Beware High Levels of Cortisol, the Stress Hormone

Cortisol, the Stress Hormone

We’ve all felt that surge of energy as we confront something threatening or startling. A barely avoided car accident. A call that your child has been hurt. The pressure to meet a deadline.

As your body perceives stress, your adrenal glands make and release the hormone cortisol into your bloodstream. Often called the “stress hormone,” cortisol causes an increase in your heart rate and blood pressure. It’s your natural “flight or fight” response that has kept humans alive for thousands of years.

Normal levels of cortisol also are released when you wake up in the morning or exercise. These levels can help regulate your blood pressure and blood sugar levels and even strengthen your heart muscle. In small doses, the hormone can heighten memory, increase your immune system, and lower sensitivity to pain.

“Stress is a lifestyle factor and a fact of life that we all face; however, reacting to stress in unhealthy ways can increase the risk of high blood pressure, heart attack and stroke,” says interventional cardiologist Dr. Sagger Mawri. The amount of stress we experience has increased since the COVID-19 pandemic, he adds. “Many people reacted to the stress of the pandemic with unhealthy weight changes, a decline in physical activity, and increased alcohol consumption. In fact, the average weight gain was 26 pounds among those who gained more weight than they wanted.” Widespread grief and other hardships caused by the pandemic have increased stress for many, Dr. Mawri adds.

If your body experiences chronic stress, you may begin to feel unpleasant and even dangerous effects, such as:

      • Fatigue
      • Irritability
      • Headaches
      • Intestinal problems, such as constipation, bloating, or diarrhea
      • Anxiety or depression
      • Weight gain
      • Increased blood pressure
      • Low libido, erectile dysfunction, or problems with regular ovulation or menstrual periods
      • Difficulty recovering from exercise
      • Poor sleep
      • Muscle pain or tension in the head, neck, jaw, or back

How Cortisol Works

When the adrenal glands release cortisol into your bloodstream, the hormone triggers a flood of glucose that supplies an immediate energy source to your large muscles. It also inhibits insulin production so the glucose won’t be stored but will be available for immediate use.

Cortisol narrows the arteries, while another hormone, epinephrine, increases your heart rate. Working together, they force your blood to pump harder and faster as you confront and resolve the immediate threat.

If your entire life is high-stress and always in high gear, your body may constantly pump out cortisol.

Hormone levels return to normal as you swerve to miss an oncoming car, find out that your child has only a few scrapes, or meet the deadline for your presentation.

Why Too Much of a Good Thing is Bad for You

If your entire life is high-stress and always in high gear, your body may constantly pump out cortisol. “This has several negative effects,” says Dr. Mawri.

      1. Increased blood sugar levels. Insulin typically helps the cells convert glucose to energy. As your pancreas struggles to keep up with the high demand for insulin, glucose levels in your blood remain high and your cells don’t get the sugar they need to perform at their best.
      2. Weight gain. As your cells are crying out for energy, your body may send signals to the brain that you are hungry and need to eat. Studies have demonstrated a direct association between cortisol levels and calorie intake in populations of women. False hunger signals can lead you to crave high-calorie foods, overeat and thus gain weight. Unused glucose in the blood is eventually stored as body fat.
      3. Suppressed immune system. Cortisol’s positive action to reduce inflammation in the body can turn against you if your levels are too high for too long. The elevated levels may actually suppress your immune system. You could be more susceptible to colds and contagious illnesses. Your risk of cancer and autoimmune diseases increases and you may develop food allergies.
      4. Digestive problems. When your body reacts to a threat, it shuts down other less critical functions, such as digestion. If the high-stress level is constant, your digestive tract can’t digest or absorb food well. It’s no coincidence that ulcers occur during stressful times and people with colitis or irritable bowel syndrome report better symptom control when they get their stress under control.
      5. Heart disease. Constricted arteries and high blood pressure can lead to blood vessel damage and plaque buildup in your arteries. They could be setting the stage for a heart attack or stroke.

How to Take Action

“Given the dramatic increase in stress in recent years, it is crucial that we all find healthy ways to cope with and manage the stress in our lives,” says Dr. Mawri. “Fortunately there are ways to do so and develop healthy behaviors that improve heart health.” He shares these tips from the American Heart Association:

      • If you are often stressed, learn the cause and constructive ways to deal with it.
      • Slow down and plan ahead to avoid feeling rushed.
      • Get 7 to 9 hours of sleep a night.
      • Let go of worry and take breaks.
      • Laugh more.
      • Make time to connect with friends and family and maintain a social support system.
      • Become more organized to stay on top of important tasks.
      • Practice giving back by volunteering and helping others.
      • Get exercise every day to relieve mental and physical tension.
      • Give up bad habits like excess alcohol, tobacco, and too much caffeine.
      • Lean into things that you can change, like a new skill or working towards a particular goal.
      • Learn to say no to things that are not a high priority.
      • Ask for help when you need it.

