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1.
Bioorg Med Chem Lett ; 98: 129596, 2024 Jan 15.
Article En | MEDLINE | ID: mdl-38142914

To identify new compounds that can effectively inhibit Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), we screened, synthesized, and evaluated a series of novel aryl fluorosulfate derivatives for their in vitro inhibitory activity against Mtb. Compound 21b exhibited an in vitro minimum inhibitory concentration (MIC) of 0.06 µM against Mtb, no cytotoxicity against both HEK293T and HepG2 mammalian cell lines, and had good in vivo mouse plasma exposure and lung concentration with a 20 mg/kg oral dose, which supports advanced development as a new chemical entity for TB treatment.


Mycobacterium tuberculosis , Tuberculosis , Animals , Humans , Mice , Antitubercular Agents , HEK293 Cells , Mammals , Microbial Sensitivity Tests , Structure-Activity Relationship , Tuberculosis/drug therapy , Sulfuric Acid Esters/chemistry , Sulfuric Acid Esters/pharmacology
2.
Nucleic Acids Res ; 51(16): 8744-8757, 2023 09 08.
Article En | MEDLINE | ID: mdl-37334863

Chemical probing experiments have transformed RNA structure analysis, enabling high-throughput measurement of base-pairing in living cells. Dimethyl sulfate (DMS) is one of the most widely used structure probing reagents and has played a pivotal role in enabling next-generation single-molecule probing analyses. However, DMS has traditionally only been able to probe adenine and cytosine nucleobases. We previously showed that, using appropriate conditions, DMS can also be used to interrogate base-pairing of uracil and guanines in vitro at reduced accuracy. However, DMS remained unable to informatively probe guanines in cells. Here, we develop an improved DMS mutational profiling (MaP) strategy that leverages the unique mutational signature of N1-methylguanine DMS modifications to enable high-fidelity structure probing at all four nucleotides, including in cells. Using information theory, we show that four-base DMS reactivities convey greater structural information than current two-base DMS and SHAPE probing strategies. Four-base DMS experiments further enable improved direct base-pair detection by single-molecule PAIR analysis, and ultimately support RNA structure modeling at superior accuracy. Four-base DMS probing experiments are straightforward to perform and will broadly facilitate improved RNA structural analysis in living cells.


Guanine , Mutagens , RNA , Sulfuric Acid Esters , Base Pairing , Mutation , Nucleic Acid Conformation , RNA/genetics , RNA/chemistry , Mutagens/pharmacology , Sulfuric Acid Esters/pharmacology
3.
Int J Mol Sci ; 23(22)2022 Nov 15.
Article En | MEDLINE | ID: mdl-36430545

Zosteric acid (ZA) is a secondary metabolite of the seagrass Zostera marina, with antibiofilm activity against fungi. Information concerning its mechanisms of action is lacking and this limits the development of more potent derivatives based on the same target and activity structure. The aim of this work was to investigate the ZA mode of action by analyzing the metabolic status of Candida albicans biofilm and its protein expression profile upon ZA treatment. Fourier-Transform Infrared Spectroscopy confirmed that ZA modified the metabolomic response of treated cells, showing changes in the spectral regions, mainly related to the protein compartment. Nano Liquid Chromatography-High-Resolution Mass Spectrometry highlighted that 10 proteins were differentially expressed in the C. albicans proteome upon ZA treatment. Proteins involved in the biogenesis, structure and integrity of cell walls as well as adhesion and stable attachment of hyphae were found downregulated, whereas some proteins involved in the stress response were found overexpressed. Additionally, ZA was involved in the modulation of non-DNA-based epigenetic regulatory mechanisms triggered by reactive oxygen species. These results partially clarified the ZA mechanism of action against fungi and provided insight into the major C. albicans pathways responsible for biofilm formation.


