ABSTRACT
Understanding the relationship between stress and breast cancer development is essential to preventing and alleviating the cancer. Recent research has shed light on the cognitive, physiological, cellular, and molecular underpinnings of how the endorphin pathway and stress pathway affect breast cancer. This chapter consists of two parts. Part 1 will discuss the role of endorphins in breast cancer development. This includes a discussion of three topics: (1) the neurophysiological effect of endorphins on breast tumor growth in vivo, along with further experiments that will deepen our knowledge of how ß-endorphin affects breast cancer; (2) how both the opioid receptor and somatostatin receptor classes alter intracellular signaling in breast cancer cells; and (3) genetic alleles in the opioid signaling pathway that are correlated with increased breast cancer risk. Part 2 will discuss the role of endorphins in recovery from breast cancer. This includes a discussion of three topics: (1) the relationship between breast cancer diagnosis and depression; (2) the effectiveness of cognitive behavioral therapy in reducing stress in breast cancer patients; and (3) the effect of psychotherapy and exercise on preserving telomere length in breast cancer patients.
Subject(s)
Breast Neoplasms , Stress, Psychological , Animals , Female , Humans , beta-Endorphin/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cognitive Behavioral Therapy , Depression/metabolism , Endorphins/metabolism , Receptors, Opioid/metabolism , Signal Transduction , Stress, Psychological/metabolismABSTRACT
This chapter will focus on the role exercise appears to have on activation and modulating factors within the central nervous system related to endogenous like opioids and its possible contribution to exercise-induced hypoalgesia. The implications for the exercise-mediated alterations of CNS activation factors related to opioids, specifically endorphins and enkephalins, will be presented. In this update, we discuss utilization of new technology and methods to monitor mechanisms of opioid involvement to suggest their contribution with exercise mediated hypoalgesia as well as their relationships to alterations of perceptions of pain and mood. Several special populations were included to suggest that not all individuals will respond to the exercise by mediating hypoalgesia. Factors that may confound the current understanding and suggestions from the recent literature will be presented as well as suggestions for future investigations.
Subject(s)
Exercise , Animals , Humans , Analgesics, Opioid/metabolism , Endorphins/metabolism , Enkephalins/metabolism , Exercise/physiology , Opioid Peptides/metabolism , Pain/metabolism , Pain Perception/physiologyABSTRACT
Beta-endorphin is secreted from the hypothalamus and pituitary in both mother and newborn. The placenta produces numerous pituitary hormones from the third month of pregnancy, one of which is ßE. It has been suggested that ßE has a role in the appetitive and precopulatory phase of sexual behavior in animals. An increase in endorphin levels during sexual activity in humans may contribute to attachment and bonding between partners, but contradictory reports in the literature question the association between sexuality and ßE levels. The level of ßE also increases during pregnancy, rises in early labor, peaks in late labor, and drops in the postpartum period. This fluctuation provides natural analgesia, raises the pain threshold, decreases the sensation of pain, or suppresses pain, and decreases fear levels during labor and birth. Beta-endorphin also protects the fetus from hypoxia during labor and birth and potential neural damage by aiding blood flow to the brain under hypoxic conditions. It has been suggested that a variety of pharmacologic and nonpharmacologic complementary therapies, when used in pregnancy, labor, and birth, activate the opioid receptors in the CNS and alter the sensation of pain during labor and birth, affect the mother-child attachment and affect sexual function. These studies report contradictory results that will be discussed in this chapter.
