Search Results (2,351)

We explored the potential functions of differentially expressed miRNAs, mRNAs, lncRNAs, and circRNAs identified in the ovaries of gilts with normal estrus (NE) and follicular cyst-associated anestrus (AE), as well as their putative competing endogenous RNA (ceRNA) regulatory networks. Ovarian morphology was assessed via ultrasonography, and serum concentrations of Follicle-stimulating hormone (FSH), (Estradiol) E2, and Progesterone(P4) were measured. Ovarian tissues were harvested after slaughter for whole-transcriptome sequencing. Bioinformatic tools were used to screen differentially expressed RNAs(DERNAs) between NE and AE gilts. We further predicted target interactions among these transcripts, conducted functional enrichment analysis on target genes, and constructed candidate ceRNA regulatory networks potentially associated with gilt estrus. Phenotypic verification confirmed that ovarian ultrasonographic characteristics, histological morphology, and serum reproductive hormone levels were consistent with the physiological status of NE and AE gilts. Under the screening thresholds of p < 0.05 and |log₂FC| ≥ 1, we identified 22 lncRNAs that may interact with 21 mRNAs via 50 miRNAs, alongside 39 circRNAs predicted to regulate 26 mRNAs through 72 miRNAs. Functional enrichment analysis indicated that target genes of these differentially expressed transcripts were predominantly enriched in the lysosome pathway, PPAR signaling pathway, chemokine signaling pathway, cholesterol metabolism and NOD-like receptor signaling pathway. Hub molecules including FGF1, GHR, TLR2, ssc-miR-370, and miR-21-5p were shared in lncRNA/circRNA-miRNA-mRNA regulatory networks; these molecules have been reported to participate in progesterone synthesis, estrus modulation, and endocrine homeostasis. Of particular interest, two non-coding RNAs, MSTRG.1285.1 and novel_circ_056113, were predicted to act as candidate ceRNAs that may sponge ssc-miR-370 and miR-21-5p, which could in turn modulate the expression of estrus-associated mRNAs including FGF1, GHR, and TLR2. The expression trends of MSTRG.1285.1, novel_circ_056113, miR-370, miR-21-5p, GHR, TLR2, and FGF1 were validated by qRT-PCR, and the quantification results agreed with transcriptome sequencing data. Collectively, this study constructed a predicted ceRNA regulatory network of ovarian transcripts comparing NE and AE gilts and uncovered multiple RNA molecules potentially involved in estrus regulation. These findings offer preliminary theoretical clues for exploring the onset of puberty in gilts. Full article

Familial hypercholesterolemia (FH) is a common hereditary dyslipidemia characterized by high levels of low-density lipoprotein (LDL) cholesterol and a risk of premature atherosclerosis. Previous studies showed that cardiovascular risks persist in FH even after hypolipidemic therapy is started and are linked to a proinflammatory status of circulating monocytes. In the current study we aimed to identify FH-specific gene expression patterns of monocyte-derived M1-like macrophages in response to lipid accumulation. RNAseq was performed for four patient and four control paired samples of M1-like macrophages before and after incubation with oxidized LDL (oxLDL). A validation step was performed in 10 patients and 10 controls using real-time PCR and ELISA. RNAseq data analysis revealed 22 DEGs between FH patients and the control group before and 47 DEGs after incubation with oxLDL. Pathway enrichment analysis suggested dysregulation of inflammatory pathways especially IL-1 and chemokine signaling in response to lipid accumulation in FH M1-like macrophages. Validation experiments demonstrated increased interleukin-1β secretion by lipid-laden M1-like macrophages in FH patients and reduced TMEM176A and TMEM176B gene expression compared to controls. Our results suggest FH M1-like macrophages may be predisposed to an accelerated immune response via interleukin-1β due to reduced TMEM176A/B activity. Full article

