ABSTRACT
Delamination of the continental lithospheric mantle is well recorded beneath several continents. However, the fate of the removed continental lithosphere has been rarely noted, unlike subducted slabs reasonably well imaged in the upper and mid mantle. Beneath former Gondwana, recent seismic tomographic models indicate the presence of at least 5 horizontal fast-wavespeed anomalies at ~600 km depths that do not appear to be related to slab subduction, including fast structures in locations consistent with delamination associated with the Paraná Flood Basalt event at ~134 Ma and the Deccan Traps event at ~66 Ma. These fast-wavespeed anomalies often lie above broad slow seismic wavespeed trunks at 500 to 700 km depths beneath former Gondwana, with slow wavespeed anomalies branching around them. Numerical experiments indicate that delaminated lithosphere tends to stagnate in the transition zone and mid-mantle above a mantle plume where it shapes subsequent plume upwelling. For hot plumes, the melt volume generated during plume-influenced delamination can easily reach ~2 to 4 × 106 km3, consistent with the basalt eruption volume at the Deccan Traps. This seismic and numerical evidence suggests that observed high-wavespeed mid-mantle anomalies beneath the locations of former flood basalts are delaminated fragments of former continental lithosphere, and that lithospheric delamination events in the presence of subcontinental plumes induced several of the continental flood basalts associated with the multiple breakup stages of Gondwanaland. Continued upwelling in these plumes can also have entrained subcontinental lithosphere in the mid-mantle to bring its distinctive geochemical signal to the modern mid-ocean spreading centers that surround southern and western Africa.
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BACKGROUND: The guts of mammals are home to trillions of microbes, forming a complex and dynamic ecosystem. Gut microbiota is an important biological barrier for maintaining immune homeostasis. Recently, the use of antibiotics to clear gut microbiota has gained popularity as a low cost and easy-to-use alternative to germ-free animals. However, the effect of the duration of the antibiotic cocktail on the gut microbiome is unclear, and more importantly, the effect of dramatic changes in the gut microbiota on intestinal tissue morphology and local immune response is rarely reported. RESULTS: We observed a significant reduction in fecal microbiota species and abundance after 1 week of exposure to an antibiotic cocktail, gavage twice daily by intragastric administration. In terms of composition, Bacteroidetes and Firmicutes were replaced by Proteobacteria. Extending antibiotic exposure to 2-3 weeks did not significantly improve the overall efficiency of microbiotal consumption. No significant histomorphological changes were observed in the first 2 weeks of antibiotic cocktail exposure, but the expression of inflammatory mediators in intestinal tissue was increased after 3 weeks of antibiotic cocktail exposure. Mendelian randomization analysis showed that Actinobacteria had a significant causal association with the increase of IL-1ß (OR = 1.65, 95% CI = 1.23 to 2.21, P = 0.007) and TNF-α (OR = 1.81, 95% CI = 1.26 to 2.61, P = 0.001). CONCLUSIONS: Our data suggest that treatment with an antibiotic cocktail lasting 1 week is sufficient to induce a significant reduction in gut microbes. 3 weeks of antibiotic exposure can lead to the colonization of persistant microbiota and cause changes in intestinal tissue and local immune responses.
Subject(s)
Anti-Bacterial Agents , Feces , Gastrointestinal Microbiome , Anti-Bacterial Agents/pharmacology , Animals , Feces/microbiology , Gastrointestinal Microbiome/drug effects , Interleukin-1beta/genetics , Mice , Bacteria/drug effects , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Mice, Inbred C57BL , Bacteroidetes/drug effects , Firmicutes/drug effectsABSTRACT
OBJECTIVES: The purpose of this study was to explore the experience of financial toxicity among caregivers of cancer patients and to provide recommendations for subsequent intervention strategies. METHODS: Computer searches of PubMed, EmBase, The Cochrane Library, Web of Science, CINAHL (EBSCO), CNKI, Wanfang database, and SinoMed for qualitative studies experience of financial toxicity among caregivers cancer patients. The search time frame was from the establishment of the database to May 2023. The quality of included studies was assessed using the Qualitative Research Checklist from the Joanna Briggs Institute (JBI) Reviewer's Manual. The meta-synthesis was integrated following the meta-aggregation method proposed by the Joanna Briggs Institute (JBI) and reported following the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) guidelines. RESULTS: A total of nine studies were included, distilling 25 qualitative findings into nine new categories and synthesizing three synthesized findings: caregivers have strong negative experiences that affect their family relationships, daily work and life; caregivers use different strategies to cope with financial toxicity; needs and expectations of caregivers coping with financial toxicity. CONCLUSIONS: Financial toxicity among caregivers of cancer patients affects their daily lives. Receiving timely recognition of this financial burden and providing assistance to enhance their coping skills are crucial in mitigating its impact. Healthcare professionals should focus on the financial toxicity experienced by caregivers of people with cancer, address their supportive needs, and develop a comprehensive support system to improve caregivers' coping abilities and quality of life.
