Publications by authors named "Zhixiu Lin"

41 Publications

β-Patchoulene Ameliorates Water Transport and the Mucus Barrier in 5-Fluorouracil-Induced Intestinal Mucositis Rats the cAMP/PKA/CREB Signaling Pathway.

Front Pharmacol 2021 25;12:689491. Epub 2021 Aug 25.

School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China.

Intestinal mucositis (IM) is the main side effect observed in patients who receive cancer chemotherapy. The characteristics of ulceration, vomiting, and severe diarrhea cause patients to delay or abandon further treatment, thereby aggravating their progress. Hence, IM cannot be overlooked. -patchoulene (-PAE) is an active ingredient isolated from (Blanco) Benth (Labiatae) and has shown a marked protective effect against gastrointestinal diseases in previous studies. However, whether -PAE plays a positive role in IM is still unknown. Herein, we explore the effects and the underlying mechanism of -PAE against 5-fluorouracil (5-FU)-induced IM in IEC-6 cells and rats. -PAE significantly recovered cell viability, upregulated the IM-induced rat body weight and food intake and improved the pathological diarrhea symptoms. Aquaporin is critical for regulating water fluid homeostasis, and its abnormal expression was associated with pathological diarrhea in IM. -PAE displayed an outstanding effect in inhibiting aquaporin 3 (AQP3) the cAMP/protein kinase A (PKA)/cAMP-response element-binding protein (CREB) signaling pathway. Besides, inflammation-induced mucus barrier injury deteriorated water transport and aggravated diarrhea in IM-induced rats. -PAE's effect on suppressing inflammation and recovering the mucus barrier strengthened its regulation of water transport and thus alleviated diarrhea in IM-induced rats. In sum, -PAE improved IM in rats mainly by improving water transport and the mucus barrier, and these effects were correlated with its function on inhibiting the cAMP/PKA/CREB signaling pathway.
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http://dx.doi.org/10.3389/fphar.2021.689491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424048PMC
August 2021

Disease Status-Dependent Drug-Herb Interactions: NASH Lowered the Risk of Hepatotoxicity in Rats Coadministered With Simvastatin and J. Ellis.

Front Pharmacol 2021 23;12:622040. Epub 2021 Apr 23.

School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong.

Concurrent use of simvastatin (SV) and J. Ellis (GJ) was adopted in patients with multi-morbidity, such as stroke rehabilitation patients with NASH. Although hepatotoxicity has been reported in both of them and NASH could alter the pharmacokinetics of drugs/herbs, the interaction between SV and GJ and the related hepatotoxicity remained uninvestigated under neither healthy nor NASH condition. The current study aimed to evaluate the potential hepatotoxicity resulted from the interactions between SV and GJ in both healthy and NASH rats. Both healthy and NASH rats received two-week SV (p. o., 8.66 mg/kg, once daily) and/or GJ (p.o., 325 mg/kg, twice daily). Pharmacokinetic profiles of SV, simvastatin acid (SVA, active metabolite of SV), and geniposide (major component in GJ); hepatic Cyp2c11/Oatp1b2/P-gp expression; and biomarker levels of liver function, lipid levels, and liver histology were compared to demonstrate the interactions in rats. To explore the mechanism of the interaction-mediated hepatotoxicity, hepatic genipin-protein adduct content and iNOS/COX-1/COX-2 expressions from related groups were compared. Moreover, liver histology of healthy/NASH rats at 90 days after discontinuation of two-week GJ in the absence and presence of SV was evaluated to estimate the long-term impact of the interactions. GJ reduced the systemic exposures of SV and SVA by up-regulating the hepatic P-gp expression in healthy but not NASH rats. Meanwhile, SV increased the systemic exposure of geniposide inhibiting the activity of P-gp in both healthy and NASH rats. Although neither SV nor GJ induced hepatotoxicity in healthy rats, their co-treatment elevated serum ALT and AST levels, which may attribute to the aggravated genipin-protein adduct formation, inflammation infiltration, and iNOS/COX-1 expressions in the liver. In NASH rats, SV and/or GJ reduced serum ALT, AST, LDL/vLDL, and TC levels via alleviating hepatic inflammation infiltration and iNOS/COX-1 expressions. Moreover, in comparison to NASH rats, more severe fibrosis was observed in the livers of healthy rats at 90 days after discontinuation of two-week SV and GJ coadministration. Although interactions between SV and GJ induced short-term and long-term liver injuries in healthy rats, NASH condition in rats could lower such risk.
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http://dx.doi.org/10.3389/fphar.2021.622040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103205PMC
April 2021

Comparative analysis and phylogenetic investigation of Hong Kong Ilex chloroplast genomes.

Sci Rep 2021 Mar 4;11(1):5153. Epub 2021 Mar 4.

Li Dak Sum Yip Yio Chin R & D Centre for Chinese Medicine and Institute of Chinese Medicine, The Chinese University of Hong Kong, ShatinHong Kong, N.T., China.

Ilex is a monogeneric plant group (containing approximately 600 species) in the Aquifoliaceae family and one of the most commonly used medicinal herbs. However, its taxonomy and phylogenetic relationships at the species level are debatable. Herein, we obtained the complete chloroplast genomes of all 19 Ilex types that are native to Hong Kong. The genomes are conserved in structure, gene content and arrangement. The chloroplast genomes range in size from 157,119 bp in Ilex graciliflora to 158,020 bp in Ilex kwangtungensis. All these genomes contain 125 genes, of which 88 are protein-coding and 37 are tRNA genes. Four highly varied sequences (rps16-trnQ, rpl32-trnL, ndhD-psaC and ycf1) were found. The number of repeats in the Ilex genomes is mostly conserved, but the number of repeating motifs varies. The phylogenetic relationship among the 19 Ilex genomes, together with eight other available genomes in other studies, was investigated. Most of the species could be correctly assigned to the section or even series level, consistent with previous taxonomy, except Ilex rotunda var. microcarpa, Ilex asprella var. tapuensis and Ilex chapaensis. These species were reclassified; I. rotunda was placed in the section Micrococca, while the other two were grouped with the section Pseudoaquifolium. These studies provide a better understanding of Ilex phylogeny and refine its classification.
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http://dx.doi.org/10.1038/s41598-021-84705-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933167PMC
March 2021

Apoptotic activities of brusatol in human non-small cell lung cancer cells: Involvement of ROS-mediated mitochondrial-dependent pathway and inhibition of Nrf2-mediated antioxidant response.

Toxicology 2021 03 16;451:152680. Epub 2021 Jan 16.

Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, P.R. China; The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, P.R. China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, P.R. China.

