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We assessed the effects of chewing behavior on the lung-metastasis-promoting impact of chronic psychological-stress in mice. Human breast-cancer cells (MDA-MB-231) were injected into the tail vein of female nude mice. Mice were randomly divided into stress, stress-with-chewing, and control groups. We created chronic stress by placing mice in small transparent tubes for 45 min, 3 times a day for 7 weeks. Mice in the stress-with-chewing group were allowed to chew wooden sticks during the experimental period. The histopathological examination showed that chronic psychological-stress increased lung metastasis, and chewing behavior attenuated the stress-related lung metastasis of breast-cancer cells. Chewing behavior decreased the elevated level of the serum corticosterone, normalized the increased expression of glucocorticoid, and attenuated the elevated expression of adrenergic receptors in lung tissues. We also found that chewing behavior normalized the elevated expression of inducible nitric oxide synthase, 4-hydroxynonenal, and superoxide dismutase 2 in lung tissues, induced by chronic stress. The present study demonstrated that chewing behavior could attenuate the promoting effects of chronic psychological-stress on the lung metastasis of breast-cancer cells, by regulating stress hormones and their receptors, and the downstream signaling-molecules, involving angiogenesis and oxidative stress.

Long-term tooth loss is associated with the suppression of hippocampal neurogenesis and impairment of hippocampus-dependent cognition with aging. The morphologic basis of the hippocampal alterations, however, remains unclear. In the present study, we investigated whether tooth loss early in life affects the hippocampal ultrastructure in senescence-accelerated mouse prone 8 (SAMP8) mice, using transmission electron microscopy. Male SAMP8 mice were randomized into control or tooth-loss groups. All maxillary molar teeth were removed at 1 month of age. Hippocampal morphologic alterations were evaluated at 9 months of age. Tooth loss early in life induced mitochondrial damage and lipofuscin accumulation in the hippocampal neurons. A thinner myelin sheath and decreased postsynaptic density length were also observed. Our results revealed that tooth loss early in life may lead to hippocampal ultrastructure remodeling and subsequent hippocampus-dependent cognitive impairment in SAMP8 mice with aging.

We aimed to investigate the effects of maternal chewing on prenatal stress-induced cognitive impairments in the offspring and to explore the molecular pathways of maternal chewing in a mice model. Maternal chewing ameliorated spatial learning impairments in the offspring in a Morris water maze test. Immunohistochemistry and Western blot findings revealed that maternal chewing alleviated hippocampal neurogenesis impairment and increased the expression of hippocampal brain-derived neurotrophic factor in the offspring. In addition, maternal chewing increased the expression of glucocorticoid receptor (GR) and 11&beta, hydroxysteroid dehydrogenase isozyme 2 (11&beta, HSD2) and decreased the expression of 11&beta, HSD1 in the placenta, thereby attenuating the increase of glucocorticoid in the offspring. Furthermore, maternal chewing increased the expression of 11&beta, HSD2, FK506-binding protein 51 (FKBP51) and FKBP52 and decreased the expression of 11&beta, HSD1, thereby increasing hippocampal nuclear GR level. In addition, maternal chewing attenuated the increase in expression of DNMT1 and DNMT3a and the decrease in expression of histone H3 methylation at lysine 4, 9, 27 and histone H3 acetylation at lysine 9 induced by prenatal stress in the offspring. Our findings suggest that maternal chewing could ameliorate prenatal stress-induced cognitive impairments in the offspring at least in part by protecting placenta barrier function, alleviating hippocampal nuclear GR transport impairment and increasing the hippocampal brain-derived neurotrophic factor (BDNF) level.

Although the understanding of the complex pathogenesis for osteoporosis is appreciable, the underlying mechanism is not yet fully elucidated. There is a great need to further characterize the available animal models in osteoporosis research. The senescence-accelerated mouse prone 6 (SAMP6) mice have been developed as the spontaneous experimental model for senile osteoporosis. Here, we provide a comprehensive overview of current research regarding the bone morphological and molecular alterations and the possible mechanisms involved in these changes. There were significant decrease in trabecular bone mass at the axial and appendicular skeletal sites, with no marked alterations of cortical bone. Decreased bone formation on the endosteal surface and trabecular bone, and increased bone marrow adiposity were observed in SAMP6 mice. The elevated expression level of proliferator activator gamma (PPARγ) in the bone marrow suggest that PPARγ might regulate osteoblastic bone formation negatively in SAMP6 mice. The expression level of secreted frizzled-related protein 4 (Sfrp4) was found to be higher in SAMP6 mice. Sfrp4 is considered to suppress osteoblastic proliferation mediated by inhibition of Wnt signaling pathway. These findings may help us to gain more insight into the potential mechanism of senile osteoporosis.

Objective To examine whether maternal chewing affects prenatal stress-induced behavioral alternations associated with the changes in apoptosis-related proteins and serotonin pathway of the mouse offspring. Design Pregnant mice were assigned to control, stress, and stress/chewing groups. Stress mice were placed in restraint tubes, from gestational day 12 until parturition. Stress/chewing mice were given a wooden stick for chewing during stress period. Morris water maze and hole-board tests were applied for behavioral alterations in one-month-old male pups. Hippocampal mRNA expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) was analyzed by quantitative real-time PCR. Serotonin and tryptophan hydroxylase expression level in the dorsal raphe nucleus was investigated immunohistochemically. Results Prenatal stress impaired the spatial learning, induced anxiety-like behavior, increased the ratio of hippocampal Bax/Bcl-2 expression, and decreased the expression of serotonin and tryptophan hydroxylase in dorsal raphe nucleus of the offspring. Maternal chewing ameliorated prenatal stress-induced cognitive impairment, anxiety-like behavior, and attenuated the increased ratio of hippocampal Bax/Bcl-2 expression, and the downregulated serotonin signaling in dorsal raphe nucleus of the offspring. Conclusions Our results indicate that maternal chewing could improve prenatal stress-related anxiety-like behavior and cognitive impairment in mouse offspring, at least in part by affecting hippocampal apoptotic response and central serotonin pathway.

