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Frontiers in Immunology 2024It is essential to understand the interactions and relationships between () and macrophages during the infection in order to design host-directed,...
It is essential to understand the interactions and relationships between () and macrophages during the infection in order to design host-directed, immunomodulation-dependent therapeutics to control . We had reported previously that ornithine acetyltransferase (MtArgJ), a crucial enzyme of the arginine biosynthesis pathway of , is allosterically inhibited by pranlukast (PRK), which significantly reduces bacterial growth. The present investigation is centered on the immunomodulation in the host by PRK particularly the activation of the host's immune response to counteract bacterial survival and pathogenicity. Here, we show that PRK decreased the bacterial burden in the lungs by upregulating the population of pro-inflammatory interstitial macrophages (IMs) and reducing the population of susceptible alveolar macrophages (AMs), dendritic cells (DCs), and monocytes (MO). Additionally, we deduce that PRK causes the host macrophages to change their metabolic pathway from fatty acid metabolism to glycolytic metabolism around the log phage of bacterial multiplication. Further, we report that PRK reduced tissue injury by downregulating the Ly6C-positive population of monocytes. Interestingly, PRK treatment improved tissue repair and inflammation resolution by increasing the populations of arginase 1 (Arg-1) and Ym1+Ym2 (chitinase 3-like 3) positive macrophages. In summary, our study found that PRK is useful not only for reducing the tubercular burden but also for promoting the healing of the diseased tissue.
Topics: Animals; Mycobacterium tuberculosis; Mice; Disease Models, Animal; Chromones; Antitubercular Agents; Tuberculosis; Macrophages; Mice, Inbred C57BL; Female; Tuberculosis, Pulmonary; Lung
PubMed: 38756781
DOI: 10.3389/fimmu.2024.1347045 -
Acta Neuropathologica Communications May 2024Activated microglia play an important role in driving photoreceptor degeneration-associated neuroinflammation in the retina. Controlling pro-inflammatory activation of...
Activated microglia play an important role in driving photoreceptor degeneration-associated neuroinflammation in the retina. Controlling pro-inflammatory activation of microglia holds promise for mitigating the progression of photoreceptor degeneration. Our previous study has demonstrated that pre-light damage treatment of hyperoside, a naturally occurring flavonol glycoside with antioxidant and anti-inflammatory activities, prevents photooxidative stress-induced photoreceptor degeneration and neuroinflammatory responses in the retina. However, the direct impact of hyperoside on microglia-mediated neuroinflammation during photoreceptor degeneration remains unknown. Upon verifying the anti-inflammatory effects of hyperoside in LPS-stimulated BV-2 cells, our results here further demonstrated that post-light damage hyperoside treatment mitigated the loss of photoreceptors and attenuated the functional decline of the retina. Meanwhile, post-light damage hyperoside treatment lowered neuroinflammatory responses and dampened microglial activation in the illuminated retinas. With respect to microglial activation, hyperoside mitigated the pro-inflammatory responses in DNA-stimulated BV-2 cells and lowered DNA-stimulated production of 2'3'-cGAMP in BV-2 cells. Moreover, hyperoside was shown to directly interact with cGAS and suppress the enzymatic activity of cGAS in a cell-free system. In conclusion, the current study suggests for the first time that the DNA sensor cGAS is a direct target of hyperoside. Hyperoside is effective at mitigating DNA-stimulated cGAS-mediated pro-inflammatory activation of microglia, which likely contributes to the therapeutic effects of hyperoside at curtailing neuroinflammation and alleviating neuroinflammation-instigated photoreceptor degeneration.
Topics: Animals; Microglia; Quercetin; Retinal Degeneration; Mice; Nucleotidyltransferases; Mice, Inbred C57BL; DNA; Cell Line; Photoreceptor Cells, Vertebrate; Male
PubMed: 38755736
DOI: 10.1186/s40478-024-01793-0 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Feb 2024Hypoxia is a common pathological phenomenon, usually caused by insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated and methoxylated...
OBJECTIVES
Hypoxia is a common pathological phenomenon, usually caused by insufficient oxygen supply or inability to use oxygen effectively. Hydroxylated and methoxylated flavonoids have significant anti-hypoxia activity. This study aims to explore the synthesis, antioxidant and anti-hypoxia activities of 6-hydroxygenistein (6-OHG) and its methoxylated derivatives.
