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1.
Antioxidants (Basel) ; 13(5)2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38790704

RESUMO

BACKGROUND: The discovery of traditional plants' medicinal and nutritional properties has opened up new avenues for developing pharmaceutical and dietary strategies to prevent atherosclerosis. However, the effect of the antioxidant Dendrobium officinale polysaccharide (DOP) on atherosclerosis is still not elucidated. PURPOSE: This study aims to investigate the inhibitory effect and the potential mechanism of DOP on high-fat diet-induced atherosclerosis in Apolipoprotein E knockout (ApoE-/-) mice. STUDY DESIGN AND METHODS: The identification of DOP was measured by high-performance gel permeation chromatography (HPLC) and Fourier transform infrared spectroscopy (FTIR). We used high-fat diet (HFD)-induced atherosclerosis in ApoE-/- mice as an animal model. In the DOP intervention stage, the DOP group was treated by gavage with 200 µL of 200 mg/kg DOP at regular times each day and continued for eight weeks. We detected changes in serum lipid profiles, inflammatory factors, anti-inflammatory factors, and antioxidant capacity to investigate the effect of the DOP on host metabolism. We also determined microbial composition using 16S rRNA gene sequencing to investigate whether the DOP could improve the structure of the gut microbiota in atherosclerotic mice. RESULTS: DOP effectively inhibited histopathological deterioration in atherosclerotic mice and significantly reduced serum lipid levels, inflammatory factors, and malondialdehyde (F/B) production. Additionally, the levels of anti-inflammatory factors and the activity of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), were significantly increased after DOP intervention. Furthermore, we found that DOP restructures the gut microbiota composition by decreasing the Firmicutes/Bacteroidota (F/B) ratio. The Spearman's correlation analysis indicated that serum lipid profiles, antioxidant activity, and pro-/anti-inflammatory factors were associated with Firmicutes, Bacteroidota, Allobaculum, and Coriobacteriaceae_UCG-002. CONCLUSIONS: This study suggests that DOP has the potential to be developed as a food prebiotic for the treatment of atherosclerosis in the future.

2.
Food Chem X ; 22: 101492, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38817982

RESUMO

Introducing Holstein cows on Qinghai-Tibetan Plateau is a potential solution to enhance local milk production. However, the relationship between milk quality and altitude in China remains unknown. Therefore, the components and plasmin (PL) system of raw milk from different altitudes (sea level, 1600, 2700, and 3800 m) were investigated. The daily milk production of Holstein cows and PL activity decreased as the altitude increased. However, the components content of raw milk, plasminogen (PLG)/PL ratio, activities of PLG and plasmin activator (PA) increased with altitude. The pasteurization resulted a significant decrease in PA activity of all milk and a significant increase in PL activity in milk collected at higher altitudes (2700 and 3800 m), suggesting the pasteurization was unsuitable for preserving milk at higher altitudes. This study offered references for the production and storage of milk after introducing Holstein cows on Qinghai-Tibetan Plateau.

3.
Phytomedicine ; 129: 155657, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38692076

RESUMO

BACKGROUND: The pentose phosphate pathway (PPP) plays a crucial role in the material and energy metabolism in cancer cells. Targeting 6-phosphogluconate dehydrogenase (6PGD), the rate-limiting enzyme in the PPP metabolic process, to inhibit cellular metabolism is an effective anticancer strategy. In our previous study, we have preliminarily demonstrated that gambogic acid (GA) induced cancer cell death by inhibiting 6PGD and suppressing PPP at the cellular level. However, it is unclear whether GA could suppress cancer cell growth by inhibiting PPP pathway in mouse model. PURPOSE: This study aimed to confirm that GA as a covalent inhibitor of 6PGD protein and to validate that GA suppresses cancer cell growth by inhibiting the PPP pathway in a mouse model. METHODS: Cell viability was detected by CCK-8 assays as well as flow cytometry. The protein targets of GA were identified using a chemical probe and activity-based protein profiling (ABPP) technology. The target validation was performed by in-gel fluorescence assay, the Cellular Thermal Shift Assay (CETSA). A lung cancer mouse model was constructed to test the anticancer activity of GA. RNA sequencing was performed to analyze the global effect of GA on gene expression. RESULTS: The chemical probe of GA exhibited high biological activity in vitro. 6PGD was identified as one of the binding proteins of GA by ABPP. Our findings revealed a direct interaction between GA and 6PGD. We also found that the anti-cancer activity of GA depended on reactive oxygen species (ROS), as evidenced by experiments on cells with 6PGD knocked down. More importantly, GA could effectively reduce the production of the two major metabolites of the PPP in lung tissue and inhibit cancer cell growth in the mouse model. Finally, RNA sequencing data suggested that GA treatment significantly regulated apoptosis and hypoxia-related physiological processes. CONCLUSION: These results demonstrated that GA was a covalent inhibitor of 6PGD protein. GA effectively suppressed cancer cell growth by inhibiting the PPP pathway without causing significant side effects in the mouse model. Our study provides in vivo evidence that elucidates the anticancer mechanism of GA, which involves the inhibition of 6PGD and modulation of cellular metabolic processes.


