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Biochimica Et Biophysica Acta.... May 2020Hepatocellular carcinoma (HCC) is an aggressive and widespread cancer. Patients with liver cirrhosis of different aetiologies are at a risk to develop HCC. It is... (Review)
Review
Hepatocellular carcinoma (HCC) is an aggressive and widespread cancer. Patients with liver cirrhosis of different aetiologies are at a risk to develop HCC. It is important to know that in approximately 20% of cases primary liver tumors arise in a non-cirrhotic liver. Lipid metabolism is variable in patients with chronic liver diseases, and lipid metabolites involved therein do play a role in the development of HCC. Of note, lipid composition of carcinogenic tissues differs from non-affected liver tissues. High cholesterol and low ceramide levels in the tumors protect the cells from oxidative stress and apoptosis, and do also promote cell proliferation. So far, detailed characterization of the mechanisms by which lipids enable the development of HCC has received little attention. Evaluation of the complex roles of lipids in HCC is needed to better understand the pathophysiology of HCC, the later being of paramount importance for the development of urgently needed therapeutic interventions. Disturbed hepatic lipid homeostasis has systemic consequences and lipid species may emerge as promising biomarkers for early diagnosis of HCC. The challenge is to distinguish lipids specifically related to HCC from changes simply related to the underlying liver disease. This review article discusses aberrant lipid metabolism in patients with HCC.
Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Diagnosis, Differential; Disease Models, Animal; Disease Progression; Humans; Lipid Metabolism; Lipids; Liver; Liver Cirrhosis; Liver Neoplasms; Oxidative Stress; Phospholipid Ethers; Phosphorylcholine; Plasmalogens; Severity of Illness Index
PubMed: 32058031
DOI: 10.1016/j.bbalip.2020.158658 -
Journal of Lipid Research 2021Endothelial-to-mesenchymal transition (EndMT), the process by which an endothelial cell (EC) undergoes a series of molecular events that result in a mesenchymal cell...
Endothelial-to-mesenchymal transition (EndMT), the process by which an endothelial cell (EC) undergoes a series of molecular events that result in a mesenchymal cell phenotype, plays an important role in atherosclerosis. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), derived from the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine, is a proinflammatory lipid found in atherosclerotic lesions. Whether POVPC promotes EndMT and how simvastatin influences POVPC-mediated EndMT remains unclear. Here, we treated human umbilical vein ECs with POVPC, simvastatin, or both, and determined their effect on EC viability, morphology, tube formation, proliferation, and generation of NO and superoxide anion (O). Expression of specific endothelial and mesenchymal markers was detected by immunofluorescence and immunoblotting. POVPC did not affect EC viability but altered cellular morphology from cobblestone-like ECs to a spindle-like mesenchymal cell morphology. POVPC increased O generation and expression of alpha-smooth muscle actin, vimentin, Snail-1, Twist-1, transforming growth factor-beta (TGF-β), TGF-β receptor II, p-Smad2/3, and Smad2/3. POVPC also decreased NO production and expression of CD31 and endothelial NO synthase. Simvastatin inhibited POVPC-mediated effects on cellular morphology, production of O and NO, and expression of specific endothelial and mesenchymal markers. These data demonstrate that POVPC induces EndMT by increasing oxidative stress, which stimulates TGF-β/Smad signaling, leading to Snail-1 and Twist-1 activation. Simvastatin inhibited POVPC-induced EndMT by decreasing oxidative stress, suppressing TGF-β/Smad signaling, and inactivating Snail-1 and Twist-1. Our findings reveal a novel mechanism of atherosclerosis that can be inhibited by simvastatin.
Topics: Phosphorylcholine
PubMed: 33711324
DOI: 10.1016/j.jlr.2021.100066 -
ACS Applied Materials & Interfaces Dec 2022Design of advanced contact lenses (CLs) demands materials that are safe and comfortable for the wearers and that preserve the normal eye microbiota, avoiding chronic...