Subject(s)
Caregivers , Neoplasms , Qualitative Research , Humans , Caregivers/psychology , Caregivers/economics , Neoplasms/psychology , Neoplasms/economics , Cost of Illness , Adaptation, Psychological , Quality of LifeABSTRACT
Pulmonary Fibrosis (PF) is a fatal disease in the interstitial lung associated with high mortality, morbidity, and poor prognosis. Transforming growth factor-ß1 (TGF-ß1) is a fibroblast-activating protein that promotes fibrous diseases. Herein, an inhalable system was first developed using milk exosomes (M-Exos) encapsulating siRNA against TGF-ß1 (MsiTGF-ß1), and their therapeutic potential for bleomycin (BLM)-induced PF was investigated. M-siTGF-ß1 was introduced into the lungs of mice with PF through nebulization. The collagen penetration effect and lysosomal escape ability were verified in vitro. Inhaled MsiTGF-ß1 notably alleviated inflammatory infiltration, attenuated extracellular matrix (ECM) deposition, and increased the survival rate of PF mice by 4.7-fold. M-siTGF-ß1 protected lung tissue from BLM toxicity by efficiently delivering specific siRNA to the lungs, leading to TGF-ß1 mRNA silencing and epithelial mesenchymal transition pathway inhibition. Therefore, M-siTGF-ß1 offers a promising avenue for therapeutic intervention in fibrosis-related disorders.
Subject(s)
Bleomycin , Collagen , Epithelial-Mesenchymal Transition , Exosomes , Lung , Milk , Pulmonary Fibrosis , RNA, Small Interfering , Transforming Growth Factor beta1 , Animals , Exosomes/metabolism , Transforming Growth Factor beta1/metabolism , Pulmonary Fibrosis/drug therapy , Mice , Collagen/metabolism , Bleomycin/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Lung/pathology , Lung/metabolism , Lung/drug effects , Milk/chemistry , Mice, Inbred C57BL , Humans , Permeability , Male , Nebulizers and VaporizersABSTRACT
BACKGROUND: This study aims to investigate the influencing factors of vascular calcification in peritoneal dialysis (PD) patients and its relationship with long-term prognosis. METHODS: This retrospective cohort study included chronic kidney disease patients undergoing peritoneal dialysis at the Peritoneal Dialysis Center of Beijing Luhu Hospital, Capital Medical University, from January 2019 to March 2019. Demographic and clinical laboratory data, including serum sclerostin (SOST), calcium (Ca), phosphate (P), serum albumin (ALB), and intact parathyroid hormone (iPTH) levels, were collected. Abdominal aortic calcification (AAC) was assessed using abdominal lateral X-ray examination to determine the occurrence of vascular calcification, and patients were divided into the AAC group and Non-AAC group based on the results. RESULTS: A total of 91 patients were included in the study. The AAC group consisted of 46 patients, while the Non-AAC group consisted of 45 patients. The AAC group had significantly older patients compared to the non-AAC group (P < 0.001) and longer dialysis time (P = 0.004). Multivariable logistic regression analysis indicated that risk factors for vascular calcification in PD patients included dialysis time, diabetes, hypertension, and SOST. Kaplan-Meier survival analysis showed that the AAC group had a significantly higher mortality rate than the non-AAC group (χ2 = 35.993, P < 0.001). Multivariable Cox regression analysis revealed that dialysis time, diabetes and AAC were risk factors for all-cause mortality in peritoneal dialysis patients. CONCLUSION: Longer dialysis time, comorbid diabetes, comorbid hypertension, and SOST are risk factors for vascular calcification in PD patients. Additionally, AAC, longer dialysis time, and comorbid diabetes are associated with increased risk of all-cause mortality in peritoneal dialysis patients.
