ABSTRACT
Acquisition of a lipid-laden phenotype by immune cells has been defined in infectious diseases and atherosclerosis but remains largely uncharacterized in cancer. Here, in breast cancer models, we found that neutrophils are induced to accumulate neutral lipids upon interaction with resident mesenchymal cells in the premetastatic lung. Lung mesenchymal cells elicit this process through repressing the adipose triglyceride lipase (ATGL) activity in neutrophils in prostaglandin E2-dependent and -independent manners. In vivo, neutrophil-specific deletion of genes encoding ATGL or ATGL inhibitory factors altered neutrophil lipid profiles and breast tumor lung metastasis in mice. Mechanistically, lipids stored in lung neutrophils are transported to metastatic tumor cells through a macropinocytosis-lysosome pathway, endowing tumor cells with augmented survival and proliferative capacities. Pharmacological inhibition of macropinocytosis significantly reduced metastatic colonization by breast tumor cells in vivo. Collectively, our work reveals that neutrophils serve as an energy reservoir to fuel breast cancer lung metastasis.
Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Lipid Metabolism , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Mesenchymal Stem Cells/metabolism , Neutrophils/metabolism , Animals , Biomarkers , Cell Proliferation , Disease Progression , Endocytosis , Female , Fluorescent Antibody Technique , Humans , Mice , Neoplasm Metastasis , Neutrophils/ultrastructureABSTRACT
Autophagy is activated by prolonged fasting but cannot overcome the ensuing hepatic lipid overload, resulting in fatty liver. Here, we describe a peroxisome-lysosome metabolic link that restricts autophagic degradation of lipids. Acyl-CoA oxidase 1 (Acox1), the enzyme that catalyzes the first step in peroxisomal ß-oxidation, is enriched in liver and further increases with fasting or high-fat diet (HFD). Liver-specific Acox1 knockout (Acox1-LKO) protected mice against hepatic steatosis caused by starvation or HFD due to induction of autophagic degradation of lipid droplets. Hepatic Acox1 deficiency markedly lowered total cytosolic acetyl-CoA levels, which led to decreased Raptor acetylation and reduced lysosomal localization of mTOR, resulting in impaired activation of mTORC1, a central regulator of autophagy. Dichloroacetic acid treatment elevated acetyl-CoA levels, restored mTORC1 activation, inhibited autophagy, and increased hepatic triglycerides in Acox1-LKO mice. These results identify peroxisome-derived acetyl-CoA as a key metabolic regulator of autophagy that controls hepatic lipid homeostasis.
Subject(s)
Acetyl Coenzyme A/metabolism , Acyl-CoA Oxidase/physiology , Autophagy , Fatty Acids/chemistry , Fatty Liver/pathology , Mechanistic Target of Rapamycin Complex 1/metabolism , Peroxisomes/chemistry , Acetylation , Animals , Autophagy-Related Protein 5/physiology , Diet, High-Fat/adverse effects , Fasting , Fatty Liver/etiology , Fatty Liver/metabolism , Female , Male , Mechanistic Target of Rapamycin Complex 1/genetics , Mice , Mice, Knockout , Mitochondria/metabolism , Oxidation-Reduction , Peroxisomes/metabolism , Regulatory-Associated Protein of mTOR/genetics , Regulatory-Associated Protein of mTOR/metabolismABSTRACT
Many real-world scenarios involve interfaces, particularly liquid-liquid interfaces, that can fundamentally alter the dynamics of colloids. This is poorly understood for chemically active colloids that release chemicals into their environment. We report here the surprising discovery that chemical micromotorsâcolloids that convert chemical fuels into self-propulsionâmove significantly faster at an oil-water interface than on a glass substrate. Typical speed increases ranged from 3 to 6 times up to an order of magnitude and were observed for different types of chemical motors and interfaces made with different oils. Such speed increases are likely caused by faster chemical reactions at an oil-water interface than at a glass-water interface, but the exact mechanism remains unknown. Our results provide valuable insights into the complex interactions between chemical micromotors and their environments, which are important for applications in the human body or in the removal of organic pollutants from water. In addition, this study also suggests that chemical reactions occur faster at an oil-water interface and that micromotors can serve as a probe for such an effect.