Assuntos
Neoplasias Pulmonares , Via de Pentose Fosfato , Xantonas , Xantonas/farmacologia , Animais , Via de Pentose Fosfato/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Humanos , Fosfogluconato Desidrogenase/metabolismo , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças
4.
Dalton Trans ; 53(17): 7257-7262, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38629404

RESUMO

A reduced polyoxometalate-based organo-metallophosphate (MOPO) framework formulated as [Co4(PO4)(C7H8N4)6](PWVI10WV2O40) (Co-PO4-PW12) with an ultra-high CO production rate of 13 676 µmol g-1 h-1 has been presented through photocatalytic CO2 reduction investigations.

5.
Environ Int ; 185: 108489, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38367553

RESUMO

Microplastics (MPs) are environmental pollutants and can be inhaled by humans to threaten health. The lung tissue, responsible for the gas exchange between the body and the environment, is vulnerable to MPs exposure. However, from the perspective of cellular senescence, the effect of MPs on lung cells and tissues has not yet been deeply dissected. In this study, we reported that all the four typical MPs exhibited the significant biological effects in term of inducing senescence of human lung derived cells A549 and BEAS-2B in vitro. We further found that polyvinyl chloride (PVC) increased the reactive oxygen species (ROS) level in A549 cells and that PVC-induced senescent characteristics could be largely reversed by antioxidant treatment. Importantly, intratracheal instillation of PVC MPs in mice could effectively impair their physical function, induce the increased systemic inflammation level, cause the accumulation of senescent cells. Our study demonstrates that MPs induce senescence in human lung epithelial cells and mouse lungs by activating ROS signaling, and provides new insight into the potential pathogenesis of MPs on lung diseases.


Assuntos
Microplásticos , Poluentes Químicos da Água , Humanos , Animais , Camundongos , Plásticos , Espécies Reativas de Oxigênio , Células Epiteliais , Pulmão
6.
JAMA Netw Open ; 7(1): e2350825, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38194235

