Articles in press have been peer-reviewed and accepted, which are not yet assigned to volumes /issues, but are citable by Digital Object Identifier (DOI).
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Tetrandrine Targeting SIRT5 Exerts Anti-melanoma Properties via Inducing ROS, ER Stress, and Blocked Autophagy
Yacong Ji, Chongyang Li, Sicheng Wan, Zhen Dong, Chaolong Liu, Leiyang Guo, Shaomin Shi, Mingxin Ci, Minghao Xu, Qian Li, Huanrong Hu, Hongjuan Cui, Yaling Liu
 doi: 10.1016/j.jpha.2024.101036
[Abstract](42) [PDF 18306KB](12)
Abstract:
Tetrandrine (TET), a natural bisbenzyl isoquinoline alkaloid extracted from Stephania tetrandra Moore, has diverse pharmacological effects. However, its effects on melanoma remain unclear. Cellular proliferation assays, multi-omics analyses, and xenograft models were used to determine the effect of TET on melanoma. The direct target of TET was identified using biotin-TET pull-down LC/MS, cellular thermal shift assays, and isothermal titration calorimetry (ITC) analysis. Our findings revealed that TET treatment induced robust cellular autophagy dependent on ATF6-mediated endoplasmic reticulum (ER) stress. Simultaneously, it hindered autophagic flux by inducing cytoskeletal protein depolymerization in melanoma cells. TET treatment resulted in excessive accumulation of reactive oxygen species (ROS) and simultaneously triggered mitophagy. Sirtuin 5 (SIRT5) was ultimately found to be a direct target of TET. Mechanistically, TET led to the degradation of SIRT5 via the ubiquitin-26s proteasome system. SIRT5 knockdown induced ROS accumulation, whereas SIRT5 overexpression attenuated the TET-induced ROS accumulation and autophagy. Importantly, TET exhibited anti-cancer effects in xenograft models that relied on SIRT5 expression. This study highlights the potential of TET as an antimelanoma agent that targets SIRT5. These findings provide a promising avenue for the use of TET in melanoma treatment and underscore its potential as a therapeutic candidate.
Determination of related substances in disulfide-rich peptide ziconotide by establishing tandem mass spectrometry methods
Yuya Cheng, Peize Wu, Peng Xiao, Ming Li
 doi: 10.1016/j.jpha.2024.101037
[Abstract](36) [PDF 3420KB](11)
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Single-cell RNA sequencing reveals the changes of the pulmonary immune environment in rat after Siegesbeckia orientalis L. treatment
Fan Zhang, Shu Gan, Jingjing Liao, Ting Jiang, Zhiqiang Shi, Xueying Fan, Hiu-Yee Kwan, Zhongqiu Liu, Tao Su
 doi: 10.1016/j.jpha.2024.101035
[Abstract](26) [PDF 4594KB](2)
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Potential of natural drug modulation of endoplasmic reticulum stress in the treatment of myocardial injury
Kai Yang, Ping Zhang, Jixin Li, Genming Zhang, Xing Chang
 doi: 10.1016/j.jpha.2024.101034
[Abstract](40) [PDF 20639KB](4)
Abstract:
Myocardial injury (MI) is a common occurrence in clinical practice caused by various factors such as ischemia, hypoxia, infection, metabolic abnormalities, and inflammation. Such damages are characterized by a reduction in myocardial function and cardiomyocyte death that can result in dangerous outcomes such as cardiac failure and arrhythmias. An endoplasmic reticulum stress (ERS) -induced unfolded protein response is triggered by several stressors, and its intricate signaling networks are instrumental in both cell survival and death. Cardiac damage frequently triggers ERS in response to different types of injuries and stress. High levels of ERS can exacerbate myocardial damage by inducing necrosis and apoptosis.
To target ERS in MI prevention and treatment, current medical research is focused on identifying effective therapy approaches. Traditional Chinese medicine (TCM) is frequently used because of its vast range of applications and low risk of adverse effects. Various studies have demonstrated that active components of Chinese medicines, including polyphenols, saponins, and alkaloids, can reduce myocardial cell death, inflammation, and modify the ERS pathway, thus preventing and mitigating cardiac injury.
Thus, this paper aims to provide a new direction and scientific basis for targeting ERS in MI prevention and treatment. We specifically summarize recent research progress on the regulation mechanism of ERS in MI by active ingredients of TCM.
