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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

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

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

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

Chronic kidney disease (CKD) is highly prevalent, incurable, and lacks effective treatments. Aging is closely linked to various kidney diseases. In this study, we combined CKD and aging using bioinformatics approaches to identify potential anti aging drugs and therapeutic targets for CKD. We analyzed datasets GSE37171 and GSE66494 from the GEO database, identifying 317 differentially expressed genes (DEGs). By intersecting these DEGs with aging related genes, we identified 23 aging associated differential genes (ARDEGs). A protein-protein interaction (PPI) network was constructed using the STRING database, and the top 10 hub ARDEGs were identified using Cytoscape software. Potential anti aging drugs, including Cinnamaldehyde, were identified through the ceRNA and transcription factor regulatory networks, as well as the DGldb database. Among the key regulatory genes identified in CKD patient samples were SOD2, FGF21, FOS, RELA, DDIT4, BMI1, DUSP6, LGALS3, CXCR2, and CEBPB. Cinnamaldehyde and other drugs were found to target aging associated pathways, suggesting their potential to delay CKD progression through modulating these pathways. Finally, we verified the low-expression of DDIT4 and DUSP6, the two targets of Cinnamaldehyde, in unilateral ureteral obstruction (UUO) animal model. Additionally, Cinnamaldehyde was shown to reduce the expression of fibrosis markers such as fibronectin (FN) and α-smooth muscle actin (α-SMA) in HK2 cells under TGF-β1 stimulation. This study provides a foundational understanding of aging related molecular targets in CKD and offers new directions for developing anti aging therapies to treat CKD. 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 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

The transcription factor achaete-scute complexhomolog 1 (ASCL1) is a lineage oncogene that is central in growth and survival of the majority of small cell lung cancers and neuroendocrine (NE) non-small cell lung cancers (NSCLC) that express it. Targeting ASCL1, or its downstream pathways, remains a challenge. Small cell lung cancers and NSCLC-NE that express ASCL1 exhibit relatively low ERK1/2 activity, in dramatic contrast to NSCLCs in which the ERK pathway plays a major role in pathogenesis. ERK1/2 inhibition in ASCL1-expressing lung tumor cells revealed downregulation of ERK1/2 pathway suppressors SPRY4, SPRED1, DUSP6, and the transcription factor ETV5, which regulates DUSP6. Chromatin immunoprecipitation sequencing demonstrated that these genes are bound by ASCL1. Availability of a pharmacologic inhibitor directed mechanistic studies toward DUSP6, an ERK1/2-selective phosphatase, in a subset of ASCL1-high NE lung tumors. Inhibition of DUSP6 increased active ERK1/2, which accumulated in the nucleus. Pharmacologic and genetic inhibition of DUSP6 reduced proliferation and survival of these cancers. Resistance developed in DUSP6-knockout cells, indicating a bypass mechanism. Although targeting ASCL1 remains a challenge, our findings suggest that expression of ASCL1, DUSP6, and low phospho-ERK1/2 identifies NE lung cancers for which DUSP6 may be a therapeutic target. Show less

Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib. This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics. Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAF Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect. gov identifier: NCT02974725. Show less

