📋 Browse Articles

Dual specific phosphatases (DUSPs) are a family of phosphatases, including DUSP4, DUSP5, and DUSP6, that function as negative regulators of the RAF/MEK/ERK pathway. These DUSPs have been extensively studied in various human cancers, particularly those with KRAS mutations. Our previous research indicated that these DUSPs are downregulated by KRAS knockdown in KRAS mutant lung cancer cell lines and upregulated in an hTERT/Cdk4-immortalized normal human bronchial cell line HBEC3-KT expressing mutant KRAS Show less

To investigate the mechanisms underlying sevoflurane-induced POCD, C57BL/6 J mice and SH-SY5Y cells were treated with sevoflurane for model establishment. After the treatment with sevoflurane, CCK-8, EdU and flow cytometry were employed to detect cell damage. The levels of N6-methyladenosine (m6A), METTL14 and DUSP6 were determined by qPCR and Western blot. The interaction between METTL14 and DUSP6 was analyzed using RIP-qPCR and Me-RIP methodologies. The cognitive function in mice were assessed by water maze test. After sevoflurane treatment, the cell viability, cell proliferation and METTL14 expression were markedly suppressed, while apoptosis was significantly enhanced. METTL14 overexpression elevated the levels of m6A and DUSP6, increased the binding level of METTL14 to DUSP6 mRNA, reducing damage to cells and cognitive dysfunction of mice. Knockdown of DUSP6 negated the beneficial effects observed with METTL14 overexpression. Sevoflurane induced POCD by regulating METTL14/DUSP6 through m6A methylation. Show less

The roles of cancer stem cells and Octamer-binding transcription factor 4 (OCT4) have been implicated in human tumorigenesis and metastasis. However, the role of OCT4 in the metastasis of non-small-cell lung cancer (NSCLC) remains undetermined, especially regarding stem cell-related pathways. Previous research has reported that dual-specificity phosphatase 6 (DUSP6), a mitogen-activated protein kinase (MAPK) phosphatase, is associated with cancer cells that display anti-apoptotic, migratory, and drug-resistance phenotypes. However, the regulation of DUSP6 in NSCLC is unclear. This study focused on the role of OCT4 in NSCLC, particularly its interaction with DUSP6. Here, we show a positive correlation between OCT4 and DUSP6 expression in NSCLC cells. Overexpression of OCT4 increased, whereas knockdown of OCT4 reduced DUSP6 expression. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays revealed that OCT4 transactivated DUSP6 expression by directly binding to the DUSP6 promoter, indicating that DUSP6 is a downstream target of OCT4. Furthermore, knockdown of DUSP6 in OCT4-overexpressing A549 human NSCLC cells decreased cell migration Show less

The aim of this review is to systematically explore the critical role of dual-specific phosphatases (DUSPs) in CKD-associated cognitive impairment and their therapeutic potential. Chronic kidney disease (CKD) is a global health burden, and the cognitive impairment it induces seriously affects patients' quality of life. Studies have shown that DUSPs are involved in pathological processes such as inflammation, oxidative stress, fibrosis, and neuronal apoptosis through the regulation of signaling pathways such as MAPK, which in turn affects the cognitive function of CKD patients. Specifically, downregulation of DUSP1 and DUSP6 expression in brain tissues of CKD patients is associated with cognitive impairment, whereas upregulation of DUSP8 and DUSP16 exacerbates cognitive deficits by promoting neuroinflammation. In addition, uremic toxins (e.g., indolephenol sulfate) can further deteriorate cognitive function by altering the activity of DUSPs and interfering with central nervous system signaling. Although there are currently no clinical drugs targeting DUSPs, small molecule inhibitors, gene modulation techniques, and natural compounds have demonstrated the potential to improve cognitive function by modulating DUSPs. Future studies need to focus on optimizing the specificity and selectivity of DUSPs inhibitors and conducting rigorous clinical validation. In-depth elucidation of the mechanism of action of DUSPs in the renal-brain axis will provide an important theoretical basis for the development of novel intervention strategies for CKD-associated cognitive impairment. Show less

