ABSTRACT
Mitochondrial biogenesis is the process of generating new mitochondria to maintain cellular homeostasis. Here, we report that viruses exploit mitochondrial biogenesis to antagonize innate antiviral immunity. We found that nuclear respiratory factor-1 (NRF1), a vital transcriptional factor involved in nuclear-mitochondrial interactions, is essential for RNA (VSV) or DNA (HSV-1) virus-induced mitochondrial biogenesis. NRF1 deficiency resulted in enhanced innate immunity, a diminished viral load, and morbidity in mice. Mechanistically, the inhibition of NRF1-mediated mitochondrial biogenesis aggravated virus-induced mitochondrial damage, promoted the release of mitochondrial DNA (mtDNA), increased the production of mitochondrial reactive oxygen species (mtROS), and activated the innate immune response. Notably, virus-activated kinase TBK1 phosphorylated NRF1 at Ser318 and thereby triggered the inactivation of the NRF1-TFAM axis during HSV-1 infection. A knock-in (KI) strategy that mimicked TBK1-NRF1 signaling revealed that interrupting the TBK1-NRF1 connection ablated mtDNA release and thereby attenuated the HSV-1-induced innate antiviral response. Our study reveals a previously unidentified antiviral mechanism that utilizes a NRF1-mediated negative feedback loop to modulate mitochondrial biogenesis and antagonize innate immune response.
Subject(s)
Antiviral Agents , Organelle Biogenesis , Animals , Mice , DNA, Mitochondrial/genetics , Immunity, Innate , Nuclear Respiratory Factor 1/geneticsABSTRACT
Ectopic lipid deposition and mitochondrial dysfunction are common etiologies of obesity and metabolic disorders. Excessive dietary uptake of saturated fatty acids (SFAs) causes mitochondrial dysfunction and metabolic disorders, while unsaturated fatty acids (UFAs) counterbalance these detrimental effects. It remains elusive how SFAs and UFAs differentially signal toward mitochondria for mitochondrial performance. We report here that saturated dietary fatty acids such as palmitic acid (PA), but not unsaturated oleic acid (OA), increase lysophosphatidylinositol (LPI) production to impact on the stability of the mitophagy receptor FUNDC1 and on mitochondrial quality. Mechanistically, PA shifts FUNDC1 from dimer to monomer via enhanced production of LPI. Monomeric FUNDC1 shows increased acetylation at K104 due to dissociation of HDAC3 and increased interaction with Tip60. Acetylated FUNDC1 can be further ubiquitinated by MARCH5 for proteasomal degradation. Conversely, OA antagonizes PA-induced accumulation of LPI, and FUNDC1 monomerization and degradation. A fructose-, palmitate-, and cholesterol-enriched (FPC) diet also affects FUNDC1 dimerization and promotes its degradation in a non-alcoholic steatohepatitis (NASH) mouse model. We thus uncover a signaling pathway that orchestrates lipid metabolism with mitochondrial quality.
Subject(s)
Fatty Acids , Mitophagy , Mice , Animals , Fatty Acids/metabolism , Dimerization , Mitochondria/metabolism , Mitochondrial Proteins/metabolism , Membrane Proteins/metabolismABSTRACT
Understanding soil organic carbon (SOC), the largest carbon (C) pool of a terrestrial ecosystem, is essential for mitigating climate change. Currently, the spatial patterns and drivers of SOC in the plantations of tea, a perennial leaf crop, remain unclear. Therefore, the present study surveyed SOC across the main tea-producing areas of China, which is the largest tea producer in the world. We analyzed the soil samples from tea plantations under different scenarios, such as provinces, regions [southwest China (SW), south China (SC), south Yangtze (SY), and north Yangtze (NY)], climatic zones (temperate, subtropical, and tropical), and cultivars [large-leaf (LL) and middle or small-leaf (ML) cultivars]. Preliminary analysis revealed that most tea-producing areas (45%) had SOC content ranging from 10 to 20 g kg-1. The highest SOC was recorded for Yunnan among the various provinces, the SW tea-producing area among the four regions, the tropical region among the different climatic zones, and the areas with LL cultivars compared to those with ML cultivars. Further Pearson correlation analysis demonstrated significant associations between SOC and soil variables and random forest modeling (RF) identified that total nitrogen (TN) and available aluminum [Ava(Al)] of soil explained the maximum differences in SOC. Besides, a large indirect effect of geography (latitude and altitude) on SOC was detected through partial least squares path modeling (PLS-PM) analysis. Thus, the study revealed a high spatial heterogeneity in SOC across the major tea-producing areas of China. The findings also serve as a basis for planning fertilization strategies and C sequestration policies for tea plantations.
