ACE-031 is a soluble form of the IIB subtype of the activin receptor type, also known as ActRIIB¹. Therefore, it is thought to have a positive effect on muscle growth via the inhibition of myostatin and other proteins involved in the regulation of muscle mass^1,2. Some researchers conclude that ActRIIB is the receptor for myostatin, and that their complex mediates a pathway leading to the negative regulation of muscle mass³. This may be substantiated by observations of significantly increased skeletal muscle in animals expressing mutant ActRIIB (i.e. ActRIIB to which myostatin could not bind)⁴. Soluble ActRIIB is synthesized through the conjugation of an active domain of this receptor (e.g. the extracellular component) with another protein such as a fragment of a murine or human immunoglobulin³. This peptide has demonstrated the ability to significantly enhance muscle mass and performance in adult, young and castrated male mice². Another study demonstrated the ability of a two-week regimen of treatment with this soluble receptor to increase skeletal muscle in mice by as much as 60%⁴. ACE-031 and Androgen Deprivation This peptide may counteract the effects of androgen deficiency⁵. This condition involves reductions in the production or biological activity of male hormones such as testosterone, and may occur as a result of aging or hypogonadism. It is associated with reductions in bone density, muscle mass and adipose tissue regulation⁵. An animal study treated both castrated and control mice with either soluble ActRIIB or an identical placebo. The soluble ActRIIB treatment resulted in significant increases in non-adipose tissue mass in both the control and castrated animals compared to changes associated with the placebo treatment⁵. Soluble ActRIIB was also associated with significant changes in adiposity compared to placebo, but only in the castrated animals⁵. The researchers also reported that treatment with the peptide also prevented steatohepatosis (the development of fatty liver disease), changed insulin levels and promoted bone density retention in castrated animals⁵. Another study of the effects of soluble ActRIIB on 18-month-old, castrated and adult mice respectively also reported positive effects on bone density and a marker of bone growth². Therefore, ACE-031 may help to prevent androgen deficiency, which is seen as a disease in mammals that requires treatment by some researchers⁵.  ACE-031 and its Role in Muscle Growth Soluble ActRIIB may significantly improve muscle mass and strength in animal studies, as outlined above. However, when researchers analyzed this effect in more detail, they found that the peptide had the most beneficial effects on muscle fiber types with reduced fatigue-resistance, compared to other more resistant types². This may be related to the actions of myostatin, which have been shown to concentrate on one specific fiber type (i.e. type II)⁶. Therefore, the positive effects of ACE-031 on muscle mass may be restricted to the acute, or relatively short-term. However, other research has shown that ACE-031 increases growth in multiple muscle fiber types indiscriminately⁶. In addition, ACE-031 does not bind exclusively to myostatin, but to other similar proteins such as GDF11 and (as the receptor name suggests) activin³. Therefore, its effects on muscle mass may extend beyond the simple antagonism of myostatin.  References: 1. Attie KM, Borgstein NG, Yang Y, et al. A single ascending-dose study of muscle regulator ACE-031 in healthy volunteers. Muscle & nerve. 2013;47(3):416-423. 2. Chiu CS, Peekhaus N, Weber H, et al. Increased muscle force production and bone mineral density in ActRIIB-Fc-treated mature rodents. The journals of gerontology. Series A, Biological sciences and medical sciences. 2013;68(10):1181-1192. 3. Rahimov F, King OD, Warsing LC, et al. Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor. Physiological genomics. 2011;43(8):398-407. 4. Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(16):9306-9311. 5. Koncarevic A, Cornwall-Brady M, Pullen A, et al. A soluble activin receptor type IIb prevents the effects of androgen deprivation on body composition and bone health. Endocrinology. 2010;151(9):4289-4300. 6. Cadena SM, Tomkinson KN, Monnell TE, et al. Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber type. Journal of applied physiology (Bethesda, Md. : 1985). 2010;109(3):635-642.

