TGF-β/Smad signaling plays an important role in diabetic nephropathy. The present study identified a novel Smad3-dependent long non-coding RNA (lncRNA) Erbb4-IR in the development of type-2 diabetic ...nephropathy (T2DN) in db/db mice. We found that Erbb4-IR was highly expressed in T2DN of db/db mice and was specifically induced by AGE via a Smad3-dependent mechanism. The functional role of Erbb4-IR in T2DN was revealed by kidney-specific silencing of Erbb4-IR to protect against the development of T2DN such as elevated microalbuminuria, serum creatinine and progressive renal fibrosis in db/db mice, and to block AGE-induced collagen I and IV expression in mouse mesangial cells (mMCs) and mouse tubular epithelial cells (mTECs). Mechanistically, we identified that the Erbb4-IR-miR-29b axis was a key mechanism of T2DN because Erbb4-IR was able to bind the 3'UTR of miR-29b genomic sequence to suppress miR-29b expression at transcriptional level. In contrast, silencing of renal Erbb4-IR increased miR-29b and therefore protected kidney from progressive renal injury in db/db mice and prevented mTECs and mMCs from AGE-induced loss of miR-29b and fibrotic response
Collectively, we identify that Erbb4-IR is a Smad3-dependent lncRNA that promotes renal fibrosis in T2DN by suppressing miR-29b. Targeting Erbb4-IR may represent a novel therapy for T2DN.
To investigate the prevalence of insomnia in college students and analyze the correlation between insomnia and perceived stress.
A cluster sampling method was used to investigate the prevalence of ...insomnia and stress levels in 3702 college students using Insomnia Severity Index (ISI) and Perceived Stress Scale-10 (PSS-10).
Insomnia was detected in 31.4% of the college students, and the symptoms were more severe in male students (
=2.047,
=0.041) and in those with poorer family economic conditions (
=20.423,
<0.001). Insomnia was positively correlated with perceived stress, perceived distress, and perceived coping ability, with correlation coefficients of 0.42, 0.38, and 0.31, respectively (
<0.001). The students with higher levels of perceived stress had higher insomnia scores (
=203.03,
<0.001) and higher detection rate of insomnia (χ
=359.784,
<0.001), and those with moderate or severe insomnia also had higher levels of perceived stress (
=293.569,
<0.001). The types of perceived stress among college studen
Inflammation and its consequent fibrosis are two main features of diabetic nephropathy (DN), but target therapy on these processes for DN remains yet ineffective. We report here that miR-29b is a ...novel therapeutic agent capable of inhibiting progressive renal inflammation and fibrosis in type 2 diabetes in db/db mice. Under diabetic conditions, miR-29b was largely downregulated in response to advanced glycation end (AGE) product, which was associated with upregulation of collagen matrix in mesangial cells via the transforming growth factor-β (TGF-β)/Smad3-dependent mechanism. These pathological changes were reversed by overexpressing miR-29b, but enhanced by knocking-down miR-29b. Similarly, loss of renal miR-29b was associated with progressive diabetic kidney injury, including microalbuminuria, renal fibrosis, and inflammation. Restored renal miR-29b by the ultrasound-based gene therapy was capable of attenuating diabetic kidney disease. Further studies revealed that inhibition of Sp1 expression, TGF-β/Smad3-dependent renal fibrosis, NF-κB–driven renal inflammation, and T-bet/Th1-mediated immune response may be mechanisms associated with miR-29b treatment in db/db mice. In conclusion, miR-29b may play a protective role in diabetic kidney disease and may have therapeutic potential for diabetic kidney complication.
Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains ...unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis.
