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In Japan, intravenous injection of a 7 % solution of sodium bicarbonate (NaHCO 3) had been originally developed to inhibit motion sickness and then have long been used to treat vertigo. Previously, we reported that Fos-positive neurons appear in the amygdala after hypergravity stimulation in rats. In the present study, we examined whether injection of 7 % NaHCO 3 inhibits hypergravity-induced Fos expression in the neurons in the central nucleus of the amygdala in rats. Rats were exposed to 2 G hypergravity in an animal centrifuge device for 3 h. A solution of 7 % NaHCO 3 at a dose of 4 mM/kg was injected intraperitoneally before 2 G hypergraviy. Fos-positive neurons in the amygdala were stained immunohistochemically. The number of Fos-positive neurons in the central nucleus of the amygdala was significantly increased after 2 G hypergravity in rats that received no drugs or saline, compared to that in rats exposed only to the noise of the centrifuge and received 7 % NaHCO 3 solution. The number of Fos-positive neurons in the central nucleus of the amygdala after 2 G hypergravity was significantly decreased in rats that received 7 % NaHCO 3 solution, compared to that in rats that received no drugs or saline. Since Fos expression is a marker of activated neurons, the present findings suggest that hypergravity activates the amygdala and that administration of 7 % NaHCO 3 suppresses hypergravity-induced activation of the amygdala. Hypergravity disturbs spatial orientation to produce motion sickness and the amygdala is involved in fear response. Recently, Ziemann et al. suggested that fear-evoking stimuli reduce the pH in the amygdala to activate it, leading to induction of fear behavior and that administering HCO 3 − attenuates fear behavior [Cell 2009; 139: 1012–1021]. Therefore, it is possible that hypergravity reduces the pH in the amygdala to activate it, thereby inducing the fear associated with motion sickness and that administration of 7 % NaHCO 3 increases the brain pH thereby suppressing hypergravity-induced activation of the amygdala and inhibiting the fear associated with motion sickness. In patients with vertigo, 7 % NaHCO 3 therapy may increase the brain pH thereby suppressing the activation of the amygdala and inhibiting the fear associated with vertigo to elicit a beneficial clinical effect. [ABSTRACT FROM AUTHOR]

Accurate prediction of employment rate of graduated students can greatly help education authorities to make informed decisions as well as for universities to adjust their teaching plans. Unfortunately, prediction of the employment rate of graduated students is still a difficult problem because the historical employment rate data exhibits fluctuations. In this paper, a new method is proposed for employment rate prediction using fractional gray GM(1,1|$$ \mid $$sin) model, which aims to alleviate the effect of data fluctuation on prediction accuracy and increase the contribution of new data in the prediction procedure. To further decrease prediction error, a Fourier series is adopted to model the residual series. The proposed model, called Fourier Fractional GM(1,1|$$ \mid $$sin) Model (FFGMsin), is used to predict the employment rate of graduated students of Yanshan University from 2010 to 2019. Results show that the proposed method can obtain more accurate prediction results than GM(1,1) model and its variants. © 2024 Institute of Electrical Engineer of Japan and Wiley Periodicals LLC. [ABSTRACT FROM AUTHOR]

Purpose: Growing concern exists worldwide about stress-related mental disorders, such as posttraumatic stress disorder (PTSD), often linked to hippocampal dysfunctions. Recognizing this connection, regular light-intensity exercise (LIE)—such as yoga, walking, or slow jogging—may offer a solution. Easily accessible even to vulnerable individuals, LIE has been found to enhance hippocampus-based cognitive functions through the stimulation of neurotrophic factors like brain-derived neurotrophic factor (BDNF). A prior study that demonstrated BDNF's role in extinguishing original fear memory further leads us to propose that a consistent LIE training might drive fear extinction learning, offering potential therapeutic benefits through BDNF signaling. Methods: Eleven-week-old Wistar rats underwent 4 wk of training under conditions of sedentary, LIE, or moderate-intensity exercise (MOE) after contextual or auditory fear conditioning. Subsequently, fear extinction tests were performed. We then administered intraperitoneal (i.p.) ANA-12, a selective antagonist of tropomyosin receptor kinase B (TrkB), or a vehicle to explore the role of BDNF signaling in exercise-induced fear extinction among the LIE rats. Following the regular exercise training, further fear extinction tests were conducted, and hippocampal protein analysis was performed using Western blotting. Results: Both LIE and MOE over 4 wk accelerated hippocampus-associated contextual fear extinction compared with sedentary. In addition, 4 wk of LIE with i.p. administered vehicle increased hippocampal BDNF and TrkB protein levels. In contrast, i.p. ANA-12 administration fully blocked the LIE-enhanced protein levels and its effect on contextual fear extinction. Conclusions: Our findings reveal that LIE regimen promotes fear extinction learning, at least partially tied to hippocampal BDNF-TrkB signaling. This suggests that even regular light exercise could alleviate the excessive fear response in anxiety disorders and PTSD, providing hope for those affected. [ABSTRACT FROM AUTHOR]

Local low‐frequency vibration promotes blood flow and wound healing in hard‐to‐heal diabetic foot ulcers (DFUs). However, vibration treatment is challenging in patients with DFUs due to wound management difficulties and low adherence. Consequently, developing wearable self‐care devices becomes imperative for effective wound healing. This study introduces a wearable vibration dressing and assesses its impact on wound healing in hyperglycemic rats. Low‐frequency vibration at 52 Hz was applied to the wound for 40 min/day in awake rats. Relative wound areas on post‐wounding days (PWDs) 4–7 were significantly smaller and the wound closure rate was significantly higher in the vibration group than in the control group (p < 0.05, respectively). The total haemoglobin at baseline and after vibration on post‐wounding day 7 was significantly larger in the vibration group than in the control group (p < 0.05). On PWD 7, the thickness of the granulation tissue was significantly higher in the vibration group than in the control group (p < 0.05). Moreover, the number of blood vessels at the wound site and vascular endothelial growth factor A protein expression were significantly higher in the vibration group than in the control group (p < 0.05, respectively). The ratio of (CD68+/iNOS+)/(CD163+) macrophages in the vibration group was significantly lower than that in the control group (p < 0.05). These results indicate the potential of wearable vibration dressings as new self‐care devices that can promote angiogenesis and blood flow, improve inflammation, and enhance wound healing in DFUs. [ABSTRACT FROM AUTHOR]

Aim: The present study aimed to develop a pharmacological evidence‐based anticholinergic burden scale (ABS) through a direct assessment of muscarinic receptor‐binding activities of 260 medications commonly used in older adults. Methods: The muscarinic receptor‐binding activities of 260 drugs were assessed by the displacement of specific [N‐methyl‐3H]scopolamine methyl chloride binding in the rat brain. The maximum blood concentrations (Cmax) of drugs after their administration to subjects were cited from their interview forms. Results: In total, 96 of 260 drugs displayed concentration‐dependent muscarinic receptor binding in rat brain. Based on muscarinic receptor‐binding activity (IC50) and Cmax after the administration at clinical doses in humans, we rated ABS 3 (strong) for 33 drugs and ABS 2 (moderate) for 37 drugs. There was an approximate similarity between muscarinic receptor‐binding activities (IC50) and Cmax of 33 drugs (ABS 3) after their administration at clinical doses in humans. Furthermore, 26 drugs were defined as ABS 1 (weak) by muscarinic receptor‐binding activity. The remaining 164 drugs exhibited slight or no significant muscarinic receptor‐binding activities at high concentration of 100 μM, and they were defined as ABS 0. There was a marked similarity for 28 drugs (ABS 3) between the present ABS data and their previous scoring data in the literature. Conclusions: To our knowledge, the present study developed the first comprehensive pharmacological evidence‐based ABS of drugs based on muscarinic receptor‐binding activity, which provides guidance as to which drugs may be discontinued to reduce anticholinergic burden. Geriatr Gerontol Int 2023; 23: 558–564. [ABSTRACT FROM AUTHOR]

Background: Goreisan is a traditional herbal formulation with diuretic properties tested as a clinical therapeutic to alleviate lymphedema in Japan. The present study aimed to determine how Goreisan and its five different components affect lymphatic pump function. Methods: Mesenteric collecting lymphatics were isolated from anesthetized Sprague–Dawley rats and mounted on resistance‐matched glass micropipettes in a 37°C physiological salt solution bath for studies. Diameter was continuously measured to obtain the following lymphatic pump parameters: contraction frequency (CF), end diastolic diameter (EDD), and end systolic diameter (ESD), contraction amplitude (AMP), ejection fraction (EF), and fractional pump flow (FPF). Goreisan and each of its components (Cinnamomi Cortex, Atractylodis Rhizoma, Alismatis Rhizoma, Polyporus, and Poria) were applied to the bath at concentrations of 1–30 μg/mL. Results: The results show that while Goreisan causes no significant changes to lymphatic pumping, Alismatis Rhizoma and Polyporus each significantly reduce CF and FPF. In addition, rats that received oral administration of Goreisan and Alismatis Rhizoma for 1 week had elevated expression of VEGFR‐3 in their mesenteric collecting lymphatics. Conclusions: Collectively, the results suggest that some components of Goreisan have a direct, rapid impact on lymphatic pumping. These findings provide new insights but also raise new questions about the therapeutic potential of Goreisan in patients with secondary lymphedema. [ABSTRACT FROM AUTHOR]