Brusatol occurs as a characteristic bioactive principle of Brucea javanica (L.) Merr., a traditional medicinal herb frequently employed to tackle cancer in China. This work endeavored to unravel the potential anti-cancer activity and action mechanism of brusatol against non-small cell lung cancer (NSCLC) cell lines. The findings indicated that brusatol remarkably inhibited the growth of wild-type NSCLC cell lines (A549 and H1650) and epidermal growth factor receptor-mutant cell lines (PC9 and HCC827) in a dose- and time-related fashion, and profoundly inhibited the clonogenic capability and migratory capacity of PC9 cells. Treatment with brusatol resulted in significant apoptosis in PC9 cells, as evidenced by Hoechst 33342 staining and flow cytometric analysis. The apoptotic effect was closely related to induction of G0-G1 cell cycle arrest, stimulation of reactive oxygen species (ROS) and malondialdehyde, decrease of glutathione levels and disruption of mitochondrial membrane potential. Furthermore, pretreatment with N-acetylcysteine, a typical ROS scavenger, markedly ameliorated the brusatol-induced inhibition of PC9 cells. Western blotting assay indicated that brusatol pronouncedly suppressed the expression levels of mitochondrial apoptotic pathway-associated proteins Bcl-2 and Bcl-xl, accentuated the expression of Bax and Bak, and upregulated the protein expression of XIAP, cleaved caspase-3/pro caspase-3, cleaved caspase-8/pro caspase-8, and cleaved PARP/total PARP. In addition, brusatol significantly suppressed the expression of Nrf2 and HO-1, and abrogated tBHQ-induced Nrf2 activation. Combinational administration of brusatol with four chemotherapeutic agents exhibited marked synergetic effect on PC9 cells. Together, the inhibition of PC9 cells proliferation by brusatol might be intimately associated with the modulation of ROS-mediated mitochondrial-dependent pathway and inhibition of Nrf2-mediated antioxidant response. This novel insight might provide further evidence to buttress the antineoplastic efficacy of B. javanica, and support a role for brusatol as a promising anti-cancer candidate or adjuvant to current chemotherapeutic medication in the therapy of EGFR-mutant NSCLC.
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http://dx.doi.org/10.1016/j.tox.2021.152680DOI Listing
March 2021

Intestinal absorption and hepatic elimination of drugs in high-fat high-cholesterol diet-induced non-alcoholic steatohepatitis rats: exemplified by simvastatin.

Br J Pharmacol 2021 02 20;178(3):582-599. Epub 2020 Nov 20.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.

Background And Purpose: Altered drug pharmacokinetics is a significant concern in non-alcoholic steatohepatitis (NASH) patients. Although high-fat high-cholesterol (HFHC) diet-induced NASH (HFHC-NASH) rats could simulate the typical dysregulation of cholesterol in NASH patients, experimental investigation on the altered drug pharmacokinetics in this model are limited. Thus, the present study comprehensive investigates the nature of such altered pharmacokinetics using simvastatin as the model drug.

Experimental Approach: Pharmacokinetic profiles of simvastatin and its active metabolite simvastatin acid together with compartmental pharmacokinetic modelling were used to identify the key factors involved in the altered pharmacokinetics of simvastatin in HFHC-NASH rats. Experimental investigations via in situ single-pass intestinal perfusion and intrahepatic injection of simvastatin were carried out. Histology, Ces1 activities and mRNA/protein levels of Oatp1b2/CYP2c11/P-gp in the small intestine/liver of healthy and HFHC-NASH rats were compared.

Key Results: Reduced intestinal absorption and more extensive hepatic elimination in HFHC-NASH rats resulted in less systemic exposures of simvastatin/simvastatin acid. In the small intestine of HFHC-NASH rats, thicker intestinal wall with more collagen fibres, increased Ces1 activity and up-regulated P-gp protein decreased the permeability of simvastatin, accelerated the hydrolysis of simvastatin and promoted the efflux of simvastatin acid respectively. In the liver of HFHC-NASH rats, higher hepatic P-gp expression accelerated the hepatic elimination of simvastatin.

Conclusion And Implications: Altered histology, Ces1 activity and P-gp expression in the small intestine/liver were identified to be the major contributing factors leading to less systemic exposure of drugs in HFHC-NASH rats, which may be applicable to NASH patients.
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http://dx.doi.org/10.1111/bph.15298DOI Listing
February 2021

Bioactive natural compounds against human coronaviruses: a review and perspective.

Acta Pharm Sin B 2020 Jul 8;10(7):1163-1174. Epub 2020 Jun 8.

Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

Coronaviruses (CoVs), a family of enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, unusually large RNA genome, and unique replication capability. CoVs are known to cause various potentially lethal human respiratory infectious diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the very recent coronavirus disease 2019 (COVID-19) outbreak. Unfortunately, neither drug nor vaccine has yet been approved to date to prevent and treat these diseases caused by CoVs. Therefore, effective prevention and treatment medications against human coronavirus are in urgent need. In the past decades, many natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19.
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http://dx.doi.org/10.1016/j.apsb.2020.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278644PMC
July 2020

Is it safe to take Radix Salvia Miltiorrhiza - Radix Pueraria Lobate product with warfarin and aspirin? A pilot study in healthy human subjects.

J Ethnopharmacol 2020 Nov 28;262:113151. Epub 2020 Jul 28.

School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. Electronic address:

Ethnopharmacological Relevance: Radix Salvia Miltiorrhiza (Danshen) and Radix Pueraria Lobate (Gegen) are officially listed in the Chinese Pharmacopoeia and have long been used together as a Compound Chinese Traditional Medicine (CCTM) for treatment of coronary heart diseases, which are often co-administered with aspirin or warfarin to patients suffering from cardiovascular diseases.

Aim Of Study: Since significant pharmacokinetic and pharmacodynamic interactions between Danshen-Gegen (DG) formula and aspirin/warfarin have been observed in our previous rat studies, the current study was proposed aiming to further verify such pharmacokinetic and pharmacodynamic interactions in healthy human subjects and explore related mechanisms.

Materials And Methods: A 5-day, multiple dose, five-session clinical trial has been carried out (n = 14) with 2-week washout periods between sessions, during which the subjects would receive different combinations of the medications. Plasma samples were collected for pharmacokinetic evaluation, and whole blood samples were collected for pharmacodynamic evaluation. In addition, an in-vitro mechanistic study is conducted to investigate the role of danshensu on the anti-thrombotic and anti-platelet aggregation effects of warfarin and aspirin respectively.

