Journal of Pharmaceutical Analysis

Insights into Euphorbia diversity: Probing the contrasts between Euphorbia fischeriana Steud and Euphorbia ebracteolata Hayata

Kaicheng Du, Yi Zhang, Lei Sun, Muke Tao, Tiantian Zuo, Yumeng Wang, Zhengfeng Zhang, Dali Meng

2024, 14(5): 100896. doi: 10.1016/j.jpha.2023.11.003

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Eco-friendly high-throughput screening of cephalosporins impurities: Utilizing 2D-carbon microfiber fractionation system combined with quadrupole time of flight high-resolution mass spectrometer

Lei Yang, Yan Wang, Zhao Wang, Meiyu Cui, Ruolan Jin, Hai-Bo Shang, Donghao Li

2024, 14(5): 100900. doi: 10.1016/j.jpha.2023.11.007

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Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis

Lifan Lin, Xinmiao Li, Yifei Li, Zhichao Lang, Yeping Li, Jianjian Zheng

2024, 14(5): 100902. doi: 10.1016/j.jpha.2023.11.009

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Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), a process associated with ferroptosis. Ginsenoside Rb1 (GRb1), a major active component extracted from Panax ginseng, inhibits HSC activation. However, the potential role of GRb1 in mediating HSC ferroptosis remains unclear. This study examined the effect of GRb1 on liver fibrosis both in vivo and in vitro, using CCl₄-induced liver fibrosis mouse model and primary HSCs, LX-2 cells. The findings revealed that GRb1 effectively inactivated HSCs in vitro, reducing alpha-smooth muscle actin (α-SMA) and type I collagen (Col1A1) levels. Moreover, GRb1 significantly alleviated CCl₄-induced liver fibrosis in vivo. From a mechanistic standpoint, the ferroptosis pathway appeared to be central to the antifibrotic effects of GRb1. Specifically, GRb1 promoted HSC ferroptosis both in vivo and in vitro, characterized by increased glutathione depletion, malondialdehyde production, iron overload, and accumulation of reactive oxygen species (ROS). Intriguingly, GRb1 increased Beclin 1 (BECN1) levels and decreased the System Xc-key subunit SLC7A11. Further experiments showed that BECN1 silencing inhibited GRb1-induced effects on HSC ferroptosis and mitigated the reduction of SLC7A11 caused by GRb1. Moreover, BECN1 could directly interact with SLC7A11, initiating HSC ferroptosis. In conclusion, the suppression of BECN1 counteracted the effects of GRb1 on HSC inactivation both in vivo and in vitro. Overall, this study highlights the novel role of GRb1 in inducing HSC ferroptosis and promoting HSC inactivation, at least partly through its modulation of BECN1 and SLC7A11.

Apatinib and gamabufotalin co-loaded lipid/Prussian blue nanoparticles for synergistic therapy to gastric cancer with metastasis

Binlong Chen, Yanzhong Zhao, Zichang Lin, Jiahao Liang, Jialong Fan, Yanyan Huang, Leye He, Bin Liu

2024, 14(5): 100904. doi: 10.1016/j.jpha.2023.11.011

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Due to the non-targeted release and low solubility of anti-gastric cancer agent, apatinib (Apa), a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects. In order to avoid these drawbacks, lipid-film-coated Prussian blue nanoparticles (PB NPs) with hyaluronan (HA) modification was used for Apa loading to improve its solubility and targeting ability. Furthermore, anti-tumor compound of gamabufotalin (CS-6) was selected as a partner of Apa with reducing dosage for combinational gastric therapy. Thus, HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue. In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating vascular endothelial growth factor receptor (VEGFR) and matrix metalloproteinase-9 (MMP-9). in vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects. In summary, we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer (GC) therapy.