176-191 is the common term for a fragment of human growth hormone (hGH). It is often regarded as a mimic of the C-terminus of hGH; in other words, it is a peptide made up of the last 16 amino acids found in the sequence of the hormone. This region of hGH has been linked to the reduction of fat and fat tissue in mammals, by promoting lipolysis and inhibiting lipogenesis¹. However, this fragment of hGH has also been associated with the inhibition of insulin, and thus increased risks of hyperglycaemia². These effects may be related to amino acids 178 to 190 in the hGH sequence². Conversely, the amino-terminus of hGH has been found to have a significant effect on glucose breakdown mediated by insulin in healthy rats³. Animal studies investigating the properties of a 177-191 fragment have found that this peptide may disrupt the regulation of glycogen synthase in vivo⁴. This may lead to altered levels of circulating glucose. When the 176th amino acid is added to this fragment, however, it becomes an analog of the growth-hormone releasing factor (GRF). This peptide, as the name suggests, plays a role in the regulation of GH release, and is also known as growth hormone releasing hormone (GHRH)⁵. GRF has demonstrated the ability to significantly increase plasma GH levels and growth, as observed in young female buffalo treated with this peptide, compared to controls⁶. Other researchers have claimed that chronic GRF administration also resulted in significant increases in the concentrations of luteinizing hormone (LH) and progesterone in similar animals⁶. GRF may also be associated with reductions in dyslipidemia (impaired lipid metabolism leading to the increased accumulation of body fat)⁷. Based on findings such as these, some scientists argue that GRF analogs may be useful in the promotion of body weight and improved body composition in livestock and other commercially-viable animals⁸. Other functions of 176-191 GRF and its analogs are associated with the release of GH, and possibly IGsF, in many animals⁹. The release of GRF is historically associated with the hypothalamus, but has been detected in other sources, including the gonads and placenta⁹. As a result, some researchers propose that it has a role in fetal development⁹. GRF is also found in leukocytes⁹. Therefore, it may also have a role in the immune response and/or the regulation of the immune system.  GRF and Neurons  GRF is released by a population of neurons in the hypothalamus and anterior pituitary of many animals¹⁰. Therefore, it can also be categorized as a neuropeptide, or a protein fragment that may also act as a neurotransmitter or other type of mediator between nerve cells. A recent imaging study using rat brains found that up to 30% of the GRF neurons in this region could take up radiolabeled estradiol¹⁰. This indicates that estradiol may have a role in stimulating GRF release, and thus in the control of GH production in turn. These findings may also further clarify the as-yet uncertain role of estradiol in the central nervous system. GRF and similar peptides may also alleviate the effects of hypoxia in murine CNS studies¹¹. References: 1. Wu Z, Ng FM. Antilipogenic action of synthetic C-terminal sequence 177-191 of human growth hormone. Biochemistry and molecular biology international. 1993;30(1):187-196. 2. Wade JD, Ng FM, Bornstein J, Pullin CO, Pearce JS. Effect of C-terminal chain shortening on the insulin-antagonistic activity of human growth hormone 177--191. Acta endocrinologica. 1982;101(1):10-14. 3. Mondon CE, Reaven GM, Ling N, Lewis UJ, Frigeri LG. Amino-terminal peptide of growth hormone enhances insulin action in normal rats. Endocrinology. 1988;123(2):827-833. 4. Macaulay SL, Armstrong JM, Bornstein J. Regulation of glycogen synthase activity in muscle by a C-terminal part sequence of human growth hormone. Archives of biochemistry and biophysics. 1983;224(1):365-371. 5. Mangili A, Falutz J, Mamputu J-C, Stepanians M, Hayward B. Predictors of Treatment Response to Tesamorelin, a Growth Hormone-Releasing Factor Analog, in HIV-Infected Patients with Excess Abdominal Fat. PLoS ONE. 2015;10(10):e0140358. 6. Haldar A, Prakash BS. Effects of growth hormone-releasing factor on growth hormone response, growth and feed conversion efficiency in buffalo heifers (Bubalus bubalis). Veterinary journal (London, England : 1997). 2007;174(2):384-389. 7. Hu M, Tomlinson B. Growth hormone-releasing factor agonists for the treatment of HIV-associated lipodystrophy. Current opinion in investigational drugs (London, England : 2000). 2010;11(10):1143-1150. 8. Sun LY, Spong A, Swindell WR, et al. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice. eLife. 2013;2:e01098. 9. Campbell RM, Scanes CG. Evolution of the growth hormone-releasing factor (GRF) family of peptides. Growth regulation. 1992;2(4):175-191. 10. Shirasu K, Stumpf WE, Sar M. Evidence for direct action of estradiol on growth hormone-releasing factor (GRF) in rat hypothalamus: localization of [3H]estradiol in GRF neurons. Endocrinology. 1990;127(1):344-349. 11. Nair D, Ramesh V, Li RC, Schally AV, Gozal D. Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia-induced oxidative stress and cognitive deficits in mouse. Journal of neurochemistry. 2013;127(4):531-540.