Subject(s)
Peritoneal Dialysis , Renal Insufficiency, Chronic , Vascular Calcification , Vascular Calcification/diagnosis , Vascular Calcification/etiology , Peritoneal Dialysis/adverse effects , Prognosis , Retrospective Studies , Renal Insufficiency, Chronic/therapy , Humans , Male , Female , Middle Aged , AgedABSTRACT
Engineering of multivariate biosensing and imaging platforms involved in disease plays a vital role in effectively discerning cancer cells from normal cells and facilitating reliable targeted therapy. Multiple biomarkers such as mucin 1 (MUC1) and nucleolin are typically overexpressed in breast cancer cells compared to normal human breast epithelium cells. Motivated by this knowledge, a dual-responsive DNA tetrahedron nanomachine (drDT-NM) is constructed through immobilizing two recognition modules, MUC1 aptamer (MA) and a hairpin H1* encoding nucleolin-specific G-rich AS1411 aptamer, in two separate vertexes of a functional DT architecture tethering two localized pendants (PM and PN). When drDT-NM identifiably binds bivariate MUC1 and nucleolin, two independent hybridization chain reactions (HCRM and HCRN) as amplification modules are initiated with two sets of four functional hairpin reactants. Among them, one hairpin for HCRM is dually ended by fluorescein and quencher BHQ1 to sense MUC1. The responsiveness of nucleolin is executed by operating HCRN utilizing another two hairpins programmed with two pairs of AS1411 splits. In the shared HCRN duplex products, the parent AS1411 aptamers are cooperatively merged and folded into G-quadruplex concatemers to embed Zn-protoporphyrin IX (ZnPPIX/G4) for fluorescence signaling readout, thereby achieving a highly sensitive intracellular assay and discernible cell imaging. The tandem ZnPPIX/G4 unities also act as imaging agents and therapeutic cargos for efficient photodynamic therapy of cancer cells. Based on drDT-NM to guide bispecific HCR amplifiers for adaptive bivariate detection, we present a paradigm of exquisitely integrating modular DNA nanostructures with nonenzymatic nucleic acid amplification, thus creating a versatile biosensing platform as a promising candidate for accurate assay, discernible cell imaging, and targeted therapy.
Subject(s)
Aptamers, Nucleotide , Biosensing Techniques , G-Quadruplexes , Humans , Nucleic Acid Hybridization/methods , DNA/genetics , DNA/chemistry , Aptamers, Nucleotide/chemistry , Biosensing Techniques/methodsABSTRACT
Rennet, an aspartate protease found in the stomach of unweaned calves, effectively cuts the peptide bond between Phe105-Met106 in κ-casein, hydrolyzing the casein micelles to coagulate the milk and is a crucial additive in cheese production. Rennet is one of the most used enzymes of animal origin in cheese making. However, using rennet al.one is insufficient to meet the increasing demand for cheese production worldwide. Numerous studies have shown that plant rennet can be an alternative to bovine rennet and exhibit a good renneting effect. Therefore, it is crucial and urgent to find a reliable plant rennet. Based on our team's research on rennet enzymes of plant origin, such as from Dregea sinensis Hemsl. and Moringa oleifer Lam., for more than ten years, this paper reviews the relevant literature on rennet sources, isolation, identification, rennet mechanism, functional active peptide screening, and application in cheese production. In addition, it proposes the various techniques for targeted isolation and identification of rennet and efficient screening of functionally active peptides, which show excellent prospects for development.