Spatial metabolomics reveal metabolic alternations in the injured mice kidneys induced by triclocarban treatment
Peisi Xie, Jing Chen, Yongjun Xia, Zian Lin, Yu He, Zongwei Cai
 doi: 10.1016/j.jpha.2024.101024
[Abstract](44) [PDF 1350KB](5)
Abstract:
Triclocarban (TCC) is a common antimicrobial agent that has been widely used in medical care. Given the close association between TCC treatment and metabolic disorders, we assessed whether long-term treatment to TCC at a human-relevant concentration could induce nephrotoxicity by disrupting the metabolic levels in a mouse model. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was applied to investigate the alterations in the spatial distributions and abundances of TCC, endogenous and exogenous metabolites in the kidney after TCC treatment. The results showed that TCC treatment induced the changes in the organ weight, organ coefficient and histopathology of the mouse kidney. MSI data reveled that TCC accumulated in the all regions of the kidney, while its five metabolites mainly distributed in the cortex regions. The abundances of 79 biomolecules associated with pathways of leukotriene E4 metabolism, biosythesis and degradation of glycerophospholipids and glycerolipids, ceramide-to-sphingomyelin signaling were significantly altered in the kidney after TCC treatment. These biomolecules showed distinctive distributions in the kidney and displayed a favorable spatial correlation with the pathological damage. This work offers new insights into the related mechanisms of TCC-induced nephrotocicity and exhibits the potential of MALDI-MSI-based spatial metabolomics as a promising approach for the risk assessment of agents in medical care.
CeFe nanofibrous carbon nanozyme integrated with smartphone for the point-of-care testing of norfloxacin in water
Yue Liu, Taimei Cai, Sen Chen, Tao Wen, Hailong Peng
 doi: 10.1016/j.jpha.2024.101023
[Abstract](40) [PDF 2680KB](6)
Abstract:
The overuse of antibiotics has led to the severe contamination of water bodies, posing a considerable hazard to human health. Therefore, the development of an accurate and rapid point-of-care testing (POCT) platform for the quantitative detection of antibiotics is necessary. In this study, Cerium oxide (CeO2) and Ferrosoferric oxide (Fe3O4) nanoparticles were simultaneously encapsulated into N-doped nanofibrous carbon microspheres to form of a novel nanozyme (CeFe-NCMzyme) with a porous structure, high surface area, and N-doped carbon material properties, leading to a considerable enhancement of the peroxidase (POD)-like activity compared with that of the CeO2 or Fe3O4 nanoparticles alone. The POD-like activity of CeFe-NCMzyme can be quenched using L-Cysteine (Cys) and subsequently restored by the addition of a quinolone antibiotic (norfloxacin, NOR). Therefore, CeFe-NCMzyme was used as a colorimetric sensor to detect NOR via an “On-Off” model of POD-like activity. The sensor possessed a wide linear range of 0.05-20.0 μM (R2 = 0.9910) with a detection limit of 35.70 nM. Furthermore, a smartphone-assisted POCT platform with CeFe-NCMzyme was fabricated for quantitative detection of NOR based on RGB analysis. With the use of the POCT platform, a linear range of 0.1-20.0 μM and a detection limit of 54.10 nM were obtained. The spiked recoveries in the water samples were ranged from 97.73% to 102.01%, and the sensor exhibited good accuracy and acceptable reliability. This study provides a portable POCT platform for the on-site and quantitative monitoring of quinolone antibiotics in real samples, particularly in resource-constrained settings.
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Review papers
Basic regulatory science behind drug substance and drug product specifications of monoclonal antibodies and other protein therapeutics
Patanachai K. Limpikirati, Sorrayut Mongkoltipparat, Thinnaphat Denchaipradit, Nathathai Siwasophonpong, Wudthipong Pornnopparat, Parawan Ramanandana, Phumrapee Pianpaktr, Songsak Tongchusak, Maoxin Tim Tian, Trairak Pisitkun
2024, 14(6): 100916.   doi: 10.1016/j.jpha.2023.12.006
Abstract(162) HTML Full Text PDF(14)
Abstract:

In this review, we focus on providing basics and examples for each component of the protein therapeutic specifications to interested pharmacists and biopharmaceutical scientists with a goal to strengthen understanding in regulatory science and compliance. Pharmaceutical specifications comprise a list of important quality attributes for testing, references to use for test procedures, and appropriate acceptance criteria for the tests, and they are set up to ensure that when a drug product is administered to a patient, its intended therapeutic benefits and safety can be rendered appropriately. Conformance of drug substance or drug product to the specifications is achieved by testing an article according to the listed tests and analytical methods and obtaining test results that meet the acceptance criteria. Quality attributes are chosen to be tested based on their quality risk, and consideration should be given to the merit of the analytical methods which are associated with the acceptance criteria of the specifications. Acceptance criteria are set forth primarily based on efficacy and safety profiles, with an increasing attention noted for patient-centric specifications. Discussed in this work are related guidelines that support the biopharmaceutical specification setting, how to set the acceptance criteria, and examples of the quality attributes and the analytical methods from 60 articles and 23 pharmacopeial monographs. Outlooks are also explored on process analytical technologies and other orthogonal tools which are on-trend in biopharmaceutical characterization and quality control.

