[Retracted] MicroRNA­320a suppresses tumour cell proliferation and invasion of renal cancer cells by targeting FoxM1.

Subsequently to the publication of the above paper, the authors drew to the attention of the Editorial Office that they made a couple of errors in terms of the data assembly in Figs. 2 and 4 in their paper; specifically, the Transwell assay data shown for the 'miR-320a+/FoxM1+' panel in Fig. 5D on p. 1923 also appeared as the 'ACTN/NC' data panel in Fig. 4E on the same page (Fig. 4E contained the erroneously duplicated panel). In addition, data featured in Fig. 2D of the above paper were strikingly similar to data that appeared in Fig. 6e of the following paper, published subsequently to this article, written by different authors (although a Dr Shiyue Zhao worked in the molecular biology laboratory of Harbin Medical University from 2017 to 2018, and the research collaboration was conducted with Dr Chenlong Li's research group): Li C, Zheng H, Hou W, Bao H, Xiong J, Che W, Gu Y, Sun H and Liang P: Long non-coding RNA linc00645 promotes. TGF-ß-induced epithelial-mesenchymal transition by regulating miR-205-3p-ZEB1 axis in glioma. Cell Death Dis 10: 17, 2019. Finally, after having conducted an independent investigation of the data in this paper, the Editorial Office noted that one of the Petri dish images in Fig. 2C was also strikingly similar to data that appeared in Fig. 2H of the abovementioned article in the journal Cell Death & Disease. After having considered the authors' request for corrigendum, in view of the problems that were identified with the data, the Editor of Oncology Reports has decided that, owing to a lack of confidence in the presented data, the paper should instead be retracted from the journal. After having informed the authors of this decision, they accepted the decision to retract this paper. The Editor apologizes to the readership for any inconvenience caused.  [Oncology Reports 40: 1917­1926, 2018; DOI: 10.3892/or.2018.6597].

Application of vacuum-sealing drainage in buttonhole-related arteriovenous fistula infection: A case report.

Few studies have reported the application of vacuum-sealing drainage of infected dialysis vascular access wounds. Herein, we present a case of buttonhole-related arteriovenous fistula infection treated with vacuum-sealing drainage. A 53-year-old female hemodialysis patient was hospitalized with an inflamed arteriovenous fistula. The patient underwent non-tunneled catheterization for dialysis and was treated with moxifloxacin and vancomycin for staphylococcal infection. On Day 3, the skin overlying the inflamed fistula was ulcerated, resulting in severe hemorrhage. Emergency surgery was performed along with vacuum-sealing drainage for fistula reconstruction. Vacuum-sealing drainage accelerated the recovery of the wound without complications. No further access complications occurred during over a 3-year follow-up.

Obesity-related glomerulopathy: recent advances in inflammatory mechanisms and related treatments.

Obesity-related glomerulopathy, which is an obesity-triggered kidney damage, has become a significant threat to human health. Several studies have recently highlighted the critical role of inflammation in obesity-related glomerulopathy development. Additionally, excess adipose tissue and adipocytes in patients with obesity produce various inflammatory factors that cause systemic low-grade inflammation with consequent damage to vascular endothelial cells, exacerbating glomerular injury. Therefore, we conducted a comprehensive review of obesity-related glomerulopathy and addressed the critical role of obesity-induced chronic inflammation in obesity-related glomerulopathy pathogenesis and progression, which leads to tubular damage and proteinuria, ultimately impairing renal function. The relationship between obesity and obesity-related glomerulopathy is facilitated by a network of various inflammation-associated cells (including macrophages, lymphocytes, and mast cells) and a series of inflammatory mediators (such as tumor necrosis factor α, interleukin 6, leptin, adiponectin, resistin, chemokines, adhesion molecules, and plasminogen activator inhibitor 1) and their inflammatory pathways. Furthermore, we discuss a recently discovered relationship between micronutrients and obesity-related glomerulopathy inflammation and the important role of micronutrients in the body's anti-inflammatory response. Therefore, assessing these inflammatory molecules and pathways will provide a strong theoretical basis for developing therapeutic strategies based on anti-inflammatory effects to prevent or delay the onset of kidney injury.

