Monocyte to high-density lipoprotein ratio based prognostic nomogram for patients following allogeneic vascular replacement pancreaticoduodenectomy.

Background: Preoperative immune-inflammatory condition influencing the metabolism of malignancies. We sought to investigate the prognostic value of a novel immune-inflammatory metabolic marker, the monocyte-to-high-density lipoprotein ratio (MHR), in patients with locally advanced pancreatic cancer. Methods: A retrospective analysis was conducted on the clinical data of 118 patients with locally advanced pancreatic cancer and obstructive jaundice who underwent allogeneic vascular replacement pancreaticoduodenectomy in our hospital from Apr. 2011 to Dec. 2023. To assess the predictive capacity of immune-inflammatory metabolic marker, we utilized the area under the receiver operating characteristic curve (AUC-ROC) and assessed the predictive potential of MHR in forecasting outcomes through both univariate and multivariate Cox proportional hazard analyses. Results: The area under AUC for MHR in predicting 1-year postoperative survival was 0.714, with an optimal cutoff value of 1.184, yielding a sensitivity of 78.9% and specificity of 66.2%. Based on this cutoff value, patients were divided into a low MHR group (MHR ≤1.184, n = 61) and a high MHR group (MHR >1.184, n = 57). The median survival times for the low and high MHR groups were 27.0 months and 12.0 months, respectively (χ2 = 30.575, p < 0.001), and the median DFS were 18.0 months and 8.0 months, respectively (χ2 = 26.330, p < 0.001). Univariate and multivariate analyses indicated that preoperative MHR, preoperative creatinine, operation duration, and TNM stage were independent predictors of postoperative mortality, while preoperative MHR, preoperative creatinine, and TNM stage were independent predictors of postoperative recurrence risk. Conclusion: MHR, as an independent immune-inflammatory metabolic predictor of OS and DFS in patients with advanced PC after pancreaticoduodenectomy. Early monitoring and reduction of MHR may be of great significance in improving prognosis.

Immune-metabolic marker of albumin-to-fibrinogen ratio based prognostic nomogram for patients following peritoneal dialysis.

Background: The nutritional status and coagulation function of peritoneal dialysis (PD) patients are closely associated with their prognosis. This study aims to investigate the prognostic value of the albumin-to-fibrinogen ratio (AFR) on mortality in PD patients and to establish a prognostic prediction model based on AFR. Methods: We retrospectively collected data from 148 PD patients treated at our hospital between Oct. 2011 and Dec. 2021. Using the "survminer" package in R, we determined the optimal cutoff value for AFR and divided the patients into low-AFR and high-AFR groups. The primary endpoint of this study was overall survival (OS). Univariate and multivariate Cox analyses were used to assess the impact of AFR and other factors on prognosis, and a corresponding prognostic prediction model was constructed using a nomogram, which was evaluated through ROC curves, the c-index, and calibration plots. Results: The optimal cutoff value for AFR was 9.06. In the entire cohort, 30 patients (20.2%) were classified into the low-AFR group. Compared to the high-AFR group, patients in the low-AFR group were older, had lower total urine output over 24 h, higher blood urea nitrogen, higher total protein and urinary microalbumin levels, and longer remission times (p < 0.05). They also had a poorer OS (HR: 1.824, 95%CI: 1.282-2.594, p < 0.05). Multivariate Cox analysis indicated that AFR was an independent prognostic factor for OS (HR: 1.824, 95% CI: 1.282-2.594, p < 0.05). A prognostic prediction model based on AFR, age, and cause of ESRD was successfully validated for predicting OS in PD patients. Conclusion: AFR represents a potential prognostic biomarker for PD patients. The prognostic prediction model based on AFR can provide accurate OS predictions for PD patients, aiding clinicians in making better-informed decisions.

SFN promotes renal fibrosis via binding with MYH9 in chronic kidney disease.

Chronic kidney disease (CKD) is a clinical syndrome characterized by persistent renal function decline. Renal fibrosis is the main pathological process in CKD, but an effective treatment does not exist. Stratifin (SFN) is a highly-conserved, multi-function soluble acidic protein. Therefore, this study explored the effects of SFN on renal fibrosis. First, we found that SFN was highly expressed in patients with CKD, as well as in renal fibrosis animal and cell models. Next, transforming growth factor-beta 1 (TGF-ß1) induced injury and fibrosis in human renal tubule epithelial cells, and SFN knockdown reversed these effects. Furthermore, SFN knockdown mitigated unilateral ureteral obstruction (UUO)-induced renal tubular dilatation and renal interstitial fibrosis in mice. Liquid chromatography-tandem mass spectrometry/mass spectrometry (LC-MS/MS), co-immunoprecipitation (Co-IP), and immunofluorescence co-localization assays demonstrated that SFN bound the non-muscle myosin-encoding gene, myosin heavy chain 9 (MYH9), in the cytoplasm of renal tubular epithelial cells. MYH9 knockdown also reduced Col-1 and α-SMA expression, which are fibrosis markers. Finally, silencing SFN decreased MYH9 expression, alleviating renal fibrosis. These results suggest that SFN promotes renal fibrosis in CKD by interacting with MYH9. This study may provide potential strategies for the treatment of CKD.

