SMARCC2 silencing suppresses oncogenic activation through modulation of chromatin accessibility in breast cancer.

SWI/SNF chromatin remodeling complexes play a key role in gene transcription as epigenetic regulators and are typically considered to act as tumor suppressors in cancers. Compared to other cancer-related components of the SWI/SNF complex, research on SMARCC2, a component of the initial BAF core, has been relatively limited. This study aimed to elucidate the role of SMARCC2 in breast cancer by employing various in vitro and in vivo methods including cell proliferation assays, mammosphere formation, and xenograft models, complemented by RNA-seq, ATAC-seq, and ChIP analyses. The results showed that SMARCC2 silencing surprisingly led to the suppression of breast tumorigenesis, indicating a pro-tumorigenic function for SMARCC2 in breast cancer, which contrasts with the roles of other SWI/SNF subunits. In addition, SMARCC2 depletion reduces cancer stem cell features of breast cancer cells. Mechanistic study showed that SMARCC2 silencing downregulated the oncogenic Ras-PI3K signaling pathway, likely by directly regulating the chromatin accessibility of the enhancers of the key genes such as PIK3CB. Together, these results expand our understanding of the SWI/SNF complex's role in cancer development and identify SMARCC2 as a promising new target for breast cancer therapies.

Study on Low-Temperature Performance Decay of Composite-Modified Porous Asphalt Mixture under Medium- and High-Temperature Water Erosion.

This paper studies the decay law of low-temperature crack resistance performance of rubber powder basalt fiber composite-modified porous asphalt concrete (CM-PAC) under medium- and high-temperature water erosion. Firstly, the prepared Marshall specimens were subjected to water erosion treatment at different temperatures of 20 °C, 40 °C, and 60 °C for 0-15 days. Then, the processed specimens were subjected to low-temperature splitting tests, and acoustic emission data during the splitting test process were collected using an acoustic emission device. It can be seen that the low-temperature splitting strength and low-temperature splitting stiffness modulus of CM-PAC gradually decrease with the increase in water erosion time. The maximum reduction rates of the two compared to the control group reached 72.63% and 91.60%, respectively. The low-temperature splitting failure strain gradually increases. Under the same erosion time, the higher the temperature of water, the more significant the amplitude of changes in the above parameters. In addition, it is shown that as the water erosion time increases, the first stage of loading on the specimen gradually shortens, and the second and third stages gradually advance. As the water temperature increases and the water erosion time prolongs, the acoustic emission energy released by the CM-PAC specimen during the splitting process slightly decreases. The application of acoustic emission technology in the splitting process can clarify the changes in the failure pattern of CM-PAC specimens during the entire loading stage, which can better reveal the impact of medium- to high-temperature water on the performance degradation of CM-PAC.

ROS-Responsive Fluorescent Sensor Array for Precise Diagnosis of Cancer via pH-Controlled Multicolor Gold Nanoclusters.

Intracellular reactive oxygen species (ROS) are closely associated with cancer cell types. Therefore, ROS-based pattern recognition is a promising strategy for precise diagnosis of cancer, but such a possibility has never been reported yet. Herein, we proposed an ROS-responsive fluorescent sensor array based on pH-controlled histidine-templated gold nanoclusters (AuNCs@His) to distinguish cancer cell types and their proliferation states. In this strategy, three types of AuNCs@His with diverse fluorescence profiles were first synthesized by only adjusting the pH value. Upon the addition of various ROS, fluorescence quenching of three types of AuNCs@His occurred with different degrees, thereby forming unique optical "fingerprints", which were well-clustered into several separated groups without overlap by principal component analysis (PCA). The sensing mechanism was attributable to the oxidation of AuNCs@His by ROS, as revealed by X-ray photoemission spectroscopy, Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy, and electrospray ionization mass spectrometry. Based on the ROS-responsive sensing pattern, cancer cell types were successfully differentiated via PCA with 100% accuracy. Additionally, the proposed sensor array exhibited excellent performance in distinguishing the proliferation states of cancer cells, which was supported by the results of the Ki-67 immunohistochemistry assay. Overall, the ROS-responsive fluorescent sensor array can serve as a promising tool for precise diagnosis of cancer, indicating great potential for clinical application.

