Press Release of Okayama UniversityOkayama University
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2022-02-01Okayama University e-Bulletin Vol.12
https://www.okayama-u.ac.jp/eng/release/index_id335.html
Source: Okayama University, Japan, Public Relations and Information Strategy Division
SUBLECT LINE: Okayama University e-Bulletin: Plants feel stress!
For immediate release: 24 September 2015
Okayama University, Japan publishes the September 2015 issue of its online newsletter, Okayama University e-Bulletin: //www.okayama-u.ac.jp/user/kouhou/ebulletin/
(Okayama, Japan, 24 September 2015) This issue includes a feature on new insights into ‘plant stress’ and how plants absorb nutrients and toxins; news of an agreement by Okayama University and IAEA on radioactive waste management and environmental remediation, the world’s first hybrid lung transplant, developing iron-controlled biology, and networking to combat infectious diseases; research highlights on high-efficiency energy transfer in photosynthetic organisms, key genes in epidermal cell differentiation for survival of plants, critical points of water in carbon nanotubes, damage-free structure of photosystem II, and synthesis of compounds for water-oxidation; an innovative method to fabricate metallic nano-surfaces for surface-enhanced Raman spectroscopy; and a ‘vista’ of Okayama’s Bizen Yaki pottery.
Okayama University e-Bulletin highlights news and views from one of Japan"s largest comprehensive universities internationally recognized for its dynamic and innovative approach to interdisciplinary scientific research and pioneering educational programs.
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2015-09-24Okayama University Medical Research Updates (OU-MRU) Vol.14
https://www.okayama-u.ac.jp/eng/release/index_id328.html
Source: Okayama University, Center for Public Affairs and Communications
For immediate release : 16 September 2015
Okayama University research : Simplified boron compound may treat brain tumours
(Okayama, 16 September) Effective and targeted uptake among malignant cells demonstrates the promise of a simplified boron compound for neutron radiation therapy, report researchers at Okayama University and Kinki University.
“Glioblastoma multiforme is the most common malignant central nervous system primary tumour that has been incurable for decades,” explain Hideki Matsui and colleagues at Okayama University Graduate School of Medicine and Kinki University in their recent report. Treatment with ‘boron neutron capture therapy’ (BNCT) has been found to double the duration of patient survival, but finding effective compounds for it has been challenging. Now Michiue and colleagues have demonstrated - both in cell lines and mice - a readily made boron compound that targets and penetrates tumour cells for effective BNCT [1].
The compound BSH is high in boron content and has the advantage of accumulating primarily in tumour tissue rather than healthy tissue. However BSH does not penetrate inside the tumour cells limiting the therapeutic effects of BNCT using it.
Previously Michiue and a collaboration of researchers in Japan demonstrated they could enhance cell penetration by fusing BSH with a large peptide comprising up to 11 amino acid ‘arginine’ groups [2]. However with the large added peptide it was difficult both to produce the compound and track its effects in the body.
Studies of protein transcription aided by a smaller version of the peptide suggested that a compromise in size may allow effective BSH cell penetration without the need for prohibitively complicated synthesis techniques. [3]. The latest results from Michiue and colleagues have now shown that while peptides with just one or two arginine groups were ineffective, three arginine groups were enough to improve cell uptake.
The BSH fused with a peptide of three arginine groups was simpler to produce and they could also track the drug in the body using positron emission tomography. They conclude, “In our present study, we discovered that BSH-3R overcame many obstacles to develop a BSH-peptide suitable for future clinical use.”
BackgroundBoron neutron capture therapyOne of the challenges with treating glioblastoma multiforme is removing all cancer cells without causing damage to the brain. The destruction of nearby healthy cells is a significant side effect for traditional radiation therapy.
BCNT has attracted particular interest because the radiation caused is highly localised. When boron is delivered to malignant cancer cells, irradiation with low-energy thermal neutrons then triggers boron fission into a high energy alpha particle and lithium atom. While lethal to cells in their direct path the high-energy alpha particle and lithium atom produced cannot travel further than roughly a cell length before their energy is absorbed leaving nearby healthy cells intact.
BNCT has already been used clinically for treating brain tumours, malignant melanoma, head and neck cancers, and hepatoma. Hospital sources for low-thermal-energy neutrons to trigger the fission are in continued development. However clinical use so far has highlighted shortcomings in the boron delivery drugs currently available.
