Welcome to the second edition of our new monthly series where we highlight the latest research findings in key research areas along with other interesting science news. The studies presented in this post represent significant advancements that could revolutionize disease treatment. We also feature the latest scientific discussion on what it takes to move a scientific field forward. Happy Reading!
Discovery of new molecular targets for treating nerve pain
Neuropathic pain is a chronic pain state arising from injury or disease within the peripheral or central nervous system. Although opioids like morphine and acetaminophens such as Tylenol® can relieve the pain, they pose the potential risk of addiction or negative side effects due to their systemic administration. As part of their long-term investigation of the central nervous system, the research group of Professor Yoshihiro Nakata, PhD at Hiroshima University induced partial sciatic nerve ligation (PSNL) in mice in order to identify molecules involved in maintaining neuropathic pain. Persistent upregulation of HMGB1 was observed following PSNL, and repeated local administration of an anti-HMGB1 antibody significantly reduced the pain and PSNL-induced mechanical hypersensitivity in mice. The authors also observed that other molecules such as matrix metalloproteinase-9 (MMP-9), tumor necrosis factor-α, interleukin-1β and cyclooxygenase-2 were also upregulated post PSNL. Treatment with the anti-HMGB1 antibody following a similar administration schedule significantly suppressed MMP-9 expression but had no effect on the other molecules. This identified MMP-9 as a molecular target in neuropathic pain, and the authors further demonstrated that single administration of a MMP-9 inhibitor had similar effects on relieving pain as repeated anti-HMGB1 treatments. This indicates that specific targeting of MMP-9 may be a more direct route to treating neuropathic pain. This is the first study to link HMGB1 and MMP-9 in the cellular process of maintaining pain. In addition, the molecular mechanisms that the drugs in this study use to inhibit HMGB1 and MMP-9 differ from common pain relievers, thus greatly reducing the risk of addiction or negative side effects.
Zhang FF et al. (2016). Perineural expression of high-mobility group box-1 contributes to long-lasting mechanical hypersensitivity via matrix metalloproteinase-9 up-regulation in mice with painful peripheral neuropathy. J Neurochem 136, 837-850.
The cells-of-origin of prostate cancer no longer a mystery
The identity of the cells that eventually lead to prostate cancer has eluded researchers for quite some time. It was traditionally believed that luminal cells are the originators of human prostate cancer due to the luminal-like phenotype of the disease. This hypothesis was however challenged by a study showing that a subset of basal cells function as the precursors of prostate cancer (Goldstein AS et al. 2010). In contrast, a later study showed that although both basal and luminal cells can function as the cells-of-origin, luminal cells are more susceptible to tumorigenesis in prostate cancer (Choi N et al. 2012, Wang ZA et al. 2014). To address this controversy, a team of researchers led by Professor Dean Tang, MD PhD at the MD Anderson Cancer Center performed a detailed transcriptome analysis of unperturbed human benign prostatic basal and luminal cells by deep RNA-Seq. The researchers demonstrate that basal cells exhibit a stem cell and epithelial-to-mesenchymal gene expression profile, and established that these cells are in fact linked to aggressive prostate cancer. In addition, they determined that basal cells express high levels of Pol I, which encodes an enzyme involved in DNA replication, and MYC, a regulator gene that plays a role in cell death and tumorigenesis. This suggests that inhibitor drugs targeted against Pol-I and MYC could potentially treat aggressive prostate cancer.
Goldstein AS et al. (2010). Identification of a cell of origin for human prostate cancer. Science 329, 568-571.
Wang ZA et al. (2014). Luminal cells are favored as the cell of origin for prostate cancer. Cell Rep 8, 1339-1346.
Zhang D et al. (2016). Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nat Comm 7, 10798.
Age and cohabitation significantly affect immunological diversity
Studies investigating the immunological diversity between healthy individuals have determined that non-genetic factors account for approximately 50-75% of the immunogenic variation in humans (Brodin P et al. 2015). However, exactly what these factors are remained poorly understood, until recently. In a new study published in the journal Nature Immunology, Carr EJ et al. (2016) profiled the immune system of 670 healthy human volunteers to determine the population-level heterogeneity in the cellular composition of the immune system. Using a systems-immunology approach, they assessed the impact of BMI, sex and psychological factors on immune composition. The authors found that age and cohabitation greatly affect the immunological landscape. An individual’s age had the most significant influence, which supports the longstanding observation that immune function declines with age. To the surprise of the authors however, immune profiles were more similar between individuals that share an environment (e.g. parents) than between people in the wider population. Future studies will explore possible mediators of this effect such as shared behavior and child rearing.
Brodin P et al. (2015). Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37-47.
