Phytochemicals for taming agitated immune-endocrine-neural axis.

Homeostasis of immune-endocrine-neural axis is paramount for human health. If this axis gets agitated due to age, genetic variations, environmental exposures or lifestyle assaults, a cascade of adverse reactions occurs in human body. Cytokines, hormones and neurotransmitters, the effector molecules of this axis behave erratically, leading to a gamut of neural, endocrine, autoimmune, and metabolic diseases. Current panel of drugs can tackle some of them but not in a sustainable, benign way as a myriad of side effects, causal of them have been documented. In this context, phytochemicals, the secondary metabolites of plants seem beneficial. These bioactive constituents encompassing polyphenols, alkaloids, flavonoids, terpenoids, tannins, lignans, stilbenoids (resveratrol), saponins, polysaccharides, glycosides, and lectins etc. have been proven to exert antioxidant, anti-inflammatory, hypolipidemic, hypotensive, antidiabetic, anticancer, immunomodulatory, anti-allergic, analgesic, hepatoprotective, neuroprotective, dermatoprotective, and antimicrobial properties, among a litany of other biological effects. This review presents a holistic perspective of common afflictions resultant of immune-endocrine-neural axis disruption, and the phytochemicals capable of restoring their normalcy and mitigating the ailments.

Jean Camus and Gustave Roussy: pioneering French researchers on the endocrine functions of the hypothalamus.

At the beginning of the twentieth century, the hypothalamus was known merely as an anatomical region of the brain lying beneath the thalamus. An increasing number of clinicopathological reports had shown the association of diabetes insipidus and adiposogenital dystrophy (Babinski-Fröhlich's syndrome), with pituitary tumors involving the infundibulum and tuber cinereum, two structures of the basal hypothalamus. The French physicians Jean Camus (1872-1924) and Gustave Roussy (1874-1948) were the first authors to undertake systematic, controlled observations of the effects of localized injuries to the basal hypothalamus in dogs and cats by pricking the infundibulo-tuberal region (ITR) with a heated needle. Their series of surgical procedures, performed between 1913 and 1922, allowed them to claim that both permanent polyuria and adiposogenital dystrophy were symptoms caused by damage to the ITR. Their results challenged the dominant doctrine of hypopituitarism as cause of diabetes insipidus and adiposogenital dystrophy that derived from the experiments performed by Paulescu and Cushing a decade earlier. With their pioneering research, Camus and Roussy influenced the experimental work on the hypothalamus performed by Percival Bailey and Frederic Bremer at Cushing's laboratory, confirming the hypothalamic origin of these symptoms in 1921. More importantly, they provided the foundations for the physiological paradigm of Neuroendocrinology, the hypothalamus' control over the endocrine secretions of the pituitary gland, as well as over water balance and fat metabolism. This article aims to credit Camus and Roussy for their groundbreaking, decisive contributions to postulate the hypothalamus being the brain region in control of endocrine homeostasis and energy metabolism.

Early life programming of pain: focus on neuroimmune to endocrine communication.

Chronic pain constitutes a challenge for the scientific community and a significant economic and social cost for modern societies. Given the failure of current drugs to effectively treat chronic pain, which are based on suppressing aberrant neuronal excitability, we propose in this review an integrated approach that views pain not solely originating from neuronal activation but also the result of a complex interaction between the nervous, immune, and endocrine systems. Pain assessment must also extend beyond measures of behavioural responses to noxious stimuli to a more developmentally informed assessment given the significant plasticity of the nociceptive system during the neonatal period. Finally integrating the concept of perinatal programming into the pain management field is a necessary step to develop and target interventions to reduce the suffering associated with chronic pain. We present clinical and animal findings from our laboratory (and others) demonstrating the importance of the microbial and relational environment in programming pain responsiveness later in life via action on hypothalamo-pituitary adrenal (HPA) axis activity, peripheral and central immune system, spinal and supraspinal mechanisms, and the autonomic nervous system.

Genomics of the fetal hypothalamic cellular response to transient hypoxia: endocrine, immune, and metabolic responses.

Fetuses respond to transient hypoxia (a common stressor in utero) with cellular responses that are appropriate for promoting survival of the fetus. The present experiment was performed to identify the acute genomic responses of the fetal hypothalamus to transient hypoxia. Three fetal sheep were exposed to 30 min of hypoxia and hypothalamic mRNA extracted from samples collected 30 min after return to normoxia. These samples were compared with those from four normoxic control fetuses by the Agilent 019921 ovine array. Differentially regulated genes were analyzed by network analysis and by gene ontology analysis, identifying statistically significant overrepresentation of biological processes. Real-time PCR of selected genes supported the validity of the array data. Hypoxia induced increased expression of genes involved in response to oxygen stimulus, RNA splicing, antiapoptosis, vascular smooth muscle proliferation, and positive regulation of Notch receptor target. Downregulated genes were involved in metabolism, antigen receptor-mediated immunity, macromolecular complex assembly, S-phase, translation elongation, RNA splicing, protein transport, and posttranscriptional regulation. We conclude that these results emphasize that the cellular response to hypoxia involves reduced metabolism, the involvement of the fetal immune system, and the importance of glucocorticoid signaling.