Long-term space missions are of growing research interest because of the space exploration. However, plenty of works focused on the impaired immune response, less attention has been paid to the activation of immunosuppressive or anti-inflammatory function. The molecular mechanism of immune disorder induced by microgravity still needs investigation. Here, we used a random positioning machine to generate a simulated microgravity environment and evaluated its effects on mouse RAW 264.7 macrophage cell line. We used ATAC-seq and RNA-seq for revealing the mechanism at chromatin level and gene level. From ATAC-seq, we obtained an average of 75,700,675 paired-end clean reads for each library and the mapping rates averaged at 96.8 %. The number of differential accessible regions were 510 for increased peaks, 638 for decreased peaks. From RNA-seq, we obtained 278 differentially expressed genes, of which 104 were down-regulated and 174 were up-regulated genes. Through ATAC-seq and RNA-seq multi-omics analysis, we identified a group of 17 genes. Then we chose 6 up-regulated genes (CD83, CEBPD, CXCR5, DUSP6, SEMA4B, TNFRSF22) that related to immunosuppressive function for further confirmation. The qRT-PCR results were consistent with sequencing results, which indicated that simulated microgravity leads to the up-regulated expression of immunosuppressive genes of macrophages. Taken together, our results offered novel insights for understanding the brief principles and mechanisms of simulated microgravity induced immune dysfunction to macrophage. Show less

Mitochondrial positioning supports localized energy and signaling requirements. Miro1 is necessary for attachment of mitochondria to microtubule motor proteins for trafficking. When Miro1 is deleted (Miro1-/-) from mouse embryonic fibroblasts (MEFs), mitochondria become sequestered to the perinuclear space, disrupting subcellular signaling gradients. Here, we show that Miro1-/- MEFs grow slower than Miro1+/+ and Miro1-/- MEFs stably re-expressing a Myc-Miro1 plasmid. Miro1-/- MEFs have a decreased percentage of cells in G1 and increased percentage of cells in S phase. We conducted the first ever RNA sequencing experiment dependent upon Miro1 expression and found differentially expressed genes related to MAPK signaling, cell proliferation and migration. ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) phosphorylation is elevated both spatially and temporally following serum stimulation in Miro1-/- MEFs, whereas the expression levels and oxidation of the dual specificity phosphatases (DUSP1-DUSP6) is unchanged. Finally, we found the oxidation status of ERK1/2 is increased in Miro1-/- MEFs compared to that seen in Miro1+/+ and Myc-Miro1 MEFs. These results highlight transcriptional control based off Miro1 expression and demonstrate the dynamic regulation of ERK1/2 upon deletion of Miro1 which might support the observed cell cycle and proliferation defects. Show less

The MAPK/ERK pathway plays a critical role in the regulation of milk production by controlling cellular processes such as proliferation, differentiation and survival, which are essential for lactogenesis and mammary gland function. Bubalus bubalis (Water buffalo), known for its unique physiological and ecological characteristics, serves as an ideal model to explore the evolutionary and molecular roles of MAPK/ERK pathway genes. This study presents the first comprehensive computational analysis of MAPK/ERK genes in B. bubalis, identifying 21 key genes involved in the pathway. Phylogenetic analysis clustered these genes into 13 distinct clades, such as MST1, GRB2, RAS, ETS1, JUN and FOS, and revealed close evolutionary relationships with Bos taurus and Camelus bactrianus. Structural characterization identified 10 conserved motifs, including essential domains like protein kinase, ETS and RAS, reflecting their functional significance. Gene structure analysis revealed substantial variation in exon-intron patterns, while synteny analysis confirmed collinearity with human orthologs, indicating genomic conservation. Physicochemical analysis highlighted a broad range of molecular weights and isoelectric points, with most proteins classified as hydrophilic and thermostable. Gene duplication and selection analyses revealed seven segmentally duplicated gene pairs, with the JUN-ETS1 and DUSP6-MST1 pairs showing evidence of positive selection, suggesting functional divergence. These findings establish a foundational understanding of MAPK/ERK pathway genes in B. bubalis and provide valuable insights into potential targets for genetic improvement, selective breeding and sustainable dairy management strategies aimed at enhancing milk production and quality. Show less

