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1.
Adv Sci (Weinh) ; : e2307254, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38946659

ABSTRACT

The rational construction of efficient hypoxia-tolerant nanocatalysts capable of generating singlet oxygen (1O2) without external stimuli is of great importance for tumor therapy. Herein, uniformly dispersed and favorable biosafety profile graphitic carbon nitride quantum dots immobilized with Fe-N4 moieties modulated by axial O atom (denoted as O-Fe-N4) are developed for converting H2O2 into 1O2 via Russell reaction, without introducing external energy. Notably, O-Fe-N4 performs two interconnected catalytic properties: glutathione oxidase-mimic activity to provide substrate for subsequent 1O2 generation, avoiding the blunting anticancer efficacy by glutathione. The O-Fe-N4 catalyst demonstrates a specific activity of 79.58 U mg-1 at pH 6.2, outperforming the most reported Fe-N4 catalysts. Density functional theory calculations demonstrate that the axial O atom can effectively modulate the relative position and electron affinity between Fe and N, lowering the activation energy, strengthening the selectivity, and thus facilitating the Russell-type reaction. The gratifying enzymatic activity stemming from the well-defined Fe-N/O structure can inhibit tumor proliferation by efficiently downregulating glutathione peroxidase 4 activity and inducing lipid peroxidation. Altogether, the O-Fe-N4 catalyst not only represents an efficient platform for self-cascaded catalysis to address the limitations of 1O2-involved cancer treatment but also provides a paradigm to enhance the performance of the Fe-N4 catalyst.

2.
Mater Today Bio ; 27: 101137, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39040221

ABSTRACT

The translation of Fe-based agents for ferroptosis tumor therapy is restricted by the unstable iron valence state, the harsh catalytic environment, and the complex tumor self-protection mechanism. Herein, we developed a stable nickel-based single-atom-metal-clusters (NSAMCs) biocatalyst for efficient tumor ferroptosis therapy. NSAMCs with a nanowire-like nanostructure and hydrophilic functional groups exhibit good water-solubility, colloidal stability, negligible systemic toxicity, and target specificity. In particular, NSAMCs possess excellent peroxidase-like and glutathione oxidase-like activities through the synergistic influence between metal clusters and single atoms. The dual-enzymatic performance enables NSAMCs to synergistically promote efficient ferroptosis of cancer cells through lipid peroxidization aggregation and glutathione peroxidase 4 inactivation. Importantly, NSAMCs highlight the boost of ferroptosis tumor therapy via the synergistic effect between single-atoms and metal clusters, providing a practical and feasible paradigm for further improving the efficiency of ferroptosis tumor treatment.

3.
Zool Res ; 45(4): 924-936, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39021081

ABSTRACT

Amyloid beta (Aß) monomers aggregate to form fibrils and amyloid plaques, which are critical mechanisms in the pathogenesis of Alzheimer's disease (AD). Given the important role of Aß1-42 aggregation in plaque formation, leading to brain lesions and cognitive impairment, numerous studies have aimed to reduce Aß aggregation and slow AD progression. The diphenylalanine (FF) sequence is critical for amyloid aggregation, and magnetic fields can affect peptide alignment due to the diamagnetic anisotropy of aromatic rings. In this study, we examined the effects of a moderate-intensity rotating magnetic field (RMF) on Aß aggregation and AD pathogenesis. Results indicated that the RMF directly inhibited Aß amyloid fibril formation and reduced Aß-induced cytotoxicity in neural cells in vitro. Using the AD mouse model APP/PS1, RMF restored motor abilities to healthy control levels and significantly alleviated cognitive impairments, including exploration and spatial and non-spatial memory abilities. Tissue examinations demonstrated that RMF reduced amyloid plaque accumulation, attenuated microglial activation, and reduced oxidative stress in the APP/PS1 mouse brain. These findings suggest that RMF holds considerable potential as a non-invasive, high-penetration physical approach for AD treatment.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Cognitive Dysfunction , Animals , Alzheimer Disease/metabolism , Alzheimer Disease/therapy , Mice , Amyloid beta-Peptides/metabolism , Mice, Transgenic , Magnetic Fields , Disease Models, Animal , Plaque, Amyloid , Brain/metabolism
4.
Eur Radiol ; 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844619

