MicroRNA-26a alleviates tubulointerstitial fibrosis in diabetic kidney disease by targeting PAR4.

Our previous study found that miR-26a alleviates aldosterone-induced tubulointerstitial fibrosis (TIF). However, the effect of miR-26a on TIF in diabetic kidney disease (DKD) remains unclear. This study clarifies the role and possible mechanism of exogenous miR-26a in controlling the progression of TIF in DKD models. Firstly, we showed that miR-26a was markedly decreased in type 2 diabetic db/db mice and mouse tubular epithelial cells (mTECs) treated with high glucose (HG, 30 mM) using RT-qPCR. We then used adeno-associated virus carrying miR-26a and adenovirus miR-26a to enhance the expression of miR-26a in vivo and in vitro. Overexpressing miR-26a alleviated the TIF in db/db mice and the extracellular matrix (ECM) deposition in HG-stimulated mTECs. These protective effects were caused by reducing expression of protease-activated receptor 4 (PAR4), which involved in multiple pro-fibrotic pathways. The rescue of PAR4 expression reversed the anti-fibrosis activity of miR-26a. We conclude that miR-26a alleviates TIF in DKD models by directly targeting PAR4, which may provide a novel molecular strategy for DKD therapy.

tRF3-IleAAT reduced extracellular matrix synthesis in diabetic kidney disease mice by targeting ZNF281 and inhibiting ferroptosis.

It is well established that the synthesis of extracellular matrix (ECM) in mesangial cells is a major determinant of diabetic kidney disease (DKD). Elucidating the major players in ECM synthesis may be helpful to provide promising candidates for protecting against DKD progression. tRF3-IleAAT is a tRNA-derived fragment (tRF) produced by nucleases at tRNA-specific sites, which is differentially expressed in the sera of patients with diabetes mellitus and DKD. In this study we investigated the potential roles of tRFs in DKD. Db/db mice at 12 weeks were adapted as a DKD model. The mice displayed marked renal dysfunction accompanied by significantly reduced expression of tRF3-IleAAT and increased ferroptosis and ECM synthesis in the kidney tissues. The reduced expression of tRF3-IleAAT was also observed in high glucose-treated mouse glomerular mesangial cells. We administered ferrostatin-1 (1 mg/kg, once every two days, i.p.) to the mice from the age of 12 weeks for 8 weeks, and found that inhibition of the onset of ferroptosis significantly improved renal function, attenuated renal fibrosis and reduced collagen deposition. Overexpression of tRF3-IleAAT by a single injection of AAV carrying tRF3-IleAAT via caudal vein significantly inhibited ferroptosis and ECM synthesis in DKD model mice. Furthermore, we found that the expression of zinc finger protein 281 (ZNF281), a downstream target gene of tRF3-IleAAT, was significantly elevated in DKD models but negatively regulated by tRF3-IleAAT. In high glucose-treated mesangial cells, knockdown of ZNF281 exerted an inhibitory effect on ferroptosis and ECM synthesis. We demonstrated the targeted binding of tRF3-IleAAT to the 3'UTR of ZNF281. In conclusion, tRF3-IleAAT inhibits ferroptosis by targeting ZNF281, resulting in the mitigation of ECM synthesis in DKD models, suggesting that tRF3-IleAAT may be an attractive therapeutic target for DKD.

Tubular TMEM16A promotes tubulointerstitial fibrosis by suppressing PGC-1α-mediated mitochondrial homeostasis in diabetic kidney disease.

