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A novel natural compound Shikonin inhibits YAP function by activating AMPK
Yan Fang-Jie, Qian Mei-Jia, Luo Hong, Zeng Chen-Ming, Yuan Tao, He Qiao-Jun, Zhu Hong, Yang Bo
TMR Modern Herbal Medicine    2018, 1 (3): 136-142.   https://doi.org/10.12032/TMRmhm2017A26
Abstract ( 647 HTML PDF (517KB) ( 183 )  

Objective: Yes Associated Protein (YAP) is a downstream effector that negatively regulated by Hippo kinase LATS1/2. As a transcriptional coactivator, YAP controls the transactivation of variety target genes to promote cell proliferation which is a critical survival input for cancer cells, thus the inhibition of YAP function is a promising strategy to treat cancer patients. The aim of this study was to explore YAP inhibitors derived from natural products using a cell-based YAP-TEADs luciferase reporter assay and investigate the functional activities of the novel inhibitor. Methods: natural compounds were used by 8×GTIIC luciferase reporter assay to screen YAP inhibitor. Phosphorylation of YAP and AMPK were detected by Western Blotting. The target genes of YAP were determined through RT-PCR. Inhibition on HepG2 cells of screened compounds were assessed by the Sulforhodamine B (SRB) assay. Results: we found that Shikonin (derived from the traditional Chinese medical herb Zicao (Lithospermum erythrorhizon)) exerted significant suppression against the transcriptional activity of YAP (inhibition ratio=74.3%), accompanied with increased phosphorylation of YAP protein upon within short-exposure to cancer cells. Shikonin treated on HepG2 induced phosphorylation of AMPK. In HepG2 cell lines, Shikonin exhibited a profound cytotoxicity in a concentration manner. Conclusion: our results indicated that the inhibition activity of Shikonin on YAP function was probably due to the activation of AMPK by phosphorylation. Moreover, Shikonin exhibited potent cytotoxicity on cancer cells. In summary, the present study identifies Shikonin as a novel natural inhibitor of YAP function and could be an anti-cancer drug candidate for cancer treatment.

Highlights

Aberrant activation of YAP, a transcriptional co-activator, would result in the transactivation of target genes, and ultimately leading to the tumor development and malignance. Thus YAP has been regarded as a promising target for cancer therapy; however it has been challenged by the lack of effective inhibitors against YAP activity, particularly those origins from the natural resources. The current study identifies Shikonin, a natural compound derived from the traditional Chinese medical herb Zicao (Lithospermum erythrorhizon), as a potent inhibitor against YAP pathway so as to exert anti-cancer activities. And the YAP inhibitory effect was probably due to the activation of AMPK pathway.

HPLC Fingerprinting and Spectrum-antitumor Effect Relationship for Discrimination between Mylabrisphalerata Pallas and Mylabriscichorii Linnaeus
Zhang Jian-Yong, Chen Qi-Hong, Pei Xian, Yan Rong, Duan Can-Can, Liu Yun, Li Xiao-Fei
TMR Modern Herbal Medicine    2018, 1 (1): 11-18.   https://doi.org/10.12032/TMRmhm2017A11
Abstract ( 452 HTML PDF (764KB) ( 153 )  

Objective: Evaluation of discrimination between two Mylabris Species based on HPLC fingerprinting and spectrum-antitumor effect relationship. Methods: In this study, a simple and efficient high-performance liquid chromatography (HPLC) method integrating with chemometric analysis and spectrum-antitumor effect relationship was developed for discrimination between two species ofMylabris: Mylabrisphalerata Pallas (MP) and MylabriscichoriiLinnaeus (MC).Results: In the fingerprint analysis, 14 characteristic peaks were selected to assess the differences between MP and MC using the similarity and pattern recognition analysis using PCA and OPLS-DA. The HPLC chromatograms of samples from 10 regions of China showed differences between MP and MC, and 7 characteristic chemical markers were found. In the spectrum-antitumor effect relationship analysis, 4 activity markers played a vital role in decreasing the IC50 and might be the antitumor components of Mylabris by grey relational analysis and multivariate linear regression analysis. The chemometric analysis in combination with spectrum-effect relationship results indicated that peaks 2(cytosine), 4 (unknown) and 14 (unknown) were important differential markers for distinguishing the two species of Mylabris. Conclusion: The method is applicable, credible and more efficient to discriminate MP and MC, and will offer a new way for facilitating quality control of insect medicines.