Alginate oligosaccharide-mediated butyrate-HIF-1α axis improves skin aging in mice

Ting Gao, Yixuan Li, Xiaoyu Wang, Fazheng Ren

2024, 14(5): 100911. doi: 10.1016/j.jpha.2023.12.001

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The “gut-skin” axis has been proved and is considered as a novel therapy for the prevention of skin aging. The antioxidant efficacy of oligomannonic acid (MAOS) makes it an intriguing target for use to improve skin aging. The present study further explored whereby MAOS-mediated gut-skin axis balance prevented skin aging in mice. The data indicated the skin aging phenotypes, oxidative stress, skin mitochondrial dysfunction, and intestinal dysbiosis (especially the butyrate and HIF-1α levels decreased) in aging mice. Similarly, fecal microbiota transplantation (FMT) from aging mice rebuild the aging-like phenotypes. Further, we demonstrated MAOS-mediated colonic butyrate-HIF-1α axis homeostasis promoted the entry of butyrate into the skin, upregulated mitophagy level and ultimately improving skin aging via HDAC3/PHD/HIF-1α/mitophagy loop in skin of mice. Overall, our study offered a better insights of the effectiveness of alginate oligosaccharides (AOS), promised to become a personalized targeted therapeutic agents, on gut-skin axis disorder inducing skin aging.

Measurement of very low-molecular weight metabolites by traveling wave ion mobility and its use in human urine samples

Alongkorn Kurilung, Suphitcha Limjiasahapong, Khwanta Kaewnarin, Pattipong Wisanpitayakorn, Narumol Jariyasopit, Kwanjeera Wanichthanarak, Sitanan Sartyoungkul, Stephen Choong Chee Wong, Nuankanya Sathirapongsasuti, Chagriya Kitiyakara, Yongyut Sirivatanauksorn, Sakda Khoomrung

2024, 14(5): 100921. doi: 10.1016/j.jpha.2023.12.011

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The collision cross-sections (CCS) measurement using ion mobility spectrometry (IMS) in combination with mass spectrometry (MS) offers a great opportunity to increase confidence in metabolite identification. However, owing to the lack of sensitivity and resolution, IMS has an analytical challenge in studying the CCS values of very low-molecular-weight metabolites (VLMs ≤ 250 Da). Here, we describe an analytical method using ultrahigh-performance liquid chromatography (UPLC) coupled to a traveling wave ion mobility-quadrupole-time-of-flight mass spectrometer optimized for the measurement of VLMs in human urine samples. The experimental CCS values, along with mass spectral properties, were reported for the 174 metabolites. The experimental data included the mass-to-charge ratio (m/z), retention time (RT), tandem MS (MS/MS) spectra, and CCS values. Among the studied metabolites, 263 traveling wave ion mobility spectrometry (TWIMS)-derived CCS values (^TWCCS_N2) were reported for the first time, and more than 70% of these were CCS values of VLMs. The ^TWCCS_N2 values were highly repeatable, with inter-day variations of <1% relative standard deviation (RSD). The developed method revealed excellent ^TWCCS_N2 accuracy with a CCS difference (△CCS) within ±2% of the reported drift tube IMS (DTIMS) and TWIMS CCS values. The complexity of the urine matrix did not affect the precision of the method, as evidenced by △CCS within ±1.92%. According to the Metabolomics Standards Initiative, 55 urinary metabolites were identified with a confidence level of 1. Among these 55 metabolites, 53 (96%) were VLMs. The larger number of confirmed compounds found in this study was a result of the addition of ^TWCCS_N2 values, which clearly increased metabolite identification confidence.

Rapid discovery of a novel “green” and natural GST inhibitor for sensitizing hepatocellular carcinoma to Cisplatin by visual screening strategy

Linxi Mao, Yan Qin, Jialong Fan, Wei Yang, Bin Li, Liang Cao, Liqin Yuan, Mengyun Wang, Bin Liu, Wei Wang

2024, 14(5): 100923. doi: 10.1016/j.jpha.2023.12.013

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Over-expression of glutathione S-transferase (GST) can promote Cisplatin resistance in hepatocellular carcinoma (HCC) treatment. Hence, inhibiting GST is an attractive strategy to improve Cisplatin sensitivity in HCC therapy. Although several synthesized GST inhibitors have been developed, the side effects and narrow spectrum for anticancer seriously limit their clinical application. Considering the abundance of natural compounds with anticancer activity, this study developed a rapid fluorescence technique to screen “green” natural GST inhibitors with high specificity. The fluorescence assay demonstrated that schisanlactone B (hereafter abbreviated as C1) isolated from Xue tong significantly down-regulated GST levels in Cisplatin-resistant HCC cells in vitro and in vivo. Importantly, C1 can selectively kill HCC cells from normal liver cells, effectively improving the therapeutic effect of Cisplatin on HCC mice by down-regulating GST expression. Considering the high GST levels in HCC patients, this compound demonstrated the high potential for sensitizing HCC therapy in clinical practice by down-regulating GST levels.

