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Mingchao Zhang - Top 30 Publications

Transcriptomic analysis uncovers novel synergistic mechanisms in combination therapy for lupus nephritis.

A recent clinical study showed that combination therapy consisting of mycophenolate mofetil, tacrolimus and steroids was shown to be more effective in achieving complete remission in patients with severe forms of lupus nephritis than conventional therapy consisting of intravenous cyclophosphamide and steroids. To explore the underlying molecular and cellular mechanisms of increased efficacy of the combination therapy regimen, we employed a mouse model of lupus nephritis, MRL/lpr mice, and treated them with monotherapies of prednisone, mycophenolate mofetil, or tacrolimus, or with their combination. Consistent with previous clinical findings, combination therapy markedly improved renal outcome compared to the monotherapies in mice with lupus nephritis. Transcriptomic analysis of their kidneys revealed distinct molecular pathways that were differentially regulated in combination therapy versus monotherapies. Combination therapy not only provided additive immunosuppressive effects, but also induced gene expression and molecular pathways to confer enhanced renoprotection. Specifically, combination therapy inhibited TLR7 expression in the kidneys of mice with lupus nephritis; combination of tacrolimus and mycophenolate mofetil led to better stabilization of the podocyte actin cytoskeleton through the reciprocal regulation of RhoA and Rac1 activities. Combination therapy strongly suppressed the IL-6/Stat3 pathway. These findings were further validated in renal biopsy samples from patients with lupus nephritis before and after treatments with mycophenolate mofetil, tacrolimus or combination therapy. Thus, our study further supports the earlier clinical finding and further provides insights into the molecular basis for increased efficacy of combination therapy.

An All-Silk-Derived Dual-Mode E-skin for Simultaneous Temperature-Pressure Detection.

Flexible skin-mimicking electronics are highly desired for development of smart human-machine interfaces and wearable human-health monitors. Human skins are able to simultaneously detect different information, such as touch, friction, temperature, and humidity. However, due to the mutual interferences of sensors with different functions, it is still a big challenge to fabricate multifunctional electronic skins (E-skins). Herein, a combo temperature-pressure E-skin is reported through assembling a temperature sensor and a strain sensor in both of which flexible and transparent silk-nanofiber-derived carbon fiber membranes (SilkCFM) are used as the active material. The temperature sensor presents high temperature sensitivity of 0.81% per centigrade. The strain sensor shows an extremely high sensitivity with a gauge factor of ∼8350 at 50% strain, enabling the detection of subtle pressure stimuli that induce local strain. Importantly, the structure of the SilkCFM in each sensor is designed to be passive to other stimuli, enabling the integrated E-skin to precisely detect temperature and pressure at the same time. It is demonstrated that the E-skin can detect and distinguish exhaling, finger pressing, and spatial distribution of temperature and pressure, which cannot be realized using single mode sensors. The remarkable performance of the silk-based combo temperature-pressure sensor, together with its green and large-scalable fabrication process, promising its applications in human-machine interfaces and soft electronics.

Clinicopathologic characteristics of light chain proximal tubulopathy with light chain inclusions involving multiple renal cell types

Light chain proximal tubulopathy (LCPT) associated with plasma cell dyscrasias is a rare abnormality, especially cases involving multiple cell types. The aim of this study is to explore the characteristics and outcomes of these diseases. We comprehensively evaluated the clinical-pathological data, treatment, and outcomes of 6 LCPT patients with involvement of multiple cell types. In 3 cases, we found that the inclusions largely existed in tubular cells, while in 2 cases they coexisted in podocytes and tubular cells, and in 1 case they coexisted in histiocytes and tubular cells. The stain features and appearances of inclusions were specific and varied. Five patients displayed κ-light chains with crystal formation, while 1 patient displayed a λ subtype with increased lysosomes instead of crystals. Six patients presented with proteinuria, 4 with renal insufficiency, and 4 with complete or partial Fanconi syndrome. Our findings indicate that tubular cells are the most common location of cytoplasmic inclusions. Cases with κ-light chain storage are more common than λ, and the formation of crystals may be associated with the subtype of light chains. Immunoelectron microscopy could be used to increase sensitivity for the detection and location of monoclonal light chains. Therefore, these patients have some common clinical features with varied pathologic characteristics and prognoses but the same subtype of light chains.

