MicroRNAs (miRNAs) are small noncoding RNAs that control gene expression at the post-transcriptional level and are involved in the pathogenesis of epilepsy. Although miRNA-32-5p (miR-32-5p) is known to be significantly upregulated at seizure onset in patients, its function and mechanism in neuron hyperexcitability and epileptic seizures remain unclear. In this study, we demonstrated elevated levels of miR-32-5p in the plasma of patients with temporal lobe epilepsy and in the hippocampus and plasma of pentylenetetrazol (PTZ)-induced seizure mice. Systemic knockout (KO) and hippocampal-specific knockdown of miR-32-5p mitigated acute seizure discharge and neuronal spiking in the experimental mice. Additionally, miR-32-5p KO attenuated chronic seizure severity and hippocampal neuronal loss of epileptic mice. Furthermore, miR-32-5p KO reversed the expression of immediate early genes (IEGs), which are neuronal activity markers significantly upregulated during acute seizure in mice. Mechanically, we found that potassium-chloride transporter 2 (KCC2), a main cation-chloride cotransporter involved in neuronal circuit excitation/inhibition (E/I) balance, is the key direct target of miR-32-5p. We further verified that miR-32-5p KO re-balanced hippocampal neuronal E/I imbalance underlying epilepsy. Gain-of-function experiment further revealed that the anti-seizure effect of miR-32-5p KO was abolished by hippocampal KCC2 knockdown. Taken together, our findings showed that hippocampal miR-32-5p promotes neuron hyperexcitability and epileptic seizures, and specifically identified miR-32-5p as a putative biomarker and therapeutic target for hippocampus-related epilepsy.

Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegenerative diseases, such as Alzheimer’s disease (AD), remain elusive. We found that TRPC3 expression is upregulated in excitatory neurons of brains with AD. We tested a selective inhibitor (JW-65) for TRPC3 over TRPC6 to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment significantly restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of late symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their significantly corrected synaptic gene expression based on hippocampal RNA-seq data analysis. JW-65 also provided synaptic protection in primary rat hippocampal neurons against soluble β-amyloid oligomers (AβOs), primarily via restoring the AβOs-impaired Ca2+/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented Ca2+ overload induced by AβOs. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca2+ dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating or preventing synaptic dysfunction of AD.

Depression is a common comorbidity of chronic pain. Gonadotropin-releasing hormone (GnRH) and its receptor (GnRHR) expressed in the central nervous system are involved in non-reproductive functions. Herein, we aimed to elucidate the role and mechanism of action of GnRH in pain-related depression like behaviour in a mouse model. And we found that both GnRH and GnRHR were down-regulated in the anterior cingulate cortex of mice that were subjected to chronic pain-induced depression with complete Freund's adjuvant. Specifically, either systemic treatment with GnRH agonists or GnRH overexpression in the anterior cingulate cortex effectively ameliorated the chronic pain-induced depression-like behaviour via GnRHR signalling. Moreover, GnRHR co-localized with both excitatory and inhibitory neurons, and GnRH agonists or overexpressed GnRH rescued the complete Freund's adjuvant-stimulated imbalance of excitatory-inhibitory neurons in the anterior cingulate cortex. Chemogenetic activation of anterior cingulate cortex neurons reversed GnRH agonist-induced improvement in depression-like behaviour in complete Freund's adjuvant-treated mice. Furthermore, this specific role of GnRH was dependent on the activation of protein kinase C and Erb-B2 receptor tyrosine kinase 4 signalling pathway. Therefore, our findings indicate that GnRH/GnRHR is involved in the development of chronic pain-related depression, which may through rebalancing the excitatory-inhibitory neurons via the activation of protein kinase C/Erb-B2 receptor tyrosine kinase 4 pathway. Thus, GnRH could be a potential target for the treatment of chronic pain-related depression.

