The histone demethylase lysine‐specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of ...H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear. Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48‐linked deubiquitin and stability. Interestingly, we found c‐Myc was a key downstream effector of the USP1‐KDM4A/androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.
This study identifies USP1 as a critical deubiquitinase for stabilizing KDM4A, thereby promoting prostate cancer growth and tumorigenesis. Targeting KDM4A stabilization through pharmacological inhibition of USP1 by ML323 could thus open an avenue for therapeutic intervention in prostate cancer patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Peritoneal fibrosis remains to be one of the most severe causes of failure in continuous peritoneal dialysis. The current study cultured peritoneal mesothelial cells in high glucose to stimulate the ...environment of peritoneal fibrosis model in rats, and investigate whether microRNA‐21 (miR‐21) targeting Sprouty‐1 affects high glucose–induced fibrosis in peritoneal mesothelial cells via the rennin angiotensin system (Ras)–mitogen‐activated protein kinase (MAPK) signaling pathway, as well as potential mechanisms. Peritoneal tissues in fibrosis rats were collected to extract peritoneal mesothelial cells, which, after in vitro culture, were transfected with a series of mimic or inhibitor of miR‐21, or the small interfering RNA (siRNA) against Sprouty‐1. Reverse‐transcription quantitative polymerase chain reaction and western blot analyses were performed to determine the levels of related genes or proteins. MTT assay and flow cytometry were conducted to observe the cell viability and cell apoptosis of peritoneal mesothelial cells. Dual‐luciferase reporter gene assay revealed that Sprouty‐1 is the target gene of miR‐21. Peritoneal fibrosis manifested with elevated miR‐21, extracellular‐signal‐regulated kinase (ERK), c‐Jun NH2‐terminal protein kinase (JNK), RAS and p38MAPK but reduced Sprouty‐1. Cells transfected with miR‐21 mimic exhibited decreased Sprouty‐1 expressions, but increased levels of ERK, JNK, RAS, and p38MAPK. As for cellular process, miR‐21 mimic or siRNA against Sprouty‐1 exposure reduced cell viability, which resulted in more cells arrested at the G1 stage, and induced apoptosis. In contrast, miR‐21 inhibitor exposure was observed to have induced effects on peritoneal mesothelial cells. These key findings provide evidence that miR‐21 inhibits Sprouty‐1 to promote the progression of fibrosis in peritoneal mesothelial cells by activating the Ras–MAPK signaling pathway.
MicroRNA‐21 inhibits Sprouty‐1 to promote the progression of fibrosis in peritoneal mesothelial cells by activating the rennin angiotensin system–mitogen‐activated protein kinase signaling pathway.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer ...in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that
NF2
loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.
Graphene-based hybrids, specifically free-standing graphene-based hybrid papers, have recently attracted increasing attention in many communities for their great potential applications. As the most ...commonly used precursors for the preparation of graphene-based hybrids, electrically-insulating graphene oxides (GO) generally must be further chemically reduced or thermally annealed back to reduced GO (RGO) if high electrical conductivity is needed. However, various concerns are generated if the hybrid structures are sensitive to the treatments used to produce RGO. In this work, we develop a highly facile strategy to fabricate free-standing magnetic and conductive graphene-based hybrid papers. Electrically conductive graphene nanosheets (GNs) are used directly to grow Fe sub(3)O sub(4) magnetic nanoparticles without additional chemical reduction or thermal annealing, thus completely avoiding the concerns in the utilisation of GO. The free-standing Fe sub(3)O sub(4)/GN papers are magnetic, electrically conductive and present sufficient magnetic shielding (>20 dB), making them promising for applications in the conductive magnetically-controlled switches. The shielding results suggest that the Fe sub(3)O sub(4)/GN papers of very small thickness (<0.3 mm) and light weight ( similar to 0.78 g cm super(-3)) exhibit comparable shielding effectiveness to polymeric graphene-based composites of much larger thickness. Fundamental mechanisms for shielding performance and associated opportunities are discussed.
The green formation of the amide bond was identified as one of the key green chemistry research areas for the pharmaceutical industry. Here, we report a catalyst- and solvent-free protocol for the ...aminolysis of the asymmetric derivatives of Evans’ N -acyloxazolidinones to deliver enantioenriched secondary amides. This constitutes an extension of the Evans asymmetric methodology for the enantioselective synthesis of chiral common amides. The reaction features simplicity (without using any catalyst, solvent, or additive), mildness (running at room temperature), versatility (viable for different types of N -acyloxazolidinone-based asymmetric products and for α-branched primary amines), and high efficiency and selectivity (high yield and high ee). The additional value of the method was demonstrated by the one-pot conversion of the amides into other classes of compounds.
Understanding spatial distribution difference and reaction kinetics of the electrode is vital for enhancing the electrochemical reaction efficiency. Here, we report a total internal reflection ...imaging sensor without background current interference to map local current distribution of the electrode in a vanadium redox flow battery during cyclic voltammetry (CV), enabling mapping of the activity and reversibility distribution with the spatial resolution of a single fiber. Three graphite felts with different activity are compared to verify its feasibility. In long-term cyclic voltammetry, the oxygen evolution reaction is proved to enhance activity distribution, and homogeneity of the electrode and its bubble kinetics with periodic fluctuation is consistent with the cyclic voltammetry curve, enabling the onset oxygen evolution/reduction potential determination. Higher activity and irreversibility distribution of the electrode is found in favor of the oxygen evolution reaction. This sensor has potential to detect in situ, among other processes, electrochemical reactions in flow batteries, water splitting, electrocatalysis and electrochemical corrosion.
