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Flavonoids from the roots and rhizomes of Sophora tonkinensis and their in vitro anti-SARS-CoV-2 activities
LI Zhuo, XIE Hang, TANG Chunping, FENG Lu, KE Changqiang, XU Yechun, SU Haixia, YAO Sheng, YE Yang
, Available online  , doi: 10.1016/S1875-5364(22)60211-5
Abstract:
Acute respiratory infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused a global pandemic since 2019, and posed a serious threat to the world public health security. Traditional Chinese medicine (TCM) has played an indispensable role in the battle against the epidemic. Many components original from the TCMs were found to inhibit the production of SARS-CoV-2 3C-like protease (3CLpro) and papain-like protease (PLpro), which are two promising therapeutic targets to inhibit the SARS-CoV-2. This study describes a systematic investigation of the roots and rhizomes of Sophora tonkinensis, which resulted in the characterization of 12 new flavonoids, including seven prenylated flavanones ( 17 ), one prenylated flavonol ( 8 ), two prenylated chalcones ( 910 ), one isoflavanone ( 11 ), and one isoflavan dimer ( 12 ), together with 43 known compounds ( 1355 ). Their structures including the absolute configurations were elucidated by comprehensive analysis of MS, 1D and 2D NMR data, and time-dependent density functional theory electronic circular dichroism (TDDFT ECD) calculations. Compounds 12 and 51 exhibited inhibitory effects against SARS-CoV-2 3CLpro with IC50 values of 34.89 and 19.88 μmol·L−1, and compounds 9 , 43 and 47 exhibited inhibitory effects against PLpro with IC50 values of 32.67, 79.38, and 16.74 μmol·L−1, respectively.
Bavachin induces apoptosis in colorectal cancer cells through Gadd45a via MAPK signaling pathway
WANG Mengru, TIAN Baopeng, SHEN Jie, XU Shilin, LIU Cong, GUAN Ling, GUO Min, DOU Jie
, Available online  , doi: 10.1016/S1875-5364(22)60241-3
Abstract:
Bavachin is a dihydroflavonoid compound isolated from Psoralea corylifolia, and is known to have anti-bacterial, anti-inflammatory, anti-tumor and lipid-lowering activities. It has been reported that bavachin could induce apoptosis in many human cancer cell lines. However, the anti-cancer effects and related mechanisms in colorectal cancer remain unknown. Here, we studied the effects and mechanisms of bavachin on colorectal cancer in vivo and in vitro. We show that bavachin could inhibit cell proliferation and induce apoptosis of human colorectal cancer cell. And these phenomenons are mediated by the activation of MAPK signaling pathway, which significantly upregulates the expression of Gadd45a. Silenced of Gadd45a by siRNA attenuate bavachin-mediated cell apoptosis obviously. Inhibition of MAPK signaling pathway by JNK/ERK/p38 inhibitors also abrogated upregulation of Gadd45a by bavachin. We further validated the anticancer effect of bavachin in xenograft model of human colorectal cancer. In summary, these findings demonstrate that bavachin could significantly inhibit colorectal cancer tumor growth and proliferation by inducing cell apoptosis, and this process was closely related to the up-regulation of Gadd45a expression level and activation of MAPK signaling pathway.
Cyasterone inhibits IL-1β-mediated apoptosis and inflammation via the NF-κB and MAPK signalling pathways in rat chondrocytes and ameliorates osteoarthritis in vivo
TENG Li, SHEN Yue, QU Yuhan, YANG Longfei, YANG Yuting, JIAN Xi, FAN Shengli, ZHANG Lele, FU Qiang
, Available online  , doi: 10.1016/S1875-5364(22)60233-4
Abstract:
As a prevalent global joint disease, osteoarthritis has the characteristics of inflammatory reaction and cartilage degradation. Cyasterone, a sterone derived from the roots of Cyathula officinalis Kuan, exerts protective effects against several inflammation-related diseases. However, its effect on osteoarthritis remains unclear. The purpose of this study was to investigate the potential anti-osteoarthritis activity of cyasterone. Primary chondrocytes isolated from rat induced by interleukin (IL)-1β and rat model stimulated by monosodium iodoacetate (MIA) were used as in vitro and in vivo models, respectively. The results of in vitro experiments showed that cyasterone apparently counteracted chondrocyte apoptosis, increased the expression of collagen II and aggrecan, and restrained the production of the inflammatory factors inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), metalloproteinase-3 (MMP-3), and metalloproteinase-13 (MMP-13) induced by IL-1β in chondrocytes. Furthermore, cyasterone ameliorated the inflammation and degenerative progression of osteoarthritis potentially by regulating the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. In vivo, cyasterone significantly alleviated the inflammatory response and cartilage destruction of rats induced by monosodium iodoacetate, with dexamethasone serving as the positive control. Overall, this study laid a theoretical foundation for the development of cyasterone as an effective drug for the alleviation of osteoarthritis.
Shen Qi Wan attenuates renal interstitial fibrosis via upregulating AQP1
Lin Yiyou, Wei Jiale, Zhang Yehui, Huang Junhao, Wang Sichen, Luo Qihan, Yu Hongxia, Ji Liting, Zhou Xiaojie, Li Changyu
, Available online  , doi: 10.1016/S1875-5364(22)60254-1
Abstract:
Shen Qi Wan (SQW), a famous traditional Chinese formula, has great effect on chronic kidney diseases (CKD). Renal interstitial fibrosis (RIF) is the crucial pathway in CKD leading to the end-stage renal failure. However, the underlying mechanism of SQW treat on RIF is unclear and needs further verification. To investigate the effect of SQW on RIF and explore the underlying mechanism of SQW on tubular epithelial-to-mesenchymal transition (EMT) through regulating of Aquaporin 1 (AQP1) expression level. An RIF mouse model was established by administration of adenine, and subsequently treated with SQW (3 or 6 g/kg/d, respectively) for 50 days. Following the treatment period, the levels of kidney functional parameters in serum were detected. The pathological renal changes and degree of fibrosis in the kidneys were analyzed by histological assessment. The expression of EMT-related markers and AQP1 gene expression in kidney tissues were measured using Real-time quantitative PCR (RT-qPCR) and Western blotting. In addition, EMT in HK-2 cells was induced using transforming growth factor-beta1 (TGF-β1), and this was followed by treatment with a serum containing SQW. Subsequently, the molecular mechanism of SQW on EMT was explored in HK-2 cells of AQP1 knockdown. SQW alleviated kidney injury and renal collagen deposition in the kidneys of mice induced by adenine, increased E-cadherin and AQP1 expression at the protein level, and decreased the expression of Vimentin and α-smooth muscle actin (α-SMA). Similarly, treatment with the serum containing SQW upregulated the expression of E-cadherin and Cytokeratin-18 (CK-18), and downregulated the expression of Vimentin and α-SMA significantly in TGF-β1 stimulated HK-2 cells. The expression levels of Snail and Slug were significantly upregulated in HK-2 cells following knockdown of AQP1. AQP1 knockdown increased the mRNA expression levels of Vimentin and α-SMA, while decreasing the expression levels of E-cadherin. The protein expression levels of Vimentin were increased, whereas E-cadherin and CK-18 expression levels were significantly decreased following AQP1 knockdown in the HK-2 cells. These results revealed that AQP1 knockdown promoted EMT. Furthermore, AQP1 knockdown abolished the protective effects of treatment with serum containing SQW on EMT in HK-2 cells. SQW halts EMT process in RIF via upregulation of the expression of AQP1 in kidneys.