Thymosin beta4 (Tβ4) is a peptide made of 43 amino acids. It is, as the name suggests, found in the thymus gland of a number of animals¹. Tβ4 plays a role in the process of cellular movement (or migration) by recruiting actin². It may regulate this by preventing the formation of actin complexes by binding the individual units of this protein². Tβ4 has the potential to orchestrate cellular differentiation and co-ordination (which is required for events such as neovascularization) through this form of control over the local populations of actin. It is mostly found within cells, but extracellular Tβ4 may be detected in plasma and in injured tissues². The peptide may have a role in recovery from tissue damage.  Tβ4 and Neural Cells Tβ4 has been observed to promote the development of nerve cells. It may be associated with the increased differentiation of progenitor-type cells into oligodendrocytes, a long, thin variety of neural cells³. Tβ4 may also have a protective effect in rat models of acquired brain injury³. The peptide stimulates increased levels of microRNA 200a (miR200a) in brain cells. miR200a has a negative effect on epidermal growth factor receptor-associated signaling, which activates p53³. As p53 would induce apoptosis in brain cells exposed to oxygen deprivation, Tβ4 ultimately promotes the preservation of nerve cells and their precursors following adverse events such as hypoxia. Another study using murine oligodendrocyte-precursor cell lines found that Tβ4 also upregulated microRNA 146a (miR146a), which in turned down-regulated an inflammatory response mediated by the Toll-like receptor. Tβ4 administration also resulted in reductions in the levels of tumor necrosis factor receptor-associated factor 6 (TRAF6) and IL-1 receptor-associated kinase 1 (IRAK1), which also promote inflammation⁴. Inflammation is related to further cellular damage and death following an injury or other similar event in environments such as oligodendrocyte-rich nervous tissue. Therefore, treatment with Tβ4 may help conserve cell health and numbers after this damage. Tβ4 in Other Tissues  Tβ4 may promote tissue healing and remodeling in additional cell types. A study investigated the effects of the peptide in a mouse model of myocardial infarction (an event associated with markedly increased inflammation and tissue damage that may be fatal⁵). Tβ4 administration for seven days after experimental infarction resulted in decreased infiltrations into cardiac tissue by inflammatory cells, as well as reduced cardiac muscle cell death, compared to animals treated with an identical sham treatment⁵. The animals receiving Tβ4 also exhibited a significant restoration of cardiac function, reduced cardiac scarring and decreased death rates after five weeks compared to control animals⁵. Tβ4 may also be associated with positive effects on the functions of hair follicles. This was investigated in a study using mice overexpressing Tβ4, mice with non-functional Tβ4 genes (or Tβ4-knockout) and normal mice as controls. The researchers removed hair from groups of all of these mouse types. They found that the number of new hair shafts in Tβ4-knockout were significantly reduced compared to control mice, and that their follicles did not form clusters as normal⁶. The mice who over-expressed Tβ4 exhibited new hair growth that was faster and thicker than that of controls⁶. These effects appeared to be mediated via MAPK signaling, and were also correlated with the expression of VEGF in the skin⁶. References: 1. Goldstein AL, Slater FD, White A. Preparation, assay, and partial purification of a thymic lymphocytopoietic factor (thymosin). Proceedings of the National Academy of Sciences of the United States of America. 1966;56(3):1010-1017. 2. Huff T, Muller CS, Otto AM, Netzker R, Hannappel E. beta-Thymosins, small acidic peptides with multiple functions. The international journal of biochemistry & cell biology. 2001;33(3):205-220. 3. Santra M, Chopp M, Santra S, et al. Thymosin beta 4 up-regulates miR-200a expression and induces differentiation and survival of rat brain progenitor cells. Journal of neurochemistry. 2015. 4. Santra M, Zhang ZG, Yang J, et al. Thymosin beta4 up-regulation of microRNA-146a promotes oligodendrocyte differentiation and suppression of the Toll-like proinflammatory pathway. The Journal of biological chemistry. 2014;289(28):19508-19518. 5. Peng H, Xu J, Yang XP, et al. Thymosin-beta4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction. American journal of physiology. Heart and circulatory physiology. 2014;307(5):H741-751. 6. Gao X, Liang H, Hou F, et al. Thymosin Beta-4 Induces Mouse Hair Growth. PloS one. 2015;10(6):e0130040.

Insulin-like growth factor 1 (IGF-1) is a hormone related to growth and development in animals. As the name suggests, it is closely related to insulin in terms of structure. IGF-1 binds to its own receptor, IGFR. Reductions in, or antagonism of, IGF-1 activity is associated with the wastage of organs associated with starvation and some forms of cancer¹. IGF-1 and Muscle Growth IGF-1, signaling through calcineurin, may have a role in the regulation of growth in muscle tissue². The expression of genes for these proteins (IGF-1 and CnAα) was found consistently in a study using duck embryos, focusing on the development of leg and breast muscle. This gene expression varied significantly over time, although it was at its highest at day 13 of embryonic development². The expression of IGF-1 and CnAα was related to type IIb fibers, but not type I or type IIa fibers². Another similar study reported that variations in the pectoralis muscles of duck chick mirrored those of MSTN (the gene for myostatin, another regulator of muscle development) and IGF-1 expression³. This indicates that IGF-1 is involved in the timing of muscle development in infant animals, and of that of the transition between muscle fiber types³. IGF-1 and Bone Growth  IGF-1 is also associated with the promotion of bone cell subtype (osteoclasts) proliferation. Reductions in the activity and populations of these cells are implicated in diseases that destroy bone, which include some forms of multiple myeloma⁴. The hormone may be used to confirm the osteoclastogenesis of proposed treatments such as glycosphingolipids in animal models of myeloma⁴. IGF-1 and Neuropathic Conditions IGF-1 is also known to be neurotrophic, or to influence the survival, function and development of neurons in the central nervous system⁵. This implies a role for this hormone in improved outcomes for animals with conditions that involve damage or death in these cells. Amyotrophic lateral sclerosis (ALS) is an example of these, in which motor neurons are affected, with an additional component of localized inflammation⁵. A study incorporating a mouse model of ALS found that the immunization of mice with a myelin-derived vaccine resulted in increases of IGF-1 in spinal tissue⁵. This led to reduced disease activity and increased survival in these animals⁵.      References: 1. Kwon Y, Song W, Droujinine IA, Hu Y, Asara JM, Perrimon N. Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Dev Cell. 2015;33(1):36-46. 2. Shu J, Li H, Shan Y, et al. Expression profile of IGF-I-calcineurin-NFATc3-dependent pathway genes in skeletal muscle during early development between duck breeds differing in growth rates. Dev Genes Evol. 2015;225(3):139-148. 3. Hu Y, Liu H, Shan Y, et al. The relative expression levels of insulin-like growth factor 1 and myostatin mRNA in the asynchronous development of skeletal muscle in ducks during early development. Gene. 2015;567(2):235-243. 4. Ersek A, Xu K, Antonopoulos A, et al. Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease. J Clin Invest. 2015;125(6):2279-2292. 5. Kunis G, Baruch K, Miller O, Schwartz M. Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS. J Neurosci. 2015;35(16):6381-6393.