“If you have more stress than you can handle on your own, it’s a good idea to seek stress management counseling or speak to a mental health professional,” Dr. Mawri recommends.

Be aware of your own stress levels and takes steps to manage your stress. Simple practices such as getting enough sleep, exercising, meditating, deep breathing techniques, and scheduling leisure activities are a good start.

Source: premierhealth.com ~ Image: Everyday Health

Dr. Israel Brekhman: “Father of Adaptogens” and His Energizing Adaptogen Blend

Dr. Israel Brekhman

It was 1960 when Russian scientist, Dr. Israel Brekhman, first had his work published in scientific literature. This first publication was a culmination of 15 years of previous research on adaptogens—a topic Brekhman dedicated the rest of his life. His continued research on adaptogens led to hundreds more publications and the discovery of the many health benefits of these protective agents. Brekhman was not only a world-renowned scientist and researcher, but also a medical doctor, teacher, and philosopher. Known as the “Father of Adaptogens,” he’s credited with introducing to the world formulas of adaptogens that promote health by helping people cope with everyday stress, maintain high levels of energy, and free the body from fatigue.

In a society plagued by chronic stress, a targeted solution to prime and protect the body from its harmful effects is necessary. Deemed “nature’s answer to stress,” Isagenix Ionix Supreme contains adaptogen compounds that work in the body by increasing its ability to adapt to stress while also improving physical and mental functioning under stressful conditions (1-2).

More specifically, and in one of his many research papers, Brekhman and his colleagues defined adaptogens as natural plant substances that:

    1. Increase the body’s ability to cope with internal and external stresses.
    2. Exhibit stimulating effects after both single-time use and prolonged use, leading to increased working capacity and mental performance under stressful and fatigue-inducing conditions.
    3. Normalize the functions of the body.
    4. Are entirely safe and have no negative side effects.

While all adaptogens are restorative to the body’s stress response and capacity to perform, certain combinations were studied by Brekhman for the exclusive purpose of boosting performance and fighting fatigue. With that purpose in mind, Isagenix has formulated the new e+ Natural Energy Shot with Brekhman’s own adaptogen formula coupled with naturally sourced caffeine—talk about the perfect pairing for energy and performance!

The first energy-boosting adaptogen in Brekhman’s formula, and now in e+ is Eleuthero (full name: Eleutherococcus senticosus). Eleuthero, also known as Siberian ginseng, is a thin, thorny shrub native to forests in southeastern Russia, northern China, Japan, and Korea.

The research behind Eleuthero has shown it to improve endurance exercise, oxygen uptake, and overall performance in athletes. One study published in 2010 echoed just that–college-aged male tennis players who supplemented with eleuthero for eight weeks had significantly enhanced endurance time and elevated cardiovascular functions (3).

Another adaptogen in e+, Rhodiola (full name: Rhodiola Rosea)—native to the arctic and mountainous regions throughout Europe, Asia, and America—also has scientific research behind it alluding to athletic improvement. A 2012 study conducted on cyclists found an improved heart rate response to exercise and a decreased perception of effort in subjects who took Rhodiola one hour before exercise (4).

The adaptogens in e+ not only can help power a workout but can also help you resist stress to stay mentally sharp after a hard day’s (or night’s) work. Rhodiola, for instance, has been found to reduce general and mental fatigue in doctors working night shifts (4).

One of the most recent reviews of adaptogens, published in October 2012, gives cause to always have e+ on hand when a pick-me-up is needed.  According to the review, adaptogens “induce increased attention and endurance in situations of decreased performance caused by fatigue and/or sensation of weakness” (5).

The bottom line is that adaptogens are plant substances that help the body to better handle external and internal stressors, they enhance the body’s ability to perform physically, and increase energy and mental alertness. Israel Brekhman spent his lifetime and career studying adaptogens and how we can use them to prime and protect the body. With e+, Isagenix is taking some of Brekhman’s best work and giving people the tool to take themselves and their health to the next level.

Source: isagenixhealth.net

Technical and Clinical Aspects of Cortisol

Technical and clinical aspects of cortisol

Stress is now recognized as a universal premorbid factor associated with many risk factors of various chronic diseases. Acute stress may induce an individual’s adaptive response to environmental demands. However, chronic, excessive stress causes cumulative negative impacts on health outcomes through “allostatic load”. Thus, monitoring the quantified levels of long-term stress mediators would provide a timely opportunity for prevention or earlier intervention of stress-related chronic illnesses. Although either acute or chronic stress could be quantified through measurement of changes in physiological parameters such as heart rate, blood pressure, and levels of various metabolic hormones, it is still elusive to interpret whether the changes in circulating levels of stress mediators such as cortisol can reflect the acute, chronic, or diurnal variations. Both serum and salivary cortisol levels reveal acute changes at a single point in time, but the overall long-term systemic cortisol exposure is difficult to evaluate due to circadian variations and its protein-binding capacity. Scalp hair has a fairly predictable growth rate of approximately 1 cm/month, and the most 1 cm segment approximates the last month’s cortisol production as the mean value. The analysis of cortisol in hair is a highly promising technique for the retrospective assessment of chronic stress. [BMB Reports 2015; 48(4): 209-216]

