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European Heart Journal Jun 2024The pathways and metabolites that contribute to residual cardiovascular disease risks are unclear. Low-calorie sweeteners are widely used sugar substitutes in processed...
BACKGROUND AND AIMS
The pathways and metabolites that contribute to residual cardiovascular disease risks are unclear. Low-calorie sweeteners are widely used sugar substitutes in processed foods with presumed health benefits. Many low-calorie sweeteners are sugar alcohols that also are produced endogenously, albeit at levels over 1000-fold lower than observed following consumption as a sugar substitute.
METHODS
Untargeted metabolomics studies were performed on overnight fasting plasma samples in a discovery cohort (n = 1157) of sequential stable subjects undergoing elective diagnostic cardiac evaluations; subsequent stable isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses were performed on an independent, non-overlapping validation cohort (n = 2149). Complementary isolated human platelet, platelet-rich plasma, whole blood, and animal model studies examined the effect of xylitol on platelet responsiveness and thrombus formation in vivo. Finally, an intervention study was performed to assess the effects of xylitol consumption on platelet function in healthy volunteers (n = 10).
RESULTS
In initial untargeted metabolomics studies (discovery cohort), circulating levels of a polyol tentatively assigned as xylitol were associated with incident (3-year) major adverse cardiovascular event (MACE) risk. Subsequent stable isotope dilution LC-MS/MS analyses (validation cohort) specific for xylitol (and not its structural isomers) confirmed its association with incident MACE risk [third vs. first tertile adjusted hazard ratio (95% confidence interval), 1.57 (1.12-2.21), P < .01]. Complementary mechanistic studies showed xylitol-enhanced multiple indices of platelet reactivity and in vivo thrombosis formation at levels observed in fasting plasma. In interventional studies, consumption of a xylitol-sweetened drink markedly raised plasma levels and enhanced multiple functional measures of platelet responsiveness in all subjects.
CONCLUSIONS
Xylitol is associated with incident MACE risk. Moreover, xylitol both enhanced platelet reactivity and thrombosis potential in vivo. Further studies examining the cardiovascular safety of xylitol are warranted.
PubMed: 38842092
DOI: 10.1093/eurheartj/ehae244 -
Advanced Materials (Deerfield Beach,... Oct 2023Engineered skin substitutes derived from human skin significantly reduce inflammatory reactions mediated by foreign/artificial materials and are consequently easier to...
Engineered skin substitutes derived from human skin significantly reduce inflammatory reactions mediated by foreign/artificial materials and are consequently easier to use for clinical application. Type I collagen is a main component of the extracellular matrix during wound healing and has excellent biocompatibility, and platelet-rich plasma can be used as the initiator of the healing cascade. Adipose mesenchymal stem cell derived exosomes are crucial for tissue repair and play key roles in enhancing cell regeneration, promoting angiogenesis, regulating inflammation, and remodeling extracellular matrix. Herein, Type I collagen and platelet-rich plasma, which provide natural supports for keratinocyte and fibroblast adhesion, migration, and proliferation, are mixed to form a stable 3D scaffold. Adipose mesenchymal stem cell derived exosomes are added to the scaffold to improve the performance of the engineered skin. The physicochemical properties of this cellular scaffold are analyzed, and the repair effect is evaluated in a full-thickness skin defect mouse model. The cellular scaffold reduces the level of inflammation and promotes cell proliferation and angiogenesis to accelerate wound healing. Proteomic analysis shows that exosomes exhibit excellent anti-inflammatory and proangiogenic effects in collagen/platelet-rich plasma scaffolds. The proposed method provides a new therapeutic strategy and theoretical basis for tissue regeneration and wound repair.
PubMed: 37342075
DOI: 10.1002/adma.202303642 -
Journal of Ethnopharmacology Sep 2023Modified Gegen Qinlian decoction (MGQD), which was first documented in Treatise on Febrile Disease, is recognized as a classic prescription to treat ulcerative colitis...
Modified Gegen Qinlian decoction ameliorated ulcerative colitis by attenuating inflammation and oxidative stress and enhancing intestinal barrier function in vivo and in vitro.
ETHNOPHARMACOLOGICAL RELEVANCE
Modified Gegen Qinlian decoction (MGQD), which was first documented in Treatise on Febrile Disease, is recognized as a classic prescription to treat ulcerative colitis (UC). However, its protective mechanism against UC remains to be fully elucidated.
AIM OF THE STUDY
To explore the impact and the potential molecular mechanism of MGQD on dextran sodium sulfate (DSS)-induced UC mice and tumor necrosis factor alpha (TNF-α)-induced Caco-2 cell monolayer model of intestinal barrier.