New perspectives on the therapeutic potential of quercetin in non-communicable diseases: Targeting Nrf2 to counteract oxidative stress and inflammation
Li Zhang, Li-Yue Xu, Fei Tang, Dong Liu, Xiao-Lan Zhao, Jing-Nan Zhang, Jia Xia, Jiao-Jiao Wu, Yu Yang, Cheng Peng, Hui Ao
2024, 14(6): 100930.   doi: 10.1016/j.jpha.2023.12.020
Abstract(40) HTML Full Text PDF(6)
Abstract:

Non-communicable diseases (NCDs), including cardiovascular diseases, cancer, metabolic diseases, and skeletal diseases, pose significant challenges to public health worldwide. The complex pathogenesis of these diseases is closely linked to oxidative stress and inflammatory damage. Nuclear factor erythroid 2-related factor 2 (Nrf2), a critical transcription factor, plays an important role in regulating antioxidant and anti-inflammatory responses to protect the cells from oxidative damage and inflammation-mediated injury. Therefore, Nrf2-targeting therapies hold promise for preventing and treating NCDs. Quercetin (Que) is a widely available flavonoid that has significant antioxidant and anti-inflammatory properties. It modulates the Nrf2 signaling pathway to ameliorate oxidative stress and inflammation. Que modulates mitochondrial function, apoptosis, autophagy, and cell damage biomarkers to regulate oxidative stress and inflammation, highlighting its efficacy as a therapeutic agent against NCDs. Here, we discussed, for the first time, the close association between NCD pathogenesis and the Nrf2 signaling pathway, involved in neurodegenerative diseases (NDDs), cardiovascular disease, cancers, organ damage, and bone damage. Furthermore, we reviewed the availability, pharmacokinetics, pharmaceutics, and therapeutic applications of Que in treating NCDs. In addition, we focused on the challenges and prospects for its clinical use. Que represents a promising candidate for the treatment of NCDs due to its Nrf2-targeting properties.

Bio-soft matter derived from traditional Chinese medicine: Characterizations of hierarchical structure, assembly mechanism, and beyond
Guiya Yang, Yue Liu, Yuying Hu, Yue Yuan, Yunan Qin, Quan Li, Shuangcheng Ma
2024, 14(6): 100943.   doi: 10.1016/j.jpha.2024.01.011
Abstract(36) HTML Full Text PDF(3)
Abstract:

Structural and functional explorations on bio-soft matter such as micelles, vesicles, nanoparticles, aggregates or polymers derived from traditional Chinese medicine (TCM) has emerged as a new topic in the field of TCM. The discovery of such cross-scaled bio-soft matter may provide a unique perspective for unraveling the new effective material basis of TCM as well as developing innovative medicine and biomaterials. Despite the rapid rise of TCM-derived bio-soft matter, their hierarchical structure and assembly mechanism must be unambiguously probed for a further in-depth understanding of their pharmacological activity. In this review, the current emerged TCM-derived bio-soft matter assembled from either small molecules or macromolecules is introduced, and particularly the unambiguous elucidation of their hierarchical structure and assembly mechanism with combined electron microscopic and spectroscopic techniques is depicted. The pros and cons of each technique are also discussed. The future challenges and perspective of TCM-derived bio-soft matter are outlined, particularly the requirement for their precise in situ structural determination is highlighted.

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Molecular immune pathogenesis and diagnosis of COVID-19
Xiaowei Li, Manman Geng, Yizhao Peng, Liesu Meng, Shemin Lu
2020, 10(2): 102-108.  