Candida albicans , Proteomics , Biofilms , Sulfuric Acid Esters/pharmacology
4.
Carbohydr Polym ; 269: 118275, 2021 Oct 01.
Article En | MEDLINE | ID: mdl-34294307

Endogenous and exogenous sulfated polysaccharides exhibit potent biological activities, including inhibiting blood coagulation and protein interactions. Controlled chemical sulfation of alternative polysaccharides holds promise to overcome limited availability and heterogeneity of naturally sulfated polysaccharides. Here, we established reaction parameters for the controlled sulfation of the abundant cereal polysaccharide, mixed-linkage ß(1,3)/ß(1,4)-glucan (MLG), using Box-Behnken Design of Experiments (BBD) and Response Surface Methodology (RSM). The optimization of the degree-of-substitution (DS) was externally validated through the production of sulfated MLGs (S-MLGs) with observed DS and Mw values deviating less than 20% and 30% from the targeted values, respectively. Simultaneous optimization of DS and Mw resulted in the same range of deviation from the targeted value. S-MLGs with DS > 1 demonstrated a modest anticoagulation effect versus heparin, and a greater P-selectin affinity than fucoidan. As such, this work provides a route to medically important polymers from an economical agricultural polysaccharide.


Anticoagulants/pharmacology , Sulfuric Acid Esters/pharmacology , beta-Glucans/pharmacology , Anticoagulants/chemical synthesis , Anticoagulants/metabolism , Carbohydrate Sequence , Chemistry Techniques, Synthetic/statistics & numerical data , Humans , P-Selectin/metabolism , Partial Thromboplastin Time , Sulfuric Acid Esters/chemical synthesis , Sulfuric Acid Esters/metabolism , beta-Glucans/chemical synthesis , beta-Glucans/metabolism
5.
Biochimie ; 189: 137-143, 2021 Oct.
Article En | MEDLINE | ID: mdl-34217821

Patients with chronic kidney disease (CKD) often exhibit increased level of oxidative stress that contribute to the deterioration of renal function and uremic complications. White adipose tissue (WAT) has been recognized as a major site of production of radical oxygen species (ROS) in the context of metabolic diseases. This study was designed to decipher whether the protein bound uremic toxin p-cresyl-sulfate (p-CS) could contribute to ROS production in WAT and promote oxidative stress. Mouse 3T3-L1 adipocytes were incubated for 2 h in culture medium containing 212 µM p-CS, a concentration chosen to mimic levels encountered in end stage renal disease patients or KCl as a control and intracellular ROS production was measured using the fluorescent probe 5-6-carboxy-2',7'-dichlorodihydrofluorescein diacetate. Oxidative insult was estimated by the measurement of malondialdehyde (MDA) content and glutathione content. The effects of probenecid (1 mM) a potent inhibitor of organic anion transporter, apocynin (1 mM) an inhibitor of NADPH oxidase or common antioxidants such as α-tocopherol (2.5 µM), ascorbate (200 µM), and N-acetylcysteine (500 µM) were further evaluated. p-CS triggered a striking increase in ROS production (+228%, p < 0.01), in MDA content (+214%, p < 0.005) and a decrease in glutathione (-47%, P < 0.01). Pre-treatment of cells with probenecid, apocynin or antioxidants prevented the p-CS induced ROS production and oxidative insults. These results suggest that in uremic state, the intracellular accumulation of p-CS in adipose cells could contribute, through an activation of NADPH oxidase, to the redox imbalance often reported in CKD patients.


Adipocytes/metabolism , Cresols/pharmacology , Lipid Peroxidation/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Renal Insufficiency, Chronic/metabolism , Sulfuric Acid Esters/pharmacology , 3T3-L1 Cells , Animals , Mice
6.
Chem Commun (Camb) ; 57(37): 4528-4531, 2021 May 06.
Article En | MEDLINE | ID: mdl-33956029

We describe a low molecular weight covalent inhibitor targeting a conserved lysine residue within the hydrophobic pocket of HIV-1 glycoprotein-41. The inhibitor bound selectively to the hydrophobic pocket and exhibited an order of magnitude enhancement of anti-fusion activity against HIV-1 compared to its non-covalent counterpart. The findings represent a significant advance in the quest to obtain non-peptide fusion inhibitors.


