Objective The nucleolar protein PES1(Pescadillo homolog 1)plays critical roles in ribosome biogenesis and cell cycle regulation,yet its involvement in cellular senescence remains poorly understood.This study aimed to ...Objective The nucleolar protein PES1(Pescadillo homolog 1)plays critical roles in ribosome biogenesis and cell cycle regulation,yet its involvement in cellular senescence remains poorly understood.This study aimed to comprehensively investigate the functional consequences of PES1 suppression in cellular senescence and elucidate the molecular mechanisms underlying its regulatory role.Methods Initially,we assessed PES1 expression patterns in two distinct senescence models:replicative senescent mouse embryonic fibroblasts(MEFs)and doxorubicin-induced senescent human hepatocellular carcinoma HepG2 cells.Subsequently,PES1 expression was specifically downregulated using siRNA-mediated knockdown in these cell lines as well as additional relevant cell types.Cellular proliferation and senescence were assessed by EdU incorporation and SA-β-gal staining assays,respectively.The expression of senescence-associated proteins(p53,p21,and Rb)and SASP factors(IL-6,IL-1β,and IL-8)were analyzed by Western blot or qPCR.Furthermore,Northern blot and immunofluorescence were employed to evaluate pre-rRNA processing and nucleolar morphology.Results PES1 expression was significantly downregulated in senescent MEFs and HepG2 cells.PES1 knockdown resulted in decreased EdU-positive cells and increased SA-β-gal-positive cells,indicating proliferation inhibition and senescence induction.Mechanistically,PES1 suppression activated the p53-p21 pathway without affecting Rb expression,while upregulating IL-6,IL-1β,and IL-8 production.Notably,PES1 depletion impaired pre-rRNA maturation and induced nucleolar stress,as evidenced by aberrant nucleolar morphology.Conclusion Our findings demonstrate that PES1 deficiency triggers nucleolar stress and promotes p53-dependent(but Rb-independent)cellular senescence,highlighting its crucial role in maintaining nucleolar homeostasis and regulating senescence-associated pathways.展开更多
OBJECTIVE:To explore the potential molecular mechanism of Qigu capsule(芪骨胶囊,QGC)improve the functional performance of skeletal muscle.METHODS:The primary components of QGC were analyzed using high-performance liqu...OBJECTIVE:To explore the potential molecular mechanism of Qigu capsule(芪骨胶囊,QGC)improve the functional performance of skeletal muscle.METHODS:The primary components of QGC were analyzed using high-performance liquid chromatography(HPLC).Muscle dysfunction was established in male C57BL/6 mice treated with dexamethasone(1 mg/kg body weight,i.p.,six weeks).Rotarod test,mitochondrial ultrastructure,respiratory chain complex V activity,succinate dehydrogenase(SDH)activity,adenosine triphosphate(ATP)content,and reactive oxygen species(ROS)levels were assessed.The mitochondrial biogenesis-related protein expressions were analyzed using Western blot or polymerase chain reaction(PCR).RESULTS:QGC treatment enhanced Rotarod test performance.Additionally,QGC significantly alleviated dexamethasone-induced mitochondrial damage,reduced mitochondrial swelling,increased respiratory chain complex enzyme activity,SDH activity,ATP content,and decreased ROS levels.PCR and western blot results revealed that QGC enhanced mitochondrial biogenesis via adenosine 5'-monophosphate-activated protein kinase(AMPK)/peroxisome proliferator-activated receptor-γcoactivator 1-alpha(PGC-1α)signaling pathway.CONCLUSIONS:QGC ameliorates dexamethasoneinduced skeletal muscle dysfunction by activating AMPK/PGC-1α,which might be developed as a therapeutic agent for treating age-related muscle weakness.展开更多
High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their inve...High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma,demonstrating positive cor-relations between PES1 and programmed death-ligand 1(PD-L1)expression(51.72%for PES1 and 58.62%for PD-L1),as well as associations with lymph node metastasis and tumor invasion depth.However,the relationship between PES1 and PD-L1 remains incompletely defined.To further address this gap,we ana-lyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+T cell infiltration,along-side a positive correlation with PD-L1 expression.Based on prior findings,we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms.While these pathways require experimental validation,our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.展开更多
BACKGROUND Gastric cancer(GC)and head and neck squamous cell carcinoma(HNSCC)are common malignancies with high morbidity and mortality rates.Traditional treatments often yield limited efficacy,especially in advanced c...BACKGROUND Gastric cancer(GC)and head and neck squamous cell carcinoma(HNSCC)are common malignancies with high morbidity and mortality rates.Traditional treatments often yield limited efficacy,especially in advanced cases.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors targeting programmed death-ligand 1(PD-L1),have shown promise.However,the expression and interaction of pescadillo ribosomal biogenesis factor 1(PES1)and PD-L1 in these cancers remain unclear.Understanding their roles could provide new insights into tumor biology and improve therapeutic strategies.AIM To investigate the expression levels of PES1 and PD-L1 in tumor tissues of patients with GC and HNSCC.METHODS A total of 58 cases of GC and HNSCC undergoing surgical resection were selected from January 2022 to January 2024.Paraffin specimens of GC and HNSCC tissues were taken from the patients,and the sections were subjected to staining with immunohistochemistry and hematoxylin-eosin staining,and the protein expression of PES1 and PD-L1 was observed microscopically.RESULTS Among 58 GC and HNSCC tissues,30 cases were positive and 28 cases were negative for PES1 expression,and 34 cases were positive and 24 cases were negative for PD-L1 expression.The positive expression rates of PES1 and PDL1 were 51.72% and 58.62%,respectively.PES1 expression was correlated with the TNM stage,lymph node metastasis,and the depth of infiltration(P<0.05),and PD-L1 expression was correlated with the differentiation degree,lymph node metastasis,and infiltration depth(P<0.05).CONCLUSION PES1 and PD-L1 were positively expressed in GC and HNSCC tissues and correlated with clinical features.They may serve as potential biomarkers for immune-targeted therapies.展开更多
BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities.The effects mediated by the silent i...BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities.The effects mediated by the silent information regulator type 2 homolog-1(SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α(PGC-1α)axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy(T2DPN),potentially breaking this harmful cycle.AIM To validate the effectiveness of electroacupuncture(EA)in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1αaxis.METHODS The effects of EA were evaluated through assessments of metabolic changes,morphological observations,and functional examinations of the sciatic nerve,along with measurements of inflammation and oxidative stress.Proteins related to the SIRT1/PGC-1αaxis,involved in the regulation of mitochondrial biogenesis and antioxidative stress,were detected in the sciatic nerve using Western blotting to explain the underlying mechanism.A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis.RESULTS In addition to diabetes-related metabolic changes,T2DPN rats showed significant reductions in pain threshold after 9 weeks,suggesting abnormal peripheral nerve function.EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats.The SIRT1/PGC-1αaxis,which was downregulated in the model group,was upregulated by EA intervention.The endogenous antioxidant system related to the SIRT1/PGC-1αaxis,previously inhibited in diabetic rats,was reactivated.A similar trend was observed in inflammatory markers.When SIRT1 was inhibited in diabetic rats,these beneficial effects were abolished.CONCLUSION EA can alleviate the symptoms of T2DNP in experimental rats,and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1αaxis.展开更多
Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheime...Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.展开更多
The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood....The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood.CCDC181,a coiled-coil domain-containing protein,is known to localize on sperm flagella and at the basal regions of motile cilia.Despite this knowledge,the specific functions of CCDC181 in flagellum biogenesis remain unclear.In this study,Ccdc181 knockout mice were generated.The absence of CCDC181 led to defective sperm head shaping and flagellum formation.Furthermore,the Ccdc181 knockout mice exhibited extremely low sperm counts,grossly aberrant sperm morphologies,markedly diminished sperm motility,and typical multiple morphological abnormalities of the flagella(MMAF).Additionally,an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified,with CCDC181 regulating the localization of LRRC46 within sperm flagella.These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.展开更多
Objective：Recent evidence indicates that dysregulation of microRNA （miRNA） biogenesis is implicated in cancer development and progression.Based on the important role of miRNA biogenesis genes in carcinogenesis,we h...Objective：Recent evidence indicates that dysregulation of microRNA （miRNA） biogenesis is implicated in cancer development and progression.Based on the important role of miRNA biogenesis genes in carcinogenesis,we hypothesized that genetic variations of the miRNA biogenesis genes may modulate susceptibility to cervical cancer.Methods：We identified three single nucleotide polymorphisms （SNPs） located in the 3＇-untranslated regions （3＇-UTR） of of miRNA biogenesis key genes （rs1057035 in DICER,rs3803012 in RAN and rs10773771 in HIWI） and genotyped these SNPs in a case-control study of 1,486 cervical cancer cases and 1,549 cancer-free controls in Chinese women.Results：Logistic regression analyses showed that no significant associations were observed between the three SNPs and cervical cancer risk [rs3803012 in RAN AG/GG vs.AA adjusted OR =1.104,95 ％ confidence interval （CI）：0.859-1.419; rs1057035 in DICER CT/CC vs.TT adjusted OR =0.962,95％ CI：0.805-1.149;rs10773771 in HIWICT/CC vs.TT adjusted OR =0.963,95％ CI：0.826-1.122].Conclusions：The findings did not suggest that genetic variants in the 3＇-UTR of RAN,DICER and HIWI of miRNA biogenesis genes were associated with the risk of cervical cancer in this Chinese population.展开更多
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...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.展开更多
Chloroplasts are the center of plant life activities including photosynthesis,growth and development,and abiotic stress response.Chloroplast development and biogenesis in rice have been studied in detail,but how does ...Chloroplasts are the center of plant life activities including photosynthesis,growth and development,and abiotic stress response.Chloroplast development and biogenesis in rice have been studied in detail,but how does abiotic stress affect chloroplasts is less studied.We obtained an albino mutant,alm1,whose chlorophyll content was greatly decreased.Transmission electron microscopy showed that chloroplast development in alm1 was blocked,especially in thylakoid-like structures,which could not form normally.The ALM1 gene encodes a chloroplast-localized superoxide dismutase.Full-length ALM1 successfully restored the non-albino phenotype,and in knockout lines,the albino phenotype reappeared.The ALM1gene is expressed mainly in young leaves.alm1 plants died as a consequence of excessive reactive oxygen accumulation after the third-leaf stage.A series of biochemical assays verified that ALM1 interacted with the OsTrxz protein,which is one of the components of plastid-encoded RNA polymerase (PEP) complexes.A western blot experiment indicated that ALM1 played an important role in stabilizing OsTrxz in rice.An overexpression test of ALM1 revealed that ALM1 can increase drought resistance by removing excess reactive oxygen in rice seedlings.This study suggests that ALM1 not only participates in rice chloroplast biogenesis,but also increases rice stress resistance by scavenging excess reactive oxygen.展开更多
Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,wh...Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,which requires further evaluation of the regulato ry mechanisms of protein aggregate degradation.Lysosomes are crucial degradative organelles that maintain cellular homeostasis.Transcription factor EB-mediated lysosome biogenesis enhances autolysosomedependent degradation,which subsequently alleviates neurodege nerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease.In this review,we start by describing the key features of lysosomes,including their roles in nutrient sensing and degradation,and their functional impairments in different neurodegenerative diseases.We also explain the mechanisms—especially the post-translational modifications—which impact transcription factor EB and regulate lysosome biogenesis.Next,we discuss strategies for promoting the degradation of toxic protein aggregates.We describe Proteolysis-Ta rgeting Chimera and related technologies for the targeted degradation of specific proteins.We also introduce a group of LYsosome-Enhancing Compounds,which promote transcription factor EB-mediated lysosome biogenesis and improve learning,memory,and cognitive function in APP-PSEN1 mice.In summary,this review highlights the key aspects of lysosome biology,the mechanisms of transcription factor EB activation and lysosome biogenesis,and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.展开更多