ABSTRACT
BACKGROUND: There is growing interest in the joint effects of hazardous trace elements (HTEs) on lung function deficits, but the data are limited. This is a critical research gap given increased global industrialisation. METHODS: A national cross-sectional study including spirometry was performed among 2112 adults across 11 provinces in China between 2020 and 2021. A total of 27 HTEs were quantified from urine samples. Generalised linear models and quantile-based g-computation were used to explore the individual and joint effects of urinary HTEs on lung function, respectively. RESULTS: Overall, there were negative associations between forced expiratory volume in 1 s (FEV1) and urinary arsenic (As) (z-score coefficient, -0.150; 95% CI, -0.262 to -0.038 per 1 ln-unit increase), barium (Ba) (-0.148, 95% CI: -0.258 to -0.039), cadmium (Cd) (-0.132, 95% CI: -0.236 to -0.028), thallium (Tl) (-0.137, 95% CI: -0.257 to -0.018), strontium (Sr) (-0.147, 95% CI: -0.273 to -0.022) and lead (Pb) (-0.121, 95% CI: -0.219 to -0.023). Similar results were observed for forced vital capacity (FVC) with urinary As, Ba and Pb and FEV1/FVC with titanium (Ti), As, Sr, Cd, Tl and Pb. We found borderline associations between the ln-quartile of joint HTEs and decreased FEV1 (-20 mL, 95% CI: -48 to +8) and FVC (-14 mL, 95% CI: -49 to+2). Ba and Ti were assigned the largest negative weights for FEV1 and FVC within the model, respectively. CONCLUSION: Our study investigating a wide range of HTEs in a highly polluted setting suggests that higher urinary HTE concentrations are associated with lower lung function, especially for emerging Ti and Ba, which need to be monitored or regulated to improve lung health.
Subject(s)
Environmental Exposure , Trace Elements , Humans , Cross-Sectional Studies , Male , Female , Middle Aged , Environmental Exposure/adverse effects , Environmental Exposure/analysis , China/epidemiology , Trace Elements/urine , Adult , Forced Expiratory Volume , Spirometry , Vital Capacity , Lung/physiopathology , AgedABSTRACT
Consolidated bioprocessing (CBP) of lignocellulosic biomass holds promise to realize economic production of second-generation biofuels/chemicals, and Clostridium thermocellum is a leading candidate for CBP due to it being one of the fastest degraders of crystalline cellulose and lignocellulosic biomass. However, CBP by C. thermocellum is approached with co-cultures, because C. thermocellum does not utilize hemicellulose. When compared with a single-species fermentation, the co-culture system introduces unnecessary process complexity that may compromise process robustness. In this study, we engineered C. thermocellum to co-utilize hemicellulose without the need for co-culture. By evolving our previously engineered xylose-utilizing strain in xylose, an evolved clonal isolate (KJC19-9) was obtained and showed improved specific growth rate on xylose by â¼3-fold and displayed comparable growth to a minimally engineered strain grown on the bacteria's naturally preferred substrate, cellobiose. To enable full xylan deconstruction to xylose, we recombinantly expressed three different ß-xylosidase enzymes originating from Thermoanaerobacterium saccharolyticum into KJC19-9 and demonstrated growth on xylan with one of the enzymes. This recombinant strain was capable of co-utilizing cellulose and xylan simultaneously, and we integrated the ß-xylosidase gene into the KJC19-9 genome, creating the KJCBXint strain. The strain, KJC19-9, consumed monomeric xylose but accumulated xylobiose when grown on pretreated corn stover, whereas the final KJCBXint strain showed significantly greater deconstruction of xylan and xylobiose. This is the first reported C. thermocellum strain capable of degrading and assimilating hemicellulose polysaccharide while retaining its cellulolytic capabilities, unlocking significant potential for CBP in advancing the bioeconomy.