Design of advanced contact lenses (CLs) demands materials that are safe and comfortable for the wearers and that preserve the normal eye microbiota, avoiding chronic inflammation and biofilm development. This work aimed to combine the natural antibiofouling phosphorylcholine and the antioxidant and prebiotic resveratrol as integral components of CLs that may have the additional performance of preventing oxidative-stress related eye diseases. Different from previous uses of 2-methacryloyloxyethyl phosphorylcholine (MPC) as coating, we explored the feasibility of adding MPC at high proportions as a comonomer of 2-hydroxyethyl methacrylate (HEMA)-based hydrogels while still allowing for the loading of the hydrophobic resveratrol. Homogeneous distribution of MPC along the hydrogel depth (confirmed by Raman spectroscopy) notably increased solvent uptake and the proportion of free water while it decreased Young's modulus. Relevantly, MPC did not hinder the uptake of resveratrol by CLs (>10 mg/g), which indeed showed network/water partition coefficients of >100. Protocols for CLs sterilization and loading of resveratrol under aseptic conditions were implemented, and the effects of tear proteins on resveratrol release rate were investigated. CLs sustained resveratrol release for more than 24 h , and sorption of albumin onto the hydrogel, although attenuated by MPC, slowed down the release. The combination of MPC and resveratrol reduced and growth as tested in a novel hydrogel disk-agar interface biofilm growth setup. The developed CLs showed excellent anti-inflammatory properties and biocompatibility in and rabbit tests and provided higher and more prolonged levels of resveratrol in tear fluid, which favored resveratrol biodistribution in anterior and posterior eye segments compared to eye drops. Correlations between the release profiles of resveratrol and were assessed. Relevantly, the CLs preserved the antioxidant properties of resveratrol during the entire 8 h of wearing. In sum, CLs prepared with high proportion in MPC may help address safety and comfort requirements while having drug releasing capabilities.
Topics: Animals; Rabbits; Antioxidants; Delayed-Action Preparations; Resveratrol; Phosphorylcholine; Staphylococcus aureus; Tissue Distribution; Contact Lenses; Hydrogels; Anti-Infective Agents; Water
PubMed: 36495267
DOI: 10.1021/acsami.2c18217 -
Journal of Materials Chemistry. B Jun 2023Phototheranostics integrating optical imaging and phototherapy has attracted extensive attention. Achieving nanophototherapeutics with near infrared (NIR)-light...
Phototheranostics integrating optical imaging and phototherapy has attracted extensive attention. Achieving nanophototherapeutics with near infrared (NIR)-light synchronously triggered photodynamic therapy (PDT) and photothermal therapy (PTT) is challenging. Herein, we develop a multifunctional theranostic nanoplatform prepared from the co-assembly of NIR boron dipyrromethene (BODIPY) with a cooperative D-π-A structure of a thiophene-BODIPY core and benzene-diethylamino, and a choline phosphate lipid. The as-fabricated nanoparticles (DBNPs) exhibited desirable NIR absorption, uniform spherical morphology and good colloidal stability. The elaborate molecular design and supramolecular assembly endowed DBNPs with desirable PDT and PTT activities. Upon 808 nm laser irradiation, the DBNPs efficiently generated active singlet oxygen and regional hyperpyrexia, with a photothermal conversion efficiency of 37.6%. The excellent PDT and PTT performance of DBNPs boosted the potent and anti-tumor effects. In addition, these nanoparticles manifested their good capability of NIR fluorescence imaging of tumors. Overall, the DBNPs provide a paradigm for delivering hydrophobic phototherapy molecules with phospholipids for enhanced tumor treatment and imaging.
Topics: Humans; Boron; Phosphorylcholine; Nanoparticles; Neoplasms; Optical Imaging; Lipids
PubMed: 37190791
DOI: 10.1039/d3tb00175j -
Auris, Nasus, Larynx Feb 2022The mucosal immune system prevents microorganism invasion through mucosal surfaces and consists of inductive and effector sites. Nasopharynx-associated lymphoid tissue... (Review)
Review
The mucosal immune system prevents microorganism invasion through mucosal surfaces and consists of inductive and effector sites. Nasopharynx-associated lymphoid tissue (NALT) functions as an inductive site, inducing mucosal immune responses in the upper respiratory tract. It follows that intranasal vaccines may prevent upper respiratory infections. To induce and enhance the immune response by administering inactivated antigens intranasally, mucosal adjuvants have been developed, including mutant cholera toxin and cationic cholesteryl pullulan nanogel, which do not accumulate in the central nervous system. Moreover, multivalent pneumococcal polysaccharide conjugate vaccines are used to prevent invasive pneumococcal infections and otitis media, although they only provide moderate protection against acute otitis media because non-vaccine serotypes of Streptococcus pneumoniae and Haemophilus influenzae also cause this infection. To address this problem, pneumococcal surface protein A of S. pneumoniae and P6 of H. influenzae are used as broad-spectrum vaccine antigens. Alternatively, phosphorylcholine (PC) is present in the cell walls of both gram-positive and gram-negative bacteria and induces immune responses through antigenic activity. The significant effects of PC as a mucosal vaccine have been demonstrated through intranasal and sublingual immunization in mice. Furthermore, intranasal administration of PC reverses increases in IgE levels and prevents allergic rhinitis. After immunization with pneumococcal polysaccharide conjugate vaccine, intranasal immunization with PC boosts immune responses to vaccine strains and to PC itself. Thus, PC may be useful as a mucosal vaccine to prevent upper respiratory infections and allergic rhinitis, and it could be used as a booster to the currently used pneumococcal vaccine as it protects against non-vaccine strains.