Ipamorelin is a synthetic peptide that binds selectively to the growth hormone secretagogue receptor (GHS-R). It contains the artificial amino acids 2-aminoisobutyric acid (i.e. 2-methylalanine or Aib) and 2-naphthylalanine (2-Nal)¹. These differentiate it from the peptide growth hormone releasing protein-1 (GHRP-1), on which it was based¹. It has been found to have an efficacy and potency in releasing growth hormone comparable to that of GHRP-6 in in vitro and animal trials¹. Ipamorelin was found to have lower potency, but higher efficacy, that GHRP-2 in a swine pharmacokinetic study¹. Unlike the peptides GHRP-2 and -6, ipamorelin appears not to be associated with the release of adrenocorticotropic hormone (ACTH) or cortisol¹. Appetite and the Gastrointestinal System Ipamorelin is known as a ghrelin mimetic. Like this natural molecule, it increases appetite and gut motility². A study incorporating a rat model of postoperative decreases in these found that repeated 0.01-1mg/kg doses of ipamorelin significantly increased food intake, fecal output and body weight in the first 48 hours after an experimental surgery². Ipamorelin and Diabetes Ghrelin has been found to elicit significant increases in the pancreatic insulin production of both normal and diabetic rats³. Therefore, ipamorelin may have similar effects. A study induced diabetes (via strepozocin administration) in rats. Pancreatic tissue samples were then taken from diabetic and control rats and incubated with a range of ipamorelin doses. This resulted in a moderately significant increase in the insulin secretion from the preparations taken from both groups of rats⁴. Ipamorelin-associated insulin release was successfully inhibited by drugs that block alpha- and beta-adrenergic receptors and calcium channels in both 'normal' and 'diabetic' samples⁴. This implies the mechanism by which ipamorelin stimulates the release of insulin⁴. Interestingly, alpha-adrenergic and calcium channel blockers fail to inhibit insulin release stimulated by ghrelin in diabetic rats³. Ipamorelin-mediated insulin release was also significantly blocked by atropine, an acetylcholine receptor antagonist⁴. Ipamorelin and Interactions  Growth hormone has been found to counteract the negative effects of repeated steroid treatments on nitrogen balance in the body⁵. These effects may lead to increased risks of liver damage. A rat study found that ipamorelin significantly reduced prednisolone-mediated urea synthesis, although to a lesser extent than growth hormone⁵. References: 1. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552-561. 2. Venkova K, Mann W, Nelson R, Greenwood-Van Meerveld B. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. J Pharmacol Exp Ther. 2009;329(3):1110-1116. 3. Adeghate E, Ponery AS. Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. J Neuroendocrinol. 2002;14(7):555-560. 4. Adeghate E, Ponery AS. Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats. Neuro Endocrinol Lett. 2004;25(6):403-406. 5. Aagaard NK, Grofte T, Greisen J, et al. Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats. Growth Horm IGF Res. 2009;19(5):426-431.

Anastrozole is a reversible competitive aromatase inhibitor (AI) with high specificity and affinity1,2. It has a chemical formula of C17H19N5 and a mass of 293.366 g/mol. Anastrozole, Estrogen and Testosterone This molecule binds to aromatase, which prevents the conversion of estrogen to testosterone¹. These reductions in estrogen are used in medicine and research to reduce the supply of the hormone to its receptors (ERs) on tumor cells³. A recent trial of the effects of anastrozole on murine ER-positive carcinoma cells found the AI significantly reduced cell viability and proliferation at a range of doses³. It may be intuitive therefore to assume a role for anastrozole in the effects of testosterone on its physiological and pathological effects. However, a recent study using male Fisher 344 rats found that anastrozole had little effect on the bone-conserving properties of testosterone. This study randomly allocated orchidectomized rats to dose-regimens of testosterone, anastrozole, trenbolone (a testosterone analog which cannot be converted to estrogen), both anastrozole and trenbolone or placebo⁴. The 'testosterone'and 'trenbolone' group suppressed the bone loss seen in the placebo group compared to intact animals, but this was not affected positively or negatively in the groups receiving anastrozole⁴. In addition, anastrozole did not affect the increases in fat mass and decreases in muscle mass seen in the placebo group⁴. Anastrozole is an azole, which leads to its classification as a non-steroidal third-generation aromatase inhibitor⁵. It is electrophilic, which suggests a role in ion channel activation⁵. Anastrozole and Pain Anastrozole has been found to produce the side-effect of pain when used as a treatment or intervention⁵. This adverse event most often arises in the form of joint or neuropathic (or nerve damage-related) pain⁵. This azole has demonstrated the ability to induce or increase pain in murine studies⁵. Anastrozole has been found to target the transient receptor potential ankyrin 1 (TRPA1) channel, which is a mediator of neuropathic pain, chemical irritation and pain related to inflammatory stimuli^5,6. Mouse models of genetic TRPA1 deficiency and blockade have shown that anastrozole administration resulted in the calcium response of this channel⁵. This indicates a role for anastrozole in models and studies of neuropathy, inflammatory pain and irriation in the future. References: 1. Geisler J. Differences between the non-steroidal aromatase inhibitors anastrozole and letrozole--of clinical importance? British journal of cancer. 2011;104(7):1059-1066. 2. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014;383(9922):1041-1048. 3. Topcul M, Cetin I, Ozlem Kolusayin Ozar M. The effects of anastrozole on the proliferation of FM3A cells. J BUON. 2013;18(4):874-878. 4. Beck DT, Yarrow JF, Beggs LA, et al. Influence of aromatase inhibition on the bone-protective effects of testosterone. J Bone Miner Res. 2014;29(11):2405-2413. 5. Fusi C, Materazzi S, Benemei S, et al. Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1. Nature Communications. 2014;5:5736. 6. Trevisani M, Siemens J, Materazzi S, et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2007;104(33):13519-13524.