Paeoniflorin Ameliorates Macrophage Infiltration and Activation by Inhibiting the TLR4 Signaling Pathway in Diabetic Nephropathy.

Paeoniflorin (PF) is the primary component of total glucosides of paeony (TGP). It exerts multiple effects, including immunoregulatory and anti-inflammatory effects. Our previous study has found that PF has a remarkable renal-protective effect in diabetic mice, but exact mechanism has not been clarified. This study mainly explores whether PF affects macrophage infiltration and activation in diabetic kidney through TLR4 pathway. Thus, this study was conducted to investigate the effect of PF on a streptozotocin (STZ)-induced experimental DN model. The results suggested that the onset and clinical symptoms of DN in mice were remarkably ameliorated after the administration of PF. Moreover, the number of infiltrating macrophages in the mouse kidneys was also markedly decreased. Instead of inhibiting the activation of macrophages directly, PF could influence macrophages by suppressing iNOS expression as well as the production of TNF-α, IL-1ß, and MCP-1 both in vivo and in vitro. These effects might be attributable to the inhibition of the TLR4 signaling pathway. The percentage of M1-phenotype cells as well as the mRNA levels of iNOS, TNF-α, IL-1ß, and MCP-1 were downregulated when PF-treated polarized macrophages were cultured under conditions of high glucose (HG) levels. In addition, the expression of TLR4, along with that of downstream signaling molecule proteins, was also reduced. Our study has provided new insights into the potential of PF as a promising therapeutic agent for treating DN and has illustrated the underlying mechanism of PF from a new perspective.

Paeoniflorin attenuates incipient diabetic nephropathy in streptozotocin-induced mice by the suppression of the Toll-like receptor-2 signaling pathway.

Toll-like receptors (TLRs) may be involved in diabetic nephropathy (DN). Paeoniflorin (PF) is an effective Chinese traditional medicine with anti-inflammatory and immunoregulatory effects that may inhibit the TLR2 signaling pathway. In this study, we investigated the effects of PF on the kidneys of mice with streptozotocin-induced type 1 diabetes mellitus using TLR2 knockout mice (TLR2-/-) and wild-type littermates (C57BL/6J-WT). After 12 weeks of intraperitoneal injection of PF at doses of 25, 50, and 100 mg/kg once a day, diabetic mice had significantly reduced albuminuria and attenuated renal histopathology. These changes were associated with substantially alleviated macrophage infiltration and decreased expression of TLR2 signaling pathway biomarkers. These data support a role of TLR2 in promoting inflammation and indicate that the effect of PF is associated with the inhibition of the TLR2 pathway in the kidneys of diabetic mice. PF thus shows therapeutic potential for the prevention and treatment of DN.

Paeoniflorin inhibits high glucose-induced macrophage activation through TLR2-dependent signal pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniflorin(PF), extracted from the root peeled of Paeonia lactiflora Pall(Family: Ranunculaceae), has therapeutic potential in many animal models of inflammatory diseases. AIM OF THE STUDY: Although the anti-inflammatory efficacy of PF has been well illustrated in several animal models, whether it could attenuate diabetic nephropathy and detailed mechanisms are still obscure. Till now, accumulating evidence has proposed the pivotal role of toll-like receptors (TLRs) in renal inflammation in diabetic patients. In this setting, the current study aimed to investigate the effects and underlying mechanism of PF on high glucose-induced activation of toll like-receptor 2 (TLR2) signaling in macrophages. MATERIALS AND METHODS: Bone marrow-derived macrophages (BMDM) were isolated from male Tlr2tm1kir (TLR2-/-) mice and wild-type littermates (C57BL/6JWT). The level of TLR2 and activation of downstream signaling were evaluated in response to 30mmol/L high glucose (HG)-containing medium. Macrophages behaviors, which include cell viability, migration and inflammatory cytokines production, were also determined. RESULTS: PF suppressed HG-induced production of TLR2, activation of downstream signaling and synthesis of inducible nitric oxide synthase (iNOS). PF could further inhibit MyD88-dependent pathway in HG-induced models in which TLR2 was knocked out. Moreover, deletion of TLR2 inhibited the HG-induced activation of MyD88-dependent pathway, but not TIR domain containing adapter inducing interferon-ß (Trif) signal pathway in BMDMs. As HG stimulation polarizes macrophages into M1 phenotype, treatment of PF or knockout of TLR2 significantly reduces M1 markers on the membrane of macrophages. Additionally, levels of inflammatory cytokines and iNOS were remarkably reduced in response to PF or TLR2 deficiency. CONCLUSION: Collectively, these data demonstrated that HG activated macrophages primarily through TLR2-dependent mechanisms which aggravated the severity of renal inflammation and eventually contributed to DN. Additionally, PF might be applied as a potential therapeutic agent in the battle against progressive DN.