The functions of clusterin in renal mesenchymal stromal cells: Promotion of cell growth and regulation of macrophage activation.

Clusterin (CLU) increases resistance to renal ischemia-reperfusion injury and promotes renal tissue repair. However, the mechanisms underlying of the renal protection of CLU remain unknown. Mesenchymal stromal cells (MSCs) may contribute to kidney cell turnover and injury repair. This study investigated the in vitro functions of CLU in kidney mesenchymal stromal cells (KMSCs). KMSCs were grown in plastic culture plates. Cell surface markers, apoptosis and phagocytosis were determined by flow cytometry, and CLU protein by Western blot. There were no differences in the expression of MSC markers (positive: CD133, Sca-1, CD44, CD117 and NG2, and negative: CD34, CD45, CD163, CD41, CD276, CD138, CD79a, CD146 and CD140b) and in the trilineage differentiation to chondrocytes, adipocytes and osteocytes between wild type (WT) and CLU knockout (KO) KMSCs. CLU was expressed intracellularly and secreted by WT KMSCs, and it was up-regulated by hypoxia. CLU did not prevent hypoxia-induced cell apoptosis but promoted cell growth in KMSC cultures. Furthermore, incubation with CLU-containing culture medium from WT KMSCs increased CD206 expression and phagocytic capacity of macrophages. In conclusion, our data for the first time demonstrate the function of CLU in the promotion of KMSCs proliferation, and it may be required for KMSCs-regulated macrophage M2 polarization and phagocytic activity.

Lysine-specific demethylase 1 aggravated oxidative stress and ferroptosis induced by renal ischemia and reperfusion injury through activation of TLR4/NOX4 pathway in mice.

Acute kidney injury (AKI) is mainly caused by renal ischaemia reperfusion injury (IRI). Lots of evidence suggests that ferroptosis and oxidative stress play the vital role in renal IRI. However, the specific mechanism of renal IRI has not been fully elucidated. lysine-specific demethylase 1 (LSD1) has been shown to regulate the pathogenesis of kidney disease. In this study, we firstly found that LSD1 was positively related to renal IRI. TCP, a classical LSD1 inhibitor, could alleviate tissue damage induced by renal IRI. Inhibition of LSD1 with either TCP or LSD1 knockdown could alleviate ferroptosis and oxidative stress caused by IRI both in vivo and in vitro. Furthermore, the results showed that suppression of LSD1 decreased the expression of TLR4/NOX4 pathway in HK-2 cells subjected to H/R. With the si-RNA against TLR4 or NOX4, it showed that the silence of TLR4/NOX4 reduced oxidative stress and ferroptosis in vitro. Moreover, to demonstrate the crucial role of TLR4/NOX4, TLR4 reduction, mediated by inhibition of LSD1, was compensated through delivering the adenovirus carrying TLR4 in vitro. The results showed that the compensation of TLR4 blunted the alleviation of oxidative stress and ferroptosis, induced by LSD1 inhibition. Further study showed that LSD1 activates TLR4/NOX4 pathway by reducing the enrichment of H3K9me2 in the TLR4 promoter region. In conclusion, our results demonstrated that LSD1 inhibition blocked ferroptosis and oxidative stress caused by renal IRI through the TLR4/NOX4 pathway, indicating that LSD1 could be a potential therapeutic target for renal IRI.

Clusterin regulates macrophage expansion, polarization and phagocytic activity in response to inflammation in the kidneys.

Clusterin (CLU) is a multifunctional protein localized extracellularly and intracellularly. Although CLU-knockout (KO) mice are more susceptible to renal ischemia-reperfusion injury (IRI), the mechanisms underlying the actions of CLU in IRI are not fully understood. Macrophages are key regulators of IRI severity and tissue repair. Therefore, we investigated the role of CLU in macrophage polarization and phagocytosis. Renal IRI was induced in wild-type (WT) or CLU-KO C57BL/6 mice by clamping the renal pedicles for 30 min at 32°C. Peritoneal macrophages were activated via an intraperitoneal injection of lipopolysaccharide (LPS). Renal tissue damage was examined using histology, whereas leukocyte phenotypes were assessed using flow cytometry and immunohistochemistry. We found that monocytes/macrophages expressed the CLU protein that was upregulated by hypoxia. The percentages of macrophages (F4/80+ , CD11b+ or MAC3+ ) infiltrating the kidneys of WT mice were significantly less than those in CLU-KO mice after IRI. The M1/M2 phenotype ratio of the macrophages in WT kidneys decreased at day 7 post-IRI when the injury was repaired, whereas that in KO kidneys increased consistently as tissue injury persisted. In response to LPS stimulation, WT mice produced fewer M1 macrophages, but not M2, than the control did. Phagocytosis was stimulated by CLU expression in macrophages compared with the CLU null controls and by the exogenous CLU protein. In conclusion, CLU suppresses macrophage infiltration and proinflammatory M1 polarization during the recovery period following IRI, and enhances phagocytic activity, which may be partly responsible for tissue repair in the kidneys of WT mice after injury.

