A Smartphone Healthcare Application, CALO mama Plus, to Promote Weight Loss: A Randomized Controlled Trial.

Mobile applications are increasingly used in healthcare. We have developed a smartphone healthcare application, CALO mama Plus, that can register daily diet, exercise, mood, and sleep quality, calculate dietary intake, and provide advice using artificial intelligence technology. This 3-month randomized controlled trial tested the hypothesis that CALO mama Plus could promote body weight reduction in Japanese adults with overweight or obesity. We recruited office workers as participants. The key eligibility criteria were an age of 20-65 years and a body mass index of 23-40 kg/m2. The primary outcome was body weight change over 3 months. We enrolled 141 participants and randomly assigned them to the intervention (n = 72) and control (n = 69) groups. The intervention group used CALO mama Plus, and the control group did not receive any intervention. The change in body weight was -2.4 ± 4.0 kg and -0.7 ± 3.3 kg in the intervention and control groups, respectively. An analysis of covariance adjusted for related variables showed a significant between-group difference in body weight change (-1.60 kg; 95% confidence interval -2.83 to -0.38; p = 0.011). The present study suggests that CALO mama Plus effectively promotes weight loss.

The Association between Milk Intake and Nutrient Intake Adequacy among Japanese Female Junior High School Students: A Cross-Sectional Study.

The consumption of dairy products, including milk, may be important for improving the overall quality of a diet. The aim of this study was to examine the relationship between milk intake and nutritional adequacy among Japanese female junior high school students. The participants of this study were Japanese female junior high school students aged between 12 and 15 years. Dietary habits over the past month were assessed by a brief self-administered diet history questionnaire. The adequacy of each nutrient intake was determined based on the Dietary Reference Intakes for Japanese 2020, with two goals: the estimated average requirement for fourteen nutrients and tentative dietary goals for preventing lifestyle-related diseases for six nutrients. The participants were classified into five groups according to milk intake (Q1 (lowest) to Q5 (highest)) by quintile. The adequacy of vitamin B2, calcium, magnesium, and potassium were higher among students with a higher milk consumption than among those with a lower milk consumption. However, the intake of saturated fatty acids was in excess among higher milk consumers. The present study suggests that milk intake was related to an adequate intake of some vitamins and minerals and an inadequate intake of saturated fatty acids among Japanese female junior high school students.

Working from home and dietary changes during the COVID-19 pandemic: A longitudinal study of health app (CALO mama) users.

It is plausible that the coronavirus disease pandemic and related changes in work and life patterns affected dietary patterns, but existing studies have limitations owing to a cross-sectional design. Using longitudinal data, we examined dietary changes in people due to the pandemic and work and life patterns. We conducted an online survey on changes in work and life patterns during the pandemic from April 30, 2020, to May 8, 2020, among users of a health app called CALO mama provided in Japan. We retrieved and linked the dietary data for 5929 participants from January 1, 2020, to May 13, 2020. Generalized linear mixed models were used to estimate the frequencies of food intake associated with the pandemic and work and life patterns. During the state of emergency, the frequency of intake of vegetables, beans, seaweeds, fish, meats, dairy products, and snacks increased, whereas alcohol intake decreased. Working from home was associated with increased intake of vegetables, fruits, dairy products, and snacks but decreased intake of seaweeds, meats, and alcohol. Time spent on childcare was associated with decreased intake of vegetables and fruits but increased intake of meats. Probable depressive symptoms were negatively associated with the frequency of food intake other than snacks and alcohol. We conclude that diet quality improved during the pandemic in general, but attention must be paid to overconsumption of snacks and negative factors such as increased burden of childcare and depression for healthy eating.

Changes in work and life patterns associated with depressive symptoms during the COVID-19 pandemic: an observational study of health app (CALO mama) users.