BackgroundRPLP0, a ribosomal protein critical for protein biosynthesis, has emerged as a multifaceted oncoprotein through its regulation of programmed cell death (PCD) pathways. Despite its established roles in tumorigenesis, its pan-cancer relevance and ferroptosis regulatory function remains unexplored.MethodsBioinformatics analyses utilized TCGA, GTEx, GEPIA, UALCAN, HPA, cBioPortal, TISIDB, FerrDb, BioGRID, HitPredict, and R Studio. Experimental validation in hepatocellular carcinoma (HCC) included RT-qPCR, IHC, CCK8, transwell, and colony formation assays. Ferroptosis was assessed via lipid ROS, ferrous iron, and GSH detection.ResultsOur comprehensive pan-cancer analysis revealed conserved RPLP0 upregulation across malignancies, positively associated with adverse clinical outcomes. Genomic profiling identified recurrent RPLP0 alterations, while tumor microenvironment analyses demonstrated significant negative correlations between RPLP0 expression and immune cell infiltration. Focusing on hepatocellular carcinoma (HCC), experimental validation confirmed that RPLP0 depletion suppressed tumor progression via ferroptosis induction through metabolic and oxidative cascades, and RPLP0 was positively correlated with key ferroptosis suppressor GPX4.ConclusionsThis work advances the understanding of ribosomal protein biology by establishing RPLP0 as a pan-cancer biomarker bridging ribosome function with immune evasion, unveiling its canonical role in HCC progression, and discovering RPLP0-GPX4-mediated ferroptosis resistance axis, providing a novel therapeutic paradigm for aggressive cancers.

Disruption of the blood-brain barrier (BBB) is an essential pathological outcome of ischemic stroke (IS). This study aimed to prove that Gata1 upregulates Hras and promotes ERK signaling, leading to BBB damage in IS. Middle cerebral artery occlusion (MCAO) was used for in vivo modeling, and cerebrovascular endothelial cell-specific adeno-associated viruses were used for Gata1/Hras expression manipulation. TTC staining, Evans blue extravasation assay, and Western blot analysis were conducted to investigate the role of Gata1 and Hras in BBB injury. Mouse bEnd.3 cells were exposed to oxygen-glucose deprivation (OGD), and lentivirus-mediated genetic interventions were performed. Viability, lactate dehydrogenase release, and BBB permeability were assessed in bEnd.3 cells. The regulation of Gata1 on Hras was examined using ChIP-qPCR and a dual-luciferase assay. Gata1 was upregulated in mice after MCAO, and Gata1 knockdown reduced cerebral infarction and decreased BBB leakage in mice. Gata1 knockdown also alleviated OGD-induced BBB permeability and bEnd.3 cell injury. Gata1 transcriptionally activated Hras and promoted the ERK signaling. Hras reactivation reversed BBB injury in MCAO mice and BBB permeability and bEnd.3 cell injury alleviated by Gata1 knockdown. Overall, Gata1 transcriptionally upregulates Hras expression and activates the ERK signaling to exacerbate BBB dysfunction in mice after MCAO.

IntroductionHealth conditions associated with rapid ascent to high altitudes remain prevalent and pose an ongoing challenge. While acute mountain sickness (AMS) typically occurs within the first few days after ascent, the physiological and molecular acclimatization processes during prolonged high-altitude exposure beyond the initial acute phase remain incompletely understood.MethodsThis cross-sectional study investigated physiological and transcriptomic dynamics during prolonged high-altitude exposure over a 23 day period at 4,104 m in 113 Chinese Han individuals. Linear regression analysis, time series analysis, enrichment analysis, and protein-protein interaction analysis were applied to reveal the physiological and molecular dynamic changes.ResultsFour physiological parameters (saturation of peripheral oxygen [SpO2], hemoglobin, hematocrit, and standard deviation of red blood cell distribution width [RDW-SD]) exhibit a significant positive linear trend with the duration of acclimatization at high altitude (DAHA). Notably, two distinct gene expression patterns (GEPs) following DAHA were characterized for the first time: a decreasing expression pattern (Pattern 1) and a “mountain-shaped” expression pattern—upregulated in the first week and then downregulated (Pattern 2). In comparing individuals who experienced or were experiencing acute mountain sickness (eAMS+, n = 56) with those who did not (eAMS-, n = 57), RNA-seq performed in a subset of 48 participants (eAMS+, n = 35; eAMS-, n = 13) identified 583 upregulated and 104 downregulated genes in the eAMS+ group. Among these, 398 upregulated genes and 10 enriched pathways were found to overlap with Pattern 2. By integrating baseline data from the GSE75665 database, five hub differentially expressed genes (DEGs)—BCL2L1, DCAF12, CDC34, PINK1, and UBB—were identified. These genes not only predict AMS susceptibility but also associated with molecular responses to prolonged high-altitude exposure. In particular, CDC34 and UBB are novel genes not previously mentioned.ConclusionThis study provides critical insights into key physiological trends and molecular expression dynamics associated with prolonged exposure to high-altitude environments.