[Abstract](694) [PDF 2284KB](18)
摘要:
Coronavirus disease 2019 (COVID-19) is a kind of viral pneumonia which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The emergence of SARS-CoV-2 has been marked as the third introduction of a highly pathogenic coronavirus into the human population after the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coro-navirus (MERS-CoV) in the twenty-first century. In this minireview, we provide a brief introduction of the general features of SARS-CoV-2 and discuss current knowledge of molecular immune pathogenesis, diagnosis and treatment of COVID-19 on the base of the present understanding of SARS-CoV and MERS-CoV infections, which may be helpful in offering novel insights and potential therapeutic targets for combating the SARS-CoV-2 infection.
Structural basis of SARS-CoV-23CLpro and anti-COVID-19 drug discovery from medicinal plants
Muhammad Tahir ul Qamar, Safar M.Alqahtani, Mubarak A.Alamri, Ling-Ling Chen
2020, 10(4): 313-319.  
[Abstract](824) [PDF 5841KB](27)
摘要:
The recent pandemic of coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has raised global health concerns. The viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme controls coronavirus replication and is essential for its life cycle. 3CLpro is a proven drug discovery target in the case of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Recent studies revealed that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Therefore, herein, we analysed the 3CLpro sequence, constructed its 3D homology model, and screened it against a medicinal plant library containing 32,297 potential anti-viral phytochemicals/traditional Chinese medicinal compounds. Our analyses revealed that the top nine hits might serve as potential anti- SARS-CoV-2 lead molecules for further optimisation and drug development process to combat COVID-19.
Recent advances and perspectives of nucleic acid detection for coronavirus
Minzhe Shen, Ying Zhou, Jiawei Ye, Abdu Ahmed Abdullah AL-maskri, Yu Kang, Su Zeng, Sheng Cai
2020, 10(2): 97-101.  
[Abstract](622) [PDF 2697KB](14)
摘要:
The recent pneumonia outbreak caused by a novel coronavirus (SARS-CoV-2) is posing a great threat to global public health. Therefore, rapid and accurate identification of pathogenic viruses plays a vital role in selecting appropriate treatments, saving people's lives and preventing epidemics. It is important to establish a quick standard diagnostic test for the detection of the infectious disease (COVID-19) to prevent subsequent secondary spread. Polymerase chain reaction (PCR) is regarded as a gold standard test for the molecular diagnosis of viral and bacterial infections with high sensitivity and specificity. Isothermal nucleic acid amplification is considered to be a highly promising candidate method due to its fundamental advantage in quick procedure time at constant temperature without thermocycler opera-tion. A variety of improved or new approaches also have been developed. This review summarizes the currently available detection methods for coronavirus nucleic acid. It is anticipated that this will assist researchers and clinicians in developing better techniques for timely and effective detection of coro-navirus infection.
Application of microfluidic chip technology in pharmaceutical analysis:A review
Ping Cui, Sicen Wang
2019, 9(4): 238-247.  
[Abstract](278) [PDF 5845KB](15)
摘要:
The development of pharmaceutical analytical methods represents one of the most significant aspects of drug development. Recent advances in microfabrication and microfluidics could provide new approaches for drug analysis, including drug screening, active testing and the study of metabolism. Microfluidic chip technologies, such as lab-on-a-chip technology, three-dimensional (3D) cell culture, organs-on-chip and droplet techniques, have all been developed rapidly. Microfluidic chips coupled with various kinds of detection techniques are suitable for the high-throughput screening, detection and mechanistic study of drugs. This review highlights the latest (2010–2018) microfluidic technology for drug analysis and dis-cusses the potential future development in this field.
Research advances in the detection of miRNA
Jiawei Ye, Mingcheng Xu, Xueke Tian, Sheng Cai, Su Zeng
2019, 9(4): 217-226.  
[Abstract](456) [PDF 6429KB](15)
摘要:
MicroRNAs (miRNAs) are a family of endogenous, small (approximately 22 nucleotides in length), noncoding, functional RNAs. With the development of molecular biology, the research of miRNA bio-logical function has attracted significant interest, as abnormal miRNA expression is identified to contribute to serious human diseases such as cancers. Traditional methods for miRNA detection do not meet current demands. In particular, nanomaterial-based methods, nucleic acid amplification-based methods such as rolling circle amplification (RCA), loop-mediated isothermal amplification (LAMP), strand-displacement amplification (SDA) and some enzyme-free amplifications have been employed widely for the highly sensitive detection of miRNA. MiRNA functional research and clinical diagnostics have been accelerated by these new techniques. Herein, we summarize and discuss the recent progress in the development of miRNA detection methods and new applications. This review will provide guidelines for the development of follow-up miRNA detection methods with high sensitivity and spec-ificity, and applicability to disease diagnosis and therapy.
Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase
Muhammad Usman Mirza, Matheus Froeyen
2020, 10(4): 320-328.  
[Abstract](401) [PDF 19436KB](12)
摘要:
Recently emerged SARS-CoV-2 caused a major outbreak of coronavirus disease 2019 (COVID-19) and instigated a widespread fear, threatening global health safety. To date, no licensed antiviral drugs or vaccines are available against COVID-19 although several clinical trials are under way to test possible therapies. During this urgent situation, computational drug discovery methods provide an alternative to tiresome high-throughput screening, particularly in the hit-to-lead-optimization stage. Identification of small molecules that specifically target viral replication apparatus has indicated the highest potential towards antiviral drug discovery. In this work, we present potential compounds that specifically target SARS-CoV-2 vital proteins, including the main protease, Nsp12 RNA polymerase and Nsp13 helicase. An integrative virtual screening and molecular dynamics simulations approach has facilitated the identifi-cation of potential binding modes and favourable molecular interaction profile of corresponding com-pounds. Moreover, the identification of structurally important binding site residues in conserved motifs located inside the active site highlights relative importance of ligand binding based on residual energy decomposition analysis. Although the current study lacks experimental validation, the structural infor-mation obtained from this computational study has paved way for the design of targeted inhibitors to combat COVID-19 outbreak.
Carbon nanotubes:Evaluation of toxicity at biointerfaces
Debashish Mohanta, Soma Patnaik, Sanchit Sood, Nilanjan Das
2019, 9(5): 293-300.  
[Abstract](317) [PDF 3216KB](9)
摘要:
Carbon nanotubes (CNTs) are a class of carbon allotropes with interesting properties that make them productive materials for usage in various disciplines of nanotechnology such as in electronics equip-ments, optics and therapeutics. They exhibit distinguished properties viz., strength, and high electrical and heat conductivity. Their uniqueness can be attributed due to the bonding pattern present between the atoms which are very strong and also exhibit high extreme aspect ratios. CNTs are classified as single-walled carbon nanotubes (SWCNTs) and multi-walled carbon nanotubes (MWCNTs) on the basis of number of sidewalls present and the way they are arranged spatially. Application of CNTs to improve the performance of many products, especially in healthcare, has led to an occupational and public exposure to these nanomaterials. Hence, it becomes a major concern to analyze the issues pertaining to the toxicity of CNTs and find the best suitable ways to counter those challenges. This review summarizes the toxicity issues of CNTs in vitro and in vivo in different organ systems (bio interphases) of the body that result in cellular toxicity.
Identification and characterization of phenolics and terpenoids from ethanolic extracts of Phyllanthus species by HPLC-ESI-QTOF-MS/MS
Sunil Kumar, Awantika Singh, Brijesh Kumar
2017, 7(4): 214-222.  
[Abstract](556) [PDF 3923KB](46)
摘要:
Phyllanthus species plants are a rich source of phenolics and widely used due to their medicinal properties. A liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed using high-pressure liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-QTOF-MS/MS) for the identification and characterization of quercetin, kaempferol, ellagic acid and their derivatives in ethanolic extracts of Phyllanthus species. The chromatographic separation was carried out on Thermo Betasil C8 column (250 mm×4.5 mm, 5 μm) using 0.1% formic acid in water and 0.1% formic acid in methanol as the mobile phase. The identification of diagnostic fragment ions and optimization of collision energies were carried out using 21 reference standards. Totally 51 compounds were identified which include 21 compounds identified and characterized unambiguously by comparison with their authentic standards and the remaining 30 were tentatively identified and characterized in ethanolic extracts of P. emblica, P. fraternus, P. amarus and P. niruri.