The key to proper implant integration in bone replacement is to orchestrate the complex interactions between materials and tissues. Moreover, due to the rapid demographic shift towards aging societies and the increase in elderly and osteoporotic patients, it is of great importance that implant materials are osteointegrative in not only healthy but also compromised bone tissues. Here, titanium (Ti) scaffolds were subjected to shifted laser surface texturing (sLST) using a nanosecond pulsed laser to create an open pore macrotopography with micro-and nano-Ti droplets. In contrast to conventional laser texturing, which leads to high heat accumulation; in sLST, the frequency of laser pulses is low, allowing for resolidification, thereby creating a surface with abundant coverage micro-/nanodroplets. The main objective was to compare the cellular responses of human mesenchymal stromal cells (hMSCs) on sLST-textured Ti surfaces (LT-Ti) for the first time with standard sand-blasted, acid-etched surfaces (SLA-Ti). In-depth analyses of cell survival, proliferation, shape, mineralization, and gene expression were performed. Cell survival/proliferation was found to be similar on both surfaces; however, SEM imaging revealed differences in hMSC morphology. On LT-Ti, cells adopted well-rounded shapes, whereas on SLA-Ti they assumed more planar shapes. Bulk RNA sequencing performed after short-term culture on both surfaces disclosed expression changes in genes such as Show less

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the β‑actin control data shown in the western blots in Fig. 3E on p. 6 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had already been published elsewhere prior to the submission of this paper to Show less

This study identified fibroblast-specific genes to develop a RiskScore model to improve prognostic accuracy and guide personalized treatment in glioblastoma (GBM). We analyzed fibroblast-specific signatures in the GSE273274 cohort using "Seurat" R package for scRNA-seq data processing. Fibroblast-related gene modules were identified via WGCNA, and functional enrichment was assessed with "clusterProfiler" package. A RiskScore model was established using univariate, Lasso Cox regression analysis, and "survival" package, validated by "timeROC" for receiver operator characteristic (ROC) curve. Finally, immune infiltration and drug sensitivity was evaluated applying "ESTIMATE," "TIMER," "MCPcounter," and "pRRophetic" packages. Experimental validation included qPCR for gene expression detection, and CCK-8, wound healing, and Transwell assays for functional measurement. The scRNA-seq analysis identified nine cell types of cells, with fibroblasts elevated in the GBM group. Fibroblast signatures were linked to tumorigenesis, cytoskeleton remodeling, and regulation of neuronal development process that affected GBM invasion. A 6-gene RiskScore divided GBM patients into high- and low-risk groups in training and validation sets, with high-risk patients exhibiting poorer survival, elevated StromalScore, and negative correlations with the infiltration of neutrophils and B_cells. Moreover, high-risk patients demonstrated heightened sensitivity to Cisplatin, MG-132, AZ628, Dasatinib, CGP-60474, A-770041, TGX221, and Bortezomib. Finally, qPCR showed that the VWA1 was upregulated in GBM cells, while knock-down of VWA1 inhibited the cell proliferation, migration, and invasion activity. We constructed a RiskScore model for predicting the survival outcomes based on fibroblasts-related genes. These findings highlighted the role of fibroblasts in GBM development and offered six potential therapeutic targets (VWA1, DUSP6, LOXL1, IGFBP4, CYGB, and ZIC3) for GBM treatment. Additionally, immune infiltration analysis and drug sensitivity prediction further supported the model's utility in guiding personalized treatment of GBM. Show less

Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation. DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S. Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival. The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets. Show less

Attention-deficit-hyperactivity disorder (ADHD) is highly heritable and increases the likelihood of nicotine dependence (ND). The self-medication hypothesis of nicotine use in ADHD proposes that ADHD patients seek nicotine for its ability to improve their symptoms, and they have less success quitting, possibly due to the worsening of ADHD symptoms in withdrawal. The present analysis compared transcriptomic data from the brains of rodent models of ADHD and those of ND, with a focus on striatal gene expression. Differential expression analysis, pathway enrichment analysis, and gene-network mapping identified signaling networks and candidate genes that may contribute to the high co-occurrence between ADHD and ND. We identified novel differentially expressed genes (PRKAG2, MAPK1), and genes with known associations to either ADHD or ND (ANK3, CALD1, CHRNA4, CHRNA7, CMTM8, DLG4, DUSP6, GNG3, GNG11, GRIK5, GRINA2, GRM5, ICAM2, KCNJ6, PRKAB1, SNAP25, SYNPO, SYT1, VAMP2). In addition, synaptic transmission (hsa04728, R-HAS-112315, R-HSA-442755) and MAPK signaling pathways (hsa04010, hsa04014, hsa04015, R-HSA-5673001, R-HSA-5684996) were enriched in both ADHD and ND. The signaling pathways implicated by this analysis mediate neurological mechanisms known to contribute to ND. The association of analogous differently expressed genes and common signaling pathways suggests an important causal relationship between ND and ADHD that may be clinically important. Show less

