CALCIUM STUDIES

Calcium calming effect
Calcium acts as a natural tranquilizer in our bodies. It has a calming effect on our nerves which in turn has a calming effect on our muscles helping to reduce chronic pain, especially pain associated with injuries that would traditionally require physical therapy.
Understanding Pain Caused by Calcium Deficiency | Be Free From …
www.freefrompaintoday.com/understanding-pain-caused-by-calcium-deficiency/
Was this helpful?

3 SURPRISING THINGS ABOUT CALCIUM - Mental Health Food
https://mentalhealthfood.net/3-surprising-things-about-calcium
Nov 06, 2014 · Calcium is one of Nature’s sedatives with calming and relaxing effects. It has recently been shown to be significantly more effective than acetaminophen in long-term pain reduction in orthodontic treatment. So, in addition to relaxation and stress relief, calcium …

Comparison of the efficacy of calcium versus acetaminophen ...
https://www.ncbi.nlm.nih.gov/pubmed/23422605
In the calcium group 9.5% and in the acetaminophen group 15.8% had anxiety that was not statistically significant (P=0.631). In both groups, no subject had depression. CONCLUSION: Calcium is more effective than acetaminophen in long-term pain reduction during orthodontic treatment.
Author: Soghra Yassaei, Alireza Vahidi, Farnaz Farahat
Publish Year: 2012

Excess Calcium Causes Inflammation - The Shocking Truth

https://juicing-for-health.com/excess-calcium-causes-inflammation

Mar 05, 2016 · In some cases, people have to take twice the amount of magnesium as calcium to undo the damage from calcium buildup, drug intake, stress and consequent inflammation in the body. Just as calcium causes inflammation, magnesium is an anti-inflammatory agent that reverses the inflammation.

3 SURPRISING THINGS ABOUT CALCIUM
Posted by admin on Nov 6, 2014 in Anti-Anxiety, Anti-Depressant, Food-Mood Connection | 9 comments
blog-post-1-1

CALCIUM DEFICIENCY IS STRONGLY LINKED TO DEPRESSION

Most of us know that calcium is important for strong teeth and bones. Your heart, muscles and nerves also need calcium to function properly. One thing that may come as a surprise is that calcium is important for regulating our mood.

Calcium is one of Nature’s sedatives with calming and relaxing effects. It has recently been shown to be significantly more effective than acetaminophen in long-term pain reduction in orthodontic treatment. So, in addition to relaxation and stress relief, calcium also provides relief from pain.

People who have depression and anxiety have been found to be deficient in calcium. A negative association was found in middle-aged Korean women between dietary intake of calcium and depression; the less calcium they consumed in their diets, the more depressed they were.

YOU NEED FAT TO ABSORB CALCIUM

Calcium needs to be consumed along with fat in order to be utilized by the body. One of the consequences of “low fat” diets is the body can’t use the calcium from fat-free foods. For instance, while cow’s milk is a good source of calcium, the calcium in skim milk is essentially wasted unless you add some other source of fat at the same time. If, along with your skim milk, you ate a piece of toast with butter, you would be able to absorb and use the calcium. But in the absence of fat, no matter how much calcium is listed on the label, you aren’t getting any of it! It’s better to drink milk with at least 1% milkfat to utilize the calcium.

CALCIUM ISN’T ONLY IN DAIRY PRODUCTS

Of course milk and cheese are excellent sources of calcium but so are dark leafy greens like kale, turnip greens and collards. Almonds are also high in calcium, making almond milk a good alternative to cow’s milk for calcium. Almonds and almond milk also naturally contain fat so the calcium is readily available. A variety of fruits are also good sources of calcium including oranges and strawberries.

An adult needs around 1000 mg of calcium each day. I include dark leafy greens in my diet every day, either in green smoothies in the morning, salad at lunch, or cooked greens with dinner or all three! I include a teaspoon of flax oil with my greens, in my smoothies, salad dressing and squirted directly on cooked greens to insure good calcium absorption and a powerpunch of omega 3’s! Flax oil has a sweet, nutty taste and is the perfect compliment to dark leafy greens. Sauteing dark green leafy vegetables in olive oil will also provide the oil needed to get the calcium benefit as well as other fat soluble nutrients like vitamins A, E, and K.