Results: Significant pharmacokinetic and pharmacodynamic herb-drug interactions were observed in healthy human subjects. pharmacokinetically, co-administration of DG with aspirin or warfarin could lead to a moderately increased AUC of aspirin and a decreased AUC of 7-hydroxyl warfarin respectively. The systemic exposure of danshensu (DSS, the marker component of DG) would be significantly increased after co-administration with warfarin. Pharmacodynamically, a reduction in systemic thromboxane B2 concentration was noticed after administration of DG with aspirin, which could be associated with the increased systemic exposure of aspirin and the synergistic effect of danshensu, aspirin and salicylic acid on cyclooxygenase (COX) inhibition. An offset on the warfarin induced soluble thrombomodulin induction was observed after its co-administration with DG, which could be partially attributed to the COX-2 inhibition effect of danshensu.

Conclusion: Our results indicated that co-administration of DG with aspirin/warfarin would lead to significant pharmacokinetic and pharmacodynamic herb-drug interactions in healthy human subjects.
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http://dx.doi.org/10.1016/j.jep.2020.113151DOI Listing
November 2020

Anti-aging role of Chinese herbel medicine: an overview of scientific evidence from 2008 to 2018.

Ann Palliat Med 2020 May 28;9(3):1230-1248. Epub 2020 Apr 28.

Institute of Geriatric Medicine, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China.

The aging of the population has become a global health problem. It is an important risk factor for major diseases such as cardiovascular disease, Alzheimer's disease, Parkinson's disease, and cancer. Presently, there is no definite and effective anti-aging treatment. Chinese herbal medicine has a long history of application and is often used for aging-related diseases in China. A large number of clinical and preclinical studies on the anti-aging effect of Chinese herbal medicine has been performed. Through literature research, we reviewed the anti-aging clinical research of Chinese herbal medicine and preclinical research of Chinese herbal medicine monomers, components, extracts, and compounds, and their mechanisms. Results from preclinical studies have shown that Chinese herbal medicines have beneficial anti-aging effects. The mechanism mainly includes anti-oxidative stress, anti-inflammatory, neuroprotection, apoptosis and mitochondrial function regulation, etc. However, more detailed high-quality clinical trials are required for future investigation of the anti-aging effects of Chinese herbal medicines.
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http://dx.doi.org/10.21037/apm.2020.04.09DOI Listing
May 2020

Significant combination of Aβ aggregation inhibitory and neuroprotective properties in silico, in vitro and in vivo by bis(propyl)-cognitin, a multifunctional anti-Alzheimer's agent.

Eur J Pharmacol 2020 Jun 20;876:173065. Epub 2020 Mar 20.

Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China. Electronic address:

Inhibition of Aβ aggregation and neurotoxicity has been developed as an attractive therapeutic strategy to combat Alzheimer's disease (AD). Bis(propyl)-cognitin (B3C) is a multifunctional dimer derived from tacrine. Herein, the anti-aggregation and disassembly effects of B3C on Aβ, together with the neuroprotective effects and underlying mechanisms of B3C against Aβ-induced neurotoxicity were investigated in silico, in vitro and in vivo. Data from Thioflavin-T fluorescence and atomic force microscopy assays indicated that B3C (1-10 μM), but not its monomer tacrine, greatly inhibited the formation of Aβ fibrils and disaggregated pre-formed mature Aβ fibrils. Comparative molecular dynamics simulation results revealed a possible binding mode that prevented Aβ fibrils formation, showing that B3C favorably bound to Aβ via hydrophobic interactions. Additionally, B3C was able to block the neurotoxicity caused by Aβ fibrils in cultured PC12 cells. Very encouragingly, B3C (0.3 and 0.45 mg/kg) markedly alleviated the cognitive impairments in rats insulted by intra-hippocampal injection of Aβ fibrils, more potently than tacrine (1 and 2 mg/kg). Furthermore, mechanistic studies demonstrated that B3C reversed the inhibition of phospho-GSK3β at Ser site in vitro and in vivo caused by Aβ, suggesting the neuroprotection of B3C was achieved through the inhibition of GSK3β pathway. These findings indicate that B3C could serve as an effective inhibitor of Aβ aggregation and neurotoxicity, and provide novel molecular insights into the potential application of B3C in AD prevention and treatment.
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http://dx.doi.org/10.1016/j.ejphar.2020.173065DOI Listing
June 2020

Patchouli alcohol attenuates 5-fluorouracil-induced intestinal mucositis via TLR2/MyD88/NF-kB pathway and regulation of microbiota.

Biomed Pharmacother 2020 Apr 28;124:109883. Epub 2020 Jan 28.

Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China. Electronic address:

Intestinal mucositis causes great suffering to cancer patients who undergo chemotherapy and radiotherapy. Owing to the uncertain side effects of anticancer drugs to attenuate patients' intestinal mucositis, many studies focused on traditional Chinese medicine (TCM). Patchouli alcohol (PA) is an active compound extracted from Pogostemon cablin, and has potent gastrointestinal protective effect. However, whether PA has an effect on intestinal mucositis is still unknown. Therefore, we established a rat model of intestinal mucositis via intraperitoneal injection of 5-fluorouracil, and intragastrically administrated PA (10, 20, and 40 mg/kg) to evaluate the effect of PA on intestinal mucositis. The routine observation (body weight, food intake, and diarrhea) in rats was used to detect whether PA had an effect on intestinal mucositis. Levels of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10, and MPO), mucosal barrier proteins (zonula occludens -1 (ZO-1), claudin-1, occludin, myosin light chain (MLC), and mucin-2) and intestinal microbiota were determined to elucidate the underlying mechanism of PA action on intestinal mucositis in rats. The results showed that PA could effectively improve body weight, food intake, and diarrhea in intestinal mucositis rats, preliminary confirming PA efficacy. Further experiments revealed that PA not only decreased the levels of TNF-α, IL-1β, IL-6, and MPO but also increased the level of IL-10 significantly. In addition, the expression of mucosal barrier proteins and microbiota community were also improved after PA treatment in diseased rats. Hence, PA may prevent the development and progression of intestinal mucositis by improving inflammation, protecting mucosal barrier, and regulating intestinal microbiota.
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http://dx.doi.org/10.1016/j.biopha.2020.109883DOI Listing
April 2020

Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway.

Pharmacol Res 2020 02 19;152:104603. Epub 2019 Dec 19.

Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China. Electronic address:

Berberine (BBR), a naturally-occurring isoquinoline alkaloid isolated from several Chinese herbal medicines, has been widely used for the treatment of dysentery and colitis. However, its blood concentration was less than 1 %, and intestinal microflora-mediated metabolites of BBR were considered to be the important material basis for the bioactivities of BBR. Here, we investigated the anti-colitis activity and potential mechanism of oxyberberine (OBB), a novel gut microbiota metabolite of BBR, in DSS-induced colitis mice. Balb/C mice treated with 3 % DSS in drinking water to induce acute colitis were orally administrated with OBB once daily for 8 days. Clinical symptoms were analyzed, and biological samples were collected for microscopic, immune-inflammation, intestinal barrier function, and gut microbiota analysis. Results showed that OBB significantly attenuated DSS-induced clinical manifestations, colon shortening and histological injury in the mice with colitis, which achieved similar therapeutic effect to azathioprine (AZA) and was superior to BBR. Furthermore, OBB remarkably ameliorated colonic inflammatory response and intestinal epithelial barrier dysfunction. OBB appreciably inhibited TLR4-MyD88-NF-κB signaling pathway through down-regulating the protein expressions of TLR4 and MyD88, inhibiting the phosphorylation of IκBα, and the translocation of NF-κB p65 from cytoplasm to nucleus. Moreover, OBB markedly modulated the gut dysbiosis induced by DSS and restored the dysbacteria to normal level. Taken together, the result for the first time revealed that OBB effectively improved DSS-induced experimental colitis, at least partly through maintaining the colonic integrity, inhibiting inflammation response, and modulating gut microflora profile.
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http://dx.doi.org/10.1016/j.phrs.2019.104603DOI Listing
February 2020

Erastin decreases radioresistance of NSCLC cells partially by inducing GPX4-mediated ferroptosis.

Oncol Lett 2019 Mar 4;17(3):3001-3008. Epub 2019 Jan 4.

Department of Head and Neck Cancer, Oncology Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524000, P.R. China.

The aim of the present study was to examine whether erastin influences radioresistance in non-small cell lung cancer (NSCLC) cells and produce a preliminary investigation into its mechanism of action. The radioresistant subtype of NSCLC cells, A549-R and H460-R, were induced by high-dose hypofractionated irradiation. Erastin was used to treat the radioresistant cells and radiosensitivity was examined by colony formation assays. Cell death was determined after the cells were treated with erastin, irradiation (IR) or erastin together with IR. The expression of glutathione peroxidase 4 (GPX4) expression in the parental cells and radioresistance cells was detected by western blotting. GPX4 expression in the radioresistance cells was subsequently inhibited, radiosensitivity and cell death was measured, and erastin enhanced radiosensitivity in A549-R and H460-R cells. Erastin and IR exhibited a combined effect on killing cells, as co-treatment with erastin and IR demonstrated a higher effect on killing cells compared with erastin or IR alone. GPX4 expression was inhibited by erastin in the radioresistant cells. Inhibiting GPX4 expression also radiosensitized NSCLC cells to radiation in the radioresistant cell lines. Erastin-induced and GPX4-inhibition-induced cell death could partially be rescued by deferoxamine, but not Z-VAD-FMK and olaparib, which indicated that erastin and GPX4-inhibition induced ferroptosis in the radioresistant cells. Erastin decreased radioresistance of NSCLC cells partially by inducing GPX4-mediated ferroptosis.
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http://dx.doi.org/10.3892/ol.2019.9888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365906PMC
March 2019

Chinese Herbal Medicine Effectively Prolongs the Overall Survival of Pancreatic Cancer Patients: A Case Series.

Integr Cancer Ther 2019 Jan-Dec;18:1534735419828836

1 The Chinese University of Hong Kong, Shatin New Town, Hong Kong.

Background And Aims: Pancreatic cancer has the lowest survival rate of all cancers (4%), and it accounts for 1.9% of new cancer cases in Hong Kong. Combined treatment with Chinese herbal medicine (CHM) and Western medicine has yielded promising results, leading to improved prognosis and overall survival. This retrospective case series aimed to illustrate the improved survival and quality of life outcomes of pancreatic cancer patients administered CHM based on traditional Chinese medicine theory.

Methods: To investigate the effectiveness of CHM in prolonging overall survival, 182 patients diagnosed with pancreatic cancer who received CHM treatment were observed from 2005 to 2015.

Results: One hundred eighty-two pancreatic cancer patients were treated with CHM; 21 patients died. The mean and median survival of these patients were 29.6 and 15.2 months, respectively; the 1-year survival rate was 76% (range = 4 months to 9 years). These results are better than those reported in patients treated with Western medicine, suggesting the need for further study of CHM.

Conclusion: A superior clinical outcome may be obtained with CHM treatment. The case series illustrates the potential benefits and safety issues of CHM in pancreatic cancer patients that could be relevant for developing strategies to increase individualization of pancreatic cancer treatment and improve survival. This study may facilitate interprofessional communication and improved clinical management of pancreatic cancer patients.
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http://dx.doi.org/10.1177/1534735419828836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432679PMC
December 2019

Bushen Yijing Fang Reduces Fall Risk in Late Postmenopausal Women with Osteopenia: A Randomized Double-blind and Placebo-controlled Trial.

Sci Rep 2019 02 14;9(1):2089. Epub 2019 Feb 14.

Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China.

Falls in late postmenopausal women with osteopenia usually cause fractures with severe consequences. This 36-month randomized, double-blind and placebo-controlled trial with a 10-year observational follow-up study aimed to investigate the long-term effect of herbal formula Bushen Yijing Fang (BSYJF) on fall risk in the late postmenopausal women with osteopenia. 140 late postmenopausal women (Femoral neck T-score, -2.5~-2 SD) were recruited and randomized to orally receive calcium carbonate 300 mg daily with either BSYJF or placebo for 36 months. The effect was further investigated for another 10-year follow-up. During the 36-month administration, there were 12 falls in BSYJF group and 28 falls in placebo group, respectively, indicating 64% lower risk of falls (RR 0.36 [95% CI, 0.18 to 0.71]; P = 0.004) in BSYJF group. During the 10-year follow-up, 36% lower fall risk (RR 0.64 [95% CI, 0.46 to 0.89]; P = 0.009) was observed in BSYJF group. No significant difference was found in safety profile between two groups. Thirty-six-month administration of BSYJF reduced fall risk with an increase in bone mass, and its latent effect on fall risk was continually observed in the 10-year follow-up in late postmenopausal women with osteopenia. This clinical trial was registered at Chinese clinical trial registry (ChiCTR-IOR-16008942).
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http://dx.doi.org/10.1038/s41598-018-38335-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375933PMC
February 2019

Brusatol ameliorates 2, 4, 6-trinitrobenzenesulfonic acid-induced experimental colitis in rats: Involvement of NF-κB pathway and NLRP3 inflammasome.

Int Immunopharmacol 2018 Nov 13;64:264-274. Epub 2018 Sep 13.

Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China. Electronic address:

Brusatol is a main bioactive component derived from the Chinese medicinal plant Brucea javanica, which is traditionally used for the treatment of dysentery (also known as ulcerative colitis, UC). Previously, we have designed a novel brusatol self-microemulsifying drug delivery system (BR-SMEDDS) to increase its solubility and bioavailability, and enhance its bioactivities. In the present study, we established 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model in vivo and lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro, to investigate the potential anti-inflammatory effect and underlying mechanism of BR-SMEDDS. Disease activity index (DAI) including body weight, stool consistency and gross bleeding was measured. Macroscopic and histological evaluations of colons were conducted. Relevant molecular events were determined by ELISA, qRT-PCR, immunohistochemistry or Western blotting. The results showed that BR notably inhibited the productions of TNF-α, pro-IL-1β, PGE and NO, and suppressed the NF-κB signaling pathway in LPS-stimulated macrophages. In parallel with the vitro experimental results, BR significantly attenuated diarrhea, colonic shortening, macroscopic damage and histological injury. BR treatment also increased the levels of TGF-β and IL-4, decreased the contents of IL-1β and IL-18, and elevated the levels of CAT, GSH and SOD in the colons. Furthermore, BR also markedly activated the Nrf2 expression and suppressed the NLRP3 inflammasome activation. Taken together, the anti-UC effect of BR might be intimately associated with the suppression of NF-κB and NLRP3-mediated inflammatory responses, and regulation of Nrf2-mediated oxidative stress. BR might have the potential to be further developed into a promising therapeutic agent for colitis treatment.
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http://dx.doi.org/10.1016/j.intimp.2018.09.008DOI Listing
November 2018

Redox-sensitive micelles composed of disulfide-linked Pluronic-linoleic acid for enhanced anticancer efficiency of brusatol.

Int J Nanomedicine 2018 13;13:939-956. Epub 2018 Feb 13.

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.

Brusatol (Bru) exhibits promising anticancer effects, with both proliferation inhibition and chemoresistance amelioration activity. However, the poor solubility and insufficient intracellular delivery of Bru greatly restrict its application. Herein, to simultaneously utilize the advantages of Pluronics as drug carriers and tumor microenvironment-responsive drug release profiles, a flexible amphiphilic copolymer with a polymer skeleton, that is, Pluronic F68 grafting with linoleic acid moieties by redox-reducible disulfide bonds (F68-SS-LA), was synthesized. After characterization by H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, the redox-sensitive F68-SS-LA micelles were self-assembled in a much lower critical micelle concentration than that of the unmodified F68 copolymer. Bru was loaded in micelles (Bru/SS-M) with high loading efficiency, narrow size distribution, and excellent storage stability. The redox-sensitive Bru/SS-M exhibited rapid particle dissociation and drug release in response to a redox environment. Based on the enhanced cellular internalization, Bru/SS-M achieved higher cytotoxicity in both Bel-7402 and MCF-7 cells compared with free Bru and nonreducible micelles. The improved anticancer effect was attributed to the remarkably decreased mitochondrial membrane potential and increased reactive oxygen species level as well as apoptotic rate. These results demonstrated that F68-SS-LA micelles possess great potential as an efficient delivery vehicle for Bru to promote its anticancer efficiency via an oxidation pathway.
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http://dx.doi.org/10.2147/IJN.S130696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815479PMC
April 2018

Characterization of brusatol self-microemulsifying drug delivery system and its therapeutic effect against dextran sodium sulfate-induced ulcerative colitis in mice.

Drug Deliv 2017 Nov;24(1):1667-1679

b Mathematical Engineering Academy of Chinese Medicine , Guangzhou University of Chinese Medicine , Guangzhou , PR China.

Brusatol (BR) is one of the main bioactive components derived from Brucea javanica, a medicinal herb historically used in the treatment of dysenteric disorders (also known as ulcerative colitis(UC)). Due to its poor aqueous solubility, a novel brusatol self-microemulsifying drug delivery system (BR-SMEDDS) nanoformulation with smaller size, higher negative zeta potential and drug content, and excellent stability was developed. The appearance of BR-SMEDDS remained clear and transparent, and transmission electron microscopy showed microemulsion droplets to be spherical with homogeneous distribution. Pharmacokinetic parameters indicated that oral bioavailability was greatly improved by BR-SMEDDS as compared with aqueous suspension. Meanwhile, the anti-colitis activity of BR-SMEDDS was evaluated on dextran sodium sulfate (DSS)-induced colitis mice model. The result illustrated that the nano-formation significantly reduced the body weight loss, recovered colon length, decreased disease activity index and microscopic score, regulated immune-inflammatory cytokines, diminished oxidative stress and repressed the colonic expression of myeloid differentiation factor 88 (MyD88), toll-like receptor 4 (TLR4) and nuclear factor kappa B p65 (NF-κB p65) proteins. Our findings demonstrated for the first time that BR could effectively attenuate colonic inflammation in mice, at least partially, via favorable regulation of anti-oxidative and anti-inflammatory status and inhibition of the TLR4-linked NF-κB signaling pathway. The BR nano-formulation was superior to BR suspension and sulphasalazine, in treating experimental UC, and exhibited similar effect with azathioprine, with much smaller dosage. The enhanced anti-UC effect of BR might be intimately associated with the improved pharmacokinetic property by SMEDDS. The developed nano-delivery system might thus be a promising candidate for colitis treatment.
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http://dx.doi.org/10.1080/10717544.2017.1384521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253134PMC
November 2017

TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis.

Cell Discov 2017 11;3:17023. Epub 2017 Jul 11.

School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China.

Pneumoconiosis, caused by inhalation of mineral dusts, is a major occupational disease worldwide. Currently, there are no effective drugs owing to a lack of potential therapeutic targets during either the inflammation or fibrosis molecular events in pneumoconiosis. Here, we performed microarrays to identify aberrantly expressed genes in the above molecular events and found a hub gene transforming growth factor-β-activated kinase 1 (), which was highly expressed and activated in pneumoconiosis patients as well as silica-exposed rats with experimental pneumoconiosis. Genetic modulation of by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9, RNA interference and overexpression indicated the important role of in both inflammation and fibrosis in experimental pneumoconiosis. To achieve pharmacological inhibition, we virtually screened out a natural product resveratrol, which targeted at both N161 and A107 residues, and significantly inhibited activation to attenuate inflammation and fibrosis . Consistently, prevention and intervention studies showed that resveratrol could inhibit pulmonary inflammation and fibrosis in silica-exposed rats.
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http://dx.doi.org/10.1038/celldisc.2017.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504492PMC
July 2017

Cigarette smoke extract induces placental growth factor release from human bronchial epithelial cells via ROS/MAPK (ERK-1/2)/Egr-1 axis.

Int J Chron Obstruct Pulmon Dis 2016 2;11:3031-3042. Epub 2016 Dec 2.

Department of Respiratory, Institute of Respiratory Diseases.