RESUMO

Importance: General anesthesia for cesarean delivery is associated with increased maternal morbidity, and Black and Hispanic pregnant patients have higher rates of general anesthesia use compared with their non-Hispanic White counterparts. It is unknown whether risk factors and indications for general anesthesia differ among patients of differing race and ethnicity. Objective: To evaluate differences in general anesthesia use for cesarean delivery and the indication for the general anesthetic by race and ethnicity. Design, Setting, and Participants: In this retrospective, cross-sectional, single-center study, electronic medical records for all 35 117 patients who underwent cesarean delivery at Northwestern Medicine's Prentice Women's Hospital from January 1, 2007, to March 2, 2018, were queried for maternal demographics, clinical characteristics, obstetric and anesthetic data, the indication for cesarean delivery, and the indication for general anesthesia when used. Data analysis occurred in August 2023. Exposure: Cesarean delivery. Main Outcomes and Measures: The rate of general anesthesia for cesarean delivery by race and ethnicity. Results: Of the 35 117 patients (median age, 33 years [IQR, 30-36 years]) who underwent cesarean delivery, 1147 (3.3%) received general anesthesia; the rates of general anesthesia were 2.5% for Asian patients (61 of 2422), 5.0% for Black patients (194 of 3895), 3.7% for Hispanic patients (197 of 5305), 2.8% for non-Hispanic White patients (542 of 19 479), and 3.8% (153 of 4016) for all other groups (including those who declined to provide race and ethnicity information) (P < .001). A total of 19 933 pregnant patients (56.8%) were in labor at the time of their cesarean delivery. Of those, 16 363 (82.1%) had neuraxial labor analgesia in situ. Among those who had an epidural catheter in situ, there were no racial or ethnic differences in the rates of general anesthesia use vs neuraxial analgesia use (Asian patients, 34 of 503 [6.8%] vs 1289 of 15 860 [8.1%]; Black patients, 78 of 503 [15.5%] vs 1925 of 15 860 [12.1%]; Hispanic patients, 80 of 503 [15.9%] vs 2415 of 15 860 [15.2%]; non-Hispanic White patients, 255 of 503 [50.7%] vs 8285 of 15 860 [52.2%]; and patients of other race or ethnicity, 56 of 503 [11.1%] vs 1946 of 15 860 [12.3%]; P = .16). Indications for cesarean delivery and for general anesthesia were not different when stratified by race and ethnicity. Conclusions and Relevance: Racial disparities in rates of general anesthesia continue to exist; however, this study suggests that, for laboring patients who had labor epidural catheters in situ, no disparity by race or ethnicity existed. Future studies should address whether disparities in care that occur prior to neuraxial catheter placement are associated with higher rates of general anesthesia among patients from ethnic and racial minority groups.


Assuntos
Anestesia Geral , Etnicidade , Disparidades em Assistência à Saúde , Grupos Raciais , Adulto , Feminino , Humanos , Gravidez , Estudos Transversais , Estudos Retrospectivos
7.
Cell Chem Biol ; 31(3): 452-464.e10, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-37913771

RESUMO

Various biological agents have been developed to target tumor necrosis factor alpha (TNF-α) and its receptor TNFR1 for the rheumatoid arthritis (RA) treatment, whereas small molecules modulating such cytokine receptors are rarely reported in comparison to the biologicals. Here, by revealing the mechanism of action of vinigrol, a diterpenoid natural product, we show that inhibition of the protein disulfide isomerase (PDI, PDIA1) by small molecules activates A disintegrin and metalloprotease 17 (ADAM17) and then leads to the TNFR1 shedding on mouse and human cell membranes. This small-molecule-induced receptor shedding not only effectively blocks the inflammatory response caused by TNF-α in cells, but also reduces the arthritic score and joint damage in the collagen-induced arthritis mouse model. Our study indicates that targeting the PDI-ADAM17 signaling module to regulate the shedding of cytokine receptors by the chemical approach constitutes a promising strategy for alleviating RA.


Assuntos
Artrite Reumatoide , Diterpenos , Camundongos , Humanos , Animais , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteômica , Artrite Reumatoide/tratamento farmacológico , Proteína ADAM17
8.
Nat Nanotechnol ; 18(9): 1067-1077, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37537273

RESUMO

Nanoparticles (NPs) in biological fluids form a layer of biomolecules known as the protein corona. The protein corona has been shown to determine the biological identity and in vivo fate of NPs, but whether and how metabolites, especially disease-related small molecules, regulate the protein corona and subsequently impact NP fate in vivo is relatively poorly understood. Here we report on the effects of cholesterol on the generation of protein corona and subsequent effects. We find that high levels of cholesterol, as in hypercholesterolemia, result in a protein corona with enriched apolipoproteins and reduced complement proteins by altering the binding affinity of the proteins to the NPs. The cholesterol-mediated protein corona can induce stronger inflammatory responses to NPs in macrophages and promote the cellular uptake of NPs in hepatocytes by enhancing the recognition of lipoprotein receptors when compared with normal protein corona. The result of in vivo biodistribution assays shows that, compared with healthy mice, NPs in hypercholesterolemic mice were more likely to be delivered to the liver, spleen and brain, and less likely to be delivered to the lungs. Our findings reveal that the metabolome profile is an unexploited factor impacting the target efficacy and safety of nanomedicines, providing a way to develop personalized nanomedicines by harnessing disease-related metabolites.


