Chemico-Biological Interactions最新文献

{"title":"Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by darolutamide: Prediction of in vivo drug-drug interactions","authors":"Shichao Xiao,&nbsp;Hang Yin,&nbsp;Xin Lv,&nbsp;Zhen Wang,&nbsp;Lili Jiang,&nbsp;Yangliu Xia,&nbsp;Yong Liu","doi":"10.1016/j.cbi.2024.111246","DOIUrl":"10.1016/j.cbi.2024.111246","url":null,"abstract":"<div><p>Darolutamide is a potent second-generation, selective nonsteroidal androgen receptor inhibitor (ARI), which has been approved by the US Food and Drug Administration (FDA) in treating castrate-resistant, non-metastatic prostate cancer (nmCRPC). Whether darolutamide affects the activity of UDP-glucuronosyltransferases (UGTs) is unknown. The purpose of the present study is to evaluate the inhibitory effect of darolutamide on recombinant human UGTs and pooled human liver microsomes (HLMs), and explore the potential for drug-drug interactions (DDIs) mediated by darolutamide through UGTs inhibition. The product formation rate of UGTs substrates with or without darolutamide was determined by HPLC or UPLC-MS/MS to estimate the inhibitory effect and inhibition modes of darolutamide on UGTs were evaluated by using the inhibition kinetics experiments. The results showed that 100 μM darolutamide exhibited inhibitory effects on most of the 12 UGTs tested. Inhibition kinetic studies of the enzyme revealed that darolutamide noncompetitively inhibited UGT1A1 and competitively inhibited UGT1A7 and 2B15, with the <em>K</em>_i of 14.75 ± 0.78 μM, 14.05 ± 0.42 μM, and 6.60 ± 0.08 μM, respectively. In particular, it also potently inhibited SN-38, the active metabolite of irinotecan, glucuronidation in HLMs with an IC₅₀ value of 3.84 ± 0.46 μM. In addition, the <em>in vitro-in vivo</em> extrapolation (IVIVE) method was used to quantitatively predict the risk of darolutamide-mediated DDI via inhibiting UGTs. The prediction results showed that darolutamide may increase the risk of DDIs when administered in combination with substrates of UGT1A1, UGT1A7, or UGT2B15. Therefore, the combined administration of darolutamide and drugs metabolized by the above UGTs should be used with caution to avoid the occurrence of potential DDIs.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111246"},"PeriodicalIF":4.7,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240103","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}

{"title":"Molecular mechanisms of zinc oxide nanoparticles neurotoxicity","authors":"Michael Aschner ,&nbsp;Anatoly V. Skalny ,&nbsp;Rongzhu Lu ,&nbsp;Airton C. Martins ,&nbsp;Aristidis Tsatsakis ,&nbsp;Sergey A. Miroshnikov ,&nbsp;Abel Santamaria ,&nbsp;Alexey A. Tinkov","doi":"10.1016/j.cbi.2024.111245","DOIUrl":"10.1016/j.cbi.2024.111245","url":null,"abstract":"<div><p>Zinc oxide nanoparticles (ZnONPs) are widely used in industry and biomedicine. A growing body of evidence demonstrates that ZnONPs exposure may possess toxic effects to a variety of tissues, including brain. Therefore, the objective of the present review was to summarize existing evidence on neurotoxic effects of ZnONPs and discuss the underlying molecular mechanisms. The existing laboratory data demonstrate that both in laboratory rodents and other animals ZnONPs exposure results in a significant accumulation of Zn in brain and nervous tissues, especially following long-term exposure. As a result, overexposure to ZnONPs causes oxidative stress and cell death, both in neurons and glial cells, by induction of apoptosis, necrosis and ferroptosis. In addition, ZnONPs may induce neuroinflammation through the activation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and lipoxygenase (LOX) signaling pathways. ZnONPs exposure is associated with altered cholinergic, dopaminergic, serotoninergic, as well as glutamatergic and γ-aminobutyric acid (GABA)-ergic neurotransmission, thus contributing to impaired neuronal signal transduction. Cytoskeletal alterations, as well as impaired autophagy and mitophagy also contribute to ZnONPs-induced brain damage. It has been posited that some of the adverse effects of ZnONPs in brain are mediated by altered microRNA expression and dysregulation of gut-brain axis. Furthermore, <em>in vivo</em> studies have demonstrated that ZnONPs exposure induced anxiety, motor and cognitive deficits, as well as adverse neurodevelopmental outcome. At the same time, the relevance of ZnONPs-induced neurotoxicity and its contribution to pathogenesis of neurological diseases in humans are still unclear. Further studies aimed at estimation of hazards of ZnONPs to human brain health and the underlying molecular mechanisms are warranted.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111245"},"PeriodicalIF":4.7,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240104","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}

