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L Zhang,
J Yu,
C C M Wong,
T K W Ling,
Z J Li,
K M Chan,
S X Ren,
J Shen,
R L Y Chan,
C C Lee,
M S M Li,
A S L Cheng,
K F To,
R L Gallo,
J J Y Sung,
W K K Wu, C H Cho
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ABSTRACT: Cathelicidin, an antimicrobial peptide of the innate immune system, has been shown to modulate microbial growth, wound healing and inflammation. However, whether cathelicidin controls Helicobacter pylori infection in vivo remains unexplored. This study sought to elucidate the role of endogenous and exogenous mouse cathelicidin (CRAMP) in the protection against H. pylori infection and the associated gastritis in mice. Results showed that genetic ablation of CRAMP in mice significantly increased the susceptibility of H. pylori colonization and the associated gastritis as compared with the wild-type control. Furthermore, replenishment with exogenous CRAMP, delivered via a bioengineered CRAMP-secreting strain of Lactococcus lactis, reduced H. pylori density in the stomach as well as the associated inflammatory cell infiltration and cytokine production. Collectively, these findings indicate that cathelicidin protects against H. pylori infection and its associated gastritis in vivo. Our study also demonstrates the feasibility of using the transformed food-grade bacteria to deliver cathelicidin, which may have potential clinical applications in the treatment of H. pylori infection in humans.Gene Therapy advance online publication, 20 December 2012; doi:10.1038/gt.2012.92.
Gene therapy 12/2012; · 4.75 Impact Factor
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ABSTRACT: This special issue of Current Pharmaceutical Design summarizes recent research advances in the relationship between microRNA (miRNAs) and gastrointestinal (GI) and liver cancers. MicroRNAs are small, non-coding RNAs that regulate gene expression mainly by binding to the 3 untranslated regions (3-UTRs) of target genes. Currently, there are 1424 known human miRNAs and it is predicted that approximately 30% of human protein-coding genes are regulated by miRNAs. In the past five years compelling studies have demonstrated that miRNAs are involved in many physiological and pathological processes, such as cancer. Many studies have shown that various miRNAs are deregulated in cancer and cancer phenotype can be modified by manipulating miRNAs expression [1]. These observations have led to an enthusiasm in exploring the role of miRNAs in cancer diagnosis, prognosis and miRNA-based therapies. Up to now, many miRNAs have been identified as potential GI cancer diagnosis markers, which can be used for tumor staging [2] and to classify tissue origin of poorly differentiated tumors [3], and also many are found to be useful in predicting survival, recurrence and metastasis related to liver cancer [4]. Most interestingly, promising results have been obtained in therapeutic studies by manipulating miRNA expression both in vitro [5] and in vivo [6], especially that a Phase I trial of the LNA anti-miR-122 is being carried out in human subjects in Denmark. To overcome delivery challenges innate with small RNA therapeutics, chemical modifications, nanoparticles, liposomes, polymers are being exploited for effective delivery of miRNAs to targeted sites [7, 8]. Nonetheless, caution should be taken in the total elucidation of biological functions of miRNAs and examination of the off-target effects in the body before they can be used as therapeutic agents for cancer treatment in humans.
Current pharmaceutical design 09/2012; · 4.41 Impact Factor
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ABSTRACT: Chinese herbal medicine has long been used as a treatment for wounds. However, the underlying cellular and molecular mechanisms remain largely unknown. In this study it was shown that the proliferation of keratinocytes, which is known to play an important role in wound healing as the major cell type in the epidermis, was promoted by three herbal extracts/natural compounds: NF3 (an extract from the mixture of Radix Astragali (RA) and Radix Rehmanniae (RR) in the ratio of 2:1), stachyose (an isolated compound from Radix Rehmanniae) and extract P2-2 (a sub-fraction from the extract of Radix Astragali). The effect of the herbal extracts/natural compounds on the growth of keratinocytes was not influenced by a high glucose level, a condition similar to diabetic patients who usually suffer from diabetic foot ulcers. Real time RT-PCR results showed that the expression of epidermal growth factor (EGF) receptor, but not transforming growth factor-β (TGF-β) receptor, was up-regulated by NF3. Moreover, treatments with the EGF receptor kinase inhibitor AG1478 and the MEK inhibitor U0126 resulted in the diminishment of the effect of the three herbal extracts/natural compounds on keratinocyte proliferation, indicating that EGF receptor might have a significant role in this action. This study has further elucidated the molecular mechanism under which herbal extracts/natural compounds exert their effects on the wound healing process. Copyright © 2012 John Wiley & Sons, Ltd.