Tubulointerstitial fibrosis (TIF) plays a crucial role in the progression of diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain obscure. The present study aimed to examine whether transmembrane member 16A (TMEM16A), a Ca2+-activated chloride channel, contributes to the development of TIF in DKD. Interestingly, we found that TMEM16A expression was significantly up-regulated in tubule of murine model of DKD, which was associated with development of TIF. In vivo inhibition of TMEM16A channel activity with specific inhibitors Ani9 effectively protects against TIF. Then, we found that TMEM16A activation induces tubular mitochondrial dysfunction in in vivo and in vitro models, with the evidence of the TMEM16A inhibition with specific inhibitor. Mechanically, TMEM16A mediated tubular mitochondrial dysfunction through inhibiting PGC-1α, whereas overexpression of PGC-1α could rescue the changes. In addition, TMEM16A-induced fibrogenesis was dependent on increased intracellular Cl-, and reducing intracellular Cl- significantly blunted high glucose-induced PGC-1α and profibrotic factors expression. Taken together, our studies demonstrated that tubular TMEM16A promotes TIF by suppressing PGC-1α-mediated mitochondrial homeostasis in DKD. Blockade of TMEM16A may serve as a novel therapeutic approach to ameliorate TIF.

The potential role of differentially expressed tRNA-derived fragments in high glucose-induced podocytes.

The prevalence of diabetic kidney disease (DKD) is increasing annually. Damage to and loss of podocytes occur early in DKD. tRNA-derived fragments (tRFs), originating from tRNA precursors or mature tRNAs, are associated with various illnesses. In this study, tRFs were identified, and their roles in podocyte injury induced by high-glucose (HG) treatment were explored. High-throughput sequencing of podocytes treated with HG was performed to identify differentially expressed tRFs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. The expression levels of nephrin, podocin, and desmin were measured in podocytes after overexpression of tRF-1:24-Glu-CTC-1-M2 (tRF-1:24) and concomitant HG treatment. A total of 647 tRFs were identified, and 89 differentially expressed tRFs (|log2FC| ≥ 0.585; p ≤ .05) were identified in the HG group, of which 53 tRFs were downregulated and 36 tRFs were upregulated. The 10 tRFs with the highest differential expression were detected by real-time quantitative polymerase chain reaction (RT-qPCR), and these results were consistent with the sequencing results. GO analysis revealed that the biological process, cellular component, and molecular function terms in which the tRFs were the most enriched were cellular processes, cellular anatomical entities, and binding. KEGG pathway analysis revealed that tRFs may be involved in signaling pathways related to growth hormones, phospholipase D, the regulation of stem cell pluripotency, and T-/B-cell receptors. Overexpression of tRF-1:24, one of the most differentially expressed tRFs, attenuated podocyte injury induced by HG. Thus, tRFs might be potential biomarkers for podocyte injury in DKD.

Programming Peptide Liquid Crystal Media to Acquire Independent Sets of Residual Dipolar Couplings and Enantiodiscrimination in Multiple Solvent Systems.

Multiple independent sets of residual dipolar couplings (RDCs) acquired by relying on different alignment media show the great potential for de novo structure determination of organic compounds. However, this methodology is severely compromised by the limited availability of multialignment media. In this work, an engineering strategy was developed to program the oligopeptide amphiphiles (OPAs) to create different peptide liquid crystal (LC) media for the acquisition of independent sets of RDCs. With no need for de novo design on peptide sequences, the molecular alignment can be simply modulated by varying the length of the hydrophobic tails within OPAs. Relying on these programmed peptide LC media, five independent sets of RDCs were extracted in a highly efficient and accurate manner. Because of the similar bulk composition of OPAs, this approach offers the significant advantage in circumventing the possible incompatibilities of analytes with one or several different alignment media, therefore avoiding the analysis complication. Notably, these peptide LC media show enantiodifferentiating properties, and the enantiodiscriminating capabilities could also be optimized through the programmed strategy. Furthermore, we show that these media are compatible with different polar solvents, allowing the possible de novo structure elucidation of organic compounds with varied polarities and solubilities.

Satellite cell-derived exosome-mediated delivery of microRNA-23a/27a/26a cluster ameliorates the renal tubulointerstitial fibrosis in mouse diabetic nephropathy.

