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Targeting NTCP for liver disease treatment: A promising strategy
Xin Tan, , Yu Xiang, Jianyou Shi, Lu Chen, Dongke Yu
 doi: 10.1016/j.jpha.2024.100979
[Abstract](0) [PDF 16399KB](0)
Abstract:
The sodium taurocholate co-transporting polypeptide (NTCP), a bile acids transporter, has been identified as a new therapeutic target for the treatment of liver disease. This paper thoroughly investigates the function of NTCP for regulating bile acid regulation, its correlation with hepatitis B and D infections, and its association with various liver diseases. Additionally, in this review we examine recent breakthroughs in creating NTCP inhibitors and their prospective applications in liver disease treatment. While this review emphasizes the promising potential of targeting NTCP, it concurrently underscores the need for broader and more detailed research to fully understand the long-term implications and potential side effects associated with NTCP inhibition.
Emerging role of Jumonji domain-containing protein D3 (JMJD3) in inflammatory diseases
Xiang Li, Ru-Yi Chen, Jin-Jin Shi, Chang-Yun Li, Yan-Jun Liu, Chang Gao, Ming-Rong Gao, Shun Zhang, Jian-Fei Lu, Jia-Feng Cao, Guan-Jun Yang, Jiong Chen
 doi: 10.1016/j.jpha.2024.100978
[Abstract](0) [PDF 18301KB](0)
Abstract:
Jumonji domain-containing protein D3 (JMJD3) is a 2-oxoglutarate-dependent dioxygenase that specifically removes transcriptional repression marks di- and tri- 6 methylated groups from lysine 27 on histone (H3K27me2/3). The erasure of these 7 marks leads to the activation of some associated genes, thereby influencing various biological processes, such as development, differentiation, and immune response. However, comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking. Here, we provide a comprehensive overview of JMJD3, including its structure, functions, and involvement in inflammatory pathways. In addition, we summarize the evidence supporting JMJD3’s role in several inflammatory diseases, as well as the potential therapeutic applications of JMJD3 inhibitors. Additionally, we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases.
Xianling Lianxia formula improves the efficacy of trastuzumab by enhancing NK cell-mediated ADCC in HER2-positive BC
Feifei Li, Youyang Shi, Mei Ma, Xiaojuan Yang, Xiaosong Chen, Ying Xie, Sheng Liu
 doi: 10.1016/j.jpha.2024.100977
[Abstract](816) [PDF 32069KB](2)
Abstract:
Trastuzumab has improved survival rates in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), but drug resistance leads to treatment failure. Natural killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC) represents an essential antitumor immune mechanism of trastuzumab. Traditional Chinese medicine (TCM) has been used for centuries to treat diseases because of its capacity to improve immune responses. Xianling Lianxia formula (XLLXF), based on the principle of “strengthening body and eliminating toxin”, exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive BC. Notably, this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC, as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention experiments. Mechanistically, the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible SH2 containing protein (CISH) expression, which in turn activates the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 5 (STAT5) pathway. Collectively, these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.
Hepatic PPP1R3G alleviates obesity and liver steatosis by affecting gut microbiota and bile acid metabolism
Chu Zhang a, Gui Wang, Xin Yin, Lingshan Gou, Mengyuan Guo, Feng Suo, Tao Zhuang, Zhenya Yuan, Yanan Liu, Maosheng Gu, Ruiqin Yao
 doi: 10.1016/j.jpha.2024.100976
[Abstract](24) [PDF 10005KB](0)
Abstract:
Intestinal dysbiosis and disrupted bile acid (BA) homeostasis are associated with obesity, but the precise mechanisms remain insufficiently explored. Hepatic protein phosphatase 1 regulatory subunit 3G (PPP1R3G) plays a pivotal role in regulating glycolipid metabolism; nevertheless, its obesity-combatting potency remains unclear. In this study, a substantial reduction was observed in serum PPP1R3G levels in highbody mass index and high-fat diet (HFD)-exposed mice, establishing a positive correlation between PPP1R3G and non-12α-hydroxylated (non-12-OH) BA content. Additionally, hepatocyte-specific overexpression of Ppp1r3g (PPP1R3G HOE) mitigated HFD-induced obesity as evidenced by reduced weight and fat mass, and an improved serum lipid profile; hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology. PPP1R3G HOE considerably impacted systemic BA homeostasis, which notably increased the non-12-OH BAs ratio, particularly lithocholate (LCA). 16S ribosomal DNA (16S rDNA) sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population, and elevating the relative abundance of Blautia, which exhibited a positive correlation with serum LCA levels. A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent. Mechanistically, PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase and sterol-12α-hydroxylase, and concurrently upregulated oxysterol 7-α hydroxylase and Takeda G protein-coupled receptor 5 expression under HFD conditions. Furthermore, LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels. These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiotaBA axis, which may serve as potential therapeutic targets for obesity-related disorders.