New synthetic opioids continue to emerge in the illicit market, and among them, fentanyl analogues pose a serious threat to the public health with their abuse and trafficking. We investigated the toxicity of fentanyl analogues on the liver and kidneys mediated by the µ-opioid receptor (MOR). Our study focused on 4-fluoro-isobutyrylfentanyl (4F-iBF), which is classified as a "narcotic" in Japan; structurally similar analogues 4-chloro-isobutyrylfentanyl (4Cl-iBF) and isobutyrylfentanyl (iBF) were also investigated. Rats that were intraperitoneally administered 4F-iBF (5 mg/kg (12.3 μmol/kg)) or iBF (12.3 μmol/kg) displayed hepatic and renal ischemic-like damage, but 4Cl-iBF (12.3 μmol/kg) did milder renal damage only. We found that the agonist activity of 4F-iBF, at MORs was approximately 7.2 times that of 4Cl-iBF, and that pretreatment with MOR antagonist naltrexone (0.8 mg/kg) alleviated liver and kidney injuries caused by 4F-iBF. These results suggested that 4F-iBF might cause ischemic damage to the liver and kidneys, induced by respiratory depression mediated by MORs. Furthermore, to elucidate the metabolism of fentanyl analogues, we investigated the change over time in the amount of 4F-iBF, 4Cl-iBF, iBF (6.15 μmol/kg, respectively), and their respective metabolites in serum after intraperitoneal administration to rats. The results showed that in 24-h post-dose serum, 4Cl-iBF and iBF were substantially eliminated while 4F-iBF remained at about 30% of the maximum level, and each of the N-dephenylethylated metabolites of 4F-iBF, 4Cl-iBF, and iBF was detected in 2-h post-dose serum. The results from this study revealed information on the hepatic and renal toxicities and metabolism related to fentanyl analogues. [ABSTRACT FROM AUTHOR]

Simple Summary: Since April 2020 in Japan, lactate dehydrogenase and alkaline phosphatase assays, which were earlier conducted using the Japan Society of Clinical Chemistry protocols, are being conducted using the International Federation of Clinical Chemistry and Laboratory Medicine protocols. The correlation between blood values measured by these methods is not known in some species; therefore, values measured using these two methods cannot be used interchangeably. In this study, the relationship between lactate dehydrogenase and alkaline phosphatase values of mice and rats using each method was determined, and coefficients were generated to convert and compare the obtained values. These coefficients can be used for the mutual conversion of measured values during the transition period from the Japan Society of Clinical Chemistry method to the International Federation of Clinical Chemistry and Laboratory Medicine method. However, it should be noted that the conversion coefficients were affected by isozyme composition. Since April 2020, the method for lactate dehydrogenase (LD) and alkaline phosphatase (ALP) activity measurements in Japan has been switched from the Japan Society of Clinical Chemistry (JSCC) reference method, which is only used in Japan, to the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) reference method. However, in some species, the relationship between the blood values of both enzymes measured by the two methods remains unclear. Hence, values measured by these two methods cannot be used interchangeably. Therefore, this relationship was examined in ICR mice and Wistar/ST rats. The LD and ALP values obtained by both methods were plotted on scatter graphs, and regression equations were obtained. To compare the JSCC (x) and IFCC (y) methods, regression equations were generated for LD values in non-hemolytic samples as follows: y = 0.954x − 4.008 for ICR mice and y = 0.963x − 6.324 for Wistar/ST rats. The conversion factors from the JSCC to the IFCC methods were 0.954 (mice) and 0.963 (rats). The conversion coefficients from the IFCC to the JSCC methods were 1.048 (mice) and 1.088 (rats). For ALP values in fasted mouse and rat samples, the regression equations were y = 0.336x − 2.247 and y = 0.314x − 17.626, respectively. The conversion factors from the JSCC to the IFCC methods were 0.336 (mice) and 0.314 (rats). The conversion coefficients from the IFCC to the JSCC methods were 2.978 (mice) and 3.188 (rats). These conversion factors can be used for the mutual conversion of both measured values during the transition period from the JSCC to the IFCC method. However, it should be noted that the conversion coefficients for both LD and ALP were affected by isozyme composition. [ABSTRACT FROM AUTHOR]

Heavy chain-only antibodies in sharks are called immunoglobulin new antigen receptors (IgNAR), consisting of one variable region (VNAR) and five constant regions (C1-C5). The variable region of IgNAR can be expressed as a monomer composed of a single domain, which has antigen specificity and is thus gaining attention as a next-generation antibody drug modality. In this study, we analyzed IgNAR of the cloudy catshark and Japanese bullhead shark, small demersal sharks available in the coastal waters of Japan. By analyzing the IgNAR gene sequence and comparing it with the constant regions of five other known shark species, high homology was observed in the C4 region. Consequently, we expressed the recombinant protein of the C4 domain from the cloudy catshark in E. coli , immunized rats, and produced antibodies. The obtained antiserum and mAbs recognized the C4 recombinant protein of the cloudy catshark, but reacted minimally with the plasma of non-immunized cloudy catsharks and instead reacted with the plasma of Japanese bullhead sharks. The results of this study imply that the protein expression levels of IgNAR in cloudy catsharks may be relatively lower compared to those in Japanese bullhead sharks, however, this interpretation remains to be determined through further studies.

Mammalian genome research has conventionally involved mice and rats as model organisms for humans. Given the recent advances in life science research, to understand complex and higher-order biological phenomena and to elucidate pathologies and develop therapies to promote human health and overcome diseases, it is necessary to utilize not only mice and rats but also other bioresources such as standardized genetic materials and appropriate cell lines in order to gain deeper molecular and cellular insights. The Japanese bioresource infrastructure program called the National BioResource Project (NBRP) systematically collects, preserves, controls the quality, and provides bioresources for use in life science research worldwide. In this review, based on information from a database of papers related to NBRP bioresources, we present the bioresources that have proved useful for mammalian genome research, including mice, rats, other animal resources; DNA-related materials; and human/animal cells and microbes., (© 2024. The Author(s).)

Kamishoyosan (KSS) is a traditional Japanese Kampo medicine that is prescribed for hormonal change-induced mood disorders including premenstrual syndrome (PMS). In clinical studies, KSS exhibited ameliorative effects on mood symptoms of PMS, such as anxiety and irritability. However, the mechanism underlying the beneficial effects of KSS is unclear. In the present study, we investigated the involvement of serotonergic machinery in the anxiolytic effects of KSS on hormonally-induced anxiety-like behavior in progesterone withdrawal (PWD) rats, which were used as a model of PMS. Female rats were injected with progesterone daily for 21 days. At 48 h after the final progesterone injection, anxiety-like behavior was evaluated using the elevated plus maze. KSS was administered orally to PWD rats 1 h prior to the test and significantly attenuated PWD-induced anxiety-like behavior. This ameliorative effect of KSS was reversed by WAY-100635, a serotonin (5-HT)1A receptor antagonist. The effect of KSS on serotonergic transmission in the prefrontal cortex of PWD rats was also evaluated using an in vivo microdialysis procedure. KSS significantly increased the extracellular 5-HT level in the prefrontal cortex of PWD rats. In conclusion, our results suggest that KSS alleviates PWD-induced anxiety-like behavior at least partly by activating 5-HT1A receptors and enhancing serotonergic transmission. [ABSTRACT FROM AUTHOR]

The aim of this research was to examine the influence of the intraperitoneal application of PFT in different doses and regimen on systemic oxidative stress and activity of antioxidative enzymes in animals. Depending on whether the animals received only saline or PFT in different doses (8, 12, 16 ml/kg body weight), and time (1, 10, or 20 hours before sacrificing and blood sampling), all animals were divided into control or experimental groups. From plasma samples we measured following biomarkers of oxidative stress: superoxide anion radical (O2−), hydrogen peroxide (H2O2), nitrites (NO2−), index of lipid peroxidation measured as TBARS (thiobarbituric acid reactive substances), and from hemolysate samples activity of the next enzymes: catalase (CAT), superoxidedismutase (SOD) and reduced glutathione (GSH). All mentioned biochemical parameters of oxidative stress were determined spectrophotometrically (Shimadzu UV-1800UV-VIS spectrophotometer, Japan). Superoxide anion radical was a molecule very affected with the PFT administration. we observed the significantly higher activity of superoxide dismutase in all PFT treated groups in comparison with the CTRL group. The highest activity was observed in group treated with the 8 and 12 ml/kg of PFT nearly to sampling (1 hour). Catalase activity was significantly higher in PFT group in comparison with the CTRL, especially in PFT 16ml/kg group (1 hour). In comparison with the CTRL group, the total content of GSH was significantly lower in the groups treated PFT in dose of 16 ml/kg 1 hour and 10 hours before blood sampling. All these changes in oxidative stress markers seems to be very clear, but we can observe that almost all changes are induced in 1 hour after PFT administration. Probably, PFT solution has short-term protective effects on reducing oxidative stress, but no long term-effects. Maybe the chemical and biological instability of PFT solution could be a reason for that transient antioxidative effects, and developing the nano-formulation of PFT could be potential option for resolving the problem with poor pharmacodynamic of PFT. [ABSTRACT FROM AUTHOR]