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Ligand exchange has been widely used to synthesize novel thiolated gold nanoclusters and to regulate their specific properties. Herein, density functional theory (DFT) calculations were conducted to investigate the kinetic profiles of the ligand exchange of the [Au23(SCy)16]- nanocluster with an aromatic thiolate (2-napthalenethiol). The three types of staple motifs (i.e., trimetallic Au3S4, monometallic AuS2, and the bridging thiolates) of the Au23 cluster precursor could be categorized into eight groups of S sites with different chemical environments. The ligand exchange of all of them occurs favorably via the SN1-like pathway, with one site starting with the Au-S dissociation and seven other sites starting with the H-transfer steps. By contrast, the SN2-like pathway (i.e., the synergistic SCy-to-SAr exchange prior to the H-transfer step) is unlikely in the target systems. Meanwhile, the Au-S bond on the capping Au atom of the bicapped icosahedral Au15 core is the most active one, while the S sites on Au3S4 (except for the one remote from the metallic core) are all competitive exchanging sites. The ligand exchange activity of the bridging thiolate and the remote S site on Au3S4 is significantly less reactive. The calculation results correlate with the multiple ligand exchange within only a few minutes and the preferential etching of the AuS2 staple with the foreign ligands reported in earlier experiments. The relative activity of different staples might be helpful in elucidating the inherent principles in the ligand exchange-induced size-evolution of metal nanoclusters.
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OBJECTIVE: Long intergenic noncoding RNA 00632 (LINC00632) regulates nasal inflammation and CD4+ T cell differentiation into T helper (Th) 2 cells in allergic rhinitis (AR). This study aimed to explore the relationship between LINC00632 and Th1/Th2 balance, and the clinical value of LINC00632 in AR patients. METHODS: In total, 120 AR patients, 20 non-atopic obstructive snoring patients as disease controls (DCs), and 20 healthy controls (HCs) were recruited. Their LINC00632 expressions in peripheral blood mononuclear cells were detected by RT-qPCR. RESULTS: LINC00632 expression was declined in AR patients compared with DCs and HCs (both P Ë 0.001). Moreover, LINC00632 could distinguish AR patients from DCs with an area under curve (AUC) of 0.795 (95% confidence interval [CI]: 0.701-0.889), and from HCs with an AUC of 0.895 (95%CI: 0.831-0.960). LINC00632 was positively related to Th1 cells (P = 0.037) and Th1/Th2 axis (P Ë 0.001) in AR patients. In addition, LINC00632 was inversely associated with Th2 cells (P Ë 0.001) and interleukin (IL)-4 (P = 0.010) in AR patients. Besides, LINC00632 was negatively related to rhinorrhea score (P = 0.019), itching score (P = 0.008), sneezing score (P = 0.004), and total nasal symptom score (TNSS) (P Ë 0.001), but no correlation between LINC00632 and congestion score was observed (P = 0.093). During treatment, LINC00632 was elevated, while TNSS score was reduced (both P Ë 0.001). Furthermore, LINC00632 increment was associated with the reduction of TNSS score during the therapy (P = 0.005). CONCLUSION: LINC00632 relates to milder Th1/Th2 imbalance, attenuated nasal symptoms, and better response during 4-week therapy in AR patients.
Subject(s)
Nasal Mucosa , Rhinitis, Allergic , Animals , Humans , Cytokines/metabolism , Disease Models, Animal , Leukocytes, Mononuclear/metabolism , Nasal Mucosa/metabolism , Rhinitis, Allergic/drug therapy , Th1 Cells , Th2 CellsABSTRACT
OBJECTIVE: To assess serum 25-hydroxyvitamin D3 (25(OH)D3), fibroblast growth factor 23 (FGF23), and C1q/tumor necrosis factor-related protein-3 (CTRP3) levels in nondialysis chronic kidney disease (CKD) patients and their relationship with coronary artery calcification (CAC). METHODS: One hundred and twenty-eight patients diagnosed with CKD were selected and all underwent cardiac computed tomography. CAC was assessed using the Agatston score, and coronary artery calcification score (CACs) >10 was identified as CAC. The differences in serum 25(OH)D3, FGF23, and CTRP3 levels between the CAC and non-CAC groups were analyzed. Their correlation with CACs was assessed by Spearman's analysis, and logistic regression analysis was used to find risk factors for CAC. RESULTS: Compared to the non-CAC group, the CAC group was older (64.21 ± 9.68 years), with a higher percentage of hypertension (93.10%) and diabetes (63.80%) and higher levels of serum CTRP3 [1079.20 (644.4-1567.2) ng/mL]. However, there was no significant difference in serum 25(OH)D3 and FGF23 between these two groups. The high level CTRP3 group had a higher prevalence of CAC (61.5%). Logistic regression results showed that age, diabetes, decreased 25(OH)D3 (odds ratio (OR) = 0.95, p = .030) and high levels of CTRP3 (OR = 3.19, p = .022) were risk factors for CAC in nondialysis CKD patients. CONCLUSIONS: Serum CTRP3 levels progressively increased with the progression of kidney disease, while 25(OH)D3 levels progressively decreased. Decreased 25(OH)D3 and high levels of CTRP3 are associated with CAC in patients with nondialysis CKD.
