Renal ischemia-reperfusion injury (IRI) is a major contributing factor to the development of acute kidney injury (AKI) and has resulted in considerable morbidity and mortality. Persistent inflammatory responses and excessive reactive oxygen species (ROS) in the kidney following IRI can severely delay tissue repair, making it challenging to effectively promote IRI regeneration. Herein, we report an approach to enhance immunotherapy using interleukin-10 (IL-10) to promote IRI regeneration by loading IL-10 onto rectangular DNA origami nanostructures (rDON). rDON can significantly enhance the renal accumulation and retention time of IL-10, enabling it to effectively polarize type 1 macrophages into type 2 macrophages, thereby significantly reducing proinflammatory factors and increasing anti-inflammatory factors. In addition, DNA origami helps mitigate the harmful effects of ROS during renal IRI. The administration of IL-10-loaded DNA origami effectively improves kidney function, resulting in a notable reduction in blood urea nitrogen, serum uric acid, and serum creatinine levels. Our study demonstrates that the integration of anti-inflammatory cytokines within DNA origami holds promise as a strategic approach for cytokine immunotherapy in patients with AKI and other renal disorders.

OBJECTIVE: This study aimed to determine long-term cost-effectiveness of continuous glucose monitoring (CGM) technology versus self-monitoring of blood glucose (SMBG) in adults with type 1 diabetes (T1D) using multiple daily injections in Iran.
METHODS: According to available data, the long-term costs and clinical outcomes of CGM and SMBG were estimated using the Sheffield Type 1 Diabetes Model, with a lifetime horizon from a payer\'s perspective. The primary outcome was the cost per quality-adjusted life year (QALY) gained.
RESULTS: The lifetime cost-effectiveness analysis demonstrated that on average, the use of CGM increased life expectancy by 1.32 years and QALYs by 1.63, compared with SMBG. The CGM group had an average discounted total cost of $40 093 US dollars, whereas the SMBG group had an average discounted total cost of $13 366. This resulted in an incremental cost-effectiveness ratio (ICER) of $16 386 per QALY gained, which is less than the threshold of 3 times the gross domestic product (GDP) per capita of Iran ($24 561).
CONCLUSIONS: Considering 3 times the GDP per capita as the threshold, CGM is likely to be cost-effective in Iran. However, for CGM to be very cost-effective (ie, have an ICER less than 1 times the GDP per capita) and presumably more accessible, the price of CGM should decrease to $40 per sensor, each with a lifespan of 14 days.

α-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy.NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.

Kidney transplantation offers a longer life expectancy and a better quality of life than dialysis to patients with end-stage kidney disease. Ischemia-reperfusion injury (IRI) is thought to be a cornerstone in delayed or reduced graft function and increases the risk of rejection by triggering the immunogenicity of the organ. IRI is an unavoidable event that happens when the blood supply is temporarily reduced and then restored to an organ. IRI is the result of several biological pathways, such as transcriptional reprogramming, apoptosis and necrosis, innate and adaptive immune responses, and endothelial dysfunction. Tubular cells mostly depend on fatty acid (FA) β-oxidation for energy production since more ATP molecules are yielded per substrate molecule than glucose oxidation. Upon ischemia-reperfusion damage, the innate and adaptive immune system activates to achieve tissue clearance and repair. Several cells, cytokines, enzymes, receptors, and ligands are known to take part in these events. The complement cascade might start even before organ procurement in deceased donors. However, additional experimental and clinical data are required to better understand the pathogenic events that take place during this complex process.

