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Advances and mechanisms of traditional Chinese medicine and its active ingredients against antibiotic-resistant Escherichia coli infections
Shuo Yang, Ping Su, Lu Li, Shuang Liu, Yi Wang
 doi: 10.1016/j.jpha.2024.101117
[Abstract](16) [PDF 1850KB](5)
Abstract:
In clinical practice, antibiotics have historically been utilized for the treatment of pathogenic bacteria. However, the gradual emergence of antibiotic resistance among bacterial strains has posed a significant challenge to this approach. In 2022, Escherichia coli, a Gram-negative bacterium renowned for its widespread pathogenicity and high virulence, emerged as the predominant pathogenic bacterium in China. The rapid emergence of antibiotic-resistant E. coli strains has rendered antibiotics insufficient to fight E. coli infections. Traditional Chinese medicine (TCM) has made remarkable contributions to the health of Chinese people for thousands of years, and its significant therapeutic effects have been proven in clinical practice. In this paper, we provide a comprehensive review of the advances and mechanisms of TCM and its active ingredients against antibiotic-resistant E. coli infections. First of all, this review introduces the classification, antibiotic resistance characteristics and mechanisms of E. coli. Then, the TCM formulas and extracts are listed along with their active ingredients against E. coli, including extraction solution, minimum inhibitory concentration (MIC) and the antibacterial mechanisms. In addition, there is growing evidence supporting the synergistic therapeutic strategy of combining TCM with antibiotics for the treatment of antibiotic-resistant E. coli infections, and we provide a summary of this evidence and its underlying mechanisms. In conclusion, we present a comprehensive review of TCM and highlight its potential and advantages in the prevention and treatment of E. coli infections. We hold the opinion that TCM will play an important role in global health, pharmaceutical development and livestock farming in the future.
Elemene as a binding stabilizer of microRNA-145-5p suppresses the growth of non-small cell lung cancer
Meirong Zhou, Jiayue Wang, Yulin Peng, Xiangge Tian, Wen Zhang, Junlin Chen, Yue Wang, Yu Wang, Youjian Yang, Yongwei Zhang, Xiaokui Huo, Yuzhuo Wu, Zhenlong Yu, Tian Xie, Xiaochi Ma
 doi: 10.1016/j.jpha.2024.101118
[Abstract](8) [PDF 30932KB](1)
Abstract:
Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (KD = 0.39 ±0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.
Integration of deep neutral network modeling and LC-MS-based pseudo-targeted metabolomics to discriminate easily confused ginseng species
Meiting Jiang, Yuyang Sha, Yadan Zou, Xiaoyan Xu, Mengxiang Ding, Xu Lian, Hongda Wang, Qilong Wang, Kefeng Li, De-an Guo, Wenzhi Yang
 doi: 10.1016/j.jpha.2024.101116
[Abstract](20) [PDF 9224KB](1)
Abstract:
Metabolomics covers a wide range of applications in life sciences, biomedicine, and phytology. Data acquisition (to achieve high coverage and efficiency) and analysis (to pursue good classification) are two key segments involved in metabolomics workflows. Various chemometric approaches utilizing either pattern recognition or machine learning have been employed to separate different groups. However, insufficient feature extraction, inappropriate feature selection, overfitting, or underfitting lead to an insufficient capacity to discriminate plants that are often easily confused. Using two