Journal of Pharmaceutical Analysis

CLDN18.2-targeted molecular imaging and precision therapy of gastrointestinal tumors

Yan Chen, Zhi Yang, Xueyun Gao, Hua Zhu

2023, 13(9): 955-957. doi: 10.1016/j.jpha.2023.08.007

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Comment on: “Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors”

Cuicui Li, Xiaoyuan Chen, Jingjing Zhang

2023, 13(9): 958-959. doi: 10.1016/j.jpha.2023.07.010

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Applications and safety of gold nanoparticles as therapeutic devices in clinical trials

Leeann Yao, Dejan Bojic, Mingyao Liu

2023, 13(9): 960-967. doi: 10.1016/j.jpha.2023.06.001

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Use of gold nanoparticles (GNPs) in medicine is an emerging field of translational research with vast clinical implications and exciting therapeutic potential. However, the safety of using GNPs in human subjects is an important question that remains unanswered. This study reviews over 20 clinical trials focused on GNP safety and aims to summarize all the clinical studies, completed and ongoing, to identify whether GNPs are safe to use in humans as a therapeutic platform. In these studies, GNPs were implemented as drug delivery devices, for photothermal therapy, and utilized for their intrinsic therapeutic effects by various routes of delivery. These studies revealed no major safety concerns with the use of GNPs; however, the number of trials and total patient number remains limited. Multi-dose, multi-center blinded trials are required to deepen our understanding of the use of GNPs in clinical settings to facilitate translation of this novel, multifaceted therapeutic device. Expanding clinical trials will require collaboration between clinicians, scientists, and biotechnology companies.

Metabolomics: A useful tool for ischemic stroke research

Wentao Li, Chongyu Shao, Chang Li, Huifen Zhou, Li Yu, Jiehong Yang, Haitong Wan, Yu He

2023, 13(9): 968-983. doi: 10.1016/j.jpha.2023.05.015

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Ischemic stroke (IS) is a multifactorial and heterogeneous disease. Despite years of studies, effective strategies for the diagnosis, management and treatment of stroke are still lacking in clinical practice. Metabolomics is a growing field in systems biology. It is starting to show promise in the identification of biomarkers and in the use of pharmacometabolomics to help patients with certain disorders choose their course of treatment. The development of metabolomics has enabled further and more biological applications. Particularly, metabolomics is increasingly being used to diagnose diseases, discover new drug targets, elucidate mechanisms, and monitor therapeutic outcomes and its potential effect on precision medicine. In this review, we reviewed some recent advances in the study of metabolomics as well as how metabolomics might be used to identify novel biomarkers and understand the mechanisms of IS. Then, the use of metabolomics approaches to investigate the molecular processes and active ingredients of Chinese herbal formulations with anti-IS capabilities is summarized. We finally summarized recent developments in single cell metabolomics for exploring the metabolic profiles of single cells. Although the field is relatively young, the development of single cell metabolomics promises to provide a powerful tool for unraveling the pathogenesis of IS.

1,8-cineole ameliorates colon injury by downregulating macrophage M1 polarization via inhibiting the HSP90-NLRP3-SGT1 complex

Shengsuo Ma, Bing Yang, Yang Du, Yiwen Lv, Jiarong Liu, Yucong Shi, Ting Huang, Huachong Xu, Li Deng, Xiaoyin Chen

2023, 13(9): 984-998. doi: 10.1016/j.jpha.2023.07.001

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Ulcerative colitis (UC) is characterized by chronic relapsing intestinal inflammation. Currently, there is no effective treatment for the disease. According to our preliminary data, 1,8-cineole, which is the main active compound of Amomum compactum Sol. ex Maton volatile oil and an effective drug for the treatment of pneumonia, showed remarkable anti-inflammatory effects on colitis pathogenesis. However, its mechanism of action and direct targets remain unclear. This study investigated the direct targets and mechanism through which 1,8-cineole exerts its anti-inflammatory effects using a dextran sulfate sodium salt-induced colitis mouse model. The effects of 1,8-cineole on macrophage polarization were investigated using activated bone marrow-derived macrophages and RAW264.7 cells. In addition, 1,8-cineole targets were revealed by drug affinity responsive target stability, thermal shift assay, cellular thermal shift assay, and heat shock protein 90 (HSP90) adenosine triphosphatases (ATPase) activity assays. The results showed that 1,8-cineole exhibited powerful anti-inflammatory properties in vitro and in vivo by inhibiting the macrophage M1 polarization and protecting intestinal barrier function. Mechanistically, 1,8-cineole directly interacted with HSP90 and decreased its ATPase activity, also inhibited nucleotide-binding and oligomerization domain-, leucine rich repeat-, and pyrin domain-containing 3 (NLRP3) binding to HSP90 and suppressor of G-two allele of SKP1 (SGT1) and suppressed NLRP3 inflammasome activation in macrophages. These results demonstrated that 1,8-cineole is a potential drug candidate for UC treatment.