The endocrine system and sarcopenia: potential therapeutic benefits.

Age related muscle loss, known as sarcopenia, is a major factor in disability, loss of mobility and quality of life in the elderly. There are many proposed mechanisms of age-related muscle loss that include the endocrine system. A variety of hormones regulate growth, development and metabolism throughout the lifespan. Hormone activity may change with age as a result of reduced hormone secretion or decreased tissue responsiveness. This review will focus on the complex interplay between the endocrine system, aging and skeletal muscle and will present possible benefits of therapeutic interventions for sarcopenia.

Iron chelation therapy in the myelodysplastic syndromes and aplastic anemia: a review of experience in South Korea.

Emerging clinical data indicate that transfusion-dependent patients with bone marrow-failure syndromes (BMFS) are at risk of the consequences of iron overload, including progressive damage to hepatic, endocrine, and cardiac organs. Despite the availability of deferoxamine (DFO) in Korea since 1998, data from patients with myelodysplastic syndromes, aplastic anemia, and other BMFS show significant iron overload and damage to the heart and liver. The recent introduction of deferasirox, a once-daily, oral iron chelator, may improve the availability of iron chelation therapy to iron-overloaded patients, and improve compliance in patients who may otherwise find adherence to the DFO regimen difficult.

Hypothalamic-endocrine aspects in Huntington's disease.

Huntington's disease (HD) is a hereditary and fatal disorder caused by an expanded CAG triplet repeat in the HD gene, resulting in a mutant form of the protein huntingtin. Wild-type and mutant huntingtin are expressed in most tissues of the body but the normal function of huntingtin is not fully known. In HD, the neuropathology is characterized by intranuclear and cytoplasmic inclusions of huntingtin aggregates, and cell death primarily in striatum and cerebral cortex. However, hypothalamic atrophy occurs at early stages of HD with loss of orexin- and somatostatin-containing cell populations. Several symptoms of HD such as sleep disturbances, alterations in circadian rhythm, and weight loss may be due to hypothalamic dysfunction. Endocrine changes including increased cortisol levels, reduced testosterone levels and increased prevalence of diabetes are found in HD patients. In HD mice, alterations in the hypothalamic-pituitary-adrenal axis occurs as well as pancreatic beta-cell and adipocyte dysfunction. Increasing evidence points towards important pathology of the hypothalamus and the endocrine system in HD. As many neuroendocrine factors are secreted into the cerebrospinal fluid, blood and urine, it is possible that their levels may reflect the disease state in the central nervous system. Investigating neuroendocrine changes in HD opens up the possibility of finding biomarkers to evaluate future therapies for HD, as well as of identifying novel targets for therapeutic interventions.

Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia.

Hypoparathyroidism is thought to be a rare consequence of iron overload seen in beta-thalassemic transfused patients. This study was conducted to determine the prevalence of hypoparathyroidism in a large number of beta-thalassemic patients, and its potential correlation with the presence of other endocrinopathies caused by iron overload. Serum and urine biochemical parameters were measured in 243 thalassemic patients (136 females and 107 males) in order to determine the prevalence of hypoparathyroidism and evaluate bone turnover. The patients were divided into two groups according to the presence of hypoparathyroidism. We compared the prevalence of other endocrinopathies and disease complications in the two groups. Hypoparathyroidism was detected in 13.5% of the patients (33 subjects; 17 males and 16 females). Serum-intact parathyroid hormone, and total and ionized calcium were significantly lower, while phosphorus was significantly higher in thalassemic patients with hypoparathyroidism. The reduction in BMD was more prominent in normal thalassemic patients (Z score = -2.246 +/- 0.97) compared with those with hypoparathyroidism (Z score = -1.975 +/- 0.89), although the difference was not statistically significant. Disturbed glucose metabolism was more common in patients with hypoparathyroidism (P < 0.05). In addition, heart dysfunction was statistically more frequent in this group (odds ratio = 2.51, P < 0.05). Hypoparathyroidism is a not infrequently observed complication in thalassemic patients. Since the concentration of ferritin is not a valuable tool in the prediction of the development of hypoparathyroidism, parathyroid function should be tested periodically, particularly when other iron overload-associated complications occur.

Evaluation of a Tier I screening battery for detecting endocrine-active compounds (EACs) using the positive controls testosterone, coumestrol, progesterone, and RU486.