Glioblastoma is a highly aggressive brain tumour that creates an immunosuppressive microenvironment. Microglia, the brain's resident immune cells, play a crucial role in this environment. Glioblastoma cells can reprogramme microglia to create a supportive niche that promotes tumour growth. However, the mechanisms controlling the acquisition of a transcriptome associated with a tumour-supportive microglial reactive state are not fully understood. In this study, we investigated changes in the transcriptional profile of BV2 microglia exposed to C6 glioma cells. RNA-sequencing analysis revealed a significant upregulation of microglial inhibitor of DNA binding 1 (Id1) and Id2, helix-loop-helix negative transcription regulatory factors. The concomitant regulation of microglial ETS proto-oncogene 2, transcription factor (ETS2)-target genes, i.e., Dusp6, Fli1, Jun, Hmox1, and Stab1, led us to hypothesize that ETS2 could be regulated by ID proteins. In fact, ID2-ETS2 protein interactions increased in microglia exposed to glioma cells. In addition, perturbation of the ID2-ETS2 transcriptional axis influenced the acquisition of a microglial tumour-supportive phenotype. ID2 and ETS2 genes were found to be expressed by the tumour-associated microglia isolated from human glioblastoma tumour biopsies. Furthermore, ID2 and ETS2 gene expressions exhibited inverse prognostic values in patients with glioma in cohorts from The Cancer Genome Atlas. Collectively, our findings indicate that the regulation of ETS2 by ID2 plays a role in the transcriptional regulation of microglia in response to stimuli originating from glioblastoma cells, information that could lead to developing therapeutic strategies to manipulate microglial tumour-trophic functions. Show less

Pulmonary fibrosis (PF) is a lethal disease caused by inordinate repair of damaged lungs, for which limited strategies are available. Polyphyllin VI (PPVI), extracted and isolated from Paris polyphylla Smith var. chinensis (Franch.) Hara, has been regarded as an important traditional Chinese herbal medicine for the treatment of respiratory system diseases. This study evaluated effects of PPVI on PF and its underlying mechanism. Experimental procedure For evaluating the anti-PF effect of PPVI, we established an in vivo PF mouse model via intratracheal infusion of bleomycin (BLM) in mice and an in vitro PF model induced by TGF-β1 in NIH/3T3, HPF and A549, respectively. Subsequently, the mechanism of PPVI effects was further explored using RNA sequencing (RNA-Seq). The in vivo and in vitro results demonstrated that PPVI significantly inhibited inflammation, oxidative damage, and epithelial-mesenchymal transition. Furthermore, RNA sequencing indicated that PPVI ameliorated PF by modulating inflammation and oxidative stress responses. Furthermore, dual specificity phosphatase 6 (DUSP6), was the shared and most significant differentially expressed gene associated with inflammation and oxidative stress response after PPVI treatment. Mechanistically, silencing DUSP6 can eliminate the suppressive impact on PPVI for the activation of fibroblast and the phosphorylation of ERK and AKT. Summarily, our findings revealed the potential of PPVI in mitigating PF via upregulating DUSP6 and highlighted the regulatory function of DUSP6 in the pathogenesis of PF. Show less

The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a function of eIF4F in the negative regulation of the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for controlling ERK signaling intensity in treatment-naïve melanoma cells harboring Show less

Mutations in GATA6 are associated with congenital heart disease, most notably conotruncal structural defects. However, how GATA6 regulates cardiac morphology during embryogenesis is undefined. We used knockout and conditional mutant zebrafish alleles to investigate the spatiotemporal role of gata6 during cardiogenesis. Loss of gata6 specifically impacts atrioventricular valve formation and recruitment of epicardium, with a prominent loss of arterial pole cardiac cells, including those of the ventricle and outflow tract. However, there are no obvious defects in cardiac progenitor cell specification, proliferation or death. Conditional loss of gata6 starting at 24 h is sufficient to disrupt the addition of late differentiating cardiomyocytes at the arterial pole, with decreased expression levels of anterior secondary heart field (SHF) markers spry4 and mef2cb. Conditional loss of gata6 in the endoderm is sufficient to phenocopy the straight knockout, resulting in a significant loss of ventricular and outflow tract tissue. Exposure to a Dusp6 inhibitor largely rescues the loss of ventricular cells in gata6-/- larvae. Thus, gata6 functions in endoderm are mediated by FGF signaling to regulate the addition of anterior SHF progenitor derivatives during heart formation. Show less

