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Artemisia argyi extract subfraction exerts an antifungal effect against dermatophytes by disrupting mitochondrial morphology and function
Chen Le, Zhu Yunyun, Guo Chaowei, Guo Yujie, Zhao Lu, Miao Yuhuan, Du Hongzhi, Liu Dahui
, Available online  , doi: 10.1016/S1875-5364(23)60458-3
Artemisia argyi has a long history as raw materials for traditional medicine and functional diet in Asia. Since ancient times, A. argyi is commonly applied by folk to bathe and soak feet to disinfect and relieve itching. However, scientific evidence supporting its antifungal effect of A. argyi water extract (AAWE) against dermatophytes has not been revealed, especially on Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum gypseum. This work aimed to clarify the scientificity of the folk usage of A. argyi by evaluating the antifungal effect and molecular mechanism of active subfraction from AAWE against dermatophytes. The results indicated that AAWE showed excellent antifungal effects against the three dermatophytes species, and its subfraction AAWE6 (separated by D101 macroporous resin) was the most effective subfraction. Exactly, the minimum inhibitory concentrations (MICs) of AAWE6 against T. rubrum, M. gypseum and T. mentagrophytes were 312.5, 312.5 and 625 μg·mL−1, respectively. Moreover, the TEM results and enzyme activities related to cell wall integrity and cell membrane function showed that AAWE6 could break through the external protective barrier of T. rubrum (“cutting small holes in the wall”) and destroy the structure of internal mitochondria (“granary”). Furthermore, transcriptome data, RT-qPCR and biochemical assays confirmed that mitochondrial function was also severely disrupted, thus showing the inhibition of the TCA cycle and energy metabolism. Additionally, chemical characterization and molecular docking revealed the functional material basis of AAWE6 was flavonoids mainly composed of eupatilin (131.16 ± 4.52 mg·g−1) and jaceosidin (4.17 ± 0.18 mg·g−1). In conclusion, the subfraction AAWE6 from A. argyi exerts antifungal effects against dermatophytes by disrupting mitochondrial morphology and function. This research verified the traditional usage of A. argyi and will provide the scientific support for its anti-dermatophytic scientific utilization (Chinese patent: ZL202111161301.9).
Design and synthesis of antiviral pseudo-natural products via effective one-step acylmethylation macrocyclization
LI Shang, WANG Xiaobing
, Available online  , doi: 10.1016/S1875-5364(23)60440-6
Network pharmacology study and experimental validation of Maxing Shigan decoction in the treatment of influenza virus-induced ferroptosis
HUANG Jiawang, MA Xinyue, LIAO Zexuan, LIU Zhuolin, WANG Kangyu, FENG Zhiying, NING Yi, LU Fangguo, LI Ling
, Available online  , doi: 10.1016/S1875-5364(23)60457-1
Influenza is an acute viral respiratory infection that has caused high morbidity and mortality worldwide. Influenza A virus (IAV) has been found to activate multiple programmed cell death pathways, including ferroptosis, a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. However, little is known about how influenza viruses induce ferroptosis in the host cells. In this study, based on network pharmacology techniques, we predicted the mechanism of action of Maxing Shigan decoction (MXSGD) in IAV-induced ferroptosis, and found that this process was related to a variety of Biological Processes, Cellular Components, Molecular Function and multiple signaling pathways, among which the HIF-1 signaling pathway plays a significant role. Subsequently, we constructed the mouse lung epithelial (MLE-12) cell model of IAV-infected mice through in vitro cell experiments, and revealed that IAV infection could induce cellular ferroptosis that is characterized by mitochondrial damage, increased ROS release, increased total iron and iron ion contents, decreased expression of ferroptosis marker gene GPX4, increased expression of ACSL4, and enhanced activation of HIF-1α, iNOS2 and VEGF in the HIF-1 signaling pathway. Treatment with MXSGD can effectively reduce the intracellular viral load, while reducing ROS, total iron and ferrous ions, repairing mitochondrial results and inhibiting the expressions of cellular ferroptosis and HIF-1 signaling pathway. Finally, through animal experiments, it was found that MXSGD could effectively alleviate pulmonary congestion, edema and inflammation in IAV-infected mice, and inhibit the expressions of ferroptosis-related protein and HIF-1 signaling pathway in the lung tissue.
Three rare anti-inflammatory sesquiterpene lactones from Magnolia grandiflora
Xu Shuang-Yu, Zhang Feng, Tao Lin-Lan, Jiang Yang-Ming, Huang Tao, Li Ya-Nan, Hu Zhan-Xing, Yang Jue, Hao Xiao-Jiang, Yuan Chun-Mao
, Available online  , doi: 10.1016/S1875-5364(23)60442-X
Four new sesquiterpene lactones (SLs) ( 14 ) along with a biosynthesized related SL ( 5 ) were isolated from the leaves of Magnolia grandiflora. Magrandate A ( 1 ) represents the first C18 homogemarane type SL with an unprecedented 1,7-dioxaspiro[4.4]nonan-6-one core, while compounds 2 and 3 are the first chlorine-substituted gemarane-type SL analogues in natural products. The structures of the isolates were established by various spectroscopic data, electronic circular dichroism calculation, and X-ray single-crystal diffraction analysis. All isolates exhibited anti-inflammatory activities in lipopolysaccharide-stimulated RAW264.7 cells. In special, three compounds ( 35 ) exhibited more potential inhibitory effect on NO production (IC50: 0.79 ± 0.05 μM ~ 4.73 ± 0.24 μM) than that of the positive control, pyrrolidine dithiocarbamate (IC50: 5.68 ± 0.53 μM). Moreover, compounds 4 and 5 exhibited moderate cytotoxic activities against three cancer cell lines with IC50 values ranging from 3.09 ± 0.13 μM to 11.23 ± 1.39 μM.
Tu-Xian decoction ameliorates diabetic cognitive impairment by inhibiting DAPK-1
, Available online  , doi: 10.1016/S1875-5364(23)60406-6
Background : Tu-Xian decoction (TXD), as traditional Chinese medicine (TCM), has frequently been used in the treatment of diabetic cognitive impairment (DCI). However, the protective mechanism of TXD on DCI remains unknown. Death-associated protein kinase-1 (DAPK-1) is a key modulator in neuronal disease. This study investigated whether TXD alleviates DCI by inhibiting DAPK-1. Method : The diabetes model was established in SD rats by a high-fat, high-sugar (HFHS) diet, and streptozotocin (STZ). This study included: Control, Diabetic, TC-DAPK6, high-dose TXD, medium-dose TXD, and low-dose TXD 6 groups. After 12 weeks of pharmaceutical intervention, the blood glucose, body weight, Morris water maze (MWM), brain magnetic resonance imaging (MRI), hematoxylin-eosin (H&E), and Nissl staining were examined. Western blotting (WB) was used to detect the protein expression of the hippocampus. Results : Diabetic rat model was successfully established. TXD underlying ameliorated spatial learning and memory ability decline, and hippocampal structural injuries in diabetic rats. Moreover, TXD underlying reduced the expression of a protein associated with neurological damage and DAPK-1 in the hippocampus of diabetic rats. Conclusion : TXD has an underlying mitigating effect on DCI, and this effect might be by inhibition of DAPK-1. Therefore, TXD may serve as a prospective therapeutics for DCI.
Bioassay-guided isolation of α-Glucosidase Inhibitory Constituents from Hypericum sampsonii
Tao Linlan, Xu Shuangyu, Zhang Zizhen, Li Yanan, Yang Jue, Gu Wei, Yi Ping, Hao Xiaojiang, Yuan Chunmao
, Available online  , doi: 10.1016/S1875-5364(22)60248-6
α-Glucosidase inhibitory activity was applied as an anti-diabetic model, and the bioactivity-guided isolation of Hypericum sampsonii led to two novel seco-PPAPs (polycyclic polyprenylated acylphloroglucinols) ( 1 and 2 ), eight phenolic derivatives ( 3-10 ), and four terpene derivatives ( 11-14 ). Compounds 1 and 2 were highly modified seco-PPAPs with unprecedented octahydro-2H-chromen-2-one ring system. Their structures were fully characterized based on extensively spectroscopic data and quantum chemistry calculation. Six compounds ( 1 , 5 - 7 , 9 , and 14 ) exhibited potential inhibitory effects on α-glucosidase with the IC50 values ranging from 0.050 ± 0.0016 μg/mL to 366.70 ± 11.08 μg/mL. Among them, compound 5 (0.050 ± 0.0016 μg/mL) was the most potential α-glucosidase inhibitor, which is about 6900 times stronger than the positive control, acarbose (IC50 = 346.63 ± 15.65 μg/mL). The docking study was conducted to predict molecular interactions between two compounds ( 1 and 5 ) and α-glucosidase. Hypothetical biosynthetic pathways of two unprecedented seco-PPAPs were also proposed.