Effect of Nano-SiO2/PVA on Corrosion Behavior of Steel Rebar Embedded in High-Volume Fly Ash Mortar under Accelerated Chloride Attack.

In this paper, the influence of Nano-silica (NS) and Polyvinyl alcohol (PVA) fibers on the corrosion behavior of steel rebar embedded in high-volume fly ash cement mortars under accelerated chloride attack was studied by using an impressed voltage technique. The PVA fibers used were 1.0 vol.%, and two mass fractions of cement (50 and 60 wt.%) were replaced by fly ash. Four NS mass fractions (0, 0.5, 1.0, and 1.5 wt.%) were utilized in this paper. In addition, the mono and hybrid effects of NS and PVA on the mechanical properties and water absorption of mortar were also studied. The results showed that the incorporation of PVA and nano-SiO2 can improve the flexural and compressive strengths of high-volume fly ash mortar. Generally, the flexural and compressive strengths increased with the increase of nano-SiO2 content. Moreover, the incorporation NS can also reduce the capillary water-absorption rate of cement mortar. The impressed voltage corrosion test indicated that the composite incorporation of nano-SiO2 and PVA can significantly delay the deterioration process of steel bars in mortar, effectively reducing the steel rebar's corrosion level and increasing the exposure time of the surface crack. With hybrid-incorporation 1.0 vol.% PVA and 1.0 wt.% nano-SiO2, the steel rebar had the lowest corrosion degree, which exhibited a mass loss of 49% and increased the broken time by 71% as compared to the control mortar.

Effect of Nano-SiO2/PVA Fiber on Sulfate Resistance of Cement Mortar Containing High-Volume Fly Ash.

Sulfate resistance of high-volume fly ash/cement mortars hybrid containing 0~1.5 wt.% of nano-silica (Nano-SiO2, NS) and 0~1.0 vol.% of polyvinyl alcohol (PVA) fibers was investigated in this study. Fly ash was replaced with Portland cement at levels of 60% by weight. The resistance to sulfate attack was investigated by exposing the mortars to 10 wt.% sodium sulfate (Na2SO4) solutions for 72 days, after which change in mass, compressive, and flexural strengths were determined. For comparison, the compressive and flexural strengths of cement mortar after 100 days of curing in water were also investigated. Microstructural deteriorations caused by sulfate attack were analyzed by using scanning electron microscope (SEM). The test results showed that the combination of NS and PVA fibers was effective in enhancing the mechanical properties and the resistance to sulfate attack. After 28 days curing, the hybrid addition of 1.5 wt.% NS and 1.0 vol.% PVA fibers increased the flexural strength by 90% over the control one without NS and PVA fiber. Moreover, regardless of PVA fibers content, due to the crystal nucleus and pore-filling effects, the adding of 0.5 wt.% NS increased the compressive strength by 67.1~118.2%. Chemical reaction took place between fly ash and Na2SO4 as no un-hydration particles could be observed in the samples immersed in Na2SO4 solutions for 72 days, while a lot of un-hydration fly ash particles could be found in the SEM image of mortar after 100 days curing in water. The chemical reaction production could increase the adhesive property and fill the pores of cement mortar. As a result, the compressive and flexural strengths of cement mortars after immersed in Na2SO4 solution for 72 days, were much higher than that after 28 days curing. Moreover, the compressive strength of mortars incorporating 1.0~1.5 wt.% NS was even higher than that after 100 days curing in water, indicating the combination of Nano-SiO2/PVA fiber is effective in enhancing the resistance to sulfate attack.

Synthesis and biological activity of squaramido-tethered bisbenzimidazoles as synthetic anion transporters.

A series of squaramido-tethered bisbenzimidazoles were synthesized from the reaction of diethyl squarate with substituted 2-aminomethylbenzimidazoles. These conjugates exhibit moderate binding affinity toward chloride anions. They are able to facilitate the transmembrane transport of chloride anions most probably via an anion exchange process, and tend to be more active at acidic pH than at physiological pH. The viability of these conjugates toward four selected solid tumor cell lines was evaluated using an MTT assay and the results suggest that some of these conjugates exhibit moderate cytotoxicity probably in an apoptotic fashion.