Study on the Dynamic Variation of the Secondary Metabolites in Viscum coloratum Using Targeted Metabolomics
Zhang Ruizhen, Duan Rong, Wang Weiqing, Yu Zhiguo, Li Yun, Zhao Yunli
, Available online  , doi: 10.1016/S1875-5364(22)60243-7
Abstract:
Viscum coloratum (Kom.) Nakai is a well-known medicinal plant. However, the optimal harvest time for V. coloratum is unknown, and few studies have evaluated its compounds variation during storage, post-harvest quality control thus lacks a theoretical basis. Our study aimed to comprehensively evaluate the quality of V. coloratum in different growth stages, and determine the dynamic variation of metabolites. Ultra-performance liquid chromatography tandem mass spectrometry was used to quantify 29 compounds in V. coloratum harvested from six growth periods, and the associated biosynthetic pathway was explored. The accumulation of different types of compounds were analyzed based on their synthesis pathways. Grey relational analysis was used to evaluate the quality of V. coloratum across different months. The compounds variation during storage was analyzed using a high-temperature high-humidity accelerated test. The results showed that V. coloratum was better in March, followed by November, and was worst in July. During storage, compounds downstream of the biosynthesis pathway were degraded to produce their upstream compounds and low-molecular-weight organic acids first, leading to a large gap in the degradation time course between different compounds. Due to the rapid rate and large degree of degradation, five compounds were tentatively designated as “early warning components” for quality control. This report provides a reference for the analysis of the biosynthesis and degradation of metabolites in V. coloratum. It provides theoretical support for the rational application of V. coloratum resources and quality control during V. coloratum storage.
Exosomes originated from Nr-CWS pretreated MSC facilitate diabetic wound healing by promoting angiogenesis via circIARS1/miR-4782-5p/VEGFA axis
Li Qiang, Guo Lei, Wang Jian, Tao Shengjun, Jin Peisheng
, Available online  , doi: 10.1016/S1875-5364(22)60226-7
Abstract:
Mesenchymal stem cell (MSC)-derived exosomes had been reported to a prospective candidate in accelerating diabetic wound healing because of the pro-angiogenic effect. MSC pretreated with chemistry or biology factors are to advance the biological activities of MSC-derived exosomes. Hence, this study intended to explore whether exosomes originated from the human umbilical cord MSC (hucMSC) preconditioned with nocardia rubra cell wall skeleton (Nr-CWS) could display superior proangiogenic effect on diabetic wound repair and its underlying molecular mechanism. We found that Nr-CWS -Exos facilitated the proliferative and migratory abilities as well as the tube formation of endothelial cells in vitro. In vivo, Nr-CWS -Exos displayed great effect on advancing the wound healing by facilitating the angiogenesis of wound tissues in contrast to Exos. Furthermore, circIARS1 expression was increased after HUVECs were treated with Nr-CWS-Exos. CircIARS1 promoted the pro-angiogenic effects of Nr-CWS -Exos on endothelial cells via miR-4782-5p/VEGFA axis. Taken together, those data reveal that exosomes derived from Nr-CWS -pretreated MSCs might serve as an underlying strategy for diabetic wound via advancing the biological function of endothelial cells through circIARS1/miR-4782-5p/VEGFA axis.
Geranylated or prenylated flavonoids from Cajanus volubilis
RAO Li, SU Yu, HE Qian, YE Jia, LIU Yu, FAN Yue, HU Feng, ZHOU Zhen, GAN Li-She, ZHANG Yonghui, ZHANG Chuan-Rui
, Available online  , doi: 10.1016/S1875-5364(22)60215-2
Abstract:
Five new flavonoid derivatives, cajavolubones A–E ( 15 ), along with six known analogues ( 611 ) were isolated from Cajanus volubilis, and their structures were elucidated by spectroscopic data analysis and quantum chemical calculations. Cajavolubones A and B ( 1 and 2 ) were identified as two geranylated chalcones. Cajavolubone C ( 3 ) was a prenylated flavone, while cajavolubones D and E ( 4 and 5 ) were two prenylated isoflavanones. Compounds 3 , 8 , 9 and 11 displayed cytotoxicity against HCT-116 cancer cell line.
Deciphering suppressive effects of the Lianhua Qingwen capsule on COVID-19 and synergistic effects of its major botanical drug pairs
Chen Yuanyuan, Zhang Cheng, Wang Ning, Feng Yibin
, Available online  , doi: 10.1016/S1875-5364(22)60252-8
Abstract:
COVID-19 has resulted in persistent death worldwide. Conventional anti-viral medicines are used as symptomatic treatment with limited therapeutic effects, while the Lianhua Qingwen capsule is reported with remarkable anti-COVID-19 effects. Our review aims to: 1) uncover the main pharmacological actions of the Lianhua Qingwen capsule for treating COVID-19; 2) verify the bioactive ingredients and pharmacological actions of the Lianhua Qingwen capsule by network analysis; 3) gather studies to investigate the compatibility effects of major botanical drug pairs in the Lianhua Qingwen capsule; 4) clarify the clinical evidence and safety of the combined therapy of the Lianhua Qingwen capsule and conventional drugs. Numerous bioactive ingredients in the Lianhu Qingwen, such as quercetin, naringenin, β-sitosterol, luteolin, stigmasterol, etc., were identified to target host cytokine, regulate the immune defence in response to COVID-19. Genes including androgen receptor (AR), myeloperoxidase (MPO), epidermal growth factor receptor (EGFR), insulin (INS), and aryl hydrocarbon receptor (AHR) were found to be significantly involved in the pharmacological actions of the Lianhua Qingwen capsule against COVID-19. Four botanical drug pairs in the Lianhua Qingwen capsule were shown to have synergistic effects in treating COVID-19. Clinical studies demonstrated the medicinal effects of the combined use of the Lianhua Qingwen capsule and conventional drugs for treating COVID-19. In conclusion, four main pharmacological mechanisms of the Lianhua Qingwen capsule for managing COVID-19 are revealed. A therapeutic effect has been noted against COVID-19 in the Lianhua Qingwen capsule.
Polygalacin D inhibits the growth of hepatoma cells through BNIP3L-mediated mitophagy and endogenous apoptosis pathways
Nan Fulong, Nan Wenlong, Yu Zhongjie, Wang Hui, Cui Xiaoni, Jiang Shasha, Zhang Xianjuan, Li Jun, Wang Zhifei, Zhang Shuyun, Wang Bin, Li Yiquan
, Available online  , doi: 10.1016/S1875-5364(22)60249-8
Abstract:
Platycodon grandiflorum (Jacq.) A. DC. is a famous medicinal plant commonly used in East Asian countries. Triterpene saponins isolated from P. grandiflorum are the main biologically active compounds, among which Polygalacin D (PGD) has been reported to be an anti-tumor agent. However, its antitumor mechanism against liver cancer is unknown. This study aimed to explore the inhibitory effect and pathway of PGD in liver cancer cells. We found that PGD had a significant inhibitory effect on liver cancer cells through apoptosis and autophagy. Analysis of the expression of apoptosis-related proteins and autophagy-related proteins revealed that this phenomenon was caused by the mitochondrial apoptosis and mitophagy pathways. Subsequently, using specific inhibitors, we found that apoptosis and autophagy have mutually reinforcing effects. In addition, further analysis of autophagy showed that PGD can induce mitophagy by increasing BCL2 interacting protein 3 like (BNIP3L) levels. In vivo experiments demonstrated that PGD can significantly inhibit tumor growth and increase the levels of apoptosis and autophagy in tumors. Overall, our findings showed that PGD induces cell death of liver cancer cells primarily through mitochondrial apoptosis and mitophagy pathways. Therefore, PGD could be used as an apoptosis and autophagy agonist in the research and development of antitumor drugs.