ginseng varieties, namely Panax japonicus and P. japonicus var. major, containing the similar ginsenosides, we integrated pseudo-targeted metabolomics and deep neural network (DNN) modeling to achieve accurate species differentiation. A pseudo-targeted metabolomics approach was optimized through data acquisition mode, ion pairs generation, comparison between multiple reaction monitoring (MRM) and scheduled MRM, and chromatographic elution gradient. In total, 1980 ion pairs were monitored within 23 min, allowing for the most comprehensive ginseng metabolome analysis. The established DNN model demonstrated excellent classification performance (in terms of accuracy, precision, recall, F1 score, area under the curve, and receiver operating characteristic) using the entire metabolome data and feature-selection dataset, exhibiting superior advantages over random forest (RF), support vector machine (SVM), extreme gradient boosting (XGBoost), and multilayer perceptron (MLP). Moreover, DNNs were advantageous for automated feature learning, nonlinear modeling, adaptability, and generalization. This study confirmed practicality of the established strategy for efficient metabolomics data analysis and reliable classification performance even when using small-volume samples. This established approach holds promise for plant metabolomics and is not limited to ginseng.
Photoaffinity probe-enabled discovery of sennoside A reductase in Bifidobacterium pseudocatenulatum
Yang Xu, Shujing Lv, Xiang Li, Chuanjia Zhai, Yulian Shi, Xuejiao Li, Zhiyang Feng, Gan Luo, Ying Wang, Xiaoyan Gao
 doi: 10.1016/j.jpha.2024.101108
[Abstract](18) [PDF 25194KB](4)
Abstract:
Sennoside A (SA), a typical prodrug, exerts its laxative effect only after its transformation into rheinanthrone catalyzed by gut microbial hydrolases and reductases. Hydrolases have been identified, but reductases remain unknown. By linking a photoreactive group to the SA scaffold, we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling. From lysates of an active strain, Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), 397 proteins were enriched and subsequently identified using mass spectrometry. Among these proteins, chromate reductase/nicotinamide adenine dinucleotide phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase/oxygen-insensitive NADPH nitroreductase (nfrA) was identified as a potent SA reductase through further bioinformatic analysis and Uniprot database screening. We also determined that recombinant nfrA could reduce SA. Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.
Radiosynthesis and preclinical evaluation of [18F]AlF-labeled HBED-CC-FAPI derivatives for imaging of cancer-associated fibroblasts
Haiyan Hong, Yan Zhang, Jinping Qiao, Wensheng Zhang, Lin Zhu, Jiehua Xu
 doi: 10.1016/j.jpha.2024.101107
[Abstract](9) [PDF 12202KB](0)
Abstract:
Altered serum metabolic profile in patients with autoimmune gastritis compared to other chronic gastritis
Jihua Shi, Yang Zhang, Yiran Wang, Yuxi Huang, Zhe Chen, Xue Xu, Wenbin Li, Dan Chen, Hao Luo, Qingfeng Luo, Ruiyue Yang, Xue Qiao
 doi: 10.1016/j.jpha.2024.101104
[Abstract](15) [PDF 3258KB](1)
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Review papers
Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis
Yini Bao, Qiyuan Shan, Keda Lu, Qiao Yang, Ying Liang, Haodan Kuang, Lu Wang, Min Hao, Mengyun Peng, Shuosheng Zhang, Gang Cao
2024, 14(8): 100933.   doi: 10.1016/j.jpha.2024.01.001
Abstract(177) HTML Full Text PDF(18)
Abstract:

