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1.
Chinese Journal of Experimental Traditional Medical Formulae ; (24): 255-263, 2024.
Article in Chinese | WPRIM | ID: wpr-999183

ABSTRACT

Diabetic peripheral neuropathy(DPN) is a neurodegenerative disease of diabetes mellitus involving peripheral nervous system damage, which is characterized by axonal degenerative necrosis, Schwann cell apoptosis and demyelination of nerve myelin sheath as the main pathological features, this disease is highly prevalent and is a major cause of disability in diabetic patients. Currently, the pathogenesis of DPN may be related to oxidative stress, inflammatory response, metabolic abnormality, and microcirculation disorder. The treatment of DPN in modern medicine mainly starts from controlling blood glucose, nourishing nerves and improving microcirculation, which can only alleviate the clinical symptoms of patients, and it is difficult to fundamentally improve the pathological damage of peripheral nerves. Mitochondrial quality control refers to the physiological mechanisms that can maintain the morphology and functional homeostasis of mitochondria, including mitochondrial biogenesis, mitochondrial dynamics, mitochondrial oxidative stress and mitochondrial autophagy, and abnormal changes of which may cause damage to peripheral nerves. After reviewing the literature, it was found that traditional Chinese medicine(TCM) can improve the low level of mitochondrial biogenesis in DPN, maintain the balance of mitochondrial dynamics, inhibit mitochondrial oxidative stress and mitochondrial autophagy, and delay apoptosis of Schwann cells and neural axon damage, which has obvious effects on the treatment of DPN. With the deepening of research, mitochondrial quality control may become one of the potential targets for the research of new anti-DPN drugs, therefore, this paper summarized the research progress of TCM in treating DPN based on four aspects of mitochondrial quality control, with the aim of providing a theoretical research basis for the discovery of new drugs.

2.
Biol. Res ; 56: 30-30, 2023. ilus, graf
Article in English | LILACS | ID: biblio-1513742

ABSTRACT

BACKGROUND: Skeletal muscle is sensitive to bile acids (BA) because it expresses the TGR5 receptor for BA. Cholic (CA) and deoxycholic (DCA) acids induce a sarcopenia-like phenotype through TGR5-dependent mechanisms. Besides, a mouse model of cholestasis-induced sarcopenia was characterised by increased levels of serum BA and muscle weakness, alterations that are dependent on TGR5 expression. Mitochondrial alterations, such as decreased mitochondrial potential and oxygen consumption rate (OCR), increased mitochondrial reactive oxygen species (mtROS) and unbalanced biogenesis and mitophagy, have not been studied in BA-induced sarcopenia.METHODS: We evaluated the effects of DCA and CA on mitochondrial alterations in C2C12 myotubes and a mouse model of cholestasis-induced sarcopenia. We measured mitochondrial mass by TOM20 levels and mitochondrial DNA; ultrastructural alterations by transmission electronic microscopy; mitochondrial biogenesis by PGC-1α plasmid reporter activity and protein levels by western blot analysis; mitophagy by the co-localisation of the MitoTracker and LysoTracker fluorescent probes; mitochondrial potential by detecting the TMRE probe signal; protein levels of OXPHOS complexes and LC3B by western blot analysis; OCR by Seahorse measures; and mtROS by MitoSOX probe signals. RESULTS: DCA and CA caused a reduction in mitochondrial mass and decreased mitochondrial biogenesis. Interestingly, DCA and CA increased LC3II/LC3I ratio and decreased autophagic flux concordant with raised mitophagosome-like structures. In addition, DCA and CA decreased mitochondrial potential and reduced protein levels in OXPHOS complexes I and II. The results also demonstrated that DCA and CA decreased basal, ATP-linked, FCCP-induced maximal respiration and spare OCR. DCA and CA also reduced the number of cristae. In addition, DCA and CA increased the mtROS. In mice with cholestasis-induced sarcopenia, TOM20, OXPHOS complexes I, II and III, and OCR were diminished. Interestingly, the OCR and OXPHOS complexes were correlated with muscle strength and bile acid levels. CONCLUSION: Our results showed that DCA and CA decreased mitochondrial mass, possibly by reducing mitochondrial biogenesis, which affects mitochondrial function, thereby altering potential OCR and mtROS generation. Some mitochondrial alterations were also observed in a mouse model of cholestasis-induced sarcopenia characterised by increased levels of BA, such as DCA and CA.


