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AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.
Subject(s)
Chlorogenic Acid , Diabetic Nephropathies , Fibrosis , Kidney , Lipid Metabolism , Receptor, Notch1 , STAT3 Transcription Factor , Signal Transduction , STAT3 Transcription Factor/metabolism , Receptor, Notch1/metabolism , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Animals , Signal Transduction/drug effects , Fibrosis/drug therapy , Chlorogenic Acid/pharmacology , Chlorogenic Acid/therapeutic use , Humans , Mice , Male , Kidney/pathology , Kidney/drug effects , Kidney/metabolism , Lipid Metabolism/drug effects , Molecular Docking Simulation , Mice, Inbred C57BL , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Cell LineABSTRACT
Three-dimensional (3D) graphene oxide (GO)-based aerogels, GO and 4-methyl-5-thiazoleethanol (MTZE) composites, were prepared by a facile hydrothermal method. Due to the hydrogen bonding and π-π stacking interactions, the produced 3D GO-MTZE composites possessed large cylindrical structures. The morphologies, composition, and chemical states of 3D GO-MTZE3:1 composite were characterized by Fourier transform infrared (FT-IR) spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and N2 adsorption-desorption isotherms based on the Brunauer-Emmett-Teller (BET) method. The existence of nitrogen (N)-containing heterocyclic system and oxygen (O)-containing branched chain of MTZE contributed to the formation of 3D structures, while the complexation effect of heterocyclic sulfur (S)- and N-containing functional groups of MTZE for metal cations dominated the adsorption performance of 3D GO-MTZE3:1 composite, which could selectively adsorb copper ions (Cu2+). In addition, the better hydrophobic property of 3D GO-MTZE3:1 composite facilitates its facile recycling from aqueous solution after adsorption. The adsorption data of 3D GO-MTZE3:1 composite toward Cu2+ fitted well (R2 = 0.9996) with the linear pseudo-second-order kinetic model, giving an equilibrium rate constant (k2) of 0.0187 g mg-1 min-1. The linear Langmuir isothermal model could more accurately describe the experimental data, indicating the adsorption process is mainly dominated by the complexation interactions between MTZE and Cu2+. The thermodynamic parameters of ΔG° (< 0), ΔH° (> 0), and ΔS° (> 0) further indicate that the adsorption is a spontaneous and endothermic, confirming that the complexation between Cu2+ and 3D GO-MTZE3:1 composite occurs. Due to its high selectivity for Cu2+, good hydrophobicity, and excellent stability, the developed 3D GO-MTZE3:1 composite possesses might be promisingly used in the aqueous selective enrichment/removal of Cu2+.
Subject(s)
Copper , Graphite , Adsorption , Copper/chemistry , Graphite/chemistry , Water Pollutants, Chemical/chemistry , Spectroscopy, Fourier Transform InfraredABSTRACT
BACKGROUND: An increasing number of individuals undergo total knee arthroplasty (TKA), which can result in pain, limited motor function and adverse complications such as infection, nausea and vomiting. Glucocorticoids have been shown anti-inflammatory and antiemetic effects, but can also elevate blood glucose levels and increase the risk of wound infection. Thus, it is essential to investigate the efficacy and safety of glucocorticoid usage in TKA. METHOD: A comprehensive systematic search of PubMed, Medline, EMBASE, Cochrane databases, to identify relevant randomized controlled trials (RCTs) of glucocorticoid application in TKA. The primary outcomes assessed were the postoperative pain assessment. Secondary outcomes included the range of motion in knee joint, levels of inflammatory cytokines, adverse complications, and the length of hospital stay. RESULTS: Thirty-six randomized controlled trials were included in the final analysis. The glucocorticoid group exhibited significant reduction in the resting VAS scores on postoperative days 1, 2 (POD1, 2)and postoperative 3 months (POM3), as well as decreased morphine consumption on POD1 and increased range of motion (ROM) in knee joint on POD1, 3. Additionally, the glucocorticoid group exhibited decreased levels of postoperative inflammatory cytokines and the incidence of PONV along with a shorter length of hospital stay. The blood glucose concentration was significantly increased in the glucocorticoid group on POD1 compared with the control group. While the blood glucose on POD2 and occurrence of postoperative adverse complications were similar between two groups including wound infection and venous thrombosis. The periarticular injection analgesia (PIA) group demonstrated lower VAS scores on POD2 comparing to the systemic administration (SA) group according to two studies. However, there was no significant difference of the resting VAS on POD1 and POD2 between PIA and SA group across all studies. CONCLUSION: Perioperative glucocorticoids treatment in TKA significantly reduced short-term pain score and opioid-use which was probably not patient relevant. The application of glucocorticoids in TKA implied a beneficial trend in analgesic, anti-inflammatory, and antiemetic effects, as well as improved range of motion and shortened hospital stay. While it will not increase the risk of continued high glucose, postoperative wound infection and venous thrombosis.