Phytotherapy Research 02/2012; 26(10):1547-54. · 2.09 Impact Factor
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Penelope M Y Or,
Francis F Y Lam,
Y W Kwan, C H Cho,
C P Lau,
H Yu,
G Lin,
Clara B S Lau,
K P Fung,
P C Leung,
John H K Yeung
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ABSTRACT: The present study investigated the effects of Radix Astragali (RA) and Radix Rehmanniae (RR), the major components of an anti-diabetic foot ulcer herbal formula (NF3), on the metabolism of model probe substrates of human CYP isoforms, CYP1A2, CYP2C9, CYP2D6, CYP2E1 and CYP3A4, which are important in the metabolism of a variety of xenobiotics. The effects of RA or RR on human CYP1A2 (phenacetin O-deethylase), CYP2C9 (tolbutamide 4-hydroxylase), CYP2D6 (dextromethorphan O-demethylase), CYP2E1 (chlorzoxazone 6-hydroxylase) and CYP3A4 (testosterone 6β-hydroxylase) activities were investigated using pooled human liver microsomes. NF3 competitively inhibited activities of CYP2C9 (IC(50)=0.98mg/ml) and CYP3A4 (IC(50)=0.76mg/ml), with K(i) of 0.67 and 1.0mg/ml, respectively. With specific human CYP2C9 and CYP3A4 isoforms, NF3 competitively inhibited activities of CYP2C9 (IC(50)=0.86mg/ml) and CYP3A4 (IC(50)=0.88mg/ml), with K(i) of 0.57 and 1.6mg/ml, respectively. Studies on RA or RR individually showed that RR was more important in the metabolic interaction with the model CYP probe substrates. RR dose-dependently inhibited the testosterone 6β-hydroxylation (K(i)=0.33mg/ml) while RA showed only minimal metabolic interaction potential with the model CYP probe substrates studied. This study showed that RR and the NF3 formula are metabolized mainly by CYP2C9 and/or CYP3A4, but weakly by CYP1A2, CYP2D6 and CYP2E1. The relatively high K(i) values of NF3 (for CYP2C9 and CYP3A4 metabolism) and RR (for CYP3A4 metabolism) would suggest a low potential for NF3 to cause herb-drug interaction involving these CYP isoforms.
Phytomedicine: international journal of phytotherapy and phytopharmacology 01/2012; 19(6):535-44. · 2.17 Impact Factor
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ABSTRACT: Ulceration in the gastrointestinal (GI) mucosa is a common disorder in humans. It has been shown that cigarette smoking is closely related to the increase of peptic ulcer and also plays an inhibitory role on ulcer healing. However, the underlying mechanisms by which cigarette smoke exerts these adverse effects remain largely unknown. It is perhaps partly due to the complexity of chemical compositions in the smoke and furthermore their pathological actions are largely undefined. In this review, we have highlighted the potential adverse effects of the toxic chemical components in cigarette smoke and summarized their possible mechanisms of actions on ulcer formation and healing in the GI tract. We also discuss in detail how cigarette smoke disturbs cell proliferation, influences mucus synthesis and secretion, delays blood vessel formation, and interferes the innate immune responses during ulceration and repair in the GI mucosa.
Current Medicinal Chemistry 01/2012; 19(1):63-9. · 4.86 Impact Factor