Methylprednisolone alleviates multiple sclerosis by expanding myeloid-derived suppressor cells via glucocorticoid receptor ß and S100A8/9 up-regulation.

Methylprednisolone is an effective drug in the treatment of autoimmune disease, such as multiple sclerosis (MS), due to long-acting anti-inflammatory, antiallergic and immunosuppressant. Previous studies have noted the importance of myeloid-derived suppressor cells (MDSC) in MS progression. However, it is still not known whether methylprednisolone could influence the ratio and function of MDSC during MS treatment. In the current study, we found an increased ratio of MDSC at the onset of EAE in mice model; but methylprednisolone pulse therapy (MPPT) did not alter the percentage and suppressive function of MDSC during disease attenuation. However, the percentage of G-MDSC in PBMC significantly increased in patients with MS. Surprisingly, relapsing MS patients showed a significant increase in both M-MDSC and G-MDSC after MPPT. The disease remission positively correlated expansion of MDSC and expression of arginase-1. Additionally, MPPT reduced the expression of inhibitory glucocorticoid (GCs) receptor ß subunit on MDSC while elevating serum levels of immune regulatory S100A8/A9 heterodimer. Thus, MDSC dynamics and function in mouse EAE differ from those in human MS during MPPT. Our study suggested that GCs treatment may help relieve the acute phase of MS by expanding MDSC through up-regulating of GR signalling and S100A8/A9 heterodimers.

Myeloid-Derived Suppressor Cells Promote the Progression of Primary Membranous Nephropathy by Enhancing Th17 Response.

Several studies have confirmed that the myeloid-derived suppressor cells (MDSCs) are closely associated with autoimmune diseases, but their exact role in these processes remains largely unclear. Here, we investigated the role MDSCs in patients with primary membranous nephropathy (PMN). Compared to healthy controls (HCs), PMN patients showed significantly increased number of HLA-DR-CD11b+CD33+ MDSCs in the peripheral blood, including both CD14+CD66b- monocytic and CD14-CD66b+ granulocytic MDSCs. The frequency of MDSCs was positively correlated with the level of serum anti-phospholipase A2 receptor (anti-PLA2R), 24-h urine protein quantification, and disease activity in PMN patients. Consistently, enhanced T helper 2 (Th2) and T helper 17 (Th17) immune responses were positively associated with plasma anti-PLA2R levels, 24-h urine protein quantification, and the disease activity in PMN patients. Moreover, compared to HCs, MDSCs from PMN patients exhibited significantly elevated arginase-1 (ARG-1) production and increased potential to promote Th17 differentiation in vitro in an ARG-1-dependent manner. This study directly demonstrates a pathogenic role for MDSCs in human PMN and provides a molecular mechanism for the pathogenesis of PMN. Our data show that MDSCs may promote PMN disease progression mainly by enhancing Th17 response. Therefore, MDSCs may be an important diagnostic, therapeutic, and prognostic marker for PMN diseases.

Effect of Carbon Nanotube and Styrene-Acrylic Emulsion Additives on Microstructure and Mechanical Characteristics of Cement Paste.

Carbon nanotubes (CNTs) are considered as one of the ideal modifiers of cement materials, since CNTs can improve the mechanical properties of cement paste effectively. However, the interfacial interaction between CNTs and the cement matrix is weak. Moreover, it is difficult to disperse CNTs within cement paste. To overcome these shortages, in this study, CNTs were firstly dispersed into a styrene-acrylic emulsion (SAE). Then the homo-dispersion CNT/SAE emulsion was incorporated into cement paste. The effect of the CNT/SAE hybrid-system on the mechanical properties and microstructure of cement paste was studied. For purposes of comparison, the properties of cement paste mono incorporating CNTs or SAE are also investigated. The results show that CNT/SAE network films could be observed in cement paste by using a field emission scanning electron microscope (FESEM). These network films could bridge the cracks and refine the pores of a cement matrix. Infrared analysis and Raman spectroscopy show that the CNT/SAE hybrid modifier has stronger interfacial adhesion and better load transfer ability over the mono adding of CNTs and SAE emulsion. As a result, the hybrid addition of CNT/SAE significantly improved the flexural strength of cement paste. Especially, the addition of 0.1% CNTs and 15% SAE by mass of cement improved the 28-day flexural strength of cement paste by 21% and 25% as compared to the mono addition of CNTs or SAE, respectively.