Highlights

This study provides an applicable, credible and more efficient HPLC method for discriminating two Mylabris species. And, the HPLC fingerprinting and spectrum-antitumor effects were integrated and the three important differential markers were found for new marker ofMylabris.

Metabolites identification and quantification of antcin H in mice tumors after oral administration of the anticancer mushroom Antrodia camphorata
Li Zi-Wei, Ji Shuai, Li Bin, Wang Shuang, Tzeng Yew-Min, Qiao Xue, Ye Min
TMR Modern Herbal Medicine    2018, 1 (2): 40-50.   https://doi.org/10.12032/TMRmhm2017A15
Abstract ( 444 HTML PDF (1080KB) ( 131 )  

Objective:Antrodia camphorata (AC), a precious medicinal mushroom in Taiwan, is popularly used for adjuvant cancer therapy. This paper aims to clarify the metabolites which are present in tumor tissues after oral administration of AC in Sarcoma-180 tumor-bearing mice, as well as their contents in tumors. Methods:Tumors of Sarcoma-180 tumor-bearing mice were obtained at 1 h and 4 h after oral administration of AC extract, and the metabolites in the tumor homogenate samples were characterized using UHPLC-orbitrap/MS analysis. Then, a fully validated LC-MS/MS method was developed for quantitative analysis of the most abundant compounds in tumor tissues, namely (25R/S)-antcin H. Results:A total of 33 compounds were characterized in tumor homogenate samples including 28 prototypes of triterpenoids and 5 metabolites. Among them, (25R)-antcin H and (25S)-antcin H had the highest contents of 2.03 and 0.66 μg/g tumor tissues for the 1 h group, and 2.04 and 0.59 μg/g tumor tissues for the 4 h group, respectively. It was obvious that (25R)-antcin H had higher tumor affinity than (25S)-antcin H, since the content of (25R)-antcin H was lower than that of (25S)-antcin H in AC extract (P < 0.01). Conclusion:Triterpenoids can enter tumor tissues after oral administration of AC. Particularly, (25R)-antcin H showed higher exposure to tumor than (25S)-antcin H. These compounds could contribute to the anticancer activities of AC.

Highlights

Metabolites of Antrodia camphorata in mice tumor tissues were profiled by UHPLC-orbitrap/MS analysis for the first time after oral administration, and a total of 33 compounds were characterized. The most abundant compounds in tumor tissues, namely (25R)-antcin H and (25S)-antcin H, were quantified by a fully validated LC-MS/MS method. The results indicated that (25R)-antcin H had higher tumor affinity than (25S)-antcin H.

Antioxidative and antiapoptotic effects of (+)-clausenamide on acetaminophen-induced nephrotoxicity in mice
Yu Hong-Min, Wang Min, Yu Zong-Chao, Li Yi-Fang, Huang Chun-Xin, Han Fang-Xuan, Liu Fan-Na, He Rong-Rong
TMR Modern Herbal Medicine    2018, 1 (3): 127-135.   https://doi.org/10.12032/TMRmhm2017A20
Abstract ( 437 HTML PDF (727KB) ( 200 )  

Objective: (+)-Clausenamide ((+)-CLA), the active ingredient of wampee, was isolated from the leaves of Clausena lansium (Lour.) Skeels. This study aimed to evaluate the protective potential of (+)-CLA against acetaminophen (APAP)-induced nephrotoxicity in mice. Methods: Mice were divided into control, APAP, high-dose (+)-CLA, and low-dose (+)-CLA groups. Then, mice were preadministered (+)-CLA (50 and 100 mg/kg) for 5 consecutive days. After the last treatment, the animals received a single intraperitoneal injection of APAP (600 mg/kg). Renal histopathology was evaluated by staining with hematoxylin and eosin. The levels of malondialdehyde (MDA) and glutathione (GSH) and the activities of catalase (CAT) and superoxide dismutase (SOD) were determined using corresponding kits. Western blotting was used to analyze the expression of apoptosis-related proteins in renal tissue. Results: Administration of APAP increased serum creatinine and blood urea nitrogen levels in comparison with the control group. An increase in renal MDA level, depletion of GSH, and reductions in CAT and SOD activities in renal tissue indicated that APAP-induced kidney injury was mediated by oxidative stress. The expressions of Bax and caspase-3, cleavage of caspase-3, and cytoplasm cytochrome c levels were up-regulated in renal tissue, whereas Bcl-2 expression and mitochondrial cytochrome c levels were down-regulated in the APAP group, which revealed that APAP-induced kidney injury significantly increased cell apoptosis in renal tubules. The histopathology of kidney tissue supported these biochemical mechanisms. (+)-CLA can reverse changes in most of the abovementioned parameters and nearly restore the normal structure of the kidney. Conclusion: Oxidative stress and apoptosis are considered to be the mechanisms underlying APAP-induced nephrotoxicity. (+)-CLA could be a promising antidote for APAP-induced acute renal damage owing to its antioxidative and antiapoptotic effects.

Highlights

(+)-Clausenamide ((+)-CLA), an acid amide isolated from the leaves of Clausena lansium (Lour.) Skeels, significantly decreases creatinine and blood urea nitrogen levels and increases the antioxidative abilities. The underlying mechanisms of (+)-CLA were involved in improving the antioxidative and antiapoptotic effects. This study provides a basis to clinical application of (+)-CLA.

External application of Chinese medicine formula combined with analgesic drugs to treat lung squamous cell carcinoma pain: A case study with mixed methods
Chen Hong, Zhao Jun-Qiang, Jiao Yun-Lan, Wang Dou, Hao Yu-Fang
TMR Modern Herbal Medicine    2018, 1 (1): 29-34.   https://doi.org/10.12032/TMRmhm2017B03
Abstract ( 433 HTML PDF (212KB) ( 143 )  

Objective: To investigate the effectiveness of the external application of Chinese medicine combined with analgesic drugs to treat lung squamous cell carcinoma pain. Methods: A 54-year-old patient with upper lobe of the left lung squamous cell carcinoma was studied, who suffered from severe cancer pain with the initial numeric rating scale (NRS) 7 point when admitted. Exterior-use formula was applied to pain spot to relieve the pain. Mixed methods approach comprising NRS, Short-form of McGill Pain Questionnaire,quality of life scale, times of breakout pain, records of adverse reactions and semi-structured interviews were utilized to evaluate the effect.Results: With the combination use of the formula and analgesic drugs, the patient’s NRS score dropped from 7 to 3 point. Quality of life scale score improved from 33 to 42 point. Times of breakout pain reduced from twice to none. The amount of oxycodone decreased from 30 mg Bid to 10 mg Bid. No adverse effect appeared. The patient’s felt more energetic with good sleep and appetite. Conclusion: This formula is effective and safe for pain relief when combined with analgesic drugs, and may be a good option in dealing with local cancer pain. Future randomized, controlled studies are needed to better evaluate the efficacy.

Highlights

When treating cancer pain, analgesic drugs can induce adverse reaction, such as nausea and peptic ulcer. Chinese medicine provides diversified approaches to remit cancer pain. Combining analgesic drug with external Chinese medicine can reduce the dosage of analgesic drug and improve the efficacy. The present study introduceda combination of analgesic drug and external application formula consisting of Chinese medicine torelieve the lung squamous cell carcinoma pain.

Mangiferin ameliorates hyperglycemia by inhibiting oxidation and α-glucosidase activity
He Chi-Chi, Luo Zhuo, Wang Lu-Lu, Xiao Xu-Xian, Hu Jian-An, Li Yi-Fang, Kurihara Hiroshi, He Rong-Rong
TMR Modern Herbal Medicine    2018, 1 (1): 4-10.   https://doi.org/10.12032/TMRmhm2017A05
Abstract ( 429 HTML PDF (650KB) ( 111 )  

Objective: Mangiferin (MF) is a polyphenol isolated from the root of AnemarrhenaasphodeloidesBge.. This study was aimed to investigate the effects of MF on hyperglycemia in animal models of insulin resistance and streptozotocin (STZ)-induced diabetes. Methods: The diabetes mellitus model was established in mice by receiving a multiple hypodermic injection of hydrocortisone sodium succinate (HCSS) (70 mg/kg) or a single intravenous injection of STZ (130 mg/kg). Meanwhile MF at different dosage (50, 100 and 200 mg/kg) were oral administrated for consecutive 10 days. Data of blood glucose were collected at different time after intraperitoneal injection of insulin (0.5 U/kg) to investigate the insulin resistant. As well as the oxygen radical absorbance capacity (ORAC) and superoxide dismutase (SOD) activity of kidney were measured. The in vitro experiment was established to investigate the inhibitory capacity of MF to α-glucosidase.Results: Oral administration of MF significantly prevented insulin resistance caused by HCSS injection. STZ-induced diabetic symptoms were also improved, including fasting blood glucose, glycated hemoglobin, plasma triglycerides, hepatic glycogen, kidney SOD and ORAC level. The in vitro experiment demonstrated that MF had potent α-glucosidase inhibitory activity. Conclusion: The obtained results demonstrate that MF ameliorates insulin resistance and STZ-induced glucose metabolism disturbance. The MF exerts the protective effects through improving the antioxidant ability, promoting hepatic glycogen synthesis and inhibiting α-glucosidase activity.

Highlights

Mangiferin (MF), a polyphenol extracted from the root of AnemarrhenaasphodeloidesBge., significantly ameliorates insulin resistance and streptozotocin (STZ)-induced diabetic symptoms. Potential mechanisms were involved in improving the antioxidant ability and inhibiting α-glucosidase activity. This study provides corresponding evidence for the clinical application of mangiferin.

Neuroprotective Effect of Bu-Shen-Huo-Xue Extract against High Glucose-induced Apoptosis in PC12 Cells
Zhao Shao-Yang, Dong Xin, Tu Peng-Fei, Zeng Ke-Wu, Wang Xue-Mei
TMR Modern Herbal Medicine    2018, 1 (3): 143-154.   https://doi.org/10.12032/TMRmhm2017A21
Abstract ( 398 HTML PDF (1116KB) ( 167 )  

Objective: To investigate the neuroprotective effect of Bu-Shen-Huo-Xue (BSHX) extract, a polyherbal formula, against High Glucose (HG)-induced neurotoxicity in PC12 cells. Methods: Cell viability assay, Lactate Dehydrogenase (LDH) assay, Reactive Oxygen Species (ROS) detection, Hoechst 33258, Acridine Orange (AO)/Ethidium Bromide (EB) double stain and Mitochondrial Membrane Potential (MMP) assay were performed. In addition, Bax, Bcl-2, caspase-3, cleaved caspase-3, PARP, cleaved PARP, cytochrome c and Mitogen-Activated Protein Kinases (MAPKs) were detected by western blot. Results: BSHX extract increased cell viability and decreased LDH leakage in a concentration-dependent manner in HG-induced PC12 cells. Moreover, BSHX extract decreased the level of intracellular ROS, increased mitochondrial membrane potential, regulated the expressions of Bax and Bcl-2, and inhibited the release of cytochrome c from mitochondria. Furthermore, BSHX extract attenuated the activation of caspase-3 and PARP, and inhibited the phosphorylations of c-Jun N-terminal kinase (JNK) and p38 MAPKs. Conclusion: BSHX extract exhibited significant neuroprotective effect on HG-induced apoptosis in PC12 cells. This effect may be associated with the suppression of ROS generation as well as mitochondria-mediated caspase and JNK/p38 MAPK signaling pathways.