Ginsenoside Rk2, a dehydroprotopanaxadiol saponin, alleviates alcoholic liver disease via regulating NLRP3 and NLRP6 inflammasome signaling pathways in mice

Jian Zou, Rujie Yang, Ruibing Feng, Jiayue Liu, Jian-Bo Wan

2023, 13(9): 999-1012. doi: 10.1016/j.jpha.2023.05.005

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Heavy alcohol consumption results in alcoholic liver disease (ALD) with inadequate therapeutic options. Here, we first report the potential beneficial effects of ginsenoside Rk2 (Rk2), a rare dehydroprotopanaxadiol saponin isolated from streamed ginseng, against alcoholic liver injury in mice. Chronic-plus-single-binge ethanol feeding caused severe liver injury, as manifested by significantly elevated serum aminotransferase levels, hepatic histological changes, increased lipid accumulation, oxidative stress, and inflammation in the liver. These deleterious effects were alleviated by the treatment with Rk2 (5 and 30 mg/kg). Acting as an nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inhibitor, Rk2 ameliorates alcohol-induced liver inflammation by inhibiting NLRP3 inflammasome signaling in the liver. Meanwhile, the treatment with Rk2 alleviated the alcohol-induced intestinal barrier dysfunction via enhancing NLRP6 inflammasome in the intestine. Our findings indicate that Rk2 is a promising agent for the prevention and treatment of ALD and other NLPR3-driven diseases.

Quantification of soluble epoxide hydrolase inhibitors in experimental and clinical samples using the nanobody-based ELISA

Huiyi Yang, Meng Qi, Qiyi He, Sung Hee Hwang, Jun Yang, Mark McCoy, Christophe Morisseau, Suqing Zhao, Bruce D. Hammock

2023, 13(9): 1013-1023. doi: 10.1016/j.jpha.2023.05.006

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To ensure proper dosage of a drug, analytical quantification of it in biofluid is necessary. Liquid chromatography mass spectrometry (LC-MS) is the conventional method of choice as it permits accurate identification and quantification. However, it requires expensive instrumentation and is not appropriate for bedside use. Using soluble epoxide hydrolase (sEH) inhibitors (EC5026 and TPPU) as examples, we report development of a nanobody-based enzyme-linked immunosorbent assay (ELISA) for such small molecules and its use to accurately quantify the drug chemicals in human samples. Under optimized conditions, two nanobody-based ELISAs were successfully established for EC5026 and TPPU with low limits of detection of 0.085 ng/mL and 0.31 ng/mL, respectively, and two order of magnitude linear ranges with high precision and accuracy. The assay was designed to detect parent and two biologically active metabolites in the investigation of a new drug candidate EC5026. In addition, the ELISAs displayed excellent correlation with LC-MS analysis and evaluation of inhibitory potency. The results indicate that nanobody-based ELISA methods can efficiently analyze drug like compounds. These methods could be easily implemented by the bedside, in the field in remote areas or in veterinary practice. This work illustrates that nanobody based assays offer alternative and supplementary analytical tools to mass spectrometry for monitoring small molecule medicines during clinical development and therapy. Attributes of nanobody based pharmaceutical assays are discussed.