METHODS
The 6-OHG and its methoxylated derivatives, including 4',6,7-trimethoxy-5-hydroxyisoflavone (compound 3), 4',5,6,7-tetramethoxyisoflavone (compound 4), 4',6-imethoxy-5,7-dihydroxyisoflavone (compound 6), and 4'-methoxy-5,6,7-trihydroxyisoflavone (compound 7), were synthesized by methylation, bromination, methoxylation, and demethylation using biochanin A as raw material. The structure of these products were characterized by hydrogen-nuclear magnetic resonance spectroscopy (H-NMR) and mass spectrometry (MS). The purity of these compounds was detected by high pressure chromatography (HPLC). The antioxidant activity in vitro was investigated by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) free radical scavenging assay. PC12 cells were divided into a normal group, a hypoxia model group, rutin (1×10-1×10 mol/L) groups, and target compounds (1×10-1×10 mol/L) groups under normal and hypoxic conditions. Cell viability was detected by cell counting kit-8 (CCK-8) assay, the target compounds with excellent anti-hypoxia activity and the drug concentration at the maximum anti-hypoxia activity were screened. PC12 cells were treated with the optimal concentration of the target compound or rutin with excellent anti-hypoxia activity, and the cell morphology was observed under light microscope. The apoptotic rate was determined by flow cytometry, and the expressions of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were detected by Western blotting.
RESULTS
The structure of 6-OHG and its 4 methylated derivatives were correct, and the purity was all more than 97%. When the concentration was 4 mmol/L, the DPPH free radical removal rates of chemical compounds 7 and 6-OHG were 81.16% and 86.94%, respectively, which were higher than those of rutin, the positive control. The removal rates of chemical compounds 3, 4, and 6 were all lower than 20%. Compared with the normal group, the cell viability of the hypoxia model group was significantly decreased (<0.01). Compared with the hypoxia model group, compounds 3, 4, and 6 had no significant effect on cell viability under hypoxic conditions. At all experimental concentrations, the cell viability of the 6-OHG group was significantly higher than that of the hypoxia model group (all <0.05). The cell viability of compound 7 group at 1×10 and 1×10 mol/L was significantly higher than that of the hypoxia model group (both <0.05). The anti-hypoxia activity of 6-OHG and compound 7 was excellent, and the optimal drug concentration was 1×10 and 1×10 mol/L. After PC12 cells was treated with 6-OHG (1×10 mol/L) and compound 7 (1×10 mol/L), the cell damage was reduced, the apoptotic rate was significantly decreased (<0.01), and the protein expression levels of HIF-1α and VEGF were significantly decreased in comparison with the hypoxia model group (both <0.01).
CONCLUSIONS
The optimized synthesis route can increase the yield of 6-OHG and obtain 4 derivatives by methylation and selective demethylation. 6-OHG and compound 7 have excellent antioxidant and anti-hypoxia activities, which are related to the structure of the A-ring ortho-triphenol hydroxyl group in the molecule.
Topics: Antioxidants; Rats; Animals; PC12 Cells; Methylation; Cell Hypoxia; Vascular Endothelial Growth Factor A; Isoflavones; Flavones
PubMed: 38755719
DOI: 10.11817/j.issn.1672-7347.2024.230228 -
BMC Veterinary Research May 2024Actinobacillus pleuropneumoniae (APP) causes porcine pleuropneumonia (PCP), which is clinically characterized by acute hemorrhagic, necrotizing pneumonia, and chronic...
Actinobacillus pleuropneumoniae (APP) causes porcine pleuropneumonia (PCP), which is clinically characterized by acute hemorrhagic, necrotizing pneumonia, and chronic fibrinous pneumonia. Although many measures have been taken to prevent the disease, prevention and control of the disease are becoming increasingly difficult due to the abundance of APP sera, weak vaccine cross-protection, and increasing antibiotic resistance in APP. Therefore, there is an urgent need to develop novel drugs against APP infection to prevent the spread of APP. Naringin (NAR) has been reported to have an excellent therapeutic effect on pulmonary diseases, but its therapeutic effect on lung injury caused by APP is not apparent. Our research has shown that NAR was able to alleviate APP-induced weight loss and quantity of food taken and reduce the number of WBCs and NEs in peripheral blood in mice; pathological tissue sections showed that NAR was able to prevent and control APP-induced pathological lung injury effectively; based on the establishment of an in vivo/in vitro model of APP inflammation, it was found that NAR was able to play an anti-inflammatory role through inhibiting the MAPK/NF-κB signaling pathway and exerting anti-inflammatory effects; additionally, NAR activating the Nrf2 signalling pathway, increasing the secretion of antioxidant enzymes Nqo1, CAT, and SOD1, inhibiting the secretion of oxidative damage factors NOS2 and COX2, and enhancing the antioxidant stress ability, thus playing an antioxidant role. In summary, NAR can relieve severe lung injury caused by APP by reducing excessive inflammatory response and improving antioxidant capacity.