{"title":"Telomerase reverse transcriptase protects against diabetic kidney disease by promoting AMPK/PGC-1a-regulated mitochondrial energy homeostasis","authors":"Nan Ma,&nbsp;Chengye Xu,&nbsp;Yan Wang,&nbsp;Kexin Cui,&nbsp;Hongyu Kuang","doi":"10.1016/j.cbi.2024.111238","DOIUrl":"10.1016/j.cbi.2024.111238","url":null,"abstract":"<div><p>Disordered glucose and lipid metabolism, coupled with disturbed mitochondrial bioenergetics, are pivotal in the initiation and development of diabetic kidney disease (DKD). While the essential role of telomerase reverse transcriptase (TERT) in regulating mitochondrial function in the cardiovascular system has been recognized, its specific function in maintaining mitochondrial homeostasis in DKD remains unclear. This study aimed to explore how TERT regulates mitochondrial function and the underlying mechanisms. <em>In vitro</em>, human renal proximal tubular HK-2 cells exposed to high glucose/high fat (HG/HF) presented significant downregulation of TERT and AMPK dephosphorylation. This led to decreased ATP production, altered NAD⁺/NADH ratios, reduced mitochondrial complex activities, increased mitochondrial dysfunction, lipid accumulation, and reactive oxygen species (ROS) production. Knockdown of TERT (si-TERT) further exacerbated mitochondrial dysfunction, decreased mitochondrial membrane potential, and lowered levels of cellular oxidative phosphorylation and glycolysis, as determined via a Seahorse X24 flux analyzer. Conversely, mitochondrial dysfunction was significantly alleviated after pcDNA-TERT plasmid transfection and adeno-associated virus (AAV) 9-TERT gene therapy <em>in vivo</em>. Notably, treatment with an AMPK inhibitor, activator, and si-PGC-1a (peroxisome proliferator-activated receptor γ coactivator-1α), resulted in mitochondrial dysfunction and decreased expression of genes related to energy metabolism and mitochondrial biogenesis. Our findings reveal that TERT protects mitochondrial function and homeostasis by partially activating the AMPK/PGC-1a signaling pathway. These results establish a crucial foundation for understanding TERT's critical role inmitochondrial regulation and its protective effect on DKD.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111238"},"PeriodicalIF":4.7,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230273","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}

