Biomolecules

Research

27 pages, 5821 KiB

Open AccessArticle

Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability

by Chao-Yun Cai, Qiu-Xu Teng, Megumi Murakami, Suresh V. Ambudkar, Zhe-Sheng Chen and Vijaya L. Korlipara

Biomolecules 2023, 13(2), 253; https://doi.org/10.3390/biom13020253 - 30 Jan 2023

Cited by 2 | Viewed by 2147

Abstract

A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine 33 showed BCRP inhibitory activity. These [...] Read more.

A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine 33 showed BCRP inhibitory activity. These lead compounds were further investigated in a battery of mechanistic experiments. Compound 22 changed the localization of BCRP and P-gp in cells, thus inhibiting the efflux of anticancer drugs by the two ATP-binding cassette (ABC) transporters. In addition, both 22 and 33 significantly stimulated the ATP hydrolysis of the BCRP transporter, indicating that they can be competitive substrates of the BCRP transporter, and thereby increase the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide derivative 33, exhibited a greater inhibitory effect on BCRP after UV activation and can serve as a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. Notably, the dual BCRP and P-gp inhibitors 4–5, 22–24, 27, and BCRP inhibitor 33 showed improved metabolic stability compared to Ko143. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)

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17 pages, 3788 KiB

Open AccessArticle

Prognostic Impacts of LL-37 in Relation to Lipid Profiles of Patients with Myocardial Infarction: A Prospective Cohort Study

by Runzhen Chen, Hanjun Zhao, Jinying Zhou, Ying Wang, Jiannan Li, Xiaoxiao Zhao, Nan Li, Chen Liu, Peng Zhou, Yi Chen, Li Song and Hongbing Yan

Biomolecules 2022, 12(10), 1482; https://doi.org/10.3390/biom12101482 - 14 Oct 2022

Cited by 3 | Viewed by 1764

Abstract

Background. In vivo studies show that LL-37 inhibits the progression of atherosclerosis and predicts a lower risk of recurrent ischemia in patients with acute myocardial infarction (AMI), which could be mediated by the modulation of lipid metabolism. The current study aimed to investigate [...] Read more.

Background. In vivo studies show that LL-37 inhibits the progression of atherosclerosis and predicts a lower risk of recurrent ischemia in patients with acute myocardial infarction (AMI), which could be mediated by the modulation of lipid metabolism. The current study aimed to investigate the effects of various lipid contents on the prognostic impacts of LL-37 in patients with AMI. Methods. A total of 1567 consecutive AMI patients were prospectively recruited from March 2017 to January 2020. Patients were firstly stratified into two groups by the median level of LL-37 and then stratified by levels of various lipid contents and proprotein convertase subtilisin/kexin type 9 (PCSK9). Cox regression with multiple adjustments was performed to analyze associations between LL-37, lipid profiles, PCSK9, and various outcomes. The primary outcome was major adverse cardiovascular event (MACE), a composite of all-cause death, recurrent MI, and ischemic stroke. Results. During a median follow-up of 786 (726–1107) days, a total of 252 MACEs occurred. A high level of LL-37 was associated with lower risk of MACE in patients with elevated lipoprotein(a) (≥300 mg/L, hazard ratio (HR): 0.49, 95% confidence interval (CI): 0.29–0.86, p = 0.012) or PCSK9 levels above the median (≥47.4 ng/mL, HR: 0.57, 95% CI: 0.39–0.82, p < 0.001), which was not observed for those without elevated lp(a) (<300 mg/L, HR: 0.96, 95% CI: 0.70–1.31, p = 0.781, p_interaction = 0.035) or PCSK9 (<47.4 ng/mL, HR: 1.02, 95% CI: 0.68–1.54, p = 0.905, p_interaction = 0.032). Conclusions. For patients with AMI, a high level of LL-37 was associated with lower ischemic risk among patients with elevated lp(a) and PCSK9. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)

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14 pages, 4505 KiB

Open AccessArticle

The Imbalance of Mitochondrial Fusion/Fission Drives High-Glucose-Induced Vascular Injury

by Yunsi Zheng, Anqi Luo and Xiaoquan Liu

Biomolecules 2021, 11(12), 1779; https://doi.org/10.3390/biom11121779 - 27 Nov 2021

Cited by 12 | Viewed by 2549

Abstract

Emerging evidence shows that mitochondria fusion/fission imbalance is related to the occurrence of hyperglycemia-induced vascular injury. To study the temporal dynamics of mitochondrial fusion and fission, we observed the alteration of mitochondrial fusion/fission proteins in a set of different high-glucose exposure durations, especially [...] Read more.

