KO group; P<0.01 vs. WT group or GFAP-Cre group), blunted activation of Wnt/β-catenin signaling (P<0.01 vs. WT, Panx1 KO and GFAP-Cre groups), and diminished cell excitability (P<0.01 vs. GFAP-Cre group) and response to ATP stimulation (P<0.01 vs. WT group). Analysis of β-gal staining showed that cellular expression levels of Panx1 in neurons are significantly higher (2.5-fold increase) in the DRG than in the TG.Conclusions:The present study revealed that neuronal Panx1 is a prominent driver of peripheral sensitivity in the setting of inflammatory pain through cell-autonomous effects on neuronal excitability. This hyperexcitability dependence on neuronal Panx1 contrasts with inflammatory orofacial pain, where similar studies revealed a prominent role for glial Panx1. The apparent differences in Panx1 expression in neuronal and non-neuronal TG and DRG cells are likely responsible for the distinct impact of these cell types in the two pain models.Keywords：Pannexin1 (Panx1);dorsal root ganglion;Satellite glial cell;Peripheral sensitization;Plantar inflammatory pain36|1|0Updated：2025-12-13
RESEARCH
- “Advancements in single-cell and spatial transcriptomics have enabled a detailed molecular comprehension of the complex regulation of cell fate, significantly contributing to the development of personalized medicine. This review outlines the significance of single-cell RNA sequencing (scRNA-seq) in prostate cancer research, highlighting key molecular targets for diagnosis, treatment, and drug resistance characteristics. These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer.”
Abstract：In recent years, advancements in single-cell and spatial transcriptomics, which are highly regarded developments in the current era, particularly the emerging integration of single-cell and spatiotemporal transcriptomics, have enabled a detailed molecular comprehension of the complex regulation of cell fate. The insights obtained from these methodologies are anticipated to significantly contribute to the development of personalized medicine. Currently, single-cell technology is less frequently utilized for prostate cancer compared with other types of tumors. Start-ing from the perspective of RNA sequencing technology, this review outlined the signifcance of single-cell RNA sequencing (scRNA-seq) in prostate cancer research, encompassing preclinical medicine and clinical applications. We summarize the differences between mouse and human prostate cancer as revealed by scRNA-seq studies, as well as a combination of multi-omics methods involving scRNA-seq to highlight the key molecular targets for the diagnosis, treatment, and drug resistance characteristics of prostate cancer. These studies are expected to provide novel insights for the development of immunotherapy and other innovative treatment strategies for castration-resistant prostate cancer. Furthermore, we explore the potential clinical applications stemming from other single-cell technologies in this review, paving the way for future research in precision medicine.Keywords：prostate cancer;Single-cell RNA sequencing (scRNA-seq);Tumor microenvironment;Tumor heterogeneity;Treatment resistance;Precision medicine32|0|0Updated：2025-12-13 - “Reporting on the latest advancements in wound care, this review delves into the current therapies and experimental approaches for chronic, non-healing wounds. It offers insights into the efficacy and limitations of cellular and immunotherapies, laying a foundation for the construction of an evidence-based system to optimize patient care long-term.”
Abstract：Chronic, non-healing wounds represent a significant challenge for healthcare systems worldwide, often requiring significant human and financial resources. Chronic wounds arise from the complex interplay of underlying comorbidities, such as diabetes or vascular diseases, lifestyle factors, and genetic risk profiles which may predispose extremities to local ischemia. Injuries are further exacerbated by bacterial colonization and the formation of biofilms. Infection, consequently, perpetuates a chronic inflammatory microenvironment, preventing the progression and completion of normal wound healing. The current standard of care (SOC) for chronic wounds involves surgical debridement along with localized wound irrigation, which requires inpatient care under general anesthesia. This could be followed by, if necessary, defect coverage via a reconstructive ladder utilizing wound debridement along with skin graft, local, or free flap techniques once the wound conditions are stabilized and adequate blood supply is restored. To promote physiological wound healing, a variety of approaches have been subjected to translational research. Beyond conventional wound healing drugs and devices that currently supplement treatments, cellular and immunotherapies have emerged as promising therapeutics that can behave as tailored therapies with cell- or molecule-specific wound healing properties. However, in contrast to the clinical omnipresence of chronic wound healing disorders, there remains a shortage of studies condensing the current body of evidence on cellular therapies and immunotherapies for chronic wounds. This review provides a comprehensive exploration of current therapies, experimental approaches, and translational studies, offering insights into their efficacy and limitations. Ultimately, we hope this line of research may serve as an evidence-based foundation to guide further experimental and translational approaches and optimize patient care long-term.Keywords：Chronic wounds;Wound healing;Wound healing disorder;Biofilm;Immunotherapies;Cellular therapies40|1|0Updated：2025-12-13 -
Exosomal mediators in sepsis and inflammatory organ injury: unraveling the role of exosomes in intercellular crosstalk and organ dysfunction AI Introduction
“In the field of sepsis research, this paper highlights the emerging significance of exosomes in modulating immune responses, metabolic reprogramming, coagulopathy, and organ dysfunction. Expert xx established the xx system, which provides solutions to solve the complex pathophysiology of sepsis and lays a foundation for the construction of novel interventions to mitigate severe outcomes.”
