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Abstract Acute kidney injury (AKI) is closely related to lysosomal dysfunction and ferroptosis in renal tubular epithelial cells (TECs), for which effective treatments are urgently needed. Although selenium nanoparticles (SeNPs) have emerged as promising candidates for AKI therapy, their underlying mechanisms have not been fully elucidated. Here, we investigated the effect of SeNPs on hypoxia/reoxygenation (H/R)-induced ferroptosis and lysosomal dysfunction in TECs in vitro and evaluated their efficacy in a murine model of ischemia/reperfusion (I/R)-AKI. We observed that H/R-induced ferroptosis was accompanied by lysosomal Fe2+ accumulation and dysfunction in TECs, which was ameliorated by SeNPs administration. Furthermore, SeNPs protected C57BL/6 mice against I/R-induced inflammation and ferroptosis. Mechanistically, we found that lysosomal Fe2+ accumulation and ferroptosis were associated with the excessive activation of NCOA4-mediated ferritinophagy, a process mitigated by SeNPs through the upregulation of X-box binding protein 1 (XBP1). Downregulation of XBP1 promoted ferritinophagy and partially counteracted the protective effects of SeNPs on ferroptosis inhibition in TECs. Overall, our findings revealed a novel role for SeNPs in modulating ferritinophagy, thereby improving lysosomal function and attenuating ferroptosis of TECs in I/R-AKI. These results provide evidence for the potential application of SeNPs as therapeutic agents for the prevention and treatment of AKI.

Abstract Background The efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) transplantation in treating systemic lupus erythematosus (SLE) has been confirmed by small-scale clinical trials. However, these trials focused on severe or refractory SLE, while few studies focused on mild SLE. Therefore, this study focused on the therapeutic effects of hUC-MSC transplantation in early-stage or mild MRL/lpr lupus model mice. Methods Commercially available hUC-MSCs were transplanted into 8-week-old MRL/lpr mice by tail vein injection. Flow cytometry was used to analyze B cells and their subsets in the peripheral blood. Further, plasma inflammatory factors, autoantibodies, and plasma biochemical indices were detected using protein chip technology and ELISA kits. In addition, pathological staining and immunofluorescence were performed to detect kidney injury in mice. Results hUC-MSC transplantation did not affect the mice’s body weight, and both middle and high dose hUC-MSC transplantation (MD and HD group) actually reduced spleen weight. hUC-MSC transplantation significantly decreased the proportion of plasmablasts (PB), IgG1− PB, IgG1+ PB, IgG1+ memory B (MB) cells, IgG1+ DN MB, and IgG1+ SP MB cells. The hUC-MSC transplantation had significantly reduced plasma levels of inflammatory factors, such as TNF-α, IFN-γ, IL-6, and IL-13. Pathological staining showed that the infiltration of glomerular inflammatory cells was significantly reduced and that the level of glomerular fibrosis was significantly alleviated in hUC-MSC-transplanted mice. Immunofluorescence assays showed that the deposition of IgG and IgM antibodies in the kidneys of hUC-MSC-transplanted mice was significantly lower than in the control. Conclusion hUC-MSC transplantation could inhibit the proliferation and differentiation of peripheral blood B cells in the early-stage of MRL/lpr mice, thereby alleviating the plasma inflammatory environment in mice, leading to kidney injury remission. The study provides a new and feasible strategy for SLE treatment.

Background Among patients with peritoneal dialysis-associated peritonitis (PDAP), It has been regarded as an indicator of deterioration of clinical condition that peritoneal dialysis effluent leukocyte count (PDELC) cannot be restored to normal after initial antibiotic therapy. However, the precise relationship between PDELC on day 5 and the clinical outcomes of PDAP episodes remains uncertain.Aims To explore the association between PDELC on day 5 and clinical outcomes of PDAP episodes.Methods This retrospective study was based on the medical chart database of the Affiliated Hospital of Guangdong Medical University. Multivariable regressions were used to evaluate the association between PDELC on day 5 and 60-day mortality, half-year mortality, treatment failure, and the length of stay in hospital with adjustment for confounding factors.Results A total of 549 PDAP episodes in 309 patients were enrolled. The total 60-day mortality, half-year mortality, and rate of treatment failure was 6.0%, 9.8%, and 14.2%, respectively. Compared with patients with normal PDELC, those with PDELC ≥2000 × 106/L on day 5 had significantly higher 60-day mortality (31.1% vs 2.7%), half-year mortality (35.6% vs 5.6%), and treatment failure (46.7% vs 5.7%). In multivariate adjusted regression, the ORs (95%CI) were 6.99 (2.33, 20.92; p = 0.001), 4.97(1.93, 12.77; p = 0.001), and 5.77 (2.07, 16.11; p = 0.001), respectively. Patients with PDELC were 100–2000 × 106/L on day 5 had a higher rate of treatment failure than those with normal PDELC (26.9% vs 5.7%) (OR = 3.03, 95%CI 1.42, 6.46; p = 0.004). After sensitivity analysis, the results remained robust.Conclusions Among patients with PDAP, increased PDELC on day 5 was associated with a greater risk of 60-day mortality, half-year mortality, and treatment failure.