Boron delivery drugsPrevious clinically used drugs for BNCT include an essential amino acid analog p-borono-Lphenylalanine (BPA) and disodium mercaptoundecahydrododecaborate ([B12HnSH]2-2Na+, BSH). BPA readily delivers high boron content to cells but it does not target malignant cells alone and is not taken up by slowly proliferating malignant cells.
In contrast accumulation of BSH is greatly enhanced in tumour regions but it is present between the cells making it less effective for BNCT. Simulations in previous work have highlighted the limitations of BNCT from outside the cell.
ArginineArginine is a type of amino acid. Previous work has shown that with an 11-arginine-strong peptide the cancer killing effect of the BSH compound was greater than with a dose 100 times stronger of BSH without the added peptide. However it is difficult to synthesise BSH with the 11-arginine peptide and it cannot be readily tracked to monitor its effects in the body. The results of this latest work resolve some of the practical issues around using arginine groups to improve BSH cell penetration for cancer treatment using BNCT.
Figure captionChemical structures of the readily synthesised BSH fused with comparatively short ‘nR’ peptides, where R is the arginine group and n is the number of arginine groups. When fused with 3R the BSH penetrates the cell for effective BNCT. The chemical is additionally readily fused with a fluorescent moiety, Tmr (a), and DOTA for positron emission tomography scans (b) to track the drug in the body.
ReferencesYoshiya Iguchi, Hiroyuki Michiue, Mizuki Kitamatsu, Yuri Hayashi, Fumiaki Takenaka, Tei-ichi Nishiki and Hideki Matsui. Tumor-specific delivery of BSH-3R for boron neutron capture therapy and positron emission tomography imaging in a mouse brain tumor model. (2015) Biomaterials 56 10e17doi: 10.1016/j.biomaterials.2015.03.061.http://www.ncbi.nlm.nih.gov/pubmed/25934274Hiroyuki Michiue, Yoshinori Sakurai, Natsuko Kondo, Mizuki Kitamatsu, Feng Bin, Kiichiro Nakajima, Yuki Hirota, Shinji Kawabata, Tei-ichi Nishiki, Iori Ohmori, Kazuhito Tomizawa, Shin-ichi Miyatake, Koji Ono and Hideki Matsui. The acceleration of boron neutron capture therapy using multi-linked mercaptoundecahydrododecaborate (BSH) fused cell-penetrating Peptide. (2014) Biomaterials 35 3396e3405doi: 10.1016/j.biomaterials.2013.12.055.http://www.ncbi.nlm.nih.gov/pubmed/24452095Takashi Hitsuda, Hiroyuki Michiue, Mizuki Kitamatsu, Atsushi Fujimura, Feifei Wang, Takahiro Yamamoto, Xiao-Jian Han, Hiroshi Tazawa, Atsuhito Uneda, Iori Ohmori, Tei-ichi Nishiki, Kazuhito Tomizawa, Hideki Matsui . A protein transduction method using oligo-arginine (3R) for the delivery of transcription factors into cell nuclei. (2012) Biomaterials 33 4665e4672doi: 10.1016/j.biomaterials.2012.02.049.http://www.ncbi.nlm.nih.gov/pubmed/22465335
Correspondence toAssistant Professor Hiroyuki Michiue, M.D., Ph.D.
Department of Physiology, Okayama University
Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, 2-5-1 Shikata-Cho,
Okayama, 700-8558, Japan.
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Okayama University Medical Research Updates (OU-MRU)Vol.1:Innovative non-invasive ‘liquid biopsy’ method to capture circulating tumor cells from blood samples for genetic testingVol.2:Ensuring a cool recovery from cardiac arrestVol.3:Organ regeneration research leaps forwardVol.4:Cardiac mechanosensitive integratorVol.5:Cell injections get to the heart of congenital defectsVol.6:Fourth key molecule identified in bone developmentVol.7:Anticancer virus solution provides an alternative to surgeryVol.8:Light-responsive dye stimulates sight in genetically blind patientsVol.9:Diabetes drug helps towards immunity against cancerVol.10:Enzyme-inhibitors treat drug-resistant epilepsyVol.11:Compound-protein combination shows promise for arthritis treatmentVol.12:Molecular features of the circadian clock system in fruit fliesVol.13:Peptide directs artificial tissue growth
About Okayama UniversityOkayama University is one of the largestcomprehensive universities in Japan with roots going back to the Medical Training Place sponsored by the Lord of Okayama and established in 1870. Now with 1,300 faculty and 14,000 students, the University offers courses in specialties ranging from medicine and pharmacy to humanities and physical sciences. Okayama University is located in the heart of Japan approximately 3 hours west of Tokyo by Shinkansen.2015-09-16Okayama University Medical Research Updates (OU-MRU) Vol.13
https://www.okayama-u.ac.jp/eng/release/index_id324.html
Source: Okayama University, Center for Public Affairs and Communications
For immediate release: 05 August 2015
Okayama University research: Peptide directs artificial tissue growth
(Okayama, 05 August) Studies on peptide-modified cultures demonstrate control over both tissue growth and location in vitro.