Subject(s)
beta-Endorphin , Animals , Female , Humans , Pregnancy , beta-Endorphin/metabolism , Endorphins/metabolism , Reproduction/physiology , Sexual Behavior/physiology , Sexuality/physiologyABSTRACT
Special attention is given to cow's milk and its variants, with ongoing discussions about health-related impacts primarily focusing on the A1 variant in contrast to the A2 variant. The difference between these variants lies in a single amino acid alteration at position 67 of ß-casein. This alteration is presumed to make the A1 variant more susceptible to enzymatic breakdown during milk digestion, leading to an increased release of the peptide ß-casomorphin-7 (BCM-7). BCM-7 is hypothesized to interact with µ-opioid receptors on immune cells in humans. Although BCM-7 has demonstrated both immunosuppressive and inflammatory effects, its direct impact on the immune system remains unclear. Thus, we examined the influence of A1 and A2 milk on Concanavalin A (ConA)-stimulated human peripheral blood mononuclear cells (PBMCs), as well as the effect of experimentally digested A1 and A2 milk, containing different amounts of free BCM-7 from ß-casein cleavage. Additionally, we evaluated the effects of pure BCM-7 on the proliferation of ConA-stimulated PBMCs and purified CD4+ T cells. Milk fundamentally inhibited PBMC proliferation, independent of the ß-casein variant. In contrast, experimentally digested milk of both variants and pure BCM-7 showed no influence on the proliferation of PBMCs or isolated CD4+ T cells. Our results indicate that milk exerts an anti-inflammatory effect on PBMCs, regardless of the A1 or A2 ß-casein variant, which is nullified after in vitro digestion. Consequently, we deem BCM-7 unsuitable as a biomarker for food-induced inflammation.
Subject(s)
Caseins , Cell Proliferation , Endorphins , Leukocytes, Mononuclear , Milk , Peptide Fragments , Humans , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/cytology , Cell Proliferation/drug effects , Milk/chemistry , Endorphins/pharmacology , Endorphins/metabolism , Animals , Caseins/pharmacology , Caseins/metabolism , Peptide Fragments/pharmacology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/cytology , Concanavalin A/pharmacology , CattleABSTRACT
Bovine milk is an essential supplement due to its rich energy- and nutrient-rich qualities. Caseins constitute the vast majority of the proteins in milk. Among these, ß-casein comprises around 37% of all caseins, and it is an important type of casein with several different variants. The A1 and A2 variants of ß-casein are the most researched genotypes due to the changes in their composition. It is accepted that the A2 variant is ancestral, while a point mutation in the 67th amino acid created the A1 variant. The digestion derived of both A1 and A2 milk is BCM-7. Digestion of A2 milk in the human intestine also forms BCM-9 peptide molecule. The opioid-like characteristics of BCM-7 are highlighted for their potential triggering effect on several diseases. Most research has been focused on gastrointestinal-related diseases; however other metabolic and nervous system-based diseases are also potentially triggered. By manipulating the mechanisms of these diseases, BCM-7 can induce certain situations, such as conformational changes, reduction in protein activity, and the creation of undesired activity in the biological system. Furthermore, the genotype of casein can also play a role in bone health, such as altering fracture rates, and calcium contents can change the characteristics of dietary products. The context between opioid molecules and BCM-7 points to a potential triggering mechanism for the central nervous system and other metabolic diseases discussed.