{"title":"Association of genetic variants in CYP3A5, DRD2 and NK1R with opioid overdose","authors":"Joshua Lambert ,&nbsp;Dan Petrovitch ,&nbsp;Katie P. Himes ,&nbsp;Caroline E. Freiermuth ,&nbsp;Robert S. Braun ,&nbsp;Jennifer L. Brown ,&nbsp;Jason J. Bischof ,&nbsp;Michael S. Lyons ,&nbsp;Brittany E. Punches ,&nbsp;Andrew K. Littlefield ,&nbsp;David F. Kisor ,&nbsp;Jon E. Sprague","doi":"10.1016/j.cbi.2024.111242","DOIUrl":"10.1016/j.cbi.2024.111242","url":null,"abstract":"<div><p>In 2023, 3651 Ohioans died because of an opioid overdose. Of those opioid overdoses, 3579 (98%) of which were attributed to fentanyl. We evaluated the association between 180 candidate single nucleotide polymorphisms (SNPs) and self-reported, nonfatal opioid overdose history from a prospective sample of 1301 adult patients (≥18 years of age) seen in three urban emergency departments in Ohio. Candidate SNPs included 120 related to the dopamine reward pathway and 60 related to pharmacokinetics. Of the 821 patients who reported having been exposed to opioids in their lifetime, 95 (11.6%) also reported having experienced an opioid-related overdose. Logistic regression, adjusting for age and biologic sex, was used to characterize the association between each SNP and opioid overdose, correcting for multiple comparisons. Three SNPs, located in three different genes were associated with opioid overdose: increased odds with <em>CYP3A5</em> (rs776746) and <em>DRD2</em> (rs4436578), and decreased odds with <em>NKIR</em> (rs6715729). Homozygotic <em>CYP3A5</em> (rs776746) had the highest adjusted odds ratio (OR) of 6.96 (95% CI [2.45, 29.23]) and homozygotic <em>NK1R</em> (rs6715729) had the lowest OR of 0.28 (95% CI [0.14, 0.54). Given that <em>CYP3A5</em> (rs776746) has been associated with increased plasma concentrations of fentanyl, rs776746 could potentially be utilized as a prognostic risk indicator for the potential of an opioid overdose. <em>NK1R</em> regulates the expression of the neurokinin-1 receptor, a regulator of respiration and <em>NK1R</em> (rs6715729) represents a novel genetic marker for a decreased risk of opioid overdose risk.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111242"},"PeriodicalIF":4.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0009279724003880/pdfft?md5=8abc43c98741a2dc03598dd5876fe0c1&pid=1-s2.0-S0009279724003880-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142172185","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}

{"title":"Ovatodiolide inhibits endometrial cancer stemness via reactive oxygen species-mediated DNA damage and cell cycle arrest","authors":"Chun-Yu Chen ,&nbsp;Yu-Zhen Ye ,&nbsp;Yu-Hao Huang ,&nbsp;Yew-Min Tzeng ,&nbsp;Ranal Gurbanov ,&nbsp;Wen-Ling Wang ,&nbsp;Wen-Wei Chang","doi":"10.1016/j.cbi.2024.111244","DOIUrl":"10.1016/j.cbi.2024.111244","url":null,"abstract":"<div><p>Endometrial cancer (EC) is a common gynecological cancer worldwide, often associated with a poor prognosis after recurrence or metastasis. Ovatodiolide (OVA) is a macrocyclic diterpenoid derived from <em>Anisomeles indica</em> that shows anticancer effects in various malignancies. This study aimed to evaluate the cytotoxic effects of OVA on EC cell proliferation and cancer stem cell (CSC) activity and explore its underlying molecular mechanisms. OVA treatment dose-dependently reduced the viability and colony formation of three EC cell lines (AN3CA, HEC-1A, and EMC6). It induced G2/M phase cell cycle arrest, associated with decreased cell division cycle 25C (<em>CDC25C</em>) expression and reduced activation of cyclin-dependent kinases 1 (CDK1) and 2 (CDK2). OVA also increased reactive oxygen species (ROS) production and DNA damage, activating the DNA damage-sensitive cell cycle checkpoint kinases 1 (CHK1) and 2 (CHK2) and upregulating the DNA damage marker γ-H2A.X variant histone (H2AX). It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated glutathione peroxidase 1 (GPX1), an antioxidant enzyme counteracting oxidative stress. Moreover, OVA reduced the self-renewal capacity of CSCs, reducing the expression of key stemness proteins Nanog homeobox (NANOG) and octamer-binding transcription factor 4 (OCT4). The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111244"},"PeriodicalIF":4.7,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240105","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}