Renal tubulointerstitial fibrosis (TIF) is considered as the final convergent pathway of diabetic nephropathy (DN) without effective therapies currently. MiRNAs play a key role in fibrotic diseases and become promising therapeutic targets for kidney diseases, while miRNA clusters, formed by the cluster arrangement of miRNAs on chromosomes, can regulate diverse biological functions alone or synergistically. In this study, we developed clustered miR-23a/27a/26a-loaded skeletal muscle satellite cells-derived exosomes (Exos) engineered with RVG peptide, and investigated their therapeutic efficacy in a murine model of DN. Firstly, we showed that miR-23a-3p, miR-26a-5p and miR-27a-3p were markedly decreased in serum samples of DN patients using miRNA sequencing. Meanwhile, we confirmed that miR-23a-3p, miR-26a-5p and miR-27a-3p were primarily located in proximal renal tubules and highly negatively correlated with TIF in db/db mice at 20 weeks of age. We then engineered RVG-miR-23a/27a/26a cluster loaded Exos derived from muscle satellite cells, which not only enhanced the stability of miR-23a/27a/26a cluster, but also efficiently delivered more miR-23a/27a/26a cluster homing to the injured kidney. More importantly, administration of RVG-miR-23a/27a/26a-Exos (100 µg, i.v., once a week for 8 weeks) significantly ameliorated tubular injury and TIF in db/db mice at 20 weeks of age. We revealed that miR-23a/27a/26a-Exos enhanced antifibrotic effects by repressing miRNA cluster-targeting Lpp simultaneously, as well as miR-27a-3p-targeting Zbtb20 and miR-26a-5p-targeting Klhl42, respectively. Knockdown of Lpp by injection of AAV-Lpp-RNAi effectively ameliorated the progression of TIF in DN mice. Taken together, we established a novel kidney-targeting Exo-based delivery system by manipulating the miRNA-23a/27a/26a cluster to ameliorate TIF in DN, thus providing a promising therapeutic strategy for DN.

Rapamycin attenuated podocyte apoptosis via upregulation of nestin in Ang II-induced podocyte injury.

BACKGROUND: Angiotensin II (Ang II) contributes to the progression of glomerulosclerosis, mainly by inducing podocyte injury. Convincing evidence indicates that the mTOR inhibitor rapamycin could play a fundamental role in protection against podocyte injury. Nestin, a major cytoskeletal protein, is stably expressed in podocytes and correlates with podocyte damage. The purpose of this study was to investigate the effect of rapamycin on podocyte injury induced by Ang II and to clarify the role and mechanism of nestin in the protective effect of rapamycin of podocyte injury. METHODS AND RESULTS: We established an Ang II perfusion animal model, and the effects of rapamycin treatment on podocytes were investigated in vivo. In vitro, podocytes were stimulated with Ang II and rapamycin to observe podocyte injury, and nestin-siRNA was transfected to investigate the underlying mechanisms. We observed that Ang II induced podocyte injury both in vivo and in vitro, whereas rapamycin treatment relieved Ang II-induced podocyte injury. We further found that nestin co-localized with p-mTOR in glomeruli, and the protective effect of rapamycin was reduced by nestin-siRNA in podocytes. Moreover, co-IP indicated the interaction between nestin and p-mTOR, and nestin could affect podocyte injury via the mTOR/P70S6K signaling pathway. CONCLUSION: We demonstrated that rapamycin attenuated podocyte apoptosis via upregulation of nestin expression through the mTOR/P70S6K signaling pathway in an Ang II-induced podocyte injury.

Design and synthesis of highly fluorescent and stable fullerene nanoparticles as probes for folic acid detection and targeted cancer cell imaging.

Rational design and construction of fullerene derivatives play significant roles in the development of applications for sensing, marking and imaging in biomedical fields. In the present work, a novel type of C60 fluorescent nanoparticle (C60 FNP) was synthesized by a combination of thiol-ene chemistry and modification with folic acid (FA). The as-prepared C60 FNPs exhibited intense blue luminescence with a relatively high quantum yield of 26%, which is higher than that of any other reported fluorescent fullerene-based nanomaterial. Moreover, they revealed superior photobleaching resistance under constant UV lamp illumination for 5 h and excellent photostablity after 9 months of storage in water. Due to the mutual hydrogen bond interaction, the obtained C60 FNPs were capable of acting as a sensitive and specific probe for FA detection and quantification, with a liner range of 0 to 80 µM and a detection limit of 0.24 µM. Satisfactory recoveries (95.4%-105.2%) were obtained from a series of actual samples, further confirming the feasibility of this nanoprobe. Additionally, taking advantage of the FA moiety, the C60 FNPs had easy access to penetrate into cancer cells with higher expression levels of folate receptors, thereby achieving the function of targeted cellular imaging.

tRNA-derived fragments (tRFs) contribute to podocyte differentiation.