Marsdenia tenacissima (Roxb.) Moon injection induces apoptosis of prostate cancer by regulating AKT/GSK3β/STAT3 signaling axis
LI Xiao-Lan, HE Song-Hua, LIANG Wei, ZHANG Wei-Quan, CHEN Xin, LI Qiao-Feng, YANG Xin, LIU Yan-Ying, ZHU Dan, LI Li, LIU Bu-Ming, SU Zhi-Heng, CHEN Jie, GUO Hong-Wei
, Available online  , doi: 10.1016/S1875-5364(22)60236-X
Abstract:
Marsdenia tenacissima (Roxb.) Moon injection, a standard Marsdenia tenacissima extract (MTE), has been approved for clinical use as an adjuvant therapeutic agent for various cancers. Our previous study showed that MTE inhibited the proliferation and metastasis of prostate cancer (PCa) cells. However, the underlying mechanisms and active ingredients of MTE against PCa have not been characterized. This study revealed that MTE induced significant decreases in cell viability and clonal growth in PCa cells. In addition, MTE induced apoptosis of DU145 cells by reducing the mitochondrial membrane potential and increasing the expression of Cleaved Caspase 3/7, Cyt c, and Bax. In vivo, DU145 xenografted NOD-SCID mice treated with MTE showed significantly decreased tumor size. TUNEL staining and Western blot confirmed the pro-apoptotic effects of MTE. Network pharmacology analysis collected 196 ingredients of MTE linked to 655 potential targets, and 709 PCa-associated targets were retrieved, from which 149 overlapped targets were screened. Pathway enrichment analysis showed that HIF-1, PI3K-AKT, and ErbB signaling pathways were closely related to tumor apoptosis. Western blot results confirmed that MTE increased the expression of p-AKTSer473 and p-GSK3βSer9, and decreased the expression of p-STAT3Tyr705 in vitro and in vivo. A total of 13 compounds in MTE were identified by HPLC-CAD-QTOF-MS/MS and UPLC-QTOF-MS/MS. Molecular docking analysis showed that six compounds may interact with AKT, GSK3β, and STAT3. In conclusion, MTE induced endogenous mitochondrial apoptosis of PCa by regulating the AKT/GSK3β/STAT3 signaling axis, resulting in the inhibition of PCa growth in vitro and in vivo.
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
Abstract:
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.
Anti-inflammatory sesquiterpene polyol esters from the stem and branch of Tripterygium wilfordii
Hu Ya-Lin, Xu Tian-Qi, Yin Wen-Jing, Cheng Huai-Yu, Zhang Xia, Liu Ying, Zhang Yu-Bo, Zhou Guang-Xiong
, Available online  , doi: 10.1016/S1875-5364(22)60218-8
Abstract:
The stem and branch extract of Tripterygium wilfordii (Celastraceae) afforded seven new dihydroagarofuran sesquiterpene polyesters [tripterysines A-G ( 1 - 7 )] and eight known ones ( 8 - 15 ). The chemical structures of new compounds were established based on combinational analysis of HR-ESI-MS and NMR techniques. The absolute configurations of tripterysines A-C ( 1 - 3 ) and E-G ( 5 - 7 ) were determined by X-ray crystallographic analysis and circular dichroism spectra. All compounds were screened for their inhibitory effects on inflammation by testing the inhibition of nitric oxide production in LPS-induced RAW 264.7 cells and the secretion level of inflammatory cytokines TNF-α and IL-6 in LPS-induced BV2 macrophages. Compound 9 exhibited significant inhibitory activity on NO production with IC50 values of 8.77 μM. Moreover, compound 7 showed the strongest inhibitory effect with the secretion level of IL-6 at 27.36%.
Maackiain inhibits proliferation and promotes apoptosis of nasopharyngeal carcinoma cells by inhibiting the MAPK/Ras signaling pathway
JIANG Xing, YANG Xiao-Nan, SHI Yan-Xia, LONG Yan, SU Wen-Qing, HE Wen-Dong, WEI Kun-Hua, MIAO Jian-Hua
, Available online  , doi: 10.1016/S1875-5364(22)60244-9
Abstract:
Nasopharyngeal carcinoma (NPC) is the third most common malignancy with a high recurrence and metastasis rate in South China. Natural compounds extracted from traditional Chinese herbal medicine have been developed and utilized for treating a variety of cancers with modest properties and slight side effects. Maackiain (MA) is a type of flavonoid that was first isolated from leguminous plants, and it has been reported to relieve various nervous system disorders and exert anti-allergic as well as anti-inflammatory effects. In this study, we demonstrated that MA could inhibit proliferation, arrest cell cycle and induce apoptosis in nasopharyngeal carcinoma CNE1 and CNE2 cells in vitro and in vivo. The expression levels of the related proteins associated with these processes were consistent with the above effects. Moreover, transcriptome sequencing and subsequent western blot experiments revealed that inhibition of MAPK/Ras pathway may be responsible to the anti-tumor effects of MA in NPC cells. Therefore, the effects of MA and an activator of this pathway, tertiary butylhydroquinone (TBHQ), alone or combination, were investigated. It was found that TBHQ could neutralize the inhibitory effects of MA. These data suggest that MA exerts its anti-tumor effects by inhibiting the MAPK/Ras signaling pathway and it has the potential to become a treatment for patients with NPC.
Qianjin Wenwu Decoction suppresses renal interstitial fibrosis by enhancing the degradation of extracellular matrix in mice with unilateral ureteral obstruction
Jin Chengshan, Wu Xiaotian, You Yue, Wang Yuling, Wu Jing, Zuo Along, Zheng Yan, Guo Jianpeng
, Available online  , doi: 10.1016/S1875-5364(22)60228-0
Abstract:
Diabetic kidney disease (DKD) is the most common complication of diabetes mellitus (DM). Qianjin Wenwu decoction (QWD), a well-known traditional korean medicine, has been clinically used to treat DKD in China with satisfactory therapeutic effects. This study aimed to investigate the active components and mechanisms of action of QWD in the treatment of DKD. The results demonstrated a total of 13 active components in five varieties of types were found in QWD, including flavonoids, flavonoid glycosides, phenylpropionic acids, saponins, coumarins, and lignins. Two key proteins, TGF-β1 and TIMP-1, were identified using molecular docking. QWD significantly suppressed Scr and BUN levels, which increased after unilateral ureteral obstruction (UUO) operation. Pathological observations implied the development of renal fibrosis. Hematoxylin & Eosin (H&E) and Masson's trichrome staining data demonstrated that QWD had a significant delaying effect on UUO-induced renal interstitial fibrosis. Furthermore, the results also showed that QWD could promote ECM degradation by regulating MMP-9/TIMP-1 homeostasis to improve renal tubulointerstitial fibrosis and interfere with the expression and activity of TGF-β1 in DKD treatment. This study clarified the mechanism of QWD treatment with DKD and provided a methodological reference for studying the mechanism of traditional medicine in treating DKD.
Seven 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)60208-5
Abstract:
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. Drimanenoids C ( 3 ), D ( 4 ) and F ( 6 ) showed antibacterial activity against five bacteria with different inhibition diameter. Drimanenoid D ( 4 ) exhibited moderate cytotoxicity against human myelogenous leukemia cell line K562 with IC50 values of 12.88±0.11 μM.
Nephroprotective mechanisms of Leontopodium leontopodioides (Willd.) Beauv extracts on lipopolysaccharide-induced models by the NF-κB/NLRP3 pathway
Bai Xue, Ma Qian Qian, Li Qi, Yin Mei Zhen, Xin Ying, Zhen Dong, Wei Chengxi
, Available online  , doi: 10.1016/S1875-5364(22)60232-2
Abstract:
Ethnopharmacological relevance: Sepsis-induced uncontrolled systemic inflammatory response syndrome (SIRS) is a critical cause of multiple organ failure. Acute kidney injury (AKI) is one of the most serious complications associated with an extremely high mortality rate in SIRS, and it lacks simple, safe, and effective treatment strategies. Leontopodium leontopodioides (Willd.) Beau (LLB) is a traditional Chinese medicine used in the treatment of acute and chronic nephritis. However, it remains unclear whether LPS affects LPS-induced AKI. To identify the effect and molecular mechanisms of LLB in LPS-induced HK-2 cells and mice. LLB was prepared through 70% methanol extract extraction. The lipopolysaccharide (LPS)-induced HK-2 cell model and an AKI model were established in this study. Renal histopathology staining was performed to observe the kidney morphology. Cell supernatant and the cells and kidney tissues were collected for determining the levels of inflammatory factors and protein expression analysis by ELISA, immunofluorescence, and Western blotting. Our results indicated that LLB could significantly reduce the expression of IL-6 and TNF-α in LPS-induced HK-2 cells, as well as the secretion of IL-6, TNF-α, and IL-1β in the supernatant. The same results were observed in the LPS-induced AKI serum. Further studies revealed that LLB could strongly improve oxidative stress and apoptosis based on the content of MDA, SOD, and CAT in the serum and from TUNEL staining results. Notably, LLB significantly reduced the mortality rate from LPS infection. Renal histopathology staining results supported these results. Furthermore, immunofluorescence and Western blotting confirmed that LLB could significantly reduce the expression of the protein related to the NF-κB signaling pathway and NLRP3, ASC, and Caspase-1, which were significantly increased through LPS stimulation. The cumulative results clearly validated the potential use of LLB in the treatment of AKI and the crucial role of the NF-κB/NLRP3 pathway in the process through which LLB attenuates the AKI induced by LPS.