MATERIALS AND METHODS
The chemical components of MGQD and MGQD drug containing serum (MGQD-DS) were characterized by LC-MS/MS. The therapeutic effect of MGQD on DSS-induced UC was evaluated based on body weight, disease activity index (DAI), colon length, colonic histopathological injury, inflammatory cytokines, oxidative stress response and intestinal barrier function. Cell Counting Kit (CCK)-8 assay was applied to detect the effect of MGQD-DS on the viability of Caco-2 cells. Additionally, TNF-α-induced Caco-2 cell monolayer model of intestinal barrier was established in vitro. The Caco-2 cell monolayers were administered blank serum or MGQD-DS to observe the effects of MGQD-DS on transepithelial electrical resistance (TEER), permeability of fluorescein isothiocyanate (FITC)-dextran, inflammatory cytokines, oxidative stress indicators and intestinal epithelial barrier (IEB).
RESULTS
MGQD significantly improved symptoms and pathological damage in UC mice by downregulating the expression of interleukin (IL)-1β and malondialdehyde (MDA), attenuating the loss of goblet cells and the destruction of intestinal epithelial ultrastructure, and upregulating the expression of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), zonula occludens-1 (ZO-1), Occludin, Claudin-1 and E-cadherin. In vitro, MGQD-DS significantly reduced the flux of FITC-dextran, increased the TEER, inhibited the expression of IL-21, IL-17A and MDA, and promoted the expression of IL-4, IL-10, transforming growth factor-β (TGF-β), SOD, CAT, GSH, Occludin and E-cadherin in TNF-α-induced Caco-2 cell monolayer model of intestinal barrier.
CONCLUSION
MGQD can ameliorate DSS-induced UC mice and TNF-α-induced Caco-2 cell monolayer model of intestinal barrier, and the protective effect is related to its inhibition of inflammation, alleviation of oxidative stress, and repair of intestinal barrier damage.
Topics: Humans; Animals; Mice; Colitis, Ulcerative; Dextrans; Occludin; Tumor Necrosis Factor-alpha; Caco-2 Cells; Chromatography, Liquid; Tandem Mass Spectrometry; Inflammation; Oxidative Stress; Cytokines; Glutathione; Dextran Sulfate; Colitis; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37086872
DOI: 10.1016/j.jep.2023.116538 -
Facial Plastic Surgery : FPS Oct 2023Critical-sized bone defects are a reconstructive challenge, particularly in the craniomaxillofacial (CMF) skeleton. The "gold standard" of autologous bone grafting has... (Review)
Review
Critical-sized bone defects are a reconstructive challenge, particularly in the craniomaxillofacial (CMF) skeleton. The "gold standard" of autologous bone grafting has been the work horse of reconstruction in both congenital and acquired defects of CMF skeleton. Autologous bone has the proper balance of the protein (or organic) matrix and mineral components with no immune response. Organic and mineral adjuncts exist that offer varying degrees of osteogenic, osteoconductive, osteoinductive, and osteostimulative properties needed for treatment of critical-sized defects. In this review, we discuss the various mostly organic and mostly mineral bone graft substitutes available for autologous bone grafting. Primarily organic bone graft substitutes/enhancers, including bone morphogenic protein, platelet-rich plasma, and other growth factors, have been utilized to support de novo bone growth in setting of critical-sized bone defects. Primarily mineral options, including various calcium salt formulation (calcium sulfate/phosphate/apatite) and bioactive glasses have been long utilized for their similar composition to bone. Yet, a bone graft substitute that can supplant autologous bone grafting is still elusive. However, case-specific utilization of bone graft substitutes offers a wider array of reconstructive options.
Topics: Animals; Horses; Bone Substitutes; Bone Transplantation; Calcium Phosphates; Bone Regeneration
PubMed: 37473765
DOI: 10.1055/s-0043-1770962 -
Journal of Thrombosis and Haemostasis :... Apr 2024Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic disorder associated with a severe deficiency of ADAMTS-13-the protease that cleaves von... (Review)
Review
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic disorder associated with a severe deficiency of ADAMTS-13-the protease that cleaves von Willebrand factor. Plasma therapy is the current standard of care for managing acute episodes of TTP, which involves removing patient plasma and replacing it with donor plasma to raise the level of ADAMTS-13 activity. Recently, therapies aimed at replacing ADAMTS-13 have been investigated as possible substitutes or add-ons to plasma therapy for congenital and immune-mediated TTP. Enzyme replacement therapy provides recombinant ADAMTS-13 via intravenous (i.v.) infusion to restore enzyme activity. Recombinant ADAMTS-13-loaded platelets localize to the site of thrombus formation in a more concentrated manner than enzyme replacement or plasma therapy. ADAMTS-13-encoding messenger RNA aims to induce a steady supply of secreted protein and gene therapy is a potentially curative strategy. Overall, targeted ADAMTS-13 replacement therapies may provide better outcomes than plasma therapy by achieving higher levels of ADAMTS-13 activity and a more sustained response with fewer adverse events. Herein, we describe targeted ADAMTS-13 replacement therapies for the treatment of TTP and discuss the advantages and limitations of each approach.
