Volume 18,Issue 1,2026 Table of Contents

1 Synthetic biology empowers development of traditional Chinese medicine

Chun Li

2026, 18(1):1-2. DOI: https://doi.org/10.1016/j.chmed.2025.11.010

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2 Herbgenomics: Unraveling natural product biosynthesis in traditional Chinese medicine

Jing Wang a , Jingyuan Song b , Shilin Chen c , ? , Zhichao Xu a , ?

2026, 18(1):3-10. DOI: https://doi.org/10.1016/j.chmed.2025.11.008

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Medicinal plants synthesize structurally diverse pharmacologically active natural products through conserved precursor pathways, which are further diversified by lineage-specific tailoring enzymes. Although the biosynthetic pathways of well-studied compounds (e.g., berberine, paclitaxel, and ginsenosides) have been extensively characterized, most bioactive components in Traditional Chinese Medicine (TCM) remain poorly understood. The emerging discipline of Herbgenomics has significantly advanced biosynthetic gene discovery and pathway elucidation. By employing genomics-driven strategies such as biosynthetic gene cluster mining, co-expression analysis, and integrated transcriptome-metabolome profiling, Herbgenomics enables systematic identification of key biosynthetic enzymes and uncovers evolutionary mechanisms (e.g., whole-genome and tandem gene duplications) driving metabolic innovation. Furthermore, it provides a foundation for drug development by leveraging gene-encoded natural diverse components and genome-wide pan-receptor platforms (e.g., pan-GPCR). Through the integration of pathway analysis, regulatory mechanisms, molecular breeding, and synthetic biology, Herbgenomics establishes a comprehensive framework for exploring and engineering TCM natural product biosynthesis, offering a sustainable pathway to the discovery and production of bioactive compounds.

3 Advanced applications of synthetic biology technology in biosynthesis of bioactive compounds from medicinal plants

Yingjun Liu a , Anying Ji a , Haiyang Jia b , Huan Sun a , ?

2026, 18(1):11-28. DOI: https://doi.org/10.1016/j.chmed.2025.11.006

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Medicinal plants serve as valuable sources of bioactive compounds with critical applications across pharmaceutical, agricultural, and industrial sectors. Compared to chemical synthesis and plant extraction, synthetic biology offers a green, efficient, and sustainable alternative for producing bioactive compounds, which represents a state of art technology. However, this technology still faces several challenges, including overly long metabolic pathways, inadequate catalytic efficiency of key enzymes in the pathway, and incompatibility between gene elements and host cells, leading to low yields of target bioactive compounds. The development and application of regulatory tools in synthetic biology hold great promise for overcoming these obstacles. This review first summarizes the classification and biosynthesis of bioactive compounds based on structural types. Subsequently, recent advancements are outlined in regulation tools and their application in the heterologous production of bioactive compounds. This review aims to establish a foundation for the efficient production of bioactive compounds based on microbial cell factories. This not only has significant practical implications for reducing the resource consumption and environmental impact of traditional production methods, but also highlights the central role of synthetic biology in promoting the sustainable production of bioactive compounds derived from medicinal plants.

4 From natural laboratory to drug discovery: Chemical structures, bioactivities, and biosynthesis of meroterpenoids from Ganoderma species

Shuang Peng a , Jianzhao Qi a , b , Chao Lin b , Zhichao Xu a , b , Zhenhao Li c , ? , Chengwei Liu a , ?

2026, 18(1):29-44. DOI: https://doi.org/10.1016/j.chmed.2025.03.003

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Meroterpenoids are secondary metabolites partially derived from the terpenoid biosynthetic pathway, and are widely distributed in plants, animals, and fungi. These natural products possess complex backbone structures and diverse bioactivities. Ganoderma meroterpenoids (GMs) form a distinct group of meroterpenoids were characterized by the presence of 1,2,4-trisubstituted phenyl and polyunsaturated terpene moieties. Various Ganoderma species have been extensively studied, leading to the discovery of several structurally unique meroterpenoids with significant pharmacological activities. After the first isolation and identification of GMs in 2 000, over 300 compounds from 14 species have been characterized for their structures and biological activities. The structures and activities of some GMs from different Ganoderma species vary greatly, probably due to significant differences in the genome and transcriptome of different Ganoderma species. We predicted the related enzymes based on the reported Ganoderma genome and proposed the biosynthetic pathway related to GMs. The results presented in this review provide a scientific foundation for the comprehensive exploration and utilization of diverse Ganoderma resources.