Certain microRNAs(miRNAs)can function as neuroprotective factors after reperfusion/ischemia brain injury.miRNA-142-3p can participate in the occurrence and development of tumors and myocardial ischemic injury by negat...Certain microRNAs(miRNAs)can function as neuroprotective factors after reperfusion/ischemia brain injury.miRNA-142-3p can participate in the occurrence and development of tumors and myocardial ischemic injury by negatively regulating the activity of Rac1,but it remains unclear whether miRNA-142-3p also participates in cerebral ischemia/reperfusion injury.In this study,a model of oxygen-glucose deprivation/re-oxygenation in primary cortical neurons was established and the neurons were transfected with miR-142-3p agomirs or miR-142-3p antagomirs.miR-142-3p expression was down-regulated in neurons when exposed to oxygen-glucose deprivation/re-oxygenation.Over-expression of miR-142-3p using its agomir remarkably promoted cell death and apoptosis induced by oxygen-glucose deprivation/re-oxygenation and improved mitochondrial biogenesis and function,including the expression of peroxisome proliferator-activated receptor-γcoactivator-1α,mitochondrial transcription factor A,and nuclear respiratory factor 1.However,the opposite effects were produced if miR-142-3p was inhibited.Luciferase reporter assays verified that Rac Family Small GTPase 1(Rac1)was a target gene of miR-142-3p.Over-expressed miR-142-3p inhibited NOX2 activity and expression of Rac1 and Rac1-GTPase(its activated form).miR-142-3p antagomirs had opposite effects after oxygen-glucose deprivation/re-oxygenation.Our results indicate that miR-142-3p down-regulates the expression and activation of Rac1,regulates mitochondrial biogenesis and function,and inhibits oxygen-glucose deprivation damage,thus exerting a neuroprotective effect.The experiments were approved by the Committee of Experimental Animal Use and Care of Central South University,China(approval No.201703346)on March 7,2017.展开更多
Ribosome biogenesis is essential for the cell growth and division. Disruptions in ribosome biogenesis result in developmental defects and a group of diseases, known as ribosomopathies. Here, we report a mutation in ze...Ribosome biogenesis is essential for the cell growth and division. Disruptions in ribosome biogenesis result in developmental defects and a group of diseases, known as ribosomopathies. Here, we report a mutation in zebrafish urb1, which encodes an essential ribosome biogenesis protein. The urb1 cq31 mutant exhibits hypoplastic digestive organs, which is caused by impaired cell proliferation with the differentiation of digestive organ progenitors unaffected. Knockdown of mtor or raptor leads to similar hypoplastic phenotypes and reduced expression of urb1 in the digestive organs. Overexpression of Urb1 results in overgrowth of digestive organs, and can efficiently rescue the hypoplastic liver and pancreas in the mtor and raptor morphants. Reduced syntheses of free ribosomal subunits and impaired assembly of polysomes are observed in the urb1 mutant as well as in the mtor and raptor morphants, which can be rescued by the Urb1 overexpression. These data demonstrate that Urb1 plays an important role in governing ribosome biogenesis and protein synthesis downstream of mammalian/mechanistic target of rapamycin complex 1（mTORC1）, thus regulating the development of digestive organs. Our study indicates the requirement of hyperactive protein synthesis for the digestive organ development.展开更多
Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear. Mitochondrial dysfunction,
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 gava...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 m RNA 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 upregulated the hepatic m RNA expression of PGC-1α,NRF-1,and NRF-2 and increased the mtD NA/nD NA 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.展开更多
Ribosome biogenesis in the nucleolus requires numerous nucleolar proteins and small non-coding RNAs.Among them is ribosome biogenesis factor Bmsl,which is highly conserved from yeast to human.In yeast,Bmsl initiates r...Ribosome biogenesis in the nucleolus requires numerous nucleolar proteins and small non-coding RNAs.Among them is ribosome biogenesis factor Bmsl,which is highly conserved from yeast to human.In yeast,Bmsl initiates ribosome biogenesis through recruiting Rcll to pre-ribosomes.However,little is known about the biological function of Bmsl in vertebrates.Here we report that Bmsl plays an essential role in zebrafish liver development.We identified a zebrafish bms1l^（sq163） mutant which carries a T to A mutation in the gene bmsl-like（bms1l）.This mutation results in L^（152） to Q^（152） substitution in a GTPase motif in Bmsll.Surprisingly,bmsll^（sq163） mutation confers hypoplasia specifically in the liver,exocrine pancreas and intestine after 3 days post-fertilization（dpf）.Consistent with the bmsll^（sq163） mutant phenotypes,whole-mount in situ hybridization（WISH） on wild type embryos showed that bmsll transcripts are abundant in the entire digestive tract and its accessory organs.Immunostaining for phospho-Histone 3（P-H3） and TUNEL assay revealed that impairment of hepatoblast proliferation rather than cell apoptosis is one of the consequences of bms1l（sq163） giving rise to an under-developed liver.Therefore,our findings demonstrate that Bmsll is necessary for zebrafish liver development.展开更多
Introduction Macroautophagy(hereafter referred as autophagy)is a process of cellular self-degradation.In response to nutrient deprivation or other stimuli,a nascent double-membrane autophagosome,encapsulating intracel...Introduction Macroautophagy(hereafter referred as autophagy)is a process of cellular self-degradation.In response to nutrient deprivation or other stimuli,a nascent double-membrane autophagosome,encapsulating intracellular materials or damaged organelles,is generated.The autophagosome is transported toward and eventually fuses with the lysosome(or the vacuole in yeast and plant cells).展开更多