IRI often occurs after detorsion of testicular torsion, which can contribute to permanent damage to sperm production function due to spermatogonia pyroptosis. Mounting data manifest that miRNAs possess a function in the IRI progression. However, the miR-153 function in testicular IRI remains unclear. We aim to elucidate the regulatory mechanism of miR-153 in regulating spermatogonia pyroptosis in testicular IRI. We developed the mouse testicular torsion/detorsion (T/D) model and the oxygen-glucose deprivation/reperfusion (OGD/R) model to examine the miR-153 function in testicular IRI. The extent of testicular ischemic damage was evaluated through HE staining the testicular tissue. Various experimental methods, including Western blotting, QRT-PCR, MDA, SOD assays, and immunohistochemistry (IHC), were deployed to examine the miR-153 levels and the generation of ROS in the testicular tissues. Furthermore, we determined the FoxO3 levels and pyroptosis-related proteins in GC-1 cells. Cell viability was assessed using the CCK-8 assay. Finally, the connection between miR-153 and FoxO3 was verified by employing dual luciferase reporter gene assays and Ago2-RIP. In the testicular IRI, we noted a significant elevation in the pyroptosis-correlated proteins NLRP3, caspase-1 (CASP1), IL-1β, and IL-18 levels. Furthermore, we noted a significant upregulation of miR-153 in the IRI testicular tissues and GC-1 cells treated with OGD/R, and the miR-153 upregulation increased cell pyroptosis. Conversely, the miR-153 downregulation and FoxO3 overexpression reduced cell pyroptosis. Subsequently, we validated that FoxO3 is a miR-153 target gene. During the OGD/R process, miR-153 increased cell pyroptosis in GC-1 cells by suppressing the FoxO3 expression. We identified that the regulation of testicular IRI-induced cell pyroptosis is mediated by miR-153 via its targeting of FoxO3.

Natural immunoglobulin M (IgM) antibodies have been shown to recognize post-ischemic neoepitopes following reperfusion of tissues and to activate complement. Specifically, IgM antibodies and complement have been shown to drive hepatic ischemia reperfusion injury (IRI). Herein, we investigate the therapeutic effect of C2 scFv (single-chain antibody construct with specificity of a natural IgM antibody) on hepatic IRI in C57BL/6 mice. Compared with PBS-treated mice, C2 scFv-treated mice displayed almost no necrotic areas, significant reduction in serum ALT, AST and LDH levels, and significantly reduced in the number of TUNEL positive cells. Moreover, C2 scFv-treated mice exhibited a notable reduction in inflammatory cells after hepatic IRI than PBS-treated mice. The serum IL-6, IL-1β, TNF-α and MPC-1 levels were also severely suppressed by C2 scFv. Interestingly, C2 scFv reconstituted hepatic inflammation and IRI in Rag1-/- mice. We found that C2 scFv promoted hepatic cell death and increased inflammatory cytokines and infiltration of inflammatory cells after hepatic IRI in Rag1-/- mice. In addition, IgM and complement 3d (C3d) were deposited in WT mice and in Rag1-/- mice reconstituted with C2 scFv, indicating that C2 scFv can affect IgM binding and complement activation and reconstitute hepatic IRI. C3d expression was significantly lower in C57BL/6 mice treated with C2 scFv compared to PBS, indicating that excessive exogenous C2 scFv inhibited complement activation. These data suggest that C2 scFv alleviates hepatic IRI by blocking complement activation, and treatment with C2 scFv may be a promising therapy for hepatic IRI.

OBJECTIVE: To determine whether WJ-MSCs pretreated with VPA would enhance their migration to improve functional recovery of renal IRI in rats.
METHODS: 150 Sprague-Dawley rats were distributed into 5 groups; Sham, IRI, WJ-MSC, VPA, and WJ-MSCs + VPA. 10 rats were sacrificed after 3, 5, and 7 days. Role of WJ-MSCs pretreated with VPA was evaluated by assessment of renal function, antioxidant enzymes together with renal histopathological and immunohistopathological analyses and finally by molecular studies.
RESULTS: WJ-MSCs and VPA significantly improved renal function and increased antioxidants compared to IRI group. Regarding gene expression, WJ-MSCs and VPA decreased BAX and TGF-β1, up-regulated Akt, PI3K, BCL2, SDF1α, and CXCR4 related to IRI. Additionally, WJ-MSCs pretreated with VPA improved the measured parameters more than either treatment alone.
CONCLUSIONS: WJ-MSCs isolated from the umbilical cord and pretreated with VPA defended the kidney against IRI by more easily homing to the site of injury.

