Biochemical pharmacology最新文献_第10页

Adipose tissue in health and disease 健康与疾病中的脂肪组织

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-14 DOI: 10.1016/j.bcp.2024.116475

引用次数: 0

Monocarbonyl analogs of curcumin C66 and B2BrBC modulate oxidative stress, JNK activity, and pancreatic gene expression in rats with streptozotocin-induced diabetes 姜黄素 C66 和 B2BrBC 的单羰基类似物可调节链脲佐菌素诱导糖尿病大鼠的氧化应激、JNK 活性和胰腺基因表达。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-13 DOI: 10.1016/j.bcp.2024.116491

{"title":"Monocarbonyl analogs of curcumin C66 and B2BrBC modulate oxidative stress, JNK activity, and pancreatic gene expression in rats with streptozotocin-induced diabetes","authors":"","doi":"10.1016/j.bcp.2024.116491","DOIUrl":"10.1016/j.bcp.2024.116491","url":null,"abstract":"<div><p>The pathogenesis of type 1 diabetes mellitus (T1DM) involves oxidative stress and inflammation. Curcumin, a natural polyphenolic compound found in turmeric, known to exhibit antioxidative and anti-inflammatory properties, is characterized by poor chemical stability, low bioavailability, and rapid metabolism. Monocarbonyl analogs of curcumin (MACs) with a structural absence of β-diketone and enhanced stability and bioavailability present a potential solution to the challenges associated with the use of curcumin. This study aimed to evaluate the effect of two MACs, C66 and B2BrBC, on oxidative stress markers, antioxidant enzyme activity, expression of diabetes-associated genes, and signaling pathway proteins in the context of T1DM. Streptozotocin (STZ)-induced male <em>Wistar</em> rats or rat pancreatic RIN-m cells were used for <em>in vivo</em> and <em>in vitro</em> experiments, respectively. C66 or B2BrBC were given either before or after STZ treatment. Oxidative stress markers and antioxidant enzyme activities were determined in various tissues. Expression of diabetes-associated genes was assessed using RT-qPCR, and the activity of signaling pathway proteins in the pancreas was determined through Western blot analysis. Treatment with C66 and B2BrBC significantly reduced oxidative stress markers and positively influenced antioxidant enzyme activities. Moreover, both compounds inhibited JNK activity in the pancreas while enhancing the expression of genes crucial for β-cell survival and glucose and redox homeostasis. The findings highlight the multifaceted potential of C66 and B2BrBC in ameliorating oxidative stress, influencing gene expression patterns linked to diabetes, and modulating key signaling pathways in the pancreas. The findings suggest that these compounds can potentially address diabetes-related pathological processes.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S000629522400474X/pdfft?md5=1f4c453a4ea33b4bd17948e624e5f38f&pid=1-s2.0-S000629522400474X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Isoquinoline small molecule ligands are agonists and probe-dependent allosteric modulators of the glucagon subfamily of GPCRs 异喹啉小分子配体是胰高血糖素亚家族 GPCR 的激动剂和探针依赖性异位调节剂。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-13 DOI: 10.1016/j.bcp.2024.116483

{"title":"Isoquinoline small molecule ligands are agonists and probe-dependent allosteric modulators of the glucagon subfamily of GPCRs","authors":"","doi":"10.1016/j.bcp.2024.116483","DOIUrl":"10.1016/j.bcp.2024.116483","url":null,"abstract":"<div><p>Class B1 G protein-coupled receptors (GPCRs) are peptide hormone receptors and well validated therapeutic targets, however development of non-peptide drugs targeting this class of receptors is challenging. Recently, a series of isoquinoline-based derivates were reported in the patent literature as allosteric ligands for the glucagon receptor subfamily, and two compounds, LSN3451217 and LSN3556672, were used to facilitate structural studies with the glucagon-like peptide-1 receptor (GLP-1R) and glucose dependent insulinotropic peptide receptor (GIPR) bound to orthosteric agonists. Here we pharmacologically characterized stereoisomers of LSN3451217 and LSN3556672, across the class B1 GPCR family. This revealed LSN3556672 isomers are agonists for the glucagon receptor (GCGR), GLP-1R, GIPR and the calcitonin receptor (CTR), albeit the degree of agonism varied at each receptor. In contrast, LSN3451217 isomers were more selective agonists at the GLP-1R, with lower potency at the GCGR and CTR and no activity at the GIPR. All compounds also modulated peptide-mediated cyclic adenosine monophosphate (cAMP) signaling at the GIPR, and to a lesser extent the GLP-1R, in a probe-dependent manner, with modest positive allosteric modulation observed for some peptides, and negligible effects observed with other peptides. In contrast neutral or weak negative/positive allosteric modulation was observed with peptides assessed at the GCGR and CTR. This study expands our knowledge on class B1 GPCR allosteric modulation and may have implications for future structural and drug discovery efforts targeting the class B1 GPCR subfamily.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224004660/pdfft?md5=a90c77b773859c0641005e42402eadb3&pid=1-s2.0-S0006295224004660-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Melatonin alleviates brain injury in copper-laden rats: Underlying benefits for Wilson’s disease 褪黑素可减轻铜负荷大鼠的脑损伤：对威尔逊氏病的潜在益处