Modified completely intrafascial radical cysprostatectomy for bladder cancer: a single-center, blinded, controlled study.

BACKGROUND: We have proposed a modified, completely intrafascial radical cysprostatectomy (RC) to treat bladder cancer patients with the aim of preserving the patients' post-surgical urinary control and erectile function. This study aimed to evaluate the oncological and functional outcomes of this innovation relatively to that with the conventional technique. METHODS: A retrospective, single-center, blinded, and controlled study was conducted using the medical data of patients since the past 5 years from the hospital database. A total of 44 patients were included, including 20 who received complete intrafascial cysprostatectomy and 24 who received conventional interfascial surgeries. The patients' continent and sexual information of 1-year follow-up after the surgery were extracted. The oncological and functional outcomes of the 2 groups were compared and analyzed. RESULTS: The demographics parameters of the 2 groups showed no significant difference. The results of follow-up of the oncological outcomes did not reveal any significant difference between the completely intrafascial group and the conventional interfascial group in terms of the positive surgical margins, local recurrences, and distant metastasis. Patients following neobladder diversion in the intrafascial group showed a faster recovery of the urinary control, with a 76.9% (10/13) daytime continent rate at 3-month, as well as 46.2% (6/13) and 58.3% (7/12) nighttime continent rates at 3-month and 6-month, respectively. Regarding the sexual functions, our results revealed significant advantages in favor of completely intrafascial technique on the post-surgical International Index of Erectile Function (IIEF)-5 score at 3-, 9-, and 12-month follow-up relative to that with the conventional interfascial process. Thus, the IIEF score of patients in the intrafascial group was 11.4 ± 3.5 at 3-month, 14.1 ± 3.6 at 9-month, and 15.2 ± 3.8 at 12-month follow-up after the cystectomy, which was significantly greater than that of the patients in the control group. CONCLUSIONS: Our novel data illustrated that the modified completely intrafascial technique could result in a better sexual function and faster continence recovery for patients following RC, without any compromise in the cancer control. Thus, this technique could be considered as an alternative extirpative technique for bladder cancer treatment in a clinical setting.

Enhancer of zeste homolog 2 modulates oxidative stress-mediated pyroptosis in vitro and in a mouse kidney ischemia-reperfusion injury model.

Enhancer of zeste homolog 2 (EZH2), a well-known methyltransferase, mediates histone H3 lysine 27 trimethylation (H3K27me3) and plays a crucial role in several kidney disease models. However, its role in renal ischemia/reperfusion (I/R) injury still remains unclear. In this study, we found that EZH2 was positively related to renal I/R injury and inhibition of EZH2 with DZNeP alleviated I/R injury and blocked the activation of oxidative stress and pyroptosis in vivo. Similarly, inhibition of EZH2 with either DZNeP or si-RNA also exerted an inhibitory effect on hypoxia/reoxygenation (H/R)-induced oxidative stress and pyroptosis in vitro. Moreover, further study revealed that ablation of reactive oxygen species (ROS) with N-acetyl-cysteine (NAC) suppressed pyroptosis in human renal proximal tubular epithelial cell line cells exposed to H/R stimulation. Furthermore, Nox4, which was positively related to the generation of ROS, was upregulated during H/R process, while it could be reversed by EZH2 inhibition. Consistently, Nox4-mediated ROS generation was attenuated upon inhibition of EZH2 with DZNeP or si-RNA. Additionally, the transcriptional activity of Nox4 was enhanced by the activation of ALK5/Smad2/3 signaling pathway, which was abolished by ALK5 knockdown in vitro. Finally, EZH2 inhibition blocked H/R and I/R-activated ALK5/Smad2/3 pathway and also resulted in an obvious decrease in the transcriptional activity and protein expression levels of Nox4. In conclusion, our results proved that EZH2 inhibition alleviated renal pyroptosis by blocking Nox4-dependent ROS generation through ALK5/Smad2/3 signaling pathway, indicating that EZH2 could be a potential therapeutic target for renal I/R injury.

