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International Journal of Biological... Jun 2024Sulfated fucan has gained interest due to its various physiological activities. Endo-1,3-fucanases are valuable tools for investigating the structure and establishing...
BACKGROUND
Sulfated fucan has gained interest due to its various physiological activities. Endo-1,3-fucanases are valuable tools for investigating the structure and establishing structure-activity relationships of sulfated fucan. However, the substrate recognition mechanism of endo-1,3-fucanases towards sulfated fucan remains unclear, limiting the application of endo-1,3-fucanases in sulfated fucan research.
SCOPE AND APPROACH
This study presented the first crystal structure of endo-1,3-fucanase (Fun168A) and its complex with the tetrasaccharide product, utilizing X-ray diffraction techniques. The novel subsite specificity of Fun168A was identified through glycomics and nuclear magnetic resonance (NMR).
KEY FINDINGS AND CONCLUSIONS
The structure of Fun168A was determined at 1.92 Å. Residues D206 and E264 acted as the nucleophile and general acid/base, respectively. Notably, Fun168A strategically positioned a series of polar residues at the subsites ranging from -2 to +3, enabling interactions with the sulfate groups of sulfated fucan through salt bridges or hydrogen bonds. Based on the structure of Fun168A and its substrate recognition mechanisms, the novel subsite specificities at the -2 and +2 subsites of Fun168A were identified. Overall, this study provided insight into the structure and substrate recognition mechanism of endo-1,3-fucanase for the first time and offered a valuable tool for further research and development of sulfated fucan.
Topics: Polysaccharides; Substrate Specificity; alpha-L-Fucosidase; Models, Molecular; Crystallography, X-Ray; Sulfates; Glycoside Hydrolases; Structure-Activity Relationship
PubMed: 38795894
DOI: 10.1016/j.ijbiomac.2024.132622 -
Nutrients May 2024Recent studies have indicated that fucoidan has the potential to improve cognitive impairment. The objective of this study was to demonstrate the protective effect and...
Recent studies have indicated that fucoidan has the potential to improve cognitive impairment. The objective of this study was to demonstrate the protective effect and possible mechanisms of fucoidan in D-galactose (D-gal)-induced cognitive dysfunction. Sprague Dawley rats were injected with D-galactose (200 mg/kg, sc) and administrated with fucoidan (100 mg/kg or 200 mg/kg, ig) for 8 weeks. Our results suggested that fucoidan significantly ameliorated cognitive impairment in D-gal-exposed rats and reversed histopathological changes in the hippocampus. Fucoidan reduced D-gal-induced oxidative stress, declined the inflammation level and improved mitochondrial dysfunction in hippocampal. Fucoidan promoted mitochondrial biogenesis by regulating the PGC-1α/NRF1/TFAM pathway, thereby improving D-gal-induced mitochondrial dysfunction. The regulation effect of fucoidan on PGC-1α is linked to the upstream protein of APN/AMPK/SIRT1. Additionally, the neuroprotective action of fucoidan could be related to maintaining intestinal flora homeostasis with up-regulation of , and and down-regulation of . In summary, fucoidan may be a natural, promising candidate active ingredient for age-related cognitive impairment interventions.
Topics: Polysaccharides; Animals; Gastrointestinal Microbiome; Galactose; Cognitive Dysfunction; Rats, Sprague-Dawley; Organelle Biogenesis; Homeostasis; Male; Hippocampus; Rats; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Mitochondria; Oxidative Stress; Neuroprotective Agents; Sirtuin 1; Disease Models, Animal; Transcription Factors
PubMed: 38794753
DOI: 10.3390/nu16101512 -
Nutrients May 2024Jacq. is traditionally applied in folk medicine in Brazil and in several Latin American countries. The leaves are used in tea form, especially in the treatment of...
INTRODUCTION
Jacq. is traditionally applied in folk medicine in Brazil and in several Latin American countries. The leaves are used in tea form, especially in the treatment of respiratory disorders, acting as an expectorant. It also has activity in gastrointestinal disorders, and it is anti-inflammatory, antioxidant, sedative, and estrogenic, among others.
AIMS
To investigate the gastroprotective activity of the methanol extract of the leaves of Jacq. (MEJP) in different experimental models of gastric ulcers.
MATERIALS AND METHODS
The adult leaves of Jacq. were collected and cultivated in beds, with an approximate spacing of 40 × 40 cm, organic fertilization, irrigation with potable water and without shelter from light. The MEJP was prepared from the dried and pulverized leaves and concentrated under reduced pressure in a rotary evaporator. For the experimental model of gastric ulcer, Swiss male albino mice were used. The inputs used in the experiment were MEJP at three different concentrations (250, 500 and 1000 mg/kg p.o.), cimetidine (50 mg/kg p.o.), indomethacin (50 mg/kg s.c.) and vehicle (10 mL/kg p.o.).