Assuntos
Nanopartículas , Coroa de Proteína , Camundongos , Animais , Coroa de Proteína/química , Distribuição Tecidual , Proteínas/química , Nanopartículas/química , Colesterol
9.
Chem Commun (Camb) ; 59(58): 8981-8984, 2023 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-37394927

RESUMO

Sofalcone (Sof), a synthetic analog of sophoradin, is a type of natural phenol derived from the traditional medicinal herb Sophora subprostrata, with potent anti-inflammatory activity. However, the mechanisms of action of Sof for treating intestinal-associated inflammation are not well known. In this work, we identified high mobility group box 1 (HMGB1) as the key covalent target of Sof for the anti-inflammatory activity in the human colonic epithelial cells through quantitative chemoproteomics profiling.


Assuntos
Chalconas , Proteína HMGB1 , Humanos , Células CACO-2 , Chalconas/farmacologia , Colo
10.
J Colloid Interface Sci ; 648: 497-510, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37307606

RESUMO

Nanoparticles (NPs) have broad application prospects in the field of biomedicine due to their excellent physicochemical properties. When entering biological fluids, NPs inevitably encountered proteins and were subsequently surrounded by them, forming the termed protein corona (PC). As PC has been evidenced to have critical roles in deciding the biological fates of NPs, how to precisely characterize PC is vital to promote the clinical translation of nanomedicine by understanding and harnessing NPs' behaviors. During the centrifugation-based separation techniques for the PC preparation, direct elution has been most widely used to strip proteins from NPs due to its simpleness and robustness, but the roles of multifarious eluents have never been systematically declared. Herein, seven eluents composed of three denaturants, sodium dodecyl sulfate (SDS), dithiothreitol (DTT), and urea (Urea), were applied to detach PC from gold nanoparticles (AuNPs) and silica nanoparticles (SiNPs), and eluted proteins in PC have been carefully characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and chromatography coupled tandem mass spectrometry (LC-MS/MS). Our results showed that SDS and DTT were the main contributors to the efficient desorption of PC on SiNPs and AuNPs, respectively. The molecular reactions between NPs and proteins were explored and verified by SDS-PAGE analysis of PC formed in the serums pretreated with protein denaturing or alkylating agents. The proteomic fingerprinting analysis indicated the difference of the eluted proteins brought by the seven eluents was the abundance rather than the species. The enrichment of some opsonins and dysopsonins in a special elution reminds us that the possibility of biased judgments on predicting NPs' biological behaviors under different elution conditions. The synergistic effects or antagonistic effects among denaturants for eluting PC were manifested in a nanoparticle-type dependent way by integrating the properties of the eluted proteins. Collectively, this study not only underlines the urgent need of choosing the appropriate eluents for identifying PC robustly and unbiasedly, but also provides an insight into the understanding of molecular interactions during PC formation.


Assuntos
Nanopartículas Metálicas , Nanopartículas , Coroa de Proteína , Coroa de Proteína/química , Ouro , Cromatografia Líquida , Dodecilsulfato de Sódio/química , Proteômica , Espectrometria de Massas em Tandem , Proteínas/química , Nanopartículas/química
11.
Front Public Health ; 11: 1113403, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37346107

RESUMO

Objective: To investigate the quality and efficacy of remote at-home rehabilitation for patients with cardiovascular disease (CVD) using personalized smart voice-based electronic prescription, and further explore the standardized health management mode of remote family cardiac rehabilitation. Trial design: A multicenter, randomized (1:1), non-blind, parallel controlled study. Methods: A total of 171 patients with CVD who were admitted to 18 medical institutions in China from April 2021 to October 2022 were randomly divided into a treatment group (86 cases) and a control group (85 cases) in a non-blinded experiment, based on the sequence of enrollment. The control group received routine at-home rehabilitation training, and the treatment group received remote feedback-based at-home cardiac rehabilitation management based on routine at-home rehabilitation training. The primary outcome was the difference in VO2peak (mL/min/kg) after 12 weeks. A linear mixed model was developed with follow-up as the dependent variable. Age and baseline data were utilized as covariates, whereas hospital and patient characteristics were adjusted as random-effect variables. As the linear mixed model can accommodate missing data under the assumption of random missing data, there was no substitute missing value for quantitative data. Results: A total of 171 participants, with 86 in the experimental group and 85 in the control group, were included in the main analysis. The analysis, which used linear mixing model, revealed significant differences in cardiopulmonary function indexes (VO2/kg peak, VO2peak, AT, METs, and maximum resistance) at different follow-up time (0, 4, and 12 weeks) in the experimental group (p < 0.05). In the control group, there was no significant difference in cardiopulmonary values at different follow-up time (0, 4, and 12 weeks; p > 0.05). VO2/kg peak (LS mean 1.49, 95%CI 0.09-2.89, p = 0.037) and other indicators of cardiopulmonary function (p < 0.05) were significantly different between the experimental group and the control group at week 12. The results were comparable in the complete case analysis. Conclusion: The remote home cardiac rehabilitation management mode using personalized smart voice-based electronic prescription provides several benefits to patients, including improvements in muscle strength, endurance, cardiopulmonary function, and aerobic metabolism. It also helps reduce risk factors for cardiovascular disease and enhances patients' self-management abilities and treatment compliance.Clinical trial registration: http://www.chictr.org.cn, identifier ChiCTR2100044063.