Several KRASG12D inhibitors (KRASG12Di) are under clinical evaluation for pancreatic ductal adenocarcinoma (PDAC). However, as seen with other first generation KRAS inhibitors, resistance may limit their long-term efficacy, necessitating combination strategies to enhance therapeutic outcomes. Exportin 1 (XPO1), a nuclear transport protein overexpressed in PDAC, represents a therapeutic vulnerability in KRAS-mutant cancers. Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. We generated KRASG12Di-resistant PDAC cells and assessed their response to Eltanexor. The antiproliferative effects of MRTX1133 and Eltanexor combinations were evaluated in 2D and 3D Eltanexor sensitized MRTX1133-resistant PDAC cells to growth inhibition. In both 2D and 3D culture models, the combination of Eltanexor and MRTX1133 significantly reduced cell viability. Mechanistically, the combination treatment suppressed key KRAS downstream signaling molecules, including p-ERK, mTOR, p-4EBP1, DUSP6, and cyclin D1. Kinome analysis further revealed reduced MAPK-related kinase activity. Combining subtherapeutic doses of Eltanexor and MRTX1133 resulted in significant tumor regression and prolonged survival in PDAC xenograft and immunocompetent orthotopic allograft models. Moreover, maintenance therapy with Eltanexor prevented tumor relapse, yielding a durable antitumor response. This study demonstrates that Eltanexor overcomes resistance to MRTX1133 and enhances its efficacy in PDAC. The combination regimen may provide a durable therapeutic response while reducing the required dose of KRASG12D inhibitors, potentially delaying resistance and improving patient outcomes. Show less

Families studies conducted in different ethnic populations worldwide have helped elucidate the molecular and genetic factors involved in the development of skeletal class III malocclusion. Therefore, the aim of this study is to provide an updated summary. The study followed the JBI Manual for Evidence Synthesis and PRISMA-scR guidelines. PubMed, Scopus, WOS, Google Scholar and DANS databases were explored using specific strategies. Eligible studies included linkage and genome-wide analyses, while association studies, case reports and in vivo/in vitro research were excluded. The included studies must have involved at least one family with one or more members exhibiting the skeletal malocclusion phenotypes. An autosomal dominant inheritance pattern with variable penetrance for skeletal class III malocclusions across East Asian, Southeast Asian, Middle Eastern, European and South American populations was identified. In contrast, skeletal class II malocclusions exhibited autosomal dominant and X-linked inheritance patterns, with a higher prevalence in Eastern Mediterranean and South American populations. Key molecular findings include missense mutations in DUSP6 (c.545C>T and c.1094C>T), which affect mandibular prognathism and maxillary deficiency via the FGF/FGFR and MAPK/ERK pathways. Additionally, mutations in ADAMTS1 (c.742I>T), ADAMTS2 (c.3506G>T) and ADAMTSL1 (c.176G>A) impact mandibular growth through aggrecan metabolism and osteogenesis, disrupting bone remodelling via the EGFR/ErbB signalling pathway. This comprehensive review highlights the complex genetic basis of skeletal malocclusions, provides insights into the underlying molecular mechanisms, suggests potential targets for therapeutic intervention, and contributes to our understanding of the genetic architecture of these conditions. Show less