Renal fibrosis is a devastating consequence of progressive chronic kidney disease, representing a major public health challenge worldwide. The underlying mechanisms in the pathogenesis of renal fibrosis remain unclear, and effective treatments are still lacking. Renal tubular epithelial cells (RTECs) maintain kidney function, and their dysfunction has emerged as a critical contributor to renal fibrosis. Cellular quality control comprises several components, including telomere homeostasis, ubiquitin-proteasome system (UPS), autophagy, mitochondrial homeostasis (mitophagy and mitochondrial metabolism), endoplasmic reticulum (ER, unfolded protein response), and lysosomes. Failures in the cellular quality control of RTECs, including DNA, protein, and organelle damage, exert profibrotic functions by leading to senescence, defective autophagy, ER stress, mitochondrial and lysosomal dysfunction, apoptosis, fibroblast activation, and immune cell recruitment. In this review, we summarize recent advances in understanding the role of quality control components and intercellular crosstalk networks in RTECs, within the context of renal fibrosis.

Multiple roles of arsenic compounds in phase separation and membraneless organelles formation determine their therapeutic efficacy in tumors
Meiyu Qu, Qiangqiang He, Hangyang Bao, Xing Ji, Tingyu Shen, Muhammad Qasim Barkat, Ximei Wu, Ling-Hui Zeng
2024, 14(8): 100957.   doi: 10.1016/j.jpha.2024.02.011
Abstract(140) HTML Full Text PDF(18)
Abstract:

Arsenic compounds are widely used for the therapeutic intervention of multiple diseases. Ancient pharmacologists discovered the medicinal utility of these highly toxic substances, and modern pharmacologists have further recognized the specific active ingredients in human diseases. In particular, Arsenic trioxide (ATO), as a main component, has therapeutic effects on various tumors (including leukemia, hepatocellular carcinoma, lung cancer, etc.). However, its toxicity limits its efficacy, and controlling the toxicity has been an important issue. Interestingly, recent evidence has pointed out the pivotal roles of arsenic compounds in phase separation and membraneless organelles formation, which may determine their toxicity and therapeutic efficacy. Here, we summarize the arsenic compounds-regulating phase separation and membraneless organelles formation. We further hypothesize their potential involvement in the therapy and toxicity of arsenic compounds, highlighting potential mechanisms underlying the clinical application of arsenic compounds.

Natural compounds improve diabetic nephropathy by regulating the TLR4 signaling pathway
Jiabin Wu, Ke Li, Muge Zhou, Haoyang Gao, Wenhong Wang, Weihua Xiao
2024, 14(8): 100946.   doi: 10.1016/j.jpha.2024.01.014
Abstract(86) HTML Full Text PDF(14)
Abstract:

Diabetic nephropathy (DN), a severe complication of diabetes, is widely recognized as a primary contributor to end-stage renal disease. Recent studies indicate that the inflammation triggered by Toll-like receptor 4 (TLR4) is of paramount importance in the onset and progression of DN. TLR4 can bind to various ligands, including exogenous ligands such as proteins and polysaccharides from bacteria or viruses, as well as endogenous ligands such as biglycan, fibrinogen, and hyaluronan. In DN, the expression or release of TLR4-related ligands is significantly elevated, resulting in excessive TLR4 activation and increased production of proinflammatory cytokines through downstream signaling pathways. This process is closely associated with the progression of DN. Natural compounds are biologically active products derived from natural sources that have advantages in the treatment of certain diseases. Various types of natural compounds, including alkaloids, flavonoids, polyphenols, terpenoids, glycosides, and polysaccharides, have demonstrated their ability to improve DN by affecting the TLR4 signaling pathway. In this review, we summarize the mechanism of action of TLR4 in DN and the natural compounds that can ameliorate DN by modulating the TLR4 signaling pathway. We specifically highlight the potential of compounds such as curcumin, paclitaxel, berberine, and ursolic acid to inhibit the TLR4 signaling pathway, which provides an important direction of research for the treatment of DN.

Original articles
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
2024, 14(8): 100975.   doi: 10.1016/j.jpha.2024.100975
Abstract(172) HTML Full Text PDF(6)
Abstract:

Breast cancer remains a leading cause of mortality in women worldwide. Triple-negative 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 (EMT)-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.

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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](913) [PDF 2284KB](19)
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](1086) [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](805) [PDF 2697KB](17)
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](331) [PDF 5845KB](19)
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](542) [PDF 6429KB](18)
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](458) [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](404) [PDF 3216KB](14)
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](645) [PDF 3923KB](48)
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](2282) [PDF 1336KB](1136)
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](119) [PDF 2055KB](59)
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](637) [PDF 707KB](311)
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](511) [PDF 9014KB](252)
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.
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](612) [PDF 5798KB](299)
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.
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](685) [PDF 2693KB](335)
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](597) [PDF 12621KB](293)
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.
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](800) [PDF 3796KB](398)
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.
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
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
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
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
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