ACE inhibitor- an important drugs to treat diabetes, hypertension, or congestive heart failure

ACE was found by Skeggs and colleagues, they reported in 1954–1956 that renin liberates a decapeptide Ang I, which is converted by a factor in horse plasma, to the active peptide to Ang II in presence of Cl−. They named this factor angiotensin converting enzyme(ACE). As we all know ACE inhibitors are important drugs with great benefit to our patients[1]

Which disease is treated by ACE inhibitors.

Early researcher Rochon.demonstrates improvement in clinical outcomes in elderly patients with heart failure who were treated with ACE inhibitors.This study reinforces and extends the known benefit of ACE inhibitors for congestive heart failure. The study’s conclusion of a causal relationship between the use of ACE inhibitors and improved outcome is strengthened by the dose-response relationship

low-dose treatment with ACE inhibitors can benefit prevent or delay diabetic nephropathy. The inclusion of ACE inhibitor therapy is an element of a combined aggressive approach shown to be effective in significantly reducing cardiovascular mortality and nephropathy in type 2 diabetes

Independent of their blood pressure lowering effect, ACE inhibitors are thought to reduce vascular inflammation[2]

Side effects induced by ACE inhibitors.

One side effects is ACE inhibitor-induced cough. The outcome of Morimoto research gives relative weights to various known associations with ACE inhibitor-induced cough, and help predict the likelihood that this adverse event will occur or recur if an ACE inhibitor is administered to a patient. with the possible exception of those who have previously developed ACE inhibitor-induced cough. The angiotensin receptor blockers (ARBs) are reasonable alternatives for patients who do develop ACE inhibitor-induced cough. Another side effects is coused by ACE inhibitors is mild renal dysfunction as the desired result of reducing intraglomerular pressure, thereby preventing damage if hypertension coexists with diabetes. A slight rise in serum creatinine is to be expected and is acceptable after starting an ACE inhibitor. If the serum creatinine rises more than 30% above baseline or progressively increases over time, the clinician should promptly discontinue the ACE inhibitor and consider renovascular disease or other conditions known to enhance ACE inhibitor nephrotoxicity. The recent research demonsted that more evidence that antihypertensive agents, particularly centrally acting ACE inhibitors (CACE-Is), which cross the blood-brain barrier, are associated with a reduced rate of cognitive decline[3]. The side effect perhaps caused by incorrect or insufficient dosing of ACE inhibitors. these agents are used for three different indications, and the therapeutic approach for each indication is different. In order to improve the delivery of this important treatment to our patients with diabetes, hypertension, or congestive heart failure, the clinical leadership in academic medical centers and affiliated sites, need to be role models in the proper use of these medications and tireless in teaching these concepts[4].

[1] Ervin G. Erdös, The ACE and I: how ACE inhibitors came to be. The FASEB Journal. 2006, 20(8),1034-1038 [2] Kortekaas KE, Meijer CA, Hinnen JW.ea al, ACE inhibitors potently reduce vascular inflammation, results of an open proof-of-concept study in the abdominal aortic aneurysm.PLoS One. 2014, 9(12) e111952 [3 ]Gao Y, O’Caoimh R, Healy L, et al, Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia. Kerins DM. BMJ Open. 2013 Jul 25;3(7) e002881 [4] Brent G Petty, The Place for ACE Inhibitors.J Gen Intern Med. 2004, 19(6): 710–711.

Cathepsin – a peptide about bone growth

Cathepsins (Ancient Greek kata- “down” and hepsein “boil”; abbreviated CTS) are proteases (enzymes that degrade proteins) found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes. Thus, the activity of this family lies almost entirely within those organelles. There are, however, exceptions such as cathepsin K, which works extracellularly after secretion by osteoclasts in bone resorption.

The earliest record of “cathepsin” found in the MEDLINE database (e.g.. via PubMed) is from the Journal of Biological Chemistry in 1949.[1] However, references within this article indicate that cathepsins were first identified and named around the turn of the 20th century. Much of this earlier work was done in the laboratory of Max Bergmann, who spent the first several decades of the century defining these proteases. [2] Probably word cathepsin have long been determined muscle enzymes active in the acidic environment. Already in 1937 the hemoglobin was using to determined the overall activity of cathepsins (Anson, 1937). First detected cathepsin was in the muscle of fish (Siebert, 1958), and later identified as cathepsin D (Mekinodan and Ikeda, 1969).