Cornus officinalis with high pressure wine steaming enhanced anti-hepatic fibrosis: Possible through SIRT3-AMPK axis

Xin Han, Yan Ning, Xinyue Dou, Yiwen Wang, Qiyuan Shan, Kao Shi, Zeping Wang, Chuan Ding, Min Hao, Kuilong Wang, Mengyun Peng, Haodan Kuang, Qiao Yang, Xianan Sang, Gang Cao

2024, 14(5): 100927. doi: 10.1016/j.jpha.2023.12.017

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Cornus officinalis, a medicinal and edible plant known for its liver-nourishing properties, has shown promise in inhibiting the activation of hepatic stellate cells (HSCs), crucial indicators of hepatic fibrosis, especially when processed by high pressure wine steaming (HPWS). Herein, this study aims to investigate the regulatory effects of cornus officinalis, both in its raw and HPWS forms, on inflammation and apoptosis in liver fibrosis and their underlying mechanisms. in vivo liver fibrosis models were established by subcutaneous injection of CCl₄, while in vitro HSCs were exposed to transforming growth factor-β (TGF-β). These findings demonstrated that cornus officinalis with HPWS conspicuously ameliorated histopathological injury, reduced the release of proinflammatory factors, and decreased collagen deposition in CCl₄-induced rats compared to its raw form. Utilizing ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS) combined with network analysis, we identified that the pharmacological effects of the changed components of cornus officinalis before and after HPWS, primarily centered on the adenosine phosphate (AMP)-activated protein kinase (AMPK) pathway. Of note, cornus officinalis activated AMPK and sirtuin 3 (SIRT3), promoting the apoptosis of activated HSCs through the caspase cascade by regulating caspase3, caspase6 and caspase9. small interfering RNA (siRNA) experiments showed that cornus officinalis could regulate AMPK activity and its mediated-apoptosis through SIRT3. In conclusion, cornus officinalis exhibited the ability to reduce inflammation and apoptosis, with the SIRT3-AMPK signaling pathway identified as a potential mechanism underlying the synergistic effect of cornus officinalis with HPWS on anti-liver fibrosis.

Discrimination of polysorbate 20 by high-performance liquid chromatography-charged aerosol detection and characterization for components by expanding compound database and library

Shi-Qi Wang, Xun Zhao, Li-Jun Zhang, Yue-Mei Zhao, Lei Chen, Jin-Lin Zhang, Bao-Cheng Wang, Sheng Tang, Tom Yuan, Yaozuo Yuan, Mei Zhang, Hian Kee Lee, Hai-Wei Shi

2024, 14(5): 100929. doi: 10.1016/j.jpha.2023.12.019

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Analyzing polysorbate 20 (PS20) composition and the impact of each component on stability and safety is crucial due to formulation variations and individual tolerance. The similar structures and polarities of PS20 components make accurate separation, identification, and quantification challenging. In this work, a high-resolution quantitative method was developed using single-dimensional high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) to separate 18 key components with multiple esters. The separated components were characterized by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) with an identical gradient as the HPLC-CAD analysis. The polysorbate compound database and library were expanded over 7-time compared to the commercial database. The method investigated differences in PS20 samples from various origins and grades for different dosage forms to evaluate the composition-process relationship. UHPLC-Q-TOF-MS identified 1329 to 1511 compounds in 4 batches of PS20 from different sources. The method observed the impact of 4 degradation conditions on peak components, identifying stable components and their tendencies to change. HPLC-CAD and UHPLC-Q-TOF-MS results provided insights into fingerprint differences, distinguishing quasi products.