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-13 DOI: 10.1016/j.bcp.2024.116490

{"title":"Melatonin alleviates brain injury in copper-laden rats: Underlying benefits for Wilson’s disease","authors":"","doi":"10.1016/j.bcp.2024.116490","DOIUrl":"10.1016/j.bcp.2024.116490","url":null,"abstract":"<div><p>Copper serves as an indispensable cofactor for all living organisms, and its excessive accumulation has been associated with a variety of diseases. Wilson’s disease (WD) serves as an illustrative example of copper toxicity in humans, frequently presenting with liver and/or neuropsychiatric symptoms. The current therapeutic drugs, penicillamine (PA) and zinc gluconate (ZnG), have constraints, and research on their combination efficacy remains insufficient. It has been reported that melatonin (MLT) plays a vital role in binding to transition metals and exhibits strong antioxidant capacity. To investigate the therapeutic efficacy of MLT and combined treatment, rats were randomly divided into the following seven groups: the control (Con) group, copper-laden model rat (Mod) group, PA-treated group, ZnG-treated group, MLT- treated group, PA-ZnG-treated group, and PA-MLT-treated group. Then potential mechanisms and targets were investigated using a combination of metabolomics and network pharmacology and verified by molecular docking and qPCR. The findings revealed that MLT and the combination significantly improved behavior, pathology and copper levels in copper-laden rats. The results of the metabolomics study showed that profoundly altered metabolites were identified, and alanine, aspartate and glutamate metabolism, pyruvate metabolism, citrate cycle (TCA cycle), and glycolysis/gluconeogenesis were explored. In addition, molecular docking showed that MLT had high binding affinity with key targets, and qPCR results revealed that MLT could reverse the mRNA expression of targets GOT2 and PKM2. It was concluded that MLT effectively improves brain injury in copper-laden rats, and this effect was linked with the altered features of the metabolite profiles.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The emergence of antidepressant drugs targeting GABAA receptors: A concise review 以 GABAA 受体为靶点的抗抑郁药物的出现：简明综述。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-13 DOI: 10.1016/j.bcp.2024.116481

{"title":"The emergence of antidepressant drugs targeting GABAA receptors: A concise review","authors":"","doi":"10.1016/j.bcp.2024.116481","DOIUrl":"10.1016/j.bcp.2024.116481","url":null,"abstract":"<div><p>Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic burden on patients, caregivers, and the public health system. Treatment with classical antidepressants (e.g. tricyclic antidepressants and selective serotonine reuptake inhibitors), which primarily affect monoaminergic systems has several limitations, such as delayed onset of action and moderate efficacy in a relatively large proportion of depressed patients. Furthermore, depression is highly heterogeneus, and its different subtypes, including post-partum depression, involve distinct neurobiology, warranting a differential approach to pharmacotherapy. Given these shortcomings, the need for novel antidepressants that are superior in efficacy and faster in onset of action is fully justified. The development and market introduction of rapid-acting antidepressants has accelerated in recent years. Some of these new antidepressants act through the GABAergic system. In this review, we discuss the discovery, efficacy, and limitations of treatment with classic antidepressants. We provide a detailed discussion of GABAergic neurotransmission, with a special focus on GABA<sub>A</sub> receptors, and possible explanations for the mood-enhancing effects of GABAergic medications (in particular neurosteroids acting at GABA<sub>A</sub> receptors), and, ultimately, we present the most promising molecules belonging to this family which are currently used in clinical practice or are in late phases of clinical development.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0006295224004647/pdfft?md5=fc4775b1aaa78ebe29e04de4ac4d8dda&pid=1-s2.0-S0006295224004647-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alamandine, a protective component of the renin-angiotensin system, reduces cellular proliferation and interleukin-6 secretion in human macrophages through MasR–MrgDR heteromerization 肾素-血管紧张素系统的保护成分阿拉曼丁通过 MasR-MrgDR 异构化减少人巨噬细胞的细胞增殖和白细胞介素-6 的分泌。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116480