Approximately 50% of patients with chronic neuropathic pain experience cognitive impairment, which negatively impacts their quality of life. The cannabinoid type 2 receptor (CB2R) may be involved in hippocampal cognitive processes. However, its role in chronic neuropathic pain-induced cognitive impairment remains elusive. Spared nerve injury (SNI) was used to induce chronic neuropathic pain in rats, while the novel-object recognition test and the Y-maze test were employed to assess cognitive function. Immunofluorescence, western blotting, and stereotaxic hippocampal microinjection were utilized to elucidate the potential mechanisms. We observed a reduction in mechanical pain threshold and cognitive impairment in SNI rats. This was accompanied by a tendency for hippocampal microglia to adopt pro-inflammatory functions. Notably, no changes were detected in CB2R expression. However, downregulation of the endogenous ligands AEA and 2-AG was evident. Hippocampal microinjection of a CB2R agonist mitigated cognitive impairment in SNI rats, which correlated with a tendency for microglia to adopt anti-inflammatory functions. Additionally, SNI-induced activation of the p-ERK/NFκB pathway in the hippocampus. Activation of CB2R reversed this process by upregulating DUSP6 expression in microglia. The effects elicited by CB2R activation could be inhibited through the downregulation of microglial DUSP6 via hippocampal adeno-associated virus (AAV) microinjection. Conversely, overexpression of hippocampal DUSP6 using AAV ameliorated the cognitive deficits observed in SNI rats, which remained unaffected by the administration of a CB2R antagonist. Our findings demonstrate that activation of hippocampal CB2R can mitigate chronic neuropathic pain-induced cognitive impairment through the modulation of the DUSP6/ERK/NFκB pathway. Show less

Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens. Histopathological examination, immunohistochemistry and whole-exome sequencing confirmed similarity between our PDX tumors and primary tumors in terms of morphology and genetic characteristics. The drug reactivity of the PDX tumor was validated in vivo. The mechanisms of acquired resistance to Osimertinib PDX tumors were investigated by WES and WB. We successfully established 13 NSCLC-PDXs derived from 62 patients, including eight adenocarcinomas, four squamous-cell carcinoma, and one large-cell neuroendocrine carcinoma. Histological subtype and clinical stage were significant factors affecting the successful PDXs establishment. The treatment responses to conventional chemotherapy in PDXs were entirely consistent with that of their corresponding patients. According to the genetic status of tumors, more appropriate targeted agents were selected in PDXs for their corresponding patients as alternative treatment options. In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure. Show less

Notch1 plays various roles in cancer development, and Notch1-induced transactivation is controlled by phosphorylation of its cleaved intracellular domain. However, it is unclear whether there are phosphatases capable of dephosphorylating the cleaved Notch1 transmembrane/intracellular region (NTM) to regulate its function. Here, we show that DUSP6 can function as a phosphatase for Notch1, thereby regulating NTM stability and transcriptional activity, thus influencing colorectal cancer (CRC) development. In human CRC cells, elevated DUSP6 expression correlates with increased NTM levels, leading to enhanced CRC cell proliferation both in vitro and in vivo. High tumoral DUSP6 protein expression is associated with poorer overall CRC patient survival. In mice, DUSP6 deficiency results in reduced CRC development. Mechanistically, DUSP6 dephosphorylates phospho-Y2116, which in turn reduces NTM ubiquitination, leading to increased NTM stability and transcriptional activity. As a result, the expression of Notch1-targeted proliferation genes is increased to promote tumour cell growth. Show less

We report targeted protein degradation through the site-specific recruitment of native ubiquitin ligases to a protein of interest via conjugation of E3 ligase ligands. Direct comparison of degradation ability of proteins displaying the corresponding bioconjugation handle at different regions of protein surfaces was explored. We demonstrate the benefit of proximal lysine residues and investigate flexibility in linker length for the design of optimal degraders. Two proteins without known small molecule ligands, EGFP and DUSP6, were differentially degraded when modified at different locations on their protein surfaces. Further, the cereblon-mediated degradation of the known PROTAC target ERRα was improved through the recruitment of the E3 ligase to regions different from the known ligand binding site. This new methodology will provide insight into overall protein degradability, even in the absence of a known small molecule ligand and inform the process of new ligand and PROTAC development to achieve optimal protein degradation. Furthermore, this approach represents a new, small molecule-based conditional OFF switch of protein function with complete genetic specificity. Importantly, the protein of interest is only modified with a minimal surface modification (< 200 Da) and does not require any protein domain fusions. Show less