Subject(s)
Arthroplasty, Replacement, Knee , Glucocorticoids , Pain, Postoperative , Randomized Controlled Trials as Topic , Humans , Glucocorticoids/administration & dosage , Glucocorticoids/adverse effects , Pain, Postoperative/drug therapy , Pain, Postoperative/prevention & control , Perioperative Care/methods , Length of Stay , Range of Motion, Articular/drug effectsABSTRACT
Technology innovation is the key driving force in achieving economic transformation and development. Financial development and the expansion of higher education can promote technological progress primarily by easing financing constraints and improving the level of human capital. This study examines the impact of financial development and higher education expansion on green technology innovation. It conducts an empirical analysis by constructing a linear panel model and a nonlinear threshold model. The present study sample is based on the urban panel data of China from 2003-2019. (1) Financial development can significantly promote the expansion of higher education. (2) The expansion of higher education can improve energy and environment-based technological progress. (3) Financial development can both directly and indirectly promote green technology evolution by expanding higher education. The joint financial development and higher education expansion can significantly empower green technology innovation. (4) In the process of promoting green technology innovation, financial development has a non-linear influence on it, with higher education as the threshold. The effect of financial development on green technology innovation varies according to the degree of higher education. Based on these findings, we put forward policy proposals for green technology innovation to promote economic transformation and development in China.
Subject(s)
Policy , Technology , Humans , China , Linear ModelsABSTRACT
BACKGROUND: As the most lethal gynecologic cancer, ovarian cancer (OV) holds the potential of being immunotherapy-responsive. However, only modest therapeutic effects have been achieved by immunotherapies such as immune checkpoint blockade. This study aims to propose a generalized stroma-immune prognostic signature (SIPS) to identify OV patients who may benefit from immunotherapy. METHODS: The 2097 OV patients included in the study were significant with high-grade serous ovarian cancer in the III/IV stage. The 470 immune-related signatures were collected and analyzed by the Cox regression and Lasso algorithm to generalize a credible SIPS. Correlations between the SIPS signature and tumor microenvironment were further analyzed. The critical immunosuppressive role of stroma indicated by the SIPS was further validated by targeting the major suppressive stroma component (CAFs, Cancer-associated fibroblasts) in vitro and in vivo. With four machine-learning methods predicting tumor immune subtypes, the stroma-immune signature was upgraded to a 23-gene signature. RESULTS: The SIPS effectively discriminated the high-risk individuals in the training and validating cohorts, where the high SIPS succeeded in predicting worse survival in several immunotherapy cohorts. The SIPS signature was positively correlated with stroma components, especially CAFs and immunosuppressive cells in the tumor microenvironment, indicating the critical suppressive stroma-immune network. The combination of CAFs' marker PDGFRB inhibitors and frontline PARP inhibitors substantially inhibited tumor growth and promoted the survival of OV-bearing mice. The stroma-immune signature was upgraded to a 23-gene signature to improve clinical utility. Several drug types that suppress stroma-immune signatures, such as EGFR inhibitors, could be candidates for potential immunotherapeutic combinations in ovarian cancer. CONCLUSIONS: The stroma-immune signature could efficiently predict the immunotherapeutic sensitivity of OV patients. Immunotherapy and auxiliary drugs targeting stroma could enhance immunotherapeutic efficacy in ovarian cancer.