Dissection of triple-negative breast cancer microenvironment and identification of potential therapeutic drugs using single-cell RNA sequencing analysis
Weilun Cheng, Wanqi Mi, Shiyuan Wang, Xinran Wang, Hui Jiang, Jing Chen, Kaiyue Yang, Wenqi Jiang, Jun Ye, Baoliang Guo, Yunpeng Zhang
 doi: 10.1016/j.jpha.2024.100975
[Abstract](16) [PDF 21088KB](1)
Abstract:
Breast cancer remains a leading cause of mortality in women worldwide. Triplenegative breast cancer (TNBC) is a particularly aggressive subtype characterized by rapid progression, poor prognosis, and lack of clear therapeutic targets. In the clinic, delineation of tumor heterogeneity and development of effective drugs continue to pose considerable challenges. Within the scope of our study, high heterogeneity inherent to breast cancer was uncovered based on the landscape constructed from both tumor and healthy breast tissue samples. Notably, TNBC exhibited significant specificity regarding cell proliferation, differentiation, and disease progression. Significant associations between tumor grade, prognosis, and TNBC oncogenes were established via pseudotime trajectory analysis. Consequently, we further performed comprehensive characterization of the TNBC microenvironment. A crucial epithelial subcluster, E8, was identified as highly malignant and strongly associated with tumor cell proliferation in TNBC. Additionally, epithelial-mesenchymal transition-associated fibroblast and M2 macrophage subclusters exerted an influence on E8 through cellular interactions, contributing to tumor growth. Characteristic genes in these three cluster cells could therefore serve as potential therapeutic targets for TNBC. The collective findings provided valuable insights that assisted in the screening of a series of therapeutic drugs, such as pelitinib. We further confirmed the anti-cancer effect of pelitinib in an orthotopic 4T1 tumor-bearing mouse model. Overall, our study sheds light on the unique characteristics of TNBC at single-cell resolution and the crucial cell types associated with tumor cell proliferation that may serve as potent tools in the development of effective anti-cancer drugs.
Fangchinoline induces antiviral response by suppressing STING degradation
Jinyong Wang, Fang Xie, Xin Jia, Xuejiao Wang, Lingdong Kong, Yiying Li, Xue Liang, Meiqi Zhang, Yuting He, Wandi Feng, Tong Luo, Yao Wang, Anlong Xu
 doi: 10.1016/j.jpha.2024.100972
[Abstract](63) [PDF 12036KB](13)
Abstract:
The stimulator of interferon genes (STING), an integral adaptor protein in the DNA-sensing pathway, plays a pivotal role in the innate immune response against infections. Additionally, it presents a valuable therapeutic target for infectious diseases and cancer. We observed that fangchinoline (Fan), a bis-benzylisoquinoline alkaloid, effectively impedes the replication of vesicular stomatitis virus (VSV), encephalomyocarditis virus (EMCV), influenza A virus (H1N1 PR8), and herpes simplex virus-1 (HSV-1) in vitro. Fan treatment significantly reduced the viral load, attenuated tissue inflammation, and improved survival in a viral sepsis mouse model. Mechanistically, Fan activates the antiviral response in a STING-dependent manner, leading to increased expression of interferon (IFN) and interferon-stimulated genes (ISGs) for potent antiviral effects in vivo and in vitro. Notably, Fan interacts with STING, preventing its degradation and thereby extending the activation of IFN-based antiviral responses. Collectively, our findings highlight the potential of Fan, which elicits antiviral immunity by suppressing STING degradation, as a promising candidate for antiviral therapy.