Chronic psychological stress is a risk factor for osteoporosis. Maternal active mastication during prenatal stress attenuates stress response. The aim of this study is to test the hypothesis that maternal active mastication influences the effect of prenatal stress on bone mass and bone microstructure in adult offspring. Pregnant ddY mice were randomly divided into control, stress, and stress/chewing groups. Mice in the stress and stress/chewing groups were placed in a ventilated restraint tube for 45 minutes, 3 times a day, and was initiated on day 12 of gestation and continued until delivery. Mice in the stress/chewing group were allowed to chew a wooden stick during the restraint stress period. The bone response of 5-month-old male offspring was evaluated using quantitative micro-CT, bone histomorphometry, and biochemical markers. Prenatal stress resulted in significant decrease of trabecular bone mass in both vertebra and distal femur of the offspring. Maternal active mastication during prenatal stress attenuated the reduced bone formation and increased bone resorption, improved the lower trabecular bone volume and bone microstructural deterioration induced by prenatal stress in the offspring. These findings indicate that maternal active mastication during prenatal stress can ameliorate prenatal stress-induced lower bone mass of the vertebra and femur in adult offspring. Active mastication during prenatal stress in dams could be an effective coping strategy to prevent lower bone mass in their offspring.

Objective Tooth loss induced neurological alterations through activation of a stress hormone, corticosterone. Age-related hippocampal morphological and functional changes were accelerated by early tooth loss in senescence-accelerated mouse prone 8 (SAMP8). In order to explore the mechanism underlying the impaired hippocampal function resulting from early masticatory dysfunction due to tooth loss, we investigated the effects of early tooth loss on plasma corticosterone levels, learning ability, neurogenesis, and synaptophysin expression in the hippocampus later in life of SAMP8 mice. Design We examined the effects of tooth loss soon after tooth eruption (1 month of age) on plasma corticosterone levels, learning ability in the Morris water maze, newborn cell proliferation, survival and differentiation in the hippocampal dentate gyrus, and synaptophysin expression in the hippocampus of aged (8 months of age) SAMP8 mice. Results Aged mice with early tooth loss exhibited increased plasma corticosterone levels, hippocampus-dependent learning deficits in the Morris water maze, decreased cell proliferation, and cell survival in the dentate gyrus, and suppressed synaptophysin expression in the hippocampus. Newborn cell differentiation in the hippocampal dentate gyrus, however, was not affected by early tooth loss. Conclusion These findings suggest that learning deficits in aged SAMP8 mice with tooth loss soon after tooth eruption are associated with suppressed neurogenesis and decreased synaptophysin expression resulting from increased plasma corticosterone levels, and that long-term tooth loss leads to impaired cognitive function in older age.

We examined whether chewing behavior affects the tumor progression-enhancing impact of psychological stress. Human breast cancer cell line (MDA-MB-231) cells were inoculated into the mammary fat pads of athymic nude mice. The mice were assigned randomly to control, stress, and stress+chewing groups. Psychological stress was created by keeping mice in a transparent restraint cylinder for 45 min, three times a day, for 35 days after cell inoculation. Animals in the stress+chewing group were provided with a wooden stick for chewing on during the psychological stress period. Chewing behavior remarkably inhibited the tumor growth accelerated by the psychological stress. Immunohistochemical and Western blot findings revealed that chewing behavior during psychological stress markedly suppressed tumor angiogenesis and cell proliferation. In addition, chewing behavior decreased serum glucocorticoid levels and expressions of glucocorticoid and β2-adrenergic receptors in tumors. Chewing behavior decreased expressions of inducible nitric oxide synthase and 4-hydroxynonenal, and increased expression of superoxide dismutase 2 in tumors. Our findings suggest that chewing behavior could ameliorate the enhancing effects of psychological stress on the progression of breast cancer, at least partially, through modulating stress hormones and their receptors, and the subsequent signaling pathways involving reactive oxygen and nitrogen species.

Objective Prolonged mild stress due to tooth loss leads to morphologic and functional alterations of the hippocampus, as well as cognitive memory impairments in aged animals. An enriched environment improves stress-induced hippocampus-dependent cognitive impairments. The potential mechanisms underlying the beneficial effects of an enriched environment, however, remain unclear. In the present study, we investigated whether an enriched environment affects morphologic remodeling of the hippocampal myelin, synapses, and spatial learning deficits caused by tooth loss in aged senescence-accelerated mouse strain P8 (SAMP8) mice. Design SAMP8 mice (8 months old) with either teeth intact or teeth extracted were raised in a standard or enriched environment for three weeks. Spatial learning and memory ability was evaluated in a Morris water maze test. The morphologic features of the myelin sheath and synapses in the hippocampus were investigated by electron microscopy. Results Mice with tooth loss had a thinner myelin sheaths and shorter postsynaptic densities in the hippocampal CA1 region, and impaired hippocampus-dependent spatial learning ability. Exposure to an enriched environment ameliorated the hypomyelination and synaptic alterations, and spatial learning and memory impairments induced by tooth loss in aged SAMP8 mice. Conclusion Our findings indicate that an enriched environment ameliorates hippocampal hypomyelination and synapse morphologic abnormalities, as well as learning deficits induced by tooth loss in aged SAMP8 mice.

