Current Issue

Volume 14, Issue 4, 2024

Review papers
Modern approaches for detection of volatile organic compounds in metabolic studies focusing on pathogenic bacteria: Current state of the art
Karolina Żuchowska, Wojciech Filipiak
2024, 14(4): 100898. doi: 10.1016/j.jpha.2023.11.005
Pathogenic microorganisms produce numerous metabolites, including volatile organic compounds (VOCs). Monitoring these metabolites in biological matrices (e.g., urine, blood, or breath) can reveal the presence of specific microorganisms, enabling the early diagnosis of infections and the timely implementation of targeted therapy. However, complex matrices only contain trace levels of VOCs, and their constituent components can hinder determination of these compounds. Therefore, modern analytical techniques enabling the non-invasive identification and precise quantification of microbial VOCs are needed. In this paper, we discuss bacterial VOC analysis under in vitro conditions, in animal models and disease diagnosis in humans, including techniques for offline and online analysis in clinical settings. We also consider the advantages and limitations of novel microextraction techniques used to prepare biological samples for VOC analysis, in addition to reviewing current clinical studies on bacterial volatilomes that address inter-species interactions, the kinetics of VOC metabolism, and species- and drug-resistance specificity.
Pretreatment and analysis techniques development of TKIs in biological samples for pharmacokinetic studies and therapeutic drug monitoring
Lan Chen, Yuan Zhang, Yi-Xin Zhang, Wei-Lai Wang, De-Mei Sun, Peng-Yun Li, Xue-Song Feng, Yue Tan
2024, 14(4): 100899. doi: 10.1016/j.jpha.2023.11.006
Tyrosine kinase inhibitors (TKIs) have emerged as the first-line small molecule drugs in many cancer therapies, exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways. However, there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites, which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments, alongside other potential side effects or adverse reactions. Therefore, an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods, clinical pharmacokinetics, and therapeutic drug monitoring of different TKIs. This paper provides a comprehensive overview of the advancements in pretreatment methods, such as protein precipitation (PPT), liquid-liquid extraction (LLE), solid-phase extraction (SPE), micro-SPE (μ-SPE), magnetic SPE (MSPE), and vortex-assisted dispersive SPE (VA-DSPE) achieved since 2017. It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS) methods, capillary electrophoresis (CE), gas chromatography (GC), supercritical fluid chromatography (SFC) procedures, surface plasmon resonance (SPR) assays as well as novel nanoprobes-based biosensing techniques. In addition, a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.
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, Yongcheng Hu, Lin Liu, Hongguang Zhu, Yuyun Wu, Bin Liu
2024, 14(4): 100905. doi: 10.1016/j.jpha.2023.11.012
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.
Contemporary strategies and approaches for characterizing composition and enhancing biofilm penetration targeting bacterial extracellular polymeric substances
Lan Lu, Yuting Zhao, Mingxing Li, Xiaobo Wang, Jie Zhu, Li Liao, Jingya Wang
2024, 14(4): 100906. doi: 10.1016/j.jpha.2023.11.013
Extracellular polymeric substances (EPS) constitutes crucial elements within bacterial biofilms, facilitating accelerated antimicrobial resistance and conferring defense against the host's immune cells. Developing precise and effective antibiofilm approaches and strategies, tailored to the specific characteristics of EPS composition, can offer valuable insights for the creation of novel antimicrobial drugs. This, in turn, holds the potential to mitigate the alarming issue of bacterial drug resistance. Current analysis of EPS compositions relies heavily on colorimetric approaches with a significant bias, which is likely due to the selection of a standard compound and the cross-interference of various EPS compounds. Considering the pivotal role of EPS in biofilm functionality, it is imperative for EPS research to delve deeper into the analysis of intricate compositions, moving beyond the current focus on polymeric materials. This necessitates a shift from heavy reliance on colorimetric analytic methods to more comprehensive and nuanced analytical approaches. In this study, we have provided a comprehensive summary of existing analytical methods utilized in the characterization of EPS compositions. Additionally, novel strategies aimed at targeting EPS to enhance biofilm penetration were explored, with a specific focus on highlighting the limitations associated with colorimetric methods. Furthermore, we have outlined the challenges faced in identifying additional components of EPS and propose a prospective research plan to address these challenges. This review has the potential to guide future researchers in the search for novel compounds capable of suppressing EPS, thereby inhibiting biofilm formation. This insight opens up a new avenue for exploration within this research domain.
