Antidepressant-Like Activity of 10-Hydroxy-Trans-2-Decenoic Acid, a Unique Unsaturated Fatty Acid of Royal Jelly, in Stress-Inducible Depression-Like Mouse Model

Symptoms of depression and anxiety appeared in mice after they had been subjected to a combination of forced swimming for 15 min followed by being kept in cages that were sequentially subjected to leaning, drenching, and rotation within 1-2 days for a total of 3 weeks. The animals were then evaluated by the tail-suspension test, elevated plus-maze test, and open-field test at 1 day after the end of stress exposure. Using these experimental systems, we found that 10-hydroxy-trans-2-decenoic acid (HDEA), an unsaturated fatty acid unique to royal jelly (RJ), protected against the depression and anxiety when intraperitoneally administered once a day for 3 weeks simultaneously with the stress loading. Intraperitoneally administered RJ, a rich source of HDEA, was also protective against the depression, but RJ given by the oral route was less effective. Our present results demonstrate that HDEA and RJ, a natural source of it, were effective in ameliorating the stress-inducible symptoms of depression and anxiety

Increased intrapharyngeal pressure with combined use of high-flow nasal cannula and a surgical face mask: a preliminary study

OBJECTIVES: Nasal high-flow (NHF) therapy provides continuous positive airway pressure (CPAP), flushes the anatomical dead space, and improves mucociliary clearance. CPAP is usually applied at a flow rate at or above an established threshold value with the mouth closed because it is hard to maintain it with an open mouth. We conducted a prospective study to validate our hypothesis that CPAP can be applied with the mouth open through a surgical face mask. METHODS: We inserted 12-Fr nasogastric tubes through the noses of 18 healthy individuals and fixed each tube within the pharynx to monitor the intrapharyngeal pressure. We monitored the pressure during the following two conditions: NHF oxygen with the mouth open (condition O) and NHF oxygen with the mouth open and wearing a surgical face mask (condition OM). We set the NHF rate at 40 L/min and the oxygen concentration at 21%, under all conditions. We measured the intrapharyngeal pressure five times during each inspiration and expiration, and calculated mean values. RESULTS: The mean expiratory intrapharyngeal pressure (median [interquartile range]) increased significantly from the baseline during conditions O (2.08 [1.58–4.02] cm H(2)O) and OM (3.35 [2.72–3.79] cm H(2)O). In addition, there was a significant difference in pressure between conditions O and OM (p=0.0263, Wilcoxon signed-rank test). CONCLUSIONS: In our healthy volunteers, the intrapharyngeal pressures increased during expiration with an open mouth while wearing a surgical face mask

Protective role of vascular endothelial growth factor in endotoxin-induced acute lung injury in mice

<p>Abstract</p> <p>Background</p> <p>Vascular endothelial growth factor (VEGF), a substance that stimulates new blood vessel formation, is an important survival factor for endothelial cells. Although overexpressed VEGF in the lung induces pulmonary edema with increased lung vascular permeability, the role of VEGF in the development of acute lung injury remains to be determined.</p> <p>Methods</p> <p>To evaluate the role of VEGF in the pathogenesis of acute lung injury, we first evaluated the effects of exogenous VEGF and VEGF blockade using monoclonal antibody on LPS-induced lung injury in mice. Using the lung specimens, we performed TUNEL staining to detect apoptotic cells and immunostaining to evaluate the expression of apoptosis-associated molecules, including caspase-3, Bax, apoptosis inducing factor (AIF), and cytochrome C. As a parameter of endothelial permeability, we measured the albumin transferred across human pulmonary artery endothelial cell (HPAEC) monolayers cultured on porous filters with various concentrations of VEGF. The effect of VEGF on apoptosis HPAECs was also examined by TUNEL staining and active caspase-3 immunoassay.</p> <p>Results</p> <p>Exogenous VEGF significantly decreased LPS-induced extravascular albumin leakage and edema formation. Treatment with anti-VEGF antibody significantly enhanced lung edema formation and neutrophil emigration after intratracheal LPS administration, whereas extravascular albumin leakage was not significantly changed by VEGF blockade. In lung pathology, pretreatment with VEGF significantly decreased the numbers of TUNEL positive cells and those with positive immunostaining of the pro-apoptotic molecules examined. VEGF attenuated the increases in the permeability of the HPAEC monolayer and the apoptosis of HPAECs induced by TNF-α and LPS. In addition, VEGF significantly reduced the levels of TNF-α- and LPS-induced active caspase-3 in HPAEC lysates.</p> <p>Conclusion</p> <p>These results suggest that VEGF suppresses the apoptosis induced by inflammatory stimuli and functions as a protective factor against acute lung injury.</p

The status of paediatric medicines initiatives around the world-what has happened and what has not?