Galectin-1 (Gal-1) is differentially expressed in normal and pathological tissues and regulates immune cell homeostasis. Restraint stress increases serum Gal-1 in rats. However, the function of stress-induced Gal-1 in serum is unknown. We determined if stress-induced Gal-1 in serum accumulates in immunocompetent organs as protection from physiological and/or psychological stress. Western blotting showed that the intensity of Gal-1 bands in stressed groups was significantly higher than that in controls. RT–PCR analysis indicated that the Gal-1 mRNA level did not increase after restraint stress. The numbers of Gal-1 immunoreactive cells in the splenic periarterial lymphatic sheath (PLS) and the thymus medulla of the stressed group were increased compared with those in controls. Furthermore, stress-induced Gal-1 immunoreactive cells corresponded to CD45 immunoreactive lymphocytes (CD45+) in the PLS of the spleen and the medulla of the thymus. Thus, stress-induced Gal-1 immediately accumulates in the spleen and thymus, and may modulate the immune response through apoptosis by binding to CD45+ lymphocytes in immune organs following physiological and/or psychological stress.

Background and objective In humans, occlusal disharmony may cause various physical complaints, including head and neck ache, stiffness in the shoulder and neck, and arthrosis of the temporomandibular joints. Occlusal disharmony induced by raising the bite in rodents, increases plasma corticosterone levels, which leads to morphologic changes in the hippocampus and altered hippocampus-related behavior. The paraventricular nucleus (PVN) of the hypothalamus regulates the hypothalamic-pituitary-adrenal system. Chronically stressed animals exposed to a novel stress exhibit higher adrenocorticotropic hormone levels than naive control animals. We hypothesized that there would be different response of the corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) to a novel acute stress with occlusal disharmony. Design In order to investigate how exposure of mice with occlusal disharmony to a novel acute stress (restraint stress) affects the PVN, we induced occlusal disharmony by raising the vertical dimension of the bite (bite-raised condition) and examined the expression of corticotrophin releasing hormone (CRH) mRNA and arginine vasopressin (AVP) mRNA in mouse PVN. Results CRH mRNA expression was increased in the PVN of the bite-raised group 90 min after the bite-raising procedure, but the expression was recovered to the control level at 14 days. AVP mRNA expression in the PVN was normal at 90 min, and increased significantly 14 days after the bite-raising procedure. Exposure to restraint stress in the bite-raised mice induced a significant increase in CRH mRNA expression in the PVN. Conclusions The bite-raising procedure induced a rapid CRH mRNA response and a slower AVP mRNA response in the parvocellular PVN of the hypothalamus. Exposure to a novel stress following the bite-raising procedure further reinforced the CRH stress response. Thus, occlusal disharmony, such as that induced by raising the bite, may be a risk factor for hypersensitivity to a novel stress.

Yokukansan (YKS) is a traditional Japanese herbal medicine. It has been currently applied for treating behavioral and psychological symptoms of dementia in Japan. We investigated the effect of YKS on learning ability, hippocampal cell proliferation, and neural ultrastructural features in senescence-accelerated mouse prone 8 (SAMP8), a proposed animal model of Alzheimer's disease. Five-month-old male SAMP8 mice were randomly assigned to control and experimental groups. The control group had drug-free water ad libitum. The experimental mice were given 0.15% aqueous solution of YKS orally for eight weeks. Learning ability was assessed in Morris water maze test. Hippocampal cell proliferation was investigated using bromodeoxyuridine immunohistochemical method. The neural ultrastructural features, including myelin sheath and synapse, were investigated electron microscopy. Administration with YKS improved the hippocampal cell proliferation in dentate gyrus, and ameliorated learning impairment in SAMP8 mice. Numerous lipofuscin inclusions were presented in hippocampal neurons of the control mice. However, little were found after treatment with YKS. Myelin sheath was thicker and postsynaptic density length was longer after treatment with YKS. Administration with YKS ameliorated learning impairment in SAMP8 mice, mediated at least partially via delaying neuronal aging process, neurogenesis, myelin sheath and synaptic plasticity in the hippocampus. These results suggest that YKS might be effective for preventing hippocampus-dependent cognitive deficits with age.

Objective To investigate whether maternal chewing during prenatal stress alters the responsivity of young offspring to novel stress, we examined the expression of hippocampal glucocorticoid receptors and mineralocorticoid receptors, and the levels of hypothalamic corticotropin-releasing hormone in young adult mouse offspring of dams exposed to restraint stress during pregnancy. Design To induce stress, the dams were placed in a ventilated restraint tube for 45 min each day from day 12 of pregnancy through parturition. While restrained in the tube, one group of dams was provided a wooden stick for chewing. Hippocampal expression of glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid was assessed in 1-month-old pups. Hypothalamic expression of corticotropin-releasing hormone messenger ribonucleic acid was examined before and after exposing the offspring to a novel stressor. Results Prenatal stress significantly decreased hippocampal expression of both glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid in the offspring, and increased the expression of corticotropin-releasing hormone messenger ribonucleic acid in the hypothalamic paraventricular nucleus in the offspring after novel stress exposure. Maternal chewing during exposure to prenatal stress attenuated the decreased hippocampal expression of both glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid, and the increased corticotropin-releasing hormone messenger ribonucleic acid expression in the hypothalamic paraventricular nucleus in the offspring. Conclusions Downregulation of hippocampal glucocorticoid receptor and mineralocorticoid receptor expression in offspring due to prenatal stress, which may be associated with increased susceptibility to novel stress in adulthood, are attenuated by allowing the dams to chew on a wooden stick.

Prenatal stress (PS) induces learning deficits and anxiety-like behavior in mouse pups by increasing corticosterone levels in the dam. We examined the effects of maternal chewing during PS on arginine vasopressin (AVP) mRNA expression in the dams and on neurogenesis, brain-derived neurotrophic factor (BDNF) mRNA expression, learning deficits and anxiety-like behavior in the offspring. Mice were divided into control, stress and stress/chewing groups. Pregnant mice were exposed to restraint stress beginning on day 12 of pregnancy and continuing until delivery. Mice in the stress/chewing group were given a wooden stick to chew during restraint stress. PS significantly increased AVP mRNA expression in the paraventricular nucleus (PVN) of the hypothalamus in the dams. PS also impaired learning ability, suppressed neurogenesis and BDNF mRNA expression in the hippocampus, and induced anxiety-like behavior in the offspring. Chewing during PS prevented the PS-induced increase in AVP mRNA expression of the PVN in the dams. Chewing during PS significantly attenuated the PS-induced learning deficits, anxiety-like behavior, and suppression of neurogenesis and BDNF mRNA expression in the hippocampus of the offspring. Chewing during PS prevented the increase in plasma corticosterone in the dam by inhibiting the hypothalamic-pituitary-adrenal axis activity, and attenuated the attenuated the PS-induced suppression of neurogenesis and BDNF expression in the hippocampus of the pups, thereby ameliorating the PS-induced learning deficits and anxiety-like behavior. Chewing during PS is an effective stress-coping method for the dam to prevent PS-induced deficits in learning ability and anxiety-like behavior in the offspring.