Etiological evidence demonstrates that there is a significant association between cigarette smoking and chronic airway inflammatory disease. Abnormal expression of placental growth factor (PlGF) has been reported in COPD, and its downstream signaling molecules have been reported to contribute to the pathogenesis of airway epithelial cell apoptosis and emphysema. However, the signaling mechanisms underlying cigarette smoke extract (CSE)-induced PlGF expression in airway microenvironment remain unclear. Herein, we investigated the effects of reactive oxygen species (ROS)-dependent activation of the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase1/2 [ERK-1/2])/early growth response-1 (Egr-1) pathway on CSE-induced PlGF upregulation in human bronchial epithelium (HBE). The data obtained with quantitative reverse transcription polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining analyses showed that CSE-induced Egr-1 activation was mainly mediated through production of ROS and activation of the MAPK (ERK-1/2) cascade. The binding of Egr-1 to the PlGF promoter was corroborated by an ELISA-based DNA binding activity assay. These results demonstrate that ROS activation of the MAPK (ERK-1/2)/Egr-1 pathway is a main player in the regulatory mechanism for CSE-induced PlGF production and that the use of an antioxidant could partly abolish these effects. Understanding the mechanisms of PlGF upregulation by CSE in the airway microenvironment may provide rational therapeutic interventions for cigarette smoking-related airway inflammatory diseases.
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http://dx.doi.org/10.2147/COPD.S120849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144910PMC
August 2017

YSL-12, a novel microtubule-destabilizing agent, exerts potent anti-tumor activity against colon cancer in vitro and in vivo.

Cancer Chemother Pharmacol 2016 06 23;77(6):1217-29. Epub 2016 Apr 23.

Department of Pharmacy, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.

Purpose: Microtubules play a central role in various fundamental cell functions and thus become an attractive target for cancer therapy. A novel compound YSL-12 is a combretastatin A-4 (CA-4) analogue with more stability. We investigated its anti-tumor activity and mechanisms in vitro and in vivo for the first time.

Methods: Cytotoxicity was evaluated by MTT method. In vitro microtubule polymerization assay was performed using a fluorescence-based method by multifunction fluorescence microplate reader. Intracellular microtubule network was detected by immunofluorescence method. Cell cycle analysis and apoptosis were measured by flow cytometry. Metabolic stability was recorded by liquid chromatography-ultraviolet detection and liquid chromatography-mass spectrometry. In vivo anti-tumor activity was assessed using HT-29 colon carcinoma xenografts established in BALB/c nude mice.

Results: YSL-12 displayed nanomolar-level cytotoxicity against various human cancer cell lines. A high selectivity toward normal cells and potent activity toward drug-resistant cells were also observed. YSL-12 was identified as tubulin polymerization inhibitor evidenced by effectively inhibits tubulin polymerization and heavily disrupted microtubule networks in living HT-29 cells. YSL-12 displayed potent disruption effect of pre-established tumor vasculature in vitro. In addition, YSL-12 treatment also caused cell cycle arrest in the G2/M phase and induced cell apoptosis in a dose-dependent manner. In vitro metabolic stability study revealed YSL-12 displayed considerable better stability than CA-4 in liver microsomes. In vivo, YSL-12 delayed tumor growth with 69.4 % growth inhibition.

Conclusions: YSL-12 is a promising microtubule inhibitor that has great potential for the treatment of colon carcinoma in vitro and in vivo and worth being a candidate for further development of cancer therapy.
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http://dx.doi.org/10.1007/s00280-016-3036-4DOI Listing
June 2016

(-)-Patchouli alcohol protects against Helicobacter pylori urease-induced apoptosis, oxidative stress and inflammatory response in human gastric epithelial cells.

Int Immunopharmacol 2016 Jun 24;35:43-52. Epub 2016 Mar 24.

School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China; Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan 523808, ,PR China. Electronic address:

(-)-Patchouli alcohol (PA), the major active principle of Pogostemonis Herba, has been reported to have anti-Helicobacter pylori and gastroprotective effects. In the present work, we aimed to investigate the possible protective effect of PA on H. pylori urease (HPU)-injured human gastric epithelial cells (GES-1) and to elucidate the underlying mechanisms of action. Results showed that pre-treatment with PA (5.0, 10.0, 20.0μM) was able to remarkably ameliorate the cytotoxicity induced by 17.0U/mg HPU in GES-1 cells. Flow cytometric analysis on cellular apoptosis showed that pre-treatment with PA effectively attenuated GES-1 cells from the HPU-induced apoptosis. Moreover, the cytoprotective effect of PA was found to be associated with amelioration of the HPU-induced disruption of MMP, attenuating oxidative stress by decreasing contents of intracellular ROS and MDA, and increasing superoxide dismutase (SOD) and catalase (CAT) enzymatic activities. In addition, pre-treatment with PA markedly attenuated the secretion of nitric oxide (NO) and pro-inflammatory cytokines such as interleukin-2 (IL-2), interleukin-4 (IL-4) and tumor necrosis factor-α (TNF-α), whereas elevated the anti-inflammatory cytokine interleukin-13 (IL-13) in the HPU-stimulated GES-1 cells. Molecular docking assay suggested that PA engaged in the active site of urease bearing nickel ions and interacted with important residues via covalent binding, thereby restricting the active urease catalysis conformation. Our experimental findings suggest that PA could inhibit the cellular processes critically involved in the pathogenesis of H. pylori infection, and its protective effects against the HPU-induced cytotoxicity in GES-1 cells are believed to be associated with its anti-apoptotic, antioxidative, anti-inflammatory and HPU inhibitory actions.
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http://dx.doi.org/10.1016/j.intimp.2016.02.022DOI Listing
June 2016

Guttiferone K induces autophagy and sensitizes cancer cells to nutrient stress-induced cell death.

Phytomedicine 2015 Sep 3;22(10):902-10. Epub 2015 Jul 3.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China; Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, 201203, P.R. China. Electronic address:

Background: Medicinal plants have long been an excellent source of pharmaceutical agents. Autophagy, a catabolic degradation process through lysosomes, plays an important role in tumorigenesis and cancer therapy.

Purpose: Through a screen designed to identify autophagic regulators from a library of natural compounds, we found that Guttiferone K (GUTK) can activate autophagy in several cancer cell lines. The objective of this study is to investigate the mechanism by which GUTK sensitizes cancer cells to cell death in nutrient starvation condition.

Methods: Cell death analysis was performed by propidium iodide staining with flow cytometry or Annexin V-FITC/PI staining assay. DCFH-DA staining was used for intracellular ROS measurement. Protein levels were analyzed by western blot analysis. Cell viability was measured by MTT assay.

