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Background: Cancer/testis antigen-45A1 (CT45A1) is overexpressed in various types of cancer but is not expressed in healthy women. The role of CT45A1 in cervical cancer has not yet been described in the literature. Purpose: The aim of this research was to study the role of CT45A1 in cervical cancer progression and drug resistance, elucidate the mechanisms underlying CT45A1-mediated tumorigenesis and investigate CT45A1 as a biomarker for cervical cancer diagnosis, prognostic prediction, and targeted therapy. Methods: The CT45A1 levels in the tumors from cervical cancer patients were measured using immunohistochemical staining. The role and mechanisms underlying CT45A1-mediated cervical cancer cell tumor growth, invasion, and drug resistance were studied using xenograft mice, cervical cancer cells, immunohistochemistry, RNA-seq, real-time qPCR, Chromatin immunoprecipitation and Western blotting. Results: CT45A1 levels were notably high in the tumor tissues of human cervical cancer patients compared to the paracancerous tissues (p < 0.001). Overexpression of CT45A1 was closely associated with poor prognosis in cervical cancer patients. CT45A1 promoted cervical cancer cell tumor growth, invasion, neovascularization, and drug resistance. Mechanistically, CT45A1 promoted the expression of 128 pro-tumorigenic genes and concurrently activated key signaling pathways, including the oncogenic SRC, ERK, CREB, and YAP/TAZ signaling pathways. Furthermore, CT45A1-mediated tumorigenesis and drug resistance were markedly inhibited by the small molecule lycorine. Conclusion: CT45A1 promotes cervical cancer cell tumorigenesis, neovascularization, and drug resistance by activating oncogenic SRC and downstream tumorigenic signaling pathways. These findings provide new insight into the pathogenesis of cervical cancer and offer a new platform for the development of novel therapeutics against cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Renal fibrosis is the late stage of many chronic kidney diseases (CKD). Clinically, there is almost no effective treatment for renal fibrosis except dialysis. Renshen Guben oral liquid (RSGB) is a Chinese patent medicine approved by National Medical Products Administration (NMPA), which is suitable for clinical patients with chronic nephritis. Currently, the chemical constituents of RSGB remains unclear, and its efficacy and mechanism on renal fibrosis have not been reported. Methods: In our research, ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was employed to describe the chemical profile of RSGB, unilateral ureteral obstruction (UUO) model in mice was established to evaluate the beneficial effect of RSGB on renal fibrosis by biochemical indexes, HE and Masson staining. RNA sequencing and "constituents-targets-pathways" multi-dimensional network was established to mine the mechanisms of RSGB. Key targets were verified by quantitative real-time PCR (qRT-PCR) and western bolt (WB). Results: A total of 201 constituents were identified or tentatively characterized, 15 of which were confirmed with standards. The number of triterpenes was the highest with 49, followed by phenols with 46. RSGB ameliorated the blood urea nitrogen (BUN) and serum creatinine (Scr) levels in serum, normalizing pathological structure of kidney tissue. RNA sequencing revealed that RSGB regulates 226 differential genes, which were involved in kidney development. According to the "constituents-targets-pathways" network, 26 key active constituents may mainly regulate the inflammatory immune system through 88 corresponding targets. qRT-PCR and WB results showed that RSGB inhibited the activation of the Tgfβ1/Smad2/3 pathway, Wnt4/β-Catenin pathway and NGFR/NF-κB pathway. Conclusions: Overall, our study, for the first time, characterized 201 chemical constituents in RSGB, and 26 of them were screened out to alleviates renal fibrosis mainly through Tgfβ1/Smad2/3 pathway, Wnt4/β-catenin pathway and NGFR/NF-κB pathway, which may provide a new research strategy for research on the mechanism of traditional Chinese Medicine. [ABSTRACT FROM AUTHOR]

Summary: Functional regulation and structural maintenance of the different organelles in plants contribute directly to plant development, reproduction and stress responses. To ensure these activities take place effectively, cells have evolved an interconnected network amongst various subcellular compartments, regulating rapid signal transduction and the exchange of biomaterial. Many proteins that regulate membrane connections have recently been identified in plants, and this is the first step in elucidating both the mechanism and function of these connections. Amongst all organelles, the endoplasmic reticulum is the key structure, which likely links most of the different subcellular compartments through membrane contact sites (MCS) and the ER–PM contact sites (EPCS) have been the most intensely studied in plants. However, the molecular composition and function of plant MCS are being found to be different from other eukaryotic systems. In this article, we will summarise the most recent advances in this field and discuss the mechanism and biological relevance of these essential links in plants. [ABSTRACT FROM AUTHOR]

Cyanidin-3-O-glucoside (C3G), an active ingredient in anthocyanins, mainly exists in dark cereals. C3G was investigated for its effect on human gastric cancer (GC) cells, together with its molecular mechanism. The CCK-8 assay results showed that C3G had significant antiproliferative effects on GC cells, but it had little effect on normal cells. Western blot and flow cytometry results showed that C3G regulated the reduction of mitochondrial membrane potential and arrested the cell cycle in the G2/M phase through the AKT signaling pathway, causing the cells to undergo apoptosis. Additionally, in MKN-45 cells, C3G markedly raised intracellular reactive oxygen species (ROS) levels. The wound healing assay and Transwell assay results showed that MKN-45 cell migration was significantly inhibited. Western blot results showed that the expression of E-cadherin protein was upregulated and the expressions of β-catenin, N-cadherin, and Vimentin were downregulated. Additionally, following N-acetylcysteine treatment, the expression levels of these proteins were reduced. In conclusion, C3G caused MKN-45 cells to undergo apoptosis; arrested the cell cycle in the G2/M phase; hindered cell migration; and activated the MAPK, STAT3, and NF-κB signaling pathways, by inducing an increase in ROS levels. Thus, C3G may be a promising new medication for the treatment of GC. [ABSTRACT FROM AUTHOR]