It is believed that eukaryotes arise from prokaryotes, which means that organelles can form de novo in prokaryotes. Such events, however, had not been observed previously. Here, we report the biogenesis of organelles ...It is believed that eukaryotes arise from prokaryotes, which means that organelles can form de novo in prokaryotes. Such events, however, had not been observed previously. Here, we report the biogenesis of organelles in the endosymbiotic cyanobacterium TDX16 (prokaryote) that was released from its senescent/necrotic host cell of green alga Haematococcus pluvialis (eukaryote). Microscopic observations showed that organelle biogenesis in TDX16 initiated with cytoplasm compartmentalization, followed by de-compartmentalization, DNA allocation, and re-compartmentalization, as such two composite organelles-the primitive chloroplast and primitive nucleus sequestering minor and major fractions of cellular DNA respectively were formed. Thereafter, the eukaryotic cytoplasmic matrix was built up from the matrix extruded from the primitive nucleus;mitochondria were assembled in and segregated from the primitive chloroplast, whereby the primitive nucleus and primitive chloroplast matured into the nucleus and chloroplast respectively. While mitochondria subsequently turned into double-membraned vacuoles after matrix degradation. Results of pigment analyses, 16S rRNA and genome sequencing revealed that TDX16 is a phycocyanin-containing cyanobacterium resembling Chroococcidiopsis thermalis, which had acquired 9,017,401 bp DNAs with 10,301 genes from its host. Accordingly, we conclude that organelle biogenesis in TDX16 is achieved by hybridizing the acquired eukaryotic DNAs with its own one and expressing the hybrid genome. The formation of organelles in cyanobacterium TDX16 is the first case of organelle biogenesis in prokaryotes observed so far, which sheds an unprecedented light on eukaryotes and their connections with prokaryotes, and thus has broad implications on biology.展开更多
In this review, we focus on the pathway of biogenesis of HDL, the essential role of apoA-I, ATP binding cassette transporter A1（ABCA1）, and lecithin： cholesterol acyltransferase（LCAT） in the formation of plasma H...In this review, we focus on the pathway of biogenesis of HDL, the essential role of apoA-I, ATP binding cassette transporter A1（ABCA1）, and lecithin： cholesterol acyltransferase（LCAT） in the formation of plasma HDL; the generation of aberrant forms of HDL containing mutant apoA-I forms and the role of apoA-IV and apoE in the formation of distinct HDL subpopulations. The biogenesis of HDL requires functional interactions of the ABCA1 with apoA-I（and to a lesser extent with apoE and apoA-IV） and subsequent interactions of the nascent HDL species thus formed with LCAT. Mutations in apoA-I, ABCA1 and LCAT either prevent or impair the formation of HDL and may also affect the functionality of the HDL species formed. Emphasis is placed on three categories of apoA-I mutations. The first category describes a unique bio-engineered apoA-I mutation that disrupts interactions between apoA-I and ABCA1 and generates aberrant prep HDL subpopulations that cannot be converted efficiently to a subpopulations by LCAT. The second category describes natural and bio-engineered apoA-I mutations that generate preβ and small size a4 HDL subpopulations, and are associated with low plasma HDL levels. These phenotypes can be corrected by excess LCAT. The third category describes bio-engineered apoA-I mutations that induce hypertriglyceridemia that can be corrected by excess lipoprotein lipase and also have defective maturation of HDL.The HDL phenotypes described here may serve in the future for diagnosis, prognoses and potential treatment of abnormalities that affect the biogenesis and functionality of HDL.展开更多
Macroautophagy （here autophagy） is a catabolic mechanism responsible for the degradation of bulk cytoplasm, long-lived proteins and organeUes. During autophagy, the cargos are engulfed by double-membrane structures ...Macroautophagy （here autophagy） is a catabolic mechanism responsible for the degradation of bulk cytoplasm, long-lived proteins and organeUes. During autophagy, the cargos are engulfed by double-membrane structures named phagophores, which expand to form the autophagosomes. Subsequently, these autophagosomes fuse with lysosomes, in which the cytoplasmic cargos are degraded. Autophagy is a constitutive pro- cess, which plays an important role in cellular homeostasis. In primary neurons autophagosome formation occurs continuously and preferentially at the distal end of axons. On the other hand, autophagy is increased by different stresses, and its dysregulation or excessive induction may lead to detrimental effects. Many neurological disorders have been associated with alterations in the autophagic pathway and an increase in autophagy during axonal degeneration was described.展开更多
文摘Objective The nucleolar protein PES1(Pescadillo homolog 1)plays critical roles in ribosome biogenesis and cell cycle regulation,yet its involvement in cellular senescence remains poorly understood.This study aimed to comprehensively investigate the functional consequences of PES1 suppression in cellular senescence and elucidate the molecular mechanisms underlying its regulatory role.Methods Initially,we assessed PES1 expression patterns in two distinct senescence models:replicative senescent mouse embryonic fibroblasts(MEFs)and doxorubicin-induced senescent human hepatocellular carcinoma HepG2 cells.Subsequently,PES1 expression was specifically downregulated using siRNA-mediated knockdown in these cell lines as well as additional relevant cell types.Cellular proliferation and senescence were assessed by EdU incorporation and SA-β-gal staining assays,respectively.The expression of senescence-associated proteins(p53,p21,and Rb)and SASP factors(IL-6,IL-1β,and IL-8)were analyzed by Western blot or qPCR.Furthermore,Northern blot and immunofluorescence were employed to evaluate pre-rRNA processing and nucleolar morphology.Results PES1 expression was significantly downregulated in senescent MEFs and HepG2 cells.PES1 knockdown resulted in decreased EdU-positive cells and increased SA-β-gal-positive cells,indicating proliferation inhibition and senescence induction.Mechanistically,PES1 suppression activated the p53-p21 pathway without affecting Rb expression,while upregulating IL-6,IL-1β,and IL-8 production.Notably,PES1 depletion impaired pre-rRNA maturation and induced nucleolar stress,as evidenced by aberrant nucleolar morphology.Conclusion Our findings demonstrate that PES1 deficiency triggers nucleolar stress and promotes p53-dependent(but Rb-independent)cellular senescence,highlighting its crucial role in maintaining nucleolar homeostasis and regulating senescence-associated pathways.