Loss of glomerular podocytes is the crucial event in the progression of chronic kidney disease (CKD). tRNA-derived fragments (tRFs), a newfangled branch of small non-coding RNA (sncRNA), recently reported to play a vital part in several diseases. In present study, we aimed to detect and reveal the role of tRFs in podocyte differentiation. The expression levels of tRFs between undifferentiated and differentiated podocytes were sequenced by illumina nextseq 500, and further verified by quantitative RT-PCR. 69 upregulated and 70 downregulated tRFs in total were singled out (Fold change > 2, P < 0.05). Gene ontology (GO) analysis indicated they are involved in the biological processes of transcription, DNA-templated, positive regulation of transcription from RNA polymerase II promoter, angiogenesis, cell adhesion. Besides, KEGG analysis suggested that these differentially tRFs are associated with PI3K-Akt signaling pathway, Rap1 signaling pathway, Ras signaling pathway, MAPK signaling pathway, and Wnt signaling pathway. Therefore, the differentially tRFs might regulate the differentiation of podocyte and the process of CKD. The functions and mechanisms of tRFs in podocytes are needed to be further explored.

Exogenous miR-26a suppresses muscle wasting and renal fibrosis in obstructive kidney disease.

Kidney fibrosis occurs in almost every type of chronic kidney disease. We found that microRNA (miR)-26a was decreased in the kidney, muscle, and exosomes of unilateral ureteral obstruction (UUO) mice. We hypothesized that exogenous miR-26 could suppresses renal fibrosis and muscle wasting in obstructive kidney disease. For this purpose, we generated exosomes that encapsulated miR-26, then injected these into skeletal muscle of UUO mice. The expression of miR-26a was elevated in serum exosomes from UUO mice following exosome-miR-26a injection. In these mice, muscle wasting has been ameliorated as evidenced by increased muscle weights. In addition, a muscle atrophy marker, myostatin, is increased in UUO muscle; provision of miR-26a abolished this increase. We detected a remote effect of exosomes containing miR-26a in UUO-induced renal fibrosis. The intervention of miR-26a attenuated UUO-induced renal fibrosis as determined by immunohistological assessment of α-smooth muscle actin and Masson's trichrome staining. Furthermore, exogenous miR-26a decreased the protein levels of 2 profibrosis proteins, connective tissue growth factor (CTGF) and TGF-ß1, in UUO kidney. Our data showed that exosomes containing miR-26a prevented muscle atrophy by inhibiting the transcription factor forkhead box O1. Likewise, the exosome-carried miR-26a limited renal fibrosis by directly suppressing CTGF. Our findings provide an experimental basis for exosome-mediated therapy of muscle atrophy and renal fibrosis.-Zhang, A., Wang, H., Wang, B., Yuan, Y., Klein, J. D., Wang, X. H. Exogenous miR-26a suppresses muscle wasting and renal fibrosis in obstructive kidney disease.

Exosome-Mediated miR-29 Transfer Reduces Muscle Atrophy and Kidney Fibrosis in Mice.