Jinyinqingre oral liquid alleviates LPS-induced acute lung injury by inhibiting the NF-κB/NLRP3/GSDMD pathway
Wang Shuhui, Lei Pan, Feng Ying, Jiang Mingzhu, Liu Zegan, Shen Ting, Ma Shinan, Wang Libo, Guo Xingrong, Du Shiming
, Available online  , doi: 10.1016/S1875-5364(23)60397-8
Background: Acute lung injury (ALI) is a critical illness in clinical with high incidence and mortality, and is characterized by inflammatory injury to the lung endothelial and epithelial barriers. Furthermore, safe and effective drugs for the treatment of ALI are not available. In our previous study, we found that Jinyinqingre oral liquid (JYQR), which is a preparation of traditional Chinese medicine made by the Taihe Hospital affiliated to Hubei University of Medicine, has shown remarkable efficacy against inflammation-related hepatitis and cholecystitis in clinic. However, whether JYQR plays a role in ALI/ARDS disease has not been reported and its anti-inflammatory mechanism remains unclear. In the present study, we investigated the role and molecular mechanisms of JYQR against ALI using mice model of Lipopolysaccharide (LPS)-induced ALI and RAW264.7 cells model. Methods: The ALI mouse model was induced by intratracheal infusion of LPS solution (5 mg/kg). In the JYQR-treatment group, the male C57B/6 mice were intragastrically administered with JYQR at doses of (high), 8 (mid) and 4 (low) g/kg for 7 days before the LPS challenge. In the positive control group, the mice were pretreated with dexamethasone (5 mg/kg, i.p.) for 3 days before the LPS stimulate. Then, the mean pulmonary arterial pressure (MPAP) and pleural thickness were measured by ultrasound 20 h after LPS treatment and the mice were sacrificed. Histopathological changes in lung tissues were assessed by Hematoxylin-eosin staining (HE staining) and Immunohistochemistry (IHC). The pro-inflammatory cytokine levels (IL-1β, TNF-α and IL-6) and total protein in mouse bronchoalveolar lavage fluid (BALF) were detected by ELISA and BCA assays, respectively. The expressions of phosphor-nuclear factor kappa B (p-NF-κB) p65, NOD-like receptor family pyrin domain containing 3 (NLRP3) and gasdermin D (GSDMD) in mouse lungs were detected by Western blotting and immunostaining. Additionally, we measured the expression changes of proinflammatory cytokine levels and the protein expression of p-NF-κB, NLRP3 and GSDMD in LPS-challenged RAW264.7 model with or without JYQR. Results: JYQR pretreatment significantly ameliorated the LPS-induced lung histological changes, total BALF protein, MPAP, and pleural thickness, indicating that JYQR played a protective role in LPS-induced ALI. The mechanism mechanism study showed that JYQR pretreatment significantly inhibited NF-κB activation, and downregulated the expression of the downstream proteins NLRP3/GSDMD expression and proinflammatory cytokine levels in mice and RAW2647 cells. Therefore, JYQR alleviated LPS-induced ALI by inhibiting the NF-κB/NLRP3/GSDMD pathway. Conclusions: JYQR protected LPS-induced ALI in mice, and its mechanism is highly related to the down-regulation of the NF-κB/NLRP3/GSDMD inflammatory pathway.
Effects of traditional Chinese medicine on treatment outcomes of severe COVID-19 patients: A single-centre study
Xiao Yongjiu, Li Binbin, Liu Chang, Huang Xiuyu, Ma Ling, Qian Zhi Rong, Zhang Xiaopeng, Zhang Qian, Li Dunqing, Cai Xiaoqing, Yan Xiangyong, Luo Shuping, Xiang Dawei, Xiao Kun
, Available online  , doi: 10.1016/S1875-5364(23)60415-7
No specific effective therapeutic drugs have been identified for COVID-19. Critically ill COVID-19 patients in the ICU experience high mortality. This project aims to study the effects of traditional Chinese medicine (TCM) treatment on deadly outcomes caused by COVID-19. A total of 110 critically ill COVID-19 patients who received close monitoring at the ICU of Vulcan Hill Hospital between February 2, 2020, and April 15, 2020 (Wuhan, China) participated in this observational study. All these ICU patients received supportive management. Eighty-one patients were given additional TCM treatment. Clinical characteristics during the treatment period (up to 39 days) and the clinical outcome of each patient were closely monitored and analysed. We observed that patients treated with TCM had lower mortality than the non-TCM treatment group (16 of 81 vs. 24 of 29; 0.3 person/month vs. 2.3 person/month). In the adjusted Cox proportional hazards models, TCM treatment was associated with improved survival [multivariate HR, 0.15; 95% confidence interval (CI), 0.08-0.30; P < 0.001]. Furthermore, we found that TCM treatment could partially improve the inflammation status by reducing the levels of proinflammatory cytokines and recovering multiple organic functions, which could improve the survival rate of critically ill COVID-19 patients.
Discovery of Proqodine A Derivatives with Antitumor Activity Targeting NAD(P)H: Quinone Oxidoreductase 1 and Nicotinamide Phosphoribosyltransferase
Song Jiangzhou, Zou Guiqing, Zhao Zhou, Zhu Ya, Xue Jiayu, Ao Lanjia, Sun Huiyong, Hao Haiping, Zhang Bo, Xu Xiaowei
, Available online  , doi: 10.1016/S1875-5364(23)60459-5
NAD(P)H: Quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. Under the catalysis of NQO1, substrates undergo a futile redox cycle to generate significant reactive oxygen species (ROS) which lead to extensive DNA damage and excessive Poly (ADP-ribose) polymerase 1 (PARP1)-mediated nicotinamide adenine dinucleotide (NAD + ) consumption, resulting in cell death. As the rate-limiting enzyme of the NAD + salvage synthesis pathway, nicotinamide phosphoribosyl-transferase (NAMPT) is considered to be an important target for cancer therapy. The combination of NQO1 substrate and NAMPT inhibitor can induce hyperactivation of PARP1 and NAD + consumption. Here, a novel series of proqodine A derivatives targeting NQO1 and NAMPT were designed, synthesized, and evaluated, among which compound T8 possessed potent antitumor activity. Compound T8 can selectively inhibit the proliferation of MCF-7 cells and induce cell apoptosis in an NQO1- and NAMPT-dependent manner. This work provides a new molecular entity for further anticancer research.
A Review on Structural Modification and Biological Activities of Oleanolic Acid
YANG Huali, DENG Minghui, JIA Hongwei, ZHANG Kaicheng, LIU Yang, CHENG Maosheng, XIAO Wei
, Available online  , doi: 10.1016/S1875-5364(23)60456-X
As a member of the pentacyclic triterpenoid family, oleanolic acid (OA) has a wide range of biological activities, such as antitumor, antiviral, antibacterial, anti-inflammatory, hepatoprotective, hypoglycemia and hypolipidemia, etc. Since it was first isolated and identified, there have been a large number of reports on the structural modifications and pharmacological activities of OA and its derivatives. However, in the past 10 or 20 years, there is little comprehensive summary about OA and its derivatives, which brings inconvenience to the follow-up studies of OA. Based on the main biological activities of OA, this paper comprehensively summarized the modification strategies and structure-activity relationships of OA and its derivatives, in order to provide valuable reference for the further study of OA.
Chemical approaches for the stereocontrolled synthesis of 1,2-cis-β-d-rhamnosides
CAI Jun-tao, YUAN Xin, KONG Yuan-fang, HU Yu-long, LI Jie-ming, JIANG Shi-qing, DONG Chun-hong, DING Kan
, Available online  , doi: 10.1016/S1875-5364(23)60408-X
The stereoselective synthesis of 1,2-cis-glycosides remains one of the most challenging issues in carbohydrate chemistry. Similar to 1,2-cis-β-d-mannosides synthesis, the synthesis of the 1,2-cis-β-d-rhamnosides is difficult since the anomeric and Δ-2 effects are not favorable. For achieving β-stereoselectivity in the d-rhamnosylation, numerous researchers have devised a variety of direct and indirect strategies over the past few decades, including the hydrogen-bond-mediated aglycone delivery (HAD) approach, the synthesis of β-d-mannoside and C6 deoxygenation, 1,2-trans-glycosylation and C2 epimerization, etc. The improvements in β-d-rhamnosylation and their applications in the total synthesis of tiacumicin B and the physiologically significant glycans have been discussed in this review.