Subject(s)
Animals , Mice , Cholestasis/metabolism , Cholestasis/pathology , Sarcopenia/metabolism , Sarcopenia/pathology , Muscle, Skeletal/metabolism , Muscle Fibers, Skeletal/metabolism , Disease Models, Animal , Mitochondria
3.
Chinese Journal of Biotechnology ; (12): 4901-4914, 2023.
Article in Chinese | WPRIM | ID: wpr-1008067

ABSTRACT

With the rapid development of gene editing technology, the study of spermatogonial stem cells (SSCs) holds great significance in understanding spermatogenesis and its regulatory mechanism, developing transgenic animals, gene therapy, infertility treatment and protecting rare species. Biogenesis of lysosome-related organelles complex 1 subunit 1 (BLOC1S1) is believed to have anti-brucella potential. Exploring the impack of BLOC1S1 on goat SSCs not only helps investigate the ability of BLOC1S1 to promote SSCs proliferation, but also provides a cytological basis for disease-resistant breeding research. In this study, a BLOC1S1 overexpression vector was constructed by homologous recombination. The BLOC1S1 overexpression cell line of goat spermatogonial stem cells was successfully constructed by lentivirus packaging, transfection and puromycin screening. The overexpression efficiency of BLOC1S1 was found to be 18 times higher using real time quantitative PCR (RT-qPCR). Furthermore, the results from cell growth curve analysis, flow cytometry for cell cycle detection, and 5-ethynyl-2'-deoxyuridine (EdU) staining showed that BLOC1S1 significantly increased the proliferation activity of goat SSCs. The results of RT-qPCR, immunofluorescence staining and Western blotting analyses revealed up-regulation of proliferation-related genes (PCNA, CDK2, CCND1), and EIF2S3Y, a key gene regulating the proliferation of spermatogonial stem cells. These findings strongly suggest that the proliferative ability of goat SSCs can be enhanced through the EIF2S3Y/ERK pathway. In summary, this study successfully created a goat spermatogonial stem cell BLOC1S1 overexpression cell line, which exhibited improved proliferation ability. This research laid the groundwork for exploring the regulatory role of BLOC1S1 in goat spermatogonia and provided a cell platform for further study into the biological function of BLOC1S1. These findings also establish a foundation for breeding BLOC1S1 overexpressing goats.


Subject(s)
Animals , Male , Goats , Stem Cells , Spermatogonia/metabolism , Cell Proliferation , Flow Cytometry , Testis/metabolism
4.
Chinese Journal of Natural Medicines (English Ed.) ; (6): 830-841, 2023.
Article in English | WPRIM | ID: wpr-1010994

ABSTRACT

In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount importance. Sanhuang Xiexin Tang (SXT) and Baihu Tang (BHT) have emerged as prominent candidates for treating metabolic disorders. SXT combined with BHT plus Cangzhu (SBC) has been used clinically for Weihuochisheng obese patients. This retrospective analysis focused on assessing the anti-obesity effects of SBC in Weihuochisheng obese patients. We observed significant reductions in body weight and hepatic lipid content among obese patients following SBC treatment. To gain further insights, we investigated the effects and underlying mechanisms of SBC in HFD-fed mice. The results demonstrated that SBC treatment mitigated body weight gain and hepatic lipid accumulation in HFD-fed mice. Pharmacological network analysis suggested that SBC may affect lipid metabolism, mitochondria, inflammation, and apoptosis-a hypothesis supported by the hepatic transcriptomic analysis in HFD-fed mice treated with SBC. Notably, SBC treatment was associated with enhanced hepatic mitochondrial biogenesis and the inhibition of the c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB pathways. In conclusion, SBC treatment alleviates NAFLD in both obese patients and mouse models by improving lipid metabolism, potentially through enhancing mitochondrial biogenesis. These effects, in turn, ameliorate inflammation in hepatocytes.


Subject(s)
Humans , Mice , Animals , Non-alcoholic Fatty Liver Disease/metabolism , NF-kappa B/metabolism , Organelle Biogenesis , Retrospective Studies , Mice, Inbred C57BL , Obesity/metabolism , Liver , Inflammation/metabolism , Body Weight , Lipid Metabolism , Lipids , Diet, High-Fat/adverse effects
5.
Acta Pharmaceutica Sinica B ; (6): 542-558, 2023.
Article in English | WPRIM | ID: wpr-971723

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), is a common hepatic manifestation of metabolic syndrome. However, there are no effective therapy to treat this devastating disease. Accumulating evidence suggests that the generation of elastin-derived peptides (EDPs) and the inhibition of adiponectin receptors (AdipoR)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis. We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix (ECM) and ameliorated liver fibrosis. However, the degradation of the ECM lead to the generation of EDPs, which could further alter liver homeostasis negatively. Thus, in this study, we successfully combined AdipoR1/2 agonist JT003 with V14, which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation. We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other. These effects are induced by the enhancement of the mitochondrial antioxidant capacity, mitophagy, and mitochondrial biogenesis via AMPK pathway. Furthermore, specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress, increased mitophagy and mitochondrial biogenesis. These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.

6.
Acta Pharmaceutica Sinica B ; (6): 577-597, 2023.
Article in English | WPRIM | ID: wpr-971714

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper and lower motor neurons (MNs) with large unmet medical needs. Multiple pathological mechanisms are considered to contribute to the progression of ALS, including neuronal oxidative stress and mitochondrial dysfunction. Honokiol (HNK) has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke, Alzheimer's disease and Parkinson's disease. Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo. Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins (SOD1-G93A cells for short). Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione (GSH) synthesis and activating the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway. Also, honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells. Importantly, honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function. The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice. Overall, honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.

