A turning point: Focusing on translational medicine

Authors

  • Jun-Ping Liu

    Editor-in-Chief, CEPP
    1. Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China
    2. Department of Immunology, Monash University Central Clinical School, Prahran, Victoria, Australia
    3. Department of Genetics, University of Melbourne, Parkville, Victoria, Australia
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Translational medical research is being accelerated in the pace and spread recently. There have been the launches of the European Infrastructure for Translational Medicine (EATRIS) and the America National Center for Advancing Translational Sciences (NCATS). Many of us in the fields of biomedical research would be facing some new opportunities, challenges and questions in the new translational research era.[1] Near 40 years, the journal Clinical and Experimental Pharmacology and Physiology (CEPP) has been making endeavours to serve translational medicine by publishing the research achievements. The view that has been held is that translation from experimental research to clinical practice is a common goal of researchers in the fields of pharmacology and physiology. Seeing that translational research has now been popular more than ever (Fig. 1), CEPP may be facing its new opportunity to serve the fields as CEPP was fortunately placed to serve in this field since 1974.

Figure 1.

Cartoon of thriving translational biomedical research.

In 1975 Cornish et al.[2] published in CEPP that following a 50 g oral glucose load, twenty-five young healthy women who used oral contraceptives were found to show a significant decrease in glucose tolerance, whereas the plasma cortisol values were increased more than two-fold. In the same year, Waal-Manning reported in CEPP that a comparative cross-over trial on thirty hypertensive patients with impaired glucose tolerance showed a significant fall of serum creatinine and uric acid in response to mefruside therapy.[3] Recently, Ohishi et al.[4] studied the relationship between the angiotensin-converting enzyme (ACE) gene and plasma glucose increases following an oral glucose load, and reported in CEPP that the insertion/deletion (I/D) polymorphism of the ACE gene occurred at the frequencies of 0.43, 0.43 and 0.14 respectively, and that the increase in plasma glucose was significantly higher in the individuals with the DD genotype than in the individuals with either the II or ID alleles, calling for further investigations to determine whether the association between the ACE genotype and the postprandial hyperglycaemia impacts on the incidences of cardiovascular disease and diabetes mellitus.

Medicinal treatment of myocardial ischaemia has long been a challenge. Recent studies as reported in CEPP by Lv et al.[5] showed that the chemical ligustrazine (2,3,5,6-tetramethylpyrazine; TMP) from Chinese herbs exhibited a potent protective effect on myocardial ischaemia reperfusion (IR), and the mechanisms of action of TMP was through increased nitric oxide (NO) production and phosphatidylinositol 3-kinase (PI3K) signaling. Sprague-Dawley rats divided into 6 groups (sham control, IR positive control, TMP pretreated, TMP + PI3K inhibitor wortmannin, NO synthase inhibitor (N(G) -nitro-L-arginine methyl ester (L-NAME)), and TMP + L-NAME)) were subjected to regional ischaemia (35 min) followed by reperfusion (120 min). TMP treatment in the rats decreased the infarct sizes and attenuated the levels of myocardial apoptosis as measured with a decrease in the apoptotic index and reduced caspase-3 activity, caused a significant increase in NO production which was blocked by wortmannin or L-NAME, and induced the phosphorylations of Akt at the Ser 473 residue and of eNOS at the Ser1177 residue which were abrogated by wortmanninn.[5] It was concluded that ligustrazine has cardioprotective effects on myocardial IR injury, and the effects are mediated by PI3K and NO synthase.[5]

Uchiyama et al.[6] recently reported in CEPP that bacteria endotoxin-induced lung damage associated with various chemokines (e.g. keratinocyte chemoattractant, macrophage inflammatory protein-1alpha and macrophage chemoattractant protein-1) regulated by oxidative stress can be protected by vitamin E. Uchlyama et al.[6] showed that the novel water-soluble vitamin E derivative TMG (2-(alpha-D-glucopyranosyl) methyl-2,5,7,8-tetramethylchroman-6-ol) suppressed the acute lung injury induced by intratracheal instillation of LPS in mice. When TMG was given intratracheally and intravenously (0.1, 1.0 or 10 mg/kg), TMG decreased the neutrophil infiltration into bronchoalveolar lavage fluid in a dose-dependent manner in response to LPS challenge.[6] Consistently, the researchers also showed that the treatment with TMG not only ameliorated the LPS-induced infiltration of neutrophils into the lungs, but also attenuated the LPS-induced increase in pulmonary expression of keratinocyte chemoattractant, macrophage inflammatory protein-1alpha and macrophage chemoattractant protein-1 at both the gene transcription and protein translation levels. Thus, TMG might be a possible treatment for acute lung injury through moderating the local expression of chemokines.[6]

Another interesting example publication recently shown in CEPP was in an effort to identify new molecular targets for brain degenerative diseases that have been difficult in early diagnosis and thereby effective management. Cheng and colleagues discussed that the tyrosine kinase c-Src is aberrantly expressed in excitation stress- or excitotoxicity-induced neuronal death in acute and chronic neurodegenerative diseases, such as stroke and Parkinson's disease.[7] Overstimulation of glutamate receptors results in calcium overload in affected neurons, and sustained high concentration of intracellular calcium activates a host of enzymes including oxide synthase.[7] However, structural and biochemical analyses pointed to a significantly aberrant involvement of c-Src activation in the glutamate receptors, and the mechanisms whereby c-Src is activated appeared to involve calpain-mediated truncation and S-nitrosylation of c-Src.[7] Thus, c-Src could be an important target of an early diagnostic marker and therapeutic intervention in terms to reduce the extent of brain damage caused by stroke.[7]