Oncological safety of intrafascial nerve-sparing radical prostatectomy compared with conventional process: a pooled review and meta-regression analysis based on available studies.

BACKGROUND: Intrafascial prostatectomy was a modified technique from the conventional nerve-sparing surgery in order to improve patients' post-surgical continence and erectile function; however, ongoing controversy exists regarding the oncological safety of this technique. In this study we aimed to provide a critical and pooled analysis based on published literatures regarding the oncological outcomes after intrafascial nerve-sparing prostatectomy. METHODS: Database searches were performed for published articles till June 2018 on PubMed. Three reviewers screened fulfilled papers and extracted data independently. Main outcome was the positive surgical margins (PSMs) rates stratified by pathological stages. We performed both one-arm and comparative meta-analysis to evaluate the oncological safety of intrafascial technique. Moreover, we built meta-regression models to assess the confounding factors. RESULTS: We retrieved a total of 117 records after electronic search, of which 21 studies were finally included in this review. There were 15 controlled studies and 6 surgical series. Our one-arm meta-analysis demonstrated that the total PSM rates after intrafascial techniques ranging from 2.2 to 35%, with a pooled rate of 14.5% on average (480 of 3151 patients, 95% confidence interval[CI]: 11.2-17.5%). Meta-regression model showed that patients' age, pT2 cancer percentage and Selection Score of Oncological Safety (SSOS) were significantly associated with total PSM rate; moreover, each 1 point of SSOS could decrease the total PSM rate by 1.3% on average. Comparative meta-analysis demonstrated that there was no significant difference between intra- and inter-fascial group regarding PSM rates. CONCLUSIONS: With stringent case selection and when performed by experienced surgeons, intrafascial prostatectomy could offer an acceptable or, at least, equivalent PSM rate compared with the conventional interfascial approach. Preoperative SSOS more than 7 points could be considered as an indication of intrafascial radical prostatectomy.

Metformin alleviated EMT and fibrosis after renal ischemia-reperfusion injury in rats.

PURPOSE: The purpose of this study is to assess the potential effects of metformin on the development of EMT and tubulointerstitial fibrosis 12 weeks after acute renal ischemia-reperfusion. METHODS: Male Sprague-Dawley rats were randomly assigned to four groups: Sham, IRI, transient administration of metformin (TAM), and continuous administration of metformin (CAM). Metformin was administered i.p. at a dose of 125 µg kg (- 1) d( - 1) 3 d prior to suffering from IRI (TAM), or from 3 d before suffering from IRI to 12 weeks after reperfusion (CAM). Renal function, histology, and expressions of IL-6, TNF-α, α-SMA, TGF-ß1, Vimentin, and E-cadherin were analyzed. RESULTS: Tubulointerstitial fibrosis worsened further in IRI, accompanied by the increased expressions of interleukin-6, TNF-α, α-SMA, TGF-ß1, Vimentin, and loss of E-cadherin. Although there were no significant differences between IRI and TAM (p > 0.05). Compared with the IRI, expressions of IL-6, TNF-α, α-SMA, TGF-ß1, and Vimentin were reduced and the expression of E-cadherin was restored in CAM (p < 0.05). CAM also significantly promoted activation of AMPK (p < 0.05), which showed no difference among Sham, IRI, and TAM (p > 0.05). CONCLUSIONS: CAM significantly attenuated tubulointerstitial fibrosis and EMT in rats, potentially via activation of AMPK and down-regulation of TGF-ß1.

Ozone therapy ameliorates tubulointerstitial inflammation by regulating TLR4 in adenine-induced CKD rats.