Zinc deficiency increases lung inflammation and fibrosis in obese mice by promoting oxidative stress.

BACKGROUND: Zinc deficiency can lead to multiple organ damage. In this study, we investigated the effects of zinc deficiency on obesity-related lung damage. METHODS: C57BL/6 J mice were fed a diet with differing amounts of zinc and fat over a 6-month period. Palmitic acid was used to stimulate A549 cells to construct a high-fat alveolar epithelial cell model. Western blotting and histopathological staining were performed on animal tissues. Nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was detected in cultured cells. A reactive oxygen species (ROS) assay kit was used to detect intracellular ROS. Furthermore, Nrf2 siRNA was used to examine zinc deficiency effects on A549 cells. RESULTS: Pathological results showed significant damage to the lung structure of mice in the high-fat and low-zinc diet group, with a significant increase in the expression of inflammatory (IL-6, TNF-α) and fibrosis (TGFß1, PAI-1) factors, combined with a decrease in the expression of Nrf2, HO-1 and NQO1 in the antioxidant pathway. In A549 cells, high fat and low zinc levels aggravated ROS production. Western blot and immunofluorescence results showed that high fat and zinc deficiency inhibited Nrf2 expression. After Nrf2-specific knockout in A549 cells, the protective effect of zinc on oxidant conditions induced by high fat was reduced. Phosphorylated Akt and PI3K levels were downregulated on the high-fat and low-zinc group compared with the high-fat group. CONCLUSIONS: Zinc attenuated lung oxidative damage in obesity-related lung injury and Nrf2 activation is one of the important mechanisms of this effect. GENERAL SIGNIFICANCE: Regulating zinc homeostasis through dietary modifications or supplemental nutritional therapy can contribute to the prevention and treatment of obesity-related lung injury.

SS-31, a Mitochondria-Targeting Peptide, Ameliorates Kidney Disease.

Mitochondria are essential for eukaryotic cell activity and function, and their dysfunction is associated with the development and progression of renal diseases. In recent years, there has been a rapid development in mitochondria-targeting pharmacological strategies as mitochondrial biogenesis, morphology, and function, as well as dynamic changes in mitochondria, have been studied in disease states. Mitochondria-targeting drugs include nicotinamide mononucleotide, which supplements the NAD+ pool; mitochondria-targeted protective compounds, such as MitoQ; the antioxidant coenzyme, Q10; and cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. However, traditional drugs targeting mitochondria have limited clinical applications due to their inability to be effectively absorbed by mitochondria in vivo and their high toxicity. Recently, SS-31, a mitochondria-targeting antioxidant, has received significant research attention as it decreases mitochondrial reactive oxygen species production and prevents mitochondrial depolarization, mitochondrial permeability transition pore formation, and Ca2+-induced mitochondrial swelling, and has no effects on normal mitochondria. At present, few studies have evaluated the effects of SS-31 against renal diseases, and the mechanism underlying its action is unclear. In this review, we first discuss the pharmacokinetics of SS-31 and the possible mechanisms underlying its protective effects against renal diseases. Then, we analyze its renal disease-improving effects in various experimental models, including animal and cell models, and summarize the clinical evidence of its benefits in renal disease treatment. Finally, the potential mechanism underlying the action of SS-31 against renal diseases is explored to lay a foundation for future preclinical studies and for the evaluation of its clinical applications.

Administration of mesenchymal stem cells in diabetic kidney disease: mechanisms, signaling pathways, and preclinical evidence.

Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes. Currently, the prevalence and mortality of DKD are increasing annually. However, with no effective drugs to prevent its occurrence and development, the primary therapeutic option is to control blood sugar and blood pressure. Therefore, new and effective drugs/methods are imperative to prevent the development of DKD in patients with diabetes. Mesenchymal stem cells (MSCs) with multi-differentiation potential and paracrine function have received extensive attention as a new treatment option for DKD. However, their role and mechanism in the treatment of DKD remain unclear, and clinical applications are still being explored. Given this, we here provide an unbiased review of recent advances in MSCs for the treatment of DKD in the last decade from the perspectives of the pathogenesis of DKD, biological characteristics of MSCs, and different molecular and signaling pathways. Furthermore, we summarize information on combination therapy strategies using MSCs. Finally, we discuss the challenges and prospects for clinical application.

Immunomodulatory Activity of Mesenchymal Stem Cells in Lupus Nephritis: Advances and Applications.

Lupus nephritis (LN) is a significant cause of various acute and chronic renal diseases, which can eventually lead to end-stage renal disease. The pathogenic mechanisms of LN are characterized by abnormal activation of the immune responses, increased cytokine production, and dysregulation of inflammatory signaling pathways. LN treatment is an important issue in the prevention and treatment of systemic lupus erythematosus. Mesenchymal stem cells (MSCs) have the advantages of immunomodulation, anti-inflammation, and anti-proliferation. These unique properties make MSCs a strong candidate for cell therapy of autoimmune diseases. MSCs can suppress the proliferation of innate and adaptive immune cells, such as natural killer cells (NKs), dendritic cells (DCs), T cells, and B cells. Furthermore, MSCs suppress the functions of various immune cells, such as the cytotoxicity of T cells and NKs, maturation and antibody secretion of B cells, maturation and antigen presentation of DCs, and inhibition of cytokine secretion, such as interleukins (ILs), tumor necrosis factor (TNF), and interferons (IFNs) by a variety of immune cells. MSCs can exert immunomodulatory effects in LN through these immune functions to suppress autoimmunity, improve renal pathology, and restore kidney function in lupus mice and LN patients. Herein, we review the role of immune cells and cytokines in the pathogenesis of LN and the mechanisms involved, as well as the progress of research on the immunomodulatory role of MSCs in LN.

Tofacitinib combined with leflunomide for treatment of psoriatic arthritis with IgA nephropathy: a case report with literature review.

Psoriasis is a systemic inflammatory disease that is associated with increased risk of several diseases, such as psoriatic arthritis (PsA), inflammatory bowel disease, and cardiovascular diseases. About 20 to 30% patients with psoriasis subsequently develop PsA. IgA nephropathy is the most common primary glomerular disease world-wide. Psoriasis and IgA nephropathy appear to be associated, but the mechanism underlying this connection is unclear. Tofacitinib and leflunomide are common treatments for psoriatic arthritis. We administered tofacitinib combined with leflunomide to a 38-year-old female patient who presented with PsA and IgA nephropathy. After treatment, she experienced significant reductions in the psoriatic lesions, pain in the right knee joint, and proteinuria. Administration of tofacitinib combined with leflunomide for treatment of a patient who had PsA complicated with IgA nephropathy led to significant resolution of the symptoms of both conditions. These results suggest similarities in the pathogenesis of PsA and IgA nephropathy and a possible new treatment for IgA nephropathy.

Relationship between hyperuricemia and serositis in patients with lupus nephritis.