Results: Exposure to GUTK was observed to markedly induce GFP-LC3 puncta formation and activate the accumulation of LC3-II and the degradation of p62 in HeLa cells, suggesting that GUTK is an autophagy inducer. Importantly, hydroxychloroquine, an autophagy inhibitor, was found to significantly prevent GUTK-induced cell death in nutrient starvation conditions, suggesting that the cell death observed is largely dependent on autophagy. We further provide evidence that GUTK inhibits Akt phosphorylation, thereby inhibiting the mTOR pathway in cancer cells during nutrient starvation. In addition, GUTK causes the accumulation of reactive oxygen species (ROS) and the phosphorylation of JNK in EBSS, which may mediate both autophagy and apoptosis.

Conclusion: These data indicate that GUTK sensitizes cancer cells to nutrient stress-induced cell death though Akt/mTOR dependent autophagy pathway.
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http://dx.doi.org/10.1016/j.phymed.2015.06.008DOI Listing
September 2015

Acupoint Sensitization, Acupuncture Analgesia, Acupuncture on Visceral Functional Disorders, and Its Mechanism.

Evid Based Complement Alternat Med 2015 2;2015:171759. Epub 2015 Aug 2.

Institute of Acupuncture, China Academy of Chinese Medical Sciences, 16 Nanxiaojie, Dongzhimen, Beijing 100700, China.

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http://dx.doi.org/10.1155/2015/171759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537726PMC
August 2015

Is Acupuncture Efficacious for Treating Phonotraumatic Vocal Pathologies? A Randomized Control Trial.

J Voice 2016 Sep 19;30(5):611-20. Epub 2015 Aug 19.

Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong, China.

Objectives: To investigate the effectiveness of acupuncture in treating phonotraumatic vocal fold lesions.

Study Design/methods: A total of 123 dysphonic individuals with benign vocal pathologies were recruited. They were given either genuine acupuncture (n = 40), sham acupuncture (n = 44), or no treatment (n = 39) for 6 weeks (two 30-minute sessions/wk). The genuine acupuncture group received needles puncturing nine voice-related acupoints for 30 minutes, two times a week for 6 weeks, whereas the sham acupuncture group received blunted needles stimulating the skin surface of the nine acupoints for the same frequency and duration. The no-treatment group did not receive any intervention but attended just the assessment sessions. One-hundred seventeen subjects completed the study (genuine acupuncture = 40; sham acupuncture = 43; and no treatment = 34), but only 84 of them had a complete set of vocal functions and quality of life measures (genuine acupuncture = 29; sham acupuncture = 33; and no-treatment = 22) and 42 of them with a complete set of endoscopic data (genuine acupuncture = 16; sham acupuncture = 15; and no treatment = 11).

Results: Significant improvement in vocal function, as indicated by the maximum fundamental frequency produced, and also perceived quality of life, were found in both the genuine and sham acupuncture groups, but not in the no-treatment group. Structural (morphological) improvements were, however, only noticed in the genuine acupuncture group, which demonstrated a significant reduction in the size of the vocal fold lesions.

Conclusions: The findings showed that acupuncture of voice-related acupoints could bring about improvement in vocal function and healing of vocal fold lesions.
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http://dx.doi.org/10.1016/j.jvoice.2015.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548836PMC
September 2016

Wound-healing effect of acupuncture for treating phonotraumatic vocal pathologies: A cytokine study.

Laryngoscope 2016 Jan 30;126(1):E18-22. Epub 2015 Jul 30.

School of Chinese Medicine, Chinese University of Hong Kong, Shatin, Hong Kong.

Objectives/hypothesis: Acupuncture is a less-invasive procedure when compared with surgical treatment for benign vocal pathologies caused by vocal overuse. This study aimed to determine the wound-healing effect of acupuncture in treating phonotraumatic vocal fold lesions.

Study Design: Two-way, mixed-model, between- and within-subjects, prospective randomized, placebo-controlled, blinded group design.

Methods: Seventeen dysphonic individuals with vocal nodules were recruited from a university clinic in Hong Kong. Each participant was randomly assigned to receive one session of either genuine or sham acupuncture. The genuine acupuncture group (n = 9) received needles puncturing nine voice-related acupoints for 30 minutes, whereas the sham acupuncture group (n = 8) received blunted needles stimulating the skin surface of the nine acupoints for the same frequency and duration. Laryngeal secretions were suctioned from the surface of the vocal folds immediately before, immediately after, and 24 hours after the acupuncture. The protein concentration levels of wound-healing-related cytokines (interleukin [IL]-1β and IL-10) in these secretion samples were measured.

Results: Following acupuncture, a significant increase in the anti-inflammatory cytokine IL-10 was found in the genuine acupuncture group (n = 9) but not in the sham acupuncture group (n = 8).

Conclusions: The findings showed that acupuncture of voice-related acupoints facilitated an anti-inflammatory process in phonotraumatic vocal pathologies. This could be considered as supporting evidence to consider acupuncture as a less-invasive alternative option, when compared to surgery, for treating phonotraumatic vocal pathologies.
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http://dx.doi.org/10.1002/lary.25483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715648PMC
January 2016

The natural compound Guttiferone F sensitizes prostate cancer to starvation induced apoptosis via calcium and JNK elevation.

BMC Cancer 2015 Apr 11;15:254. Epub 2015 Apr 11.

School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, P.R. China.

Background: In a cytotoxicity screen in serum-free medium, Guttiferone F showed strong growth inhibitory effect against prostate cancer cells.

Methods: Prostate cancer cells LNCaP and PC3 were treated with Guttiferone F in serum depleted medium. Sub-G1 phase distributions were estimated with flow cytometry. Mitochondrial disruption was observed under confocal microscope using Mitotracker Red staining. Gene and protein expression changes were detected by real-time PCR and Western blotting. Ca(2+) elevation was examined by Fluo-4 staining under fluorescence microscope. PC3 xenografts in mice were examined by immunohistochemical analysis.

Results: Guttiferone F had strong growth inhibitory effect against prostate cancer cell lines under serum starvation. It induced a significant increase in sub-G1 fraction and DNA fragmentation. In serum-free medium, Guttiferone F triggered mitochondria dependent apoptosis by regulating Bcl-2 family proteins. In addition, Guttiferone F attenuated the androgen receptor expression and phosphorylation of ERK1/2, while activating the phosphorylation of JNK and Ca(2+) flux. Combination of caloric restriction with Guttiferone F in vivo could increase the antitumor effect without causing toxicity.

Conclusions: Guttiferone F induced prostate cancer cell apoptosis under serum starvation via Ca(2+) elevation and JNK activation. Combined with caloric restriction, Guttiferone F exerted significant growth inhibition of PC3 cells xenograft in vivo. Guttiferone F is therefore a potential anti-cancer compound.
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http://dx.doi.org/10.1186/s12885-015-1292-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394563PMC
April 2015

Role of microRNA-95 in the anticancer activity of Brucein D in hepatocellular carcinoma.

Eur J Pharmacol 2014 Apr 11;728:141-50. Epub 2014 Feb 11.

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, NT, Hong Kong; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China. Electronic address:

Brucea javanica fruit has been used to treat amebic dysentery, malaria and various parasites and it has been applied as an anti-cancer agent in Traditional Chinese Medicine. Brucein D (BD) is a naturally occurring compound extracted from Brucea javanica fruit which shows anti-cancer activity against pancreatic cancer. Here, we further demonstrated that BD inhibited hepatocellular carcinoma (HCC) cell growth in vitro and tumor growth in vivo that were attributed to the induction of cell apoptosis. BD did not exert growth inhibition on non-tumorigenic human hepatocytes. MTT assay was used to measure cell viability. Annexin V and TUNEL assay were applied to identify apoptotic cells in cell suspension and in tissue section respectively. Downstream micro-RNA (miRNA) targets of BD were screened out by miRNA array. miRNAs and their target proteins were identified by bioinformatics analysis and luciferase reporter assay. 39 miRNAs regulated by BD in HCC were identified. miR-95 was found to be a potential drug target of BD. We further identified CUG triplet repeat RNA-binding protein 2 (CUGBP2) as the downstream target of miR-95. Our data suggested that BD exerted its anti-cancer activity against HCC through modulation of miR-95 expression.
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http://dx.doi.org/10.1016/j.ejphar.2014.02.002DOI Listing
April 2014

Quercetin deformable liposome: preparation and efficacy against ultraviolet B induced skin damages in vitro and in vivo.

J Photochem Photobiol B 2013 Oct 20;127:8-17. Epub 2013 Jul 20.

School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China; School of Chinese Medicine, Faculty of Science, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong 999077, PR China.

Ultraviolet (UV) radiation has deleterious effects on cells through direct damage to DNA or through increasing generation of reactive oxygen species (ROS). The flavonol quercetin (Qu) provides cellular protection against UV radiation and the current investigation was carried out to develop a deformable liposome formulation of Qu to enhance its delivery into human skin and to improve its anti-UVB effect. The influence of surfactants (including Span 20, Tween 80 and sodium cholate) on the properties of Qu deformable liposomes was investigated. Liposomes composed of Qu, phosphatidylcholine (PC), cholesterol (Chol), and Tween 80 showed high entrapment efficiencies (80.41±4.22%), small particle sizes (132±14nm), high elasticity (10.48±0.71), and prolonged drug release. The cell viability in UVB-irradiated HaCaT cells increased to 89.89±4.5% at 24h and 78.8±3.19% at 48h following treatment with Qu defomable liposomes. The ROS and malondialdehyde (MDA) level were also reduced. The penetration rate was 3.8-fold greater than that of the Qu suspension. Moreover, the edema and inflammation was alleviated by Qu deformable liposomes. These results showed the potential of deformable liposomes to enhance the anti-UVB effects of Qu both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.jphotobiol.2013.07.014DOI Listing
October 2013

Salidroside improves homocysteine-induced endothelial dysfunction by reducing oxidative stress.

Evid Based Complement Alternat Med 2013 26;2013:679635. Epub 2013 Mar 26.

School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong.

Hyperhomocysteinemia is associated with an increased risk for cardiovascular diseases through increased oxidative stress. Salidroside is an active ingredient of the root of Rhodiola rosea with documented antioxidative, antihypoxia and neuroprotective properties. However, the vascular benefits of salidroside against endothelial dysfunction have yet to be explored. The present study, therefore, aimed to investigate the protective effect of salidroside on homocysteine-induced endothelial dysfunction. Functional studies on the rat aortas were performed to delineate the vascular effect of salidroside. DHE imaging was used to evaluate the reactive oxygen species (ROS) level in aortic wall and endothelial cells. Western blotting was performed to assess the protein expression associated with oxidative stress and nitric oxide (NO) bioavailability. Exposure to homocysteine attenuated endothelium-dependent relaxations in rat aortas while salidroside pretreatment rescued it. Salidroside inhibited homocystein-induced elevation in the NOX2 expression and ROS overproduction in both aortas and cultured endothelial cells and increased phosphorylation of eNOS which was diminished by homocysteine. The present study shows that salidroside is effective in preserving the NO bioavailability and thus protects against homocysteine-induced impairment of endothelium-dependent relaxations, largely through inhibiting the NOX2 expression and ROS production. Our results indicate a therapeutic potential of salidroside in the management of oxidative-stress-associated cardiovascular dysfunction.
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http://dx.doi.org/10.1155/2013/679635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622309PMC
April 2013

The anti-cancer agent SU4312 unexpectedly protects against MPP(+) -induced neurotoxicity via selective and direct inhibition of neuronal NOS.

Br J Pharmacol 2013 Mar;168(5):1201-14

Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong, China.

Background And Purpose: SU4312, a potent and selective inhibitor of VEGF receptor-2 (VEGFR-2), has been designed to treat cancer. Recent studies have suggested that SU4312 can also be useful in treating neurodegenerative disorders. In this study, we assessed neuroprotection by SU4312 against 1-methyl-4-phenylpyridinium ion (MPP(+) )-induced neurotoxicity and further explored the underlying mechanisms.

Experimental Approach: MPP(+) -treated neurons and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated zebrafish were used to study neuroprotection by SU4312. NOS activity was assayed in vitro to examine direct interactions between SU4312 and NOS isoforms.

Key Results: SU4312 unexpectedly prevented MPP(+) -induced neuronal apoptosis in vitro and decreased MPTP-induced loss of dopaminergic neurons, reduced expression of mRNA for tyrosine hydroxylase and impaired swimming behaviour in zebrafish. In contrast, PTK787/ZK222584, a well-studied VEGFR-2 inhibitor, failed to prevent neurotoxicity, suggesting that the neuroprotective actions of SU4312 were independent of its anti-angiogenic action. Furthermore, SU4312 exhibited non-competitive inhibition of purified neuronal NOS (nNOS) with an IC(50) value of 19.0 μM but showed little or no effects on inducible and endothelial NOS. Molecular docking simulations suggested an interaction between SU4312 and the haem group within the active centre of nNOS.

Conclusions And Implication: SU4312 exhibited neuroprotection against MPP(+) at least partly via selective and direct inhibition of nNOS. Because SU4312 could reach the brain in rats, our study also offered a support for further development of SU4312 to treat neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity.
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http://dx.doi.org/10.1111/bph.12004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594677PMC
March 2013
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