Topics: Animals; Actinobacillus pleuropneumoniae; Flavanones; Acute Lung Injury; NF-E2-Related Factor 2; Actinobacillus Infections; Mice; NF-kappa B; Kelch-Like ECH-Associated Protein 1; Signal Transduction; Female; Membrane Proteins; Heme Oxygenase-1
PubMed: 38755662
DOI: 10.1186/s12917-024-04055-2 -
BMC Complementary Medicine and Therapies May 2024Luteolin (3,4,5,7-tetrahydroxy flavone) is reported to strongly protect from acute carbon tetrachloride (CCl) -induced liver injury or fibrosis. Ferroptosis can be...
BACKGROUND
Luteolin (3,4,5,7-tetrahydroxy flavone) is reported to strongly protect from acute carbon tetrachloride (CCl) -induced liver injury or fibrosis. Ferroptosis can be induced by hepatic injury, and contributes to liver fibrosis development. The exact functional mechanism underlying luteolin inhibition of hepatic injury and whether ferroptosis is involved are unclear.
METHODS
Mice model and cell model of liver injury were constructed or induced to explore the effect and molecular mechanisms of Luteolin in the treatment of hepatic injury using CCl4. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to evaluate HepG2 cell viability and apoptosis. The differential expressed genes involved in liver injury were scanned using RNA-seq and confirmed using functional study. Western blot was used to detect the indicators related to ferroptosis.
RESULTS
Luteolin attenuated hepatic injury by alleviating cell morphology and decreasing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) levels in vivo mice models, and increasing cell viability, downregulating arachidonate 12-lipoxygenase (ALOX12), cyclooxygenase-2 (COX-2) and P21 protein expression, suppressing apoptosis in vitro cell models. Luteolin also inhibited ferroptosis by stimulating glutathione peroxidase 4 (GPX4) and mitochondrial ferritin (FTMT) protein expression, increasing glutathione (GSH) content, and minimizing Fe and malondialdehyde (MDA) levels. Solute carrier family 7a member 11 (SLC7A11) was identified to be a key regulatory gene that participated in luteolin attenuation of CCl-induced hepatic injuries in HepG2 cells using Microarray assay. Functional study showed that SLC7A11 can alleviate hepatic injury and ferroptosis.
CONCLUSION
Luteolin attenuated CCl-induced hepatic injury by inhibiting ferroptosis via SLC7A11. SLC7A11 may serve as a novel alternative therapeutic target for hepatic injury.
Topics: Luteolin; Ferroptosis; Animals; Mice; Humans; Chemical and Drug Induced Liver Injury; Carbon Tetrachloride; Amino Acid Transport System y+; Hep G2 Cells; Male; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 38755566
DOI: 10.1186/s12906-024-04486-2 -
Scientific Reports May 2024Contamination of soils by Molybdenum (Mo) has raised increasing concern worldwide. Both fulvic acid (FA) and humic acid (HA) possess numerous positive properties, such...
Contamination of soils by Molybdenum (Mo) has raised increasing concern worldwide. Both fulvic acid (FA) and humic acid (HA) possess numerous positive properties, such as large specific surface areas and microporous structure that facilitates the immobilization of the heavy metal in soils. Despite these characteristics, there have been few studies on the microbiology effects of FA and HA. Therefore, this study aimed to assess the Mo immobilization effects of FA and HA, as well as the associated changes in microbial community in Mo-contaminated soils (with application rates of 0%, 0.5% and 1.0%). The result of the incubation demonstrated a decrease in soil pH (from 8.23 ~ 8.94 to 8.05 ~ 8.77). Importantly, both FA and HA reduced the exchangeable fraction and reducible fraction of Mo in the soil, thereby transforming Mo into a more stable form. Furthermore, the application of FA and HA led to an increase in the relative abundance of Actinobacteriota and Firmicutes, resulting in alterations to the microbial community structure. However, it is worth noting that due to the differing structures and properties of FA and HA, these outcomes were not entirely consistent. In summary, the aging of FA and HA in soil enhanced their capacity to immobilization Mo as a soil amendment. This suggests that they have the potential to serve as effective amendments for the remediation of Mo-contaminated soils.
