Identification of KU-55933 as an anti-atherosclerosis compound by using a hemodynamic-based high-throughput drug screening platform.

Several compounds have been used for atherosclerosis treatment, including clinical trials; however, no anti-atherosclerotic drugs based on hemodynamic force-mediated atherogenesis have been discovered. Our previous studies demonstrated that "small mothers against decapentaplegic homolog 1/5" (Smad1/5) is a convergent signaling molecule for chemical [e.g., bone morphogenetic proteins (BMPs)] and mechanical (e.g., disturbed flow) stimulations and hence may serve as a promising hemodynamic-based target for anti-atherosclerosis drug development. The goal of this study was to develop a high-throughput screening (HTS) platform to identify potential compounds that can inhibit disturbed flow- and BMP-induced Smad1/5 activation and atherosclerosis. Through HTS using a Smad1/5 downstream target inhibitor of DNA binding 1 (Id-1) as a luciferase reporter, we demonstrated that KU-55933 and Apicidin suppressed Id-1 expression in AD-293 cells. KU-55933 (10 µM), Apicidin (10 µM), and the combination of half doses of each [1/2(K + A)] inhibited disturbed flow- and BMP4-induced Smad1/5 activation in human vascular endothelial cells (ECs). KU-55933, Apicidin, and 1/2(K + A) treatments caused 50.6%, 47.4%, and 73.3% inhibitions of EC proliferation induced by disturbed flow, respectively, whereas EC inflammation was only suppressed by KU-55933 and 1/2(K + A), but not Apicidin alone. Administrations of KU-55933 and 1/2(K + A) to apolipoprotein E-deficient mice inhibited Smad1/5 activation in ECs in athero-susceptible regions, thereby suppressing endothelial proliferation and inflammation, with the attenuation of atherosclerotic lesions in these mice. A unique drug screening platform has been developed to demonstrate that KU-55933 and its combination with Apicidin are promising therapeutic compounds for atherosclerosis based on hemodynamic considerations.

Benzobisthiadiazole-Based Small Molecular Near-Infrared-II Fluorophores: From Molecular Engineering to Nanophototheranostics.

Organic fluorescent molecules with emission in the second near-infrared (NIR-II) biological window have aroused increasing investigation in cancer phototheranostics. Among these studies, Benzobisthiadiazole (BBT), with high electron affinity, is widely utilized as the electron acceptor in constructing donor-acceptor-donor (D-A-D) structured fluorophores with intensive near-infrared (NIR) absorption and NIR-II fluorescence. Until now, numerous BBT-based NIR-II dyes have been employed in tumor phototheranostics due to their exceptional structure tunability, biocompatibility, and photophysical properties. This review systematically overviews the research progress of BBT-based small molecular NIR-II dyes and focuses on molecule design and bioapplications. First, the molecular engineering strategies to fine-tune the photophysical properties in constructing the high-performance BBT-based NIR-II fluorophores are discussed in detail. Then, their biological applications in optical imaging and phototherapy are highlighted. Finally, the current challenges and future prospects of BBT-based NIR-II fluorescent dyes are also summarized. This review is believed to significantly promote the further progress of BBT-derived NIR-II fluorophores for cancer phototheranostics.

In Vitro Anti-Tumor and Hypoglycemic Effects of Total Flavonoids from Willow Buds.