Physiological and transcriptional responses to heat stress in a typical phenotype of Pinellia ternata
WANG Jia-Lu, CHEN Jia-Lei, ZHANG Xiang-Yu, FENG Xue, LI Xi-Wen
, Available online  , doi: 10.1016/S1875-5364(22)60250-4
Abstract:
Pinellia ternata is an important medicinal plant, its growth and development are easily threatened by high temperature. In this study, comprehensive research on physiological, cytological and transcriptional responses to different levels of heat stress were conducted on a typical phenotype of P. ternata. Firstly, P. ternata exhibited tolerance to the rosed temperature, which was supported by normal growing leaves, decreased and sustained photosynthetic parameters. Severe stress aggravated the damages, and P. ternata displayed obvious leaf senescence phenotype, significantly increased SOD and POD activities (46% and 213%). In addition, mesophyll cells were seriously damaged, chloroplast thylakoid was fuzzy, grana lamellae and stroma lamellae were obviously broken, and the grana thylakoids were stacked, resulting in dramatically declined photosynthetic rate (74.6%). Moreover, a total of 16,808 genes were significantly differential expressed during this process, and most of these genes were involved in photosynthesis, transmembrane transporter activity and plastid metabolism. The number of differentially expressed transcription factors in MYB and bHLH families was the largest, indicating that these genes might be participated in heat stress response in P. ternata. This study could provide insight into the response to high temperature and guide the standardized cultivation of P. ternata.
Antimalarial and neuroprotective ent-abietane diterpenoids from the aerial parts of Phlogacanthus curviflorus
LI Jia, MENG Xiao, YIN Cheng-Yue, ZHANG Li-Xia, LIN Bin, LIU Peng, ZHU Ling-Juan, WANG Hai-Feng, LIU Hong-Wei, ZHANG Xue, YAO Xin-Sheng
, Available online  , doi: 10.1016/S1875-5364(22)60258-9
Abstract:
Six undescribed ent-abietane diterpenoids, abientaphlogatones A–F (1-6), two undescribed ent-abietane diterpenoid glucosides, abientaphlogasides A–B (7-8), together with four known analogues were isolated from the aerial parts of Phlogacanthus curviflorus. Their structures were elucidated by HRESIMS, 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 , 7 - 10 and 12 displayed antimalarial activity in β-hematin formation inhibition assay with IC50 values of 12.97-65.01 μM. Compounds 4 , 5 , 8 and 10 showed neuroprotective activity in PC12 cells injury model induced by H2O2 and MPP + .
Modulation of type I interferon signaling by natural products in the treatment of immune-related diseases
Li Shuo, Fan Guifang, Li Xiaojiaoyang, Cai Yajie, Liu Runping
, Available online  , doi: 10.1016/S1875-5364(22)60227-9
Abstract:
As the first cytokine family to be described, type I interferon (IFN) is considered as a bridge between innate and adaptive immunity. Proper activation or inhibition of type I IFN signaling is essential for host defense against pathogens invasion, tumor cells proliferation, and overactive immune responses. Due to intricate and diverse chemical structures, natural products and their derivatives have become an invaluable source inspiring innovative drug discovery. In addition, some natural medicines have been applied in clinical practice for infection, cancer, and autoimmunity over thousands of years and their promising curative effects and safety have been well-accepted, although, whether these natural products are primarily targeting type I IFN signaling and specific molecular targets involved are not fully elucidated. In the current review, we thoroughly summarize recent advances in the pharmacology researches of natural products for their type I IFN activities, including both agonism/activation and antagonism/inhibition, and their potential application as therapies. Furthermore, the source and chemical nature of natural products with type I IFN activities are highlighted and their specific molecular targets in the type I IFN pathway and mode of action are classified. In conclusion, natural products possessing type I IFN activities represent promising therapeutic strategies and have a bright prospect in the clinical treatment of infection, cancer, and autoimmune diseases.
Targeted isolation and identification of bioactive pyrrolidine alkaloids from Codonopsis pilosula via using characteristic fragmentation-assisted mass spectral networking
TANG Xi-Yang, FAN Cai-Lian, ZENG Jia-Xing, ZHAO Peng-Cheng, WANG Xiao-Xing, CAI Wan-Jun, LI Ting, DAI Yi, YAO Zhi-Hong, YAO Xin-Sheng
, Available online  , doi: 10.1016/S1875-5364(22)60216-4
Abstract:
Codonopsis pilosula (CP), a well-known food medicine homology plant, is commonly used in many countries. In our preliminary study, a series of pyrrolidine alkaloids were detected as characteristic absorbed constituents in rat plasma after oral administration of CP extract with high MS response. However, their structures were unclear due to various isomers and lack of reference standards. In the present study, a MS-guided targeted isolation of pyrrolidine alkaloids of CP extract was performed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS). For data analysis under fast data directed acquisition mode (Fast-DDA), an effective approach named characteristic fragmentation-assisted mass spectral networking was successfully applied to discover new pyrrolidine alkaloids with high MS response in CP extract. As a result, seven new pyrrolizidine alkaloids (codonopyrrolidiums C–I ( 3–9 )), together with two known ones ( 1 and 2 ), were isolated and identified by NMR spectral analysis. Among them, codonopyrrolidium B ( 1 ), codonopyrrolidium D ( 4 ) and codonopyrrolidium E ( 5 ) were evaluated for lipid-lowering activity, and they could improve high fructose-induced lipid accumulation in HepG2 cells. In addition, the characteristic MS/MS fragmentation patterns of these pyrrolizidine alkaloids were investigated, and then, 17 pyrrolidine alkaloids were identified. This approach could accelerate novel natural products discovery and characterize a class of natural products with MS/MS fragmentation patterns from similar chemical scaffolds. The research also provides a chemical basis for revealing in vivo effective substances in CP.
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
Abstract:
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.
Chang Wei Qing decoction enhances the anti-tumor effect of the PD-1 inhibitor by regulating the immune microenvironment and gut microbiota in colorectal cancer
Wang Ting, Wu Linguangjin, Wang Shuyun, Shi Xiaolan, Liu Hui, Deng Wanli
, Available online  , doi: 10.1016/S1875-5364(22)60245-0
Abstract:
The anti-tumor effects of PD-1 inhibitor have long been shown to be strongly related to the tumor immune microenvironment (TIME). This study aimed to mechanistically assess whether Chang Wei Qing decoction (CWQ) can enhance the anti-tumor effect of the PD-1 inhibitor. The PD-1 inhibitor showed a significant anti-tumor effect in mismatch repair-deficient/microsatellite instable (dMMR/MSI) colorectal cancer (CRC), but not in mismatch repair-proficient/microsatellite stable (pMMR/MSS) CRC. Hence, immunofluorescence double-label staining was utilized to explore the difference in the TIME between dMMR/MSI and pMMR/MSS patients. Flow cytometry was used to analyze the T-lymphocytes in tumors from mice. Western blotting was used to measure the levels of the PD-L1 protein in mice tumors. The intestinal mucosal barrier was evaluated via hematoxylin-eosin staining and immunohistochemistry in mice. 16S rRNA-gene sequencing was used to examine the structure of the gut microbiota in mice. Subsequently, Spearman’s correlation analysis was used to analyze the relationship between the gut microbiota and TIME. The patients with dMMR/MSI had more CD8+T cells and higher levels of PD-1 and PD-L1. In vivo, CWQ enhanced the anti-tumor effect of the PD-1 inhibitor and increased the tumor infiltration of CD8+ and PD-1+CD8+ T cells. Additionally, combination of CWQ with the PD-1 inhibitor resulted in a lower inflammation in the intestinal mucosa than that induced by the PD-1 inhibitor alone. CWQ and the PD-1 inhibitor co-treatment upregulated PD-L1 potein and reduced the proportion of Bacteroides in the gut microbiota but increased the proportions of Akkermansia, Firmicutes, and Actinobacteria. Additionally, the populations of infiltrating CD8+PD-1+, CD8+, and CD3+ T cells were found to be positively correlated with the proportion of Akkermansia. Accordingly, CWQ modulates the TIME by modifying the gut microbiota and consequently enhances the anti-tumor effect of the PD-1 inhibitor.