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.

A novel mutation of MIP in a Chinese family with congenital nuclear cataract identified by whole-exome sequencing.

Extremely Black Vertically Aligned Carbon Nanotube Arrays for Solar Steam Generation.

The unique structure of a vertically aligned carbon nanotube (VACNT) array makes it behave most similarly to a blackbody. It is reported that the optical absorptivity of an extremely black VACNT array is about 0.98-0.99 over a large spectral range of 200 nm-200 μm, inspiring us to explore the performance of VACNT arrays in solar energy harvesting. In this work, we report the highly efficient steam generation simply by laminating a layer of VACNT array on the surface of water to harvest solar energy. It is found that under solar illumination the temperature of upper water can significantly increase with obvious water steam generated, indicating the efficient solar energy harvesting and local temperature rise by the thin layer of VACNTs. We found that the evaporation rate of water assisted by VACNT arrays is 10 times that of bare water, which is the highest ratio for solar-thermal-steam generation ever reported. Remarkably, the solar thermal conversion efficiency reached 90%. The excellent performance could be ascribed to the strong optical absorption and local temperature rise induced by the VACNT layer, as well as the ultrafast water transport through the VACNT layer due to the frictionless wall of CNTs. Based on the above, we further demonstrated the application of VACNT arrays in solar-driven desalination.

The susceptibility of FSHB -211G > T and FSHR G-29A, 919A > G, 2039A > G polymorphisms to men infertility: an association study and meta-analysis.

Male infertility is a complex disorder caused by genetic, developmental, endocrine, or environmental factors as well as unknown etiology. Polymorphisms in the follicle stimulating hormone beta subunit (FSHB) (rs10835638, c.-211G > T) and follicle stimulating hormone receptor (FSHR) (rs1394205, c.-29G > A; rs6165, c.919A > G; rs6166, c.2039 A > G) genes might disturb normal spermatogenesis and affect male reproductive ability.

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.

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.

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

Intrinsically Stretchable and Conductive Textile by a Scalable Process for Elastic Wearable Electronics.

The prosperous development of stretchable electronics poses a great demand on stretchable conductive materials that could maintain their electrical conductivity under tensile strain. Previously reported strategies to obtain stretchable conductors usually involve complex structure-fabricating processes or utilization of high-cost nanomaterials. It remains a great challenge to produce stretchable and conductive materials via a scalable and cost-effective process. Herein, a large-scalable pyrolysis strategy is developed for the fabrication of intrinsically stretchable and conductive textile in utilizing low-cost and mass-produced weft-knitted textiles as raw materials. Due to the intrinsic stretchability of the weft-knitted structure and the excellent mechanical and electrical properties of the as-obtained carbonized fibers, the obtained flexible and durable textile could sustain tensile strains up to 125% while keeping a stable electrical conductivity (as shown by a Modal-based textile), thus ensuring its applications in elastic electronics. For demonstration purposes, stretchable supercapacitors and wearable thermal-therapy devices that showed stable performance with the loading of tensile strains have been fabricated. Considering the simplicity and large scalability of the process, the low-cost and mass production of the raw materials, and the superior performances of the as-obtained elastic and conductive textile, this strategy would contribute to the development and industrial production of wearable electronics.

The P20R mutation of αB-crystallin diminishes its anti-apoptotic activity in human lens epithelial cells.

αB-crystallin acts as an anti-apoptosis protein in human lens epithelial (HLE) cells. We recently identified a missense mutation in αB-crystallin that changes proline 20 to an arginine (P20R) in a Chinese family with autosomal dominant congenital posterior polar cataract. The impact of the P20R mutation on the anti-apoptosis function remains unclear. To explore the anti-apoptotic activity of αB-crystallin wild type (αB-wt) and its P20R mutant under oxidative stress, HLE cells were transfected with αB-wt and αB-P20R constructs and expression was measured by western blotting. Flow cytometry and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP digoxigenin nick end-labelling (TUNEL) staining were performed to investigate apoptosis. We found that αB-wt performed a dominant role in inhibiting stress-induced apoptosis, but this function was impeded in cells expressing αB-P20R. The P20R mutant of αB-crystallin exhibits diminished anti-apoptotic activity compared with the native protein.