Wilms' tumour 1 (WT1) can function as an oncogene or a tumour suppressor. Our previous clinical cohort studies showed that low WT1 expression at diagnosis independently predicted poor outcomes in acute myeloid leukaemia (AML) with RUNX1::RUNX1T1, whereas it had an opposite role in AML with non-favourable cytogenetic risk (RUNX1::RUNX1T1-deficient). The molecular mechanism by which RUNX1::RUNX1T1 affects the prognostic significance of WT1 in AML remains unknown. In the present study, first we validated the prognostic significance of WT1 expression in AML. Then by using the established transfected cell lines and xenograft tumour model, we found that WT1 suppresses proliferation and enhances effect of cytarabine in RUNX1::RUNX1T1(+) AML but has opposite functions in AML cells without RUNX1::RUNX1T1. Furthermore, as a transcription factor, WT1 physically interacts with RUNX1::RUNX1T1 and acts as a co-factor together with RUNX1::RUNX1T1 to activate the expression of its target gene DUSP6 to dampen extracellular signal-regulated kinase (ERK) activity. When RUNX1::RUNX1T1-deficient, WT1 can activate the mitogen-activated extracellular signal-regulated kinase/ERK axis but not through targeting DUSP6. These results provide a mechanism by which WT1 together with RUNX1::RUNX1T1 suppresses cell proliferation through WT1/DUSP6/ERK axis in AML. The current study provides an explanation for the controversial prognostic significance of WT1 expression in AML patients. Show less

Increased production of Prostaglandin D2 (PGD2) is linked to development and progression of asthma and allergy. PGD2 is rapidly degraded to its metabolites, which initiate type 2 innate lymphoid cells (ILC2) migration and IL-5/IL-13 cytokine secretion in a PGD2 receptor 2 (DP2)-dependent manner. Blockade of DP2 has shown therapeutic benefit in subsets of asthma patients. Cellular mechanisms of ILC2 activity in response to PGD2 and its metabolites are still unclear. We hypothesized that ILC2 respond non-uniformly to PGD2 metabolites. ILC2s were isolated from peripheral blood of patients with atopic asthma. ILC2s were stimulated with PGD2 and four PGD2 metabolites (Δ12-PGJ2, Δ12-PGD2, 15-deoxyΔ12,14-PGD2, 9α,11β-PGF2) with or without the selective DP2 antagonist fevipiprant. Total RNA was sequenced, and differentially expressed genes (DEG) were identified by DeSeq2. Differential gene expression analysis revealed an upregulation of pro-inflammatory DEGs in ILC2s stimulated with PGD2 (14 DEGs), Δ12-PGD2 (27 DEGs), 15-deoxyΔ12,14-PGD2 (56 DEGs) and Δ12-PGJ2 (136 DEGs), but not with 9α,11β-PGF2. Common upregulated DEGs were i.e. ARG2, SLC43A2, LAYN, IGFLR1, or EPHX2. Inhibition of DP2 via fevipiprant mainly resulted in downregulation of pro-inflammatory genes such as DUSP4, SPRED2, DUSP6, ETV1, ASB2, CD38, ADGRG1, DDIT4, TRPM2, or CD69. DEGs were related to migration and various immune response-relevant pathways such as "chemokine (C-C motif) ligand 4 production", "cell migration", "interleukin-13 production", "regulation of receptor signaling pathway via JAK-STAT", or "lymphocyte apoptotic process", underlining the pro-inflammatory effects of PGD2 metabolite-induced immune responses in ILC2s as well as the anti-inflammatory effects of DP2 inhibition via fevipiprant. Furthermore, PGD2 and metabolites showed distinct profiles in ILC2 activation. Overall, these results expand our understanding of DP2 initiated ILC2 activity. Show less