BACKGROUND: During the COVID-19 pandemic, many people refrained from going out, started working from home (WFH), and suspended work or lost their jobs. This study examines how such pandemic-related changes in work and life patterns were associated with depressive symptoms. METHODS: An online survey among participants who use a health app called CALO mama was conducted from 30 April to 8 May 2020 in Japan. Participants consisted of 2846 users (1150 men (mean age=50.3) and 1696 women (mean age=43.0)) who were working prior to the government declaration of a state of emergency (7 April 2020). Their daily steps from 1 January to 13 May 2020 recorded by an accelerometer in their mobile devices were linked to their responses. Depressive symptoms were assessed using the Two-Question Screen. RESULTS: On average, participants took 1143.8 (95% CI -1557.3 to -730.2) fewer weekday steps during the declaration period (from 7 April to 13 May). Depressive symptoms were positively associated with female gender (OR=1.58, 95% CI 1.34 to 1.87), decreased weekday steps (OR=1.22, 95% CI 1.03 to 1.45) and increased working hours (OR=1.73, 95% CI 1.32 to 2.26). Conversely, starting WFH was negatively associated with depressive symptoms (OR=0.83, 95% CI 0.69 to 0.99). CONCLUSIONS: Decreased weekday steps during the declaration period were associated with increased odds of depressive symptoms, but WFH may mitigate the risk in the short term. Further studies on the longitudinal effects of WFH on health are needed.

Amyloidogenic processing of amyloid ß protein precursor (APP) is enhanced in the brains of alcadein α-deficient mice.

Alzheimer's disease (AD) is a very common neurodegenerative disorder, chiefly caused by increased production of neurotoxic ß-amyloid (Aß) peptide generated from proteolytic cleavage of ß-amyloid protein precursor (APP). Except for familial AD arising from mutations in the APP and presenilin (PSEN) genes, the molecular mechanisms regulating the amyloidogenic processing of APP are largely unclear. Alcadein α/calsyntenin1 (ALCα/CLSTN1) is a neuronal type I transmembrane protein that forms a complex with APP, mediated by the neuronal adaptor protein X11-like (X11L or MINT2). Formation of the ALCα-X11L-APP tripartite complex suppresses Aß generation in vitro, and X11L-deficient mice exhibit enhanced amyloidogenic processing of endogenous APP. However, the role of ALCα in APP metabolism in vivo remains unclear. Here, by generating ALCα-deficient mice and using immunohistochemistry, immunoblotting, and co-immunoprecipitation analyses, we verified the role of ALCα in the suppression of amyloidogenic processing of endogenous APP in vivo We observed that ALCα deficiency attenuates the association of X11L with APP, significantly enhances amyloidogenic ß-site cleavage of APP, especially in endosomes, and increases the generation of endogenous Aß in the brain. Furthermore, we noted amyloid plaque formation in the brains of human APP-transgenic mice in an ALCα-deficient background. These results unveil a potential role of ALCα in protecting cerebral neurons from Aß-dependent pathogenicity in AD.

Effect of heat processing on the chemical constituents and NO-suppressing activity of Bletilla Tuber.

Bletilla Tuber (dried tuber of Bletilla striata) is used as an astringent hemostatic medicine for the treatment of ulcers, bleeding, and burns in traditional Chinese medicine (TCM). The Chinese Pharmacopoeia describes the heat processing methods used on raw tubers of Bletilla striata to produce the herbal medicine "Bletilla Tuber". In this study, we compared the chemical constituents of well-processed Bletilla Tuber (BT1) and normally processed Bletilla Tuber (BT2) derived from the same origin. In addition, as an indicator of the hemostatic activity of Bletilla Tuber, the NO inhibitory activities of extracts obtained from BT1 and BT2 and the isolated compounds were examined. As a result of LC-MS analysis, three types of compounds, glucosyloxybenzyl 2-isobutylmalates, bibenzyl derivatives and phenanthrene derivatives, were detected. Comparison of the chemical profiles of the extracts indicated that the relative contents of glucosyloxybenzyl 2-isobutylmalates had changed by heat processing, whereas the relative contents of bibenzyls and phenanthrenes had not changed. The extracts of BT1 and BT2 showed similar IC50 values on NO production suppressing activity. Furthermore, phenanthrenes and bibenzyls were identified as the compounds responsible for suppressing the NO activity. These results suggest that the biological activities, such as the anti-inflammatory and hemostatic activities, of Bletilla Tuber are not affected by heat processing.

Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2.

