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In septic acute kidney injury (SAKI), the positive feedback between damaged mitochondria and accumulation of reactive oxygen species results in cell and tissue damage through multiple mechanisms. Removing the damaged mitochondria or neutralizing the reactive oxygen species has been considered beneficial to alleviating cell damage. The antioxidant Procyanidin B2 has been reported to inhibits reactive oxygen species and thereby reduces cell injury. However, it is unclear whether this effect is associated with clearance of damaged mitochondria. Here, we evaluated the efficacy of procyanidin B2 on SAKI, and focused on its effects on mitochondrial dynamics and removing damaged mitochondria via mitophagy. The results showed that the renal function, renal tubular cell vacuolization and oxidative stress were decreased in SAKI mice treated with procyanidin B2, moreover, skewed mitochondrial fusion/fission, mitochondrial mediated apoptosis and impaired mitophagy were improved in SAKI mice treated with procyanidin B2. In mechanism, the improvement of procyanidin B2 on mitochondrial dynamics were associated with increased nuclear translocation of the transcription factor, Nrf2. In summary, our findings highlighted that the protective efficacy of procyanidin B2 in reducing cellular damage in SAKI, and mechanisms improving mitochondrial dynamics and quality control at least in part by promoting Nrf2 translocation into the nucleus.

Lysosomes are organelles involved in cell metabolism, waste degradation, and cellular material circulation. They play a key role in the maintenance of cellular physiological homeostasis. Compared with the lysosomal content of other organs, that of the kidney is abundant, and lysosomal abnormalities are associated with the occurrence and development of certain renal diseases. Lysosomal structure and function in intrinsic renal cells are impaired in diabetic kidney disease (DKD). Promoting lysosomal biosynthesis and/or restoring lysosomal function can repair damaged podocytes and proximal tubular epithelial cells, and delay the progression of DKD. Lysosomal homeostasis maintenance may be advantageous in alleviating DKD. Here, we systematically reviewed the latest advances in the relationship between lysosomal dyshomeostasis and progression of DKD based on recent literature to further elucidate the mechanism of renal injury in diabetes mellitus and to highlight the application potential of lysosomal homeostasis maintenance as a new prevention and treatment strategy for DKD. However, research on screening effective interventions for lysosomal dyshomeostasis is still in its infancy, and thus should be the focus of future research studies. The screening out of cell-specific lysosomal function regulation targets according to the different stages of DKD, so as to realize the controllable targeted regulation of cell lysosomal function during DKD, is the key to the successful clinical development of this therapeutic strategy.

Mitochondrial injury plays an important role in the occurrence and development of kidney diseases. However, the existing assays to determine mitochondrial function restrict our ability to understand the relationship between mitochondrial dysfunction and kidney damage. These limitations may be overcome by recent findings on urinary mitochondrial DNA (UmtDNA). Elevated UmtDNA level may serve as a surrogate biomarker of mitochondrial dysfunction, kidney damage, and progression and prognosis of kidney diseases. Herein, we review the recent research progress on UmtDNA in kidney diseases diagnosis and highlight the research areas that should be expanded in future as well as discuss the future perspectives.

Background Persistent elevated concentrations of urinary protein can destroy proximal tubule epithelial cells (PTECs) by inducing lysosomal abnormalities, thereby aggravating PTEC damage and renal fibrosis. However, the specific mechanisms of these serial biochemical events and methods for treating or preventing PTEC damage upon proteinuria need further investigation. Results In this study, electron microscopy and dual-labeled immunofluorescence analysis for identifying lysosome type revealed inadequate primary lysosome biogenesis and secondary lysosome accumulation in the PTECs of patients with minimal change nephrotic syndrome or membranous nephropathy who suffered from proteinuria. In vitro studies on HK-2 cells indicated that this abnormality was associated with decreased expression of transcription factor EB (TFEB). In contrast, TFEB overexpressing HK-2 cells under urinary protein overload exhibited significantly reduced accumulation of secondary lysosomes and increased proportion and quantity of primary lysosomes as indicated by dual-labeled immunofluorescence. Further, these cells could upregulate lysosomal degradation functions, as determined using Cathepsin L activity assays and flow cytometry for dye quenched-albumin. Conclusions These results indicate that abnormal TFEB expression is a key mechanism of lysosomal dyshomeostasis caused by protein overload in PTECs. TFEB is thus a potential therapeutic target for the treatment of urinary protein-related kidney disease.

