Aberrant activation of the NLRP3 inflammasome promotes the pathogenesis of many inflammatory diseases. The development of the NLRP3 inflammasome inhibitors from existing drugs for new therapeutic ...purposes is becoming more important. Candesartan is an angiotensin II receptor antagonist widely used as a blood pressure-lowering drug; however, the inhibitory potential of candesartan on the NLRP3 inflammasome has not yet been investigated. We demonstrated that candesartan significantly inhibited the NLRP3 inflammasome and pyroptosis in macrophages. Mechanistic analysis revealed that candesartan inhibited the expression of NLRP3 and proIL-1β by suppressing NF-κB activation and reducing the phosphorylation of ERK1/2 and JNK1/2. Candesartan reduced mitochondrial damage and inhibited the NLRP3 inflammasome assembly by suppressing NLRP3 binding to PKR, NEK7 and ASC. In addition, candesartan inhibited IL-1β secretion partially through autophagy induction. Furthermore, oral administration of candesartan reduced peritoneal neutrophil influx, NLRP3 and ASC expression in peritoneal cells, and lavage fluid concentrations of active caspase-1, IL-1β, IL-6 and MCP-1 in uric acid crystal-injected mice. These results indicated that candesartan has board anti-inflammatory effects and has the potential to be repositioned to ameliorate inflammatory diseases or NLRP3-associated complications.
Chronic liver dysfunction usually begins with hepatic fibrosis. To date, no effective anti-fibrotic drugs have been approved for clinical use in humans. In the current work, titanium dioxide (TiO2) ...nanoparticles (NPs) and silicon dioxide (SiO2) NPs are used as active inhibitors with intrinsic chemico-physico properties to block fibrosis and the associated phenotypes through acting on hepatic stellate cells (HSCs, the liver machinery for depositing scar tissues seen in fibrosis). Using LX-2 cells as the HSC model, internalized nanomaterials are found to suppress classical outcomes of cellular fibrosis, for example, inhibiting the expression of collagen I (Col-I) and alpha smooth muscle actin (α-SMA), initiated by transforming growth factor β (TGF-β)-activated HSCs in both a concentration-dependent and a time-dependent manner. Biochemically, these nanomaterials could also facilitate the proteolytic breakdown of collagen by up-regulation of matrix metalloproteinases (MMPs) and down-regulation of tissue inhibitors of MMPs (TIMPs). Furthermore, through regulating epithelial–mesenchymal transition (EMT) genes e.g., E-cadherin (E-Cad) and N-cadherin (N-Cad), the adhesion and migration profiles of TGF-β-activated LX-2 cells treated with nanomaterials were further inhibited, reverting them to a more quiescent state. Thus, the collective results pave the new way that nanomaterials can be used as potential therapeutic inhibitors for the treatment of in vivo fibrosis.
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IJS, KILJ, NUK, PNG, UL, UM
Polyploidy often confers emergent properties, such as the higher fibre productivity and quality of tetraploid cottons than diploid cottons bred for the same environments. Here we show that an abrupt ...five- to sixfold ploidy increase approximately 60 million years (Myr) ago, and allopolyploidy reuniting divergent Gossypium genomes approximately 1-2 Myr ago, conferred about 30-36-fold duplication of ancestral angiosperm (flowering plant) genes in elite cottons (Gossypium hirsutum and Gossypium barbadense), genetic complexity equalled only by Brassica among sequenced angiosperms. Nascent fibre evolution, before allopolyploidy, is elucidated by comparison of spinnable-fibred Gossypium herbaceum A and non-spinnable Gossypium longicalyx F genomes to one another and the outgroup D genome of non-spinnable Gossypium raimondii. The sequence of a G. hirsutum A(t)D(t) (in which 't' indicates tetraploid) cultivar reveals many non-reciprocal DNA exchanges between subgenomes that may have contributed to phenotypic innovation and/or other emergent properties such as ecological adaptation by polyploids. Most DNA-level novelty in G. hirsutum recombines alleles from the D-genome progenitor native to its New World habitat and the Old World A-genome progenitor in which spinnable fibre evolved. Coordinated expression changes in proximal groups of functionally distinct genes, including a nuclear mitochondrial DNA block, may account for clusters of cotton-fibre quantitative trait loci affecting diverse traits. Opportunities abound for dissecting emergent properties of other polyploids, particularly angiosperms, by comparison to diploid progenitors and outgroups.