國家衛生研究院

Abstract Multiple members (DUSP1–29) of dual-specificity phosphatase (DSP) family are key regulators of mitogen-activated protein kinases (MAPKs), which regulate numerous physiological responses. Eight DUSPs are also named MAPK phosphatases (MKPs). DUSP dysregulation contributes to the pathogenesis of various human inflammatory and chronic diseases. Downregulation of DUSP1, DUSP3, DUSP11, and DUSP22, as well as upregulation of DUSP4, DUSP6, and DUSP23 are involved in human autoimmune diseases. Besides autoimmune diseases, reduction of DUSP1, DUSP2, and DUSP14, as well as induction of DUSP8 contribute to the pathogenesis of allergic diseases. Additionally, decreased levels of DUSP2, DUSP11, DUSP22, and DUSP28 are associated with human inflammatory bowel diseases. Moreover, deficiency of 10 DUSPs, as well as induction of DUSP4 are associated with metabolic diseases. Downregulation of 5 DUSPs are involved in cardiovascular disease pathogenesis; in contrast, upregulation of other 5 DUSPs are correlated with cardiovascular diseases. Collectively, dysregulated DUSPs could be diagnostic biomarkers and therapeutic targets for inflammatory diseases. Due to complex expression patterns of DUSPs, it is crucial to study the regulatory mechanisms of individual DUSPs in various inflammatory and chronic diseases. In this review, we summarize the roles and regulatory mechanisms of DUSPs in human inflammatory and chronic diseases. We also discuss the potential therapeutic applications of DUSP agonists/inhibitors in human inflammatory and chronic diseases.

The limited efficacy of immunotherapy in colorectal cancer (CRC) underscores the need to better define immunosuppressive mechanisms within the tumor microenvironment (TME). We applied single-cell RNA sequencing (scRNA-seq) to characterize stromal–immune interactions shaping the CRC TME. Paired tumor and adjacent normal mucosa samples from eight patients with CRC were analyzed by scRNA-seq. Integrated bioinformatic approaches, including trajectory inference, transcriptional regulon analysis, and cell–cell communication modeling, were used to define cellular differentiation and intercellular signaling. Key findings were validated using The Cancer Genome Atlas datasets, multiplex immunofluorescence staining, and in vitro functional assays. Trajectory analysis demonstrated a progressive increase in triggering receptor expressed on myeloid cells 1 (TREM1) expression during tumor-associated myeloid differentiation. TREM1-positive myeloid cells exhibited enriched M2-like signatures and were preferentially associated with consensus molecular subtype 4 tumors, characterized by stromal activation and poor clinical outcomes. Stromal profiling identified an α-smooth muscle actin (ACTA2)-positive population associated with CRC progression. Spatial analyses revealed close localization of TREM1-positive myeloid cells and ACTA2-positive cancer-associated fibroblasts (CAFs) in tumor tissues. Mechanistically, integrated bioinformatic analyses indicated that TREM1-positive myeloid cells engage CAFs primarily through secreted phosphoprotein 1 (SPP1) signaling, while CAFs reinforce immunosuppressive myeloid phenotypes via TGF-β-associated extracellular matrix pathways. Functional assays showed that TREM1 inhibition reduced SPP1 expression and attenuated M2 macrophage polarization. These findings identify a bidirectional interaction between TREM1-positive myeloid cells and CAFs that contributes to a profibrotic and immunosuppressive CRC microenvironment, highlighting the TREM1–SPP1 axis as a pathway of potential translational relevance.