CHD4/NuRD complex regulates complement gene expression and correlates with CD8 T cell infiltration in human hepatocellular carcinoma.

BACKGROUNDS: The NuRD (Nucleosome Remodeling and Deacetylation) complex is a repressive complex in gene transcription by modulating chromatin accessibility of target genes to transcription factors and RNA polymerase II. Although individual subunits of the complex have been implicated in many other cancer types, the complex's role in human hepatocellular carcinoma (HCC) is not fully understood. More importantly, the NuRD complex has not yet been investigated as a whole in cancers. METHODS: We analyzed the expression of the NuRD complex in HCC and evaluated the prognostic value of NuRD complex expression in HCC using the RNA-seq data obtained from the TCGA project. We examined the effect of CHD4 knockdown on HCC cell proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition, colony-forming ability, and on complement gene expression. We also performed bioinformatic analyses to investigate the correlation between the NuRD complex expression and immune infiltration. RESULTS: We found that nine subunits, out of 14 subunits of the NuRD complex examined, were significantly overexpressed in HCC, and their expression levels were positively correlated with cancer progression. More importantly, our data also demonstrated that these subunits tended to be overexpressed as a whole in HCC. Subsequent studies demonstrated that knockdown of CHD4 in HCC cells inhibits cell proliferation, migration, invasion, and colony-forming ability and promotes apoptosis of HCC cells, indicating that the CHD4/NuRD complex plays oncogenic roles in HCC. Further analysis revealed that the CHD4/NuRD complex regulates complement gene expression in HCC. Intriguingly, we found that the CHD4/NuRD complex expression was inversely correlated with CD8 T cell infiltration in HCC. CONCLUSIONS: Our data demonstrate that the CHD4/NuRD complex plays an oncogenic role in human HCC and regulates complement gene expression in HCC cells. The results of inverse correlation between the CHD4/NuRD complex and CD8 T cell and DC cell infiltration in HCC suggest that the CHD4/NuRD complex not only plays direct regulatory roles in HCC cells, but also has an impact on the immune microenvironment of HCC.

Experimental study on radon exhalation behavior of heap leaching uranium ore column with dilute sulfuric acid.

In order to study the radon release behavior when heap leaching uranium ores with dilute sulfuric acid, unleached uranium ores from a uranium mine in southern China were selected as test samples. Adopting parameters from leaching processes commonly used in uranium mines, a laboratory experiment was carried out for 21 days with a one-dimensional acid heap leaching experimental column. The surface radon exhalation rate of uranium ore column was determined by static accumulation method while spraying with deionized water and dilute sulfuric acid. The uranium leaching rate and ore column height for all 21 days of the experiment were also measured. The results show that (1) when sprayed with a leaching agent, the surface radon exhalation rate of uranium ore column initially increased with time sharply. After a maximum value was reached, the rate gradually decreased and stabilized. When the spraying stopped, the surface radon exhalation rate of uranium ore column initially decreased, before increasing until it tended to stabilize. (2) During the entirety of the 21-day leaching experiment, the cumulative leaching rate of uranium increased gradually with time. On the other hand, the surface radon exhalation rate of uranium ore column fluctuated, but the leaching of uranium from uranium ores had almost no effect on the radon exhalation rate. (3) There was no linear correlation between the surface radon exhalation rate and the residual height of ore column during leaching, but the collapsing event of ore column was the direct inducing factor of the fluctuation of surface radon exhalation rate.

High FOXK1 expression correlates with poor outcomes in hepatocellular carcinoma and regulates stemness of hepatocellular carcinoma cells.