Some sources of calcium:

Dairy products like milk, yoghurt, and cheese
Dark leafy greens
Sardines
Flax seeds
Almonds
Soy products like soybeans, soy milk, and tofu
Sesame seeds
Brazil nuts
Many common cooking herbs, especially savory

Calcium is a key player in both depression relief and stress reduction, working closely with magnesium, vitamin D, potassium and other nutrients to maximize its benefits. Foods that are high in calcium tend to also be good sources of potassium, magnesium, and so forth, because all of these nutrients work together. The best way to ensure consuming adequate amounts of calcium, along with the other nutrients calcium needs to do its job properly, is to eat a wide variety of whole, healthy foods including dairy products, almonds, and dark green leafy vegetables.

Very few people recognize that calcium is a building block for our entire planetary system, but most people understand the value of calcium for our bodies. The greatest function of calcium in the body is its work with phosphorus to build and maintain healthy strong bones and teeth. The calcium state in our bodies and more specifically our bones is constantly fluctuating depending on our intake and our body’s needs. While many people understand what calcium means to bones and teeth, it is important to understand that our calcium also plays a role the soft tissues, intercellular fluids and blood meaning that it affects so much more and a deficiency in calcium could even be the problem behind your chronic pain.
The symptoms of calcium deficiency blend so well into our everyday lives that they often go unnoticed or at least don’t set off any alarms for greater attention. Often times people lacking in calcium will appear pale and listless, feel very tired and sort of come off as lazy. This behavior may be misunderstood as an illness rather than a deeper level problem. It isn’t uncommon for a simple calcium deficiency to become far more complex when it begins to cause heart palpitations, muscle cramps, insomnia, chronic pain and an overall feeling of discomfort associated with activity. These are actually the signs of a serious calcium deficiency.
Chronic pain and specifically leg pain can be a clear indication of calcium deficiency and is often an early sign of osteoporosis. Tetany is a nervous condition caused by calcium deficiency that is also characterized by muscle cramps, chronic pain, and numbness or tingling in your appendages. Additionally, calcium deposits can grow to a point where they interfere with muscles and create chronic pain with movement.
How Can Calcium Help With Your Pain?

Calcium acts as a natural tranquilizer in our bodies. It has a calming effect on our nerves which in turn has a calming effect on our muscles helping to reduce chronic pain, especially pain associated with injuries that would traditionally require physical therapy. Calcium therapy is a known treatment for various forms of arthritis and is an obvious treatment for tetany.
When looking at patients for treatment with our primal reflex release technique, we examine their diet and make suggestions to add calcium as well as its helpers phosphorus and vitamin D. As most of our clients are dealing with pain related to injuries that are muscular and ligature in nature, it is important that their bodies have the appropriate nutrients to help aid in the healing process after primal reflex release technique is administered.

Adding Calcium
foods with calcium for painCalcium is found in a variety of food. How much calcium our bodies absorb and how efficiently that absorption occurs is a job handled by the parathyroid gland. There are many dietary combinations that inhibit the absorption of calcium including things like caffeine, fatty acids, and fluoride. There are a variety of calcium supplements available and the average adult requires between 800 and 1000 milligrams of calcium a day. If you do choose to take supplements, then you should select one that is strictly a calcium supplement. Most multi-vitamins are not adequate sources of calcium as the calcium itself may block the absorption of other nutrients.
Obviously, there are many foods we can eat that are high in calcium and you’ll be happy to know that although tinned fish with bones is one of the best sources, a good old fashioned glass of 2% milk is almost a match with 297 milligrams of calcium. Other sources include yogurt, tofu, peanuts, cheese, and soybeans. You should always consult a physician before altering your diet or taking supplements of any kind and this especially true when you are looking for answers to chronic pain.