“In vitro fabricated biological tissue would be a valuable tool to screen newly synthesized drugs or understand the tissue development process,” explain Takuya Matsumoto and his colleagues in a recent report. However tissues grown so far have not reached the size and final shape of natural tissue. Matsumoto and colleagues at Okayama, Osaka and Kansai Universities in Japan have now identified a tripeptide sequence that can be used to overcome both limitations. With hydrogel modified with the tripeptide they demonstrate enhanced tissue growth of a salivary gland both across a sheet of tissue and at specified localised points.
The salivary gland studied - the submandibular gland - develops a branched structure through budding and the elongation of ducts, which is also typical of other structures such as lungs, kidneys, mammary glands and spleen. Previous research revealed the importance of the glycoprotein fibronectin in the morphological development and growth of salivary gland tissue. Consequently Matsumoto and colleagues focused their investigations on the effects of the specific tripeptide sequence arginine-glycine aspartic acid (RGD) that acts as a cell binding site on fibronectin.
The researchers studied the growth of salivary gland tissue on hydrogel both modified with different concentrations of RGD and without and found significant growth enhancements that increased with RGD concentrations. They then experimented with RGD-modified hydrogel beads and demonstrated that localised growth enhancement occurred where the beads were situated, which could provide control over morphology in artificial tissue growth. Further studies also suggested that neuronal growth and the enhancement of growth factor proteins were responsible for the enhanced gland tissue growth observed.
In their report of the work the researchers conclude, “This in vitro SMG tissue growth modulation system can have a variety of uses including tissue arrays for drug screening and as a biologic tool to understand tissue development.”
BackgroundTripeptide in previous studiesThe shape development or morphogenesis of the submandibular gland develops through the formation of clefts that occur through a change in cell adhesion so that they bind to the surrounding extracellular matrix instead of each other. Previous research has shown that expression of the glycoprotein fibronectin is crucial for cleft formation.
Integrin is a receptor protein that bridges interactions between cells and the extracellular matrix. The domain of fibronectin that binds to integrin is the tripeptide sequence arginine-glycine aspartic acid (RGD) prompting studies of this tripeptide sequence on tissue growth.
Investigations have already shown that transplanting composites containing RGD peptides onto the back of a mouse can result in the development of growth plates – the tissue at the ends of bones in growing children and adolescents. However so far there have been no studies into the growth and morphology of tissues in vitro. The ability to grow tissues in vitro is particularly important for drug screening and studies to better understand tissue growth.
The role of FGFsFibroblast growth factors (FGFs) are a family of proteins involved in embryonic development, wound healing and signalling pathways. Two specific FGFs play a crucial role in the growth of the two main tissue types in the submandible salivary gland – FGF7 induces budding in the epithelial tissue and FGF10 induces the elongation of ducts in the mesenchymal tissue.
Matsumoto and colleagues imaged the salivary gland tissues grown in RGD-modified hydrogels using immunofluorescent staining and found both FGF7 and FGF10 were highly expressed. Experiments to grow the salivary gland tissues in the presence of FGF7 and FGF10 antibodies revealed that these antibodies inhibited tissue growth. The RGD-modified hydrogel was also ineffective at enhancing tissue budding in isolated epithelial cells alone.
The role of neuritesPrevious studies have also suggested that neuron outgrowths – ‘neurites’ – from a region known as the parasympathetic ganglion in submandibular gland tissue are key to tissue growth. The researchers observed an even distribution of the neurite network throughout the gland tissues they had grown. Antibodies to the neurotrophic factors, which are responsible for neuron growth and survival, also inhibited submandibular gland tissue growth in RGD-modified hydrogels.
Figure captiona) Schematic illustration of the RGD-modified hydrogel (left) and the submandibular gland (SMG) tissue culture on hydrogel (right). b,c) SMG cultured on hydrogel sheets modified by introducing various RGD concentrations (0–0.18 mol/l), and SMG cultured on a tissue culture dish without any hydrogel substrate as a negative control (Bar = 50 μ m). A stiffer gel sheet normally attenuates SMG growth, but the SMG growth was enhanced when RGD was introduced. The SMG growth changed in accordance with the introduced amount of RGD. SMG was completely dissociated when cultured on the traditional tissue culture dish instead of hydrogel.
