Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.
Effectively
preventing the structural destruction of joints, particularly bone and
cartilage, which progresses due to resistance to conventional anti-inflammatory
drugs, is one of the unmet medical needs in the treatment of rheumatoid
arthritis (RA). In this study, the authors investigated the therapeutic effects
of JTE-952, a novel colony-stimulating factor-1 receptor (CSF1R) kinase
inhibitor, on methotrexate-resistant joint destruction using a rat model of RA,
adjuvant-induced arthritis. Blocking CSF1/CSF1R signaling with JTE-952 did not
suppress paw swelling under inflammatory conditions, but it did suppress the
destruction of joint structural components, including bone and cartilage, in
inflamed joints and may improve subsequent joint dysfunction.
Metallothionein (MT) 1 and 2 are ubiquitously expressed cysteine-rich, low molecular weight proteins. MT expression is upregulated in skeletal muscle during aging. MTs also play role in multiple types of skeletal muscle atrophy. Meanwhile, it has been reported that MT1 and MT2 gene deficiency increases myogenesis in MT knockout (MTKO) mice. However, little is known about the effect of MTs on muscle formation and atrophy. In this study, we investigated the effect of MT1 and MT2 gene knock-out using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (CRISPR-Cas9) system in an in vitro skeletal muscle differentiation model (C2C12 cell line). MT deficiency promoted myogenic differentiation and myotube formation in C2C12 cells. Muscle-specific transcription factors MyoD and myogenin were found to be upregulated at the late stage of myotube differentiation in MTKO cells. Furthermore, the fast-twitch myosin heavy chain (MyHC) protein expression was similar in MTKO and mock-transfected myotubes, but slow-MyHC expression was higher in MTKO cells than in mock cells. The MT gene deletion did not affect the number of fast MyHC-positive myotubes but increased the number of slow MyHC-positive myotubes. Treatment with the antioxidant N-acetylcysteine (NAC) inhibited the increase in the number of slow MyHC-positive myotubes as well as slow-MyHC expression in MTKO cells. In contrast, NAC treatment did not alter the number of fast MyHC-positive myotubes or the expression of fast-MyHC in MTKO cells. These results suggest that the antioxidant effects of MTs may be involved in slow-twitch myofiber formation in skeletal muscle.
Fast-to-slow fiber transition in skeletal muscle occurs
during aging and has been implicated in muscle atrophy in sarcopenia, but the
mechanism is unclear. Authors showed that metallothionein 1 and 2 gene knockout
(MTKO) using the CRISPR-Cas9 system promoted to myogenic differentiation of
C2C12 myoblasts, which was accompanied by an increased number of slow-twitch
myotubes. The increased slow-type myotubes in MTKO cells was inhibited by an
antioxidant N-acetylcysteine, suggesting that MT may be involved in
specification of skeletal muscle fiber-type due to its antioxidant capacity. This
study may help to elucidate the mechanisms of age-related muscle weakness.
A shift towards obtaining emergency contraceptives without a prescription have been discussed in Japan. In response to this social background, we aimed at investigating the background of sexual intercourse, emergency contraceptive use, and knowledge of sexual and reproductive health education among women of reproductive age in Japan. In this study, we conducted a national wide cross-sectional questionnaire survey using a total of 4 web-based domains (background, sexual history, emergency contraceptives, and sexual and reproduction-related knowledge) composed of 50 questions. We obtained responses from a total of 4,631 participants of varying age groups (18–25, 26–35, and 36–45 years old) and 47 prefectures (84 to 118 from each prefecture). Among participant responses, 69.7% are sexually active, of which 49.0% had experiences of sexual intercourse with an unknown person. The responses from a total of 737 participants who have sexual intercourse, know of emergency contraceptives, and have experienced a situation that necessitated the use of emergency contraceptives, were analyzed. Of these participants, 46.4% (342/737) took emergency contraceptives, while 43.6% (321/737) participants did not take emergency contraceptives. Participants who have the knowledge for obtaining emergency contraceptives through the correct means were 52.6% (2438/4631). This study showed that approximately half of participants may not have correct knowledge of emergency contraceptives. In addition, approximately half of sexually active participants are facing unintended pregnancies due to a lack of sexual and reproductive awareness. Hence, comprehensive sex education is necessary to achieve social and regulatory changes centered on emergency contraceptives.
