Diabetic nephropathy (DN) is a common secondary kidney disease. Immune and inflammatory responses play an influential role in the development of DN. This study aims to explore the role and mechanisms of immune- and inflammatory-related factors in DN. Participants from the NHANES 2013-2018 were included to evaluate the association between the SII and DN. Considering the skewed distribution of SII, log SII was used for subsequent analysis. Then, the DEGs were extracted from the GSE96804 dataset by the \"limma\" package of R, which were further screened out genes in the key module based on WGCNA. The intersection genes between DEGs and key module genes were the key genes for the following mechanism exploration. The CyTargetlinker plug-in of Cytoscape software was used to construct the drug-genes network. Molecular docking was used to calculate the binding affinity between potential drugs and the hub genes. Among the 8236 participants from NHANES 2013-2018, Log SII was significantly associated with DN (p < 0.05). DEG and WGCNA revealed 30 DN-related genes, which mainly regulated immune- and inflammation pathways, and the NOD-like receptor signaling pathway was the core pathway highly involved in the DN occurrence. Moreover, NAIP, ZFP36, and DUSP1 were identified as hub genes in DN progression and there was a strong binding interaction between resveratrol and DUSP1.In conclusion, immune inflammation plays an influential role in the occurrence and development of DN. SII is an effective diagnostic marker for DN and resveratrol might have potential value in treating DN.

OBJECTIVE: C-C motif chemokine receptor 7 (CCR7) significantly influences tumors onset and progression, yet its impact on the tumor microenvironment (TME) and specific mechanisms remain elusive. Inflammatory Cancer-Associated Fibroblasts (iCAF), a vital subtype of Cancer-Associated Fibroblasts (CAF), play a critical role in regulating the TME and tumor growth, though the underlying molecular mechanisms are not fully understood. This study aims to determine whether CCR7 participates in tumor regulation by iCAF and to elucidate the specific mechanisms involved.
METHODS: Differential gene analysis of CAF subtypes in CCR7 knockout and wild-type groups was conducted using single-cell data. Animal models facilitated the extraction of primary iCAF cells via flow cytometry sorting. Changes in DUSP1 expression and the efficiency of lentivirus-mediated knockdown and overexpression were examined through qPCR and Western Blot. MOC1 and MOC2 cells were co-cultured with iCAF, with subsequent validation of changes in tumor cell proliferation, migration, and invasion using CCK8, EdU, and wound healing assays. ELISA was employed to detect changes in TGF-β1 concentration in the iCAF supernatant.
RESULTS: CAF was categorized into three subtypes-myCAF, iCAF, and apCAF-based on single-cell data. Analysis revealed a significant increase in DUSP1 expression in iCAF from the CCR7 knockout group, confirmed by in vitro experiments. Co-culturing MOC1 and MOC2 cells with iCAF exhibiting lentivirus-mediated DUSP1 knockdown resulted in inhibited tumor cell proliferation, invasion, and migration. In contrast, co-culture with iCAF overexpressing DUSP1 enhanced these capabilities. Additionally, the TGF-β1 concentration in the supernatant increased in the DUSP1 knockdown iCAF group, whereas it decreased in the DUSP1 overexpression group.
CONCLUSIONS: The CCR7/DUSP1 signaling axis regulates tumor growth by modulating TGF-β1 secretion in iCAF.

Binge drinking causes a range of problems especially damage to the nervous system, and the specific neural mechanism of brain loss and behavioral abnormalities caused by which is still unclear. Extracellular regulated protein kinases (ERK) maintain neuronal survival, growth, and regulation of synaptic plasticity by phosphorylating specific transcription factors to regulate expression of brain-derived neurotrophic factor (BDNF). Dual-specific phosphatase 1 (DUSP1) and DUSP6 dephosphorylate tyrosine and serine/threonine residues in ERK1/2 to inactivate them. To investigate the molecular mechanism by which alcohol affects memory and emotion, a chronic intermittent alcohol exposure (CIAE) model was established. The results demonstrated that mice in the CIAE group developed short-term recognition memory impairment and anxiety-like behavior; meanwhile, the expression of DUSP1 and DUSP66 in the mPFC was increased, while the levels of p-ERK and BDNF were decreased. Micro-injection of DUSP1/6 inhibitor BCI into the medial prefrontal cortex (mPFC) restored the dendritic morphology by reversing the activity of ERK-BDNF and ultimately improved cognitive and emotional impairment caused by CIAE. These findings indicate that CIAE inhibits ERK-BDNF by increasing DUSP1/6 in the mPFC that may be associated with cognitive and emotional deficits. Consequently, DUSP1 and DUSP6 appear to be potential targets for the treatment of alcoholic brain disorders.

