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Zhihong Liu - Top 30 Publications

Dual-activator codoped upconversion nanoprobe with core-multishell structure for in vitro and in vivo detection of hydroxyl radical.

Monitoring the fluctuation of hydroxyl radical (•OH) in the body can serve as an effective tool for the prediction of relative diseases, which, however, is highly challenging due to its short lifetime, high reactivity and extremely low concentration. Sandwich structured lanthanide-doped upconversion nanoparticles (UCNPs) exhibit unique luminescence properties and great prospects in bioimaging. Nonetheless, their rather low luminescence efficiency and intensity are serious limitations for their application. Herein, we report on dual-activator codoped UCNPs with a core-multishell structure that greatly improve the luminescence intensity and lifetime by 46-fold and 2.6-fold, respectively, than those of the mono-activator doped sandwich structured UCNPs. Moreover, emitting ions in the designed CMS-UCNPs were confined in a homogenous and thin shell layer (~2 nm), thus the luminescence resonance energy transfer (LRET)-based [email protected] dye nanoprobe exhibited a largely shortened energy transfer distance and a pronounced luminescence quenching yield (97%), affording the nearly zero background signal and achieving an ultrahigh sensitivity for the detection of •OH (with LOQ of 0.10 fM). With good biocompatibility, low biotoxicity, enhanced luminescence intensity and lifetime, the developed nanoprobe was competent in monitoring the subtle fluctuation of •OH concentration both in vitro and in vivo.

Urinary Fibrinogen as a Predictor of Progression of CKD.

Fibrinogen has been reported to be involved in kidney tubulointerstitial fibrosis and podocyte injury in mouse models. However, the relationship between urinary fibrinogen and kidney outcomes has not been clarified in patients with CKD.

A de novo substructure generation algorithm for identifying the privileged chemical fragments of liver X receptorβ agonists.

Liver X receptorβ (LXRβ) is a promising therapeutic target for lipid disorders, atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. Druggable LXRβ agonists have been explored over the past decades. However, the pocket of LXRβ ligand-binding domain (LBD) is too large to predict LXRβ agonists with novel scaffolds based on either receptor or agonist structures. In this paper, we report a de novo algorithm which drives privileged LXRβ agonist fragments by starting with individual chemical bonds (de novo) from every molecule in a LXRβ agonist library, growing the bonds into substructures based on the agonist structures with isomorphic and homomorphic restrictions, and electing the privileged fragments from the substructures with a popularity threshold and background chemical and biological knowledge. Using these privileged fragments as queries, we were able to figure out the rules to reconstruct LXRβ agonist molecules from the fragments. The privileged fragments were validated by building regularized logistic regression (RLR) and supporting vector machine (SVM) models as descriptors to predict a LXRβ agonist activities.

Bevacizumab significantly increases the risks of hypertension and proteinuria in cancer patients: A systematic review and comprehensive meta-analysis.

Published data regarding the overall risks and incidence of hypertension and proteinuria associated with bevacizumab were still unclear. To quantify the precise risks and incidence, we performed this comprehensive meta-analysis of 72 published clinical trials including 21902 cases and 20608 controls. The overall incidence, risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated using a fixed or random-effect model based on the heterogeneity. The incidence of all-grade and high-grade hypertension were 25.3% (95% CI: 21.5%-29.5%) and 8.2% (95% CI: 7%-9.8%) for patients treated with bevacizumab. And the incidence of all-grade and high-grade proteinuria were 18% (95% CI: 11.7%-26.6%) and 2.4% (95% CI: 1.8%-3.2%), respectively. Compared with controls, bevacizumab significantly increased the risks of all-grade (RR: 3.595, 95% CI: 2.952-4.378) and high-grade hypertension (RR: 5.173, 95% CI: 4.188-6.390). Obviously increased risks of all-grade (RR: 3.369, 95% CI: 2.492-4.556) and high-grade proteinuria (RR: 5.494, 95% CI: 3.991-7.564) were also observed. In the subgroup analysis, the risks of hypertension and proteinuria may significantly vary with bevacizumab dosage, cancer types and concomitant drugs. Whereas, no obvious difference were discovered when stratified based on phase of trials, age of patients, treatment line and duration. So, close monitor and effective management were highly recommended for the safe use of bevacizumab.