Assuntos
Reabilitação Cardíaca , Doenças Cardiovasculares , Prescrição Eletrônica , Humanos , Reabilitação Cardíaca/métodos , Retroalimentação , Cooperação do Paciente
12.
Inorg Chem ; 62(13): 5200-5206, 2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-36959113

RESUMO

In the field of recycling CO2, the photocatalytic CO2 reduction reaction (CO2RR) is a typical example, and researchers have designed a variety of photocatalysts to improve the conversion rate of CO2 over the years. In this paper, two metal-oxygen clusters are designed and formulated as [Co3Zn(OH)6(SO4)]·4H2O (1) and [Ni3Zn(OH)6(SO4)]·4H2O (2). As for compound 1, the main structure is composed of {CoO6} octahedra connected by edge-sharing to form a two-dimensional layer, on which {ZnO4} and {SO4} tetrahedra are supported. More interestingly, compound 1 has outstanding photocatalytic activity, which is mainly attributed to the open-framework structure and the cobalt ions as active sites. Upon catalysis for eight hours, its maximum CO generation rate is 9982.13 µmol g-1 h-1, with a selectivity of 81.8%. Additionally, compound 1 takes on weak antiferromagnetic coupling due to Co(II) ions.

13.
J Colloid Interface Sci ; 630(Pt B): 179-192, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36327721

RESUMO

As a kind of novel functional material, graphene-related nanomaterials (GRMs) have great potentials in industrial and biomedical applications. Meanwhile, the production and wide application of GRMs will increase the risk of unintended or intentional oral exposure to human beings, attracting safety concerns about their biological fates and toxicological effects. The normal enzymatic activity of digestive enzymes is essential for the proper functioning of the gastrointestinal tract system. However, whether and how orally entered GRMs and their surface groups affect digestive enzymes' activity are still scarce. In this paper, we systematically studied the effects of graphene oxide (GO), graphene modified with hydroxyl groups (OH-G), carboxyl groups (COOH-G), and amino groups (NH2-G) on enzymatic activity of three typical digestive enzymes (pepsin, trypsin, and α-pancreatic amylase). The results showed that the activity of trypsin and α-pancreatic amylase could be greatly changed after GRMs incubation in a surface chemistry dependent manner, while the activity of pepsin was not affected. To elucidate the mechanisms at the molecular level, the interactions between trypsin and GRMs were studied by spectrometry, thermophoresis, and computational simulation approaches, and the key roles of surface chemistry of GRMs in tailoring the activity of trypsin were finally figured out. GO allosterically inhibited trypsin's activity in the non-competitive manner because of the conformation transition induced by the intensive interactions. COOH-G could effectively hamper enzymatic activity of trypsin in the competitive manner by blocking the active catalytic pocket. As for NH2-G and OH-G, they had little impact on the activity of trypsin due to the weak binding affinity or limited conformational change. Our findings not only indicate surface chemistry plays an important role in tailoring the effects of GRMs on the activity of digestive enzymes but also provide new insights for understanding the oral safety of nanomaterials from daily products and the environment.