Calming Calcium and Magnesium
Posted November 11, 2019

Let’s talk about the calming effect of calcium and magnesium.
Is the impending holiday season stressing you out? The anticipation of spending time with relatives, the financial strain and the craziness that comes with it all. You need to relax, but it seems almost impossible. Let’s talk about the calming effect of calcium and magnesium.

Calcium is an essential nutrient for maintaining total body health. It’s necessary not just for keeping your bones and teeth strong, but also to ensure proper functioning of muscles and nerves. Calcium works in harmony with magnesium, but too much calcium can actually deplete your body’s supply of magnesium.

Calcium and magnesium work harmoniously together when the balance is correct. Calcium acts to excite nerves and is necessary for muscle contraction. Magnesium, on the other hand, calms nerves and is needed for muscle relaxation. Calcium makes bones stiff and hard, but magnesium is needed to avoid their becoming brittle.

You very tangibly experience the tensing (calcium) and relaxing (magnesium) interaction of these two elements each time your heart beats, when you feel your pulse, and every time you breathe.

When we are under stress, the balance of calcium and magnesium surrounding our cells gets out of whack. Calcium enters the cells and the calcium level temporarily becomes high. This is the tensing of muscles you feel as you’re getting worked up. Magnesium then saves the day by pushing the calcium out of the cell and the cell is again in its resting, relaxed state.

To maintain homeostasis – that is, the correct balance of calcium and magnesium – you need to ensure you aren’t magnesium deficient. Much emphasis has been placed on the importance of calcium, but not enough attention has been called to magnesium. Magnesium helps your muscles function properly; it keeps your heart rhythm steady and supports a healthy immune system. This essential mineral helps regulate blood sugar levels, promotes normal blood pressure and is required for producing and storing energy.

Unfortunately, many of us are magnesium deficient. According to population studies of average magnesium intake, less than 30 percent of US adults consume the Recommended Daily Allowance (RDA) of magnesium and nearly 20 percent get only half the magnesium they need daily.

So, if you’re having a hard time calming down, chances are your calcium and magnesium levels are out of whack and not working together properly. You should consider taking a high-quality calcium magnesium supplement.

Indian J Dent Res. 2012 Sep-Oct;23(5):608-12. doi: 10.4103/0970-9290.107349.
Comparison of the efficacy of calcium versus acetaminophen on reduction of orthodontic pain.

Yassaei S1, Vahidi A, Farahat F.
Author information
1
Department of Orthodontics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Abstract
BACKGROUND:
Pain and discomfort are common during orthodontic treatment.

AIM:
The aim of this single blind clinical trial was to compare the effectiveness of oral calcium versus acetaminophen in pain reduction.

MATERIALS AND METHODS:
In this study, the patients recorded their pain on a 100-mm visual analogue scale (VAS). Forty female patients (14-19 years old) who had passed at least 2 months of their first orthodontic archwire placement and their pain intensity was 40-100 mm (VAS) were selected and randomly assigned to two groups. Psychotic status was measured using Hospital Anxiety and Depression Scale (HADS). In group 1 calcium forte tablets (500 mg) and in group 2 acetaminophen (325 mg) tablets were prescribed to be taken one tablet per day. After consumption of all tablets (n=60), pain intensity was measured and compared with that before drug therapy.

RESULTS:
The results indicated that the difference in pain intensity before and after drug administration in the calcium group was statistically significant (P<0.001), but not significant in the acetaminophen group (P=0.468). The difference between the pain reduction in the two groups were also statistically significant (P<0.001). In the calcium group 9.5% and in the acetaminophen group 15.8% had anxiety that was not statistically significant (P=0.631). In both groups, no subject had depression.

CONCLUSION:
Calcium is more effective than acetaminophen in long-term pain reduction during orthodontic treatment.

PMID: 23422605 DOI: 10.4103/0970-9290.107349
[Indexed for MEDLINE] Free full text

Semin Cell Dev Biol.