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Review paper
Chemical derivatization strategies for enhancing the HPLC analytical performance of natural active triterpenoids
Xiao-Feng Huang, Ying Xue, Li Yong, Tian-Tian Wang, Pei Luo, Lin-Sen Qing
2024, 14(3): 295-307.   doi: 10.1016/j.jpha.2023.07.004
Abstract(244) HTML Full Text PDF(30)
Abstract:
Triterpenoids widely exist in nature, displaying a variety of pharmacological activities. Determining triterpenoids in different matrices, especially in biological samples holds great significance. High-performance liquid chromatography (HPLC) has become the predominant method for triterpenoids analysis due to its exceptional analytical performance. However, due to the structural similarities among botanical samples, achieving effective separation of each triterpenoid proves challenging, necessitating significant improvements in analytical methods. Additionally, triterpenoids are characterized by a lack of ultraviolet (UV) absorption groups and chromophores, along with low ionization efficiency in mass spectrometry. Consequently, routine HPLC analysis suffers from poor sensitivity. Chemical derivatization emerges as an indispensable technique in HPLC analysis to enhance its performance. Considering the structural characteristics of triterpenoids, various derivatization reagents such as acid chlorides, rhodamines, isocyanates, sulfonic esters, and amines have been employed for the derivatization analysis of triterpenoids. This review comprehensively summarized the research progress made in derivatization strategies for HPLC detection of triterpenoids. Moreover, the limitations and challenges encountered in previous studies are discussed, and future research directions are proposed to develop more effective derivatization methods.
Potentials of ribosomopathy gene as pharmaceutical targets for cancer treatment
Mengxin Wang, Stephen Vulcano, Changlu Xu, Renjian Xie, Weijie Peng, Jie Wang, Qiaojun Liu, Lee Jia, Zhi Li, Yumei Li
2024, 14(3): 308-320.   doi: 10.1016/j.jpha.2023.10.001
Abstract(107) HTML Full Text PDF(9)
Abstract:
Ribosomopathies encompass a spectrum of disorders arising from impaired ribosome biogenesis and reduced functionality. Mutation or dysexpression of the genes that disturb any finely regulated steps of ribosome biogenesis can result in different types of ribosomopathies in clinic, collectively known as ribosomopathy genes. Emerging data suggest that ribosomopathy patients exhibit a significantly heightened susceptibility to cancer. Abnormal ribosome biogenesis and dysregulation of some ribosomopathy genes have also been found to be intimately associated with cancer development. The correlation between ribosome biogenesis or ribosomopathy and the development of malignancies has been well established. This work aims to review the recent advances in the research of ribosomopathy genes among human cancers and meanwhile, to excavate the potential role of these genes, which have not or rarely been reported in cancer, in the disease development across cancers. We plan to establish a theoretical framework between the ribosomopathy gene and cancer development, to further facilitate the potential of these genes as diagnostic biomarker as well as pharmaceutical targets for cancer treatment.
Original article
Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy
Rangrang Fan, Linrui Cai, Hao Liu, Hongxu Chen, Caili Chen, Gang Guo, Jianguo Xu
2024, 14(3): 321-334.   doi: 10.1016/j.jpha.2023.09.015
Abstract(251) HTML Full Text PDF(14)
Abstract:
Despite decades of laboratory and clinical trials, breast cancer remains the main cause of cancer-related disease burden in women. Considering the metabolism destruction effect of metformin (Met) and cancer cell starvation induced by glucose oxidase (GOx), after their efficient delivery to tumor sites, GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ. Herein, a pH-responsive epigallocatechin gallate (EGCG)-conjugated low-molecular-weight chitosan (LC-EGCG, LE) nanoparticle (Met–GOx/Fe@LE NPs) was constructed. The coordination between iron ions (Fe3+) and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction. Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability. Moreover, this pH-responsive nanoplatform presents controllable drug release behavior. An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug. The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation. This triple-combination therapy approach is promising for efficient and targeted cancer treatment.