Salix babylonica L. is a species of willow tree that is widely cultivated worldwide as an ornamental plant, but its medicinal resources have not yet been reasonably developed or utilized. Herein, we extracted and purified the total flavonoids from willow buds (PTFW) for component analysis in order to evaluate their in vitro anti-tumor and hypoglycemic activities. Through Q-Orbitrap LC-MS/MS analysis, a total of 10 flavonoid compounds were identified (including flavones, flavan-3-ols, and flavonols). The inhibitory effects of PTFW on the proliferation of cervical cancer HeLa cells, colon cancer HT-29 cells, and breast cancer MCF7 cells were evaluated using an MTT assay. Moreover, the hypoglycemic activity of PTFW was determined by investigating the inhibitory effects of PTFW on α-amylase and α-glucosidase. The results indicated that PTFW significantly suppressed the proliferation of HeLa cells, HT-29 cells, and MCF7 cells, with IC50 values of 1.432, 0.3476, and 2.297 mg/mL, respectively. PTFW, at different concentrations, had certain inhibitory effects on α-amylase and α-glucosidase, with IC50 values of 2.94 mg/mL and 1.87 mg/mL, respectively. In conclusion, PTFW at different doses exhibits anti-proliferation effects on all three types of cancer cells, particularly on HT-29 cells, and also shows significant hypoglycemic effects. Willow buds have the potential to be used in functional food and pharmaceutical industries.

Exploring the potential mechanisms of Tongmai Jiangtang capsules in treating diabetic nephropathy through multi-dimensional data.

Background: Diabetic nephropathy (DN) is a prevalent and debilitating disease that represents the leading cause of chronic kidney disease which imposes public health challenges Tongmai Jiangtang capsule (TMJT) is commonly used for the treatment of DN, albeit its underlying mechanisms of action are still elusive. Methods: This study retrieved databases to identify the components and collect the targets of TMJT and DN. Target networks were constructed to screen the core components and targets. Samples from the GEO database were utilized to perform analyses of targets and immune cells and obtain significantly differentially expressed core genes (SDECGs). We also selected a machine learning model to screen the feature genes and construct a nomogram. Furthermore, molecular docking, another GEO dataset, and Mendelian randomization (MR) were utilized for preliminary validation. We subsequently clustered the samples based on SDECG expression and consensus clustering and performed analyses between the clusters. Finally, we scored the SDECG score and analyzed the differences between clusters. Results: This study identified 13 SDECGs between DN and normal groups which positively regulated immune cells. We also identified five feature genes (CD40LG, EP300, IL1B, GAPDH, and EGF) which were used to construct a nomogram. MR analysis indicated a causal link between elevated IL1B levels and an increased risk of DN. Clustering analysis divided DN samples into four groups, among which, C1 and CI were mainly highly expressed and most immune cells were up-regulated. C2 and CII were the opposite. Finally, we found significant differences in SDECG scores between C1 and C2, CI and CII, respectively. Conclusion: TMJT may alleviate DN via core components (e.g. Denudatin B, hancinol, hirudinoidine A) targeting SDECGs (e.g. SRC, EGF, GAPDH), with the involvement of feature genes and modulation of immune and inflammation-related pathways. These findings have potential implications for clinical practice and future investigations.

A biomimetic nanoplatform for precise reprogramming of tumor-associated macrophages and NIR-II mediated antitumor immune activation.

The therapeutic effects of photothermal therapy (PTT) are dependent on the photothermal conversion efficiency of photothermal agents (PTAs) in tumors and the subsequent activation of the antitumor immune system. However, the insufficient tumor accumulation of current PTAs and the inevitable recruitment of tumor-associated macrophages (TAMs) could further compromise the antitumor activities of PTT. To address these issues, a biomimetic photothermal nanoplatform Au@Fe-PM is developed for the targeted remodeling of TAMs, which promotes the antitumor immunity of PTT. Au nanorods with second near-infrared (NIR-II) absorptions are fabricated to serve as PTAs to induce immunogenic cell death in tumor cells. The ferric hydroxide shell coated on Au nanorods can release iron ions to repolarize M2-like TAMs into the tumoricidal M1 phenotype via P38 and STAT1-mediated signaling pathways. Moreover, the surface decoration of platelet membranes endows biomimetic nanoplatform with enhanced tumor targeting ability for precise tumor ablation and TAM regulation. Consequently, Au@Fe-PM under NIR-II laser irradiation exhibits significantly higher inhibitory effects in a poor immunogenic 4T1 tumor-bearing mouse model with a 50% complete remission rate compared to conventional PTT (0%). By simultaneously reversing the immunosuppressive tumor microenvironment, this biomimetic nanoplatform offers a promising strategy for enhancing the antitumor efficacy of PTT. STATEMENT OF SIGNIFICANCE: The therapeutic effects of current photothermal therapy (PTT) are hindered by the insufficient tumor accumulation of conventional photothermal agents and the recruitment of immunosuppressive tumor-associated macrophages (TAMs) after PTT. Herein, we report a biomimetic iron-based second near-infrared (NIR-II) photothermal nanoplatform (Au@Fe-PM) for targeted TAMs reprogramming and NIR-II mediated anti-tumor immunity. Au@Fe-PM can actively target the tumor site with the help of surface-decorated platelet membranes. Meanwhile, iron ions would be released from Au@Fe-PM in acidic lysosomes to reprogram TAMs into tumoricidal M1-like macrophages, which promotes the antitumor responses elicited by NIR-II PTT, thereby contributing to remarkable tumor inhibitory effects, with 50% higher complete remission rate than that of conventional PTT.