Semin Cell Dev Biol. 2016 Jan;

The Role of the Calcium-Sensing Receptor in Gastrointestinal Inflammation

Jennifer L. Owen,a Sam X. Cheng,b Yong Ge,c,d Bikash Sahay,c,d and Mansour Mohamadzadehc,d,*
Author information Copyright and License information Disclaimer
aDepartment of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, USA
bDivision of Gastroenterology, Department of Pediatrics, University of Florida, Gainesville, FL, USA
cDepartment of Infectious Diseases and Pathology, University of Florida, Gainesville, FL, USA
dDivision of Hepatology, Gastroenterology, and Nutrition, University of Florida, Gainesville, FL, USA

In addition to its expression within bones, kidney, and parathyroid gland, the CaSR can be found in the lung, breast, liver, placenta [], throughout the vasculature, and in the gut.

Abstract
The gastrointestinal (GI) tract must balance the extraction of energy and metabolic end-products from ingested nutrition and resident gut microbes and the maintenance of a symbiotic relationship with this microbiota, with the ability to mount functional immune responses to pathogenic organisms to maintain GI health. The gut epithelium is equipped with bacteria-sensing mechanisms that discriminate between pathogenic and commensal microorganisms and regulate host responses between immunity and tolerance. The epithelium also expresses numerous nutrient-sensing receptors, but their importance in the preservation of the gut microbiota and immune homeostasis remains largely unexplored. Observations that a deficiency in the extracellular calcium-sensing receptor (CaSR) using intestinal epithelium-specific receptor knockout mice resulted in diminished intestinal barrier integrity, altered composition of the gut microbiota, modified expression of intestinal pattern recognition receptors, and a skewing of local and systemic innate responses from regulatory to stimulatory, may change the way that this receptor is considered as a potential immunotherapeutic target in gut homeostasis. These findings suggest that pharmacologic CaSR activators and CaSR-based nutrients such as calcium, polyamines, phenylalanine, tryptophan, and oligo-peptides might be useful in conditioning the gut microenvironment, and thus, in the prevention and treatment of disorders such as inflammatory bowel disease (IBD), infectious enterocolitis, and other inflammatory and secretory diarrheal diseases. Here, we review the emerging roles of the CaSR in intestinal homeostasis and its therapeutic potential for gut pathology.

The extracellular calcium-sensing receptor (CaSR) is extremely multifaceted due to its ability to participate in various different signaling pathways that are ligand and tissue specific, enabling this receptor to play a variety of critical roles in the physiology and pathophysiology of both calcium regulation and other cellular functions which appear unrelated to calcium homeostasis [25]. First identified in 1993 by Brown et al., the CaSR was the first heptahelical guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) that was identified as having an ion, Ca2+, as its physiological ligand. The main function of the CaSR is the control of the concentration of extracellular free ionized Ca2+ (Ca2+o) by regulating parathyroid hormone (PTH) secretion from chief cells of the parathyroid glands [26, 27]. More recent evidence suggests that the CaSR located in intestinal epithelial cells may also regulate calcium absorption by modifying responsiveness to 1,25-dihydroxyvitamin D3 (the hormonally active form of Vitamin D) independently of PTH [28].

2. 观测中缺乏细胞外calcium-sensing受体(CaSR)使用肠道epithelium-specific受体基因敲除小鼠导致减少肠道屏障的完整性,改变肠道微生物群组成,修改的肠道模式识别受体的表达,和扭曲的地方和系统性先天从监管到刺激的反应。

3.药理学CaSR活化剂和CaSR-based营养素,如钙,多胺,苯丙氨酸,色氨酸,和oligo-peptides可能是有用的在调节肠道微环境,因此,预防和治疗的疾病,如炎症性肠病(IBD),感染小肠结肠炎和其他炎症和分泌性腹泻疾病。