ABSTRACT
Albino tea plants generally have higher theanine, which causes their tea leaves to taste fresher, and they are an important mutant for the breeding of tea plant varieties. Earlier, we reported an albino germplasm, 'Menghai Huangye' (MHHY), from Yunnan Province and found that it has a lower chlorophyll content during the yellowing stage, but the mechanism underlying low chlorophyll and the yellowing phenotype is still unclear. In this study, the pigment contents of MHHY_May (yellowing, low chlorophyll), MHHY_July (regreening, normal chlorophyll), and YK10_May (green leaves, normal chlorophyll) were determined, and the results showed that the lower chlorophyll content might be an important reason for the formation of the yellowing phenotype of MHHY. Through transcriptome sequencing, we obtained 654 candidates for differentially expressed genes (DEGs), among which 4 genes were related to chlorophyll synthesis, 10 were photosynthesis-related, 34 were HSP family genes, and 19 were transcription factor genes. In addition, we analysed the transcription levels of the key candidate genes in MHHY_May and MHHY_July and found that they are consistent with the expression trends in MHHY_May and YK10_May, which further indicates that the candidate differential genes we identified are likely to be key candidate factors involved in the low chlorophyll content and yellowing of MHHY. In summary, our findings will assist in revealing the low chlorophyll content of MHHY and the formation mechanism of yellowing tea plants and will be applied to the selection and breeding of albino tea cultivars in the future.
Subject(s)
Camellia sinensis , Transcriptome , Camellia sinensis/genetics , China , Gene Expression Regulation, Plant , Plant Breeding , Plant Leaves/genetics , Plant Leaves/metabolism , Plant Proteins/metabolismABSTRACT
Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality control via selectively removing damaged or unwanted mitochondria. Interactions between LC3 and mitophagy receptors such as FUNDC1, which harbors an LC3-interacting region (LIR), are essential for this selective process. However, how mitochondrial stresses are sensed to activate receptor-mediated mitophagy remains poorly defined. Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation. Our results reveal a mechanistic signaling pathway linking mitochondria-damaging signals to the dephosphorylation of FUNDC1 by PGAM5, which ultimately induces mitophagy.
Subject(s)
Carrier Proteins/metabolism , Casein Kinase II/metabolism , Membrane Proteins/metabolism , Mitochondrial Proteins/metabolism , Mitophagy , Protein Processing, Post-Translational , Amino Acid Sequence , Consensus Sequence , Feedback, Physiological , HeLa Cells , Humans , Membrane Proteins/chemistry , Microtubule-Associated Proteins/metabolism , Mitochondrial Proteins/chemistry , Molecular Sequence Data , Phosphoprotein Phosphatases , PhosphorylationABSTRACT
Hereditary spherocytosis (HS) with hemolysis, splenomegaly, and jaundice as the main clinical symptoms varied in different population and SPTB mutated rate is common except for ANK1 in the Chinese population, whereas only a few studies have been reported. Here, 11 Chinese pediatric patients with newly SPTB mutations detected by targeted next generation sequencing technology were included and analyzed in our study. The characteristics of mutation separation were verified among family members by bidirectional Sanger sequencing. The detected 11 mutations were novel, all of which were heterozygotes, including five de novo mutations, five maternal mutations, and one paternal mutation. Meanwhile, the 11 different novel mutation sites distributed on and near the seven exons included four pathogenic sites and seven likely pathogenic sites. The detection of 11 novel mutation sites gene expanded the mutant spectrum of the SPTB gene, and provided corresponding clinical data, which laid a foundation for the subsequent studies on HS in Chinese population, especially in pediatric patients.