Albuterol Albuterol is an agonist of the [beta]-adrenergic receptor (β2-AR). It is commonly available in two forms, R-albuterol (or levalbuterol) and S-albuterol¹. Levalbuterol is often regarded as the active form of this molecule, as S-albuterol as been found to remain in circulation for up to twelve times longer than its other isomer¹. Albuterol and Respiration This class of drug elicits bronchodilation through the recruitment of sodium/potassium ATPases in the alveoli of animal lungs via changes in calcium concentrations². A recent study has found that this is associated with calcium release-activated calcium channels linked to stromal interaction molecule 1 (STIM1)². A rat model of acute respiratory distress syndrome (ARDS) found that the genes for sodium/potassium ATPase-α were significantly increased in response to intratracheal and intravenous albuterol, but only if alveolar ion channel and aquaporin gene expression were elevated beforehand (i.e. by experimental ARDS induction)³. Albuterol is often used as a standard when assessing the binding (and other) properties of novel β2-AR agonists⁴. It was also recently used to validate the bronchoconstrictive properties of insulin in a study using guinea pigs⁵. Albuterol has also been found to potentiate concurrently-available corticosteroids and modulate inflammatory responses when inhaled¹. Albuterol and Cardiovascular Research Albuterol has been proposed as a preventative against hypoxia (oxygen deprivation) in anesthetized animals. However, it is also linked to increased risks of cardiac complications (e.g. changes in heart rate) due to its effects on β2-ARs outside the lungs⁶. An electrophysiological study using mice with experimentally-induced heart failure found that this intervention resulted in significantly decreased bronchial tissue responses to albuterol⁷. This was most probably due to significant decreases in β2-AR expression following heart failure⁷. Albuterol and Body Composition(?) Albuterol may also have positive effects on fat accumulation and metabolism. A group of researchers have claimed that doses of albuterol, caffeine or both increased lipid breakdown in cultured lipocytes⁸. They also reported a long-term trend of increased metabolic rates in rats, although increases in lean body mass and reductions in fat mass in response to the combination of caffeine and albuterol was greater compared to those associated with albuterol alone⁸. References: 1. Ameredes BT, Calhoun WJ. Levalbuterol versus albuterol. Curr Allergy Asthma Rep. 2009;9(5):401-409. 2. Keller MJ, Lecuona E, Prakriya M, et al. Calcium release-activated calcium (CRAC) channels mediate the beta(2)-adrenergic regulation of Na,K-ATPase. FEBS Lett. 2014;588(24):4686-4693. 3. Uhlig C, Silva PL, Ornellas D, et al. The effects of salbutamol on epithelial ion channels depend on the etiology of acute respiratory distress syndrome but not the route of administration. Respir Res. 2014;15:56. 4. Baker JG, Proudman RG, Hill SJ. Salmeterol's extreme beta2 selectivity is due to residues in both extracellular loops and transmembrane domains. Mol Pharmacol. 2015;87(1):103-120. 5. Sharif M, Khan BT, Ajmal K, Anwar MA. Acute effect of insulin on guinea pig airways and its amelioration by pre-treatment with salbutamol. J Pak Med Assoc. 2014;64(8):932-935. 6. Casoni D, Spadavecchia C, Adami C. Cardiovascular changes after administration of aerosolized salbutamol in horses: five cases. Acta Veterinaria Scandinavica. 2014;56(1):49-49. 7. Rinaldi B, Capuano A, Gritti G, et al. Effects of chronic administration of beta-blockers on airway responsiveness in a murine model of heart failure. Pulm Pharmacol Ther. 2014;28(2):109-113. 8. Liu AG, Arceneaux KP, 3rd, Chu JT, et al. The effect of caffeine and albuterol on body composition and metabolic rate. Obesity (Silver Spring). 2015.