Cathepsins have a vital role in mammalian cellular turnover, e.g. bone resorption. They degrade polypeptides and are distinguished by their substrate specificities.

Deficiencies in this protein are linked to multiple forms of galactosialidosis. The cathepsin A activity in lysates of metastatic lesions of malignant melanoma is significantly higher than in primary focus lysates. Cathepsin A increased in muscles moderately affected by muscular dystrophy and denervating diseases.

Cathepsin B seems to actually break down the proteins that cause amyloid plaque, the root of Alzheimer’s symptoms, and may even be a pivotal part of the natural defense against this disease used by people who do not get it. Overexpression of the encoded protein, which is a member of the peptidase C1 family, has been associated with esophageal adenocarcinoma and other tumors. Cathepsin B has also been implicated in the progression of various human tumors including ovarian cancer. Cathepsin B is also involved in apoptosis as well as degradation of myofibrillar proteins in myocardial infarction.

Cathepsin D (an aspartyl protease) appears to cleave a variety of substrates such as fibronectin and laminin. Unlike some of the other cathepsins, cathepsin D has some protease activity at neutral pH.[3] High levels of this enzyme in tumor cells seems to be associated with greater invasiveness. Cathepsin K is the most potent mammalian collagenase. Cathepsin K is involved in osteoporosis, a disease in which a decrease in bone density causes an increased risk for fracture. Osteoclasts are the bone resorbing cells of the body, and they secrete cathepsin K in order to break down collagen, the major component of the non-mineral protein matrix of the bone.[2] Cathepsin K, among other cathepsins, plays a role in cancer metastasis through the degradation of the extracellular matrix.[1] The genetic knockout for cathepsin S and K in mice with atherosclerosis was shown to reduce the size of atherosclerotic lesions.[1] The expression of cathepsin K in cultured endothelial cells is regulated by shear stress.[3] Cathepsin K has also been shown to play a role in arthritis.

Mouse cathepsin L is homologous to human cathepsin V.[1] Mouse cathepsin L has been shown to play a role in adipogenesis and glucose intolerance in mice. Cathepsin L degrades fibronectin, insulin receptor (IR), and insulin-like growth factor 1 receptor (IGF-1R). Cathepsin L-deficient mice were shown to have less adipose tissue, lower serum glucose and insulin levels, more insulin receptor subunits, more glucose transporter (GLUT4) and more fibronectin than wild type controls.

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Reference [1] Nomura T, Katunuma N (February 2005). “Involvement of cathepsins in the invasion, metastasis and proliferation of cancer cells”. J. Med. Invest. 52 (1–2): 1–9. [2] Yamashima T (2013). “Reconsider Alzheimer’s disease by the ‘calpain-cathepsin hypothesis’–a perspective review”. PROGRESS IN NEUROLOGY 105: 1–23. [3] Salminen-Mankonen HJ, Morko J, Vuorio E (February 2007). “Role of cathepsin K in normal joints and in the development of arthritis”. Curr Drug Targets 8 (2): 315–23.

Calcitonin – a peptide associated with osteoporosis

Calcitonin (also known as thyrocalcitonin) is a 32-amino acid linear polypeptide hormone that is produced in humans primarily by the parafollicular cells (also known as C-cells) of the thyroid, and in many other animals in the ultimobranchial body.[2] It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).[3]

Calcitonin has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis. It belongs to the calcitonin-like protein family.

Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene. The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.

The hormone participates in calcium (Ca2+) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH).

More specifically, calcitonin lowers blood Ca2+ levels in four ways: Inhibits Ca2+ absorption by the intestines Inhibits osteoclast activity in bones Stimulates osteoblastic activity in bones. [3] Inhibits renal tubular cell reabsorption of Ca2+ allowing it to be excreted in the urine[9][10] However, effects of calcitonin that mirror those of PTH include the following: Inhibits phosphate reabsorption by the kidney tubules[2]

In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation.

Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca2+. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS action involving the regulation of feeding and appetite.

almon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.

Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).

Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.

Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.

Oral calcitonin may have a chondroprotective role in osteoarthritis (OA), according to data in rats presented in December, 2005, at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts. Although calcitonin is a known antiresorptive agent, its disease-modifying effects on chondrocytes and cartilage metabolisms have not been well established until now.

This new study, however, may help to explain how calcitonin affects osteoarthritis. “Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation,” says researcher Morten Karsdal, MSC, PhD, of the department of pharmacology at Nordic Bioscience in Herlev, Denmark. “Therefore, calcitonin may be a future efficacious drug for OA.”[2]

Subcutaneous injections of calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder. [3] However no further work on this potential application of calcitonin has been reported.