Subject(s)
Coronary Artery Disease , Renal Insufficiency, Chronic , Vascular Calcification , Humans , Fibroblast Growth Factor-23 , Calcifediol , Complement C1q , Vascular Calcification/diagnostic imaging , Vascular Calcification/etiology , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/etiology , Risk Factors , Tumor Necrosis FactorsABSTRACT
Three isostructural dl-serine covalently functionalized and multinuclear lanthanide (Ln3+)-embedded arsenotungstates, K2[{As4W44O137(OH)18(H2O)2(dl-Ser)2}{Ln2(H2O)4(dl-Ser)}2{Ln(H2O)7}2]·70H2O (Ln = Sm (1), Eu (2), and Gd (3); dl-Ser = C3H7NO3), were prepared, where the centrosymmetric [{As4W44O137(OH)18(H2O)2(dl-Ser)2}{Ln2(H2O)4(dl-Ser)}2]8- polyanion consists of two {As2W19O59(OH)8(H2O)}6- fragments, integrated with a two-dl-serine-ornamented [W6O23(OH)2(dl-Ser)2{Ln2(H2O)4}2]8- segment. In addition, the photochromic transformation of solid-state compounds 1-3 was observed from colorless to blue after a UV illumination of 4 min, and the decay process lasted as long as â¼20 h in the dark. The coloration kinetic half-life (t1/2) values of compounds 1, 2, and 3 were calculated to be 0.597, 0.920, and 0.723 min, respectively. Furthermore, the luminescent properties and energy migration from arsenotungstates and organic chromophores to Sm3+ and Eu3+ ions in 1 and 2 have been intensively investigated. Further analysis manifests that 1 possesses an effective luminescent switchable behavior, triggered by its fast-responsive photochromism effect.
Subject(s)
Lanthanoid Series Elements , Luminescence , Amino Acids , Ions , Lanthanoid Series Elements/chemistry , SerineABSTRACT
AIMS: Staphylococcus aureus has emerged as a serious threat to food safety owing to biofilm formation. The study aimed to examine the antibiofilm mechanism of a novel milk-derived antimicrobial peptide BCp12 against it. METHODS AND RESULTS: Antibiofilm activity of BCp12 was studied by crystal violet staining, MTT assay, motility, SEM and CLSM. TMT proteome, real-time PCR and molecular docking in silico were conducted to evaluate the mechanism of BCp12 against S. aureus biofilm. The results showed that BCp12 had significant antibiofilm activity at 1 × MIC and sub-MIC. BCp12 induced the dispersion of structure of S. aureus biofilm BCp12 inhibited the movement of S. aureus. A total of 703 proteins were downregulated and 334 proteins were upregulated after BCp12 treatment. The proteins (agrA, agrB, agrC and psmß) of the QS systems were downregulated. Additionally, the expression of the agr-related genes, agrA, agrB, agrC and psmß, was downregulated. BCp12 was bound to the receptor proteins agrA and agrC through hydrogen bonds and π-π bonds. CONCLUSIONS: The results showed the antibiofilm activity of BCp12 and it inhibits the biofilm formation by interfering agr QS system. SIGNIFICANCE AND IMPACT OF STUDY: BCp12 has the potential to be a novel antibiofilm agent against S. aureus biofilm and used in the food industry.