5 Advances in microbial biosynthesis of indirubin

Keqian Li a , Fangyu Xiang a , Xin Yang a , Mengqi Liu a , Rui Long a , Li Han a , Ming Yang b , Dingku a , c , ? , Yanan He a , ?

2026, 18(1):45-58. DOI: https://doi.org/10.1016/j.chmed.2025.11.004

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Indirubin (IND), a bisindole alkaloid with remarkable pharmacological activities, has attracted significant attention in the pharmaceutical field due to its antileukemic, anti-inflammatory, and immunomodulatory properties. Currently, indirubin primarily relies on plant extraction and chemical synthesis, which are hindered by complex processes, low yields, and poor environmental compatibility. These challenges pose serious obstacles to clinical supply and sustainable industrial development. In recent years, microbial synthesis technology, which is based on synthetic biology and metabolic engineering, has provided a novel approach for the efficient production of indirubin. This method offers several advantages, including high efficiency, environmental sustainability, and eco-friendliness. Hence, this manuscript systematically summarizes the biosynthesis mechanisms of indirubin, the catalytic characteristics of key enzymes, the construction strategies of engineered bacteria, and the progress in fermentation condition. To address challenges such as the difficult separation of indirubin isomers, by-product inhibition, and industrialization bottlenecks, potential solutions are proposed, aiming to promote the green biomanufacturing of indirubin.

6 A review of Siraitia grosvenorii: Applications, breeding, and biosynthesis of mogrosides

Zuliang Luo a , b , Yimei Zang a , Jiaxian Su a , Qi Tang b , c , Limei Pan d , Xiaojun Ma a , Chongnan Wang a , ? , Changming Mo e , ?

2026, 18(1):59-76. DOI: https://doi.org/10.1016/j.chmed.2025.11.005

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Siraitia grosvenorii is a premier food-medicine homologous species recognised by China’s National Health Commission and produces mogrosides as its primary active component. These compounds exhibit biological activities, including the regulation of blood sugar, fat metabolism, and immune function regulation. They are classified as high-intensity, non-nutritive sweeteners with significant medicinal potential and nutritional value. This review systematically explores the applications of S. grosvenorii in traditional medicine and foods, with a focus on advances in the conservation of germplasm resources and the traditional breeding of elite varieties, mogroside biosynthetic pathways and the characterization of key genes, and synthetic biology platforms for mogroside production. We have identified the low content of mogroside V in S. grosvenorii as the main reason for its limited application. To address this issue, we propose two strategic approaches: enhancing mogroside content in vivo through molecular design breeding and developing three synthetic biology platforms for mogrosides synthesis to increase yields. These solutions offer viable ways to reduce production costs and expand the commercial use of S. grosvenorii medicines and sweeteners.

7 Natural novel vitamin C derivative, 2-O-b-D-glucopyranosyl-L-ascorbic acid: Resources, biosynthesis, and applications

Mengyue Wang a , Haotian Wu a , Li Xiang a , Ranran Gao a , Qinggang Yin a , Yang Chu a , Lan Wu a , Yanyan Su b , Gangqiang Dong b , ? , Yuhua Shi a , ?

2026, 18(1):77-88. DOI: https://doi.org/10.1016/j.chmed.2025.11.002

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As the only naturally occurring stable derivative of L-ascorbic acid (AA; vitamin C), 2-O-b-Dglucopyranosyl-L-ascorbic acid (AA-2bG) is hydrolyzed in vivo to release active AA. AA-2bG exhibits strong antioxidant and antiphotoaging effects comparable to those of AA, and it plays a key role in maintaining organismal health. Owing to its superior stability and bioavailability, AA-2bG is considered as a promising, longer-lasting natural alternative to conventional vitamin C. It was first identified and is particularly abundant in Lycii Fructus (Gouqizi in Chinese) but has been detected in several crop plants. This review offers a comprehensive overview of recent advances in AA-2bG research, covering key aspects including discovery, structure, natural sources, extraction and detection methods, chemical and in vitro enzymatic synthesis, biosynthetic pathways, as well as applications in health care, skin care, and functional foods. Additionally, we highlight strategies for leveraging plant resources and enhancing AA-2bG biosynthesis, which are expected to accelerate future research and support the sustainable development and utilization of AA-2bG and other high-value natural products.