ABSTRACT

OBJECTIVES: Despite some existing studies on the safety of high static magnetic fields (SMFs), the effects of ultra-high SMFs above 20.0 T for embryonic development in early pregnancy are absent. The objective of this study is to evaluate the influence of 16.8-22.0 T SMF on the development of zebrafish embryos, which will provide important information for the future application of ultra-high field magnetic resonance imaging (MRI). METHODS: Two-hour exposure to homogenous (0 T/m) 22.0 T SMF, or 16.8 T SMFs with 123.25 T/m spatial gradient of opposite magnetic force directions was examined in the embryonic development of 200 zebrafish. Their body length, heart rate, spontaneous tail-wagging movement, hatching and survival rate, photomotor response, and visual motor response (VMR) were analyzed. RESULTS: Our results show that these ultra-high SMFs did not significantly affect the general development of zebrafish embryos, such as the body length or spontaneous tail-wagging movement. However, the hatching rate was reduced by the gradient SMFs (p < 0.05), but not the homogenous 22.0 T SMF. Moreover, although the zebrafish larva activities were differentially affected by these ultra-high SMFs (p < 0.05), the expression of several visual and neurodevelopmental genes (p < 0.05) was generally downregulated in the eyeball. CONCLUSIONS: Our findings suggest that exposure to ultra-high SMFs, especially the gradient SMFs, may have adverse effects on embryonic development, which should cause some attention to the future application of ultra-high field MRIs. CLINICAL RELEVANCE STATEMENT: As technology advances, it is conceivable that very strong magnetic fields may be adapted for use in medical imaging. Possible dangers associated with these higher Tesla fields need to be considered and evaluated prior to human use. KEY POINTS: Ultra-High static magnetic field may affect early embryonic development. High strength gradient static magnetic field exposure impacted zebrafish embryonic development. The application of very strong magnetic fields for MR technologies needs to be carefully evaluated.

5.
Mol Med ; 30(1): 93, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38898476

ABSTRACT

BACKGROUND: The epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells (HBECs) is essential for airway remodeling during asthma. Wnt5a has been implicated in various lung diseases, while its role in the EMT of HBECs during asthma is yet to be determined. This study sought to define whether Wnt5a initiated EMT, leading to airway remodeling through the induction of autophagy in HBECs. METHODS: Microarray analysis was used to investigate the expression change of WNT5A in asthma patients. In parallel, EMT models were induced using 16HBE cells by exposing them to house dust mites (HDM) or interleukin-4 (IL-4), and then the expression of Wnt5a was observed. Using in vitro gain- and loss-of-function approaches via Wnt5a mimic peptide FOXY5 and Wnt5a inhibitor BOX5, the alterations in the expression of the epithelial marker E-cadherin and the mesenchymal marker protein were observed. Mechanistically, the Ca2+/CaMKII signaling pathway and autophagy were evaluated. An autophagy inhibitor 3-MA was used to examine Wnt5a in the regulation of autophagy during EMT. Furthermore, we used a CaMKII inhibitor KN-93 to determine whether Wnt5a induced autophagy overactivation and EMT via the Ca2+/CaMKII signaling pathway. RESULTS: Asthma patients exhibited a significant increase in the gene expression of WNT5A compared to the healthy control. Upon HDM and IL-4 treatments, we observed that Wnt5a gene and protein expression levels were significantly increased in 16HBE cells. Interestingly, Wnt5a mimic peptide FOXY5 significantly inhibited E-cadherin and upregulated α-SMA, Collagen I, and autophagy marker proteins (Beclin1 and LC3-II). Rhodamine-phalloidin staining showed that FOXY5 resulted in a rearrangement of the cytoskeleton and an increase in the quantity of stress fibers in 16HBE cells. Importantly, blocking Wnt5a with BOX5 significantly inhibited autophagy and EMT induced by IL-4 in 16HBE cells. Mechanistically, autophagy inhibitor 3-MA and CaMKII inhibitor KN-93 reduced the EMT of 16HBE cells caused by FOXY5, as well as the increase in stress fibers, cell adhesion, and autophagy. CONCLUSION: This study illustrates a new link in the Wnt5a-Ca2+/CaMKII-autophagy axis to triggering airway remodeling. Our findings may provide novel strategies for the treatment of EMT-related diseases.