The dual specificity phosphatase 6 (DUSP6) was recently implicated in autoimmune arthritis pathogenesis. However, it remains unclear which cell mediates its pathogenic activity in a mouse model of rheumatoid arthritis (RA). Bone marrow (BM) CD11b + Gr1 + cells were isolated from DUSP6 +/+ mice and transferred into DUSP6 -/- recipients. Six weeks later mice were administered the KRN serum to induce arthritis (KSIA), and analyzed for arthritis severity clinical scores. The same strategy was used in the opposite direction with cells from DUSP6-/- cells transferred in DUSP6 +/+ mice. BM CD11b + Gr1 + cells from DUSP6 +/+ and DUSP6 -/ - were stimulated with PMA and used for RNA sequencing, and also used for real-time measurements of mitochondrial respiration with the Seahorse XF Analyzer. Transfer of CD11 + Gr1 + cells DUSP6 We describe a new arthritogenic role for DUSP6, which is mediated by CD11b + Gr1 + cells and their glycolytic activity and oxidative burst. Our findings also implicate these myeloid cells in arthritis pathogenesis and raise the possibility that DUSP6 may be a good target for the development of new therapies for RA. Show less

Squamous cell carcinomas arising in patients with recessive dystrophic epidermolysis bullosa are highly aggressive and often cause premature death. Current treatment options are limited, highlighting the need for innovative drug development concepts. Through transcriptome-guided computational drug screening, we identified selumetinib, a MAPK/extracellular signal-regulated kinase inhibitor, as a candidate drug for recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas. To verify the therapeutic potential of selumetinib against recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas, we assessed its efficacy in vitro and in vivo. In vitro, selumetinib decreased tumor cell viability, significantly reduced phosphorylation of extracellular signal-regulated kinase, and induced a mesenchymal-to-epithelial phenotypic shift, as indicated by increased E-cadherin and decreased vimentin expression. Functionally, it impaired tumor cell motility and invasion. Moreover, selumetinib significantly decreased PD-L1 and increased major histocompatibility complex class I levels and modulated the expression of immune-related cytokines. In vivo, selumetinib significantly suppressed tumor growth and reduced phosphorylated extracellular signal-regulated kinase levels in xenograft tumors. RNA sequencing identified EGR1 (early growth response protein 1), FOS (fos proto-oncogene), and DUSP6 (dual-specificity phosphatase 6) as candidate biomarkers of treatment response. Selumetinib, identified by computational drug screening, demonstrates efficacy against recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas in vitro and in vivo, suggesting its potential for clinical use. Show less

One serious consequence of diabetes mellitus is diabetic retinopathy (DR), which impairs eyesight to the point of blindness. While glucocorticoid medications are commonly employed in the management of DR, their therapeutic efficacy requires enhancement. Due to the tight association between glucocorticoid-related genes and the onset and development of DR, a comprehensive examination of its root cause of activity may be able to overcome the drawbacks of existing treatment approaches. R programming tools were used to examine the single-cell RNA sequencing (scRNA-seq) dataset GSE178121, which was obtained from the Gene Expression Omnibus (GEO) database. To evaluate glucocorticoid activity, a gene set related to glucocorticoid phenotypes was sourced from the Molecular Signatures Database (MSigDB), followed by the identification of key cellular populations within DR tissues. Subsequently, these key cells underwent pseudotime analysis, transcription factor (TF) evaluation, cell-cell communication assessment, differential gene screening, and the construction of a regulatory network. Our investigation demonstrated that vascular endothelial cells (VECs) in DR tissue exhibited markedly elevated glucocorticoid activity. KLF4 is among the TFs that are intimately linked to the onset of DR, and hydroxyurea could be a beneficial medication. Cell-cell communication analysis highlighted the PTN and ANGPTL signaling pathways as important signaling pathways in DR. In the meanwhile, we identified 25 Hub genes, including DUSP6, AP1S2, and PTPRB, which were verified to be differentially expressed in DR. In conclusion, our comprehensive study elucidated the complex interactions of glucocorticoids in the pathogenesis of DR, thereby revealing potential signaling pathways and therapeutic targets. Show less