Visual Abstract, Highlights • Optimal treatment for patients with diabetes and myocardial infarction remains a challenge. • Hyperglycemia- and hyperinsulinemia-induced miR-24 reduction and O-GlcNAcylation in the diabetic heart contributes to poor survival in diabetic myocardial I/R and increased infarct size post-I/R. • Overexpression of miR-24 in murine hearts significantly reduces myocardial infarct size. • miR-24 targets multiple key proteins including O-GlcNac transferase, ATG4A (a key protein in autophagy), and BIM (a pro-apoptosis protein) to protect the myocardium from I/R injury. • miR-24 is a promising therapeutic candidate for diabetic I/R injury., Summary Management for patients with diabetes experiencing myocardial infarction remains a challenge. Here the authors show that hyperglycemia- and hyperinsulinemia-induced microRNA-24 (miR-24) reduction and O-GlcNAcylation in the diabetic heart contribute to poor survival and increased infarct size in diabetic myocardial ischemia/reperfusion (I/R). In a mouse model of myocardial I/R, pharmacological or genetic overexpression of miR-24 in hearts significantly reduced myocardial infarct size. Experimental validation revealed that miR-24 targets multiple key proteins, including O-GlcNac transferase, ATG4A, and BIM, to coordinately protect the myocardium from I/R injury. These results establish miR-24 as a promising therapeutic candidate for diabetic I/R injury.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by inflammation and abnormal production of autoantibody, but the mechanisms of the aberrant immune responses are currently unknown. Recently, growing evidence has suggested that infection plays a pivotal role in SLE. Here, we investigate the role of infectious agents (e.g., Epstein-Barr virus, parvovirus B19, human T-lymphotropic virus type 1, human immunodeficiency virus type 1, and endogenous retroviruses) in the pathogenesis of SLE. More importantly, we explore the known mechanisms underlying the involvement of infectious agents in the pathogenesis of SLE, including molecular mimicry, epitope spreading, superantigen production, bystander activation, persistent viral infection, altered apoptosis, clearance deficiency, and epigenetic alterations (e.g., DNA methylation and microRNAs). However, some infectious agents (e.g., malaria parasites, hepatitis B virus, Toxoplasma gondii, and Helicobacter pylori) may exert protective effects on SLE. Therefore, the relationship between infection and SLE is multifaceted and multidirectional, including causative and/or protective associations, which warrant further investigation in the future.

Aims The renal tubule cells require a large number of mitochondria to supply ATP due to their high-energy demand during reabsorption and secretion against chemical gradients and result in mitochondria susceptible to disorder and injury during stress conditions. Injured mitochondria are eventually degraded by mitophagy, and disturbances in mitophagy are associated with the pathogenesis of acute kidney injury (AKI) such as diabetic nephropathy and glomerulosclerosis. However, whether a disturbance in mitophagy has occurred and the role it plays in (SAKI) is still unclear. Therefore, the aim of this study was to investigate the key features of mitophagy and mitochondrial dynamics in sepsis-induced acute kidney injury (SAKI). Main methods In this study, a murine septic AKI model induced by cecal ligation and puncture (CLP) was built; mitophagy and mitochondrial dynamics were measured in mice kidney in different time point. Key findings The results showed that mitochondrial dynamics were characterized by fission/fusion aberrant, however more inclined to fission, and mitochondrial associated apoptosis was elevated over-time during SAKI. Furthermore, mitophagy was impaired in the later phase of SAKI, although elevated in early stage of SAKI. The results indicate that the underlying mechanisms of impaired mitophagy may associate with the cleavage of Parkin via caspases activated by NLRP3, at least partly. Significance It is conceivable that this selective autophagic process and quality control machinery was impaired, leading to the accumulation of damaged mitochondria, oxidative stress, and cell death. Therefore, a targeted approach, by enhancing mitophagy during SAKI, may be a promising therapeutic strategy.

In the cerebrovascular endothelium, monocarboxylic acid transporter 1 (Mct1) controls blood–brain transport of short chain monocarboxylic and keto acids, including pyruvate and lactate, to support brain energy metabolism. Mct1 function is acutely decreased in rat brain cerebrovascular endothelial cells by β-adrenergic signaling through cyclic adenosine monophosphate (cAMP); however, the mechanism for this acute reduction in transport capacity is unknown. In this report, we demonstrate that cAMP induces the dephosphorylation and internalization of Mct1 from the plasma membrane into caveolae and early endosomes in the RBE4 rat brain cerebrovascular endothelial cell line. Additionally, we provide evidence that Mct1 constitutively cycles through clathrin vesicles and recycling endosomes in a pathway that is not dependent upon cAMP signaling in these cells. Our results are important because they show for the first time the regulated and unregulated vesicular trafficking of Mct1 in cerebrovascular endothelial cells; processes which have significance for better understanding normal brain energy metabolism, and the etiology and potential therapeutic approaches to treating brain diseases, such as stroke, in which lactic acidosis is a key component.