Topics: Humic Substances; Soil Microbiology; Metals, Heavy; Soil Pollutants; Benzopyrans; Molybdenum; Soil; Hydrogen-Ion Concentration; Bacteria; Microbiota
PubMed: 38755178
DOI: 10.1038/s41598-024-61575-5 -
Scientific Reports May 2024Nutraceutical interventions supporting microbiota and eliciting clinical improvements in metabolic diseases have grown significantly. Chronic stress, gut dysbiosis, and... (Randomized Controlled Trial)
Randomized Controlled Trial
Nutraceutical interventions supporting microbiota and eliciting clinical improvements in metabolic diseases have grown significantly. Chronic stress, gut dysbiosis, and metainflammation have emerged as key factors intertwined with sleep disorders, consequently exacerbating the decline in quality of life. This study aimed to assess the effects of two nutraceutical formulations containing prebiotics (fructooligosaccharides (FOS), galactooligosaccharides (GOS), yeast β-glucans), minerals (Mg, Se, Zn), and the herbal medicine Silybum marianum L. Gaertn., Asteraceae (Milk thistle or Silymarin). These formulations, namely NSupple (without silymarin) and NSupple_Silybum (with silymarin) were tested over 180 days in overweight/obese volunteers from Brazil's southeastern region. We accessed fecal gut microbiota by partial 16S rRNA sequences; cytokines expression by CBA; anthropometrics, quality of life and sleep, as well as metabolic and hormonal parameters, at baseline (T0) and 180 days (T180) post-supplementation. Results demonstrated gut microbiota reshaping at phyla, genera, and species level post-supplementation. The Bacteroidetes phylum, Bacteroides, and Prevotella genera were positively modulated especially in the NSupple_Silybum group. Gut microbiota modulation was associated with improved sleep patterns, quality-of-life perception, cytokines expression, and anthropometric parameters post-supplementation. Our findings suggest that the nutraceutical blends positively enhance cardiometabolic and inflammatory markers. Particularly, NSupple_Silybum modulated microbiota composition, underscoring its potential significance in ameliorating metabolic dysregulation. Clinical trial registry number: NCT04810572. 23/03/2021.
Topics: Humans; Dietary Supplements; Gastrointestinal Microbiome; Male; Quality of Life; Brazil; Female; Double-Blind Method; Adult; Cytokines; Middle Aged; Prebiotics; Feces; Silymarin; Minerals; Obesity; Oligosaccharides
PubMed: 38750102
DOI: 10.1038/s41598-024-61909-3 -
Scientific Reports May 2024Candida species have been responsible for a high number of invasive infections worldwide. In this sense, Rottlerin has demonstrated a wide range of pharmacological...
Candida species have been responsible for a high number of invasive infections worldwide. In this sense, Rottlerin has demonstrated a wide range of pharmacological activities. Therefore, this study aimed to evaluate the antifungal, antibiofilm and antivirulence activity of Rottlerin in vitro against Candida spp. and its toxicity and antifungal activity in vivo. Rottlerin showed antifungal activity against all yeasts evaluated, presenting Minimum Inhibitory and Fungicidal Concentration (MIC and MFC) values of 7.81 to > 1000 µg/mL. Futhermore, it was able to significantly inhibit biofilm production, presenting Biofilm Inhibitory Concentration (MICB) values that ranged from 15.62 to 250 µg/mL and inhibition of the cell viability of the biofilm by 50% (IC) from 2.24 to 12.76 µg/mL. There was a considerable reduction in all hydrolytic enzymes evaluated, with emphasis on hemolysin where Rottlerin showed a reduction of up to 20%. In the scanning electron microscopy (SEM) analysis, Rottlerin was able to completely inhibit filamentation by C. albicans. Regarding in vivo tests, Rottlerin did not demonstrate toxicity at the therapeutic concentrations demonstrated here and was able to increase the survival of C. elegans larvae infected. The results herein presented are innovative and pioneering in terms of Rottlerin's multipotentiality against these fungal infections.