Peimine (PM), a natural product extracted from Fritillaria, has anti‐inflammatory, drug resistance reversal, and other pharmacological effects. The purpose of this study was to investigate the antitumor effects and the molecular mechanisms of PM using gastric cancer MKN‐45 cells. Cell counting kit‐8 assays were used to evaluate the viability of gastric cancer cells after treatment with PM. The results showed that PM significantly reduced the activity of gastric cancer cells, and the effect was most obvious in MKN‐45 cells. Annexin V‐FITC/propidium iodide staining and flow cytometry were used to assess apoptosis of MKN‐45 cells after PM treatment. Our results showed that PM‐induced apoptosis of MKN‐45 cells. Flow cytometry was also used to determine the mitochondrial membrane potential and reactive oxygen species (ROS) levels, and to assess PM‐induced cell‐cycle arrest. Additionally, Western blot was used to analyze the expression of signaling pathway proteins and the relationship between apoptosis and ROS accumulation. Our findings showed that PM destroyed the mitochondria by diminishing the mitochondrial membrane potential. In addition, PM regulated the mitogen‐activated protein kinase (MAPK), signal transducer and activator of transcription 3, and nuclear factor kappa‐B signaling pathways by promoting the accumulation of ROS in MKN‐45 cells. PM also caused cell‐cycle arrest in the G2/M phase by increasing ROS accumulation. Furthermore, PM inhibited cell migration by regulating the Wnt/β‐catenin pathway. In conclusion, PM plays an anticancer role through endogenous apoptosis pathways and by inhibiting cell migration, and it has the potential to be a useful treatment for gastric cancers. [ABSTRACT FROM AUTHOR]

The SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE (SPL) transcription factor play vital roles in plant growth and development. Although 15 SPL family genes have been recognized in the model medical plant Salvia miltiorrhiza Bunge, most of them have not been functionally characterized to date. Here, we performed a careful characterization of SmSPL2, which was expressed in almost all tissues of S. miltiorrhiza and had the highest transcriptional level in the calyx. Meanwhile, SmSPL2 has strong transcriptional activation activity and resides in the nucleus. We obtained overexpression lines of SmSPL2 and rSmSPL2 (miR156-resistant SmSPL2). Morphological changes in roots, including longer length, fewer adventitious roots, decreased lateral root density, and increased fresh weight, were observed in all of these transgenic lines. Two rSmSPL2-overexpressed lines were subjected to transcriptome analysis. Overexpression of rSmSPL2 changed root architectures by inhibiting biosynthesis and signal transduction of auxin, while triggering that of cytokinin. The salvianolic acid B (SalB) concentration was significantly decreased in rSmSPL2-overexpressed lines. Further analysis revealed that SmSPL2 binds directly to the promoters of Sm4CL9, SmTAT1, and SmPAL1 and inhibits their expression. In conclusion, SmSPL2 is a potential gene that efficiently manipulate both root architecture and SalB concentration in S. miltiorrhiza. [ABSTRACT FROM AUTHOR]

Atractylodin (ATR) has anticancer effects on some tumor cells by inducing apoptosis, but its mechanism in lung cancer remains unclear. This study investigates the inhibitory effect of ATR on A549 lung cancer cells. Cell viability was detected by the Cell Counting Kit-8 assay, and results showed that ATR could significantly inhibit the proliferation of A549 cells. Apoptosis was detected by Annexin V-FITC/PI staining, and apoptosis rate and mitochondrial membrane potential were detected by flow cytometry. Results showed that the effect of ATR on the apoptosis of A549 cells was negatively correlated with the change in mitochondrial membrane potential. Western blot analysis showed that ATR regulated apoptosis induced by mitogen-activated protein kinase, signal transducer and activator of transcription 3, and nuclear factor kappa B signaling pathways. Analyses of reactive oxygen species (ROS), cell cycle, and cell migration showed that ATR induced intracellular ROS accumulation as an initiation signal to induce cell cycle arrest regulated by the AKT signaling pathway and cell migration inhibition regulated by the Wnt signaling pathway. Results showed that ATR can inhibit cell proliferation, induce cell apoptosis, induce cell cycle arrest, and inhibit the migration of A549 cells (p < 0.05 was considered statistically significant, * p < 0.05, ** p < 0.01 and *** p < 0.001). [ABSTRACT FROM AUTHOR]

B cell lymphoma/leukemia 10 (BCL10) is an important member of the caspase recruitment domain-containing (CARD) protein family, which plays crucial roles in mediating the host inflammatory response. In the present study, a BCL10 homologue was identified from Pacific oyster Crassostrea gigas (designed as Cg BCL10). The full length cDNA of Cg BCL10 was of 897 bp with an open reading frame of 522 bp encoding a polypeptide of 174 amino acids containing a classical CARD domain. The deduced amino acid sequence of Cg BCL10 shared low similarity with the previously identified BCL10s from other species. In the phylogenetic tree, Cg BCL10 was firstly clustered with Cv BCL10 from Crassostrea virginica and then assigned into the branch of invertebrate BCL10s. The mRNA transcripts of Cg BCL10 were highly expressed in gonad, gill, adductor muscle, and haemocytes. After Vibrio splendidus stimulation, the mRNA expression level of Cg BCL10 in haemocytes increased significantly (p < 0.01) at 24, 72 and 96 h. In Cg BCL10-RNAi oysters, the phosphorylation level of mitogen-activated protein kinases (MAPKs), nuclear translocation of NF-κB/Rel and activator protein-1 (AP-1) in haemocytes were inhibited, and the mRNA expressions of inflammatory cytokines including Cg IL17-1, Cg IL17-2, Cg IL17-3, Cg IL17-6 and Cg TNF all decreased significantly (p < 0.01) at 12 h after V. splendidus stimulation. These results suggested that Cg BCL10 regulated the expression of inflammatory cytokines by activating MAPK kinase, and nuclear translocation of NF-κB/Rel and AP-1 to defense pathogen. • A BCL10 homologue (Cg BCL10) was identified from oyster. • The expression of Cg BCL10 in haemocytes was up-regulated after the stimulation of V. splendidus. • Cg BCL10 mediated the phosphorylation of Cg JNK and Cg P38 to activate MAPK inflammatory signaling pathway. • BCL10 regulated Cg NF-κB/Rel and Cg AP-1 to promote the production of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

1,4-naphthoquinone and its derivatives have attracted widespread attention due to their multiple biological activities, such as induction of cancer cell apoptosis; however, most of these compounds have high cytotoxicity. In this study, in order to reduce their toxicity and increase their potential anti-tumor effects, we synthesized a novel 1,4-naphthoquinone derivative named 2-(naphthalene-2-thio)-5,8-dimethoxy-1,4-naphthoquinone (NTDMNQ), and investigated its apoptotic effects and underlying mechanism. Our results showed that NTDMNQ inhibited the viability of HepG2, Hep3B, and Huh7 human hepatocellular carcinoma (HCC) cells. It also increased the accumulation of cells in the G0/G1 phase of the cell cycle by increasing the expression levels of p-p53, p21 and p27, while decreasing the levels of Cyclin D1, Cyclin E, Cyclin-dependent kinase 2 (CDK2), CDK4, and CDK6. Inhibition of reactive oxygen species (ROS) by the ROS scavenger N-acetyl-L-cysteine (NAC) decreased apoptosis in NTDMNQ-treated cells. Western blot analysis showed that NTDMNQ increased the phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and decreased the phosphorylation of extracellular signal-regulated kinase (ERK), AKT, and signal transducer and activator of transcription-3 (STAT3); these effects were blocked by NAC. Both the JNK inhibitor (SP600125) and p38 inhibitor (SB203580) reversed the phosphorylation of STAT3, and the ERK inhibitor (FR180204) and AKT inhibitor (LY294002) reduced the expression of STAT3. Taken together, these findings suggest that NTDMNQ induces apoptosis via ROS-mediated MAPK, AKT and STAT3 signaling pathways in HepG2 cells, and may be a potent anticancer agent. [ABSTRACT FROM AUTHOR]