8 Enhancement of levopimaradiene production in Escherichia coli via engineering isopentenol utilization pathway

Chenhao Jia a , b , Junying Ma a , b , Lingli Fang a , b , Huanzi Guo a , b , Meiling Ding a , b , Yishuang Wang a , b , ? , Renxiang Tan c

2026, 18(1):89-96. DOI: https://doi.org/10.1016/j.chmed.2025.11.003

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Objective: Plant-derived terpenoid ginkgolides exhibit significant pharmacological efficacy, however, their extraction remains costly. Given that levopimaradiene is a key biosynthetic precursor to ginkgolides, its high-yield production via heterologous gene expression therefore establishes a critical foundation for scaling up their manufacture. This study primarily aims to enhance the yield of levopimaradiene in Escherichia coli (LB medium) by remodeling the unnatural isopentenol utilization pathway (IUP). Methods: Plasmid construction was driven by the mechanism of homologous recombination, which utilizes recombinase to facilitate the ligation process. The expression of kinase was carried out using type 7 (T7) promoter and isopropyl b-D-1-thiogalactopyranoside (IPTG) as the inducer. The quantification of levopimaradiene produced by E. coli was determined by comparison with a standard curve that we constructed. Results: Combining the selection of kinases, ribosome-binding site (RBS) screening, protein directed evolution and optimization of fermentation parameters, the production of levopimaradiene in E. coli was ultimately enhanced to 2691.3 mg/L, surpassing the highest reported titers of levopimaradiene with 6-fold in E. coli to date. Additionally, the engineered E. coli was designed to collaborate with farnesyl pyrophosphate (FPP) synthase and geranylfarnesyl pyrophosphate (GFPP) synthase to efficiently produce FPP and GFPP for sesquiterpene and sesterterpene synthesis. Conclusion: Our work showcases a combinatorial engineering strategy that employs an IUP-enhanced E. coli chassis for the microbial production of levopimaradiene, as well as other natural terpenoids.

9 Genome-wide identification and characterization of methyltransferase involved in benzylisoquinoline alkaloids biosynthesis from Menispermum dauricum

Yuwei Ma a , b , Yaning Fu a , Ge Bai a , c , Shancen Zhao a , Ya Tian b , Ziyuan Zhao d , Yan Wang d , Zhichao Xu b , Yong Chen a , Zhoujie An b , ? , Ranran Gao e , ?

2026, 18(1):97-109. DOI: https://doi.org/10.1016/j.chmed.2025.11.007

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Objective: Benzylisoquinoline alkaloids (BIAs) are valuable plant metabolites whose structural diversity largely depends on O-/N-methyltransferases (OMTs/NMTs). Although the CYP450-mediated backbone formation of BIAs was previously elucidated in Menispermum dauricum DC., the specific OMTs/NMTs responsible for their functional methylation remain unknown. This study aims to systematically identify and characterize these methyltransferases to define their roles in BIA biosynthesis. Methods: Combining genomic and biochemical approaches, a genome-wide identification of methyltransferase (MT) genes was conducted using the published M. dauricum genome. The candidate MTs were functionally evaluated through in vitro enzymatic assays employing diverse BIA substrates to determine their methylation specificities. The substrate-binding modes of MdOMT1 and MdOMT11 were predicted and compared by protein modeling and molecular docking. Results: Functional characterization of the 75 methyltransferases identified in the M. dauricum genome revealed four key enzymes (three OMTs and one NMT) that contribute to the diversification of BIA scaffolds through their distinct substrate specificities and positional preferences. Specifically, MdOMT1 preferentially catalyzed O-methylation at C7 position of 1-benzylisoquinolines (1-BIAs) and C2 position of tetrahydroprotoberberines. In contrast, MdOMT11 exhibited superior affinity and a strong preference for O-methylation at the C9 position of (S)-scoulerine. Meanwhile, MdNMT3 demonstrated effective Nmethylation activity toward both 1-BIAs and tetrahydroprotoberberines. Conclusion: This research elucidates the functional landscape of OMTs/NMTs in M. dauricum, revealing their crucial roles in BIA structural diversification. The newly identified enzymes provide valuable biocatalytic tools for synthetic biology approaches aimed at the sustainable and optimized production of highvalue BIAs.