Synergic Anti-Pruritus Mechanisms of Action for the Radix Sophorae Flavescentis and Fructus Cnidii Herbal Pair.

Radix Sophorae Flavescentis (RSF) and Fructus Cnidii (FC) compose a typical herbal synergic pair in traditional Chinese medicine (TCM) for pruritus symptom treatments. The mechanisms of action for the synergy are not understood. This paper aims at predicting the anti-pruritus targets and the main active ingredients for the RSF and FC herbal pair. We demonstrate that the RSF-FC herbal pair can be elucidated by mining the chemical structures of compounds derived from RSF and FC. Based on chemical structure data, the putative targets for RSF and FC were predicted. Additional putative targets that interact with the anti-pruritus targets were derived by mapping the putative targets onto a PPI network. By examining the annotations of these proteins, we conclude that (1) RSF's active compounds are mainly alkaloids and flavonoids. The representative putative targets of the alkaloids are inflammation-related proteins (MAPK14, PTGS2, PTGS2, and F2) and pruritus-related proteins (HRH1, TRPA1, HTR3A, and HTR6). The representative putative targets of the flavonoids are inflammation-related proteins (TNF, NF-κB, F2, PTGS2, and PTGS2) and pruritus-related proteins (NR3C1 and IL2). (2) FC's active compounds are mainly coumarins. Their representative putative targets are CNS-related proteins (AChE and OPRK1) and inflammation-related proteins (PDE4D, TLR9, and NF-κB). (3) Both RSF and FC display anti-inflammatory effects, though they exhibit their anti-pruritus effects in different ways. Their synergy shows that RSF regulates inflammation-related pruritus and FC regulates CNS-related pruritus.

Therapeutic Mechanism of Glucocorticoids on Cellular Crescent Formation in Patients With Antiglomerular Basement Membrane Disease.

This study aimed to explore the therapeutic mechanism of glucocorticoids (GCs) in antiglomerular basement membrane disease.

Proteomic profile‑based screening of potential protein biomarkers in the urine of patients with nephrotic syndrome.

Nephrotic syndrome is not a single disease; rather, it is a term for numerous diseases and pathological types. Renal biopsy is of use in determining the diagnosis and prognosis, and for guiding treatment; however, the use of this intervention is limited due to its invasive nature. Abnormal kidney‑derived proteins in the urine of patients provide useful information regarding numerous pathological processes that occur in the kidneys, and may be considered a potential non‑invasive biomarker for kidney disease. Proteomic analysis exhibits the advantage of being high‑throughput and has previously been used to identify biomarkers of disease. The present study aimed to identify abnormal kidney‑derived proteins in the urine of patients with nephrotic syndrome using a novel proteomic strategy. Urine samples from 5 patients with nephrotic syndrome were subjected to acetone precipitation and albumin/immunoglobulin G depletion prior to analysis by two‑dimensional liquid chromatography tandem mass spectrometry. The resulting data were compared to a publicly available proteomic database of normal human plasma/urine and normal human kidney in PeptideAtlas, and of normal human kidney in the Human Protein Atlas. Candidate biomarkers were validated using ELISA analysis in 60 patients with nephrotic syndrome: 30 with focal segmental glomerulosclerosis (FSGS) and 30 with minimal change disease (MCD), as well as in 30 healthy controls. The initial screening identified 809 proteins in the urine of patients with nephrotic syndrome. A total of 13/809 proteins were additionally present in the kidney proteome of PeptideAtlas and the Human Protein Atlas, although not in normal human urine and normal human plasma according to PeptideAtlas; these were referred to as 'kidney‑derived disease‑associated proteins'. One of the kidney‑derived disease‑associated proteins, ubiquitin‑60S ribosomal protein L40 (UBA52) was observed to be increased in the urine of patients compared with normal controls [Creatinine, 637 ng/mg (216‑1,851) vs. 1.89 ng/mg (1.37‑3.33), P<0.001; and 18.58 ng/mg (11.11‑46.25) vs. 1.89 ng/mg (1.37‑3.33), P<0.001)], and the urinary UBA52 levels were significantly increased in patients with FSGS compared with in patients with MCD (P<0.001). In conclusion, the present study identified potential novel urinary protein biomarkers for nephrotic syndrome, in addition to an extensive urinary proteomic profile of patients with nephrotic syndrome.