Tubulointerstitium inflammation is a common pathway aggravating chronic kidney disease (CKD) progression and the mechanism is partly associated with excessive activation of toll-like receptor 4 (TLR4) in tubulointerstitium. Ozone therapy is demonstrated to alleviate inflammation in some experiments. The aim of this study is to examine whether ozone therapy could ameliorate chronic tubulointerstitium inflammation by suppressing TLR4 in adenine-induced CKD rats. Sprague-Dawley rats were fed with 0.75% adenine-containing diet to induce CKD and tubulointerstitium inflammation injury. Ozone therapy (1.1 mg/kg) was simultaneously administrated by rectal insufflations (i.r.). After 4 weeks, serum and kidney samples were collected for detection. Renal function and systemic electrolyte were detected. Renal pathological changes were assessed by hematoxylin-eosin (H&E) staining and Masson trichrome (MT) staining. Immunohistochemistry, Western blot and Real-time PCR were applied to evaluate tubulointerstitium inflammation as well as the expression of TLR4 and phosphorylated nuclear factor kappa B P65 (p-NF-κB P65) in rats. The results showed ozone therapy improved serious renal insufficiency, systemic electrolyte disorder and tubulointerstitium morphology damages in adenine-induced CKD rats. In addition, ozone therapy suppressed excessive activation of TLR4 and p-NF-κB P65 in the tubulointerstitium of adenine-induced CKD rats, accompanied by the reduction of inflammation-related cytokines including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6). The protein expression of TLR4 was positively correlated with the protein expression levels of MCP-1 (r = 0.7863, p < 0.01) and TNF-α (r = 0.7547, p < 0.01) in CKD rats. These findings indicated ozone therapy could attenuate tubulointerstitium inflammation injury in adenine-induced CKD rats and the mechanism might associate with the mediation of TLR4.

Inhibition of LSD1 by Pargyline inhibited process of EMT and delayed progression of prostate cancer in vivo.

Recently, lysine-specific demethylase 1 (LSD1) was identified as the first histone demethylase. LSD1 interacted with androgen receptor (AR) and promoted androgen-dependent transcription of target genes, such as PSA, by ligand-induced demethylation of mono- and dimethylated histone H3 at Lys 9 (H3K9). Meanwhile, the phenomenon of epithelial-mesenchymal transition (EMT) had received considerable attention in tumor recurrence and metastasis. This study examined the effect of Pargyline (an inhibitor of LSD1) on the process of EMT in vitro and in vivo. SCID mice were injected subcutaneously with LNCap cells. Pargyline was given intraperitoneally or not after castration (implemented with Bilateral orchidectomy), then PSA levels in serum and tumor were determined to assess time to androgen-independent progression. The results showed that LSD1 expression was up-regulated when PCa progressed to Castration Resistant Prostate Cancer (CRPC). Pargyline reduced LNCap cells migration and invasion ability, and inhibited the process of EMT by up-regulating expression of E-cadherin, and down-regulating expressions of N-cadherin and Vimentin in vitro and in vivo. Although, Pargyline did not change the level of AR, it reduced PSA expression both in vitro and in vivo. Furthermore, Pargyline delayed prostate cancer transition from androgen-dependent to androgen-independent state (CRPC). These findings indicated that inhibition of LSD1 might be a promise adjunctive therapy with androgen deprivation therapy (ADT) for locally advanced or metastatic prostate cancer.

The protective effect of nesfatin-1 against renal ischemia-reperfusion injury in rats.

INTRODUCTION: The pathogenetic mechanisms underlying ischemia-reperfusion (I/R) injury involve oxidative stress, inflammation and apoptosis. Nesfatin-1, a novel peptide, has been reported to possess antioxidant, anti-inflammatory and anti-apoptic properties. The study was to examine the potential protective effects of nesfatin-1 on renal I/R injury. MATERIALS AND METHODS: I/R model was induced by placing a clamp across left renal artery for 45 min followed by 24 h reperfusion, along with a contralateral nephrectom. Twenty-four rats divided into three groups: sham-operated group, vehicle-treated I/R and nesfatin-1-treated I/R. Nesfatin-1 was intraperitoneally injected 30 min before renal ischemia. We harvested serum and kidneys at 24 h after reperfusion. Renal function and histological changes were assessed. Marker of oxidative stress and cells in kidney were also evaluated. RESULTS: The animals with nesfatin-1 significantly improved renal functional and histologic lesions induced by I/R injury. The malondialdehyde (MDA) level decreased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were significantly increased. Moreover, nesfatin-1-treated rats had a markedly decrease in apoptotic tubular cells, as well as a decrease in caspase-3 activity and an increase in the bcl-2/Bax ratio. CONCLUSIONS: This is the first evidence that nesfatin-1 treatment ameliorates acute renal I/R injury by suppressing oxidative stress and cell apoptosis. Therefore, it is promising as a potential therapeutic agent for renal IR injury.