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Reference [1] Boron WF, Boulpaep EL (2004). “Endocrine system chapter”. Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. [2] Costanzo, Linda S. (2007). BRS Physiology. Lippincott, Williams, & Wilkins. p. 263. [3] Tran de QH, Duong S, Finlayson RJ (July 2010). “Lumbar spinal stenosis: a brief review of the nonsurgical management”. Can J Anaesth 57 (7): 694–703.

Angiotensin – a peptide can control blood pressure

Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex. Aldosterone promotes sodium retention in the distal nephron, in the kidney, which also drives blood pressure up.

Angiotensin is an oligopeptide and is a hormone and a powerful dipsogen. It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver. It plays an important role in the renin-angiotensin system. Angiotensin was independently isolated in Indianapolis and Argentina in the late 1930s (as ‘angiotonin’ and ‘hypertensin’, respectively) and subsequently characterised and synthesized by groups at the Cleveland Clinic and Ciba laboratories in Basel, Switzerland.[1]

Angiotensinogen is an α-2-globulin produced constitutively and released into the circulation mainly by the liver. It is a member of the serpin family, although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma corticosteroid, estrogen, thyroid hormone, and angiotensin II levels.

Angiotensinogen is also known as renin substrate. Human angiotensinogen is 453 amino acids long, but other species have angiotensinogen of varying sizes. The first 12 amino acids are the most important for activity.

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-… Angiotensin I (CAS# 11128-99-7) is formed by the action of renin on angiotensinogen. Renin cleaves the peptide bond between the leucine (Leu) and valine (Val) residues on angiotensinogen, creating the ten-amino acid peptide (des-Asp) angiotensin I. Renin is produced in the kidneys in response to renal sympathetic activity, decreased intrarenal blood pressure ( Angiotensin I appears to have no biological activity and exists solely as a precursor to angiotensin II.

Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE), primarily through ACE within the lung (but also present in endothelial cells and kidney epithelial cells). ACE found in other tissues of the body has no physiological role (ACE has a high density in the lung, but activation here promotes no vasoconstriction, angiotensin II is below physiological levels of action). Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrine hormone.

ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of AII production. Angiotensin II increases blood pressure by stimulating the Gq protein in vascular smooth muscle cells (which in turn activates an IP3-dependent mechanism leading to a rise in intracellular calcium levels and ultimately causing contraction). In addition, angiotensin II acts at the Na/H exchanger in the proximal tubules of the kidney to stimulate Na reabsorption and H excretion which is coupled to bicarbonate reabsorption. This ultimately results in an increase in blood volume, pressure, and pH.[3] Hence, ACE inhibitors are major anti-hypertensive drugs. Other cleavage products of ACE, seven or 9 amino acids long, are also known; they have differential affinity for angiotensin receptors, although their exact role is still unclear. The action of AII itself is targeted by angiotensin II receptor antagonists, which directly block angiotensin II AT1 receptors.

Angiotensin II is degraded to angiotensin III by angiotensinases located in red blood cells and the vascular beds of most tissues. It has a half-life in circulation of around 30 seconds, whereas, in tissue, it may be as long as 15–30 minutes.

Angiotensin III has 40% of the pressor activity of angiotensin II, but 100% of the aldosterone-producing activity. Increases mean arterial pressure.

Angiotensin IV is a hexapeptide that, like angiotensin III, has some lesser activity. The sequence of angiotensin I: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu. The sequence of angiotensin II: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe. The sequence of angiotensin III: Arg-Val-Tyr-Ile-His-Pro-Phe. The sequence of angiotensin IV: Val-Tyr-Ile-His-Pro-Phe.

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Reference [1] Basso N, Terragno NA; Terragno (December 2001). “History about the discovery of the renin-angiotensin system”. Hypertension 38 (6): 1246–9. [2] Le, Tao (2012). First Aid for the Basic Sciences. Organ Systems. McGraw-Hill. p. 625. [3] Yvan-Charvet L, Quignard-Boulangé A (2011). “Role of adipose tissue renin-angiotensin system in metabolic and inflammatory diseases associated with obesity”. Kidney Int. 79 (2): 162–8.