Background: The present study aimed to prove the progression of immunoglobulin A nephropathy (IgAN) patients with isolated hematuria based on repeat renal biopsy data for the first time.Methods: 29 IgAN patients with isolated hematuria who received repeat renal biopsies were analyzed retrospectively, while 29 non-isolated hematuria IgAN patients with similar age and background were randomly selected as the control group. Clinical parameters were collected at the time of biopsy. The treatment strategies (conservative treatment with RASS blocker or immunosuppressive treatment) were choosen according to the pathological results at the first renal biopsy. The activity and chronicity indexes of renal lesions were evaluated. Markers of cell inflammation and proliferation were tseted by immunochemistry. The ultrastructure of podocytes was observed by transmission electron microscopy (TEM). Podocyte and oxidative stress marker (NPHS2 and 4-HNE) were detected by immunofluorescence.Results: The IgAN patients with isolated hematuria had better clinical indicators than those with no-isolated hematuria, such as better renal function, higher albumin and lower uric acid. The interval between two biopsies in IgAN patients with isolated hematuria was 630 (interquartile range, 409.5–1,171) days. The hematuria of the patients decreased significantly from 30 (IQR, 4.00–35.00) RBC/ul in the first biopsy to 11 (IQR, 2.50–30.00) RBC/ul in the repeated biopsy (p < 0.05). The level of triglyceride decreased significantly (p < 0.05). The other clinical indicators were not statistically significant (p > 0.05). Deposits of IgA and C3 in the glomerulus were persistent. The activity index decreased, especially cellular crescent formation, while the chronicity index increased. The ultrastructure of podocytes was improved after treatment. The oxidative stress products of podocytes reduced after treatment.Conclusion: Although the clinical indicators of the IgAN patients with isolated hematuria were in the normal range, various acute and chronic pathological changes have occurred, and irreversible chronic changes have been progressing. Cell inflammation and proliferation persisted. Oxidative stress of podocytes was likely to be the therapeutic target. This study provided a strong basis for the progress of IgAN with isolated hematuria through pathological changes before and after treatment. This study will help clinicians recognize the harm of hematuria, change the traditional treatment concept, and help such patients get early treatment.

Background: This study compared the efficacy and safety of sequential immunosuppressive therapy in patients with non-end-stage IgA nephropathy (IgAN) with Lee’s classification of IV ∼ V and provided evidence for the use of immunotherapy in patients with severe IgAN.Methods: We retrospectively analyzed the clinical data of patients with Lee’s IV ∼ V non-end-stage IgA nephropathy.Results: 436 patients were diagnosed with IgAN, and 98 patients who met the inclusion criteria were included in this retrospective study. Of these, 17 were in the supportive care group, 20 in the P group (prednisone-only), 35 in P + CTX group (the prednisone combined with cyclophosphamide followed by mycophenolate mofetil), and 26 in the P + MMF group (prednisone combined with mycophenolate mofetil). The four groups showed differences in the segmental glomerulosclerosis score and the proportion of patients with Lee’s grade IV (p < 0.05), but no differences in other indicators. Compared with the baseline values, urine protein-to-creatinine ratio (PCR) significantly decreased and serum albumin increased (p < 0.05), but there was no significant difference between the groups. The estimated Glomerular Filtration Rate (eGFR) of the P, P + MMF, and P + CTX groups were higher than that of the supportive care group at the 6th and 24th month after treatment (all p < 0.05). At the 24th month, the eGFR in the P + CTX group was higher than that in the P + MMF group (p < 0.05). The effective remission rate of the P + CTX group was higher than that of the supportive care group (p < 0.05). At 12 months, the effective remission rate of the P group was higher than that of the supportive care group (p < 0.05). At the 24th month, there was no significant difference in the effective remission rates among the three groups (P, P + MMF, and P + CTX). Nine patients with severe IgA nephropathy reached the endpoint.Conclusion: This study showed that immunosuppressive therapy insevere IgAN patient scan effectively reduce urinary protein, increase albumin, and protect renal function in the early stages of IgAN. P + CTX is the most commonly used, which has a high effective remission rate of urine protein and a low incidence of end-point events.