Potentially hazardous metals in the sediment of a subtropical bay in South China: Spatial variability, contamination assessment and source apportionment.

Potentially hazardous metals (PHMs) in the coastal environment have become a great concern due to their easy bioaccumulation, poor biodegradability and high toxicity. Surface sediment samples were collected in a subtropical bay in South China to analyse the spatial variations, contamination level and potential sources of PHMs. The results indicated that the order of average contents of PHMs in Qinzhou Bay sediment was Zn > Pb > Cr > Cu > As > Hg > Cd. The most important potential ecological risk factor was Hg pollution in the Qinzhou Bay sediments. The positive matrix factorization (PMF) model results indicated that Cu, Pb, Zn, Cd and Cr mainly originated from natural sources while Hg and As were related to coal fired industrial inputs and petroleum production activities. The results could provide a basis for marine management to formulate relevant pollution prevention and control measures.

Capsaicin ameliorates renal fibrosis by inhibiting TGF-ß1-Smad2/3 signaling.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD), characterized by renal fibrosis, is a global refractory disease with few effective therapeutic strategies. It has been reported that capsaicin exerts many pharmacological effects including liver and cardiac fibrosis. However, whether capsaicin plays a therapeutic role in renal fibrosis remains unclear. METHODS: We investigated antifibrotic effects of capsaicin in two mouse renal fibrosis models as follows: C57BL/6J mice were subjected to unilateral ureteral obstruction (UUO) and fed with an adenine-rich diet. We uncovered and verified the mechanisms of capsaicin in human proximal tubular epithelial cells (HK2). We mainly used histochemistry, immunohistochemistry and immunofluorescence staining, western blot assay, biochemical examination and other tools to examine the effects of capsaicin on renal fibrosis and the underlying mechanisms. RESULTS: Capsaicin treatment significantly alleviated fibronectin and collagen depositions in the tubulointerstitium of the injured kidneys from UUO and adenine-fed mice. Meanwhile, capsaicin treatment obviously reduced α-SMA expression. Moreover, capsaicin treatment dramatically protected against the phenotypic alteration of tubular epithelial cells by increasing E-cadherin expression and decreasing vimentin expression during renal fibrosis. Mechanistically, capsaicin treatment effectively suppressed α-SMA and vimentin expressions but promoted E-cadherin expression in HK2 cells mainly through the inhibition of TGF-ß1-Smad2/3 signaling. CONCLUSION: Capsaicin significantly ameliorated renal fibrosis possibly by retarding the activation of myofibroblasts and protecting against the phenotypic alteration of tubular epithelial cells mainly through the inhibition of TGF-ß1-Smad2/3 signaling. Thus, our findings may provide a new insight into the clinical application of capsaicin in renal fibrosis.

Endothelial Yin Yang 1 Phosphorylation at S118 Induces Atherosclerosis Under Flow.