Osteocytes are the most abundant cells in bone and are the major orchestrators of bone remodeling and mineral homeostasis. They possess a specialized cellular morphology and a unique molecular feature. Osteocytes are a stellate shape with numerous long, slender dendritic processes. The osteocyte cell body resides in the bone matrix of the lacuna and the dendritic processes extend within the canaliculi to adjacent osteocytes and other cells on the bone surface. Osteocytes form extensive intercellular network to sense and respond to environmental mechanical stimulus by the lacunar-canalicular system and gap junction. Osteocytes are long-lived bone cells. They can undergo apoptosis, which may have specific regulatory effects on osteoclastic bone resorption. Osteocytes can secrete several molecules, including sclerostin, receptor activator of nuclear factor κB ligand and fibroblast growth factor 23 to regulate osteoblastic bone formation, osteoclastic bone resorption and mineral homeostasis. A deeper understanding of the complex mechanisms that mediate the control of osteoblast and osteoclast function by osteocytes may identify new osteocyte-derived molecules as potential pharmacological targets for treating osteoporosis and other skeletal diseases.

Objective The aim of this study was to examine, after setting several restorations, the influence of adjusted occlusal interference during gum chewing on blood flow in the prefrontal area as determined using near-infrared spectroscopy. Material and methods The physiological rate was assessed using a visual analog scale (VAS) questionnaire. We selected 16 patients who desired prosthetic restorative treatment on the lateral dentition, and eight healthy volunteers. Subjects were divided into three eight-person groups. One group received restorations on the premolar area (PA), another group received restorations on the molar area (MA), and the control group (CT) received no prosthetic restorations. The spectroscope was fastened to the frontal region of the head after placement of the final restoration, but before adjustment. Results Pre-adjustment (first gum chewing for CT) blood flow in the prefrontal cortex was measured during gum chewing. Blood flow was again measured during gum chewing after the restoration (second gum chewing for CT) had been adjusted in accordance with the subjective assessment of the patient while wearing the device. The VAS provided quantification of comfort during gum chewing before and after restoration adjustment. For the PA and MA groups, adjusting restorations decreased discomfort significantly during gum chewing. Moreover, in the MA group, prefrontal blood flow was significantly reduced, and blood flow correlated with discomfort. Conclusions Activation of the prefrontal area may provide an objective criterion for judging the functionality of occlusion after prosthetic occlusal reconstruction and/or orthodontics.

Both osteoporosis and tooth loss are health concerns that affect many older people. Osteoporosis is a common skeletal disease of the elderly, characterized by low bone mass and microstructural deterioration of bone tissue. Chronic mild stress is a risk factor for osteoporosis. Many studies showed that tooth loss induced neurological alterations through activation of a stress hormone, corticosterone, in mice. In this study, we tested the hypothesis that tooth loss early in life may accelerate age-related bone deterioration using a mouse model. Male senescence-accelerated mouse strain P8 (SAMP8) mice were randomly divided into control and toothless groups. Removal of the upper molar teeth was performed at one month of age. Bone response was evaluated at 2, 5 and 9 months of age. Tooth loss early in life caused a significant increase in circulating corticosterone level with age. Osteoblast bone formation was suppressed and osteoclast bone resorption was activated in the toothless mice. Trabecular bone volume fraction of the vertebra and femur was decreased in the toothless mice with age. The bone quality was reduced in the toothless mice at 5 and 9 months of age, compared with the age-matched control mice. These findings indicate that tooth loss early in life impairs the dynamic homeostasis of the bone formation and bone resorption, leading to reduced bone strength with age. Long-term tooth loss may have a cumulative detrimental effect on bone health. It is important to take appropriate measures to treat tooth loss in older people for preventing and/or treating senile osteoporosis.

Osteoporosis, the most common metabolic skeletal disease, is characterized by decreased bone mass and deteriorated bone quality, leading to increased fracture risk. With the aging of the population, osteoporotic fracture is an important public health issue. Organisms are constantly exposed to various stressful stimuli that affect physiological processes. Recent studies showed that chronic psychological stress is a risk factor for osteoporosis by various signaling pathways. The purpose of this article is to review the recent progress of the association between chronic psychological stress and osteoporosis. Increasing evidence confirms the physiological importance of the central nervous system, especially the hypothalamus, in the regulation of bone metabolism. Both animal and human studies indicate that chronic psychological stress induces a decrease of bone mass and deterioration of bone quality by influencing the hypothalamic-pituitary-adrenocortical (HPA) axis, sympathetic nervous system, and other endocrine, immune factors. Active mastication, proven to be an effective stress-coping behavior, can attenuate stress-induced neuroendocrine responses and ameliorate stress-induced bone loss. Therefore, active mastication may represent a useful approach in preventing and/or treating chronic stress-associated osteoporosis. We also discuss several potential mechanisms involved in the interaction between chronic stress, mastication and osteoporosis. Chronic stress activates the HPA axis and sympathetic nervous system, suppresses the secretion of gonadal hormone and growth hormone, and increases inflammatory cytokines, eventually leading to bone loss by inhibiting bone formation and stimulating bone resorption.