Stigmasterol protects human brain microvessel endothelial cells from ischemia-reperfusion injury via suppressing EPHA2 phosphorylation
Li Suping, Xu Fei, Yu Liang, Yu Qian, Yu Nengwei, Fu Jing
, Available online  , doi: 10.1016/S1875-5364(22)60240-1
Abstract:
Stigmasterol is a plant sterol with anti-apoptotic antioxidation and anti-inflammation effects through multiple mechanisms. In this study, we further assessed whether it exerts protective effects on human brain microvessel endothelial cells (HBMEC) against ischemia-reperfusion injury and the possible underlying mechanisms. HBMEC was used for in vitro oxygen and glucose deprivation/reperfusion (OGD/R) model. Middle cerebral artery occlusion (MCAO) models were constructed in rats. The interaction between stigmasterol and EPHA2 was detected by surface plasmon resonance (SPR) technology and cellular thermal shift assay (CETSA). Our data showed that 10 μM stigmasterol treatment can significantly protect cell viability, alleviate the loss of tight junction proteins and attenuate in-vitro model of blood-brain barrier (BBB) damage induced by OGD/R. Subsequent molecular docking showed that stigmasterol might interact with EPHA2 at multiple sites, including T692, a critical gatekeep residue of this receptor. Exogenous ephrin-A1 (an EPHA2 ligand) exacerbated OGD/R-induced EPHA2 phosphorylation at S897, facilitated ZO-1/claudin-5 loss, and promoted in vitro BBB leakage. Stigmasterol treatment significantly attenuated these alterations. Rat middle cerebral artery occlusion (MCAO) models confirmed these protective effects in vivo. In summary, this study revealed that stigmasterol protects HBMEC against ischemia-reperfusion injury by maintaining cell viability, reducing tight junction protein loss, and attenuating BBB damage. These protective effects are at least meditated by its interaction with EPHA2 and the inhibiting effect on EPHA2 phosphorylation.
Hepatic metabolomics combined with network pharmacology approach to reveal the correlation of anti-depression effect and nourishing blood effect of Angelicae Sinensis Radix
Gong Wenxia, Xu Shaohua, Song Yapeng, Zhou Yuzhi, Qin Xuemei
, Available online  , doi: 10.1016/S1875-5364(22)60257-7
Abstract:
Angelicae Sinensis Radix (AS) has been proved to exert anti-depression effect (ADE) and nourishing blood effect (NBE) in rat model of depression. The correlation of two therapeutic effects and its underlying mechanisms deserved further study. The purpose of this study was to explore the underlying mechanisms of the correlation between ADE and NBE of AS based on hepatic metabonomics, network pharmacology and molecular docking. Metabolomics analysis found that 30 metabolites participate in 11 metabolic pathways were identified as potential metabolites for depression. Further principal component analysis and correlation analysis showed that glutathione, sphinganine, and ornithine were related to pharmacodynamics indicators including behavioral indicators and haematological indicators, indicating that metabolic pathways such as sphingolipid metabolism were in ADE and NBE of AS. Target-pathway network of depression and blood deficiency syndrome was constructed by network pharmacology analysis, and a total of 107 pathways were collected. 37 active components obtained from Ultra Performance Liquid Chromatography-Triple-Time of Flight Mass Spectrometer (UPLC-Triple-TOF/MS) in AS extract passed the filtering criteria were used for network pharmacology, and 46 targets were associated with ADE and NBE of AS. Pathway enrichment analysis further indicated that sphingolipid metabolism were in ADE and NBE of AS. Molecular docking analysis showed that the E-Ligustilide in AS extract had strong binding activity with target proteins (PIK3CA, PIK3CD) in sphingolipid metabolism. Besides, further analysis by western blotting verified that AS could modulate the expression of PIK3CA and PIK3CD on sphingolipid metabolism. Our results demonstrated that sphingolipid metabolic pathway was the core pathway in the mechanism of the correlation between ADE and NBE of AS.
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
Abstract:
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.
Lysohexaenetides A and B, linear lipopeptides from Lysobacter sp. DSM 3655 identified by heterologous expression in Streptomyces
XU Qiu-Shuang, ZOU Hao-Chen, PAN Chen, WANG Hao-Xin, SHEN Yue-Mao, LI Yao-Yao
, Available online  , doi: 10.1016/S1875-5364(22)60247-4
Abstract:
Lysobacter harbors a large number of cryptic biosynthetic gene clusters (BGCs), but only a few of them have been characterized. Here we report 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, two novel linear lipopeptides, lysohexaenetides A ( 1 ) and B ( 2 ), were identified from the recombinant strain S001-lsh. In addition, the biosynthetic pathway of lysohexaenetides was proposed, and the single-module LshA represents another example of entirely iterative bacteria PKSs. Since genetic manipulation tools for Lysobacter is still lacking, this study highlights the utility of heterologous expression system to uncover cryptic biosynthetic pathways in Lysobacter genomes.
Comprehensive chemical profiling and quantitative analysis of ethnic Yi medicine Miao-Fu-Zhi-Tong granules using UHPLC-MS/MS
LEI Xiao-Ying, ZHANG Chen, ZHAO Su-Qing, CHENG Shuo-Han, ZHOU Wen-Bin, XU Jia-Peng, ZHAN Ping, ZEPER Abliz
, Available online  , doi: 10.1016/S1875-5364(22)60223-1
Abstract:
Developing analytical methods for chemical components of natural medicines remains a challenge since its diversity and complexity. Miao-Fu-Zhi-Tong (MFZT) granules, an ethnic Yi herbal prescription, was consisted of 10 herbs and clinically applied to gouty arthritis (GA) therapy. Herein, a chemical profiling strategy comprising in-house library matching, molecular networking and MS/MS fragmentation behaviors validation based on ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was developed for the qualitative analysis of MFZT granules. A total of 207 compounds were thus identified or characterized in which a series of rare guanidine alkaloids were discovered and profiled into alkyl substituted or cyclic subtypes. Moreover, network pharmacology analysis indicated that MFZT’s anti-gout mechanism was mostly involved into the NF-κB signaling, NOD-like signaling and rheumatoid arthritis pathways with the synergistic effect of 84 potential active compounds. In addition, a quantitative analytical method was developed to simultaneously determine the 29 potential effective components. Among them, berberine, pellodendrine, 3-feruloylquinic acid, neoastilbin, isoacteoside and chlorogenic acid derivatives with higher concentration are proposed as chemical markers for quality control. These findings provide a holistic chemical basis for MFZT granules and assist in the development of effective analytical methods for herbal formulas of natural medicines.
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  
Abstract:
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.
10,11-dehydrocurvularin attenuates inflammation by suppressing NLRP3 inflammasome activation
Zhao Qun, Feng Meng-Yuan, Jin Shu, Liu Xiao-Bo, Li Sheng-Bao, Guo Jian, Cheng Xin-Ran, Zhou Guang-Biao, Yu Xian-Jun
, Available online  , doi: 10.1016/S1875-5364(22)60239-5
Abstract:
10,11-dehydrocurvularin (DCV) is a natural-product macrolide that has been shown to exert anti-inflammatory activity. However, the underlying mechanism of its anti-inflammatory activity remains poorly understood. Aberrant activation of the NLRP3 inflammasome is involved in diverse inflammation-related diseases, and it must be controlled. We showed that DCV specifically inhibited the activation of the NLRP3 inflammasome in association with reduced IL-1β secretion and caspase-1 activation but had no effects on the NLRC4 and AIM2 inflammasomes. Mechanistically, DCV disturbed the interaction between NEK7 and NLRP3, resulting in the inhibition of NLRP3 inflammasome activation. The C=C double bond of DCV is required for the NLRP3 inflammasome inhibition induced by DCV. Importantly, DCV ameliorates inflammation in vivo via inhibition of the NLRP3 inflammasome. Considering the findings together, our study revealed a novel mechanism through which DCV suppresses inflammation and indicates the potential use of DCV in NLRP3 inflammasome-driven inflammatory disorders.