Subject(s)
Genetic Association Studies , Genetic Predisposition to Disease , Mutation , Spectrin/genetics , Spherocytosis, Hereditary/diagnosis , Spherocytosis, Hereditary/genetics , Alleles , DNA Mutational Analysis , Genetic Association Studies/methods , Genotype , High-Throughput Nucleotide Sequencing , Humans , PhenotypeABSTRACT
BACKGROUND: miRNAs are a type of conserved, small RNA molecule that regulate gene expression and play an important role in the growth and development of plants. miRNAs are involved in seed germination, root development, shoot apical meristem maintenance, leaf development, and flower development by regulating various target genes. However, the role of miRNAs in the mechanism of tea plant flower sterility remains unclear. Therefore, we performed miRNA sequencing on the flowers of fertile male parents, female parents, and sterile offspring. RESULTS: A total of 55 known miRNAs and 90 unknown miRNAs were identified. In the infertile progeny, 37 miRNAs were differentially expressed; 18 were up-regulated and 19 were down-regulated. miR156, miR157, miR164, miR167, miR169, miR2111 and miR396 family members were down-regulated, and miR160, miR172 and miR319 family members were up-regulated. Moreover, we predicted that the 37 differentially expressed miRNAs target a total of 363 genes, which were enriched in 31 biological functions. We predicted that miR156 targets 142 genes, including ATD1A, SPL, ACA1, ACA2, CKB22 and MADS2. CONCLUSION: We detected a large number of differentially expressed miRNAs in the sterile tea plant flowers, and their target genes were involved in complex biological processes. Among these miRNAs, the down-regulation of miR156 may be one of the factor in the formation of sterile floral buds in tea plants.
Subject(s)
Camellia sinensis/genetics , MicroRNAs/genetics , Plant Infertility/genetics , Flowers/genetics , Gene Expression Profiling , Gene Expression Regulation, Plant , RNA, Plant/genetics , Sequence Analysis, RNAABSTRACT
BACKGROUND: KLF5 is a member of the Kruppel-like factor, subfamily of zinc finger proteins that are involved in cancers. KLF5 functions as a transcription factor and regulates the diverse protein-coding genes (PCGs) in colorectal cancer (CRC). However, the long non-coding RNAs (lncRNAs) regulated by KLF5 in CRC are currently unknown. METHODS: In this study, we first designed a computational pipeline to determine the PCG and lncRNA targets of KLF5 in CRC. Then we analyzed the motif pattern of the binding regions for the lncRNA targets. The regulatory co-factors of KLF5 were then searched for through bioinformatics analysis. We also constructed a regulatory network for KLF5 and annotated its functions. Finally, one of the KLF5 lncRNA targets, SNHG12, was selected to further explore its expression pattern and functions in CRC. RESULTS: We were able to identify 19 lncRNA targets of KLF5 and found that the motifs of the lncRNA binding sites were GC-enriched. Next, we pinpointed the transcription factors AR and HSF1 as the regulatory co-factors of KLF5 through bioinformatics analysis. Then, through the analysis of the regulatory network, we found that KLF5 may be involved in DNA replication, DNA repair, and the cell cycle. Furthermore, in the cell cycle module, the SNHG12 up-regulating expression pattern was verified in the CRC cell lines and tissues, associating it to CRC invasion and distal metastasis. This indicates that SNHG12 may play a critical part in CRC tumorigenesis and progression. Additionally, expression of SNHG12 was found to be down-regulated in CRC cell lines when KLF5 expression was knocked-down by siRNA; and a strong correlation was observed between the expression levels of SNHG12 and KLF5, further alluding to their regulatory relationship. CONCLUSIONS: In conclusion, the network analysis of KLF5 targets indicates that SNHG12 may be a significant lncRNA in CRC.