Topics: Administration, Intranasal; Animals; Antigens, Bacterial; Haemophilus influenzae; Humans; Immune System; Immunity, Mucosal; Immunoglobulin A, Secretory; Mice; Mucous Membrane; Phosphorylcholine; Pneumococcal Vaccines; Respiratory System; Rhinitis, Allergic; Streptococcus pneumoniae; Vaccines
PubMed: 34304944
DOI: 10.1016/j.anl.2021.07.003 -
PLoS Neglected Tropical Diseases Nov 2023Treatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of paromomycin/miltefosine/liposomal amphotericin B combinations for the treatment of post-kala-azar dermal leishmaniasis in Sudan: A phase II, open label, randomized, parallel arm study.
BACKGROUND
Treatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the limitations of current therapies, namely toxicity and long hospitalization. We assessed the safety and efficacy of miltefosine combined with paromomycin and liposomal amphotericin B (LAmB) for the treatment of PKDL in Sudan.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with persistent (stable or progressive disease for ≥ 6 months) or grade 3 PKDL, aged 6 to ≤ 60 years in Sudan. The median age was 9.0 years (IQR 7.0-10.0y) and 87% of patients were ≤12 years old. Patients were randomly assigned to either daily intra-muscular paromomycin (20mg/kg, 14 days) plus oral miltefosine (allometric dose, 42 days)-PM/MF-or LAmB (total dose of 20mg/kg, administered in four injections in week one) and oral miltefosine (allometric dose, 28 days)-LAmB/MF. The primary endpoint was a definitive cure at 12 months after treatment onset, defined as clinical cure (100% lesion resolution) and no additional PKDL treatment between end of therapy and 12-month follow-up assessment. 104/110 patients completed the trial. Definitive cure at 12 months was achieved in 54/55 (98.2%, 95% CI 90.3-100) and 44/55 (80.0%, 95% CI 70.2-91.9) of patients in the PM/MF and AmB/MF arms, respectively, in the mITT set (all randomized patients receiving at least one dose of treatment; in case of error of treatment allocation, the actual treatment received was used in the analysis). No SAEs or deaths were reported, and most AEs were mild or moderate. At least one adverse drug reaction (ADR) was reported in 13/55 (23.6%) patients in PM/MF arm and 28/55 (50.9%) in LAmB/MF arm, the most frequent being miltefosine-related vomiting and nausea, and LAmB-related hypokalaemia; no ocular or auditory ADRs were reported.
CONCLUSIONS/SIGNIFICANCE
The PM/MF regimen requires shorter hospitalization than the currently recommended 60-90-day treatment, and is safe and highly efficacious, even for patients with moderate and severe PKDL. It can be administered at primary health care facilities, with LAmB/MF as a good alternative. For future VL elimination, we need new, safe oral therapies for all patients with PKDL.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03399955, https://clinicaltrials.gov/study/NCT03399955 ClinicalTrials.gov ClinicalTrials.gov.
Topics: Humans; Child; Paromomycin; Leishmaniasis, Visceral; Antiprotozoal Agents; Leishmaniasis, Cutaneous; Phosphorylcholine; Treatment Outcome
PubMed: 37988402
DOI: 10.1371/journal.pntd.0011780 -
The Journal of Physical Chemistry. B Jul 2022Recently, we had reported a synthetic positively charged leucine-rich 14-residue-long antimicrobial peptide (AMP, LL-14: NH-LKWLKKLLKWLKKL-CONH), which was highly active...