10 Protein S-acylation: Pathological mechanisms and novel therapeutic targets for diabetic complications

Ruiting Liu a , b , Nuo Xu a , b , Xuejiao Song a , b , Yanying Li a , b , Jie Bu a , b , Runtao Su a , b , Hong Guo a , b , Chen Jiang c , d , Pengwei Zhuang a , b , c , d , Yanjun Zhang a , b , c , d , ? , Qingsheng Yin a , b , ?

2026, 18(1):110-123. DOI: https://doi.org/10.1016/j.chmed.2025.02.009

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Diabetes involves multi-organ complications that seriously threaten human life and health, and has become a major public health problem of global concern. Unfortunately, clinical management strategies for diabetic complications are still in their ‘‘infancy”, restricted by a limited understanding of their complex pathological mechanism. As is well established, lipid metabolism disorder is the characteristic pathological factors of diabetes, but the detailed molecular mechanisms driving the progression of multi-organ complications remain obscure. Protein S-acylation (often referred to as S-palmitoylation) is a reversible lipid modification that reversibly binds fatty acids to protein-specific cysteine (Cys) residues through palmitoyl acyl transferases (PATs, also known as DHHCs) and deacylation enzymes, which is involved in the pathological progression of a variety of complex diseases such as cancer, neurological disorders and metabolic syndrome. Notably, recent studies have shown that protein S-acylation drives the progression of diabetes and its multiple complications, and targeted intervention in the protein Sacylation process significantly alleviates the progression of diabetes and its complications, suggesting that protein S-acylation may be a common pathological link and intervention target of diabetes complications. Therefore, this review systematically comprehends the contribution of protein S-acylation to the progression of diabetes and its complications, summarizes the influence of the diabetic environment on S-acylation related enzymes, as well as providing an in-depth analysis of current drugs, measures, and challenges in targeting S-acylation. Finally, the accessibility of targeting protein S-acylation to prevent diabetes and its complications and the focus of future in-depth studies are envisioned, with a view to providing comprehensive and in-depth references and rationale for future novel strategies targeting protein S-acylation to prevent and treat diabetes and its multi-organ complications.

11 Contribution of proteomics and metabolomics data to understanding of health benefits of tea

Danicke Willemse ? , Mariam Rado , Mariska Lilly

2026, 18(1):124-141. DOI: https://doi.org/10.1016/j.chmed.2025.11.009

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Tea is the second most widely consumed non-alcoholic beverage globally. While most teas originate from Camellia sinensis (L.) Kuntze plants, rooibos and honeybush teas are produced from Aspalathus linearis (Burm.f.) R.Dahlgren and Cyclopia species tea plants. Interest in tea and tea-derived components, has increased due to their well-known health benefits. The mechanisms of these health benefits are however poorly understood. Proteomics and metabolomics provide valuable tools to assess the mechanisms of the therapeutic effects of tea in disease treatment. This review summarizes the role played by proteomic and metabolomic studies in investigating the health benefits of C. sinensis, A. linearis, and Cyclopia spp. teas. Surprisingly, no proteomic and metabolomic studies investigating the health benefits of A. linearis and Cyclopia spp. teas and/or their components were identified in a literature search. However, 25 studies using proteomics and 16 studies using metabolomics to investigate the health benefits of C. sinensis teas and/or their components were identified in a literature search. Proteomics and metabolomics have been valuable tools for investigating the health benefits of C. sinensis teas and tea components, and will likely also prove valuable for investigating the effects of A. linearis and Cyclopia spp. teas on human health.

12 Design and synthesis of butyrolactone V derivatives and its anti-inflammatory activity analysis

Wen Liu a , Biqiong Zhang a , Zhengxi Hu a , Si Yao b , Yunpeng Zhao a , Fengqing Wang a , Yuanyuan Wang a , Xinxin Yang a , Jie Yin a , Weiguang Sun a , Qingyi Tong a , Lianghu Gu a , ? , Yonghui Zhang a , ?