Development of a Silicon-Rhodamine Based Near-Infrared Emissive Two-Photon Fluorescent Probe for Nitric Oxide.

Two-photon (TP) fluorescent probes are potential candidates for near-infrared (NIR) imaging which holds great promise in biological research. However, currently, most TP probes emit at wavelength <600 nm, which impedes their practical applications. In this work, we explored the TP properties of a silicon-rhodamine (SiR) derivative and hence developed the first SiR scaffold based "NIR-to-NIR" TP probe (SiRNO) for nitric oxide (NO). SiRNO exhibited high sensitivity and specificity, as well as fast response for NO detection. It was able to track the subtle variation of intracellular NO content in live cells. Owing to the NIR excitation and emission, SiRNO enabled the detection of NO in situ in the xenograft tumor mouse model, revealing the NO generation during the tumor progression. This work indicates that SiR can be an ideal platform for the development of NIR emissive TP probe and may thus promote the advancement of NIR imaging.

Genome-wide Target Enrichment-aided Chip Design: a 66 K SNP Chip for Cashmere Goat.

Compared with the commercially available single nucleotide polymorphism (SNP) chip based on the Bead Chip technology, the solution hybrid selection (SHS)-based target enrichment SNP chip is not only design-flexible, but also cost-effective for genotype sequencing. In this study, we propose to design an animal SNP chip using the SHS-based target enrichment strategy for the first time. As an update to the international collaboration on goat research, a 66 K SNP chip for cashmere goat was created from the whole-genome sequencing data of 73 individuals. Verification of this 66 K SNP chip with the whole-genome sequencing data of 436 cashmere goats showed that the SNP call rates was between 95.3% and 99.8%. The average sequencing depth for target SNPs were 40X. The capture regions were shown to be 200 bp that flank target SNPs. This chip was further tested in a genome-wide association analysis of cashmere fineness (fiber diameter). Several top hit loci were found marginally associated with signaling pathways involved in hair growth. These results demonstrate that the 66 K SNP chip is a useful tool in the genomic analyses of cashmere goats. The successful chip design shows that the SHS-based target enrichment strategy could be applied to SNP chip design in other species.

Multitarget Therapy for Maintenance Treatment of Lupus Nephritis.

Our previous studies showed that multitarget therapy is superior in efficacy to intravenous cyclophosphamide as an induction treatment for lupus nephritis in Asian populations. We conducted an open label, multicenter study for 18 months as an extension of the prior induction therapy trial in 19 renal centers in China to assess the efficacy and safety of multitarget maintenance therapy in patients who had responded at 24 weeks during the induction phase. Patients who had undergone multitarget induction therapy continued to receive multitarget therapy (tacrolimus, 2-3 mg/d; mycophenolate mofetil, 0.50-0.75 g/d; prednisone, 10 mg/d), and patients who had received intravenous cyclophosphamide induction treatment received azathioprine (2 mg/kg per day) plus prednisone (10 mg/d). We assessed the renal relapse rate during maintenance therapy as the primary outcome. We recruited 116 patients in the multitarget group and 90 patients in the azathioprine group. The multitarget and azathioprine groups had similar cumulative renal relapse rates (5.47% versus 7.62%, respectively; adjusted hazard ratio, 0.82; 95% confidence interval, 0.25 to 2.67; P=0.74), and serum creatinine levels and eGFR remained stable in both groups. The azathioprine group had more adverse events (44.4% versus 16.4% for multitarget therapy; P<0.01), and the multitarget group had a lower withdrawal rate due to adverse events (1.7% versus 8.9% for azathioprine; P=0.02). In conclusion, multitarget therapy as a maintenance treatment for lupus nephritis resulted in a low renal relapse rate and fewer adverse events, suggesting that multitarget therapy is an effective and safe maintenance treatment for patients with lupus nephritis.