5. 5. 事实上，上述任何特征的结构改变和/或改变都与炎症性肠病(IBD)或胃肠道慢性炎症(GI)的发展密切相关，包括克罗恩病和溃疡性结肠炎[5]。

细胞外calcium-sensing受体(CaSR)非常多方面的因其能够参与各种不同的配体和组织特定的信号通路,使这种受体发挥关键角色的各种生理和病理生理学的监管和其他细胞功能出现钙与钙稳态[25]。CaSR最早于1993年由Brown等人鉴定，它是第一个被鉴定为具有离子Ca2+作为其生理配体的七螺旋鸟嘌呤核苷酸结合蛋白(G蛋白)偶联受体(GPCR)。CaSR的主要功能是通过调节甲状旁腺主要细胞分泌的甲状旁腺激素(PTH)来控制细胞外游离离子Ca2+ (Ca2+o)的浓度[26,27]。最近的证据表明，位于肠上皮细胞的CaSR也可能通过改变对1,25-二羟维生素D3(维生素D的激素活性形式)的反应而不依赖于PTH[28]来调节钙吸收。

The role of the CaSR in secretory diarrhea and colitis
To accomplish its functions, the normal colonic mucosa is organized as a sheet of epithelial cells with invaginations forming stereotypical crypts, which make up about 90% of the epithelial mass of the colon. Each crypt contains distinct functional compartments with stem cells at the base that are responsible for continuous renewal of aged epithelial cells, a proliferating transit amplifying zone extending to the mid crypt, and the most mature epithelial cells located at the crypt apex [63]. Under baseline conditions (in the absence of drugs, hormones, or other factors), the net fluid transport by colonic crypts is absorptive in nature. However, upon exposure to cell-permeable cyclic AMP (cAMP) analogs, forskolin (an herbal extract commonly used to raise levels of cyclic AMP in the study of cellular physiology isolated from Coleus forskohlii, a plant belonging to the mint family) or other agents that activate adenylate cyclase, or modifiers of cAMP metabolism such as phosphodiesterase (PDE) inhibitors, crypts change the direction of net fluid transport from absorption to secretion [41, 64]. The addition of cAMP-generating hormones/factors such as 5-hydroxytryptophan (5-HTP) or prostaglandin E2 (PGE2) to the blood/interstitial surface of the crypt epithelium also upregulates fluid secretion in the colon [65, 66]. When cyclic nucleotides (cAMP or cGMP) modulate these fluid transport processes, profound fluid and electrolyte losses from the colon with secretory diarrheas, such as cholera [66] result [41].

Using established CaSR agonists, Ca2+o, gadolinium (Gd3+), and the antibiotic, neomycin, it has recently been found that both apical and basolateral CaSRs on crypt cells from proximal and distal colonic sections excised from rats and human biopsy specimens were functionally active [49]. In rat distal colonic epithelial cells, increasing Ca2+o generated intracellular D-myo-inositol 1,4,5-trisphosphate (IP3) and Ca2+, “typical” CaSR second messengers, and significantly attenuated forskolin-stimulated net fluid secretion. These experiments demonstrated pathways modulating net intestinal fluid transport that could have important implications for the prevention and treatment of certain diarrheal diseases associated with elevated cAMP, such as cholera [49].

CaSR在分泌性腹泻和结肠炎中的作用

为完成其功能，正常结肠粘膜被组织成一层上皮细胞，内陷形成典型隐窝，约占结肠上皮肿块的90%。每个隐窝都有不同的功能隔间，其中位于基部的干细胞负责老化上皮细胞的持续更新，增殖的转运扩增带延伸至隐窝中部，最成熟的上皮细胞位于隐窝顶[63]。在基线条件下(在没有药物、激素或其他因素的情况下)，结肠隐窝的净液体运输本质上是吸收性的。然而,在接触cell-permeable环腺苷酸(营)类似物,forskolin(一个草本提取物通常用于提高环腺苷酸水平研究细胞生理隔绝锦紫苏forskohlii,植物属于薄荷家族)或其他代理激活腺苷酸环化酶,或修饰符营地代谢如磷酸二酯酶(PDE)抑制剂,隐窝改变净流体运输的方向从吸收分泌[64]。在隐窝上皮的血液/间质表面添加camp生成激素/因子，如5-羟色氨酸(5-HTP)或前列腺素E2 (PGE2)，也会上调结肠中的液体分泌[65,66]。当环核苷酸(cAMP或cGMP)调节这些液体运输过程时，结肠中深层液体和电解质的损失会导致分泌性腹泻，如霍乱[66]，从而导致[41]。