2026, 18(1):142-152. DOI: https://doi.org/10.1016/j.chmed.2025.03.004

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Objective: To design and synthesize an amount of butyrolactone V derivatives, evaluate the antiinflammatory effects of all the derivatives, look for potential drugs that inhibit inflammatory bowel disease (IBD), and determine the structure-activity relationship (SAR). Methods: The butyrolactone V derivatives were synthesized with high yield by oxidation reaction, substitution reaction, and esterification reaction in sequence, and the production of nitric oxide was assessed in RAW264.7 cells treated with the lipopolysaccharide and the compounds. Then, the target compounds were studied for their activity in dextran sodium sulfate (DSS)-induced ulcerative colitis. Results: A total of three series of compounds encompassing 60 derivatives of the natural product butyrolactone V were designed and synthesized. The results showed that compounds 5p and 7e could alleviate the symptoms of DSS-induced colitis in mice, including alleviating diarrhea, inhibiting the reduction of colon length, and reducing tissue damage. The preliminary mechanism exploration indicated that compounds 5p and 7e could improve the symptoms of IBD in mice mainly by reducing the expression of chemokines and exerting anti-inflammatory effects. Conclusion: This study reports the synthesis and the derivatization of butyrolactone V and analysis on anti-inflammatory activity. The most effective compounds 5p and 7e have the potential to be further developed as drugs to treat IBD.

13 Precise subcellular organelle-targeted analyses of hepatotoxicity of Polygonum multiflorum

Yijie Li a , Shuni Duan b , Yinhao Zhang a , Runping Liu b , Rong Sun c , Jianzhi Wu a , Zhi Ma a , Xiaojiaoyang Li a , ?

2026, 18(1):153-166. DOI: https://doi.org/10.1016/j.chmed.2025.03.001

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Objective: Drug-induced liver injury (DILI) is an undesirable reaction caused by drugs, herbal medicines or supplements and may lead to acute liver failure. Polygoni Multiflori Radix (PMR, Heshouwu in Chinese) originated from the roots of Polygonum multiflorum is a popular traditional Chinese medicine (TCM) while potential hepatotoxicity limits its clinical application. The present study aims to elucidate the in-depth mechanism of PMR-induced organelle heterogeneity of hepatotoxicity. Methods: Network pharmacology and available TCM transcriptomics databases including Integrated Traditional Chinese Medicine (ITCM) and HERB databases were conducted to identify the active ingredients of PMR with the potent ability to injure organelles including microsome, mitochondria, endoplasmic reticulum (ER), Golgi apparatus (GA), and lysosome. Organelles were isolated and cultured with adenosine triphosphate (ATP)-supplemented system. Western blotting and particle size characterization techniques were further performed to clarify the organelle heterogeneity of PMR-induced hepatotoxicity. Results: Five representative organelles were isolated from mouse livers or hepatocytes and administrated with PMR-derived active components and monomers. The results of network pharmacology and virtual screening initially identified the components of PMR that may damage different organelles. By combining experimental verification, we found that five organelles studied in this research were the target organelles for flavonoid (FVN)’s affiliated compound quercetin (QC). Mitochondria were damaged mainly by kaempferol, anthraquinone (AQ) and its monomeric components. Meanwhile, QC and emodin showed effective toxicity on endoplasmic reticulum. For microsome, QC remained the most toxic monomer. For Golgi apparatus, trans-stilbene glycosides (trans-SG), AQ and emodin were the major toxic components in PMR. For lysosomes, total-SG, emodin and QC were the major toxic components in PMR. Conclusion: Collectively, our findings revealed the organelle heterogeneity of PMR-induced hepatotoxicity and identified quercetin as a potential toxic component in PMR. This study provides a novel conjunct strategy to screen and discover potential toxic components and shapes the understanding of toxicity warning and clinically safe use of herbal medicines such as PMR.

14 Chelidonine overcomes P-gp-mediated adriamycin resistance in MCF-7/ADR cells by inhibiting PDGFRb/PI3K/Akt pathway

Xiang Zou a , Yuhang Zhang a , Kaili Liu a , Liyue Zhang a , Jianli Li a , Yue Zhang a , Xuerui Zhang a , Lei Yu a , ? , Zhongyuan Qu b , ?