Anti-HIV Agents/pharmacology , HIV Envelope Protein gp41/antagonists & inhibitors , HIV Fusion Inhibitors/pharmacology , HIV/drug effects , Small Molecule Libraries/pharmacology , Sulfuric Acid Esters/pharmacology , Anti-HIV Agents/chemistry , HIV/metabolism , HIV Envelope Protein gp41/metabolism , HIV Fusion Inhibitors/chemistry , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Molecular Structure , Molecular Weight , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Sulfuric Acid Esters/chemistry
7.
Biol Pharm Bull ; 44(3): 437-441, 2021.
Article En | MEDLINE | ID: mdl-33642552

We recently reported that aripiprazole (ARP), an antipsychotic drug, binds strongly to human serum albumin (HSA), the major drug binding protein in serum. It is known that uremic toxins that accumulate during renal disease affect the interaction between HSA and drug binding. In this study, the issue of how uremic toxins (indoxyl sulfate, indole acetic acid and p-cresyl sulfate) affect the binding of ARP to HSA was investigated. Equilibrium dialysis experiments revealed that all uremic toxins inhibited the binding of ARP to HSA although the inhibitory effects differed, depending on the specific uremic toxin. The potency of inhibition can be partially explained by the affinities of uremic toxins to HSA. Fluorescence displacement experiments suggested that ARP as well as all uremic toxins bind to site II of HSA. The inhibitory effects of the toxins on the binding of ARP for the drugs binding to the diazepam subsite are significantly larger, comparing with those for binding to arylpropionic acids subsite. Interestingly, induced circular dichroism (CD) spectra indicated that the spatial orientation of p-cresyl sulfate in the binding pocket is different from that for indoxyl sulfate and indole acetic acid. The limited findings obtained herein are important data in considering the effects of uremic toxins on the pharmacokinetics of ARP and the drugs that bind to site II on HSA, particularly drugs binding to diazepam binding site in site II.


Antipsychotic Agents/pharmacology , Aripiprazole/pharmacology , Cresols/pharmacology , Indican/pharmacology , Indoleacetic Acids/pharmacology , Serum Albumin, Human/metabolism , Sulfuric Acid Esters/pharmacology , Binding Sites , Humans , Oleic Acid/pharmacology , Protein Binding , Uremia
8.
Nat Methods ; 18(3): 249-252, 2021 03.
Article En | MEDLINE | ID: mdl-33619392

RNA structure heterogeneity is a major challenge when querying RNA structures with chemical probing. We introduce DRACO, an algorithm for the deconvolution of coexisting RNA conformations from mutational profiling experiments. Analysis of the SARS-CoV-2 genome using dimethyl sulfate mutational profiling with sequencing (DMS-MaPseq) and DRACO, identifies multiple regions that fold into two mutually exclusive conformations, including a conserved structural switch in the 3' untranslated region. This work may open the way to dissecting the heterogeneity of the RNA structurome.


Algorithms , Genome, Viral/genetics , Nucleic Acid Conformation , RNA, Viral/chemistry , SARS-CoV-2/genetics , 3' Untranslated Regions/genetics , COVID-19 , Humans , Mutation/drug effects , Mutation/genetics , RNA, Viral/genetics , Sulfuric Acid Esters/pharmacology
9.
Mar Drugs ; 19(2)2021 Jan 22.
Article En | MEDLINE | ID: mdl-33499103

Extracellular ATP mediates proinflammatory and antiproliferative effects via activation of P2 nucleotide receptors. In contrast, its metabolite, the nucleoside adenosine, is strongly immunosuppressive and enhances tumor proliferation and metastasis. The conversion of ATP to adenosine is catalyzed by ectonucleotidases, which are expressed on immune cells and typically upregulated on tumor cells. In the present study, we identified sulfopolysaccharides from brown and red sea algae to act as potent dual inhibitors of the main ATP-hydrolyzing ectoenzymes, ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) and ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39), showing nano- to picomolar potency and displaying a non-competitive mechanism of inhibition. We showed that one of the sulfopolysaccharides tested as a representative example reduced adenosine formation at the surface of the human glioblastoma cell line U87 in a concentration-dependent manner. These natural products represent the most potent inhibitors of extracellular ATP hydrolysis known to date and have potential as novel therapeutics for the immunotherapy of cancer.