INTRODUCTION

Stress can lead to both physical and psychological health issues. Some stress can be beneficial at times by producing a boost that provides the drive and energy to help people get through situations like exams or work deadlines. However, an extreme amount of stress can lead to negative consequences and adversely affect the immune, cardiovascular, neuroendocrine, and central nervous systems . In particular, chronic stress can have a serious impact due to sustained high levels of the chemicals released in the “fight or flight” response, which involves the endocrine system releasing glucocorticoids .

Cortisol, which is synthesized from cholesterol, is the main glucocorticoid in the zona fasciculate of the human adrenal cortex. Its secretion in response to biochemical stress contributes to the well-characterized suppression of the hypothalamic-pituitary-adrenal (HPA) axis on health and cognition events . Since the vast majority of cortisol actions rely on binding to cytosolic receptors, only a small fraction of unbound, free cortisol is revealed to be biologically active. It comes out of the mitochondrion and migrates out of the cell into the extracellular space and into the bloodstream. Due to its low molecular weight and lipophilic nature, unbound cortisol enters the cells through passive diffusion, which makes it feasible to measure the free cortisol in many body fluids .

In general, cortisol levels in the blood increase during the early morning (highest at about 8 a.m.) and decrease slightly in the evening and during the early phase of sleep . The timing of blood sampling is therefore very important. While its assessment in sweat or tears is only of theoretical importance and urinary cortisol is of decreasing interest, salivary cortisol may have some advantages over the assessment of cortisol in the blood . Since the hormone levels in biological fluids fluctuate on a daily basis, cortisol extracted from the hair fiber has been investigated . This review discusses on the methods involved in mass spectrometry-based metabolomic studies for the identification of biomarkers in chronic stress, which is more focused on hair cortisol. Comparative statistical analyses of crucial aspects are also included to facilitate the understanding of recent advances in the metabolic platform on mining biomarkers.

STRESS AND THE ADRENAL GLAND

The two adrenal glands are located on top of the kidneys, and these glands produce hormones in response to stress. Each adrenal gland consists of a central area, called the medulla, and an outer area of the cortex (Fig. 1). In case of the apparent threat, the hypothalamus sends direct signals via the sympathetic nervous system to the adrenal glands, causing them to release a catecholamine and epinephrine (same as adrenaline). It leads to urgent action by stimulating faster breathing and heart rates. The adrenal medullar also secretes another catecholamine, norepinephrine, which works with epinephrine to stimulate liver cells to release glucose to make more fuel available for cellular respiration. These hormones have short-term effects as the nerve impulses are sent from the hypothalamus. Due to the short half-life of blood catecholamine, meticulous care must be taken to obtain blood samples consistently vis-à-vis the stress immersion experience .

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The differential stress hormones are secreted by the adrenal cortex and medullar. Catecholamines cause general physiological changes that prepare the body for physical activity (fight-or-flight response) in the short-term response. Some typical effects include increases in heart rate, blood pressure, blood glucose levels, and other general reactions of the sympathetic nervous system. Corticoids are involved in a wide range of physiological processes including chronic stress response, immune response, and regulations of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Data are taken from “https://www.studyblue.com/notes/note/n/07-adrenalglands/deck/1109539”.

Finding a “gold standard” biomarker for chronic stress has been proven to be challenging, given its complex etiology and highly individual manifestations, while the biomarkers of acute stress have been well-defined and are primarily used to assess the release of catecholamine. Hormones secreted by the adrenal cortex provide a slower, longer-acting (chronic) response to stress. In this event, the hypothalamus secretes a releasing hormone which causes the anterior pituitary to secrete an adrenal-stimulating hormone, adrenocorticotrophic hormone (ACTH); and this signals the cells in the adrenal cortex to produce and secrete corticosteroids. Among them, mineralocorticoids, like aldosterone, can regulate water and sodium re-absorption in the kidneys. It also regulates the active secretion of potassium in the principal cells of the cortical collecting tubule and protons via proton ATPases in the luminal membrane of the intercalated cells of the collecting tubule, which results in an increase in blood pressure and blood volume. Glucocorticoids promote fat and protein breakdown and glucose synthesis. Cortisol is the major glucocorticoid, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions .

ALLOSTASIS AND ALLOSTATIC LOAD

The term, stress, was originally adopted from engineering (a measure of the internal forces induced by the deformation of a body), but it is now referred to as ‘threats or anticipation of threats to an organism’s homeostasis’ . Thus stress events could be understood as any stimuli that cause alterations in homeostasis for adaptation to the environment. These changes in homeostasis are referred to as ‘allostasis’, which can be exemplified by increased heart rate or blood pressure and enhanced systemic metabolism. In general, allostasis can be adaptive or maladaptive depending on its degree or contextual relevance; mediators of allostasis, such as metabolic hormones, could contribute to healthy adaptation and pathophysiology . The concept of ‘allostatic load’ indicates an altered, ‘new set point’ of homeostasis, resulting from cumulative effects of allostatic responses which are chronic, excessive, or poorly regulated . For example, the increased serum glucose level is responsible for a single acute stressful event, which can be called as ‘allostatic response’. Also, diabetes (insulin resistance) resulting from repetitive chronic stress can be understood as an ‘allostatic overload’, in which the baseline fasting glucose level has been newly set to a higher level than before (Fig. 2). Therefore, the biomarkers of allostatic load, if available, could be used for measuring and predicting the cumulative biological risks of impending illnesses, and they are ideal indicators for detecting the ‘pre-phase’ of illnesses .

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Stress, allostasis, and allostatic load. Stress is any stimulus inducing either adaptive or maladaptive allostasis (changes in homeostasis) of stress mediators, which constitute the autonomic nervous system (blood pressure, catecholamines), metabolic hormones (cortisol, insulin), and pro- & anti-inflammatory cytokines. If stress stimuli are excessive and repetitive, recovery to the original homeostatic levels may be incomplete (indicated by the second blue arrow). As a result, chronic stress can make a body system anticipate, as if such a new (stressful) environment would persist, demanding a newly defined set point for future adaptation. Thus, the difference between the new and old set points can be understood as a ‘cumulative burden of adaptation to stress’- i.e., allostatic load. Examples of allostatic load may be found in the primary mediators (hypercortisolemia, increased inflammatory cytokines), secondary outcomes (elevated blood pressure, overweight, insulin resistance), or tertiary outcomes (hypertension, diabetes, obesity, coronary heart disease, neurodegenerative disorders). For more details, see reference # 6.

Mediators of allostasis constitute the autonomic nervous system (catecholamines), metabolic hormones, and various cytokines . Among these, cortisol is the one that has been paid great attention based on the concept of the ‘glucocorticoid cascade hypothesis’ . This hypothesis explains how and why the cortisol actions could be related to pathophysiology upon an overload of stress. Psychological and physical stresses increase the circulating cortisol levels. In the acute state, increased cortisol induces adaptive responses via enhancing catabolic processes to supply more energy to the body. In general, increased cortisol levels return to the basal levels by feedback inhibition mechanisms through the hypothalamus, prefrontal cortex, and most importantly, hippocampus . When stressful stimuli are repeated chronically, circulating cortisol is maintained at higher levels over a prolonged period. Chronically elevated cortisol levels now cause damage on hippocampal and cortical neurons , which are the main regions where feedback inhibition starts. As a result, even when stress stimuli disappear, cortisol levels could be maintained at higher levels beyond the physiologically normal range due to a vicious cycle caused by the already damaged feedback mechanism.

Consequently, a great number of studies have explored the potential of utilizing cortisol as a biomarker for various chronic illnesses or their pre-disease states . Currently, it seems that such the role of cortisol, as one of the biomarkers for the allostatic load, may be largely accepted . However, there are still controversial issues regarding the sampling and measurement methods of these hormones that are fluctuated by environmental contexts as well as by the circadian cycle. However, the most important issue might be the possibility that the level measured once at a current point could reflect the past history of an individual’s stress load, just as HbA1c indicates the degree of ‘glucose load’ for the past 3 months. The level of cortisol in scalp hair is now considered a promising biomarker for assessing the average level of one’s past stress burden during a given period, and it will be further discussed in this paper. Its utility has been demonstrated across diverse clinical settings from neonates to old age, indicated by associations of hair cortisol levels with babies’ stress in the neonatal intensive care unit , children’s stress at school entry , and various metabolic and neuropsychiatric disorders including acute myocardial infarction , heart failure , metabolic syndrome , and post-traumatic stress disorder .

ADVANCES IN CORTISOL DETECTION IN METABOLITE PROFILING

Because more than 90% of circulating cortisol in human serum is protein-bound, changes in the binding proteins can alter the levels of serum total cortisol without influencing the free concentrations of cortisol. Total cortisol could be misleadingly lower than anticipated, resulting in the incorrect interpretation that adrenal function is impaired. This is important because the current standards for defining normal adrenal functions are based on healthy people who have normal levels of binding proteins. Measuring serum-free cortisol levels in critical illnesses may help to prevent the unnecessary use of glucocorticoid therapy . Although the free cortisol hypothesis has been widely used, it has also been suggested that cortisol-binding globulin (CBG)-bound cortisol may have physiological effects on target tissues .

