The systemic immune-inflammatory index (SII) and the systemic inflammatory response index (SIRI) have shown prognostic value in diabetes mellitus (DM). However, the impact of the inflammatory prognosis index (IPI) remains unexamined. This retrospective cohort study investigates the predictive value of IPI, along with SIRI and SII, on all-cause and cardiovascular disease (CVD) mortality in individuals with DM and prediabetes mellitus (pre-DM). We analyzed DM and pre-DM individuals from the National Health and Nutrition Examination Survey (NHANES) (1999-2018), with follow-up conducted until December 31, 2019. Cox models assessed the correlation of IPI, SIRI, and SII with mortalities, yielding hazard ratios (HRs) and 95% confidence intervals (CIs). We also utilized restricted cubic spline (RCS) analysis, Kaplan-Meier curves, and subgroup analyses. The final analysis included 10,049 individuals with DM and pre-DM. Over a mean follow-up of 9 years, 2233 all-cause mortalities occurred, with 612 attributed to CVD. Fully adjusted Cox regression analysis revealed a significant correlation between continuous and higher tertiles (T3) of IPI, SIRI, and SII and increased risk of all-cause and CVD mortality across all models (all p < 0.05). Kaplan-Meier curves showed higher IPI, SIRI, and SII associated with elevated mortality risk (all log-rank p < 0.001). RCS analysis demonstrated a nonlinear correlation between IPI and all-cause and CVD mortality, as well as between SII and all-cause mortality (nonlinear p < 0.001). However, SIRI exhibited a linear association with both all-cause and CVD mortality. Elevated IPI, along with SIRI and SII, is linked to increased all-cause and CVD-related mortality in DM and pre-DM, suggesting that incorporating IPI in routine screening could help identify high-risk individuals for earlier interventions.

The progression of diabetic kidney disease (DKD) is strongly associated with a chronic inflammatory microenvironment, with macrophage polarization imbalance recognized as a pivotal driver. Maresin 1 (MaR1), a specialized proresolving lipid mediator, plays a crucial role in restoring immune homeostasis across various inflammatory conditions. However, its precise role in ameliorating kidney injury through macrophage polarization in DKD remains unclear. The type 2 diabetes mouse model was established using a high-fat diet combined with streptozotocin induction. The therapeutic efficacy of MaR1 was assessed by evaluating metabolic parameters (blood glucose, lipid profile), renal function (urine albumin-to-creatinine ratio [ACR], serum creatinine, and blood urea nitrogen [BUN]), and renal pathology (HE staining and Masson staining). In vitro, bone marrow-derived macrophages (BMDMs) were exposed to high glucose, and the modulatory effect of MaR1 on M1/M2 polarization was assessed using RT-qPCR, immunohistochemistry, and immunofluorescence. MaR1 treatment significantly ameliorated metabolic abnormalities in diabetic mice (lower blood glucose and cholesterol), improved renal function (reduced ACR, serum creatinine, and BUN), and attenuated renal fibrosis (all p < 0.05). Mechanistically, MaR1 reversed macrophage polarization imbalance both in vivo and in vitro, promoting a shift from the M1 phenotype (downregulation of iNOS and TNF-α) to the M2 phenotype (upregulation of Arg-1 and IL-10). MaR1 improves metabolic disturbances and renal injury in DKD by driving macrophage polarization toward the M2 phenotype and restoring immune homeostasis. These findings highlight MaR1 as a promising candidate for targeted immunomodulatory therapies in DKD.

PurposeTo investigate the therapeutic potential of recombinant thrombomodulin domain 1 (rTMD1) in diabetic corneal wound healing and to elucidate its underlying mechanisms using in vitro and in vivo models.MethodsrTMD1 was produced using the Pichia pastoris expression system and purified. Human corneal epithelial cells (HCECs) were cultured under normal glucose (NG) and high glucose (HG) conditions, with or without rTMD1 treatment. Wound healing rates were evaluated using a scratch assay. Diabetes was induced in C57BL/6 mice via streptozotocin (STZ) injections. Corneal wounds were created and treated with rTMD1 or PBS, and wound healing was assessed via fluorescein staining. Inflammatory markers, including HMGB1, TLR4, NLRP3, and IL‐1β, were analyzed via quantitative PCR (qPCR), Western blot, and immunofluorescence staining.ResultsIn vitro, HCECs treated with rTMD1 under HG conditions demonstrated a higher wound healing rate compared to untreated cells (p = 0.0049). In vivo, rTMD1 significantly enhanced corneal wound healing in diabetic mice, with faster wound closure compared to PBS‐treated controls at 24 h (p = 0.005) and 48 h (p < 0.0001). rTMD1 treatment reduced the expression of HMGB1, TLR4, NLRP3, and IL‐1β at both mRNA and protein levels, indicating suppression of inflammation.ConclusionsTopical application of rTMD1 promotes corneal epithelial wound healing in diabetic conditions by inhibiting HMGB1/TLR4/NLRP3‐mediated inflammation. rTMD1 holds promise as a potential therapeutic agent for diabetic keratopathy, although further studies are needed to validate its clinical efficacy and safety.