However, what has been published of the great scientific achievements by CEPP in the last four decades or so is in fact merely a minute fraction, and there is a new trend of rapid developments of translational research. New hubs and nexuses, translational research centers and infrastructures, are emerging around the world to integrate expertise from different sectors between academia, pharmaceutical companies and biotech industries for translation research.[8] NCATS was last year formed and funded with US$575 million to facilitate translational medicine,[9] and EATRIS launched recently in June had already a series of conferences aiming to promote the collaborations between industry, small enterprises and academic institutions in their translational biomedical research.[10] There have been ongoing hot debates though in how these centers like NCATS, the Patient-Centered Outcomes Research Institute (PCORI), and the Cures Acceleration Network (CAN) might bring about the changes to accelerate translational research by bridging the gap between experiments and routine practice.[11, 12] The stride and scope of translational medicine seem more sought after in rapidly developing regions and areas. A number of translational medical research centers have been fostered in China (Fig. 2). Although the progresses will strongly facilitate the translations from experimental to clinical, there are barriers to doing so including the uses of standardized methods, measures and markers in diagnosis, treatment and prognosis, highlighting further needs of research and dada sharing.

Figure 2.

Recently announced translational medical research centers in China.

Can physiology zap therapeutic sweet spots[13]? The fields of pharmacology and physiology are interrelated in that the goal of both is to understand clinical medicine, and converge on translational medicine of the mechanisms of how body systems work and respond to different drug behaviours in experiments for clinical considerations. Research from physiology to pharmacology reflects some process of translational medicine from experiments to clinical practice with shared mechanisms (Fig. 3). While physiology focuses on internal machineries, and increasingly at cellular and molecular levels, to observe various responses to stimuli using classical and modern approaches under non-disease conditions, pharmacology concentrates on external drug molecules and responses of the physiological and pathophysiological systems to treatments in terms of both adverse effects and treatment efficacy. Interactions between pharmacology and physiology manifests in many diverse areas including molecular interactions between drugs and drug targets such as drug-metabolizing enzymes, drug transporters, and genes involved in diseases and individual differences in terms of treatment efficacy, effectiveness, and adverse effects. Pharmacological and clinical physiologies are studies that concern the physiological systems and mechanisms responding to treatment and disease environments using various physiological observations to identify fundamental patterns and genetic determinants that impact on drug effects in animal and clinical settings.[13] The study of genomic factors, gene expression and regulation, and genome stability and plasticity could be readily integrated into physiological and pharmacological studies along with non-genetic, epigenetic or environmental factors, leading to a natural convergence of the two fields.

Figure 3.

A focus on translational medicine from experimental research to clinical practice through pharmacology and physiology.

Thanks to Mike Rand, Paul Korner, John Coghlan and Austin Doyle who started CEPP, and to the previous predecessors (Table 1), as the new Editor-in-Chief from July of this year, I was excited about the opportunities of what CEPP should be able to contribute in the booming time of translational medicine, given the missions set up about four decades ago in serving the interdisciplinary translational research from experimental to clinical. I was trained in medicine about 35 years ago at the Bethune Medical University in China and practiced at both Bethune Medical University and Peking University affiliated hospitals before embarking Melbourne Australia to do PhD at Monash University. My academic backgrounds include trainings in endocrinology (1987–1991), neurochemistry (1992–1996), cancer and cardiovascular researches (1996–2001), and lecturing undergraduates in cell biology, immunology and pathology (2002–2010) in Australia. Since 2002, my research has been focused on molecular oncology and system biology of ageing. Assuming the role of Editor-in-Chief of CEPP would be a new turning point for me, so I am prepared to learn and make the changes. To continue and develop the significant publication traditions of CEPP as reflected above by embracing the rapidly turning and gearing up of translational biomedical research, I would envisage a new turning point for CEPP.

Table 1. Editors-in-Chief of CEPP
YearPostNameDoctorateOrganization
1974–1988Co-Editors-in-ChiefMike RandPhDUniversity of Melbourne
Paul KornerMDBaker Medical Research Institute
John CoghlanPhD, MDUniversity of Melbourne
Austin DoylePhDUniversity of Melbourne
1989–1992Editor-in-ChiefAustin DoylePhDUniversity of Melbourne
1993–2005Editor-in-ChiefWarwick AndersonPhDBaker Medical Research Institute and Monash University
2006Acting Editor-in-ChiefRoger EvansPhDMonash University
2007–2011Co-Editors-in-ChiefRoger EvansPhDMonash University
Ding-Feng SuMDSecond Military Medical University
2011–2012Editor-in-ChiefRoger EvansPhDMonash University
2012Editor-in-ChiefJun-Ping LiuPhD, MDHangzhou Normal University

Acknowledgements

The author wishes to thank Ms Jincai Xu for preparing the table and figures. The author's research was supported by grants from the National Basic Research Program of China (2012CB911201), and the National Health and Medical Research Council of Australia (1007427).

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