A haplotype in CFH family genes confers high risk of rare glomerular nephropathies.

Despite distinct renal lesions, a series of rare glomerular nephropathies are reportedly mediated by complement overactivation. Genetic variations in complement genes contribute to disease risk, but the relationship of genotype to phenotype has not been straightforward. Here, we screened 11 complement genes from 91 patients with atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G) and membranoproliferative glomerulonephritis type I (MPGN I), and identified the concomitant presence of three missense variations located within the human complement Factor H (CFH) gene cluster. The three variations, rs55807605, rs61737525 and rs57960694, have strong linkage disequilibrium; subsequent haplotype analysis indicated that ATA increased the susceptibility of these renal diseases. In silico analysis, the CFHR3 rs61737525-T risk allele altered the physical and structural properties and generated a reduction in binding affinity of the CFHR3/C3b complex. Surface plasmon resonance (SPR) binding analysis further demonstrated the substitution induced a decrease of two orders of magnitude in C3b-binding properties, with a declined cofactor activity in fluid phase. These data suggest that the haplotype carrying the causative allele behaves as a partial C3 convertase deficiency, predisposing individuals to diverse pathologic lesions underlying complement overactivation. Such genotype-phenotype discrepancies allow better understanding about these nephropathies mediated by genetic complement disorders.

Expression of Fox-related genes in the skin follicles of Inner Mongolia Cashmere Goat.

The aim of this study was to investigate the expression of genes in cashmere goats at different periods of their fetal development.

Genome-wide identification of genes essential for podocyte cytoskeletons based on single-cell RNA sequencing.

Gene expression differs substantially among individual cells of the same type. We speculate that genes that are expressed in all but a portion of cells of a given cell type would be likely essential and required for either the cell survival (housekeeping) or for the cell type's unique structure and function, enabling the organism to survive. Here, we performed RNA-seq of 20 mouse podocytes using the Fluidigm C1 system and identified 335 genes that were expressed in all of them. Among them, 239 genes were also expressed in mesangial and endothelial cells and were involved in energy metabolism, protein synthesis, etc., as housekeeping genes. In contrast, 92 genes were preferentially expressed in podocytes (over five-fold versus expression in mesangial and endothelial cells) and are, therefore, the essential candidate genes specific for podocytes. Assessments by bioinformatics, conserved expression in human podocytes, and association with injury/disease all support the essentiality of these genes for podocytes. Factually, 27 of the 92 genes are already known to be essential for podocyte structure and function. Thirty-seven novel genes were functionally analyzed by siRNA silencing, and we found that a deficiency of 30 genes led to either cytoskeletal injury (FGFR1, AOX1, AIF1L, HAUS8, RAB3B, LPIN2, GOLIM4, CERS6, ARHGEF18, ARPC1A, SRGAP1, ITGB5, ILDR2, MPP5, TSC22D1, DNAJC11, SEPT10, MOCS2, FNBP1L, and TMOD3) or significant downregulation of CD2AP and synaptopodin (IFT80, MYOM2, ANXA4, CYB5R4, GPC1, ZNF277, NSF, ITGAV, CRYAB, and MTSS1). Thus, the list of genes essential for podocyte cytoskeletons is expanded by single-cell RNA sequencing. It appears that podocyte-specific essential genes are mainly associated with podocyte cytoskeletons.

Curative effect of 1.88-mg and 3.75-mg gonadotrophin-releasing hormone agonist on stage III-IV endometriosis: Randomized controlled study.

To compare the therapeutic effect of 1.88-mg and 3.75-mg gonadotrophin-releasing hormone agonist (GnRHa) in the treatment of stage III-IV endometriosis after laparoscopic surgery.

Effect of CYP3A4 and CYP3A5 Genetic Polymorphisms on the Pharmacokinetics of Sirolimus in Healthy Chinese Volunteers.