BackgroundIntestinal barrier dysfunction is a key driver of ulcerative colitis (UC) recurrence and chronic persistence. Modulating group 3 innate lymphoid cells (ILC3) activity and tryptophan‐derived metabolites is crucial for enhancing mucosal repair in UC. Robinia pseudoacacia L. flower exosome‐like nanoparticles (RFELNs) could ameliorate intestinal mucosal injury in mice. This study aimed to investigate the impact of RFELNs on intestinal barrier repair in UC mice and explore the underlying mechanisms.MethodsChanges in body weight, food intake, DAI score, colon length, pathological score, and inflammatory factor level were performed to assess the therapeutic effect of RFELNs on DSS‐stimulated UC mouse models. The effects of RFELNs on intestinal barrier integrity were assessed by intestinal barrier permeability analysis, Alcian Blue staining, immunohistochemistry (IHC), and western blot assays. IL‐22 level was measured by immunofluorescent staining and ELISA assay. Besides, flow cytometry was performed to detect the proportions of ILC3 and NCR+ILC3 in the colon. Subsequently, an in vitro culture system consisting of NCM460 cells and MNK3 cells was established to determine potential mechanism of RFELNs’ influence on UC.ResultsRFELNs prominently relieved pathological symptoms in UC mice, including weight loss, enhanced DAI score, shortened colon, and pathological colon damage. Moreover, RFELNs decreased the concentration of FITC‐dextran and DAO level and enhanced D‐lactate levels. Additionally, RFELNs significantly enhanced the number of colonic goblet cells, restored epithelial tight junctions (TJs), and upregulated TJ protein levels. Moreover, RFELNs enhanced IL‐22 expression and the proportion of ILC3 cells and NCR+ILC3 cells. The protective effect of RFELNs on UC depends on AhR. Further, RFELNs activated AhR pathway by increasing the content of indole derivatives produced by tryptophan metabolism, thus promoting the repair of intestinal barrier damage.ConclusionRFELNs restored intestinal barrier function in UC mice by activating AhR/IL‐22 signaling through regulation of gut microbiota‐dependent tryptophan metabolism.

ObjectivePrevious studies suggest a complex interaction between 3,3′,5‐triiodo‐L‐thyronine (T3) and inflammation, but this relationship remains unclear. This study investigates the association between free triiodothyronine (FT3) levels and inflammatory markers in the US population using National Health and Nutrition Examination Survey (NHANES) data.MethodsThis study analyzed NHANES data from three cycles between 2007 and 2012, using Spearman correlation tests and multivariate linear regression. Subgroup analyses and interaction tests were conducted based on age, gender, race, body mass index (BMI), thyroid‐stimulating hormone, and free thyroxine (T4) to determine the correlations between FT3 and seven systemic inflammatory markers: C‐reactive protein (CRP), neutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐white blood cell ratio (PWR), platelet‐to‐lymphocyte ratio (PLR), monocyte‐to‐lymphocyte ratio (MLR), systemic immune‐inflammation index (SII), and systemic inflammation response index (SIRI).ResultsA total of 2306 participants were included in this study. Univariate correlation analysis showed that CRP, NLR, MLR, and PLR were significantly negatively correlated with FT3 levels (all p < 0.05). After adjusting for confounders, FT3 levels were significantly negatively associated with CRP, NLR, and PLR (all p < 0.05). Subgroup analysis showed that age significantly modified the associations between FT3 and systemic inflammatory markers, such as CRP, NLR, MLR, SII, and SIRI (p‐interaction < 0.05). The inverse associations were more consistent among individuals aged ≥ 65 years.ConclusionIn the general population, FT3 levels exhibit inverse associations with systemic inflammatory markers.