2026, 18(1):167-177. DOI: https://doi.org/10.1016/j.chmed.2025.01.005

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Objective: Chemoresistance represents a major obstacle in breast cancer (BC) treatment. Chelidonine could prevent various tumor cell types. However, the effect and mechanism of chelidonine against BC chemotherapy resistance have not been elucidated. This paper aimed to explore the effect and mechanism of chelidonine on BC chemoresistance. Methods: A CCK-8 assay, flow cytometry and fluorescence microscopy were applied to evaluate the resistance reversal effect of chelidonine on MCF-7/ADR cells. The signaling pathways by which chelidonine suppresses BC were predicted by network pharmacology and validated by Western blotting. The chemoresistant reversal mechanism of chelidonine was clarified using platelet-derived growth factor receptor-b (PDGFRb) silencing with small interfering RNA (siRNA), platelet-derived growth factor-BB (PDGF-BB) stimulation, Western blotting and real-time quantitative polymerase chain reaction (RTqPCR). Results: Chelidonine remarkably reversed adriamycin (ADR) resistance by decreasing P-glycoprotein (P-gp) expression and the efflux of ADR in MCF-7/ADR cells. Additionally, PDGFRb expression in MCF-7/ADR cells was markedly higher than that in MCF-7 cells (P < 0.01), and PDGFRb knockdown prevented P-gp expression and intracellular ADR accumulation. Network pharmacology identified phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) as a primary pathway of chelidonine-inhibiting BC, which was verified by the marked underexpression of phosphorylated kappa B inhibitor protein kinase (p-IKK), phosphorylated inhibitor of nuclear factor-jB (p-IKB), and nuclear factor-jB (NF-jB) and phosphatase and tensin homolog (PTEN) hyperexpression by chelidonine treatment (P < 0.01). Notably, PDGFRb silencing enhanced the inhibitory effect of chelidonine on the activation of the PI3K/Akt pathway. Moreover, chelidonine suppressed PDGF-BB stimulation of the PDGFRb/PI3K/Akt axis. Conclusion: These findings underscore the potential role of PDGFRb in regulating chemotherapy resistance in BC. Chelidonine could effectively overcome the resistance of MCF-7/ADR cells to ADR by targeting the PDGFRb/PI3K/Akt axis. Meanwhile, these findings highlight the potential of chelidonine as a promising natural chemoresistant agent for BC treatment.

15 Astragalus polysaccharides inhibit arsenic trioxide-induced BMSCs damage through inhibition of Jnk and p38 signaling pathways

Wei Wu a , Djibril Bamba a , Zheng Zhang b , Feng Wu c , Yuan Li d , Wenyi Qi a , Yingzhe Liu a , Tingting Zhang a , Ying Su a , Xinyue Wang a , Hongbo Wang a , Shuqin Duan a , Jingwen Ne a , Wenbo Wang b , Jingwei Liu b , Jianyong Tang b , Fengda Li b , Qingchao Wu b , Yang Li e , f , Fan Yang a , g , h , ? , Lei Yang a , b , g , h , ?

2026, 18(1):178-187. DOI: https://doi.org/10.1016/j.chmed.2025.03.007

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Objective: Arsenic trioxide (ATO) is a clinically effective anticancer agent used in the treatment of leukemia. However, it exerts adverse effects on non-tumor cells, including bone marrow mesenchymal stem cells (BMSCs). This study aims to investigate the protective role and molecular mechanism of traditional Chinese medicine Astragalus polysaccharides (APS) in mitigating ATO-induced apoptosis in BMSCs. Methods: BMSCs exposed to ATO (0.5 lmol/L) were treated with APS (20, 40, 100, and 200 lg/mL). Cell viability, proliferation, and migration were assessed by using MTT, EdU staining, Transwell, and scratch wound healing assays. Apoptosis was evaluated via TUNEL assay, Hoechst 33258 staining, and flow cytometry. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by using DCFH-DA and JC-1 staining. Apoptotic protein expression was analyzed by Western blotting. Results: ATO exposure significantly inhibited the proliferation and migration of BMSCs and induced apoptosis, while APS markedly attenuated the apoptosis of BMSCs induced by ATO, and significantly improved cell proliferation and migration (P < 0.01). Mechanistically, APS effectively reduced ATOinduced ROS (P < 0.01), while the protein expression of Bcl-2-associated X protein (Bax) and cleaved Caspase-3 was significantly decreased (P < 0.05), and the protein expression of Bcl-2 was significantly increased (P < 0.01). In addition, APS markedly decreased the protein expression of c-Jun N-terminal kinase (Jnk) and p38 in ATO-activated BMSCs (P < 0.05), and significantly decreased the protein expression of p16 and p53 (P < 0.01), and increased the protein expression of phosphorylated protein kinase B (p-Akt) and phosphorylated extracellular signal-regulated kinase (p-Erk) (P < 0.01, 0.05). Conclusion: Our study reveals that APS exert significant protective effects against ATO-induced apoptosis in BMSCs. The mechanisms involve suppressing ROS generation, maintaining mitochondrial membrane stability, enhancing cell viability, migration, and proliferation, as well as inhibiting Jnk and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways. The findings highlight potential molecular targets and novel strategies for the clinical prevention and treatment of ATO-related toxicity