Adenosine Triphosphate/antagonists & inhibitors , Apyrase/antagonists & inhibitors , Polysaccharides/physiology , Pyrophosphatases/antagonists & inhibitors , Seaweed , Sulfuric Acid Esters/pharmacology , Adenosine Triphosphate/metabolism , Apyrase/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Hydrolysis/drug effects , Phosphoric Diester Hydrolases/metabolism , Polysaccharides/chemistry , Polysaccharides/isolation & purification , Pyrophosphatases/metabolism , Seaweed/chemistry , Seaweed/isolation & purification , Sulfuric Acid Esters/chemistry , Sulfuric Acid Esters/isolation & purification
10.
Int J Mol Sci ; 21(18)2020 Sep 12.
Article En | MEDLINE | ID: mdl-32932690

Protein-bound uremic toxins, such as p-cresol sulfate (PCS), can be accumulated with declined renal function and aging and is closely linked with central nervous system (CNS) diseases. In the periphery, PCS has effects on oxidative stress and inflammation. Since oxidative stress and inflammation have substantial roles in the pathogenesis of neurological disorders, the CNS effects of PCS were investigated in unilateral nephrectomized C57/BL/6 mice. Unlike intact mice, unilateral nephrectomized mice showed increased circulating levels of PCS after exogenous administration. Upon PCS exposure, the unilateral nephrectomized mice developed depression-like, anxiety-like, and cognitive impairment behaviors with brain PCS accumulation in comparison with the nephrectomy-only group. In the prefrontal cortical tissues, neuronal cell survival and neurogenesis were impaired along with increased apoptosis, oxidative stress, and neuroinflammation. Circulating brain-derived neurotrophic factors (BDNF) and serotonin were decreased in association with increased corticosterone and repressor element-1 silencing transcription factor (REST), regulators involved in neurological disorders. On the contrary, these PCS-induced changes were alleviated by uremic toxin absorbent AST-120. Taken together, PCS administration in mice with nephrectomy contributed to neurological disorders with increased oxidative stress and neuroinflammation, which were alleviated by PCS chelation. It is suggested that PCS may be a therapeutic target for chronic kidney disease-associated CNS diseases.


Cresols/pharmacology , Inflammation/chemically induced , Mental Disorders/chemically induced , Neurodegenerative Diseases/chemically induced , Neurons/drug effects , Oxidative Stress/drug effects , Sulfuric Acid Esters/pharmacology , Animals , Brain-Derived Neurotrophic Factor/metabolism , Carbon/pharmacology , Cell Survival/drug effects , Corticosterone/metabolism , Inflammation/metabolism , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Mental Disorders/metabolism , Mental Disorders/pathology , Mice , Mice, Inbred C57BL , Nephrectomy/methods , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Neurons/metabolism , Neurons/pathology , Oxides/pharmacology , Repressor Proteins/metabolism , Serotonin/metabolism , Toxins, Biological/pharmacology , Uremia/chemically induced , Uremia/metabolism , Uremia/pathology
11.
J Cell Mol Med ; 24(15): 8379-8390, 2020 08.
Article En | MEDLINE | ID: mdl-32639656

Increased circulating level of uraemic solute p-cresyl sulphate (PCS) in patients with chronic kidney disease (CKD) is known to increase myocardial burden relevant to mitochondrial abnormalities. This study aimed at investigating mitochondrial response to PCS in H9C2 cardiomyoblasts. H9C2 cardiomyoblasts were treated with four different concentrations of PCS (3.125, 6.25, 12.5 and 25.0 µg/mL) to study the changes in cell proliferation, cell size and mitochondrial parameters including morphology, respiration, biogenesis and membrane potential. The lowest effective dose of PCS (6.25 µg/mL) induced mitochondrial hyperfusion with enhanced mitochondrial connectivity, mitochondrial oxygen consumption rates, mitochondrial mass, mitochondrial DNA copy number and increased volume of cardiomyoblasts. After PCS treatment, phosphorylation of energy-sensing adenosine monophosphate-activated protein kinase (AMPK) was increased without induction of apoptosis. In contrast, mitochondrial mass was recovered after AMPK silencing. Additionally, mitochondrial hyperfusion and cell volume were reversed after cessation of PCS treatment. The results of the present study showed that low-level PCS not only caused AMPK-dependent mitochondrial hyperfusion but also induced cell enlargement in H9C2 cardiomyoblasts in vitro.