LGD-4033. By Yikrazuul (Own work) [Public domain], via Wikimedia Commons   LGD-4033 is a selective androgen receptor modulator (SARMs). It has a high affinity (approximately 1nM) for the receptor, and has attracted much interest in some areas of medical research¹. SARMs are associated with potential in the treatment of age-related decreases in muscle mass and function and in bone density¹. These effects may be due to decreases in circulating levels of androgen-receptor agonists (e.g. testosterone and its analogs found in the body) and/or degradations in the receptor protein or its regulators (which are proteins that are required to form a complex with the androgen receptor and ensure that it carries out its functions, which are mainly binding to certain locations on DNA following activation) over time². Age-related bone and muscle loss (or osteopenia and sarcopenia respectively) are associated with reductions in mobility, function and life quality¹. They may also be associated with conditions such as some types of cancer, kidney failure and chronic obstructive pulmonary disease¹. SARMs may also have potential in the treatment of muscle loss related to causes other than aging. These may include hypogonadism, recovering from burns, osteoporosis or cancer³. Some researchers assert that these compounds have additional therapeutic applications related to conditions and applications such as depression, anemia, wound healing and benign prostate growths⁴. However, many SARMs are testosterone analogs (i.e. steroids). These are linked to prostate disease and other adverse effects. LGD-4033, on the other hand, binds to the androgen receptor, but is not a steroid¹. Therefore, it may have positive effects on muscle and bone mass retention, without adverse effects on other organs and systems. It has demonstrated these effects in animal studies, without reports of damage or diseases of the prostate in males¹. Another advantage of LGD-4033 and other similar SARMs is that they may be administered orally¹. LGD-4033 and other SARMs interact with the ligand-binding domain (LBD) of the androgen receptor, but in a different manner to natural androgens². LGD-4033 is associated with improvements in the bending strength, density and growth of bone in preclinical studies¹. Other similar nonsteroidal SARMs have demonstrated similar effects on bone and muscle, and also on sexual function, in rats, compared to control animals⁵. Administration with these has also been associated with the prevention of prostate tumor growth in rats, and a significant reduction in the rate of tumor growth in mice transfected with human prostate cancer cells⁶. Some models of age-related bone loss (or osteopenia) are achieved through orchidectomy (or castration) of older male rats⁶. The administration of non-steroidal SARMs resulted in significantly reduced rates of bone volume and mineral density loss compared to these values in control orchidectomized rats⁶. This intervention was also associated with improvements in the conservation of lean body mass in orchidectomized rats⁶. The administration of another non-steroidal SARM significantly increased muscle strength in a mouse model of Duchenne's muscular dystrophy⁷. The SARM also had beneficial effects on the running ability of these mice, whereas similar animals in control groups or groups receiving a steroid instead (nandrolone or alpha-methylprednisolone), exhibited significant increases in fatigue⁷.  References:  1. Basaria S, Collins L, Dillon EL, et al. The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2013;68(1):87-95. 2. Narayanan R, Mohler ML, Bohl CE, Miller DD, Dalton JT. Selective androgen receptor modulators in preclinical and clinical development. Nuclear Receptor Signaling. 2008;6:e010. 3. Segal S, Narayanan R, Dalton JT. Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery. Expert opinion on investigational drugs. 2006;15(4):377-387. 4. Omwancha J, Brown TR. Selective androgen receptor modulators: in pursuit of tissue-selective androgens. Current opinion in investigational drugs (London, England : 2000). 2006;7(10):873-881. 5. Miner JN, Chang W, Chapman MS, et al. An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate. Endocrinology. 2007;148(1):363-373. 6. Allan G, Lai MT, Sbriscia T, et al. A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats. The Journal of steroid biochemistry and molecular biology. 2007;103(1):76-83. 7. Cozzoli A, Capogrosso RF, Sblendorio VT, et al. GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy. Pharmacological research : the official journal of the Italian Pharmacological Society. 2013;72:9-24.