RATIONALE: Disturbed flow occurring in arterial branches and curvatures induces vascular endothelial cell (EC) dysfunction and atherosclerosis. We postulated that disturbed flow plays important role in modulating phosphoprotein expression profiles to regulate endothelial functions and atherogenesis. OBJECTIVE: The goal of this study is to discover novel site-specific phosphorylation alterations induced by disturbed flow in ECs to contribute to atherosclerosis. METHODS AND RESULTS: Quantitative phosphoproteomics analysis of ECs exposed to disturbed flow with low and oscillatory shear stress (0.5±4 dynes/cm2) versus pulsatile shear stress (12±4 dynes/cm2) revealed that oscillatory shear stress induces phospho-YY1S118 (serine [S]118 phosphorylation of Yin Yang 1) in ECs. Elevated phospho-YY1S118 level in ECs was further confirmed to be present in the disturbed flow regions in experimental animals and human atherosclerotic arteries. This disturbed flow-induced EC phospho-YY1S118 is mediated by CK2α (casein kinase 2α) through its direct interaction with YY1. Yeast 2-hybrid library screening and in situ proximity ligation assays demonstrate that phospho-YY1S118 directly binds ZKSCAN4 (zinc finger with KRAB [krüppel-associated box] and SCAN [SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA] domains 4) to induce promoter activity and gene expression of HDM2 (human double minute 2), which consequently induces EC proliferation through downregulation of p53 and p21CIP1. Administration of apoE-deficient (ApoE-/-) mice with CK2-specific inhibitor tetrabromocinnamic acid or atorvastatin inhibits atherosclerosis formation through downregulations of EC phospho-YY1S118 and HDM2. Generation of novel transgenic mice bearing EC-specific overexpression of S118-nonphosphorylatable mutant of YY1 in ApoE-/- mice confirms the critical role of phospho-YY1S118 in promoting atherosclerosis through EC HDM2. CONCLUSIONS: Our findings provide new insights into the mechanisms by which disturbed flow induces endothelial phospho-YY1S118 to promote atherosclerosis, thus indicating phospho-YY1S118 as a potential molecular target for atherosclerosis treatment.

Nanoscale metal-organic frameworks for tumor phototherapy.

Metal-Organic Frameworks (MOFs) are constructed from metal ions/cluster nodes and functional organic ligands through coordination bonds. Owing to the advantages of diverse synthetic methods, easy modification after synthesis, large adsorption capacity for heavy metals, and short equilibrium time, considerable attention has recently been paid to MOFs for tumor phototherapy. Through rational tuning of metal ions and ligands, MOFs present abundant properties for various applications. Light-triggered phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is an emerging cancer treatment approach. Nanosized MOFs can be applied as phototherapeutic agents to accomplish phototherapy with excellent phototherapeutic efficacy. This review outlines the latest advances in the field of phototherapy with various metal ion-based MOFs.

Effect of Foot Reflexology Intervention on Depression, Anxiety, and Sleep Quality in Adults: A Meta-Analysis and Metaregression of Randomized Controlled Trials.

OBJECTIVES: The aim of this study was to conduct a systematic review, meta-analysis, and metaregression to determine the current best available evidence of the efficacy and safety of foot reflexology for adult depression, anxiety, and sleep quality. METHODS: Electronic databases (PubMed, ClinicalKey, ScienceDirect, EMBASE, PsycINFO, and the Cochrane Library) were searched till August, 10, 2020, and the validity of the eligible studies was critically appraised. Randomized controlled trials comparing foot reflexology groups with control groups for adult depression, anxiety, and sleep quality were included. Twenty-six eligible studies were included to assess the effect of foot reflexology intervention on the reducing symptoms of depression and anxiety and improving quality of sleep, respectively, as the primary outcome. RESULTS: Twenty-six randomized controlled trials involving 2,366 participants met the inclusion criteria. The meta-analyses showed that foot reflexology intervention significantly improved adult depression (Hedges' g = -0.921; 95% CI: -1.246 to -0.595; P < 0.001), anxiety (Hedges' g = -1.237; 95% CI -1.682 to -0.791; P < 0.001), and sleep quality (Hedges' g = -1.665; 95% CI -2.361 to -0.970; P < 0.001). Metaregression reveals that an increase in total foot reflexology time (P = 0.002) and duration (P = 0.01) can significantly improve sleep quality. CONCLUSIONS: Foot reflexology may provide additional nonpharmacotherapy intervention for adults suffering from depression, anxiety, or sleep disturbance. However, high quality and rigorous design RCTs in specific population, along with an increase in participants, and a long-term follow-up are recommended in the future.