{"title":"Inhibition of 5-alpha reductase attenuates cardiac oxidative damage in obese and aging male rats via the enhancement of antioxidants and the p53 protein suppression","authors":"Nattayaporn Apaijai ,&nbsp;Hiranya Pintana ,&nbsp;Thiraphat Saengmearnuparp ,&nbsp;Apisek Kongkaew ,&nbsp;Busarin Arunsak ,&nbsp;Titikorn Chunchai ,&nbsp;Siriporn C. Chattipakorn ,&nbsp;Nipon Chattipakorn","doi":"10.1016/j.cbi.2024.111240","DOIUrl":"10.1016/j.cbi.2024.111240","url":null,"abstract":"<div><p>In aging and metabolic syndrome oxidative stress is a causative factor in the cardiovascular pathology. Upregulation of 5-⍺ reductase is associated with cardiac hypertrophy but how inhibition of 5-⍺ reductase affects cardiometabolic function during oxidative damage under those conditions is unclear. Our hypothesis was that Finasteride (Fin), a 5-⍺ reductase inhibitor, promotes an antioxidant response, leading to an improvement in cardiac function in obese and aging rats. Male rats were divided into 3 groups including normal diet (ND) fed rats, ND-fed rats treated with <span>d</span>-galactose (D-gal) to induce aging, and high-fat diet (HFD) fed rats to induce obesity. Rats received their assigned diet or D-gal for 18 weeks. At week 13, rats in each group were divided into 2 subgroups and received either a vehicle or Fin (5 mg/kg/day, oral gavage). Cardiometabolic and molecular parameters were subsequently investigated. Both D-gal and HFD successfully induced cardiometabolic dysfunction, oxidative stress, mitochondrial dysfunction, and DNA fragmentation. Fin treatment did not affect metabolic disturbances; however, it reduced cardiac sympathovagal imbalance, cardiac dysfunction through the inhibition of oxidative stress and promoted antioxidants, resulting in reduced p53 protein levels and DNA fragmentation. Surprisingly, Fin induced insulin resistance in ND-fed rats. Fin effectively improved cardiac function in both models by enhancing antioxidant levels, suppressing oxidative stress and DNA fragmentation. However, Fin treatment did not confer any beneficial effects on metabolic status<strong>.</strong> Fin administration effectively improved cardiac sympathovagal balance and cardiac function in rats with oxidative damage induced by either D-gal or HFD.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111240"},"PeriodicalIF":4.7,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142230241","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}

{"title":"Cardioprotection of Canagliflozin, Dapagliflozin, and Empagliflozin: Lessons from preclinical studies","authors":"Rayla Rodrigues Soares ,&nbsp;Larissa Freitas Viggiani ,&nbsp;Juliano Moreira Reis Filho ,&nbsp;Julliane V. Joviano-Santos","doi":"10.1016/j.cbi.2024.111229","DOIUrl":"10.1016/j.cbi.2024.111229","url":null,"abstract":"<div><p>Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111229"},"PeriodicalIF":4.7,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142147122","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}

{"title":"The CYP3A inducer dexamethasone affects the pharmacokinetics of sunitinib by accelerating its metabolism in rats","authors":"Guang-rong Lu ,&nbsp;Rui-zhen Wang ,&nbsp;Xin-yu Zhao ,&nbsp;Jun-er Xu ,&nbsp;Cheng-ke Huang ,&nbsp;Wei Sun ,&nbsp;Rui-jie Chen ,&nbsp;Zhe Wang","doi":"10.1016/j.cbi.2024.111228","DOIUrl":"10.1016/j.cbi.2024.111228","url":null,"abstract":"<div><p>Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC_(0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC_(0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111228"},"PeriodicalIF":4.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142147125","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}