New Phenylbutenoids and Terpene Glycosides from Ginkgo biloba Leaves
Sun Zeshi, Lin Shan, Wu Zhi-li, Dong Hong-Yuan, Xu Xi-Ke, Li Hui-Liang, Wang Jinxin
, Available online  , doi: 10.1016/S1875-5364(23)60414-5
Our continued works on the chemical constituents of Ginkgo biloba leaves resulted in the isolation of two new phenylbutenoids ( 1 , 2 ), together with five new terpene glycosides ( 3 - 7 ). Among them, compounds 1 and 2 were unique (Z)-phenylbutenoids, 3 - 6 were megastigmane glycosides, and 7 was a rare bilobanone glycoside. It is a remarkable fact that phenylbutenoid and bilobanone glycoside were first obtained from Ginkgo biloba. Their chemical structures were determined by comprehensive analysis of spectroscopic date, including HRESIMS and various 1D- and 2D-NMR experiments, and their absolute configurations were established by Mosher’s method, ECD experiments and Cu-Kα X-ray crystallographic analyses.
Scutellaria baicalensis as an excellent natural plant for the treatment of viral diseases
Huang QiuJu, Wang MuYang, Wang Min, Lu Yuhui, Wang Xiaohua, Chen Xin, Yang Xin, Guo Hongwei, He Rong-Rong, Luo Zhuo
, Available online  , doi: 10.1016/S1875-5364(23)60401-7
Viruses, the smallest of all microbes, pose a growing threat on human health. Over the decades, although therapy and vaccination against viral diseases have gained great success, viral infection still remains the major cause of mortality worldwide. The lack of effective vaccines, the severe side effects of present drugs, and the emergence of drug resistance have prompted an urgent need for the development of novel alternative agents. Natural plants, particularly traditionally-used herbs, are often considered an excellent source of medicinal drugs with potent antiviral efficacy, as well as a substantial safety profile. Scutellaria baicalensis, a traditional Chinese medicine, has been extensively studied in diverse therapeutic areas for its diverse biological properties, showing significant efficacy in both preclinical and clinical trials. In this review, we mainly focused on the potential antiviral activities of ingredients in Scutellaria baicalensis while detailing its underlying mechanism and therapeutic application in the treatment of viral infections.
Commentary on ‘A population of stem cells with strong regenerative potential discovered in deer antlers (Qin et al., Science 379, 840–847 (2023))’
Liu Jing, Shao Li, Huang Wei-Hua
, Available online  , doi: 10.1016/S1875-5364(23)60430-3
A Comprehensive Review of Natural Products with Anti-Hypoxia Activity
LIU Jun-Cai, GE Zhen, JIANG Xiao, ZHANG Jing-Jing, SUN Jian-An, MAO Xiang-Zhao
, Available online  , doi: 10.1016/S1875-5364(23)60410-8
Natural products have been shown to have substantial impacts on the field of antihypoxia. Hypoxia can cause altitude sickness and other negative effects on the body. Headache, coma, exhaustion, vomiting and, in severe cases, death are some of the clinical signs. Currently, hypoxia is no longer just a concern in the plateau region; it is also one of the issues that urban residents cannot ignore. This review covered polysaccharides, alkaloids, saponins, flavonoids, peptides and Chinese compound prescriptions as natural products to protect against hypoxia. The active ingredients, effectiveness and mechanism were discussed. The anti-hypoxia mechanisms could involve increasing the hemoglobin (HB) content, glycogen content and adenosine triphosphate (ATP) content, removing excessive reactive oxygen species (ROS), reducing lipid peroxidation, regulating the level of related enzymes in cells, protecting the structural and functional integrity of mitochondria and regulating the expression of apoptosis-related genes. These comprehensive summaries are beneficial to anti-hypoxia research and provide useful information on anti-hypoxia product development.
Heterologous production of bioactive xenoacremone analogs in Aspergillus nidulans
LIU Zhiguo, LI Wei, ZHANG Peng, SUN Yi, YIN Wenbing
, Available online  , doi: 10.1016/S1875-5364(23)60412-1
Tyrosine-decahydrofluorene derivatives are polyketide-nonribosomal peptide hybrid type compounds. They feature a [6.5.6] tricarbocyclic core and one para-cyclophane ether in their structure and exhibit antitumor and antimicrobial activities. Here, we constructed the biosynthetic pathway of xenoacremones from Xenoacremonium sinensis in the Aspergillus nidulans host and obtained four novel tyrosine-decahydrofluorene analogs, xenoacremones I–L ( 14 ), along with two known analogs, xenoacremones A and B. Moreover, compounds 3 and 4 were two tyrosine-decahydrofluorene analogs containing a 12-membered para-cyclophane ring system. This study provides one additional case to obtain the chemical diverse natural products with potential activity by the heterologous expression strategy.
Chuanxiong Rhizoma extracts prevent cholestatic liver injury by targeting H3K9ac-mediated and cholangiocyte-derived secretory protein PAI-1 and FN
Li Yajing, Ma Zhi, Ding Mingning, Jia Kexin, Xu Bing, Zhou Fei, Luo Ranyi, Xue Xiaoyong, Wu Ruiyu, Gao Feng, Li Xiaojiaoyang
, Available online  , doi: 10.1016/S1875-5364(23)60416-9
Chuanxiong Rhizoma (CX, the dried rhizome of Ligusticum wallichii Franch.), a well-known traditional Chinese medicine, is clinically used for treating cardiovascular, cerebrovascular and hepatobiliary diseases. Cholestatic liver damage is one of the chronic liver diseases with limited effective therapeutic strategies at present. Currently, little is known about the mechanism links between CX-induced anti-cholestatic action and intercellular communication between cholangiocytes and hepatic stellate cells (HSCs). The study aimed to evaluate the hepatoprotective activities of different CX extracts including aqueous, alkaloid, phenolic acid and phthalide extracts of CX (CXAE, CXAL, CXPA and CXPHL) and investigate the intercellular communication-related mechanism of most effective extracts on cholestatic liver injury. The active compounds of different CX extracts were identified by UPLC-MS/MS. A cholestatic liver injury mouse model induced by bile duct ligation (BDL) and TGF-β-treated human intrahepatic biliary epithelial cholangiocytes (HIBECs) and HSC cell line (LX-2 cells) were used for in vivo and in vitro studies. Histological and other biological techniques were also applied. CXAE, CXAL and CXPHL significantly reduced ductular reaction (DR) and improved liver fibrosis in the BDL mice. Meanwhile, both CXAE and CXPHL suppressed DR in injured HIBECs and reduced collagen contraction force and expression of fibrosis biomarkers in LX-2 cells treated with TGF-β. CXPHL suppressed the transcription and transfer of plasminogen activator inhibitor-1 (PAI-1) and fibronectin (FN) from the ‘DR-like’ cholangiocytes to activated HSCs. Mechanistically, the inhibition of PAI-1 and FN by CXPHL was attributed to the untight combination of acetyltransferase KAT2A and SMAD3 and following the suppression of histone 3 lysine 9 acetylation (H3K9ac)-mediated transcription in cholangiocytes. In conclusion, CXPHL showed the most significant anti-cholestatic activities in vivo and in vitro compared with other CX extracts, and its protective effects on the intracellular communication between cholangiocytes and HSCs were achieved by reducing KAT2A/H3K9ac-mediated transcription and release of PAI-1 and FN.
Isolation and Biological Activity of Seven New Drimane-Type Sesquiterpenoids from an Earwig-Associated Aspergillus sp. NF2396
Salman Khan, ZHU Hong-Jie, SUN Zi-Qian, Li Yi-Lin, WANG Lan, WANG Rong, GUO Zhi-Kai, JIAO Rui-Hua
, Available online  , doi: 10.1016/S1875-5364(22)60207-3
Drimane-type sesquiterpenoids are widely distributed in fungi. From the ethyl acetate extract of the earwig-derived Aspergillus sp. NF2396, seven new drimane-type sesquiterpenoids, named drimanenoids A-G ( 1 - 7 ), were isolated. Their structures were elucidated by diverse spectroscopic analysis including high-resolution ESI-MS, one- and two-dimensional NMR spectroscopy. Drimanenoids A-F ( 1 - 6 ) are new members of drimane-type sesquiterpenoid esterified with unsaturated fatty acid side chain at C-6. The antibacterial and cytotoxic activity of these new compounds were evaluated. Compound 4 exhibited moderate cytotoxicity against human myelogenous leukemia cell line K562 with IC50 values of 12.88 ± 0.11 μM.