ReferenceHiroaki Taketa, Gulsan Ara Sathi, Mahmoud Farahat, Kazi Anisur Rahman, Takayoshi Sakai, Yoshiaki Hirano, Takuo Kuboki, Yasuhiro Torii, Takuya Matsumoto. Peptide-modified Substrate for Modulating Gland Tissue Growth and Morphology In Vitro. Scientific Reports 5, Article number: 11468 (2015).
DOI: 10.1038/srep11468
http://www.nature.com/articles/srep11468
Correspondence toProfessor Takuya Matsumoto, D.D.S., Ph.D.
Department of Biomaterials, Okayama University,
2-5-1 Shikata-Cho, Okayama, 700-8558, Japan.
E-mail: tmatsu@md.okayama-u.ac.jp
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Okayama University Medical Research Updates (OU-MRU)Vol.1:Innovative non-invasive ‘liquid biopsy’ method to capture circulating tumor cells from blood samples for genetic testingVol.2:Ensuring a cool recovery from cardiac arrestVol.3:Organ regeneration research leaps forwardVol.4:Cardiac mechanosensitive integratorVol.5:Cell injections get to the heart of congenital defectsVol.6:Fourth key molecule identified in bone developmentVol.7:Anticancer virus solution provides an alternative to surgeryVol.8:Light-responsive dye stimulates sight in genetically blind patientsVol.9:Diabetes drug helps towards immunity against cancerVol.10:Enzyme-inhibitors treat drug-resistant epilepsyVol.11:Compound-protein combination shows promise for arthritis treatmentVol.12:Molecular features of the circadian clock system in fruit flies
About Okayama UniversityOkayama University is one of the largestcomprehensive universities in Japan with roots going back to the Medical Training Place sponsored by the Lord of Okayama and established in 1870. Now with 1,300 faculty and 14,000 students, the University offers courses in specialties ranging from medicine and pharmacy to humanities and physical sciences. Okayama University is located in the heart of Japan approximately 3 hours west of Tokyo by Shinkansen.2015-08-05Artificial Retina Developed by Okayama University Promises to Provide Effective and Safe Treatment for Vision Loss
https://www.okayama-u.ac.jp/eng/release/index_id311.html
A photoelectric dye-coupled polyethylene film developed by Okayama University is a retinal prosthesis called OUReP™. It generates light-evoked surface electric potentials and stimulates neurons.
Researchers in Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences have shown the recovery of vision in rats with retinitis pigmentosa (RP) and electroretinographic responses in their eyes following the implantation of the retinal prosthesis “OUReP™”.
The findings were published on March 3, 2015 in the Journal of Artificial Organs.
http://link.springer.com/article/10.1007/s10047-015-0825-1
Alamusi, T. Matsuo and their colleagues studied rats with RP that had OUReP™ implanted at the age of 14 weeks. The vision recovery of the rats was shown by behavior tests. They also implanted the dye-coupled film in rats with RP at the age of 6 weeks and observed no additional retinal changes at the site of the implantation after five months. The study showed the safety and the efficacy of the retinal prosthesis “OUReP™”.
The dye-coupled film is sufficiently thin and soft so that the implantation can be done by existing procedures. In addition, the prosthesis would be available at a reasonable price because the film materials are not expensive. The function of the prosthesis is expected to allow for a large field of view and high vision resolution.
Contact Information
Mototaka Senda, Ph.D.
Director, Okayama University Silicon Valley Office
Organization for Research Promotion and Collaboration, Okayama University
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Fremont, California USA
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Toshihiko Matsuo, M.D.
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan2015-06-30Neurons in Drosophila Related to Recovery of Jet-lag Identified
https://www.okayama-u.ac.jp/eng/release/index_id310.html
Researchers in Okayama University and University of Würzburg have shown that approximately fourteen neurons of the brain in Drosophila are critical in the recovery of jet lag.
The findings were published on April 15, 2015 in the Journal of Neuroscience.
http://www.jneurosci.org/content/35/15/6131.short
T. Yoshii and his colleagues have searched for neurons in the brain of Drosophila related to entrainment to new light/dark cycles of the circadian clock. They have found that specific subsets of neurons have a major role of rapid recovery of jet lag when a protein called Cryptochrome is expressed in the cells.