The aim of this research was to examine the influence of the intraperitoneal application of PFT in different doses and regimen on systemic oxidative stress and activity of antioxidative enzymes in animals. Depending on whether the animals received only saline or PFT in different doses (8, 12, 16 ml/kg body weight), and time (1, 10, or 20 hours before sacrificing and blood sampling), all animals were divided into control or experimental groups. From plasma samples we measured following biomarkers of oxidative stress: superoxide anion radical (O2−), hydrogen peroxide (H2O2), nitrites (NO2−), index of lipid peroxidation measured as TBARS (thiobarbituric acid reactive substances), and from hemolysate samples activity of the next enzymes: catalase (CAT), superoxidedismutase (SOD) and reduced glutathione (GSH). All mentioned biochemical parameters of oxidative stress were determined spectrophotometrically (Shimadzu UV-1800UV-VIS spectrophotometer, Japan). Superoxide anion radical was a molecule very affected with the PFT administration. we observed the significantly higher activity of superoxide dismutase in all PFT treated groups in comparison with the CTRL group. The highest activity was observed in group treated with the 8 and 12 ml/kg of PFT nearly to sampling (1 hour). Catalase activity was significantly higher in PFT group in comparison with the CTRL, especially in PFT 16ml/kg group (1 hour). In comparison with the CTRL group, the total content of GSH was significantly lower in the groups treated PFT in dose of 16 ml/kg 1 hour and 10 hours before blood sampling. All these changes in oxidative stress markers seems to be very clear, but we can observe that almost all changes are induced in 1 hour after PFT administration. Probably, PFT solution has short-term protective effects on reducing oxidative stress, but no long term-effects. Maybe the chemical and biological instability of PFT solution could be a reason for that transient antioxidative effects, and developing the nano-formulation of PFT could be potential option for resolving the problem with poor pharmacodynamic of PFT. [ABSTRACT FROM AUTHOR]

Background: In Japan, six workers handling cross-linked water-soluble acrylic acid polymer (CWAAP) at a chemical plant suffered from lung diseases, including fibrosis, interstitial pneumonia, emphysema, and pneumothorax. We recently demonstrated that inhalation of CWAAP-A, one type of CWAAP, causes pulmonary disorders in rats. It is important to investigate dose–response relationships and recoverability from exposure to CWAAPs for establishing occupational health guidelines, such as setting threshold limit value for CWAAPs in the workplace. Methods: Male and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m3 CWAAP-A for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 h, 4 weeks, and 13 weeks after the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. In a second experiment, male rats were pre-treated with clodronate liposome or polymorphonuclear leukocyte-neutralizing antibody to deplete macrophages or neutrophils, respectively, and exposed to CWAAP-A for 6 h/day for 2 days. Results: CWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m3 and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m3. Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m3 CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m3 was irreversible due to the development of interstitial lung lesions. There was a gender difference in the recovery from CWAAP-A induced pulmonary disorders, with females recovering less than males. Finally, acute lung effects caused by CWAAP-A were significantly reduced by depletion of alveolar macrophages. Conclusions: Pulmonary damage caused by inhalation exposure to CWAAP-A was dose-dependent, specific to the lung and lymph nodes, and acute lung damage was ameliorated by depleting macrophages in the lungs. CWAAP-A had both a LOAEC and a NOAEC, and tissue damage caused by exposure to 1 mg/m3 CWAAP-A was reversible: recovery in female rats was less than for males. These findings indicate that concentration limits for CWAAPs in the workplace can be determined. [ABSTRACT FROM AUTHOR]

Background: Wnt/β-catenin signaling suppresses the differentiation of cultured tenocytes, but its roles in tendon repair remain mostly elusive. No chemical compounds are currently available to treat tendon injury. Hypothesis: We hypothesized that the inhibition of Wnt/β-catenin signaling would accelerate tendon healing. Study Design: Controlled laboratory study. Methods: Tendon-derived cells (TDCs) were isolated from rat Achilles tendons. The right Achilles tendon was injured via a dermal punch, while the left tendon was sham operated. A Wnt/β-catenin inhibitor, IWR-1, and an antihistamine agent, promethazine (PH), were locally and intramuscularly injected, respectively, for 2 weeks after surgery. The healing tendons were histologically and biomechanically evaluated. Results: The amount of β-catenin protein was increased in the injured tendons from postoperative weeks 0.5 to 2. Inhibition of Wnt/β-catenin signaling by IWR-1 in healing tendons improved the histological abnormalities and decreased β-catenin, but it compromised the biomechanical properties. As we previously reported that antihistamine agents suppressed Wnt/β-catenin signaling in human chondrosarcoma cells, we examined the effects of antihistamines on TDCs. We found that a first-generation antihistamine agent, PH, increased the expression of the tendon marker genes Mkx and Tnmd in TDCs. Intramuscular injection of PH did not improve histological abnormalities, but it decreased β-catenin in healing tendons and increased the peak force and stiffness of the healing tendons on postoperative week 2. On postoperative week 8, however, the biomechanical properties of vehicle-treated tendons became similar to those of PH-treated tendons. Conclusion: IWR-1 and PH suppressed Wnt/β-catenin signaling and improved the histological abnormalities of healing tendons. IWR-1, however, compromised the biomechanical properties of healing tendons, whereas PH improved them. Clinical Relevance: PH is a candidate repositioned drug that potentially accelerates tendon repair. [ABSTRACT FROM AUTHOR]

Not only free amino acids and normal short-chain peptides but also modified amino acids, such as N -acetyl- and N -formyl amino acids, monoamines, polyamines, and modified peptides, such as isomerized aspartyl peptides, pyroglutamyl peptides, and diketopiperazines, were identified in Japanese fermented soy paste ( miso ) prepared using different fungal starters, rice, barley, and soybean- koji. One hour after oral administration of water extract of soybean- koji miso to rats, the modified peptides increased significantly in the lumen upon the ingestion, while the normal peptides did not. In the blood from the portal vein and abdominal vena cava, 17 and 15 diketopiperazines, 16 and 12 isomerized aspartyl peptides, and 2 and 1 pyroglutamyl peptides significantly increased to approximately 10-400 nM, respectively. The modified peptides, which increased in rat blood, showed angiotensin-converting enzyme (ACE) inhibitory activity in a dose-dependent manner, indicating multiple ACE inhibitory peptides with high bioavailability in miso. Among them, l-β-Asp-Pro showed the highest ACE inhibitory activity (IC 50 4.8 μM).

BACKGROUND: Rice α‐globulin has been reported to have serum cholesterol‐lowering activity in rats. However, it is still unclear whether α‐globulin exerts this effect when taken as one of the dietary components. In the present study, we investigated the effect of two cultivars of rice, low glutelin content (LGC)‐1 and LGC‐Jun, on reducing serum cholesterol in exogenously hypercholesterolemic (ExHC) rats. LGC‐1 is enriched in α‐globulin (10.6 mg g−1 rice flour, which is an approximately 1.5 times higher α‐globulin content than in Koshihikari a predominant rice cultivar in Japan), whereas LGC‐Jun is a globulin‐negative cultivar. METHODS: ExHC rats, the model strain of diet‐induced hypercholesterolemia, were fed 50% LGC‐1 or LGC‐Jun and 0.5% cholesterol‐containing diets for 2 weeks, followed by measurement of cholesterol metabolism parameters in serum and tissues. RESULTS: Serum cholesterol and non‐high‐density lipoprotein cholesterol levels were significantly lower in the LGC‐1 group compared to the LGC‐Jun group. Cholesterol intestinal absorption markers, hepatic and serum levels of campesterol and β‐sitosterol, and lymphatic cholesterol transport were not different between the two groups. Levels of 7α‐hydroxycholesterol, an intermediate of bile acid synthesis, showed a downward trend in the livers of rats that were fed LGC‐1 (P = 0.098). There was a significant decrease in the hepatic mRNA expression of Cyp7a1 (a synthetic enzyme for 7α‐hydroxycholesterol) in the LGC‐1 group compared to the LGC‐Jun group. CONCLUSION: Dietary LGC‐1 significantly decreased serum cholesterol levels in ExHC rats. The possible mechanism for the cholesterol‐lowering activity of LGC‐1 is partial inhibition of bile acid and cholesterol synthesis in the liver. © 2021 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether bone regeneration can be accelerated by using a conditioned medium (CM) and guided bone regeneration (GBR) technique. Materials and Methods: CM was harvested from rat bone marrow stromal cells (BMSCs). The components of CM were immobilized using a polylactide-co-glycolide (PLGA) membrane treated with and without 0.5 mol/L sodium hydroxide (NaOH) to elevate the hydrophilicity. Four experimental groups were prepared: PLGA membrane treated with (1) phosphate-buffered saline (PBS; PBS-M), (2) PBS and 0.5 mol/L NaOH (hydrophilic treatment; PBS-HM), (3) CM (CM-M), and (4) CM and 0.5 mol/L NaOH (CM-HM). These experimental membranes were observed using scanning electron microscopy. Proteins derived from BMSCs immobilized on the PLGA membrane were detected with liquid chromatography-tandem mass spectrometry (LC/MS/MS). Cell proliferation and alkaline phosphatase (ALP) activity were measured to analyze the effect of CM on the BMSCs. Experimental membranes were transplanted into a rat calvarial bone defect model. Microcomputed tomography and histologic analyses were performed 4 and 8 weeks after transplantation. Results: The CM derived from BMSCs can be immobilized on the PLGA membrane. Hydrophilic treatment of the PLGA membrane enhanced the amount of CM immobilization. LC/MS/MS analysis showed that the immobilized proteins on the surface of PLGA membrane were extracellular matrix, such as collagen, decorin, and fibronectin. The proteins in the CM, which were released from the PLGA membrane, enhanced cell proliferation and ALP activity in rat BMSCs. Newly formed bone area at the bone defects that had been treated with CM-HM was significantly high compared with those at bone defects treated with the other membranes. Conclusion: The PLGA membrane treated with 0.5 mol/L NaOH and CM promoted bone regeneration in this rat calvarial defect model. [ABSTRACT FROM AUTHOR]