Polysaccharides from Chinese Herbal Medicine: A review on the hepatoprotective and molecular mechanism
Li Jifeng, Guo Haolin, Dong Ying, Yuan Shuo, Wei Xiaotong, Zhang Yuxin, Dong Lu, Wang Fei, Bai Ting, Yang Yong
, Available online  , doi: 10.1016/S1875-5364(23)60448-0
Polysaccharides are the main bioactive ingredient extracted from Chinese herbal medicine Lycium barbarum Linn, Angelica sinensis (Oliv.) Diels, Astragalus membranaceus (Fisch.) Bge., Dendrobium officinale Kimura & Migo, Ganoderma lucidum (Leyss. Ex Fr.) Karst and Poria cocos (Schw.) Wolf, are prescribed widely in China and have significant anti-inflammatory, especially anti-liver injury activities with almost no side effects. This review summarizes recent studies that discuss and explore the role of herbal polysaccharides with anti-liver injury effects and their mechanisms. Traditional Chinese herbal polysaccharides can slow down hepatocyte apoptosis by affecting liver function, regulating immunity, and improving antioxidant capacity, which can play a role in liver protection. Molecular mechanism studies also indicated the relevant pathway mechanisms, which further indicate the complex role and indispensable importance of traditional Chinese herbal polysaccharides in liver injury. Therefore, this review summarized the hepatoprotective and molecular mechanism of traditional medicinal polysaccharides, providing enlightenment for our researchers to design, and research for the development of polysaccharides and further clinical studies.
Deciphering chemical and metabolite profiling of Chang-Kang-Fang by UPLC-Q-TOF-MS/MS and its potential active components identification
Yang Fengge, Zhang Sihao, Tian Danmei, Zhou Guirong, Tang Xiyang, Miao Xinglong, He Yi, Yao Xinsheng, Tang Jinshan
, Available online  , doi: 10.1016/S1875-5364(22)60251-6
Chang-Kang-Fang (CKF) formula, a traditional Chinese medicine (TCM) prescription, has been widely used for the treatment of irritable bowel syndrome (IBS). However, its potential material basis and underlying mechanism remains elusive. In this study, an integrated strategy combined UPLC-Q/TOF-MS with network pharmacology was employed to systematically depict the phytochemical components and metabolites of CKF, and elucidate its underlying mechanism. As a result, a total of 150 components were identified or tentatively characterized from CKF, in which 6 N-acetyldopamine oligomers from Cicadae Periostracum and 8 resin glycosides from Cuscutae Semen were characterized from this formula for the first time. Meanwhile, 149 xenobiotics (58 prototypes and 91 metabolites) were detected in plasma, urine, feces, brain, and intestinal contents, while the in vivo metabolic modes of resin glycosides were elaborated for the first time. Furthermore, network pharmacology and molecular docking investigation revealed that alkaloids, flavonoids, chromones, monoterpenes, N-acetyldopamine dimers, p-hydroxycinnamic acid, and Cus-3/isomer may be responsible for the IBS treatment effects of CKF formula, and CASP8, MARK14, PIK3C, PIK3R1, TLR4, and TNF may be its potential targets. These discoveries comprehensively make clear the potential material basis and clarify the underlying mechanism of CKF formula for the treatment of IBS, which is helpful for its wide application in clinic.
Discovery and bioassay of disubstituted β-elemene-NO donor conjugates: Synergistic enhancement in the treatment of leukemia
Zhu Junlong, Jiang Xiaoying, Luo Xinyu, Gao Yuan, Zhao Rui, Li Junjie, Cai Hong, Dang Xiawen, Ye Xiang-Yang, Bai Renren, Xie Tian
, Available online  , doi: 10.1016/S1875-5364(23)60404-2
Natural products are essential sources of antitumor drugs. β-Elemene is an effective antitumor natural product extracted from Curcuma wenyujin. A series of novel 13,14-disubstituted nitric oxide (NO)-donor β-elemene derivatives were designed, taking β-elemene as the lead and synthesized as the potential agents in this study for treating leukemia. Among these, compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line, with a high NO release. Compound 13d could effectively inhibit tumor growth without apparent toxicity, and the relative tumor growth inhibitory rate was 62.9% in the K562 xenograft tumor mouse model. The study suggested that compound 13d could be used for treating leukemia.
Abietane Diterpenoids and Iridoids from Caryopteris mongolica
ZHANG Shan-Shan, MAO Xu-Dong, XU Hong-Tao, WEI Xiao-Hui, CHOU Gui-Xin
, Available online  , doi: 10.1016/S1875-5364(23)60409-1
Six new abietane diterpenoids ( 1−6 ) and five undescribed iridoids ( 7−11 ) have been isolated from the aerial parts of Caryopteris mongolica. Their structures were determined using spectroscopic analyses, DP4 + probability analyses, and electronic circular dichroism (ECD) calculations. The cytotoxicity of all the isolates was evaluated. Compound 3 exhibited significant cytotoxic activity against HeLa cell with an IC50 value of 7.83 ± 1.28 μmol·L−1, compounds 1 , 2 , 4 , 9 , and 10 were found to show moderate cytotoxic activities against some cell lines with IC50 values ranging 11.7−20.98 μmol·L−1.
Alkaloids extract from Codonopsis Radix attenuates fat deposition by regulation of mitochondrial energy metabolism and endoplasmic reticulum stress in NAFLD mice
Fan Cai-lian, Wang Guan, Chen Miao, Li Yao, Tang Xi-yang, Dai Yi
, Available online  , doi: 10.1016/S1875-5364(23)60403-0
Alkaloids are a kind of natural active ingredients, that widely exist in food and traditional Chinese medicine. In the present study, the therapeutic effect and potential mechanisms of alkaloids extract from Codonopsis Radix (ACR) on ameliorating fat accumulation in a NAFLD mice model induced by a high-fat diet (HFD) were investigated. Results showed that ACR treatment could effectively reduce the abnormal weight gain and liver injury caused by HFD. Meanwhile, ACR successfully improved the disordered lipid metabolism in NAFLD mice, which was reflected by decreasing the levels of serum triglyceride, total cholesterol and low-density lipoprotein and increasing the level of high-density lipoprotein. In addition, ACR significantly alleviated HFD-induced oxidative stress and increased ATP production by promoting the activities of mitochondrial electron transfer chain complexes Ⅰ, Ⅱ, Ⅳ and Ⅴ and activating the AMPK/PGC-1α pathway, implying that ACR could improve HFD-induced mitochondrial energy metabolism disorder. Moreover, HFD-induced endoplasmic reticulum stress (ER stress) and overexpression of ubiquitin-specific protease 14 (USP14) were obviously inhibited by ACR treatment in NAFLD mice. Taken together, our research demonstrated that ACR could effectively alleviate the lipid deposition of NAFLD by improving energy metabolism, reducing oxidative stress and ER stress, which is worthy of further research and development.
2,3-seco and 3-nor guaianolides from Achillea alpina with antidiabetic activity
XUE Gui-Min, ZHAO Chen-Guang, XUE Jin-Feng, DUAN Jiang-Jing, PAN Hao, ZHAO Xuan, YANG Zhi-Kang, CHEN Hui, SUN Yan-Jun, FENG Wei-Sheng
, Available online  , doi: 10.1016/S1875-5364(23)60411-X
Eight new seco-guaianolide sesquiterpenoids ( 18 ), along with two known guaianolide derivatives ( 9 and 10 ) were isolated from the aerial part of Achillea alpina L. Compounds 13 represented three unique 2,3-oxygen inserted guaianolides and 48 were five special 3-nor guaianolide sesquiterpenoids. The new structures of 18 including their absolute configurations were determined by spectroscopic data analysis, combined with quantum electronic circular dichroism (ECD) calculations. To evaluate the antidiabetic activity of 110 , glucose consumption was used to investigate in palmitic acid (PA)-mediated HepG2-insulin resistance (IR) cells, and compound 7 displayed the strongest reversal IR activity. Moreover, a mechanistic study demonstrated that compound 7 exhibited antidiabetic activity via reduction of the production of the pro-inflammatory cytokine IL-1β, resulting from suppression of NLRP3 pathway.