Subject(s)
Caseins , Endorphins , Humans , Animals , Caseins/chemistry , Caseins/metabolism , Caseins/genetics , Endorphins/chemistry , Endorphins/metabolism , Milk/chemistry , Milk/metabolism , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Peptide Fragments/genetics , Opioid Peptides/chemistry , Opioid Peptides/metabolism , CattleABSTRACT
The aim of this study was to evaluate the influence of ß-endorphins and serotonin on the course of treatment, disease-free time, and overall survival of patients with ovarian cancer. This study may contribute to the identification of modifiable factors that may influence the treatment of ovarian cancer. The research was carried out in a group of 162 patients of which 139 respondents were included in the research; ovarian cancer was diagnosed in 78 of these patients. The study consisted of three stages. In the first stage of diagnostics, a survey among the patients was carried out. In the second stage-5 mL of blood was collected from each patient (n = 139) in the preoperative period to determine the concentration of ß-endorphin and serotonin. In the third stage-blood samples were collected from those patients who had completed chemotherapy treatment or had surgery. Concentrations of ß-endorphin and serotonin were measured by the Luminex method, using the commercial Luminex Human Discovery Assay kit. The average age of the patients was 62.99 years. The level of ß-endorphin significantly differs among patients diagnosed with ovarian cancer and among patients in the control group (202.86; SD-15.78 vs. 302.00; SD-24.49). A lower level of ß-endorphins was found in the patients with a recurrence of the neoplastic process compared to those without recurrence (178.84; SD-12.98 vs. 205.66; SD-13.37). On the other hand, the level of serotonin before chemotherapy was higher in the group of people with disease recurrence compared to those without recurrence (141.53; SD-15.33 vs. 134.99; SD-10.08). Statistically significantly positive correlations were found between the level of ß-endorphin and both disease-free time (ß-endorphin levels before chemotherapy: rho Spearman 0.379, p < 0.027; ß-endorphin levels after chemotherapy: rho Spearman 0.734 p < 0.001) and survival time (ß-endorphin levels before chemotherapy: rho Spearman 0.267, p < 0.018; ß-endorphin levels after chemotherapy: rho Spearman 0.654 p < 0.001). 1. The levels of serotonin and ß-endorphin levels are significantly related to ovarian cancer and change during treatment. 2. High mean preoperative concentrations of ß-endorphins were significantly related to overall survival and disease-free time.
Subject(s)
Endorphins , Ovarian Neoplasms , Serotonin , beta-Endorphin , Biological Factors , Endorphins/chemistry , Endorphins/metabolism , Female , Humans , Middle Aged , Ovarian Neoplasms/drug therapy , Serotonin/chemistry , Serotonin/metabolism , beta-Endorphin/metabolismABSTRACT
Physical exercise has wide-ranging benefits to cognitive functioning and mental state, effects very closely resembling enhancements to hippocampal functioning. Hippocampal neurogenesis has been implicated in many of these mental benefits of exercise. However, precise mechanisms behind these effects are not well known. Released peripherally during exercise, beta-endorphins are an intriguing candidate for moderating increases in neurogenesis and the related behavioral benefits of exercise. Although historically ignored due to their peripheral release and status as a peptide hormone, this review highlights reasons for further exploring beta-endorphin as a key mediator of hippocampal neurogenesis. This includes possible routes for beta-endorphin signaling into the hippocampus during exercise, direct effects of beta-endorphin on cell proliferation and neurogenesis, and behavioral effects of manipulating endogenous opioid signaling. Together, beta-endorphin appears to be a promising mechanism for understanding the specific ways that exercise promotes adult neurogenesis specifically and brain health broadly.
Subject(s)
Endorphins/metabolism , Exercise , Hippocampus/metabolism , Neurogenesis , Neurons/metabolism , Adult , Animals , Hippocampus/cytology , Humans , Mice , Neurons/cytologyABSTRACT
Infant biscuits (IBs) are commonly used during the complementary feeding of infants from the 6th month of life. They contain wheat flour and dairy ingredients, which can release the opioid-acting peptides ß-casomorphins (BCMs) and gluten exorphins (GEs) after gastrointestinal digestion. In the present study, five model IBs were prepared with or without gluten and different powdered milk derivatives in the formulations. IBs were digested simulating an in vitro static gastrointestinal digestion for infants aged 6-12 months. BCMs and GEs were identified and quantified by UPLC/HR-MS. The amounts of BCM7 and the GE A5 were related to the ß-CN and gluten content of the formulations. To date, levels of BCMs and GEs in digests of IBs have not been reported in literature. This work represents an in vitro investigation regarding the release of opioid-acting peptides in IBs. It could add additional knowledge on complementary foods for infant health.