Drosophila has approximately 150 neurons in the brain related to its circadian clock. The study showed that fourteen neurons among them have distinct functions in light entrainment and might have a central role in the circadian clock.
Jet lag is caused by traveling abroad, night shift work and irregular habits in ordinary life. Many people are suffering from jet lag. The findings could lead to the development of the inhibition of jet lag.
Contact Information
Mototaka Senda, Ph.D.
Director, Okayama University Silicon Valley Office
Organization for Research Promotion and Collaboration, Okayama University
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Fremont, California USA
TEL: 1-510-396-2031
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Taishi Yoshii, Ph.D.
Graduate School of Natural Science and Technology, Okayama University, Okayama Japan
2015-06-30Mn4Ca-cluster Mimicking the Oxygen-evolving Center of Photosynthesis Synthesized
https://www.okayama-u.ac.jp/eng/release/index_id314.html
A collaborative research group of Okayama University, Chinese Academy of Sciences and Free University Berlin has succeeded in synthesizing a Mn4Ca-cluster similar to the native oxygen-evolving center (OEC) of photosynthesis.
The findings were published on May 8, 2015 in the journal of Science.
www.ncbi.nlm.nih.gov/pubmed/?term=Science+8+May+2015:++Vol.+348+no.+6235+pp.+690-693+DOI:10.1126/science.aaa6550
Photosynthetic splitting of water into oxygen by plants, algae, and cyanobacteria is catalyzed by the OEC. Synthetic mimics of the OEC, composed of an asymmetric manganese-calcium-oxygen cluster bound to organic groups, may promote insight into the structural and chemical determinants of biological water oxidation.
The collaborative research group synthesized a Mn4Ca-cluster similar to the native OEC in both the metal-oxygen core and the binding ligand groups. The synthetic cluster can undergo four redox transitions and shows two magnetic resonance signals assignable to redox and structural isomerism like the native OEC. However, there are slight differences in the number of oxo-bridges between the metal ions and the water ligands between the native cluster and the synthetic one, which may be important for the activity of water oxidization.
The findings could provide a useful model system for the study of the mechanism of water oxidation in the native cluster and lead to the implementation of artificial photosynthesis.
Contact Information
Mototaka Senda, Ph.D.
Director, Okayama University Silicon Valley Office
Organization for Research Promotion and Collaboration, Okayama University
2450 Peralta Blvd. #119
Fremont, California USA
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Jian-Ren Shen, Ph.D.
Graduate School of Natural Science and Technology, Okayama University, Okayama Japan2015-06-30Okayama University Medical Research Updates (OU-MRU) Vol.12
https://www.okayama-u.ac.jp/eng/release/index_id315.html
Source: Okayama University, Center for Public Affairs and Communications
For immediate release: 26 June 2015
Okayama University research: Molecular features of the circadian clock system in fruit flies
(Okayama, 26 June) Studies of mutant fruit flies reveal how both photoreceptors and the visual system influence circadian clock neurons in response to changing light-dark cycles. The results are reported in the Journal of Neuroscience give new insights into sleep disorders including jet-lag.
Our bodies can respond to shifts in day and night patterns by reprogramming our so-called ‘circadian clock’ - a molecular system which responds to light-dark cycles (LD cycles). Now, Taishi Yoshii and Kenji Tomioka at the Graduate School of Natural Science and Technology, Okayama, in collaboration with scientists in Germany, have revealed how protein photoreceptors called ‘cryptochromes’ (CRY), together with the visual system, influence circadian clock neurons in Drosophila, or fruit flies[1].
Circadian clock neurons can be divided into two groups; morning neurons (M) and evening neurons (E). CRY proteins are expressed in most clock neurons and send signals in response to light, but the specific role of CRY in different types of clock neurons is unclear.
Yoshii and colleagues generated mutant fly-lines, some without CRY and others expressing CRY in different neuron subsets. They also wanted to determine the influence of the eyes and visual system signals on the neurons. Their aim was to test the flies’ ability to synchronise to changes in LD cycles, a process known as LD entrainment.
They exposed the flies to an 8-hour delay in the 16-hour/8-hour LD-cycle. Control flies responded to the shift within a day, but those flies without CRY, and without eyes, were incapable of any LD entrainment. Mutant flies with E neurons were able to re-entrain, but their response was slow. The team discovered this entrainment ability was due to a molecular cycling process involving a protein called par domain protein 1 (PDP1), which is triggered by the visual input pathways, independent of CRY.