Classical intracranial chondrosarcoma: A case report.

Intracranial chondrosarcoma is a rare malignant cartilage-forming tumor, with only a small number of cases in the posterior cranial fossa reported previously. The present study reports the case of a 40-year-old male patient who was admitted to Tianjin Huanhu Hospital with a progressive headache and dizziness that had lasted for 2 years. Physical and neurological examinations were normal. Radiography of the skull identified an opaque lesion in the left frontal region of the brain. Cranial computed tomography and magnetic resonance imaging revealed a lesion with calcification and homogenous contrast enhancement in the left frontal region. Subsequently, the patient underwent bicoronal craniotomy and gross total resection of the tumor. Pathological examination confirmed the diagnosis of classical intracranial chondrosarcoma. The patient was discharged 10 days after surgery, with no neurological deficit. One month after initial discharge, the patient underwent γ-knife treatment. A follow-up examination 9 months after surgery revealed that the patient was still alive and had returned to work, with no obvious symptoms or evidence of recurrence.

HLA-DR, and not PLA2R, is expressed on the podocytes in kidney allografts in de novo membranous nephropathy.

Idiopathic membranous nephropathy (IMN) is known to be associated with antibodies acting on the M-type phospholipase A2 receptor (PLA2R) of the podocyte. However, the mechanism underlying de novo membranous nephropathy (dn MN) posttransplantation remains unclear. In this study, we aimed to elucidate the mechanism underlying dn MN.We selected 8 cases with dn MN and compared them to 20 IMN cases. Fifteen cases of stable grafts were selected as controls.Several differences between the dn MN group and the IMN group were detected. IgG4 showed negligible positive staining in patients with dn MN, while it was predominant in the IMN group (1/8 vs 20/20, P < 0.001). Serum anti-PLA2R antibodies and anti-PLA2R antibodies of the podocyte were very few in the dn MN patients; however, these antibodies were detected in most of the IMN patients (serum anti-PLA2R antibodies: 1/8 vs 16/20, P = 0.002, anti-PLA2R antibodies of the podocyte: 0/8 vs 17/20, P < 0.001). The dn MN patients also showed higher ratio of interstitial inflammation, peritubular capillaritis, and peritubular capillary C4d deposition. Importantly, human leukocyte antigens (HLA)-DR expression was detected on the podocytes in most of the dn MN patients, but none of the IMN patients and stable graft patients showed HLA-DR expression.These data suggested that the PLA2R pathway, which is known to play a role in IMN, was not involved in the mechanism underlying dn MN. On the contrary, dn MN might be associated with the alloimmune response directed against the podocyte.

Feeding Single-Walled Carbon Nanotubes or Graphene to Silkworms for Reinforced Silk Fibers.

Silkworm silk is gaining significant attention from both the textile industry and research society because of its outstanding mechanical properties and lustrous appearance. The possibility of creating tougher silks attracts particular research interest. Carbon nanotubes and graphene are widely studied for their use as reinforcement. In this work, we report mechanically enhanced silk directly collected by feeding Bombyx mori larval silkworms with single-walled carbon nanotubes (SWNTs) and graphene. We found that parts of the fed carbon nanomaterials were incorporated into the as-spun silk fibers, whereas the others went into the excrement of silkworms. Spectroscopy study indicated that nanocarbon additions hindered the conformation transition of silk fibroin from random coil and α-helix to β-sheet, which may contribute to increased elongation at break and toughness modules. We further investigated the pyrolysis of modified silk, and a highly developed graphitic structure with obviously enhanced electrical conductivity was obtained through the introduction of SWNTs and graphene. The successful generation of these SWNT- or graphene-embedded silks by in vivo feeding is expected to open up possibilities for the large-scale production of high-strength silk fibers.

Sheath-Core Graphite/Silk Fiber Made by Dry-Meyer-Rod-Coating for Wearable Strain Sensors.