ABSTRACT
BACKGROUND: The growth process of the tea plant (Camellia sinensis) includes vegetative growth and reproductive growth. The reproductive growth period is relatively long (approximately 1.5 years), during which a large number of nutrients are consumed, resulting in reduced tea yield and quality, accelerated aging, and shortened economic life of the tea plant. The formation of unisexual and sterile flowers can weaken the reproductive growth process of the tea plant. To further clarify the molecular mechanisms of pistil deletion in the tea plant, we investigated the transcriptome profiles in the pistil-deficient tea plant (CRQS), wild tea plant (WT), and cultivated tea plant (CT) by using RNA-Seq. RESULTS: A total of 3683 differentially expressed genes were observed between CRQS and WT flower buds, with 2064 upregulated and 1619 downregulated in the CRQS flower buds. These genes were mainly involved in the regulation of molecular function and biological processes. Ethylene synthesis-related ACC synthase genes were significantly upregulated and ACC oxidase genes were significantly downregulated. Further analysis revealed that one of the WIP transcription factors involved in ethylene synthesis was significantly upregulated. Moreover, AP1 and STK, genes related to flower development, were significantly upregulated and downregulated, respectively. CONCLUSIONS: The transcriptome analysis indicated that the formation of flower buds with pistil deletion is a complex biological process. Our study identified ethylene synthesis, transcription factor WIP, and A and D-class genes, which warrant further investigation to understand the cause of pistil deletion in flower bud formation.
Subject(s)
Camellia sinensis/genetics , Flowers/genetics , Gene Expression Profiling , Gene Expression Regulation, Plant , Phenotype , Transcriptome , Computational Biology/methods , Flowers/growth & development , Gene Expression Profiling/methods , Gene OntologyABSTRACT
BACKGROUND: The tea plant is a crucial economic crop. The floral organ development consumes a large amount of nutrients, which affects the leaf yield. To understand the mechanism by which the tea plant produces sterile floral buds, we obtained a sterile tea plant by artificial hybridization. RNA-sequencing based transcriptome analysis was implemented in three samples to determine the differentially expressed genes (DEGs) related to flower development. RESULTS: In this study, a total of 1991 DEGs were identified; 1057 genes were up-regulated and 934 genes were down-regulated in sterile hybrid floral buds. These were mainly distributed in the regulation of biological and metabolic processes. Significantly, auxin biosynthesis genes YUCCA, AUX1 and PIN were dramatically down-regulated, and ARF gene was up-regulated in the sterile hybrid floral buds, and flower development-related genes AP1, AP2 and SPL were changed. A total of 12 energy transfer-related genes were significantly decreased. Furthermore, the expression of 11 transcription factor genes was significantly different. CONCLUSION: The transcriptome analysis suggested that the production of sterile floral buds is a complex bioprocess, and that low auxin-related gene levels result in the formation of sterile floral buds in the tea plant.
Subject(s)
Flowers/genetics , Gene Expression Profiling , Gene Expression Regulation, Plant , Genes, Plant , Reproduction/genetics , Tea/genetics , Transcriptome , Computational Biology/methods , Gene Ontology , Molecular Sequence Annotation , Plant Development/geneticsABSTRACT
Adult hippocampal neurogenesis plays a pivotal role in learning and memory. The suppression of hippocampal neurogenesis induced by an increase of oxidative stress is closely related to cognitive impairment. Neural stem cells which persist in the adult vertebrate brain keep up the production of neurons over the lifespan. The balance between pro-oxidants and anti-oxidants is important for function and surviving of neural stem cells. Ginsenoside Rg1 is one of the most active components of Panax ginseng, and many studies suggest that ginsenosides have antioxidant properties. This research explored the effects and underlying mechanisms of ginsenoside Rg1 on protecting neural stem cells (NSCs) from oxidative stress. The sub-acute ageing of C57BL/6 mice was induced by subcutaneous injection of D-gal (120 mg kg-1 day-1) for 42 day. On the 14th day of D-gal injection, the mice were treated with ginsenoside Rg1 (20 mg kg-1 day-1, intraperitoneally) or normal saline for 28 days. The study monitored the effects of Rg1 on proliferation, senescence-associated and oxidative stress biomarkers, and Akt/mTOR signalling pathway in NSCs. Compared with the D-gal group, Rg1 improved cognitive impairment induced by D-galactose in mice by attenuating senescence of neural stem cells. Rg1 also decreased the level of oxidative stress, with increased the activity of superoxide dismutase and glutathione peroxidase in vivo and in vitro. Rg1 furthermore reduced the phosphorylation levels of protein kinase B (Akt) and the mechanistic target of rapamycin (mTOR) and down-regulated the levels of downstream p53, p16, p21 and Rb in D-gal treated NSCs. The results suggested that the protective effect of ginsenoside Rg1 on attenuating cognitive impairment in mice and senescence of NSCs induced by D-gal might be related to the reduction of oxidative stress and the down-regulation of Akt/mTOR signaling pathway.