Williams-Beuren Syndrome (WBS), is a neurodevelopmental disorder characterized by anxiety, hypersociality and neurocognitive abnormalities, resulting from a heterozygous microdeletion on chromosome 7q11.23. A cytosine-5 RNA methyltransferase, NSUN5, is one of the deleted genes, which has been linked to cognitive deficits in WBS patients. However, the relation of NSUN5 to anxiety disorders and underlying mechanisms remain unknown. Here, we report that NSUN5 deficiency triggers anxiety-like behaviors without hypersociality in both adult male and female mice. NSUN5 exhibits specific expression in oligodendrocyte precursor cells (OPCs) within the basolateral amygdala (BLA), which is one of the main brain regions linked to anxiety. In addition, NSUN5 deficiency in mice leads to reduced OPCs proliferation accompanied with microglial activation. Mechanistically, we revealed that the specific decline in secretion of OPCs-derived fibroblast growth factor 2 (FGF2) resulted in microglial activation and exacerbated the levels of TNFα and IL-1β cytokines in NSUN5-deficient mice. Field excitatory postsynaptic potentials (fEPSPs) slopes at external capsule BLA synapse were increased in NSUN5-deficient mice. Moreover, an increase in paired-pulse inhibition and an impairment of long-term depression (LTD) induction were observed in NSUN5-deficient mice, which could be rescued either by intra-BLA injection of recombinant mouse FGF2 (rmFGF2) or by pharmacological suppression of microglial activation with minocycline. Furthermore, the anxiety-like behaviors in NSUN5-deficient mice were also relieved by rmFGF2 or minocycline treatments. Taken together, our study unveils a previously unknown effect of NSUN5 on anxiety disorders and a role of NSUN5 in regulating OPCs-microglia interaction and synaptic plasticity of BLA.

Background:Hypertrophic scars are a major clinical challenge with limited treatments. Adipose-derived stem cells (ADSCs) play an important role in inhibiting pathological scar formation. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate the function, mechanism, and therapeutic potential of adipose-derived stem cell peptide 5 (ADSCP5), a novel peptide from adipose-derived stem cell-conditioned medium. Methods:We used in vitro hypertrophic scar fibroblast, macrophage-fibroblast coculture and human umbilical vein endothelial cell (HUVEC) assays, RNA sequencing, pathway analysis, peptide pull-down, molecular docking, cellular thermal shift assays, surface plasmon resonance, immunofluorescence colocalization analysis, western blotting, rescue experiments, reactive oxygen species (ROS), autophagy tests, and mitochondrial membrane potential assays and untargeted metabolomics. The efficacy of ADSCP5 was validated in rabbit and porcine scar models. Results:In hypertrophic scar fibroblasts, ADSCP5 significantly downregulated the expression of collagen genes (COL1A1, COL1A2, and COL3A1) and actin alpha 2, smooth muscle, without affecting cell proliferation, apoptosis, or migration. Transcriptomic, enrichment, and western blot analyses confirmed that ADSCP5 reduced the protein levels of phosphorylated p65 (p-p65, NF-κB subunit), p-PI3K, p-AKT, and p-mTOR. Moreover, ADSCP5 decreased IL-6 transcription. Mechanistically, ADSCP5 bound directly to pyruvate carboxylase or the NF-κB subunit p50. This interaction resulted in the downregulation of PC or the upregulation of p50, ultimately inhibiting collagen expression, a finding confirmed by rescue assays. Furthermore, ADSCP5 induced ROS generation and autophagy, altered global metabolism, and modulated macrophage-fibroblast crosstalk to suppress fibrosis. It also exhibited antiangiogenic effects in HUVECs. In both the rabbit and porcine scar models, ADSCP5 treatment effectively attenuated collagen deposition and scar hyperplasia, increased the number of macrophages (increased CD68), reduced angiogenesis (decreased VEGFA and CD34), and promoted autophagy (reduced p62). Conclusions:Overall, this study demonstrate that ADSCP5 alleviates hypertrophic scarring by directly binding to PC and p50, suppressing the PI3K/AKT/mTOR and NF-κB pathways, reducing IL-6 and collagen production, promoting ROS and autophagy, and modulating metabolic, macrophage and angiogenic responses. These findings position ADSCP5 as a promising therapeutic agent for hypertrophic scar prevention and treatment.