Osteoarthritis (OA) as a debilitating affliction of joints currently affects millions of people and remains an unsolved problem. The disease involves multiple cellular and molecular pathways that ...converge on the progressive destruction of cartilage. Activation of cartilage regenerative potential and specific targeting pathogenic mediators have been the major focus of research efforts aimed at slowing the progression of cartilage degeneration and preserve joint function. This review will summarize recent key discoveries toward better understanding of the complex mechanisms behind OA development and highlight the latest advances in basic and clinical research in the approach for cartilage regeneration. Prospectively, more potent therapeutic strategies against progressive cartilage deterioration may use a combination of cytotherapy, pharmacotherapy, and bioscaffoldings for improved chondrogenic differentiation and stem/progenitor cell homing as well as the concomitant reduced enzymatic matrix degradation and inflammation. Further, treatments need to be provided with increased preciseness of targeted therapy. One might expect that the regenerative therapies could potentially control or even possibly cure OA if performed at early stages of the disease.
Increasing evidence shows that microRNAs play an important role in kidney disease. However, functions of long noncoding RNAs (lncRNAs) in kidney diseases remain undefined. We have previously shown ...that TGF-β1 plays a diverse role in renal inflammation and fibrosis and Smad3 is a key mediator in this process. In this study, we used RNA-sequencing to identify lncRNAs related to renal inflammation and fibrosis in obstructive nephropathy induced in Smad3 wild-type and knockout mice. We found that Arid2-IR was a Smad3-associated lncRNA as a Smad3 binding site was found in the promoter region of Arid2-IR and deletion of Smad3 abolished upregulation of Arid2-IR in the diseased kidney. In vitro knockdown of Arid2-IR from tubular epithelial cells produced no effect on TGF-β-induced Smad3 signaling and fibrosis but inhibited interleukin-1β-stimulated NF-κB-dependent inflammatory response. In contrast, overexpression of Arid2-IR promoted interleukin-1β-induced NF-κB signaling and inflammatory cytokine expression without alteration of TGF-β1-induced fibrotic response. Furthermore, treatment of obstructed kidney with Arid2-IR shRNA blunted NF-κB-driven renal inflammation without effect on TGF-β/Smad3-mediated renal fibrosis. Thus, Arid2-IR is a novel lncRNA that functions to promote NF-κB-dependent renal inflammation. Blockade of Arid2-IR may represent a novel and specific therapy for renal inflammatory disease.
TGF-β/Smad3 signaling promotes fibrosis, but the development of therapeutic interventions involving this pathway will require the identification and ultimate targeting of downstream fibrosis-specific ...genes. In this study, using a microRNA microarray and real-time PCR, wild-type mice had reduced expression of miR-29 along with the development of progressive renal fibrosis in obstructive nephropathy. In contrast, Smad3 knockout mice had increased expression of miR-29 along with the absence of renal fibrosis in the same model of obstruction. In cultured fibroblasts and tubular epithelial cells, Smad3 mediated TGF-β(1)-induced downregulation of miR-29 by binding to the promoter of miR-29. Furthermore, miR-29 acted as a downstream inhibitor and therapeutic microRNA for TGF-β/Smad3-mediated fibrosis. In vitro, overexpression of miR-29b inhibited, but knockdown of miR-29 enhanced, TGF-β(1)-induced expression of collagens I and III by renal tubular cells. Ultrasound-mediated gene delivery of miR-29b either before or after established obstructive nephropathy blocked progressive renal fibrosis. In conclusion, miR-29 is a downstream inhibitor of TGF-β/Smad3-mediated fibrosis and may have therapeutic potential for diseases involving fibrosis.
Smad7 plays a protective role in chronic kidney disease; however, its role in acute kidney injury (AKI) remains unexplored. Here, we report that Smad7 protects against AKI by rescuing the G1 cell ...cycle arrest of tubular epithelial cells (TECs) in ischemia/reperfusion-induced AKI in mice in which Smad7 gene is disrupted or restored locally into the kidney. In Smad7 gene knockout (KO) mice, more severe renal impairment including higher levels of serum creatinine and massive tubular necrosis was developed at 48 h after AKI. In contrast, restored renal Smad7 gene locally into the kidney of Smad7 KO mice protected against AKI by promoting TEC proliferation identified by PCNA+ and BrdU+ cells. Mechanistic studies revealed that worsen AKI in Smad7 KO mice was associated with a marked activation of TGF-β/Smad3-p21/p27 signaling and a loss of CDK2/cyclin E activities, thereby impairing TEC regeneration at the G1 cell cycle arrest. In contrast, restored Smad7 locally into the kidneys of Smad7 KO mice protected TECs from the G1 cell cycle arrest and promoted TEC G1/S transition via a CDK2/cyclin E-dependent mechanism. In conclusion, Smad7 plays a protective role in AKI. Blockade of TGF-β/Smad3-p21/p27-induced G1 cell cycle arrest may be a key mechanism by which Smad7 treatment inhibits AKI. Thus, Smad7 may be a novel therapeutic agent for AKI.