Progress and prediction of multicomponent quantification in complex systems with practical LC-UV methods
Xi Chen, Zhao Yang, Yang Xu, Zhe Liu, Yanfang Liu, Yuntao Dai, Shilin Chen
2023, 13(2): 142-155.   doi: 10.1016/j.jpha.2022.11.011
[Abstract](2202) [PDF 1336KB](1095)
Abstract:
Complex systems exist widely, including medicines from natural products, functional foods, and biological samples. The biological activity of complex systems is often the result of the synergistic effect of multiple components. In the quality evaluation of complex samples, multicomponent quantitative analysis (MCQA) is usually needed. To overcome the difficulty in obtaining standard products, scholars have proposed achieving MCQA through the “single standard to determine multiple components (SSDMC)” approach. This method has been used in the determination of multicomponent content in natural source drugs and the analysis of impurities in chemical drugs and has been included in the Chinese Pharmacopoeia. Depending on a convenient (ultra) high-performance liquid chromatography method, how can the repeatability and robustness of the MCQA method be improved? How can the chromatography conditions be optimized to improve the number of quantitative components? How can computer software technology be introduced to improve the efficiency of multicomponent analysis (MCA)? These are the key problems that remain to be solved in practical MCQA. First, this review article summarizes the calculation methods of relative correction factors in the SSDMC approach in the past five years, as well as the method robustness and accuracy evaluation. Second, it also summarizes methods to improve peak capacity and quantitative accuracy in MCA, including column selection and two-dimensional chromatographic analysis technology. Finally, computer software technologies for predicting chromatographic conditions and analytical parameters are introduced, which provides an idea for intelligent method development in MCA. This paper aims to provide methodological ideas for the improvement of complex system analysis, especially MCQA.
Potential of RP-UHPLC-DAD-MS for the qualitative and quantitative analysis of sofosbuvir in film coated tablets and profiling degradants
María del Mar Contreras, Aránzazu Morales-Soto, Antonio Segura-Carretero, Javier Valverde
2017, 7(4): 208-213.  
[Abstract](77) [PDF 2055KB](38)
Abstract:
Sofosbuvir is one of the new direct-acting antiviral drugs against hepatitis C virus (HCV) infection. This drug has recently been launched into the market, and generic versions of the medication are expected to be produced by local drug producers in some countries. Therefore, new methods are required to control sofosbuvir in pharmaceuticals. In the present study, a new method based on reversed phase (RP)-ultra-high performance liquid chromatography (UHPLC) coupled to diode array detection (DAD) and mass spectrometry (MS) was developed to facilitate the qualitative and quantitative analysis of sofosbuvir in film coated tablets. A wavelength of 260 nm was selected to perform a cost-effective quantification and the method showed adequate linearity, with an R2 value of 0.9998, and acceptable values of accuracy (75%–102%) and precision (residual standard deviation < 5%). The detection and quantification limits were 0.07 μg/mL and 0.36 μg/mL, respectively. Furthermore, the use of high-resolution MS enabled us to ensure the specificity, check impurities and better sensitivity. Therefore, this methodology promises to be suitable not only for the routine analysis of sofosbuvir in pharmaceutical dosage forms, but also for potential degradants.
Single-cell RNA-sequencing and subcellular spatial transcriptomics facilitate the translation of liver microphysiological systems for regulatory application
Dan Li, Zhou Fang, Qiang Shi, Nicholas Zhang, Binsheng Gong, Weida Tong, Ahmet F. Coskun, Joshua Xu
2023, 13(7): 691-693.   doi: 10.1016/j.jpha.2023.06.013
[Abstract](583) [PDF 707KB](284)
Abstract:
Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer
Xiaofan Sun, Lisha Zhou, Yi Wang, Guoliang Deng, Xinran Cao, Bowen Ke, Xiaoqi Wu, Yanhong Gu, Haibo Cheng, Qiang Xu, Qianming Du, Hongqi Chen, Yang Sun
2023, 13(7): 726-744.   doi: 10.1016/j.jpha.2023.04.013
[Abstract](473) [PDF 9014KB](233)
Abstract:
Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.
Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium: Integration of herbal medicine, enzyme engineering, and nanotechnology
Yi Lu, Qiulan Luo, Xiaobin Jia, James P. Tam, Huan Yang, Yuping Shen, Xin Li
2023, 13(3): 239-254.   doi: 10.1016/j.jpha.2022.12.001
[Abstract](737) [PDF 3796KB](367)
Abstract:
Flavonoids such as baohuoside I and icaritin are the major active compounds in Epimedii Folium (EF) and possess excellent therapeutic effects on various diseases. Encouragingly, in 2022, icaritin soft capsules were approved to reach the market for the treatment of hepatocellular carcinoma (HCC) by National Medical Products Administration (NMPA) of China. Moreover, recent studies demonstrate that icaritin can serve as immune-modulating agent to exert anti-tumor effects. Nonetheless, both production efficiency and clinical applications of epimedium flavonoids have been restrained because of their low content, poor bioavailability, and unfavorable in vivo delivery efficiency. Recently, various strategies, including enzyme engineering and nanotechnology, have been developed to increase productivity and activity, improve delivery efficiency, and enhance therapeutic effects of epimedium flavonoids. In this review, the structure-activity relationship of epimedium flavonoids is described. Then, enzymatic engineering strategies for increasing the productivity of highly active baohuoside I and icaritin are discussed. The nanomedicines for overcoming in vivo delivery barriers and improving therapeutic effects of various diseases are summarized. Finally, the challenges and an outlook on clinical translation of epimedium flavonoids are proposed.
Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors
Yan Chen, Xingguo Hou, Dapeng Li, Jin Ding, Jiayue Liu, Zilei Wang, Fei Teng, Hongjun Li, Fan Zhang, Yi Gu, Steven Yu, Xueming Qian, Zhi Yang, Hua Zhu
2023, 13(4): 367-375.   doi: 10.1016/j.jpha.2023.02.011
[Abstract](582) [PDF 2693KB](285)
Abstract:
Claudin18.2 (CLDN18.2) is a tight junction protein that is overexpressed in a variety of solid tumors such as gastrointestinal cancer and oesophageal cancer. It has been identified as a promising target and a potential biomarker to diagnose tumor, evaluate efficacy, and determine patient prognosis. TST001 is a recombinant humanized CLDN18.2 antibody that selectively binds to the extracellular loop of human Claudin18.2. In this study, we constructed a solid target radionuclide zirconium-89 (89Zr) labled-TST001 to detect the expression of in the human stomach cancer BGC823CLDN18.2 cell lines. The [89Zr]Zr-desferrioxamine (DFO)-TST001 showed high radiochemical purity (RCP, >99%) and specific activity (24.15±1.34 GBq/μmol), and was stable in 5% human serum albumin, and phosphate buffer saline (>85% RCP at 96h). The EC50 values of TST001 and DFO-TST001 were as high as 0.413±0.055 and 0.361±0.058nM(P>0.05), respectively. The radiotracer had a significantly higher average standard uptake values in CLDN18.2-positive tumors than in CLDN18.2-negative tumors (1.11±0.02 vs. 0.49±0.03, P=0.0016) 2 days post injection (p.i.). BGC823CLDN18.2 mice models showed high tumor/muscle ratios 96h p.i. with [89Zr]Zr-DFO-TST001 was much higher than those of the other imaging groups. Immunohistochemistry results showed that BGC823CLDN18.2 tumors were highly positive (+++) for CLDN18.2, while those in the BGC823 group did not express CLDN18.2 (-). The results of exvivo biodistribution studies showed that there was a higher distribution in the BGC823CLDN18.2 tumor bearing mice (2.05±0.16 %ID/g) than BGC823 mice (0.69±0.02 %ID/g) and blocking group (0.72±0.02 %ID/g). A dosimetry estimation study showed that the effective dose of [89Zr]Zr-DFO-TST001 was 0.0705 mSv/MBq, which is within the range of acceptable doses for nuclear medicine research. Taken together, these results suggest that Good Manufacturing Practices produced by this immuno-positron emission tomography probe can detect CLDN18.2-overexpressing tumors.
Ginsenoside Rk3 is a novel PI3K/AKT-targeting therapeutics agent that regulates autophagy and apoptosis in hepatocellular carcinoma
Linlin Qu, Yannan Liu, Jianjun Deng, Xiaoxuan Ma, Daidi Fan
2023, 13(5): 463-482.   doi: 10.1016/j.jpha.2023.03.006
[Abstract](538) [PDF 12621KB](264)
Abstract:
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Ginsenoside Rk3, an important and rare saponin in heat-treated ginseng, is generated from Rg1 and has a smaller molecular weight. However, the anti-HCC efficacy and mechanisms of ginsenoside Rk3 have not yet been characterized. Here, we investigated the mechanism by which ginsenoside Rk3, a tetracyclic triterpenoid rare ginsenoside, inhibits the growth of HCC. We first explored the possible potential targets of Rk3 through network pharmacology. Both in vitro (HepG2 and HCC-LM3 cells) and in vivo (primary liver cancer mice and HCC-LM3 subcutaneous tumor-bearing mice) studies revealed that Rk3 significantly inhibits the proliferation of HCC. Meanwhile, Rk3 blocked the cell cycle in HCC at the G1 phase and induced autophagy and apoptosis in HCC. Further proteomics and siRNA experiments showed that Rk3 regulates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway to inhibit HCC growth, which was validated by molecular docking and surface plasmon resonance. In conclusion, we report the discovery that ginsenoside Rk3 binds to PI3K/AKT and promotes autophagy and apoptosis in HCC. Our data strongly support the translation of ginsenoside Rk3 into novel PI3K/AKT-targeting therapeutics for HCC treatment with low toxic side effects.