Alternative splicing of DSP1 enhances snRNA accumulation by promoting transcription termination and recycle of the processing complex.

Small nuclear RNAs (snRNAs) are the basal components of the spliceosome and play crucial roles in splicing. Their biogenesis is spatiotemporally regulated. However, related mechanisms are still poorly understood. Defective in snRNA processing (DSP1) is an essential component of the DSP1 complex that catalyzes plant snRNA 3'-end maturation by cotranscriptional endonucleolytic cleavage of the primary snRNA transcripts (presnRNAs). Here, we show that DSP1 is subjected to alternative splicing in pollens and embryos, resulting in two splicing variants, DSP1α and DSP1ß. Unlike DSP1α, DSP1ß is not required for presnRNA 3'-end cleavage. Rather, it competes with DSP1α for the interaction with CPSF73-I, the catalytic subunit of the DSP1 complex, which promotes efficient release of CPSF73-I and the DNA-dependent RNA polymerease II (Pol II) from the 3' end of snRNA loci thereby facilitates snRNA transcription termination, resulting in increased snRNA levels in pollens. Taken together, this study uncovers a mechanism that spatially regulates snRNA accumulation.

The effect of yoga on sleep quality and insomnia in women with sleep problems: a systematic review and meta-analysis.

BACKGROUND: To examine the effectiveness and safety of yoga of women with sleep problems by performing a systematic review and meta-analysis. METHODS: Medline/PubMed, ClinicalKey, ScienceDirect, Embase, PsycINFO, and the Cochrane Library were searched throughout the month of June, 2019. Randomized controlled trials comparing yoga groups with control groups in women with sleep problems were included. Two reviewers independently evaluated risk of bias by using the risk of bias tool suggested by the Cochrane Collaboration for programming and conducting systematic reviews and meta-analyses. The main outcome measure was sleep quality or the severity of insomnia, which was measured using subjective instruments, such as the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), or objective instruments such as polysomnography, actigraphy, and safety of the intervention. For each outcome, a standardized mean difference (SMD) and confidence intervals (CIs) of 95% were determined. RESULTS: Nineteen studies in this systematic review included 1832 participants. The meta-analysis of the combined data conducted according to Comprehensive Meta-Analysis showed a significant improvement in sleep (SMD = - 0.327, 95% CI = - 0.506 to - 0.148, P < 0.001). Meta-analyses revealed positive effects of yoga using PSQI scores in 16 randomized control trials (RCTs), compared with the control group in improving sleep quality among women using PSQI (SMD = - 0.54; 95% CI = - 0.89 to - 0.19; P = 0.003). However, three RCTs revealed no effects of yoga compared to the control group in reducing insomnia among women using ISI (SMD = - 0.13; 95% CI = - 0.74 to 0.48; P = 0.69). Seven RCTs revealed no evidence for effects of yoga compared with the control group in improving sleep quality for women with breast cancer using PSQI (SMD = - 0.15; 95% CI = - 0.31 to 0.01; P = 0.5). Four RCTs revealed no evidence for the effects of yoga compared with the control group in improving the sleep quality for peri/postmenopausal women using PSQI (SMD = - 0.31; 95% CI = - 0.95 to 0.33; P = 0.34). Yoga was not associated with any serious adverse events. DISCUSSION: This systematic review and meta-analysis demonstrated that yoga intervention in women can be beneficial when compared to non-active control conditions in term of managing sleep problems. The moderator analyses suggest that participants in the non-breast cancer subgroup and participants in the non-peri/postmenopausal subgroup were associated with greater benefits, with a direct correlation of total class time with quality of sleep among other related benefits.