Topics: Biofilms; Antifungal Agents; Benzopyrans; Animals; Microbial Sensitivity Tests; Acetophenones; Caenorhabditis elegans; Candida; Candidiasis; Candida albicans
PubMed: 38750088
DOI: 10.1038/s41598-024-61179-z -
The Journal of International Medical... May 2024Traumatic splenic rupture is rare in pregnant women; and multiple venous thromboses of the portal vein system, inferior vena cava and ovarian vein after caesarean...
Traumatic splenic rupture is rare in pregnant women; and multiple venous thromboses of the portal vein system, inferior vena cava and ovarian vein after caesarean section and splenectomy for splenic rupture has not been previously reported. This case report describes a case of multiple venous thromboses after caesarean section and splenectomy for traumatic splenic rupture in late pregnancy. A 34-year-old G3P1 female presented with abdominal trauma at 33 weeks of gestation. After diagnosis of splenic rupture, she underwent an emergency caesarean section and splenectomy. Multiple venous thromboses developed during the recovery period. The patient eventually recovered after anticoagulation therapy with low-molecular-weight heparin and warfarin. These findings suggest that in patients that have had a caesarean section and a splenectomy, which together might further increase the risk of venous thrombosis, any abdominal pain should be thoroughly investigated and thrombosis should be ruled out, including the possibility of multiple venous thromboses. Anticoagulant therapy could be extended after the surgery.
Topics: Humans; Female; Splenectomy; Venous Thrombosis; Adult; Splenic Rupture; Pregnancy; Cesarean Section; Postpartum Period; Anticoagulants; Heparin, Low-Molecular-Weight; Warfarin
PubMed: 38749907
DOI: 10.1177/03000605241255507 -
Texas Heart Institute Journal May 2024Current venous thromboembolism guidelines recommend using direct oral anticoagulants (DOACs) over warfarin regardless of obesity status; however, evidence remains... (Comparative Study)
Comparative Study
BACKGROUND
Current venous thromboembolism guidelines recommend using direct oral anticoagulants (DOACs) over warfarin regardless of obesity status; however, evidence remains limited for the safety and efficacy of DOAC use in patients with obesity. This retrospective analysis sought to demonstrate the safety and efficacy of DOACs compared with warfarin in a diverse population of patients with obesity in light of current prescribing practices.
METHODS
A retrospective cohort study was conducted at a large academic health system between July 2014 and September 2019. Adults with an admission diagnosis of deep vein thrombosis (DVT) or pulmonary embolism, with weight greater than 120 kg or a body mass index greater than 40, and who were discharged on an oral anticoagulant were included. Outcomes included occurrence of a thromboembolic event (DVT, pulmonary embolism, or ischemic stroke), bleeding event requiring hospitalization, and all-cause mortality within 12 months following index admission.
RESULTS
Out of 787 patients included, 520 were in the DOAC group and 267 were in the warfarin group. Within 12 months of index hospitalization, thromboembolic events occurred in 4.23% of patients in the DOAC group vs 7.12% of patients in the warfarin group (hazard ratio, 0.6 [95% CI, 0.32-1.1]; P = .082). Bleeding events requiring hospitalization occurred in 8.85% of DOAC patients vs 10.1% of warfarin patients (hazard ratio, 0.93 [95% CI, 0.57-1.5]; P = .82). A DVT occurred in 1.7% and 4.9% of patients in the DOAC and warfarin groups, respectively (hazard ratio, 0.35 [95% CI, 0.15-0.84]; P = .046).
CONCLUSION
No significant differences could be determined between DOACs and warfarin for cumulative thromboembolic or bleeding events, pulmonary embolism, ischemic stroke, or all-cause mortality. The risk of DVT was lower with apixaban and rivaroxaban. Regardless of patient weight or body mass index, physicians prescribed DOACs more commonly than warfarin.
Topics: Humans; Retrospective Studies; Female; Male; Warfarin; Obesity; Anticoagulants; Middle Aged; Venous Thromboembolism; Administration, Oral; Aged; Treatment Outcome; Factor Xa Inhibitors; Hemorrhage; Follow-Up Studies
PubMed: 38748549
DOI: 10.14503/THIJ-23-8260