Purpose: This review was conducted to examine the current status of paediatric medicines initiatives across the globe. Methods: The authors made a non-systematic descriptive review of current world situation. Results: Two regions, the United States (US) and the European Union (EU), and the World Health Organization (WHO) have introduced strong paediatric initiatives to improve children's health through improving access to better paediatric medicines. The experience from the US initiative indicates that it is possible to stimulate development and study of paediatric medicines and provide important new information for improvement of paediatric therapy. The early results from the EU initiative are similarly encouraging. In Canada, Japan, Australia and other developed countries, specific paediatric medicines initiatives have been less extensive and weaker, with modest results. Disappointingly, current evidence suggests that results from clinical trials outside the US often do not benefit children in the country in which the trials were largely conducted. Pharmaceutical companies that have derived a financial benefit commensurate with the cost of doing the paediatric trials in one country do not seem to be making the results of these trials available to all countries if there is no financial incentive to the company. The WHO campaign 'make medicines child size' has produced substantive accomplishments in building improved foundations to improve mechanisms that will enhance children's access to critical medicines in resource-limited settings. However, practically all of this work has been performed using an amalgamation of short-term funding from a variety of sources as opposed to a sustained, programmatic commitment. Conclusions: Although much still needs to be done, it's clear that with concerted efforts and appropriate resources, change is possible but slow. Retaining and fostering public and political interest in paediatric medicines is challenging, but pivotal for success.Fil: Hoppu, Kalle. Helsinki University Central Hospital; FinlandiaFil: Anabwani, Gabriel. Botswana-Baylor Children’s Clinical Centre of Excellence; BotsuanaFil: Garcia Bournissen, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Gazarian, Madlen. University of New South Wales; Australia. Sydney Children’s Hospital; AustraliaFil: Kearns, Gregory L.. The Children’s Mercy Hospital; Estados Unidos. University of Missouri; Estados UnidosFil: Nakamura, Hidefumi. National Center for Child Health and Development; JapónFil: Peterson, Robert G.. University of British Columbia; CanadáFil: Sri Ranganathan, Shalini. University Of Colombo. Faculty Of Medicine; Sri LankaFil: De Wildt, Saskia N.. Sophia Children’s Hospital; Países Bajo

PAX2 promoted prostate cancer cell invasion through transcriptional regulation of HGF in an in vitro model

AbstractElucidating the mechanism of prostate cancer cell invasion may lead to the identification of novel therapeutic strategies for its treatment. Paired box 2 (PAX2) and hepatocyte growth factor (HGF) proteins are promoters of prostate cancer cell invasion. We found that PAX2 protein activated the HGF gene promoter through histone H3 acetylation and upregulated HGF gene expression. Deletion analysis revealed that the region from −637 to −314 of the HGF gene was indispensable for HGF promoter activation by PAX2. This region contains consensus PAX2 binding sequences and mutations of the sequences attenuated HGF promoter activation. Using an in vitro invasion model, we found that PAX2 and HGF promoted prostate cancer cell invasion in the same pathway. Knockdown of HGF expression attenuated the cells' invasive capacity. Moreover, in tissue samples of human prostate cancers, HGF and PAX2 expression levels were positively correlated. These results suggested that upregulation of HGF gene expression by PAX2 enhanced the invasive properties of prostate cancer cells. The PAX2/HGF pathway in prostate cancer cells may be a novel therapeutic target in prostate cancer patients

Therapeutic regimen of l-arginine for MELAS: 9-year, prospective, multicenter, clinical research

ObjectiveTo examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).MethodsIn the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined.ResultsOral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated.ConclusionsThe systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS

The Current States, Challenges, Ongoing Efforts, and Future Perspectives of Pharmaceutical Excipients in Pediatric Patients in Each Country and Region

A major hurdle in pediatric formulation development is the lack of safety and toxicity data on some of the commonly used excipients. While the maximum oral safe dose for several kinds of excipients is known in the adult population, the doses in pediatric patients, including preterm neonates, are not established yet due to the lack of evidence-based data. This paper consists of four parts: (1) country-specific perspectives in different parts of the world (current state, challenges in excipients, and ongoing efforts) for ensuring the use of safe excipients, (2) comparing and contrasting the country-specific perspectives, (3) past and ongoing collaborative efforts, and (4) future perspectives on excipients for pediatric formulation. The regulatory process for pharmaceutical excipients has been developed. However, there are gaps between each region where a lack of information and an insufficient regulation process was found. Ongoing efforts include raising issues on excipient exposure, building a region-specific database, and improving excipient regulation; however, there is a lack of evidence-based information on safety for the pediatric population. More progress on clear safety limits, quantitative information on excipients of concern in the pediatric population, and international harmonization of excipients’ regulatory processes for the pediatric population are required

TDP-43 regulates cholesterol biosynthesis by inhibiting sterol regulatory element-binding protein 2

Dyslipidemia is considered an essential component of the pathological process of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease. Although TAR DNA Binding Protein 43 kDa (TDP-43) links both familial and sporadic forms of ALS and cytoplasmic aggregates are a hallmark of most cases of ALS, the molecular mechanism and the in vivo relation of ALS dyslipidemia with TDP-43 have been unclear. To analyze the dyslipidemia-related gene expression by TDP-43, we performed expression microarray and RNA deep sequencing (RNA-Seq) using cell lines expressing high levels of TDP-43 and identified 434 significantly altered genes including sterol regulatory element-binding protein 2 (SREBP2), a master regulator of cholesterol homeostasis and its downstream genes. Elevated TDP-43 impaired SREBP2 transcriptional activity, leading to inhibition of cholesterol biosynthesis. The amount of cholesterol was significantly decreased in the spinal cords of TDP-43-overexpressed ALS model mice and in the cerebrospinal fluids of ALS patients. These results suggested that TDP-43 could play an essential role in cholesterol biosynthesis in relation to ALS dyslipidemia

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection