Hor-Yue Tan

The Role of Oxidative Stress and Antioxidants in Liver Diseases

A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed.

The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases

High heterogeneity of macrophage is associated with its functions in polarization to different functional phenotypes depending on environmental cues. Macrophages remain in balanced state in healthy subject and thus macrophage polarization may be crucial in determining the tissue fate. The two distinct populations, classically M1 and alternatively M2 activated, representing the opposing ends of the full activation spectrum, have been extensively studied for their associations with several disease progressions. Accumulating evidences have postulated that the redox signalling has implication in macrophage polarization and the key roles of M1 and M2 macrophages in tissue environment have provided the clue for the reasons of ROS abundance in certain phenotype. M1 macrophages majorly clearing the pathogens and ROS may be crucial for the regulation of M1 phenotype, whereas M2 macrophages resolve inflammation which favours oxidative metabolism. Therefore how ROS play its role in maintaining the homeostatic functions of macrophage and in particular macrophage polarization will be reviewed here. We also review the biology of macrophage polarization and the disturbance of M1/M2 balance in human diseases. The potential therapeutic opportunities targeting ROS will also be discussed, hoping to provide insights for development of target-specific delivery system or immunomodulatory antioxidant for the treatment of ROS-related diseases.

Berberine-induced tumor suppressor p53 up-regulation gets involved in the regulatory network of MIR-23a in hepatocellular carcinoma

AIM OF THE STUDYnTo investigate the involvement of p53 in the regulatory network of microRNA-23a (miR-23a) in berberine-treated hepatocellular carcinoma (HCC) cells.nnnMETHODSnThe biogenesis of miR-23a upon berberine treatment was monitored by detecting the transcript expression of primary precursor, precursor and mature forms of miR-23a. Protein expression was detected with immunoblotting. The binding capacity between p53 and chromatin DNA was determined by chromatin immunoprecipitation. The role of miR-23a in mediating suppression of HCC by berberine was determined both in vitro and in vivo.nnnRESULTSnmiR-23a was up-regulated upon berberine treatment in human HCC cells, and berberine could increase the expression of primary precursor, precursor and mature forms of miR-23a. The up-regulation of miR-23a by berberine is p53-dependent. Inhibition of p53 expression and activity could block the up-regulation of miR-23a induced by berberine. Furthermore, berberine-induced miR-23a expression may mediate the transcription activation of p53-related tumor suppressive genes p21 and GADD45α. Inhibition of miR-23a abolishes the binding of p53 onto chromatin and attenuates transcription activation of p21 and GADD45α. Target prediction and experimental validation demonstrate that berberine-induced miR-23a may target to Nek6 to suppress its expression. Berberine-induced G2/M cell cycle arrest in HCC was attenuated when miR-23a was inhibited. Berberine-induced cell death and in vivo tumor growth inhibition are attenuated upon inhibition of miR-23a.nnnCONCLUSIONnOur study reveals that miR-23a may be involved in regulating the anti-HCC effect of berberine by mediating the regulation of p53.

Berberine and Coptidis Rhizoma as potential anticancer agents: Recent updates and future perspectives.

ETHNOPHARMACOLOGICAL RELEVANCEnThe antineoplastic property of Coptidis Rhizoma and berberine was correlated with its traditional use of clearing internal fire, removing damp-heat and counteracting toxic pathogens.nnnAIM OF THE STUDYnThe anti-tumor effect of Coptidis Rhizoma and berberine was extensively studied since our last comprehensive review in 2009. This study aims to summarize the recent updates and give rise to perspectives of Coptidis Rhizoma and berberine as potential novel antineoplastic agents.nnnMETHODSnQuality studies in recent 5 years were retrieved from PubMed, Medline and CNKI with keywords including Coptis, Coptidis Rhizoma, huanglian, berberine, tumor and cancer. Studies were focused on the pharmacological actions of Coptidis Rhizoma and berberine in cancer progression.nnnRESULTSnIt was shown that Coptidis Rhizoma extract and berberine may repress tumor progression by regressing abnormal cell proliferation, arresting cell cycle and inducing cell death. Studies also highlighted the actions of Coptidis Rhizoma extract and berberine in inhibiting tumor cell invasion and angiogenesis, which in turn abolish cancer metastasis. Some studies have also been conducted to reveal the potential effect of Coptidis Rhizoma extract and berberine in regulating tumor stromal microenvironment, as well as in preventing carcinogenesis. Most of the results have been demonstrated with in vivo models, but results of high-quality clinical trials are not yet available. Unspecified cancer type and staging, fluctuated dose information and variants of targets across studies of berberine/ Coptidis Rhizoma impede their clinical use for cancer treatment.nnnCONCLUSIONnRecent advances highlighted by this review may shed light on future direction of studies featuring Coptidis Rhizoma and berberine as novel antineoplastic agents, which should be repeatedly proven in future animal and clinical studies. Although more evidences on its specificity and clinical efficacy are necessary to support its clinical use, Coptidis Rhizoma and berberine are highly expected to be effective, safe and affordable treatments for cancer patients.

Insights into the Role and Interdependence of Oxidative Stress and Inflammation in Liver Diseases.

The crucial roles of oxidative stress and inflammation in the development of hepatic diseases have been unraveled and emphasized for decades. From steatosis to fibrosis, cirrhosis and liver cancer, hepatic oxidative stress, and inflammation are sustained and participated in this pathological progressive process. Notably, increasing evidences showed that oxidative stress and inflammation are tightly related, which are regarded as essential partners that present simultaneously and interact with each other in various pathological conditions, creating a vicious cycle to aggravate the hepatic diseases. Clarifying the interaction of oxidative stress and inflammation is of great importance to provide new directions and targets for developing therapeutic intervention. Herein, this review is concerned with the regulation and interdependence of oxidative stress and inflammation in a variety of liver diseases. In addition to classical mediators and signaling, particular emphasis is placed upon immune suppression, a potential linkage of oxidative stress and inflammation, to provide new inspiration for the treatment of liver diseases. Furthermore, since antioxidation and anti-inflammation have been extensively attempted as the strategies for treatment of liver diseases, the application of herbal medicines and their derived compounds that protect liver from injury via regulating oxidative stress and inflammation collectively were reviewed and discussed.

Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian-Jiedu decoction in human hepatocellular carcinoma

ETHNOPHARMACOLOGICAL RELEVANCEnAn oriental medicinal formulation, Huanglian Jiedu Decoction (HLJDD), has been well documented in few Traditional Chinese Medicine Classics 1300 years ago for treatment of heat and dampness-related diseases. Its effect is well accepted in Asian community, including China, Japan and Korea. Recent studies have postulated HLJDD as a regimen for cancer treatment, especially liver cancer, but the underlying mechanism is unknown. The aim of this study was to examine the suppressive effect of HLJDD on the growth of hepatocellular carcinoma (HCC) and its possible underlying mechanism.nnnMETHODSnChemical composition of HLJDD was analyzed by high performance liquid chromatography. The tumor suppressive effect of HLJDD was determined on both HCC cells and xenograft model. Nascent protein synthesis was detected with Click-IT protein labeling technology; protein expression was determined by immunoblotting and imunnohistochemical analysis.nnnRESULTSnQuality analysis revealed that HLJDD of different batches is consistent in both chemical composition and bioactivities. HLJDD inhibited HCC cell proliferation at its non-toxic doses, and suppressed growth and angiogenesis in xenografted murine model. HLJDD suppressed the synthesis of nascent protein via inactivation of eEF2 without deregulating the translation initiation factors. The major components in HLJDD, geniposide, berberine and baicalin, additively act on eEF2, and contributed to the responsible activity. HLJDD-activated eEF2 kinase (eEF2K) led to eEF2 inactivation, and activation of AMPK signaling may be responsible for the eEF2K induction. Blocked AMPK activity in HLJDD-treated HCC cells attenuated eEF2K activation as well as the inhibitory effect of the formula. In nutrient deprived HCC cells with inactivated eEF2, the inhibitory effect of HLJDD in tumor cell expansion was interfered.nnnCONCLUSIONnOur results indicate that HLJDD has potential in blocking HCC progression with involvement of eEF2 inhibition.

A Biomedical Investigation of the Hepatoprotective Effect of Radix salviae miltiorrhizae and Network Pharmacology-Based Prediction of the Active Compounds and Molecular Targets

Radix salviae miltiorrhizae (Danshen in Chinese), a classic traditional Chinese medicine (TCM) herb, has been used for centuries to treat liver diseases. In this study, the preventive and curative potential of Danshen aqueous extract on acute/chronic alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) was studied. The in vivo results indicated that Danshen could alleviate hepatic inflammation, fatty degeneration, and haptic fibrogenesis in ALD and NAFLD models. In the aspect of mechanism of action, the significant reduction in MDA levels in both ALD and NAFLD models implies the decreased levels of oxidative stress by Danshen. However, Danshen treatment could not activate the internal enzymatic antioxidant system in ALD and NAFLD models. To further explore the hepatoprotective mechanism of Danshen, an in silico-based network pharmacology approach was employed in the present study. The pharmacological network analysis result revealed that six potential active ingredients such as tanshinone iia, salvianolic acid b, and Danshensu may contribute to the hepatoprotective effects of Danshen on ALD and NAFLD. The action mechanism may relate with regulating the intracellular molecular targets such as PPARα, CYP1A2, and MMP2 for regulation of lipid metabolism, antioxidant and anti-fibrogenesis by these potential active ingredients. Our studies suggest that the combination of network pharmacology strategy with in vivo experimental study may provide a forceful tool for exploring the mechanism of action of traditional Chinese medicine (TCM) herb and developing novel bioactive ingredients.

IRE1α inhibition by natural compound genipin on tumour associated macrophages reduces growth of hepatocellular carcinoma

Accumulating evidences postulated the influential roles of macrophages in mediating hepatocellular carcinoma (HCC) initiation and progression. In this study, we demonstrate that a small molecule, genipin reduced HCC growth through suppressing IRE1α-mediated infiltration and priming of tumour associated macrophages (TAMs). Oral administration of genipin (30mg/kg/2days) suppressed orthotopic HCC tumour growth without challenging the viability and proliferation of HCC cells. Genipin reduced infiltration of inflammatory monocytes into liver and tumour thereby suppressed TAMs presence in HCC microenvironment. Suppression of HCC growth was diminished in HCC-implanted mice with depletion of TAMs by liposome clodronate. Genipin inhibited the TAMs migration, and reduced expression of TAMs-derived inflammatory cytokines that favors HCC proliferation. This is revealed by the in vivo deletion of IRE1α on TAMs in genipin-treated HCC-implanted mice. Diminishing IRE1α neutralised the inhibitory effect of genipin on TAMs. Silencing the expression of IRE1α greatly reduced TAMs migration and expression of inflammatory cytokines that prime HCC proliferation. Suppression of IRE1α led to reduced XBP-1 splicing and NF-κB activation. The reduced association of IRE1α with TRAF2 and IKK complex may be responsible for the genipin-mediated inactivation of NF-κB. The findings show the important role of TAMs in inhibitory effect of genipin on HCC, and TAMs-expressing IRE1α as a promising target for disrupting the tumour environment that favor of HCC development.

Supplementation of Micronutrient Selenium in Metabolic Diseases: Its Role as an Antioxidant

Selenium is an essential mineral naturally found in soil, water, and some of the food. As an antioxidant, it is one of the necessary trace elements in human body and has been suggested as a dietary supplement for health benefit. Although the human body only needs a trace amount of selenium every day, plenty of recent studies have revealed that selenium is indispensable for maintaining normal functions of metabolism. In this study, we reviewed the antioxidant role of nutritional supplementation of selenium in the management of major chronic metabolic disorders, including hyperlipidaemia, hyperglycaemia, and hyperphenylalaninemia. Clinical significance of selenium deficiency in chronic metabolic diseases was elaborated, while clinical and experimental observations of dietary supplementation of selenium in treating chronic metabolic diseases, such as diabetes, arteriosclerosis, and phenylketonuria, were summarized. Toxicity and recommended dose of selenium were discussed. The mechanism of action was also proposed via inspecting the interaction of molecular networks and predicting target protein such as xanthine dehydrogenase in various diseases. Future direction in studying the role of selenium in metabolic disorders was also highlighted. In conclusion, highlighting the beneficial role of selenium in this review would advance our knowledge of the dietary management of chronic metabolic diseases.

Scutellaria baicalensis and Cancer Treatment: Recent Progress and Perspectives in Biomedical and Clinical Studies

Scutellaria baicalensis (Huangqin in Chinese) is a major traditional Chinese medicine (TCM) herb, which has a long history of use in the treatment of a variety of symptoms correlated with cancer. In the past decade, the potential of S. baicalensis and single compounds derived from it as anticancer agents targeting various pathways has received extensive research attention. Specifically, the proliferation and metastases inhibiting properties of the single compounds in cancer have been studied; however, the underlying mechanisms remain unclear. This review summarizes the various mechanisms, pathways and molecular targets involved in the anticancer activity of S. baicalensis and its single compounds. However, the aim of this review is to provide a more thorough view of the last 10 years to link traditional use with modern research and to highlight recently discovered molecular mechanisms. Extracts and major flavonoids derived from S. baicalensis have been found to possess anticancer effects in multiple cancer cell lines both in vitro and in vivo. Further investigation is warranted to better understand the underlying mechanisms and to discover novel targets and cancer therapeutic drugs that may improve both the survival and quality of life of cancer patients.