Protein tyrosine phosphatases (PTPs) are a family of enzymes essential for numerous cellular processes, such as cell growth, inflammation, differentiation, immune-mediated responses and oncogenic transformation. The aim of this review is to review the literature concerning the role of several PTPs-PTPN22, PTPN2, PTPN6, PTPN11, PTPσ, DUSP2, DUSP6 and PTPRK-at the level of the intestinal mucosa in inflammatory bowel disease (IBD), celiac disease (CeD) and type 1 diabetes (T1D) in both in vitro and in vivo models. The results revealed shared features, at the level of the intestinal mucosa, between these diseases characterized by alterations of different biological processes, such as proliferation, autoimmunity, cell death, autophagy and inflammation. PTPs are now actively studied to develop new drugs. Also considering the availability of organoids as models to test new drugs in personalized ways, it is very likely that soon these proteins will be the targets of useful drugs. Show less

Atherosclerosis (AS) and Non-alcoholic fatty liver disease (NAFLD) are chronic metabolic disorders with high prevalence and significant health impacts. Both conditions share common pathophysiological pathways including abnormal lipid metabolism and inflammation. Berberine (BBR), an isoquinoline alkaloid, is known for its beneficial effects on various metabolic and cardiovascular disorders. This study investigates BBR's impact on AS and NAFLD through bioinformatics analysis and experimental models. This study utilized various bioinformatics methods, including transcriptome analysis, weighted gene co-expression network analysis (WGCNA), machine learning, and molecular docking, to identify key genes and pathways involved in AS and NAFLD. Subsequently an animal model of AS combined with NAFLD was established using ApoE-/- mice fed a high-fat diet. The efficacy and mechanism of action of BBR were verified using methods such as hematoxylin and eosin (HE) staining, Oil Red O staining, and real-time quantitative PCR (RTqPCR). Through transcriptome analysis, WGCNA, and machine learning, this study identified 48 key genes involved in both AS and NAFLD. Function analysis revealed that the implicated genes were significantly involved in pathways like cytokine-cytokine receptor interaction, chemokine signaling, and IL-17 signaling pathway, suggesting their role in inflammation and immune responses. Single cell validation identified six key genes: dual specificity phosphatase 6 (DUSP6), chemokine ligand 3 (CCL3), complement component 5a receptor 1 (C5AR1), formyl peptide receptor 1 (FPR1), myeloid nuclear differentiation antigen (MNDA), and proviral integration site of murine 2(PIM2). Finally, molecular docking and animal experiments showed that BBR significantly reduced lipid deposits and inflammatory markers in liver and aortic tissues. In conclusion, BBR can improve AS combined with NAFLD by regulating genes like MNDA, PIM2, DUSP6, CCL3, C5AR1, and FPR1, with the mechanism related to inflammation control. The findings suggest potential clinical benefits of BBR in reducing the progression of both AS and NAFLD, warranting further investigation. Show less