There is a high correlation between salivary cortisol levels and unbound cortisol in plasma and serum, which remains high during the circadian cycle and under different dynamic tests such as ACTH stimulation . Since free cortisol represents the biologically active hormone fraction, salivary cortisol measures have early been considered a better method than serum cortisol for the evaluation of adrenocortical function . Recently, late-night salivary cortisol has been showing a superior diagnostic performance as the primary biochemical diagnostic test for Cushing’s syndrome . Cortisol in biological fluids has been extensively evaluated with cortisone, which may reveal the activity of 11β-hydroxysteroid dehydrogenase (11β-HSD) by mass spectrometry-based metabolite profiling techniques . These analytical methods have shown acceptable analytical sensitivity and selectivity in trace amounts of biological samples such as urine and serum. However, the methods have still been hampered by incorrect physiological levels of adrenal steroids, including cortisol, due to the sampling problems with a circadian variation. In general, acute cortisol levels fluctuate markedly depending on many physiological factors including circadian rhythmicity, and it may provide a rather poor reflection of normal, chronic cortisol secretion .

In contrast to the biological fluids, hair can provide biological information about long-term exposure because its growth rate is about 1 cm/month (Fig. 3). The hormones are mainly delivered from the blood circulation to the capillaries of the dermal papilla, which is located in the hair follicles . This phenomenon enables retrospective examination of cortisol production at the times when a stressor is most salient, without needing to take a sample right at that time. Alternatively, it can provide a baseline cortisol assessment for a time period during which the stress has not yet occurred. In addition, its non-invasive nature in sampling and easy storage at room temperature has been highlighted as an advantage in clinical applications . In hair analysis, steroid hormones are extracted by solubilization or digestion of the hair matrix with alkaline hydrolysis for androgen and estrogens . Also, acid hydrolysis or methanol extraction can enable an analysis of corticoids in hair due to their insufficient chemical stability . When 62 biologically active steroids were analyzed by an optimized extraction technique, only 20 hair steroids, including cortisol and cortisone, were quantitatively detectable .

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A proposed mechanism of cortisol incorporation into hair and retrospective reflection of its chronic secretion. Cortisol may be incorporated into hair via passive diffusion from (A) blood capillary, (B) sweat, and (C) sebum, as well as from (D) external sources. Data are taken from reference #12.

STRESS-MEDIATED HAIR CORTISOL IN THE ENDOCRINE SYSTEM

Because more than 70% of diseases are believed to be stress-related, the prediction of chronic stress is an important step in reducing the incidence of chronic illnesses. Hair cortisol may provide an objective measurement of stress over time rather than just a ‘day in the life’. The symptoms of the metabolic syndrome resemble those of Cushing’s syndrome, a disease that is characterized by hypercortisolism. One of the questions raised is whether chronically elevated cortisol concentrations play a role in the development of obesity and metabolic syndromes. The increased hair cortisol levels are also associated with children’s obesity caused by long-term activation of the HPA-axis , which is in accordance with the urinary levels of cortisol in obese children . The risk of cardiovascular disease (CVD) is associated with an increase in hair cortisol levels by 2.7 times, which was similar to the risk associated with hypertension or obesity. This suggests that high cortisol levels in a long term might be an important risk factor for CVD .

Mitotane, an anti-neoplastic agent for adrenocortical cancer (ACC), increases CBG and induces CYP3A4 activity, which leads to high doses of hydrocortisone; however, there has been no efficient biomarker to evaluate this therapy. Hair cortisol levels were higher in ACC patients compared to healthy individuals, and they were associated with body mass index . However, there was no correlation between hair cortisol levels and hydrocortisone doses. As a measure of long-term cortisol exposure, the hair cortisol analysis in patients receiving glucocorticoid replacement therapy may be a useful tool. Also, the hair cortisol content is correlated with hydrocortisone dose in the patients with adrenal insufficiency, who had significantly higher subjective stress scores than the control subjects .

METABOLOMIC IDENTIFICATIONS IN CHRONIC STRESS

The main benefit of the metabolomic strategy is the high likelihood of identifying unpredicted changes in metabolic profiles cued by abnormal conditions . In particular, the metabolomic information may offer novel diagnostic indicators and therapeutic targets in clinical applications , as well as in mechanistic studies heading to elucidate metabolic modules that can regulate dysfunctional processes in disease statuses .