Subject(s)
Staphylococcal Infections , Staphylococcus aureus , Animals , Antimicrobial Peptides , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Bacterial Proteins/pharmacology , Biofilms , Gentian Violet/metabolism , Humans , Milk/metabolism , Molecular Docking Simulation , Proteome/metabolism , Quorum Sensing/physiology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/physiologyABSTRACT
A cysteine peptidase was previously identified from germinated Moringa oleifera seeds, but its milk-clotting properties on bovine caseins was still unclear. In this study, this novel cysteine peptidase (MoCP) showed preferential activity on κ-casein (κ-CN), with greater hydrolytic activity compared with calf rennet, whereas weak hydrolysis of α-casein and ß-casein made MoCP suitable for application in cheesemaking and may yield various functional peptides. All 3 evaluated caseins were hydrolyzed to form relatively stable peptide bands within 3 h of proteolysis with MoCP. Cleavage sites were determined by gel electrophoresis, liquid chromatography mass spectrometry/mass spectrometry, and peptide sequencing, which revealed that cleavage of κ-CN by MoCP occurred at residue Ile129-Pro130 and generated a 14,895.37-Da peptide. The flocculation reaction between MoCP and κ-CN determined by 3-dimensional microscopy with super-depth of field revealed that the initial 30 min of reaction were key for milk coagulation, which may affect curd yield. Overall, the findings presented herein suggest that the cysteine peptidase from germinated M. oleifera seeds can be considered a promising plant-derived rennet alternative for use in cheese manufacture.
Subject(s)
Cheese , Cysteine Proteases , Moringa oleifera , Animals , Caseins/chemistry , Cattle , Cheese/analysis , Cysteine/analysis , Milk/chemistry , Moringa oleifera/chemistry , Peptides/analysis , Seeds/chemistryABSTRACT
PURPOSE: It is of obvious interest to identify clinical prognosis-related oncogenes in HNSCC (head and neck squamous cell carcinoma). METHODS: Based on the available datasets within the TCGA (The Cancer Genome Atlas) and the GEO (Gene Expression Omnibus) databases, the potential mechanism of action of the SEC61G (SEC61 translocon subunit gamma) gene in HNSCC tumorigenesis was explored by several bioinformatics approaches. RESULTS: There was a higher expression level of SEC61G in primary HNSCC tumor tissues than in normal tissues. Moreover, highly expressed SEC61G was statistically associated with the poor survival prognosis of HNSCC patients. When HPV (human papilloma virus) was considered, we also observed a relatively lower proportion of "arm-level gain" and "high amplification" types of CNA (copy-number alteration) in the HNSCC-HPV (+) group than in the HNSCC-HPV (-) group. Additionally, we identified SEC61G CAN-correlated genes, such as CCT6A (chaperonin-containing TCP1 subunit 6A) and HUS1 (HUS1 checkpoint clamp component), and found a correlation between SEC61G copy-number segments and prognosis related to overall and progression-free survival intervals of HNSCC patients. Moreover, the molecular regulation mechanisms of the spliceosome, ribosome, proteasome degradation, cell adhesion, and immune infiltration of B and CD8+ T cells may contribute to the involvement of SEC61G in the pathogenesis of HNSCC. CONCLUSIONS: The SEC61G gene was identified for the first time as a prognostic biomarker of HNSCC. The detailed underlying mechanism merits further research.
Subject(s)
CD8-Positive T-Lymphocytes , Head and Neck Neoplasms , Biomarkers , Chaperonin Containing TCP-1 , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/genetics , Humans , Prognosis , SEC Translocation Channels/genetics , Squamous Cell Carcinoma of Head and Neck/geneticsABSTRACT
Sphingosine kinase 2 (SphK2) inhibitors are developed for tumor therapy as considering its anti-tumor effect. Many studies also explored SphK2 modulated glucose and lipid homeostasis, which extended its potential function for metabolic diseases therapy. In this study, we discovered a significant reduction of hepatic lipid accumulation as well as recovery of liver function in ob/ob mice with intraperitoneal injection of K145. Also, db/db mice received K145 showed improvement of both NALFD and hyperglycemia. We furtherly analyzed the genes associated with lipid metabolism and found a remarkable decreased expression of lipogenic genes including FAS, ACC1 and SREBP1c whereas elevated mitochondrial fatty acid ß-oxidation (FAO) related genes expression including CPT1A, MCAD, LCAD, PPAR-α, UCP2. Consistent to in vivo study, in vitro study also confirmed the role of K145 in decreasing lipid accumulation in human HL7702 cells, while inhibiting FAS, ACC1 and SREBP1c mRNA expression. It indicated a possible mechanism of K145 induced improvement of hepatic lipid accumulation partly via inhibition of lipigenesis. Our study suggested a promising role of K145 in drug development for NAFLD and diabetes therapy.