Assuntos
Grafite , Humanos , Grafite/química , Tripsina/química , Pepsina A/metabolismo , alfa-Amilases/metabolismo , Amilases
14.
Inorg Chem ; 61(50): 20397-20404, 2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36459670

RESUMO

Hydrogen energy is a renewable and clean source, which makes a great difference in future sustainable energy systems. Visible-light-driven photocatalysis reaction involves harnessing the abundance of sunlight for hydrogen production among many catalytic technologies. However, the fabrication of photocatalysts that have distinctive performance in visible light is still the primary challenge. Herein, two new Cu-modified polyoxotungstate hybrids, {[Cu2(bim)4(H2O)2](HBW12O40)2·(H2bim)2·8H2O} (1) (bim = [1,1'-methylenebis(1H-imidazole)]) and {[Cu2(bim)4(H2O)2](H3PW10Ti2O40)2·(H2bim)2·8H2O} (2), have been successfully isolated by bridging two saturated Keggin polyoxotungstates and copper-azole complexes. Not surprisingly, 2 holds higher reduction activity due to the more negative charge and stronger basicity on the terminal oxygen of Ti═O and bridge oxygen of Ti-O-W. The H2 yield was 17075 µmol g-1 h-1 for 2 in the tunable light-driven H2 production system, which is promising in the field of photocatalysis.

15.
Chem Commun (Camb) ; 58(95): 13250-13253, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36367053

RESUMO

Most of the known senolytics are anti-cancer drugs or their derivative molecules. However, senolytics derived from the active ingredients of traditional Chinese medicine (TCM) are rarely reported. Here, we identified oridonin as a novel senolytic and further revealed that it might target a class of glutathione S-transferases to activate ROS-p38 signaling and induce apoptosis in senescent cells.


Assuntos
Apoptose , Senoterapia , Espécies Reativas de Oxigênio , Senescência Celular , Glutationa/farmacologia , Transferases/farmacologia
16.
Metabolites ; 12(11)2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36422270

RESUMO

Tripterygium glycoside tablet (TGT), as a common clinical drug, can easily cause liver damage due to the narrow therapeutic window. Glycyrrhizic acid (GA) has a hepatoprotective effect, but the characteristics and mechanism of GA's impact on TGT-induced acute liver injury by regulating oxidative stress remain unelucidated. In this study, TGT-induced acute liver injury models were established in vitro and in vivo. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), lactate dehydrogenase (LDH), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were quantified. The anti-apoptotic effect of GA was tested using flow cytometry. Potential target proteins of GA were profiled via activity-based protein profiling (ABPP) using a cysteine-specific (IAA-yne) probe. The results demonstrate that GA markedly decreased the concentrations of ALT, AST, AKP, MDA, LDH, TNF-α, IL-1ß and IL-6, whereas those of SOD, GSH and CAT increased. GA could inhibit TGT-induced apoptosis in BRL-3A cells. GA bound directly to the cysteine residue of PKM2. The CETSA and enzyme activity results validate the specific targets identified. GA could mitigate TGT-induced acute liver injury by mediating PKM2, reducing oxidative stress and inflammation and reducing hepatocyte apoptosis.

17.
Adv Sci (Weinh) ; 9(30): e2202706, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36031409

RESUMO

Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomics data of tonsillar microbiome, a deficiency of the encoding genes of lantibiotic peptides salivaricins in RA patients is identified, which shows strong correlation with circulating immune cells. Evidence is provided that the salivaricins exert immunomodulatory effects in inhibiting T follicular helper (Tfh) cell differentiation and interleukin-21 (IL-21) production. Mechanically, salivaricins directly bind to and induce conformational changes of IL-6 and IL-21 receptors, thereby inhibiting the bindings of IL-6 and IL-21 to their receptors and suppressing the downstream signaling pathway. Finally, salivaricin administration exerts both prophylactic and therapeutic effects against experimental arthritis in a murine model of RA. Together, these results provide a mechanism link of microbial peptides-mediated immunomodulation.