Mastication (chewing) is important not only for food intake, but also for preserving and promoting the general health. Recent studies have showed that mastication helps to maintain cognitive functions in the hippocampus, a central nervous system region vital for spatial memory and learning. The purpose of this paper is to review the recent progress of the association between mastication and the hippocampus-dependent cognitive function. There are multiple neural circuits connecting the masticatory organs and the hippocampus. Both animal and human studies indicated that cognitive functioning is influenced by mastication. Masticatory dysfunction is associated with the hippocampal morphological impairments and the hippocampus-dependent spatial memory deficits, especially in elderly. Mastication is an effective behavior for maintaining the hippocampus-dependent cognitive performance, which deteriorates with aging. Therefore, chewing may represent a useful approach in preserving and promoting the hippocampus-dependent cognitive function in older people. We also discussed several possible mechanisms involved in the interaction between mastication and the hippocampal neurogenesis and the future directions for this unique fascinating research.

Chronic psychologic stress increases corticosterone levels, which decreases bone density. Active mastication or chewing attenuates stress-induced increases in corticosterone. We evaluated whether active mastication attenuates chronic stress-induced bone loss in mice. Male C57BL/6 (B6) mice were randomly divided into control, stress, and stress/chewing groups. Stress was induced by placing mice in a ventilated restraint tube (60 min, 2x/day, 4 weeks). The stress/chewing group was given a wooden stick to chew during the experimental period. Quantitative micro-computed tomography, histologic analysis, and biochemical markers were used to evaluate the bone response. The stress/chewing group exhibited significantly attenuated stress-induced increases in serum corticosterone levels, suppressed bone formation, enhanced bone resorption, and decreased trabecular bone mass in the vertebrae and distal femurs, compared with mice in the stress group. Active mastication during exposure to chronic stress alleviated chronic stress-induced bone density loss in B6 mice. Active mastication during chronic psychologic stress may thus be an effective strategy to prevent and/or treat chronic stress-related osteopenia.

Mastication is mainly involved in food intake and nutrient digestion with the aid of teeth. Mastication is also important for preserving and promoting general health, including hippocampus-dependent cognition. Both animal and human studies indicate that mastication influences hippocampal functions through the end product of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoid (GC). Epidemiologic studies suggest that masticatory dysfunction in aged individuals, such as that resulting from tooth loss and periodontitis, acting as a source of chronic stress, activates the HPA axis, leading to increases in circulating GCs and eventually inducing various physical and psychological diseases, such as cognitive impairment, cardiovascular disorders, and osteoporosis. Recent studies demonstrated that masticatory stimulation or chewing during stressful conditions suppresses the hyperactivity of the HPA axis via GCs and GC receptors within the hippocampus, and ameliorates chronic stress-induced hippocampus-dependent cognitive deficits. Here, we provide a comprehensive overview of current research regarding the association between mastication, the hippocampus, and HPA axis activity. We also discuss several potential molecular mechanisms involved in the interactions between mastication, hippocampal function, and HPA axis activity.

Chronic mild stress is a risk factor for osteoporosis and chewing inhibits the stress response. We examined the effect of chewing on chronic stress-induced bone loss and bone microstructural deterioration in mice. The senescence-accelerated mouse strain P8 (SAMP8) was randomly divided into control, stress, and stress with chewing groups of fifteen animals each. Mice in the stress and stress with chewing groups were placed in a ventilated restraint tube for 60minutes, twice a day for 4weeks. The restrained mice were simultaneously subjected daily to one of the following stressors: water immersion, physical shaking and flashing lights. Mice in the stress with chewing group were allowed to chew a wooden stick during the experimental period. After the experiment, the bone response was evaluated using quantitative micro computed tomography, bone histomorphometry, and biochemical markers. Exposure of SAMP8 mice to chronic stress resulted in significant increase of the blood corticosterone and noradrenaline levels, and adrenal weight. The bone resorption was activated and the bone formation was suppressed. Trabecular bone volume and trabecular number were decreased in both the vertebra and distal femur of the stress group. Chewing under chronic stress prevented the increase in the blood corticosterone and noradrenaline levels, attenuated the reduced bone formation and increased bone resorption, improved the trabecular bone loss and bone microstructural deterioration induced by chronic mild stress. These findings indicate that chewing can ameliorate chronic stress-induced bone loss in SAMP8 mice. Thus, chewing may represent a useful method preventing and/or treating chronic stress-related osteoporosis.

Prenatal stress in dams induces learning deficits and suppresses neurogenesis in the hippocampal dentate gyrus (DG) of offspring via increasing corticosterone levels in the dam. Chewing under stressful conditions prevents stress-induced behavioral impairments and morphologic changes. Here, we examined whether chewing during prenatal stress prevents the stress-induced learning deficits and the suppression of cell proliferation in the hippocampal DG in adult offspring. Pregnant mice were exposed to restraint stress beginning on day 12 of pregnancy and continuing until delivery. Half of the dams were given a wooden stick to chew on during restraint. The pups were raised to adulthood, and learning ability and cell proliferation in the hippocampal DG were assessed. In dams, chewing during prenatal stress attenuated the stress-induced increase in plasma corticosterone levels. In the adult offspring, prenatal stress impaired learning and decreased cell proliferation in the DG, whereas maternal chewing during prenatal stress significantly attenuated the prenatal stress-induced learning deficits and decreased cell proliferation in the DG in their offspring. These findings suggest that maternal chewing during prenatal stress is an effective stress-coping method for the dam to prevent learning deficits and suppression of cell proliferation in offspring.

Occlusal disharmony is associated with increased plasma corticosterone levels, learning deficits, and morphologic alterations in the hippocampus via chronic stress. Here, we investigated the occlusal disharmony-induced impairment of hippocampal function. We first examined the effects of raising the bite on newborn cell proliferation in the hippocampal dentate gyrus (DG) in senescence-accelerated prone mice. Raising the bite significantly decreased cell proliferation in the hippocampal DG in an age-dependent manner. Immediately after raising the bite, cell proliferation decreased abruptly in the aged mice, then gradually increased, but did not recover to control levels within 2wk. Further, learning-induced cell proliferation was impaired in aged bite-raised mice. These findings suggest that occlusal disharmony induced by raising the bite impaired cell proliferation in the hippocampal DG, leading to learning deficits.