AIMS: Forkhead box (FOX) proteins constitute a huge family of transcriptional regulators, which are involved in a wide range of cancers. FOXK1 is a little studied member of FOXK subfamily. This study aimed to investigate the potential prognostic value of FOXK1 in human hepatocellular carcinoma (HCC) and explore potential underlying mechanisms. MAIN METHODS: We performed bioinformatic analyses to evaluate the prognostic value of FOXK1 expression in human HCC and to reveal the underlying mechanism by which FOXK1 regulates HCC. RT-PCR, FACS analysis and sphere formation assay were carried out to investigate the role of FOXK1 in regulating liver cancer stem cells. KEY FINDINGS: Our results demonstrated that FOXK1 was overexpressed in human HCC and positively correlated with cancer progression. DNA hypomethylation and gene copy number variation contributed to the overexpression of FOXK1. Importantly, high FOXK1 expression was associated with both low overall survival probability (OS) and low relapse free survival probability (RFS) of HCC patients. Intriguingly, we found that high FOXK1 expression was correlated with activation of stem cell-regulating pathways in human HCC. Knockdown of FOXK1 resulted in downregulation of the cancer stem cell marker EpCAM and ALDH1 and decreased sphere-forming ability of hepatocellular carcinoma cells. SIGNIFICANCE: Overall, our study identified FOXK1 as a new biomarker for prognosis of HCC patients and revealed its role in regulating stemness of hepatocellular carcinoma cells.

Lipo-Dipeptide as an Emulsifier: Performance and Possible Mechanism.

A lipo-dipeptide (C13-lysine-arginine, C13-KR) was designed as a potential emulsifier with good emulsifying properties under acidic condition. Compared with two traditional emulsifiers (whey protein isolate and Tween 80), C13-KR emulsion had the minimum mean size but the highest zeta potential (around +100 mV). Moreover, C13-KR emulsion showed better stability against environmental stresses, such as high salt concentrations and high temperature. The C13-KR particles had the fastest move rate around 400 Hz when it attained an equilibrium state. Furthermore, C13-KR emulsifier could sharply reduce the interfacial tension and had the lowest tension value at the oil/water interface. The interfacial tension of C13-KR emulsifier was only 3.6 mN/m (0.5% w/v). In conclusion, the lipo-dipeptide C13-KR could be considered as an emulsifier to produce emulsion under acidic condition.

[Monocarboxylate transporter 1 enhances the sensitivity of breast cancer cells to 3-bromopyruvate in vitro].

OBJECTIVE: To investigate the role of monocarboxylate transporter 1 (MCT1) in enhancing the sensitivity of breast cancer cells to 3-bromopyruvate (3-BrPA). METHODS: The inhibitory effect of 3-BrPA on the proliferation of breast cancer cells was assessed with MTT assay, and brominated propidium bromide single staining flow cytometry was used for detecting the cell apoptosis. An ELISA kit was used to detect the intracellular levels of hexokinase II, lactate dehydrogenase, lactate, and adenosine triphosphate, and Western blotting was performed to detect the expression of MCT1. MDA-MB-231 cells were transiently transfected with MCT1 cDNA for over-expressing MCT1, and the effect of 3-BrPA on the cell proliferation and adenosine triphosphate level was deteced. RESULTS: 3-BrPA did not produce significant effects on the proliferation and apoptosis of MDA-MB-231 cells, and the cells treated with 200 µmol/L 3-BrPA for 24 h showed an inhibition rate and an apoptosis rate of only 8.72% and 7.8%, respectively. The same treatment, however, produced an inhibition rate and an apoptosis rate of 84.6% and 82.3% in MCF-7 cells, respectively. In MDA-MB-231 cells with MCT1 overexpression, 200 µmol/L 3-BrPA resulted in an inhibition rate of 72.44%, significantly higher than that in the control cells (P<0.05); treatment of the cells with 25, 50, 100, and 200 µmol/L 3-BrPA for 6 h resulted in intracellular adenosine triphosphate levels of 96.98%, 88.44%, 43.3% and 27.56% relative to the control level respectively. CONCLUSION: MCT1 can enhance the sensitivity of breast cancer cells to 3-BrPA possibly by transporting 3-BrPA into cells to inhibit cell glycolysis.