使用已建立的CaSR激动剂，Ca2+o，钆(Gd3+)和抗生素，新霉素，最近发现，从大鼠和人类活检标本中摘取的近端和远端结肠隐埋细胞的根尖和基底外侧CaSRs都具有功能活跃的[49]。在大鼠远端结肠上皮细胞中，Ca2+o的增加产生细胞内d -肌醇1,4,5-三磷酸(IP3)和Ca2+，“典型”CaSR第二信使，并显著减弱福斯科林刺激的净液体分泌。这些实验证明了调节肠道净液运输的途径，这可能对预防和治疗某些与cAMP升高相关的腹泻疾病，如霍乱[49]具有重要意义。

7. Summary and future perspectives
Acute infectious diarrhea remains the number one cause of deaths in children around the world, even before the recent Ebola virus outbreak. It is estimated that 1.3 million children die each year, not due to infection per se, but as a result of the associated diarrhea and dehydration [90–92]. Although it is valuable for correcting dehydration, oral rehydration solution does not “halt” intestinal fluid loss and thus, does not reduce the severity or duration of diarrhea. It also does not treat the inflammatory component of diarrhea, and its use in treating diarrhea has dropped significantly by medical practitioners [93]. Diarrhea can be pathologically grouped into two types: secretory (as seen in cholera, travelers’ diarrhea, and rotavirus) and inflammatory (as observed in enterocolitis caused by Salmonella and Shigella, as well as IBD). The CaSR is expressed along the majority of the GI tract and also on inflammatory cells, as well as other cells that regulate inflammatory diarrhea [94, 95], suggesting a potential protective role in this setting.

Since emerging evidence has shown the importance of intestinal barrier function in maintaining gut immune homeostasis, increased efforts and investment in developing strategies by which to manipulate epithelial innate immunity and permeability have been made in order to achieve therapeutic effects in human disease. Presently, a number of approaches have been made and/or proposed to improve intestinal barrier function using several different strategies [23]. Such drug development targeting the CaSR could enhance epithelial innate immunity, gut homeostasis, decrease the permeability of the epithelial barrier, and/or decrease the likelihood of gut dysbiosis that can lead to or exacerbate IBD, infectious colitis, and secretory diarrhea. In particular, it will be critical to explore the role of innate and adaptive immune cells and the effects of the CaSR on their ability to protect the gut.

7. 总结与未来展望

即使在最近埃博拉病毒爆发之前，急性传染性腹泻仍然是全世界儿童死亡的头号原因。据估计，每年有130万儿童死亡，不是因为感染本身，而是因为相关的腹泻和脱水[90-92]。虽然口服补液对纠正脱水有价值，但口服补液不能“停止”肠道液体的流失，因此，不能减轻腹泻的严重程度或持续时间。它也不治疗腹泻的炎症成分，其用于治疗腹泻的使用量已明显下降[93]。从病理学上可将腹泻分为两种类型:分泌性(如霍乱、旅行者腹泻和轮状病毒)和炎性(如由沙门氏菌、志贺氏菌和IBD引起的肠炎)。CaSR在胃肠道大部分区域表达，也在炎症细胞以及其他调节炎症腹泻的细胞上表达[94,95]，这表明CaSR在这种情况下具有潜在的保护作用。