Steroids and dihydroisocoumarin glycosides from Xylaria sp. KYJ-15 by the one strain many compounds strategy and their bioactivities
GAN Dong, LI Chen-Zhe, SHU Yan, WANG Jia-Peng, WANG Cheng-Yao, ZHU Li, YANG Yu-Jun, LIU Jia-Qi, HE Bi-Jian, CAI Le, DING Zhong-Tao
, Available online  , doi: 10.1016/S1875-5364(22)60231-0
Abstract:
The fungus Xylaria sp. KYJ-15 was isolated from Illigera celebica. Inspired by the one strain many compounds (OSMAC) strategy, the strain was fermented on potato and rice solid medium, respectively. As a result, two novel steroids, xylarsteroids A ( 1 ) and B ( 2 ), being both the first examples of C28-steroid with an unusual β- and γ-lactone ring, respectively, along with two new dihydroisocoumarin glycosides, xylarglycosides A ( 3 ) and B ( 4 ), were identified. Their structures were elucidated by spectroscopic methods, X-ray diffraction and electronic circular dichroism (ECD) experiments. All isolated compounds were evaluated for cytotoxic, DPPH radical scavenging, acetylcholinesterase inhibitory and antimicrobial activities. Compound 1 exhibited potent AChE inhibitory activity with an IC50 value of 2.61 ± 0.05 μM. The β-lactone ring unit of 1 is critical for its AChE inhibitory activity. The result that explored the interaction of 1 with AChE by molecular docking further confirmed this notion. In addition, Compounds 1 and 2 both exhibited obvious antibacterial activities against Bacillus subtilis with a minimum inhibitory concentration (MIC) of 2 μg/mL. Compounds 3 and 4 exhibited antibacterial activities against Staphylococcus aureus with MICs of 4 and 2 μg/mL, respectively, which also exhibited DPPH radical scavenging activities comparable to the positive control with IC50 values of 9.2 ± 0.03 and 13.3 ± 0.01 μM, respectively.
Five new spirosterol saponins from Allii Macrostemonis Bulbus
Wang Rong, Wang Lulu, Zhang Manli, Guo Yadi, Zhang Jing, Ma Guoxu
, Available online  , doi: 10.1016/S1875-5364(22)60229-2
Abstract:
Five new spirostanol saponins ( 1-5 ), seven known compounds ( 6-12 ), were isolated from the n-butanol fraction of ethanol extract of Allii Macrostemonis Bulbus. The identification and structural elucidation of all the isolates were based on a combination of extensive 1D- and 2D-NMR experiments, HR-ESI-MS data analysis and comparisons with literature reports. Antioxidant evaluation showed that compounds 6-11 exhibited certain scavenging effects on ABTS radical, compounds 6, 7 and 11 with IC50 values of 0.208 mg·mL−1、0.057 mg·mL−1 and 0.014 mg·mL−1, respectively.
Potentilla anserina L. polysaccharide alleviates cadmium-induced oxidative stress and apoptosis of H9c2 cells by regulating the MG53-mediated RISK pathway
Zhao Li-xia, Cheng Ju, Liu Di, Gong Hong-xia, Bai De-cheng, Sun Wei
, Available online  , doi: 10.1016/S1875-5364(22)60256-5
Abstract:
Oxidative stress plays a crucial role in cadmium (Cd)‐induced myocardial injury. Mitsugumin 53 (MG53) and its mediated reperfusion injury salvage kinase (RISK) pathway have been demonstrated to be closely related to myocardial oxidative damage. Potentilla anserina L. polysaccharide (PAP) is a polysaccharide endowed with antioxidant capacity and the ability to incur a protective effect on Cd‐induced kidney damage. However, it remains unknown whether PAP can prevent and treat Cd‐induced cardiomyocyte damages. The present study explored the impact of PAP on Cd‐induced damage in H9c2 cells based on MG53 and the mediated RISK pathway. For in vitro evaluation, cell viability and apoptosis rate were analyzed by CCK‐8 assay and flow cytometry, respectively. Furthermore, the status of oxidative stress was detected by 2′,7′-dichlorodihydrofluorescein diacetate (DCFH‐DA) staining and by using superoxide dismutase (SOD), catalase (CAT), and glutathione/oxidized glutathione (GSH/GSSG) kits. The Mitochondrial function was measured by JC‐10 staining and ATP detection assay. Western blotting was performed to detect the expression of proteins related to MG53, the RISK pathway,and apoptosis. The results of the study revealed that Cd could increase the levels of reactive oxygen species (ROS) in H9c2 cells. Cd decreased the activities of SOD and CAT and the ratio of GSH/GSSG, resulting in a decrease in cell viability and an increase in apoptosis. Interestingly, PAP could reverse Cd‐induced oxidative stress and cell apoptosis. Meanwhile, Cd reduced the expression of MG53 in H9c2 cells and inhibited the RISK pathway, which was mediated by a decrease in the ratio of p-AktSer473/Akt, p-GSK3βSer9/GSK3β and p‐ERK1/2/ERK1/2. In addition, Cd impaired mitochondrial function, which involved a reduction in ATP content and mitochondrial membrane potential (MMP), and an increase in the ratio of Bax/Bcl‐2, cytoplasmic Cytochrome c/mitochondrial Cytochrome c, and Cleaved-Caspase 3/Pro-Caspase 3. Importantly, PAP alleviated Cd‐induced MG53 reduction, activated the RISK pathway, and reduced mitochondrial damage. Interestingly, knockdown of MG53 or inhibition of the RISK pathway attenuated the protective effect of PAP on Cd‐induced H9c2 cells. Altogether, PAP could reduce Cd‐induced damage in H9c2 cells, which was mediated by an increase in the MG53 expression and activation of the RISK pathway.
Ephedra herb extract ameliorates adriamycin-induced nephrotic syndrome in rats via the CAMKK2/AMPK/mTOR signaling pathway
Zhang Yuhan, Zeng Mengnan, Li Benke, Zhang Beibei, Cao Bing, Wu Yuanyuan, Ye Shan, Xu Ruiqi, Zheng Xiaoke, Feng Weisheng
, Available online  , doi: 10.1016/S1875-5364(22)60255-3
Abstract:
Objective: This study aimed to investigate the effects and mechanisms of Ephedra herb (EH) extract on adriamycin-induced nephrotic syndrome (NS), providing an experimental basis for the clinical treatment of NS. Methods: Hematoxylin and eosin staining, creatinine, urea nitrogen, and kidney injury molecule-1 were used to evaluate the activities of EH extract on kidney function. The levels of inflammatory factors and oxidative stress were detected by kits. The levels of reactive oxygen species, immune cells, and apoptosis were measured by flow cytometry. A network pharmacological approach was used to predict the potential targets and mechanisms of EH extract in the treatment of NS. The protein expression levels of apoptosis-related proteins and CAMKK2, p-CAMKK2, AMPK, p-AMPK, mTOR, p-mTOR were detected in the kidney by western blotting. The effective material basis of EH extract was screened by MTT method. The AMPK pathway inhibitor (compound C, CC) was added to investigate the effect of the potent substance base on adriamycin-induced cell injury. Results: The results showed that EH extract significantly improved kidney injury and reduced the levels of inflammation, oxidative stress, apoptosis in rats. Network pharmacology and Western blotting results show that EH extract treatment of NS may be via the CAMKK2/AMPK/mTOR signaling pathway. Moreover, it showed that methylephedrine (LH) significantly ameliorated adriamycin-induced NRK-52e cell injury. Methylephedrine also significantly improved the phosphorylation of AMPK and mTOR, but CC blocked these effects. Discussion and Conclusion: EH extract may ameliorate kidney injury through the CAMKK2/AMPK/mTOR signaling pathway. Moreover, methylephedrine may be one of the material bases of EH extract.