The Saccharomyces cerevisiae Cell Wall Integrity (CWI) pathway responds to cell wall stress and is composed of MAP3K Bck1, MAP2Ks Mkk1 and Mkk2 and MAPK Slt2. Although human ERK5 has been considered the functional orthologue of Slt2, our results indicate that human ERK1 and ERK2 exhibit a much greater ability than ERK5 to replace Slt2 under various cell wall stresses. ERK5 is only able to slightly complement an slt2Δ mutant phenotype in the presence of tunicamycin, and the constitutively active truncated version ERK5ΔCt did not improve this complementation ability. Like Slt2, ERK1, ERK2 and ERK5ΔCt are concentrated in the nucleus, and show higher phosphorylation than ERK5 upon CWI pathway stimulation. Expression of a hyperactive version of the human MAP2K MEK5 leads to specific ERK5 and ERK5ΔCt phosphorylation, leading to a partial replacement of the Mkk1/2-Slt2 function under cell wall stress. Expressed in yeast, the human Dual Specificity Phosphatases DUSP3 and DUSP6 reduce the level of ERK5 phosphorylation to a similar extent, whereas DUSP6 shows higher activity than DUSP3 on ERK1 or ERK2. Our results show the different degree of integration of human ERKs and DUSPs into the yeast CWI signalling circuit, which can be exploited for functional analysis or pharmacological screenings. Show less

Large-scale genomic studies focusing on the genetic contribution to human aging have mostly relied on cross-sectional data. With the release of longitudinally curated aging phenotypes by the UK Biobank (UKBB), it is now possible to study aging over time at genome-wide scale. In this work, we evaluated the suitability of competing models of change in realistic simulation settings, performed genome-wide association scans on simulation-validated measures of age-related deweekcline, and followed up with LD-score regression and Mendelian Randomization (MR) analyses. Focusing on global cognitive and physical function, we observed marked differences between baseline function (θ) and accelerated decline (Δ). Both outcomes showed distinct heritability levels (e.g., 31.38% Show less

Repeated ketamine treatment to maintain a rapid antidepressant effect can lead to side effects over time, highlighting an unmet clinical need for sustaining this drug's antidepressant action from a single administration. Ketamine-induced synaptic potentiation at CA3-CA1 synapses has been proposed to be a key synaptic substrate for antidepressant action. Here, we found that ketamine-induced CA3-CA1 synaptic potentiation could be augmented by transiently increasing extracellular signal-regulated kinase (ERK) activity through pharmacological inhibition of dual-specificity phosphatases 6 (DUSP6). The antidepressant-like behavioral effects of acute ketamine treatment were extended by DUSP6 inhibition for up to 2 months. The selective deletion of tropomyosin receptor kinase B (TrkB) in excitatory neurons abolished these DUSP6 inhibition-mediated synaptic and behavioral effects. These data suggest that ketamine's rapid antidepressant effects can be sustained by selectively targeting downstream intracellular signaling. Show less

The beak bean, found only in waterfowl and Galliformes, aids in foraging, self-defense and pecking hard objects. Its rich coloration results from prolonged evolutionary adaptation. This study analyzed beak bean phenotypes of duck at 10, 20, 30 and 40 days of age, revealing that the most common type is the black beak bean, characterized by melanin deposition on the beak surface. This study performed single nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) to investigate the genetic basis of beak bean color, identifying signals on chromosome 1. The copy number variation region-based GWAS revealed a consistent candidate region overlapping with the SNP-based GWAS signals, further supporting the importance of this genomic region. Locus zoom analysis further refined the candidate regions to 48.5-50.5 and 50.8-52.8 Mb. Functional enrichment analysis highlighted six candidate genes within these regions: KITLG, DUSP6, GALNT4, MGAT4C, ATP2B1 and NTS. Notably, KITLG and DUSP6, which are linked to melanin production, were identified as key candidate genes for beak bean color. Our finding revealed the genetic basis of the bean color traits for the first time in ducks, providing a theoretical foundation and technological framework for enhancing duck beak coloration. Show less

Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial-mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-β1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-β1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM. Show less

Based on the Caco-2 cell heat stress model, the study explored the heat stress preventive regulatory mechanisms of key polyphenol fractions in mung bean by metabolomics and transcriptomics association analysis. Results Mung bean polyphenol intervention before heat stress significantly reduced the elevated expression level of heat shock protein 70 (HSP70) caused by 39 °C temperature. At the metabolic level, mung bean polyphenols could play a role in heat stress regulation by alleviating oxidative stress damage. At the gene level, mung bean polyphenols showed regulation of cell proliferation, differentiation, and DNA damage, with DUSP6 and NEURL3 as key regulatory genes. The correlation analysis showed that nucleotide metabolism, and oxidative phosphorylation metabolism were the key pathways in the regulation of mung bean polyphenols by heat stress. Then mung bean polyphenols can exert heat stress preventive activity through the regulation of cellular oxidative damage and energy metabolism. This study provides a good idea for the research and development of dietary intervention products for heat stress. Show less