Subject(s)
Cognitive Dysfunction/drug therapy , Galactose/pharmacology , Ginsenosides/metabolism , Neural Stem Cells/drug effects , Oxidative Stress/drug effects , Animals , Antioxidants/pharmacology , Cognitive Dysfunction/metabolism , Glutathione Peroxidase/metabolism , Mice, Inbred C57BL , Proto-Oncogene Proteins c-akt/drug effects , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/metabolismABSTRACT
Circular RNAs are a special class of endogenous RNAs characterized by jointing 3' and 5' ends together via exon or intron circularization. Recent studies found that circular RNAs are involved in the development of some human diseases. However, little is known about their roles in human gastric cancer. In this study, we chose hsa_circ_0001895 as a targeted circRNA to investigate its clinical significances in gastric cancer patients. Hsa_circ_0001895 expression levels in five gastric cancer cell lines and 257 specimens of tissues were measured by real-time quantitative reverse transcription polymerase chain reaction. Then, the potential relationship between hsa_circ_0001895 expression levels and patients' clinicopathological factors was investigated. A receiver operating characteristic curve was constructed for evaluating the diagnostic value of hsa_circ_0001895. Hsa_circ_0001895 expression levels in five detected gastric cancer cell lines (AGS, BGC-823, HGC-27, MGC-803, and SGC-7901) were all significantly downregulated than those in normal gastric epithelial GES-1 cells. Besides, compared with healthy control tissues, it was downregulated not only in 69.8% (67/96) gastric cancer tissues but also in gastric precancerous lesions. Moreover, hsa_circ_0001895 expression levels were significantly correlated with cell differentiation, Borrmann type, and tissue carcino-embryonic antigen expression. Our results suggested that hsa_circ_0001895 may play crucial roles during gastric cancerogenesis and is a potential biomarker for clinical prognosis prediction.
Subject(s)
Biomarkers, Tumor/biosynthesis , Prognosis , RNA/biosynthesis , RNA/genetics , Stomach Neoplasms/genetics , Adult , Aged , Biomarkers, Tumor/genetics , Carcinogenesis/genetics , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , RNA, Circular , Stomach Neoplasms/pathologyABSTRACT
Myelosuppression is the most common complication of chemotherapy. Decline of self-renewal capacity and stress-induced premature senescence (SIPS) of hematopoietic stem cells (HSCs) induced by chemotherapeutic agents may be the cause of long-term myelosuppression after chemotherapy. Whether the mechanism of SIPS of hematopoietic cells relates to chemotherapeutic injury occurred in hematopoietic microenvironment (HM) is still not well elucidated. This study explored the protective effect of Angelica sinensis polysaccharide (ASP), an acetone extract polysaccharide found as the major effective ingredients of a traditional Chinese medicinal herb named Chinese Angelica (Dong Quai), on oxidative damage of homo sapiens bone marrow/stroma cell line (HS-5) caused by 5-fluorouracil (5-FU), and the effect of ASP relieving oxidative stress in HM on SIPS of hematopoietic cells. Tumor-suppressive doses of 5-FU inhibited the growth of HS-5 in a dose-dependent and time-dependent manner. 5-FU induced HS-5 apoptosis and also accumulated cellular hallmarks of senescence including cell cycle arrest and typical senescence-associated ß-galactosidase positive staining. The intracellular reactive oxygen species (ROS) was increased in 5-FU treated HS-5 cells and coinstantaneous with attenuated antioxidant capacity marked by superoxide dismutase and glutathione peroxidase. Oxidative stress initiated DNA damage indicated by increased γH2AX and 8-OHdG. Oxidative damage of HS-5 cells resulted in declined hematopoietic stimulating factors including stem cell factor (SCF), stromal cell-derived factor (SDF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), however, elevated inflammatory chemokines such as RANTES. In addition, gap junction channel protein expression and mediated intercellular communications were attenuated after 5-FU treatment. Significantly, co-culture on 5-FU treated HS-5 feeder layer resulted in less quantity of human umbilical cord blood-derived hematopoietic cells and CD34⺠hematopoietic stem/progenitor cells (HSPCs), and SIPS of hematopoietic cells. However, it is noteworthy that ASP ameliorated SIPS of hematopoietic cells by the mechanism of protecting bone marrow stromal cells from chemotherapeutic injury via mitigating oxidative damage of stromal cells and improving their hematopoietic function. This study provides a new strategy to alleviate the complication of conventional cancer therapy using chemotherapeutic agents.