Gut microbiota-based pharmacokinetic-pharmacodynamic study and molecular mechanism of specnuezhenide in the treatment of colorectal cancer targeting carboxylesterase

Hang Yu, Hui Xu, Xinyu Yang, Zhengwei Zhang, Jiachun Hu, Jinyue Lu, Jie Fu, Mengmeng Bu, Haojian Zhang, Zhao Zhai, Jingyue Wang, Jiandong Jiang, Yan Wang

2023, 13(9): 1024-1040. doi: 10.1016/j.jpha.2023.06.012

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Specnuezhenide (SNZ) is among the main components of Fructus Ligustri Lucidi, which has anti-inflammation, anti-oxidation, and anti-tumor effect. The low bioavailability makes it difficult to explain the mechanism of pharmacological effect of SNZ. In this study, the role of the gut microbiota in the metabolism and pharmacokinetics characteristics of SNZ as well as the pharmacological meaning were explored. SNZ can be rapidly metabolized by the gut microbiome, and two intestinal bacterial metabolites of SNZ, salidroside and tyrosol, were discovered. In addition, carboxylesterase may be the main intestinal bacterial enzyme that mediates its metabolism. At the same time, no metabolism was found in the incubation system of SNZ with liver microsomes or liver homogenate, indicating that the gut microbiota is the main part involved in the metabolism of SNZ. In addition, pharmacokinetic studies showed that salidroside and tyrosol can be detected in plasma in the presence of gut microbiota. Interestingly, tumor development was inhibited in a colorectal tumor mice model administered orally with SNZ, which indicated that SNZ exhibited potential to inhibit tumor growth, and tissue distribution studies showed that salidroside and tyrosol could be distributed in tumor tissues. At the same time, SNZ modulated the structure of gut microbiota and fungal group, which may be the mechanism governing the antitumoral activity of SNZ. Furthermore, SNZ stimulates the secretion of short-chain fatty acids by intestinal flora in vitro and in vivo. In the future, targeting gut microbes and the interaction between natural products and gut microbes could lead to the discovery and development of new drugs.

Rapid metabolic fingerprinting with the aid of chemometric models to identify authenticity of natural medicines: Turmeric, Ocimum, and Withania somnifera study

Samreen Khan, Abhishek Kumar Rai, Anjali Singh, Saudan Singh, Basant Kumar Dubey, Raj Kishori Lal, Arvind Singh Negi, Nicholas Birse, Prabodh Kumar Trivedi, Christopher T. Elliott, Ratnasekhar Ch

2023, 13(9): 1041-1057. doi: 10.1016/j.jpha.2023.04.018

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Herbal medicines are popular natural medicines that have been used for decades. The use of alternative medicines continues to expand rapidly across the world. The World Health Organization suggests that quality assessment of natural medicines is essential for any therapeutic or health care applications, as their therapeutic potential varies between different geographic origins, plant species, and varieties. Classification of herbal medicines based on a limited number of secondary metabolites is not an ideal approach. Their quality should be considered based on a complete metabolic profile, as their pharmacological activity is not due to a few specific secondary metabolites but rather a larger group of bioactive compounds. A holistic and integrative approach using rapid and nondestructive analytical strategies for the screening of herbal medicines is required for robust characterization. In this study, a rapid and effective quality assessment system for geographical traceability, species, and variety-specific authenticity of the widely used natural medicines turmeric, Ocimum, and Withania somnifera was investigated using Fourier transform near-infrared (FT-NIR) spectroscopy-based metabolic fingerprinting. Four different geographical origins of turmeric, five different Ocimum species, and three different varieties of roots and leaves of Withania somnifera were studied with the aid of machine learning approaches. Extremely good discrimination (R² > 0.98, Q² > 0.97, and accuracy = 1.0) with sensitivity and specificity of 100% was achieved using this metabolic fingerprinting strategy. Our study demonstrated that FT-NIR-based rapid metabolic fingerprinting can be used as a robust analytical method to authenticate several important medicinal herbs.

Eight Zhes Decoction ameliorates the lipid dysfunction of nonalcoholic fatty liver disease using integrated lipidomics, network pharmacology and pharmacokinetics

Yuping Zhou, Ze Dai, Kaili Deng, Yubin Wang, Jiamin Ying, Donghui Chu, Jinyue Zhou, Chunlan Tang

2023, 13(9): 1058-1069. doi: 10.1016/j.jpha.2023.05.012

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Nonalcoholic fatty liver disease (NAFLD) has developed into the most common chronic liver disease and can lead to liver cancer. Our laboratory previously developed a novel prescription for NAFLD, “Eight Zhes Decoction” (EZD), which has shown good curative effects in clinical practice. However, the pharmacodynamic material basis and mechanism have not yet been revealed. A strategy integrating lipidomics, network pharmacology and pharmacokinetics was used to reveal the active components and mechanisms of EZD against NAFLD. The histopathological results showed that EZD attenuated the degrees of collagen deposition and steatosis in the livers of nonalcoholic steatofibrosis model mice. Furthermore, glycerophospholipid metabolism, arachidonic acid metabolism, glycerolipid metabolism and linoleic acid metabolism with phospholipase A2 group IVA (PLA2G4A) and cytochrome P450 as the core targets and 12,13-cis-epoxyoctadecenoic acid, 12(S)-hydroxyeicosatetraenoic acid, leukotriene B4, prostaglandin E2, phosphatidylcholines (PCs) and triacylglycerols (TGs) as the main lipids were found to be involved in the treatment of NAFLD by EZD. Importantly, naringenin, artemetin, canadine, and bicuculline were identified as the active ingredients of EZD against NAFLD; in particular, naringenin reduces PC consumption by inhibiting the expression of PLA2G4A and thus promotes sufficient synthesis of very-low-density lipoprotein to transport excess TGs in the liver. This research provides valuable data and theoretical support for the application of EZD against NAFLD.

Characterization of natural peptides in Pheretima by integrating proteogenomics and label-free peptidomics

Xiaoxiao Luo, Qirui Bi, Dongdong Huang, Yun Li, Changliang Yao, Jianqing Zhang, Wenlong Wei, Jiayuan Li, Zhenwei Li, Jingxian Zhang, Shen Ji, Yurong Wang, De-an Guo

2023, 13(9): 1070-1079. doi: 10.1016/j.jpha.2023.06.006

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Pheretima, also called “earthworms”, is a well-known animal-derived traditional Chinese medicine that is extensively used in over 50 Chinese patent medicines (CPMs) in Chinese Pharmacopoeia (2020 edition). However, its zoological origin is unclear, both in the herbal market and CPMs. In this study, a strategy for integrating in-house annotated protein databases constructed from close evolutionary relationship-sourced RNA sequencing data from public archival resources and various sequencing algorithms (restricted search, open search, and de novo) was developed to characterize the phenotype of natural peptides of three major commercial species of Pheretima, including Pheretima aspergillum (PA), Pheretima vulgaris (PV), and Metaphire magna (MM). We identified 10,477 natural peptides in the PA, 7,451 in PV, and 5,896 in MM samples. Five specific signature peptides were screened and then validated using synthetic peptides; these demonstrated robust specificity for the authentication of PA, PV, and MM. Finally, all marker peptides were successfully applied to identify the zoological origins of Brain Heart capsules and Xiaohuoluo pills, revealing the inconsistent Pheretima species used in these CPMs. In conclusion, our integrated strategy could be used for the in-depth characterization of natural peptides of other animal-derived traditional Chinese medicines, especially non-model species with poorly annotated protein databases.

Targeted bile acids metabolomics in cholesterol gallbladder polyps and gallstones: From analytical method development towards application to clinical samples

Jiaojiao Wei, Tao Chen, Yamin Liu, Shuai Sun, Zhiqing Yuan, Yixin Zhang, Aizhen Xiong, Linnan Li, Zhengtao Wang, Li Yang

2023, 13(9): 1080-1087. doi: 10.1016/j.jpha.2023.06.003

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Bile acids (BAs) are synthesized by the liver from cholesterol through several complementary pathways and aberrant cholesterol metabolism plays pivotal roles in the pathogeneses of cholesterol gallbladder polyps (CGP) and cholesterol gallstones (CGS). To date, there is neither systematic study on BAs profile of CGP or CGS, nor the relationship between them. To explore the metabolomics profile of plasma BAs in healthy volunteers, CGP and CGS patients, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous determination of 42 free and conjugated BAs in human plasma. The developed method was sensitive and reproducible to be applied for the quantification of BAs in the investigation of plasma samples. The results show that, compared to healthy volunteers, CGP and CGS were both characterized by the significant decrease in plasma BAs pool size, furthermore CGP and CGS shared aberrant BAs metabolic characteristics. Chenodeoxycholic acid, glycochenodeoxycholic acid, λ-muricholic acid, deoxycholic acid, and 7-ketolithocholic acid were shared potential markers of these two cholesterol gallbladder diseases. Subsequent analysis showed that clinical characteristics including cysteine, ornithine and body mass index might be closely related to metabolisms of certain BA modules. This work provides metabolomic information for the study of gallbladder diseases and analytical methodologies for clinical target analysis and efficacy evaluation related to BAs in medical institutions.

2023 Vol. 13, No. 9