Intervertebral disc degeneration is a major contributor to discogenic low back pain and is characterized by a pro-inflammatory and catabolic microenvironment within the nucleus pulposus. We previously showed that the phosphatase PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) is positively correlated with intervertebral disc degeneration and that its deficiency promoted nucleus pulposus cell survival and matrix homeostasis; however, its role in inflammatory signaling during intervertebral disc degeneration remained unknown. Here, we show that PHLPP1 functions as an upstream regulator of inflammatory and catabolic networks in the degenerating intervertebral disc. In aged mice, Phlpp1 deficiency attenuated spontaneous intervertebral disc degeneration and reduced expression of IL1B and IL6. Notably, severe age-associated degeneration and inflammation were observed primarily in male wildtype mice, where the protective effects of Phlpp1 deletion were most apparent. To define the underlying mechanisms in human disease, we performed transcriptomic profiling of degenerated human nucleus pulposus cells following siRNA-mediated PHLPP1 silencing. PHLPP1 depletion induced widespread transcriptional reprogramming characterized by suppression of inflammatory cytokines, chemokines, and matrix-degrading enzymes, while promoting expression of extracellular matrix-associated genes. Pathway enrichment and network analyses identified coordinated inhibition of cytokine–cytokine receptor interaction, TNF, IL17, chemokine, and NFKB signaling pathways, revealing PHLPP1 as a central node linking cytokine amplification, immune cell recruitment, and matrix degradation. These findings were validated by reduced expression of IL1A, IL1B, IL6, CXCL2, CCL20, and STAT1, alongside increased ACAN expression. Furthermore, PHLPP1 silencing attenuated IL1B-induced inflammatory activation and matrix suppression and reduced STAT1 phosphorylation after IL1B stimulation. Collectively, our findings identify PHLPP1 as a critical regulator coupling inflammatory amplification to matrix remodeling in degenerating intervertebral discs and nominate PHLPP1 inhibition as a potential disease-modifying therapeutic strategy for intervertebral disc degeneration. Full article

Polyploid giant cancer cells (PGCCs) are increasingly recognized as major drivers of therapy resistance and tumor relapse, yet the conserved molecular programs underlying their persistence remain incompletely defined. To identify genes consistently deregulated across eight independent datasets, we performed an integrative transcriptomic analysis of PGCCs derived from prostate, ovarian, and breast cancers. By focusing on consistently up- or down-regulated genes that were expressed in at least five datasets and showed a concordant direction of expression across more than 70% of datasets and met a significance threshold of adjusted p < 0.05, we defined the core regulatory architecture stabilizing the PGCC state under therapeutic stress. Our analysis reveals that PGCCs exhibit a paradoxical ranscriptomic signature consistent with cytolytic activity alongside reduced immune detection. These cells activated pro-inflammatory cytokine and chemokine signaling while simultaneously engaging immune-evasion mechanisms, including PD-L1-associated and virus-like escape programs. Concurrently, PGCCs displayed transcriptional features characteristic of immune-privileged cellular states, including embryonic development, reproductive programs, senescence-associated survival, apoptosis resistance, and deep dormancy marked by coordinated suppression of major housekeeping processes. Notably, PGCCs also activated neuronal differentiation and neurodegeneration-associated pathways, including axon guidance, neurogenesis, and calcium signaling. This neuron-like, calcium-dependent stress adaptation program may further enhance immune privilege and long-term survival capacity. We propose that PGCCs represent an immune-adaptive polyploid survival state in which inflammatory and ontogenetic pathways are repurposed to support immune evasion and tumor persistence. By identifying actionable vulnerabilities within calcium signaling, neuronal mimicry, and checkpoint-associated pathways, this study provides a framework for therapeutic strategies aimed at dismantling the PGCC reservoir and preventing tumor relapse. Full article