Oxytocin (Oxt) is known to regulate social communication, stress and body weight. The activation of Oxt receptors (OTR) has clinical potential to abate stress disorders and metabolic syndrome. Kamikihito (KKT) is a traditional Japanese medicine used to treat psychological stress-related disorders. We investigated the effects of KKT, its ingredients and chemical components on Oxt neurons and OTR. C-Fos expression was examined after oral and peripheral administration of KKT in rats. Electrophysiological change of Oxt neurons and Oxt release upon application of KKT were measured in rat brain slice. The direct effect of KKT, its ingredients and its chemical components were examined by cytosolic Ca2+ ([Ca2+]i) measurement in Oxt neurons and OTR-expressing HEK293 cells. Both intraperitoneal and oral administration of KKT in rats induced c-Fos expression in neurons of the paraventricular nucleus (PVN) including Oxt neurons. Application of KKT induced activation of Oxt neurons and Oxt release. KKT increased [Ca2+]i in OTR-expressing HEK293 cells, and failed to activate with OTR antagonist. KKT-induced PVN Oxt neuron activation was also attenuated by OTR antagonist. Seven chemical components (rutin, ursolic acid, (Z )-butylidenephtalide, p-cymene, senkunolide, [6]-shogaol, [8]-shogaol) of three ingredients (Zizyphi Fructus, Angelicae Acutilobae Radix, Zingiberis Rhizoma) from KKT had potential to activate OTR. KKT can directly activate PVN Oxt neurons by interacting with OTR. The interaction of seven chemical components from KKT may contribute to activate OTR. Effect of KKT on Oxt neurons and OTR may contribute to the treatment of Oxt related disorders. [ABSTRACT FROM AUTHOR]

Brown rats (Rattus norvegicus) and roof rats (Rattus rattus) are among the most common mammals worldwide. Little is known about the effects of season on rat population size, which is important for understanding rat ecology and/or performing effective rat control campaigns. Tsukiji Market was a metropolitan central wholesale market in Tokyo and was located within 1 km from one of the biggest downtown areas. To control rats in the market, a pest management professional exclusively conducted annual campaigns at two fixed time points for many years. In addition, the pest management professional successfully confined all rats to the market and exterminated them when the market was closed and demolished. We analyzed these records to assess whether this rat population in Tokyo showed seasonal fluctuation and to provide information regarding rat management in a facility located in a downtown area. Multiple regression analyses revealed that trap success was affected by human activities (total trading volume and number of foreign tourists in Japan), but not by the month the campaign was performed. These results suggest that the rat population in this market did not show seasonal fluctuation. The results also suggest the importance of the effect of human activities on the ecological dynamics of rats in urban cities. We also described details of the campaigns performed as the market prepared to close to provide information regarding how to control rats in facilities in a downtown area. [ABSTRACT FROM AUTHOR]

The definitive hosts of Metagonimus hakubaensis are reported to be hamsters, rats, mice, dogs, cats, chickens, and quails in experimental infection and Japanese water shrews in natural infection. Here we report that raccoon dogs are new natural definitive hosts of M. hakubaensis, based on morphological and molecular analyses of Metagonimus flukes collected from the host species from Aomori Prefecture, Japan. Moreover, M. hakubaensis recovered from raccoon dogs showed higher fecundity than those recovered from Japanese water shrews. Therefore, raccoon dogs were considered as a more suitable natural definitive host of M. hakubaensis than Japanese water shrews. [ABSTRACT FROM AUTHOR]

Context: T-cadherin (T-cad) is a glycosylphosphatidylinositol (GPI)-anchored cadherin that mediates adiponectin to induce exosome biogenesis and secretion, protect cardiovascular tissues, promote muscle regeneration, and stimulate therapeutic heart protection by transplanted mesenchymal stem cells. CDH13, the gene locus of T-cad, affects plasma adiponectin levels most strongly, in addition to affecting cardiovascular disease risk and glucose homeostasis. Recently, it has been suggested that T-cad exists in human serum, although the details are still unclear.Objective: To validate the existence of T-cad forms in human serum and investigate the association with clinical parameters of type 2 diabetes patients.Methods: Using newly developed monoclonal antibodies against T-cad, pooled human serum was analyzed, and novel T-cad enzyme-linked immunosorbent assays (ELISAs) were developed. The serum T-cad concentrations of 183 Japanese type 2 diabetes patients were measured in a cross-sectional observational study. The main outcome measure was the existence of soluble T-cad in human serum.Results: There were 3 forms of soluble T-cad: a 130-kDa form with a prodomain, a 100-kDa mature form, and a 30-kDa prodomain in human serum. Using newly developed ELISAs to measure them simultaneously, we found that the 130-kDa form of T-cad positively correlated with plasma adiponectin (r = 0.28, P < .001), although a physiological interaction with adiponectin was not observed in serum. The unique 30-kDa prodomain was associated with several clinical parameters in diabetes patients.Conclusion: We identified 3 novel forms of soluble T-cad. Their importance as disease markers and/or biomarkers of adiponectin function and the possible bioactivity of the respective molecules require further investigation. [ABSTRACT FROM AUTHOR]

Brown (Rattus norvegicus) and black (R. rattus sensu lato) rats are among the world's most widespread and important invasive animals; however, there are very few studies of their natural history in natural habitats within their native ranges. Both taxa are native to Japan and still occur in natural habitats there, but have been traditionally treated by zoologists working in the country as invasive pests limited to cities and agricultural lands. We used thermal imaging and snow tracking to conduct the first study of status, distribution and behavioural ecology of remnant human-independent populations of these species in Japan. We found both species still living in natural habitats away from human settlements: brown rat is a rare species in wetlands on the main islands and in upland forests on Hokkaido, while the native taxon of R. rattus species complex, the Asian house rat (R. tanezumi sensu stricto) inhabits remnant deciduous old-growth forests, as well as evergreen subtropical forests, in the south of the country. Such knowledge is critically important for understanding the rats' evolutionary history, invasion biology and behaviour. Future molecular studies should aim to clarify the origin of these populations: possibly they are Pleistocene relicts threatened by hybridisation with rats of related non-native taxa. [ABSTRACT FROM AUTHOR]

Background: Nobiletin is contained in Shiikuwasa fruit, a popular citrus fruit from Okinawa Prefecture in Japan. Nobiletin reportedly acts as a strong antioxidant, an anti-inflammatory agent, and an anti-cancer agent, and it suppresses the expression of TF which triggers blood coagulation. However, in vivo verification of in vitro reports is necessary. This study used a rat model of LPSinduced microthrombosis based on the in vivo studies as previously reported. Sustained intravenous injection of LPS changed all blood coagulation indicators in the direction of thrombus formation. The aim of this study was to determine if intake of nobiletin could suppress DIC-like symptoms. Methods: Experimental SD rats were fully anesthetized and fixed to an operating table. Either LPS alone or nobiletin (50 mg/kg) plus LPS was given to rats to investigate the repressive effects of nobiletin on the expression of blood coagulation factors. Results: After 4 h of LPS infusion (12.5 mg/kg/h, i.v.), PLT counts and Fbg levels in rat plasma decreased by 80% and 74%, respectively. PT and APTT were extended by 180% and 256%, respectively. TF activity and PAI-1 antigen levels were remarkably increased (54- and 86-fold, respectively vs. control). Pretreatment on nobiletin (50 mg/kg, p.o.) reduced or suppressed fluctuations in blood coagulation indices caused by LPS. TF activity was repressed almost completely by nobiletin pretreatment. After 4 h, PAI-1 antigen levels in nobiletin-treated animals were repressed 82.6% compared to LPS-treated rats. Nobiletin repressed LPS-induced changes in TF and PAI-1 more effectively than other parameters. Further, nobiletin repressed fibrin thrombi formation in the renal glomeruli induced by LPS treatment. Conclusions: Nobiletin was found to reduce LPS-induced DIC-like symptoms in rats. In the fluctuations of blood indices related to the coagulation cascade, nobiletin suppressed the LPS-induced expression of PAI-1 and TF more effectively than other indices. The binding sites of transcription factors that are activated by LPS-induced signals reside in the promoter areas of TF and PAI-1 gene sequences. Thus, the suppression of TF and PAI-1 expression by nobiletin appears similar to mechanisms previously evaluated during in vitro experiments. Importantly, nobiletin repressed fibrin deposition in the renal glomeruli induced by LPS treatment and improved overall health. Nobiletin may function as an anti-thrombogenic agent when ingested daily. [ABSTRACT FROM AUTHOR]