Guijiajiao (Colla Carapacis et Plastri, CCP) improved spermatogenic ability of male infertility rats by gut microbiota
Sheng Wen, Xu Wenjing, Ding Jin, Lu Baowei, Liu Lumei, He Qinghu, Zhou Qing
, Available online  , doi: 10.1016/S1875-5364(22)60253-X
Abstract:
Objective : Male factors cause infertility in about 50 percent of couples unable to conceive, leading to severe psychosocial and marital stress. Guijiajiao (Colla Carapacis et Plastri, CCP) was often used to treat male infertility. This study attempted to explore the potential mechanisms of CCP in the prevention of male infertility. Methods : Cyclophosphamide (CTX) was used to construct male infertile rat model, and CCP was given for treatment and prevention. Fecal microbiota transplantation (FMT) was also performed to explore the role of gut microbiota in CCP to prevent male infertility rats. Semi-automatic sperm classification analyzer was used to detect sperm motility and concentration. The pathological changes of small intestine and testis were analyzed by HE staining. Serum LPS and testosterone levels were measured by ELISA. CD3 expression in small intestine was detected by immunohistofluorescence. The expression of IL-1β, CD3, MCP-1 and CXCL-10 in small intestine and epididymis were detected by RT-qPCR. Gut microbiota was analyzed by 16S rRNA sequencing. Results : CCP improved sperm motility, number and sperm concentration in CTX-induced male infertility rats. CCP increased the serum testosterone level, inhibited the immune cell infiltration of intestinal lamina propria, and promoted the aggregation of CD3 + T cells in CTX-induced male infertility rats. CCP inhibited the expression of MCP-1, CXCL-10 and IL-1β in epididymis of male infertility rats. At the genus level, CTX induced a decrease in Lactobacillus, Clostridia_UCG.014 and Romboutsia in the intestinal tract of rats. CCP induced the decrease of Ruminococcus, and the increase of Romboutsia in male infertility rats. FMT proved that the gut microbiota of CCP promoted the recovery and spermatogenesis of testicular tissue, and reduced the serum LPS level of male infertility rats. Conclusion : CCP improved spermatogenic ability of male infertility rats by restoring gut microbiota diversity and inhibiting epididymal inflammation.
Antimicrobial indole alkaloids from Tabernaemontana corymbosa
FAN Kun, ZHANG Lan-Chun, TAN Bang-Yin, Guy S.S. Njateng, QIN Ma-Long, GUO Rui-Rong, HUANG Xiao-Juan, DING Cai-Feng, GAO Wei-Min, ZHANG Rong-Ping, YU Hao-Fei
, Available online  , doi: 10.1016/S1875-5364(22)60222-X
Abstract:
Four unreported monoterpene indole alkaloids, tabernaecorymines B–E ( 14 ), together with twenty-one known indole alkaloids ( 525 ) were obtained from the stem bark of Tabernaemontana corymbosa. Their structures and absolute configurations were elucidated by extensive spectroscopy, quantum chemical calculations, DP4 + probability analyses and Mo2(OAc)4-induced electronic circular dichroism experiment. The antibacterial and antifungal activities of all compounds were evaluated and some of them showed significant activity against Staphylococcus aureus, Bacillus subtilis, Streptococcus dysgalactiae and Candida albicans.
Review
Bioactive peptides from scorpion venoms: therapeutic scaffolds and pharmacological tools
Peter Muiruri Kamau, ZHONG Jian, YAO Bing, LAI Ren, LUO Lei
, Available online  , doi: 10.1016/S1875-5364(22)60221-8
Abstract:
Evolution and natural selection have accorded animal venoms, including scorpion venoms, a wide range of pharmacological properties. Consequently, scorpions, their venoms, and/or their body parts have been used since time immemorial in traditional medicines, especially in Africa and Asia. Considering their pharmacological potential and significance, bioactive peptides from scorpion venoms have been an important source of scientific research. Additionally, with the rapid increase in the characterization of various components from scorpion venoms, plentiful peptides have been identified with an aim of combating a myriad of emerging global health problems. Moreover, some scorpion venoms-derived peptides have been established as potential scaffolds helpful for drug development. In this review, we summarize the promising scorpion venoms-derived peptides as drug candidates. Accordingly, we highlight the data and knowledge needed for the continued characterization, and development of additional natural peptides from scorpion venoms, as potential drugs that can treat related ailments.
Potential of ginsenoside Rh2 and its derivatives as anti-cancer agents
LI Keke, LI Zhongyu, Men Lei, LI Wei, GONG Xiaojie
, Available online  , doi: 10.1016/S1875-5364(22)60193-6
Abstract:
As a steroid skeleton-based saponin, ginsenoside Rh2 (G-Rh2) is one of the major bioactive ginsenosides from the plants of genus Panax L. Many studies have reported the notable pharmacological activities of G-Rh2 such as anticancer, antiinflammatory, antiviral, antiallergic, antidiabetic, and anti-Alzheimer’s activities. Numerous preclinical studies have demonstrated the great potential of G-Rh2 in the treatment of a wide range of carcinomatous diseases in vitro and in vivo. G-Rh2 is able to inhibit proliferation, induce apoptosis and cell cycle arrest, retard metastasis, promote differentiation, enhance chemotherapy and reverse multi-drug resistance against multiple tumor cells. The present review mainly summarizes the anticancer effects and related mechanisms of G-Rh2 in various models as well as the recent advances in G-Rh2 delivery systems and structural modification to ameliorate its anticancer activity and pharmacokinetics characteristics.
Original article
Chemical Composition-Based Characterization of the Anti-Allergic Effect of Guominkang Formula on IgE-Mediated Mast Cells Activation and Passive Cutaneous Anaphylaxis
TANG Ding, WANG Chen, GAN Qianying, WANG Zhixin, JIANG Renwang
, Available online  , doi: 10.1016/S1875-5364(22)60225-5
Abstract:
Guominkang (GMK), a Chinese medicine formula, has been used to treat allergic diseases in clinical settings for many years. To evaluate the antiallergic effect and molecular mechanism of action of GMK extract, RBL-2H3 cell models and passive cutaneous anaphylaxis (PCA) mouse models were established. High performance liquid chromatography (HPLC) and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) analyses were performed to characterize the chemical composition of GMK. A total of 94 compounds were identified or tentatively identified from GMK. Three of them, emodin, ursolic acid, and hamaudol, were identified for the first time as potential active compounds in GMK, since they inhibited the degranulation of mast cells. The anti-allergic effect of hamaudol was the first to be discovered. GMK could markedly mitigate the shade of Evans Blue extravasation and ear incrassation in PCA mouse models. Additionally, GMK significantly inhibited the degranulation of mast cells, suppressed mast cell degranulation by reducing Ca2+ influx and the levels of TNF-α, IL-4, and histamine, and markedly inhibited the phosphorylation of Lyn, Syk, PLCγ1, IκBα, and NF-κB p65. Molecular docking results indicated that hamaudol and emodin had strong interaction with FcεRI and NF-κB related proteins, while ursolic acid only interacted with NF-κB associated proteins. These results suggest GMK suppresses the activation of MCs both in vivo and in vitro. The underlying mechanism of its anti-allergic activity is associated with the inhibition of FcεRI and NF-κB activation.
Berberine targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia with IDH1 mutation
HUANG Zhe, SHEN Yunfu, LIU Wenjun, YANG Yan, GUO Ling, YAN Qin, WEI Chengming, FAN Xianming, MA Wenzhe
, Available online  , doi: 10.1016/S1875-5364(22)60242-5
Abstract:
Metabolic reprogramming, a newly recognized trait of tumor biology, is an intensively studied prospect for oncology medicines. For numerous tumor and cancer cell subpopulations, oxidative phosphorylation (OXPHOS) is essential for their biosynthetic and bioenergetic functions. Cancer cells with mutations in isocitrate dehydrogenase 1 (IDH1) exhibit differentiation arrest, epigenetic and transcriptional reprogramming, and sensitivity to mitochondrial OXPHOS inhibitors. In this study, we report the discovery that berberine, which is widely used in China to treat intestinal infections, acted solely at the mitochondrial electron transport chain(ETC) complex I, and that its association with IDH1 mutant inhibitor (IDH1mi) AG-120 decreased mitochondrial activity and enhanced antileukemic efficacy in vitro and in vivo. Our study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia (AML) patients using combinatory mitochondrial targeted medicine, particularly those who relapse from or are resistant to after treatment with IDH1mi.