Donor liver scarcity is exacerbated by preservation-related injury, particularly ischemia-reperfusion injury (IRI), which reduces organ utilization and increases discard rates. Liver sinusoidal endothelial cells (LSECs) play a critical role in mediating IRI, yet their response to static cold storage (SCS) remains poorly understood. Here, we investigate the impact of SCS on isolated rat LSECs. Isolated rat hepatocytes, stellate cells, Kupffer cells, and LSECs were subjected to up to 3 days of SCS followed by up to 2 days of recovery, with LSECs also receiving apoptosis and/or oxidative stress inhibition. Afterwards, changes in survivability, functionality, and morphology were measured. Additionally, changes in gene, cytokine, and chemokine expression were also measured. We found that SCS reduced cell viability by approximately 40%, accompanied by a 60% reduction in metabolic activity and ATP levels, indicating substantial impairment in cellular energetics. SCS also doubled reactive oxygen species (ROS) production and upregulated oxidative stress and apoptosis-related genes, leading to functional decline in LSECs. Importantly, combined inhibition of apoptosis and oxidative stress improved LSEC viability by 20% and metabolic activity and ATP levels by 30% and 40%, respectively, and reduced ROS production by 50%. These findings highlight LSEC vulnerability to preservation injury and the importance of understanding LSEC-specific injury mechanisms to provide a foundation for the development of endothelial-targeted preservation strategies to significantly improve liver transplantation outcomes, subsequently increasing access to this life-saving treatment. Full article

Background/Objectives: The chemokine receptor CXCR4 plays a pivotal role in tumor progression, metastasis, and therapy resistance and is frequently overexpressed in hematologic malignancies, including multiple myeloma and lymphoma. This study investigates a CXCR4-targeted theranostic platform comprising a PET imaging agent and two therapeutic radioconjugates derived from the high-affinity CXCR4 antagonist LY2510924. Methods: The PET tracer [¹⁸F]AlF-NOTA-SC and therapeutic radioconjugates [¹⁷⁷Lu]Lu-BL02 and [¹⁶¹Tb]Tb-BL02 were synthesized and evaluated. Radiolabeling efficiency, molar activity, and in vitro binding affinity were assessed. Specificity and uptake were evaluated in CXCR4-expressing U87.CD4.CXCR4 and MM.1S cells, with cytotoxic potential being analyzed via clonogenic survival assays. In vivo biodistribution and pharmacokinetics were evaluated in MM.1S xenograft mouse models, supported by longitudinal SPECT imaging. Results: All radioconjugates were obtained with high radiochemical purity (>98%). The constructs showed nanomolar affinity for human CXCR4; in vitro assays confirmed specific uptake in CXCR4-positive cells, and both therapeutic agents demonstrated dose-dependent cytotoxicity. In vivo, all compounds displayed comparable tumor uptake with low off-target accumulation. Co-injection studies confirmed consistent pharmacokinetics across agents, while SPECT/CT imaging demonstrated gradual tumor clearance of [¹⁷⁷Lu]Lu-BL02 over seven days. Conclusions: The radiopharmaceutical trio [¹⁸F]AlF-NOTA-SC, [¹⁷⁷Lu]Lu-BL02, and [¹⁶¹Tb]Tb-BL02 demonstrates the feasibility of a CXCR4-targeted theranostic approach for imaging and treating hematologic malignancies. The observed tumor washout highlights the need for further structural optimization to enhance tumor retention and therapeutic efficacy, providing a clear direction for future development toward clinical translation. Full article

Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are typically produced in a 3:1:1 ratio, respectively, via microbial fermentation of non-digestible carbohydrates, and to a lesser degree, from undigested protein. The effects of individual SCFAs on adipocyte function have been described; however, the effects of SCFAs in combination on adipocyte function remain unknown. Mature 3T3-L1 adipocytes were treated with a 1 mM total dose of acetate, propionate, and butyrate combined in a 3:1:1 ratio, respectively, for 24 h ± lipopolysaccharide (LPS, 10 ng/mL) under both normoxic and hypoxic (via the addition of 100 µM cobalt chloride) environmental conditions. In both normoxic and hypoxic LPS-stimulated conditions, SCFAs increased the secretion of adiponectin and reduced the secretion of resistin, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1/C-C motif chemokine ligand (CCL)2, and RANTES/CCL5, in addition to reducing intracellular protein levels of activated (i.e., the ratio of phosphorylated-to-total) nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) p65 and signal transducer and activator of transcription 3 (STAT3) (p < 0.05). Additionally, SCFA treatment reduced leptin secretion only in LPS-stimulated normoxic environmental conditions compared to control (p < 0.05). In normoxic conditions, SCFA + LPS increased mRNA expression of genes involved in fat storage), fatty acid recycling, and lipolysis, whereas in hypoxic conditions, SCFA + LPS decreased mRNA expression of genes involved in fat storage and triglyceride synthesis (p < 0.05), indicating different effects of SCFAs on adipocyte metabolic function depending on hypoxia status. Collectively, combined SCFAs in a 3:1:1 ratio beneficially modify the adipocyte adipokine secretory profile under both normoxic and hypoxic environmental conditions. Full article

Probiotic strains with multifunctional skin-beneficial properties represent promising candidates for next-generation cosmetic ingredients. In this study, a systematic stepwise screening strategy was applied to an in-house bacterial library comprising 302 isolates to identify candidates with antioxidant, anti-inflammatory, antimicrobial, wound-healing, and skin barrier-supportive activities. From this library, 33 strains were selected based on preliminary assessments and subjected to comprehensive in vitro evaluation. Cell viability and cytotoxicity assays confirmed the safety of all selected strains in RAW264.7 macrophages and HaCaT keratinocytes. Several strains exhibited strong DPPH radical scavenging activity and significantly inhibited nitric oxide production in LPS-stimulated macrophages. Among the selected candidates, Lacticaseibacillus rhamnosus DM073 demonstrated the most potent anti-inflammatory activity, whereas Lactiplantibacillus plantarum DM043 exhibited the greatest wound-healing capacity. All five selected strains displayed antimicrobial activity against Cutibacterium acnes. Furthermore, selected strains, particularly Lactiplantibacillus plantarum DM175 and Ligilactobacillus salivarius DM079, enhanced the expression of skin barrier-related genes, including zonula occludens-1 (ZO-1), occludin (OCLN), claudin-1 (Cla-1), and filaggrin (FLG), and partially restored their expression under TNF-α/IFN-γ-induced inflammatory conditions. Selected strains also reduced the expression of inflammatory chemokines in stimulated keratinocytes. Collectively, these findings demonstrate that the selected probiotic strains possess complementary multifunctional activities associated with skin health. In particular, DM073 exhibited superior anti-inflammatory activity, DM043 showed strong wound-healing potential, and DM175 demonstrated remarkable skin barrier-supportive effects. These strain-specific properties support their potential application in the development of probiotic-derived postbiotic cosmetic ingredients for skin soothing, barrier reinforcement, skin recovery, and microbiome-friendly skincare formulations. Further studies are warranted to evaluate their efficacy and safety in advanced skin models and clinical cosmetic applications. Full article