PURPOSE: To investigate the clinical and pathological characteristics of lupus nephritis (LN) patients with serositis and analyse the relationship between serositis and hyperuricemia (HUA) in LN patients in northeast China. METHODS: The data of patients with LN diagnosed by renal biopsy in our hospital from April 2013 to May 2020 were retrospectively analyzed. The differences between the non-serositis and serositis groups were compared by t tests and Chi-square test. Factors with P < 0.05 in the univariate analyses were investigated further using binary logistic regression analysis to investigate the independent risk factors of serositis in patients with LN. RESULTS: LN patients with serositis were more likely to have fever, hypertension, neuropsychiatric and hematological involvement than those without serositis (P < 0.05). Compared with the non-serositis group, LN patients with serositis were prone to have HUA, high D-dimer, high triglycerides, and had significant differences in the levels of plasma albumin (Alb), estimated glomerular filtration rate (eGFR), erythrocyte sedimentation rate, C-reactive protein, complement C3, 24-h urinary protein, pathological types, pathological score and SLEDAI score. Logistic regression analysis showed that HUA was one of risk factors for serositis in LN patients. The rate of complete remission in LN patients with serositis was significantly lower (P < 0.05) and the rate of no remission and mortality were significantly higher (P < 0.05) than LN patients without serositis. CONCLUSION: LN patients with serositis had more severe clinical and pathological manifestations, higher systemic lupus erythematosus (SLE) activity and worse prognosis. Hyperuricemia is associated with serositis in LN patients.

Elabela protects against podocyte injury in mice with streptozocin-induced diabetes by associating with the PI3K/Akt/mTOR pathway.

Diabetic nephropathy is a common complication of diabetes characterized by an increased rate of protein excretion in urine and kidney function loss. Elabela is a newly discovered peptide whose role in the regulation of diabetes is the major focus of this research. We established an in vivo model of Type 1 diabetes mellitus by injecting mice intraperitoneally with streptozotocin. The treatment group was administered Elabela for 6 months. In the present study, Elabela administration under diabetic conditions was found to reduce renal inflammation and fibrosis markers, leading to improvement in renal pathology and kidney dysfunction. Furthermore, Elabela acts through the phosphoinositide 3-kinase /Akt/mammalian target of rapamycin signaling pathway and decreases podocyte apoptosis, thereby exhibiting a nephroprotective effect against diabetic nephropathy. Our findings provide the first evidence that Elabela has a potential renoprotective effect in patients of diabetes.

Clinical and Pathological Analysis of 4910 Patients Who Received Renal Biopsies at a Single Center in Northeast China.

PURPOSE: To identify the epidemiology and pathological types of kidney diseases and their changes during the past decade, in a population from Northeast China. METHODS: We retrospectively analysed clinical and renal pathological data from 4910 patients who received renal biopsies in the Second Hospital of Jilin University from 2008 to 2017. RESULTS: Males received more renal biopsies than females (p < 0.001). The average age (p < 0.001) and percentage of elderly patients (p < 0.001) increased over time. The pathological types were primary glomerulonephritis (PGN, 73.2%), secondary glomerulonephritis (SGN, 23.7%), tubular-interstitial nephropathy (TIN, 2.8%), and hereditary nephropathy (HN, 0.3%). The most common forms of PGN were membranous nephropathy (MN, 37.2%) and IgA nephropathy (IgAN, 29.9%). Over time, the prevalence of IgAN decreased, but the prevalence of MN increased. MN was more common in middle-aged and elderly patients, but IgAN was most common in young adults. Analysis of SGN data indicated that lupus nephritis (LN, 34.0%), Henoch-Schönlein purpura glomerulonephritis (HSPN, 17.9%), and diabetic nephropathy (DN, 11.7%) were the most common forms. Over time, the prevalence of DN (p = 0.003), hypertension-associated renal damage (p = 0.005), and systemic vasculitis-associated nephritis (SVARD, p < 0.001) increased, but the prevalence of HSPN (p < 0.001) and hepatitis B virus-associated glomerulonephritis (HBV-GN, p = 0.001) decreased. Nephrotic syndrome was the main clinical manifestation of PGN. CONCLUSION: From 2008 to 2017, renal biopsies were increasingly performed in the elderly. There were notable changes in the epidemiology and pathological types of kidney disease among renal biopsy patients at our centre.

Development of a recombinant human IL-15·sIL-15Rα/Fc superagonist with improved half-life and its antitumor activity alone or in combination with PD-1 blockade in mouse model.