UNASSIGNED: The morbidity and mortality of sepsis are increasing year by year. Statistically, 40-50% of patients with sepsis have concomitant myocardial injury, and its mortality rate is higher than that of patients with sepsis only. Therefore, it is of great significance to elucidate the mechanism of sepsis-induced myocardial injury.
UNASSIGNED: Human monocytes (THP-1) were used to induce M0 macrophages, followed by treated with lipopolysaccharide (LPS). Cardiomyocytes (AC16) were co-cultured with the conditioned medium of LPS-induced macrophages to induce injury. Quantitative real-time PCR was employed to detect the mRNA levels of peroxisome proliferator-activated receptor α (PPARA) and dual specificity phosphatase 1 (DUSP1). Protein levels of PPARA, macrophage polarization-related markers, apoptosis-related markers, mitochondria-related proteins, and DUSP1 were analyzed by Western blot. Flow cytometry was used to assess M1/M2 cell rates and apoptosis. Low PPARA expression could serve as a biomarker for patients with sepsis. PPARA overexpression enhanced M2 polarization and suppressed M1 polarization in LPS-induced macrophages, and it could alleviate cardiomyocyte injury in co-cultured system. PPARA bound to the DUSP1 promoter region and facilitated its expression. DUSP1 knockdown reversed the effect of PPARA overexpression on M2 polarization and cardiomyocyte injury.
UNASSIGNED: PPARA attenuated cardiomyocyte injury by promoting macrophage M2 polarization through increasing DUSP1 expression, suggesting that PPARA might be a therapy target for sepsis-induced myocardial injury.

Chemotherapy is a commonly effective treatment for most types of cancer. However, many patients experience a relapse due to minimal residual disease (MRD) after chemotherapy. Previous studies have analyzed the changes induced by chemotherapy for specific types of cancer, but our study is the first to comprehensively analyze MRD across various types of cancer. We included both bulk and single-cell RNA sequencing datasets. We compared the expression of the entire genome and calculated scores for canonical pathway signatures and immune infiltrates before and after chemotherapy across different types of cancer. Our findings revealed that DUSP1 was the most significantly and widely enriched gene in pan-cancer MRD. DUSP1 was found to be essential for MRD formation and played a role in T cell-fibroblast communications and the cytotoxic function of CD4 + T cells. Overall, our analysis provides a comprehensive understanding of the changes caused by chemotherapy and identifies potential targets for preventing and eliminating MRD, which could lead to long-term survival benefits for patients.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC) patients, which remarkably improve the clinical outcomes. However, drug resistance has greatly impaired the efficacy of EGFR-TKIs and contributes to cancer treatment failure. DUSP1, a negative regulator of MAPK signaling pathway, was discovered to mediate drug resistance in multiple types of cancers. Our study aimed to explore the role of DUSP1 in NSCLC cell resistance to osimertinib, a third-generation EGFR-TKI. Human NSCLC cell lines PC-9 and HCC827 were exposed to increasing concentrations of osimertinib for over 6 months to generate osimertinib resistant cells (PC-9-OR and HCC827-OR). The viabilities of osimertinib-resistant and parental sensitive NSCLC cells in response to osimertinib stimulation were detected by MTS assay and the IC50 values for osimertinib were obtained. The differentially expressed genes in osimertinib-resistant and sensitive NSCLC cells were identified by analyzing the GEO dataset GSE106765 using bioinformatic tools. DUSP1 expression was knocked down by using the short hairpin RNAs (shRNAs). Then, the effects of DUSP1 silencing on osimertinib-resistant and sensitive NSCLC cell resistance to osimertinib, viability, proliferation and apoptosis were assessed through loss-of-function experiments. The expression of key molecules (JNK, ERK, and p38 MAPK) in the MAPK signaling pathway was detected through western blotting analysis. DUSP1 was overexpressed in osimertinib-resistant NSCLC cells versus parental sensitive cells. DUSP1 silencing attenuated the resistance of NSCLC cells to osimertinib. DUSP1 silencing markedly inhibited osimertinib-resistant and sensitive NSCLC cell proliferation but enhanced cell apoptosis. Mechanically, DUSP1 knockdown increased phosphorylated-JNK, ERK, and p38 MAPK levels in NSCLC cells. Treatment with SB203580, the p38 MAPK inhibitor, reversed the effects of DUSP1 silencing on osimertinib-resistant NSCLC cell resistance to osimertinib, cell proliferation and apoptosis. DUSP1 downregulation restores the sensitivity of NSCLC cells to osimertinib via activating the MAPK signaling pathway.

Chronic low-grade inflammation, particularly elevated tumor necrosis factor (TNF) levels, occurs due to advanced age and is associated with greater susceptibility to infection. One reason for this is age-dependent macrophage dysfunction (ADMD). Herein, we use the adoptive transfer of alveolar macrophages (AM) from aged mice into the airway of young mice to show that inherent age-related defects in AM were sufficient to increase the susceptibility to Streptococcus pneumoniae, a Gram-positive bacterium and the leading cause of community-acquired pneumonia. MAPK phosphorylation arrays using AM lysates from young and aged wild-type (WT) and TNF knockout (KO) mice revealed multilevel TNF-mediated suppression of kinase activity in aged mice. RNAseq analyses of AM validated the suppression of MAPK signaling as a consequence of TNF during aging. Two regulatory phosphatases that suppress MAPK signaling, Dusp1 and Ptprs, were confirmed to be upregulated with age and as a result of TNF exposure both ex vivo and in vitro. Dusp1 is known to be responsible for glucocorticoid-mediated immune suppression, and dexamethasone treatment increased Dusp1 and Ptprs expression in cells and recapitulated the ADMD phenotype. In young mice, treatment with dexamethasone increased the levels of Dusp1 and Ptprs and their susceptibility to infection. TNF-neutralizing antibody reduced Dusp1 and Ptprs levels in AM from aged mice and reduced pneumonia severity following bacterial challenge. We conclude that chronic exposure to TNF increases the expression of the glucocorticoid-associated MAPK signaling suppressors, Dusp1 and Ptprs, which inhibits AM activation and increases susceptibility to bacterial pneumonia in older adults.