16 Safflower yellow in Carthami Flos is responsible for Xuebijing Injectioninduced immediate hypersensitivity reaction through activating complement C3

Wenjing Li , Yuan Gao , Jingjing Yan , Min Cai , Chenchen Zang , Zhuangzhuang Liu , Ximeng Li , Runlan Cai , Yun Qi

2026, 18(1):188-199. DOI: https://doi.org/10.1016/j.chmed.2024.06.003

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Objective: Xuebijing Injection (XBJI) is mainly used for treating sepsis in China, and even COVID-19 recently. This study aimed to clarify the molecular mechanism(s) and identify the potential ‘‘common culprit(s)” for XBJI-caused immediate hypersensitivity reaction (IHR) which is the main type of its adverse reactions. Methods: Antiserum against XBJI was prepared by intraperitoneal immunization in combination with aluminum adjuvant for five weeks. Antagonistic experiments were performed by using several antagonists against different mediators in Evans Blue leakage model. Propranolol-pretreated mice were used to determine the capacity of XBJI to trigger systemic IHR. Serum total IgE (tIgE) and mouse mast cell protease 1 (MCPT-1) levels, complement activation, and the levels of supernatant inflammatory mediators were determined by ELISAs. Lipopolysaccharide (LPS)-activated RAW264.7 macrophages were used for evaluating the anti-inflammatory activity of XBJI, while human mast cells (LAD2) were used for assessing the effect of XBJI on mast cell degranulation. Results: Continuous treatment (i.p.) with XBJI along with aluminum adjuvant did not elevate the levels of serum tIgE and MCPT-1. In vitro, XBJI could not directly cause the degranulation of LAD2 cells. It induced a robust Evans Blue leakage after the first injection in mouse paw. Mechanism study demonstrated that antagonists for histamine H1/H2 receptors and complement C3a receptor counteracted XBJI-induced IHR. XBJI also directly activated complement C3 in human serum. Through screening five herbs of XBJI and the constituents, only safflower yellow (SY) in Carthami Flos was able to induce IHR. The discolored-XBJI not only did not induce IHR locally and systemically, but also could suppressing the production of proinflammatory mediators in LPS-activated RAW264.7 macrophages. Conclusion: XBJI failed to induce immune IHR, but potently triggered non-immune IHR through direct activating complement C3 to provoke histamine release. SY in Carthami Flos was the underlying ‘‘common culprit” responsible for XBJI-caused IHR. The anti-inflammatory action of XBJI can be retained after decolorization. Our study provides a scientific basis for not only preventing and treating XBJI-caused IHR clinically, but also improving its production process.

17 Comprehensive genomic identification and functional analysis of bHLH transcription factors in Ganoderma lucidum

Jun Li a , b , Xuewen Zhu a , b , Yupeng Du c , Wenxiao Chen c , Jing Xu d , Ying Wang d , Shasha Zhou e , Zhichao Xu c , Shuangcheng Ma f , g , Zhenhao Li d , e , Wei Sun a , b , ? , Yaolei Mi a , b , c , ?