Maternal chewing during prenatal stress attenuates both the development of stress-induced learning deficits and decreased cell proliferation in mouse hippocampal dentate gyrus. Hippocampal myelination affects spatial memory and the synaptic structure is a key mediator of neuronal communication. We investigated whether maternal chewing during prenatal stress ameliorates stress-induced alterations of hippocampal myelin and synapses, and impaired development of spatial memory in adult offspring. Pregnant mice were divided into control, stress, and stress/chewing groups. Stress was induced by placing mice in a ventilated restraint tube, and was initiated on day 12 of pregnancy and continued until delivery. Mice in the stress/chewing group were given a wooden stick to chew during restraint. In 1-month-old pups, spatial memory was assessed in the Morris water maze, and hippocampal oligodendrocytes and synapses in CA1 were assayed by immunohistochemistry and electron microscopy. Prenatal stress led to impaired learning ability, and decreased immunoreactivity of myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) in the hippocampal CA1 in adult offspring. Numerous myelin sheath abnormalities were observed. The G-ratio [axonal diameter to axonal fiber diameter (axon plus myelin sheath)] was increased and postsynaptic density length was decreased in the hippocampal CA1 region. Maternal chewing during stress attenuated the prenatal stress-induced impairment of spatial memory, and the decreased MBP and CNPase immunoreactivity, increased G-ratios, and decreased postsynaptic-density length in the hippocampal CA1 region. These findings suggest that chewing during prenatal stress in dams could be an effective coping strategy to prevent hippocampal behavioral and morphologic impairments in their offspring.

Identification of functional molecules in the brain related to improvement of motor dysfunction after stroke will contribute to establish a new treatment strategy for stroke rehabilitation. Hence, monoamine changes in basal ganglion related to motor control were examined in groups with/without voluntary exercise after cerebral infarction. Cerebral infarction was produced by photothrombosis in rats. Voluntary exercise using a running wheel was initiated from 2 days after surgery. Motor performance was measured by the accelerated rotarod test. Monoamine concentrations in striatum were analyzed using HPLC and immunohistochemical staining performed with anti-tyrosine hydroxylase antibody. In behavioral evaluation, the mean latency until falling from the rotating rod in the group with exercise (infarction-EX group) was significantly longer than that in the group without exercise (infarction-CNT group). When concerning the alteration of monoamine concentration between before and 2 days after infarction, dopamine level showed a significant increase 2 days after infarction. Subsequently, dopamine level was significantly decreased in the infarction-EX group at 10 days after infarction; in contrast, both norepinephrine and 5-HT concentrations were significantly higher in the infarction-EX group than in the infarction-CNT group. Furthermore, duration of rotarod test showed a significant inverse correlation with dopamine levels and a significant positive correlation with 5-HT levels. In immunohistochemical analysis, tyrosine hydroxylase immunoreactivity in substantia nigra pars compacta was shown to increase in the infarction-CNT group. In the present study, at least some of the alterations of monoamines associated with the improvement of paralysis in the basal ganglion related to motor control might have been detected.

Ethnopharmacological relevance Hachimi-jio-gan is one of the most common recipes in traditional Chinese, Japanese and Korean medicines and has been used for preventing and treating various diseases associated with aging, including osteoporosis. Aim of the study The present study was performed to examine the combined effects of a traditional Chinese medicine, Hachimi-jio-gan (HJG) and antiresorptive agent, alendronate (ALN) on ovariectomy-induced bone loss in rats. Materials and methods Six-month-old female Sprague-Dawley rats were underwent ovariectomy (OVX) or sham operation. Eight weeks later, the OVX rats were treated either with HJG or ALN alone or in combination of both. The skeletal response was evaluated using micro-computed tomography (micro-CT), image analysis software, and biochemical markers. Results This study demonstrated that treatment with HJG or ALN alone increased trabecular bone volume and bone mineral density (BMD), and partially improved bone microstructure of the proximal tibia and vertebra in OVX rats. Treatment with ALN to OVX rats resulted in significant reduction in both bone resorption and bone formation. Treatment with HJG to OVX rats inhibited bone resorption, with no marked effects on bone formation. Combined treatment of HJG and ALN significantly improved trabecular bone mass and bone microstructure, compared with either agent alone. Conclusions We conclude that the combined treatment with HJG and ALN has beneficial effects on trabecular bone mass, improving the structural properties of both tibia and vertebra in OVX rats.

Early toothlessness in senescence-accelerated prone (SAMP8) mice leads to increased plasma corticosterone levels, learning deficits, neuronal death, and increased astroglial responsiveness in the hippocampus. New cells are generated in the hippocampal dentate gyrus (DG) throughout life in animals as well as humans. Neurogenesis in the hippocampal DG is sensitive to glucocorticoid levels and environmental triggers such as learning. Here we investigated the mechanisms underlying impaired hippocampal function resulting from early masticatory dysfunction, by examining the effects of tooth loss soon after tooth eruption on plasma corticosterone levels, learning ability in the Morris water maze test, and cell proliferation in the hippocampal DG of 1-, 5-, and 9-mo-old SAMP8 mice. Bromodeoxyuridine, a marker of newborn cells, was injected, and BrdU-positive cells were quantitatively analyzed to detect cell proliferation in the hippocampal DG using immunohistochemical techniques. Early toothlessness enhanced the age-related increase in plasma corticosterone levels and learning deficits, and led to a decrease in the number of BrdU-positive cells in the hippocampal DG. Plasma corticosterone levels, learning deficits, and the number of BrdU-positive cells in the hippocampal DG was significantly different between in 5- and 9-mo-old early toothless mice and age-matched control mice, but not between 1-mo-old early toothless mice and controls. These findings suggest that early toothlessness leads to increased plasma corticosterone levels and a decrease in cell proliferation in the hippocampal DG, thereby leading to learning deficits.