Hapln1 promotes dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping
Ding-Jun Hao, Yue Qin, Shi-Jie Zhou, Bu-Huai Dong, Jun-Song Yang, Peng Zou, Li-Ping Wang, Yuan-Ting Zhao
2024, 14(3): 335-347.   doi: 10.1016/j.jpha.2023.09.013
Abstract(85) HTML Full Text PDF(12)
Abstract:
Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and an adult mouse model of myocardial infarction. HiPSC-CMs and adult mice with myocardial infarction were used as in vitro and in vivo models, respectively. Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration. The results showed that recombinant human Hapln1 (rhHapln1) promotes the proliferation of hiPSC-CMs in a dose-dependent manner. As a physical binding protein of Hapln1, versican interacted with Nodal growth differentiation factor (NODAL) and growth differentiation factor 11 (GDF11). GDF11, but not NODAL, was expressed by hiPSC-CMs. GDF11 expression was unaffected by rhHapln1 treatment. However, this molecule was required for rhHapln1-mediated activation of the transforming growth factor (TGF)-β/Drosophila mothers against decapentaplegic protein (SMAD)2/3 signaling in hiPSC-CMs, which stimulates cell dedifferentiation and proliferation. Recombinant mouse Hapln1 (rmHapln1) could induce cardiac regeneration in the adult mouse model of myocardial infarction. In addition, rmHapln1 induced hiPSC-CM proliferation. In conclusion, Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF-β/SMAD2/3 signaling pathway. Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts.
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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](522) [PDF 2284KB](13)
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](566) [PDF 5841KB](25)
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](441) [PDF 2697KB](10)
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](210) [PDF 5845KB](13)
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](314) [PDF 6429KB](9)
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](322) [PDF 19436KB](10)
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](217) [PDF 3216KB](4)
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](403) [PDF 3923KB](37)
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](2105) [PDF 1336KB](1048)
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.
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](420) [PDF 9014KB](207)
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.
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](521) [PDF 707KB](253)
Abstract:
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](394) [PDF 9277KB](193)
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.
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](604) [PDF 3796KB](300)
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.
Rabdosia serra alleviates dextran sulfate sodium salt-induced colitis in mice through anti-inflammation, regulating Th17/Treg balance, maintaining intestinal barrier integrity, and modulating gut microbiota
Hongyi Li, Yi Wang, Shumin Shao, Hui Yu, Deqin Wang, Chuyuan Li, Qin Yuan, Wen Liu, Jiliang Cao, Xiaojuan Wang, Haibiao Guo, Xu Wu, Shengpeng Wang
2022, 12(6): 824-838.   doi: 10.1016/j.jpha.2022.08.001
[Abstract](419) [PDF 5798KB](205)
Abstract:
Rabdosia serra (R. serra), an important component of Chinese herbal tea, has traditionally been used to treat hepatitis, jaundice, cholecystitis, and colitis. However, the chemical composition of R. serra and its effect against colitis remain unclear. In this study, the chemical composition of the water extract of R. serra was analyzed using ultra performance liquid chromatography coupled with a hybrid linear ion trap quadrupole-orbitrap mass spectrometer (UPLC-LTQ-Orbitrap-MS). A total of 46 compounds, comprising ent-kaurane diterpenoids, flavonoids, phenolic acids, and steroids, were identified in the water extract of R. serra, and the extract could significantly alleviate dextran sulfate sodium salt-induced colitis by improving colon length, upregulating anti-inflammatory factors, downregulating proinflammatory factors, and restoring the balance of T helper 17/T regulatory cells. R. serra also preserved intestinal barrier function by increasing the level of tight junction proteins (zonula occludens 1 and occludin) in mouse colonic tissue. In addition, R. serra modulated the gut microbiota composition by increasing bacterial richness and diversity, increasing the abundance of beneficial bacteria (Muribaculaceae, Bacteroides, Lactobacillus, and Prevotellaceae_UCG-001), and decreasing the abundance of pathogenic bacteria (Turicibacter, Eubacterium_fissicatena_group, and Eubacterium_xylanophilum_group). Gut microbiota depletion by antibiotics further confirmed that R. serra alleviated colitis in a microbiota-dependent manner. Overall, our findings provide chemical and biological evidence for the potential application of R. serra in the management of colitis.
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](437) [PDF 12621KB](214)
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.
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](499) [PDF 2693KB](244)
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.
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
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
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 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
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
Rabdosia serra alleviates dextran sulfate sodium salt-induced colitis in mice through anti-inflammation, regulating Th17/Treg balance, maintaining intestinal barrier integrity, and modulating gut microbiota
Hongyi Li , Yi Wang etc.
2022, 12(6): 824-838.   doi: 10.1016/j.jpha.2022.08.001
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
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
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