Caregiver stress is a global health issue, particularly acute in Taiwan due to demographic and cultural factors. While mindfulness meditation is effective for burnout, research on culturally adapted, digitally delivered interventions for Taiwanese caregivers is lacking. This study aimed to evaluate the feasibility and preliminary efficacy of a brief, 5-week, digitally supported meditation program for professional and informal caregivers in Taiwan. We conducted a randomized, stratified, wait-list control trial with 57 meditation-naïve caregivers (42 professional, 15 informal). The intervention combined weekly live online sessions with daily guided practice via the AIZEN digital platform. Primary outcomes for professionals were personal, work-related, and client-related burnout, measured by the Copenhagen Burnout Inventory. The secondary outcome for informal caregivers was burden, measured by the Zarit Burden Interview. Outcomes were assessed at baseline (T1), post-intervention (T2), and 5-week follow-up (T3). Compared to the wait-list group, the immediate-intervention professional caregivers showed significantly greater reductions from T1 to T2 in personal burnout (β = 12.50, p = 0.011) and work-related burnout (β = 11.43, p = 0.015). The effect on work-related burnout was replicated in the primary analysis and maintained at follow-up, though this lost significance in a sensitivity analysis. No significant effects were found for client-related burnout or informal caregiver burden. A brief, digitally supported mindfulness meditation program is a feasible, effective approach for reducing personal and work-related burnout among professional caregivers in Taiwan. These findings support the implementation of scalable digital mental health tools and warrant investigation in larger trials. ClinicalTrials.gov NCT07188454.

AI-derived bone mineral density from routine radiographs showed strong agreement with DXA and comparable ability to predict incident fractures. This opportunistic approach may support osteoporosis screening and early identification of high-risk individuals without reliance on dedicated DXA examinations. Osteoporosis is a major cause of fragility fractures, yet limited access to DXA leads to underdiagnosis and delayed treatment. Recent advances in artificial intelligence enable extraction of bone structural information from routine radiographs, providing a potential tool for opportunistic osteoporosis screening. Whether AI-derived BMD can approximate DXA and predict real-world fracture risk remains unclear. Adults aged ≥ 20 years who underwent both lumbar DXA and radiographic examinations (lumbosacral or kidney–ureter–bladder) within six months between January 2014 and December 2024 were retrospectively analyzed. Lumbar BMD was estimated using DeepXray Spina and compared with DXA using Pearson correlation, intraclass correlation coefficient (ICC), and Bland–Altman analysis. Diagnostic performance for osteoporosis (T-score ≤ − 2.5) and fracture prediction was evaluated using receiver operating characteristic (ROC) analysis, Cohen’s κ, and logistic regression. Among 540 participants (73.9

Sepsis is a life-threatening clinical syndrome caused by a dysregulated innate immune response to infection, resulting in excessive systemic inflammation, multi-organ failure, and persistently high mortality rates. In fatal human sepsis, PP4 expression is markedly reduced in myeloid cells, suggesting a protective role against dysregulated innate immunity. However, its role in macrophage-neutrophil crosstalk during sepsis environment remains unclear. To delineate its cell-type specificity, we generated myeloid cell-specific PP4 knockout mice and investigated PP4's function in innate immune regulation during sepsis. PP4-deficient mice exhibited significantly increased susceptibility to sepsis, with severe tissue damage following cecal ligation and puncture (CLP) or endotoxin challenge. Mechanistically, PP4 modulates macrophage-neutrophil crosstalk during the sepsis environment, with its loss leading to dysregulated CCL5/CCR5 signaling, driving excessive neutrophil activation. Elevated macrophage-derived CCL5 enhanced PAD4-dependent NETosis, ROS production, and elastase activity via CCR5, while CCR5 inhibition effectively mitigated neutrophil hyperactivity. At the molecular level, PP4 directly dephosphorylated TBK1, thereby inactivating IRF3 and suppressing macrophage-driven CCL5 production. Furthermore, ERK1/2 phosphorylation upregulated CCR5 expression in PP4-deficient neutrophils post-CLP, amplifying the CCL5/CCR5-mediated NETosis response. Notably, transfection with wild-type PP4-but not a phosphatase-deficient mutant-reduced LPS-mediated CCR5 expression in neutrophils, thereby limiting ROS production and NETs formation. These findings establish PP4 as a critical regulator of CCL5/CCR5-driven NETosis, uncovering a novel therapeutic target for modulating innate immune responses in sepsis.