7.
Chinese Journal of Experimental Traditional Medical Formulae ; (24): 137-143, 2023.
Article in Chinese | WPRIM | ID: wpr-960916

ABSTRACT

ObjectiveTo investigate the effect of rutin on the browning of 3T3-L1 preadipocytes and the mechanism. MethodCell counting kit-8 (CCK-8) assay was used to detect the effect of different concentration of rutin (3.125, 6.25, 12.5, 25, 50, 100, 200 μmol·L-1) on 3T3-L1 cell activity, and Western blot to examine the effect of rutin (12.5, 25, 50 μmol·L-1) on the expression of thermogenesis-associated proteins uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in adipocytes. After the optimal concentration of rutin was determined, the effect of rutin on lipid droplet formation in adipocytes was observed based on oil red O staining, and the expression of nuclear respiratory factor 1 (NRF1), nuclear respiratory factor 2 (NRF2) and mitochondrial transcription factor A (TFAM), which were the landmark proteins of mitochondrial biosynthesis, was detected by Western blot. ResultCompared with the blank group, 200 μmol·L-1 rutin inhibited 3T3-L1 cell activity (P<0.01). Compared with the blank group, at the concentration of 12.5, 25, 50 μmol·L-1 rutin significantly promoted the expression of thermogenesis-associated proteins (UCP1, PRDM16, and PGC-1α) (P<0.01), which was determined as the optimal concentration. Compared with the blank group, 50 μmol·L-1 rutin significantly increased the immunofluorescence intensity of mitochondrial UCP1 protein in 3T3-L1 cells (P<0.01) and the expression of the markers of mitochondrial biosynthesis (NRF1, NRF2, and TFAM) (P<0.01). In addition, 50 μmol·L-1 rutin significantly inhibited lipid droplet formation of 3T3-L1 adipocytes (P<0.01). ConclusionRutin inhibited lipid droplet deposition in 3T3-L1 adipocytes and increased the expression of thermogenesis-related proteins (UCP1, PRDM16, and PGC-1α) and markers of mitochondrial biosynthesis (NRF1, NRF2, and TFAM), thereby inducing the browning of 3T3-L1 adipocytes. This lays a basis for the development of drugs that safely regulate the browning of white cells.

8.
Journal of Medical Biomechanics ; (6): E156-E163, 2023.
Article in Chinese | WPRIM | ID: wpr-987929

ABSTRACT

Objective To investigate the effect of pathologically elevated-cyclic stretch induced by hypertension on mitochondrial biogenesis of vascular smooth muscle cells (VSMCs), and the role of PGC1α in this process. Methods The Flexcell-5000T stretch loading system in vitro was applied to VSMCs with a frequency of 1. 25 Hz and an amplitude of 5% or 15% to simulate the mechanical environment under normal physiological or hypertensive pathological conditions respectively. Western blotting and qPCR were used to detect the expression of PGC1α, citrate synthase and mitochondrial DNA (mtDNA) copy number in VSMCs under normal physiological or hypertensive pathological conditions. VSMCs were treated with PGC1α specific activator ZLN005 to promote PGC1α expression or specific interfering fragment siRNA to inhibit PGC1α expression in order to detect the effect on citrate synthase and mtDNA copy number. Results Compared with 5% physiological cyclic stretch, 15% pathologically elevated-cyclic stretch significantly suppressed the expression of PGC1α, citrate synthase and mtDNA copy number in VSMCs. Compared with control group, the protein expression of PGC1α was significantly decreased and increased respectively. When VSMCs transfected with PGC1α siRNA or incubated PGC1α activator ZLN005, the expression of citrate synthase and mtDNA copy number were also significantly down regulated and up-regulated in VSMCs accordingly. Under physiological cyclic stretch conditions, the protein level of PGC1α was significantly down-regulated by PGC1α siRNA, which also significantly down-regulated citrate synthase expression and mtDNA copy number. The protein expression of PGC1α was significantly up-regulated by ZLN005, which also enhanced the expression of citrate synthase and mtDNA copy number. Conclusions The pathological cyclic stretch induced by hypertension significantly down-regulated the expression of citrate synthase and mtDNA copy number via suppressing the expression of PGC1α, resulting in mitochondrial dysfunction of VSMCs. PGC1α may be a potential therapeutic target molecule to alleviate the progression of hypertension.