Background Long-term trends in children's weight and height during the recent three decades in China remain scarce. This study aimed to examine long-term growth changes and urban-suburban disparities in body weight and height among children aged 3–7 years in Nanjing, China, from 1995 to 2025. Methods Data were obtained from four repeated cross-sectional surveys conducted in the same urban and suburban areas of Nanjing in 1995, 2005, 2015, and 2025. A multistage, stratified, cluster sampling method was used, and healthy boys and girls aged 3–7 years were included. Body weight and height were measured using standardized methods by trained investigators. One-Way ANOVA and independent samples t-test were employed to assess differences among different populations or periods. Results Positive secular growth in both weight and height was observed from 1995 to 2025. Compared with the first decade (1995–2005), urban children showed smaller increments during the second decade (2005–2015), whereas suburban children maintained rapid growth rates. Notably, during the third decade (2015–2025), certain urban age groups exhibited negative changes in weight and height. Overall, suburban children showed greater increases in weight and height than their urban peers over the 30-year period. The urban-suburban disparity progressively diminished over time, becoming statistically non-significant by 2025. Conclusions While socioeconomic development initially promoted physical growth in Nanjing children, this effect has plateaued in urban areas. The convergence of urban and suburban anthropometric measures suggests equitable improvements in child health outcomes.

Audiological and vestibular function tests are the most commonly used noninvasive evaluation methods for vertigo diseases. Preliminary studies have shown that detailed medical history, audiological, and vestibular function evaluation are effective methods to distinguish Meniere's disease and vestibular migraine diseases. This study retrospectively included 503 patients with vestibular migraine and 1,125 patients with Meniere's disease. Patients underwent pure tone audiometry and videonystagmography (VNG), including spontaneous nystagmus testing and the caloric test. In our study, we found that patients with Meniere's disease often exhibit abnormal unilateral weakness, while those with vestibular migraine show changes in vestibular function characterized by labyrinthine hyperactivity. Compared to vestibular migraine patients, Ménière's disease patients are more likely to experience unilateral full-frequency hearing loss. This study systematically compared the vestibular function and audiological characteristics of vestibular migraine and Ménière's disease, providing an evidence-based foundation for clinical differential diagnosis.