BNP – a peptide about cardiovascular and cerebrovascular diseases

Brain natriuretic peptide (BNP), now known as B-type natriuretic peptide or Ventricular Natriuretic Peptide (still BNP), is a 32-amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells (cardiomyocytes). The release of BNP is modulated by calcium ions.[1] BNP is named as such because it was originally identified in extracts of porcine brain, although in humans it is produced mainly in the cardiac ventricles.

BNP is secreted along with a 76-amino acid N-terminal fragment (NT-proBNP) that is biologically inactive. BNP binds to and activates the atrial natriuretic factor receptors NPRA, and to a lesser extent NPRB, in a fashion similar to atrial natriuretic peptide (ANP) but with 10-fold lower affinity. The biological half-life of BNP, however, is twice as long as that of ANP, and that of NT-proBNP is even longer, making these peptides better targets than ANP for diagnostic blood testing.

The physiologic actions of BNP are similar to those of ANP and include decrease in systemic vascular resistance and central venous pressure as well as an increase in natriuresis. Thus, the net effect of BNP and ANP is a decrease in blood volume, which lowers systemic blood pressure and afterload, yielding an increase in cardiac output, partly due to a higher ejection fraction.

BNP is synthesized as a 134-amino acid preprohormone (preproBNP), encoded by the human gene NPPB. Removal of the 25-residue N-terminal signal peptide generates the prohormone, proBNP, which is stored intracellularly as an O-linked glycoprotein; proBNP is subsequently cleaved between arginine-102 and serine-103 by a specific convertase (probably furin or corin) into NT-proBNP and the biologically active 32-amino acid polypeptide BNP-32, which are secreted into the blood in equimolar amounts.[2] Cleavage at other sites produces shorter BNP peptides with unknown biological activity.[3] Processing of proBNP may be regulated by O-glycosylation of residues near the cleavage sites.

The main clinical utility of either BNP or NT-proBNP is that a normal level rules out acute heart failure in the emergency setting. An elevated BNP or NT-proBNP should never be used to “rule in” acute or heart failure in the emergency setting due to lack of specificity. [3] It appears to have become a common misconception in many emergency departments that ordering brain natriuretic peptide studies in a routine manner has reliable positive predictive value (PPV). However, the value of the test in terms of PPV has simply not been shown. Using these studies inappropriately in such a way would likely result in increased healthcare costs, however an extensive study regarding the potential cost has yet to be performed.

BNP can be elevated in renal failure. BNP is cleared by binding to natriuretic peptide receptors (NPRs) and neutral endopeptidase (NEP). Less than 5% of BNP is cleared renally. NT-proBNP is the inactive molecule resulting from cleavage of the prohormone Pro-BNP and is reliant solely on the kidney for excretion. The achilles heel of the NT-proBNP molecule is the overlap in kidney disease in the heart failure patient population.

Recombinant BNP, nesiritide, is used to treat decompensated heart failure. However, a recent clinical trial failed to show a benefit of nesiritide in patients with acute decompensated heart failure, and the authors could not recommend its use.

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Reference [1] Ziskoven D, Forssmann WG, Holthausen U, et al. (1989). “Calcium Calmodulin antagonists Influences the release of Cardiodilatin/ANP from Atrial Cardiocytes”. In Kaufmann W, Wambach G. Handbook Endocrinology of the Heart. Berlin: Verlag: Springer. pp. 233–4. [2] Schellenberger U, O’Rear J, Guzzetta A,et al. (July 2006). “The precursor to B-type natriuretic peptide is an O-linked glycoprotein”. Arch. Biochem. Biophys. 451 (2): 160–6. [3] Niederkofler EE, Kiernan UA, O’Rear J,et al.(November 2008). “Detection of endogenous B-type natriuretic peptide at very low concentrations in patients with heart failure”. Circ Heart Fail 1 (4): 258–64.

Peptide YY- a peptide can reduce appetite

Peptide YY (PYY) also known as peptide tyrosine tyrosine or pancreatic peptide YY3-36 is a peptide that in humans is encoded by the PPY gene.[1] Peptide YY is a short (36-amino acid) peptide released by cells in the ileum and colon in response to feeding. In the blood, gut, and other elements of periphery, PYY acts to reduce appetite; but when injected directly into the central nervous system, PYY is orexigenic, i.e., it increases appetite.

Peptide YY can be produced as the result of enzymatic breakdown of crude fish proteins and ingested as a food product.