Subject(s)
Non-alcoholic Fatty Liver Disease/drug therapy , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Thiazolidinediones/therapeutic use , Animals , Cell Line , Humans , Lipid Metabolism/drug effects , Male , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolismABSTRACT
BACKGROUND: Protein lysine malonylation, a novel post-translational modification (PTM), has been recently linked with energy metabolism in bacteria. Staphylococcus aureus is the third most important foodborne pathogen worldwide. Nonetheless, substrates and biological roles of malonylation are still poorly understood in this pathogen. RESULTS: Using anti-malonyl-lysine antibody enrichment and high-resolution LC-MS/MS analysis, 440 lysine-malonylated sites were identified in 281 proteins of S. aureus strain. The frequency of valine in position - 1 and alanine at + 2 and + 4 positions was high. KEGG pathway analysis showed that six categories were highly enriched, including ribosome, glycolysis/gluconeogenesis, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), valine, leucine, isoleucine degradation, and aminoacyl-tRNA biosynthesis. In total, 31 malonylated sites in S. aureus shared homology with lysine-malonylated sites previously identified in E. coli, indicating malonylated proteins are highly conserved among bacteria. Key rate-limiting enzymes in central carbon metabolic pathways were also found to be malonylated in S. aureus, namely pyruvate kinase (PYK), 6-phosphofructokinase, phosphoglycerate kinase, dihydrolipoyl dehydrogenase, and F1F0-ATP synthase. Notably, malonylation sites were found at or near protein active sites, including KH domain protein, thioredoxin, alanine dehydrogenase (ALD), dihydrolipoyl dehydrogenase (LpdA), pyruvate oxidase CidC, and catabolite control protein A (CcpA), thus suggesting that lysine malonylation may affect the activity of such enzymes. CONCLUSIONS: Data presented herein expand the current knowledge on lysine malonylation in prokaryotes and indicate the potential roles of protein malonylation in bacterial physiology and metabolism.
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The baculovirus expression vector system (BEVS) is an attractive manufacturing platform for recombinant protein production in insect cells. However, baculovirus infection commonly induces host apoptosis in 3-4 days which would subsequently terminate the protein expression. Previous studies have proved that protein production by BEVS can be elevated in apoptosis-suppressed insect cells. We also developed a baculovirus vector in our previous report to inhibit the apoptosis and improve protein production in Sf9 cells. In this study, we designed five short hairpin RNA (shRNA) expression cassettes targeting a conserved region in Spodoptera frugiperda caspase-1 (Sf-caspase-1) and Trichoplusia ni caspase-1 (Tn-caspase-1), and found that introduction of C to T mutations within the stem region of the expression cassette was beneficial for the heterologous protein expression. One of the improved shRNA expression cassettes was knocked into a bacmid with the deletion of several nonessential genes. The novel baculovirus vector demonstrated the ability to suppress cell apoptosis in both Sf9 and High Five cells, and exhibited superior recombinant protein productivity of intracellularly expressed GFP and firefly luciferase and secreted glycoprotein OD-Fc. The antiapoptotic baculovirus vector developed in this study could serve as a useful tool for the protein production in scientific research and pharmaceutical industries.
Subject(s)
Apoptosis , Caspase 1 , Genetic Vectors , Insect Proteins , Animals , Baculoviridae/genetics , Baculoviridae/metabolism , Caspase 1/genetics , Caspase 1/metabolism , Genetic Engineering , Genetic Vectors/genetics , Genetic Vectors/metabolism , Insect Proteins/antagonists & inhibitors , Insect Proteins/genetics , Insect Proteins/metabolism , Sf9 Cells , SpodopteraABSTRACT
As the power conversion efficiencies of organic solar cells (OSCs) have been improved continuously in recent years, more attention will be paid to the industrial production and practical application of OSCs. However, there are still many problems to be solved in the process of large-scale production. Among them, reducing the costs of the materials and enhancing the film-thickness tolerance of the active layer are the two key points. Therefore, it is urgent to develop organic semiconductor materials which are easy to synthesize and suitable for the construction of high-efficiency, thick-film OSCs. In this work, we have focused on the (E)-2-[2-(thiophen-2-yl)vinyl]thiophene (TVT) unit because of its unique coplanar structure. And we noticed that TVT was mostly used as an electron-donating unit in the previous reports. However, we have modified TVT into electron-withdrawing unit by the introduction of fluorine atoms/ester groups. And two new donor-acceptor (D-A) copolymers have been obtained by combining the electron-withdrawing TVT unit with benzo[2,1-b:4,5-b']dithiophene (BDT) unit. Among them, the polymer based on the ester modified TVT unit presents excellent photovoltaic performance by virtue of its good solubility and preferable molecular stacking mode, and the corresponding devices also show extraordinarily high-thickness tolerance. The emergence of this new electron-withdrawing TVT unit will undoubtedly further promote the development of low-cost, high-efficiency, thick-film OSCs.
