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Sonodynamic therapy for the treatment of atherosclerosis
Yan Zhang, Ying Yang, Yudi Feng, Xueyan Gao, Liping Pei, Xiaopan Li, Bingxin Gao, Lin Liu, Chengzeng Wang, Shuochen Gao
 doi: 10.1016/j.jpha.2023.11.016
[Abstract](20) [PDF 2693KB](2)
Abstract:
Atherosclerosis (AS) is a chronic inflammatory disease of large and medium-sized arteries that leads to ischemic heart disease, stroke, and peripheral vascular disease. Despite the current treatments, mortality and disability still remain high. Sonodynamic therapy (SDT), as a non-invasive and local methodology, has been developed as a promising new treatment for inhibiting atherosclerotic progression and stabilizing plaques. Promising progress has been made through cell and animal assays, as well as clinical trials. For example, the effect of SDT on apoptosis and autophagy of cells in AS, especially macrophages, and the concept of non-lethal SDT has also been proposed. In this review, we summarize the ultrasonic parameters and known sonosensitizers utilized in SDT for AS; we elaborate on SDT’s therapeutic effects and mechanisms in terms of macrophages, T lymphocytes, neovascularization, smooth muscle cells, lipid, extracellular matrix and efferocytosis within plaques; additionally, we discuss the safety of SDT. A comprehensive summary of the confirmed effects of SDT on AS is conducted to establish a framework for future researchers.
Apatinib and gamabufotalin co-loaded lipid/prussian blue nanoparticles for synergistic therapy to gastric cancer with metastasis
Binlong Chen, Yanzhong Zhao, Zichang Lin, Jiahao Liang, Jialong Fan, Yanyan Huang, Leye He, Bin Liu
 doi: 10.1016/j.jpha.2023.11.011
[Abstract](20) [PDF 35361KB](7)
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Due to the non-targeted release and low solubility of anti-gastric cancer agent, apatinib (Apa), a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects, as well. In order to avoid these drawbacks, lipid-film-coated Prussian blue nanoparticles (PB NPs) with hyaluronan (HA) modification was used for Apa loading to improve its solubility and targeting ability. Furthermore, anti-tumor compound of gamabufotalin (CS-6) was selected as a partner of Apa with reducing dosage for combinational gastric therapy. Thus, HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue. In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating VEGFR and MMP-9. In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects. In summary, we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer (GC) therapy.
An integrated strategy of UPLC-Q-TOF/MS and HPTLC/PAD-DESI-MSI for the analysis of chemical variations: A case study of Tibetan medicine Tiebangchui
Yue Liu, Mengjia Li, Xing Fu, Yi Zhang, Ce Tang
 doi: 10.1016/j.jpha.2023.11.014
[Abstract](26) [PDF 6725KB](3)
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Targeting the chromatin structural changes of antitumor immunity
Nian-nian Li, Deng-xing Lun, Ningning Gong, Gang Meng, Xin-ying Du, He Wang, Xiangxiang Bao, Xin-yang Li, Ji-wu Song, Kewei Hu, Lala Li, Si-ying Li, Wenbo Liu, Wanping Zhu, Yunlong Zhang, Jikai Li, Ting Yao, Leming Mou, Xiaoqing Han, Furong Hao, Lei Wang, Yongcheng Hu, Lin Liu, Hongguang Zhu, Yuyun Wu, Bin Liu
 doi: 10.1016/j.jpha.2023.11.012
[Abstract](20) [PDF 2635KB](6)
Abstract:
Epigenomic imbalance drives abnormal transcriptional processes, promoting the onset and progression of cancer. Although defective gene regulation generally affects carcinogenesis and tumor suppression networks, tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes, which may have significant implications for the development and application of epigenetic therapy, cancer immunotherapy, and their combinations. Herein, we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes, DNA methylation, histone post-translational modification, and chromatin structure in tumor immunogenicity, and introduce these epigenetic research methods. We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immunotherapy through the complex interaction between cancer epigenetics and cancer immunology.
Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis
Lifan Lin, Xinmiao Li, Yifei Li, Zhichao Lang, Yeping Li, Jianjian Zheng
 doi: 10.1016/j.jpha.2023.11.009
[Abstract](12) [PDF 45908KB](2)
Abstract:
Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), a process associated with ferroptosis. Ginsenoside Rb1 (GRb1), a major active component extracted from Panax ginseng, inhibits HSC activation. However, the potential role of GRb1 in mediating HSC ferroptosis remains unclear. This study examined the effect of GRb1 on liver fibrosis both in vivo and in vitro, using CCl4-induced liver fibrosis mouse model and primary HSCs, LX-2 cells. The findings revealed that GRb1 effectively inactivated HSCs in vitro, reducing alpha-smooth muscle actin and Type I collagen levels. Moreover, GRb1 significantly alleviated CCl4-induced liver fibrosis in vivo. From a mechanistic standpoint, the ferroptosis pathway appeared to be central to the antifibrotic effects of GRb1. Specifically, GRb1 promoted HSC ferroptosis both in vivo and in vitro, characterized by increased glutathione depletion, malondialdehyde production, iron overload, and accumulation of reactive oxygen species. Intriguingly, GRb1 increased Beclin 1 (BECN1) levels and decreased the System Xc-key subunit SLC7A11. Further experiments showed that BECN1 silencing inhibited GRb1-induced effects on HSC ferroptosis and mitigated the reduction of SLC7A11 caused by GRb1. Moreover, BECN1 could directly interact with SLC7A11, initiating HSC ferroptosis. In conclusion, the suppression of BECN1 counteracted the effects of GRb1 on HSC inactivation both in vivo and in vitro. Overall, this study highlights the novel role of GRb1 in inducing HSC ferroptosis and promoting HSC inactivation, at least partly through its modulation of BECN1 and SLC7A11.
Integrated Spatial Metabolomics and Transcriptomics Decipher the Hepatoprotection Mechanisms of Wedelolactone and Demethylwedelolactone on Non-alcoholic Fatty Liver Disease
Panpan Chen, Zihan Zhu, Haoyuan Geng, Xiaoqing Cui, Yuhao Han, Lei Wang, Yaqi Zhang, Heng Lu, Xiao Wang, Yun Zhang, Chenglong Sun
 doi: 10.1016/j.jpha.2023.11.017
[Abstract](22) [PDF 16783KB](2)
Abstract:
Eclipta prostrata L. has been used in traditional medicine and known for its liver-protective properties for centuries. Wedelolactone (WEL) and demethylwedelolactone (DWEL) are the major coumarins found in Eclipta prostrata L.. However, the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease (NAFLD) still remains to be explored. Utilizing a well-established zebrafish model of thioacetamide (TAA)-induced liver injury, the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis. Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver. The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped, and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized. Based on spatial metabolomics and transcriptomics, we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL. Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD, and presents a ''multi-omics'' platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.
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Review paper
Protective effects of catalpol on cardio-cerebrovascular diseases: A comprehensive review
Zixi Zhang, Yongguo Dai, Yichao Xiao, Qiming Liu
2023, 13(10): 1089-1101.   doi: 10.1016/j.jpha.2023.06.010
Abstract(98) HTML Full Text PDF(22)
Abstract:
Catalpol, an iridoid glucoside isolated from Rehmannia glutinosa, has gained attention due to its potential use in treating cardio-cerebrovascular diseases (CVDs). This extensive review delves into recent studies on catalpol's protective properties in relation to various CVDs, such as atherosclerosis, myocardial ischemia, infarction, cardiac hypertrophy, and heart failure. The review also explores the compound's anti-oxidant, anti-inflammatory, and anti-apoptotic characteristics, emphasizing the role of vital signaling pathways, including PGC-1α/TERT, PI3K/Akt, AMPK, Nrf2/HO-1, estrogen receptor (ER), Nox4/NF-κB, and GRP78/PERK. The article discusses emerging findings on catalpol's ability to alleviate diabetic cardiovascular complications, thrombosis, and other cardiovascular-related conditions. Although clinical studies specifically addressing catalpol's impact on CVDs are scarce, the compound's established safety and well-tolerated nature suggest that it could be a valuable treatment alternative for CVD patients. Further investigation into catalpol and related iridoid derivatives may unveil new opportunities for devising natural and efficacious CVD therapies.
Recent advancements in single-cell metabolic analysis for pharmacological research
Ying Hou, Hongren Yao, Jin-Ming Lin
2023, 13(10): 1102-1116.   doi: 10.1016/j.jpha.2023.08.014
Abstract(93) HTML Full Text PDF(22)
Abstract:
Cellular heterogeneity is crucial for understanding tissue biology and disease pathophysiology. Pharmacological research is being advanced by single-cell metabolic analysis, which offers a technique to identify variations in RNA, proteins, metabolites, and drug molecules in cells. In this review, the recent advancement of single-cell metabolic analysis techniques and their applications in drug metabolism and drug response are summarized. High-precision and controlled single-cell isolation and manipulation are provided by microfluidics-based methods, such as droplet microfluidics, microchamber, open microfluidic probe, and digital microfluidics. They are used in tandem with variety of detection techniques, including optical imaging, Raman spectroscopy, electrochemical detection, RNA sequencing, and mass spectrometry, to evaluate single-cell metabolic changes in response to drug administration. The advantages and disadvantages of different techniques are discussed along with the challenges and future directions for single-cell analysis. These techniques are employed in pharmaceutical analysis for studying drug response and resistance pathway, therapeutic targets discovery, and in vitro disease model evaluation.