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pipelines are typically used to transport oil, natural gas, water, etc. It is one of the most effective methods for transferring fluids over long distances. However, long-term usage of these pipes ...without maintenance results in the formation of residues, which will pave the way for pipeline accidents and soil contamination. To ensure the safety and protection of resources, these sustainable pipelines need to be inspected to avoid losses. This work aims to investigate various internal defect leaks in the non-uniform thickness of sustainable water pipes that are joined with a pipe expander. The magnetic flux leakage technique was implemented to evaluate these defects by means of a flexible GMR sensor array. An inspection robot containing two units was fabricated with the aid of 3D printing. The power unit provides the necessary thrust to actuate the entire robot whereas the sensing unit is responsible for analyzing the leaks. The robot’s movement is predicted by the MPU6050 and ultrasonic distance sensors that are plotted as motion plots. The sensing unit consists of permanent magnets and a giant magnetoresistance (GMR) array to interrogate the flux leakage in the defect region. The flux leakage from the defects was stored with the help of an Arduino microcontroller, which controls the overall process. In addition, the spring suspension is provided to regulate the motion of the robot. The flux leakage from the defect region was plotted as waveform graphs. Thus, the results are effectively presented and compared. The calculated signal-to-noise ratio (SNR) of the magnetic flux leakages (MFLs) for 4.5 mm-thick pipe defects was 12 to 20.8 dB, and for 6.52 mm-thick pipe defects, it was 9.5 to 19 dB. In sum, the MFL technique provides a reliable method for the sustainable development of water supply to wide areas.
Schistosomiasis is an important tropical disease caused by Schistosoma. Although the pathogenesis of liver fibrosis has been intensively studied, the choice of effective treatment is still ...inadequate. In this study, we aimed to investigate the potential of using Casticin to treat Schistosoma mansoni-induced liver fibrosis.
BALB/c mice were divided into three groups – control, infection, and treatment group. The infection and treatment group were percutaneously infected with 100–120 cercariae. Mice from the treatment group were treated with 20 mg/kg/day Casticin for 14 consecutive days to investigate the potential protective effects of Casticin. Mice were sacrificed and were used for histological, RNA, protein, and parasite burden analysis.
Our results showed that hepatic fibrosis was significantly attenuated, as indicated by histology and reduction of fibrotic markers such as collagen AI, transforming growth factor β (TGF-β), and α-smooth muscle actin (α-SMA). Furthermore, Casticin treatment significantly reduced worm burden. Anthelmintic effect of Casticin was also observed by scanning electron microscopy.
Collectively, our study suggested that Casticin may be a beneficial candidate in treating S. mansoni infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Containing the largest number of species, the orchid family provides not only materials for studying plant evolution and environmental adaptation, but economically and culturally important ornamental ...plants for human society. Previously, we collected genome and transcriptome information of Dendrobium catenatum, Phalaenopsis equestris, and Apostasia shenzhenica which belong to two different subfamilies of Orchidaceae, and developed user-friendly tools to explore the orchid genetic sequences in the OrchidBase 4.0. The OrchidBase 4.0 offers the opportunity for plant science community to compare orchid genomes and transcriptomes and retrieve orchid sequences for further study.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we ...identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized “pattern-block” correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.