Mutations in a synaptic organizing pathway contribute to autism. Autism-associated mutations in MDGA2 (MAM domain containing glycosylphosphatidylinositol anchor 2) are thought to reduce excitatory/inhibitory transmission. However, we show that mutation of Mdga2 elevates excitatory transmission, and that MDGA2 blocks neuroligin-1 interaction with neurexins and suppresses excitatory synapse development. Mdga2(+/-) mice, modeling autism mutations, demonstrated increased asymmetric synapse density, mEPSC frequency and amplitude, and altered LTP, with no change in measures of inhibitory synapses. Behavioral assays revealed an autism-like phenotype including stereotypy, aberrant social interactions, and impaired memory. In vivo voltage-sensitive dye imaging, facilitating comparison with fMRI studies in autism, revealed widespread increases in cortical spontaneous activity and intracortical functional connectivity. These results suggest that mutations in MDGA2 contribute to altered cortical processing through the dual disadvantages of elevated excitation and hyperconnectivity, and indicate that perturbations of the NRXN-NLGN pathway in either direction from the norm increase risk for autism.

Anti-inflammatory and Antinociceptive Constituents of Atractylodes japonica Koidzumi.

The rhizomes of many Atractylodes species, including Atractylodes chinensis Koidzumi, Atractylodes macrocephala Koidzumi, and Atractylodes japonica Koidzumi, are collectively termed Atractylodis Rhizoma. We prepared n-hexane extracts of the three species and evaluated their anti-inflammatory effects on lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among all n-hexane extracts, those of A. japonica most strongly inhibited nitric oxide (NO) production in LPS-induced RAW 264.7 cells; five sesquiterpenes, atractylon, atractylenolide I, atractylenolide II, atractylenolide III, and 8-epiasterolid, were isolated from A. japonica. The phytochemical content of A. japonica was similar to those of A. chinensis and A. macrocephala. Moreover, the atractylon concentration was higher in A. japonica than in A. chinensis and A. macrocephala. Atractylon significantly inhibited NO and prostaglandin E2 production as well as inducible NO synthase and cyclooxygenase-2 expression in LPS-induced RAW 264.7 cells. Atractylon (40 mg/kg) also significantly reduced the acetic-acid-induced writhing response, carrageenan-induced paw edema, and hot-plate latent pain response in mice. According to the results, A. japonica has anti-inflammatory and antinociceptive effects and atractylon is the major active component of A. japonica. Therefore, atractylon can be used as a bioactivity marker in A. japonica.

Inhibitory Activity of Yokukansankachimpihange against Nerve Growth Factor-Induced Neurite Growth in Cultured Rat Dorsal Root Ganglion Neurons.

Chronic pruritus is a major and distressing symptom of many cutaneous diseases, however, the treatment remains a challenge in the clinic. The traditional Chinese-Japanese medicine (Kampo medicine) is a conservative and increasingly popular approach to treat chronic pruritus for both patients and medical providers. Yokukansankachimpihange (YKH), a Kampo formula has been demonstrated to be effective in the treatment of itching of atopic dermatitis in Japan although its pharmacological mechanism is unknown clearly. In an attempt to clarify its pharmacological actions, in this study, we focused on the inhibitory activity of YKH against neurite growth induced with nerve growth factor (NGF) in cultured rat dorsal root ganglion (DRG) neurons because epidermal hyperinnervation is deeply related to itch sensitization. YKH showed approximately 200-fold inhibitory activity against NGF-induced neurite growth than that of neurotropin (positive control), a drug used clinically for treatment of chronic pruritus. Moreover, it also found that Uncaria hook, Bupleurum root and their chemical constituents rhynchophylline, hirsutine, and saikosaponin a, d showed inhibitory activities against NGF-induced neurite growth, suggesting they should mainly contribute to the inhibitory activity of YKH. Further study on the effects of YKH against epidermal nerve density in "itch-scratch" animal models is under investigation.

Effect in dedicator of cytokinesis 6 (DOCK6) on steroid production in theca cells of follicular cysts.