9.
Chinese Journal of Reparative and Reconstructive Surgery ; (12): 748-757, 2023.
Article in Chinese | WPRIM | ID: wpr-981664

ABSTRACT

OBJECTIVE@#To summarize the role of chondrocyte mitochondrial homeostasis imbalance in the pathogenesis of osteoarthritis (OA) and analyze its application prospects.@*METHODS@#The recent literature at home and abroad was reviewed to summarize the mechanism of mitochondrial homeostasis imbalance, the relationship between mitochondrial homeostasis imbalance and the pathogenesis of OA, and the application prospect in the treatment of OA.@*RESULTS@#Recent studies have shown that mitochondrial homeostasis imbalance, which is caused by abnormal mitochondrial biogenesis, the imbalance of mitochondrial redox, the imbalance of mitochondrial dynamics, and damaged mitochondrial autophagy of chondrocytes, plays an important role in the pathogenesis of OA. Abnormal mitochondrial biogenesis can accelerate the catabolic reaction of OA chondrocytes and aggravate cartilage damage. The imbalance of mitochondrial redox can lead to the accumulation of reactive oxygen species (ROS), inhibit the synthesis of extracellular matrix, induce ferroptosis and eventually leads to cartilage degradation. The imbalance of mitochondrial dynamics can lead to mitochondrial DNA mutation, decreased adenosine triphosphate production, ROS accumulation, and accelerated apoptosis of chondrocytes. When mitochondrial autophagy is damaged, dysfunctional mitochondria cannot be cleared in time, leading to ROS accumulation, which leads to chondrocyte apoptosis. It has been found that substances such as puerarin, safflower yellow, and astaxanthin can inhibit the development of OA by regulating mitochondrial homeostasis, which proves the potential to be used in the treatment of OA.@*CONCLUSION@#The mitochondrial homeostasis imbalance in chondrocytes is one of the most important pathogeneses of OA, and further exploration of the mechanisms of mitochondrial homeostasis imbalance is of great significance for the prevention and treatment of OA.


Subject(s)
Humans , Reactive Oxygen Species/metabolism , Chondrocytes/metabolism , Osteoarthritis/metabolism , Homeostasis , Mitochondria/metabolism , Cartilage, Articular/metabolism
10.
Acta Pharmaceutica Sinica ; (12): 3339-3348, 2023.
Article in Chinese | WPRIM | ID: wpr-999079

ABSTRACT

Isoliquiritigenin (ISL) is a flavonoid compound isolated from licorice. It possesses excellent antioxidant and anti-diabetic activities. This study aims to investigate the molecular mechanism underlying the alleviatory effect of ISL on energy metabolism imbalance caused by type 2 diabetes mellitus (T2DM). 8-week-old male C57BL/6J mice were used in in vivo experiments. The high-fat-high-glucose diet combined with intraperitoneal injection of streptozotocin was applied to establish T2DM animal model. All animal experiments were performed in accordance with the Institutional Guidelines of Laboratory Animal Administration issued by the Committee of Ethics at Beijing University of Chinese Medicine. HepG2 cells were used in in vitro experiments. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR) were used to examine the protein and mRNA levels of mitochondrial function-related targets. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) in HepG2 cells were measured by the flow cytometry. Additionally, the molecular docking of ISL and key target proteins was analyzed. It was found that ISL significantly inhibited the activity of mitochondrial respiratory chain complex I and increased the protein levels of uncoupling protein 2 (UCP2) in the livers of mice and HepG2 cells. It also obviously decreased the ROS levels and increased the MMP levels in cultured HepG2 cells. In addition, ISL promoted mitochondrial biogenesis by activating proliferator-activated receptor gamma co-activator 1α (PGC-1α) and enhanced mitophagy by upregulating Parkin. It also improved mitochondrial fusion by increasing the mRNA and protein levels of mitofusin 2 (MFN2). In conclusion, ISL alleviates energy metabolism imbalance caused by T2DM through suppression of excessive mitochondrial oxidative phosphorylation and promotion of mitochondrial biogenesis, mitophagy, and fusion.