  Liothyronine is a synthetic form of triidothyronine (or T3). T3 is a thyroid hormone with many physiological functions. It is present in the hypothalamus, adipose tissue and skeletal muscle tissue¹. T3 is associated with the regulation of glucose metabolism by modulating the response to insulin in the liver¹. It is also associated with the metabolism of cholesterol¹. It plays a role in the adaptation to cold in humans and animals, through the T3 receptors-alpha and -beta². T3 also regulates uncoupling protein-3, which is involved in the production of heat in brown adipose tissue and skeletal muscle³. Thyroid hormones may also have important roles in the immune system. T3 levels in the immune cells of female (but not male) rats have been shown to decrease significantly in response to the administration of insulin⁴. Infusions of T3 have been shown to reverse the effects of thyroidectomy (i.e. reduced thyroxine turnover) in rats⁵. T3 is inhibited by type 3 iodothyronine deiodinase (D3), which inactivates this hormone by converting it to inactive T2⁶. A recent murine-cell in vitro study found that D3 is regulated by glucagon-like peptide-1 (GLP-1)⁶. Reduced free T3 levels are also associated with cardiac ischemia⁷. Supplemental T3 improved mitochrondrial function and cell viability in rat models of post-cardiac event ischemia⁸. Deficiencies in the levels of thyroid hormones, including T3, are known as hypothyroidism. This condition may be associated with many adverse effects on health, including fatigue, weight gain and constipation. It may be associated with additional physiological effects such as mitochrondrial dysfunction or damage and hepatic cell death⁹. The administration of T3 reduced apoptosis in the liver cells, and oxidative damage in the mitochrondria, of rats with experimentally-induced hypothyroidism⁹. T3 may also promote the proliferation of liver cells¹⁰. Hepatocytes from rats fed T3 for two to seven days showed that this is mediated through beta-catenin phosphorylated by protein kinase A (PKA)¹⁰. Decreased thyroid hormone levels may also affect pain sensitivity and other CNS functions¹¹. Treatment with T3 (compared to a control treatment) significantly restored normal thermal (but not mechanical) pain thresholds in a mouse model of hypothyroidism¹¹. T3 also restored the normal levels of pain-regulating neurotransmitters in the anterior cingulate cortex of mice with hypothyroidism¹¹. T3 is also associated with bone development¹². This is due to the fact that T3 receptors alpha and beta are present in bone cells¹². Some studies have demonstrated that younger animals with hypothyroidism exhibit bone malformations and dysfunctions¹². A study used a mutation to generate mice with inactive T3 alpha-receptors. This resulted in dysfunctional chrondrocyte proliferation and differentiation¹². However, mature chondrocytes were not affected by mutated T3 alpha-receptors¹². Thyroid hormones may also have cardioprotective functions, especially in response to adverse events¹³. Rats that underwent an experimental myocardial infarction treated with T3 and T4 for 26 days demonstrated a quicker return to normal cardiac function compared to similar untreated rats¹⁴. Treatment with T3 is also associated with the maturation of cardiac muscle cells derived from stem cells¹³. References: 1. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiological reviews. 2014;94(2):355-382. 2. Maslov LN, Vychuzhanova EA, Gorbunov AS, Tsybul'nikov S, Khaliulin IG, Chauski E. [Role of thyroid system in adaptation to cold]. Rossiiskii fiziologicheskii zhurnal imeni I.M. Sechenova / Rossiiskaia akademiia nauk. 2014;100(6):670-683. 3. Branco M, Ribeiro M, Negrao N, Bianco AC. 3,5,3'-Triiodothyronine actively stimulates UCP in brown fat under minimal sympathetic activity. The American journal of physiology. 1999;276(1 Pt 1):E179-187. 4. Pallinger E, Csaba G. In vivo effect of insulin on the hormone production of immune cells in mice - gender differences. Acta microbiologica et immunologica Hungarica. 2014;61(4):417-423. 5. Nagao H, Sasaki M, Imazu T, Takahashi K, Aoki H, Minato K. Effects of triiodothyronine on turnover rate and metabolizing enzymes for thyroxine in thyroidectomized rats. Life sciences. 2014;116(2):74-82. 6. Akiyama S, Ogiwara T, Aoki T, Tsunekawa K, Araki O, Murakami M. Glucagon-like peptide-1 stimulates type 3 iodothyronine deiodinase expression in a mouse insulinoma cell line. Life sciences. 2014;115(1-2):22-28. 7. Novitzky D, Cooper DK. Thyroid hormone and the stunned myocardium. The Journal of endocrinology. 2014;223(1):R1-8. 8. Forini F, Kusmic C, Nicolini G, et al. Triiodothyronine prevents cardiac ischemia/reperfusion mitochondrial impairment and cell loss by regulating miR30a/p53 axis. Endocrinology. 2014;155(11):4581-4590. 9. Mukherjee S, Samanta L, Roy A, Bhanja S, Chainy GB. Supplementation of T3 recovers hypothyroid rat liver cells from oxidatively damaged inner mitochondrial membrane leading to apoptosis. BioMed research international. 2014;2014:590897. 10. Fanti M, Singh S, Ledda-Columbano GM, Columbano A, Monga SP. Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent beta-catenin activation in rodents. Hepatology (Baltimore, Md.). 2014;59(6):2309-2320. 11. Yi J, Zheng JY, Zhang W, Wang S, Yang ZF, Dou KF. Decreased pain threshold and enhanced synaptic transmission in the anterior cingulate cortex of experimental hypothyroidism mice. Molecular pain. 2014;10:38. 12. Desjardin C, Charles C, Benoist-Lasselin C, et al. Chondrocytes play a major role in the stimulation of bone growth by thyroid hormone. Endocrinology. 2014;155(8):3123-3135. 13. Yang X, Rodriguez M, Pabon L, et al. Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. Journal of molecular and cellular cardiology. 2014;72:296-304. 14. de Castro AL, Tavares AV, Campos C, et al. Cardioprotective effects of thyroid hormones in a rat model of myocardial infarction are associated with oxidative stress reduction. Molecular and cellular endocrinology. 2014;391(1-2):22-29.