PYY is found in L cells in the mucosa of gastrointestinal tract, especially in ileum and colon. Also, a small amount of PYY, about 1-10%, is found in the esophagus, stomach, duodenum and jejunum. PYY concentration in the circulation increases postprandially (after food ingestion) and decreases by fasting.[4] In addition, PYY is produced by a discrete population of neurons in the brainstem, specifically localized to the gigantocellular reticular nucleus of the medulla oblongata. C. R.

Gustavsen et al. had found PYY-producing cells located in the islets of Langerhans in rats. They were observed either alone or co-localized with glucagon or PP.

PYY exerts its action through NPY receptors; it inhibits gastric motility and increases water and electrolyte absorption in the colon. PYY may also suppress pancreatic secretion. It is secreted by the neuroendocrine cells in the ileum and colon in response to a meal, and has been shown to reduce appetite. PYY works by slowing the gastric emptying; hence, it increases efficiency of digestion and nutrient absorption after a meal. Research has also indicated PYY may be useful in removing aluminium accumulated in the brain.

Several studies have shown acute peripheral administration of PYY3-36 inhibits feeding of rodents and primates. Other studies on Y2R-knockout mice have shown no anorectic effect on them. These findings indicate PYY3-36 has an anorectic (losing appetite) effect, which is suggested to be mediated by Y2R. PYY-knockout female mice increase in body weight and fat mass. PYY-knockout mice, on the other hand, are resistant to obesity, but have higher fat mass and lower glucose tolerance when fed a high-fat diet, compared to control mice. Thus, PYY also plays a very important role in energy homeostasis by balancing food intake. PYY oral spray was found to promote fullness. Viral gene therpy of the salivary glands resulted in long-term intake reduction. Leptin also reduces appetite in response to feeding, but obese people develop a resistance to leptin. Obese people secrete less PYY than non-obese people, and attempts to use PYY directly as a weight-loss drug have met with some success. Researchers noted the caloric intake during a buffet lunch offered two hours after the infusion of PYY was decreased by 30% in obese subjects (P<0.001) and 31% in lean subjects (P<0.001).[2]

While some studies have shown obese persons have lower circulating level of PYY postprandially, other studies have reported they have normal sensitivity to the anorectic effect of PYY3-36. Thus, reduction in PYY sensitivity may not be one of the causes of obesity, in contrast to the reduction of leptin sensitivity. The anorectic effect of PYY could possibly be a future obesity drug.[4]

The consumption of protein boosts PYY levels, so some benefit was observed in experimental subjects in reducing hunger and promoting weight loss.[3] This would help explain the weight-loss experienced with high-protein diets.

Obese patients undergoing gastric bypass showed marked metabolic adaptations, resulting in frequent diabetes remission 1 year later. When the confounding of calorie restriction is factored out, β-cell function improves rapidly, very possibly under the influence of enhanced GLP-1 responsiveness. Insulin sensitivity improves in proportion to weight loss, with a possible involvement of PYY.

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Karebay (www.karebaybio.com) has a professional team devoted to peptide products synthesis and development. We offer high-quality peptide synthesis products for sale around the world, including over 1,000 catalog peptides, and nearly 100 pharmaceutical peptides and cosmetic peptides products.

Reference [1] Murphy KG, Bloom SR (December 2006). “Gut hormones and the regulation of energy homeostasis”. Nature 444 (7121): 854–9. [2] Gustavsen CR, Pillay N, Heller RS (2008). “An immunohistochemical study of the endocrine pancreas of the African ice rat, Otomys sloggetti robertsi”. Acta Histochem. 110 (4): 294–301. [3] Batterham RL, Heffron H, Kapoor S, Chivers J, Chandarana K, Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ (2006). “Critical role for peptide YY in protein-mediated satiation and body-weight regulation”. Cell Metabolism 4 (3): 223–233.

TGF-β – An important peptide in cancer

Transforming growth factor beta (TGF-β) is a peptide that controls proliferation, cellular differentiation, and other functions in most cells. It is a type of cytokine which plays a role in immunity, cancer, bronchial asthma, heart disease, diabetes, Hereditary hemorrhagic telangiectasia, Marfan syndrome, Vascular Ehlers-Danlos syndrome,[1] Loeys–Dietz syndrome, Parkinson’s disease and AIDS.