Recent years have witnessed the explosive development of flexible strain sensors. Nanomaterials have been widely utilized to fabricate flexible strain sensors, because of their high flexibility and electrical conductivity. However, the fabrication processes for nanomaterials and the subsequent strain sensors are generally complicated and are manufactured at high cost. In this work, we developed a facile dry-Meyer-rod-coating process to fabricate sheath-core-structured single-fiber strain sensors using ultrafine graphite flakes as the sheath and silk fibers as the core by virtue of their flexibility, high production, and low cost. The fabricated strain sensor exhibits a high sensitivity with a gauge factor of 14.5 within wide workable strain range up to 15%, and outstanding stability (up to 3000 cycles). The single-fiber-based strain sensors could be attached to a human body to detect joint motions or easily integrated into the multidirectional strain sensor for monitoring multiaxial strain, showing great potential applications as wearable strain sensors.

Hyperhomocysteinaemia in rats is associated with erectile dysfunction by impairing endothelial nitric oxide synthase activity.

To investigate the effect of hyperhomocysteinaemia (HHCy) on penile erectile function in a rat model, a methionine-rich diet was used in which erectile function, the reproductive system, and nitric oxide synthase were characterized. The intracavernous pressure, apomorphine experiments, measurement of oxidative stress, hematoxylin and eosin staining, immunohistochemistry analysis, reverse transcription-polymerase chain reactions and measurement of endothelial nitric oxide synthase activity were utilized. Our results showed that erections in the middle-dose, high-dose, and interference (INF) groups were significantly lower than the control (P < 0.05). INF group, being fed with vitamins B and folic acid, demonstrated markedly improved penile erections compared with the middle-dose group (P < 0.05). HHCy-induced eNOS and phospho-eNOS protein expression was reduced and the antioxidant effect was markedly impaired. The data of the present data provide evidence that HHCy is a vascular risk factor for erectile dysfunction by impairing cavernosa endothelial nitric oxide synthase activity. Intake of vitamins B can alleviate this abnormality.

Malate-aspartate shuttle inhibitor aminooxyacetic acid leads to decreased intracellular ATP levels and altered cell cycle of C6 glioma cells by inhibiting glycolysis.

NADH shuttles, including malate-aspartate shuttle (MAS) and glycerol-3-phosphate shuttle, can shuttle the reducing equivalents of cytosolic NADH into mitochondria. It is widely accepted that the major function of NADH shuttles is to increase mitochondrial energy production. Our study tested the hypothesis that the novel major function of NADH shuttles in cancer cells is to maintain glycolysis by decreasing cytosolic NADH/NAD(+) ratios. We found that AOAA, a widely used MAS inhibitor, led to decreased intracellular ATP levels, altered cell cycle and increased apoptosis and necrosis of C6 glioma cells, without affecting the survival of primary astrocyte cultures. AOAA also decreased the glycolytic rate and the levels of extracellular lactate and pyruvate, without affecting the mitochondrial membrane potential of C6 cells. Moreover, the toxic effects of AOAA were completely prevented by pyruvate treatment. Collectively, our study has suggested that AOAA may be used to selectively decrease glioma cell survival, and the major function of MAS in cancer cells may be profoundly different from its major function in normal cells: The major function of MAS in cancer cells is to maintain glycolysis, instead of increasing mitochondrial energy metabolism.

MicroRNA-196a/b Mitigate Renal Fibrosis by Targeting TGF-β Receptor 2.