Two-Dimensional Tin Selenide (SnSe) Nanosheets Capable of Mimicking Key Dehydrogenases in Cellular Metabolism.

While dehydrogenases play crucial roles in tricarboxylic acid (TCA) cycle of cell metabolism, which are extensively explored for biomedical and chemical engineering uses, it is a big challenge to overcome the shortcomings (low stability and high costs) of recombinant dehydrogenases. Herein, it is shown that two-dimensional (2D) SnSe is capable of mimicking native dehydrogenases to efficiently catalyze hydrogen transfer from 1-(R)-2-(R')-ethanol groups. In contrary to susceptible native dehydrogenases, lactic dehydrogenase (LDH) for instance, SnSe is extremely tolerant to reaction condition changes (pH, temperature, and organic solvents) and displays extraordinary reusable capability. Structure-activity analysis indicates that the single-atom structure, Sn vacancy, and hydrogen binding affinity of SnSe may be responsible for their catalytic activity. Overall, this is the first report of a 2D SnSe nanozyme to mimic key dehydrogenases in cell metabolism.

DSP1 and DSP4 Act Synergistically in Small Nuclear RNA 3' End Maturation and Pollen Growth.

Small nuclear RNAs (snRNAs) play essential roles in spliceosome assembly and splicing. Most snRNAs are transcribed by the DNA-dependent RNA polymerase II (Pol II) and require 3'-end endonucleolytic cleavage. We have previously shown that the Arabidopsis (Arabidopsis thaliana) Defective in snRNA Processing 1 (DSP1) complex, composed of at least five subunits, is responsible for snRNA 3' maturation and is essential for plant development. Yet it remains unclear how DSP1 complex subunits act together to process snRNAs. Here, we show that DSP4, a member of the metallo-ß-lactamase family, physically interacts with DSP1 through its ß-Casp domain. Null dsp4-1 mutants have pleiotropic developmental defects, including impaired pollen development and reduced pre-snRNA transcription and 3' maturation, resembling the phenotype of the dsp1-1 mutant. Interestingly, dsp1-1 dsp4-1 double mutants exhibit complete male sterility and reduced pre-snRNA transcription and 3'-end maturation, unlike dsp1-1 or dsp4-1 In addition, Pol II occupancy at snRNA loci is lower in dsp1-1 dsp4-1 than in either single mutant. We also detected miscleaved pre-snRNAs in dsp1-1 dsp4-1, but not in dsp1-1 or dsp4-1 Taken together, these data reveal that DSP1 and DSP4 function is essential for pollen development, and that the two cooperatively promote pre-snRNA transcription and 3'-end processing efficiency and accuracy.

Inhibited fatty acid ß-oxidation impairs stress resistance ability in Nile tilapia (Oreochromis niloticus).

Energy metabolism plays important roles in stress resistance and immunity in mammals, however, such functions have not been established in fish. In the present study, Nile tilapia (Oreochromis niloticus) was fed with mildronate, an inhibitor of mitochondrial fatty acid (FA) ß-oxidation, for six weeks subsequently challenged with Aeromonas hydrophila and ammonia nitrogen exposure. Mildronate treatment reduced significantly l-carnitine concentration and mitochondrial FA ß-oxidation efficiency, while it increased lipid accumulation in liver. The fish with inhibited hepatic FA catabolism had lower survival rate when exposed to Aeromonas hydrophila and ammonia nitrogen. Moreover, fish fed mildronate supplemented diet had lower immune enzymes activities and anti-inflammatory cytokine genes expressions, but had higher pro-inflammatory cytokine genes expressions. However, the oxidative stress-related biochemical indexes were not significantly affected by mildronate treatment. Taken together, inhibited mitochondrial FA ß-oxidation impaired stress resistance ability in Nile tilapia mainly through inhibiting immune functions and triggering inflammation. This is the first study showing the regulatory effects of lipid catabolism on stress resistance and immune functions in fish.