The duplication of the inferior vena cava (IVC) is a rare, but well-recognized anomaly. Duplicated IVC has a significant relevance for retroperitoneal surgery and venous interventional radiology. We report a case of duplicated IVC, which was observed during routine dissection of an 84-year-old Japanese female cadaver. The interiliac vein between the duplicated IVC ran obliquely upwards from left to right. We performed systematic literature review of published reports based on Pubmed and Medline from 1967 to 2011. Of 109 cases with IVC anomalies identified by the literature search, 22 cases (20.2%) displayed no interiliac anastomosis. The interiliac vein connecting duplicated IVC existed in 74 cases (67.9%). According to the running direction of the interiliac vein, we found that the vein ran from left to right in 42 cases, coursed from right to left in 19 cases, and ran horizontally in 13 cases. Thirteen left IVC displayed symmetrical-to-normal connection with the bilateral common iliac veins. Awareness of these venous variations is necessary to reduce surgical risk and to determine strategy in interventional radiology.

We investigated the effect of tooth absence and masticatory abnormalities due to powdered food feeding starting during the juvenile period on light and dark period activity cycles in senescence-accelerated mice (SAMP1). SAMP1 were divided into 5 groups: Group 1, maxillo-mandibular molar tooth extraction; Group 2, maxillary molar tooth extraction; Group 3, mandibular molar tooth extraction; Group 4, powdered food; and Group 5, sham-operated control. Senescence was observed earliest in the powdered food group. Total 24-hour activity was higher in the control group than in the four other groups. In the powdered food group, the dark period activity decreased to less than 60% of the total activity in the 36th week. In the tooth extraction groups (Groups 1-3), dark period activity decreased to less than 60% of the total activity in the 40th week. The control group dark period activity remained above 60% for the entire experimental period. Thus, the distinction between the light and dark periods disappeared earlier in the four experimental groups compared with the control group. Significant correlations were noted among total activity, degree of senescence, and percent dark period activity in each experimental group. Functional masticatory insufficiency promoted dementia and behavioral abnormalities in SAMP1.

PURPOSE: Recent studies have shown that occlusal disharmony (OD) causes deterioration in learning and memory via neuropathological processes in the mouse hippocampus. METHODS: To elucidate the mechanism(s) by which this deterioration occurs, we examined the effect of a bite-raised condition, which induced OD, on long-term potentiation (LTP) in the rat hippocampal CA1 region. In addition, plasma levels of corticosterone and catecholamines, body weight, and food intake were measured to evaluate the involvement of the hypothalamic-pituitary-adrenal (HPA) axis and/or the sympathetic-adrenergic-medullary (SAM) system. RESULTS: Ten days after bite-raising surgery, the amplitude of LTP was reduced by 62% in rats that underwent OD compared to sham-operated rats. The OD condition also caused a significant elevation in plasma levels of corticosterone and norepinephrine compared to control rats. Body weight decreased in OD rats, but the amount of food intake was not different between bite-raised and control conditions. CONCLUSION: These findings suggest that a disharmonious occlusal condition in rats induces not only impaired hippocampal plasticity but also chronic activation of the HPA axis and modulation of the autonomic nervous system.

Galectin-1(Gal-1), a carbohydrate-binding protein with an affinity for beta-galactoside, is widely expressed in various normal and pathological tissues and it also plays an important role in regulating immune cell homeostasis and tumorigenesis. This study investigated the effects of restraint stress on serum Gal-1 by Western blot analyses and enzyme-linked immunosorbent assays. The Gal-1 levels of the restraint-stress group were significantly higher than those of the control group. However, this increase by stress was not obvious in adolescent rats. The pattern of these changes was similar to that of corticosterone. Furthermore, this Gal-1 increase in the serum was prevented by pre-treatment with a neurotoxin 6-hydroxydopamine (6-OHDA), which destroys the noradrenergic nerve terminals. However, a bilateral adrenalectomy (ADX) had no effect on the Gal-1 increase. These results suggest that Gal-1 is a candidate stress marker protein and that the stress-induced increase of Gal-1 in serum is regulated by the sympathetic nervous system under stress conditions.

The effects of early tooth extractions on age-associated changes in cognitive function were evaluated. Specifically, teeth were extracted at an early age in senescence-accelerated mice (SAM)P8, and the number of glial fibrillary acid protein (GFAP)-positive astrocytes and spatial perception were evaluated at young, mature, and old ages. The following results were obtained: 1. Concerning spatial perception evaluated by the Morris water maze test, the shortening of the time until the animals reached the platform was significantly slower in mature or old mice of the tooth extraction group compared with age-matched controls. However, no significant difference was noted in the rate of shortening in young mice between the tooth extraction and control groups. 2. The number of GFAP-positive cells was significantly higher in the CA3 region of the hippocampus in the mature or old mice of the tooth extraction group compared with age-matched controls. However, no significant difference was observed in the CA1 and dentate gyrus (DG) region of the hippocampus in the mature or old mice and in the CA1, CA3, and DG region in the young mice between the two groups. These results suggest that the loss of teeth at an early age accelerated aging and that GFAP-positive astrocytes increased to compensate for a decrease in pyramidal cells.