Dammarane-type triterpenoids from Gynostemma longipes and their protective activities on hypoxia-induced injury in PC12 cells
LIANG Hai-Zhen, CHEN Xiao-Juan, LI Qi, ZHANG Meng-Meng, LU Peng-Xin, ZHANG Jie, SONG Juan, ZHANG Tao, GUO Bao-Lin, MA Bai-Ping
, Available online  , doi: 10.1016/S1875-5364(23)60450-9
Sixteen new dammarane-type triterpenoid saponins ( 116 ) with structurally diverse side chains at C-17 and twenty-one known analogues ( 1737 ), were isolated from the rhizomes of Gynostemma longipes C. Y. Wu, a famous medicinal and edible plant. Their structures were elucidated by means of comprehensive analysis of 1D and 2D NMR and HRMS spectroscopic data, and comparison with the reported data. Then, the isolates were assayed for their protective effects on hypoxia induced damage in pheochromocytoma cells (PC12 cells), and nine saponins exhibited potent anti-hypoxia activities. The possible anti-hypoxia mechanism of the representative saponins was further evaluated. Compounds 22 and 36 significantly suppressed the levels of hypoxia-induced apoptosis. Moreover, these two compounds could decrease the release of lactate dehydrogenase (LDH), malondialdehyde (MDA) and increase the activity of superoxide dismutase (SOD). These results demonstrated that the saponins could prevent hypoxia-induced injuries through the amelioration of apoptosis and oxidative stress. The above findings supply a valuable proof for the future use and development of G. longipes and dammarane-type triterpenoid saponins are disclosed to be its anti-hypoxic constituents.
Liver metabonomics study on the protective effect of glycyrrhetinic acid against realgar-induced liver injury
Huo Taoguang, Fang Ying, Zhang Yinghua, Feng Cong, Jiang Hong
, Available online  
Glycyrrhetinic acid (GA) is the bioactive ingredient in Glycyrrhizae Radx et Rhizoma. Our previous study has reported that GA has protective effect on realgar- induced hepatotoxicity. However, the details of the hepatoprotective mechanisms of GA on realgar-induced liver injury remain to be elucidated. In the study, mice were divided into control, GA-control, realgar, and co-treated groups. Their liver tissues were used for metabonomics study by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method. The results illustrate that GA significantly ameliorate the liver injury and metabolic perturbations caused by realgar. Some metabolites, such as phenylalanine, pyroglutamic acid (PGA), proline, carnitine, nicotinamide, choline, lysophosphatidylcholine (LPC) 16:0 and LPC 18:2 were found responsible for the hepatoprotective effect of GA. These metabolites are associated with the methylation metabolism of arsenic, cell membrane structure, energy metabolism and oxidative stress. From the results of this study, we infer that the potential hepatoprotective mechanism of GA on realgar-induced liver injury may be associated with reducing arsenic accumulation and its methylation metabolism in the liver, promoting the conjugation of arsenic and GSH to play detoxification effect, and ameliorating the liver metabolic perturbations caused by realgar.
Bear bile powder alleviates Parkinson's disease-like behavior in mice by inhibiting astrocyte-mediated neuroinflammation
Wang Lupeng, Bai Yuyan, Tao Yanlin, Shen Wei, Zhou Houyuan, He Yixin, Wu Hui, Huang Fei, Shi Hailian, Wu Xiaojun
, Available online  , doi: 10.1016/S1875-5364(23)60449-2
Parkinson's disease (PD) is a common neurodegenerative disease in middle-aged and elderly people. In particular, more and more evidences show that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD. As a precious traditional Chinese medicine, bear bile powder (BBP) has a long history in clinic. It has numerous efficacies such as clearing heat, calming liver wind and anti-inflammation, and also has a good therapeutic effect on convulsive epilepsy. However, whether BBP can prevent the development of PD has not been elucidated. Hence, this study was aimed to explore the efficacy and mechanism of BBP in suppressing astrocyte-mediated neuroinflammation in a mouse model of PD. PD-like behavior was induced in mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg) for 5 days, followed by daily BBP (50, 100, 200 mg/kg) treatment for 10 days. LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation. BBP treatment significantly ameliorated dyskinesia, increased tyrosine hydroxylase (TH) protein level and inhibited astrocyte hyperactivation in the substantia nigra (SN) of PD mice. Additionally, BBP decreased the protein levels of glial fibrillary acidic protein (GFAP), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS), and up-regulated Takeda G protein-coupled receptor 5 (TGR5) protein level in SN. Moreover, BBP significantly activated TGR5 in a dose-dependent manner, and decreased the expression of GFAP, iNOS and COX2 proteins, as well as the mRNA levels of GFAP, iNOS, COX2, interleukin (IL) -1β, IL-6 and tumor necrosis factor-α (TNF-α) in LPS-stimulated C6 cells. Furthermore, BBP suppressed the phosphorylation of protein kinase B (AKT), inhibitor of NF-κB (IκBα) and nuclear factor-κB (NFκB) proteins in vivo and in vitro. In addition, we observed that the TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP in LPS-stimulated C6 cells. Taken together, BBP could alleviate the disease progression in PD mice by suppressing astrocyte-mediated inflammation via TGR5.
Puerarin inhibits inflammatory and lipid accumulation in alcoholic liver disease via regulation of MMP8
Hu Ying, Wang Shuxian, Wu Lan, Yang Kai, Yang Fan, Yang Junfa, Hu Shuang, Yao Yan, Xia Xun, Liu Yixin, Peng Li, Wan Jihong, Shen Chuanpu, Xu Tao
, Available online  , doi: 10.1016/S1875-5364(23)60399-1
Alcohol-associated liver disease (ALD) is a growing global health concern, and its early pathogenesis includes steatosis and steatohepatitis. Inhibiting lipid accumulation and inflammation is a crucial step in relieving ALD. Evidence shows that puerarin (Pue), an isoflavone isolated from Pueraria lobata, exerts cardio-protective, neuroprotective, anti-inflammatory, antioxidant activities. However, the therapeutic potential of Pue in alcoholic liver disease (ALD) remains unknown. In the study, both the NIAAA mice model and ethanol (EtOH)-induced AML-12 cell model of ALD were established to explore the protective effect of Pue on alcoholic liver injury in vivo and in vitro and the potential mechanism. Results showed that Pue (100 mg/kg) attenuated EtOH-induced liver injury and inhibited the expression level of SREBP-1c, TNF-α, IL-6 and IL-1β, compared to silymarin (100 mg/kg). In vitro results were consistent with in vivo results. Mechanistically, Pue might suppress liver lipid accumulation and inflammation by regulating MMP8. In conclusion, Pue might be a promising clinical candidate for ALD treatment.
Artemdubinoids A–N, undescribed sesquiterpenoids and their antihepatoma cytotoxicity from Artemisia dubia
GAO Zhen, LI Tian-Ze, MA Yun-Bao, HUANG Xiao-Yan, GENG Chang-An, ZHANG Xue-Mei, CHEN Ji-Jun
, Available online  , doi: 10.1016/S1875-5364(23)60441-8
Continuing the search for active ingredients against hepatocellular carcinoma from plants of the Artemisia genus, our preliminary study suggested that the EtOH extract and the EtOAc fraction of aerial parts of Artemisia dubia Wall. ex Bess. showed cytotoxicity against HepG2 cells with inhibitory ratios of 57.1% and 84.2% (100 μg/mL). Fourteen unreported sesquiterpenes, artemdubinoids A–N ( 114 ) were isolated by the bioassay-guided method from the EtOAc fractions, and their structures were confirmed by comprehensive spectral analyses, comparison of the experimental and calculated ECD spectra. Artemdubinoids A, D, F, and H were determined unambiguously by the single crystal X-ray diffraction analysis. Structurally, artemdubinoids A and B ( 12 ) represented unique sesquiterpenes featuring a 6/5-fused bicyclic carbon skeleton, and their putative biosynthetic pathways were discussed; artemdubinoid C ( 3 ) was a novel guaianolide derivative that might be formed by the [4 + 2] Diels–Alder reaction; artemdubinoids D and E ( 45 ) were rare 1,10-seco-guaianolides; artemdubinoids F–K ( 611 ) were chlorine-containing guaianolides. Eleven compounds exhibited cytotoxicity against three human hepatoma cell lines (HepG2, Huh7, and SK-Hep-1) with IC50 values in the range of 7.5−82.5 μM. Artemdubinoid M ( 13 ) exhibited the most active cytotoxicity with IC50 values of 14.5, 7.5 and 8.9 μM on the HepG2, Huh7, and SK-Hep-1 cell lines, respectively, which were equivalent to the positive control, sorafenib.
