The metabolic syndrome encompasses a state of inflammation and metabolic dysfunction, possibly mediated via a disturbed intestinal barrier. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as liraglutide, have shown promising anti-inflammatory effects beyond glucose lowering and weight loss, but the underlying mechanism remains to be elucidated. We hypothesised that GLP-1RAs improve the intestinal barrier function and overall inflammatory status by direct gene activation in mucus-secreting Brunner's glands in the mouse duodenum, known for their high density of glucagon-like peptide-1 receptors (GLP-1Rs).
Using bulk RNA sequencing, in situ hybridisation, and immunohistochemistry, we analysed the change in the genetic phenotype of mouse Brunner's gland cells following GLP-1R activation by liraglutide.
We show that liraglutide induces a novel and robust upregulation of the gene for the Cystic fibrosis transmembrane conductance regulator, Cftr, in Brunner's glands as a part of an overall genetic phenotype involved in ion channel activity, mucus secretion, and hydration via GLP-1R activation. Additionally, we found a robust upregulation of the genes Muc5b, Il33, Ren1, and Vldlr in Brunner's glands.
Collectively, our results imply an enhanced mucus response from Brunner's glands following GLP-1R activation, which might play a role in the effect of GLP-1.
RETRACTION: Ting Z, Zhi-xin Y, You-wen Y, et al. Exosomes derived from human umbilical cord Wharton's Jelly Mesenchymal stem cells ameliorate experimental lymphedema. Clinical and Translational Medicine 2021;11(7):e384. https://doi.org/10.1002/ctm2.384.
The above article, published online on 19 July 2021 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Xiangdong Wang; the Shanghai Institute of Clinical Bioinformatics; and John Wiley & Sons Australia, Ltd.
The retraction has been agreed due to concerns raised by third parties. Specifically, instances of image duplication were detected within Figure 2H. Further investigation by the publisher detected additional instances of image duplication between Figures 1L and 3G, and between Figures 1J and 3H. The clarification and data provided by the authors was insufficient to address the concerns, and the extent of the detected issues undermined the editors’ trust in the accuracy and integrity of the whole body of work. Accordingly, the article has been retracted, as the editors consider its conclusions invalid. The corresponding author, Yan Yong-min, agreed with the retraction decision; no confirmation was obtained by the remaining co-authors.
Sarcomas are a heterogeneous group of mesenchymal malignancies with poor prognosis and limited response to standard therapies, including immune checkpoint inhibitors (ICIs). Tumour-intrinsic factors—such as telomere maintenance mechanisms (TMMs) and metabolic reprogramming—play central roles in driving immune evasion and therapeutic resistance. Telomerase activation and alternative lengthening of telomeres sustain replicative immortality while influencing the tumour immune microenvironment. In parallel, metabolic adaptations, including glutamine dependency and arginine auxotrophy, further suppress antitumour immunity. Together, TMMs and metabolism form an integrated axis that shapes immune modulation and treatment outcomes. Recent advances—ranging from telomerase-based vaccines and TMM-targeted immunotherapies to metabolic modulators combined with ICIs—demonstrate the translational promise of targeting this axis. This review synthesises current knowledge on telomere‒metabolism crosstalk in sarcomas, highlights its impact on immunotherapy response, and outlines future directions for biomarker-driven, combinatorial strategies to overcome resistance and improve patient outcomes.
Epigenetic regulation plays a crucial role in skeletal degenerative diseases, including osteoporosis. As an epigenetic reader, bromodomain protein 4 (Brd4) is known as a key driver of gene activation; however, its role in maintaining skeletal homeostasis remains largely unknown.
We examined Brd4 expression in bone specimens from osteoporotic patients and mouse models, and generated two types of Brd4 conditional knockout mice using Lyz2-Cre and Ctsk-Cre systems. Bone mass, osteoclast differentiation, and metabolic activity were assessed under physiological and pathological conditions, including ovariectomy and lipopolysaccharide (LPS) challenge. Mechanistic analyses were performed using transcriptomic screening, gene overexpression, and pharmacological interventions.
Brd4 expression was markedly elevated in bones from osteoporotic patients and mice compared with normal controls. Deletion of Brd4 increased basal bone mass and prevented bone loss induced by ovariectomy or LPS, primarily by suppressing osteoclastogenesis through inhibition of glycolysis. Unbiased screening identified solute carrier family 9 member B2 (Slc9b2) as a downstream effector of Brd4. Overexpression of Slc9b2 partially rescued the impaired osteoclastogenesis caused by Brd4 depletion. Moreover, phosphatidylserine-containing nanoliposomes loaded with Brd4-targeting PROTACs (e.g., dBET6) effectively suppressed osteoclastogenesis and alleviated pathological bone loss.