Using functional magnetic resonance imaging (fMRI) in eight healthy human subjects, the present study measured blood oxygenation level-dependent (BOLD) signals during clenching in a malocclusion model, using a custom-made splint that forced the mandible to a retrusive position and a splint of no modification for control, and compared the results to the BOLD signals during the corresponding resting conditions. An individual visual analog scale (VAS) score was also examined during clenching to evaluate the interactions between fMRI data and psychiatric changes. During both clenchings, activations in four brain regions (premotor cortex, prefrontal cortex, sensorimotor cortex, and insula) were seen. However, clenching in the malocclusion model, with psychological discomfort, increased additionally BOLD signals in the anterior cingulate cortex and the amygdala. Furthermore, there was a parallel relationship between BOLD signal intensities and VAS scores in these two regions. The findings may suggest the involvement of clenching with malocclusal conditions in the emotion and/or pain-related neural processing in the brain.

To study the anti-infectious effect of a vascular allograft, the antimicrobial activity of tryptophan metabolites mediated by indoleamine 2,3-dioxygenase was determined. The growth of methicillin-resistant Staphylococcus aureus (MRSA) over 10 h in extracts from post-transplantation vascular allograft was significantly slower than that of extracts from non-transplantation vascular allograft regardless of the presence of tryptophan (p

We evaluated whether long-term tooth loss induces functional and morphologic changes in the hippocampus in senescence-accelerated mice (SAMP8) maintained until old age after tooth extraction shortly after tooth eruption. First, to examine whether early tooth loss acts as a stressor, plasma concentration was measured as an index of stress. Plasma corticosterone concentration was significantly higher in old or mature mice with tooth extraction than in the age-matched controls. Plasma corticosterone concentration did not differ between the young tooth extraction and their age-matched control groups. Next, hippocampal function was assessed by evaluating spatial memory performance in the Morris water maze. In the Morris water maze learning and memory trials was significantly slower in the mature or old tooth extraction groups compared with the age-matched controls. There was no significant difference, however, between the young tooth extraction and control groups. Finally, hippocampal neuronal morphology was assessed by counting Nisslstained cells. The number of hippocampal neurons was significantly reduced in the CA3 region in the mature and old tooth extraction groups compared with their age-matched controls, but there was no significant difference in the CA1-region or dentate gyrus between the mature or old tooth extraction groups and their age-matched controls. In young mice, there was no significant difference in the number of neurons in CA1, CA3, or dentate gyrus region between the tooth extraction and control groups. The findings indicated that tooth extraction after tooth eruption enhances the effects of aging on the hippocampus in mice.

BACKGROUND: The relationships between possible physiological properties of insoluble fibre and the viscosity of digesta are poorly understood. The aim of this study was to investigate the effect of insoluble fibres with different water-holding capacity, swelling, oil-holding capacity and cation exchange capacity on gastric, small intestinal and caecal contents in rats fed a semi-purified diet containing either no fibre (control), 50 g kg−1 tossa jute fibre or 50 g kg−1 shiitake fibre. RESULTS: The water-holding capacity, swelling, oil-holding capacity and cation exchange capacity of insoluble fibres of tossa jute were higher than those of shiitake (P < 0.001). The order of the viscosities of digesta was control group < shiitake fibre group < tossa jute fibre group in gastric, small intestinal and caecal contents (P < 0.05). The digesta viscosity at a shear rate of 40 s−1 was strongly correlated with the free water content of digesta (r = − 0.89; P < 0.01). The free water content of digesta depended on the water-holding capacity of insoluble fibres represented as a linear function with negative slope (P < 0.001). CONCLUSION: The viscosity of digesta depends on the free water content, and this is reduced by fibre that holds water and can swell. Copyright © 2008 Society of Chemical Industry

The bite raised condition decreases the number of neurons and increases the amount of glial fibrillary acidic protein in the hippocampus of aged SAMP8 mice. In the present study, we examined whether these effects differ between the dorsal and ventral hippocampus. In bite-raised SAMP8 mice, the number of neurons was significantly lower in the hippocampal CA1 and dentate gyrus (DG) subfields compared to control mice. In the bite raised condition, the number of neurons was significantly lower in both the dorsal and ventral CA3 subfields, and the number of glial fibrillary acidic protein-labeled astrocytes was increased in the CA1, CA3, and DG subfields, compared to control mice. These data suggest that in aged SAMP8 mice, the bite-raised condition enhanced aging processes in both the dorsal and ventral hippocampus.

In the present study, we examined whether the effects induced by the bite-raised condition on glucocorticoid receptor (GR) expression differ between the dorsal and ventral hippocampus in SAMP8 mice. In the bite-raised condition, the number of GR-immunoreactive cells was significantly decreased in both the dorsal and ventral CA1 and dentate gyrus (DG) subfields of the hippocampus compared to control mice, as revealed by immunohistochemical analysis. The decrease in the number of GR-immunoreactive cells tended to be greater in the dorsal hippocampus than in the ventral hippocampus. Only in the DG subfield was there a significant difference in the number of GR-immunoreactive cells between the dorsal and ventral hippocampus. These findings suggest that in aged SAMP8 mice, the bite-raised condition decreases the number of GR-immunoreactive cells in both the dorsal and ventral hippocampus.

We evaluated the effect of the duration of occlusal disharmony induced chronic stress on hippocampal function by examining spatial memory in the Morris water maze and on the number of hippocampal neurons in aged senescence-accelerated prone (SAMP8) mice. The bite of SAMP8 mice was raised 0.1 mm using dental adhesive. Groups of mice were tested in the Morris water maze 8, 11, or 22 d after raising the bite. The results indicated that the longer the duration of the bite-raised condition, the greater the impairment in spatial learning ability and the greater the decrease in the number of neurons in the hippocampal CA3 subfield. Thus, behavioral and morphologic deficits induced by the bite-raised condition in aged SAMP8 mice are influenced by the duration of the occlusal disharmony.

This study examined the effect of tube feeding on hippocampal Fos induction and spatial performance in a water maze task in senescenceaccelerated mice (SAMP1). Tube feeding accelerated the age-related decline in spatial memory and decreased Fos induction in the hippocampal CA1 region in aged SAMP1 mice. The results suggest that tube feeding in aged SAMP1 mice reduces input activity in the hippocampus, thereby leading to senile memory deficits.