Background: 18β-glycyrrhetinic acid (18β-Gly), which is extracted from licorice root, has various pharmacological properties; however, its anti-cancer effects on lung cancer cells have not been fully established. Purpose: In this study, we investigated the underlying molecular mechanisms of 18β-Gly. Results: Our results showed that 18β-Gly had significant cytotoxic effects and no apparent side effects. 18β-Gly induced mitochondria-dependent apoptosis of A549 lung cancer cells. In addition, after treatment with 18β-Gly, intracellular reactive oxygen species (ROS) levels were significantly increased, and G2/M cell cycle arrest and inhibition of cell migration were induced via the mitogen-activated protein kinase (MAPK)/signal transducer and activator of transcription 3 (STAT3)/nuclear factor kappa (NF-κB) signaling pathways. After pretreatment with the ROS scavenger N-acetyl-L-cysteine or MAPK inhibitors, the expression levels of phosphorylated p38 (p-p38), phosphorylated c-Jun N-terminal kinase, inhibitor of nuclear factor kappa B, cleaved caspase-3 (cle-cas-3), cleaved poly (ADP ribose) polymerase (cle-PARP), p-p53, p27, p21, and E-cadherin were decreased; and levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, NF-κB, Bcl-2, cyclin B1, cyclase-dependent kinase 1/2 (CDK1/2), N-cadherin, vimentin, and snail homolog 1 (SNAI 1) were increased. In addition, the percentage of cells in the G2/M phase was decreased, and inhibition of migration was reduced. Conclusion: In summary, 18β-Gly induced apoptosis and G2/M cell cycle arrest and inhibited migration via the ROS/MAPK/STAT3/NF-κB signaling pathways in A549 lung cancer cells. Therefore, 18β-Gly is a novel promising candidate for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

10-Hydroxy-2-decenoic acid (10-HDA), also known as royal jelly acid, has a variety of physiological functions, and recent studies have shown that it also has anticancer effects. However, its anticancer mechanisms have not been clearly defined. In this study, we investigated the underlying mechanisms of 10-HDA in A549 human lung cancer cells. We used Cell Counting Kit-8 assay, scratch wound healing assay, flow cytometry, and western blot analysis to investigate its apoptotic effects and underlying mechanism. Our results showed that 10-HDA inhibited the proliferation of three types of human lung cancer cells and had no significant toxic effects on normal cells. Accompanying reactive oxygen species (ROS), 10-HDA induced A549 cell apoptosis by regulating mitochondrial-associated apoptosis, and caused cell cycle arrest at the G0/G1 phase in a time-dependent manner. Meanwhile, 10-HDA also regulated mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) signaling pathways by increasing the expression levels of phosphorylated c-Jun N-terminal kinase, p-p38, and I-κB, and additionally, by decreasing the expression levels of phosphorylated extracellular signal-regulated kinase, p-STAT3, and NF-κB. These effects were blocked by MAPK inhibitors and N-acetyl-L-cysteine. Furthermore, 10-HDA inhibited cell migration by regulating transforming growth factor beta 1 (TGF-β1), SNAI1, GSK-3β, E-cadherin, N-cadherin, and vimentin. Taken together, the results of this study showed that 10-HDA induced cell cycle arrest and apoptosis in A549 human lung cancer cells through ROS-mediated MAPK, STAT3, NF-κB, and TGF-β1 signaling pathways. Therefore, 10-HDA may be a potential therapy for human lung cancer. [ABSTRACT FROM AUTHOR]

BYSL , which encodes the human bystin protein, is a sensitive marker for astrocyte proliferation during brain damage and inflammation. Previous studies have revealed that BYSL has important roles in embryo implantation and prostate cancer infiltration. However, the role and mechanism of BYSL in glioblastoma (GBM) cell migration and invasion remain unknown. We found that knockdown of BYSL inhibited cell migration and invasion, downregulated the expression of mesenchymal markers (e.g., β-catenin and N-cadherin), and upregulated the expression of epithelial marker E-cadherin in GBM cell lines. Overexpression of BYSL promoted GBM cell migration, invasion, and epithelial-mesenchymal transition (EMT). In addition, the role of BYSL in promoting EMT was further confirmed in a glioma stem cell line derived from a GBM patient. Mechanistically, overexpression of BYSL increased the phosphorylation of GSK-3β and the nuclear distribution of β-catenin. Inhibition of GSK-3β by 1-Azakenpaullone could partially reverse the effects of BYSL downregulation on the transcriptional activity of β-catenin, the expression of EMT markers, and GBM cell migration/invasion. Moreover, immunohistochemical analysis showed strong expression of BYSL in GBM tissues, which was positively correlated with markers of mesenchymal GBM. These results suggest that BYSL promotes GBM cell migration, invasion, and EMT through the GSK-3β/β-catenin signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: Plasmablasts play important roles in autoimmune diseases, including systemic lupus erythematosus (SLE). Activation of mechanistic target of rapamycin complex 1 (mTORC1) is regulated by amino acid levels. In patients with SLE, mTORC1 is activated in B cells and modulates plasmablast differentiation. However, the detailed mechanisms of amino acid metabolism in plasmablast differentiation remain elusive. We undertook this study to evaluate the effects of methionine in human B cells. Methods: Purified CD19+ cells from healthy donors (n = 21) or patients with SLE (n = 35) were cultured with Toll‐like receptor 7/9 ligand, interferon‐α (IFNα), and B cell receptor crosslinking, and we determined the types of amino acids that were important for plasmablast differentiation and amino acid metabolism. We also identified the transcriptional regulatory mechanisms induced by amino acid metabolism, and we assessed B cell metabolism and its relevance to SLE. Results: The essential amino acid methionine strongly committed cells to plasmablast differentiation. In the presence of methionine, Syk and mTORC1 activation synergistically induced methyltransferase EZH2 expression. EZH2 induced H3K27me3 at BTB and CNC homolog 2 (Bach2) loci and suppressed Bach2 expression, leading to induction of B lymphocyte–induced maturation protein 1 and X‐box binding protein 1 expression and plasmablast differentiation. CD19+ cells from patients with SLE overexpressed EZH2, which was correlated with disease activity and autoantibody production. Conclusion: Our findings show that methionine activated signaling by controlling immunologic metabolism in B cells and played an important role in the differentiation of B cells into plasmablasts through epigenome modification of Bach2 by the methyltransferase EZH2. [ABSTRACT FROM AUTHOR]