Our previous study showed that miR-29 attenuates muscle wasting in chronic kidney disease. Other studies found that miR-29 has anti-fibrosis activity. We hypothesized that intramuscular injection of exosome-encapsulated miR-29 would counteract unilateral ureteral obstruction (UUO)-induced muscle wasting and renal fibrosis. We used an engineered exosome vector, which contains an exosomal membrane protein gene Lamp2b that was fused with the targeting peptide RVG (rabies viral glycoprotein peptide). RVG directs exosomes to organs that express the acetylcholine receptor, such as kidney. The intervention of Exo/miR29 increased muscle cross-sectional area and decreased UUO-induced upregulation of TRIM63/MuRF1 and FBXO32/atrogin-1. Interestingly, renal fibrosis was partially depressed in the UUO mice with intramuscular injection of Exo/miR29. This was confirmed by decreased TGF-ß, alpha-smooth muscle actin, fibronectin, and collagen 1A1 in the kidney of UUO mice. When we used fluorescently labeled Exo/miR29 to trace the Exo/miR route in vivo and found that fluorescence was visible in un-injected muscle and in kidneys. We found that miR-29 directly inhibits YY1 and TGF-ß3, which provided a possible mechanism for inhibition of muscle atrophy and renal fibrosis by Exo/miR29. We conclude that Exo/miR29 ameliorates skeletal muscle atrophy and attenuates kidney fibrosis by downregulating YY1 and TGF-ß pathway proteins.

Measurement of Residual Dipolar Couplings of Organic Molecules in Multiple Solvent Systems Using a Liquid-Crystalline-Based Medium.

Residual dipolar coupling (RDC), a robust anisotropic NMR parameter for structural elucidation of organic molecules, is only accessible in an anisotropic environment. Herein, we introduce a novel alignment medium based on the molecular self-assembly of oligopeptide amphiphile (OPA). This medium is compatible with different intermediate and polar solvent systems, such as CD3 OD, [D6 ]DMSO, and D2 O. The preparation of the OPA-based medium is simple and rapid, while only very weak background signals were observed from OPAs. Furthermore, we show that the purity of OPA has only a minor influence on the quality of the RDC data. These advantages allow RDC measurements of organic molecules with different polarities and solubilities with high efficiency and accuracy.

Peptidomic analysis reveals multiple protection of human breast milk on infants during different stages.

It has been shown that human breast milk (HBM) is an important nutrient for the growth and development of newborns. Currently, peptide drugs provide promising regimes in neonatal disease treatment, especially peptides from HBM that exhibit multiple functions within cells. To explore the potential biological function peptides among the colostrum, transition and mature milk from mother of extremely low birth weight children (the samples were collected from Women's Hospital of Nanjing Medical University from December 2016 to February 2017). A total of 3,182 nonredundant peptides were identified and compared among colostrum, transitional and mature milk using liquid chromatography/mass spectrometry technology, and the numbers and fragments of peptides were various. The isoelectric point and molecular weight analysis of the differentially expressed peptides basically accord with the range of mass spectrometry identification (<3 kDa). Gene Ontology analysis and Pathway analysis, restriction sites analysis, as well as bioinformatics analysis showed that these differentially expressed peptides enriched a variety of biological processes. We identified several putative peptides that might have bioactive effects in diseases and development of newborns, which will inform further functional investigations. Our preliminary research provided a better understanding of the function of peptides during the newborn periods. Furthermore, it laid a foundation for discovering new peptide drugs in neonatal disease treatment.

Profile analysis reveals transfer RNA fragments involved in mesangial cells proliferation.

Mesangial cell (MCs) proliferation is an essential component of glomerulonephritis. To find some bio-markers of mesangial cell proliferation, we investigate the relationship between transfer RNA fragments (tRFs) and proliferating mesangial cells. The model of proliferating mesangial cells was built by using transforming growth factor-1(TGF-ß1) treated mesangial cells. Then we analyzed the expression of tRFs in normal mesangial cells and mesangial cells treated by TGF-ß1 through high-throughput sequencing technique. qRT-PCR was conducted to validate the differently expressed tRFs in normal mesangial cells and mesangial cells treated by TGF-ß1. tDR-000064 and tDR-000103 were notably down-regulated in mesangial cells treated by TGF-ß1 compared with normal mesangial cells. Then we confirmed that tDR-000064 and tDR-000103 were correlated with proliferation of mesangial cells through receiver operating characteristic curve analysis. Furthermore, Gene ontology (GO) and pathway analysis demonstrated that the two dys-regulated tRFs were mostly involved in mesangial cells and TGF-ß1 receptor-mediated signaling pathway. Our research provides a comprehensive analysis of tRFs in proliferating mesangial cells. (Figure 1A).