由于新出现的证据显示肠屏障功能在维持肠道免疫稳态中的重要性，为了达到对人类疾病的治疗效果，人们加大了努力和投资，以制定控制上皮先天免疫和通透性的策略。目前，人们已经提出了几种不同的改善肠屏障功能的方法。这种以CaSR为靶点的药物开发可以增强上皮固有免疫、肠道稳态、降低上皮屏障的通透性和/或降低肠道生态失调的可能性，肠道生态失调可导致或加剧IBD、感染性结肠炎和分泌性腹泻。特别是，探索先天免疫细胞和适应性免疫细胞的作用以及CaSR对它们保护肠道能力的影响将是至关重要的。

Keywords: calcium-sensing receptor, diarrhea, intestinal inflammation, intestinal permeability, microbiota, polyamines

Involvement of calcium-sensing receptor activation in the alleviation of intestinal inflammation in a piglet model by dietary aromatic amino acid supplementation

Hongnan Liu (a1) (a2), Bie Tan (a1), Bo Huang (a1) (a3), Jianjun Li (a1) ...
Cambridge University Press: 30 October 2018

Abstract
Ca2+-sensing receptor (CaSR) represents a potential therapeutic target for inflammatory bowel diseases and strongly prefers aromatic amino acid ligands. We investigated the regulatory effects of dietary supplementation with aromatic amino acids – tryptophan, phenylalanine and tyrosine (TPT) – on the CaSR signalling pathway and intestinal inflammatory response. The in vivo study was conducted with weanling piglets using a 2 × 2 factorial arrangement in a randomised complete block design. Piglets were fed a basal diet or a basal diet supplemented with TPT and with or without inflammatory challenge. The in vitro study was performed in porcine intestinal epithelial cell line to investigate the effects of TPT on inflammatory response using NPS-2143 to inhibit CaSR. Dietary supplementation of TPT alleviated histopathological injury and decreased myeloperoxidase activity in intestine challenged with lipopolysaccharide. Dietary supplementation of TPT decreased serum concentration of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, IL-12, granulocyte-macrophage colony-stimulating factor, TNF-α), as well as the mRNA abundances of pro-inflammatory cytokines in intestine but enhanced anti-inflammatory cytokines IL-4 and transforming growth factor-β mRNA levels compared with pigs fed control diet and infected by lipopolysaccharide. Supplementation of TPT increased CaSR and phospholipase Cβ2 protein levels, but decreased inhibitor of NF-κB kinase α/β and inhibitor of NF-κB (IκB) protein levels in the lipopolysaccharide-challenged piglets. When the CaSR signalling pathway was blocked by NPS-2143, supplementation of TPT decreased the CaSR protein level, but enhanced phosphorylated NF-κB and IκB levels in IPEC-J2 cells. To conclude, supplementation of aromatic amino acids alleviated intestinal inflammation as mediated through the CaSR signalling pathway.

Involvement of calcium-sensing receptor activation in the ...

https://www.cambridge.org/core/journals/british-journal-of-nutrition/article...

Oct 30, 2018 · Ca 2+ -sensing receptor (CaSR) represents a potential therapeutic target for inflammatory bowel diseases and strongly prefers aromatic amino acid ligands.

Frontier Immunology, 10 March 2020 |
The Role of Calcium–Calcineurin–NFAT Signaling Pathway in Health and Autoimmune Diseases

Calcium (Ca2+) is an essential signaling molecule that controls a wide range of biological functions. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca2+ store and then activates store-operated Ca2+ entry (SOCE) to raise the intracellular Ca2+ concentration, which is mediated by the Ca2+ release-activated Ca2+ (CRAC) channels. Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca2+ signaling in lymphocytes. Repetitive or prolonged increase in intracellular Ca2+ is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT). Recent data indicate that Ca2+-calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases. Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis. Here, we review the role of the Ca2+-calcineurin–NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases.