Subject(s)
Clostridium thermocellum , Metabolic Engineering , Polysaccharides , Clostridium thermocellum/metabolism , Clostridium thermocellum/genetics , Polysaccharides/metabolism , Polysaccharides/genetics , Xylose/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Cellulose/metabolism , Xylosidases/metabolism , Xylosidases/geneticsABSTRACT
The hematopoietic stem cells (HSCs) that produce blood for the lifetime of an animal arise from RUNX1+ hemogenic endothelial cells (HECs) in the embryonic vasculature through a process of endothelial-to-hematopoietic transition (EHT). Studies have identified inflammatory mediators and fluid shear forces as critical environmental stimuli for EHT, raising the question of how such diverse inputs are integrated to drive HEC specification. Endothelial cell MEKK3-KLF2/4 signaling can be activated by both fluid shear forces and inflammatory mediators, and it plays roles in cardiovascular development and disease that have been linked to both stimuli. Here we demonstrate that MEKK3 and KLF2/4 are required in endothelial cells for the specification of RUNX1+ HECs in both the yolk sac and dorsal aorta of the mouse embryo and for their transition to intraaortic hematopoietic cluster (IAHC) cells. The inflammatory mediators lipopolysaccharide and interferon-γ increase RUNX1+ HECs in an MEKK3-dependent manner. Maternal administration of catecholamines that stimulate embryo cardiac function and accelerate yolk sac vascular remodeling increases EHT by wild-type but not MEKK3-deficient endothelium. These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT and provide a molecular basis for the integration of diverse environmental inputs, such as inflammatory mediators and hemodynamic forces, during definitive hematopoiesis.
Subject(s)
Core Binding Factor Alpha 2 Subunit , Hemangioblasts , Hematopoiesis , Animals , Cell Differentiation , Core Binding Factor Alpha 2 Subunit/metabolism , Endothelium/metabolism , Hemangioblasts/cytology , Hemangioblasts/metabolism , Hemodynamics , Inflammation Mediators/metabolism , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , MAP Kinase Kinase Kinase 3/metabolism , MiceABSTRACT
Concave nanocrystals stand out as a testament to the importance of the nanoscale morphology in dictating the functional properties of materials. In this report, we introduce a facile synthesis method for producing gold (Au) nanocrystals with a truncated octahedral morphology that features surface concavities (Au CNTOs). The incorporation of selenium (Se) doping into the truncated octahedral Au seeds was essential for their enlargement and the formation of concave structures. By simply adjusting the quantity of seeds, we could control the size of the nanocrystals while maintaining their distinctive morphology and surface concavity. The formation mechanism suggests that Se doping likely passivates the side faces, thereby slowing growth and promoting atomic deposition at the edges and corners. The resulting Se-doped Au CNTOs exhibited strong localized surface plasmon resonance (LSPR) absorptions in the visible spectrum and the SERS performance of their assemblies was demonstrated through crystal violet detection, reaching enhancement factors around 105. This study presents an innovative approach to synthesizing concave Au nanocrystals through the incorporation of selenium during a seeded growth process, offering insights into the strategic design of plasmonic nanostructures.
ABSTRACT
Methyltransferase like 3 (METTL3) has been reported to promote tumorigenesis of multiple myeloma (MM), however, the molecular mechanism still needs further research. The N6-methyladenosine (m6A) level in tissues or cells was measured by m6A kit and dot blot assay. The mRNA and protein expression were detected by quantitative real-time PCR (RT-qPCR) and Western blot, respectively. The cell counting kit-8 and colony formation assay were used to detect the cell proliferation. Coimmunoprecipitation (Co-IP) experiment verified the binding of two proteins. The luciferase reporter experiment demonstrated the targeted binding of miR-182-5p and CaMKII inhibitor 1 (CAMK2N1). More importantly, tumor growth was measured in xenograft mice. Our data showed that the expression of METTL3 was significantly increased in MM patients' samples and MM cells. METTL3 overexpression promoted MM cells proliferation, and METTL3 knockdown inhibited MM cells proliferation. Mechanically, METTL3-dependent m6A participated in DiGeorge syndrome critical region 8 (DGCR8)-mediated maturation of pri-miR-182. Upregulation of miR-182-5p further enhanced the promoting proliferation effect of METTL3 overexpression on MM cells. Moreover, the luciferase reporter gene experiment proved that miR-182-5p targetedly regulated CAMK2N1 expression. Xenograft tumor in nude mice further verified that METTL3 promoted MM tumor growth through miR-182/CAMK2N1 signal axis. In summary, the METTL3/miR-182-5p/CAMK2N1 axis plays an important role in MM tumorigenesis, which may provide a new target for MM therapy.