Organ-specific microRNAs have essential roles in maintaining normal organ function. However, the microRNA profile of the kidney and the role of microRNAs in modulating renal function remain undefined. We performed an unbiased assessment of the genome-wide microRNA expression profile in 14 mouse organs using Solexa deep sequencing and found that microRNA-196a (miR-196a) and miR-196b are selectively expressed in kidney, with 74.37% of mouse total miR-196a and 73.19% of mouse total miR-196b distributed in the kidneys. We confirmed the predominant expression of miR-196a/b in mouse and human kidney, particularly in the glomeruli and tubular epithelium, by quantitative RT-PCR and in situ hybridization assays. During unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis, renal miR-196a/b levels rapidly decreased. Elevation of renal miR-196a/b expression by hydrodynamic-based delivery of a miR-196a/b-expressing plasmid before or shortly after UUO significantly downregulated profibrotic proteins, including collagen 1 and α-smooth muscle actin, and mitigated UUO-induced renal fibrosis. In contrast, depletion of renal miR-196a/b by miR-196a/b antagomirs substantially aggravated UUO-induced renal fibrosis. Mechanistic studies further identified transforming growth factor beta receptor II (TGFβR2) as a common target of miR-196a and miR-196b. Decreasing miR-196a/b expression in human HK2 cells strongly activated TGF-β-Smad signaling and cell fibrosis; whereas increasing miR-196a/b levels in mouse primary cultured tubular epithelial cells inhibited TGF-β-Smad signaling. In the UUO model, miR-196a/b silenced TGF-β-Smad signaling, decreased the expression of collagen 1 and α-smooth muscle actin, and attenuated renal fibrosis. Our findings suggest that elevating renal miR-196a/b levels may be a novel therapeutic strategy for treating renal fibrosis.

Predictive value of GGN and CAG repeat polymorphisms of androgen receptors in testicular cancer: a meta-analysis.

The risk of testicular cancer (TC) is markedly increased in subjects with androgen insensitivity, and previous studies have proposed that GGN and CAG repeats in androgen receptors (AR) could be related to the risk of TC. To evaluate the association between the length of GGN and CAG repeats in AR and TC, a meta-analysis involving 3255 TC cases and 2804 controls was performed. The results suggested that long GGN repeats are associated with an increased risk of TC compared with those < 23 [odds ratio (OR) = 1.22, 95% confidence interval (CI) = 1.05-1.41]; similarly, a subgroup analysis revealed that this association occurred in studies with case sizes > 200, and in the mid-latitude, and seminoma subgroups. The subgroup analysis based on populations, high-latitude, and seminomas/non-seminomas suggested that AR CAG repeat polymorphisms with > 25 and < 21 + > 25 repeats might confer a protective effect to the patients with TC (in the high-latitude subgroup analysis, for > 25 vs. 21-25: OR = 0.54, 95% CI = 0.41-0.70). In contrast, an increased risk of TC was observed for AR CAG repeat polymorphisms with > 25 and < 21 + > 25 repeats in the mid-latitude subgroup (for > 25 vs. 21-25: OR = 1.65, 95% CI = 1.09-2.50). In addition, no associations between the remaining subgroups and male infertility were observed. In short, this meta-analysis suggested that AR GGN and CAG repeat polymorphisms may be involved in the etiology of TC.

Polymorphisms in Protamine 1 and Protamine 2 predict the risk of male infertility: a meta-analysis.

Several studies have investigated the association between polymorphisms in protamine 1 and 2 genes and male infertility risk, with inconsistent results to date. This meta-analysis based on the 13 published case-control studies, including 7350 cases and 6167 controls, was performed to further establish the potential association between the 6 common single nucleotide polymorphisms (rs35576928, rs737008, rs35262993, rs2301365, rs1646022, rs2070923) in protamines 1 and 2 and male infertility. The -190C > A (rs2301365) polymorphism was identified as a risk factor for male infertility under all models. Interestingly, rs1646022 and rs737008 polymorphisms exerted protective effects against male sterility in Asian and population-based under some models. No associations between the remaining SNPs and male sterility were observed.

Aralar plays a significant role in maintaining the survival and mitochondrial membrane potential of BV2 microglia.

NADH shuttles mediate the transfer of the reducing equivalents of cytosolic NADH into mitochondria. Increasing evidence has suggested that malate-aspartate shuttle (MAS), one of the two types of NADH shuttles, plays important roles in certain biological processes. Aralar/AGC1, a Ca(2+)-dependent aspartate-glutamate carrier on mitochondrial membrane, is a component of MAS. It has been reported that Aralar plays crucial roles in linking increased cytosolic Ca(2+) concentrations to enhanced mitochondrial energy metabolism of neurons under certain conditions, while the role of the carrier in cell survival remains unknown. In the current study, we tested our hypothesis that Aralar plays an important role in cell survival, using BV2 microglia as a cellular model. Our study showed that Aralar siRNA-produced decrease in the Aralar level led to a significant reduction of the cell survival. Our FACS-based Annexin V/7-AAD assays also showed that the Aralar siRNA treatment led to a significant increase in apoptosis of the cells. Moreover, the Aralar siRNA treatment led to both mitochondrial depolarization and decreases in the intracellular ATP level of the cells. Collectively, our study has provided the first evidence suggesting that Aralar plays a significant role in cell survival, at least for such cell types as BV2 microglia, possibly by producing mitochondrial depolarization. These observations have also provided novel information for understanding the roles of NADH shuttles in cell survival.