Among dysfunctional health conditions, chronic diseases are mostly composed of subtle and long-term dysregulations of cellular and physiological functions that are often not measurable even during disease onset . The stress-inducing abnormal status is chronically developed with an unpredictable combination of various types of etiological factors. Therefore, the molecular characterization, as well as clinical definition, may not be clear in specific disease courses and it may not be homologous across individuals . The diversity of pathological traits induced by chronic stress makes it even harder to properly diagnose the abnormality and classify the progress stage. Most of the studies are mainly focused on a targeted single molecule and one-point interaction, which may be insufficient to reflect the dynamics and systematic effects of chronic stress . In this context, metabolite profiling can be an effective tool for biomarker discovery and understanding of the molecular mechanism, particularly for cases where a diagnostic/prognostic indicator is unknown and the molecular mechanism remains veiled. Recently, a chronic unpredictable mild stress in an animal model showed aberrant profiling of amino acids that were grouped into neurotransmitters and branched-chain amino acids . The metabolic signatures under acute and chronic stress in a rat models and the biochemical cues are also closely associated with behavior and physiological readouts .

DATA MINING IN METABOLOMICS

To capture disease-specific metabolic signatures, many studies, including the case studies described above, primarily explored the multiple molecular constituents (metabolites), robustly managed variability and heterogeneity of disease progression, and defined the individuality of metabolic contents, which could lead to well-defined diagnoses and prognoses. In this context, multivariate statistics such as principal component analysis (PCA) or partial least squared algorithm is a useful data mining tool that can distinguish different groups with minimized loss of information . By this nature, unidentified variation sources caused by transient (time-course) or individual specificity can be handled within the reconstructed statistical model, which in turn offers more robust candidates for diagnostic/prognostic information in clinical cases (Fig. 4).

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Reconstructed metabolic network for systematic screening of therapeutic target point. The re-modeled metabolic structure is composed of metabolites, which consist of node (e.g. metabolite) and edge (e.g. correlation, structural similarity). The model may be extended to protein information via reaction pair that has already been built in the assembly, which could unravel “hidden” or veiled metabolic modulation, particularly in chronic disease. In this example, node color and size indicate significant differences and fold change compared to control (e.g. disease vs control), while edge presents two layers of information on structural similarity and reaction likelihood, which leads to automatic rearrangement as seen in the figure indicating proximity of biochemical module.

In many studies, the metabolomic approach has been limitedly applied to biomarker discovery with either a single target or a group of metabolites. Yet, an ideal exploratory use of the technology would not only be able to capture the metabolite changes associated with pathology, but it would also elucidate the molecular mechanism responsible for the dysfunction and propose the logical candidate for regulating the abnormality. Pathway (enrichment) analysis, a systematic approach for data mining from metabolite sets, can provide metabolic pathway-wise information rather than the readouts of an individual or few metabolite contents . This bioinformatics tool, which is rooted in gene ontology enrichment analysis, assigns groups of metabolites at the level of the metabolic pathway. The analysis provides a P value that presents significant differences at the levels of metabolic pathways and information on pathway centrality (pathway importance), which demonstrates how much connectivity is formed surrounding the metabolites of interest in the pathway . The output can be further investigated for a mechanistic understanding of the disease, and it can be applied for targeting and controlling the functional points of the disease process. However, although metabolic signatures can be identified at the level of either single molecule, groups of metabolites, or metabolic pathways, metabolite assessment cannot by itself provide a complete understanding of the disease process. To gain comprehensive causality and mechanism in given experimental designs, the integrative analysis should be accompanied by other molecular information such as mRNA expression levels and protein abundances . Since metabolomics joins systems with biology, mRNA has been the first partner for integrative analysis mainly due to the well-establishment of technical platforms and advancements in statistical analysis. However, the expression level of mRNA showed a low correlation with enzyme activity and protein expression levels, which is a direct molecular companion with metabolites, the substrate, and products. Thus protein information is the more suitable counterpart of metabolite readout .

Most importantly, in order to have molecular information (mRNA, protein, and metabolite) located at the cornerstone of clinical application, various types of molecular levels should be linked to physiological traits (e.g. clinical parameters) in a statistically sound manner. This has been mainly done by ‘qualitative’ assessment in which the final readout of molecular behaviors is linked to logical phenotypes of disease. For example, aberrant glycolytic activity can be associated with tumor metabolism, in which glycolytic intermediates and key enzymes are overexpressed in tumor cells. But in the case of chronic disease, we may not be able to detect “the standardized feature” like cancer metabolism case. Alternatively, we can track and correlate the quantitative traits of pathology with molecular dynamics, which can bear the variability caused by individuality and differential disease progress. One relevant statistical approach is canonical correlation analysis (CCA), which has been often applied in psychological, climate, and ecological studies to enumerate the correlations between two distinct data sets measured on identical experimental units . These statistics can analyze significant relations between two different datasets (e.g. metabolite contents and the associated clinical parameters). It is similar to PCA, in the way that CCA seeks linear combinations of the variables to reduce the dimension of the data sets; but at the same time, it explores to maximize the correlation between the two variates .