When the team then expressed CRY in the E neurons the LD entrainment process sped up considerably. If CRY was expressed only in M neurons, no LD entrainment occurred. The results indicate that CRY expression in E neurons is important to LD entrainment and that molecular cycling of PDP1 supports this process.
BackgroundCryptochromesCircadian clock neurons respond to signals from a class of proteins called ‘cryptochromes’ (CRY), which are found in animals and plants. The CRY protein is photoreceptive; when exposed to blue light, CRY undergoes conformational changes, allowing it to bind to a circadian clock protein called TIMELESS (TIM). This action triggers the degradation of TIM, thereby resetting the body’s circadian clock.
Previous research has shown that Drosophila (fruit flies) are highly light-sensitive - TIM degradation occurs even after exposure to a short, weak light pulse during darkness. However, how CRY and the visual system help the body to respond to changes in light-dark cycles (so-called LD entrainment) has not been fully explored.
MethodologyTo determine whether separate clock neurons have different functions in CRY-dependent light responses, the researchers generated various Drosophila fruit fly lines, with different CRY expression in individual subsets of clock neurons. They also used control flies with no alterations, null-CRY lines to examine the effect of knocking out CRY altogether, and flies with null-CRY and no eyes, to examine the influence of the visual system in the LD entrainment process. The team also analyzed par domain protein 1 (PDP1), a protein important for the molecular mechanism of the circadian clock.
They exposed all the different fly groups to an 8-hour shift in LD cycle. Control flies shifted their circadian clock within a day. The mutant flies exhibited different patterns of LD entrainment, depending on CRY expression and visual inputs.
They found PDP1 worked independently of CRY to help in LD entrainment, but only in evening (E) neurons. Null-CRY E neurons were still capable of LD entrainment, but it was very slow. Reinstating CRY into two particular E neurons (fifth s-LNv and LNd), sped up the process considerably.
Future workCRY expression in E neurons is particularly important for the rapid adjustment of the circadian clock in the event of LD cycle changes. Further work is needed to understand how morning (M) neurons factor in the LD entrainment of E neurons, and whether M cells (and another subset of neurons called PDF neurons) can contribute to LD entrainment in the absence of CRY.
Figure captionThe circadian neurons responsible for response to changing light-dark cycles. The brain and the distribution of the circadian clock neurons of the fruit fly Drosophila melanogaster (Left). The enlarged picture of E neurons (fifth s-LNv and LNd) (Right).
Reference T. Yoshii, C. Hermann-Luibl, C. Kistenpfennig, B. Schmid, K. Tomoika, & C. Helfrich-Förster. Cryptochrome-dependent and - independent circadian entrainment circuits in Drosophila. The Journal of Neuroscience 35 (15) April 15th 2015, 35(15):6131-6141・6131.
DOI:10.1523/JNEUROSCI.0070-15.2015
http://www.ncbi.nlm.nih.gov/pubmed/25878285
Correspondence toAssociate Professor Taishi Yoshii, Ph.D.
Laboratory of Chronobiology, Graduate School of Natural
Science and Technology, Okayama University,
Tsushima-Naka 3-1-1, Kita-ku, Okayama 700-8530, Japan.
E-mail: yoshii@okayama-u.ac.jp.
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Okayama University Medical Research Updates (OU-MRU)Vol.1:Innovative non-invasive ‘liquid biopsy’ method to capture circulating tumor cells from blood samples for genetic testingVol.2:Ensuring a cool recovery from cardiac arrestVol.3:Organ regeneration research leaps forwardVol.4:Cardiac mechanosensitive integratorVol.5:Cell injections get to the heart of congenital defectsVol.6:Fourth key molecule identified in bone developmentVol.7:Anticancer virus solution provides an alternative to surgeryVol.8:Light-responsive dye stimulates sight in genetically blind patientsVol.9:Diabetes drug helps towards immunity against cancerVol.10:Enzyme-inhibitors treat drug-resistant epilepsyVol.11:Compound-protein combination shows promise for arthritis treatment
About Okayama UniversityOkayama University is one of the largestcomprehensive universities in Japan with roots going back to the Medical Training Place sponsored by the Lord of Okayama and established in 1870. Now with 1,300 faculty and 14,000 students, the University offers courses in specialties ranging from medicine and pharmacy to humanities and physical sciences. Okayama University is located in the heart of Japan approximately 3 hours west of Tokyo by Shinkansen.2015-06-26Okayama University Medical Research Updates (OU-MRU) Vol.11
https://www.okayama-u.ac.jp/eng/release/index_id304.html
Source: Okayama University, Center for Public Affairs and Communications
For immediate release: 30 May 2015
Okayama University research: Compound-protein combination shows promise for arthritis treatment
(Okayama, 30 May) Screening over 700 compounds reveals a steroid hormone with the capability to promote the repair of cartilage in joints.