Subject(s)
DiGeorge Syndrome , Ovarian Neoplasms , Female , Animals , Mice , Humans , Receptor, Platelet-Derived Growth Factor beta , Prognosis , Ovarian Neoplasms/drug therapy , Immunosuppressive Agents , Immunotherapy , Tumor MicroenvironmentABSTRACT
Millifluidics, the manipulation of liquid flow in millimeter-sized channels, has been a revolutionary concept in chemical processing and engineering. The solid channels that contain the liquids, though, are not flexible in their design and modification, and prevent contact with the external environment. All-liquid constructs, on the other hand, while flexible and open, are imbedded in a liquid environment. Here, we provide a route to circumvent these limitations by encasing the liquids in a hydrophobic powder in air that jams on the surface, containing and isolating flowing fluids, offering flexibility and adaptability in design, as manifest in the ability to reconfigure, graft, and segment the constructs. Along with the open nature of these powder-contained channels that allow arbitrary connections/disconnections and substance addition/extraction, numerous applications can be opened in the biological, chemical, and material arenas.
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BACKGROUND: This study aimed to explore the changes of programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) expression on antigen-presenting cells (APCs) and evaluate their association with organ failure and mortality during early sepsis. METHODS: In total, 40 healthy controls and 198 patients with sepsis were included in this study. Peripheral blood was collected within the first 24 h after the diagnosis of sepsis. The expression of PD-L1 and PD-1 was determined on APCs, such as B cells, monocytes, and dendritic cells (DCs), by flow cytometry. Cytokines in plasma, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-6, IL-10, and IL-17A were determined by Luminex assay. RESULTS: PD-1 expression decreased significantly on B cells, monocytes, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs) as the severity of sepsis increased. PD-1 expression was also markedly decreased in non-survivors compared with survivors. In contrast, PD-L1 expression was markedly higher on mDCs, pDCs, and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors. The PD-L1 expression on APCs (monocytes and DCs) was weakly related to organ dysfunction and inflammation. The area under the receiver operating characteristic curve (AUC) of the PD-1 percentage of monocytes (monocyte PD-1%)+APACHE II model (0.823) and monocyte PD-1%+SOFA model (0.816) had higher prognostic value than other parameters alone. Monocyte PD-1% was an independent risk factor for 28-day mortality. CONCLUSION: The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs. PD-L1 in monocytes and DCs was weakly correlated with inflammation and organ dysfunction during early sepsis. The combination of SOFA or APACHE II scores with monocyte PD-1% could improve the prediction ability for mortality.
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The adjustment of cellular redox homeostasis is essential in when responding to environmental perturbations, and the mechanism by which cells distinguish between normal and oxidized states through sensors is also important. In this study, we found that acyl-protein thioesterase 1 (APT1) is a redox sensor. Under normal physiological conditions, APT1 exists as a monomer through S-glutathionylation at C20, C22 and C37, which inhibits its enzymatic activity. Under oxidative conditions, APT1 senses the oxidative signal and is tetramerized, which makes it functional. Tetrameric APT1 depalmitoylates S-acetylated NAC (NACsa), and NACsa relocates to the nucleus, increases the cellular glutathione/oxidized glutathione (GSH/GSSG) ratio through the upregulation of glyoxalase I expression, and resists oxidative stress. When oxidative stress is alleviated, APT1 is found in monomeric form. Here, we describe a mechanism through which APT1 mediates a fine-tuned and balanced intracellular redox system in plant defence responses to biotic and abiotic stresses and provide insights into the design of stress-resistant crops.