Growth traits are crucial for poultry breeding and production. Marker-assisted selection (MAS) and genomic selection (GS) of growth traits require a substantial number of accurate genetic markers. A genome-wide association study (GWAS) for body size traits was performed on 248 Luning chickens to identify significant single-nucleotide polymorphisms (SNPs) and insertions and deletions (INDELs) related to the growth and development of chickens. A total of 30 significant SNPs and 13 INDELs were obtained for body size traits. Two notable regions, spanning from 43.072 to 43.219 Mb on chromosome 1 and from 4.751 to 4.800 Mb on chromosome 11, were found to be significantly associated with growth traits in the GWAS of both SNPs and INDELs. Some genes, including Show less

Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. However, the physiological function of the DUSP6 gene on white adipocyte adipogenesis in farm animals remains unknown. In this study, we aimed to clarify the effect of DUSP6 on porcine subcutaneous preadipocyte proliferation and differentiation. We first make clear that the patterns of DUSP6 expression is associated with fat contents in porcine fat deposition related tissues. Porcine subcutaneous preadipocytes were isolated and induced to differentiation. Small interfering RNAs were applied to deplete DUSP6. MTT assay, CCK-8 analysis, Oil Red O staining, triglyceride determination and reverse transcription quantitative polymerase chain reaction were applied to study the regulatory role of DUSP6 during adipocyte adipogenesis in pigs. We found that the expression levels of DUSP6 were significantly higher in backfat and longissimus dorsi tissues from fat-type pigs than in those from lean-type pigs. Consistently, the significantly induced expression of DUSP6 was also observed in differentiated adipocytes. In addition, knockdown of DUSP6 greatly inhibited preadipocytes proliferation, through the decreased cell viability and downregulated mRNA expressions of cell proliferation-associated genes, including PCNA, CDK1, CDK2. Furthermore, knockdown of DUSP6 significantly inhibited preadipocytes differentiation, as evidenced by markedly reduced lipid droplet formation, attenuated triglyceride accumulation and downregulated expression levels of adipogenic transcription masters (PPARγ, C/EBPβ, FASN and FABP4) in DUSP6 knockdown cells. Our results demonstrate that DUSP6 is required for white adipocyte adipogenesis in pigs. Show less

Ovarian carcinoma has still a poor prognosis. CRISPR/Cas9 loss-of-function screen revealed a relationship between the PSMC6 proteasome subunit expression and survival of cisplatin-sensitive and -resistant ovarian carcinoma cells. Increased levels of PSMC6 were evidenced in multiple ovarian carcinoma cell lines versus normal cells. An association between PSMC6 levels and tumour stages as well as with a reduced progression-free survival was found. Since a PSMC6 interactome analysis evidenced limited knowledge on PSMC6 biology, mechanistic studies were carried out. PSMC6 knockdown indicated reduced cell growth and clonogenicity in cisplatin-sensitive IGROV-1 and -resistant IGROV-1/Pt1 cells, with a higher impact in resistant cells. This behaviour was accompanied by the accumulation of ubiquitinated proteins and down-regulation of ERK1/2 phosphorylation mediated by increased DUSP6. PSMC6 silencing increased sensitivity to cisplatin in IGROV-1/Pt1 cells as shown by clonogenic assay and 3D spheroids. Since PSMC6 knockdown did not change sensitivity to 20S and 19S proteasome inhibitors, we suggest a new mode of proteasome targeting by interference with a proteasome ATPase. Overall, a link between PSMC6 and ovarian carcinoma aggressiveness is envisioned, highlighting PSMC6 as a potential diagnostic and therapeutic target. Show less