BACKGROUND:Hypertrophic scarring represents a major clinical challenge worldwide, with current treatment strategies showing limited effectiveness. Gluconic acid (GLA), a naturally occurring glucose metabolite found in fruits, honey, kombucha tea, and wine, may provide new approach for scar treatment. PURPOSE:This study aimed to investigate the anti-scarring properties of GLA and underlying molecular mechanisms. STUDY DESIGN:A comprehensive experimental study combined in vitro hypertrophic scar fibroblasts and in vivo rabbit ear scar model assays. METHODS:Hypertrophic scar fibroblasts were treated with GLA. Cell counting kit-8 (CCK-8) and flow cytometry were used to evaluate cell viability and apoptosis. The collagen and ACTA2 (actin alpha 2, smooth muscle) expressions were analyzed by qPCR and western blot. A rabbit ear scar model was applied to assess GLA's effects on scar formation and collagen deposition. Transcriptome sequencing, pull-down assays, western blotting and rescue experiments using AKT agonist SC79 were employed to identify GLA-regulated pathways. Molecular docking, pull-down, cellular thermal shift assays and co-localization studies were used to assess GLA's interaction with PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1). E64d, MG132 and QX77 were added to analyze GLA's function mechanisms on PLOD1 protein expression. Autophagy activation was evaluated through autophagic flux assay, transmission electron microscopy and autophagy related protein expression analysis. Mitochondrial membrane potential was detected by JC-1 staining. RESULTS:GLA suppresses collagen and ACTA2 expressions and exerted a mild inhibitory effect on cell proliferation or apoptosis in hypertrophic scar fibroblasts. And it diminishes scar formation and collagen content in the rabbit ear scar model. AKT (protein kinase B) and phosphorylated AKT (p-AKT) levels were significantly reduced after GLA treatment. Rescue experiments confirmed that GLA's effects are mediated through the AKT pathway. Moreover, GLA interacts with PLOD1, resulting in its autophagy-lysosomal degradation. Additionally, GLA treatment activated autophagy, reduced mTOR protein expressions, and had no significant effect on mitochondrial membrane depolarization, further contributing to its anti-scarring effects. CONCLUSION:Our findings demonstrate that GLA attenuates hypertrophic scarring through multi-modal mechanisms involving PLOD1 targeting, AKT/mTOR pathway inhibition, and autophagy activation. This study provides both mechanistic insights and therapeutic potential for GLA in scar treatment.

Hypertrophic scars, caused by abnormal wound healing after injury, involve excessive fibroblast activity, ECM dysregulation, and inflammation. Bioactive peptides show antifibrotic potential. Based on our previous discovery of scar-modulating peptides from adipose-derived stem cells, this study reveals how ADSCP6 (Adipose-derived stem cell peptide 6) suppresses hypertrophic scarring. In vitro analyses revealed that ADSCP6 significantly downregulated type I collagen and ACTA2 (alpha smooth muscle actin) expression in human hypertrophic scar fibroblasts (HSFs), without altering proliferative/apoptotic activity. In vivo, topical ADSCP6 administration enhanced wound healing and attenuated collagen content in a murine excisional wound model. Transcriptomic profiling (RNA-seq) identified 328 differentially expressed genes (182 upregulated, 146 downregulated) post-treatment, with KEGG (kyoto encyclopedia of genes and genomes) pathway enrichment implicating NF-κB (nuclear factor kappa-B) signaling as a primary mechanism. Protein interaction assays (pull-down/cellular thermal shift assays) identified KANK2 (KN motif and ankyrin repeat domains 2) and ADGRE2/EMR2 (adhesion G protein-coupled receptor E2) as ADSCP6-binding partners, while western blot confirmed NF-κB1 (p50) upregulation. Functional validation demonstrated that NF-κB pathway blockade abrogated ADSCP6's antifibrotic effects. ADSCP6 reduced the expression of FAK, STAT3, and SMAD2 proteins. Macrophage-conditioned media from ADSCP6-treated cultures suppressed HSFs collagen synthesis, and ADSCP6 significantly enhanced HUVEC (human umbilical vein endothelial cells) tubulogenesis, suggesting pro-angiogenic activity. Overall, these findings establish ADSCP6 as a multifunctional therapeutic peptide that concurrently attenuates fibrotic progression and accelerates wound healing, positioning it as a novel candidate for clinical scar management.