Cresols/pharmacology , Mitochondria/drug effects , Myocytes, Cardiac/drug effects , Sulfuric Acid Esters/pharmacology , AMP-Activated Protein Kinases/metabolism , Animals , Apoptosis/drug effects , Cell Line , Cell Proliferation/drug effects , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Myocytes, Cardiac/metabolism , Oxygen Consumption/drug effects , Rats
12.
Int J Mol Sci ; 21(5)2020 Feb 29.
Article En | MEDLINE | ID: mdl-32121406

Human cytomegalovirus (HCMV) infections are wide-spread among the general population with manifestations ranging from asymptomatic to severe developmental disabilities in newborns and life-threatening illnesses in individuals with a compromised immune system. Nearly all current drugs suffer from one or more limitations, which emphasizes the critical need to develop new approaches and new molecules. We reasoned that a 'poly-pharmacy' approach relying on simultaneous binding to multiple receptors involved in HCMV entry into host cells could pave the way to a more effective therapeutic outcome. This work presents the study of a synthetic, small molecule displaying pleiotropicity of interactions as a competitive antagonist of viral or cell surface receptors including heparan sulfate proteoglycans and heparan sulfate-binding proteins, which play important roles in HCMV entry and spread. Sulfated pentagalloylglucoside (SPGG), a functional mimetic of heparan sulfate, inhibits HCMV entry into human foreskin fibroblasts and neuroepithelioma cells with high potency. At the same time, SPGG exhibits no toxicity at levels as high as 50-fold more than its inhibition potency. Interestingly, cell-ELISA assays showed downregulation in HCMV immediate-early gene 1 and 2 (IE 1&2) expression in presence of SPGG further supporting inhibition of viral entry. Finally, HCMV foci were observed to decrease significantly in the presence of SPGG suggesting impact on viral spread too. Overall, this work offers the first evidence that pleiotropicity, such as demonstrated by SPGG, may offer a new poly-therapeutic approach toward effective inhibition of HCMV.


Cytomegalovirus Infections/drug therapy , Cytomegalovirus/drug effects , Glucosides/pharmacology , Heparan Sulfate Proteoglycans/genetics , Sulfuric Acid Esters/pharmacology , Cells, Cultured , Cytomegalovirus/genetics , Cytomegalovirus/pathogenicity , Cytomegalovirus Infections/genetics , Cytomegalovirus Infections/virology , Fibroblasts/drug effects , Host-Pathogen Interactions/drug effects , Humans , Infant, Newborn , Virus Internalization/drug effects , Virus Replication/drug effects
13.
Int J Mol Sci ; 21(4)2020 Feb 13.
Article En | MEDLINE | ID: mdl-32070049

Indoxyl sulphate (IS) and p-cresyl sulphate (PCS) are two protein bound uraemic toxins accumulated in chronic kidney disease (CKD) and associated with adverse outcomes. The purpose of this study isto evaluate the effect of the new activated charcoal, CharXgen, on renal function protection and lowering serum uraemic toxins in CKD animal model. The physical character of CharXgen was analyzed before and after activation procedure by Scanning Electron Microscope (SEM) and X-ray diffractometer (XRD). The effect of CharXgen on biochemistry and lowering uremic toxins was evaluated by in vitro binding assay and CKD animal model. CharXgen have high interior surface area analyzed by SEM and XRD and have been produced from local bamboo after an activation process. CharXgen was able to effectively absorb IS, p-cresol and phosphate in an in vitro gastrointestinal tract simulation study. The animal study showed that CharXgen did not cause intestine blackening. Serum albuminand liver function did not change after feeding with CharXgen. Moreover, renal function was improved in CKD rats fed with CharXgen as compared to the CKD group, and there were no significant differences in the CKD and the CKD + AST-120 groups. Serum IS and PCS were higher in the CKD group and lower in rats treated with CharXgen and AST-120. In rats treated with CharXgen, Fibroblast growth factor 23 was significantly decreased as compared to the CKD group. This change cannot be found in rats fed with AST-120.It indicates that CharXgen is a new safe and non-toxic activated charcoal having potential in attenuating renal function deterioration and lowering protein-bound uraemic toxins. Whether the introduction of this new charcoal could further have renal protection in CKD patients will need to be investigated further.