Subject(s)
Asthma , Autophagy , Epithelial Cells , Epithelial-Mesenchymal Transition , Wnt-5a Protein , Humans , Wnt-5a Protein/metabolism , Wnt-5a Protein/genetics , Asthma/metabolism , Asthma/pathology , Asthma/genetics , Epithelial Cells/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Bronchi/metabolism , Bronchi/pathology , Male , Cell Line , Female , Middle Aged , Signal Transduction , Adult
6.
Nat Prod Rep ; 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38888170

ABSTRACT

Covering: 1987 to 2023Naturally existing glycoproteins through post-translational protein glycosylation are highly heterogeneous, which not only impedes the structure-function studies, but also hinders the development of their potential medical usage. Chemical synthesis represents one of the most powerful tools to provide the structurally well-defined glycoforms. Being the key step of glycoprotein synthesis, glycosylation usually takes place at serine, threonine, and asparagine residues, leading to the predominant formation of the O- and N-glycans, respectively. However, other amino acid residues containing oxygen, nitrogen, sulfur, and nucleophilic carbon atoms have also been found to be glycosylated. These diverse glycoprotein linkages, occurring from microorganisms to plants and animals, play also pivotal biological roles, such as in cell-cell recognition and communication. The availability of these homogenous rare glycopeptides and glycoproteins can help decipher the glyco-code for developing therapeutic agents. This review highlights the chemical approaches for assembly of the functional glycopeptides and glycoproteins bearing these "rare" carbohydrate-amino acid linkages between saccharide and canonical amino acid residues and their derivatives.

7.
Front Microbiol ; 15: 1332105, 2024.
Article in English | MEDLINE | ID: mdl-38800758

ABSTRACT

Introduction: Research on the mechanism of marine polysaccharide utilization by Bacteroides thetaiotaomicron has drawn substantial attention in recent years. Derived from marine algae, the marine algae polysaccharides could serve as prebiotics to facilitate intestinal microecological balance and alleviate colonic diseases. Bacteroides thetaiotaomicron, considered the most efficient degrader of polysaccharides, relates to its capacity to degrade an extensive spectrum of complex polysaccharides. Polysaccharide utilization loci (PULs), a specialized organization of a collection of genes-encoded enzymes engaged in the breakdown and utilization of polysaccharides, make it possible for Bacteroides thetaiotaomicron to metabolize various polysaccharides. However, there is still a paucity of comprehensive studies on the procedure of polysaccharide degradation by Bacteroides thetaiotaomicron. Methods: In the current study, the degradation of four kinds of marine algae polysaccharides, including sodium alginate, fucoidan, laminarin, and Pyropia haitanensis polysaccharides, and the underlying mechanism by Bacteroides thetaiotaomicron G4 were investigated. Pure culture of Bacteroides thetaiotaomicron G4 in a substrate supplemented with these polysaccharides were performed. The change of OD600, total carbohydrate contents, and molecular weight during this fermentation were determined. Genomic sequencing and bioinformatic analysis were further performed to elucidate the mechanisms involved. Specifically, Gene Ontology (GO) annotation, Clusters of Orthologous Groups (COG) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were utilized to identify potential target genes and pathways. Results: Underlying target genes and pathways were recognized by employing bioinformatic analysis. Several PULs were found that are anticipated to participate in the breakdown of these four polysaccharides. These findings may help to understand the interactions between these marine seaweed polysaccharides and gut microorganisms. Discussion: The elucidation of polysaccharide degradation mechanisms by Bacteroides thetaiotaomicron provides valuable insights into the utilization of marine polysaccharides as prebiotics and their potential impact on gut health. Further studies are warranted to explore the specific roles of individual PULs and their contributions to polysaccharide metabolism in the gut microbiota.

8.
Org Biomol Chem ; 22(19): 3986-3994, 2024 05 15.
Article in English | MEDLINE | ID: mdl-38695061

ABSTRACT

Algae-based marine carbohydrate drugs are typically decorated with negative ion groups such as carboxylate and sulfate groups. However, the precise synthesis of highly sulfated alginates is challenging, thus impeding their structure-activity relationship studies. Herein we achieve a microwave-assisted synthesis of a range of highly sulfated mannuronate glycans with up to 17 sulfation sites by overcoming the incomplete sulfation due to the electrostatic repulsion of crowded polyanionic groups. Although the partially sulfated tetrasaccharide had the highest affinity for the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, the fully sulfated octasaccharide showed the most potent interference with the binding of the RBD to angiotensin-converting enzyme 2 (ACE2) and Vero E6 cells, indicating that the sulfated oligosaccharides might inhibit the RBD binding to ACE2 in a length-dependent manner.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antiviral Agents , Microwaves , Polysaccharides , SARS-CoV-2 , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Chlorocebus aethiops , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/chemistry , Vero Cells , Polysaccharides/chemistry , Polysaccharides/pharmacology , Polysaccharides/chemical synthesis , Humans , Animals , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Hexuronic Acids/chemistry , Hexuronic Acids/pharmacology , Hexuronic Acids/chemical synthesis , Sulfates/chemistry , Sulfates/pharmacology , Sulfates/chemical synthesis , COVID-19 Drug Treatment , Structure-Activity Relationship
9.
J Cosmet Dermatol ; 2024 May 07.
Article in English | MEDLINE | ID: mdl-38712728