Sirolimus is a promising immunosuppressive drug for preventing the rejection of organ transplants. However, inter-individual variability in sirolimus pharmacokinetics causes adverse drug reactions, compromising therapeutic efficacy. Sirolimus is primarily metabolized by cytochrome CYP3A4 and CYP3A5. This study aimed to clarify the effect of CYP3A genetic polymorphisms, including the CYP3A4*1G and CYP3A5*3 polymorphisms, on the pharmacokinetics of sirolimus.

Oxygen Uptake Efficiency Slope Predicts Poor Outcome in Patients With Idiopathic Pulmonary Arterial Hypertension.

Few published studies have evaluated the power of the oxygen uptake efficiency slope (OUES) to predict outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH), who typically die of right-sided heart failure. Our study sought to evaluate the power of OUES to predict clinical worsening and mortality in patients with IPAH.

An N-nitrosation reactivity-based two-photon fluorescent probe for the specific in situ detection of nitric oxide.

In situ fluorescence imaging of nitric oxide (NO) is a powerful tool for studying the critical roles of NO in biological events. However, the selective imaging of NO is still a challenge because most currently available fluorescent probes rely on the o-phenylenediamine (OPD) recognition site, which reacts with both NO and some abundant reactive carbonyl species (RCS) (such as dehydroascorbic acid and methylglyoxal) and some reactive oxygen/nitrogen species (ROS/RNS). To address this problem, a new fluorescent probe, NCNO, based on the N-nitrosation of aromatic secondary amine was designed to bypass the RCS, ROS, and RNS interference. As was expected, the probe NCNO could recognize NO with pronounced selectivity and sensitivity among ROS, RNS, and RCS. The probe was validated by detecting NO in live cells and deep tissues owing to its two-photon excitation and red-light emission. It was, hence, applied to monitor NO in ischemia reperfusion injury (IRI) in mice kidneys by two-photon microscopy for the first time, and the results vividly revealed the profile of NO generation in situ during the renal IRI process.

Digital pathology imaging as a novel platform for standardization and globalization of quantitative nephropathology.

The introduction of digital pathology to nephrology provides a platform for the development of new methodologies and protocols for visual, morphometric and computer-aided assessment of renal biopsies. Application of digital imaging to pathology made substantial progress over the past decade; it is now in use for education, clinical trials and translational research. Digital pathology evolved as a valuable tool to generate comprehensive structural information in digital form, a key prerequisite for achieving precision pathology for computational biology. The application of this new technology on an international scale is driving novel methods for collaborations, providing unique opportunities but also challenges. Standardization of methods needs to be rigorously evaluated and applied at each step, from specimen processing to scanning, uploading into digital repositories, morphologic, morphometric and computer-aided assessment, data collection and analysis. In this review, we discuss the status and opportunities created by the application of digital imaging to precision nephropathology, and present a vision for the near future.

SENP2 suppresses epithelial-mesenchymal transition of bladder cancer cells through deSUMOylation of TGF-βRI.

SUMO-specific protease 2 (SENP2) is a deSUMOylation protease that plays an important role in the regulation of transforming growth factor-β (TGF-β) signaling. Aberrant TGF-β signaling is common in human cancers and contributes to tumor metastasis by inducing an epithelial-mesenchymal transition (EMT). In previous studies, we demonstrated that SENP2 suppresses bladder cancer cell migration and invasion. However, little is known about whether SENP2 inhibits EMT by regulating TGF-β signaling in bladder cancer progression. Here, we investigated the role of SENP2 in regulating TGF-β signaling and bladder cancer metastasis in vitro and in vivo. We found that SENP2 is frequently downregulated in bladder cancer, especially in metastatic bladder cancer. SENP2 downregulation is associated with more aggressive phenotypes and poor patient outcomes. SENP2 knockdown results in a decrease of E-cadherin and an increase of N-cadherin and fibronectin at both transcript and protein levels, indicating that SENP2 negatively regulates EMT. On the contrary, SENP2 overexpression suppresses TGF-β signaling and TGF-β-induced EMT. We further demonstrated that SENP2 regulates TGF-β signaling partly through deSUMOylation of TGFβ receptor I (TGF-βRI). Functionally, SENP2 suppresses bladder cancer cell invasion in vitro and tumor metastasis in vivo, acts as a tumor suppressor gene in bladder cancer. Our results establish a function of SENP2 in metastatic progression and suggest its candidacy as a new prognostic biomarker and target for clinical management of bladder cancer.