{"title":"Human Urinary Kallidinogenase improves vascular endothelial injury by activating the Nrf2/HO-1 signaling pathway","authors":"Xiong Zhang ,&nbsp;Jiaying Yang ,&nbsp;Yini Lu ,&nbsp;Yi Liu ,&nbsp;Tianyin Wang ,&nbsp;Feng Yu","doi":"10.1016/j.cbi.2024.111230","DOIUrl":"10.1016/j.cbi.2024.111230","url":null,"abstract":"<div><p>Vascular endothelial injury is closely related to the progression of various cardio-cerebrovascular diseases. Whether Human Urinary Kallidinogenase (HUK) has a protective effect on endothelial injury remains unclear. This study established an <em>in vivo</em> model of rat common carotid artery intima injury and an <em>in vitro</em> model of human umbilical vein endothelial cell (HUVECs) injury induced by hydrogen peroxide (H₂O₂). To explore the protective effect and mechanism of HUK on endothelial injury. <em>In vivo</em>, HUK can reduce the hyperplasia and lumen stenosis of rat common carotid artery after intimal injury, and promote the fluorescence expression of vWF in the common carotid artery. HUK also activated the Nrf2/HO-1 signaling pathway in rat common carotid artery tissue to reduce endothelial damage. <em>In vitro</em>, HUK can inhibit the H₂O₂-induced decline in HUVECs activity, improve the migration ability of HUVECs induced by H₂O₂, inhibit the apoptosis and necrosis of HUVECs and the generation of ROS, and regulate the expression of VEGFA, ET-1 and eNOS proteins related to endothelial function in cells. The Nrf2/HO-1 signaling pathway is activated, and the HO-1 specific inhibitor zinc porphyrin (ZnPP) can partially reverse the protective effect of HUK on H₂O₂-induced HUVECs injury in terms of cell migration, necrosis and oxidative stress. The Nrf2/HO-1 signaling pathway plays an important role in the regulation of migration, necrosis and oxidative stress of HUVECs cells. HUK has a protective effect on vascular endothelial injury. HUK can inhibit oxidative stress and apoptotic necrosis by activating Nrf2/HO-1 signaling pathway.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111230"},"PeriodicalIF":4.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142147123","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}

{"title":"A derivative of honokiol HM568 has an anti-neuroinflammatory effect in Parkinson's disease","authors":"Changfeng Zhong ,&nbsp;Changmei Wang ,&nbsp;Wei Li ,&nbsp;Wenyuan Li ,&nbsp;Xuemei Chen ,&nbsp;Jieqing Guo ,&nbsp;Yifan Feng ,&nbsp;Xia Wu","doi":"10.1016/j.cbi.2024.111212","DOIUrl":"10.1016/j.cbi.2024.111212","url":null,"abstract":"<div><p>Parkinson's disease (PD) is the fastest growing neurodegenerative disease in the world at present. Neuroinflammation plays an important role in Parkinson's disease. In our study, we initially screened magnolol/honokiol derivatives synthesized by our group for their potential anti-neuroinflammatory properties. This was done using LPS-activated BV-2 microglial cell and MPP + -induced PC-12 cell models. Most of derivatives had increased anti-inflammatory activities and decreased toxicities compared to raw materials. Then, compounds were scored with inflammatory factors IL-1β, TNF-α and IL-6 by molecular docking <em>in silico</em>. Our studies revealed the strongest binding compound HM568 which binds with honokiol and metformin. Furthermore, HM568 showed no acute toxicity in mice through acute toxicity. And it is stable under high temperature, high humidity and strong light irradiation. Combining cell experiments and computer results, HM568 was considered for further <em>in vivo</em> pharmacological validations. Intraperitoneal injection administration of MPTP into C57BL/6 mice was utilized as Parkinson's animal model. Results showed that administration of HM568 for 14 days in MPTP-PD mice led to a significant alleviation in weight loss and movement disorders. Further HM568 could significantly down-regulate the expression levels of inflammatory factors IL-1β, IL-6 and TNF-α in brain tissue of the mouse model, reduce the level of caspase-3 and the ratio of Bcl-2/Bax, and up-regulate the level of transforming factor TGF-β, thus producing anti-apoptosis and anti-neuroinflammatory effects on neuronal cells. In terms of pathological features, HM568 could reduce the infiltration of neuronal cells and alleviate the development of lesions, promote the transformation of microglia from M1 negative phenotype to M2 type, and reverse the reduction of TH-positive immune cells in mouse neurons induced by MPTP. The administration of HM568 could reduce the abnormal accumulation of α-syn, and thus produce neuroprotective effect on MPTP-PD mice. Cell experiments, molecular docking and animal experiments thus depict HM568 as a promising agent to delay neuronal degeneration in PD, and its mechanism is related to anti-neuroinflammation.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111212"},"PeriodicalIF":4.7,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142147126","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}