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BACKGROUND: The use of drug nanocarriers to encapsulate drugs for oral administration may become an important strategy in addressing the challenging oral absorption of some drugs. In this study-with the premise of controlling single variables-we prepared model nanoparticles with different particle sizes, surface charges, and surface hydrophobicity/hydrophilicity. The two key stages of intestinal nanoparticles (NPs) absorption-the intestinal mucus layer penetration stage and the trans-intestinal epithelial cell stage-were decoupled and analyzed. The intestinal absorption of each group of model NPs was then investigated. RESULTS: Differences in the behavioral trends of NPs in each stage of intestinal absorption were found to result from differences in particle properties. Small size, low-magnitude negative charge, and moderate hydrophilicity helped NPs pass through the small intestinal mucus layer more easily. Once through the mucus layer, an appropriate size, positive surface charge, and hydrophobic properties helped NPs complete the process of transintestinal epithelial cell transport. CONCLUSIONS: To achieve high drug bioavailability, the basic properties of the delivery system must be suitable for overcoming the physiological barrier of the gastrointestinal tract.
Subject(s)
Drug Carriers/metabolism , Intestinal Absorption , Nanoparticles/metabolism , Administration, Oral , Animals , Caco-2 Cells , Drug Carriers/administration & dosage , Drug Carriers/chemistry , HT29 Cells , Humans , Hydrophobic and Hydrophilic Interactions , Mucus/metabolism , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Particle Size , Rats, Sprague-Dawley , Static ElectricityABSTRACT
Lipid metabolism reprogramming is now accepted as a new hallmark of cancer. Hence, targeting the lipogenesis pathway may be a potential avenue for cancer treatment. Valproic acid (VPA) emerges as a promising drug for cancer therapy; however, the underlying mechanisms are not yet fully understood. In this study, we aimed to investigate the effects and mechanisms of VPA on cell viability, lipogenesis, and apoptosis in human prostate cancer PC-3 and LNCaP cells. The results showed that VPA significantly reduced lipid accumulation and induced apoptosis of PC-3 and LNCaP cells. Moreover, the expression of CCAAT/enhancer-binding protein α (C/EBPα), as well as sterol regulatory element-binding protein 1 (SREBP-1) and its downstream effectors, including fatty acid synthase (FASN), acetyl CoA carboxylase 1 (ACC1), and anti-apoptotic B-cell lymphoma 2 (Bcl-2), was markedly decreased in PC-3 and LNCaP cells after VPA administration. Mechanistically, the overexpression of C/EBPα rescued the levels of SREBP-1, FASN, ACC1, and Bcl-2, enhanced lipid accumulation, and attenuated apoptosis of VPA-treated PC-3 cells. Conversely, knockdown of C/EBPα by siRNA further decreased lipid accumulation, enhanced apoptosis, and reduced the levels of SREBP-1, FASN, ACC1, and Bcl-2. In addition, SREBP-1a and 1c enhanced the expressions of FASN and ACC1, but only SREBP-1a had a significant effect on Bcl-2 expression in VPA-treated PC-3 cells. Based on the results, we concluded that VPA significantly inhibits cell viability via decreasing lipogenesis and inducing apoptosis via the C/EBPα/SREBP-1 pathway in prostate cancer cells. Therefore, VPA that targets lipid metabolism and apoptosis is a promising candidate for PCa chemotherapy.