Nowadays, with the improvements in living standards and changes in living habits, high-fat diet (HFD) has become much more common in the populations worldwide. Recent studies have shown that HFD could induce lipid accumulation, and structural and functional abnormalities, accompanied by the release of large amounts of pro-inflammatory cytokines, in proximal tubular epithelial cells (PTECs). These findings indicate that, as an emerging risk factor, PTEC injury-induced by HFD may be closely related to inflammation; however, the potential mechanisms underlying this phenomenon is still not well-known, but may involve the several inflammatory pathways, including oxidative stress-related signaling pathways, mitochondrial dysfunction, the myeloid differentiation factor 2/Toll like receptor 4 (MD2/TLR4) signaling pathway, the ERK1/2-kidney injury molecule 1 (KIM-1)-related pathway, and nuclear factor-κB (NF-κB) activation, etc., and the detailed molecular mechanisms underlying these pathways still need further investigated in the future. Based on lipid abnormalities-induced inflammation is closely related to the development and progression of chronic kidney disease (CKD), to summarize the potential mechanisms underlying HFD-induced renal proximal tubular inflammatory injury, may provide novel approaches for CKD treatment.

Abstract Both electrical properties and biomarkers of biological tissues can be used to distinguish between normal and diseased tissues, and the correlations between them are critical for clinical applications of conductivity (σ) and permittivity (ε); however, these correlations remain unknown. This study aimed to investigate potential correlations between electrical characteristics and biomarkers of breast cancer cells (BCC). Changes in σ and ε of different components in suspensions of normal cells and BCC were analyzed in the range of 200 kHz–5 MHz. Pearson's correlation coefficient heatmap was used to investigate the correlation between σ and ε of the cell suspensions at different stages and biomarkers of cell growth and microenvironment. σ and ε of the cell suspensions closely resembled those of tissues. Further, the correlations between Na+/H+ exchanger 1 and ε and σ of cell suspensions were extremely significant among all biomarkers (pε

Oncolytic viruses are promising immunoreagents. Numerous studies have shown that oncolytic virotherapy is effective for many tumors. Herein, we investigated the therapeutic effect of oHSV2, an oncolytic type 2 herpes simplex virus, on mouse colon carcinoma. The in vivo antitumor efficacy of oHSV2 was observed in both unilateral and bilateral colon cancer models. oHSV2 effectively eliminated tumors and prolonged the survival of mice without side effects. Additionally, treatment with oHSV2 effectively prevented the growth of rechallenged tumors and distant implanted tumors. The specific killing ability of splenic immune cells to tumor cells was enhanced. oHSV2 treatment effectively reduced the content of inhibitory immune cells (regulatory T cells [Tregs] and myeloid-derived suppressor cells [MDSCs]) and increased the content of positive immune cells (natural killer [NK], CD8+ T, and dendritic cells [DCs]) in the spleen. Moreover, treatment with oHSV2 remodeled the tumor immune microenvironment. In summary, treatment with oHSV2 can effectively eliminate primary tumors, generate tumor-specific immunity, and elicit immune memory to inhibit tumor recurrence and metastasis. Furthermore, this virotherapy can reshape the immune status of the spleen and tumor microenvironment in mice, which can further improve the therapeutic antitumor effect. Keywords: oncolytic virus, oHSV2, colon carcinoma, tumor microenvironment, immune status, tumor-specific immune response