Damaged cartilage leads to pain and reduced joint mobility in millions of arthritis sufferers worldwide, yet there remains a lack of effective treatments. Now Emilio Satoshi and Takuo Kaboki and colleagues at Okayama University Graduate School of Medicine, the National Institutes of Health in the US and Harvard School of Dental Medicine identify a steroid hormone that could help cartilage development - ‘chondrogenesis’ – thereby regenerating the damaged joint tissue.
The researchers screened cultures of cartilage stem cells with over 700 compounds for substances associated with chondrogenesis, and identified enhancements to these substances in the presence of the steroid hormone fluocinolone acetonide (FA). The researchers then studied cultures of the stem cells that develop into bone and cartilage cells in cultures of FA and transforming growth factor beta 3 (TGF-β3). Previous studies have reported that TGF-β3 plays an important role in chondrogenesis, but antagonistic effects on the development and proliferation of cartilage cells have also been observed, particularly in the presence of certain other bioactive proteins.
In experiments in vitro the researchers found that both TGF-β3 and FA inhibit chondrogenesis, but when present together they upregulate both a key marker and a regulator for chondrocytes. Further experiments highlighted the cellular pathways for the enhanced activity.
In addition the researchers confirmed the effects of the combined compounds in experiments with mice. “The in vivo cartilage repair model confirmed that FA/TGF-β3 is uniquely able to promote cartilage repair,” report the researchers. They add that the combination could have potential for clinical applications based on the development of stem cells into cartilage cells.
Background
ChondrogenesisThe only cells that exist in healthy cartilage are chondrocytes. Previous efforts to promote chondrogenesis using growth factors, gene therapy and compounds have had limited success as the cartilage does not readily regenerate. Harnessing the ability to develop cartilage cells from stem cells offers a promising approach to aiding cartilage regeneration but has not yet been achieved.
Previous research has pointed towards transforming growth factor beta and insulin-like growth factors as the main contributors towards chondrogenesis. This suggests that some combination of these proteins would enhance differentiation of human bone marrow stem/progenitor cells (hBMSCs) - the stem cells that develop into bone and cartilage cells. However previous experiments to study the effects of different combinations of these proteins revealed antagonistic effects on chondrogenesis.
The screening testsThe researchers screened a Food and Drug Administration (FDA)-approved drug library containing 640 compounds and an orphan ligand library containing 84 compounds. They checked the cultures of the compounds for the presence of the promoter for a gene of a type of collagen that makes up the majority of the cartilage protein in joints (Col2a1 promoter), as well as a known marker (Acan) and a known regulator of chondrocytes (Sox9).
They found 86 compounds that enhance Col2a1 promoter, 8 that regulated Acan but just one that upregulated Sox9 as well, that is, FA. FA is a gluococorticoid, a type of hormone that takes its name from its steroid structure, its role in glucose metabolism, and because it is synthesised in the adrenal cortex and plays an important.
Clinical use of glucocorticoidsGlucocorticoids are already used for clinical applications. FA is currently mainly used for dermal, dental and ophthalmological prescriptions and TA and DEX, which have similar structures, have already been used in injections for the management of joint diseases. While glucocorticoid injections are widely used to treat in rheumatoid arthritis and other joint diseases, they have been recognised as harmful to cartilage over prolonged use, possibly due to inhibiting effects on the development of cartilage cells from stem cells. Investigation of alternative glucocorticoids may decrease cartilage damage from long-term use.
The researchers found that FA/TMFβ3 enhanced chondrogenesis by enhancing the activity of the mTORC1/AKT pathway. As AKT inhibitors have been used as a chemotherapeutic treatment for tumors, exploitation of these effects to treat arthritis will require caution.
Figure captionAmong glucocorticoids, FA/TGF-β3 is uniquely able to promote articular surface regeneration. Substantial cartilage repair of the knee joints in mice was observed only in the group transplanted with hBMSCs treated with FA/TGF-β3. Arrowheads show the borders of the surgical defect. The asterisk shows the regenerated superficial layer of the articular cartilage only in FA/TGF-β3 group. Arrows indicate articular surface damage in the groups that received TA/TGF-β3-treated hBMSCs.