Review of pharmacological effects, chemical constituents of Pien Tze Huang and prediction of its Q-markers
DONG Zhao-Min, WANG Hong, WANG Guang-Ji
, Available online  , doi: 10.1016/S1875-5364(23)60400-5
Pien Tze Huang (PTH) was documented as an imperial prescription compsed of Panax notoginseng, Calculus bovis, snake gallbladder and musk, is famous in China and Asian countries due to its excellent the functions of heat clearing, detoxifying, swelling reducing, and pain relieving. Modern pharmacological studies show that PTH shows excellent effects against various inflammatory diseases, liver diseases, and carcinomas. This review summaries and discussesits pharmacological effects, clinical application, and mainchemical components. More importantly, its quality markers (Q-markers) are then forecasted and analyzed based on the “five core principles” of Q-markers, of Traditional Chinese Medicine, including transfer and traceability, specificity, efficacy, compatibility, and measurability. Ginsenosides Rb1, ginsenoside Rg1, ginsenoside Rd, ginsenoside Re, notoginsenoside R1, dencichine, bilirubin, biliverdin, taurocholic acid, and muscone are speculated as the Q-markers of PTH. This review provides a reference and basis for the construction of a quality control system for PTH.
The thalamic-primary auditory cortex circuit: A pathway to resilience in the face of stress and a potential target for depression treatment
Tan Jianling, Ye Ling
, Available online  , doi: 10.1016/S1875-5364(23)60447-9
The circadian clock of anti-tumor immunity
XIANG Shuting, LI Mingxi, LI Suxin
, Available online  , doi: 10.1016/S1875-5364(23)60431-5
Original article
Total glucosides of Rhizoma Smilacis Glabrae alleviates psoriasis by stabilizing Th17/Treg balance
TANG Yingzhan, YU Jingyi, ZHAO Wen, LIU Juyan, PENG Hongying, ZHANG Haoran, JIANG Zhenzhou, YU Qinwei, ZHANG Luyong
, Available online  , doi: 10.1016/S1875-5364(23)60413-3
Total glucosides of Rhizoma Smilacis Glabrae (RSG) tablet is a selective immunosuppressant for treating rheumatoid arthritis through selective inhibition of activated T cells in clinical. In this study, we aimed to investigate whether RSG could be applied in the treatment of psoriasis and clarify its mechanism and material basis. The results revealed that RSG could increase the number of tail scales in mice remarkably, and improve the skin erythema, ulceration, and flaking in imiquimod-induced psoriasis significantly. By transcriptome sequencing and T-cell flow sorting assay, we found that RSG could significantly down-regulate the ratio of th17/Treg in damaged skin tissue, down-regulate the ratio of G2 phase cells, and improve the proliferation and differentiation of epithelial cells. Among them, β-sitosterol, sitostenone, stigmasterol, smiglanin, and cinchonain Ib showed better inhibitory effects on the IL-17 mediated inflammatory response in HaCaT cell. Summary, RSG has certain therapeutic effects on psoriasis by stabilizing Th17/Treg balance, and the results provide a theoretical basis for the development of new indications of RSG tablets.
Neotuberostemonine and tuberostemonine ameliorate pulmonary fibrosis by suppressing TGF-β and SDF-1 secreted by macrophages and fibroblasts via PI3K-dependent AKT and ERK pathways
FU San, SONG Xianrui, HU Yingying, ZHU Qingwei, LV Xinmiao, TANG Xiaoyan, ZHANG Mian
, Available online  , doi: 10.1016/S1875-5364(22)60263-2
Activated fibroblasts and M2-polarized macrophages may contribute to the progression of pulmonary fibrosis by forming a positive feedback loop. This study was aimed to investigate whether fibroblasts and macrophages form this loop by secreting SDF-1 and TGF-β and the impacts of neotuberostemonine (NTS) and tuberostemonine (TS). Mice were intratracheally injected with 3 U·kg−1 bleomycin and orally administered with 30 mg·kg−1 NTS or TS. Primary pulmonary fibroblasts (PFBs) and MH-S cells (alveolar macrophages) were used in vitro. The animal experiments showed that NTS and TS improved fibrosis related indicators, inhibited fibroblast activation and macrophage M2 polarization, and reduced TGF-β and SDF-1 levels in alveolar lavage fluid. Cell experiments showed that TGF-β1 may activated fibroblasts into myofibroblasts secreting SDF-1 by activating PI3K/AKT/HIF-1α and PI3K/PAK/RAF/ERK/HIF-1α pathways. It was also found for the first time that SDF-1 could directly polarize macrophages into M2 phenotype secreting TGF-β through the same pathways mentioned above. Moreover, the results of the cell coculture confirmed that fibroblasts and macrophages actually create a feedback loop to promote fibrosis, and the secretions of TGF-β and SDF-1 are crucial for maintaining this loop. NTS and TS may disturb this loop through inhibiting both PI3K/AKT/HIF-1α and PI3K/PAK/RAF/ERK/HIF-1α pathways to improve pulmonary fibrosis. NTS and TS are stereoisomeric alkaloids with pyrrole[1,2-a]azapine skeleton, and their effect in improving pulmonary fibrosis may be mainly attributed to their parent nucleus. Moreover, this study also found that inhibition of both AKT and ERK pathways is essential for maximizing the improvement of pulmonary fibrosis.
Ginsenoside-rg1 combined with a conditioned medium from induced neuron-like hUCMSCs alleviated the apoptosis in a cell model of ALS via regulating the NF-κB/Bcl-2 pathway
HUANG Yu, YANG Huili, YANG Biying, ZHENG Yu, HOU Xiaomei, CHEN Guiling, ZHANG Wenqi, ZENG Xiang, DU Baoxin
, Available online  , doi: 10.1016/S1875-5364(22)60264-4
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons in the brain, brainstem, and spinal cord. Superoxide dismutase 1 (SOD1) mutant−mediated mitochondrial toxicity leading to apoptosis in neurons is one of the cores of pathogenesis. This study aimed to evaluate the neural protective synergistic effects of ginsenosides Rg1 (G-Rg1) and conditioned medium (CM) on the mutational SOD1 cell model, revealing its underlying mechanisms. We found that the contents of nerve growth factor, glial cell line-derived neurotrophic factor, and brain-derived neurotrophic factor significantly increased in CM after human umbilical cord mesenchymal stem cells (hUCMSCs) were cultured with neuron differentiation reagent for 7 days. CM or G-Rg1 could decrease the apoptotic rate of SOD1G93A-NSC34 cells to a certain extent, but their combination brought about the least apoptosis compared with CM or G-Rg1 used alone. Further research showed that the anti-apoptotic protein Bcl-2 was upregulated in all treatment groups. Proteins associated with mitochondrial apoptotic pathways, including Bax, caspase 9 (Cas-9), and cytochrome c (Cyt c), were downregulated. In addition, CM or G-Rg1 also inhibited the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by reducing the phosphorylation of p65 and IκBα. Furthermore, CM/G-Rg1 or their combination could reduce the apoptotic rate induced by betulinic acid (BetA), an agonist of the NF-κB signaling pathway. In summary, the combination of CM and G-Rg1 effectively reduced the apoptosis of SOD1G93A-NSC34 cells via suppressing the NF-κB/Bcl-2 signaling pathway (Fig. 1 is a graphical representation of the abstract).
Antimalarial and neuroprotective ent-abietane diterpenoids from the aerial parts of Phlogacanthus curviflorus
LI Jia, MENG Xiao, YIN Chengyue, ZHANG Lixia, LIN Bin, LIU Peng, ZHU Lingjuan, WANG Haifeng, LIU Hongwei, ZHANG Xue, YAO Xinsheng
, Available online  , doi: 10.1016/S1875-5364(22)60258-9
Six undescribed ent-abietane diterpenoids, abientaphlogatones A−F ( 16 ), two undescribed ent-abietane diterpenoid glucosides, abientaphlogasides A−B ( 78 ), together with four known analogues were isolated from the aerial parts of Phlogacanthus curviflorus. Their structures were elucidated by HR-ESI-MS, 1D and 2D NMR, electronic circular dichroism spectra and quantum chemical calculations. Abientaphlogatones E and F were the first report of ent-norabietane diterpenoids from the genus of Phlogacanthus. Compounds 2 , 4 , 710 and 12 displayed antimalarial activity in β-hematin formation inhibition assay with IC50 values of 12.97−65.01 μmol·L−1. Compounds 4 , 5 , 8 and 10 showed neuroprotective activity in PC12 cells injury model induced by H2O2 and MPP+.