Currently, gastric cancer treatment is mainly based on first-line intervention with oxaliplatin (OXA) after surgical resection, but the application of OXA has been limited due to the toxic side effects caused by the cumulative dose. The toxicity of OXA mainly includes hepatotoxicity, nephrotoxicity, and ototoxicity, and there is an urgent clinical need to find alternatives that are less toxic and more effective. Rutin (RT) is a natural flavonoid with many biological activities. Studies have found that RT inhibits tumor cell growth and enhances their sensitivity toward certain drugs. As the underlying impact of RT on gastric cancer and its molecular mechanism remain poorly understood, we performed a series of experiments to determine whether RT has the effect of treating gastric cancer, and whether it can cooperate with OXA to treat gastric cancer and its related mechanisms. In the present study, we founded that RT suppressed cell viability, inhibited cell proliferation by causing G0/G1 arrest, and induced apoptosis in SGC 7901 cells. And RT can play as an antitumor agent together with OXA. The mechanism of RT-induced apoptosis may be associated with the activation of the p38/Caspase signal pathway. These results demonstrated the potential of RT as a promising therapeutic compound to treat gastric cancer. At the same time, RT can synergize with OXA to reduce the dose of OXA and reduce the toxicity. [ABSTRACT FROM AUTHOR]

Objective. Icariin plays a pivotal role in ameliorating atherosclerosis for animal models although its comprehensive biological role remains largely unexplored. This study aimed to fully understand the effects of icariin on atherosclerosis in high-fat diet-induced ApoE-/- mice and investigate mRNA-miRNA regulation based on microarray and bioinformatics analysis. Methods. The areas of atherosclerotic lesions in en face aorta were evaluated. Microarray analysis was performed on atherosclerotic aortic tissues. The integrative analysis of mRNA and miRNA profiling was utilized to suggest specific functions of gene and supply an integrated and corresponding method to study the protective effect of icariin on atherosclerosis. Results. Icariin attenuated the development of atherosclerosis that the mean atherosclerotic lesion area was reduced by 5.8% (P < 0.05). Significant changes were observed in mRNA and miRNA expression patterns. Several miRNAs obtained from the miRNA-Gene-Network might play paramount part in antiatherosclerotic effect of icariin, such as mmu-miR-6931-5p, mmu-miR-3547-5p, mmu-miR-5107-5p, mmu-miR-6368, and mmu-miR-7118-5p. Specific miRNAs and GO terms associated with icariin in the pathogenesis of atherosclerosis were validated using GO analysis and miRNA-GO-Network. MiRNA-Pathway-Network indicated that icariin induced miRNAs mainly regulate the signaling pathways of PI3K/Akt signaling pathway, Ras signaling pathway, ErbB signaling pathway, and VEGF signaling pathway in aorta atherosclerotic lesion. Conclusions. Our data provides evidence that icariin is able to exhibit one antiatherosclerotic action by mediating multiple biological processes or cascades, suggesting the pleiotropic effects of icariin in atherosclerosis alleviation. The identified gene functional categories and pathways are potentially valuable targets for future development of RNA-guided gene regulation to fight disease. [ABSTRACT FROM AUTHOR]

The RIO (right open reading frame) protein kinases include RIOK1, RIOK2 and RIOK3. Emerging evidence has suggested an important role of RIO kinases in cancer cell proliferation, apoptosis, migration and invasion. However, the expression profile and specific roles of RIOK3 are largely unknown during glioma progression. In the current study, quantitative real-time PCR, Western blot, and immunohistochemical analysis showed that RIOK3 was upregulated in glioma tissues. Available database analysis revealed that higher levels of RIOK3 were associated with poorer survival outcome in glioma patients. Flow cytometry, CCK8 and EdU assays showed that downregulation of RIOK3 arrested cell cycle progression and inhibited glioma cell proliferation. Wound healing, transwell and gelatin zymography assays revealed that silencing RIOK3 decreased glioma cell migration and invasion. Furthermore, the downregulation of RIOK3 significantly decreased the activity of AKT/mTOR signaling and induced apoptosis in glioma cells. Overexpression of RIOK3 showed the opposite effects on glioma cell proliferation, migration, invasion and the AKT/mTOR pathway. These results indicate that high RIOK3 levels in gliomas appear to contribute to the growth and expansion of this cancer, and may thus serve as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Moxibustion is a traditional medical intervention of traditional Chinese medicine. It refers to the direct or indirect application of ignited moxa wool made of mugwort leaves to acupuncture points or other specific parts of the body for either treating or preventing diseases. Moxibustion has been proven to be effective in treating skin lesions of psoriasis. This study was performed to elucidate molecular mechanisms underlying the effects of moxibustion treatment on imiquimod-induced psoriatic mice. We established an imiquimod (IMQ)-induced psoriatic mice (Model) and assessed the effects of moxibustion (Moxi) treatment on skin lesions of psoriatic mice by the PASI scores and expressions of inflammation-related factors relative to normal control mice (NC). We then performed nuclear magnetic resonance (NMR)-based metabolomic analysis on the skin tissues of the NC, Model and Moxi-treated mice to address metabolic differences among the three groups. Moxi mice showed reduced PASI scores and decreased expressions of the pro-inflammatory cytokines IL-8, IL-17A and IL-23 relative to Model mice. Compared with the Model group, the NC and Moxi groups shared 9 characteristic metabolites and 4 significantly altered metabolic pathways except for taurine and hypotaurine metabolism uniquely identified in the NC group. To a certain extent, moxibustion treatment improved metabolic disorders of skin lesions of psoriatic mice by decreasing glucose, valine, asparagine, aspartate and alanine-mediated cell proliferation and synthesis of scaffold proteins, alleviating histidine-mediated hyperproliferation of blood vessels, and promoting triacylglycerol decomposition. This study reveals the molecular mechanisms underlying the effects of moxibustion treatment on the skin lesions of psoriasis, potentially improving the clinical efficacy of moxibustion. [Display omitted] [ABSTRACT FROM AUTHOR]

B Cover Caption: b The cover image is based on the Research Article I Peimine-induced apoptosis and inhibition of migration by regulating reactive oxygen species-mediated MAPK/STAT3/NF- B and Wnt/ -catenin signaling pathways in gastric cancer MKN-45 cells i by Tong Zhang et al., https://doi.org/10.1002/ddr.21987 GLO:OBD/01nov22:ddr22018-gra-0001.jpg PHOTO (COLOR): . gl Footnotes 1 Tong Zhang and Guo-Yan Liu contributed equally to this study as first authors. [Extracted from the article]