ABSTRACT
Climate change is threatening fragile alpine ecosystems and their resident ungulates, particularly the wild yak (Bos mutus) that inhabits alpine areas between the tree line and glaciers on the Tibetan Plateau. Although wild yaks tend to shift habitats in response to changes in climatic factors, the precise impacts of climate change on their habitat distribution and climate refugia remain unclear. Based on over 1000 occurrence records, the maximum entropy (MaxEnt) algorithm was applied to simulate habitat ranges in the last glacial maximum (LGM), Mid-Holocene, current stage, and three greenhouse gas emission scenarios in 2070. Three habitat patches were identified as climate refugia for wild yaks that have persisted from the LGM to the present and are projected to persist until 2070. These stable areas account for approximately 64% of the current wild yak habitat extent and are sufficiently large to support viable populations. The long-term persistence of these climate refugia areas is primarily attributed to the unique alpine environmental features of the Tibetan Plateau, where relatively stable arid or semi-arid climates are maintained, and a wide range of forage resource supplies are available. However, habitat loss by 2070 caused by insufficient protection is predicted to lead to severe fragmentation in the southeastern and northwestern Kunlun, Hengduan, central-western Qilian, and southern Tanggula-northern Himalaya Mountains. Habitat disturbance has also been caused by increasing anthropogenic effects in the southern Tanggula and northern Himalaya Mountains. We suggest that sufficient protection, transboundary cooperation, and community involvement are required to improve wild yak conservation efforts. Our combined modeling method (MaxEnt-Zonation-Linkage Mapper-FRAGSTAT) can be utilized to identify priority areas and linkages between habitat patches while assessing the conservation efficiency of protected areas and analyzing the coupled relationship between climate change and anthropogenic impacts on the habitat distribution of endangered species.
Subject(s)
Climate Change , Ecosystem , Animals , Tibet , Cattle , Refugium , Conservation of Natural ResourcesABSTRACT
The CCCTC-binding factor (CTCF) mediates transcriptional regulation and implicates epigenetic modifications in cancers. However, the systematically unveiling inverse regulatory relationship between CTCF and epigenetic modifications still remains unclear, especially the mechanism by which histone modification mediates CTCF binding. Here, we developed a systematic approach to investigate how epigenetic changes affect CTCF binding. Through integration analysis of CTCF binding in 30 cell lines, we concluded that CTCF generally binds with higher intensity in normal cell lines than that in cancers, and higher intensity in genome regions closed to transcription start sites. To facilitate the better understanding of their associations, we constructed linear mixed-effect models to analyze the effects of the epigenetic modifications on CTCF binding in four cancer cell lines and six normal cell lines, and identified seven epigenetic modifications as potential epigenetic patterns that influence CTCF binding intensity in promoter regions and six epigenetic modifications in enhancer regions. Further analysis of the effects in different locations revealed that the epigenetic regulation of CTCF binding was location-specific and cancer cell line-specific. Moreover, H3K4me2 and H3K9ac showed the potential association with immune regulation of disease. Taken together, our method can contribute to improve the understanding of the epigenetic regulation of CTCF binding and provide potential therapeutic targets for treating tumors associated with CTCF.