Aged kidneys are refractory to ischemic postconditioning in a rat model.

BACKGROUND: Ischemic postconditioning (IPoC) is defined as a series of intermittent interruptions of blood flow in the early phase of reperfusion that mechanically alters the hydrodynamics of reperfusion and it attenuates renal damage after ischemia/reperfusion (I/R) injury in vivo. But all of these data had been obtained in adult populations and whether this protection was maintained in aging kidneys was unknown. The objective of this study was to establish whether the efficacy of IPoC is maintained in aging kidneys. MATERIALS AND METHODS: The aged (24-month-old) and young (3-month-old) Wistar rats were used. Rats were subjected to 45 min of renal ischemia, both with and without treatment with IPoC. Serum urea nitrogen and creatinine levels, histological examination and apoptosis were assessed at 24 h. Oxidative stress was evaluated and apoptosis-related molecules were studied by Western blotting. RESULTS: In young rat kidneys, IPoC significantly attenuated the renal dysfunction and cell apoptosis induced by I/R. In contrast, IPoC failed to limit renal dysfunction, possibly a consequence of increased apoptosis in aged rat kidneys. CONCLUSIONS: Our data indicated that IPoC was ineffective in aged rat kidneys. These findings may have major implications in that severe apoptosis in aged kidneys might be refractory to anti-apoptotic effect by IPoC.

Picroside II decreases the development of fibrosis induced by ischemia/reperfusion injury in rats.

In kidney transplantation, renal ischemia and reperfusion injury was one of the leading factors to the development of renal fibrosis, which was the main cause of graft loss. The fibrogenic changes were associated with the long term inflammation elicited by ischemia and reperfusion injury. In the present study, we investigated the role of the Picroside II, the main active constituents of the extract of picrorrhiza scrophulariiflora roots, in attenuating renal fibrosis in a renal ischemia and reperfusion injury model. We induced ischemia and reperfusion injury in kidneys treated with or without Picroside II. We observed that inflammation and tissue fibrosis were increased in ischemia and reperfusion injury group compared to Picroside II group, however, these changes were significantly decreased by the treatment with Picroside II. We concluded that Picroside II can protect the ischemic kidney against renal fibrosis and its mechanism may be through the inhibition of the long term inflammation.

The protective effect of ozone oxidative preconditioning against hypoxia/reoxygenation injury in rat kidney cells.

Abstract Ozone (O3) has been viewed as a novel treatment for different diseases in these years and oxidative stress and apoptosis play a key role in the pathogenesis of kidney diseases including renal ischemia and reperfusion (I/R). In the present study, we investigated the role of ozone oxidative preconditioning (OzoneOP) in attenuating oxidative stress and apoptosis in a hypoxia/reoxygenation (H/R) injury model using rat kidney cells. We induced H/R injury in kidney cells treated with or without OzoneOP. Oxidative stress parameters such as superoxide dismutase (SOD), malondialdehyde (MDA) and lactate dehydrogenase (LDH) were determined, as well as some apoptotic proteins. We observed that oxidative stress and apoptosis were increased in H/R group compared to OzoneOP group; however, these changes were significantly decreased by the treatment with OzoneOP. We concluded that OzoneOP can protect the kidney cells against H/R injury and its mechanism may be through the reduction of oxidative stress and apoptosis.

Species Composition of a Small Mammal Community and Prevalence of Echinococcus spp. in the Alpine Pastoral Area of the Eastern Tibetan Plateau.