基金Supported by Shanghai Clinical Research Center for Chronic Musculoskeletal Diseases(20MC1920600)Shanghai Key Clinical Specialty"Traditional Chinese Medicine Orthopaedic Traumatology"(shslczdzk03901)+4 种基金the Second Round of Construction Project of National TCM Academic School Inheritance Studio"Shi's Trauma Department"[Letter of the People's Education of Traditional Chinese Medicine(2019)No.62]Shanghai High-level Local Universities"Chronic Muscle and Bone Damage Research and Transformation"Innovation Team[No.3 of Shanghai Education Commission(2022)]"Extension Plan for the Inheritance of Shanghai Style Traditional Chinese Medicine Schools",Construction of TCM Specialty Alliance for Muscle and Bone Injury in East China Region and City Level"[ZY(2021-2023)-0302]Program for Shanghai High-Level Local University Innovation Team(SZY20220315)Shanghai Shenkang Hospital Development Center Clinical Three-year Action Plan(SHDC2020CR3090B)。
文摘OBJECTIVE:To explore the potential molecular mechanism of Qigu capsule(芪骨胶囊,QGC)improve the functional performance of skeletal muscle.METHODS:The primary components of QGC were analyzed using high-performance liquid chromatography(HPLC).Muscle dysfunction was established in male C57BL/6 mice treated with dexamethasone(1 mg/kg body weight,i.p.,six weeks).Rotarod test,mitochondrial ultrastructure,respiratory chain complex V activity,succinate dehydrogenase(SDH)activity,adenosine triphosphate(ATP)content,and reactive oxygen species(ROS)levels were assessed.The mitochondrial biogenesis-related protein expressions were analyzed using Western blot or polymerase chain reaction(PCR).RESULTS:QGC treatment enhanced Rotarod test performance.Additionally,QGC significantly alleviated dexamethasone-induced mitochondrial damage,reduced mitochondrial swelling,increased respiratory chain complex enzyme activity,SDH activity,ATP content,and decreased ROS levels.PCR and western blot results revealed that QGC enhanced mitochondrial biogenesis via adenosine 5'-monophosphate-activated protein kinase(AMPK)/peroxisome proliferator-activated receptor-γcoactivator 1-alpha(PGC-1α)signaling pathway.CONCLUSIONS:QGC ameliorates dexamethasoneinduced skeletal muscle dysfunction by activating AMPK/PGC-1α,which might be developed as a therapeutic agent for treating age-related muscle weakness.
文摘High expression of pescadillo ribosomal biogenesis factor 1(PES1)has been re-ported across multiple cancer types and is significantly associated with poor prog-nosis.Hu et al in their recent paper described their investigation of PES1 in gastric cancer and head and neck squamous cell carcinoma,demonstrating positive cor-relations between PES1 and programmed death-ligand 1(PD-L1)expression(51.72%for PES1 and 58.62%for PD-L1),as well as associations with lymph node metastasis and tumor invasion depth.However,the relationship between PES1 and PD-L1 remains incompletely defined.To further address this gap,we ana-lyzed The Cancer Genome Atlas gastric adenocarcinoma dataset and found a negative correlation between PES1 expression and CD8+T cell infiltration,along-side a positive correlation with PD-L1 expression.Based on prior findings,we hypothesize that PES1 may regulate PD-L1 through the phosphatidylinositol 3-kinase/protein kinase B pathway or cellular Myc-mediated mechanisms.While these pathways require experimental validation,our observations highlight PES1 as a potential regulator of immune evasion and a promising target for cancer immunotherapy.
文摘BACKGROUND Gastric cancer(GC)and head and neck squamous cell carcinoma(HNSCC)are common malignancies with high morbidity and mortality rates.Traditional treatments often yield limited efficacy,especially in advanced cases.Recent advancements in immunotherapy,particularly immune checkpoint inhibitors targeting programmed death-ligand 1(PD-L1),have shown promise.However,the expression and interaction of pescadillo ribosomal biogenesis factor 1(PES1)and PD-L1 in these cancers remain unclear.Understanding their roles could provide new insights into tumor biology and improve therapeutic strategies.AIM To investigate the expression levels of PES1 and PD-L1 in tumor tissues of patients with GC and HNSCC.METHODS A total of 58 cases of GC and HNSCC undergoing surgical resection were selected from January 2022 to January 2024.Paraffin specimens of GC and HNSCC tissues were taken from the patients,and the sections were subjected to staining with immunohistochemistry and hematoxylin-eosin staining,and the protein expression of PES1 and PD-L1 was observed microscopically.RESULTS Among 58 GC and HNSCC tissues,30 cases were positive and 28 cases were negative for PES1 expression,and 34 cases were positive and 24 cases were negative for PD-L1 expression.The positive expression rates of PES1 and PDL1 were 51.72% and 58.62%,respectively.PES1 expression was correlated with the TNM stage,lymph node metastasis,and the depth of infiltration(P<0.05),and PD-L1 expression was correlated with the differentiation degree,lymph node metastasis,and infiltration depth(P<0.05).CONCLUSION PES1 and PD-L1 were positively expressed in GC and HNSCC tissues and correlated with clinical features.They may serve as potential biomarkers for immune-targeted therapies.