2026, 18(1):200-211. DOI: https://doi.org/10.1016/j.chmed.2025.05.005

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Objective: The basic helix-loop-helix (bHLH) transcription factors (TFs) are pivotal in regulating fungal growth, development, and secondary metabolism. However, the knowledge about the Ganoderma lucidum bHLHs (GlbHLHs) in ganoderic acid (GA) biosynthesis of G. lucidum was limited. This study aimed to explore the functions of bHLH genes in ganoderic acid biosynthesis during G. lucidum growth development. Methods: First, the genome-wide identification of GlbHLHs was performed through Hidden Markov model searches and Two-way blast. Furthermore, through physicochemical properties, gene structure, and phylogenetic analysis, as well as combining the transcriptome and metabolome data from different developmental stages of G. lucidum, candidate GlbHLHs were screened. Subsequently, their regulatory roles in ganoderic acid biosynthesis were explored using yeast one-hybrid and dual luciferase reporter assays. Results: A total of 11 GlbHLH members were characterized in G. lucidum. The upstream promoter regions of these genes enriched hormones and abiotic stress responsive elements. Although individual ganoderic acid monomers demonstrated marked differences in accumulation patterns across specific growth phases and tissue types, overall, the total GA content was consistently higher in caps than in stipes throughout development. In addition, all GlbHLHs exhibited high expression in whole G. lucidum from the primordium to maturation stages. Among them, GlbHLH5 and GlbHLH7 showed the highest expression in any stage and highly correlated with key genes associated with GA pathway. Functional validation through dual-luciferase assays and yeast one-hybrid experiments had demonstrated that GlbHLH5 activated the P2 region of the lanosterol synthase promoter, while GlbHLH7 activated the promoters of squalene epoxidase and squalene synthase. Conclusion: Compared to plants, G. lucidum harbored a small number of bHLH members but all high expression in any stages. Additionally, GlbHLH5 and GlbHLH7 with the highest expression among GlbHLHs showed activation in regulating the biosynthesis of GA. These results provide a theoretical reference for further research on ganoderic acid regulation in G. lucidum, and thereby providing a molecular foundation for enhancing ganoderic acid yield to optimize the medicinal value of G. lucidum.

18 Morphological, physiological and biochemical changes and effects of polyamines on regulation of Anoectochilus roxburghii during flowering period

Weiwei Jiang a , b , Xiaoyun Yan a , b , Chenfei Lu a , b , Xiaowei Xu c , Enting Xu a , b , Dandan Chen a , b , Yuqiu Huang a , b , Qingsong Shao a , b , ? , Aimin Lv a , b , ?

2026, 18(1):212-224. DOI: https://doi.org/10.1016/j.chmed.2025.05.007

[Abstract](2) [HTML](0) [PDF 0.00 Byte](0)

Abstract:
Objective: Anoectochilus roxburghii is a valuable medicinal and ornamental plant. The aim of this study is to investigate the morphological and biochemical responses during the flower development stages of A. roxburghii, and to assess the effects of exogenous polyamines (PAs) on bud differentiation and metabolism, thereby providing a theoretical basis for understanding the flowering form and physiology of A. roxburghii. Methods: In this study, morphological and biochemical responses in flower development stages of A. roxburghii were investigated using paraffin sections and stereomicroscope. A. roxburghii was divided into five periods, including vegetative growth period, flower bud period, flowering period, late flowering period and fruiting period. During the flowering phase, specific biochemical parameters were measured, including soluble sugar content, superoxide dismutase (SOD) activity, soluble protein content, peroxidase (POD) activity, and catalase (CAT) activity. These measurements were conducted to understand the biochemical changes occurring within A. roxburghii during its flowering process. Furthermore, the effects of PAs on bud differentiation were examined. Additionally, the activities of S-adenosylmethionine decarboxylase (SAMDC) and polyamine oxidase (PAO), as well as the content of polyphenols, polysaccharides, and flavonoids in A. roxburghii, were measured after PA treatment to evaluate the metabolic changes induced by exogenous PAs. Results: During the flowering phase of A. roxburghii, soluble sugar content and SOD activity were steadily declining. Soluble protein content was initially increasing and then reducing, and POD and CAT activities showed opposite pattern. In addition, the effects of exogenous PAs on bud differentiation were investigated. Results showed that 3 mmol/L putrescine or 0.3 mmol/L spermidine significantly promoted the bud differentiation of A. roxburghii and advanced the flowering. The activities of SAMDC, PAO, and the content of polyphenols, polysaccharides and flavonoids in A. roxburghii significantly increased after PA treatment, demonstrating that exogenous PA can accelerate metabolism and improved the active ingredients content. Conclusion: The flower development of A. roxburghii was divided into five stages, with significant changes in soluble sugar, protein, POD, SOD, CAT, MDA, and PRO levels. Exogenous putrescine and spermidine enhanced bud differentiation and accelerated flowering, increasing SAMDC and PAO activities, suggesting accelerated PA metabolism. PAs also improved active component content. These findings provide a theoretical basis for studying flower morphology and PA-induced flowering regulation of A. roxburghii.

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