Congenital hypogonadotropic hypogonadism (CHH) is a rare and heterogeneous genetic disorder with variable penetrance caused by GnRH deficiency, leading to delayed puberty and infertility. In 50-60% of cases, CHH is associated with non-reproductive abnormalities, most commonly anosmia/hyposmia (Kallmann syndrome, KS). Over 60 genes have been implicated in CHH pathogenesis. We aimed to perform genetic screening in a cohort of 14 patients (10 males, 4 females; mean age 22 ± 7.72 years) with suspected or diagnosed HH/KS. Genetic analysis was conducted using next-generation sequencing (NGS) with a custom panel of 46 candidate genes. Variant interpretation followed ACMG standards and guidelines. Multiple tools were used to predict the structural effects of variants on tertiary protein structure, assessing their pathogenicity. Novel variants were functionally characterized by qRT-PCR on mRNA extracted from peripheral leukocytes. NGS identified nine rare variants and four novel variants in genes previously associated with normosmic isolated HH (nHH) and/or KS ( Show less

Glioma, characterized by its cellular and molecular heterogeneity, presents formidable challenges in treatment strategy and prognostic assessment. The tumor microenvironment (TME) profoundly influences tumor behavior and treatment response, with tumor-associated neutrophils (TANs) playing a complex but understudied role. This study aimed to investigate the heterogeneity and role of TANs in glioma and to develop a prognostic model. Analysis of scRNA-seq data identified cellular subpopulations and differentially expressed neutrophil-related genes (DE-NRGs). Bulk RNA-seq was obtained from four independent datasets. Molecular subtypes of glioma samples were determined by consensus clustering. WGCNA was conducted to elucidate the association between gene modules and subtypes. We developed a risk score model. Expression of selected genes was confirmed using immunohistochemistry (IHC). In vitro experiments were also performed for functional verification, including CCK8, EdU, Transwell, and TUNEL assays. A total of 108 DE-NRGs for TANs were identified based on scRNA-seq data. Two molecular subtypes were characterized, showing significant differences in prognosis and clinical features. Immune-related analyses demonstrated varied immunological characteristics between subtypes. The risk score model was constructed with 7 genes, including AEBP1, CAVIN1, DCTD, DEPP1, DUSP6, FKBP9, and UGCG. It showed significant prognostic value and was validated across three external datasets. The mutation landscape highlighted higher IDH mutation prevalence in low-risk groups. Drug sensitivity analysis indicated TMZ resistance in high-risk groups. In vitro experiments showed that UGCG could promote glioma cell proliferation, migration, and invasion, while decreasing apoptosis. This study explored the heterogeneity of TANs and developed a prognostic model, providing insights for prognostic prediction and guiding personalized treatment strategies in glioma. Declaration of Generative AI in Scientific Writing: The authors declare nonuse of generative AI and AI-assisted technologies in the writing process. Show less

Atherosclerosis is characterized by persistent inflammatory condition, leading to various cardiovascular complications. Foam cell formation, resulting from macrophage uptake of oxidized low-density lipoprotein (ox-LDL), contributes significantly to atherosclerosis progression. This study was designed to investigate the involvement of bispecific phosphatase-6 (DUSP6) and its potential regulatory mechanisms in foam cell formation and atherosclerosis. We employed THP-1 cells to induce foam cell formation. The lipid droplet accumulation, cholesterol content, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 levels were evaluated using Oil Red O staining, cholesterol assay, ELISA, and qRT-PCR techniques. We investigated DUSP6 ubiquitination via immunoprecipitation and western blot (WB) analysis. A bioinformatics approach identified FBXL14 as a potential E3 ligase involved in DUSP6 ubiquitination, further confirmed by siRNA and overexpression experiments. The impact of FBXL14 on the NRF2 signaling pathway was assessed using WB analysis. DUSP6 interference suppressed foam cell formation and inflammatory factor secretion. Upon ox-LDL treatment, DUSP6 underwent deubiquitylation, with FBXL14 emerging as the candidate E3 ligase. FBXL14 overexpression induced DUSP6 ubiquitination, leading to the NRF2 signaling pathway activation. It counteracted with DUSP6 overexpression on foam cell formation and inflammation. In ApoE-/- mice, sh-DUSP6 adenovirus injection mitigated atherosclerotic lesion progression and improved the lipid profile, with increased the proteins expression of NQO1, HO-1, and NRF2 in aortic tissue. DUSP6 and FBXL14 play vital roles in modulating foam cell formation and inflammatory responses in atherosclerosis. Targeting these molecules could offer therapeutic potential in attenuating atherosclerosis-related complications. Not applicable. Show less