SPME as a green sample-preparation technique for the monitoring of phytocannabinoids and endocannabinoids in complex matrices
Katarzyna Woźniczka, Paweł Konieczyński, Alina Plenis, Tomasz Bączek, Anna Roszkowska
2023, 13(10): 1117-1134.   doi: 10.1016/j.jpha.2023.06.014
Abstract(64) HTML Full Text PDF(10)
Abstract:
The endocannabinoid system (ECS), particularly its signaling pathways and ligands, has garnered considerable interest in recent years. Along with clinical work investigating the ECS’ functions, including its role in the development of neurological and inflammatory conditions, much research has focused on developing analytical protocols enabling the precise monitoring of the levels and metabolism of the most potent ECS ligands: exogenous phytocannabinoids (PCs) and endogenous cannabinoids (endocannabinoids, ECs). Solid-phase microextraction (SPME) is an advanced, non-exhaustive sample-preparation technique that facilitates the precise and efficient isolation of trace amounts of analytes, thus making it appealing for the analysis of PCs and ECs in complex matrices of plant and animal/human origin. In this paper, we review recent forensic medicine and toxicological studies wherein SPME has been applied to monitor levels of PCs and ECs in complex matrices, determine their effects on organism physiology, and assess their role in the development of several diseases.
Original article
Monoclonal antibody targeting mu-opioid receptor attenuates morphine tolerance via enhancing morphine-induced receptor endocytosis
Jia-Jia Zhang, Chang-Geng Song, Miao Wang, Gai-Qin Zhang, Bin Wang, Xi Chen, Peng Lin, Yu-Meng Zhu, Zhi-Chuan Sun, Ya-Zhou Wang, Jian-Li Jiang, Ling Li, Xiang-Min Yang, Zhi-Nan Chen
2023, 13(10): 1135-1152.   doi: 10.1016/j.jpha.2023.06.008
Abstract(182) HTML Full Text PDF(31)
Abstract:
Morphine is a frequently used analgesic that activates the mu-opioid receptor (MOR), which has prominent side effects of tolerance. Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance, currently, there is no effective therapy to treat morphine tolerance. In the current study, we aimed to develop a monoclonal antibody (mAb) precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms. We successfully prepared a mAb targeting MOR, named 3A5C7, by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization, and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation. Treatment of two cell lines, HEK293T and SH-SY5Y, with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2 (GRK2)/β-arrestin2-dependent mechanism, as demonstrated by immunofluorescence staining, flow cytometry, Western blotting, coimmunoprecipitation, and small interfering ribonucleic acid (siRNA)-based knockdown. This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR. We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid. Western blot, enzyme-linked immunosorbent assays, and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase, the in vitro biomarker of morphine tolerance, via the GRK2/β-arrestin2 pathway. Furthermore, in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice, and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence. Finally, intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/β-arrestin2 pathway. Collectively, our study provided a therapeutic mAb, 3A5C7, targeting MOR to treat morphine tolerance, mediated by enhancing morphine-induced MOR endocytosis. The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.
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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](307) [PDF 2284KB](8)
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](298) [PDF 5841KB](19)
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](199) [PDF 2697KB](6)
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](118) [PDF 5845KB](9)
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.
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](140) [PDF 19436KB](6)
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.
Research advances in the detection of miRNA
Jiawei Ye, Mingcheng Xu, Xueke Tian, Sheng Cai, Su Zeng
2019, 9(4): 217-226.  
[Abstract](157) [PDF 6429KB](2)
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.
Carbon nanotubes:Evaluation of toxicity at biointerfaces
Debashish Mohanta, Soma Patnaik, Sanchit Sood, Nilanjan Das
2019, 9(5): 293-300.  
[Abstract](97) [PDF 3216KB](2)
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](159) [PDF 3923KB](25)
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](2000) [PDF 1336KB](996)
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](320) [PDF 9014KB](158)
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](429) [PDF 707KB](208)
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](308) [PDF 9277KB](152)
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.
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](333) [PDF 5798KB](163)
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](392) [PDF 2693KB](192)
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](275) [PDF 12621KB](134)
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](382) [PDF 3796KB](189)
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
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
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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