In Japan, the move towards
non-prescription emergency contraceptives is under discussion. A nation-wide
survey of 4,631 women conducted by the authors revealed that nearly half of
them lacked accurate knowledge about emergency contraceptives. Total of 43.6%
of women with previous experience needing emergency contraceptives chose not to
use them voluntarily. To address this, the authors emphasize the importance of
comprehensive sex education, and promoting understanding of emergency
contraceptives among women in Japan.
Recently, microneedling as a cosmetic product has attracted attention as one way to improve skin barrier function and moisturizing function to reduce wrinkle formation. However, some cases of erythema and edema have been reported as side effects. In order to develop safer microneedle cosmetics, we investigated whether microneedles can improve skin barrier function and moisturizing function even when applied in a non-invasive manner that does not penetrate the stratum corneum. We established the condition of non-penetrating microneedle application on reconstructed human full-thickness skin models and examined the effect on the skin models when microneedles were applied under this condition. Microneedle application increased the gene expression of serine palmitoyltransferase long chain base subunit (SPTLC) 3, filaggrin, and transglutaminase 1. The amount of ceramide produced by SPTLC was also increased by microneedle application. Gene expression of filaggrin-degrading enzymes and the amount of free amino acids, a product of filaggrin degradation, were also increased by microneedling. These results suggest that non-invasive microneedle application can improve skin barrier function and moisturizing function by increasing the amount of ceramide and natural moisturizing factors.
Microneedles are microscopic needle
structures with lengths of several hundred micrometers, and have
attracted attention as one way to improve skin barrier and moisturizing
functions as cosmetic product. However, conventional
microneedles are thought to work by penetrating the stratum corneum, which carries
the risk of side effects. Therefore, in this study, the authors applied
microneedles non-invasively without penetrating the stratum corneum and
investigated their effects on the skin. The results showed that microneedles
can improve skin barrier and moisturizing functions even when applied non-invasively.
This study provides valuable insights for the development of new cosmetic techniques
using microneedles.
Cav3.2 channels belong to the T-type calcium channel (T-channel) family, i.e., low voltage-activated calcium channels, and are abundantly expressed in the nociceptors, playing a principal role in the development of pathological pain. The channel activity of Cav3.2 is suppressed by zinc under physiological conditions. We thus tested whether dietary zinc deficiency would cause Cav3.2-dependent nociceptive hypersensitivity in mice. In the mice fed with zinc deficient diet for 2 weeks, plasma zinc levels declined by more than half, and mechanical allodynia developed. The dietary zinc deficiency-induced allodynia was restored by T-channel inhibitors or by Cav3.2 gene silencing. These data demonstrate that zinc deficiency induces Cav3.2-dependent nociceptive hypersensitivity in mice, thereby suggesting that pain experienced by patients with diseases accompanied by zinc deficiency (e.g., chronic kidney disease) might involve the increased Cav3.2 activity.
The activity of Cav3.2 T-type calcium channels expressed
in the sensory neurons is reduced by physiological concentrations of zinc. Sulfides
including hydrogen sulfide (H2S), a gasotransmitter, enhance the channel
activity by removing zinc from Cav3.2, leading to the increased pain
sensitivity. Dietary zinc deficiency causes Cav3.2-dependent mechanical
allodynia in mice. Exogenously applied sulfides produce Cav3.2-dependent
allodynia in the mice fed with normal diet, but do not affect the already
developed allodynia in the mice fed with zinc-deficient diet. Thus, the authors
suggest that the enhanced Cav3.2 activity participates in the development of
pathological pain associated with zinc deficiency.
Total Purine and Purine Base Content of Common Foodstuffs for Facilitating Nutritional Therapy for Gout and Hyperuricemia
Released on J-STAGE: May 01, 2014 | Volume 37 Issue 5 Pages 709-721
Kiyoko Kaneko, Yasuo Aoyagi, Tomoko Fukuuchi, Katsunori Inazawa, Noriko Yamaoka
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Effect of Psilocin on Extracellular Dopamine and Serotonin Levels in the Mesoaccumbens and Mesocortical Pathway in Awake Rats
Released on J-STAGE: January 01, 2015 | Volume 38 Issue 1 Pages 134-138
Yuichi Sakashita, Kenji Abe, Nobuyuki Katagiri, Toshie Kambe, Toshiaki Saitoh, Iku Utsunomiya, Yoshie Horiguchi, Kyoji Taguchi
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