基金National Natural Science Foundation of China,No.82074532,No.82374577,No.82305375,No.82305376,and No.82405567The Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘BACKGROUND Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities.The effects mediated by the silent information regulator type 2 homolog-1(SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α(PGC-1α)axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy(T2DPN),potentially breaking this harmful cycle.AIM To validate the effectiveness of electroacupuncture(EA)in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1αaxis.METHODS The effects of EA were evaluated through assessments of metabolic changes,morphological observations,and functional examinations of the sciatic nerve,along with measurements of inflammation and oxidative stress.Proteins related to the SIRT1/PGC-1αaxis,involved in the regulation of mitochondrial biogenesis and antioxidative stress,were detected in the sciatic nerve using Western blotting to explain the underlying mechanism.A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis.RESULTS In addition to diabetes-related metabolic changes,T2DPN rats showed significant reductions in pain threshold after 9 weeks,suggesting abnormal peripheral nerve function.EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats.The SIRT1/PGC-1αaxis,which was downregulated in the model group,was upregulated by EA intervention.The endogenous antioxidant system related to the SIRT1/PGC-1αaxis,previously inhibited in diabetic rats,was reactivated.A similar trend was observed in inflammatory markers.When SIRT1 was inhibited in diabetic rats,these beneficial effects were abolished.CONCLUSION EA can alleviate the symptoms of T2DNP in experimental rats,and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1αaxis.
基金supported by the National Natural Science Foundation of China,Nos.82171194 and 81974155(both to JL)the Shanghai Municipal Science and Technology Commission Medical Guide Project,No.16411969200(to WZ)Shanghai Municipal Science and Technology Commission Biomedical Science and Technology Project,No.22S31902600(to JL)。
文摘Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.
基金supported by the National Natural Science Foundation of China(82071709,81971446,82171599,82374212)Global Select Project(DJK-LX-2022010)of the Institute of Health and Medicine,Hefei Comprehensive National Science CenterJoint Fund for New Medicine of USTC(YD9100002034)。
文摘The structural integrity of the sperm flagellum is essential for proper sperm function.Flagellar defects can result in male infertility,yet the precise mechanisms underlying this relationship are not fully understood.CCDC181,a coiled-coil domain-containing protein,is known to localize on sperm flagella and at the basal regions of motile cilia.Despite this knowledge,the specific functions of CCDC181 in flagellum biogenesis remain unclear.In this study,Ccdc181 knockout mice were generated.The absence of CCDC181 led to defective sperm head shaping and flagellum formation.Furthermore,the Ccdc181 knockout mice exhibited extremely low sperm counts,grossly aberrant sperm morphologies,markedly diminished sperm motility,and typical multiple morphological abnormalities of the flagella(MMAF).Additionally,an interaction between CCDC181 and the MMAF-related protein LRRC46 was identified,with CCDC181 regulating the localization of LRRC46 within sperm flagella.These findings suggest that CCDC181 plays a crucial role in both manchette formation and sperm flagellum biogenesis.
文摘Objective：Recent evidence indicates that dysregulation of microRNA （miRNA） biogenesis is implicated in cancer development and progression.Based on the important role of miRNA biogenesis genes in carcinogenesis,we hypothesized that genetic variations of the miRNA biogenesis genes may modulate susceptibility to cervical cancer.Methods：We identified three single nucleotide polymorphisms （SNPs） located in the 3＇-untranslated regions （3＇-UTR） of of miRNA biogenesis key genes （rs1057035 in DICER,rs3803012 in RAN and rs10773771 in HIWI） and genotyped these SNPs in a case-control study of 1,486 cervical cancer cases and 1,549 cancer-free controls in Chinese women.Results：Logistic regression analyses showed that no significant associations were observed between the three SNPs and cervical cancer risk [rs3803012 in RAN AG/GG vs.AA adjusted OR =1.104,95 ％ confidence interval （CI）：0.859-1.419; rs1057035 in DICER CT/CC vs.TT adjusted OR =0.962,95％ CI：0.805-1.149;rs10773771 in HIWICT/CC vs.TT adjusted OR =0.963,95％ CI：0.826-1.122].Conclusions：The findings did not suggest that genetic variants in the 3＇-UTR of RAN,DICER and HIWI of miRNA biogenesis genes were associated with the risk of cervical cancer in this Chinese population.
基金supported by grants from the National Key R&D Program of China(2017YFA0105803)the National Natural Science Foundation of China(82270886,82070811)+2 种基金the Science and Technology Plan Project of Guangzhou City(202007040003,202201020497)the 5010 Clinical Research Projects of Sun Yat-Sen University(2015015)the Dengfeng Plan High-level Hospital Construction Opening Project of Foshan Fourth People's Hospital(FSSYKF-2020011 and FSSYKF-2020009)。
文摘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.
基金supported by Key Laboratory of Joint CAAS/ IRRI Laboratory for Photosynthetic Enhancement, Biotechnology Research Institute/National Key Facility for Genetic Resources and Gene Improvementsupported by the National Key Research and Development Program of China (2020YFA0907600)+1 种基金the Agricultural Science and Technology Innovation Program (CAAS-ZDXT2019003)Fundamental Research Funds for Central Non-profit Scientific Institution。
文摘Chloroplasts are the center of plant life activities including photosynthesis,growth and development,and abiotic stress response.Chloroplast development and biogenesis in rice have been studied in detail,but how does abiotic stress affect chloroplasts is less studied.We obtained an albino mutant,alm1,whose chlorophyll content was greatly decreased.Transmission electron microscopy showed that chloroplast development in alm1 was blocked,especially in thylakoid-like structures,which could not form normally.The ALM1 gene encodes a chloroplast-localized superoxide dismutase.Full-length ALM1 successfully restored the non-albino phenotype,and in knockout lines,the albino phenotype reappeared.The ALM1gene is expressed mainly in young leaves.alm1 plants died as a consequence of excessive reactive oxygen accumulation after the third-leaf stage.A series of biochemical assays verified that ALM1 interacted with the OsTrxz protein,which is one of the components of plastid-encoded RNA polymerase (PEP) complexes.A western blot experiment indicated that ALM1 played an important role in stabilizing OsTrxz in rice.An overexpression test of ALM1 revealed that ALM1 can increase drought resistance by removing excess reactive oxygen in rice seedlings.This study suggests that ALM1 not only participates in rice chloroplast biogenesis,but also increases rice stress resistance by scavenging excess reactive oxygen.