  GHRP-6 is a synthetic hexapeptide associated with the secretion of growth hormone in the pituitary glands of humans and animals¹. It is thought to achieve this through increases in intracellular calcium (Ca²⁺), activated PKC and the DAG/IP3 pathway^2,3. There are two main forms of this molecule: GHRP-6 and [D-Lys (3)]GHRP-6. The latter is a ghrelin receptor (GHS-R) antagonist⁴. In other words, it countermands the actions of GHRP-6. This is useful in many studies, as its use can validate a putative effect of GHRP-6; i.e. if GHRP-6 stimulates a particular pathway, this can be confirmed by its inhibition by [D-Lys (3)]GHRP-6. This version of the peptide can also confirm the role of ghrelin in novel applications⁴. [D-Lys (3)]GHRP-6 may also have its own potential in research and medicine. It has been associated with improvements in the biomarkers of obesity (or the metabolic syndrome), including ghrelin levels, leptin levels, blood cholesterol and blood glucose⁵. In addition, the administration of [D-Lys (3)]GHRP-6 may be associated with reductions in body mass⁵. New applications for GHRP-6 Some researchers have reported novel properties and/or functions of GHRP-6 or[D-Lys (3)]GHRP-6 that may affect how they are used in science and medicine in the near future. Alternatively, these peptides may be used to quantify the putative effects of ghrelin. Ghrelin is thought to have beneficial effects in situations such as adverse cardiac effects, cardiomyopathy, cerebrovascular complications (e.g. stroke), and vascular protection following retinopathy (in which new blood vessels may be abnormal and non-functional)^1,6. Most of these are based on in vitro or in vivo (animal) trials and studies. Intraperitoneal administration of combined EGF and GHRP-6 reduced clinical signs, and conserved nerve cell density, in an animal model of stroke⁷. GHRP-6 demonstrated the ability to significantly reduce infarct sizes, necrosis and oxidative stress (caused by reactive oxygen species) compared to a control treatment (saline) in an animal model of myocardial infarction. The control treatment was also associated with significant increases in IGF-1 expression compared to GHRP-6¹. This indicates that GHRP-6 initiates cardioprotective mechanisms that are distinct from those associated with IGF-1. Treatment with GHRP-6 significantly conserved vascular density, increased IGF-1 levels and increased VEGF levels in a rat model of retinopathy⁶. The addition of [D-Lys (3)]GHRP-6 negated these effects⁶. A study using a rat model of Alzheimer's disease found that the relevant markers (acetylcholinesterase and amyloid-beta) were reduced in animals treated with [D-Lys (3)]GHRP-6 compared to controls⁵. Rats treated with this peptide also showed improved performance in a spatial orientation task⁵. Other research indicates that ghrelin anatagonists may reduce alcohol intake behaviours, e.g. preference for this rather than water in animal studies⁸. However, a study randomizing C57BL/6J mice to [D-Lys (3)]GHRP-6 or another ghrelin antagonist (JMV2959) found that [D-Lys (3)]GHRP-6 reduced ethanol intake and preference on the first day of treatment only⁸. JMV2959 reduced this intake at all time-points, but also reduced food and water intake⁸. [D-Lys (3)]GHRP-6 was also used to confirm the role of ghrelin in relaxing the dilator and sphincter muscles of the rabbit iris⁹. References: 1. Berlanga J, Cibrian D, Guevara L, et al. Growth-hormone-releasing peptide 6 (GHRP6) prevents oxidant cytotoxicity and reduces myocardial necrosis in a model of acute myocardial infarction. Clinical science (London, England : 1979). 2007;112(4):241-250. 2. Bresson-Bepoldin L, Dufy-Barbe L. GHRP6-stimulated hormone secretion in somatotrophs: involvement of intracellular and extracellular calcium sources. Journal of neuroendocrinology. 1996;8(4):309-314. 3. Mau SE, Witt MR, Bjerrum OJ, Saermark T, Vilhardt H. Growth hormone releasing hexapeptide (GHRP-6) activates the inositol (1,4,5)-trisphosphate/diacylglycerol pathway in rat anterior pituitary cells. Journal of receptor and signal transduction research. 1995;15(1-4):311-323. 4. Luque EM, Torres PJ, de Loredo N, et al. Role of ghrelin in fertilization, early embryo development, and implantation periods. Reproduction (Cambridge, England). 2014;148(2):159-167. 5. Madhavadas S, Kutty BM, Subramanian S. Amyloid beta lowering and cognition enhancing effects of ghrelin receptor analog [D-Lys (3)] GHRP-6 in rat model of obesity. Indian journal of biochemistry & biophysics. 2014;51(4):257-262. 6. Zaniolo K, Sapieha P, Shao Z, et al. Ghrelin modulates physiologic and pathologic retinal angiogenesis through GHSR-1a. Investigative ophthalmology & visual science. 2011;52(8):5376-5386. 7. Garcia Del Barco-Herrera D, Martinez NS, Coro-Antich RM, et al. Epidermal growth factor and growth hormone-releasing peptide-6: combined therapeutic approach in experimental stroke. Restorative neurology and neuroscience. 2013;31(2):213-223. 8. Gomez JL, Ryabinin AE. The effects of ghrelin antagonists [D-Lys(3) ]-GHRP-6 or JMV2959 on ethanol, water, and food intake in C57BL/6J mice. Alcoholism, clinical and experimental research. 2014;38(9):2436-2444. 9. Rocha-Sousa A, Saraiva J, Henriques-Coelho T, Falcao-Reis F, Correia-Pinto J, Leite-Moreira AF. Ghrelin as a novel locally produced relaxing peptide of the iris sphincter and dilator muscles. Experimental eye research. 2006;83(5):1179-1187.