Original articles
YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling
Hua Sui, Wanli Deng, Qiong Chai, Bing Han, Yuli Zhang, Zhenzhen Wei, Zan Li, Ting Wang, Jiling Feng, Man Yuan, Qingfeng Tang, Hongxi Xu
2024, 14(4): 100901. doi: 10.1016/j.jpha.2023.11.008
The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer. Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis (YTE-17), attributing these effects to the regulation of multiple signaling pathways. However, knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited. In this study, we conducted isobaric tags for relative and absolute quantification (iTRAQ) analysis on intestinal epithelial cells (IECs) exposed YTE-17, both in vitro and in vivo, revealing a significant inhibition of the Wnt family member 5a (Wnt5a)/c-Jun N-terminal kinase (JNK) signaling pathway. Subsequently, we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment (TME), specifically focusing on macrophage-mediated T helper 17 (Th17) cell induction in a colitis-associated cancer (CAC) model with Wnt5a deletion. Additionally, we performed the single-cell RNA sequencing (scRNA-seq) on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition, lineage, and functional status of immune mesenchymal cells during different stages of colorectal cancer (CRC) progression. Remarkably, our findings demonstrate a significant reduction in M2 macrophage polarization and Th17 cell phenotype upon treatment with YTE-17, leading to the restoration of regulatory T (Treg)/Th17 cell balance in azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Furthermore, we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages. Notably, our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical β-catenin oncogenic pathway in vivo. Specifically, we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with β-catenin activity within the TME, involving macrophages and T cells. In summary, our study undergoes the potential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment, thereby mitigating the risk of malignancies.
An environmentally sensitive zinc-selective two-photon NIR fluorescent turn-on probe and zinc sensing in stroke
Junfeng Wang, Qibing Liu, Yingbo Li, Yi Pang
2024, 14(4): 100903. doi: 10.1016/j.jpha.2023.11.010
A two-photon near infrared (NIR) fluorescence turn-on sensor with high selectivity and sensitivity for Zn2+ detection has been developed. This sensor exhibits a large Stokes' shift (∼300 nm) and can be excited from 900 to 1000 nm, with an emission wavelength of ∼785 nm, making it ideal for imaging in biological tissues. The sensor's high selectivity for Zn2+ over other structurally similar cations, such as Cd2+, makes it a promising tool for monitoring zinc ion levels in biological systems. Given the high concentration of zinc in thrombi, this sensor could provide a useful tool for in vivo thrombus imaging.
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
2024, 14(4): 100910. doi: 10.1016/j.jpha.2023.11.017
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 E. 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.
Model informed precision medicine of Chinese herbal medicines formulas-A multi-scale mechanistic intelligent model
Yuanyuan Qian, Xiting Wang, Lulu Cai, Jiangxue Han, Zhu Huang, Yahui Lou, Bingyue Zhang, Yanjie Wang, Xiaoning Sun, Yan Zhang, Aisong Zhu
2024, 14(4): 100914. doi: 10.1016/j.jpha.2023.12.004
Recent trends suggest that Chinese herbal medicine formulas (CHM formulas) are promising treatments for complex diseases. To characterize the precise syndromes, precise diseases and precise targets of the precise targets between complex diseases and CHM formulas, we developed an artificial intelligence-based quantitative predictive algorithm (DeepTCM). DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling, molecular and theoretical levels of traditional Chinese medicine (TCM). As an example, our model simulated the optimal CHM formulas for the treatment of coronary heart disease (CHD) with depression, and through model sensitivity analysis, we calculated the balanced scoring of the formulas. Furthermore, we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions. Finally, we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice. This novel multiscale model opened up a new avenue to combine “disease syndrome” and “macro micro” system modeling to facilitate translational research in CHM formulas.