Charcoal/pharmacology , Renal Insufficiency, Chronic/drug therapy , Sasa/chemistry , Toxins, Biological/blood , Uremia/drug therapy , Alginates/chemistry , Alginates/pharmacology , Animals , Carbon/pharmacology , Cell Line , Cresols/pharmacology , Disease Models, Animal , Humans , Indican/pharmacology , Microscopy, Electron, Scanning , Microspheres , Oxides/pharmacology , Rats , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/pathology , Sulfuric Acid Esters/pharmacology , Uremia/blood , Uremia/complications , Uremia/pathology
14.
Biochem Biophys Res Commun ; 523(1): 123-129, 2020 02 26.
Article En | MEDLINE | ID: mdl-31837804

Chronic kidney disease (CKD) is associated with high mortality rates, mainly due to cardiovascular diseases (CVD). Uremia has been considered a relevant risk factor for CVD in CKD patients, since uremic toxins (UTs) promote systemic and vascular inflammation, oxidative stress and senescence. Here, we demonstrate that uremic toxins indoxyl sulfate (IxS), p-cresyl sulfate (pCS) and indole acetic acid (IAA) are incorporated by human endothelial cells and inhibit the autophagic flux, demonstrated by cellular p62 accumulation. Moreover, isolated and mixed UTs impair the lysosomal stage of autophagy, as determined by cell imaging of the mRFP-GFP-LC3 protein. Endothelial cells exposed to UTs display accumulation of carbonylated proteins and increased sensitivity to hydrogen peroxide. Rapamycin, an autophagy activator which induces both autophagosome formation and clearance, prevented these effects. Collectively, our findings demonstrate that accumulation of oxidized proteins and enhanced cell sensitivity to hydrogen peroxide are consequences of impaired autophagic flux. These data provide evidence that UTs-induced impaired autophagy may be a novel contributor to endothelial dysfunction.


Cresols/pharmacology , Hydrogen Peroxide/pharmacology , Indican/pharmacology , Indoleacetic Acids/pharmacology , RNA-Binding Proteins/metabolism , Sulfuric Acid Esters/pharmacology , Toxins, Biological/pharmacology , Animals , Apoptosis/drug effects , Cell Survival/drug effects , Cells, Cultured , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Lysosomes/drug effects , Lysosomes/metabolism , Mice , NIH 3T3 Cells , Oxidative Stress/drug effects
15.
Molecules ; 24(16)2019 Aug 18.
Article En | MEDLINE | ID: mdl-31426594

Background: Increasing attention has been given to the search for neuroprotective ingredients from natural plants. Myrica rubra bark (MRB) has been used in traditional oriental medicine for over thousand years and has potential neuroprotection. Methods and Results: Ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was used to identify the compounds in MRB extract, and the MTT assay was performed to evaluate the neuroprotection of six major compounds from MRB against glutamate-induced damage in PC12 cells. The result displayed nineteen compounds were identified, and myricitrin and myricanol 11-sulfate were shown to have neuroprotection, which prevented cell apoptosis through alleviating oxidative stress by reducing the levels of reactive oxygen species and methane dicarboxylic aldehyde, as well as by enhancing the activities of superoxide dismutase. Conclusions: Several active compounds from MRB may offer neuroprotection and have the potential for the development of new drugs against central nervous system diseases.


Diarylheptanoids/chemistry , Flavonoids/chemistry , Myrica/chemistry , Neuroprotective Agents/chemistry , Plant Bark/chemistry , Sulfuric Acid Esters/chemistry , Animals , Apoptosis/drug effects , Diarylheptanoids/isolation & purification , Diarylheptanoids/pharmacology , Enzyme Activation/drug effects , Flavonoids/isolation & purification , Flavonoids/pharmacology , Humans , Medicine, Chinese Traditional , Neuroprotective Agents/isolation & purification , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , PC12 Cells , Plant Extracts/chemistry , Plants, Medicinal , Rats , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Sulfuric Acid Esters/isolation & purification , Sulfuric Acid Esters/pharmacology , Superoxide Dismutase/metabolism
16.
Carbohydr Polym ; 222: 115010, 2019 Oct 15.
Article En | MEDLINE | ID: mdl-31320102

Two sulfated polysaccharides (SPs), F2 and F3, isolated from Codium isthmocladum were found to contain galactose, sulfate, and pyruvate. The apparent molecular weights of F2 and F3 were determined to be 62 and 61 kDa, respectively. NMR spectroscopy combined with chemical analysis showed that F2 and F3 have the same structural features. However, F3 showed higher sulfate/sugar ratio (1/2.6) than F2 (1/4). F2 and F3 are essentially (1 → 3)-ß-D-galactans with some branching at C6. Pyruvylation occurs at O3 and O4, forming 3,4-O-(1-carboxyethylidene)-ß-D-Galp residues; some of these pyruvylated residues contain sulfate groups at C6. Some non-branching residues contain sulfate at C4. None of the SPs exhibited antioxidant activity. MTT results indicated that 1 mg/mL of both SPs about 40% of PANC-1 cell viability. At 10 µg/mL, F2 and F3 had 1.7-fold longer clotting times compared to that of Clexane® at the same concentration. The higher sulfate content of F3 is not a determining factor for pharmacological activities of galactans, considering that both F2 and F3 exerted the effects.