基金STI2030-Major Projects,No.2022ZD0213000the National Natural Science Foundation of China,Nos.92057103 and 31872820+1 种基金Shanghai Basic Research Program,No.18ZR1 404000State Key Laboratory of Drug Research,No.SIMM2004KF-09 (all to YL)。
文摘Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,which requires further evaluation of the regulato ry mechanisms of protein aggregate degradation.Lysosomes are crucial degradative organelles that maintain cellular homeostasis.Transcription factor EB-mediated lysosome biogenesis enhances autolysosomedependent degradation,which subsequently alleviates neurodege nerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease.In this review,we start by describing the key features of lysosomes,including their roles in nutrient sensing and degradation,and their functional impairments in different neurodegenerative diseases.We also explain the mechanisms—especially the post-translational modifications—which impact transcription factor EB and regulate lysosome biogenesis.Next,we discuss strategies for promoting the degradation of toxic protein aggregates.We describe Proteolysis-Ta rgeting Chimera and related technologies for the targeted degradation of specific proteins.We also introduce a group of LYsosome-Enhancing Compounds,which promote transcription factor EB-mediated lysosome biogenesis and improve learning,memory,and cognitive function in APP-PSEN1 mice.In summary,this review highlights the key aspects of lysosome biology,the mechanisms of transcription factor EB activation and lysosome biogenesis,and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.
基金supported by the National Natural Science Foundation of China,No.81771422(to ZY)
文摘Certain microRNAs(miRNAs)can function as neuroprotective factors after reperfusion/ischemia brain injury.miRNA-142-3p can participate in the occurrence and development of tumors and myocardial ischemic injury by negatively regulating the activity of Rac1,but it remains unclear whether miRNA-142-3p also participates in cerebral ischemia/reperfusion injury.In this study,a model of oxygen-glucose deprivation/re-oxygenation in primary cortical neurons was established and the neurons were transfected with miR-142-3p agomirs or miR-142-3p antagomirs.miR-142-3p expression was down-regulated in neurons when exposed to oxygen-glucose deprivation/re-oxygenation.Over-expression of miR-142-3p using its agomir remarkably promoted cell death and apoptosis induced by oxygen-glucose deprivation/re-oxygenation and improved mitochondrial biogenesis and function,including the expression of peroxisome proliferator-activated receptor-γcoactivator-1α,mitochondrial transcription factor A,and nuclear respiratory factor 1.However,the opposite effects were produced if miR-142-3p was inhibited.Luciferase reporter assays verified that Rac Family Small GTPase 1(Rac1)was a target gene of miR-142-3p.Over-expressed miR-142-3p inhibited NOX2 activity and expression of Rac1 and Rac1-GTPase(its activated form).miR-142-3p antagomirs had opposite effects after oxygen-glucose deprivation/re-oxygenation.Our results indicate that miR-142-3p down-regulates the expression and activation of Rac1,regulates mitochondrial biogenesis and function,and inhibits oxygen-glucose deprivation damage,thus exerting a neuroprotective effect.The experiments were approved by the Committee of Experimental Animal Use and Care of Central South University,China(approval No.201703346)on March 7,2017.
基金supported by the National Key Basic Research Program of China(2015CB942800)the National Natural Science Foundation of China(Nos.31330051 and 31730060)+2 种基金the 111 Program(B14037)the Natural Science Foundation Project of Chongqing(cstc2014jcyj A10088)the Fundamental Research Funds for the Central Universities(XDJK2015B011)
文摘Ribosome biogenesis is essential for the cell growth and division. Disruptions in ribosome biogenesis result in developmental defects and a group of diseases, known as ribosomopathies. Here, we report a mutation in zebrafish urb1, which encodes an essential ribosome biogenesis protein. The urb1 cq31 mutant exhibits hypoplastic digestive organs, which is caused by impaired cell proliferation with the differentiation of digestive organ progenitors unaffected. Knockdown of mtor or raptor leads to similar hypoplastic phenotypes and reduced expression of urb1 in the digestive organs. Overexpression of Urb1 results in overgrowth of digestive organs, and can efficiently rescue the hypoplastic liver and pancreas in the mtor and raptor morphants. Reduced syntheses of free ribosomal subunits and impaired assembly of polysomes are observed in the urb1 mutant as well as in the mtor and raptor morphants, which can be rescued by the Urb1 overexpression. These data demonstrate that Urb1 plays an important role in governing ribosome biogenesis and protein synthesis downstream of mammalian/mechanistic target of rapamycin complex 1（mTORC1）, thus regulating the development of digestive organs. Our study indicates the requirement of hyperactive protein synthesis for the digestive organ development.
文摘Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear. Mitochondrial dysfunction,
基金financially supported by Shiraz University of Medical Sciences(Grant number:95-01-70-12474).
文摘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 m RNA 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 upregulated the hepatic m RNA expression of PGC-1α,NRF-1,and NRF-2 and increased the mtD NA/nD NA 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.