Recently, we had reported a synthetic positively charged leucine-rich 14-residue-long antimicrobial peptide (AMP, LL-14: NH-LKWLKKLLKWLKKL-CONH), which was highly active and cytotoxic relative to its valine analogue (VV-14). However, the thermodynamics underlying this differential toxicity and antimicrobial activity was unclear. Understanding the energetics of peptide binding to micelles (simplest membrane mimic, viz., SDS as a bacterial membrane and DPC as a eukaryotic membrane) and the effect of Leu → Val peptide mutations on the stability of the peptide:micelle complexes are of great academic interest and relevant for the rational design of potent and selective AMPs for therapeutic use. Here, we have reported the molecular dynamics free energy simulations that allowed us to quantitatively estimate the strength of peptide discrimination (based on single- or multiple-site Leu/Val mutations in LL-14) by membrane mimetic micelles (SDS and DPC) and decipher the energetics underlying peptide selectivity by micelles. The Leu-containing peptide (LL-14) was found to be preferred for micelle (SDS and DPC) binding relative to its Val analogues (single or multiple Val mutants). The strength of the preference depended on the position of the Leu/Val mutation in the peptide. Surprisingly, the N-terminal LL-14 single mutation (Leu → Val: L1V) was found to fine-tune the electrostatic interactions, resulting in the highest peptide selectivity (ΔΔ ∼ 8 kcal/mol for both SDS and DPC). However, the mechanism of L1V peptide selectivity was distinctly different for SDS and DPC micelles. SDS ensured high selectivity by disrupting the peptide:micelle salt bridge, whereas DPC desolvated the broken-peptide-backbone hydrogen bond in the V1 peptide:micelle complex. Mutations (Leu → Val) in the middle positions of the LL-14 (4th, 7th, 8th, and 11th) were disfavored by the micelles primarily due to the loss of peptide:micelle hydrophobic interactions. Peptides differing at the C-terminal (i.e., L14V) were recognized by SDS micelles (ΔΔ ∼ 4 kcal/mol) by altering peptide:micelle interactions. L14V mutation, on the other hand, did not play any role in the peptide:DPC binding, as no direct interactions between the C-terminal and DPC micelle were observed due to obvious electrostatic reasons. The strength of selectivity favoring LL-14 binding against VV-14 was found to be much higher for DPC micelles (ΔΔ ∼ 25 kcal/mol) relative to SDS micelles (ΔΔ ∼ 19 kcal/mol). The loss of the peptide:micelle hydrophobic contact in response to LL-14 → VV-14 mutation was found to be significantly larger for DPC relative to SDS micelles, resulting in higher discriminatory power for the former. Peptide:SDS salt bridges seemed to prevent the loss of peptide:micelle hydrophobic contact to some extent, leading to weaker selectivity for SDS micelles. High selectivity of DPC micelles provided an efficient mechanism for VV-14 dissociation from DPC micelles, whereas low-selectivity of SDS micelles ensured binding of both LL-14 and VV-14. To the best of our knowledge, this is the first study in which the experimental observations (antimicrobial activity and toxicity) between leucine-rich and valine-rich peptides have been explained by establishing a direct link between the energetics and structures.
Topics: Anti-Infective Agents; Antimicrobial Cationic Peptides; Antimicrobial Peptides; Leucine; Micelles; Mutation; Nuclear Magnetic Resonance, Biomolecular; Phosphorylcholine; Sodium Dodecyl Sulfate; Valine
PubMed: 35815580
DOI: 10.1021/acs.jpcb.2c01293 -
Biomacromolecules Jul 2022Zwitterionic methacrylate polymers with either choline phosphate (CP) (poly(MCP)) or phosphorylcholine (PC) (poly(MPC)) side groups were analyzed to characterize the...
Zwitterionic methacrylate polymers with either choline phosphate (CP) (poly(MCP)) or phosphorylcholine (PC) (poly(MPC)) side groups were analyzed to characterize the bound hydration water molecules as nonfreezing water (NFW), intermediate water (IW), or free water (FW). This characterization was carried out by differential scanning calorimetry (DSC) of polymer/water systems, and the enthalpy changes of cold crystallization and melting were determined. The electron pair orientation of CP is opposite to that of PC, and the former binds the alkyl terminal groups at the phosphate esters. The numbers of NFW and IW molecules per monomer unit of poly(MCP) with an isopropyl terminal group were estimated to be 10.7 and 11.3 mol/mol, respectively, which were slightly greater than those of the poly(MCP) bearing an ethyl terminal group. More NFW and IW molecules hydrated the phosphobetaine polyzwitterions, poly(MCP) and poly(MPC), compared with carboxybetaine and sulfobetaine polymers. Moreover, the hydration states of polyelectrolytes were compared with the zwitterionic polymers. Finally, we discuss the relationship between the amount of hydration water and bio-inert properties.