Subject(s)
Angelica sinensis , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/metabolism , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Oxidative Stress/drug effects , Plant Extracts/pharmacology , Polysaccharides/pharmacology , Angelica sinensis/chemistry , Angelica sinensis/metabolism , Biomarkers , Cellular Senescence/drug effects , DNA Damage , Fluorouracil/pharmacology , Humans , Protective Agents , Reactive Oxygen Species/metabolismABSTRACT
Human umbilical cord blood-derived stromal cells (hUCBDSCs) possess strong capability of supporting hematopoiesis and immune regulation, whereas some stress conditions cause reactive oxygen species (ROS) accumulation and then lead to oxidative injury and cell apoptosis. Ginsenoside Rg1 (G-Rg1) has been demonstrated to exert antioxidative and prosurvival effects in many cell types. In this study, the tert-Butyl hydroperoxide (t-BHP), an analog of hydroperoxide, was utilized to mimic the oxidative damage to hUCBDSCs. We aimed to investigate the effects of Ginsenoside Rg1 on protecting hUCBDSCs from t-BHP-induced oxidative injury and apoptosis, as well as the possible signaling pathway involved. It was shown that the treatment of hUCBDSCs with G-Rg1 markedly restored the t-BHP-induced cell viability loss, promoted the CFU-F formation, and inhibited cell apoptosis. G-Rg1 also caused a reduced production of LDH and MDA while significantly enhancing the activity of SOD. Mechanistically, G-Rg1 promoted the phosphorylation of Akt and FoxO3a and led to the cytoplasmic translocation of FoxO3a, which in turn suppressed FoxO3a-modulated expression of proapoptotic Bim and elevated the ratio of Bcl-2 to Bax. All these results suggest that G-Rg1 enhances the survival of t-BHP-induced hUCBDSCs and protects them against apoptosis at least partially through Akt-FoxO3a-Bim signaling pathway.
Subject(s)
Apoptosis/drug effects , Bcl-2-Like Protein 11/metabolism , Fetal Blood/metabolism , Forkhead Box Protein O3/metabolism , Ginsenosides/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , tert-Butylhydroperoxide/toxicity , Fetal Blood/cytology , Humans , Stromal Cells/cytology , Stromal Cells/metabolismABSTRACT
Stem cell senescence is an important and current hypothesis accounting for organismal aging, especially the hematopoietic stem cell (HSC). Ginsenoside Rg1 is the main active pharmaceutical ingredient of ginseng, which is a traditional Chinese medicine. This study explored the protective effect of ginsenoside Rg1 on Sca-1⺠hematopoietic stem/progenitor cells (HSC/HPCs) in a mouse model of d-galactose-induced aging. The mimetic aging mouse model was induced by continuous injection of d-gal for 42 days, and the C57BL/6 mice were respectively treated with ginsenoside Rg1, Vitamin E or normal saline after 7 days of d-gal injection. Compared with those in the d-gal administration alone group, ginsenoside Rg1 protected Sca-1⺠HSC/HPCs by decreasing SA-ß-Gal and enhancing the colony forming unit-mixture (CFU-Mix), and adjusting oxidative stress indices like reactive oxygen species (ROS), total anti-oxidant (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-px) and malondialdehyde (MDA). In addition, ginsenoside Rg1 decreased ß-catenin and c-Myc mRNA expression and enhanced the phosphorylation of GSK-3ß. Moreover, ginsenoside Rg1 down-regulated advanced glycation end products (AGEs), 4-hydroxynonenal (4-HNE), phospho-histone H2A.X (r-H2A.X), 8-OHdG, p16(Ink4a), Rb, p21(Cip1/Waf1) and p53 in senescent Sca-1⺠HSC/HPCs. Our findings indicated that ginsenoside Rg1 can improve the resistance of Sca-1⺠HSC/HPCs in a mouse model of d-galactose-induced aging through the suppression of oxidative stress and excessive activation of the Wnt/ß-catenin signaling pathway, and reduction of DNA damage response, p16(Ink4a)-Rb and p53-p21(Cip1/Waf1) signaling.