RESULTS
MEJP (250, 500 and 1000 mg/kg p.o.) demonstrated gastroprotective activity, with levels of protection of 45.65%, 44.80% and 40.22%, respectively, compared to the control (vehicle). Compared with cimetidine (48.29%), MEJP showed similar gastroprotective activity.
CONCLUSIONS
This study demonstrated the gastroprotective activity of MEJP and contributes to validate the traditional use the species for gastric disorders and provides a pharmacological basis for its clinical potential.
Topics: Animals; Plant Extracts; Mice; Stomach Ulcer; Plant Leaves; Male; Anti-Ulcer Agents; Methanol; Justicia; Disease Models, Animal; Cimetidine; Acanthaceae; Indomethacin; Brazil; Gastric Mucosa
PubMed: 38794668
DOI: 10.3390/nu16101430 -
Pharmaceutics May 2024Curcumin and resveratrol are polyphenolic compounds that have been shown to exhibit synergistic therapeutic properties including anti-inflammatory, anticancer, and...
Curcumin and resveratrol are polyphenolic compounds that have been shown to exhibit synergistic therapeutic properties including anti-inflammatory, anticancer, and antiulcer activities, which may be exploited for the treatment of gastric diseases. However, both compounds have poor aqueous solubility and rapid metabolism, resulting in a low oral bioavailability. In situ gelling, liquid formulations were developed to produce a gastroretentive, raft-forming delivery vehicle to improve bioavailability. Solid dispersions containing a mixture of curcumin and resveratrol with Eudragit EPO (Cur/Res-SD) were first prepared using solvent evaporation, to improve the solubility and dissolution of the compounds. Solid dispersions of a weight ratio of 1:10 curcumin/resveratrol to Eudragit EPO were subsequently incorporated into in situ gelling, liquid formulations based on the gelling polymers, sodium alginate (low viscosity and medium viscosity), pectin, and gellan gum, respectively. Calcium carbonate and sodium bicarbonate were included to produce carbon dioxide bubbles in the gel matrix, on exposure to gastric fluid, and to achieve flotation. Moreover, the calcium ions acted as a crosslinking agent for the hydrogels. Optimized formulations floated rapidly (<60 s) in simulated gastric fluid (pH = 1.2) and remained buoyant, resulting in the gradual release of more than 80% of the curcumin and resveratrol content within 8 h. The optimized formulation based on medium-viscosity sodium alginate exhibited enhanced cytotoxic activity toward human gastric adenocarcinoma cell lines (AGS), compared with unformulated curcumin and resveratrol compounds, and increased anti-inflammatory activity against RAW 264.7 macrophage cells compared with the NSAID, indomethacin. These findings demonstrate that in situ gelling, liquid formulations, loaded with a combination of curcumin and resveratrol in the form of solid dispersions, show potential as gastroretentive delivery systems for local and systemic effects.
PubMed: 38794303
DOI: 10.3390/pharmaceutics16050641 -
Molecules (Basel, Switzerland) May 2024The 1092 bp F3H gene from Roxb., which was named TbF3H, was cloned and it encodes 363 amino acids. Bioinformatic and phylogenetic tree analyses revealed the high...
The 1092 bp F3H gene from Roxb., which was named TbF3H, was cloned and it encodes 363 amino acids. Bioinformatic and phylogenetic tree analyses revealed the high homology of TbF3H with flavanone 3-hydroxylase from other plants. A functional analysis showed that TbF3H of Roxb. encoded a functional flavanone 3-hydroxylase; it catalyzed the formation of dihydrokaempferol (DHK) from naringenin in . The promoter strengths were compared by fluorescence microscopy and flow cytometry detection of the fluorescence intensity of the reporter genes initiated by each constitutive promoter (FITC), and DHK production reached 216.7 mg/L by the promoter adjustment strategy and the optimization of fermentation conditions. The results presented in this study will contribute to elucidating DHK biosynthesis in Roxb.
Topics: Saccharomyces cerevisiae; Flavanones; Phylogeny; Promoter Regions, Genetic; Cloning, Molecular; Flavonoids; Plant Proteins; Fermentation
PubMed: 38792058
DOI: 10.3390/molecules29102196 -
International Immunopharmacology Jun 2024Geranylgeranylacetone (GGA), an isoprenoid compound widely utilized as an antiulcer agent in Asia, confers protection against ischemia, anoxia, and oxidative stress by...