Circulating regulatory B cell subsets in patients with neuromyelitis optica spectrum disorders.

This study analyzed the populations of three different subsets of regulatory B cells (Bregs) in the peripheral blood mononuclear cells (PBMCs) of patients with neuromyelitis optica spectrum disorders (NMOSDs) and explored the relationship between the changes in these subsets of Bregs and the severity of NMOSD. A total of 22 patients with relapsed NMOSDs before treatment were recruited in our study, along with 20 age and gender-matched healthy controls, from May 2015 to March 2016. The percentages and numbers for three different subsets of Bregs including the CD19+CD24hiCD38hi, CD19+CD24hiCD27+, and CD19+CD5+CD1dhi populations were evaluated in parallel by flow cytometry. Afterwards, correlations between the change of three different subsets of Bregs and disease severity were analyzed. We found significantly lower percentages of CD19+CD24hiCD38hi and CD19+CD5+CD1dhi Bregs in NMOSDs patients than in healthy individuals. In contrast, the CD19+CD24hiCD27+ Bregs population was significantly higher in NMOSDs patients than in healthy individuals. However, the three different Bregs subsets showed no significant correlation with expanded disability status scale (EDSS) or annualized relapse rate (ARR). Our findings suggest that the subsets of Bregs may play complex roles in the pathogenesis of NMOSDs and are not correlated with clinical disease severity. Further insights into the potential role of subsets of Bregs could increase our basic knowledge of NMOSDs pathogenesis.

Let-7a gene knockdown protects against cerebral ischemia/reperfusion injury.

The microRNA (miRNA) let-7 was one of the first miRNAs to be discovered, and is highly conserved and widely expressed among species. let-7 expression increases in brain tissue after cerebral ischemia/reperfusion injury; however, no studies have reported let-7 effects on nerve injury after cerebral ischemia/reperfusion injury. To investigate the effects of let-7 gene knockdown on cerebral ischemia/reperfusion injury, we established a rat model of cerebral ischemia/reperfusion injury. Quantitative reverse transcription-polymerase chain reaction demonstrated that 12 hours after cerebral ischemia/reperfusion injury, let-7 expression was up-regulated, peaked at 24 hours, and was still higher than that in control rats after 72 hours. Let-7 gene knockdown in rats suppressed microglial activation and inflammatory factor release, reduced neuronal apoptosis and infarct volume in brain tissue after cerebral ischemia/reperfusion injury. Western blot assays and luciferase assays revealed that mitogen-activated protein kinase phosphatase-1 (MKP1) is a direct target of let-7. Let-7 enhanced phosphorylated p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) expression by down-regulating MKP1. These findings suggest that knockdown of let-7 inhibited the activation of p38 MAPK and JNK signaling pathways by up-regulating MKP1 expression, reduced apoptosis and the inflammatory reaction, and exerted a neuroprotective effect following cerebral ischemia/reperfusion injury.

Role of regulatory b cells in neuroimmunologic disorders.

B lymphocytes augment the immune response by producing antibodies and activating T cells by antigen presentation. Recent studies have highlighted a specific and functionally significant B-cell subset that could downregulate excessive immune and inflammatory responses through a vast array of inhibitory cytokines, such as interleukin (IL)-10 and transforming growth factor-ß (TGF-ß). This subset of B cells is generally referred to as regulatory B cells (Bregs). In addition, recent studies have shown that IL-35-producing Bregs also play a role in downregulation of immunity. Diverse phenotypes of Bregs have been proposed to underlie human disorders and their animal models. Most studies have focused on the role of different subsets of Bregs and Bregs-associated molecules such as IL-10, TGF-ß, and IL-35 in the pathogenesis of neuroimmunologic disorders. Furthermore, Bregs exert regulatory function mainly through suppressing the differentiation of Th1/Th17 cells and promoting regulatory T-cell expansion. Reduced presence of Bregs is reportedly associated with progression of several neuroimmunologic disorders. This Review summarizes the current knowledge on the role of Bregs in neuroimmunologic disorders, including multiple sclerosis, neuromyelitis optica, and myasthenia gravis. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

Alleviation of Lead-Induced Apoptosis by Puerarin via Inhibiting Mitochondrial Permeability Transition Pore Opening in Primary Cultures of Rat Proximal Tubular Cells.