Background/Objectives: Watercress (Nasturtium officinale), a cruciferous vegetable rich in phenethyl isothiocyanate (PEITC) and bioactive phytochemicals, has demonstrated anti-inflammatory and cytoprotective activities in multiple disease models; however, its effects on colitis remain insufficiently characterized. In the present study, we investigated the effects of watercress extract supplementation in dextran sulfate sodium (DSS)-induced experimental colitis. Methods: Male C57BL/6 mice were fed either a standard AIN-93G diet or a diet supplemented with 0.5% (w/w) watercress extract for 4 weeks, followed by DSS administration to induce acute colitis. Colonic histopathological injury, immune responses, barrier integrity, and gut microbiota composition were evaluated. In addition, the activity of PEITC, a major bioactive constituent of watercress, was examined in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages in vitro. Results: Watercress extract attenuated DSS-induced colon shortening and reduced histopathological injury. The supplementation of watercress extract also decreased colonic immune cell accumulation, suppressed the expression of pro-inflammatory mediators, and preserved intestinal barrier integrity. The 16S rRNA gene amplicon sequencing further revealed that watercress extract reshaped gut microbial composition, including increased abundance of Monoglobus and Adlercreutzia, and reduced abundance of microbial taxa such as Enterococcus and Enterorhabdus. Moreover, PEITC suppressed LPS-induced inflammatory activation in RAW264.7 macrophages by reducing nitric oxide production, inhibiting p38 MAPK phosphorylation, and downregulating multiple inflammatory cytokines and chemokines. Conclusions: These findings demonstrate that watercress extract alleviates experimental colitis through attenuating mucosal inflammation, preserving intestinal barrier function, and modulating the gut microbiota, highlighting watercress as a promising dietary strategy for improving gut health and mitigating intestinal inflammation. Full article

Twenty-seven cytochalasans, including thirteen previously undescribed analogs with a 5/6/6/6 tetracyclic skeleton (curtachalasins Y1–Y13), were isolated from the rice-based culture of a soil-derived fungus, Xylaria sp. Y01. Their structures were determined through comprehensive analysis of spectroscopic data and quantum chemical calculations. All isolates were evaluated for their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide-stimulated RAW264.7 macrophages. Curtachalasin Y1 (12), 5,6-dihydro-7-oxo-18-desoxy-19,20-epoxycytochalasin C (21), and 7-oxo-19,20-epoxycytochalasin C (22) exhibited potent inhibition, with IC₅₀ values of 55.4, 43.8, and 17.8 µM, respectively, compared to 14.9 μM for the positive control dexamethasone. Furthermore, these compounds suppressed lipopolysaccharide (LPS)-induced release of pro-inflammatory cytokines IL-6, MCP-1, and TNF-α, confirming their anti-inflammatory activity. Preliminary mechanistic investigation indicated that compound 22 exerts its anti-inflammatory effects in RAW264.7 cells by downregulating CXC motif chemokine ligand 10 (CXCL10) and upregulating suppressor of cytokine signaling 3 (SOCS3) expression. These results expand the structural diversity of cytochalasans from Xylaria species and provide a basis for further exploration of their anti-inflammatory potential. Full article

Background: Bladder cancer (BCa) is characterized by frequent recurrence and limited durable responses to immunotherapy, in part due to poor T-cell infiltration into tumors. While the chemokine CCL2 and its receptor CCR2 have traditionally been associated with recruitment of immunosuppressive myeloid cells and tumor promotion, we reveal an unexpected anti-tumor role for this pathway in BCa. Methods: Using orthotopic and carcinogen-induced murine BCa models, we demonstrate that genetic deletion or antibody blockade of CCL2 or CCR2 accelerates tumor progression, reduces intratumoral CD4⁺ and CD8⁺ T-cell infiltration, and shortens survival. Results: Mechanistic studies show that CCL2 promotes recruitment of CCR2⁺ effector T cells with enhanced activation and cytotoxicity. Mixed bone marrow chimeras, T-cell-specific CCR2 knockouts, and adoptive transfers confirm that CCR2 signaling within T cells is essential for their trafficking and anti-tumor function. In human BCa, CCL2 expression is reduced in tumors compared to adjacent urothelium, correlating with diminished T-cell infiltration. Importantly, high tumor CCL2 levels are associated with improved recurrence-free survival in patients with BCa. To therapeutically leverage this pathway, we developed a novel intravesical recombinant CCL2 (rCCL2) approach. rCCL2 delivery significantly increased CCR2⁺ T-cell infiltration, reduced tumor burden, and extended survival in both syngeneic MB49 and double-humanized patient-derived xenograft (PDX) BCa models. Conclusions: These findings redefine the CCL2-CCR2 axis as a T-cell-mediated tumor-suppressive pathway in BCa and support rCCL2-based therapy as a strategy to enhance immune infiltration and improve outcomes in treatment-resistant BCa. Full article