Subject(s)
Aging/metabolism , Antioxidants/pharmacology , Ginsenosides/pharmacology , Hematopoietic Stem Cells/metabolism , Oxidative Stress , Wnt Signaling Pathway , Aging/drug effects , Animals , Galactose/pharmacology , Glutathione Peroxidase/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/drug effects , Histones/metabolism , Male , Malondialdehyde/metabolism , Mice , Mice, Inbred C57BL , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolism , Vitamin E/pharmacology , Vitamins/pharmacology , beta Catenin/metabolismABSTRACT
Cadmium (Cd) is a widely used heavy metal and has recently been recognized as a possible source of human toxicity due to its ability to accumulate in organs. Accumulation of heavy metals has several adverse effects, including inducing inflammation, in multiple organs, such as the testis. However, how Cd ions are sensed by host cells and how tissue inflammation eventually occurs remains unclear. Here, we show that Cd activates the AIM2 inflammasome by mediating genomic DNA release into the cytoplasm after DNA damage via oxidative stress, to trigger IL-1ß secretion and pyroptosis. Specifically, the toxicity effects induced by Cd in cells were prevented by melatonin, which served as an antagonist of oxidative stress. Accordingly, in a mouse model, Cd-induced inflammation in the testis and consequential male reproductive dysfunction were effectively reversed by melatonin. Thus, our results suggest a function of AIM2 in Cd-mediated testis inflammation and identify AIM2 as a major pattern recognition receptor in response to heavy metal Cd ions.
Subject(s)
Cadmium , DNA-Binding Proteins , Immunity, Innate , Inflammasomes , Testis , Animals , Inflammasomes/metabolism , Inflammasomes/drug effects , Cadmium/toxicity , Male , Mice , Immunity, Innate/drug effects , Humans , DNA-Binding Proteins/metabolism , Testis/drug effects , Testis/metabolism , Mice, Inbred C57BL , Oxidative Stress/drug effects , Interleukin-1beta/metabolism , Melatonin/pharmacology , DNA Damage/drug effects , Inflammation/chemically induced , Inflammation/metabolism , Pyroptosis/drug effectsABSTRACT
Dietary habits and exercise play an important role in the well-being of human health. Currently, how long of drinking tea combined with exercise could efficiently ameliorate hepatic steatosis and obesity still needs to be investigated. Here, short-term and long-term green tea drinking combined with exercise were studied to improve hepatic steatosis and obesity in high-fat diet-induced (HF) mice. Our results showed that Yunkang 10 green tea (GT) combined with exercise (Ex) exhibited synergistic prevention effects on ameliorating hepatic steatosis and obesity. Especially, 22-week intervention with GT or Ex improved all symptoms of obesity, which indicated that long-term intervention exhibited profound preventive effects than the short term. Moreover, the combined intervention of 22 weeks inhibited the activation of NF-κB pathway and the expression of proinflammatory cytokines, which suggests that tea combined exercise may improve liver steatosis mainly by inhibiting inflammation. The key molecules for regulating lipid and glucose metabolism SCD1 were obviously downregulated, and GLU2 and PPARγ were significantly upregulated by GT and exercise in the liver of high-fat diet-induced mice. This study demonstrated that long-term intervention with GT and exercise effectively relieved hepatic steatosis and obesity complications by ameliorating hepatic inflammation, reducing lipid synthesis, and accelerating glucose transport.