Previous study has demonstrated that mitochondrial-dependent apoptotic pathway is involved in the nephroprotective effect of puerarin (PU) against lead-induced cytotoxicity in primary cultures of rat proximal tubular (rPT) cells. To further clarify how PU exerts its antiapoptotic effects, this study was designed to investigate the role of mitochondrial permeability transition (MPT) and subsequent apoptotic events in the process of PU against Pb-induced cytotoxicity in rPT cells. The results showed that Pb-mediated mitochondrial permeability transition pore (MPTP) opening together with mitochondrial cytochrome c release, activations of caspase-9 and caspase-3, and subsequent poly-ADP-ribose polymerase (PARP) cleavage can be effectively blocked by the addition of PU. Simultaneously, upregulation and downregulation of Bcl-2 and Bax with increased Bcl-2/Bax ratio due to PU administration further alleviated Pb-induced mitochondrial apoptosis. Moreover, PU can reverse Pb-induced ATP depletion by restoring mitochondrial fragmentation to affect ATP production and by regulating expression levels of ANT-1 and ANT-2 to improve ATP transport. In summary, PU produced a significant protection against Pb-induced mitochondrial apoptosis in rPT cells by inhibiting MPTP opening to ameliorate the mitochondrial dysfunction.

Mitochondrial permeability transition and its regulatory components are implicated in apoptosis of primary cultures of rat proximal tubular cells exposed to lead.

Previous studies have already demonstrated that mitochondria play a key role in Pb-induced apoptosis in primary cultures of rat proximal tubular (rPT) cells. To further clarify the underlying mechanism of Pb-induced mitochondrial apoptosis, this study was designed to investigate the role of mitochondrial permeability transition (MPT) and its regulatory components in Pb-induced apoptosis in rPT cells. Mitochondrial permeability transition pore (MPTP) opening together with disruption of mitochondrial ultrastructure, translocation of cytochrome c from mitochondria to cytoplasm and subsequent caspase-3 activation were observed in this study, suggesting that MPT is involved in Pb-induced apoptosis in rPT cells. Simultaneously, Pb-induced caspase-3 activation and apoptosis can be significantly inhibited by three MPTP inhibitors (CsA, DIDS, BA), which target different regulatory components of MPTP (Cyp-D, VDAC, ANT), respectively, demonstrating that Cyp-D, VDAC and ANT participate in MPTP regulation during lead exposure. Moreover, decreased ATP levels and increased ADP/ATP ratio induced by lead treatment can be significantly reversed by BA, indicating that Pb-mediated ANT dysfunction resulted in ATP depletion. In addition, up-regulation of VDAC-1, ANT-1 together with down-regulation of Cyp-D, VDAC-2 and ANT-2 at both the levels of transcription and translation were revealed in rPT cells under lead exposure conditions. In conclusion, Pb-mediated mitochondrial apoptosis in rPT cells is dependent on MPTP opening. Different expression levels in each isoform of three regulatory components contribute to alteration in their functions, which may promote the MPTP opening.

Muscle biopsy and UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene mutation analysis in two Chinese patients with distal myopathy with rimmed vacuoles.

Distal myopathy with rimmed vacuoles is an autosomal recessive genetic disease characterized by weakness of the anterior compartment of the lower limbs, sparing the quadriceps muscle, and rimmed vacuoles in muscle biopsies. The disease is caused by a mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene located on chromosome 9p13.3. We present two cases of Chinese patients with progressive lower extremity weakness. Clinical presentation, laboratory evaluation, electrodiagnostic testing, muscle pathology, and genetic analysis are described. Patient 1 was found to have heterozygous missense mutations (p.C13S and p.G576R) in the GNE gene and patient 2 had a homozygous missense mutation (p.C13S). The mutation p.C13S has been reported previously in China, Japan, and South Korea; however, the mutation p.G576R has not been described previously.