Sinomenine Attenuates Angiotensin II-Induced Autophagy via Inhibition of P47-Phox Translocation to the Membrane and Influences Reactive Oxygen Species Generation in Podocytes.

BACKGROUND/AIMS: Sinomenine, a pure alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, and sinomenine hydrochloride (SN) has been successfully used for the therapy of rheumatoid arthritis (RA) and kidney diseases. Autophagy is a cytoprotective mechanism used by podocytes and other cells to alleviate the effects of oxidative stress, and angiotensin II (Ang II) significantly promotes podocyte autophagy. However, excessive autophagy may lead to cell death and podocyte depletion. The present study evaluated the effect of SN in podocytes induced by Ang II. METHODS: Podocytes were pretreated with graded concentrations (10(-8) M ∼ 10(-4) M) of SN and then stimulated with Ang II. The LC3B protein and the p47-phox membrane fraction were measured by Western blot. Autolysosomes were assessed by transmission electron microscopy. FACS was used to quantify the ROS produced by podocytes. The translocation of p47-phox to the membrane was investigated by immunofluorescence. RESULTS: The 10(-8) M ∼ 10(-4) M of SN alone did not effect ROS generation or podocyte autophagy. The 10(-8) M and 10(-6) M SN attenuated Ang II-induced autophagy in podocytes. Furthermore, SN decreased the level of ROS generation in Ang II-induced podocytes via inhibition of NOX subunit p47-phox translocation to the membrane. CONCLUSION: The appropriate concentration of SN attenuated Ang II-induced podocyte autophagy through ROS generation, at least in part, by regulating NOX subunit p47-phox translocation to the membrane.

IgA nephropathy with anti-neutrophil cytoplasmic antibody seropositivity.

BACKGROUND: There are few reports of IgA nephropathy (IgAN) with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: The authors report the clinical and pathological findings in 14 patients with IgAN and ANCA seropositivity. RESULTS: These retrospective cases consisted of 4 men and 10 women with a mean age of 44.4 ± 12.7 years. ANCA-positivity was documented by EUROBlot kits and indirect immunofluorescence in all patients. The results of EUROBlot kits were positive in 14 patients (12 MPO-ANCA, 2 PR3-ANCA). Indirect immunofluorescence was positive in 14 patients (12 P-ANCA, 2 C-ANCA). Three of 14 IgAN with ANCA-positive patients showed severe clinical manifestations with crescents involving a mean of 56% glomeruli, including heavy proteinuria (mean 24-hour urine protein: 3.8 g/d), hematuria and acute renal failure (mean creatinine: 4.5 ± 3.7 mg/dL). The remaining 11 patients with no crescents showed various degrees of proteinuria (mean 24-hour urine protein: 2.4 ± 2.4 g/d), hematuria and serum creatinine levels (median creatinine: 0.9 (IQR, 0.5 - 1.4) mg/dL). The follow-up period for 10 patients had an average length of 14.0 ± 11.2 months. Among the three patients with crescents who had been treated with steroids and cyclophosphamide, one patient became dialysis dependent at the time of biopsy and remained on dialysis after treatment, another died of acute heart failure, and the last one showed improvement in renal function after treatment and did not develop end-stage renal disease (ESRD) 26 months after renal biopsy. The remaining 7 patients with no crescents were treated with steroids, cyclophosphamide, renin-angiotensin system inhibitors, and/or Traditional Chinese Medicine; 6 had stabilized or improved renal function and one progressed to ESRD with worsening renal function. CONCLUSIONS: These findings suggest not all ANCAs are involved in the pathology of IgAN. In patients with IgAN and ANCAs, identification of pathogenic vs. non-pathogenic ANCAs is recommended.