Mitogen-activated protein kinase (MPK) cascades are highly conserved signaling pathways that respond to environmental cues. Arabidopsis MPK4 has been identified as a stress-responsive protein kinase. Here we demonstrate that Brassica napus MPK4 (BnMPK4) is activated by hydrogen peroxide (H 2 O 2 ) and phytohormone abscisic acid (ABA). Transient expression of a constitutively active BnMPK4 causes H 2 O 2 production and cell death in Nicotiana benthamiana leaves. However, little is known about how H 2 O 2 contributes to the regulation of MPK4 kinase function. Biochemical analysis revealed that recombinant BnMPK4 autophosphorylates on both threonine and tyrosine residues in the activation loop. In the presence of H 2 O 2 , phosphorylation of BnMPK4 caused protein aggregation in vitro . The aggregation of BnMPK4 could be reversed to the monomeric form by reducing reagents. Point-mutation of cysteine codons indicated that cysteine 232 is involved in protein aggregation. Our results suggest that BnMPK4 is involved in reactive oxygen species (ROS) signaling and metabolism, and its aggregation may be modulated by redox. [ABSTRACT FROM AUTHOR]

Zearalenone (ZEN) is a non-steroidal estrogen mycotoxin produced by Fusarium fungi, which inevitably exists in human and animal food or feed. Previous studies indicated that apoptosis seems to be a key determinant of ZEN-induced toxicity. This experiment aimed to investigate the protective effects of Glutamine (Gln) on ZEN-induced cytotoxicity in IPEC-J2 cells. The experimental results showed that Gln was able to alleviate the decline of cell viability and reduce the production of reactive oxygen species and calcium (Ca2+) induced by ZEN. Meanwhile, the mRNA expression of antioxidant enzymes such as glutathione reductase, glutathione peroxidase, and catalase was up-regulated after Gln addition. Subsequently, Gln supplementation resulted in the nuclear fission and Bad-fluorescence distribution of apoptotic cells were weakened, and the mRNA expression and protein expression of pro-apoptotic genes and apoptotic rates were significantly reduced. Moreover, ZEN reduced the phosphorylation Akt, decreased the expression of Bcl-2, and increased the expression of Bax. Gln alleviated the above changes induced by ZEN and the antagonistic effects of Gln were disturbed by PI3K inhibitor (LY294002). To conclude, this study revealed that Gln exhibited significant protective effects on ZEN-induced apoptosis, and this effect may be attributed to the PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

J Oral Pathol Med (2011) : 37-45 Involvement of Notch signaling in several tumors is well known, but its role in tongue squamous cell carcinoma remains poorly characterized. The purpose of this study was to evaluate the roles of Notch signaling in the oncogenesis of tongue carcinoma. Tumor specimens and adjacent non-neoplastic tongue tissues from 74 patients with tongue carcinoma and human tongue carcinoma cell line Tca8113 were examined using immunohistochemistry and RT-PCR to determine the expressions of Notch1, Notch3, Jagged1, and Jagged2. The mRNA expressions of Notch1, Notch3, Jagged1, and Jagged2 were detected in Tca8113, tongue carcinoma, and adjacent non-neoplastic tongue tissues. The expression levels of mRNAs in tongue carcinoma were higher than those in adjacent non-neoplastic tongue tissues ( P < 0.05) . Immunohistochemical examination showed that the Notch signal molecules were expressed in Tca8113, tongue carcinoma, and adjacent non-neoplastic tongue tissues. The expression rates of Notch1 and Notch3 protein in tongue carcinoma were higher than those in adjacent non-neoplastic tongue tissues (χ=6.10, P = 0.013; χ =3.94, P = 0.047). Notch1 and jagged1 were significantly more highly expressed in lymph node metastasis-positive tongue carcinoma (χ = 6.108, P = 0.013; χ = 7.354, P = 0.025). In addition, expressions of Notch3 and Jagged2 were highly correlated in tongue carcinoma tissues (χ =42.130, P < 0.001). Expressions of Notch receptors and ligands in tongue carcinoma and adjacent non-neoplastic tongue tissues suggest that Notch signaling may control cell differentiation and proliferation of carcinoma cells. The disorder of Notch signaling may be a mechanism of the tongue carcinoma development. [ABSTRACT FROM AUTHOR]

Abstract: Sirtuins comprise a family of NAD+-dependent protein deacetylases and ADP-ribosyltransferases. Mammalian SIRT1 – a homolog of yeast Sir2, the prototypical member of the sirtuin family – is an important regulator of metabolism, cell differentiation and senescence, stress response, and cancer. As an NAD+-dependent enzyme, SIRT1 regulates gene expression programs in response to cellular metabolic status, thereby coordinating metabolic adaptation of the whole organism. Several important mechanisms have emerged for SIRT1-dependent regulation of transcription. First, SIRT1 can modulate chromatin function through direct deacetylation of histones as well as by promoting alterations in the methylation of histones and DNA, leading to the repression of transcription. The latter is accomplished through the recruitment of other nuclear enzymes to chromatin for histone methylation and DNA CpG methylation, suggesting a broader role of SIRT1 in epigenetic regulation. Second, SIRT1 can interact and deacetylate a broad range of transcription factors and coregulators, thereby regulating target gene expression both positively and negatively. Cellular energy state, specifically NAD+ metabolism, plays a major role in the regulation of SIRT1 activity. Recent studies on the NAD+ biosynthetic enzymes in the salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1), have revealed important functions for these enzymes in SIRT1-dependent transcription regulation. The collective molecular actions of SIRT1 control specific patterns of gene expression that modulate a wide variety of physiological outcomes. [Copyright &y& Elsevier]

Ca2+/calmodulin-dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKIIdelta, was genetically deleted (KO mice), and found that these mice showed no gross baseline changes in ventricular structure or function. In WT and KO mice, transverse aortic constriction (TAC) induced comparable increases in relative heart weight, cell size, HDAC5 phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKIIdelta deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure, such as chamber dilation, ventricular dysfunction, lung edema, cardiac fibrosis, and apoptosis. The ratio of IP3R2 to ryanodine receptor 2 (RyR2) and the fraction of RyR2 phosphorylated at the CaMKII site increased significantly during development of heart failure in WT mice, but not KO mice, and this was associated with enhanced Ca2+ spark frequency only in WT mice. We suggest that CaMKIIdelta contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca2+ leak and that attenuating CaMKIIdelta activation can limit the progression to heart failure. [ABSTRACT FROM AUTHOR]