基金supported by the grants from the National Natural Science Foundation of China(NSFC)(No.31171391) to LJLan NSFC grant(No. 30825025) to JRP and a grant from the National Research Foundation of Singapore(R-154-000-529-281) to YHH
文摘Ribosome biogenesis in the nucleolus requires numerous nucleolar proteins and small non-coding RNAs.Among them is ribosome biogenesis factor Bmsl,which is highly conserved from yeast to human.In yeast,Bmsl initiates ribosome biogenesis through recruiting Rcll to pre-ribosomes.However,little is known about the biological function of Bmsl in vertebrates.Here we report that Bmsl plays an essential role in zebrafish liver development.We identified a zebrafish bms1l^（sq163） mutant which carries a T to A mutation in the gene bmsl-like（bms1l）.This mutation results in L^（152） to Q^（152） substitution in a GTPase motif in Bmsll.Surprisingly,bmsll^（sq163） mutation confers hypoplasia specifically in the liver,exocrine pancreas and intestine after 3 days post-fertilization（dpf）.Consistent with the bmsll^（sq163） mutant phenotypes,whole-mount in situ hybridization（WISH） on wild type embryos showed that bmsll transcripts are abundant in the entire digestive tract and its accessory organs.Immunostaining for phospho-Histone 3（P-H3） and TUNEL assay revealed that impairment of hepatoblast proliferation rather than cell apoptosis is one of the consequences of bms1l（sq163） giving rise to an under-developed liver.Therefore,our findings demonstrate that Bmsll is necessary for zebrafish liver development.
基金funded by Beijing Natural Science Foundation(JQ20028)the National Natural Science Foundation of China(32130023,91854114,32061143009)Ministry of Science and Technology of the People’s Republic of China(2019YFA0508602,2021YFA0804802)。
文摘Introduction Macroautophagy(hereafter referred as autophagy)is a process of cellular self-degradation.In response to nutrient deprivation or other stimuli,a nascent double-membrane autophagosome,encapsulating intracellular materials or damaged organelles,is generated.The autophagosome is transported toward and eventually fuses with the lysosome(or the vacuole in yeast and plant cells).
文摘It is believed that eukaryotes arise from prokaryotes, which means that organelles can form de novo in prokaryotes. Such events, however, had not been observed previously. Here, we report the biogenesis of organelles in the endosymbiotic cyanobacterium TDX16 (prokaryote) that was released from its senescent/necrotic host cell of green alga Haematococcus pluvialis (eukaryote). Microscopic observations showed that organelle biogenesis in TDX16 initiated with cytoplasm compartmentalization, followed by de-compartmentalization, DNA allocation, and re-compartmentalization, as such two composite organelles-the primitive chloroplast and primitive nucleus sequestering minor and major fractions of cellular DNA respectively were formed. Thereafter, the eukaryotic cytoplasmic matrix was built up from the matrix extruded from the primitive nucleus;mitochondria were assembled in and segregated from the primitive chloroplast, whereby the primitive nucleus and primitive chloroplast matured into the nucleus and chloroplast respectively. While mitochondria subsequently turned into double-membraned vacuoles after matrix degradation. Results of pigment analyses, 16S rRNA and genome sequencing revealed that TDX16 is a phycocyanin-containing cyanobacterium resembling Chroococcidiopsis thermalis, which had acquired 9,017,401 bp DNAs with 10,301 genes from its host. Accordingly, we conclude that organelle biogenesis in TDX16 is achieved by hybridizing the acquired eukaryotic DNAs with its own one and expressing the hybrid genome. The formation of organelles in cyanobacterium TDX16 is the first case of organelle biogenesis in prokaryotes observed so far, which sheds an unprecedented light on eukaryotes and their connections with prokaryotes, and thus has broad implications on biology.
基金supported by National Institute of Health Grant HL-48739 and HL-68216
文摘In this review, we focus on the pathway of biogenesis of HDL, the essential role of apoA-I, ATP binding cassette transporter A1（ABCA1）, and lecithin： cholesterol acyltransferase（LCAT） in the formation of plasma HDL; the generation of aberrant forms of HDL containing mutant apoA-I forms and the role of apoA-IV and apoE in the formation of distinct HDL subpopulations. The biogenesis of HDL requires functional interactions of the ABCA1 with apoA-I（and to a lesser extent with apoE and apoA-IV） and subsequent interactions of the nascent HDL species thus formed with LCAT. Mutations in apoA-I, ABCA1 and LCAT either prevent or impair the formation of HDL and may also affect the functionality of the HDL species formed. Emphasis is placed on three categories of apoA-I mutations. The first category describes a unique bio-engineered apoA-I mutation that disrupts interactions between apoA-I and ABCA1 and generates aberrant prep HDL subpopulations that cannot be converted efficiently to a subpopulations by LCAT. The second category describes natural and bio-engineered apoA-I mutations that generate preβ and small size a4 HDL subpopulations, and are associated with low plasma HDL levels. These phenotypes can be corrected by excess LCAT. The third category describes bio-engineered apoA-I mutations that induce hypertriglyceridemia that can be corrected by excess lipoprotein lipase and also have defective maturation of HDL.The HDL phenotypes described here may serve in the future for diagnosis, prognoses and potential treatment of abnormalities that affect the biogenesis and functionality of HDL.
基金the National Council for Scientific and Technological Development(CNPq)the International Foundation for Research in Paraplegia(IRP-P 112)+1 种基金the Deutsche Forschungsgemeinschaft(DFG-LI 1308/3-1)the Else Kr?ner-Fresenius-Stiftung
文摘Macroautophagy （here autophagy） is a catabolic mechanism responsible for the degradation of bulk cytoplasm, long-lived proteins and organeUes. During autophagy, the cargos are engulfed by double-membrane structures named phagophores, which expand to form the autophagosomes. Subsequently, these autophagosomes fuse with lysosomes, in which the cytoplasmic cargos are degraded. Autophagy is a constitutive pro- cess, which plays an important role in cellular homeostasis. In primary neurons autophagosome formation occurs continuously and preferentially at the distal end of axons. On the other hand, autophagy is increased by different stresses, and its dysregulation or excessive induction may lead to detrimental effects. Many neurological disorders have been associated with alterations in the autophagic pathway and an increase in autophagy during axonal degeneration was described.