Brd4 serves as a crucial regulator of osteoclast metabolism and differentiation. Targeting Brd4 represents a promising therapeutic strategy for the prevention and treatment of osteoporosis and pathological bone loss.
Dear Editor,
Human immunodeficiency virus (HIV) presents a significant public health burden. By 2023, the prevalence of HIV was estimated at 39.9 million globally, while newly acquired infections reached 1.3 million.1 Although the widespread use of antiretroviral therapy (ART) has led to a substantial reduction in fatalities linked to HIV/AIDS, approximately 10% to 40% of people living with HIV (PLHIV) still cannot achieve full immune reconstitution despite long-term viral suppression through ART, and thus face a higher risk of opportunistic infections and mortality.2 Metabolic transformation following ART constitutes a multi-stage abnormal accumulation process in PLHIV. Previous studies have reported several metabolites that could predict the immune response to ART. Nevertheless, prior investigations overlooked metabolite alterations, and were limited by small sample size.3
Using dynamic untargeted metabolomics design, fasting plasma was collected pre-ART and serially at 12, 24, 36, 48, 72, and 96 weeks post-treatment initiation (n = 116) to capture the metabolic transformation following ART, defined as the temporal changes in metabolite profiles (Table 1 and Figure 1A). PLHIV in IR group demonstrated a clearly distinguishable metabolic profile compared to those in the INR group (Figure 1B). Figure 1C revealed 10 significantly changed metabolites after ART, with 8 increased metabolites and 2 decreased metabolites (p-value < .05) (Table S1). The increased metabolites were mostly amino acids, peptides, and analogues, while urate and pantothenate demonstrated monotonic downtrend after ART. According to fuzzy c-means clustering, two distinct change pattern was found among plasma metabolites, including gradual-increasing cluster (Cluster 1) and W-shape cluster (Cluster 2) (Figure 1D).
In total, five metabolites with the VIP of multilevel PLS-DA > 1 and p-value tested by linear mixed model < .05 were selected as dynamic differential metabolites (Table S2 and Figure S1). It is worth noting that the plasma arginine levels of PLHIV in the IR group and the INR group not only differed at multiple time points before and after ART, but also exhibited significant differences in dynamic changes after ART (Figure 2A). These findings indicating that focusing solely on the single time point differences in metabolites, while neglecting their dynamic trends, may not fully capture their relationship with the immune response to ART in PLHIV. We further investigated the alteration of clinical characteristics (blood cell, liver function and blood lipids) within 96 weeks after initiating ART, categorised by the immune response of ART (Figure S2). The trajectories of CD4 among PLHIV in both the IR and INR groups exhibit a degree of similarity during the initial 12 to 24 weeks post-ART. However, these patterns start to diverge after the 36-week time p
Immunosuppressive tumour-associated macrophages (TAMs) represent a promising target for cancer immunotherapy; however, existing TAM-directed therapies have shown limited clinical efficacy. C-type lectin domain family 4 member E (CLEC4E), a pro-inflammatory molecule expressed on macrophages, was recently found to be highly enriched in TAMs. This study aims to elucidate the role of CLEC4E in TAMs and identify potential therapeutic agents targeting CLEC4E, and to clarify the mechanism of Bromodomain and extraterminal domain (BET) inhibitor NHWD-870 in downregulating CLEC4E.
We first assessed the correlation between CLEC4E expression and survival in melanoma patients. Clec4eflox/flox Lyz2-cre (knockout) and Clec4eflox/flox (control) mice were generated and implanted with melanoma or ovarian cancer models. Single-cell RNA sequencing was performed to characterise macrophage phenotypic changes following CLEC4E knockout, with validation via RT-PCR, flow cytometry and proteomic sequencing. A drug screen identified BET inhibitors targeting CLEC4E, and their mechanisms were further investigated using RNA silencing, Chromatin Immunoprecipitation (ChIP)-seq and luciferase reporter assays.
In melanoma patients, high CLEC4E+ TAM infiltration was associated with poor prognosis. CLEC4E knockout significantly suppressed tumour growth compared to control mice. TAMs from knockout mice exhibited downregulated proliferation markers and upregulated genes related to antigen presentation and pro-inflammatory responses. Mechanistically, CLEC4E deletion inhibited TAM proliferation via the Erk signalling pathway, enhanced TAM‒T cell interactions, and increased granzyme B expression in T cells. The BET inhibitor NHWD-870 was shown to disrupt BRD4‒CEBPβ interaction, leading to downregulation of CLEC4E expression.
CLEC4E+ TAMs promote an immunosuppressive microenvironment by enhancing their own proliferation and impairing anti-tumour functions, thereby limiting T-cell cytotoxicity. Targeting the BRD4/CEBPβ/CLEC4E axis with BET inhibitors represents a promising therapeutic strategy for reprogramming TAMs and enhancing anti-tumour immunity.
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