Many recent reports have suggested a possible association between Japanese traditional (Kampo) medicines containing Gardeniae Fructus (GF, the fruit of Gardenia jasminoides J. Ellis) and the mesenteric phlebosclerosis (MP). MP is a chronic orphan disease characterized by venous calcification extending from the colonic wall to the mesentery, usually developing in the proximal colon. In the present study, we administered GF to Wistar/ST female rats as 1% and 2% feed in the diet for 11 months to evaluate any calcification and/or fibrosis of veins in the colonic wall and mesentery. The reversibility of GF's effects was examined by feeding a normal diet for an additional 3 months. A significant decrease in body weight gain and food consumption occurred in the 2% GF group. Pigmentation of the liver, kidney, and spleen in macroscopic or histopathological examination was observed after 11-month administration, which disappeared after the 3-month recovery period. Histopathological findings such as fibrous thickening and calcification of vein walls, characteristic of human MP, were not observed. Fibrosis in the colonic lamina propria was observed in the 2% GF group but not in the 1% GF group during the treatment period, but the incidence as well as grade of this type of fibrosis decreased in the recovery period, suggesting that the effects of GF were reversible. In the present study, chronic GF administration did not result in any venous pathological changes but induced pigmentation in the liver, kidneys, and spleen and moderate fibrosis in the colonic lamina propria, all of which being reversible. Further studies are required to determine the association between GF and MP. [ABSTRACT FROM AUTHOR]

Due to finalization of the ICH S3A Q&A focusing on microsampling, application of microsampling technique to regular non-clinical animal studies is expected for non-clinical safety assessment of pharmaceuticals. In Europe, microsampling from the tail vein or saphenous vein has often been used, whereas sampling from the jugular vein is thought to be more common for non-clinical studies in Japan. Therefore, we assessed the toxicological effects of serial microsampling from the jugular vein of SD rats in a common 28-day study at 4 independent organizations. Fifty microliter sampling was performed at 6 timepoints on day 1 to 2 and 7 timepoints on day 27 to 28 and its toxicological influences on body weight, food consumption, hematological and clinical chemistry parameters, and organ weights (on day 29 for 3 and day 28 for 1 organizations) were evaluated. The serial microsampling was shown to have no or minimal influences on the assessed parameters. The observed statistical differences for the 18 parameters were sporadic and did not appear to be systemically associated with microsampling. However, the sporadic changes were more often observed in females (14/18 parameters) than in males (6/18), suggesting the possibility that female rats were more susceptible to treatment-based influences. The current results indicate that serial 50 µL sampling from the jugular vein of SD rats had no or very slight toxicological effects, suggesting that this microsampling condition is applicable for toxicokinetic evaluation of non-clinical rat toxicity studies. [ABSTRACT FROM AUTHOR]

The efficacy of a Sabin-derived inactivated polio vaccine (sIPV) can be evaluated by measuring the immunogenicity and the contents of D-antigens, which induce the neutralizing antibodies. The immunogenic potency test in rats was done as a national assay in Japan. The two manufacturers of sIPV in Japan have performed both assays since development, and there is no clear discrepancy between the results obtained in the two assays. To further know the relationship between the two assays, we analyzed the effects of the heat treatment of sIPV on the D-antigenicity and the immunogenicity. We observed that the marginal D-antigen that remained after the thermal treatment was capable of inducing relatively high neutralizing antibodies in rats. This indicates that the measurement of the D-antigen contents as part of the quality control of sIPV is more sensitive and appropriate to detect denatured vaccines. [ABSTRACT FROM AUTHOR]

Citrus spp. is useful for the prevention and treatment of circulatory and gastrointestinal disorders. In Japan, some Citrus peels (eg. Citrus unshiu M. and C, aurantium L.) have been used as Kampo medicines and for maintaining healthy condition. Recently, Shonan Gold (C. flaviculpm hort ex. Tanaka cv. Shonan-gold) (SG), a hybrid of C. flaviculpus hort ex. Tanaka and C. unshiu M., was bred by Kanagawa Agricultural Research Institute. SG contains various flavonoids, so that is expected to have many physiological activities. In the present study, we focused on the effect of SG on cardiovascular disease and then investigated the vasorelaxant effect of SG peel extract using rat isolated aorta. As a result, SG peel extract showed an endothelium-dependent and -independent relaxant effect on noradrenaline-contracted aortic tissue. Among them, the endothelium-dependent effect was significantly attenuated by endothelial detachment or N-nitro-L-arginine pretreatment. In addition, the major flavonoids (flavonoid glucoside: hesperidin; narirutin, flavonoid aglycon: hesperetin; naringenin, and nobiletin) contained in SG also showed a vasorelaxant effect. A mix of these flavonoids having the same content as the SG peel extract was prepared, and its vasorelaxant effect was examined. The effect was weaker than that of the SG peel extract and the endothelium-dependent relaxation was unclear. Therefore, this extract could be considered to contain some active constituents other than the main flavonoids. These results suggest that SG peel extract has several beneficial effects on cardiovascular disease. [ABSTRACT FROM AUTHOR]

The Bonin Archipelago is a United Nations Educational, Scientific and Cultural Organization's World Natural Heritage Site in Japan with a unique ecosystem; however, the invasive rodents preying on endemic species have been a significant concern. The anticoagulant rodenticide, diphacinone, sprayed by the Ministry of the Environment, has succeeded; however, its repeated use leads to rodenticide resistance. This study evaluated the sensitivity by in vivo pharmacokinetics/pharmacodynamics (PK/PD) analysis and physiologically-based pharmacokinetic modeling to diphacinone in black rats (Rattus rattus) captured on the Bonin Archipelago in February 2022. The Bonin rats exhibited prolonged coagulation time after diphacinone administration. They recovered earlier than susceptible black rats, indicating that Bonin rats were less susceptible, though there were no genetic mutations in Vkorc1 , the target enzyme of diphacinone. After the administration of diphacinone, hepatic expression levels of Fsp1 , identified as the vitamin K reductase, was decreased, however, the Bonin rats exhibited the most minor suppression. The PK analysis showed that the excretion capacity of the Bonin rats was lower than that of the resistant black rats. In the PBPK modeling, the resistant black rats showed higher clearance than the Bonin and susceptible black rats due to high hepatic metabolic capacity. The Bonin rats demonstrated slow absorption and relatively low clearance. This study highlighted the reduced rodenticide-sensitive tendency of wild black rats in the Bonin Archipelago at an in vivo phenotype level. At the same time, they do not have known rodenticide resistance mechanisms, such as hepatic metabolic enhancement or Vkorc1 mutations. It is crucial to monitor the biological levels to evaluate rodenticide sensitivity accurately. [Display omitted] • Evaluation of rodenticide sensitivity in invasive rats in the Bonin Islands, Japan. • Bonin rats showed lower sensitivity characterized by prothrombin time measurement. • No genetic mutations in Vkorc1 : a target enzyme of rodenticides. • Bonin rats exhibited excretion capacities similar to those of sensitive rats. • Diphacinone treatment suppressed the expression of novel vitamin K reductase, Fsp1. [ABSTRACT FROM AUTHOR]