An elevated level of von Willebrand factor (VWF) in diabetic patients is associated with increased risk of thrombotic cardiovascular events. The underlying mechanism of how VWF expression is upregulated in diabetes mellitus is poorly understood. We now report that hyperglycemia-induced repression of microRNA-24 (miR-24) increases VWF expression and secretion in diabetes mellitus. In diabetic patients and diabetic mouse models (streptozotocin/high-fat diet-induced and db/db mice), miR-24 is reduced in both tissues and plasma. Knockdown of miR-24 in mice leads to increased VWF mRNA and protein levels and enhanced platelet tethering (spontaneous thrombosis). miR-24 tightly controls VWF levels through pleiotropic effects, including direct binding to the 3′ untranslated region of VWF and targeting FURIN and the histamine H1 receptor, known regulators of VWF processing and secretion in endothelial cells. We present a novel mechanism for miR-24 downregulation through hyperglycemia-induced activation of aldose reductase, reactive oxygen species, and c-Myc. These findings support a critical role for hyperglycemic repression of miR-24 in VWF-induced pathology. miR-24 represents a novel therapeutic target to prevent adverse thrombotic events in patients with diabetes mellitus.

To demonstrate the computed tomography, conformal irradiation, and treatment planning capabilities of a small animal radiation research platform (SARRP).The SARRP uses a dual-focal spot, constant voltage X-ray source mounted on a gantry with a source-to-isocenter distance of 35 cm. Gantry rotation is limited to 120 degrees from vertical. X-rays of 80-100 kVp from the smaller 0.4-mm focal spot are used for imaging. Both 0.4-mm and 3.0-mm focal spots operate at 225 kVp for irradiation. Robotic translate/rotate stages are used to position the animal. Cone-beam computed tomography is achieved by rotating the horizontal animal between the stationary X-ray source and a flat-panel detector. The radiation beams range from 0.5 mm in diameter to 60 x 60 mm(2). Dosimetry is measured with radiochromic films. Monte Carlo dose calculations are used for treatment planning. The combination of gantry and robotic stage motions facilitate conformal irradiation.The SARRP spans 3 ft x 4 ft x 6 ft (width x length x height). Depending on the filtration, the isocenter dose outputs at a 1-cm depth in water were 22-375 cGy/min from the smallest to the largest radiation fields. The 20-80% dose falloff spanned 0.16 mm. Cone-beam computed tomography with 0.6 x 0.6 x 0.6 mm(3) voxel resolution was acquired with a dose of1 cGy. Treatment planning was performed at submillimeter resolution.The capability of the SARRP to deliver highly focal beams to multiple animal model systems provides new research opportunities that more realistically bridge laboratory research and clinical translation.

271 Background: Modern radiation oncology departments contain an extensive array of complex therapies and technologies. Adoption of new treatments and staff changes challenge each team in maintaining high levels of performance and standards. Fewer than 15% of US centers have independent certification of quality. We plan to achieve American College of Radiology (ACR) Accreditation for all USA and UK Radiation Oncology Centers of HCA. Methods: A GAP analysis tool was developed to enable each center to approach the ACR application with the coordinated and simultaneous efforts of all sections of the radiation oncology department. Data was prospectively gathered for each department, highlighting areas of strength and aspects that need focused attention to improve. A scale of 1-5 was assigned to each task regarding the initial and ongoing level of progress towards meeting the standard with documentation for each required. Our intent is for each of the 52 radiation oncology departments to achieve full ACR Accreditation in a timeframe of no more than 4.5 months from start of the GAP analysis. Results: One program was fully accredited when the program began in July 2013. Since then 6 have achieved full accreditation and 12 are in process with the GAP tool. Analyses of full GAP data are available from eight programs thus far. High achievement in compliance with ACR Standards (95-100% compliance) was found in policies monitoring complications, adverse reactions and ‘time out’ procedures. Areas needing improvement s (