Highlights

High glucose (HG)-induced neurotoxicity is implicated in the pathology of diabetic encephalopathy (DE). In our study, Bu-Shen-Huo-Xue extract (BSHX), a polyherbal formula, exhibits neuroprotective activity on HG-induced PC12 cells and the possible mechanisms may be associated with the suppression of reactive oxygen species (ROS) generation as well as mitochondria-mediated caspase and JNK/p38 MAPK signaling pathways. This study provids a promising agent for the treatment of DE in clinical applications.

Pharmacological effects of Paeoniflorin and Albiflorin on IL-3, GM-CSF, IL-6 and TNF-α in the rats of syndrome of stagnation of liver qi and blood deficiency
Wang Cheng-long, Qin Yu-wang, Pan Shi-xia, Zhang Jian-jun, Teng Hong-li
TMR Modern Herbal Medicine    2018, 1 (3): 155-163.   https://doi.org/10.12032/TMRmhm2017A22
Abstract ( 387 HTML PDF (530KB) ( 143 )  

Objective: To observe the effect of paeoniflorin (PF), albiflorin (AF) on the hemogram, visceral index and hematopoiesis cytokine in the rats of syndrome of stagnation of liver qi and blood deficiency, and to discuss the material base and mechanism of effect of nourishing blood and smoothing the liver of Baishao (Radix Paeoniae Alba). Methods: Male SD rats were randomly divided into groups according to the sucrose preference test and body weight (n = 12). Except the normal control, the other groups were treated with the chronic stress stimulation combined with radiation respectively to establish the model of syndrome of stagnation of liver qi and blood deficiency. The body weight, visceral index and the quantity of Leucocyte, Red Blood Cells, Hemoglobin in peripheral hemogram were monitored, then plasma and serum were separated. Radioimmunoassay was used to analyze the levels of Lnterleukin-3, Granulocyte-macrophage Colony-stimulating Factor, Lnterleukin-6 and Tumor Necrosis Factor-α in plasma. Results: Compared with that of model group, 30 mg?kg-1 PF and 30 mg?kg-1 AF of the weight, spleen index, quantity of Leucocyte were increased significantly (P < 0.05, P < 0.01). The results of Radioimmunoassay showed that the levels of Interleukin-3 increased (P < 0.05, P < 0.05) and the levels of Tumor Necrosis Factor-α decreased in both 30 mg?kg-1 PF and 30 mg?kg-1 AF groups (P < 0.05, P < 0.05). Conclusion: The effect of PF and AF on the regulation of bone marrow hematopoietic system and immune system play a role in the blood of rats with syndrome of stagnation of liver qi and blood deficiency, which suggests that both of them are the main active ingredients of nourishing blood and smoothing the liver of Baishao.

Highlights

Baishao (Radix Paeoniae Alba), a well-known Chinese herbal, has been widely used in Chinese Medicine for thousands of years. And Paeoniflorin (PF), albiflorin (AF) are the main active ingredients of Baishao. PE and AF can significantly increase the body weight, spleen index, WBC count and IL-3 level in models of Syndrome of Stagnation of Liver Qi and Blood Deficiency. Experimental results show that the effect of PF and AF on the regulation of bone marrow hematopoietic system and immune system play a role in the blood of rats with syndrome of stagnation of liver qi and blood deficiency, which suggests that both of them are the main active ingredients of nourishing blood and smoothing the liver of Baishao.

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