ABSTRACT

BACKGROUND: Papulopustular rosacea (PPR) is a chronic inflammatory disease with a significant impact on facial aesthetics. An impaired skin barrier is an important factor in the development and exacerbation of PPR. Tranexamic acid (TXA) has immune regulatory and anti-inflammatory effects, inhibits angiogenesis and endothelial hyperplasia, and promotes skin barrier repair. AIMS: We investigated the efficacy and safety of oral TXA for PPR treatment. PATIENTS/METHODS: In total, 70 patients were randomly assigned to receive traditional therapy plus oral TXA or traditional therapy alone for 8 weeks, with a 4-week follow-up period. The subjective improvement in rosacea was assessed using the clinical erythema assessment (CEA), investigator's global assessment (IGA), patient self-assessment (PSA) score, rosacea-specific quality of life (RQoL) score, and global aesthetic improvement score (GAIS). An objective improvement in rosacea was assessed using skin hydration, trans-epidermal water loss (TEWL), clinical photography, and an eight spectrum facial imager. RESULTS: CEA/IGA/PSA, dryness, and RQoL scores were significantly lower and GAIS was higher in the TXA group than in the traditional therapy group. Furthermore, oral TXA significantly improved skin barrier function, increased skin hydration, and decreased TEWL, with no significant side effects. Notably, we observed better outcomes and a greater improvement in skin barrier function with TXA treatment in patients with dry-type rosacea than in patients with oily skin. CONCLUSIONS: The addition of oral TXA to traditional therapy can lead to rapid and effective improvements in PPR, which may be attributed to improvements in skin barrier function.

10.
J Am Heart Assoc ; 13(9): e033043, 2024 May 07.
Article in English | MEDLINE | ID: mdl-38686862

ABSTRACT

BACKGROUND: This study examines the association between traditional cardiovascular health (CVH) metrics and major adverse cardiovascular events (MACE) incidence in individuals with diverse sleep patterns. METHODS AND RESULTS: We analyzed data from 208 621 participants initially free of cardiovascular disease (CVD) in the UK Biobank study. Sleep patterns were assessed using scores for chronotype, duration, insomnia, snoring, and daytime dozing. Traditional CVH scores were derived from the Life's Simple 7 metrics. Cox proportional hazards multivariate regression assessed associations between distinct combinations of CVH and sleep scores and MACE, including nonfatal myocardial infarction, nonfatal stroke, and CVD mortality. Over a mean follow-up of 12.73 years, 9253 participants experienced incident MACE. Individuals with both a healthy sleep pattern and ideal CVH levels had the lowest MACE risk compared with those with a poor sleep pattern and poor CVH levels (hazard ratio, 0.306 [95% CI, 0.257-0.365]; P<0.001). Elevated CVH scores were associated with a reduced risk of MACE across different sleep patterns. Similar trends were observed for individual MACE components, heart failure, and all-cause mortality. These findings remained robust in sensitivity analyses and across various subgroups. CONCLUSIONS: In individuals without known CVD, maintaining a favorable sleep pattern and achieving optimal CVH levels, as measured by traditional metrics, were associated with the lowest MACE risk. Enhanced CVH significantly reduced CVD risk, even in individuals with a poor sleep pattern. These results emphasize the importance of considering multiple dimensions of sleep health alongside CVH to mitigate CVD risk. REGISTRATION: URL: https://www.ukbiobank.ac.uk; Unique identifier: 91090.


Subject(s)
Cardiovascular Diseases , Sleep , Humans , Male , Female , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Prospective Studies , Middle Aged , United Kingdom/epidemiology , Aged , Incidence , Risk Factors , Risk Assessment/methods , Adult , Heart Disease Risk Factors , Sleep Quality , Health Status , Time Factors
11.
Diabetes Obes Metab ; 26(7): 2673-2683, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38558498

ABSTRACT

AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.


Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Diabetic Angiopathies , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Male , Female , Prospective Studies , Middle Aged , Diabetic Angiopathies/epidemiology , Diabetic Angiopathies/etiology , United Kingdom/epidemiology , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Adult , Risk Factors , Body Mass Index , Smoking/adverse effects , Smoking/epidemiology , Glycated Hemoglobin/analysis , Glycated Hemoglobin/metabolism , Exercise , Follow-Up Studies , Blood Pressure , Incidence
12.
Zool Res ; 45(3): 478-491, 2024 May 18.
Article in English | MEDLINE | ID: mdl-38682430

ABSTRACT

Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.


Subject(s)
Acetaminophen , Analgesics, Non-Narcotic , Chemical and Drug Induced Liver Injury , Drug Overdose , Acetaminophen/toxicity , Animals , Mice , Analgesics, Non-Narcotic/toxicity , Oxidative Stress/drug effects , Male , Magnetic Fields , Acetylcysteine/therapeutic use , Acetylcysteine/pharmacology
13.
Sci Adv ; 10(15): eadn1305, 2024 Apr 12.
Article in English | MEDLINE | ID: mdl-38608021

ABSTRACT

The structural identification and efficient synthesis of bioactive 2,6-dideoxyglycosides are daunting challenges. Here, we report the total synthesis and structural revision of a series of 2,6-dideoxyglycosides from folk medicinal plants Ecdysanthera rosea and Chonemorpha megacalyx, which feature pregnane steroidal aglycones bearing an 18,20-lactone and glycans consisting of 2,6-dideoxy-3-O-methyl-ß-pyranose residues, including ecdysosides A, B, and F and ecdysantheroside A. All the eight possible 2,6-dideoxy-3-O-methyl-ß-pyranoside stereoisomers (of the proposed ecdysantheroside A) have been synthesized that testify the effective gold(I)-catalyzed glycosylation methods for the synthesis of various 2-deoxy-ß-pyranosidic linkages and lays a foundation via nuclear magnetic resonance data mapping to identify these sugar units which occur promiscuously in the present and other natural glycosides. Moreover, some synthetic natural compounds and their isomers have shown promising anticancer, immunosuppressive, anti-inflammatory, and anti-Zika virus activities.


Subject(s)
Gold , Magnetic Resonance Imaging , Glycosylation , Technology , Magnetic Resonance Spectroscopy
14.
J Nanobiotechnology ; 22(1): 153, 2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38580995

ABSTRACT

BACKGROUND: Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis. RESULTS: Osteoclasts' microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model. CONCLUSION: The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis.


Subject(s)
Bone Resorption , Osteoporosis , Mice , Animals , Osteoclasts , Nanomedicine , Osteoporosis/drug therapy , Bone Resorption/drug therapy , Bone and Bones/pathology , Cell Differentiation
15.
BMC Cardiovasc Disord ; 24(1): 226, 2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38664632

ABSTRACT

BACKGROUND: Pathogenesis and diagnostic biomarkers of aortic dissection (AD) can be categorized through the analysis of differential metabolites in serum. Analysis of differential metabolites in serum provides new methods for exploring the early diagnosis and treatment of aortic dissection. OBJECTIVES: This study examined affected metabolic pathways to assess the diagnostic value of metabolomics biomarkers in clients with AD. METHOD: The serum from 30 patients with AD and 30 healthy people was collected. The most diagnostic metabolite markers were determined using metabolomic analysis and related metabolic pathways were explored. RESULTS: In total, 71 differential metabolites were identified. The altered metabolic pathways included reduced phospholipid catabolism and four different metabolites considered of most diagnostic value including N2-gamma-glutamylglutamine, PC(phocholines) (20:4(5Z,8Z,11Z,14Z)/15:0), propionyl carnitine, and taurine. These four predictive metabolic biomarkers accurately classified AD patient and healthy control (HC) samples with an area under the curve (AUC) of 0.9875. Based on the value of the four different metabolites, a formula was created to calculate the risk of aortic dissection. Risk score = (N2-gamma-glutamylglutamine × -0.684) + (PC (20:4(5Z,8Z,11Z,14Z)/15:0) × 0.427) + (propionyl carnitine × 0.523) + (taurine × -1.242). An additional metabolic pathways model related to aortic dissection was explored. CONCLUSION: Metabolomics can assist in investigating the metabolic disorders associated with AD and facilitate a more in-depth search for potential metabolic biomarkers.