Human viral entry receptor mouse models exist to overcome a fundamental experimental barrier: many clinically important viruses bind their human entry factors far more efficiently than the corresponding murine orthologs, leaving conventional mice unable to support authentic infection, physiological tissue tropism, or meaningful countermeasure evaluation. This review is organized around the receptor-humanization concept rather than around a single coronavirus model. Engineering strategies compared here include random transgenesis, endogenous-locus knock-in, minimal receptor-interface humanization, conditional and inducible expression, and transient vector-mediated delivery. Receptor systems covered span human angiotensin-converting enzyme 2 (hACE2)-dependent sarbecoviruses, human dipeptidyl peptidase 4 (hDPP4)-dependent Middle East respiratory syndrome coronavirus (MERS-CoV), human cluster of differentiation 4/human C-C chemokine receptor type 5 (hCD4/hCCR5)-dependentt human immunodeficiency virus type 1 (HIV-1), adenovirus receptor models, human intercellular adhesion molecule 1 (hICAM-1) rhinovirus systems, hepatitis C virus (HCV), hepatitis B virus (HBV), and hepatitis D virus (HDV) entry-factor models, measles receptor models, poliovirus receptor/CD155 (PVR/CD155) models, human scavenger receptor class B member 2 (hSCARB2) enterovirus systems, and human transferrin receptor 1 (hTfR1) arenavirus models. We then discuss how these platforms support antibody evaluation, Fc-effector analysis, vaccine protection, variant benchmarking, and safety assessment. These models yield the most reliable data when the experimental question is explicitly entry-dependent and when receptor expression level, anatomical distribution, pathology window, and immune context have all been independently validated. They are least informative when receptor expression is non-physiological, when disease readouts are driven by promoter artifacts, or when post-entry species barriers remain the dominant bottleneck. A validation-centered framework is therefore proposed to guide the selection of each model for the specific antiviral antibody or vaccine question it can legitimately answer. Full article

Intradermal injections of anti-canine immunoglobulin E (IgE) in healthy dogs have been utilized in preclinical drug testing to evaluate the efficacy of anti-allergic drugs used to treat canine atopic dermatitis (AD). However, the molecular effects of established canine anti-allergic drugs on this acute canine IgE-mediated atopic model remain largely uninvestigated. The objective of this study was to characterize the effect of proactive oclacitinib and prednisolone treatments on the immune and skin barrier transcriptome of IgE-mediated late-phase reactions (LPRs) in an acute model of canine AD. Sixteen healthy adult research-bred beagles were randomized to receive either oclacitinib or prednisolone orally for six days, followed by an intradermal anti-canine IgE injection. Biopsies were collected 24 h post-injection for RNA isolation and sequencing; previously analyzed transcriptomes (healthy skin, saline-injected skin, IgE lesions without drug modulation) from the same colony of dogs served as controls. Administration of prednisolone and oclacitinib prior to intradermal anti-IgE injections reduced the number of differentially expressed genes (DEGs) in 24 h samples to 1251 and 1471, respectively. Both treatments resulted in a decrease in expression of several significantly upregulated T helper-(Th)1 (e.g., MX1, OAS1, STAT1), Th2 (e.g., CCL13, CCL8, IL13RA1, IL-33, IL5RA, OSM), chemokine and receptor (e.g., CCL19, CCL2, CCL3, CCR1, CCR3) genes in comparison to the untreated IgE-mediated lesions. Interestingly, only prednisolone treatment significantly reduced IL-13 upregulation, an important gene in the Th2 immune response. In conclusion, both prednisolone and oclacitinib reduced the transcriptomic changes observed in the acute lesions of the canine IgE-induced atopic dermatitis model, with prednisolone inducing a broader inhibitory immune response. Full article