Type-3 cardiorenal syndrome (CRS-3) is acute kidney injury followed by cardiac injury/dysfunction. Mitochondrial injury may impair myocardial function during CRS-3. Since dual-specificity phosphatase 1 (DUSP1) and prohibitin 2 (PHB2) both promote cardiac mitochondrial quality control, we assessed whether these proteins were dysregulated during CRS-3-related cardiac depression. We found that DUSP1 was downregulated in heart tissues from a mouse model of CRS-3. DUSP1 transgenic (DUSP1Tg) mice were protected from CRS-3-induced myocardial damage, as evidenced by their improved heart function and myocardial structure. CRS-3 induced the inflammatory response, oxidative stress and mitochondrial dysfunction in wild-type hearts, but not in DUSP1Tg hearts. DUSP1 overexpression normalized cardiac mitochondrial quality control during CRS-3 by suppressing mitochondrial fission, restoring mitochondrial fusion, re-activating mitophagy and augmenting mitochondrial biogenesis. We found that DUSP1 sustained cardiac mitochondrial quality control by binding directly to PHB2 and maintaining PHB2 phosphorylation, while CRS-3 disrupted this physiological interaction. Transgenic knock-in mice carrying the Phb2S91D variant were less susceptible to cardiac depression upon CRS-3, due to a reduced inflammatory response, suppressed oxidative stress and improved mitochondrial quality control in their heart tissues. Thus, CRS-3-induced myocardial dysfunction can be attributed to reduced DUSP1 expression and disrupted DUSP1/PHB2 binding, leading to defective cardiac mitochondrial quality control.

The dual-specificity phosphatase (DUSP) family plays key roles in the maintenance of cellular homeostasis and apoptosis etc. In this study, the DUSP member DUSP1 of Epinephelus coioides was characterized: the length was 2371 bp including 281 bp 5\' UTR, 911 bp 3\' UTR, and a 1125 bp open reading frame encoding 374 amino acids. E. coioides DUSP1 has two conserved domains, a ROHD and DSPc along with a p38 MAPK phosphorylation site, localized at Ser308. E. coioides DUSP1 mRNA can be detected in all of the tissues examined, and the subcellular localization showed that DUSP1 was mainly distributed in the nucleus. Singapore grouper iridovirus (SGIV) infection could induce the differential expression of E. coioides DUSP1. Overexpression of DUSP1 could inhibit SGIV-induced cytopathic effect (CPE), the expressions of SGIV key genes, and the viral titers. Overexpression of DUSP1 could also regulate SGIV-induced apoptosis, and the expression of apoptosis-related factor caspase 3. The results would be helpful to further study the role of DUSP1 in viral infection.

OBJECTIVE: Ovarian cancer is one of the leading causes of cancer-related death among women. CSGALNACT2 is a vital Golgi transferase and is related to a variety of human diseases. However, its expression pattern and function in ovarian cancer remain uncertain.
METHODS: The Cancer Genome Atlas and GEPIA databases were used to assess the expression of CSGALNACT2 in ovarian cancer patients. RNA-seq, qRT-PCR, and IHC were used to verify the expression of CSGALNACT2 in ovarian cancer tissues. Then, in vivo and in vitro experiments were conducted to evaluate the role of CSGALNACT2 in the progression of ovarian cancer. RNA-seq and GSEA were used to reveal the potential biological function and oncogenic pathways of CSGALNACT2.
RESULTS: We demonstrated that the mRNA expression and protein level of CSGALNACT2 were significantly downregulated in ovarian cancer and ovarian cancer metastatic tissues. CSGALNACT2 can significantly inhibit the migration, invasion, and clonogenic growth of ovarian cancer in vitro and is progressively lost during ovarian cancer progression in vivo. CSGALNACT2 suppresses ovarian cancer migration and invasion via DUSP1 modulation of the MAPK/ERK pathway through RNA-seq, KEGG analysis, and Western blotting. Moreover, CSGALNACT2 expression was correlated with immune cell infiltration and had prognostic value in different immune cell-enriched or decreased ovarian cancer. In addition, patients with CSGALNACT2 downregulation are less likely to benefit from immunotherapy.
CONCLUSIONS: As an ovarian cancer suppressor gene, CSGALNACT2 inhibits the development of ovarian cancer, and it might be used as a prognostic biomarker in patients with ovarian cancer.