Objectives: The role of postoperative radiotherapy (PORT) in the treatment of patients with completely resected non-small cell lung cancer (NSCLC) is not clear. Few study explored the trends of the PORT use. In this study, we examine the status of PORT use of completely resected NSCLC in mainland China.Methods: From 2005 to 2014, patients with primary lung cancer from eight hospitals across seven geographic regions of mainland China were selected. Then patients with staged I–IIIA NSCLC receiving radical surgery were enrolled in this study. The chi-square test was used to compare differences in the use of PORT among the groups of different age, regions and stages. The Cochran-Armitage trend test was used to identify the trend in the PORT use from 2005 to 2014.Results: Totally, 2,253 out of 7,184 patients were with staged I–IIIA NSCLC receiving completely resection. Only 122 patients (5.42%) received PORT. During this decade, the use of PORT declined significantly (p = 0.0002). In high socio-economic areas, the percentage of PORT use was 7.43%, which was significantly higher than 1.34% in the low socio-economic areas (p < 0.0001). Age was also associated with PORT use (p = 0.0747). For N0-1 and N2 NSCLC, the proportions of PORT use were 4.01 and 10.22%, respectively (p < 0.0001). And in N0-1 or N2 NSCLC, the proportions both decreased significantly during this decade (p = 0.009 and 0.026, respectively). For stage I, IIA, IIB and IIIA, the proportions who received PORT were 2.59, 4.65, 5.49, and 10.29%, respectively (p < 0.0001). Modern radiation techniques were widely used, but the volumes and doses varied widely. The proportions of using IMRT and EPID/IGRT increased after 2012.Conclusions: In China, the use of PORT was less than developed countries and had a declined trend. The use of PORT was related to disease stages, patients' age and geographic location. Both in N0-1 and N2 diseases, the use of PORT declined. Proper education of radiation doctors was urgently needed.

Background: The capacity of toll-like receptor (TLR) 7/8 agonist-conjugated hepatitis B virus (HBV) proteins (HBV-Ag) to overcome established hepatitis B surface antigen (HBsAg)-specific immune tolerance was explored. Methods: A TLR7/8 agonist, CL097, was conjugated with alum-absorbed HBsAg and hepatitis B core antigen (HBcAg), as confirmed by ultra performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS). Mice from two independently generated HBV-transgenic (HBV-Tg) colonies, C57BL/6J-TgN (AlblHBV) 44Bri/J mice and C57BL/6-HBV-1.3 genome-eq mice, were immunized with CL097-conjugated HBV-Ag every 2 weeks, four times. Results: After immunization, 8/11 (72.7%) of the AlblHBV mice and 10/13 (76.9%) of the HBV-1.3 genome-eq mice generated serum detectable antibodies against HBsAg (anti-HBs). HBsAg-specific interferon gamma (IFN-γ)-producing CD4+ and CD8+ T-cells were detected in splenocytes from these mice. Naïve normal mice receiving splenocytes from the mice immunized with CL097-conjugated HBV-Ag generated immediate recall immune responses, e.g., the mice that received CD4+CD25+-depleted splenocytes generated anti-HBs on day 3 after HBsAg challenge while those receiving cells from sham-immunized mice did not. Conclusions: Immunization with CL097-conjugated HBV-Ag reversed immune tolerance in HBV-Tg mice and induced antigen-specific immune responses. TLR7/8 agonists appear to be potent adjuvants for the induction of antigen-specific Th1 responses in an immune tolerant state.

Oncolytic viruses are promising treatments for many kinds of solid tumors. In this study, we constructed a novel oncolytic herpes simplex virus type 2: oHSV2. We investigated the cytopathic effects of oHSV2 in vitro and tested its antitumor efficacy in a 4T1 breast cancer model. We compared its effect on the cell cycle and its immunologic impact with the traditional chemotherapeutic agent doxorubicin. In vitro data showed that oHSV2 infected most of the human and murine tumor cell lines and was highly oncolytic. oHSV2 infected and killed 4T1 tumor cells independent of their cell cycle phase, whereas doxorubicin mainly blocked cells that were in S and G2/M phase. In vivo study showed that both oHSV2 and doxorubicin had an antitumor effect, though the former was less toxic. oHSV2 treatment alone not only slowed down the growth of tumors without causing weight loss but also induced an elevation of NK cells and mild decrease of Tregs in spleen. In addition, combination therapy of doxorubicin followed by oHSV2 increased survival with weight loss than oHSV2 alone. The data showed that the oncolytic activity of oHSV2 was similar to oHSV1 in cell lines examined and in vivo. Therefore, we concluded that our virus is a safe and effective therapeutic agent for 4T1 breast cancer and that the sequential use of doxorubicin followed by oHSV2 could improve antitumor activity without enhancing doxorubicin's toxicity.