Colorectal cancer (CRC) exhibits a highly heterogeneous tumor immune microenvironment (TME), ranging from “immune-inflamed” to “immune-desert” or “immune-excluded” phenotypes. Understanding how immune cell composition, cytolytic activity (CYT) and genomic alternations shape tumor-immune interactions is critical for improving immunotherapy outcomes. We analyzed TCGA-COAD and TCGA-READ datasets to evaluate immune competency, CYT, immune subtypes, microsatellite instability (MSI), and genomic instability, including somatic mutations, copy number aberrations (CNAs), and chromothriptic events. Immune cell infiltration was correlated with CYT levels, immune checkpoint expression, and immune-related gene signatures. Immune-competent (IC) tumors were predominantly CYT-high, enriched in stromal and immune scores, and exhibited distinct TME characteristics compared with immune-deficient (ID) tumors. IC/CYT-high tumors expressed higher levels of immune checkpoints (PD-1, PD-L1, CTLA-4, IDO1/2, LAG-3) and cytokines/chemokines (C1QA/B/C, CXCL9/10/11, CXCL13). Differences in immune infiltration were observed across tumors with significant mutations and copy number alterations. No prognostic difference was observed between CYT-high and CYT-low patients, indicating that CYT reflects immune activation rather than clinical outcome. Functionally, stimulated CD8⁺ T cells exhibited cytotoxicity activity against MSI-high (HCT-116) and microsatellite-stable (HT-29) CRC cells, with MSI-H cells showing higher sensitivity. Dynamic 3D co-culture demonstrated tumor-guided T cell infiltration and retention of CD8 expression, and co-culture was associated with moderate upregulation of cytotoxicity-related genes GZMA and PRF1 within the system. Cytotoxic activity decreased at lower effector-to-target ratios, highlighting the importance of effector dose. Overall, these findings link CYT, immune competency, MSI status, and genomic instability to T cell cytotoxic responses, providing insights into tumor-immune interactions, and suggest potential associations relevant for immunotherapy research in CRC. Full article

Diabetic kidney disease (DKD) progression results from complex interactions between metabolic stress, inflammatory activation, maladaptive intracellular signalling, and fibrotic remodelling. While previous studies demonstrated renoprotective effects of cell-specific Adam17 deletion, the impact of global Adam17 deficiency on the integrated renal response to diabetes remains incompletely understood. Here, we investigated the effects of tamoxifen-induced global Adam17 deletion in a streptozotocin-induced murine model of type 1 diabetes. Renal function, structural injury, inflammatory responses, stress-related signalling pathways, and fibrotic remodelling were comprehensively assessed in diabetic Adam17 knockout and control mice. Despite persistent hyperglycemia and ongoing albuminuria, diabetic Adam17 knockout mice exhibited preservation of glomerular filtration rate together with marked attenuation of diabetes-associated kidney injury. Global Adam17 deletion reduced mesangial expansion and structural damage, limited macrophage infiltration and chemokine expression, and significantly attenuated fibrotic remodelling. At the molecular level, Adam17 deficiency was associated with selective modulation of stress-related signalling pathways, including reduced activation of the PI3K/Akt axis and partial preservation of mitochondrial stress regulators, without evidence of generalized suppression of cellular stress responses. Notably, preservation of renal function occurred despite persistent albuminuria, supporting a partial dissociation between glomerular permeability alterations and progressive renal dysfunction. These findings demonstrate that global Adam17 deletion confers robust protection against diabetes-associated kidney injury through coordinated attenuation of inflammatory, stress-related, and profibrotic pathways. Our results extend previous cell-specific observations and highlight the context-dependent role of Adam17 in DKD progression, supporting the concept that integrated Adam17-related signalling may represent a relevant therapeutic target in diabetic kidney disease. Full article