Subject(s)
CCCTC-Binding Factor/metabolism , Epigenesis, Genetic , Histone Code , CCCTC-Binding Factor/chemistry , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Genomics/methods , Humans , Organ Specificity , Protein BindingABSTRACT
BACKGROUND: Progressive peritoneal fibrosis is a worldwide public health concern impacting patients undergoing peritoneal dialysis (PD), yet there is no effective treatment. Our previous study revealed that a novel compound, micheliolide (MCL) inhibited peritoneal fibrosis in mice. However, its mechanism remains unclear. Brahma-related gene 1 (BRG1) is a key contributor to organ fibrosis, but its potential function in PD-related peritoneal fibrosis and the relationship between MCL and BRG1 remain unknown. METHODS: The effects of MCL on BRG1-induced fibrotic responses and TGF-ß1-Smads pathway were examined in a mouse PD model and in vitro peritoneal mesothelial cells. To investigate the targeting mechanism of MCL on BRG1, coimmunoprecipitation, MCL-biotin pulldown, molecular docking and cellular thermal shift assay were performed. RESULTS: BRG1 was markedly elevated in a mouse PD model and in peritoneal mesothelial cells cultured in TGF-ß1 or PD fluid condition. BRG1 overexpression in vitro augmented fibrotic responses and promoted TGF-ß1-increased-phosphorylation of Smad2 and Smad3. Meanwhile, knockdown of BRG1 diminished TGF-ß1-induced fibrotic responses and blocked TGF-ß1-Smad2/3 pathway. MCL ameliorated BRG1 overexpression-induced peritoneal fibrosis and impeded TGF-ß1-Smad2/3 signaling pathway both in a mouse PD model and in vitro. Mechanically, MCL impeded BRG1 from recognizing and attaching to histone H3 lysine 14 acetylation by binding to the asparagine (N1540) of BRG1, in thus restraining fibrotic responses and TGF-ß1-Smad2/3 signaling pathway. After the mutation of N1540 to alanine (N1540A), MCL was unable to bind to BRG1 and thus, unsuccessful in suppressing BRG1-induced fibrotic responses and TGF-ß1-Smad2/3 signaling pathway. CONCLUSION: Our research indicates that BRG1 may be a crucial mediator in peritoneal fibrosis and MCL targeting N1540 residue of BRG1 may be a novel therapeutic strategy to combat PD-related peritoneal fibrosis.
Subject(s)
Peritoneal Dialysis , Peritoneal Fibrosis , Animals , Mice , Disease Models, Animal , Molecular Docking Simulation , Peritoneal Dialysis/adverse effects , Peritoneal Fibrosis/drug therapy , Transforming Growth Factor beta1ABSTRACT
PKM2 mediates the Warburg effects and is crucial for tumorigenesis, but its role in hyperplastic skin disorders remains elusive. In this study, we investigated the function of PKM2 in psoriatic keratinocytes. We found that PKM2 expression and its nuclear translocation were induced in the epidermis of psoriasis patients, contributing to aerobic glycolysis and cell growth. Moreover, mass spectrometry combined with immunoprecipitation analysis revealed that PKM2 could interact with TRIM33, an E3 ubiquitin ligase in the nucleus, and this interaction is critical for the nuclear retention of PKM2. As a result of TRIM33-mediated ubiquitination, PKM2 nuclear protein kinase function is promoted, thus leading to the phosphorylation of STAT3. In addition, blocking PKM2 nuclear translocation abrogated TRIM33-triggered glycolysis and cell proliferation in keratinocytes. Taken together, our experiments demonstrate that ubiquitination regulates the nuclear retention of PKM2 in keratinocytes. Moreover, our results highlight a novel mechanism accounting for the metabolic reprogramming of keratinocytes in psoriasis patients.