Objectives: The Japanese herbal medicine kyoseihatekigan (KHG) has been used to alleviate the symptoms of croaky voice and globus hystericus, and each of its components has anti-inflammatory and antioxidant effects. However, the mechanisms underlying these beneficial actions of KHG on the vocal folds remain largely unknown. We examined the effects of KHG on rat vocal fold wound healing and assessed its anti-inflammatory and antioxidant properties., Study Design: Animal model., Methods: The vocal folds of Sprague-Dawley rats were unilaterally injured under endoscopy. Rats were divided into three groups based on KHG dosing from pre injury day 4 to post injury day 3: 0 mg/kg/day (sham group), 500 mg/kg/day (1% KHG group) and 1000 mg/kg/day (2% KHG group). Histologic changes were examined to assess the degree of inflammation and oxidative stress at day 3, and fibrosis at day 56. In addition, gene expression related to pro-inflammatory cytokines and transforming growth factor-beta1 (TGF-β1) signaling was examined by quantitative real-time polymerase chain reaction (qPCR)., Results: Histologic analysis showed that the 1% and 2% KHG treatments significantly decreased cell infiltration and the 4-hydroxy-2-nonenalx-immunopositive area, and increased hyaluronic acid at day 3. Both KHG treatments significantly decreased fibrosis at day 56. qPCR revealed that mRNA of interleukin-1β and cyclooxygenase-2 were significantly suppressed at day 1 and TGF-β1 mRNA was significantly downregulated at day 5 in both KHG groups., Conclusions: The current findings suggest that KHG has anti-inflammatory and antioxidant effects in the early phase of vocal fold wound healing, which can lead to better wound healing with less scar formation., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to examine the superiority of peroxidase detection of macroscopic observations using rat wounds, and to test the external validity of the peroxidase analysis in pressure ulcers (PU) in humans. Method: In the animal study, rat wounds were analysed. A crosssectional study analysed, by wound blotting, exudate samples from full-thickness PUs. Peroxidase activity was divided into two groups (ring and non-ring signals). Scores in the 'inflammation/infection' and 'necrotic tissue' components of DESIGN, a classification tool of PUs, were compared between the groups. Results: In the animal study, 20 rat wounds were assessed and in the clinical study, 62 samples were collected from 26 full-thickness PUs of 21 patients aged ≥ 65 years. In the animal study, five of six wounds with clinical inflammation signs showed ring signal (defined as a signal on the wound edge and no signal on the wound bed). While the tissue sections of three wounds with a ring signal showed inflammatory features, they showed no clinical signs of 'inflammation/infection'. In the clinical study, which analysed 630 ring and 32 non-ring signals, 13 samples in the ring signal group and five in the non-ring signal group had 'inflammation/infection; scores of ≥1 (p=0.016). Despite having no clinical signs, 17 samples showed the ring signal. Conclusion: This study revealed the external validity of the wound blotting analysis of peroxidase and demonstrated its use to detect subclinical inflammation. Declaration of interest: The authors have no conflicts of interest. [ABSTRACT FROM AUTHOR]

Shiitake (Lentinula edodes) extract, eritadenine, has been shown to reduce cholesterol levels, and its hypocholesterolemic actions are involved in the metabolism of methionine. However, the mechanisms by which eritadenine affects cholesterol metabolism in animals fed a high-fat diet containing different sources of lipids have not yet been elucidated in detail. This study was conducted to investigate the effects of shiitake supplementation on serum lipid concentrations in rats fed a diet including a high amount of a plant oil (HO [high oil] and HOS [high oil with shiitake] groups), animal fat (HF [high fat] and HFS [high fat with shiitake] groups), or MCT- (medium-chain triglyceride-) rich plant oil (HM [high MCT] and HMS [high MCT with shiitake] groups). Rats in the HOS, HFS, and HMS groups were fed shiitake. When rats were fed a diet containing shiitake, serum triglyceride, cholesterol levels, and LCAT (lecithin-cholesterol acyltransferase) activities were lower in rats given MCT-rich plant oil than in those that consumed lard. The lipid type in the diet with shiitake also affected serum cholesterol levels and LCAT activities. The diet containing MCT-rich plant oil showed the greatest rates of decrease in all serum lipid profiles and LCAT activities. These results suggest that shiitake and MCT-rich plant oil work together to reduce lipid profiles and LCAT activity in serum. [ABSTRACT FROM AUTHOR]

A different type of biologically active compound from Kuji amber (Late Cretaceous, Japan) before the K-Pg boundary [65 million years ago (Ma)] was isolated based on the growth-restoring activity of a mutant yeast involving Ca2+ signal transduction. It was identified as a spirolactone norditerpenoid, (4R*, 5S*, 8R*, 9R*, 10S*)-14,15,16,19-tetranor-labdan-13,9-olide (1) from spectral analyses with high-resolution electron ionization mass spectrometry (HREIMS), 1D and 2D nuclear magnetic resonance (NMR). Although the planar structure of 1 is known as an artificial derivative from marrubiin, it was isolated as a natural product from Kuji amber and its structure was elucidated for the first time. It had a growth-restoring activity against the mutant yeast through the direct or indirect inhibition of calcineurin activity [protein phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A) activation]. Furthermore, the compound had potent inhibitory effect against the degranulation of rat basophilic leukemia 2H3 (RBL-2H3) cells. Unlabelled Image [ABSTRACT FROM AUTHOR]

Brown rats (Rattus norvegicus), roof rats (Rattus rattus), and house mice (Mus musculus) are considered to be important pests on livestock farms. Although the diel activity patterns of rodents are key to their control, information on this aspect of their ecology is limited. Furthermore, the effect of carnivores on rodent activity patterns as well as the carnivore species present on livestock farms is unclear. Here, we set camera traps in an open-type cow barn and in an enclosed pig barn on the same livestock farm in Japan from August through October 2021. The only rodents observed in both barns were roof rats, and the carnivore species observed were dogs (Canis familiaris), cats (Felis catus), and Japanese weasels (Mustela itatsi). Roof rats showed different patterns of activity and behavior between the barns. However, because the pattern in both barns was nocturnal, the activity patterns of roof rats and carnivores showed a moderate to high degree of overlap. Therefore, roof rats did not appear to shift their activity patterns to avoid nocturnal carnivores. Taken together, the present study provides valuable information for rodent control on livestock farms in Japan., (© 2024 The Author(s). Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.)

This review seeks to highlight and celebrate Professor Tomizo Yoshida's famous work on "Establishment and characterization of a rat ascites sarcoma, later named "Yoshida ascites sarcoma". Considering the tremendous contribution of this ascites tumor system to the subsequent promotion of research on cancer biology and cancer chemotherapy, his paper should be regarded as a monumental one in the cancer field. The research was carried out during 1943 and the results were submitted to this Journal in October 1944, when Japan was approaching a debilitating defeat in World War II in August 1945. In 1947, when "Research on Ascites sarcoma" was first comprehensively introduced to researchers in a special lecture at the Annual Meeting of the Japanese Society of Pathology, the whole audience was deeply impressed and was encouraged to resume scientific activity in Japan.

Background: Recently, the successful delivery of organs for transplantation using drones was reported. We investigated the influence of transportation by drones on the quality of liver grafts using a rat model., Methods: Livers of 12 rats (8 and 32 weeks old) were divided into 2 groups of six. Livers were split into 2 parts and allocated to the drone or control groups (both n = 12). The drone experiment was conducted between islands in Nagasaki Prefecture, Japan. The distance between the islands was 12 km. Livers of the drone group were transported by a multicopter at a speed of 30 km-40 km/h over 60 m above sea level. Transported liver quality was analyzed by histology, and biochemistry data were compared between groups., Results: Cold ischemia time did not differ between groups (902 min and 909 min, respectively). There were no differences in macroscopic findings regarding coloration and damage between groups. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in preservation fluid were graft weight-corrected and compared, and no significant differences were found between groups: AST/g (4.61 vs 4.81 IU/L), ALT/g (2.78 vs 2.92 IU/L), and ALP/g (39.1 vs 37.0 IU/L). Immunochemical staining showed no significant difference between groups for terminal deoxynucleotidyl transferase dUTP nick and labeling staining (141 vs 113 cells), CD163 (818 vs 870 cells), and TNF-α (1.25 vs 1.41 scores)., Conclusions: The simulation experiment of organ transport for transplantation by drones was successfully conducted. There were no differences in the quality of livers transported by drones or other means. Further studies including large-animal experiments could lead to future clinical applications., Competing Interests: Declaration of Competing Interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Astrocytes carry two glutamate transporters—GLAST and GLT-1—the latter of which is responsible for >90% of glutamate uptake activity in the brain; however, under culture conditions, the GLT-1 expression in astrocytes is exceedingly low, as is the glutamate uptake activity mediated by GLT-1. This study aimed to elucidate the effects of yokukansan (YKS) in relation to the GLT-1-mediated regulation of extracellular glutamate concentrations. Thus, we treated cultured astrocytes with tumor necrosis factor-α (TNF-α) and dibutyryl-cAMP (dBcAMP) (hereinafter, referred to as “TA”) to increase GLT-1 expression and then functionally examined how YKS would affect glutamate uptake ability derived from GLT-1. Contrary to expectations, although the TA treatments did not affect the uptake activity, YKS significantly augmented it. Conversely, GLAST-derived glutamate uptake was significantly reduced by TA treatments but was unaffected by YKS. Subsequently, we analyzed the GLT-1 protein and mRNA levels and found that TA treatments had significantly increased them, which were then further augmented by YKS. These findings suggest that YKS enhances GLT-1-derived glutamate transport functions in TA-treated cultured astrocytes and that this process entails increased GLT-1 protein and mRNA levels. This type of mechanism may contribute to the YKS-mediated regulation of extracellular glutamate concentrations. [ABSTRACT FROM AUTHOR]

A compound (WJD-A-1) was previously reported as a candidate prodrug of Am80 (tamibarotene), which was approved in Japan in 2005 as a therapeutic agent for recurrent refractory acute promyelocytic leukaemia. A rapid, selective and sensitive ultra high-performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS) method was developed for the first time to simultaneously determine WJD-A-1 and its major phase-I metabolites AM80 in rat plasma. After a simple sample preparation procedure by protein precipitation with methanol and acetonitrile, WJD-A-1, AM80 and the internal standard were chromatographed on an ACQUITY UPLCTM BEH C18 column. The mobile phase consisted of methanol–0.1% formic acid (80:20, v/v) and the flow rate was 0.20 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. Each plasma sample was chromatographed within 2.6 min. The linear calibration curves for WJD-A-1 and the AM80 were obtained in the concentration range of 5.40–5.40 × 103 and 5.08–5.08 × 103 ng/mL, respectively (r ≥ 0.99). The intra- and inter-day precision (relative standard deviation, RSD) values were less than 8% and the accuracy (relative error, RE) was within ±6.8%, determined from quality control (QC) samples for the analytes. The method herein described was fully validated and successfully applied to pharmacokinetic study of WJD-A-1 following an intravenous administration of 300 μg/kg WJD-A-1 to rats. [ABSTRACT FROM AUTHOR]

Secondary cerebral edema regulation is of prognostic significance in hypoxic-ischemic encephalopathy (HIE), and aquaporin 4 (AQP4) plays an important role in the pathogenesis of cerebral edema. The traditional Japanese herbal medicine Goreisan relieves brain edema in adults; however, its effect and pharmacological mechanism in children are unknown. We investigated the effects of Goreisan on HIE-associated brain edema and AQP4 expression in a juvenile rat model, established by combined occlusion of middle cerebral and common carotid arteries. Magnetic resonance imaging showed that the lesion areas were significantly smaller in the Goreisan- (2 g/kg) treated group than in the nontreated (saline) group at 24 and 48 h postoperatively. AQP4 mRNA levels in the lesion and nonlesion sides were significantly suppressed in the Goreisan group compared with the nontreated group 36 h postoperatively. Western blotting revealed that levels of AQP4 protein were significantly decreased in the Goreisan group compared with the nontreated group in the lesion side 72 h postoperatively, but not at 12 or 36 h. After 14 days, the Goreisan group had a significantly better survival rate. These findings suggest that Goreisan suppresses brain edema in HIE and improves survival in juvenile rats, possibly via regulation of AQP4 expression and function. [ABSTRACT FROM AUTHOR]

Background and Objective During orthodontic tooth movement (OTM), periodontal ligament (PDL) is remodeled dynamically, which requires sufficient blood supply for the regeneration of PDL. However, little is known about the remodeling of blood vessels during OTM. In this study, we hypothesized that the orthodontic tensile strain upregulates matrix metalloproteinase-12 (MMP-12) expression in the tension zone and induces angiogenesis via degradation of type IV collagen (Col-IV) in vascular endothelial basement membrane during the early stage of OTM. Material and Methods Temporal and spatial MMP-12 expression in the tension zone of PDL, during the early stage of OTM, were examined by immunohistochemistry in rats. Continuous tensile strain was applied to cultured human immortalized PDL cell lines (HPL cells) and MMP-12 expression was examined in vitro. Colocalization of MMP-12 and Col-IV in vivo were examined by immunohistochemistry. To investigate whether MMP-12 produced by HPL cells could degrade Col-IV, recombinant Col-IV was incubated in the culture supernatants of HPL cells. Intact Col-IV in vitro was also examined by western blot analysis. Finally, the changes in blood vessels in the PDL were examined by micro-computed tomography analysis with perfused contrast agents and by conventional histological analysis. Results Orthodontic tensile strain induced MMP-12 expression in PDL cells in vivo and in vitro. Immunohistochemistry revealed that MMP-12-positive cells were observed adjacent to the Col-IV-positive tubular area in the tension zone of PDL. MMP-12 in culture supernatant of HPL cells degraded recombinant Col-IV, and specific MMP-12 inhibitor blocked the Col-IV degradation. Micro-computed tomography analysis and conventional histological analysis demonstrated that the areas of blood vessels were increased in the tension zone of the PDL after OTM. Conclusion We discovered that the orthodontic tensile strain upregulates MMP-12 expression in the tension zone of PDL and induces angiogenesis via degradation of Col-IV in the vascular endothelial basement membrane. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor β1 (TGF-β1) positively regulates the tenogenic marker genes scleraxis (Scx) and tenomodulin (Tnmd) in mesenchymal progenitors in vitro. However, little is known about the effect of TGF-β1 on the expression of tenogenic markers during rotator cuff (RC) healing in rats. Hypothesis: TGF-β1 improves the biomechanical properties and histological maturity of reparative tissue in a rat RC repair model by stimulating the growth of tenogenic cells. Study Design: Controlled laboratory study. Methods: Adult male Sprague-Dawley rats (N = 180) underwent unilateral supraspinatus tendon-to-bone surgical repair and were randomly treated with a gelatin hydrogel presoaked in TGF-β1 (100 ng) or phosphate-buffered saline. The effects of TGF-β1 on RC healing were investigated at 2, 4, 6, 8, and 12 weeks postoperatively by immunostaining for proliferating cell nuclear antigen, by real-time reverse transcription polymerase chain reaction and in situ hybridization or immunostaining for enthesis-related markers (SRY-box containing gene 9 [Sox9], Scx, and Tnmd), and by real-time reverse transcription polymerase chain reaction and immunostaining for type I and III collagen. At 6 and 12 weeks postoperatively, biomechanical testing, micro–computed tomography, and biochemical analysis were also performed. At 2 and 4 weeks postoperatively, mesenchymal stem cell–related markers, phospho-Smad2, and matrix metalloproteinase 9 (MMP-9) and MMP-13 were assessed by immunostaining. Results: The TGF-β1-treated group had significantly higher ultimate load to failure and tissue volume at 6 and 12 weeks postoperatively and a higher collagen content at 12 weeks compared with the saline group. Tendon-related gene expression, histological maturity, cell proliferation, and mesenchymal stem cell–related marker immunoreactivity were not affected by exogenously administrated TGF-β1 at all time points. In the TGF-β1-treated group, the percentage of phospho-Smad2-positive cells within the healing tissue increased, whereas the expression of MMP-9 and MMP-13 significantly decreased at 2 and 4 weeks postoperatively. Conclusion: TGF-β1 enhances formation of tough fibrous tissues at the healing site by inhibiting MMP-9 and MMP-13 expression to increase collagen accumulation but without the growth of tenogenic lineage cells. Clinical Relevance: These findings suggest that TGF-β1 could be used for enhancing biomechanical strength after RC surgical repair. [ABSTRACT FROM AUTHOR]

Oketsu is a characteristic condition that plays an important role in Kampo, Japanese traditional medicine, and includes multiple aspects of hemodynamic disorders. This study aims to clarify the microcirculation of Oketsu and the pharmacological effect of Keishibukuryogan, an anti-Oketsu Kampo prescription, using live imaging techniques. Oral administration of Keishibukuryogan induced significant vasodilation of murine subcutaneous arterioles compared to the preadministration level. This vasodilatation peaked 60 min after administration and persisted for 90 min. The blood velocity in the subcutaneous capillary was also increased by Keishibukuryogan in generally the same manner. In rat mesenteric arterioles, Keishibukuryogan administration improved microhemodynamic parameters, including the resolution of erythrocyte congestion and the cell-free layer, which are representative of Oketsu pathology. Live imaging revealed an increase of diaminofluorescein-2 diacetate fluorescence, a nitric oxide (NO) specific reagent, in the arterial endothelium following Keishibukuryogan administration. This fluorescence was most remarkable at vascular bifurcations but was present throughout the mesenteric arterioles. This study demonstrates the successful imaging of Oketsu pathology with respect to microcirculation and the anti-Oketsu effects of Keishibukuryogan, namely, vasodilation of arterioles, increased blood velocity, and resolution of erythrocyte congestion. The anti-Oketsu effect of Keishibukuryogan is related to endothelial NO production. [ABSTRACT FROM AUTHOR]

Background: Vascular CD34+ cells in anterior cruciate ligament (ACL) tissue have the potential for high proliferation and multilineage differentiation that can accelerate tendon-bone healing. While patient characteristics, such as age, can affect tendon-bone healing, the influence of elapsed time after injury on the healing process is unclear. Hypothesis: Cells obtained during the early phase after injury will exhibit a greater tendon-bone healing potential compared with chronic phase counterparts when applied to an immunodeficient rat model of ACL reconstruction. Study Design: Controlled laboratory study. Methods: Adult human ACL-ruptured tissue was harvested from patients undergoing arthroscopic primary ACL reconstruction and classified into 2 groups based on the time elapsed between injury and surgery: (1) early group (≤3 months from injury) and (2) chronic group (>3 months from injury). In addition, 76 ten-week-old female immunodeficient rats underwent ACL reconstruction, followed by intracapsular administration of one of the following: (1) ACL-derived cells from the early group (n = 5), (2) ACL-derived cells from the chronic group (n = 5), or (3) phosphate-buffered saline (PBS) only (n = 5). During the 8 weeks after surgery, histological (weeks 2, 4, 8), immunohistochemical (week 2), radiographic (weeks 0, 2, 4, 8), and biomechanical (week 8) analyses were performed to evaluate tendon-bone healing. Results: In the early group, the histological evaluation showed early healing, induction of endochondral ossification–like integration, and mature bone ingrowth. Micro–computed tomography showed that the tibial bone tunnels at week 4 and week 8 were significantly reduced in the early group compared with those in the chronic group and PBS group (P < .05). Moreover, biomechanical tensile strength was significantly greater in the early group than in the other groups (P < .05). An accelerated healing potential in the early group was further demonstrated by the enhancement of intrinsic angiogenesis/osteogenesis and human-derived vasculogenesis/osteogenesis. Conclusion: Compared with human ACL-derived cells obtained during the chronic phase, cells obtained during the early phase after injury have a greater tendon-bone healing potential when used in an immunodeficient rat model of ACL reconstruction. Clinical Relevance: During ACL reconstruction surgery, transplanting ACL remnant tissue in the early phase after injury could accelerate and enhance tendon-bone healing. [ABSTRACT FROM AUTHOR]

The live-attenuated oral polio vaccine has long been used as the standard for polio prevention, but in order to minimize the emergence of pathogenic revertants, the inactivated polio vaccine (IPV), which is administered intramuscularly or subcutaneously, is being increasingly demanded worldwide. However, there is a global shortage of IPV, and its cost is an obstacle in developing countries. Therefore, dose-sparing with intradermal administration of IPV has been investigated. In this study, rats were immunized by intradermal (ID) and intramuscular (IM) administration of Sabin-derived inactivated polio vaccine (sIPV) produced in Japan, and the immune responses were evaluated. The results showed that one-fifth (1/5)-dose of ID administration yielded neutralizing antibody titers comparable to the full-dose IM administration, whereas 1/5-dose of IM administration was less effective than the full dose. Furthermore, a vertical puncture-type ID injection device (Immucise) that was originally developed for humans was modified for rats, resulting in successful and stable ID administration into the thin skin of rats. Based on these results, the ID administration of sIPV using Immucise in clinical use is expected to offer benefits such as reduced amounts of vaccine per dose, cost-effectiveness, and thereby the feasibility of vaccination for more people. [ABSTRACT FROM AUTHOR]

alpha-Glycosyl isoquercitrin (AGIQ) is a flavonoid that possesses antioxidant and tumor suppressive capabilities and is marketed as a food additive in Japan. The aim of this study was to assess the potential for oral chronic toxicity and carcinogenicity of AGIQ in male and female Sprague Dawley rats following up to 5.0% dietary exposure. In the chronic toxicity study, rats were exposed to AGIQ or vehicle for one year with a 6-month interim termination point; for the carcinogenicity study, rats were treated for 24 months. No signs of AGIQ-related toxicity clinically or histologically were observed for up to one year except for yellow discoloration of bone. In the carcinogenicity study, a statistically significant increase in the incidence of malignant glioma of the brain or spinal cord was observed in female rats exposed to 5.0% AGIQ compared to those exposed to control feed. A Scientific Advisory Panel of experienced neuropathologists reviewed the gliomas (routine stains and glial cell markers) and concluded that the gliomas were a rare, spontaneous, rat-specific neoplasm: malignant microglial tumor. The lesions could not definitively be attributed to AGIQ exposure and have limited implications with respect to predicting human cancer risk. • Alpha glycosyl isoquercitrin (AGIQ) is a currently marketed food additive. • Rat carcinogenicity study identified a microglial brain tumor response. • Scientific Advisory Panel concluded microglial tumors are rat specific. [ABSTRACT FROM AUTHOR]

Background: Cold exposure induces lower urinary tract symptoms, including nocturia. Cold-induced detrusor overactivity can be alleviated by increasing skin temperature in rats. However, no study has shown an association between passive heating via hot-water bathing and nocturia among humans., Methods: We included 1,051 Japanese community-dwelling older adults (mean age: 71.7 years) in this cross-sectional study from 2010 to 2014. The number of nocturnal voids was recorded in a self-administered urination diary. Nocturia was defined as ≥2 nocturnal voids. We evaluated bathing conditions in the participants' houses., Results: Hot-water bathing (n = 888) was associated with a lower prevalence of nocturia than no bathing (n = 163), independent of potential confounders, including age, sex, obesity, income, physical activity, diabetes, medication (diuretics, nondiuretic antihypertensives, and hypnotics), depressive symptoms, indoor/outdoor temperature, and day length (odds ratio [OR] 0.68; 95% confidence interval [CI], 0.48-0.97; P = 0.035). Compared with the quartile group with the longest bath-to-bed interval (range: 161-576 min), the second and third quartile groups (range: 61-100 and 101-160 min, respectively) were associated with a lower prevalence of nocturia, after adjusting for water temperature and bathing duration besides the same covariates (OR 0.60; 95% CI, 0.38-0.96; P = 0.031 and OR 0.59; 95% CI, 0.37-0.94; P = 0.025, respectively)., Conclusion: Hot-water bathing, particularly with a bath-to-bed interval of 61-160 min, was significantly associated with a lower prevalence of nocturia among older adults.

Ninjin'yoeito (NYT), a traditional Japanese Kampo medicine consisting of 12 herbs, has been reported to improve cognitive dysfunction, depression, and neurological recovery in patients with neurovascular diseases such as Alzheimer's disease and stroke. Several studies have reported that the NYT components exert neurotrophic, neurogenic, and neuroprotective effects. In addition, exercise enhances neuroprotection and functional recovery after stroke. Rehabilitative exercises and pharmacological agents induce neurophysiological plasticity, leading to functional recovery in stroke patients. These reports indicate that NYT treatment and exercise may promote functional recovery following stroke through their beneficial effects. However, no study has determined the effects of NYT and the possible mechanisms of neurorepair and functional recovery after stroke. This study aimed to investigate the combined effects of NYT and exercise on neuroprotection and functional recovery and the underlying mechanisms in a rat ischemic stroke model. Stroke was induced with 60-min middle cerebral artery occlusion (MCAO) followed by reperfusion in adult male Sprague-Dawley rats. After stroke, the rats were assigned to four groups: ischemia reperfusion (IR), NYT, exercise (Ex), and NYT + Ex. NYT-treated rats were fed a diet containing 1% NYT one day after stroke. Exercise was performed using a motorized treadmill for 5 days a week (8–15 m/min, 20 min/day), starting 3 days after stroke. The NYT treatment and exercise were continued for 4 weeks after the stroke. Infarct volume, neurological deficits, sensorimotor functions, expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase A (TrkA) and B (TrkB), caspase-3 activity, and the p-Akt/Akt ratio were examined by immunohistochemistry and western blotting. Compared to the IR group, all treated groups indicated reduced infarct volumes. The NYT + Ex group showed significantly improved waking time and beam walking score compared with the IR group. The expression of NGF/TrkA/p-TrkA and BDNF/TrkB was significantly increased in the NYT + Ex group compared with those in the IR group, whereas the number of caspase-3 positive cells around the lesion was significantly lower in the NYT + Ex group than in the IR group. In addition, the ratio of p-Akt/Akt was significantly higher in the NYT + Ex group than in the IR group. This study suggests that NYT in combination with exercise provides neuroprotective effects and improves sensorimotor function by stimulating NGF/TrkA and BDNF/TrkB, and by activating the Akt pathway in ischemic stroke of rats. NYT may be an effective adjunctive agent in post-stroke rehabilitation. [Display omitted] • Ninjin'yoeito and/or physical exercise provide neuroprotection, enhance neuronal plasticity, reduce apoptotic activity, and improve sensorimotor function after stroke. • Ninjin'yoeito and/or physical exercise stimulated the expression of neurotrophic factors NGF/TrkA and BDNF/TrkB and by activating the Akt pathway. • Ninjin'yoeito in combination with exercise, may have potential acute therapeutic effects after stroke. [ABSTRACT FROM AUTHOR]

A Pseudomonas aeruginosa quorum-sensing system, which produces N-(3-oxododecanoyl)- l-homoserine lactone (3-oxo- C12-HSL) and N-butanoyl- l-homoserine lactone ( C4-HSL), regulates the virulence factors. In our previous study, 3-oxo- C12-HSL, encoded by lasI gene, was shown to promote wound healing. However, the effect of C4-HSL, encoded by rhlI gene, remains to be elucidated. We addressed the effect of C4-HSL on wounds in P. aeruginosa infection. Wounds were created on the backs of Sprague-Dawley SD rats, and P. aeruginosa PAO1 ( PAO1) or its rhlI deletion mutant (Δ rhlI) or lasI deletion mutant (Δ lasI) was inoculated onto the wound. Rats were injected intraperitoneally with anti- C4-HSL antiserum or treated with C4-HSL at the wound surface. PAO1 inoculation led to significant acceleration of wound healing, which was associated with neutrophil infiltration and TNF-α synthesis. These responses were reversed, except for TNF-α production, when Δ rhlI was inoculated instead of PAO1 or when rats were co-treated with PAO1 and anti-C4-HSL . In contrast, the healing process and neutrophil infiltration, but not TNF-α synthesis, were accelerated when C4-HSL was administered in the absence of PAO1. This acceleration was not affected by anti- TNF-α antibody. These results suggest that C4-HSL may be involved in the acceleration of acute wound healing in P. aeruginosa infection by modifying the neutrophilic inflammation. [ABSTRACT FROM AUTHOR]