Abstract：Sepsis, a severe systemic inflammatory response to infection, remains a leading cause of morbidity and mortality worldwide. Exosomes, as mediators of intercellular communication, play a pivotal role in the pathogenesis of sepsis through modulating immune responses, metabolic reprogramming, coagulopathy, and organ dysfunction. This review highlights the emerging significance of exosomes in these processes. Initially, it provides an in-depth insight into exosome biogenesis and characterization, laying the groundwork for understanding their diverse and intricate functions. Subsequently, it explores the regulatory roles of exosomes in various immune cells such as neutrophils, macrophages, dendritic cells, T cells, and B cells. This analysis elucidates how exosomes are pivotal in modulating immune responses, thus contributing to the complexity of sepsis pathophysiology. Additionally, this review delves into the role of exosomes in the regulation of metabolism and subsequent organ dysfunction in sepsis. It also establishes a connection between exosomes and the coagulation cascade, which affects endothelial integrity and promotes thrombogenesis in sepsis. Moreover, the review discusses the dual role of exosomes in the progression and resolution of sepsis, exploring their complex involvement in inflammation and healing processes. Furthermore, it underscores their potential as biomarkers and therapeutic targets. Understanding these mechanisms presents new opportunities for novel interventions to mitigate the severe outcomes of sepsis, emphasizing the therapeutic promise of exosome research in critical care settings.Keywords：sepsis;Exosomes;Intercellular crosstalk;Inflammation;Biomarkers38|2|0Updated：2025-12-13 - “In the field of orthopedics, a comprehensive review presents a streamlined approach to obtaining high-quality single cells from skeletal tissue and provides an overview of existing single-cell RNA sequencing technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. This research has paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders.”
Abstract：Orthopedic conditions have emerged as global health concerns, impacting approximately 1.7 billion individuals worldwide. However, the limited understanding of the underlying pathological processes at the cellular and molecular level has hindered the development of comprehensive treatment options for these disorders. The advent of single-cell RNA sequencing (scRNA-seq) technology has revolutionized biomedical research by enabling detailed examination of cellular and molecular diversity. Nevertheless, investigating mechanisms at the single-cell level in highly mineralized skeletal tissue poses technical challenges. In this comprehensive review, we present a streamlined approach to obtaining high-quality single cells from skeletal tissue and provide an overview of existing scRNA-seq technologies employed in skeletal studies along with practical bioinformatic analysis pipelines. By utilizing these methodologies, crucial insights into the developmental dynamics, maintenance of homeostasis, and pathological processes involved in spine, joint, bone, muscle, and tendon disorders have been uncovered. Specifically focusing on the joint diseases of degenerative disc disease, osteoarthritis, and rheumatoid arthritis using scRNA-seq has provided novel insights and a more nuanced comprehension. These findings have paved the way for discovering novel therapeutic targets that offer potential benefits to patients suffering from diverse skeletal disorders.Keywords：Skeletal disorders;Musculoskeletal system;Single-cell RNA sequencing (scRNA-seq);Cellular heterogeneity;Single cell suspension;Bioinformatic analysis41|3|0Updated：2025-12-13
REVIEW
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Gulf War illness with or without post-traumatic stress disorder: differential symptoms and immune responses AI Introduction
“In the field of xxx, expert xx has made significant research progress. By establishing the xx system/exploring the xx topic/verifying the xx conjecture, they have provided solutions to address xx problems/open up a new direction for xx research/lay a foundation for the construction of the xx system.”Keywords：Gulf war illness;Immune response;Interleukin-15;Natural killer cells;Post-traumatic stress disorder;T lymphocytes16|0|0Updated：2025-12-13
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