Topics: Calorimetry, Differential Scanning; Methacrylates; Phosphorylcholine; Polymers; Water
PubMed: 35736642
DOI: 10.1021/acs.biomac.2c00484 -
Journal of Immunology (Baltimore, Md. :... Oct 2020Abs against phosphorylcholine (anti-PC) and Abs against malondialdehyde (anti-MDA) may be protective in chronic inflammation, like atherosclerosis and cardiovascular... (Clinical Trial)
Clinical Trial
Abs against phosphorylcholine (anti-PC) and Abs against malondialdehyde (anti-MDA) may be protective in chronic inflammation, like atherosclerosis and cardiovascular disease. It is not known how they develop early in life. Ab titers were measured using ELISA in healthy women ( = 105; born into life study) and their children. Plasma samples were collected from the mothers before conception and from the children at birth as well as at 1 and 2 y after birth. Extracted Abs were compared using a proteomics de novo sequencing approach. It was observed that children were born with very low levels of IgM anti-PC, whereas IgM anti-MDA was present at birth. Both IgM anti-PC and anti-MDA increased during the first 2 y of life, but IgM anti-PC in contrast to IgM anti-MDA was still significantly lower than in the mothers. IgG anti-PC decreased after 1 y but reached similar levels as mothers' after 2 y, whereas IgG anti-MDA reached similar levels as mothers' already after 1 y. Proteomics peptide sequencing analysis indicated large peptide sequence variation without specific clone expression during the early stage of life compared with the adult stage for which specific peptide sequences dominated. IgM anti-PC levels develop much slower than anti-MDA and are still relatively low at 2 y. We hypothesize that anti-PC is developed by a combination of preprogramming and exposure to the external world, in which infectious agents may play a role. For anti-MDA, preprogramming is likely to play a major role and at an earlier stage than for anti-PC.
Topics: Adolescent; Adult; Antibodies, Antiphospholipid; Child, Preschool; Female; Humans; Immunoglobulin G; Immunoglobulin M; Infant; Infant, Newborn; Male; Malondialdehyde; Middle Aged; Phosphorylcholine; Prospective Studies
PubMed: 32887753
DOI: 10.4049/jimmunol.2000437 -
Scientific Reports Jul 2020IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here...
IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here compare these antibodies in systemic rheumatic conditions and study their properties. Anti-PC and anti-MDA was measured using ELISA in patients with SLE (374), RA (354), Mixed connective tissue disease (MCTD, 77), Systemic sclerosis (SSc, 331), Sjögren's syndrome (SjS, 324), primary antiphospholipid syndrome (PAPs, 65), undifferentiated connective tissue disease (UCTD, 118) and 515 matched healthy controls (HC). Cardiovascular score (CV) was broadly defined based on clinical disease symptoms. Anti-PC and anti-MDA peptide/protein characterization were compared using a proteomics de novo sequencing approach. anti-MDA and anti-PC were extracted from total IgM. The proportion of Treg cells was determined by flow cytometry. The maximal difference between cases and controls was shown for MCTD: significantly lower IgM Anti-PC but not anti-MDA among patients (median 49.3RU/ml vs 70.4 in healthy controls, p(t-test) = 0.0037). IgM low levels were more prevalent in MCTD, SLE, SjS, SSc and UCTD. IgM anti-PC variable region profiles were different from and more homologous than anti-MDA. Anti-PC but not anti-MDA were significantly negatively correlated with CV in the whole patient group. In contrast to IgM anti-PC, anti-MDA did not promote polarization of Tregs. Taken together, Anti-PC is decreased in MCTD and also in SLE, SjS and SSc but not in other studied diseases. Anti-PC may thus differentiate between these. In contrast, anti-MDA did not show these differences between diseases studied. Anti-PC level is negatively correlated with CV in the patient group cohort. In contrast to anti-PC, anti-MDA did not promote Treg polarization. These findings could have both diagnostic and therapeutic implications, one possibility being active or passive immunization with PC in some rheumatic conditions.
Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Case-Control Studies; Female; Humans; Immunoglobulin M; Male; Malondialdehyde; Middle Aged; Phosphorylcholine; Proteomics; Rheumatic Diseases; Young Adult
PubMed: 32620913
DOI: 10.1038/s41598-020-66981-z