Recombinant human interleukin-15 (IL-15) is a potent cancer immunotherapeutic candidate due to its excellent immune stimulating effects. Previous work demonstrated that IL-15 appeared with short half-life in circulation system, while the complex with its receptor can prolong the half-life as well as benefit its activities in vivo. Therefore, IL-15 complex was more favorably considered for clinical development. Herein we developed IL-15·sIL-15Rα/Fc, a complex comprising of IL-15 and the extracellular region of its receptor alpha subunit which fused to Immunoglobulin G (IgG1) Fc to further prolong the half-life in plasma. Through transient gene expression in HEK293 cells, we expressed the superagonist by co-transfection of plasmids encoding IL-15 and sIL-15Rα/Fc respectively, yielding 36 mg/L of product after purification. Pharmacokinetic study demonstrated that the combination profoundly prolonged the half-life of IL-15 to 13.1 h in mice, about 18 folds longer than that of IL-15 monomer which is around 0.7 h. The bioactivity of the superagonist was characterized by CTLL-2 cells proliferation assay in vitro, showing its capability of stimulating the expansion of memory CD8+ T cells (cluster of differentiation) in mouse spleen. Using a HT-29 xenograft NOD-SCID mouse model, we observed tumor growth inhibition in all groups that received the superagonist, indicating its anti-tumor efficacy via stimulating infused human immune cells. In addition, combo cancer treatment by IL-15·sIL-15Rα/Fc and programmed death-1 (PD-1) antibody have shown stronger inhibitory effects as compared with treatment with either single molecule. Therefore, we developed IL-15·sIL-15Rα/Fc to be a long half-life potential cancer immunotherapy candidate that can be applied alone or in synergy with PD-1/PD-L1 blockade.

Elabela, a newly discovered APJ ligand: Similarities and differences with Apelin.

The Apelin/APJ system is involved in a wide range of biological functions. For a long time, Apelin was thought to be the only ligand for APJ. Recently, a new peptide that acts via APJ and has similar functions, called Elabela, was identified. Elabela has beneficial effects on body fluid homeostasis, cardiovascular health, and renal insufficiency, as well as potential benefits for metabolism and diabetes. In this review, the properties and biological functions of this new peptide are discussed in comparison with those of Apelin. Important areas for future study are also discussed, with the consideration that research on Apelin could guide future research on Elabela.

MicroRNA­320a suppresses tumour cell proliferation and invasion of renal cancer cells by targeting FoxM1.

An increasing body of evidence has indicated that microRNAs (miRNAs/miRs) may play an important role in tumourigenesis and tumour progression. Recent studies have demonstrated that miR­320a is aberrantly expressed in a variety of different types of human cancer. The results of the present study confirmed that the expression of miR­320a was decreased in clinical specimens and cell lines. Expression of miR­320a inhibited the growth and invasive ability of ACHN and Caki­1 cells. Bioinformatics analysis and a luciferase reporter assay demonstrated that forkhead box protein M1 (FoxM1) was directly regulated by miR­320a. Rescue experiments in vitro revealed that the upregulation of FoxM1 antagonized the miR­320a­mediated malignant phenotype in renal cancer. Furthermore, experiments employing a xenograft mouse model revealed that the upregulation of miR­320a inhibited the proliferation of renal cancer cells in nude mice when FoxM1 protein expression was reduced. Collectively, the present study demonstrated a novel molecular interaction regulated by miR­320a, which may provide a novel insight into the treatments for renal cancer.

Long Noncoding RNA Small Nucleolar RNA Host Gene 1 (SNHG1) Promotes Renal Cell Carcinoma Progression and Metastasis by Negatively Regulating miR-137.