Geranylgeranylacetone (GGA), an isoprenoid compound widely utilized as an antiulcer agent in Asia, confers protection against ischemia, anoxia, and oxidative stress by rapidly enhancing the expression of HSP70. Nevertheless, the impact of GGA on sepsis-associated intestinal injury remains unexplored. Thus, this study is crafted to elucidate the protective efficacy and underlying mechanisms of GGA against septic intestinal damage. Our findings revealed that GGA significantly extended the survival duration of septic mice, and mitigated lipopolysaccharide (LPS)-induced alterations in intestinal permeability and tissue damage. Furthermore, GGA effectively suppressed LPS-induced cytokine release, attenuated levels of reactive oxygen species (ROS) and malondialdehyde, and bolstered antioxidant-related parameters within the intestinal tissue of LPS-stimulated mice. Mechanistically, GGA significantly increased HSP70 expression and promoted E3 ubiquitin ligase CHIP to play the role in ubiquitination and degradation of karyopherin-α2 (KPNA2), resulting in inhibition of nuclear translocation of NF-κB and reduced NOX1, NOX2 and NOX4 expression. The inhibitory action of GGA on cytokine release and ROS generation was abolished by CHIP knockdown in IEC-6 cells treated with LPS. Simultaneously, the downregulation of CHIP reversed the suppressive role of GGA in the LPS-induced NF-κB activation and the expression of NOX1, NOX2 and NOX4 in IEC-6 cells. The effects of GGA on mitigating intestinal damage, inflammation and oxidative stress caused by LPS were eliminated in CHIP knockout mice. Our results demonstrate that the protective effect of GGA against LPS-caused intestinal injury of mice is dependent on CHIP activation, which promotes KPNA2 degradation and restrains translocation of NF-κB into nucleus, leading to suppressing LPS-induced inflammatory response and oxidative stress.
Topics: Animals; Diterpenes; Sepsis; Male; Anti-Inflammatory Agents; Mice; Lipopolysaccharides; Oxidative Stress; Mice, Inbred C57BL; Antioxidants; Cell Line; Cytokines; Reactive Oxygen Species; Rats; NF-kappa B; Intestines; Intestinal Mucosa; Intestinal Diseases; HSP70 Heat-Shock Proteins
PubMed: 38788444
DOI: 10.1016/j.intimp.2024.112263 -
Marine Drugs May 2024Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and chronic inflammation, accompanied by high oxidative stress. In this...
Osteoarthritis (OA) is a debilitating joint disorder characterized by cartilage degradation and chronic inflammation, accompanied by high oxidative stress. In this study, we utilized the monosodium iodoacetate (MIA)-induced OA model to investigate the efficacy of oligo-fucoidan-based formula (FF) intervention in mitigating OA progression. Through its capacity to alleviate joint bearing function and inflammation, improvements in cartilage integrity following oligo-fucoidan-based formula intervention were observed, highlighting its protective effects against cartilage degeneration and structural damage. Furthermore, the oligo-fucoidan-based formula modulated the p38 signaling pathway, along with downregulating cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, contributing to its beneficial effects. Our study provides valuable insights into targeted interventions for OA management and calls for further clinical investigations to validate these preclinical findings and to explore the translational potential of an oligo-fucoidan-based formula in human OA patients.
Topics: Nitric Oxide Synthase Type II; Osteoarthritis; Animals; Cyclooxygenase 2; Polysaccharides; Male; Mice; Disease Models, Animal; Iodoacetic Acid; Oxidative Stress; Humans; Cartilage, Articular; Iodoacetates
PubMed: 38786602
DOI: 10.3390/md22050211 -
Marine Drugs May 2024The applications of fucoidan in the food industry were limited due to its high molecular weight and low solubility. Moderate degradation was required to depolymerize...
The applications of fucoidan in the food industry were limited due to its high molecular weight and low solubility. Moderate degradation was required to depolymerize fucoidan. A few studies have reported that fucoidan has potential antibacterial activity, but its antibacterial mechanism needs further investigation. In this study, the degraded fucoidans were obtained after ultraviolet/hydrogen peroxide treatment (UV/HO) at different times. Their physicochemical properties and antibacterial activities against and were investigated. The results showed that the average molecular weights of degraded fucoidans were significantly decreased (up to 22.04 times). They were mainly composed of fucose, galactose, and some glucuronic acid. Fucoidan degraded for 90 min (DFuc-90) showed the strongest antibacterial activities against and , with inhibition zones of 27.70 + 0.84 mm and 9.25 + 0.61 mm, respectively. The minimum inhibitory concentrations (MIC) were 8 mg/mL and 4 mg/mL, respectively. DFuc-90 could inhibit the bacteria by damaging the cell wall, accumulating intracellular reactive oxygen species, reducing adenosine triphosphate synthesis, and inhibiting bacterial metabolic activity. Therefore, UV/HO treatment could effectively degrade fucoidan and enhance its antibacterial activity.