TGF-β is secreted by many cell types, including macrophages, in a latent form in which it is complexed with two other polypeptides, latent TGF-beta binding peptide (LTBP) and latency-associated peptide (LAP). Serum peptideases such as plasmin catalyze the release of active TGF-β from the complex. This often occurs on the surface of macrophages where the latent TGF-β complex is bound to CD36 via its ligand, thrombospondin-1 (TSP-1). Inflammatory stimuli that activate macrophages enhance the release of active TGF-β by promoting the activation of plasmin. Macrophages can also endocytose IgG-bound latent TGF-β complexes that are secreted by plasma cells and then release active TGF-β into the extracellular fluid.[2]

TGF-β is a secreted peptide that exists in at least three isoforms called TGF-β1, TGF-β2 and TGF-β3. It was also the original name for TGF-β1, which was the first member of this family to be discovered. The TGF-β family is part of a superfamily of peptides known as the transforming growth factor beta superfamily, which includes inhibins, activin, anti-müllerian hormone, bone morphogenetic peptide, decapentaplegic and Vg-1.

Most tissues have high expression of the genes encoding TGF-β. That contrasts with other anti-inflammatory cytokines such as IL-10, whose expression is minimal in unstimulated tissues and seems to require triggering by commensal or pathogenic flora.

TGF-β acts as an antiproliferative factor in normal epithelial cells and at early stages of oncogenesis.

Some cells that secrete TGF-β also have receptors for TGF-β. This is known as autocrine signalling. Cancerous cells increase their production of TGF-β, which also acts on surrounding cells. In normal cells, TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-β signaling pathway are mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β acts on the surrounding stromal cells, immune cells, endothelial and smooth-muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-β also converts effector T-cells, which normally attack cancer with an inflammatory (immune) reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction.

Although TGF-β is important in regulating crucial cellular activities, only a few TGF-β activating pathways are currently known, and the full mechanism behind the suggested activation pathways is not yet well understood. Some of the known activating pathways are cell or tissue specific, while some are seen in multiple cell types and tissues. Proteases, integrins, pH, and reactive oxygen species are just few of the currently know factors that can activate TGF-β. It is well known that perturbations of these activating factors can lead to unregulated TGF-β signaling levels that may cause several complications including inflammation, autoimmune disorders, fibrosis, cancer and cataracts. In most cases an activated TGF-β ligand will initiate the TGF-β signaling cascade as long as TGF-β receptors I and II are within reach, this is due to high affinity between TGF-β and its receptors, suggesting why the TGF-β signaling recruits a latency system to mediate its signaling.[3] Karebay can synthetic TGF-β with Modified amino acids, so that scientists can knew more details about its molecular mechanism. We can also synthesis inhibition for TGF-β，like GW788388、A 83-01 and so on.

Karebay (www.karebaybio.com) has a professional team devoted to peptide products synthesis and development. We offer high-quality peptide synthesis products for sale around the world, including over 1,000 catalog peptides, and nearly 100 pharmaceutical peptides and cosmetic peptides products.

Reference [1] Li X, Mai J, Virtue A,et al. (March 2012). “IL-35 is a novel responsive anti-inflammatory cytokine–a new system of categorizing anti-inflammatory cytokines”. PLoS ONE 7 (3): e33628. [2] Herpin A, Lelong C, Favrel P (2004). “Transforming growth factor-beta-related peptides: an ancestral and widespread superfamily of cytokines in metazoans”. Dev Comp Immunol 28 (5): 461–85. [3] Wipff PJ, Hinz B (September 2008). “Integrins and the activation of latent transforming growth factor beta1 — an intimate relationship”. Eur. J. Cell Biol. 87 (8-9): 601–15.

AMPS in organism

As we know, we call antimicrobial peptides and proteins AMPs for short. AMPS possess critical biological functions in organism.

The species of AMPS

Antimicrobial substances might have been noticed long time ago,discovered in saliva by Alexander Fleming in 1922 , is recognized as the first antimicrobial protein. AMPS we have found including:human definsins. Human Histatins: Two Genes Multiple Peptides, Human Cathelicidins: One Gene Multiple Peptides, Human Dermcidin, Human Hepcidins, Human AMPs Derived from Known Proteins, Antimicrobial Chemokines and AMPs from Human Immune Cells, Antimicrobial Neuropeptides, Beta-Amyloid Peptides, Human Antimicrobial Proteins.