11.
São Paulo; s.n; s.n; 2022. 263 p. tab, graf.
Thesis in Portuguese | LILACS | ID: biblio-1379332

ABSTRACT

Os ribossomos são complexos ribonucleoproteicos conservados formados por duas subunidades assimétricas (40S e 60S em eucariotos) responsáveis pela tradução da informação genética e catálise da síntese proteica. A montagem destes complexos em eucariotos é mais bem descrita em S. cerevisiae, constituindo um processo celular energeticamente dispendioso e com múltiplas etapas. Ela tem origem no nucléolo com a transcrição do pré-rRNA 35S e requer o recrutamento hierárquico e transiente de cerca de 200 fatores de montagem para garantir a formação correta dos centros funcionais aptos à tradução. Neste processo, que se estende no núcleo e citoplasma, 79 proteínas ribossomais associam-se gradativamente à medida que o prérRNA é dobrado, modificado e processado. O processamento do pré-rRNA 35S consiste na remoção progressiva de espaçadores internos (ITS1 e ITS2) e externos (5ETS e 3ETS), que separam e flanqueiam os rRNAs maduros componentes de ambas subunidades ribossomais. A clivagem do ITS1 separa as vias de maturação do pré-60S e do pré-40S. O ITS2, que, em associação a fatores de montagem, forma uma estrutura denominada ITS2-foot, é o último espaçador do pré-60S a ser removido. A composição do ITS2-foot permanece inalterada no nucléolo até a transição entre o estado E nucleolar e a formação da partícula Nog2 nuclear. Nesta etapa, a liberação do fator Erb1 permite o recrutamento do fator de montagem conservado e essencial Nop53. Na base do ITS2-foot, Nop53 recruta o exossomo via RNA helicase Mtr4 para a clivagem 3-5 exonucleolítica de parte do ITS2 levando à desmontagem do ITS2-foot. O fato de Nop53 atuar como ponte entre dois grandes complexos e apresentar uma estrutura flexível e estendida nos levou a aprofundar a caracterização de seu papel durante a maturação do pré60S. Neste trabalho, usando análise proteômica quantitativa label-free baseada em espectrometria de massas, caracterizou-se o interactoma de Nop53, e avaliou-se o impacto da depleção de Nop53 no interactoma da subunidade catalítica do exossomo Rrp6 e na composição de pré-ribossomos representativos de quase todas as etapas de maturação do pré-60S. Em paralelo, foram caracterizados mutantes truncados de Nop53 e avaliada por pull-down a interação de Nop53 com componentes do exossomo. Os resultados obtidos mostraram que Nop53 é capaz de interagir com o cofator do exossomo Mpp6, sugerindo pontos adicionais de interação durante o recrutamento do exossomo ao pré-60S. A análise do interactoma de Rrp6 mostrou uma associação precoce do exossomo aos intermediários pré-ribossomais nucleolares mais iniciais, anteriores aos previamente descritos. Mudanças na composição dos intermediários pré-60S revelaram que a depleção de Nop53 afeta a transição entre o estado E e a partícula Nog2, afetando eventos tardios de maturação como o recrutamento de Yvh1. Comparando-se o efeito da depleção de Nop53 com o de mutantes nop53 desprovidos da região de recrutamento do exossomo, obtivemos evidências bioquímicas do papel estrutural de Nop53 na base do ITS2- foot. Em conjunto, estas observações, à luz de estruturas de intermediários pré-ribossomais recentemente descritas, nos permitiram concluir que o recrutamento de Nop53 ao pré-60S contribui para a estabilização de eventos de remodelamento do rRNA que antecedem a formação da partícula Nog2


Ribosomes are conserved ribonucleoprotein complexes formed by two asymmetric subunits (the 40S and the 60S in eukaryotes) responsible for translating the genetic information and catalyzing protein synthesis. The assembly of these complexes in eukaryotes is best described in S. cerevisiae. It is an energetically demanding, multi-step cellular process, that starts in the nucleolus with the transcription of the 35S pre-rRNA. It requires the hierarchical and transient recruitment of about 200 assembly factors to ensure the correct formation of the functional centers suitable for translation. In this process, which extends into the nucleus and cytoplasm, 79 ribosomal proteins gradually associate as the pre-rRNA is folded, modified, and processed. The 35S pre-rRNA processing happens with the progressive removal of internal (ITS1 and ITS2) and external (5'ETS and 3'ETS) transcribed spacers, which separate and flank the mature rRNA components of both ribosomal subunits. The cleavage at the ITS1 separates the pre-60S and pre40S maturation pathways. The ITS2, which in association with assembly factors constitutes a structure called ITS2-foot, is the last pre-60S spacer to be removed. The composition of the ITS2- foot remains unchanged in the nucleolus until the transition between the nucleolar state E and the nuclear Nog2 particle. At this stage, the release of Erb1 allows the recruitment of the conserved and essential assembly factor Nop53. At the base of the ITS2-foot, Nop53 recruits the exosome via the RNA helicase Mtr4 for the ITS2 3'-5' exonucleolytic cleavage leading to the ITS2-foot disassembly. The fact that Nop53 acts as a bridge between these two large complexes and exhibits a flexible and extended structure led us to further characterize its role in the pre-60S maturation. In this work, using mass spectrometry-based label-free quantitative proteomics, we characterized the interactome of Nop53, as well as the impact of the depletion of Nop53 on the interactome of the exosome catalytic subunit Rrp6 and on the composition of pre-ribosomes representative of almost all pre-60S maturation stages. In parallel, we characterized nop53 truncated mutants and evaluated the interaction of Nop53 with exosome components by pulldown assays. The results showed that Nop53 can interact with the exosome cofactor Mpp6, suggesting the contribution of additional points of interaction during the exosome recruitment to the pre-60S. The analysis of the Rrp6 interactome revealed an early association of the exosome with pre-ribosomal intermediates at very early nucleolar stages, before those previously described. Changes in the composition of pre-60S intermediates revealed that Nop53 depletion affects the transition between the state E and the Nog2 particle, affecting late pre-60S maturation events, such as the Yvh1 recruitment. Comparing the effect of Nop53 depletion with that of nop53 mutants lacking the exosome interacting region, we obtained biochemical evidence of the structural role of Nop53 at the base of the ITS2-foot. Altogether, and in light of recently described structures of pre-ribosomal intermediates, these observations allowed us to conclude that the recruitment of Nop53 to the pre-60S contributes to the stabilization of rRNA remodeling events that precede the formation of the Nog2 particle