ABSTRACT
Agriophara rhombata is a tea leaf moth that is considered one of the most destructive pests of Camellia sinensis (tea plant). Several recent studies have shown that many insects acquire part of the microbiome from their host and soil, but the pattern and diversity of their microbiome have not been clearly demonstrated. The present study aimed to investigate the bacterial and fungal communities present in the rhizospheric soil and leaf of tea plant compared to the gut of tea moth at different developmental stages (larvae, pupae, adult female and male) using Illumina MiSeq technology. Alpha diversity (Shannon index) showed higher (p < 0.05) bacterial and fungal diversity in soil samples than in leaf and tea moth larvae, pupae, and adult gut samples. However, during different developmental stages of tea moth, bacterial and fungal diversity did not differ (p > 0.05) between larvae, pupae, female, and male guts. Beta diversity also revealed more distinct bacterial and fungal communities in soil and leaf samples compared with tea moth gut samples, which had a more similar microbiome. Furthermore, Proteobacteria, Firmicutes, and Tenericutes were detected as the dominant bacterial phyla, while Ascomycota, Basidiomycota, and Mortierellomycota were the most abundant fungal phyla among all groups, but their relative abundance was comparatively higher (p < 0.05) in soil and leaf samples compared to tea moth gut samples. Similarly, Klebsiella, Streptophyta, and Enterococcus were the top three bacterial genera, while Candida, Aureobasidium, and Strelitziana were the top three fungal genera, and their relative abundance varied significantly (p < 0.05) among all groups. The KEGG analysis also revealed significantly higher (p < 0.5) enrichment of the functional pathways of bacterial communities in soil and leaf samples than in tea moth gut samples. Our study concluded that the bacterial and fungal communities of soil and tea leaves were more diverse and were significantly different from the tea moth gut microbiome at different developmental stages. Our findings contribute to our understanding of the gut microbiota of the tea moth and its potential application in the development of pest management techniques.
ABSTRACT
Background: Ginsenoside Rg1 is a major component of ginseng with antioxidative and antiaging effects, which is a traditional Chinese medicine. In this study, we investigated the potential spillover and mechanism of action of Rg1 on LiCl-driven hematopoietic stem cell aging. Results: Collect the purified Sca-1+ hematopoietic cells for differentiation ability detection and biochemical and molecular labeling. The experiment found that Rg1 plays an antiaging role in reversing the SA-ß-gal staining associated with LiCl-induced hematopoietic stem cell senescence, the increase in p53 and p21 proteins, and sustained DNA damage. At the same time, Rg1 protects hematopoietic cells from the reduced differentiation ability caused by LiCl. In addition, Rg1 increased the excessive inhibition of intracellular GSK-3ß protein, resulting in the maintenance of ß-catenin protein levels in hematopoietic cells after LiCl treatment. Then, the target gene level of ß-catenin can be maintained. Conclusions: Rg1 exerts the pharmacological effect of maintaining the activity of GSK-3ß in Sca-1+ hematopoietic cells, enhances the antioxidant potential of cells, improves the redox homeostasis, and thus protects cells from the decline in differentiation ability caused by aging. This study provides a potential therapeutic strategy to reduce stem cell pool failure caused by chronic oxidative damage to hematopoietic stem cells.
ABSTRACT
Background: Ovarian cancer (OC) is the most fatal gynecologic cancer. The branched-chain α-keto acid dehydrogenase kinase (BCKDK) plays an important role in many serious human diseases, including cancers. Its function in promoting cell proliferation and migration has been reported in various cancers. However, the biological role of BCKDK and its molecular mechanisms underlying OC initiation and progression are unclear. Methods: First, the expression level of BCKDK in OC cell lines or tissues was determined using tissue microarray- (TMA-) based immunohistochemistry or western blotting. Then, growth curve analysis, anchorage-independent cell transformation assays, wound healing assays, cell migration assays, and tumor xenografts were used to test whether BCKDK could promote cell transformation or metastasis. Finally, the signaling pathways involved in this process were investigated by western blotting or immunoprecipitation. Results: We found that the expression of BCKDK was upregulated in OC tissues and the high expression of BCKDK was correlated with an advanced pathological grade in patients. The ectopic overexpression of BCKDK promoted the proliferation and migration of OC cells, and the knockdown of BCKDK with shRNAs inhibited the proliferation and migration of OC ex vivo and in vivo. Moreover, BCKDK promoted OC proliferation and migration by activating MEK. Conclusions: Our results demonstrate that BCKDK promotes OC proliferation and migration by activating the MEK/ERK signaling pathway. Targeting the BCKDK-MEK axis may provide a new therapeutic strategy for treating patients with OC.