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•GWAS identifies variants associated with fingerprint type across all digits•Fingerprint-associated genes are strongly enriched for limb development functions•Evi1 alters dermatoglyphs in mice by modulating limb rather than skin development•Fingerprint patterns are genetically correlated with hand and finger proportions
Genome-wide association scans in Han Chinese individuals and a trans-ethnic meta-analysis reveal genetic regions that are associated with specific fingerprint patterning; functional studies in mouse models confirm a role of EVI1 in early limb development and ridge patterning.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The recent report of superconductivity in nitrogen-doped lutetium hydride (Lu-H-N) at 294 K and 1 GPa brought hope for long-sought-after ambient-condition superconductors. However, the failure of ...scientists worldwide to independently reproduce these results has cast intense skepticism on this exciting claim. In this work, using a reliable experimental protocol, we synthesized Lu-H-N while minimizing extrinsic influences and reproduced the sudden change in resistance near room temperature. With quantitative comparison of the temperature-dependent resistance between Lu-H-N and the pure lutetium before reaction, we were able to clarify that the drastic resistance change is most likely caused by a metal-to-poor-conductor transition rather than by superconductivity. Herein, we also briefly discuss other issues recently raised in relation to the Lu-H-N system.
Stromal cell-derived factor-1 (SDF-1), also known as CXCL12, and its receptor CXC chemokine receptor 4 (CXCR4) express in various kinds of cells in central nervous system. The SDF-1/CXCR4 signaling ...pathway is regulated by diverse biological effects. SDF-1 is up-regulated in the ischemic penumbra following stroke and has been known to be associated with the homing of bone marrow cells to injury. However, the effect of SDF-1α/CXCR4 on cytokine production in microglia is mostly unknown. Here, we demonstrated that SDF-1α enhanced IL-6 production in both primary cultured microglia and BV-2 microglia. We further investigated the signaling pathway involved in IL-6 production stimulated by SDF-1α in microglia. SDF-1α increased IL-6 production in both protein and mRNA levels. These effects were attenuated by ERK, phosphatidylinositol 3-kinase (PI3K), NF-κB inhibitors, and IκB protease inhibitor. Stimulation of microglia with SDF-1α also increased Akt and ERK1/2 phosphorylation. In addition, SDF-1α treatment also increased IκB kinase α/β (IKK α/β) phosphorylation, IκBα phosphorylation, IκBα degradation, p65 phosphorylation at Ser
276, translocation of p65 and p50 from cytosol to nucleus and κB-luciferase activity. Moreover, SDF-1α-mediated increase of κB-luciferase activity was inhibited by pre-transfection of DN-p85, DN-Akt or DN-ERK2. Increase of IKK α/β phosphorylation and binding of p65 and p50 to the NF-κB element were both antagonized by PI3K and ERK inhibitors. Our results demonstrate a mechanism linking SDF-1α and IL-6, and provide additional support for the notion that SDF-1α plays a regulatory role in microglia activation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Liver fibrosis is a histological change often attributed to the activation of hepatic stellate cells (HSCs) and the excessive formation of scar tissues in the liver. Advanced stages of the disease ...frequently lead to cirrhosis. Magnesium isoglycyrrhizinate (MgIG) has been accepted as a hepatoprotective drug with the potential of alleviating inflammatory conditions and thus promote liver recovery from viral- or drug-induced injury. While MgIG has been empirically integrated into the clinics to treat some liver diseases, its anti-fibrotic effect and the associated mechanisms remain poorly characterized. Herein, we demonstrated that 1 mg/ml MgIG attenuated the production of αSMA and collagen-1 in activated HSCs using TGF-β1-induced human HSCs LX2 as the fibrotic cell model. We found that MgIG exerts an inhibitory effect on the TGF-β-SMAD signaling pathway by arresting the binding of downstream transcription factors SMAD2/3 and SMAD4. Furthermore, MgIG was shown to suppress proliferation and induce senescence of activated LX2 cells. Protein expression of p27 and enzymatic activity of senescence-associated β-galactosidase were elevated upon exposure to MgIG. In addition, we observed that exposure of activated LX2 cells to MgIG reduces TGF-β-induced apoptosis. Interestingly, a lower toxicity profile was observed when human fetal hepatocytes LO2 were exposed to the same concentration and duration of the drug, suggesting the specificity of MgIG effect toward activated HSCs. Overall, hepatoprotective concentrations of MgIG is shown to exert a direct effect on liver fibrosis through inhibiting TGF-β-signaling, in which SMAD2/3 pathway could be one of the mechanisms responsible for the fibrotic response, thereby restoring the surviving cells toward a more quiescent phenotype. This provides critical mechanistic insights to support an otherwise empirical therapy.
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