Xuebijing alleviates LPS-induced acute lung injury by downregulating pro-inflammatory cytokine production and inhibiting gasdermin-E-mediated pyroptosis of alveolar epithelial cells
ZHANG Cuiping, CHEN Xiaoyan, WEI Tianchang, SONG Juan, TANG Xinjun, BI Jing, CHEN Cuicui, ZHOU Jian, SU Xiao, SONG Yuanlin
, Available online  , doi: 10.1016/S1875-5364(22)60265-6
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a diffuse alveolar injury mainly caused by an excessive inflammatory response, with high mortality due to a lack of effective pharmacotherapy. Xuebijing (XBJ) Injection is a traditional Chinese medicine with a potent anti-inflammatory effect, which has potential clinical value in the treatment of ALI/ARDS. This study was designed to investigate the preventive effect of XBJ on ALI and its underlying mechanism. We established LPS-induced ALI and treated ALI mice with XBJ. Our results confirmed that pretreatment with XBJ significantly reduced lung inflammation and increased the survival rate of ALI by 37.5%. In addition, XBJ dramatically downregulated the gene expression of Tnfa, Il6 and Il1b in lung tissues and suppressed the release of TNF-α, IL-6, and IL-1β in the lung tissue and bronchoalveolar lavage fluid. Then, we screened potential targets of XBJ in treating ALI by constructing a network pharmacology analysis. We identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death in addition to anti-inflammatory responses. According to this, we found that XBJ could inhibit gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-α production. Therefore, this study proves the preventive effect of XBJ on ALI and reveals that XBJ protects alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-α release.
Lysohexaenetides A and B, linear lipopeptides from Lysobacter sp. DSM 3655 identified by heterologous expression in Streptomyces
XU Qiushuang, ZOU Haochen, PAN Chen, WANG Haoxin, SHEN Yuemao, LI Yaoyao
, Available online  , doi: 10.1016/S1875-5364(22)60247-4
Lysobacter harbors a plethora of cryptic biosynthetic gene clusters (BGCs), albeit only a limited number have been analyzed to date. In this study, we described the activation of a cryptic polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) gene cluster (lsh) in Lysobacter sp. DSM 3655 through promoter engineering and heterologous expression in Streptomyces sp. S001. As a result of this methodology, we were able to isolate two novel linear lipopeptides, lysohexaenetides A ( 1 ) and B ( 2 ), from the recombinant strain S001-lsh. Furthermore, we proposed the biosynthetic pathway for lysohexaenetides and identified lshA, a single module that represents another example of entirely iterative bacterial PKSs. This study highlights the potential of heterologous expression systems in uncovering cryptic biosynthetic pathways in Lysobacter genomes, particularly in the absence of genetic manipulation tools.
Targeted trace ingredients coupled with chemometric analysis for consistency evaluation of Panax Notoginseng saponins injectable formulations
ZHANG Jingxian, Zhang Zijia, Wang Zhaojun, Zhang Tengqian, Zhou Yang, Chen Ming, Huang Zhanwen, He Qingqing, Long Huali, Hou Jinjun, Wu Wanying, Guo Dean
, Available online  , doi: 10.1016/S1875-5364(23)60396-6
Evaluating the consistency of herb injectable formulations could improve their product quality and clinical safety, especially regarding to the composition and content level of the trace ingredients. Panax Notoginseng Saponins Injection (PNSI), widely used in China for treating acute cardiovascular diseases, has 10% to 25% of low abundant and trace saponins other than the five main ones (notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, and ginsenoside Rd). A liquid chromatography - triple quadrupole mass spectrometry (LC-MS/MS) with multiple ions monitoring (MIM) method was developed by adopting a “post-column valve switching” strategy to remove the high abundant peaks (NR1, Rg1, and Re) at 26 min. The 51 ingredients that covered most of the low abundant and trace saponins in PNSI were selected and quantified or relatively quantified using 18 saponins standards, with digoxin as the internal standard. The inter- and intra- repeatability of the method was 3% to 14%, and the recovery was 85% to 120% by adding standards into samples. The linear range, which covered the limit of detection (1 ng·mL−1), was R2 > 0.9980. A total of 119 batches of PNSI provided by seven vendors were evaluated quantitatively, and it was found that the trace saponins were significantly varied among different vendors and formulation types. These results indicated that more attention should be given to hose low abundant and trace saponins regarding the consistency of PNSI to achieve better product control and clinical safety for PNSI.
Eucommia Lignans alleviate the progression of diabetic nephropathy through the mediation of the AR/Nrf2/HO-1/AMPK axis in vivo and in vitro
HUANG Qi, ZHANG Yinfan, JIANG Yueping, HUANG Ling, LIU Qiong, OUYANG Dongsheng
, Available online  , doi: 10.1016/S1875-5364(23)60427-3
Lignans derived from Eucommia ulmoides Oliver (Eucommia Lignans) inhibit the progression of inflammatory diseases, while their effects on Diabetic nephropathy (DN) progression remained unclear. This work decided to assess the function of Eucommia Lignans in DN. The major constituents of Eucommia Lignans were analyzed by UPLC-Q-TOF-MS/MS. The binding between Eucommia Lignans and aldose reductase (AR) was predicted by molecular docking. Eucommia Lignans (200, 100, and 50 mg/kg) were used to process model animals to analyze rat renal function. Rat glomerular mesangial cells (HBZY-1) were transfected with sh-AR, sh-AMPK, and oe-AR in the presence of high glucose (HG) or HG combined with Eucommia Lignans to evaluate whether Eucommia Lignans affected HG-induced cell injury and mitochondrial dysfunction through the AR/Nrf2/HO-1/AMPK axis. Eucommia Lignans significantly attenuated the progression of DN in vivo. Eucommia Lignans notably reversed HG-induced upregulation of inflammatory cytokines and mitochondrial injury, while downregulating the expression of Cyto c, caspase 9, AR, and NOX4 in HBZY-1 cells. In contrast, HG-induced downregulation of Nrf2, HO-1 and p-AMPKα levels were abolished by Eucommia Lignans. Meanwhile, the knockdown of AR exerted a similar therapeutic effect of Eucommia Lignans on DN progression, and AR overexpression could reverse the effect of Eucommia Lignans. Eucommia Lignans alleviate kidney injury through the AR/Nrf2/HO-1/AMPK axis. Thus, our study might provide a rationale for using Eucommia Lignans in treating DN.
New di-spirocyclic labdane diterpenoids from the aerial parts of Leonurus japonicus
CAO Xinxin, WANG Xinxin, ZHANG Yu, XU Defeng, SONG Xiuqing, YU Jinhai, BAO Jie, ZHANG Junsheng, ZHANG Hua
, Available online  , doi: 10.1016/S1875-5364(22)60262-0
Phytochemical investigation on the ethanol extract of a well-known medicinal herb Leonurus japonicus, led to the separation of 18 labdane type diterpenoids ( 118 ). On the basis of comprehensive spectroscopic analyses and quantum chemical calculations, these molecules were structurally characterized as six new interesting 5,5,5-di-spirocyclic ones ( 16 ), two new ( 7 and 8 ) and six known ( 1318 ) interesting 6,5,5-di-spirocyclic ones, a new rare 14,15-dinor derivative ( 9 ), and three new ones incorporating a γ-lactone unit ( 1012 ). An in vitro neuroprotective assay in RSC96 cells revealed that compounds 7 and 12 exhibited neuroprotective activity in a concentration-dependent way, comparable to the reference drug N-acetylcysteine.
Biotransformation differences of ginsenoside Compound K mediated by gut microbiota from diabetic patients and healthy subjects
HUANG Sutianzi, SHAO Li, CHEN Manyun, WANG Lin, LIU Jing, ZHANG Wei, HUANG Weihua
, Available online  , doi: 10.1016/S1875-5364(23)60402-9
Many natural products can be bio-converted by gut microbiota to influence the pertinent efficiency. Ginsenoside compound K (GCK) is a potential anti-type 2 diabetes (T2D) saponin, which is mainly bio-transformed into protopanaxadiol (PPD) by gut microbiota. Studies have shown that gut microbiota between the diabetic patients and healthy subjects are significantly different. Herein, we aimed to characterize the biotransformation of GCK mediated by gut microbiota from diabetic patients and healthy subjects. Based on 16S rRNA gene sequencing, the data indicated the bacterial profiles were considerably different between the two groups, especially with Alistipes and Parabacteroides increased in healthy subjects. The quantitative analysis of GCK and PPD showed that gut microbiota from the diabetic patients metabolized GCK slower than healthy subjects by a liquid chromatography tandem mass spectrometry (LC-MS/MS). The selected strain A. finegoldii and P. merdae exhibited a different metabolic capability of GCK. In conclusion, the different biotransformation capacity for GCK might impact its anti-diabetic potency.