Subject(s)
Glutathione , Lactoylglutathione Lyase , Medicago truncatula , Cell Nucleus/metabolism , Glutathione/metabolism , Glutathione Disulfide/metabolism , Lactoylglutathione Lyase/metabolism , Medicago truncatula/genetics , Medicago truncatula/metabolism , Oxidation-Reduction , Oxidative Stress , Thiolester HydrolasesABSTRACT
Soil microbial necromass is considered a persistent component of soil organic carbon (SOC), constituting the final product of the microbial carbon pump (MCP). However, the mechanisms involved in the effects of tillage and rice residue managements on the vertical distribution of microbial necromass and plant residues in rice paddy soils remain unclear, limiting knowledge of SOC sequestration mechanisms. Therefore, we estimated microbial- and plant-derived C by biomarker amino sugars (AS) and lignin phenols (VSC) at the 0-30 cm soil depth, as well as their relationships with SOC contents and mineralization in a rice paddy soil under contrasting tillage practices, namely no-tillage (NT), reduced tillage (RT), and conventional tillage (CT). The results showed that the SOC contents in the rice paddy soil were positively correlated with soil AS and VSC contents. The NT resulted in significantly higher (P < 0.05) AS (expressed as per kilogram soil) at the 0-10 cm and 10-30 cm soil depths by 45-48 % than RT and CT. However, microbial-derived C contents and SOC mineralization were not significantly changed by NT. In contrast, the plant-derived C contents in the total SOC decreased significantly under the NT scenario, suggesting the consumption of plant-derived C even with more rice residue inputs (at the 0-10 cm soil depth). In summary, 5-year short-term NT management with more rice residue mulch on the soil surface in rice paddy maintained a low plant-derived C content (at a sampling date before rice transplanting), suggesting a different mode of C sequestration, except for the protection of plant-derived C under anaerobic conditions.
Subject(s)
Oryza , Soil , Soil/chemistry , Agriculture/methods , Oryza/chemistry , Carbon , LigninABSTRACT
Time-resolved spectroscopies and DFT calculations were utilized to investigate the photoredox mechanisms of naphthoquinone compounds. 5-Methoxy-8-tetrahydropyrane-1,4-naphthoquinone (NQ) and 2-methyl-3-(3-methylbut-2-en-1-yl) 1,4-naphthoquinone (MNQ) were excited to singlet excited species (labeled NQ(S1) and MNQ(S1), respectively). NQ(S1) underwent intersystem crossing to produce a triplet NQ, which further underwent hydrogen atom transfer to form a biradical intermediate. The biradical underwent electron transfer to form a zwitterion, followed by cyclization and proton transfer to generate a photoproduct. MNQ(S1) underwent a 1,4-proton transfer process to produce a quinone methide intermediate (1,3-QM) with zwitterionic character, which tautomerized to 1,2-QM. Then, 1,2-QM underwent electrocyclization. The substituent on the parent naphthoquinone is the key factor leading to the different reaction processes for NQ and MNQ.
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BACKGROUND: We aimed to evaluate the epidemiology of sepsis in secondary and tertiary hospitals in Beijing, China between 2012 and 2018 using information derived from the Beijing Public Health System. METHODS: The Beijing Public Health System accessed hospital homepage databases and identify patients who diagnosed sepsis or associated condition according to the International Classification of Diseases, 10th Edition, Clinical Modification codes. There are 125 hospitals involved in this study, including 61 secondary hospitals, accounting for 49.2%, and 63 tertiary hospitals, accounting for 50.8%. Patients were stratified by age as minors (0-17 years old), adults (18-64 years old), seniors (65-84 years old), and the elderly (≥ 85 years old). Patient's demographic information, treatments, outcomes, and all-cause hospitalization cost were evaluated. RESULTS: This study involved 8,597 patients. Patients treated in tertiary hospitals or received blood transfusion decreased with age, while patients who were male, received ventilation, or took Traditional Chinese Medicine, and in-hospital mortality and hospitalization cost, increased with age. There were 2,729 (31.7%) deaths in this study. A slight increase in in-hospital mortality occurred from 2012 to 2018. Median hospitalization cost for all patients was ¥29,453 (15,011, 65,237). Hospitalization cost showed no significant change from 2012 to 2016, but increased in 2017 and 2018. CONCLUSION: Sepsis is associated with high mortality and cost. From 2012 to 2018, in-hospital mortality and hospitalization cost of sepsis in Beijing increased significantly with age, and slightly by year.