An observation study of the emergency intervention in placenta accreta spectrum.

OBJECTIVE: This study explored the probability and outcome of delivery in women with placenta accreta spectrum (PAS) according to gestational age at delivery. METHODS: A retrospective cohort study among women with PAS who had cesarean section was conducted. The gestational week (gw) of delivery and estimated blood loss (EBL) were recorded. The proportion of urgent delivery beyond 32 gw and EBL in women with or without antepartum suspected diagnosis of placenta accreta was compared. RESULTS: Totally, 180 women with PAS were enrolled. Of these, 54 (30.0%, 95% CI 23.8-37.1%) were delivered by urgent cesarean delivery and 126 (70.0%, 95% CI 62.9-76.2%) by elective cesarean section. The probability of emergent delivery was increased from 3.1 to 5.7% at 33-36 weeks, and increased by > 10% beyond 37 weeks. Among 121 antenatal suspected PAS patients, 25 (20.7%, 95% CI 14.4-28.7%) had emergency cesarean section, and 96 (79.3%, 95% CI 71.3-85.6%) experienced elective cesarean. The EBL of PAS in both emergent group (r = - 0.276, p = 0.044) and elective group (r = - 0.370, p < 0.001) was significantly decreased with gestational age progression. The antepartum hemorrhage increased the risk of urgent delivery [OR 2.54 (1.19, 5.44)] (p = 0.016), while PAS with antepartum diagnosis decreased the risk [OR 0.21 (0.10, 0.43)] (p < 0.001). CONCLUSION: Although the incidence of emergency operation in PAS patients was increased at 32-36 gw, there was no significant difference among the groups. The decision of timing for pregnancy termination should be made cautiously. We recommend scheduled operation at around 36-37 gw. In serious cases, the termination time could be arranged as early as appropriate.

p53/Drp1-dependent mitochondrial fission mediates aldosterone-induced podocyte injury and mitochondrial dysfunction.

Mitochondrial dysfunction is increasingly recognized as an important factor in glomerular diseases. Previous study has shown that mitochondrial fission contributed to mitochondrial dysfunction. However, the mechanism of mitochondrial fission on mitochondrial dysfunction in aldosterone-induced podocyte injury remains ambiguous. This study aimed to investigate the pathogenic effect of mitochondrial fission both in vivo and in vitro. In an animal model of aldosterone-induced nephropathy, inhibition of the mitochondrial fission protein dynamin-related protein 1 (Drp1) suppressed aldosterone-induced podocyte injury. In cultured podocytes, aldosterone dose dependently induced Drp1 expression. Knockdown of Drp1 inhibited aldosterone-induced mitochondrial fission, mitochondrial dysfunction, and podocyte apoptosis. Furthermore, aldosterone dose dependently induced p53 expression. Knockdown of p53 inhibited aldosterone-induced Drp1 expression, mitochondrial dysfunction, and podocyte apoptosis. These findings implicated that aldosterone induced mitochondrial dysfunction and podocyte injury mediated by p53/Drp1-dependent mitochondrial fission, which may provide opportunities for therapeutic intervention for podocyte injury.

FOXO1, a Potential Therapeutic Target, Regulates Autophagic Flux, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis in Human Cholangiocarcinoma QBC939 Cells.

BACKGROUND/AIMS: Autophagy is an evolutionarily conserved catabolic mechanism to maintain energy homeostasis and to remove damaged cellular components, which plays an important role in the survival of various cells. Inhibiting autophagy is often applied as a new strategy to halt the growth of cancer cells. METHODS: The effect of FOXO1 gene on cellular function and apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methylthiazoletetrazolium (MTT) assay, western blot, DCFDA mitochondrial membrane potential, and ATP content measurement. FOXO1 siRNA was applied to down-regulate FOXO1 expression in QBC939 cells. RESULTS: Here we reported that FOXO1, acetylation of FOXO1 (Ac-FOXO1) and the following interaction between Ac-FOXO1 and Atg7 regulated the basal and serum starvation (SS)-induced autophagy as evidenced by light chain 3 (LC3) accumulation and p62 degration. Either treatment with FOXO1 siRNA or resveratrol, a sirt1 agonist, inhibited autophagic flux, resulting in oxidative stress, mitochondrial dysfunction (MtD) and apoptosis in QBC939 cells, which were attenuated by enhancing autophagy with rapamycin. On the contrary, inhibiting autophagic flux with 3-MA worsened all these effects in QBC939 cells. CONCLUSIONS: Taken together, our study for the first time identified FOXO1 as a potential therapeutic target to cure against human cholangiocarcinoma via regulation of autophagy, oxidative stress and MtD.