Topics: Polysaccharides; Hydrogen Peroxide; Anti-Bacterial Agents; Ultraviolet Rays; Escherichia coli; Staphylococcus aureus; Microbial Sensitivity Tests; Molecular Weight; Reactive Oxygen Species
PubMed: 38786600
DOI: 10.3390/md22050209 -
Journal of Ethnopharmacology Oct 2024Zingiberis rhizoma recens-/wine-/euodiae fructus-processed Coptidis Rhizoma (CR, zCR/wCR/eCR) are the commonly used processed products of CR in clinic. After being...
Untargeted serum and gastric metabolomics and network pharmacology analysis reveal the superior efficacy of zingiberis rhizoma recens-/euodiae fructus-processed Coptidis Rhizoma on gastric ulcer rats.
ETHNOPHARMACOLOGICAL RELEVANCE
Zingiberis rhizoma recens-/wine-/euodiae fructus-processed Coptidis Rhizoma (CR, zCR/wCR/eCR) are the commonly used processed products of CR in clinic. After being processed with different excipients, the efficacy of CR will change accordingly. I.e., wCR could resolve excessive heat of the upper energizer, zCR could eliminate gastric heat and harmonize the stomach, eCR could smooth the liver and harmonize the stomach. However, the underlying mechanisms were still unclear.
AIM OF THE STUDY
To further verify the differential efficacy of the three processed CR products and compare the mechanisms on gastric ulcer.
MATERIAL AND METHODS
First, a GU model, whose onset is closely related to the heat in stomach and the disharmony between liver and stomach, was established, and the therapeutic effects of zCR/wCR/eCR/CR were evaluated by pathologic observation and measurement of cytokine levels. Second, metabolomics analysis and network pharmacology were conducted to reveal the differential intervening mechanism of zCR/eCR on GU. Third, the predicted mechanisms from metabolomics analysis and network pharmacology were validated using western blotting, flow cytometry and immunofluorescence.
RESULTS
zCR/wCR/eCR/CR could alleviate the pathologic damage to varying degrees. In metabolomics research, fewer metabolic pathways were enriched in serum samples, and most of them were also present in the results of gastric tissue samples. The gastroprotective, anti-inflammatory, antioxidant, and anti-apoptotic effects of zCR/wCR/eCR/CR might be due to their interference on histidine, arachidonic acid, and glycerophospholipids metabolism. Quantitative results indicated that zCR/eCR had a better therapeutic effect than wCR/CR in treating GU. A comprehensive analysis of metabolomics and network pharmacology revealed that zCR and eCR exerted anti-GU effects via intervening in five core targets, including AKT, TNF, IL6, IL1B and PPARG. In the validation experiment, zCR/eCR could significantly reverse the abnormal expression of proteins related to apoptosis, inflammation, oxidative stress, gastric function, as well as the PI3K/AKT signaling pathways.
CONCLUSION
zCR and eCR could offer gastroprotective benefits by resisting inflammation and apoptosis, inhibiting gastric-acid secretion, as well as strengthening gastric mucosal defense and antioxidant capacity. Integrating network pharmacology and metabolomics analysis could reveal the acting mechanism of drugs and promote the development of medications to counteract GU.
Topics: Animals; Stomach Ulcer; Metabolomics; Network Pharmacology; Drugs, Chinese Herbal; Male; Rats, Sprague-Dawley; Rats; Evodia; Gastric Mucosa; Coptis chinensis; Disease Models, Animal; Anti-Ulcer Agents; Cytokines
PubMed: 38782310
DOI: 10.1016/j.jep.2024.118376 -
Biomedicine & Pharmacotherapy =... Jun 2024Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for...
Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25-2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38 µM. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia.
Topics: Linezolid; Humans; Thrombocytopenia; HEK293 Cells; Animals; Male; Female; Middle Aged; Retrospective Studies; Aged; Rats; Proton Pump Inhibitors; Lansoprazole; Biological Transport; Rats, Sprague-Dawley; Risk Factors; Adult; Organic Anion Transporters, Sodium-Independent
PubMed: 38781867
DOI: 10.1016/j.biopha.2024.116801