BACKGROUND Data on the expression of RCC tissues from the GEO database and patient survival data from TCGA were used to explore the prognostic significance of long noncoding RNA SNHG1. SNHG1 has been reported to participate in the development of several cancers, but, the underlying mechanism of SNHG1 in renal cell carcinoma (RCC) has not been reported. The purpose of our study was to investigate the potential function of SNHG1 in RCC. MATERIAL AND METHODS The expression of SNHG1 in 40 cases of RCC and adjacent normal tissues and 5 cell lines was detected by qRT-PCR. Cell proliferation, Transwell assay, and Western blotting assay were carried out to investigate the biological function of SNHG1. A rescue experiment was performed to verify that miR-137 can partly impede the effect of SNHG1 on renal cancer cells. RESULTS SNHG1 was identified to be overexpressed in RCC tissues and RCC cell lines. High levels of SNHG1 were correlated with poor prognosis of RCC patients. Knockdown of SNHG1 suppressed the proliferation, invasion, and EMT capacity in RCC. Moreover, miR-137 abrogated the effect of SNHG1 on RCC. CONCLUSIONS SNHG1 is significantly upregulated in RCC and renal cancer cell lines. Overexpression of SNHG1 participates in RCC tumorigenesis by regulating miR-137.

From the Cover: Zinc Deficiency Worsens and Supplementation Prevents High-Fat Diet Induced Vascular Inflammation, Oxidative Stress, and Pathological Remodeling.

Obesity has become a common public health problem in the world and raises the risk of various cardiovascular diseases. Zinc is essential for multiple organs in terms of normal structure and function. The present study investigated the effects of high fat diet (HFD) induced obesity on the aorta in mice, and evaluated whether it can be affected by zinc deficiency or supplementation. Four-week-old male C57BL/6J mice were fed HFD with varied amounts of zinc (deficiency, adequate and supplementation) for 3 and 6 months. Results showed that HFD feeding induced a time-dependent aortic remodeling, demonstrated by increased vessel wall thickness, tunica cell proliferation and fibrotic responses, and inflammatory response, reflected by increased expression of inflammatory cytokines (tumor necrosis factor-α and vascular cell adhesion molecule 1). HFD feeding also caused aortic oxidative damage, reflected by 3-nitrotyrosine and 4-hydroxy-2-nonenal accumulation, and down-regulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and function, shown by down-regulation of its downstream antioxidants, catalase, NAD(P)H dehydrogenase (quinone 1), and metallothionein expression. The vascular effects of obesity-induced by HFD was exacerbated by zinc deficiency but significantly improved by zinc supplementation. In addition, down-regulation of Nrf2 function and associated antioxidants expression were also worsened by zinc deficiency but improved by zinc supplementation. These results suggest that HFD induces aortic remodeling, which can be exacerbated by zinc deficiency and improved by zinc supplementation.

Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells.

Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL), a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG) and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G1/S-CDK suppresser CDKN1B (p21) and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G1 and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway.

Metallothionein plays a prominent role in the prevention of diabetic nephropathy by sulforaphane via up-regulation of Nrf2.

Sulforaphane (SFN) prevents diabetic nephropathy (DN) in type 1 diabetes via up-regulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, it has not been addressed whether SFN also prevents DN from type 2 diabetes or which Nrf2 downstream gene(s) play(s) the key role in SFN renal protection. Here we investigated whether Nrf2 is required for SFN protection against type 2 diabetes-induced DN and whether metallothionein (MT) is an Nrf2 downstream antioxidant using Nrf2 knockout (Nrf2-null) mice. In addition, MT knockout mice were used to further verify if MT is indispensable for SFN protection against DN. Diabetes-increased albuminuria, renal fibrosis, and inflammation were significantly prevented by SFN, and Nrf2 and MT expression was increased. However, SFN renal protection was completely lost in Nrf2-null diabetic mice, confirming the pivotal role of Nrf2 in SFN protection from type 2 diabetes-induced DN. Moreover, SFN failed to up-regulate MT in the absence of Nrf2, suggesting that MT is an Nrf2 downstream antioxidant. MT deletion resulted in a partial, but significant attenuation of SFN renal protection from type 2 diabetes, demonstrating a partial requirement for MT for SFN renal protection. Therefore, the present study demonstrates for the first time that as an Nrf2 downstream antioxidant, MT plays an important, though partial, role in mediating SFN renal protection from type 2 diabetes.