Emerging evidence shows that mitochondria fusion/fission imbalance is related to the occurrence of hyperglycemia-induced vascular injury. To study the temporal dynamics of mitochondrial fusion and fission, we observed the alteration of mitochondrial fusion/fission proteins in a set of different high-glucose exposure durations, especially in the early stage of hyperglycemia. The in vitro results show that persistent cellular apoptosis and endothelial dysfunction can be induced rapidly within 12 hours’ high-glucose pre-incubation. Our results show that mitochondria maintain normal morphology and function within 4 hours’ high-glucose pre-incubation; with the extended high-glucose exposure, there is a transition to progressive fragmentation; once severe mitochondria fusion/fission imbalance occurs, persistent cellular apoptosis will develop. In vitro and in vivo results consistently suggest that mitochondrial fusion/fission homeostasis alterations trigger high-glucose-induced vascular injury. As the guardian of mitochondria, AMPK is suppressed in response to hyperglycemia, resulting in imbalanced mitochondrial fusion/fission, which can be reversed by AMPK stimulation. Our results suggest that mitochondrial fusion/fission’s staged homeostasis may be a predictive factor of diabetic cardiovascular complications. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)

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15 pages, 1909 KiB

Open AccessArticle

The Prognostic Value of Locoregional Interventions for BRAF V600E Metastatic Colorectal Cancer: A Retrospective Cohort Analysis

by Liu-Fang Ye, Xiao-Meng Ji, Chao Ren, Zhi-Qiang Wang, Chun-Ping Lin, Dong-Liang Chen, Yan-Qing Cai, Ying Jin, Miao-Zhen Qiu, Zi-Ming Du, Shao-Yan Xi, Dong-Sheng Zhang, Feng Wang, Feng-Hua Wang, Rui-Hua Xu, Yu-Hong Li and De-Shen Wang

Biomolecules 2021, 11(9), 1268; https://doi.org/10.3390/biom11091268 - 25 Aug 2021

Cited by 3 | Viewed by 2503

Abstract

The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served [...] Read more.

The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served as an independent prognosticator, where curative locoregional interventions (LRIs) were associated with superior clinical outcomes (adjusted hazard ratio (HR): 0.46, 95% confidence interval (CI): 0.22–0.98; p = 0.044). The LRIs group showed an improved median OS of 49.4 months versus 18.3 months for the palliative treatments (PTs) group. The median OS of patients with colorectal liver metastasis (CRLM) was significantly prolonged after undergoing LRIs (42.4 vs. 23.7 months; HR: 0.11, 95% CI: 0.01–1.22; p = 0.030), and patients in the LRIs plus liver-limited or lung-limited metastasis (LLM) group benefited more than those in the LRIs plus non-LLM group when compared to the PTs group (LLM from LRIs vs. PTs, HR: 0.16, 95% CI: 0.04–0.68; p = 0.006. Non-LLM from LRIs vs. PTs, HR: 0.47, 95% CI: 0.21–1.05; p = 0.074). In conclusion, we confirmed the positive prognostic value of LRIs in BRAF V600E mCRC, particularly in patients with CRLM or LLM. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)

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11 pages, 938 KiB

Open AccessArticle

C-Reactive Protein Is an Independent Predictor of 30-Day Bacterial Infection Post-Liver Transplantation

by Jiong Yu, Xiaowei Shi, Jing Ma, Ronggao Chen, Siyi Dong, Sen Lu, Jian Wu, Cuilin Yan, Jian Wu, Shusen Zheng, Lanjuan Li, Xiao Xu and Hongcui Cao

Biomolecules 2021, 11(8), 1195; https://doi.org/10.3390/biom11081195 - 12 Aug 2021

Cited by 4 | Viewed by 2430

Abstract

The relationship between aseptic systemic inflammation and postoperative bacterial infection is unclear. We investigated the correlation of systemic inflammation biomarkers with 30-day clinically significant bacterial infections (CSI) after liver transplantation (LT). This retrospective study enrolled 940 patients who received LT and were followed [...] Read more.

The relationship between aseptic systemic inflammation and postoperative bacterial infection is unclear. We investigated the correlation of systemic inflammation biomarkers with 30-day clinically significant bacterial infections (CSI) after liver transplantation (LT). This retrospective study enrolled 940 patients who received LT and were followed for 30 days. The primary end point was 30-day CSI events. The cohort was divided into exploratory (n = 508) and validation (n = 432) sets according to different centers. Area under the receiver operated characteristic (AUROC) and Cox regression models were fitted to study the association between baseline systemic inflammation levels and CSI after LT. A total of 255 bacterial infectious events in 209 recipients occurred. Among systemic inflammation parameters, baseline C-reactive protein (CRP) was independently associated with 30-day CSI in the exploratory group. The combination of CRP and organ failure number showed a good discrimination for 30-day CSI (AUROC = 0.80, 95% CI, 0.76–0.84) and the results were confirmed in an external verification group. Additionally, CRP levels were correlated with bacterial product lipopolysaccharide. In conclusion, our study suggests that pre-transplantation CRP is independent of other prognostic factors for 30-day CSI post-LT, and can be integrated into tools for assessing the risk of bacterial infection post-LT or as a component of prognostic models. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)