Subject(s)
Keratinocytes , Psoriasis , Humans , Cell Line, Tumor , Glycolysis , Phosphorylation , Protein Transport , Transcription Factors , Thyroid Hormone-Binding ProteinsABSTRACT
Controlled colloidal levitation is key to many applications. Recently, it was discovered that polymer microspheres were levitated to a few micrometers in aqueous solutions in alternating current (AC) electric fields. A few mechanisms have been proposed to explain this AC levitation such as electrohydrodynamic flows, asymmetric rectified electric fields, and aperiodic electrodiffusiophoresis. Here, we propose an alternative mechanism based on dielectrophoresis in a spatially inhomogeneous electric field gradient extending from the electrode surface micrometers into the bulk. This field gradient is derived from electrode polarization, where counterions accumulate near electrode surfaces. A dielectric microparticle is then levitated from the electrode surface to a height where the dielectrophoretic lift balances gravity. The dielectrophoretic levitation mechanism is supported by two numerical models. One model assumes point dipoles and solves for the Poisson-Nernst-Planck equations, while the second model incorporates a dielectric sphere of a realistic size and permittivity and uses the Maxwell-stress tensor formulation to solve for the electrical body force. In addition to proposing a plausible levitation mechanism, we further demonstrate that AC colloidal levitation can be used to move synthetic microswimmers to controlled heights. This study sheds light on understanding the dynamics of colloidal particles near an electrode and paves the way to using AC levitation to manipulate colloidal particles, active or passive.
ABSTRACT
Biological circuits such as neural or gene regulation networks use internal states to map sensory input to an adaptive repertoire of behavior. Characterizing this mapping is a major challenge for systems biology. Though experiments that probe internal states are developing rapidly, organismal complexity presents a fundamental obstacle given the many possible ways internal states could map to behavior. Using C. elegans as an example, we propose a protocol for systematic perturbation of neural states that limits experimental complexity and could eventually help characterize collective aspects of the neural-behavioral map. We consider experimentally motivated small perturbations-ones that are most likely to preserve natural dynamics and are closer to internal control mechanisms-to neural states and their impact on collective neural activity. Then, we connect such perturbations to the local information geometry of collective statistics, which can be fully characterized using pairwise perturbations. Applying the protocol to a minimal model of C. elegans neural activity, we find that collective neural statistics are most sensitive to a few principal perturbative modes. Dominant eigenvalues decay initially as a power law, unveiling a hierarchy that arises from variation in individual neural activity and pairwise interactions. Highest-ranking modes tend to be dominated by a few, "pivotal" neurons that account for most of the system's sensitivity, suggesting a sparse mechanism of collective control.
Subject(s)
Caenorhabditis elegans , Neurons , Animals , Mathematics , Neurons/physiologyABSTRACT
AIMS: To evaluate the efficacy and safety of janagliflozin, a selective renal sodium-glucose cotransporter-2 inhibitor, as monotherapy in drug-naive Chinese patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3 trial included a 24-week, multicentre, randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. A total of 432 patients with glycated haemoglobin (HbA1c) levels ≥7.0% (53 mmol/mol) and ≤10.5% (91 mmol/mol) were randomized (1:1:1) to receive once-daily placebo, 25 mg or 50 mg janagliflozin. After 24 weeks, patients on placebo were switched and re-randomized (1:1) to 25 mg or 50 mg janagliflozin, whereas patients on janagliflozin maintained the initial therapy. The primary endpoint was change from baseline in HbA1c after 24 weeks. RESULTS: At Week 24, the placebo-adjusted least squares mean changes in HbA1c were -0.80% (95% confidence interval [CI] -0.98% to -0.62%)/-8.7 mmol/mol (95% CI -10.7 mmol/mol to -6.8 mmol/mol) and -0.88% (95% CI -1.06% to -0.70%)/-9.6 mmol/mol (95% CI -11.6 mmol/mol to -7.7 mmol/mol), respectively (P < 0.001 for both). A higher proportion of patients achieved HbA1c <7.0% (53 mmol/mol) with janagliflozin 25 mg and janagliflozin 50 mg compared with placebo (47.2%, 49.3%, and 23.5%, respectively). Both janagliflozin doses significantly decreased fasting plasma glucose, 2-hour postprandial glucose, body weight and systolic blood pressure, as well as increased high-density lipoprotein (HDL) cholesterol and insulin sensitivity compared with placebo (P < 0.05 for all). The trends in improvement of these variables were sustained during the 28-week extension period. Overall incidences of adverse events were 67.8%, 71.5% and 60.7% with janagliflozin 25 mg, janagliflozin 50 mg and placebo, respectively. The incidence of urinary tract infections and genital fungal infections was low. No severe hypoglycaemia or ketoacidosis occurred. CONCLUSIONS: Janagliflozin 25 mg and 50 mg monotherapy once-daily effectively improved glycaemic control, reduced body weight and blood pressure, improved HDL cholesterol and insulin sensitivity, and was generally well tolerated.