{"title":"Alamandine, a protective component of the renin-angiotensin system, reduces cellular proliferation and interleukin-6 secretion in human macrophages through MasR–MrgDR heteromerization","authors":"","doi":"10.1016/j.bcp.2024.116480","DOIUrl":"10.1016/j.bcp.2024.116480","url":null,"abstract":"<div><p>Alamandine (ALA) exerts protective effects similar to angiotensin (Ang) (1–7) through Mas-related G protein-coupled receptor type D receptor (MrgDR) activation, distinct from Mas receptor (MasR). ALA induces anti-inflammatory effects in mice but its impact in human macrophages remains unclear. We aimed to investigate the anti-inflammatory effects of ALA in human macrophages. Interleukin (IL)-6 and IL-1β were measured by ELISA in human THP-1 macrophages and human monocyte-derived macrophages exposed to lipopolysaccharide (LPS). Consequences of MasR–MrgDR heteromerization were investigated in transfected HEK293T cells. ALA decreased IL-6 and IL-1β secretion in LPS-activated THP-1 macrophages. The ALA-induced decrease in IL-6 but not in IL-1β was prevented by MasR blockade and MasR downregulation, suggesting MasR–MrgDR interaction. In human monocyte-derived M1 macrophages, ALA decreased IL-1β secretion independently of MasR. MasR–MrgDR interaction was confirmed in THP-1 macrophages, human monocyte-derived macrophages, and transfected HEK293T cells. MasR and MrgDR formed a constitutive heteromer that was not influenced by ALA. ALA promoted Akt and ERK1/2 activation only in cells expressing MasR–MrgDR heteromers, and this effect was prevented by MasR blockade. While Ang-(1–7) reduced cellular proliferation in MasR −but not MrgDR- expressing cells, ALA antiproliferative effect was elicited in cells expressing MasR–MrgDR heteromers. ALA also induced an antiproliferative response in THP-1 cells and this effect was abolished by MasR blockade, reinforcing MasR–MrgDR interaction. MasR–MrgDR heteromerization is crucial for ALA-induced anti-inflammatory and antiproliferative responses in human macrophages. This study broaden our knowledge of the protective axis of the RAS, thus enabling novel therapeutic approaches in inflammatory-associated diseases.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Trimetazidine attenuates Ischemia/Reperfusion-Induced myocardial ferroptosis by modulating the Sirt3/Nrf2-GSH system and reducing Oxidative/Nitrative stress 曲美他嗪通过调节 Sirt3/Nrf2-GSH 系统和减少氧化/硝化应激，减轻缺血/再灌注诱导的心肌铁蛋白沉积。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116479

{"title":"Trimetazidine attenuates Ischemia/Reperfusion-Induced myocardial ferroptosis by modulating the Sirt3/Nrf2-GSH system and reducing Oxidative/Nitrative stress","authors":"","doi":"10.1016/j.bcp.2024.116479","DOIUrl":"10.1016/j.bcp.2024.116479","url":null,"abstract":"<div><p>Ferroptosis is a newly defined mode of cellular demise. The increasing investigation supports that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia–reperfusion (I/R) injury. Hence, targeting ferroptosis is a novel strategy for treating myocardial injury. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. This study aimed to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. To this end, researchers have constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. Here, I/R mediated the onset of ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated cardiomyocyte injury. Mechanistically, we found that TMZ upregulated the expression of Sirt3. Therefore, we used si-Sirt3 and 3-TYP to interfere with Sirt3 action in vitro and in vivo, respectively. Both si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. These results indicate that TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway. Our study offers insights into the mechanism underlying the cardioprotective benefits of TMZ and establishes a groundwork for expanding its potential applications.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endothelial Birc3 promotes renal fibrosis through modulating Drp1-mediated mitochondrial fission via MAPK/PI3K/Akt pathway 内皮细胞 Birc3 通过 MAPK/PI3K/Akt 通路调节 Drp1 介导的线粒体裂变，从而促进肾脏纤维化。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116477