AIMS:Obesity is a chronic metabolic inflammatory disease caused by energy excess, characterized by excessive adipose tissue accumulation, and is often accompanied by multiple complications such as type 2 diabetes mellitus, metabolic-associated fatty liver disease (MAFLD), and neurological disorders. Adipose tissue plays a central role in maintaining energy homeostasis. Under conditions of energy excess, pro-inflammatory M1-type adipose tissue macrophages (ATMs) are activated, secrete inflammatory factors, inhibit lipolysis and thermogenesis pathways, and exacerbate metabolic disorders. Insulin-like growth factor 2 (IGF2) possesses both metabolic and immunomodulatory functions and is associated with obesity risk; however, its role in ATM polarization remains unclear. This study aims to clarify the regulatory role and mechanism of IGF2 in obesity-related metabolic inflammation and cognitive function. MATERIALS AND METHODS:A high-fat diet (HFD)-induced obese mouse model was established, and interventions were performed via intraperitoneal injection of recombinant IGF2 (rIGF2). Phenotypic polarization of ATMs and expression of inflammatory factors were analyzed by quantitative polymerase chain reaction (qPCR) and immunofluorescence staining. Western blotting was used to detect the expression levels of key proteins in the adrenergic signaling pathway and molecules related to lipolysis/thermogenesis in adipose tissue. Changes in the expression of hippocampal synaptic proteins and cognitive function were evaluated by Western blotting and cognition-related behavioral tests. RESULTS:The study found that rIGF2 intervention significantly promoted the polarization of ATMs from the pro-inflammatory M1 type to the anti-inflammatory M2 type, reduced the levels of inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), thereby relieving the inhibition of the β-adrenergic signaling pathway, activating the expression of hormone-sensitive lipase (HSL) and uncoupling protein 1 (UCP1), promoting lipolysis and thermogenesis, and effectively improving metabolic abnormalities such as insulin resistance and hepatic steatosis in obese mice. Meanwhile, rIGF2 treatment upregulated the expression of synaptic proteins (e.g., PSD-95, Synapsin-1) in the hippocampus of obese mice and significantly ameliorated HFD-induced cognitive impairment. CONCLUSIONS:This study is the first to systematically clarify the dual mechanism of IGF2 in regulating ATM polarization to improve metabolic inflammation, lipolysis-thermogenesis balance, and central cognitive impairment in obesity. The results suggest that IGF2 is not only a key regulator of energy metabolism but also possesses immunomodulatory and neuroprotective potential, providing a new theoretical basis and potential therapeutic target for the prevention and treatment of obesity and its related complications.

The primary effector cells involved in the formation of hypertrophic scars are fibroblasts. A potential peptide, ADSCP2 (adipose-derived stem cell peptide 2, the peptide fragment of ALCAM protein), derived from adipose-derived stem cell-conditioned medium, has been identified as having the potential to mitigate hypertrophic scar formation by targeting pyruvate carboxylase. However, the underlying mechanisms remain incompletely understood. Whether ADSCP2 attenuates hypertrophic scar fibrosis at the transcription level remains unclear. Consequently, this study sought to elucidate the potential mechanism associated with ADSCP2 by examining genome-wide transcriptional alterations and changes in chromatin accessibility in fibroblasts. This was achieved through the integrated analysis of assay for transposase accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq). In the ADSCP2 treatment group, ATAC-seq identified a total of 7,805 differential peaks associated with 3,176 genes. RNA-seq analysis revealed 345 upregulated and 399 downregulated transcripts in the same group. A combined Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of both downregulated genes and close-ACRs (accessible chromatin regions) genes within the ADSCP2 treatment group indicated regulation of the oxidative phosphorylation pathway (OXPHOS) by ADSCP2. The amalgamation of ATAC-seq and RNA-seq data elucidates that two OXPHOS associated genes, namely COX6B1 (cytochrome c oxidase subunit 6B1) and NDUFA1 (NADH dehydrogenase (ubiquinone) alpha subcomplex-1), demonstrate significant downregulation in the presence of ADSCP2. Further analysis using the integrative genomics viewer indicates that the promoter regions of both COX6B1 and NDUFA1 exhibit a higher degree of closure in the ADSCP2 treatment group. Quantitative PCR analysis demonstrated that ADSCP2 treatment resulted in a reduction of COX6B1 and NDUFA1 mRNA expression levels. Furthermore, cellular ATP and lactic acid concentrations were diminished in the ADSCP2-treated group. Collectively, these findings suggest potential avenues for future research into the therapeutic application of the peptide ADSCP2 in the treatment of hypertrophic scars.