CONCLUDING REMARKS

Because single cortisol assessments are strongly affected by the acute context of the measurement situation (time of day, day of the week, and other circumstances such as distress for blood sampling), the assessment of long-term cortisol secretion from the biological fluids, such as blood, urine, and saliva, is highly labor-intensive and rather difficult to be implemented in physical and psychological studies. Hair growth patterns also vary across different regions of the scalp, and the precise mechanisms of substances incorporating into hair are still incompletely understood. But a growing observation supports the notion that hair cortisol analysis provides a valid and reliable reflection of long-term cortisol secretion . We mainly discussed about the advantages of hair analysis as an index of chronic cortisol response. Due to their association with various aspects of biochemical stress in adrenal steroids and other steroid metabolites, the advantages of hair analysis may not only be restricted to cortisol . Further research on establishing the reference values of hair cortisol may be needed to enhance the current knowledge on particular aspects of chronic stress and other metabolic changes in many endocrine diseases.

Source:  ncbi.nlm.nih.gov ~ By: Do Yup Lee, Eosu Kim, and Man Ho Choi ~ Image: ncbi.nlm.nih.gov

How to Not Stress Over Cortisol

How to Not Stress Over Cortisol

Cortisol is the “stress hormone” with a bad rap. Most people think of it as the evil villain within the body. It’s associated with weight gain, less muscle, and a compromised immune system. But is there anything you can do about it? Digging in a little deeper, you’ll learn that, yes, you can. And—in recognition of April as National Stress Awareness Month—we’ll break down here what to do.

To start with, it’s important to understand why the body makes cortisol in the first place. Cortisol is a hormone produced by the adrenal gland that is released in response to physical and mental stress. Its purpose is to help mobilize fuel to better feed the body during times of stress, and to signal the immune system to stop responding to inflammation. For this reason, cortisol shots are commonly prescribed to control allergic reactions, arthritis, and other inflammatory conditions.

Cortisol levels also fluctuate throughout the day. In fact, cortisol levels that are variable indicate the endocrine system is responsive and healthy. If the body lost its ability to respond to stress, severe health consequences would result.

When Not to Worry

Healthy cortisol levels are important for the body to respond to stressors and put it on high alert when something unexpected happens.  When the body is experiencing some sort of problem or trauma, the first response is inflammation. Think of when you jam your finger or bump your knee. It gets swollen and inflamed. This is caused by the rush of blood to the area of injury to deliver important nutrients that aid in the healing process. But you don’t want that inflammation to last forever and this is where cortisol comes in. Cortisol is one of the hormones released by the body to turn inflammation off and get things back to business as usual (1). Without cortisol, chronic inflammation would result, leading to increased disease risks such as inflammatory bowel disease or autoimmune disorders.

Another role of cortisol is to direct pathways in the body to provide fuel when there is not enough glucose present in times of stress. For example, let’s say a dog chases you down the street. Cortisol helps you get the fuel you need quickly to run away. Fast. Or, cortisol can be useful for that super hard leg workout in the gym. In these instances, the body draws amino acids from muscle and converts them to energy through a process known as gluconeogenesis (2). Without cortisol’s effect on directing fuel usage, the body would not be able to function efficiently.

When Cortisol Goes Bad

Now for the other side of the cortisol coin: When levels are chronically elevated, cortisol begins to function in ways that are outside of the norm. The thing with stressors in life is that they come in multiple forms. Some produce a “fight or flight” type of response and exist in the short term. But others like continuous psychological stress could lead to continually elevated cortisol. That is when cortisol turns bad and could lead to serious health consequences including muscle loss, insulin resistance, and cardiovascular risk factors (3, 4).

Keeping Cortisol in Check

When it comes to cortisol, it’s all about finding a healthy balance. Here are four tips for keeping cortisol in check:

1. Exercise, then eat carbs. Intense exercise can increase cortisol levels as much as 50 percent (2). But that doesn’t mean you shouldn’t hit the gym. Regular physical activity has significant benefits for your health, including long-term stress reduction. Consuming carbohydrates just before, during, and/or after an intense workout helps mitigate the cortisol response. When carbohydrates are supplied in the diet—such as from e+ before a workout or Want More Energy? during a workout—the body doesn’t need to produce its own sugar so there is no increase in cortisol or accompanied breakdown in muscle. By eating protein along with a source of carbohydrates during and directly after exercise, cortisol and muscle breakdown decrease, and muscle growth and glycogen repletion increase (5, 6).

2. Add Adaptogens. Priming your body with Adaptogens can help strengthen its capacity to resist and reduce stress. Adaptogens—such as ashwagandha, eleuthero, and wolfberry—are unique plants that have been studied for their abilities to act as metabolic regulators and support mental and physical performance. To supply your body with stress-fighting Adaptogens, reach for any of the Isagenix products with potent blends of Adaptogens: Ionix Supremee+, or t+ Chai.

3. Meditate. Psychological stress not only affects our minds but can also have an impact on telomeres, the biological markers of aging within our cells. Chronically elevated levels of stress hormones including cortisol could lead to shortened telomeres and accelerated aging. To mitigate physiological stress, try meditation, which has been shown in studies to ease mental stress and protect telomere length (7). For further protection of telomeres, also add Ageless Essentials with Product B to your regimen.