Subject(s)
Aortic Aneurysm , Aortic Dissection , Biomarkers , Metabolomics , Predictive Value of Tests , Humans , Aortic Dissection/blood , Aortic Dissection/diagnosis , Male , Biomarkers/blood , Female , Middle Aged , Case-Control Studies , Aortic Aneurysm/blood , Aortic Aneurysm/diagnosis , Aged , Adult , Metabolome , Risk Assessment
16.
Nanoscale ; 16(18): 8900-8906, 2024 May 09.
Article in English | MEDLINE | ID: mdl-38563321

ABSTRACT

Two-dimensional (2D) materials have shown unique chemical and physical properties; however, their synthesis is highly dependent on the layered structure of building blocks. Herein, we developed monolayer Dy2O3-phosphomolybdic acid (PMA) nanosheets and nanotubes based on microwave synthesis. Microwave-assisted synthesis with high-energy input gives a faster and dynamically driven growth of nanomaterials, resulting in high-purity nanostructures with a narrow size distribution. The reaction times of the nanosheets and nanotubes under microwave synthesis are significantly reduced compared with oven-synthesis. Dy2O3-PMA nanosheets and nanotubes exhibit enhanced activity and stability in photoconductance, with higher sensitivities (0.308 µA cm-2 for nanosheets and 0.271 µA cm-2 for nanotubes) compared to the individual PMA (0.12 µA cm-2) and Dy2O3 (0.025 µA cm-2) building blocks. This work demonstrates the promising application potential of microwave-synthesized 2D heterostructures in superconductors and photoelectronic devices.

17.
J Am Chem Soc ; 146(12): 8768-8779, 2024 03 27.
Article in English | MEDLINE | ID: mdl-38483318

ABSTRACT

2'-Deoxynucleosides and analogues play a vital role in drug development, but their preparation remains a significant challenge. Previous studies have focused on ß-2'-deoxynucleosides with the natural ß-configuration. In fact, their isomeric α-2'-deoxynucleosides also exhibit diverse bioactivities and even better metabolic stability. Herein, we report that both α- and ß-2'-deoxynucleosides can be prepared with high yields and stereoselectivity using a remote directing diphenylphosphinoyl (DPP) group. It is particularly efficient to prepare α-2'-deoxynucleosides with an easily accessible 3,5-di-ODPP donor. Instead of acting as a H-bond acceptor on a 2-(diphenylphosphinoyl)acetyl (DPPA) group in our previous studies for syn-facial O-glycosylation, the phosphine oxide moiety here acts as a remote participating group to enable highly antifacial N-glycosylation. This proposed remote participation mechanism is supported by our first characterization of an important 1,5-briged P-heterobicyclic intermediate via variable-temperature NMR spectroscopy. Interestingly, antiproliferative assays led to a α-2'-deoxynucleoside with IC50 values in the low micromole range against central nervous system tumor cell lines SH-SY5Y and LN229, whereas its ß-anomer exhibited no inhibition at 100 µM. Furthermore, the DPP group significantly enhanced the antitumor activities by 10 times.


Subject(s)
Neuroblastoma , Phosphines , Humans , Glycosylation
18.
Org Lett ; 26(12): 2425-2429, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38506225

ABSTRACT

The synthesis of gwanakoside A, a chlorinated naphthol bis-glycoside, and its analogues was achieved through stepwise chlorination and donor-equivalent controlled regioselective phenol glycosylation with glycosyl N-phenyltrifluoroacetimidates as donors. Gwanakoside A displayed considerable inhibitory effects against various cancer cells and Staphylococcus aureus strains.


Subject(s)
Cardiac Glycosides , Glycosides , Glycosides/pharmacology , Glycosylation , Halogenation
19.
JACS Au ; 4(2): 697-712, 2024 Feb 26.
Article in English | MEDLINE | ID: mdl-38425910

ABSTRACT

The evaluation of Bacteroides vulgatus mpk (BVMPK) lipopolysaccharide (LPS) recognition by DC-SIGN, a key lectin in mediating immune homeostasis, has been here performed. A fine chemical dissection of BVMPK LPS components, attained by synthetic chemistry combined to spectroscopic, biophysical, and computational techniques, allowed to finely map the LPS epitopes recognized by DC-SIGN. Our findings reveal BVMPK's role in immune modulation via DC-SIGN, targeting both the LPS O-antigen and the core oligosaccharide. Furthermore, when framed within medical chemistry or drug design, our results could lead to the development of tailored molecules to benefit the hosts dealing with inflammatory diseases.

20.
Natl Sci Rev ; 11(2): nwae030, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38333067

ABSTRACT

Vaccines have been the primary remedy in the global fight against coronavirus disease 2019 (COVID-19). The receptor-binding domain (RBD) of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure-function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope (Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N-glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpep elicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N-glycans and Tpep conjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection.

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