Neuroprotective effect of ethyl acetate extract from gastrodia elata against transient focal cerebral ischemia in rats induced by middle cerebral artery occlusion.

OBJECTIVE: To investigate the protective effect of neuroprotection against transient focal cerebral ischemia of the extract from Tianma (Rhizoma Gastrodiae) and the possible mechanisms underlying the action. METHODS: Cerebral ischemia-reperfusion injury was induced through middle cerebral artery occlusion (MCAO). Adult male Sprague-Dawley rats were randomly divided into four groups: sham-operated, ischemia-reperfusion model, 102.6 mg/kg extract treated and 11.4 mg/kg extract treated groups. The extract was prepared from gastrodia elata with ethyl acetate. The effect of the extract tested on rat neurological deficits and Cerebral index, cerebral infarct volume, brain injury, terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and B-cell lymphoma-2 (Bcl-2) positive cells. RESULTS: The extract was able to reduce neurological scores, cerebral index and cerebral infarction rate. The brain injury was also relieved by the extract. The results of immunofluorescence staining analysis indicated that the extract increased the expression of Bcl-2 and reduced TUNEL-positive cells significantly in the extract treated groups. CONCLUSION: These results suggested that the extract relieved ischemic injury induced by transient focal cerebral ischemia in rats, and this neuroprotective effect might be partially due to the attenuated apoptosis pathway.

Isolation of active compounds from methanol extracts of Toddalia asiatica against Ichthyophthirius multifiliis in goldfish (Carassius auratus).

The parasitic ciliate Ichthyophthirius multifiliis infests all species of freshwater fish and can cause severe economic losses in fish breeding. The present study aims to evaluate the antiparasitic activity of the active components from Toddalia asiatica against I. multifiliis. Bioassay-guided fractionation and isolation of compounds with antiparasitic activity were performed on the methanol extract of T. asiatica yielding two bioactive compounds: chelerythrine and chloroxylonine identified by comparing spectral data (NMR and ESI-MS) with literature values. Results from in vitro antiparasitic assays revealed that chelerythrine and chloroxylonine could be 100% effective against I. multifiliis at the concentration of 1.2 mg L(-1) and 3.5 mg L(-1), with the median effective concentration (EC50) values of 0.55 mg L(-1) and 1.90 mg L(-1) respectively. In vivo experiments demonstrated that fish treated with chelerythrine and chloroxylonine at the concentrations of 1.8 and 8.0 mg L(-1) carried significantly fewer parasites than the control (P<0.05). The acute toxicity (LC50) of chelerythrine for goldfish was 3.3 mg L(-1).

Enhancing effect of a sea cucumber Stichopus japonicus sulfated polysaccharide on neurosphere formation in vitro.

Neural stem/progenitor cells (NSPCs) exhibit therapeutic potential in neuronal diseases. Previously, we reported that a sulfated polysaccharide (HS) from the sea cucumber Stichopus japonicus increased the proliferation of NSPCs. Since the formation of neurospheres is related with NSPCs proliferation, we investigated the mechanism leading to neurosphere formation with and without HS. The results showed that HS significantly promoted neurosphere formation in a dose-dependent manner at concentrations between 2 and 8 µg/ml. Cell cycle analysis showed that HS increased the percentage of cells in S phase by 2.8-fold, as compared with the control. On the other hand, we observed a significantly rapid aggregation of NSPCs, resulting in formation of neurospheres as early as 2 h after HS treatment. However, the aggregation was not caused by chemotactic migration of NSPCs, as evidenced by the transwell chamber assay. Furthermore, the effect of HS on NSPCs was similar to the tumor necrosis factor-α (TNF-α) that activated nuclear factor NF-κB. Thus, we demonstrated that HS was able to promote cell proliferation and aggregation of NSPCs which could lead to the formation of neurospheres, and suggested that HS can serve as an adjuvant for promoting proliferation of NSPCs and formation of neurospheres.