Subject(s)
Digestion , Endorphins/metabolism , Infant Food/analysis , Peptides/chemistry , Animals , Dairy Products , Flour , Glutens/chemistry , Humans , Infant , Infant Food/standards , Milk/chemistry , Peptides/analysis , Peptides/metabolismABSTRACT
A runner's high describes a sense of well-being during endurance exercise characterized by euphoria and anxiolysis. It has been a widespread belief that the release of endogenous opioids, such as endorphins, underlie a runner's high. However, exercise leads to the release of two classes of rewarding molecules, endocannabinoids (eCBs) and opioids. In mice, we have shown that core features of a runner's high depend on cannabinoid receptors but not opioid receptors. In the present study, we aimed to corroborate in humans that endorphins do not play a significant role in the underlying mechanism of a runner's high. Thus, we investigated whether the development of two core features of a runner's high, euphoria and reduced anxiety levels, depend on opioid signaling by using the opioid receptor antagonist naltrexone (NAL) in a double-blind, randomized, placebo (PLA)-controlled experiment. Participants (N = 63) exhibited increased euphoria and decreased anxiety after 45 min of running (RUN) on a treadmill in a moderate-intensity range compared to walking (WALK). RUN led to higher plasma levels of the eCBs anandamide (AEA) and 2-arachidonoglycerol (2-AG). Opioid blockade did not prevent the development of euphoria and reduced anxiety as well as elevation of eCB levels following exercise. Moreover, the fraction of participants reporting a subjective runner's high was comparable in the NAL and PLA-treated group. Therefore, this study indicates that the development of a runner's high does not depend on opioid signaling in humans, but makes eCBs strong candidates in humans, as previously shown in mice.
Subject(s)
Endorphins , Euphoria , Running , Animals , Endorphins/metabolism , Euphoria/physiology , Humans , Mice , Running/psychologyABSTRACT
The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion-specific manner. However, it is unknown how mu-opioid signaling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in vitro patch-clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist DAMGO produced a concentration-dependent inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long lasting and not reversed on washout of DAMGO or by application of the mu-opioid receptor antagonist CTAP, suggesting an inhibitory long-term depression (LTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/protein kinase A (PKA) signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC.SIGNIFICANCE STATEMENT Considering that both the orbitofrontal cortex (OFC) and the opioid system regulate reward, motivation, and food intake, understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Second, mu-opioids recruit parvalbumin inputs to suppress inhibitory synaptic transmission in the mOFC. Third, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.
Subject(s)
Analgesics, Opioid/pharmacology , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Frontal Lobe/drug effects , Pyramidal Cells/drug effects , Receptors, Opioid, mu/drug effects , Synaptic Transmission/drug effects , gamma-Aminobutyric Acid , Animals , Cyclic AMP-Dependent Protein Kinases , Endorphins/metabolism , In Vitro Techniques , Interneurons/drug effects , Long-Term Synaptic Depression/drug effects , Male , Mice , Mice, Inbred C57BL , Parvalbumins , Patch-Clamp Techniques , Signal Transduction/drug effectsABSTRACT
Skin aging is influenced by several genetic, physiological, and environmental factors. In particular, ultraviolet (UV) exposure is an important factor involved in inducing skin photoaging. Autophagy controlling homeostatic balance between the synthesis, degradation, and recycling of cellular organelles and proteins plays important regulatory roles in several biological processes, including aging. The opioid neuropeptide α-neoendorphin (named NEP) is an endogenous decapeptide (N-YGGFLRKYPK-C) that activates the kappa opioid receptor and exhibits certain anti-aging and anti-wrinkling effects on skin cells; however, its action mechanism has not yet been elucidated. Therefore, the aim of this study was to determine the effects of NEP on anti-skin aging and autophagy activation in human dermal fibroblast cells. Western blot results showed that NEP down-regulates the production of phospho-mammalian target of rapamycin (p-mTOR), whereas increases the expression of key autophagy-related molecules such as Beclin-1, Atg5-Atg12, and LC3-II. The immunocytochemical analysis performed with anti-LC3-II antibody also showed that the autophagic indicators, autophagosomes are formed by NEP. These results suggest that NEP can activate cellular autophagy through mTOR-Beclin-1-mediated signaling pathway. It was also revealed by CM-H2DCF-DA assay and Western blottings that NEP can reduce the production of ultraviolet B (UVB)-induced reactive oxygen species (ROS) like with N-acetylcysteine (NAC), resulting in decreasing the expression levels of skin aging-related proteins, such as phospho-ERK (p-ERK), phospho-p38 (p-p38), and phospho-JNK (p-JNK). Furthermore, NEP could increase the type I procollagen production, while decreasing MMP-1, MMP-2, and MMP-9 activities. Taken together, the results demonstrate that NEP can reduce UVB-induced photoaging by activating autophagy.