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Sodium-Glucose Transporter 2 Inhibitors , Humans , Hypoglycemic Agents/therapeutic use , Glycated Hemoglobin , East Asian People , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Treatment Outcome , Diet , Body Weight , Drug Therapy, Combination , Glucose/therapeutic use , Double-Blind Method , Blood GlucoseABSTRACT
AIM: To evaluate the efficacy and safety of janagliflozin in Chinese patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy. MATERIALS AND METHODS: This multicentre phase 3 trial included a 24-week, randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. Patients (N = 421) with HbA1c of 7.0% or higher and 10.5% or less were randomized (1:1:1) to receive once-daily placebo, janagliflozin 25 or 50 mg. After the 24-week treatment period, patients on placebo were re-randomized (1:1) to janagliflozin 25 or 50 mg for the additional 28-week treatment, whereas patients on janagliflozin maintained the same therapy. The primary endpoint was the change from baseline in HbA1c to week 24. RESULTS: At week 24, the placebo-adjusted least squares mean changes of HbA1c were -0.58% and -0.58% with janagliflozin 25 and 50 mg, respectively (P < .0001 for both). The proportion of patients achieving HbA1c less than 7.0% was higher with janagliflozin 25 and 50 mg compared with placebo (41.8%, 41.7% and 28.0%, respectively). Both janagliflozin doses provided significant reductions in fasting plasma glucose, 2-hour postprandial glucose, body weight and systolic blood pressure, and improvements in high-density lipoprotein cholesterol and insulin sensitivity compared with placebo (P < .05 for all). The trends in improvement of these variables were retained during the 28-week extension period. No severe hypoglycaemia occurred throughout the whole 52-week treatment. CONCLUSIONS: Janagliflozin 25 or 50 mg once-daily added to metformin therapy significantly improved glycaemic control, reduced body weight and systolic blood pressure, improved high-density lipoprotein cholesterol and insulin sensitivity, and was generally well-tolerated by Chinese T2D patients who had poor glycaemic control with metformin monotherapy.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Metformin , Sodium-Glucose Transporter 2 Inhibitors , Humans , Blood Glucose , Body Weight , Cholesterol , Double-Blind Method , Drug Therapy, Combination , East Asian People , Glycated Hemoglobin , Hypoglycemic Agents/therapeutic use , Lipoproteins, HDL , Metformin/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Testicular volume in neonates is a potential indicator of testicular development during the fetal period, particularly the masculinization programming window. Reliable measurements of testicular volume provide an opportunity for early detection of testicular abnormalities. This study aimed to assess the testicular volume in neonates and evaluate its relationship with gestational week and birth weight in Hainan Province, China. METHODS: Data on 458 neonates who underwent ultrasonography examinations at our institution from 2018 to 2022 were collected. The neonates were categorized by gestational week, birth weight, and presence of cryptorchidism. We evaluated the testicular volume among different groups and its relationship to gestational week and birth weight. RESULTS: There was no significant difference between the right and left testicular volume in neonates without cryptorchidism. However, a significant difference was observed between normal birth weight and low birth weight neonates in terms of testicular volume. Similarly, there was a significant difference between premature and full-term neonates in testicular volume. Bilateral testicular volume showed positive and significant correlations with gestational week and birth weight. Additionally, a significant difference was noted in testicular volume between the affected side in neonates with cryptorchidism and the same side in normal birth weight full-term neonates. CONCLUSIONS: We established the normal range of testicular volume for neonates in Hainan Province and demonstrated that testicular volume is positively correlated with both birth weight and gestational week. Cryptorchidism also affects testicular volume during the neonatal period, likely due to reduced androgenic exposure in utero, particularly during the masculinization programming window. The findings of this study have significant implications for assessing testis development during fetal development.