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Review

Jump to: Research, Other

16 pages, 14527 KiB

Open AccessReview

Structure-Guided Strategies of Targeted Therapies for Patients with EGFR-Mutant Non–Small Cell Lung Cancer

by Zhenfang Du, Jinghan Sun, Yunkai Zhang, Nigaerayi Hesilaiti, Qi Xia, Heqing Cui, Na Fan and Xiaofang Xu

Biomolecules 2023, 13(2), 210; https://doi.org/10.3390/biom13020210 - 20 Jan 2023

Cited by 2 | Viewed by 3144

Abstract

Oncogenic mutations within the EGFR kinase domain are well-established driver mutations in non–small cell lung cancer (NSCLC). Small-molecule tyrosine kinase inhibitors (TKIs) specifically targeting these mutations have improved treatment outcomes for patients with this subtype of NSCLC. The selectivity of these targeted agents [...] Read more.

Oncogenic mutations within the EGFR kinase domain are well-established driver mutations in non–small cell lung cancer (NSCLC). Small-molecule tyrosine kinase inhibitors (TKIs) specifically targeting these mutations have improved treatment outcomes for patients with this subtype of NSCLC. The selectivity of these targeted agents is based on the location of the mutations within the exons of the EGFR gene, and grouping mutations based on structural similarities has proved a useful tool for conceptualizing the heterogeneity of TKI response. Structure-based analysis of EGFR mutations has influenced TKI development, and improved structural understanding will inform continued therapeutic development and further improve patient outcomes. In this review, we summarize recent progress on targeted therapy strategies for patients with EGFR-mutant NSCLC based on structure and function analysis. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)

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13 pages, 1002 KiB

Open AccessEditor’s ChoiceReview

Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms

by Valentina Pozzi, Roberto Campagna, Davide Sartini and Monica Emanuelli

Biomolecules 2022, 12(9), 1173; https://doi.org/10.3390/biom12091173 - 24 Aug 2022

Cited by 14 | Viewed by 2221

Abstract

Gastrointestinal (GI) neoplasms include esophageal, gastric, colorectal, hepatic, and pancreatic cancers. They are characterized by asymptomatic behavior, being responsible for diagnostic delay. Substantial refractoriness to chemo- and radiotherapy, exhibited by late-stage tumors, contribute to determine poor patient outcome. Therefore, it is of outmost [...] Read more.

Gastrointestinal (GI) neoplasms include esophageal, gastric, colorectal, hepatic, and pancreatic cancers. They are characterized by asymptomatic behavior, being responsible for diagnostic delay. Substantial refractoriness to chemo- and radiotherapy, exhibited by late-stage tumors, contribute to determine poor patient outcome. Therefore, it is of outmost importance to identify new molecular targets for the development of effective therapeutic strategies. In this study, we focused on the enzyme nicotinamide N-methyltransferase (NNMT), which catalyzes the N-methylation reaction of nicotinamide and whose overexpression has been reported in numerous neoplasms, including GI cancers. The aim of this review was to report data illustrating NNMT involvement in these tumors, highlighting its contribution to tumor cell phenotype. Cited works clearly demonstrate the interesting potential use of enzyme level determination for both diagnostic and prognostic purposes. NNMT was also found to positively affect cell viability, proliferation, migration, and invasiveness, contributing to sustain in vitro and in vivo tumor growth and metastatic spread. Moreover, enzyme upregulation featuring tumor cells was significantly associated with enhancement of resistance to treatment with chemotherapeutic drugs. Taken together, these results strongly suggest the possibility to target NNMT for setup of molecular-based strategies to effectively treat GI cancers. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)

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Other

Jump to: Research, Review

6 pages, 852 KiB

Open AccessOpinion

Secreted Protein Acidic and Rich in Cysteine as a Molecular Physiological and Pathological Biomarker

by Abdelaziz Ghanemi, Mayumi Yoshioka and Jonny St-Amand

Biomolecules 2021, 11(11), 1689; https://doi.org/10.3390/biom11111689 - 13 Nov 2021

Cited by 12 | Viewed by 1933

Abstract

Secreted protein acidic and rich in cysteine (SPARC) is expressed in diverse tissues and plays roles in various biological functions and processes. Increased serum levels of SPARC or its gene overexpression have been reported following numerous physiological and pathological changes including injuries, exercise, [...] Read more.

Secreted protein acidic and rich in cysteine (SPARC) is expressed in diverse tissues and plays roles in various biological functions and processes. Increased serum levels of SPARC or its gene overexpression have been reported following numerous physiological and pathological changes including injuries, exercise, regeneration, obesity, cancer, and inflammation. Such expression pattern interrelation between these biological changes and the SPARC expression/secretion points to it as a biomarker. This property could lead to a variety of potential applications ranging from mechanistic studies and animal model validation to the clinical and therapeutic evaluation of both disease prognosis and pharmacological agents. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)

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