Reference Emilio Satoshi Hara, Mitsuaki Ono, Pham Thanh Hai, Wataru Sonoyama, Satoshi Kubota, Masaharu Takigawa, Takuya Matsumoto, Marian F. Young, Bjorn R. Olsen, Takuo Kuboki. Fluocinolone acetonide is a potent synergistic factor of TGF-β3-associated chondrogenesis of bone marrow-derived mesenchymal stem cells for articular surface regeneration. Journal of Bone and Mineral Research, 2015.
DOI: 10.1002/jbmr.2502
http://onlinelibrary.wiley.com/doi/10.1002/jbmr.2502/abstract
Correspondence toProfessor and Chair Takuo Kuboki, D.D.S., Ph.D.
Department of Oral Rehabilitation and Regenerative Medicine
Okayama University Graduate School of Medicine, Dentistry and
Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi,
Okayama-ken, 700-8525, Japan.
E-mail: kuboki@md.okayama-u.ac.jp
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About Okayama UniversityOkayama University is one of the largestcomprehensive universities in Japan with roots going back to the Medical Training Place sponsored by the Lord of Okayama and established in 1870. Now with 1,300 faculty and 14,000 students, the University offers courses in specialties ranging from medicine and pharmacy to humanities and physical sciences. Okayama University is located in the heart of Japan approximately 3 hours west of Tokyo by Shinkansen.2015-05-30Acetaldehyde Concentration in Mouth Air Associated with Tongue Coating Volume
https://www.okayama-u.ac.jp/eng/release/index_id295.html
A research group at the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Hokkaido University has found that physiological acetaldehyde concentration in mouth air was associated with tongue coating volume.
Tongue coating is made with food debris and dead cells. Oral microorganisms live in the tongue coating and cause bad breath. Acetaldehyde is known to possess carcinogenic activity.
Aya Yokoi, Prof. Morita and their colleagues investigated the relationship between physiological acetaldehyde concentration and oral condition in sixty-five healthy volunteers. Acetaldehyde concentration in mouth air was measured using a portable monitor. Tongue coating status was assessed according to distribution area as follows: score 0: none visible; 1: less than one third of the tongue dorsum surface covered; 2: less than two thirds; 3: more than two thirds. Acetaldehyde concentration in participants with a tongue coating status score of 3 was significantly higher than in those with score of 0/1. After removing the tongue coating, acetaldehyde concentration decreased significantly.
The findings were published online March 6, 2015 in the Journal of Applied Oral Science.
http://www.scielo.br/pdf/jaos/v23n1/1678-7757-jaos-23-1-0064.pdf
It is suggested that acetaldehyde in the mouth may cause cancer of the mouth and throat. This and further studies could prove that removing tongue coating prevents these cancers.
The study was funded by Japan Society for the Promotion of Science.
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Mototaka Senda, Ph.D.
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Organization for Research Promotion and Collaboration, Okayama University
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Manabu Morita, DDS, PhD
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2015-05-11New Antibiotic that has Activity Against Both MRSA and VRE
https://www.okayama-u.ac.jp/eng/release/index_id296.html
A research group at the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences has found a compound in Nuphar japonicum that shows activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).
Associate Professor Kuroda and his colleagues have isolated 6,6-dihydroxythiobinupharidine (DTBN) from a plant called Nuphar japonicum and identified it as an antimicrobial compound. They have shown that DTBN has activity against various MRSA and VRE strains and also demonstrated that DTBN inhibits DNA topoisomerase IV.
The findings were published on February 27, 2015 in the journal of Biochimica et Biophysica Acta – General Subjects.
http://www.ncbi.nlm.nih.gov/pubmed/25731981
In addition, the research group has demonstrated that DTBN enhances anti-MRSA activity of arbekacin when the two are combined. They also have shown that when DTBN and vancomycin are used concurrently, vancomycin activity against VRE is recovered.
DTBN could become a useful seed in developing a novel anti-MRSA and anti-VRE drug. DTBN is also expected to reduce the risk of the emergence of drug-resistant bacteria because DTBN enhances the activity of existing antibiotics and thus requires less of those antibiotics to be used.
Contact Information
Mototaka Senda, Ph.D.
Director of Okayama University Silicon Valley Office
Deputy Director of Intellectual Property Office
Organization for Research Promotion and Collaboration, Okayama University
2450 Peralta Blvd. #119 Fremont, California USA
TEL: 1-510-396-2031
Email: takasenda(a)okayama-u.ac.jp
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Teruo Kuroda, Ph.D.
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan2015-05-11