Subject(s)
Cryptorchidism , Male , Infant, Newborn , Humans , Birth Weight , Cryptorchidism/diagnostic imaging , China , Fetal Development , Health FacilitiesABSTRACT
A new series of donor-acceptor (D-A)-type semiconductive polymers were generated by the integration of electron-deficient alkyl chain anchored triazole (TA) moieties and electron-rich pyrene units into the polymer skeleton. The polymer series demonstrated satisfactory light-harvesting ability and suitable band gaps. In the series, polymer P-TAME benefits from a minimized exciton binding energy, strongest D-A interaction, and favorable hydrophilicity, affording an outstanding photocatalytic H2 evolution rate of ca. 100â µmol h-1 (10â mg polymer, AQY420 nm =8.9 %) and H2 O2 production rate of ca. 190â µmol h-1 (20â mg polymer) under visible-light irradiation, which is superior to most currently reported polymers. All polymers in the series can mediate water oxidation reactions to evolve O2 . Thus, these TA-based polymers open up a new avenue toward tailor-made efficient photocatalysts with broad photocatalytic activities.
ABSTRACT
Diabetic kidney disease (DKD) is one of the most common and devastating complications of diabetic mellitus, and its prevalence is rising worldwide. Klotho, an anti-aging protein, is kidney protective in DKD. However, its large size, prohibitive cost and structural complexity hamper its potential utility in clinics. Here we report that Klotho-derived peptide 6 (KP6) mimics Klotho function and ameliorates DKD. In either an accelerated model of DKD induced by streptozotocin and advanced oxidation protein products in unilateral nephrectomized mice or db/db mice genetically prone to diabetes, chronic infusion of KP6 reversed established proteinuria, attenuated glomerular hypertrophy, mitigated podocyte damage, and ameliorated glomerulosclerosis and interstitial fibrotic lesions, but did not affect serum phosphorus and calcium levels. KP6 inhibited ß-catenin activation in vivo and blocked the expression of its downstream target genes in glomerular podocytes and tubular epithelial cells. In vitro, KP6 prevented podocyte injury and inhibited ß-catenin activation induced by high glucose without affecting Wnt expression. Co-immunoprecipitation revealed that KP6 bound to Wnt ligands and disrupted the engagement of Wnts with low density lipoprotein receptor-related protein 6, thereby interrupting Wnt/ß-catenin signaling. Mutated KP6 with a scrambled amino acid sequence failed to bind Wnts and did not alleviate DKD in db/db mice. Thus, our studies identified KP6 as a novel Klotho-derived peptide that ameliorated DKD by blocking Wnt/ß-catenin. Hence, our findings also suggest a new therapeutic strategy for the treatment of patients with DKD.
Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Podocytes , Animals , Diabetes Mellitus/metabolism , Diabetic Nephropathies/pathology , Mice , Peptides/pharmacology , Peptides/therapeutic use , Podocytes/pathology , Wnt Signaling Pathway/physiology , beta Catenin/metabolismABSTRACT
Ferroptosis is primarily caused by intracellular iron catalytic activity and lipid peroxidation. The potential interplay between ferroptosis and apoptosis remains poorly understood. Here, we show that the expression of a nuclear long non-coding RNA (lncRNA), LINC00618, is reduced in human leukemia and strongly increased by vincristine (VCR) treatment. Furthermore, LINC00618 promotes apoptosis by increasing the levels of BCL2-Associated X (BAX) and cleavage of caspase-3. LINC00618 also accelerates ferroptosis by increasing the levels of lipid reactive oxygen species (ROS) and iron, two surrogate markers of ferroptosis, and decreasing the expression of solute carrier family 7 member 11 (SLC7A11). Interestingly, VCR-induced ferroptosis and apoptosis are promoted by LINC00618, and LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis. LINC00618 attenuates the expression of lymphoid-specific helicase (LSH), and LSH enhances the transcription of SLC7A11 after the recruitment to the promoter regions of SLC7A11, further inhibiting ferroptosis. Knowledge of these mechanisms demonstrates that lncRNAs related to ferroptosis and apoptosis are critical to leukemogenesis and chemotherapy.