Subject(s)
Autophagy , Endorphins/metabolism , Protein Precursors/metabolism , Skin Aging/radiation effects , Ultraviolet Rays/adverse effects , Cell Line , Dermis/cytology , Dermis/metabolism , Dermis/radiation effects , Fibroblasts/cytology , Fibroblasts/metabolism , Fibroblasts/radiation effects , Humans , Procollagen/metabolism , Reactive Oxygen Species/metabolismABSTRACT
Affectations of the opioid system have been related to exacerbated alcohol consumption. The objectives of this work were to assess whether a deficit of ß-endorphinergic neurons differentially affects alcohol intake in female rats with low (LC) and high alcohol consumption (HC), and to determine changes in the µ-opioid receptors (MOR) related to alcohol consumption and chronic exposure to alcohol in structures of the mesolimbic system. Female wild-type rats were selected according to their baseline alcohol intake levels and then exposed to chronic voluntary alcohol consumption after a single injection of either the vehicle or estradiol valerate (EV) to produce a ß-endorphin neuronal deficit. Changes in alcohol consumption and MOR expression levels were assessed in the nucleus accumbens (NAc), amygdala (Amy) and ventral tegmental area (VTA) at 5 and 10 weeks after EV treatment. The LC rats increased alcohol intake from baseline to the initial weeks after EV treatment and this consumption remained stable throughout the studied period. In contrast, alcohol consumption increased steadily over time in the HC rats. The HC vehicle rats had a 38% higher MOR protein expression in the NAc than the LC vehicle rats. In addition, chronic alcohol consumption increased MOR expression in the Amy regardless of consumption level, whereas EV treatment produced a decrease in MOR expression in the VTA in all groups. These results suggest intrinsic differences in MOR expression related to alcohol consumption levels. Also, the EV treatment and chronic exposure to alcohol produced adaptive changes in MOR expression.
Subject(s)
Alcohol Drinking/metabolism , Amygdala/metabolism , Central Nervous System Depressants/pharmacology , Endorphins/metabolism , Estradiol/pharmacology , Ethanol/pharmacology , Nucleus Accumbens/metabolism , Receptors, Opioid, mu/metabolism , Ventral Tegmental Area/metabolism , Alcoholism/metabolism , Amygdala/drug effects , Animals , Central Nervous System Depressants/administration & dosage , Disease Models, Animal , Endorphins/drug effects , Estradiol/administration & dosage , Ethanol/administration & dosage , Female , Nucleus Accumbens/drug effects , Rats , Rats, Wistar , Receptors, Opioid, mu/drug effects , Ventral Tegmental Area/drug effectsABSTRACT
It has been demonstrated that smoking is associated with an increase in postoperative and chronic pain. The changes in the pain-related neural pathways responsible for these effects are unknown. Additionally, the effects of nicotine withdrawal, resulting from smoking abstinence preoperatively, has not been evaluated in terms of its impact on pain sensation. In this study, an animal model has been used to assess these effects. A rat model of long-term nicotine exposure was used. Von Frey mechanical sensory tests were performed. Western Blot and immunohistological analysis were conducted on spinal cord samples. Mechanical sensory thresholds increased in the initial period (1-3 weeks), indicating hyposensitivity. Long-term (410 weeks) and under nicotine withdrawal, the mechanical sensory thresholds decreased, indicating hyperalgesia. During short-term nicotine exposure, glutamate decarboxylase 67 (GAD67), GAD65, and µ-opioid receptors (MOR) up-regulated. Beta-endorphins down-regulated. Increased γ -aminobutyric acid (GABA) and MOR appear responsible for the hyposensitivity since the GABA receptor antagonist, bicuculline and opioid receptor antagonist, naloxone decreased the mechanical thresholds of nicotine-induced hyposensitivity. In long-term nicotine exposure, the expression of GAD67, MOR, and GABA decreased. Baclofen, a derivative of GABA, reversed the hyperalgesia seen with nicotine withdrawal. Therefore, nicotine acts as an analgesic when used acutely or short-term. Long-term exposure or nicotine withdrawal (similar to smoking cessation) results in hyperalgesia. Nicotine appears to alter pain sensitivity by affecting the expression of GAD65, GAD67, MOR, endorphins, and GABA. This may partially explain the increased pain and opioid use seen in chronic smokers in the postoperative period.