Anticoagulants/pharmacology , Antioxidants/pharmacology , Chlorophyta/chemistry , Galactans/pharmacology , Seaweed/chemistry , Anticoagulants/chemistry , Anticoagulants/isolation & purification , Antioxidants/chemistry , Antioxidants/isolation & purification , Carbohydrate Sequence , Cell Line, Tumor , Cell Proliferation/drug effects , Galactans/chemistry , Galactans/isolation & purification , Humans , Pyruvates/chemistry , Pyruvates/isolation & purification , Pyruvates/pharmacology , Sulfuric Acid Esters/chemistry , Sulfuric Acid Esters/isolation & purification , Sulfuric Acid Esters/pharmacology
17.
Carbohydr Polym ; 221: 120-126, 2019 Oct 01.
Article En | MEDLINE | ID: mdl-31227150

Sulfated fucose-containing glycopolymers are currently of great interest because of their wide spectrum of bioactivity, including anti-tumor properties. In this study, the structure of O-polysaccharide (OPS) of the marine bacterium Vadicella arenosi KMM 9024T, its effect on the proliferation of human breast cancer MCF-7 cells and cancer preventive properties were investigated. Two OPS fractions with different molecular weights were isolated and purified from the lipopolysaccharide by mild acid hydrolysis followed by anion-exchange chromatography. The OPS was found to consist of α-(1→3)-linked 2-O-sulfate-d-fucopyranosyl residues, whose structure was deduced by sugar analysis along with 2D NMR spectroscopy. The biological assay indicated that polysaccharide significantly reduced the proliferation and inhibited colony formation of MCF-7 cells in a dose-dependent manner. Besides, the experiment indicated the inhibitory role of polysaccharide on EGF-induced neoplastic cell transformation in mouse epidermal cells. The investigated polysaccharide is the first sulfated fucan isolated from the bacteria.


Antineoplastic Agents/pharmacology , Galactans/pharmacology , Rhodobacteraceae/chemistry , Sulfuric Acid Esters/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Carbohydrate Sequence , Cell Proliferation/drug effects , Galactans/chemistry , Galactans/isolation & purification , Humans , MCF-7 Cells , Mice , Sulfuric Acid Esters/chemistry , Sulfuric Acid Esters/isolation & purification
18.
Carbohydr Polym ; 216: 204-212, 2019 Jul 15.
Article En | MEDLINE | ID: mdl-31047058

Sulfated polysaccharides (SPSs) are polysaccharides (PSs) with high sulfate functionalization and possess bioactivities. This study aimed to increase the sulfate content of SPSs in Antrodia cinnamomea through sulfate feeding. Feeding A. cinnamomea with sodium thiosulfate was found to increase yields of PSs and SPSs in A. cinnamomea. The SPSs thus obtained (ST-SPS) were further isolated, showing enhanced sulfate content of 2.5 mmol/g. Sodium thiosulfate induced changes in molecular weight from 320 kDa to 1342 kDa, and area percentage of low-molecular-weight ST-SPS (< 20 kDa) was decreased. Functional studies revealed that sodium thiosulfate increased the ST-SPS anticancer efficacy in cancer cells via inhibition of EGFR/AKT signaling. Moreover, the ST-SPS enhanced synergistically cisplatin-, gefitinib- and 5 FU-induced cytotoxic effects in lung cancer H1975 cells and colon cancer CT26 cells. This study is the first to demonstrate that sodium thiosulfate induced changes in properties of A. cinnamomea with the anticancer mechanisms of ST-SPS.