The etiology of hypertrophic scar formation continues to elude researchers, despite advancements in the understanding of skin scarring. Several long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of hypertrophic scars, yet the role and molecular mechanisms of LINC00525 in this process remain unclear. This study demonstrates that LINC00525 enhances cell proliferation and collagen expression through knockdown and overexpression techniques. Further analysis, including nuclear and cytoplasmic localization studies, RNA pulldown assays, bioinformatics predictions, and PCR validation, reveals that LINC00525 interacts with miR-29a5p. The downregulation of LINC00525 enhances the expression of miR-29a-5p and suppresses the TGF(3/Smad signaling pathway. Additionally, TGF-(31 induces the upregulation of LINC00525. Collectively, these findings indicate that LINC00525 operates through a feedforward mechanism to regulate TGF-(3 signaling in hypertrophic scar fibroblasts. This research offers novel insights for the prevention and treatment of scars.

>Preterm birth and suboptimal fetal growth remain significant perinatal challenges worldwide.Recent data indicate that China's perinatal profile has improved due to reductions in preterm birth rates. However, the country has a 6.5% prevalence of small-for-gestational-age（SGA）, ranking fifth globally in total SGA birth numbers [1,2] .

To investigate how dysregulated transient receptor potential canonical channels (TRPCs) are associated with Alzheimer’s disease (AD), we challenged primary neurons with amyloid-β (Aβ). Both the naturally secreted or synthetic Aβ oligomers (AβOs) induced long-lasting increased TRPC3 and downregulated the TRPC6 expression in mature excitatory neurons (CaMKIIα-high) via a Ca2+-dependent calcineurin-coupled NFAT transcriptionally and calpain-mediated protein degradation, respectively. The TRPC3 expression was also found to be upregulated in pyramidal neurons of human AD brains. The selective downregulation of the Trpc6 gene induced synaptotoxicity, while no significant effect was observed from the Trpc3-targeting siRNA, suggesting potentially differential roles of TRPC3 and 6 in modulating the synaptic morphology and functions. Electrophysiological recordings of mouse hippocampal slices overexpressing TRPC3 revealed increased neuronal hyperactivity upon the TRPC3 channel activation by its agonist. Furthermore, the AβO-mediated synaptotoxicity appeared to be positively correlated with the degrees of the induced dendritic Ca2+ flux in neurons, which was completely prevented by the co-treatment with two pyrazole-based TRPC3-selective antagonists Pyr3 or Pyr10. Taken together, our findings suggest that the aberrantly upregulated TRPC3 is another ion channel critically contributing to the process of AβO-induced Ca2+ overload, neuronal hyperexcitation, and synaptotoxicity, thus representing a potential therapeutic target of AD.

Doxorubicin-induced cardiotoxicity (DIC) is pathologically characterized by oxidative stress and inflammatory cascades, creating an urgent need to identify therapeutic targets modulating these processes. While tumor necrosis factor alpha-induced protein 8 (TNFAIP8) has emerged as a regulator of inflammation and apoptosis, its functional role in DIC remains unexplored. This study systematically investigates TNFAIP8’s cardioprotective mechanisms against DIC. A chronic DIC model was established in male C57BL/6 mice through intraperitoneal doxorubicin (DOX) administration (4 mg/kg weekly for 4 weeks; cumulative dose 16 mg/kg). TNFAIP8 knockdown was achieved via AAV9-delivered shRNA through tail vein injection. Multimodal assessment integrating echocardiography, histopathology analysis, and molecular profiling elucidated TNFAIP8’s functional and mechanistic contributions. In DOX-induced cardiomyocytes, TNFAIP8 expression was upregulated. The absence of TNFAIP8 markedly reduced DOX-triggered oxidative stress and inflammatory responses. The potential protective mechanism of TNFAIP8 deficiency against DIC involves toll-like receptor 4 (TLR4)/NF-κB signaling pathway. Importantly, administration of the TLR4 activator lipopolysaccharide (LPS) substantially reversed the cardioprotective effects observed with TNFAIP8 deletion. Our findings establish TNFAIP8 as a critical regulator of DIC pathophysiology through TLR4/NF-κB axis modulation. Pharmacological TNFAIP8 inhibition represents a viable therapeutic strategy for mitigating chemotherapy-induced cardiac dysfunction. Future investigations should prioritize developing cardiac-targeted TNFAIP8 inhibitors and validating their efficacy in large-animal DIC models.