Biomass-involved synthesis of N-substituted benzofuro2,3-dpyrimidine-4-amines and biological evaluation as novel EGFR tyrosine kinase inhibitors.

Shikimic acid (1) is a renewable biomass which could be obtained sustainably through natural product isolation or metabolic engineering. Owing to its great potential in chemical conversion, the value-added utilization of this non-grain biomass has received much attention in recent years. Based on the established transformation route from shikimic acid (1) to methyl 3-dehydroshikimate (3-MDHS, 2) and to the multi-functionalized methyl 2-amino-3-cyanobenzofuran-5-carboxylate (3), we disclose a facile and transition metal-free method to access a series of N-substituted benzofuro[2,3-d]pyrimidine-4-amines in 63%-90% yields. The identification of these compounds as EGFR tyrosine kinase inhibitors has also been described. Among them, compound 5h exhibited the most potent inhibitory effect against EGFR tyrosine kinase with an IC50 of 1.7 nM and excellent antiproliferative activity against A431 and A549 cell lines with a GI50 of 5.1 and 12.3 μM, respectively.

Angiotensin II induces calcium/calcineurin signaling and podocyte injury by downregulating microRNA-30 family members.

Angiotensin II (AngII) is capable of inducing calcium/calcineurin signaling and podocyte injury; however, the precise underlying mechanism is not well understood. Because we have previously demonstrated that microRNA-30s (miR-30s) inhibit calcium/calcineurin signaling in podocytes, we hypothesize that AngII may induce podocyte injury by downregulating miR-30s and thereby activating calcium/calcineurin signaling. To test this hypothesis, we used an AngII-induced podocyte injury mouse model. The mice were treated with AngII via infusion for 28 days, which resulted in hypertension, albuminuria, and glomerular damage. AngII treatment also resulted in a significant reduction of miR-30s and upregulation of calcium/calcineurin signaling components, including TRPC6, PPP3CA, PPP3CB, PPP3R1, and NFATC3, which are the known targets of miR-30s in podocytes. The delivery of miR-30a-expressing lentivirus to the podocytes on day 14 of the infusion ameliorated the AngII-induced podocyte and glomerular injury and attenuated the upregulation of the calcium/calcineurin signaling components. Similarly, treatment with losartan, which is an AngII receptor blocker, also prevented AngII-induced podocyte injury and calcium/calcineurin signaling activation. Notably, losartan was found to sustain miR-30 levels during AngII treatment both in vivo and in vitro. In conclusion, the effect of AngII on podocytes is in part mediated by miR-30s through calcium/calcineurin signaling, a novel mechanism underlying AngII-induced podocyte injury.

A Superior Polymer Electrolyte with Rigid Cyclic Carbonate Backbone for Rechargeable Lithium Ion Batteries.

The fabricating process of well-known Bellcore poly(vinylidene fluoride-hexafluoropropylene) (PVdF-HFP)-based polymer electrolytes is very complicated, tedious, and expensive owing to containing a large amount of fluorine substituents. Herein, a novel kind of poly(vinylene carbonate) (PVCA)-based polymer electrolyte is developed via a facile in situ polymerization method, which possesses the merits of good interfacial compatibility with electrodes. In addition, this polymer electrolyte presents a high ionic conductivity of 5.59 × 10(-4) S cm(-1) and a wide electrochemical stability window exceeding 4.8 V vs Li(+)/Li at ambient temperature. In addition, the rigid cyclic carbonate backbone of poly(vinylene carbonate) endows polymer electrolyte a superior mechanical property. The LiFe0.2Mn0.8PO4/graphite lithium ion batteries using this polymer electrolyte deliver good rate capability and excellent cyclability at room temperature. The superior performance demonstrates that the PVCA-based electrolyte via in situ polymerization is a potential alternative polymer electrolyte for high-performance rechargeable lithium ion batteries.