We aimed to investigate the species composition of a small mammal community and the prevalence of Echinococcus spp. in a typical endemic area of the Tibetan Plateau. One pika and five rodent species were identified based on the morphological characteristics of 1278 small mammal specimens collected during 2014-2019. Detection of Echinococcus DNA in tissue samples from small mammal specimens revealed that Ochotona curzoniae (pika, total prevalence: 6.02%, 26/432), Neodon fuscus (5.91%, 38/643), N. leucurus (2.50%, 3/120), and Alexandromys limnophilus (21.74%, 10/46) were infected by both E. multilocularis and E. shiquicus; Cricetulus longicaudatus (16.67%, 1/6) was infected by E. shiquicus; and no infection was detected in N. irene (0/15). Neodon fuscus and O. curzoniae were the two most abundant small mammal species. There was no significant difference in the prevalence of pika and the overall rodent species assemblage (6.26%, 53/846); however, the larger rodent populations suggested that more attention should be paid to their role in the transmission of echinococcosis in the wildlife reservoir, which has long been underestimated. Moreover, although DNA barcoding provides a more efficient method than traditional morphological methods for identifying large numbers of small mammal samples, commonly used barcodes failed to distinguish the three Neodon species in this study. The close genetic relationships between these species suggest the need to develop more powerful molecular taxonomic tools.

GOLM1 Promotes Epithelial-Mesenchymal Transition by Activating TGFß1/Smad2 Signaling in Prostate Cancer.

Background: Prostate cancer (PC) is one of the most commonly diagnosed cancer in men worldwide. Epithelial-mesenchymal transition (EMT) is considered to play a crucial role in the development of the metastatic castration-resistant prostate cancer, which causes the majority of the death cases in PC. Golgi membrane protein 1 (GOLM1) is highly expressed in PC and has been identified as a driver factor for EMT in various cancers. However, its biological functions and underlying mechanisms remain ambiguous in PC. Method: GOLM1 expression level of PC was detected by Western blot and immunohistochemistry analyses. To investigate GOLM1 functions in cancer cells, we overexpressed and knocked down GOLM1 in different prostate cancer cell lines. Transwell assay and wound healing assay were used to determine the role of GOLM1 in cell EMT, such as migration and invasion abilities. TGF-ß1/Smad2 signaling pathway downstream of GOLM1 was detected by Western blot and Transwell assay. Result: GOLM1 expression is up-regulated in PC and correlated with a worse prognosis. GOLM1 promotes the abilities of migration and invasion in PC cell lines (DU145 and LNCaP). Furthermore, TGF-ß1/Smad2 signaling is positively regulated by GOLM1 to facilitate EMT in PC, whereas this role can be restored by TGF-ß1 after GOLM1 knockdown or be abrogated by p-Smad inhibitor SB431542. Conclusion: GOLM1 is significantly upregulated in PC and acts as a critical oncogene by promoting PC cell EMT process by activating TGF-ß1/Smad2 signaling pathway. Therefore, GOLM1 has the potential to be a biomarker for PC diagnosis and to predict the prognosis of PC patients. It is of great significance to seek effective and specific inhibitor of GOLM1 for PC treatment as well.

A Reliability System Evaluation Model of NoC Communication with Crosstalk Analysis from Backend to Frontend.

Network on chip (NoC) is the main solution to the communication bandwidth of a multi-processor system on chip (MPSoC). NoC also brings more route requirements and is highly prone to errors caused by crosstalk. Crosstalk has become a major design problem in deep-submicron NoC communication design. Hence, a crosstalk error model and corresponding reliable system with error correction code (ECC) are required to make NoC communication reliable. In this paper, a reliability system evaluation model (RSE) of NoC communication with analysis from backend to frontend has been proposed. In the backend, a crosstalk error rate model (CER) is established with a three-wire RLC coupling model and timing constraints. The CER is used to establish functional relations between interconnect spacing, length and signal frequency, and test system reliability. In the frontend, a reliability system performance model (RSP) is established with a CER, reliability method cost and bandwidth. The RSE summarizes the frontend and backend model. In order to verify the RSE model, we propose a reliability system with a hybrid automatic repeat request technique (RSHARQ). Simulation demonstrates that the CER model is close to real circuit design. Through the CER and RSP model, the performance of RSHARQ could be simulated.

DOT1L promotes cell proliferation and invasion by epigenetically regulating STAT5B in renal cell carcinoma.