Assuntos
Artrite Reumatoide , Bacteriocinas , Microbiota , Tonsila Palatina , Receptores de Interleucina-21 , Receptores de Interleucina-6 , Animais , Humanos , Camundongos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Bacteriocinas/uso terapêutico , Interleucina-6/metabolismo , Receptores de Interleucina-21/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Tonsila Palatina/microbiologia , Receptores de Interleucina-6/metabolismo
18.
Inorg Chem ; 61(30): 11775-11786, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35858285

RESUMO

Sulfur oxides from the combustion of petrol and excessive emissions of carbon dioxide (CO2) are currently the main causes of environmental pollution. Considerable interest has been paid to solving the challenge, and catalytic reactions seem to be the desired choice. Due to the high density of Lewis acid active sites, polyoxometalates are considered to be the ideal choice for these catalytic reactions. Herein, two captivating polyoxometalate-based metal-organic complexes, formulated as [Co(H2O)2DABT]2[CrMo6(OH)5O19] ({Co-CrMo6}) and [Zn(H2O)2DABT]2[CrMo6(OH)5O19] ({Zn-CrMo6}) (DABT = 3,3'-diamino-5,5'-bis(1H-1,2,4-triazole)) were successfully obtained under hydrothermal conditions. The structural analysis demonstrates that {Co-CrMo6} and {Zn-CrMo6} are isostructural with two different transition metal (Co/Zn) ions based on quadridentate Anderson-type [CrMo6(OH)5O19]4- polyanions. A fan-shaped unit of {Co-CrMo6}/{Zn-CrMo6} is linked to generate a one-dimensional (1D) ladder-like structure. Intriguingly, benefitting from rich Co centers with a suitable energy band structure, {Co-CrMo6} displays better photocatalytic activity than {Zn-CrMo6} for converting CO2 into CO, endowing the CO formation of 1935.3 µmol g-1 h-1 with high selectivity. Meanwhile, {Co-CrMo6} also exhibits a satisfactory removal rate of 99% for oxidizing dibenzothiophene at 50 °C, which suggests that {Co-CrMo6} may be utilized as a potential dual functional material with immense prospects in photocatalytic CO2 reduction and sulfur oxidation for the first time.

19.
Chem Commun (Camb) ; 58(64): 9030-9033, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35876000

RESUMO

Whether or not the anticancer activity of gambogic acid is achieved via regulating the cellular metabolic process remains unclear. Here we report that gambogic acid suppresses the pentose phosphate pathway (PPP) by covalently inhibiting the 6-phosphogluconate dehydrogenase (6PGD) protein. This study elucidates the mechanism of action of gambogic acid from the perspective of metabolic reprogramming regulation in cancer cells.


Assuntos
Neoplasias , Xantonas , Neoplasias/metabolismo , Via de Pentose Fosfato , Fosfogluconato Desidrogenase/metabolismo , Xantonas/farmacologia
20.
J Integr Plant Biol ; 64(6): 1264-1280, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35352463

RESUMO

The mechanisms that balance plant growth and stress responses are poorly understood, but they appear to involve abscisic acid (ABA) signaling mediated by protein kinases. Here, to explore these mechanisms, we examined the responses of Arabidopsis thaliana protein kinase mutants to ABA treatment. We found that mutants of BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1 (BAK1) were hypersensitive to the effects of ABA on both seed germination and primary root growth. The kinase OPEN STOMATA 1 (OST1) was more highly activated by ABA in bak1 mutant than the wild type. BAK1 was not activated by ABA treatment in the dominant negative mutant abi1-1 or the pyr1 pyl4 pyl5 pyl8 quadruple mutant, but it was more highly activated by this treatment in the abi1-2 abi2-2 hab1-1 loss-of-function triple mutant than the wild type. BAK1 phosphorylates OST1 T146 and inhibits its activity. Genetic analyses suggested that BAK1 acts at or upstream of core components in the ABA signaling pathway, including PYLs, PP2Cs, and SnRK2s, during seed germination and primary root growth. Although the upstream brassinosteroid (BR) signaling components BAK1 and BR INSENSITIVE 1 (BRI1) positively regulate ABA-induced stomatal closure, mutations affecting downstream components of BR signaling, including BRASSINOSTEROID-SIGNALING KINASEs (BSKs) and BRASSINOSTEROID-INSENSITIVE 2 (BIN2), did not affect ABA-mediated stomatal movement. Thus, our study uncovered an important role of BAK1 in negatively regulating ABA signaling during seed germination and primary root growth, but positively modulating ABA-induced stomatal closure, thus optimizing the plant growth under drought stress.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Brassinosteroides/metabolismo , Regulação da Expressão Gênica de Plantas , Mutação/genética , Estômatos de Plantas/fisiologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética
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