NAD⁺/NADH metabolism and NAD⁺-dependent enzymes in cell death and ischemic brain injury: current advances and therapeutic implications.

NAD(+) and NADH play crucial roles in a variety of biological processes including energy metabolism, mitochondrial functions, and gene expression. Multiple studies have indicated that NAD(+) administration can profoundly decrease oxidative cell death as well as ischemic and traumatic brain injury, suggesting NAD(+) metabolism as a promising therapeutic target for cerebral ischemia and head injury. Cumulating evidence has suggested that NAD(+) can produce its protective effects by multiple mechanisms, including preventing mitochondrial alterations, enhancing energy metabolism, preventing virtually all forms of cell death including apoptosis, necrosis and autophagy, inhibiting inflammation, directly increasing antioxidation capacity of cells and tissues, and activating SIRT1. Increasing evidence has also suggested that NADH metabolism is a potential therapeutic target for treating several neurological disorders. A number of studies have further indicated that multiple NAD(+)-dependent enzymes such as sirtuins, polymerase(ADP-ribose) polymerases (PARPs) and CD38 mediate cell death and multiple biological processes. In this article, an overview of the recent findings regarding the roles of NAD(+)/NADH and NAD(+)-dependent enzymes in cell death and ischemic brain injury is provided. These findings have collectively indicated that NAD(+)/NADH and NAD(+)-dependent enzymes play fundamental roles in oxidative stress-induced cell death and ischemic brain injury, which may become promising therapeutic targets for brain ischemia and multiple other neurological disorders.

Fluorescent carbon nanoparticles for the fluorescent detection of metal ions.

Fluorescent carbon nanoparticles (F-CNPs) as a new kind of fluorescent nanoparticles, have recently attracted considerable research interest in a wide range of applications due to their low-cost and good biocompatibility. The fluorescent detection of metal ions is one of the most important applications. In this review, we first present the general detection mechanism of F-CNPs for the fluorescent detection of metal ions, including fluorescence turn-off, fluorescence turn-on, fluorescence resonance energy transfer (FRET) and ratiometric response. We then focus on the recent advances of F-CNPs in the fluorescent detection of metal ions, including Hg(2+), Cu(2+), Fe(3+), and other metal ions. Further, we discuss the research trends and future prospects of F-CNPs. We envision that more novel F-CNPs-based nanosensors with more accuracy and robustness will be widely used to assay and remove various metal ions, and there will be more practical applications in coming years.

Capillary dilation and rarefaction are correlated with intracapillary inflammation in antibody-mediated rejection.

Antibody-mediated rejection (ABMR) remains one of the major causes of graft loss after renal transplantation. It is dominated by endothelial damage in microcirculation. Clarifying the mechanism of microcirculating damage is obviously a key step to understand the pathogenesis of ABMR. Here we characterized capillary variation in ABMR and its possible mechanisms. Compared with T cell-mediated rejection and stable grafts, there was a significant dilation and rarefaction in peritubular capillaries (PTCs) of the ABMR group; Image-Pro Plus revealed a significantly larger intra-PTC area. Interestingly, the dilation of PTCs was strongly correlated with the intra-PTC cell counting. Moreover, peritubular capillary inflammation is correlated with in situ T-bet expression, and there was a good correlation between the intra-PTC expression of T-bet and the PTC diameter. HIF-1α up-regulation could be observed in ABMR but it was not necessary for capillary dilation. In general, ABMR is characterized with early capillary dilation and rarefaction; our data confirmed that the dilation is strongly correlated with intracapillary inflammation, which in turn is correlated with in situ T-bet expression. T-bet plays an important role in the development of microcirculating injury, and thus it is a potential target for the treatment of ABMR.