Traditional digital holographic imaging algorithms need multiple iterations to obtain focused reconstructed image, which is time-consuming. In terms of phase retrieval, there is also the problem of ...phase compensation in addition to focusing task. Here, a new method is proposed for fast digital focus, where we use U-type convolutional neural network (U-net) to recover the original phase of microscopic samples. Generated data sets are used to simulate different degrees of defocused image, and verify that the U-net can restore the original phase to a great extent and realize phase compensation at the same time. We apply this method in the construction of real-time off-axis digital holographic microscope and obtain great breakthroughs in imaging speed.
Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson's disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to glycolysis) converts ...glucose-6-phosphate into pentoses and generates ribose-5-phosphate and NADPH thereby governing anabolic biosynthesis and redox homeostasis. Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. However, spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. More importantly, it is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD.
We examined expression/activity of G6PD and its association with microglial activation and dopaminergic neurodegeneration in multiple chronic PD models generated by an intranigral/intraperitoneal injection of LPS, daily subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 6 days, or transgenic expression of A53T α-synuclein. Primary microglia were transfected with G6PD siRNAs and treated with lipopolysaccharide (LPS) to examine effects of G6PD knockdown on microglial activation and death of co-cultured neurons. LPS alone or with G6PD inhibitor(s) was administrated to mouse substantia nigra or midbrain neuron-glia cultures. While histological and biochemical analyses were conducted to examine microglial activation and dopaminergic neurodegeneration in vitro and in vivo, rotarod behavior test was performed to evaluate locomotor impairment in mice.
Expression and activity of G6PD were elevated in LPS-treated midbrain neuron-glia cultures (an in vitro PD model) and the substantia nigra of four in vivo PD models. Such elevation was positively associated with microglial activation and dopaminergic neurodegeneration. Furthermore, inhibition of G6PD by 6-aminonicotinamide and dehydroepiandrosterone and knockdown of microglial G6PD attenuated LPS-elicited chronic dopaminergic neurodegeneration. Mechanistically, microglia with elevated G6PD activity/expression produced excessive NADPH and provided abundant substrate to over-activated NADPH oxidase (NOX2) leading to production of excessive reactive oxygen species (ROS). Knockdown and inhibition of G6PD ameliorated LPS-triggered production of ROS and activation of NF-кB thereby dampening microglial activation.
Our findings indicated that G6PD-mediated PPP dysfunction and neuroinflammation exacerbated each other mediating chronic dopaminergic neurodegeneration and locomotor impairment. Insight into metabolic-inflammatory interface suggests that G6PD and NOX2 are potential therapeutic targets for PD.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
T cells play a key role in immune-mediated glomerulonephritis, but how cytotoxic T cells interact with podocytes remains unclear. To address this, we injected EGFP-specific CD8+ T cells from just ...EGFP death inducing (Jedi) mice into transgenic mice with podocyte-specific expression of EGFP. In healthy mice, Jedi T cells could not access EGFP+ podocytes. Conversely, when we induced nephrotoxic serum nephritis (NTSN) and injected Jedi T cells, EGFP+ podocyte transgenic mice showed enhanced proteinuria and higher blood urea levels. Morphometric analysis showed greater loss of EGFP+ podocytes, which was associated with severe crescentic and necrotizing glomerulonephritis. Notably, only glomeruli with disrupted Bowman's capsule displayed massive CD8+ T cell infiltrates that were in direct contact with EGFP+ podocytes, causing their apoptosis. Thus, under control conditions with intact Bowman's capsule, podocytes are not accessible to CD8+ T cells. However, breaches in Bowman's capsule, as also noted in human crescentic glomerulonephritis, allow access of CD8+ T cells to the glomerular tuft and podocytes, resulting in their destruction. Through these mechanisms, a potentially reversible glomerulonephritis undergoes an augmentation process to a rapidly progressive glomerulonephritis, leading to end-stage kidney disease. Translating these mechanistic insights to human crescentic nephritis should direct future therapeutic interventions at blocking CD8+ T cells, especially in progressive stages of rapidly progressive glomerulonephritis.
Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer that is mainly used in the production of polyvinyl alcohol-containing chloride products, has attracted attention due to potential threats to human ...health and the environment. Nevertheless, knowledge of DEHP-induced nephrotoxicity is still limited. To explore the mechanism of DEHP-induced nephrotoxicity, quail were treated with 0, 250, 500 and 1000 mg/kg DEHP by oral gavage for 45 days. Based on the results of histopathological analysis, DEHP exposure induced a disorganized renal structure, a partially dilated glomerulus and an atrophied Bowman’s space. Renal tubular epithelial cells were unclear, and swelling of columnar epithelial cells was observed, suggesting that DEHP exposure caused renal disease and renal injury. Notably, DEHP interfered with the homeostasis of cytochrome P450 systems (CYP450s) by increasing the activities or contents of CYP450s (total CYP450, Cyt b5, ERND, APND, AH and NCR). The expression levels of certain CYP450 isoforms (CYP1A, CYP1B, CYP2C, CYP2D, CYP2J and CYP3A) were significantly downregulated in the kidney in DEHP-treated quail. Furthermore, DEHP induced the expression of nuclear receptors (AHR, CAR and PXR) in a dose-dependent manner. The results of this study suggested that DEHP-induced nephrotoxicity in quail was associated with the induction of nuclear xenobiotic receptor (NXR) responses and interference with CYP450 homeostasis. In conclusion, all data indicated that DEHP induced nephrotoxicity by triggering NXRs and modulating the cytochrome P450 system. The results of this study provide a new basis for understanding the nephrotoxicity of DEHP.
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•DEHP exposure induces the renal injury.•DEHP exposure triggers the AHR/PXR/CAR pathway responses in kidney.•DEHP exposure disrupts the cytochrome P450 homeostasis in kidney.•DEHP exposure impacts the transcription of CYPs via activating the NXRs responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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