Topics: Humans; Purpura, Thrombotic Thrombocytopenic; ADAMTS13 Protein; Blood Platelets; Plasma; Thrombosis; von Willebrand Factor
PubMed: 38142844
DOI: 10.1016/j.jtha.2023.11.030 -
Survey of Ophthalmology 2024Polyvinyl pyrrolidone or povidone-iodine (PVP-I) is a water-soluble complex formed by the combination of iodine and a water-soluble polymer, polyvinyl pyrrolidone. This... (Review)
Review
Polyvinyl pyrrolidone or povidone-iodine (PVP-I) is a water-soluble complex formed by the combination of iodine and a water-soluble polymer, polyvinyl pyrrolidone. This complex exerts bactericidal, fungicidal, and virucidal action by gradually releasing free iodine at the site of application to react with pathogens. In ophthalmology, PVP-I is used as a disinfectant and antiseptic agent for preoperative preparation of the skin and mucous membranes and for treating contaminated wounds. PVP-I has been shown to reduce effectively the risk of endophthalmitis in various ocular procedures, including cataract surgery and intravitreal injections; however, it has also been used in the treatment of conjunctivitis, keratitis, and endophthalmitis, with promising results especially in low-resource situations. PVP-I has been associated with complications such as postoperative eye pain, persistent corneal epithelial defects, ocular inflammation, and an attendant risk of keratitis. In cases of poor PVP-I tolerance, applying PVP-I at lower concentrations or using alternative antiseptics such as chlorhexidine should be considered. We provide an update on the efficacy of PVP-I in the prophylaxis and treatment of conjunctivitis, keratitis, and endophthalmitis and a comprehensive analysis of the current literature regarding the use of PVP-I in the management of these ocular conditions. Also, PVP-I-related adverse effects and toxicities and its alternatives are discussed. The goal is to present a thorough evaluation of the available evidence and to offer practical recommendations for clinicians regarding the therapeutic usage of PVP-I in ophthalmology.
Topics: Humans; Povidone-Iodine; Ophthalmology; Polyvinyls; Anti-Infective Agents, Local; Iodine; Cataract Extraction; Endophthalmitis; Povidone; Conjunctivitis; Keratitis; Water
PubMed: 37944600
DOI: 10.1016/j.survophthal.2023.11.002 -
Advanced Science (Weinheim,... Jul 2023Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC...
Malignant ascites in advanced hepatocellular carcinoma (HCC) is a complex clinical problem that lacks effective treatments. Due to the insensitivity of advanced HCC cells to traditional chemotherapies, low drug accumulation, and limited drug residence time in the peritoneal cavity, the therapeutic effects of malignant ascites in HCC are not satisfactory. In this study, an injectable hydrogel drug delivery system based on chitosan hydrochloride and oxidized dextran (CH-OD) is designed to load sulfasalazine (SSZ), an FDA-approved drug with ferroptosis-inducing ability, for effective tumor-killing and activation of anti-tumor immunity. Compared to free SSZ, SSZ-loaded CH-OD (CH-OD-SSZ) hydrogel exhibits greater cytotoxicity and induces higher levels of immunogenic ferroptosis. In the preclinical model of hepatoma ascites, intraperitoneal administration of CH-OD-SSZ hydrogel can significantly suppress tumor progression and improve the immune landscape. Both in vitro and in vivo, CH-OD-SSZ hydrogel induces the repolarization of macrophages to an M1-like phenotype and promotes the maturation and activation of dendritic cells. Combination treatment with CH-OD-SSZ hydrogel and anti-programmed cell death protein 1 (PD-1) immunotherapy achieves more than 50% ascites regression and generates long-term immune memory. Collectively, CH-OD-SSZ hydrogel exhibits promising therapeutic potential in the treatment of peritoneal dissemination and malignant ascites in advanced HCC, especially when combined with anti-PD-1 immunotherapy.
Topics: Humans; Carcinoma, Hepatocellular; Hydrogels; Chitosan; Dextrans; Ascites; Ferroptosis; Liver Neoplasms; Sulfasalazine; Immunotherapy
PubMed: 37132587
DOI: 10.1002/advs.202300517 -
Journal of Nuclear Medicine : Official... Nov 2023Inflammatory bowel disease (IBD), which includes both Crohn disease and ulcerative colitis, is a relapsing inflammatory disease of the gastrointestinal tract. Long-term...