Ovarian follicular cysts are one of the most common causes of reproductive failure in mammals. A comparative gene expression approach may aid in elucidating the causes of ovarian cyst disease. In the present study, the differential display technique was used to identify mRNA sequences that accumulate preferentially in theca cells of bovine cystic follicles. Dedicator of cytokinesis 6 (Dock6) expression was observed in the theca cells of cystic follicles. Small interfering RNA (siRNA) knockdown of Dock6 increased progesterone (P4) production and StAR expression in theca cells of high-estrogen follicular cysts, but did not affect androstenedione (A4) production. We propose that Dock6 may be a marker associated with the development of follicular cysts. Additionally, Dock6 may be involved in the development of cystic follicles by suppressing P4 production rather than increasing A4 production in theca cells.

Effects of Hachimijiogan, a Kampo powder, on epididymidis sperm characteristics in healthy male rats.

Purpose: Hachimijiogan (HJG, Rehmannia Eight Formula), a kidney-replenishing Kampo formula, is clinically known to be effective in the treatment of male infertility with oligozoospermia. The purpose of this study was to evaluate the effect of HJG on the epididymal sperm characteristics and related serum hormone changes in rats in an attempt to determine its mechanism. Methods: Male Wistar-Imamichi rats (233.4 ± 5.2 g, nine weeks old) were assigned randomly to four groups (n = 6 for each group). Apart from one control group treated with distilled water, the other groups were administered HJG consecutively for 9-11 days with doses of 250, 500 and 1,000 mg/kg. After the last administration the caude epididymides were quickly removed under anesthesia for assessing sperm characteristics. Additionally, the testes, seminal vesicles, prostate and adrenal glands were removed surgically and their wet weights measured. Results: Results showed that HJG increased sperm numbers and motility as well as the weights of seminal vesicles and adrenal glands at lower doses. Moreover, HJG decreased serum levels of testosterone and luteinizing hormone while increasing follicle-stimulating hormone levels. Conclusions: Our findings may support the conclusion that a lower dosage of HJG has an effect on improving local spermatogenous environments by activating adrenal functions and/or promoting local androgen activity.

Pharmacological effects of "jutsu" (Atractylodis rhizome and Atractylodis lanceae rhizome) on 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitch response in mice (I).

Hallucinations are a common non-motor symptom of Parkinson's disease and various forms of dementias. Yokukansan and Yokukansankachimpihange have attracted attention due to their effectiveness in the treatment of hallucinations of dementia. To clarify which component in these formulas contribute to the effects, at first, we focused on their differences in compositions to examine the pharmacological effects on the selective 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head-twitch response (HTR) in mice that has been used as animal hallucination model. Results indicated that water extract of Byaku-jutsu (Atractylodes japonica) showed a stronger inhibitory effect on DOI-induced HTR than that of So-jutsu (A. lancea) corresponding to their major constituents of atractylenolide III and ß-eudesmol, and suggested that the major constituents should be active constituents contributing to the antihallucination effects of Byaku- and So-jutsu. Besides, the part B-C ring (butenolide) in atractylenolide III was found to be similar to the structure of serotonin and suggested that the B-C ring may partially play role in antagonistic activity against serotonin receptors. Thus, a novel, rational design of butenolide-related compounds may as potential lead compounds for new drug development. Analysis of the chemical components of Byaku- and So-jutsu and further study on their structure-activity relationships are currently in progress.

Inhibitory activity of the flower buds of Lonicera japonica Thunb. against histamine production and L-histidine decarboxylase in human keratinocytes.

In previous studies we found that anionic surfactants such as sodium laurate (SL) and/or sodium dodecylsulfate (SDS) exert actions on epidermal keratinocytes rather than mast cells to give rise of histamine production and skin itching through increasing the expression of the 53-kDa active form of L-histidine decarboxylase (HDC). In addition, with treatment of SL in a three-dimensional human keratinocyte culture, increases in both the 53-kDa HDC and histamine production are detected and thus this culture assay is applied to screen anti-itching materials from natural resources. In this study, the inhibitory activity of "Kin-gin-ka" (flower buds of Lonicera japonica Thunb., FLJ) against histamine production and expression of the active form of HDC were examined in this culture assay. FLJ is a well-known traditional Chinese medicine, being used to treat fevers, coughs and some infectious diseases. The result showed both FLJ and chlorogenic acid had inhibitory activities against the expression of 53-kDa HDC and histamine production. However, chlorogenic acid showed a weaker effect on histamine production than that of FLJ, suggesting that other chemical constituents besides chlorogenic acid could contribute to the inhibitory activities. Thus, a further chemical study of FLJ is now under investigation.