Sonodynamic therapy for the treatment of atherosclerosis

Yan Zhang, Ying Yang, Yudi Feng, Xueyan Gao, Liping Pei, Xiaopan Li, Bingxin Gao, Lin Liu, Chengzeng Wang, Shuochen Gao

2024, 14(5): 100909. doi: 10.1016/j.jpha.2023.11.016

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Atherosclerosis (AS) is a chronic inflammatory disease of large and medium-sized arteries that leads to ischemic heart disease, stroke, and peripheral vascular disease. Despite the current treatments, mortality and disability still remain high. Sonodynamic therapy (SDT), a non-invasive and localized methodology, has been developed as a promising new treatment for inhibiting atherosclerotic progression and stabilizing plaques. Promising progress has been made through cell and animal assays, as well as clinical trials. For example, the effect of SDT on apoptosis and autophagy of cells in AS, especially macrophages, and the concept of non-lethal SDT has also been proposed. In this review, we summarize the ultrasonic parameters and known sonosensitizers utilized in SDT for AS; we elaborate on SDT's therapeutic effects and mechanisms in terms of macrophages, T lymphocytes, neovascularization, smooth muscle cells, lipid, extracellular matrix and efferocytosis within plaques; additionally, we discuss the safety of SDT. A comprehensive summary of the confirmed effects of SDT on AS is conducted to establish a framework for future researchers.

New advances of adiponectin in regulating obesity and related metabolic syndromes

Yanqi Han, Qianwen Sun, Wei Chen, Yue Gao, Jun Ye, Yanmin Chen, Tingting Wang, Lili Gao, Yuling Liu, Yanfang Yang

2024, 14(5): 100913. doi: 10.1016/j.jpha.2023.12.003

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Obesity and related metabolic syndromes have been recognized as important disease risks, in which the role of adipokines cannot be ignored. Adiponectin (ADP) is one of the key adipokines with various beneficial effects, including improving glucose and lipid metabolism, enhancing insulin sensitivity, reducing oxidative stress and inflammation, promoting ceramides degradation, and stimulating adipose tissue vascularity. Based on those, it can serve as a positive regulator in many metabolic syndromes, such as type 2 diabetes (T2D), cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), sarcopenia, neurodegenerative diseases, and certain cancers. Therefore, a promising therapeutic approach for treating various metabolic diseases may involve elevating ADP levels or activating ADP receptors. The modulation of ADP genes, multimerization, and secretion covers the main processes of ADP generation, providing a comprehensive orientation for the development of more appropriate therapeutic strategies. In order to have a deeper understanding of ADP, this paper will provide an all-encompassing review of ADP.

GLP-1 receptor agonists and myocardial metabolism in atrial fibrillation

Jiani Zhong, Hang Chen, Qiming Liu, Shenghua Zhou, Zhenguo Liu, Yichao Xiao

2024, 14(5): 100917. doi: 10.1016/j.jpha.2023.12.007

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Atrial fibrillation (AF) is the most common cardiac arrhythmia. Many medical conditions, including hypertension, diabetes, obesity, sleep apnea, and heart failure (HF), increase the risk for AF. Cardiomyocytes have unique metabolic characteristics to maintain adenosine triphosphate production. Significant changes occur in myocardial metabolism in AF. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been used to control blood glucose fluctuations and weight in the treatment of type 2 diabetes mellitus (T2DM) and obesity. GLP-1RAs have also been shown to reduce oxidative stress, inflammation, autonomic nervous system modulation, and mitochondrial function. This article reviews the changes in metabolic characteristics in cardiomyocytes in AF. Although the clinical trial outcomes are unsatisfactory, the findings demonstrate that GLP-1 RAs can improve myocardial metabolism in the presence of various risk factors, lowering the incidence of AF.

Nitrosamines crisis in pharmaceuticals-Insights on toxicological implications, root causes and risk assessment: A systematic review

Hemanth P. R. Vikram, Tegginamath Pramod Kumar, Gunjan Kumar, Narasimha M. Beeraka, Rajashree Deka, Sheik Mohammed Suhail, Sandeep Jat, Namitha Bannimath, Gayatiri Padmanabhan, Ravandur S. Chandan, Pramod Kumar, Bannimath Gurupadayya

2024, 14(5): 100919. doi: 10.1016/j.jpha.2023.12.009

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The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients (APIs), drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.

2024 Vol. 14, No. 5