Antineoplastic Agents/pharmacology , Antrodia/chemistry , Antrodia/metabolism , Polysaccharides/pharmacology , Sulfuric Acid Esters/pharmacology , Thiosulfates/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Cell Line, Tumor , Cisplatin/pharmacology , Drug Synergism , ErbB Receptors/metabolism , Fluorouracil/pharmacology , Gefitinib/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Molecular Weight , Phosphorylation/drug effects , Polysaccharides/biosynthesis , Polysaccharides/chemistry , Polysaccharides/isolation & purification , Signal Transduction/drug effects , Sulfuric Acid Esters/chemistry , Sulfuric Acid Esters/isolation & purification , Sulfuric Acid Esters/metabolism
19.
Food Chem Toxicol ; 125: 520-527, 2019 Mar.
Article En | MEDLINE | ID: mdl-30735752

At intestinal level, after acute or chronic exposure to iNOS-derived NO, a toxic mechanism of action leads to inflammation and degenerative diseases. The aim of this study was to investigate the effect of glucuronide and sulfate metabolites of the extra virgin olive oil phenols tyrosol (Tyr) and hydroxytyrosol (HT), in comparison with their parent compounds, on the release of NO following exposure to a pro-inflammatory stimulus, the bacterial lipopolysaccharide (LPS). Human colon adenocarcinoma cells (Caco-2), differentiated as normal enterocytes, were treated with pathological concentrations of LPS, in order to stimulate iNOS pathway, which involves NF-ĸB activation through IĸBα phosphorylation and subsequent degradation induced by Akt or MAPKs. All the tested metabolites inhibited NO release induced by LPS, acting as inhibitors of iNOS expression, with an efficacy comparable to that of the parent compounds. HT and Tyr metabolites were effective in the inhibition of IĸBα degradation. No one of the compounds was able to inhibit Akt activation, whereas they modulated p38 and ERK1/2 MAPK. Obtained data show that HT and Tyr metabolites are able to prevent a pathological NO overproduction at intestinal level, where they concentrate, thus significantly contributing to the protective activity exerted by their parent compounds against inflammation.


Anti-Inflammatory Agents/pharmacology , Glucuronides/pharmacology , Nitric Oxide/antagonists & inhibitors , Phenylethyl Alcohol/analogs & derivatives , Sulfuric Acid Esters/pharmacology , Anti-Inflammatory Agents/toxicity , Caco-2 Cells , Escherichia coli/chemistry , Glucuronides/toxicity , Humans , Lipopolysaccharides/adverse effects , NF-KappaB Inhibitor alpha/metabolism , Nitric Oxide Synthase Type II/metabolism , Olea/chemistry , Olive Oil , Phenylethyl Alcohol/pharmacology , Phenylethyl Alcohol/toxicity , Signal Transduction/drug effects , Sulfuric Acid Esters/toxicity
20.
Nat Prod Res ; 33(4): 494-499, 2019 Feb.
Article En | MEDLINE | ID: mdl-29117742

Marine micro-organisms in the deep-sea hydrothermal vent systems are considered as potential sources of bioactive natural products. Sixteen bacterial strains were isolated from a deep-sea hydrothermal field and screened for bioactive metabolism studies. After the strains were subjected to bioactive testing at different culture media, chemical dereplication by HPLC coupled to high-resolution mass spectrometer was performed to analyse or determine the main secondary metabolisms in those strains. Strain 06204 was large-scale fermented with relative optimal media, for isolating the desired sulphur compound. Butyrolactone I 3-sulphate was isolated and structurally identified from the extract, guided by dereplication and showed moderate antivirus activities against H3N2 and EV71 viruses. Our study suggests that deep-sea hydrothermal bacteria are good sources of sulphur natural products. Meanwhile, the described approach, mainly bioactive screening, dereplication and targeted isolation, is effective and efficient to discover interesting bioactive compounds in hydrothermal bacteria.


Antiviral Agents/pharmacology , Bacteria/metabolism , Hydrothermal Vents/microbiology , Lactones/chemistry , Sulfuric Acid Esters/chemistry , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Bacteria/genetics , Bacteria/isolation & purification , Chromatography, High Pressure Liquid , Drug Evaluation, Preclinical/methods , Enterovirus A, Human/drug effects , Fermentation , Hep G2 Cells , Humans , Influenza A Virus, H3N2 Subtype/drug effects , Lactones/isolation & purification , Lactones/pharmacology , Mass Spectrometry , Secondary Metabolism , Sulfuric Acid Esters/isolation & purification , Sulfuric Acid Esters/pharmacology
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