After previously examining 12 compounds with known endocrine activities, we have now evaluated 4 additional compounds in a Tier I screening battery for detecting endocrine-active compounds (EACs): a weak estrogen receptor (ER) agonist (coumestrol; COUM), an androgen receptor (AR) agonist (testosterone; TEST), a progesterone receptor (PR) agonist (progesterone; PROG), and a PR antagonist (mifepristone; RU486). The Tier I battery incorporates 2 short-term in vivo tests (5-day ovariectomized female battery; 15-day intact male battery) and an in vitro yeast transactivation system (YTS). The Tier I battery is designed to identify compounds that have the potential to act as agonists or antagonists to the estrogen, androgen, progesterone, or dopamine receptors; steroid biosynthesis inhibitors (aromatase, 5alpha-reductase, and testosterone biosynthesis); or compounds that alter thyroid function. In addition to the Tier I battery, a 15-day dietary restriction experiment was performed using male rats to assess confounding due to treatment-related decreases in body weight. In the Tier I female battery, TEST administration increased uterine weight, uterine stromal cell proliferation, and altered hormonal concentrations (increased serum testosterone [T] and prolactin [PRL]; and decreased serum FSH and LH). In the male battery, TEST increased accessory sex gland weights, altered hormonal concentrations (increased serum T, dihydrotestosterone [DHT], estradiol [E2], and PRL; decreased serum FSH and LH), and produced microscopic changes of the testis (Leydig cell atrophy and spermatid retention). In the YTS, TEST activated gene transcription in the yeast containing the AR or PR. In the female battery, COUM administration increased uterine weight, uterine stromal cell proliferation, and uterine epithelial cell height, and increased serum PRL concentrations. In the male battery, COUM altered hormonal concentrations (decreased serum T, DHT, E2; increased serum PRL) and, in the YTS, COUM activated gene transcription in the yeast containing the ER. In the female battery, PROG administration increased uterine weight, uterine stromal cell proliferation, and uterine epithelial cell height and altered hormonal concentrations (increased serum progesterone and decreased serum FSH and LH). In the male battery, PROG decreased epididymis and accessory sex gland weights, altered hormonal concentrations (decreased serum T, PRL, FSH, and LH; increased serum progesterone and E2), and produced microscopic changes of the testis (Leydig cell atrophy). In the YTS, PROG activated gene transcription in the yeast containing the AR or PR. In the female battery, RU486 administration increased uterine weight and decreased uterine stromal cell proliferation. In the male battery, RU486 decreased epididymis and accessory sex gland weights and increased serum FSH and LH concentrations. In the YTS, RU486 activated gene transcription in the yeast containing the ER, AR, or PR. Dietary restriction data demonstrate that confounding due to decrements in body weight are not observed when body weight decrements are 10% or less in the Tier I male battery. In addition, minimal confounding is observed at body decrements of 15% (relative liver weight, T3, and T4). Hence, compounds can be evaluated in this Tier I at levels that produce a 10% decrease in body weight without confounding of the selected endpoints. Using the responses obtained for all the endpoints in the Tier I battery, a distinct "fingerprint" was produced for each type of endocrine activity against which compounds with unknown activity can be compared. These data demonstrate that the described Tier I battery is useful for identifying EACs and they extend the compounds evaluated to 16.

An ongoing validation of a Tier I screening battery for detecting endocrine-active compounds (EACs).

After previously examining an estrogen receptor agonist (17beta-estradiol), several additional compounds have been evaluated in a Tier I screening battery for detecting endocrine-active compounds (EACs): an estrogen receptor antagonist (ICI-182,780, ICI), an androgen receptor antagonist (flutamide, FLUT), a testosterone biosynthesis inhibitor (ketoconazole, KETO), a 5alpha-reductase inhibitor (finasteride, FIN), and an aromatase inhibitor (anastrozole, ANA). The Tier I battery incorporates two short-term in vivo tests (a 5-day ovariectomized female battery and a 15-day intact male battery) and an in vitro yeast transactivation system (YTS). The Tier I battery is designed to identify compounds that have the potential to act as agonists or antagonists to the estrogen, androgen, progesterone, or dopamine receptors, steroid biosynthesis inhibitors (aromatase, 5alpha-reductase, and testosterone biosynthesis), or compounds that alter thyroid function. ICI administration decreased uterine estrogen and progesterone receptor number in the female battery, increased serum follicle-stimulating hormone (FSH) levels and caused spermatid retention in the male battery, and activated gene transcription in the YTS containing the estrogen receptor. FLUT administration increased uterine stromal cell proliferation in the female battery and decreased weights for all androgen-dependent tissues, induced Leydig cell hyperplasia, and caused hormonal alterations (increased testosterone (T), estradiol (E2), dihydrotestosterone (DHT), luteinizing hormone (LH), and FSH) in the male battery, and competed for binding to the androgen receptor in the YTS competition assay. In the male battery KETO decreased weights for all androgen-dependent tissues, caused hormonal alterations (decreased T and DHT and increased LH and FSH), and induced spermatid retention. FIN decreased seminal vesicle and accessory sex gland (ASG) unit weight and caused hormonal alterations (decreased DHT and increased LH, and PRL) in the male battery. KETO was judged not to affect any of the endpoints in the female battery. ANA decreased ASG unit weight and serum E2 levels in the male battery. Using the responses obtained for all the endpoints in the Tier I battery, a distinct "fingerprint" was produced for each type of endocrine activity against which compounds with unknown activity can be compared. These data demonstrate that the described Tier I battery is useful for identifying EACs.