Subject(s)
Nicotine/pharmacology , Pain Perception/drug effects , Pain Threshold/drug effects , Substance Withdrawal Syndrome/psychology , Animals , Baclofen/pharmacology , Bicuculline/pharmacology , Disease Models, Animal , Down-Regulation/drug effects , Endorphins/metabolism , Glutamate Decarboxylase/metabolism , Hyperalgesia/chemically induced , Male , Naloxone/pharmacology , Rats , Receptors, Opioid, mu/metabolism , Spinal Cord/metabolism , Time Factors , Up-Regulation/drug effects , gamma-Aminobutyric Acid/metabolismABSTRACT
This work aimed to study the opioid peptide ß-casomorphin-7 (BCM7) degradation or stability during digestion using human gastrointestinal (GI) juices and porcine jejunal brush border membrane (BBM) peptidases. Synthetic BCM7 was subjected to in vitro digestion by GI fluids obtained from human volunteers for 180 min, and to downstream degradation with porcine BBM vesicles. The BCM7 was sampled at 4 time points over 24 h after BBM addition. The digests were profiled by HPLC-electrospray ionization mass spectrometry (ESI/MS) to monitor BCM7 during GI digestion, and intact BCM7 through BBM digestion was quantified by reverse-phase (RP)-HPLC. We found that BCM7 was partly digested with human GI enzymes, as 3 proteolytic fragments in addition to f(60-66) YPFPGPI were detected: f(62-66) FPGPI, f(60-65) YPFPGP and f(61-66) PFPGPI. The RP-HPLC analysis revealed that 42% of the initial peptide was degraded after only 2 h of BBM digestion, and as much as 79% was degraded after 4-h digestion with supplementation of BBM. In conclusion, this study showed that most of BCM7 was degraded during GI and BBM digestion, although a small amount (5%) was still detected after 24-h digestion. It remains to be studied whether the small amount of intact BCM7 detected after in vitro digestion is transported via active transceptors in the human intestinal epithelial cells and enters blood circulation.
Subject(s)
Endorphins/metabolism , Gastrointestinal Tract/metabolism , Jejunum/metabolism , Microvilli/metabolism , Peptide Fragments/metabolism , Animals , Chromatography, High Pressure Liquid , Digestion , Humans , Microvilli/enzymology , Peptide Hydrolases/metabolism , SwineABSTRACT
OBJECTIVES: In this study, we hypothesized that replacing conventional milk, which contains A1 and A2 ß-casein proteins, with milk that contains only A2 ß-casein in the diet of dairy or milk-intolerant preschoolers (age 5 to 6 years) would result in reduced gastrointestinal symptoms associated with milk intolerance, and that this would correspond with cognitive improvements. METHODS: This randomized, double-blind, crossover study aimed to compare the effects of 5 days' consumption of conventional milk versus milk containing only A2 ß-casein on gastrointestinal symptoms, as assessed via visual analog scales, average stool frequency and consistency, and serum inflammatory and immune biomarkers in healthy preschoolers with mild-to-moderate milk intolerance. The study also aimed to compare changes in the cognitive behavior of preschoolers, based on Subtle Cognitive Impairment Test scores. RESULTS: Subjects who consumed milk containing only A2 ß-casein had significantly less severe gastrointestinal symptoms as measured by visual analog scales, reduced stool frequency, and improvements in stool consistency, compared with subjects consuming conventional milk. There were significant increases from baseline in serum interleukin-4, immunoglobulins G, E, and G1, and beta-casomorphin-7 coupled to lower glutathione levels, in subjects consuming conventional milk compared with milk containing only A2 ß-casein. Subtle Cognitive Impairment Test analysis showed significant improvements in test accuracy after consumption of milk containing only A2 ß-casein. There were no severe adverse events related to consumption of either milk product. CONCLUSIONS: Replacing conventional milk with milk containing only A2 ß-casein reduced gastrointestinal symptoms associated with milk intolerance in Chinese preschool children, with corresponding improvements in aspects of cognitive performance.