Inflammatory bowel disease (IBD), which includes both Crohn disease and ulcerative colitis, is a relapsing inflammatory disease of the gastrointestinal tract. Long-term chronic inflammatory conditions elevate the patient's risk of colorectal cancer (CRC). Currently, diagnosis requires endoscopy with biopsy. This procedure is invasive and requires a bowel-preparatory regimen, adding to patient burden. Interleukin 12 (IL12) and interleukin 23 (IL23) play key roles in inflammation, especially in the pathogenesis of IBD, and are established therapeutic targets. We propose that imaging of IL12/23 and its p40 subunit in IBD via immuno-PET potentially provides a new noninvasive diagnostic approach. Our aim was to investigate the potential of immuno-PET to image inflammation in a chemically induced mouse model of colitis using dextran sodium sulfate by targeting IL12/23p40 with a Zr-radiolabeled anti-IL12/23p40 antibody. High uptake of the IL12/23p40 immuno-PET agent was exhibited by dextran sodium sulfate-administered mice, and this uptake correlated with increased IL12/23p40 present in the sera. Competitive binding studies confirmed the specificity of the radiotracer for IL12/23p40 in the gastrointestinal tract. These promising results demonstrate the utility of this radiotracer as an imaging biomarker of IBD. Moreover, IL12/23p40 immuno-PET can potentially guide treatment decisions for IBD management.
Topics: Humans; Animals; Mice; Interleukin-12; Dextrans; Inflammatory Bowel Diseases; Colitis; Inflammation; Positron-Emission Tomography; Dextran Sulfate; Disease Models, Animal
PubMed: 37474270
DOI: 10.2967/jnumed.123.265649 -
Arteriosclerosis, Thrombosis, and... Oct 2023High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB-containing particle attached to the...
BACKGROUND
High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a).
METHODS
Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting.
RESULTS
The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis.
CONCLUSIONS
These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and some antidepressant compounds.
Topics: Humans; Plasminogen; Lipoprotein(a); Annexin A2; Dextrans; Phosphatidylinositol 3-Kinases; Carrier Proteins; Apolipoproteins A
PubMed: 37589135
DOI: 10.1161/ATVBAHA.123.319344 -
Phytomedicine : International Journal... Feb 2024Ferroptosis is a crucial contributor to impaired osteoblast function in osteoporosis. Mangiferin, a xanthonoid glucoside isolated from mangoes, exhibits...
BACKGROUND
Ferroptosis is a crucial contributor to impaired osteoblast function in osteoporosis. Mangiferin, a xanthonoid glucoside isolated from mangoes, exhibits anti-osteoporosis effects. However, its potential mechanism is not fully understood.
PURPOSE
This study explores the potencies of mangiferin on osteoblastic ferroptosis and deciphers its direct target in the context of solute carrier family 7-member 11 (SLC7A11)/glutathione peroxidases 4 (GPX4) pathway.
METHODS
In vivo models include bilateral ovariectomy induced osteoporosis mice, iron-dextran induced iron-overloaded mice, and nuclear factor-erythroid 2-related factor 2 (Nrf2)-knockout mice. Mice are orally administrated mangiferin (10, 50 or 100 mg.kgd) for 12 weeks. In vitro osteoblast models include iron-dextran induced iron-overloaded cells, erastin induced ferroptosis cells, and gene knockout cells. RNA sequencing is applied for investigating the underlying mechanisms. The direct target of mangiferin is studied using a cellular thermal shift assay, silico docking, and surface plasmon resonance.
RESULTS
Mangiferin promotes bone formation and inhibits ferroptosis in vivo models (osteoporosis mice, iron-overloaded mice) and in vitro models (ferroptosis osteoblast, iron-overloaded osteoblasts). Mechanismly, mangiferin directly binds to the kelch-like ECH-associated protein 1 (Keap1) and activates the downstream Nrf2/SLC7A11/GPX4 pathway in both the in vivo and in vitro models. Mangiferin failed to restore the osteoporosis and ferroptosis in Nrf2-knockout mice. Silencing Nrf2, SLC7A11 or GPX4 abolished the anti-ferroptosis effect of mangiferin in erastin-induced cells. Addition of the ferroptosis agonist RSL-3 also blocked the protective effects of mangiferin on iron-overloaded cells. Furthermore, mangiferin had better effects on osteogenesis than the ferroptosis inhibitor (ferrostatin-1) and the Nrf2 agonists (sulforaphane, dimethyl fumarate, and bardoxolone).
CONCLUSIONS
We identify for the first time mangiferin as a ferroptosis inhibitor and a direct Keap1 conjugator that promotes bone formation and alleviates osteoporosis. This work also provides a potentially practical pharmacological approach for treating ferroptosis-driven diseases.
Topics: Female; Animals; Mice; Kelch-Like ECH-Associated Protein 1; Phospholipid Hydroperoxide Glutathione Peroxidase; NF-E2-Related Factor 2; Dextrans; Ferroptosis; Mice, Knockout; Iron; Xanthones
PubMed: 38176266
DOI: 10.1016/j.phymed.2023.155282