Previous work showed that calmodulin (CaM) and Ca2+-CaM-dependent protein kinase II (CaMKII) are somehow involved in cardiac hypertrophic signaling, that inositol 1,4,5-trisphosphate receptors (InsP3Rs) in ventricular myocytes are mainly in the nuclear envelope, where they associate with CaMKII, and that class II histone deacetylases (e.g., HDAC5) suppress hypertrophic gene transcription. Furthermore, HDAC phosphorylation in response to neurohumoral stimuli that induce hypertrophy, such as endothelin-1 (ET-1), activates HDAC nuclear export, thereby regulating cardiac myocyte transcription. Here we demonstrate a detailed mechanistic convergence of these 3 issues in adult ventricular myocytes. We show that ET-1, which activates plasmalemmal G protein-coupled receptors and InsP3 production, elicits local nuclear envelope Ca2+ release via InsP3R. This local Ca2+ release activates nuclear CaMKII, which triggers HDAC5 phosphorylation and nuclear export (derepressing transcription). Remarkably, this Ca2+-dependent pathway cannot be activated by the global Ca2+ transients that cause contraction at each heartbeat. This novel local Ca2+ signaling in excitation-transcription coupling is analogous to but separate (and insulated) from that involved in excitation-contraction coupling. Thus, myocytes can distinguish simultaneous local and global Ca2+ signals involved in contractile activation from those targeting gene expression. [ABSTRACT FROM AUTHOR]

Vascular disease (VD) is a kind of common disease harmful to the health of the middle-aged and elderly, which has the characteristics of long treatment cycle and high recurrence rate, and without effective method to treat so far. Traditional Chinese medicine (TCM) has the characteristics of multi-components and multi-targets to treat diseases. Kai-Xin-San is a TCM formula applied for treating psychiatric diseases such as depression in China for thousands of years, and it has been used in clinical treatment of VD. But up to now, its active composition and mechanism are not clear. To explore the effective components of Kai-Xin-San, investigate the effect of Kai-Xin-San on angiogenesis, screen and verify the related targets and possible mechanisms of Kai-Xin-San against VD. UPLC-Q-Exactive Orbitrap MS was performed to identify the chemical components of Kai-Xin-San. The mechanism of multi-components, multi-targets, and multi-pathways of Kai-Xin-San in the treatment of VD were explored by network pharmacology. And then, quail chick chorioallantoic membrane (qCAM) assays were used to evaluate the vascular protective activity of Kai-Xin-San. Evaluation of angiogenesis by calculating the relative vessels area. The levels of VEGFA and Akt1 in qCAM were measured by RT-PCR. Twenty-five male SD rats were randomly divided into the sham group, model group, Donepezil (0.45 mg/kg) group, Kai-Xin-San low dose group (0.1575 g/kg), Kai-Xin-San high dose group (0.63 g/kg). Two-vessel occlusion (2-VO) rat model is established to evaluate the therapeutic effect of Kai-Xin-San pretreatment. Hematoxylin-eosin (HE) staining is conducted to detect the morphological changes of neurons in the hippocampus. Data showed that 62 compounds were identified in Kai-Xin-San. The network pharmacology results showed 73 compounds in Kai-Xin-San play a role in the treatment of VD, such as Ginsenoside Rh 4 , kaempferol, and Poricoic acid C. A total of 7 main targets are predicted, including Akt1, TNF and so on. Kai-Xin-San could increase VEGFA and Akt1 expression, promote angiogenesis and regulate the PI3K-Akt signaling pathway. The results depict that Kai-Xin-San has dose-dependently improved the cognitive function in 2-VO model rats. It has also been showed that Kai-Xin-San can rescue neuron damage in the hippocampus. The complex chemical components of Kai-Xin-San play a synergistic role in the treatment of VD, and involve multiple pathways and targets. To protect blood vessels by promoting angiogenesis is one of the potential mechanisms of Kai-Xin-San in the treatment of VD. This study reveals that Kai-Xin-San protects the 2-VO model rats from ischemic injury by alleviating neuron damage in the hippocampus. [Display omitted] [ABSTRACT FROM AUTHOR]

Swertiamarin (SW), which belongs to iridoid glycosides, is one of the main components of Swertia plants in Gentianaceae family, including Swertia pseudochinensis H. Hara and Swertia mileensis T. N. Ho et W. L. Shi. There are mainly used in traditional Chinese medicine for the treatment of hepatic and biliary disease such as jaundice. This experiment aimed to explore the protective mechanism of SW on cholestasis induced by alpha-naphthylisothiocyanate in rats. Healthy rats were randomly divided into the control, model (ANIT, 50 mg/kg), ursodeoxycholic acid (UDCA, 80 mg/kg), and low-dose (SW, 80 mg/kg), medium-dose (SW, 100 mg/kg), and high-dose (SW, 150 mg/kg) groups. The hepatic protective effect of SW was preliminarily evaluated by measurement of serum biochemical indicators and liver morphological evaluation. Moreover, metabolomics and proteomics analysis were used to explore the protective mechanism of SW on cholestasis. The expression of related proteins was determined by Western blot and polymerase chain reaction, and the important proteins were verified by cell experiments in vitro. SW (100 mg/kg) can reduce the serum levels of the model group. The hepatocyte of the medium-dose treatment group was arranged neatly without evident inflammation. SW can partially reverse the changes in cholestasis metabolites, such as taurocholic acid, SM (d18:1/16:0), all-trans-retinoic acid and other products of rats. The main metabolic pathways affected were primary bile acid synthesis, glycerophospholipid metabolism, sphingolipid metabolism and retinol metabolism. SW medium-dose treatment group showed effective reversal of 25 related proteins and it can remarkably reduce the contents of NTCP and CYP27A1 in rat liver and increase the protein expressions of CYP7A1, CYP8B1, bile salt export pump, multidrug resistance-associated protein and FXR. SW can alleviate ANIT-induced cholestasis, which by activating the farnesoid X receptor and bile acid excretion pathway. [Display omitted] • Multiomics technology were combined to study cholestasis. • Swertiamarin indeed attenuated ANIT-induced cholestasis. • The protective effect was processed by activating FXR and bile acid excretion pathways. • The involved proteins were verified by WB, RT-qPCR and immunofluorescence analysis. [ABSTRACT FROM AUTHOR]