Single-cell analysis of cellular heterogeneity and interactions in the ischemia-reperfusion injured mouse intestine
Lianhong Yin, Meng Gao, Lina Xu, Yan Qi, Lan Han, Jinyong Peng
2023, 13(7): 760-775.   doi: 10.1016/j.jpha.2023.02.002
[Abstract](447) [PDF 9277KB](220)
Abstract:
Nine major cell populations among 46,716 cells were identified in mouse intestinal ischemia‒reperfusion (II/R) injury by single-cell RNA sequencing. For enterocyte cells, 11 subclusters were found, in which enterocyte cluster 1 (EC1), enterocyte cluster 3 (EC3), and enterocyte cluster 8 (EC8) were newly discovered cells in ischemia 45 min/reperfusion 720 min (I 45 min/R 720 min) group. EC1 and EC3 played roles in digestion and absorption, and EC8 played a role in cell junctions. For TA cells, after ischemia 45 min/reperfusion 90 min (I 45 min/R 90 min), many TA cells at the stage of proliferation were identified. For Paneth cells, Paneth cluster 3 was observed in the resting state of normal jejunum. After I 45 min/R 90 min, three new subsets were found, in which Paneth cluster 1 had good antigen presentation activity. The main functions of goblet cells were to synthesize and secrete mucus, and a novel subcluster (goblet cluster 5) with highly proliferative ability was discovered in I 45 min/R 90 min group. As a major part of immune system, the changes in T cells with important roles were clarified. Notably, enterocyte cells secreted Guca2b to interact with Gucy2c receptor on the membranes of stem cells, TA cells, Paneth cells, and goblet cells to elicit intercellular communication. One marker known as glutathione S-transferase mu 3 (GSTM3) affected intestinal mucosal barrier function by adjusting mitogen-activated protein kinases (MAPK) signaling during II/R injury. The data on the heterogeneity of intestinal cells, cellular communication and the mechanism of GSTM3 provide a cellular basis for treating II/R injury.
Progress and prediction of multicomponent quantification in complex systems with practical LC-UV methods
Xi Chen , Zhao Yang etc.
2023, 13(2): 142-155.   doi: 10.1016/j.jpha.2022.11.011
Potential of RP-UHPLC-DAD-MS for the qualitative and quantitative analysis of sofosbuvir in film coated tablets and profiling degradants
María del Mar Contreras , Aránzazu Morales-Soto etc.
2017, 7(4): 208-213.  
Single-cell RNA-sequencing and subcellular spatial transcriptomics facilitate the translation of liver microphysiological systems for regulatory application
Dan Li , Zhou Fang etc.
2023, 13(7): 691-693.   doi: 10.1016/j.jpha.2023.06.013
Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer
Xiaofan Sun , Lisha Zhou etc.
2023, 13(7): 726-744.   doi: 10.1016/j.jpha.2023.04.013
Multidisciplinary strategies to enhance therapeutic effects of flavonoids from Epimedii Folium: Integration of herbal medicine, enzyme engineering, and nanotechnology
Yi Lu , Qiulan Luo etc.
2023, 13(3): 239-254.   doi: 10.1016/j.jpha.2022.12.001
Development of a CLDN18.2-targeting immuno-PET probe for non-invasive imaging in gastrointestinal tumors
Yan Chen , Xingguo Hou etc.
2023, 13(4): 367-375.   doi: 10.1016/j.jpha.2023.02.011
Ginsenoside Rk3 is a novel PI3K/AKT-targeting therapeutics agent that regulates autophagy and apoptosis in hepatocellular carcinoma
Linlin Qu , Yannan Liu etc.
2023, 13(5): 463-482.   doi: 10.1016/j.jpha.2023.03.006
Single-cell analysis of cellular heterogeneity and interactions in the ischemia-reperfusion injured mouse intestine
Lianhong Yin , Meng Gao etc.
2023, 13(7): 760-775.   doi: 10.1016/j.jpha.2023.02.002
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