{"title":"Endothelial Birc3 promotes renal fibrosis through modulating Drp1-mediated mitochondrial fission via MAPK/PI3K/Akt pathway","authors":"","doi":"10.1016/j.bcp.2024.116477","DOIUrl":"10.1016/j.bcp.2024.116477","url":null,"abstract":"<div><p>Renal fibrosis serves as the shared pathway in chronic kidney disease (CKD) progression towards end-stage renal disease (ESRD). Endothelial-mesenchymal transition (EndMT) is a vital mechanism leading to the generation of myofibroblasts, thereby contributing to the advancement of fibrogenesis. Baculoviral IAP Repeat Containing 3(Birc3) was identified as a crucial inhibitor of cell death and a significant mediator in inflammatory signaling and immunity. However, its involvement in the development of renal interstitial fibrosis via EndMT still needs to be clarified. Herein, elevated levels of Birc3 expression along with EndMT-associated alterations, including increased α-smooth muscle actin (α-SMA) levels and decreased CD31 expression, were observed in fibrotic kidneys of Unilateral Ureteral Obstruction (UUO)-induced mouse models and transforming growth factor-β (TGF-β)-induced EndMT in Human Umbilical Vein Endothelial Cells (HUVECs). Functionally, Birc3 knockdown inhibited EndMT and mitochondrial fission mediated by dynamin-related protein 1 (Drp1) both <em>in vivo</em> and <em>in vitro</em>. Mechanistically, endothelial Birc3 exacerbated Drp-1-induced mitochondrial fission through the MAPK/PI3K/Akt signaling pathway in endothelial cell models stimulated TGF-β. Collectively, these findings illuminate the mechanisms and indicate that targeting Birc3 could offer a promising therapeutic strategy to improve endothelial cell survival and mitigate the progression of CKD.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S000629522400460X/pdfft?md5=4864ea6de89f8edc2035fbd508e60605&pid=1-s2.0-S000629522400460X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The ‘ABC’ of split-nanoluciferase HIF heterodimerization bioassays: Applications, Benefits & Considerations 分体荧光素酶 HIF 异源二聚体生物测定的 "ABC"：应用、益处和注意事项。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116478

{"title":"The ‘ABC’ of split-nanoluciferase HIF heterodimerization bioassays: Applications, Benefits & Considerations","authors":"","doi":"10.1016/j.bcp.2024.116478","DOIUrl":"10.1016/j.bcp.2024.116478","url":null,"abstract":"<div><p>Hypoxia-inducible factors (HIF) are interesting targets for multiple therapeutic indications. While HIF activation is desired for the treatment of anemia-related and ischemic diseases, HIF inhibition is of tremendous interest to anti-cancer drug development. Different signaling events within the HIF pathway are being targeted by drug discovery programs, with a special interest in HIF-selective (possibly also HIF1/2 isoform-selective) compounds. In this study, we applied recently developed cell-based split-nanoluciferase HIF heterodimerization assays to study the effects of compounds, targeting HIF activity by various mechanisms of action. This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Changes in treatment time and in the assay protocol allowed to assess direct and indirect effects on HIFα-HIFβ heterodimerization. In addition to the evaluation of applications of these new bioassays regarding pharmacological characterizations, benefits and considerations are discussed related to the use of cellular, luminescent-based bioassays. Briefly, benefits include the bidirectional nature of the biological readout, the upstream mechanism of detection, the differentiation between HIF1 and HIF2 effects and the simulation of various conditions. Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Zn(II) enhances the antimicrobial effect of chloroxine and structural analogues against drug-resistant ESKAPE pathogens in vitro Zn(II) 可增强氯氧嘧啶和结构类似物在体外对耐药性 ESKAPE 病原体的抗菌效果。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-08-10 DOI: 10.1016/j.bcp.2024.116482

{"title":"Zn(II) enhances the antimicrobial effect of chloroxine and structural analogues against drug-resistant ESKAPE pathogens in vitro","authors":"","doi":"10.1016/j.bcp.2024.116482","DOIUrl":"10.1016/j.bcp.2024.116482","url":null,"abstract":"<div><p>The emerging antibiotic-resistant bacteria, especially the “<em>ESKAPE</em>” pathogens, pose a continuous threat to global health. In this study, we explored metalloantibiotics as promising therapeutics and innovative antimicrobial agents. The role of metal in the antimicrobial activity of chloroxine (5,7-dichloro-8-hydroxyquinoline), as a metalloantibiotic, was investigated by minimal inhibit concentration (MIC) assay and a series of assays, including growth curve, time-killing, and UV–visible spectroscopy and PAR (4-(2-pyridylazo)-resorcinol) competition assays. Both chloroxine and its structural analogues exhibited increased antibacterial potency against Gram-positive bacteria compared to Gram-negative bacteria. The introduction of exogenous manganese or zinc ions significantly boosted chloroxine’s antibacterial efficacy against Gram-negative bacteria, including the notorious <em>ESKAPE</em> pathogens. However, the enhanced antibacterial activity induced by zinc ions could be negated in the presence of copper or ferrous iron ions, as well as changes in oxygen availability, highlighting the involvement of proton motive force, oxidative and antioxidative systems. Notably, chloroxine effectively inhibited the enzymatic activity of superoxide dismutase (SOD). In addition, chloroxine could reverse polymyxin and carbapenem resistance in <em>E. coli in vitro</em>. Therefore, these results suggested that chloroxine with zinc ions are promising therapeutics and antibiotics potentiator to combat multidrug-resistant <em>ESKAPE</em> pathogens.</p></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0