Subject(s)
Saccharomyces cerevisiae/classification , Ribosome Subunits/chemistry , Ribonucleoproteins , Ribosomal Proteins , Mass Spectrometry/methods , Cell Nucleolus , Ribosome Subunits, Large , Eukaryota
12.
Chinese Journal of Clinical Pharmacology and Therapeutics ; (12): 498-504, 2022.
Article in Chinese | WPRIM | ID: wpr-1014841

ABSTRACT

AIM: To investigate the effect of flutamide on mitochondrial biogenesis and the regulating effect of anoxidative pathway Nrf2 on it. METHODS: Human hepatocyte HepG2 cells were treated with flutamide (0-50 μmol/L) for 24 h, then mtDNA copy number and protein expression of mitochondrial biogenesis were detected by RT-PCR and WB. The effects of ERK1/2 and the role of Nrf2 pathway in mitochondrial biogenesis were further observed by gene knockdown and protein activation/inhibition methods. RESULTS: Flutamide interfered mitochondrial biogenesis concentration-dependently, the mtDNA copy number, ERK1/2 and PGC-1α proteins increased with the dose. ERK1/2 inhibition and activation regulated flutamide-induced mtDNA copy number and PGC-1α expression, and inhibition of Nrf2 pathway also affected flutamide-induced mtDNA copy number and expression of PGC-1α, as well as ERK1/2 expression. CONCLUSION: Flutamide affects mitochondrial biogenesis, and the antioxidant pathway Nrf2 may be involved in the regulation of flutamine-induced mitochondrial biogenesis by regulating ERK1/2.

13.
Chinese Journal of Biotechnology ; (12): 1706-1723, 2022.
Article in Chinese | WPRIM | ID: wpr-927813

ABSTRACT

With the development of high-throughput sequencing technology, circular RNAs (circRNAs) have gradually become a hotspot in the research on non-coding RNA. CircRNAs are produced by the covalent circularization of a downstream 3' splice donor and an upstream 5' splice acceptor through backsplicing, and they are pervasive in eukaryotic cells. CircRNAs used to be considered byproducts of false splicing, whereas an explosion of related studies in recent years has disproved this misconception. Compared with the rich studies of circRNAs in animals, the study of circRNAs in plants is still in its infancy. In this review, we introduced the discovery of plant circRNAs, the discovery of plant circRNAs, the circularization feature, expression specificity, conservation, and stability of plant circRNAs and expounded the identification tools, main types, and biogenesis mechanisms of circRNAs. Furthermore, we summarized the potential roles of plant circRNAs as microRNA (miRNA) sponges and translation templates and in response to biotic/abiotic stress, and briefed the degradation and localization of plant circRNAs. Finally, we discussed the challenges and proposed the future directions in the research on plant circRNAs.


Subject(s)
Animals , MicroRNAs/metabolism , Organelle Biogenesis , Plants/metabolism , Protein Biosynthesis/physiology , RNA, Circular/metabolism , RNA, Plant/metabolism , Research/trends , Stress, Physiological/genetics
14.
Chinese Critical Care Medicine ; (12): 429-433, 2022.
Article in Chinese | WPRIM | ID: wpr-955985

ABSTRACT

Exosomes are small vesicles with a diameter of about 40-160 nm actively secreted by cells. They participate in a variety of pathophysiological processes and are closely related to the occurrence and development of diseases. As a newly carrier of intercellular communication and circulating biomarkers of disease diagnosis and prognosis, exosomes have attracted great attention for their potential clinical applications. However, many aspects such as exosome biogenesis, targeted transport, and mechanism of action are still unclear. This paper focuses on the exosome biogenesis, summarizes the exosome biogenesis pathways, and describes relevant molecular modulation mechanisms of importance. And this review provides a theoretical basis for disease treatment based on regulating exosome production.

15.
Int. j. morphol ; 39(2): 571-576, abr. 2021. ilus, tab
Article in English | LILACS | ID: biblio-1385373

ABSTRACT

SUMMARY: The world population is going through an obesity epidemic that has severe consequences for the health system. This study focused on studying hepatic mitochondria in obese animals induced by a high-fat (HF) diet and used the model-based stereology in electron micrographs for the quantitative study. Besides, the gene expressions of molecular markers of mitochondrial biogenesis carnitine palmitoyltransferase 1a (Cpt 1α), mitochondrial transcription factor a (Tfam), uncoupling protein 3 (Ucp 3), and nuclear respiratory factor 1 (Nrf 1) were analyzed. The HF diet caused a weight gain of +1820 % comparing the control group (C) with the HF group (from 0.32±0.31 g to 5.5±0.39 g, P<0.001). The HF group showed fat droplets in the hepatocyte cytoplasm (steatosis) and less dense and large mitochondria in transmission electron microscopy. The mitochondria size (cross-section) did not show a significant difference between the groups C and HF. However, the mitochondria numerical density per area was 30 % less, the mitochondrial surface density (outer membrane) was 20 % less, and the mitochondrial volume density was 22 % less in the HF group than the C group. The gene expressions of molecular markers of mitochondrial biogenesis Cpt 1α, Tfam, Ucp 3, and Nrf 1 decreased in the HF group compared to the C group. The quantitative results match perfectly with the molecular ones of mitochondrial biogenesis markers. In the future, it will be crucial to verify if and how these data recover with the reduction of obesity, which would be of significant interest given the current obesity epidemic that affects the world population.