•EV noises with different characteristics can yield the same subjective feeling.•Sharpness and loudness are highly correlated with subjective evaluations in EVs.•Features extracted adaptively using ...the LS-DBN can better represent the EV noise.•The LS-DBN outperformed DBN and BPNN models in effectiveness and efficiency.
Interior noise substantially influences the physiological and psychological sensations of passengers in pure electric vehicles (EVs). Numerous studies have examined the development of acoustic prediction models and acoustic metrics to evaluate EV interior sound quality. However, the existing studies have the following four deficiencies: (1) the interior noise of EVs was studied only on general roads, and few EV samples were tested; (2) the physical acoustical metrics and psychoacoustic metrics did not comprehensively reflect all the characteristics of the interior noise of EVs; (3) features added to the acoustic prediction models were manually extracted and selected and were highly dependent on prior knowledge of acoustic theory and experience; and (4) the most common acoustic prediction models used to evaluate interior noise have shallow architectures. To overcome these deficiencies, we introduce a novel intelligent acoustic model based on deep neural networks (DNNs) called the Laplacian score-deep belief network (LS-DBN). We used the LS-DBN to evaluate the sound quality of EV interior noise. To verify the effectiveness of the proposed method, the interior noises of ten EVs were recorded on eight different road surfaces and corresponding subjective evaluations were conducted. In addition, noise features were extracted adaptively using the LS-DBN, and adaptively extracted features and manually extracted features were compared. The performance of the LS-DBN was validated against a conventional DBN and a back-propagation neural network (BPNN). The results show that the proposed LS-DBN model is superior to the conventional DBN and BPNN in terms of accuracy and stability, and it is highly efficient. Thus, the LS-DBN can achieve good prediction results when evaluating the interior sound quality of EVs.
TGF-β is a multifunctional cytokine affecting many cell types and implicated in tissue remodeling processes. Due to its many functions and cell-specific effects, the consequences of TGF-β signaling ...are process-and stage-dependent, and it is not uncommon that TGF-β exerts distinct and sometimes opposing effects on a disease progression depending on the stage and on the pathological changes associated with the stage. The mechanisms underlying cell- and process-specific effects of TGF-β are poorly understood. We are describing a novel pathway that mediates induction of angiogenesis in response to TGF-β1. We found that in endothelial cells (EC) thrombospondin-4 (TSP-4), a secreted extracellular matrix (ECM) protein, is upregulated in response to TGF-β1 and mediates the effects of TGF-β1 on angiogenesis. Upregulation of TSP-4 does not require the synthesis of new protein, is not caused by decreased secretion of TSP-4, and is mediated by activation of SMAD3. Using Thbs4
mice and TSP-4 shRNA, we found that TSP-4 mediated pro-angiogenic functions in cultured EC and angiogenesis in vivo in response to TGF-β1. We observed~3-fold increases in tumor mass and levels of angiogenesis markers in animals injected with TGF-β1, and these effects did not occur in Thbs4
animals. Injections of an inhibitor of TGF-β1 signaling SB-431542 also decreased the weights of tumors and cancer angiogenesis. Our results from in vivo angiogenesis models and cultured EC document that TSP-4 mediates upregulation of angiogenesis by TGF-β1. Upregulation of pro-angiogenic TSP-4 and selective effects of TSP-4 on EC may contribute to stimulation of tumor growth by TGF-β despite the inhibition of cancer cell proliferation.
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