Ischemia-reperfusion injury is an event concerning any organ under a procedure of transplantation. The early result of ischemia is hypoxia, which causes malfunction of mitochondria and decrease in cellular ATP. This leads to disruption of cellular metabolism. Reperfusion also results in cell damage due to reoxygenation and increased production of reactive oxygen species, and later by induced inflammation. In damaged and hypoxic cells, the endoplasmic reticulum (ER) stress pathway is activated by increased amount of damaged or misfolded proteins, accumulation of free fatty acids and other lipids due to inability of their oxidation (lipotoxicity). ER stress is an adaptive response and a survival pathway, however, its prolonged activity eventually lead to induction of apoptosis. Sustaining cell functionality in stress conditions is a great challenge for transplant surgeons as it is crucial for maintaining a desired level of graft vitality. Pathways counteracting negative consequences of ischemia-reperfusion are autophagy and lipid droplets (LD) metabolism. Autophagy remove damaged organelles and molecules driving them to lysosomes, digested simpler compounds are energy source for the cell. Mitophagy and ER-phagy results in improvement of cell energetic balance and alleviation of ER stress. This is important in sustaining metabolic homeostasis and thus cell survival. LD metabolism is connected with autophagy as LD are degraded by lipophagy, a source of free fatty acids and glycerol-thus autophagy and LD can readily remove lipotoxic compounds in the cell. In conclusion, monitoring and pharmaceutic regulation of those pathways during transplantation procedure might result in increased/improved vitality of transplanted organ.

The comprehension of the factors affecting the adsorption of ethanol over metals and metal alloys is a crucial step for the rational development of new catalysts for hydrogen production through ethanol reforming. In this work, we analyze the effect of combining Pt and Sn on a metal cluster on the complexation energy and reactivity for OH dehydrogenation of ethanol. Metal clusters of Pt10, Sn10 and Pt5Sn5 had their putative minimum located with the help of the artificial bee colony algorithm. Whereas the isolated Pt cluster shows a high degree of polarization (ESP surface), the Sn cluster shows a quite uniform electron density surface. The PtSn cluster is strongly polarized, with Pt atoms withdrawing electron density of Sn atoms. Complexation occurs with the oxygen atom of ethanol directed towards the point of highest electron potential in the ESP surface. Pt presents the highest complexation energy, -20.90 kcal/mol, against only -7.83 kcal/mol (at the B97-3c level). For the PtSn cluster, the value is intermediate, namely -12.39 kcal/mol. The more malleable electron density of Pt and its electron affinity are responsible for its highest complexation energy. These characteristics are partially transferred to the PtSn cluster. QTAIM results show that, for the PtSn cluster, the O-H bond in ethanol is somewhat weaker than for pure Pt and Sn. As a consequence, the energy barrier for the O-H dehydrogenation has its lowest value for the PtSn cluster, which shows that the alloying of two metals can lead to quite quite unexpected results opening the perspective for a more rational fine tuning of catalysts properties.

Ischemia-reperfusion injury (IRI) is a major contributor to acute and chronic kidney failure, heart failure, and ischemic stroke. This study aimed to investigate the therapeutic potential of Iberin, known for its anti-inflammatory, antioxidant, and antiapoptotic properties, in a rat model of renal IRI. Twenty-four adult male rats were randomly divided into four groups: Group I (Sham group) underwent laparotomy without IRI induction; Group II (Control group) underwent laparotomy followed by renal artery clamping for 30 minutes to induce ischemia, followed by 2 hours of reperfusion; Group III (Iberin treatment group) received a pre-injection of Iberin (15 mg/kg) and underwent 30 minutes of ischemia followed by 2 hours of reperfusion; and Group IV (Vehicle-treated group) received the vehicle (ethanol) 1 hour prior to ischemia and reperfusion induction. Iberin was diluted with ethanol. Biomarkers associated with inflammation, oxidative stress, and apoptosis were measured using enzyme-linked immunosorbent assay. Iberin treatment significantly reduced levels of inflammatory cytokines interleukin-1β (IL-1β) and IL-6, Bcl-2-associated X protein (BAX), tumor necrosis factor α (TNF-α), nuclear factor kappa p56, high mobility group B1, and neutrophil gelatinase-associated lipocalin. Moreover, Iberin increased levels of heat shock protein and Bcl2 compared to the control and vehicle groups. Iberin treatment prolonged the ischemic tolerance of renal tissue, potentially preventing or delaying irreversible injuries. These findings highlight the potential of Iberin as a promising candidate for mitigating renal injury caused by ischemia-reperfusion, due to its ability to modulate inflammatory markers.