Houttuynia cordata polysaccharides alleviate ulcerative colitis by restoring intestinal homeostasis
CEN Lifeng, Yi Tong, HAO Yuanzhen, SHI Chenchen, SHI Xunlong, Lu Yan, CHEN Daofeng, ZHU Haiyan
, Available online  , doi: 10.1016/S1875-5364(22)60220-6
Abstract:
Houttuynia cordata is traditionally used as phytoantibiotics for treating lung disease in China. Houttuynia cordata polysaccharides (HCPs) have been reported to alleviate influenza virus-induced intestinal and lung immune injury by regulating the gut-lung axis. The present study aims to investigate the effects and mechanisms of HCPs on ulcerative colitis (UC). Male C57BL/6 mice were induced by dextran sodium sulfate (DSS) to establish the UC animal model. Our results showed that HCPs significantly reduced the weight loss and the shortening of colon length in colitis mice, and relieved the pathological damage of colon mucosa and inhibited the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, etc. It was suggested that HCPs could significantly improve DSS-induced colitis in mice. HCPs directly protected intestinal epithelial cells, ameliorated epithelial barrier dysfunction and cell apoptosis, which was also proved in H2O2 stimulated cell apoptosis model. HCPs inhibited inflammation in the colon, which was related to suppressing the infiltration of macrophages, inhibiting the expression of pro-inflammatory cytokines and proteins (TLR4, NF-κB), and restoring the dysfunction of Th17 and Treg cells. HCPs also restored the alteration of intestinal flora induced by DSS, increased the abundance of Firmicutes and Bacteroides, and reduced the abundance of Proteobacteria. This study confirmed the protective effect of Houttuynia cordata polysaccharide extracted from traditional Chinese medicine on ulcerative colitis, of which the mechanism was closely related to the maintenance of intestinal homeostasis (intestinal barrier , immune cells , and intestinal bacteria).
Five Rutaceae family ethanol extracts alleviate H2O2 and LPS-induced inflammation via NF-κB and JAK-STAT3 pathway in HaCaT cells
HONG Mengsa, XIAO Kun, LIN Pei, LIN Jun
, Available online  , doi: 10.1016/S1875-5364(22)60217-6
Abstract:
This study was designed to investigate the effects of five Rutaceae family ethanol extracts (FRFEE): Citrus medica Linn (CML), Citrus aurantium L. Cv. Daidai (CAD), Citrus medica Linn. var. sarcodactylis (Noot.) Swingle (CMS), Citrus sinensis (L) Osbeck (CSO) and Zanthoxylum bungeanum Maxim (ZBM) on retarding the progression of H2O2 and LPS-induced HaCaT cells. Cell inflammatory injury model was established by H2O2 and LPS. The alleviative effects of FRFEE were evaluated by detecting the activity of superoxide dismutase (SOD), glutathione (GSH) and the generation of reactive oxygen species (ROS). The inflammatory signaling pathways of NF-κB and JAK-STAT3 were detected by Western blotting, the mRNA expression levels of inflammatory factors and skin barrier factors were detected by RT-PCR. 50% ethanol extracts of five medicinal and food homologous herbs of Rutaceae family showed different levels of anti-oxidant and anti-inflammatory activities. The FRFEE effectively improved SOD and GSH content and decreased ROS levels. Meanwhile, FRFEE strongly suppressed two inflammatory signaling pathways NF-κB and JAK-STAT3. The RT-PCR examination of inflammatory factors and skin barrier factor revealed significant anti-inflammatory effects of FRFEE. It was worth noting that among the five extracts, Zanthoxylum bungeanum Maxim extract had the best anti-inflammatory and anti-oxidation effects. In addition, it could strongly inhibit the expression of psoriasis factor CCL20. In summary, these results suggested that Zanthoxylum bungeanum Maxim extract could be used as an anti-psoriatic agent in the treatment of psoriasis among FRFEE.
Original research
Screening the effective components in treating dampness stagnancy due to spleen deficiency syndrome and elucidating the potential mechanism of Poria water extract
LI Huijun, ZHANG Dandan, WANG Tianhe, LUO Xinyao, XIA Heyuan, PAN Xiang, HAN Sijie, YOU Pengtao, WEI Qiong, LIU Dan, ZOU Zhongmei, YE Xiaochuan
, Available online  , doi: 10.1016/S1875-5364(22)60237-1
Abstract:
Poria is an important medicine for inducing diuresis to drain dampness from the middle energizer. However, the specific effective components and the potential mechanism of Poria remain largely unknown. To identify the effective components and the mechanism of Poria water extract (PWE) to treat dampness stagnancy due to spleen deficiency syndrome (DSSD), a rat model of DSSD was established using weight-loaded forced swimming, intragastric ice-water stimulation, subjecting to a humid environment, and alternate-day fasting for 21 days. After 14 days of treatment with PWE, the results indicated that PWE could increase the fecal moisture percentage, urine output, D-xylose levels, and weight; amylase, albumin, and total protein levels; and the swimming time of rats with DSSD to different extents. Eleven highly related components were screened out using the spectrum-effect relationship and LC-MS. Mechanistic studies revealed that PWE could significantly increase the expression of serum motilin (MTL), gastrin (GAS), ADCY5/6, P-PKAα/β/γcat, and phosphorylated cAMP-response element binding protein in the stomach, and AQP3 expression in the colon. Moreover, it could decrease serum ADH levels, the expression of AQP3 and AQP4 in the stomach, AQP1 and AQP3 in the duodenum, and AQP4 in the colon. PWE could induce diuresis to drain dampness in rats with DSSD. Eleven main effective components were identified in PWE. They could exert a therapeutic effect by regulating the AC-cAMP-AQP signaling pathway in the stomach, MTL and GAS levels in the serum, AQP1 and AQP3 expression in the duodenum, and AQP3 and AQP4 expression in the colon.
Original aiticle
Er-xian ameliorates myocardial ischemia-reperfusion injury in rats through RISK pathway involving estrogen receptors
QIANG Mingmin, HAO Jiping, LIU Huihui, YIN Jia, ZHANG Hui, YANG Jinxin, MENG Hudie, CHEN Yuqing, GAO Yuqin
, Available online  , doi: 10.1016/S1875-5364(22)60213-9
Abstract:
Curculigo orchioides (CUR) and Epimedium (EPI) are traditional Chinese medicines with estrogen-like biological activity, called Xianmao and Xianlingpi (Er-xian) in Chinese. However, whether Er-xian exerts protective effects on myocardial ischemia-reperfusion injury (MIRI) is unknown. This study aimed to investigate the cardioprotective effects of Er-xian preconditioning against MIRI and the underlying mechanisms. CUR or EPI was administered intragastrically to aged female rats as a monotherapy or combination therapy. 2 weeks later, a rat MIRI model was established. Myocardial infarction size, myocardial morphology, cTnT, cell apoptosis rate, intracellular calcium concentration, mitochondrial permeability transition pore (MPTP) opening and reperfusion injury salvage kinase (RISK) signaling pathway molecules were observed after the surgery. To evaluate the mechanisms of Er-xian, estrogen receptors antagonists ICI 182780 and G15 were used. In this study, Er-xian notably alleviated myocardial tissue damage, maintained mitochondrial morphology, reduced infarct size and cardiac markers, and increased sera levels of E2. Moreover, Er-xian inhibited calcium overload and mPTP opening, and decreased cardiomyocyte apoptosis. We found that the dual therapy of CUR and EPI elicited more noticeable results than CUR or EPI monotherapy. The significant protective effects of Er-xian on ischemia-reperfusion myocardium were attributed to the up-regulation of AKT, ERK1/2 and GSK-3β phosphorylation levels. The cardioprotective effects of Er-xian were significantly reduced after estrogen receptor blockade, especially GPER30. These results indicate that Er-xian attenuates MIRI through RISK signaling pathway and estrogen receptors are the critical mediators.