Subject(s)
Endorphins/metabolism , Food, Fortified , Lactose Intolerance/diet therapy , Milk/metabolism , Peptide Fragments/metabolism , Animals , Asian People , Child , Child Nutritional Physiological Phenomena , Child, Preschool , Digestion , Female , Humans , Lactose Intolerance/metabolism , Male , Treatment OutcomeABSTRACT
Neurotransmitters and neurochemicals can act on lymphocytes by binding to receptors expressed by lymphocytes. This review describes lymphocyte expression of receptors for a selection of neurotransmitters and neurochemicals, the anatomical locations where lymphocytes can interact with neurotransmitters, and the effects of the neurotransmitters on lymphocyte function. Implications for health and disease are also discussed.
Subject(s)
Adenosine/metabolism , Endocannabinoids/metabolism , Endorphins/metabolism , Lymphocytes/metabolism , Neuroimmunomodulation/physiology , Neurotransmitter Agents/metabolism , Animals , Bone Marrow/innervation , Brain/physiology , Humans , Lymphoid Tissue/innervation , Neurons/metabolism , Nociception/physiology , Receptors, Neurotransmitter/immunology , Receptors, Neurotransmitter/metabolism , Reward , Thymus Gland/innervationABSTRACT
BACKGROUND The aim of this study was to investigate the protective effect of ß-casomorphin-7 (ß-CM-7) and its possible mechanisms on acute kidney injury (AKI). MATERIAL AND METHODS Rats were randomly divided into a sham group, a cecal ligation and puncture (CLP) group, and a CLP+ß-CM-7 group. Kidney index, kidney function, and histopathology changes were assessed. The expression of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Kim-1), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), and p-IκBα in kidney tissues were detected by Western blotting. Inflammatory and oxidative stress factors were detected by ELISA kits. RESULTS The results showed that treatment with ß-CM-7 reduced the levels of creatinine (Cre), blood urea nitrogen (BUN), NGAL, and Kim-1 induced by CLP, weakening the pathological damage. In the CLP + ß-CM-7 group, the tumor necrosis factor-α (TNF-α) level and the DNA-binding activity of NF-κB p65 were significantly reduced and the interleukin-10 (IL-10) level was significantly increased compared with the CLP group. ß-CM-7 decreased the expression of p-IκBα/IκBα. In addition, ß-CM-7 increased the activity of superoxide dismutase (SOD) and decreased the level of malondialdehyde (MDA) in kidney tissue. CONCLUSIONS ß-CM-7 attenuated sepsis-induced AKI through reducing inflammation and oxidative stress and by inhibition of nuclear factor (NF)κB activities. This study provides a new therapeutic agent for attenuating sepsis-induced kidney injury.