Subject(s)
Public Health , Sepsis , Adult , Aged , Humans , Male , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Young Adult , Middle Aged , Aged, 80 and over , Female , Sepsis/epidemiology , Databases, Factual , Hospital Mortality , Tertiary Care CentersABSTRACT
The enantioselective Friedel-Crafts addition of naphthols with isatin-derived ketimines was developed with H8-BINOL-derived chiral biaryl phosphoric acid. A wide range of isatin-derived ketimines and naphthols were successfully applied and gave a series of chiral 3-amino-2-oxindoles in excellent yields with high optical purities.
Subject(s)
Isatin , Naphthols , Stereoisomerism , Molecular Structure , CatalysisABSTRACT
Chiral α-aminoboronic acids and their derivatives are generally useful as bioactive compounds and some have been approved as therapeutic agents. Here we report a NiH-catalysed asymmetric hydroamidation process that with a simple amino alcohol ligand can easily produce a wide range of highly enantioenriched α-aminoboronates from alkenyl boronates and dioxazolones under mild conditions. The reaction is proposed to proceed by an enantioselective hydrometallation followed by an inner-sphere nitrenoid transfer and C-N bond forming sequence. The synthetic utility of this transformation was demonstrated by the efficient synthesis of a current pharmaceutical agent, Vaborbactam.
Subject(s)
Amino Alcohols , Catalysis , Ligands , Pharmaceutical Preparations , StereoisomerismABSTRACT
BACKGROUND: Augmentation cystoplasty, first described by Mikulicz in 1899 involves segments of bowel, stomach or mega-ureter to increase bladder capacity in those with inadequate bladder function or lack of detrusor compliance. The most widely used bowel segment is a detubularised patch of ileum. When ileum is not suitable for augmentation, sigmoid colon is the alternative. However, only eight pregnancies after sigmoidocystoplasty have been reported without detail and clinicians may be uncertain about the effects of sigmoidocystoplasty on reproductive health and pregnancy. CASE SUMMARY: We followed the patient from gestational week 32+3 until 6 wk after delivery. During pregnancy, our patient suffered urinary tract infection twice and had to undergo percutaneous nephrostomy drainage due to progressive hydronephrosis. Despite a dense adhesion between the uterus and neobladder, we were able to deliver a healthy baby by cesarian section in the presence of the attending urologist. CONCLUSION: Augmentation cystoplasty-afflicted women can have a healthy reproductive life. Certain perioperative measures may be advisable to avoid serious surgical complications.