RESUMEN: La población mundial atraviesa una epidemia de obesidad que tiene graves consecuencias para el sistema de salud. Este estudio se centró en el análisis de las mitocondrias hepáticas en animales obesos inducidos por una dieta alta en grasas (HF) y utilizó la estereología basada en modelos en micrografías electrónicas para el estudio cuantitativo. Además, se analizaron las expresiones génicas de los marcadores moleculares de la biogénesis mitocondrial carnitina palmitoiltransferasa 1a (Cpt 1α), factor de transcripción mitocondrial a (Tfam), proteína desacoplante 3 (Ucp 3) y factor respiratorio nuclear 1 (Nrf 1). La dieta HF provocó un aumento de peso de +1820 % comparando el grupo de control (C) con el grupo HF (de 0,32 ± 0,31 g a 5,5 ± 0,39 g, P <0,001). El grupo HF mostró gotas de grasa en el citoplasma de los hepatocitos (esteatosis) y mitocondrias menos densas y grandes en la microscopía electrónica de transmisión. El tamaño de las mitocondrias (sección transversal) no mostró una diferencia significativa entre los grupos C y HF. Sin embargo, la densidad numérica de mitocondrias por área fue 30% menor, la densidad de superficie mitocondrial (membrana externa) fue 20 % menor y la densidad de volumen mitocondrial fue 22 % menor en el grupo HF que en el grupo C. Las expresiones génicas de los marcadores moleculares de la biogénesis mitocondrial Cpt 1α, Tfam, Ucp 3 y Nrf 1 disminuyeron en el grupo HF en comparación con el grupo C. Los resultados cuantitativos coinciden perfectamente con los moleculares de los marcadores de biogénesis mitocondrial. En el futuro, será crucial verificar si estos datos se recuperan y cómo se recuperan con la reducción de la obesidad, lo que sería de gran interés dada la actual epidemia de obesidad que afecta a la población mundial.


Subject(s)
Animals , Male , Mice , Mitochondria, Liver/metabolism , Diet, High-Fat , Liver/metabolism , Obesity/metabolism , Organelle Biogenesis , Mitochondria, Liver/genetics , Mitochondria, Liver/ultrastructure , Weight Gain , Genetic Markers , Real-Time Polymerase Chain Reaction , Mice, Inbred C57BL
16.
Journal of Integrative Medicine ; (12): 439-450, 2021.
Article in English | WPRIM | ID: wpr-888766

ABSTRACT

OBJECTIVE@#To evaluate the synergic effects of a novel oral supplement formulation, containing prebiotics, yeast β-glucans, minerals and silymarin (Silybum marianum), on lipid and glycidic metabolism, inflammatory and mitochondrial proteins of the liver, in control and high-fat diet-induced obese mice.@*METHODS@#After an acclimation period, 32 male C57BL/6 mice were divided into the following groups: nonfat diet (NFD) vehicle, NFD supplemented, high-fat diet (HFD) vehicle and HFD supplemented. The vehicle and experimental formulation were administered orally by gavage once a day during the last four weeks of the diet (28 consecutive days). We then evaluated energy homeostasis, inflammation, and mitochondrial protein expression in these groups of mice.@*RESULTS@#After four weeks of supplementation, study groups experienced reduced glycemia, dyslipidemia, fat, and hepatic fibrosis levels. Additionally, proliferator-activated receptor-α, AMP-activated protein kinase-1α, peroxisome proliferator-activated receptor γ co-activator-1α, and mitochondrial transcription factor A expression levels were augmented; however, levels of inhibitor of nuclear factor-κB kinase subunit α and p65 nuclear factor-κB expression, and oxidative markers were reduced. Notably, the cortisol/C-reactive protein ratio, a well-characterized marker of the hypothalamic-pituitary-adrenal axis immune interface status, was found to be modulated by the supplement.@*CONCLUSION@#We discovered that the novel supplement was able to modify different antioxidant, metabolic and inflammatory pathways, improving the energy homeostasis and inflammatory status, and consequently alleviated hepatic steatosis.