Monoamine oxidase (MAO) inhibitors reduce inflammation in a number of in vitro and in vivo models. This finding led to the development of a novel MAO-B selective inhibitor (RG0216) designed to reduce blood-brain barrier penetration. To elucidate RG0216's regulatory role in inflammation-relevant signaling pathways, we employed a transcriptome analytic approach to identify genes that are differentially regulated by RG0216 and then globally identified which inflammation-relevant biological signaling pathways were altered by this drug. Primary human gingival keratinocyte (HGK) cells were treated with RG0216, and RNA was extracted (4 h). RNAseq transcriptome analysis was utilized to identify differentially expressed genes (DEGs), while Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to identify significantly enriched biological pathways. Relevant genes associated with these pathways and RG0216 regulation of Porphyromonnas gingivalis lipopolysaccharide (PgLPS)-induced cytokine/chemokine expression were evaluated using the real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) approach. RG0216 significantly altered the expression of 50 DEGs in HGK cells. Using GO and KEGG analytic approaches, these genes were associated with the biological pathways relevant to mitogen-activated protein kinase (MAPK) and MAPK phosphatases. These phosphatases are part of the 10-member catalytically active dual-specificity phosphatase (DUSP) family. RG0216 induced the expression of DUSP10, reduced the expression of DUSP4 and DUSP6, and decreased IL-6 and IL-8 expression in control and PgLPS-stimulated cultures. In HGK cells, a novel MAO-B inhibitor (RG0216) significantly altered DUSP4, DUSP6, and DUSP10 expression. DUSPs play a regulatory role in MAPK activity and, therefore, can alter cellular inflammatory responses. We found that RG0216 inhibited IL-6 and IL-8 expression. Further studies are planned to examine RG0216's regulatory role in DUSP expression and its impact on the regulation of cytokine/chemokine expression. Show less

There is growing evidence that the protein family of Gasdermins (GSDMs) play an essential role during the progression of colorectal cancer (CRC). However, it is not completely clear that how GSDMB, abundantly expressed in epithelial cells of gastrointestinal tract, regulates the tumorigenesis of CRC. A wealth of evidence linking GSDMB to the pathogenesis of cancer has come from genome-wide association studies. Here, we provide evidence that aberrantly upregulated GSDMB is responsible for suppressing the CRC progression by using in vitro cell and intestinal organoid, as well as in vivo GSDMB transgenic mice models. Mechanistically, GSDMB interacts with insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which directly binds to and recognizes the 3'-UTR of dual specificity phosphatase 6 (DUSP6) mRNA, enhances the translation of DUSP6 protein and inhibits downstream ERK phosphorylation, thereby facilitating cell death and restraining cell proliferation. Our results suggest that GSDMB has potential as a novel therapeutic target for CRC treatment. Show less

Receptor tyrosine kinases (RTKs) have an important role in arthritis severity and in models of rheumatoid arthritis (RA), but their regulation is not fully understood. The dual specificity phosphatase 6 (DUSP6) has been implicated in the regulation of RTK signaling, but never in the context of arthritis and autoimmunity. We used the KRN serum-induced arthritis (KSIA) model of RA and showed that DUSP6 Show less

Drinking alcohol is considered one of the risk factors for development of diabetes mellitus. Recently, it was reported that selenoprotein P levels in blood are increased by ethanol intake. However, the mechanism by which ethanol increases selenoprotein P has not been elucidated. The expression of selenoprotein P protein and its mRNA were increased in a concentration- and time-dependent manner when human liver-derived HepG2 cells were treated with ethanol. Levels of AMPK and JNK proteins, which have been known to regulate selenoprotein P transcription, were unchanged by ethanol treatment. However, the amount of nuclear FoxO3a, a transcription factor of SeP, was increased. This was associated with dephosphorylation of ERK1 but not ERK2. It was found that ERK1 was dephosphorylated by activation of dual-specific phosphatase 5 and dual-specific phosphatase 6. However, the phosphorylation of MEK by ERK phosphokinase was not affected by ethanol treatment. These results suggest that the ethanol-induced increase in SeP levels occurs by enhanced transcription of SeP mRNA via the DUSP5/6-ERK1-FoxO3a pathway. Show less