Tu-Xian decoction ameliorates diabetic cognitive impairment by inhibiting DAPK-1
WANG Danyang, YAN Bin, WANG An, SUN Qing, PANG Junyi, CUI Yangming, TIAN Guoqing
, Available online  , doi: 10.1016/S1875-5364(23)60428-5
Background: Tu-Xian decoction (TXD), as traditional Chinese medicine (TCM), has frequently been used in the treatment of diabetic cognitive impairment (DCI). However, the protective mechanism of TXD on DCI remains unknown. Death-associated protein kinase-1 (DAPK-1) is a key modulator in neuronal disease. This study investigated whether TXD alleviates DCI by inhibiting DAPK-1 activity. Method: The diabetes model was established in SD rats by a high-fat, high-sugar (HFHS) diet, and streptozotocin (STZ). This study included: Control, Diabetic, TC-DAPK6, high-dose TXD, medium-dose TXD, and low-dose TXD 6 groups. After 12 weeks of pharmaceutical intervention, the blood glucose, body weight, Morris water maze (MWM), brain magnetic resonance imaging (MRI), hematoxylin-eosin (H&E), and Nissl staining were examined. Western blotting (WB) was used to detect the protein expression of the hippocampus. Results: Diabetic rat model was successfully established. TXD underlying ameliorated spatial learning and memory ability decline, and hippocampal structural injuries in diabetic rats. Moreover, TXD underlying reduced the expression of a protein associated with neurological damage and the DAPK-1 activity in the hippocampus of diabetic rats. Conclusion: TXD has an underlying mitigating effect on DCI, and this effect might be by inhibition of DAPK-1 activity. Therefore, TXD may serve as a prospective therapeutics for DCI.
Guijiajiao (Colla Carapacis et Plastri, CCP) prevents male infertility via gut microbiota modulation
SHENG Wen, XU Wenjing, DING Jin, LU Baowei, LIU Lumei, HE Qinghu, ZHOU Qing
, Available online  , doi: 10.1016/S1875-5364(22)60253-X
Male infertility is a significant cause of psychosocial and marital distress in approximately 50% of couples who are unable to conceive, with male factors being the underlying cause. Guijiajiao (Colla Carapacis et Plastri, CCP) is a Traditional Chinese Medicine commonly used to treat male infertility. The present study aimed to investigate the potential mechanisms underlying the preventive effects of CCP on male infertility. An infertile male rat model was established using cyclophosphamide (CTX), and CCP was administered for both treatment and prevention. Fecal microbiota transplantation (FMT) was also performed to explore the role of gut microbiota in the CCP-mediated prevention of male infertility in rats. Sperm motility and concentration were determined using a semi-automatic sperm classification analyzer. Subsequently, histopathological analysis using HE staining was performed to examine the changes in the small intestine and testis. Moreover, the serum levels of lipopolysaccharide (LPS) and testosterone were measured by ELISA. In addition, immunohistochemistry was conducted to detect CD3 expression in the small intestine, while RT-qPCR was employed to assess the expressions of interleukin-1 beta (IL-1β), cluster of differentiation 3 (CD3), Monocyte chemoattractant protein-1 (MCP-1), and C-X-C motif chemokine ligand 10 (CXCL-10) in the small intestine and epididymis. Finally, gut microbiota was analyzed by 16S rRNA sequencing. CCP improved sperm motility, number, and concentration in CTX-induced infertile male rats. CCP increased the serum testosterone level, inhibited the immune cell infiltration of the intestinal lamina propria, and promoted the aggregation of CD3+ T cells in CTX-induced male infertility rats. CCP also inhibited the expressions of MCP-1, CXCL-10, and IL-1β in the epididymis of male infertility rats. At the genus level, CTX led to a reduction in the abundance of Lactobacillus, Clostridia_UCG.014, and Romboutsia in the intestinal tract of rats. In contrast, CCP decreased the abundance of Ruminococcus and increased the abundance of Romboutsia in infertile male rats. Additionally, FMT experiments proved that the gut microbiota of CCP-treated rats facilitated testicular tissue recovery and spermatogenesis while also reducing the serum LPS level in infertile male rats. CCP improves the spermatogenic ability of infertile male rats by restoring gut microbiota diversity and inhibiting epididymal inflammation.
Original Article
Dihydroartemisinin attenuates ischemia/reperfusion-induced renal tubular senescence by activating autophagy
LIU Huiling, HUANG Zhou, JIANG Hong, SU Ke, SI Zilin, WU Wenhui, WANG Hanyu, LI Dongxue, TAN Ninghua, ZHANG Zhihao
, Available online  , doi: 10.1016/S1875-5364(23)60398-X
Acute kidney injury (AKI) is an important factor in the occurrence and development of CKD. The protective effect and underlying mechanism of dihydroartemisinin on AKI have not been reported. In this study, we used two animal models including ischemia-reperfusion and UUO, as well as a high-glucose-stimulated HK-2 cell model, to evaluate the protective effect of dihydroartemisinin on premature senescence of renal tubular epithelial cells in vitro and in vivo. We demonstrated that dihydroartemisinin improves renal aging and renal injury by activating autophagy. In addition, we found that co-treatment with chloroquine, an autophagy inhibitor, abolished the anti-renal aging effects of dihydroartemisinin in vitro. Our results suggested that activation of autophagy/elimination of senescent cell might be a useful strategy to prevent AKI/UUO induced renal tubular senescence and fibrosis.
Herbal medicines for insomnia work by regulating 5-hydroxytryptamine receptors: a systematic review
WANG Haoran, GU Yanqiu, KHALID Rahman, CHEN Xiaofei, HAN Ting
, Available online  , doi: 10.1016/S1875-5364(23)60405-4
Insomnia is a common sleep disorder lacking effective therapy and can affect a person’s life. The mechanism of the disease progression, remain obscure, hence, there is a need to understand the targets related to insomnia in order to develop innovative therapies and new compounds. The interest in complementary and alternative medicines for treating or preventing insomnia has increased recently. Research into their molecular components revealed that their sedative and sleep-promoting properties rely on interactions with various neurotransmitter systems in the brain. This review summarizes the role of 5-hydroxytryptamine (5-HT) in insomnia development and performs a systematic analysis of studies assessing the mechanisms of various herbal medicines on different subtypes of 5-HT receptors in the context of sleep control to provide a valuable reference for subsequent research.
Therapeutic potential and mechanism of Chinese herbal medicine in treating fibrotic liver disease
LI Yanwei, LU Yunrui, NIAN Mozuo, SHENG Qiuju, ZHANG Chong, HAN Chao, DOU Xiaoguang, DING Yang
, Available online  , doi: 10.1016/S1875-5364(23)60443-1
Liver fibrosis is a pathological condition characterized by the replacement of normal liver tissue with scar tissue, and it is the leading cause of liver-related death globally. For the treatment of liver fibrosis, in addition to antiviral therapy or removal of inducers, there remains a lack of specific and effective medical treatments. For thousands of years, Chinese herbal medicine (CHM) has been widely used to treat liver fibrosis in clinical settings. CHM is effective for liver fibrosis despite its unclear mechanism of action. In recent years, many studies have attempted to determine the possible mechanism of action of CHM in treating liver fibrosis. There have been substantial improvements in the experimental investigation of CHM which have greatly promoted the understanding of anti-liver fibrosis mechanisms. In this review, the role of CHM in the treatment of liver fibrosis is described, based on studies over the past 10 years, which have addressed the various mechanisms and signaling pathways that mediate therapeutic efficacy. Among them, the inhibition of stellate cell activation is identified as the most common mechanism. This article provides insights into the research direction of CHM to expand its clinical application range and improve its effectiveness.
Original atricle
Dammarane-type triterpenoid saponins isolated from Gynostemma pentaphyllum ameliorate liver fibrosis via agonizing PP2Cα and inhibiting deposition of extracellular matrix
LIU Yue, YANG Yating, WANG Hanghang, LI Han, LV Qi, WANG Xiachang, WU Dalei, HU Lihong, ZHANG Yinan
, Available online  , doi: 10.1016/S1875-5364(23)60395-4
Gypenosides, the congeneric structure but sustainable resource of ginsenoside, have been recognized to be the main active ingredients of the Chinese medicinal plant Gynostemma pentaphyllum that used to treat metabolic syndrome. By bioactive tracking isolation of the plants collected from different habitants of China, we obtained four new gypenosides ( 14 ), together with nine known gypenosides ( 513 ) from the methanol extract of the plant. The structures of new gypenosides were elucidated by 1D and 2D NMR spectra interpretation as well as chemical degradation. After evaluation on COL1A1 promoter and PP2Cα activity assays, the structure-activity relationship of these dammarane-type triterpenoids concluded that C-3 saccharide chain and C-17 lactone ring are necessary to inhibit the deposition of extracellular matrix on the liver stellate cells. Further in vivo study on the CCl4-induced liver damage mouse model corroborated that compound 5 significantly ameliorated the process of hepatic fibrosis by oral administration. These results together indicate the dammarane-type triterpenoid would be a potential anti-fibrotic lead and prevalent structure in the treatment of chronic liver disorders.