The biological activity of AMPS

Antimicrobial activity is a common property of human AMPs, Understanding the elegant balance of AMPs in these processes in the healthy state as well as the factors that could tilt the balance to a diseased state may yield useful means for cancer treatment. The main role of AMPS is in warding off invading microbial pathogens. In addition, AMPs can possess other biological functions such as apoptosis, wound healing, and immune modulation. The activity of invading microbial pathogens is such as Antibacterial Activities, Antiviral Activity, Antifungal Activity, Antiparasitic Activity, Anticancer Activity, Cytotoxic Effects of Human AMPs.

As reported, By now, over 100 human AMPs have been identified and characterized. They were either isolated from human tissues or predicted from the human genome by bioinformatics. including skin, eyes, ears, mouths, gut, immune, nervous and urinary systems. These peptides vary from 10 to 150 amino acids with a net charge between −3 and +20 and a hydrophobic content below 60%. The sequence diversity of AMPs in directly determines their structural and functional diversity. We hope we can find more AMPS and know the functional mechanism more clearly in future as the biotechnology developing.

Reference Guangshun Wang, Human Antimicrobial Peptides and Proteins,Pharmaceuticals (Basel). 2014,7(5): 545–594.

Amylin-A kind of peptide associated with diabetes

Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone.[1] It is cosecreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1. Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

IAPP is processed from an 89-residue coding sequence. Proislet Amyloid Polypeptide (proIAPP,Proamylin, Proislet Protein) is produced in the pancreatic beta cells (β-cells) as a 67 amino acid, 7404 Dalton pro-peptide and undergoes post-translational modifications including protease cleavage to produce amylin.[2]

The human form of IAPP has the amino acid sequence KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, with a disulfide bridge between cysteine residues 2 and 7. Both the amidated C-terminus and the disulfide bridge are necessary for the full biological activity of amylin. IAPP is capable of forming amyloid fibrils in vitro. Within the fibrillization reaction, the early prefibrillar structures are extremely toxic to beta-cell and insuloma cell cultures.[2] Later amyloid fiber structures also seem to have some cytotoxic effect on cell cultures. Studies have shown that fibrils are the end product and not necessarily the most toxic form of amyloid proteins/peptides in general. A non-fibril forming peptide (1-19 residues of human amylin) is toxic like the full-length peptide but the respective segment of rat amylin is not. It was also demonstrated by solid-state NMR spectroscopy that the fragment 20-29 of the human-amylin fragments membranes. Rats and mice have six substitutions (three of which are proline substitions at positions 25, 28 and 29) that are believed to prevent the formation of amyloid fibrils. Rat IAPP is nontoxic to beta-cells, even when overexpressed.

Amylin functions as part of the endocrine pancreas and contributes to glycemic control. The peptide is secreted from the pancreatic islets into the blood circulation and is cleared by peptidases in the kidney. It is not found in the urine.

Amylin’s metabolic function is well-characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma. It thus functions as a synergistic partner to insulin, with which it is cosecreted from pancreatic beta cells in response to meals. The overall effect is to slow the rate of appearance (Ra) of glucose in the blood after eating; this is accomplished via coordinate slowing down gastric emptying, inhibition of digestive secretion [gastric acid, pancreatic enzymes, and bile ejection], and a resulting reduction in food intake. Appearance of new glucose in the blood is reduced by inhibiting secretion of the gluconeogenic hormone glucagon. These actions, which are mostly carried out via a glucose-sensitive part of the brain stem, the area postrema, may be over-ridden during hypoglycemia. They collectively reduce the total insulin demand.

Amylin also acts in bone metabolism, along with the related peptides calcitonin and calcitonin gene related peptide.

Rodent amylin knockouts are known to fail to achieve the normal anorexia following food consumption. Because it is an amidated peptide, like many neuropeptides, it is believed to be responsible for the anorectic effect. A synthetic analog of human amylin with proline substitutions in positions 25, 26 and 29, or pramlintide (brand name Symlin), was recently approved for adult use in patients with both diabetes mellitus type 1 and diabetes mellitus type 2. Insulin and pramlintide, injected separately but both before a meal, work together to control the post-prandial glucose excursion.[3]

Amylin is degraded in part by insulin-degrading enzyme.

Karebay can synthetic amylin with Cyanine or other fluorescent moleculars , so that scientists can knew more details about its molecular mechanism.

Karebay (www.karebaybio.com) has a professional team devoted to peptide products synthesis and development. We offer high-quality peptide synthesis products for sale around the world, including over 1,000 catalog peptides, and nearly 100 pharmaceutical peptides and cosmetic peptides products.