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Background: Hyperglycaemia in pregnancy (HIP) is closely associated with short- and long-term adverse fetal and maternal outcomes. However, the screening and diagnostic strategies for pregnant women with risk factors for HIP are not set. This prospective study aimed to explore a screening strategy for women at high risk for HIP. Methods: A total of 610 pregnant women were divided into experimental (n=305) and control (n=305) groups. Pregnant women underwent a 75-g OGTT in early (<20 weeks), middle (24-28 weeks), and late pregnancy (32-34 weeks) in the experimental group and only in middle pregnancy in the control group. The general conditions, HIP diagnosis, and perinatal outcomes of the two groups were compared. Results: In the experimental group, HIP was diagnosed in 29.51% (90/305), 13.44% (41/305), and 10.49% (32/305) of patient in early, middle, and late pregnancy, respectively. The total HIP diagnosis rate was significantly higher in the experimental group (53.44% vs. 35.74%, P<0.001). Multivariate logistic regression analysis revealed that previous gestational diabetes mellitus (GDM) (odds ratio, OR=9.676, P<0.001), pre-pregnancy body mass index (BMI) ≥23 kg/m2 (OR=4.273, P<0.001), and maternal age ≥35 years (OR=2.377, P=0.010) were risk factors for HIP diagnosis in early pregnancy. Previous GDM (OR=8.713, P=0.002) was a risk factor for HIP diagnosis in late pregnancy. No significant differences in perinatal clinical data were observed between the experimental and control groups. The gestational age at delivery was significantly earlier in the experimental subgroup with early-HIP than in the experimental and control subgroups with normal blood glucose (NBG). The weight gain during pregnancy was lower in the experimental early-HIP, middle-HIP, and control NBG subgroups. Conclusions: We recommend sequential screening in early and middle pregnancy for high-risk pregnant women with maternal age ≥35 years or pre-pregnancy BMI ≥23 kg/m2, and in early, middle, and late pregnancy for high-risk pregnant women with a previous history of GDM. Trial Registration: This study was registered in the Chinese Clinical Trial Registry (no. ChiCTR2000041278).
Subject(s)
Diabetes, Gestational , Hyperglycemia , Adult , Body Mass Index , Diabetes, Gestational/diagnosis , Diabetes, Gestational/epidemiology , Female , Humans , Hyperglycemia/diagnosis , Pregnancy , Prospective Studies , Weight GainABSTRACT
OBJECTIVE: To investigate gut microbiota and intestinal barrier function changes after orthopedic surgery in elderly patients with either normal cognition (NC) or a prodromal Alzheimer disease phenotype (pAD) comprising either subjective cognitive decline (SCD) or amnestic mild cognitive impairment (aMCI). BACKGROUND: Homeostatic disturbances induced by surgical trauma and/or stress can potentially alter the gut microbiota and intestinal barrier function in elderly patients before and after orthopedic surgery. METHODS: In this prospective cohort study, 135 patients were subject to preoperative neuropsychological assessment and then classified into: NC (n=40), SCD (n=58), or aMCI (n=37). Their gut microbiota, bacterial endotoxin (lipopolysaccharide), tight junction (TJ) protein, and inflammatory cytokines in blood were measured before surgery and on postsurgical day 1, 3, and 7 (or before discharge). RESULTS: The short-chain fatty acid (SCFA)-producing bacteria were lower while the gram-negative bacteria, lipopolysaccharide and TJ were higher preoperatively in both the SCD and aMCI (pAD) groups compared with the NC group. After surgery, a decrease in SCFA-producing bacteria, and an increase in both gram-negative bacteria and plasma claudin were significant in the pAD groups relative to the NC group. SCFA-producing bacteria were negatively correlated with TJ and cytokines in pAD patients on postsurgical day 7. Furthermore, surgery-induced perioperative metabolic stress and inflammatory responses were associated with gut microbiota alterations. CONCLUSIONS: Surgery exacerbates both preexisting microbiota dysbiosis and intestinal barrier dysfunction in pAD patients, all of which may be associated with systemic inflammation and, in turn, may lead to further cognitive deterioration.
Subject(s)
Alzheimer Disease , Gastrointestinal Microbiome , Intestinal Diseases , Orthopedic Procedures , Alzheimer Disease/metabolism , Bacteria , Cytokines/metabolism , Dysbiosis/metabolism , Dysbiosis/microbiology , Humans , Intestinal Mucosa/metabolism , Lipopolysaccharides/metabolism , Prospective StudiesABSTRACT
D-2-Hydroxyglutarate (D-2HG) is an α-ketoglutarate-derived mitochondrial metabolite that causes D-2-hydroxyglutaric aciduria, a devastating developmental disorder. How D-2HG adversely affects mitochondria is largely unknown. Here, we report that in Caenorhabditis elegans, loss of the D-2HG dehydrogenase DHGD-1 causes D-2HG accumulation and mitochondrial damage. The excess D-2HG leads to a build-up of 3-hydroxypropionate (3-HP), a toxic metabolite in mitochondrial propionate oxidation, by inhibiting the 3-HP dehydrogenase HPHD-1. We demonstrate that 3-HP binds the MICOS subunit MIC60 (encoded by immt-1) and inhibits its membrane-binding and membrane-shaping activities. We further reveal that dietary and gut bacteria affect mitochondrial health by modulating the host production of 3-HP. These findings identify a feedback loop that links the toxic effects of D-2HG and 3-HP on mitochondria, thus providing important mechanistic insights into human diseases related to D-2HG and 3-HP.
Subject(s)
Brain Diseases, Metabolic, Inborn , Propionates , Brain Diseases, Metabolic, Inborn/metabolism , Feedback , Glutarates/metabolism , Humans , Isocitrate Dehydrogenase/metabolism , Mitochondria/metabolism , Oxidoreductases , Propionates/metabolismABSTRACT
Droplet-based microreactors often uncover fascinating phenomena and exhibit diverse functionality, which make them applicable in various fields. Liquid marbles (LMs) are non-wetting droplets coated with particles, and these features highlight their potential as microreactors. However, sophisticated experimental designs are typically hindered because it is difficult to obtain sufficient substance mixing in these miniature, damage-prone, self-supporting liquid containers. Here, we demonstrate that subjecting LMs to vertical oscillations by audio signals represents a controllable approach that allows sufficient mixing with variable dynamic modes. The characteristics and key issues in LM oscillation are systematically explored. The effects of oscillation on application potential are examined. Under oscillation conditions, homogeneous mixing can be achieved within a few seconds in LMs consisting of either water or viscous liquids. Importantly, the structures of materials synthesized in LMs can be regulated by modulating the oscillation modes. The variable modes, flexible adjustability, high efficiency, and wide applicability of this oscillation method make it a verified manipulation strategy for advancing the functionality of LM microreactors.
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The present study was aimed at investigating the interactive effects of starvation and dietary lipid level in the previous feeding period on lipid-related composition of turbot. Turbot with an average initial body weight of 26 g were firstly fed diets with different lipid levels, namely, 8%, 12%, and 16%, for 9 weeks, and then subjected to starvation for 30 days. Each diet was fed to sextuplicate tanks of 35 fish in the feeding trial. Tissue samples were collected at the end of the feeding trial and at 10, 20, and 30 days after starvation. The results showed that 30-day starvation decreased the lipid content in the liver and the subcutaneous tissue around the fin (STF), but increased the lipid content in the muscle. A synergetic increase of muscle lipid by starvation and dietary lipid level was observed. Starvation mobilized different fatty acids among the three tissues, namely, MUFA (16:1n-7 and 18:1n-9) in the muscle, SFA (14:0 and 16:0), MUFA (16:1n-7, 18:1n-9 and 20:1n-9), and 18C-PUFA (18:2n-6 and 18:3n-3) in the liver, and unexpectedly n-3 PUFA (18:3n-3, EPA, and DHA) in the STF, respectively. The 30-day starvation decreased the muscle hardness and resilience, but affected other texture parameters in a starvation time-dependent manner. Up-regulation of expression of lipolytic genes by starvation occurred later in the STF than in the liver. Interactive effects of starvation and dietary lipid level were observed mainly on tissue fatty acid compositions. Results of this study suggested that combined manipulation of starvation time and dietary lipid level could be used as an effective means of fish quality regulation in terms of lipid/fatty acid-related composition.