High-mobility group box 1 (HMGB1), a highly conserved nucleoprotein, functions in immune recognition, inflammation and antibacterial immunization in vertebrates. In the present study, the mediation mechanism of Cg HMGB1 in activating MAPK and NF-κB / Rel signaling pathways to induce the expressions of immune effectors was investigated. Cg HMGB1 mRNA was detected in all tested developmental stages from fertilized egg to D-larvae, with the higher expressions in 4 cells and 8 cells stages. Cg HMGB1 proteins were mainly distributed in haemocyte granulocytes. The expressions of Cg HMGB1 mRNA in haemocytes increased significantly after Vibrio splendidus stimulation, and Cg HMGB1 protein translocated into the haemocyte cytoplasm and release into cell-free haemolymph. The phosphorylation of Cg ERK and Cg P38 were induced, the nuclear translocation of Cg Rel were promoted, and the mRNA expressions of Cg IL17-5 and Cg defh2 increased significantly after r Cg HMGB1 treatment. Obvious branchial swelling and cilium shedding were observed after r Cg HMGB1 treatment. r Cg HMGB1 exhibited binding activity to different polysaccharides, bacteria, and fungi. r Cg HMGB1 also displayed obvious antibacterial activity to V. splendidus and E. coli. These results indicated that Cg HMGB1 functioned as an immune recognition molecule to recognize various PAMPs and bacteria to induce the mRNA expressions of Cg IL17-5 and Cg defh2 via the activation of MAPK and NF-κB signaling pathways in oysters. • Cg HMGB1 functioned as an immune recognition molecule; • Cg HMGB1 activated MAPK and NF-κB signaling pathways in oysters; • Cg HMGB1 induced the mRNA expressions of Cg IL17-5 and Cg defh2; • r Cg HMGB1 displayed antibacterial activity to V. splendidus and E. coli. [ABSTRACT FROM AUTHOR]

Shuganzhi Tablet (SGZT) originates from a famous traditional Chinese herbal formula Chaihu Decoction which can be applied to treat liver diseases, however, the pharmacodynamic mechanism of SGZT needs to be evaluated. To study the mechanism of SGZT in the treatment of non-alcoholic fatty liver disease (NAFLD), and screen out its effective ingredients. In this study, firstly, the main components of SGZT were analyzed qualitatively. And a rat model of NAFLD was established by feeding high-fat diet. Serum biochemical indexes and liver pathological analysis were used to evaluate the pharmacodynamic effect of SGZT in the treatment of NAFLD. In order to explore the pharmacodynamic mechanism, proteomics and metabolomics analysis were used. Western blotting was used to verify the expression of important differential proteins. And L02 cells were treated with free fatty acids (FFA) and the main substances of SGZT to establish the cell model of NAFLD in vitro and to reveal the pharmacodynamic substance of SGZT. Twelve components were detected in SGZT, and according to the results of serum biochemical indexes and liver pathological analysis, SGZT could effectively treat NAFLD. Combined with the results of bioinformatics analysis, we found that 133 differentially expressed proteins were reversed in liver samples of rats treated with SGZT. The important proteins in PPAR signaling pathway, steroid biosynthesis, cholesterol metabolism and fatty acid metabolism were mainly regulated to maintain cholesterol homeostasis and improve lipid metabolism. SGZT also affected various metabolites in rat liver, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and taurine. In addition, the main components contained in SGZT (hesperidin, polydatin, naringin, emodin, specnuezhenide, saikosaponin A) and a metabolite (resveratrol) could significantly reduce FFA-induced intracellular lipid accumulation. SGZT effectively treated NAFLD, and PPAR-γ, Acsl4, Plin2 and Fads1 may be the main targets of SGZT. And Fads1-EPA/DHA-PPAR-γ may be the potential pharmacodynamic pathway. Cell experiments in vitro revealed that the main components of SGZT and their metabolites, such as hesperidin, polydatin, naringin, emodin, specnuezhenide, saikosaponin A and resveratrol may be the main components of its efficacy. Further research is needed to reveal and validate the pharmacodynamic mechanism. [Display omitted] • Shuganzhi Tablet could effectively treat non-alcoholic fatty liver. • PPAR-γ, Acsl4, Plin2 and Fads1 may be the pharmacodynamic targets. • Shuganzhi Tablet could regulate the changes of metabolites in vivo. • The main components of Shuganzhi tablets have lipid-lowering effect in vitro. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Herbal medicines including Tanshinone IIA (TanIIA) and Astragaloside IV (AsIV) are widely used in Asia as therapeutic agents for cardiovascular diseases, due to their complementary roles and shared properties based on the theory of traditional Chinese medicine and pharmacological researches. However, the underlying pathological mechanisms for their efficacy are still unclear. In addition, the compatibility or incompatibility of the herbal medicines when administered with other herbal remedies or with prescription drugs is unknown. Aim of the study We aimed to investigate the compatibility of TanIIA and AsIV in protecting cardiomyocytes against hypoxia-induced injury. Materials and methods Cultured cardiomyocytes were stimulated in hypoxia condition, in the absence or presence of the two herbal compounds, TanIIA and AsIV. Indicators were determined by cytotoxicity assay, quantitative PCR, ELISA, flow cytometry assay, immunofluorescence staining and western blot. Results Either TanIIA alone or the combined herbal compounds inhibited hypoxia-triggered chemokines production including CCL2/5/19, CXCL2 and Transwell assay-indicated monocyte/macrophage recruitment, cytokines production including TNF-α and IL-6. While AsIV alone or the combined herbal compounds attenuated hypoxia-induced cell apoptosis indicated by decreased Annexin V + cells and the ratio of Bax/Bcl-2, but no significant effect of the herbal compounds was observed in modulating cell apoptosis following both hypoxia and TNF-α stimulation. As an anti-apoptotic factor, stress granule formation was further enhanced by AsIV alone or the combined herbal compounds in hypoxia or heat shock stress. Moreover, immunoblotting analysis indicated that stress-responsive mitogen-activated protein kinases (MAPK) pathways including the phosphorylation of ERK1/2, p38 and JNK were inhibited while the phosphorylation of Akt in phosphatidylinositol 3-kinase (PI3K) -Akt pathway for cell survival was restored by the herbal compounds. Among these results, the combination of TanIIA and AsIV comprised most of the beneficial properties tested, although their combination did not improve the maximal effects achieved by any of the compounds alone. Conclusions Taken together, these data suggest a compatibility of TanIIA and AsIV in protecting cardiomyocyte against hypoxia-induced injury. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Bitter and cold traditional Chinese medicines (TCMs) have been long used to treat diabetes mellitus (DM) based on unique medical theory system since ancient China. As one of bitter and cold TCMs, the stromatas of Shiraia bambusicola have been used for the treatment of DM and exerted clinical effects to a certain extent. However, the corresponding active principles and antidiabetic mechanism of the TCM still remain unknown. Therefore, the aim of the present investigation was to evaluate the potential antidiabetic effect of the active Shiraia bambusicola EtOAc extract (SB-EtOAc) in vitro and in vivo , and elucidate its probable antidiabetic mechanism. Materials and methods A LC-PDA-ESIMS protocol was developed to determine the chemical principles of the active EtOAc extract rapidly and unambiguously. The effect of SB-EtOAc on the glucose transporter type 4 (GLUT4) translocation and glucose uptake in L6 cells was examined. SB-EtOAc was orally administration at the dose of 30, 60 and 120 mg/kg/d in KK-Ay mice, for 21 days. Body weight, plasma glucose, oral glucose tolerance test, fasted blood glucose levels, oral glucose tolerance test and insulin tolerance test, serum insulin and blood–lipid indexes were measured. GLUT4 on L6 cells membrane and phosphorylation of the AMP-activated protein kinase (p-AMPK) expression in L6 cells were measured. The GLUT4 and p-AMPK expression in KK-Ay mice skeletal muscle were measured. Phosphorylation of the acetyl-CoA carboxylase (p-ACC) and p-AMPK were measured. Results In vitro , SB-EtOAc exhibited a strong effect of stimulation on GLUT4 translocation by 3.2 fold in L6 cells compared with basal group, however, the selective AMPK inhibitor compound C can completely inhibit the AMPK pathway and prevent the GLUT4 translocation caused by SB-EtOAc. The further western blotting experiments showed that SB-EtOAc can stimulate AMPK phosphorylation in L6 cells and improve the expression of GLUT4. In vivo , SB-EtOAc can improve the KK-Ay mice insulin resistant and oral glucose tolerance to a certain extent. And the body weight, blood glucose levels and the serum TC, TG, FFA, AST, ALT and LDL-C were significantly reduced and HDL-C were increased after 3 weeks treatment. Mechanistically, phosphorylation of the AMPK and ACC had been improved obviously and the levels of AMPK phosphorylation and GLUT4 had been also enhanced. Conclusion In vitro, SB-EtOAc exhibited a strong effect of stimulation on GLUT4 translocation and improved significantly the glucose uptake. In vivo, SB-EtOAc significantly improved oral glucose tolerance and the insulin resistant as well as glucolipid metabolism. In this study, SB-EtOAc displayed promising positive antidiabetic activity in vitro and in vivo , partly by modulating AMPK-GLUT4 and AMPK-ACC signaling pathways. [ABSTRACT FROM AUTHOR]