Subject(s)
Acute Kidney Injury/physiopathology , Endorphins/pharmacology , NF-kappa B/metabolism , Peptide Fragments/pharmacology , Acute Kidney Injury/drug therapy , Animals , Blood Urea Nitrogen , Cecum/pathology , Cell Adhesion Molecules , Creatinine/metabolism , Endorphins/metabolism , Inflammation/pathology , Kidney/injuries , Kidney/pathology , Ligation , Lipocalin-2 , Male , Malondialdehyde/metabolism , NF-KappaB Inhibitor alpha , NF-kappa B/drug effects , Oxidative Stress , Peptide Fragments/metabolism , Rats , Rats, Sprague-Dawley , Sepsis/complications , Sepsis/drug therapy , Signal Transduction/drug effectsABSTRACT
This study addresses the hypothesis that the extracellular cell-associated X-prolyl dipeptidyl-peptidase activity initially described in Streptococcus thermophilus could be attributable to the intracellular X-prolyl dipeptidyl-peptidase PepX. For this purpose, a PepX-negative mutant of S. thermophilus LMD-9 was constructed by interrupting the pepX gene and named LMD-9-ΔpepX. When cultivated, the S. thermophilus LMD-9 wild type strain grew more rapidly than its ΔpepX mutant counterpart. Thus, the growth rate of the LMD-9-ΔpepX strain was reduced by a factor of 1.5 and 1.6 in milk and LM17 medium (M17 medium supplemented with 2% lactose), respectively. The negative effect of the PepX inactivation on the hydrolysis of ß-casomorphin-7 was also observed. Indeed, when incubated with this peptide, the LMD-9-ΔpepX mutant cells were unable to hydrolyze it, whereas this peptide was completely degraded by the S. thermophilus LMD-9 wild type cells. This hydrolysis was not due to leakage of intracellular PepX, as no peptide hydrolysis was highlighted in cell-free filtrate of wild type strain. Therefore, based on these results, it can be presumed that though lacking an export signal, the intracellular PepX might have accessed the ß-casomorphin-7 externally, perhaps via its galactose-binding domain-like fold, this domain being known to help enzymes bind to several proteins and substrates. Therefore, the identification of novel distinctive features of the proteolytic system of S. thermophilus will further enhance its credibility as a starter in milk fermentation.
Subject(s)
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism , Peptide Hydrolases/metabolism , Streptococcus thermophilus/enzymology , Animals , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Endorphins/metabolism , Hydrolysis , Milk/chemistry , Milk/microbiology , Peptide Fragments/metabolism , Peptides/analysis , Peptides/metabolism , Proteolysis , Streptococcus thermophilus/genetics , Streptococcus thermophilus/growth & developmentABSTRACT
Objective Beta-casein is a major protein in breast milk and an important source for several bioactive peptides that are encrypted within the sequence. Beta-casomorphins (BCMs) are short-chain proteolytic peptides that are derived from the beta-casein protein and have opioid effects in newborns. Human milk is known to contain naturally occurring milk-protein-derived bioactive peptides but the identification of naturally occurring beta-casein-derived BCMs in human breast milk has been limited due to difficulties in the detection of BCM peptides, which are small and circulate in low concentrations. Methods The present study aimed to identify the naturally occurring BCM peptides from beta-casein in human breast milk using liquid chromatography-tandem mass spectrometry. The BCM peptides identified in the breast milk were analysed to predict the milk proteases responsible for the cleavage patterns using a computational tool EnzymePredictor. Results In-depth peptidomics analysis of breast milk samples that were collected at different lactation stages during human lactation revealed the presence of BCMs including BCM-8, -9, -10, and -11 as well as precursors and truncated forms of the original peptide, which suggests that milk protease activity in the mammary gland generates biologically relevant BCMs. Conclusions To our knowledge, this is the first report to describe the presence of naturally occurring human BCM-10 and -11 in breast milk. Our study provides evidence of beta-casein-derived BCM peptides in human milk before infant digestion. Proteases that are present in milk are likely specific in their proteolysis of beta-casein. The identified bioactive BCM-8, -9, -10, and -11 as well as the precursor peptides meet the structural requirements to elicit opioid, immunomodulatory, antioxidative, and satiety functions in newborns.