The research progress of genomic selection in livestock.

With the development of gene chip and breeding technology, genomic selection in plants and animals has become research hotspots in recent years. Genomic selection has been extensively applied to all kinds of economic livestock, due to its high accuracy, short generation intervals and low breeding costs. In this review, we summarize genotyping technology and the methods for genomic breeding value estimation, the latter including the least square method, RR-BLUP, GBLUP, ssGBLUP, BayesA and BayesB. We also cover basic principles of genomic selection and compare their genetic marker ranges, genomic selection accuracy and operational speed. In addition, we list common indicators, methods and influencing factors that are related to genomic selection accuracy. Lastly, we discuss latest applications and the current problems of genomic selection at home and abroad. Importantly, we envision future status of genomic selection research, including multi-trait and multi-population genomic selection, as well as impact of whole genome sequencing and dominant effects on genomic selection. This review will provide some venues for other breeders to further understand genome selection.

RNA Extracted from Formalin-Fixed, Paraffin-Embedded Renal Biopsy Biospecimens: An Evaluation of Alternative Extraction Kits and the Effects of Storage Time.

Klotho restoration via acetylation of Peroxisome Proliferation-Activated Receptor γ reduces the progression of chronic kidney disease.

Klotho is an anti-aging protein mainly expressed in the kidney. Reduced Klotho expression closely correlates with the development and progression of chronic kidney disease (CKD). Klotho is also a downstream gene of Peroxisome Proliferation-Activated Receptor γ (PPARγ), a major transcription factor whose functions are significantly affected by post-translational modifications including acetylation. However, whether PPARγ acetylation regulates renal Klotho expression and function in CKD is unknown. Here we test whether renal damage and reduced Klotho expression in the adenine CKD mouse model can be attenuated by the pan histone deacetylase (HDAC) inhibitor trichostatin A. This inhibition up-regulated Klotho mainly through an enhancement of PPARγ acetylation, stimulation of PPARγ binding to Klotho promoter, and PPARγ-dependent increase in Klotho transcription, with a substantial control of the regulation occurring via PPARγ acetylations on K240 and K265. Consistently trichostatin A-induced reversal of Klotho loss and renoprotective effects were abrogated in PPARγ knockout mice, supporting that PPARγ is an essential acetylation target for Klotho restoration and renal protection. Intriguingly, the kidneys of adenine-fed CKD mice displayed deregulated HDAC3 up-regulation. Selective HDAC3 inhibition effectively alleviated Klotho loss and kidney injury, whereas the protective effects were largely abolished when Klotho was knocked down by siRNA, suggesting that aberrant HDAC3 and Klotho loss are crucial components involved in the renal damage of mice with CKD. Our study identified an important signaling cascade and key components contributing to the pathogenesis of CKD. Thus, targeting Klotho loss by HDAC3 inhibition has promising therapeutic potential for the reduction of CKD progression.

Fibrinogen links podocyte injury with Toll-like receptor 4 and is associated with disease activity in FSGS patients.

Fibrinogen (Fg) is reported to participate in inflammation through Toll-like receptor 4 (TLR4). However, it remains unknown whether Fg might induce podocyte damage through TLR4 and be related to disease activity in patients with focal segmental glomerulosclerosis (FSGS).

The Association of a Genetic Variant in SCAF8-CNKSR3 with Diabetic Kidney Disease and Diabetic Retinopathy in a Chinese Population.

Background. Genome-wide association studies found rs955333 located in 6q25.2 was associated with diabetic kidney disease in multiple ethnic populations, including European Americans, African Americans, and Mexican Americans. We aimed to investigate the association between the variant rs955333 in SCAF8-CNKSR3 and DKD susceptibility in Chinese type 2 diabetes patients. Methods. The variant rs955333 was genotyped in 1884 Chinese type 2 diabetes patients. Associations of the variant rs955333 with DKD and DR susceptibility and related quantitative traits were evaluated. Results. The variant rs955333 was not associated with DKD in our samples, while subjects with genotype GG were associated with DR (P = 0.047, OR = 0.5525 [0.308,0.9911]), and it also showed association with microalbuminuria (P = 0.024, beta = -0.1812 [-0.339, -0.024]). Conclusion. Our data suggests the variant rs955333 was not associated with DKD but showed association with diabetic retinopathy in Chinese type 2 diabetes patients.

Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice.

Bone loss and increased fracture are the devastating outcomes of chronic kidney disease-mineral and bone disorder (CKD-MBD) resulting from Klotho deficit-related mineral disturbance and hyperparathyroidism. Because Klotho down-regulation after renal injury is presumably affected by aberrant histone deacetylase (HDAC) activities, here we assess whether HDAC inhibition prevents Klotho loss and attenuates the CKD-associated bone complication in a mouse model of CKD-MBD. Mice fed adenine-containing diet developed the expected renal damage, a substantial Klotho loss and the deregulated key factors causally affecting bone remodeling, which were accompanied by a marked reduction of bone mineral density. Intriguingly, administration of a potent HDAC inhibitor trichostatin A (TSA) impressively alleviated the Klotho deficit and the observed alterations of serum, kidney and bone. TSA prevented Klotho loss by increasing the promoter-associated histone acetylation, therefore increasing Klotho transcription. More importantly the mice lacking Klotho by siRNA interference largely abolished the TSA protections against the serum and renal abnormalities, and the deranged bone micro-architectures. Thus, our study identified Klotho loss as a key event linking HDAC deregulation to the renal and bone injuries in CKD-MBD mice and demonstrated the therapeutic potentials of endogenous Klotho restoration by HDAC inhibition in treating CKD and the associated extrarenal complications.

A two-photon fluorescent probe for nitroreductase imaging in living cells, tissues and zebrafish under hypoxia conditions.

A two-photon fluorescent probe FNTR for nitroreductase was synthesized by using 9,9-dimethyl-2-acetyl-fluoren-7-methylamino (1) as a two-photon fluorophore and a p-nitrobenzyl carbamate group as a recognition domain for nitroreductase (NTR). The probe and the fluorophore were tested under one- and two-photon modes respectively. After reacting with nitroreductase, FNTR had a 130-fold fluorescence enhancement at 563 nm in 10 min and the maximal two-photon action cross-section value was detected as 66 GM at 750 nm. The probe showed a high sensitivity with a detection limit as low as 23.67 ng ml(-1), high selectivity, low cytotoxicity and good photostability. In the presence of reduced nicotinamide adenine dinucleotide (NADH), endogenous NTR was detected in living cells, tissues and zebrafish. Cobalt chloride was used to induce chemical hypoxia to produce NTR, which generated enhanced fluorescence in cells and tumor tissues. Finally, two-photon fluorescence imaging of NTR was achieved in zebrafish at a penetration depth of up to 200 μm.

A ratiometric two-photon fluorescent probe for imaging hydrogen sulfide in lysosomes.

Hydrogen sulfide (H2S) is a kind of gaseous signalling molecule that plays pivotal role in various biological processes. So far, it is still a challenge to develop convenient and reliable methods for H2S detection in lysosomes. Herein, we developed a novel ratiometric two-photon fluorescent probe LR-H2S for imaging H2S in lysosomes. Upon the addition of H2S (using Na2S as a donor) to LR-H2S in buffer solution, the azide group is reduced to amino group and subsequently the carbamate ester is cleaved by 1,6-elimination, resulting in a fluorescence emission increase at 541nm and a concomitant emission decrease at 475nm. Under two-photon excitation of 840nm, an 80-fold fluorescence ratio (F541/F475) enhancement was observed with a wide linear range of 25-2500μM. The detection limit was calculated to be 0.70μM based on 3σ/k method, indicating that the probe can detect H2S with a high sensitivity. The probe also shows excellent selectivity toward H2S among other biological interference species and features with low cytotoxicity and favorable two-photon properties. Furthermore, LR-H2S can easily localize in lysosomes and vividly illuminate endogenous/exogenous H2S level and distribution in lysosomes of living SGC-7901 cells.