Cognitive impairment is a defining feature of neurodegenerative diseases such as Alzheimer's disease (AD) and vascular dementia (VaD). However, the pathogenesis of cognitive impairment remains unclear, mainly because it involves complex pathological processes in which multiple cytokines and pathways contribute to its progression. Among key molecular regulators, cyclic nucleotide phosphodiesterase 1 (PDE1), a Calcium/calmodulin (Ca²⁺/CaM) activated enzyme that regulates intracellular levels of cAMP and cGMP by degrading them to inactive forms. PDE1 may play a critical role in influencing cognitive function through modulating these second messengers. PDE1 integrates calcium fluctuations with cyclic nucleotide metabolism, affecting a series of events including synaptic plasticity, neuronal survival, vascular tone, and neuroinflammatory responses. This review summarizes the distribution of PDE1 and its isoforms, and their regulatory mechanisms and functional roles, particularly those of PDE1A, PDE1B, and PDE1C, in the central nervous system (CNS) disorders. We also discussed the involvement of PDE1 in modulating cAMP/PKA and cGMP/PKG signaling pathways, and its impact on oxidative stress, neuroinflammation, and apoptotic cascades associated with cognitive dysfunction. In addition, this review integrates current evidence on PDE1 isoforms in both neuronal and vascular regulation of cognition, emphasizing their dual neurovascular roles in cognitive impairment. We further summarized recent progress on PDE1 target validation and the reported efficacy of PDE1A inhibitors in alleviating memory deficits associated with neurodegenerative disorders, such as AD and VaD.

Prolonged psychological stress can cause intestinal barrier dysfunction, increasing its permeability and allowing harmful substances present in the gut, such as bacteria and toxins, to readily traverse the intestinal barrier and enter the bloodstream, ultimately precipitating systemic inflammation. This study used the chronic restraint stress (CRS) model to stimulate intestinal inflammation induced by prolonged psychological stress in humans. Endoplasmic reticulum (ER) stress is closely linked to intestinal diseases. Unresolved and persistent ER stress can damage the intestinal barrier, activating inflammation through the unfolded protein response, leading to intestinal diseases, such as inflammatory bowel disease and irritable bowel syndrome. By examining proteins associated with the PERK pathway, upregulated levels of PERK, P-eIF2α, and C/EBP homologous proteins were observed in the jejunum and colon during CRS-induced intestinal inflammation. Integrated stress response inhibitor (ISRIB), a potent inhibitor of the PERK pathway, plays a crucial role in suppressing integrated stress responses. Herein, ISRIB ameliorated CRS-induced jejunal and colonic mucosal injury and barrier dysfunction by inhibiting ER stress. Prolonged ER stress exposure can lead to the onset of cellular apoptosis. ISRIB effectively prevented the upregulation of CRS-induced apoptosis markers (Caspase-3, Bax/Bcl-2) in the jejunum and colon. Furthermore, ISRIB intervention reversed the CRS-induced elevation of NLRP3 inflammasome and pyroptosis marker GSDMD in the jejunum and colon. Therefore, ISRIB has emerged as a promising therapeutic candidate for treating intestinal inflammation related to prolonged psychological stress.