Traditional Chinese medicine Pien-Tze-Huang ameliorates LPS-induced sepsis through bile acid-mediated activation of TGR5-STAT3-A20 signalling
Bei Li, Yong Zhang, Xinyuan Liu, Ziyang Zhang, Shuqing Zhuang, Xiaoli Zhong, Wenbo Chen, Yilin Hong, Pingli Mo, Shuhai Lin, Shicong Wang, Chundong Yu
2024, 14(4): 100915. doi: 10.1016/j.jpha.2023.12.005
Pien Tze Huang (PZH), a class-1 nationally protected traditional Chinese medicine (TCM), has been used to treat liver diseases such as hepatitis; however, the effect of PZH on the progression of sepsis is unknown. Here, we reported that PZH attenuated lipopolysaccharide (LPS)-induced sepsis in mice and reduced LPS-induced production of proinflammatory cytokines in macrophages by inhibiting the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalling. Mechanistically, PZH stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation to induce the expression of A20, which could inhibit the activation of NF-κB and MAPK signalling. Knockdown of the bile acid (BA) receptor G protein-coupled bile acid receptor 1 (TGR5) in macrophages abolished the effects of PZH on STAT3 phosphorylation and A20 induction, as well as the LPS-induced inflammatory response, suggesting that BAs in PZH may mediate its anti-inflammatory effects by activating TGR5. Consistently, deprivation of BAs in PZH by cholestyramine resin reduced the effects of PZH on the expression of phosphorylated-STAT3 and A20, the activation of NF-κB and MAPK signalling, and the production of proinflammatory cytokines, whereas the addition of BAs to cholestyramine resin-treated PZH partially restored the inhibitory effects on the production of proinflammatory cytokines. Overall, our study identifies BAs as the effective components in PZH that activate TGR5-STAT3-A20 signalling to ameliorate LPS-induced sepsis.
Dynamic gut microbiome-metabolome in cationic bovine serum albumin induced experimental immune-complex glomerulonephritis and effect of losartan and mycophenolate mofetil on microbiota modulation
Wenying Shi, Zhaojun Li, Weida Wang, Xikun Liu, Haijie Wu, Xiaoguang Chen, Xunrong Zhou, Sen Zhang
2024, 14(4): 100931. doi: 10.1016/j.jpha.2023.12.021
Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis (ICGN). However, an in-depth study on this topic is currently lacking. Herein, we report an ICGN model to address this gap. ICGN was induced via the intravenous injection of cationized bovine serum albumin (c-BSA) into Sprague-Dawley (SD) rats for two weeks, after which mycophenolate mofetil (MMF) and losartan were administered orally. Two and six weeks after ICGN establishment, fecal samples were collected and 16S ribosomal DNA (rDNA) sequencing and untargeted metabolomic were conducted. Fecal microbiota transplantation (FMT) was conducted to determine whether gut normalization caused by MMF and losartan contributed to their renal protective effects. A gradual decline in microbial diversity and richness was accompanied by a loss of renal function. Approximately 18 genera were found to have significantly different relative abundances between the early and later stages, and Marvinbryantia and Allobaculum were markedly upregulated in both stages. Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN, characterized by the overproduction of indole and kynurenic acid, while the serotonin pathway was reduced. Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces. FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes (F/B) ratio but did not improve renal function. These findings indicate that ICGN induces serous gut dysbiosis, wherein an altered tryptophan metabolism may contribute to its progression. MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis, which partially contributed to their renoprotective effects.
Analysis of GC×GC fingerprints from medicinal materials using a novel contour detection algorithm: A case of Curcuma wenyujin
Xinyue Yang, Yingyu Sima, Xuhuai Luo, Yaping Li, Min He
2024, 14(4): 100936. doi: 10.1016/j.jpha.2024.01.004
This study introduces an innovative contour detection algorithm, PeakCET, designed for rapid and efficient analysis of natural product image fingerprints using comprehensive two-dimensional gas chromatogram (GC×GC). This method innovatively combines contour edge tracking with affinity propagation (AP) clustering for peak detection in GC×GC fingerprints, the first in this field. Contour edge tracking significantly reduces false positives caused by “burr” signals, while AP clustering enhances detection accuracy in the face of false negatives. The efficacy of this approach is demonstrated using three medicinal products derived from Curcuma wenyujin. PeakCET not only performs contour detection but also employs inter-group peak matching and peak-volume percentage calculations to assess the compositional similarities and differences among various samples. Furthermore, this algorithm compares the GC×GC fingerprints of Radix/Rhizoma Curcumae Wenyujin with those of products from different botanical origins. The findings reveal that genetic and geographical factors influence the accumulation of secondary metabolites in various plant tissues. Each sample exhibits unique characteristic components alongside common ones, and variations in content may influence their therapeutic effectiveness. This research establishes a foundational data-set for the quality assessment of Curcuma products and paves the way for the application of computer vision techniques in two-dimensional (2D) fingerprint analysis of GC×GC data.
Short communications