Micro-fragmented adipose tissue (MFAT) is regarded as one of the simplest and most practical biological preparations for clinical applications in tissue regenerative medicine. The clinical effectiveness of MFAT is attributed to its content of cells and growth factors that facilitate tissue regeneration. In this study, we investigated the biological activity of the secretome derived from cultured MFAT. Our primary focus was on its ability to influence the production of two inflammatory cytokines, RANTES (Regulated and Normal T Cell Expressed and Secreted) and MCP-1 (Monocyte Chemoattractant Protein-1), using ELISA assays, as well as its impact on the expression of Cell Adhesion Molecules (CAMs) on U-937 macrophages via flow cytometry. We also explored the potential of the MFAT secretome to affect the proliferation of both normal and cancer cells. Our results showed that the MFAT secretome inhibited the production of MCP-1 and RANTES, significantly reduced the expression of ICAM-1 (Intercellular Adhesion Molecule 1) on U-937 macrophages, and had no impact on the proliferation of normal or cancer cells. These findings suggest that the MFAT secretome is relatively safe and exhibits anti-inflammatory properties, supporting the idea that its clinical effectiveness in treating joint inflammation may, in part, be due to its paracrine effects.

L-Histidine, a parent structure of environmental contaminants (e.g., pesticides and preservatives), may undergo bioaccumulation through the food chain and be metabolized by the gut microbiota into deleterious compounds, ultimately compromising human health. Recent studies have identified abnormally elevated levels of the histidine-derived metabolite imidazole propionate (ImP) in the serum of type 2 diabetes mellitus patients. However, the pathophysiological implications of excessive ImP on renal function and its underlying molecular mechanisms remain poorly characterized. This study is the first to elucidate the detrimental effects of ImP on renal function in mice and its molecular mechanisms. Our findings demonstrate that ImP exacerbates renal dysfunction and induces structural and functional abnormalities in renal tubules. Mechanistically, ImP significantly suppresses autophagy in renal tubular epithelial cells and activates the reactive oxygen species (ROS)-NOD-like receptor pyrin domain-containing 3 (NLRP3) signaling pathway, thereby promoting the expression of the pro-inflammatory cytokine interleukin-1β (IL-1β). Notably, the mechanistic target of rapamycin (mTOR) inhibitor rapamycin (Rap) restores autophagy, inhibits the ROS/NLRP3/IL-1β axis, and mitigates ImP-induced renal injury. Transcriptomic sequencing of mouse kidneys reveals that ImP upregulates the expression of autophagy- and inflammation-related genes, while its inhibitor suppresses these genetic alterations. This study highlights the potential nephrotoxic effects of ImP and underscores the therapeutic value of Rap, providing a theoretical foundation for understanding the role of gut microbiota metabolites in the pathogenesis, prevention, and treatment of kidney diseases.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with a poor prognosis and limited effective treatment options. Our study comprehensively explores the complex role of programed cell death (PCD) mechanisms in PDAC development, examining 18 distinct PCD pathways and their genetic underpinnings. Using an advanced machine learning framework incorporating 429 algorithmic variations, we have developed an innovative PCD-based molecular signature that demonstrates robust prognostic capabilities. This signature exhibits superior performance across diverse patient cohorts, significantly outperforming traditional clinicopathological indicators. Through integrated pathway analysis, we revealed that high-risk patients show distinct activation of oncogenic pathways and significant alterations in the tumor immune microenvironment. These alterations include reduced infiltration of cytotoxic T lymphocytes and increased levels of immunosuppressive regulatory T cells (Tregs). Furthermore, leveraging the TISCH (Tumor Immune Single Cell Hub) database, we conducted detailed single-cell expression profiling of our signature genes across different cell populations within the tumor microenvironment (TME). This analysis uncovered cell-type-specific expression patterns of key PCD-related genes. Our results highlight the critical involvement of PCD in PDAC progression and introduce a promising tool for clinical risk stratification. The integration of bulk and single-cell transcriptomic analyses not only validates our molecular signature but also reveals potential cellular targets for therapeutic intervention. This PCD-focused approach may support the development of personalized therapeutic strategies and ultimately improve outcomes for PDAC patients.

G protein-coupled receptor 34 (GPR34) is an orphan receptor within the G protein-coupled receptor (GPCR) superfamily, and its specific role in anaplastic thyroid carcinoma (ATC) remains to be elucidated. In this study, we observed that GPR34 was aberrantly upregulated in ATC and the deletion of GPR34 inhibited tumor progression both in vivo and in vitro. Additionally, suppression of GPR34 promoted ferroptosis in ATC cells. We further identified USP8 as a deubiquitinase (DUB) for GPR34, and the effects induced by GPR34 deletion were reversible through USP8 overexpression. Moreover, targeting USP8 with the inhibitor DUB-IN-3 effectively restrained ATC growth. Together, the present study revealed the role of GPR34 in ATC progression and ferroptosis, discovered its corresponding DUBs, and proposed GPR34 as a promising target for ATC therapy.