Recent Advances in Targeted Tumor Chemotherapy Based on Smart Nanomedicines.

Efficacy and safety of chemotherapeutic drugs constitute two major criteria in tumor chemotherapy. Nanomedicines with tumor-targeted properties hold great promise for improving the efficacy and safety. To design targeted nanomedicines, the pathological characteristics of tumors are extensively and deeply excavated. Here, the rationale, principles, and advantages of exploiting these pathological characteristics to develop targeted nanoplatforms for tumor chemotherapy are discussed. Homotypic targeting with the ability of self-recognition to source tumors is reviewed individually. In the meanwhile, the limitations and perspective of these targeted nanomedicines are also discussed.

MicroRNA-23a and MicroRNA-27a Mimic Exercise by Ameliorating CKD-Induced Muscle Atrophy.

Muscle atrophy is a frequent complication of CKD, and exercise can attenuate the process. This study investigated the role of microRNA-23a (miR-23a) and miR-27a in the regulation of muscle mass in mice with CKD. These miRs are located in a gene cluster that is regulated by the transcription factor NFAT. CKD mice expressed less miR-23a in muscle than controls, and resistance exercise (muscle overload) increased the levels of miR-23a and miR-27a in CKD mice. Injection of an adeno-associated virus encoding the miR-23a/27a/24-2 precursor RNA into the tibialis anterior muscles of normal and CKD mice led to increases in mature miR-23a and miR-27a but not miR-24-2 in the muscles of both cohorts. Overexpression of miR-23a/miR-27a in CKD mice attenuated muscle loss, improved grip strength, increased the phosphorylation of Akt and FoxO1, and decreased the activation of phosphatase and tensin homolog (PTEN) and FoxO1 and the expression of TRIM63/MuRF1 and FBXO32/atrogin-1 proteins. Provision of miR-23a/miR-27a also reduced myostatin expression and downstream SMAD-2/3 signaling, decreased activation of caspase-3 and -7, and increased the expression of markers of muscle regeneration. Lastly, in silico miR target analysis and luciferase reporter assays in primary satellite cells identified PTEN and caspase-7 as targets of miR-23a and FoxO1 as a target of miR-27a in muscle. These findings provide new insights about the roles of the miR-23a/27a-24-2 cluster in CKD-induced muscle atrophy in mice and suggest a mechanism by which exercise helps to maintain muscle mass.

Towards Secure and Privacy-Preserving Data Sharing in e-Health Systems via Consortium Blockchain.

Electronic health record sharing can help to improve the accuracy of diagnosis, where security and privacy preservation are critical issues in the systems. In recent years, blockchain has been proposed to be a promising solution to achieve personal health information (PHI) sharing with security and privacy preservation due to its advantages of immutability. This work proposes a blockchain-based secure and privacy-preserving PHI sharing (BSPP) scheme for diagnosis improvements in e-Health systems. Firstly, two kinds of blockchains, private blockchain and consortium blockchain, are constructed by devising their data structures, and consensus mechanisms. The private blockchain is responsible for storing the PHI while the consortium blockchain keeps records of the secure indexes of the PHI. In order to achieve data security, access control, privacy preservation and secure search, all the data including the PHI, keywords and the patients' identity are public key encrypted with keyword search. Furthermore, the block generators are required to provide proof of conformance for adding new blocks to the blockchains, which guarantees the system availability. Security analysis demonstrates that the proposed protocol can meet with the security goals. Furthermor, we implement the proposed scheme on JUICE to evaluate the performance.