4. Sleep. Quality sleep is remarkable in its role in body maintenance and renewal. When you’re sleeping, the body is going to work on itself, building and mending. But when you don’t get enough quality sleep, stress hormones including cortisol can become elevated leading to a suppressed immune system (8). Focus on getting seven to nine hours of quality sleep each night to support healthy cortisol levels.

With these tips, there’s no need to worry over cortisol—that might just run cortisol levels up higher. Instead, remember that cortisol is not necessarily the bad guy; in fact, we need it to survive. It’s just important to keep the hormone levels in check by following a healthy diet and lifestyle.

Source: isagenixhealth.net ~ Image: isagenixhealth.net

6 Ways To Communicate With More Authority

6 Ways To Communicate With More Authority

It takes courage to voice your ideas and stick up for them. These tips can help.

Hierarchy is disappearing in many companies, and that’s opening the door for employees at every level to contribute–and even lead. The trouble is, many of us haven’t picked up the skills we need to make our voices heard. These six tips can help you get comfortable with communicating with more authority across your entire organization and even outside it.

1. DECIDE ON YOUR CONVICTIONS

It takes some courage to share your ideas at work. Especially if the goal is to influence people outside your immediate team, including those you don’t have any power over—your boss, a senior executive, a prospective client, you name it—you might feel like you’re stepping out of line.

But consider this: The word “courage” includes the Latin root “cor,” meaning “heart.” Don’t share ideas or beliefs that aren’t heartfelt. You need to have a strong conviction in your ideas before asking others to consider them. But if you believe you have a contribution to make, go for it!

2. DON’T HEDGE

Once you’ve decided that the point you have to make is worthwhile, state it boldly, clearly, and confidently. Never lead with an apology (“I’m sorry if I’m saying something you already know”), introduce caveats (“I’m not sure about this, but let me give it a try”), insert tentative language (“It could be that . . . “; “My best guess is . . . ”), fill in the background information first.

Get right to your point. Clarity and directness give you power and authority, especially when you’re trying to communicate with higher-level leaders.

3. STAND YOUR GROUND

Defend your ideas if it turns out that you need to. It may be tough to stand up to dissenting views, particularly if the opposition comes from people more senior than you. But remember that the ideas most worth sharing are likely to be at least a little controversial. So when you say something new, expect to be challenged, then rise to the occasion by showing why you’ve taken your position.

When you do respond, be careful not to be defensive or aggressive–that will only make you look less confident and undermine your message. Instead, acknowledge the other person’s point of view, and succinctly, politely explain why you see things differently. Remember that every challenge gives you an opportunity to reaffirm your point. Welcome it as an opportunity.

4. BE WILLING TO CHALLENGE OTHERS

I’ve coached leaders at all levels, and often senior officers tell me that they value thoughtful input that sparks dialogue—they like it when people challenge each other and share contrary views. “That’s what we’re paying them for,” one CEO told me. “We want their best ideas.”

So when you bring critical thinking to the table, do it in a collaborative spirit. When you challenge a plan, don’t just say, “You’re wrong” or “I disagree.” Instead, say, “I understand where you’re coming from, but let’s take your logic one step further.” Or ask, “Could we achieve the same goal more cost-effectively, by . . .” That dialogue builds better solutions than either staying quiet or getting combative.

5. ALWAYS SHOW RESPECT

It takes courage to communicate in the same open, confident way to everyone. Most of us are conditioned to address people differently, according to their relative authority. So keep that in mind. Don’t talk to senior leaders sycophantically. Phrases like “with all due respect” or “to be honest” sound condescending. By the same token, don’t let executives take over the conversation or silence you. There’s always a temptation to defer to those who have more power than you. But they won’t respect you for that. Ultimately, the best way to show respect for upper-level managers is by sharing your best ideas with them.

And when you address those less senior to you, show an equal degree of respect. Listen to them carefully, acknowledge their views, and build on their ideas wherever you can. Communicating forcefully isn’t possible if it doesn’t come from a place of respect, no matter where it’s directed.

6. BE AUTHENTIC

Finally, it can take extraordinary courage simply to be yourself while you’re sharing your ideas, especially if you work in a company on a team where you aren’t necessarily seen as someone to voice your views.

Sometimes that isn’t always personal–it’s cultural. As you look around at your peers, you might feel there’s a normal way of dressing, speaking, looking, and acting. There’s no need to resist corporate culture in your effort to become a more powerful communicator.

But you also need to have the courage to preserve your spontaneity, creative energy, vitality, and sense of humor. Suppressing those qualities won’t serve you, your message, or your company.

Source: fastcompany.com ~ By: JUDITH HUMPHREY ~ Image: Canva Pro

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