DOT1L, the only histone H3 lysine 79 methyltransferase, has a prominent effect on promoting the progression of various malignancies, yet the functional contribution of DOT1L to renal cell carcinoma (RCC) progression remains unclear. DOT1L is overexpressed in RCC and linked to poor clinical outcomes. Chemical (SGC0946) or genetic suppression of DOT1L attenuates the growth and invasion of renal cancer cells and results in S-phase arrest. STAT5B expression was suppressed after DOT1L knockdown, and STAT5B overexpression rescued the DOT1L silencing-induced decrease in cell proliferation. DOT1L was found to epigenetically promote the transcription of STAT5B via H3K79me2, and CDK6 acted as a downstream effector of STAT5B to mediate cell cycle arrest. Our study confirmed that DOT1L promotes STAT5B expression in a histone methyltransferase-dependent manner. Downregulation of DOT1L inhibited RCC proliferation and invasion. Thus, targeting DOT1L might be a potential therapeutic intervention for RCC.

Overcoming the compensatory increase in NRF2 induced by NPL4 inhibition enhances disulfiram/copper-induced oxidative stress and ferroptosis in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer, and it appears to be highly susceptible to ferroptosis. Disulfiram, an alcoholism drug, has been shown to have anticancer properties in various studies, including those on RCC. However, the mechanism of the anticancer effect of disulfiram/copper on RCC remains unclear. In this study, we investigated the impact of disulfiram/copper on RCC treatment using both RCC cells and mouse subcutaneous tumor models. Our findings demonstrate that disulfiram/copper treatment reduced the viability of RCC cells, inhibited their invasion and migration, and disrupted mitochondrial homeostasis, ultimately leading to oxidative stress and ferroptosis. Mechanistically, disulfiram/copper treatment prolonged the half-life of NRF2 and reduced its degradation, but had no effect on transcription, indicating that the disulfiram/copper-induced increase in NRF2 was not related to transcription. Furthermore, we observed that disulfiram/copper treatment reduced the expression of NPL4, a ubiquitin protein-proteasome system involved in NRF2 degradation, while overexpression of NPL4 reversed NRF2 levels and enhanced disulfiram/copper-induced oxidative stress and ferroptosis. These results suggest that overcoming the compensatory increase in NRF2 induced by NPL4 inhibition enhances disulfiram/copper-induced oxidative stress and ferroptosis in RCC. In addition, our in vivo experiments revealed that disulfiram/copper synergized with sorafenib to inhibit the growth of RCC cells and induce ferroptosis. In conclusion, our study sheds light on a possible mechanism for disulfiram/copper treatment in RCC and provides a potential synergistic strategy to overcome sorafenib resistance.

[Retracted] Effects of cisplatin on the LSD1-mediated invasion and metastasis of prostate cancer cells.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the cell invasion assay data shown for the 'LSD1siRNA+DDP' experiment in Fig. 3A on p. 2515 were strikingly similar to data appearing in different form in Fig. 3 in another article written by different authors at different research institutes [Liu Y, Li M, Zhang G and Pang Z: MicroRNA-10b overexpression promotes non-small cell lung cancer cell proliferation and invasion. Eur J Med Res 18: 41, 2013]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 14: 2511-2517, 2016; DOI: 10.3892/mmr.2016.5571].

Over-expressing transporters associated with antigen processing increases antitumor immunity response in prostate cancer.

As we know, prostate cancer down-regulates expression of HLA-1 Antigen Processing Machinery (APM) and has defects in the antigen presentation pathway. In vitro, the prostate cancer cell (PC-3 cells) infected with Lentivirus TAP1 can efficiently over-express TAP1 and Tapasin, and HLA-1 was also up-regulated on the surface of the infected cells. The lentivirus TAP1 infection increased the apoptosis rate of PC-3 cells. In addition, with the co-cluture PC-3 cells and lymphocytes, TAP1 augmented the expression of CD3⁺CD8⁺CD38⁺ T cell. Importantly, administration of Lentivirus TAP1 to prostate cancer cells in a xenograft mouse model can prolong survival and increase the CD4⁺ T cells, and CD8⁺ T cells as well as decrease Foxp3⁺ T cells in the tumor microenvironment. In summary, a recombinant lentivirus expressing TAP1 can effectively increase prostate cancer tumor-specific immune response.