Subject(s)
Animals , Mice , Antioxidants , Dietary Supplements , Glucans , Hypothalamo-Hypophyseal System , Liver , Mice, Inbred C57BL , Mice, Obese , Silybum marianum , Minerals , Pituitary-Adrenal System , Prebiotics , Saccharomyces cerevisiae
17.
Chinese Journal of Tissue Engineering Research ; (53): 4383-4388, 2020.
Article in Chinese | WPRIM | ID: wpr-847380

ABSTRACT

BACKGROUND: Research evidence shows that skeletal muscle contractile activity can induce ribosomal biogenesis, which plays an important role in the control of skeletal muscle mass. OBJECTIVE: To review the main mechanism of ribosome biogenesis in skeletal muscle hypertrophy, upstream regulatory signals of ribosomal biogenesis in skeletal muscle, and effect of exercise on ribosomal biogenesis, and to explore the ribosome biogenesis mechanism of exercise-induced skeletal muscle hypertrophy. METHODS: Relevant studies about exercise, skeletal muscle hypertrophy and ribosome biogenesis in CNKI, Wanfang, and PubMed databases were searched. The key words were “exercise, resistance training, skeletal muscle hypertrophy, protein synthesis, ribosome biogenesis” in English and Chinese. Relevant literatures published from 1999 to 2019 were searched and screened according to inclusion and exclusion criteria. RESULTS AND CONCLUSION: (1) Ribosome biogenesis as a main source of translational capacity plays an important role in muscle growth. (2) A single bout of resistance exercise can promote the ribosome biogenesis. However, cumulative bouts of resistance exercise eventually lead to the accumulation of mature rRNAs, leading to increased concentration of total RNA, which promote the growth of skeletal muscle. (3) Ribosome biogenesis may be the key molecular mechanism for the regulation of skeletal muscle hypertrophy induced by resistance training. (4) Moderate-volume resistance training led to adaptations to resistance training. This hypertrophy was associated with volume-dependent regulation of total RNA. This suggests that ribosomal biogenesis regulates the dose-effect relationship between training volume and muscle hypertrophy.

18.
West China Journal of Stomatology ; (6): 425-430, 2020.
Article in Chinese | WPRIM | ID: wpr-827519

ABSTRACT

Circular RNA, a non-coding RNA that forms a covalently closed continuous loop, exists widely in eukaryotic cells. The biogenesis and biological function of this type of RNA indicate that it can play a crucial role in diseases such as tumors, neural system diseases, and cardiovascular diseases; moreover, this RNA may have great potential use as a biomarker in these diseases. Oral squamous cell carcinoma (OSCC) is a common malignancy in oral surgery that is difficult to cure, metastasizes easily, and has poor prognosis. In this review, we summarize the loop-forming mechanisms and functions of circular RNA and describe the progress of current research in the development of oral cancer.


Subject(s)
Humans , Carcinoma, Squamous Cell , Mouth Neoplasms , RNA , RNA, Circular
19.
Asian Pacific Journal of Tropical Biomedicine ; (12): 111-119, 2020.
Article in Chinese | WPRIM | ID: wpr-823923

ABSTRACT

Objective: To determine the effects of syringic acid on hepatic damage in diabetic rats.Methods: Diabetes was induced by streptozotocin. Diabetic rats were given syringic acid at doses of 25, 50 and 100 mg/kg by oral gavage for 6 weeks. Syringic acid effects on the liver were evaluated by examination of plasma biochemical parameters, and pathological study. In addition, biomarkers of lipid peroxidation and antioxidant status of liver tissues were assessed. Real time-PCR was performed to investigate the mRNA expression levels of mitochondrial biogenesis indices in different groups. Results: Syringic acid significantly attenuated the increase in most of plasma biochemical parameters in diabetic rats. Moreover, syringic acid treatment increased the catalase activity while it reduced the superoxide dismutase activity and hepatic malondialdehyde level in diabetic rats. There was no difference between the glutathione content of the treated and untreated groups. These findings were supported by alleviation of histopathological damages in the syringic acid-treated groups compared to the untreated diabetic group. Syringic acid also significantly up-regulated the hepatic mRNA expression of PGC-1α, NRF-1, and NRF-2 and increased the mtDNA/nDNA ratio in diabetic rats. Conclusions: Syringic acid can be considered as a suitable candidate against hepatic complications since it can reduce oxidative damages in diabetic cases. Furthermore, it has the potential of targeting hepatic mitochondria in diabetes.

20.
Asian Pacific Journal of Tropical Biomedicine ; (12): 47-53, 2020.
Article in Chinese | WPRIM | ID: wpr-823916

ABSTRACT

MircroRNAs (miRNAs) are short non-coding RNAs with a length of approximately 20-22 nucleotides, which interact with their target mRNAs at 3'-untranslated region by partial pairing. The miRNA-mRNA interaction leads to induction of mRNA degradation and eventually translational inhibition. Thus, miRNAs play an important role in virtually all cellular processes, especially differentiation, proliferation, migration, and apoptosis. The deregulation of miRNAs may lead to serious diseases including cancer. There is mounting evidence demonstrating the participation of miRNA regulation during carcinogenesis. In this review, we discuss an updated miRNA biogenesis, mechanisms involved in their deregulation, and their role in cancer development. This review also summarizes updated information on potential medicinal plants which regulate miRNA expression as a promising molecular miRNA therapeutic approach for cancers.

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