Psoriasis
Psoriasis is a chronic inflammatory skin disease characterized by various sized thick scaly erythematous plaques (108). The histopathology of psoriatic plaques shows epidermal proliferation and inflammation of the dermis (109). Both innate and adaptive immune cells, including keratinocytes and T cells, participate in the initiation and perpetuation of psoriasis (58, 110). Psoriasis is a well-established T cell-mediated skin disease (110, 111). In particular, various cytokines induce the activation of immune cells, particular Th1 and Th17 cells (111), and the functional imbalance of Th1 or Th17 over Tregs is considered a key pathway for the progression of psoriasis (111). For example, psoriatic skin lesions show a strong IFN-γ signature and have an abundance of IFN-γ (+) Th1 cells (112). An imbalance between Tregs and effector T (Teff) cells is observed in the peripheral blood of psoriasis patients (113). Moreover, the Tregs of psoriasis patients are functionally deficient in suppressing Teff cells (114). Recently, the association between IL-9 and the Th17 pathway has been reported in psoriasis. Expressions of IL-9 and IL-9R are markedly increased in psoriatic skin lesions (115), and IL-9 stimulates the production of IL-17A by CD4+ T cells isolated from patients with psoriasis (116).

It is well-established that calcineurin inhibitors suppress T cell activation and the differentiation of naive T cells to memory T cells (117). In particular, calcineurin inhibitors downregulate the expression of STAT1, IFN-γ, and several IFN-γ-downstream genes, repressing the generation of Th1 cells (118). Moreover, the expressions of IL-17, IL-22, and IL-17-inducible genes, including DEFB-2, LCN2, IL-1β, S100A12, and CCL20, are markedly suppressed by calcineurin inhibitors (119). Given the importance of Th1 and Th17 cells in psoriasis pathogenesis, the inhibition of the calcineurin–NFAT pathway seems to be therapeutically relevant to psoriasis. Interestingly, the actions of calcineurin inhibitors are not limited to T cells. NFAT1 expression was first described by Northrop et al. (120) in mice skin, and then calcineurin expression was subsequently reported in the human epidermis (121). Calcineurin inhibitors reduce antigen presentation by Langerhans' cells and suppress neutrophil chemotaxis through the inhibition of psoriatic monocytes (122). Epidermal IL-1 and IL-8 expressions in psoriatic skin can be blocked by the calcineurin inhibitor cyclosporine (123). Indeed, cyclosporine and tacrolimus, both calcineurin inhibitors, have been widely used in psoriasis treatment with high efficacy (124).

STIM1 and Orai1 in keratinocytes, CRAC channels, have been implicated in the proliferation and differentiation of keratinocytes. It has been demonstrated that keratinocyte differentiation is induced by the change of extracellular Ca2+ concentration (125). Increased extracellular Ca2+ concentration triggers phospholipase C-mediated intracellular Ca2+ signals, which activate SOCE. Moreover, siRNA-mediated knockdown of either STIM1 or Orai1 suppresses SOCE and almost completely abolishes the Ca2+-mediated keratinocyte differentiation and growth (125). Menon and Elias (126) reported a defective Ca2+ gradient in the keratinocytes of psoriasis patients. Keratinocytes isolated from psoriasis patients showed a decreased response after Ca2+ store depletion as well as reduced mRNA/protein expression of CRAC channels (127, 128). In line with these findings, another study reported reduced mRNA and protein expression of TRPC channels (128), and the incubation of keratinocytes isolated from psoriasis patients with the TRPC6 agonist partly restores their differentiation and proliferation defect (129). Therefore, it remains to be determined whether Ca2+ sensing and signaling pathway plays an inductive or protective role in the pathologic differentiation and proliferation of keratinocytes in psoriasis.

Taken together, the earlier reports indicate that Ca2+ sensing and signaling pathway can be an excellent target for the treatment of psoriasis. Currently, phase 1 of a clinical trial of CRAC channel inhibitor for plaque psoriasis is in progress. CRAC channel inhibitors, a new class of oral immunomodulatory drugs, potently inhibit Orai1, Th1, Th2, and Th17-derived cytokine production and T cell proliferation, which are involved in chronic inflammatory responses in psoriasis (130).

Excess Calcium Causes Inflammation - The Shocking Truth

Involvement of calcium-sensing receptor activation in the ...