During a sepsis infection, the lung is extremely susceptible to damage. A condition known as acute respiratory distress syndrome (ARDS) may develop in extreme circumstances. The primary objective of this research is to identify important genes that are related with both sepsis and lung injury. These genes have the potential to act as novel biomarkers in the investigation of sepsis-induced lung injury prevention strategies. It was possible to download from GEO data both the sepsis-related dataset (GSE64457) and the lung injury-related dataset (GSE40839). In the GSE64457 dataset, using the "limma" package in R revealed 429 differentially expressed genes (DEGs) with logFC values more than or equal to -1 and p values <0.05. There were 266 genes that were up-regulated and 163 genes that were down-regulated. Through the use of Gene Ontology (GO), it was discovered that the majority of the DEGs were associated with the inflammatory response (BP terms), a particular granule lumen (CC terms), and protein binding (MF terms). By doing a pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG), researchers were able to identify DEGs that were mostly associated with the NOD-like receptor signalling pathway, the TNF signalling pathway, and Epstein-Barr virus infection. Within the GSE40839 dataset, Weighted Gene Co-Expression Network Analysis (WGCNA) yielded a total of 7 modules, from which it was possible to screen out 2 critical modules and 693 key genes. The important genes and DEGs were both subjected to a Venn analysis. Finally, 14 genes that overlapped (ARL4A, LAIR1, MTHFD2, TSPAN13, DUSP6, PECR, CBS, TES, ASNS, SYNE1, FGF13, LCN2, KLF10, BCAT1) were closely associated to the incidence and development of sepsis-induced lung injury. This indicates that these genes are the essential genes to avoid the occurrence of sepsis-induced lung injury. This study provides novel strategies for preventing lung harm brought on by sepsis. Show less

The vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), its nuclear receptor VDR (vitamin D receptor) and hundreds of their target genes are not only key regulators of calcium homeostasis, but also important modulators of the immune system. Innate immune cells like monocytes use VDR for efficient differentiation and are very responsive to vitamin D. So far, most information on the gene regulatory function of vitamin D and its physiological impact had been obtained from in vitro studies using supraphysiological doses of 1,25(OH)2D3. Therefore, medical experiments like the study VitDHiD (NCT03537027), where 25 healthy individuals were supplemented once with a vitamin D3 bolus (80,000 IU), provide important insight into the response to vitamin D under in vivo conditions. In this study, we inspected 452 in vivo vitamin D target genes from peripheral blood mononuclear cells (PBMCs) detected in VitDHiD and found 61 of them involved in eight major KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways of innate immunity. Under in vivo conditions in healthy individuals vitamin D either silences five pathways of innate immunity, stabilizes two and increases one, so that acute inflammation is suppressed and the release of cytokines is kept under control. A ranking of the 61 target genes by inducibility, basal expression and multiple involvements in the pathways highlighted the genes NFKBIA (NFκB inhibitor alpha), NFKBIZ, FOSL2 (FOS like 2, AP1 transcription factor subunit), JDP2 (Jun dimerization protein 2), PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1), CLEC7A (C-type lectin domain containing 7A), DUSP6 (dual specificity phosphatase 6), NCF2 (neutrophil cytosolic factor 2), PLCB1 (phospholipase C beta 1), PLCG2 and TNFAIP3 (TNF alpha induced protein 3). In conclusion, vitamin D's in vivo effect on innate immunity in healthy adults is mediated by the interconnection of the pathways of neutrophil extracellular trap formation, Toll-like receptor, chemokine and phagosome signaling, NOD-like receptor, C-type lectin receptor, apoptosis and interleukin 17 through a limited set of proteins encoded by key target genes. Show less

Centromere protein U (CENPU) is key for mitosis in the carcinogenesis of cancers. However, the roles of CENPU have not been inspected in nasopharyngeal carcinoma (NPC). Thus, we aimed to explore the functions and mechanisms of CENPU in NPC. Expression of CENPU was evaluated by real-time quantitative polymerase chain reaction, western blotting and immunohistochemistry. The biological functions of CENPU were evaluated CENPU was highly expressed in NPC. High expression of CENPU was associated with advanced tumor, node and metastasis (TNM) stage and poor overall survival. Cox regression analysis demonstrated that CENPU expression was an independent prognostic factor in NPC. Knockdown of CENPU inhibited proliferation and migration CENPU acts as an oncogene in NPC by interacting with DUSP6, and may represent a promising prognostic biomarker for patients with NPC. Show less