Reference [1] Qi D, Cai K, Wang O,et al. Le (January 2010). “Fatty acids induce amylin expression and secretion by pancreatic beta-cells”. Am. J. Physiol. Endocrinol. Metab. 298 (1): E99–E107. [2] Brender JR, Lee EL, Cavitt MA, et al. (May 2008). “Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide”. J. Am. Chem. Soc. 130 (20): 6424–9. [3] Amylin Pharmaceuticals, Inc. 2006. Archived from the original on 13 June 2008. Retrieved 2008-05-28.

Angiogenin – An important link for the treatment of cancer

Angiogenin (Ang) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ANG gene.[1] Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular RNA, resulting in modulated levels of protein synthesis and interacts with DNA causing a promoter-like increase in the expression of rRNA.[2][3] Ang is associated with cancer and neurological disease through angiogenesis and through activating gene expression that suppresses apoptosis.

Angiogenin is a key protein implicated in angiogenesis in normal and tumor growth. Angiogenin interacts with endothelial and smooth muscle cells resulting in cell migration, invasion, proliferation and formation of tubular structures.[1] Ang binds to actin of both smooth muscle and endothelial cells to form complexes that activate proteolytic cascades which upregulate the production of proteases and plasmin that degrade the laminin and fibronectin layers of the basement membrane.[2] Degradation of the basement membrane and extracellular matrix allows the endothelial cells to penetrate and migrate into the perivascular[disambiguation needed] tissue.[1] Signal transduction pathways activated by Ang interactions at the cellular membrane of endothelial cells produce extracellular signal-related kinase1/2 (ERK1/2) and protein kinase B/Akt.[1] Activation of these proteins leads to invasion of the basement membrane and cell proliferation associated with further angiogenesis. The most important step in the angiogenesis process is the translocation of Ang to the cell nucleus. Once Ang has been translocated to the nucleus, it enhances rRNA transcription by binding to the CT-rich (CTCTCTCTCTCTCTCTCCCTC) angiogenin binding element (ABE) within the upstream intergenic region of rDNA, which subsequently activates other angiogenic factors that induce angiogenesis.

Ang has a prominent role in the pathology of cancer due to its functions in angiogenesis and cell survival. Since Ang possesses angiogenic activity, it makes Ang a possible candidate in therapeutic treatments of cancer. Studies of Ang and tumor relationships provide evidence for a connection between the two. The translocation of Ang to the nucleus causes an upregulation of transcriptional rRNA, while knockdown strains of Ang cause downregulation.[1] The presence of Ang inhibitors that block translocation resulted in a decrease of tumor growth and overall angiogenesis.[1][10] HeLa cells translocate Ang to the nucleus independent of cell density. In human umbilical vein endothelial cells(HUVEC), translocation of Ang to the nucleus stops after cells reach a specific density, while in HeLa cells translocation continued past that point.Inhibition of Ang affects the ability of HeLa cells to proliferate, which proposes an effective target for possible therapies. Due to the ability of Ang to protect motoneurons (MNs), causal links between Ang mutations and Amyotrophic lateral sclerosis (ALS) are likely. The angiogenic factors associated with Ang may protect the central nervous system and MNs directly.[1] Experiments with wild type Ang found that it slows MN degeneration in mice that had developed ALS, providing evidence for further development of Ang protein therapy in ALS treatment. Angiogenin expression in Parkinson’s disease is dramatically decreased in the presence of alpha-synuclein (α-syn) aggregations. Exogenous angiogenin applied to dopamine-producing cells leads to the phosphorylation of PKB/AKT and the activation of this complex inhibits cleavage of caspase 3 and apoptosis when cells are exposed to a Parkinson’s-like inducing substance[3].

Karebay can synthetic Angiogenin with Cyanine or other fluorescent moleculars , so that scientists can knew more details about its molecular mechanism.

Karebay (www.karebaybio.com) has a professional team devoted to peptide products synthesis and development. We offer high-quality peptide synthesis products for sale around the world, including over 1,000 catalog peptides, and nearly 100 pharmaceutical peptides and cosmetic peptides products.

Reference [1] Gao X, Xu Z (2008). “Mechanisms of action of angiogenin”. Acta Biochimica et Biophysica Sinica 40 (7): 619–624. [2] Li S, Yu W, Hu GF (2012). “Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner”. Journal of Cellular Physiology 227 (4). [3] Li S, Hu G (2012). “Emerging role of angiogenin in stress response and cell survival under adverse conditions”. Journal of Cell Physiology 227 (7): 2822–6.

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