Autophagy is a lysosomal degradation pathway, which is essential for cell survival, proliferation, differentiation and homeostasis. It is well known that beta-amyloid (Aβ) aggregation is one of key characteristics for Alzheimer’s disease (AD), which triggers a complex pathological cascade, leading to neurodegeneration. Recent studies have shown that Aβ peptide is generated from amyloid β precursor protein (APP) during autophagic turnover of APP-rich organelles by autophagy. Aβ generation during normal autophagy is subsequently degraded by lysosomes. Curcumin, a nature plant extraction, has been reported to inhibit the generation and deposition of Aβ; however, the underlying mechanisms are not fully understood yet. In the present study, we reported that curcumin treatment not only attenuated cognitive impairment detected by Morris water maze test, but also inhibited the generation of Aβ investigated by immunohistochemistry in APP/PS1 double transgenic AD mice. Moreover, curcumin induced autophagy in the mice, evidenced by LC3 immunofluorescence analysis and western blot assays on LC3. Furthermore, we found that curcumin significantly decreased the expression of Phosphatidylinositol 3-Kinase (PI3K), phosphorylated Akt and rapamycin (mTOR) at protein levels, respectively. Taken together, our data suggests that curcumin inhibits Aβ generation and induces of autophagy by downregulating PI3K/Akt/mTOR signaling pathway, and further shows a neuroprotective effect. Meanwhile curcumin might be a candidate neuroprotective agent for AD patients treatment by inducing autophagy. [ABSTRACT FROM AUTHOR]

Abstract: Mesenchymal stem cells (MSCs) are pluripotent progenitors that can differentiate into a variety of cell types. Vascular endothelial growth factor (VEGF) is one of the major factors of initiating and regulating angiogenesis. It has been reported that VEGF can induce MSCs differentiated into endothelial cells (ECs). However, the mechanism that VEGF-induced MSC differentiation is not completely understood. Here, we showed that VEGF induced human and rat bone marrow-derived MSCs differentiation to ECs. Rho family plays an important role in VEGF-induced endothelial cell migration and angiogenesis. Our results indicated that in MSCs, VEGF activated Rho/ROCK signaling pathway and promoted nuclear translocation of myocardin-related transcription factor-A (MRTF-A), which is controlled by Rho/ROCK signaling. In addition, Rho inhibitor C3 transferase, ROCK inhibitor Y27632 or depletion of endogenous MRTF-A abolished the VEGF-induced differentiation of MSCs into ECs. Furthermore, VEGF also enhanced the expression levels of CYR61/CCN1, as a regulator of vascular development and angiogenesis, and knockdown of endogenous MRTF-A reduced VEGF-induced the upregulation of CYR61/CCN1. Report assays with site-direct mutation analysis of CYR61/CCN1 promoter demonstrated that MRTF-A transactivated CYR61/CCN1 promoter mainly depending on CArG box. In this study, we identify the Rho/MRTF-A signaling pathway as a main actor in controlling VEGF-induced differentiation of human and rat bone marrow-derived MSCs into endothelial cells. [Copyright &y& Elsevier]

Stat3 is a member of the signal transducer and activator of transcription family, which is important in cytokine signaling. Gene ablation studies have revealed a requirement for Stat3 in diverse biological processes (Akira, S. 2000. Oncogene. 19:2607-2611; Levy, D.E., and C.K. Lee. 2002. J. Clin. Invest. 109:1143-1148). Previously, the function of Stat3 had been attributed exclusively to its transcriptional activity in the nucleus. In this study, we reveal an interaction between Stat3 and the microtubule (MT)-destabilizing protein stathmin. Stathmin did not overtly affect ligand-stimulated Stat3 activation. In contrast, the expression of Stat3 is required for the stabilization of MTs and cell migration. We further demonstrate that Stat3-containing cells are resistant to the MT-destabilizing effect of stathmin overexpression. In addition, down-regulation of stathmin protein levels in Stat3-deficient cells partially reversed the MT and migration deficiencies. Recombinant Stat3 was also capable of reversing stathmin inhibition of tubulin polymerization in vitro. Our results indicate that Stat3 modulates the MT network by binding to the COOH-terminal tubulin-interacting domain of stathmin and antagonizing its MT destabilization activity. [ABSTRACT FROM AUTHOR]