HLA-DR overexpression in tubules of renal allografts during early and late renal allograft injuries.

We sought to discover which types of injuries were related to human leukocyte antigen DR expression in acute rejection and late chronic injury in renal allografts.

The diagnostic value of transcription factors T-bet/GATA3 ratio in predicting antibody-mediated rejection.

Previous data showed that the predominance of intraglomerular T-bet or GATA3 is correlated with different mechanisms of rejection, suggesting that the ratio of T-bet/GATA3 might be used to distinguish antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR).

Downregulation of microRNA-30 facilitates podocyte injury and is prevented by glucocorticoids.

MicroRNAs (miRNAs) are essential for podocyte homeostasis, and the miR-30 family may be responsible for this action. However, the exact roles and clinical relevance of miR-30s remain unknown. In this study, we examined the expression of the miR-30 family in the podocytes of patients with FSGS and found that all members are downregulated. Treating cultured human podocytes with TGF-β, LPS, or puromycin aminonucleoside (PAN) also downregulated the miR-30 family. Podocyte cytoskeletal damage and apoptosis caused by treatment with TGF-β or PAN were ameliorated by exogenous miR-30 expression and aggravated by miR-30 knockdown. Moreover, we found that miR-30s exert their protective roles by direct inhibition of Notch1 and p53, which mediate podocyte injury. In rats, treatment with PAN substantially downregulated podocyte miR-30s and induced proteinuria and podocyte injury; however, transfer of exogenous miR-30a to podocytes of PAN-treated rats ameliorated proteinuria and podocyte injury and reduced Notch1 activation. Finally, we demonstrated that glucocorticoid treatment maintains miR-30 expression in cultured podocytes treated with TGF-β, LPS, or PAN and in the podocytes of PAN-treated rats. Glucocorticoid-sustained miR-30 expression associated with reduced Notch1 activation and alleviated podocyte damage. Taken together, these findings demonstrate that miR-30s protect podocytes by targeting Notch1 and p53 and that the loss of miR-30s facilitates podocyte injury. In addition, sustained miR-30 expression may be a novel mechanism underlying the therapeutic effectiveness of glucocorticoids in treating podocytopathy.

Rhein protects pancreatic β-cells from dynamin-related protein-1-mediated mitochondrial fission and cell apoptosis under hyperglycemia.

Rhein, an anthraquinone compound isolated from rhubarb, has been shown to improve glucose metabolism disorders in diabetic mice. The mechanism underlying the protective effect of rhein, however, remains unknown. Here, we demonstrate that rhein can protect the pancreatic β-cells against hyperglycemia-induced cell apoptosis through stabilizing mitochondrial morphology. Oral administration of rhein for 8 or 16 weeks in db/db mice significantly reduced fasting blood glucose (FBG) level and improved glucose tolerance. Cell apoptosis assay using both pancreatic sections and cultured pancreatic β-cells indicated that rhein strongly inhibited β-cell apoptosis. Morphological study showed that rhein was mainly localized at β-cell mitochondria and rhein could preserve mitochondrial ultrastructure by abolishing hyperglycemia-induced mitochondrial fission protein dynamin-related protein 1 (Drp1) expression. Western blot and functional analysis confirmed that rhein protected the pancreatic β-cells against hyperglycemia-induced apoptosis via suppressing mitochondrial Drp1 level. Finally, mechanistic study further suggested that decreased Drp1 level by rhein might be due to its effect on reducing cellular reactive oxygen species. Taken together, our study demonstrates for the first time that rhein can serve as a novel therapeutic agent for hyperglycemia treatment and rhein protects pancreatic β-cells from apoptosis by blocking the hyperglycemia-induced Drp1 expression.

CD20+ B-cell infiltration is related to the time after transplant and poor prognosis of acute cellular rejection in renal transplant.

This study sought to determine the relation between CD20+ B-cell infiltration and time after transplant and outcome of acute cellular rejection in renal allografts.