Comparison of cadherin and integrin localization in bovine cystic and healthy follicles.

As stage progresses in the cystic follicle, granulosa cells are lost. We hypothesized that the granulosa and theca interna layers are detached in association with weakened expression of cell adhesion molecules such as cadherin (cell-cell adhesion) and integrin (cell-extracellular matrix adhesion) in cystic follicles. To elucidate this hypothesis, we immunolocalized these molecules in the granulosa and theca interna and compared them between cystic and small healthy follicles. Sections were immunostained with cadherin and integrin ß1 antibodies and their localizations were compared. Cadherin-positive reaction was seen in the cytoplasma of all granulosa cells. No increase in the frequency of cadherin-positive area in the granulosa layers and the intensity of cadherin immunoreaction in the theca interna was detected in cystic follicles compared with healthy ones. A dense immunoreaction product of integrin ß1 was detected in the theca interna in both cystic and healthy follicles. Intensity of integrin ß1 -immuno reaction in the granulosa layers and integrin ß1 -positive area in the theca interna was significantly lower in the cystic follicle than in the healthy follicles. These results suggest that granulosa and theca interna cells are detached while maintaining the cell-cell adhesion, resulting in the consequent loss of these layers from the cystic follicle.

Interleukin-8 stimulates progesterone production via the MEK pathway in ovarian theca cells.

Interleukin 8 (IL-8) is a chemoattractant associated with ovulation in the mammalian ovary. This chemokine is also involved in the recruitment and activation of neutrophils. Using bovine tissue, we examined the possible role of IL-8 in steroid production by theca cells of the large ovarian follicles. IL-8 promoted progesterone production and stimulated StAR expression in cultured theca cells. The inhibitor of p38 did not disturb the P4 production and StAR expression in IL-8-treated theca cells. On the other hand, the inhibitor of MEK disturbed the P4 production and expression of StAR in theca cells treated with IL-8. These results suggest that IL-8 is associated with progesterone production in bovine theca cells via the MEK pathway.

Bone morphogenetic protein (BMP)-4 and BMP-7 suppress granulosa cell apoptosis via different pathways: BMP-4 via PI3K/PDK-1/Akt and BMP-7 via PI3K/PDK-1/PKC.

BMP-4 and BMP-7 are associated with the suppression of granulosa cell apoptosis. LY294002 (PI3K inhibitor) or UCN-01 (PDK-1 inhibitor) increased the percentage of apoptotic cells in the granulosa cells treated with BMP-4 or BMP-7. The inhibitors of ERK and p38 (SB203580) did not increase the percentage of apoptotic cells in the granulosa cells treated with BMP-4 or BMP-7. Akt inhibitor did not induce apoptosis in the BMP-4-treated granulosa cells, whereas it did induce apoptosis of the BMP-7-treated granulosa cells. In the granulosa cells treated with BMP-4, the PKC inhibitor increased the percentage of apoptotic cells. Our data show that BMP-4 and BMP-7 are associated with granulosa cell survival via several non-Smad specific pathways: BMP-4 via the PI3K/PDK-1/PKC and BMP-7 via the PI3K/PDK-1/Akt.

Luteinizing hormone (LH) regulates production of androstenedione and progesterone via control of histone acetylation of StAR and CYP17 promoters in ovarian theca cells.

Although luteinizing hormone (LH) affects androstenedione (A4) and progesterone (P4) production in theca cells, it is still unknown how LH influences molecular mechanism of A4 and P4 production. To examine the relationship between LH and transcription factors involved in A4 and P4 production, ovarian theca cells were cultured in the presence or absence of high concentrations of LH for 24 h (pre-treatment with high concentration of LH) and then cultured in the presence or absence of low concentration of LH for 48 h. Low LH enhanced production of A4 and P4, and expressions of CYP17 and StAR mRNA in theca cells without pre-treatment with high LH. In addition, low LH stimulated the expression of SF-1 protein in nuclear fractions from theca cells with or without pre-treatment with high LH. The binding of SF-1 to the CYP17 and StAR promoter regions increased in theca cells treated with low LH. Although GATA-4 and GATA-6 are both found in the nuclear fraction but not in the cytosol of theca cells, low LH enhanced the binding of GATA-6, but not of GATA-4, to the CYP17 promoter region without pre-treatment with high LH. Acetylation histone H3 in StAR and CYP17 promoter regions were changed by different LH-dosage. Overall, we showed that LH regulates the production of A4 and P4 by affecting the nuclear localization and switching of transcription factors in theca cells and that target transcription factors involved in steroid production in theca cells are changed by different LH concentration.