Carr EJ et al. (2016). The cellular composition of the human immune system is shaped by age and cohabitation. Nat Immunol doi: 10.1038/ni.3371 [Epub ahead of print].
Further insight into the mechanisms of nonesterified fatty acid mediated diseases in ruminants
Elevated plasma levels of nonesterified fatty acids (NEFAs) have been linked to the incidence of metabolic and infectious bovine diseases such as fatty hepatitis, metabolic ketosis and endometritis, which often cause high economic loss to the cattle industry worldwide. Studies demonstrate that primary bovine tissues and endothelial cells are highly susceptible to NEFA exposure via the bovine G-protein-coupled free fatty acid receptor known as bGPR40. In order to determine the mechanisms involved in this process, researchers at the Austral University of Chile assessed the effect of NEFAs on key inflammatory and disease biomarkers in bovine umbilical vein endothelial cells (BUVECs). They demonstrate for the first time that different NEFAs affect BUVECs in different ways with regards to intracellular calcium (Ca2+i) influx, nitric oxide production and ICAM-1 and IL-8 expression. In addition, they show that GPR40 is involved in the increase in calcium induced by the NEFA myristic acid. This study provides new insight into the molecular mechanisms mediating endothelial cell activation by NEFAs, which serves as a platform for developing effective therapies against bovine diseases mediated by elevated NEFA levels.
Loaiza A et al. (2016). Differential intracellular calcium influx, nitric oxide production, ICAM-1 and IL8 expression in primary bovine endothelial cells exposed to nonesterified fatty acids. BMC Vet Res 12, 38.
Pressure induces sprouting of blood vessels
Sprouting angiogenesis is the process by which new cells grow from the walls of existing nearby capillaries. When the capillaries begin to sprout, they are initially endothelial cells without a lumen, which is the internal space through which the blood flows. Up until recently, scientists were unsure as to how the lumen actually forms during this process to form blood vessels. A team of researchers recently published the answer to this puzzle in the Nature Cell Biology journal. Studying embryogenesis in zebrafish, in which the endothelial cell membrane was fluorescently labeled, Gebala V et al. showed that blood pressure drives lumen formation. Blood pressure at a sufficiently high rate induces invagination of the cell membrane, which spreads further into the cell, thus creating the lumen. This process occurs under the guidance of the endothelial cells via actomyosin filaments. The authors termed the process “inverse membrane blebbing”. Now that the mechanism of lumen formation is understood, the authors propose that the next step is to understand how this mechanism functions in disease states such as cancer, in which angiogenesis plays a key role in tumor progression.
Gebala MM et al. (2016). Blood flow drives lumen formation by inverse membrane blebbing during angiogenesis in vivo. Nat Cell Biol doi: 10.1038/ncb3320, [Epub ahead of print].
Role of S. pneumoniae virulence factor during pneumococcal lung disease identified
Streptococcus pneumoniae is a Gram positive anaerobe that is responsible for approximately 850,000 deaths per year in children under five years old. It is the leading cause of bacteremia, otitis media, sinusitis and meningitis worldwide, which are more prevalent in developing countries. How S. pneumoniae changes from being asymptomatic to causing pneumoniae is not yet understood. In a recent article published in the Journal of Immunology, Walker MM et al. (2014) address this issue by investigating the role of a key S. pneumoniae virulence factor, PcpA during pneumococcal lung disease using two distinct mouse models. They found that PcpA is involved in innate immune modulation during pneumococcal pneumonia and is associated with increased bacterial burden in the lung, spleen and liver, as well as increased inflammation and negative regulation of innate immune cell recruitment. These findings suggest that PcpA could be a useful candidate in vaccines against pneumococcal infection.
Walker MM et al. (2016). PcpA promotes higher levels of infection and modulates recruitment of myeloid-derived suppressor cells during pneumococcal pneumonia. J Immunol 196, 2239-2248.
The balance between replicating findings and moving a scientific field forward
While the reproducibility crisis in science is still a major area of concern, scientists are also addressing another critical issue in the research arena. A number of researchers took to social media to ask how many times should a scientific observation be validated by other scientists before it is considered reasonable to build upon the findings and move a field forward. Professor Dorothy Bishop, PhD FRS FBA FMedSci, a neuropsychologist at the University of Oxford described this perpetual replication of similar research findings as “stasis”, “the opposite of the reproducibility crisis”. This stagnation in biomedical research has been described as wasteful, in that promising findings often don’t lead to improved health care (Macleod MR et al. 2014). Improved clinical patient outcomes rely on consistent advancement in biomedical research; therefore it is important that scientists weigh the pros and cons of the current system. To learn more, check out the recent Nature News article on the topic.
Macleod MR et al. (2014). Biomedical research: increasing value, reducing waste. Lancet 383, 101-104.
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