Effects of interleukin-8 on estradiol and progesterone production by bovine granulosa cells from large follicles and progesterone production by luteinizing granulosa cells in culture.

Interleukin 8 (IL-8) is a chemoattractant involved in the recruitment and activation of neutrophils and is associated with the ovulate process. We examined the possible role of IL-8 in steroid production by bovine granulosa cells before and after ovulation. The concentration of IL-8 in the follicular fluid of estrogen-active dominant (EAD) and pre-ovulatory follicles (POF) was higher than that of small follicles (SF). CXCR1 mRNA expression was higher in the granulosa cells of EAD and POF than that of SF. In contrast, CXCR2 mRNA expression was lower in granulosa cells of EAD and POF than in SF. IL-8 inhibited estradiol (E2) production in follicle-stimulating hormone (FSH)-treated granulosa cells at 48 h of culture. IL-8 also suppressed CYP19A1 mRNA expression in FSH-treated granulosa cells. IL-8 stimulated progesterone (P4) production in luteinizing hormone (LH)-treated granulosa cells at 48 h of culture. Although IL-8 did not alter the expression of genes associated with P4 production, it induced StAR protein expression in LH-treated granulosa cells. The expression of CXCR1 mRNA in corpus luteum (CL) did not change during the luteal phase. In contrast, the expression of CXCR2 mRNA in middle CL was significantly higher than in early and regression CL during the luteal phase. In luteinizing granulosa cells, an in vitro model of granulosa cell luteinization, CXCR2 mRNA expression was downregulated, whereas CXCR1 mRNA expression was unchanged. IL-8 also stimulated P4 production in luteinizing granulosa cells. These data provide evidence that IL-8 functions not only as a chemokine, but also act as a regulator of steroid synthesis in granulosa cells to promote luteinization after ovulation.

Circadian Clock genes Per2 and clock regulate steroid production, cell proliferation, and luteinizing hormone receptor transcription in ovarian granulosa cells.

Circadian Clock genes are associated with the estrous cycle in female animals. Treatment with Per2 and Clock siRNAs decreased the number of granulosa cells and LHr expression in follicle-stimulating hormone FSH-treated granulosa cells. Per2 siRNA treatment did not stimulate the production of estradiol and expression of P450arom, whereas Clock siRNA treatment inhibited the production of estradiol and expression of P450arom mRNA. Per2 and Clock siRNA treatment increased and unchanged, respectively, progesterone production in FSH-treated granulosa cells. Similarly, expression of StAR mRNA was increased by Per2 siRNA and unchanged by Clock siRNA. Our data provide a new insight that Per2 and Clock have different action on ovarian granulosa cell functions.

Expression of sorting nexin 18 (SNX18) is dynamically regulated in developing spinal motor neurons.

The sorting nexin (SNX) family proteins, which contain a Phox homology (PX) domain, play crucial roles in regulating the intracellular membrane trafficking of the endocytic pathway. The proper coordination of this pathway is important for axonal elongation; however, little is known about the expression and intracellular dynamics of the SNX members during the formation of the nervous system. Here the authors found that SNX18, which belongs to the Src-homology-3-PX-Bin/Amphiphysin/Rvs domain-containing SNX subfamily, was specifically expressed in differentiating motor neurons in the chick and mouse embryonic spinal cord. The expression of SNX18 in embryonic spinal motor neurons was transient and was downregulated as the neurons matured. The authors further demonstrated that the localization of EGFP-SNX18 in growth cones was dynamically regulated and accumulated especially at areas in contact with permissive substrates. These findings collectively suggest that SNX18 may play an active role in axonal elongation.