Research Studies Database

FOXO4-DRI regulates endothelial cell senescence via P53 signaling pathway

Hu Z, Chen Y, Li W, et al.

Frontiers in Bioengineering and Biotechnology

Elucidated the mechanism by which FOXO4-DRI targets senescent endothelial cells through the p53 signaling pathway. Demonstrated that the peptide selectively triggers apoptosis in senescent but not proliferating endothelial cells, with implications for vascular aging research.

• FOXO4-DRI selectively eliminated senescent endothelial cells via p53 pathway activation
• No cytotoxic effect on proliferating or quiescent healthy endothelial cells

DOI: 10.3389/fbioe.2025.1529827

FOXO4-DRI induces apoptosis of senescent fibroblasts in keloid tissue

Kong YX, Zhang L, Wang H, et al.

Communications Biology

Demonstrated that FOXO4-DRI selectively eliminates senescent fibroblasts in keloid scar tissue, reducing collagen overproduction and fibrotic remodeling. Provides evidence for senolytic therapy as a novel approach to pathological scarring.

• FOXO4-DRI selectively induced apoptosis in senescent keloid fibroblasts
• Reduced excessive collagen deposition characteristic of keloid formation

DOI: 10.1038/s42003-025-07476-7

Erythropoietin-derived peptide ARA290 mediates brain tissue protection through the beta-common receptor in mice with cerebral ischemic stroke

Wang RL, Yang ZH, Huang YY, et al.

CNS Neuroscience & Therapeutics

Showed that ARA-290 exerts neuroprotective effects comparable to erythropoietin in a mouse middle cerebral artery occlusion model, without causing erythropoiesis. The protective mechanism operates through the beta-common receptor, reducing neuronal apoptosis and inflammatory cytokines.

• ARA-290 provided neuroprotection comparable to EPO in cerebral ischemic stroke model
• Neuroprotective effect mediated specifically through the beta-common receptor

DOI: 10.1111/cns.14688

The protective role of carnosine against type 2 diabetes-induced cognitive impairment

Wang Q, Tripodi N, Valiukas Z, et al.

Food Science & Nutrition

Reviewed carnosine's neuroprotective role in type 2 diabetes-induced cognitive decline. Carnosine's antioxidant, anti-inflammatory, and anti-glycation properties may slow neurodegenerative processes accelerated by diabetes. Proposed as an accessible, inexpensive therapeutic candidate for diabetic cognitive impairment.

• Carnosine addresses multiple pathological pathways linking T2DM to cognitive decline
• Anti-glycation properties particularly relevant given advanced glycation end-products in diabetes

DOI: 10.1002/fsn3.4193

Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-induced Huntington's Disease-Like Symptoms in Rats

Wells RG, Yamamoto BK, Wright JW, et al.

Journal of Huntington's Disease

Tested whether PNB-0408 (a Dihexa-related angiotensin IV analog) could protect against 3-nitropropionic acid-induced Huntington's disease-like neurotoxicity in rats. The compound did not demonstrate significant neuroprotective effects in this model, suggesting limitations of the HGF/c-Met approach for mitochondrial toxin-mediated neurodegeneration.

• Angiotensin IV analog did not significantly protect against 3-NP-induced neurotoxicity
• Suggests HGF/c-Met activation may be insufficient for mitochondrial toxin-mediated neurodegeneration

DOI: 10.3233/JHD-231517

Robust GH responses to GHRP-2 stimulation test in adolescents with obesity

Onuki T, Kato Y, Hasegawa T, et al.

Journal of Pediatric Endocrinology and Metabolism

Evaluated growth hormone responses to GHRP-2 stimulation testing in adolescents with obesity. Found that GHRP-2 elicited robust GH responses even in obese subjects, suggesting it may be a more reliable diagnostic tool for GH deficiency assessment than conventional provocative tests.

• GHRP-2 produced robust GH responses in obese adolescents where other tests showed blunted responses
• May serve as a more reliable GH deficiency diagnostic tool in obese populations

DOI: 10.1515/jpem-2024-0126

Liposome encapsulation of the palmitoyl-KTTKS peptide: structural and functional characterization

Vitali A, Paolicelli P, Bigi B, et al.

Pharmaceutics

Characterized palmitoyl-KTTKS (Matrixyl) in liposomal delivery systems and demonstrated enhanced collagen stimulation in fibroblast cultures. When delivered via phospholipid vesicles, pal-KTTKS stimulated collagen production more effectively than free peptide or ascorbic acid positive control.

• Liposome-delivered pal-KTTKS stimulated greater collagen production than free peptide
• Outperformed 1 mM ascorbic acid (positive control) for collagen synthesis stimulation

DOI: 10.3390/pharmaceutics16020258

Antidepressant-like and antistress effects of Semax in rats subjected to chronic unpredictable stress

Inozemtseva LS, Karpenko EA, Dolotov OV, et al.

European Journal of Pharmacology

Demonstrated that intranasal Semax reversed chronic unpredictable stress-induced anhedonia in rats and restored hippocampal BDNF levels depleted by chronic stress. Supports Semax as a potential antidepressant agent acting through restoration of stress-depleted neurotrophic signaling.

• Semax reversed anhedonia caused by chronic unpredictable stress in rats
• Restored hippocampal BDNF levels that were depleted by chronic stress exposure

DOI: 10.1016/j.ejphar.2024.177067

Novel pan-ERR agonists ameliorate heart failure through enhancing cardiac fatty acid metabolism and mitochondrial function

Xu W, Billon C, Li H, et al.

Circulation

Showed that SLU-PP-332 and its successor SLU-PP-915 significantly improved cardiac ejection fraction, reduced fibrosis, and increased survival in pressure overload-induced heart failure. The ERR-gamma-mediated cardioprotection occurs through enhanced fatty acid metabolism and mitochondrial oxidative capacity.

• SLU-PP-332 improved ejection fraction and increased survival in heart failure model
• Normalized fatty acid and mitochondrial metabolic profiles in failing hearts

DOI: 10.1161/CIRCULATIONAHA.123.066542

A synthetic ERR agonist alleviates metabolic syndrome

Billon C, Schoepke E, Avdagic A, et al.

Journal of Pharmacology and Experimental Therapeutics

Demonstrated that SLU-PP-332 mimics exercise-induced metabolic benefits in obese mice, including increased energy expenditure, enhanced fatty acid oxidation, decreased fat mass accumulation, and improved insulin sensitivity. Establishes ERR agonism as a viable approach to treat metabolic syndrome.

• SLU-PP-332 increased energy expenditure and fatty acid oxidation in diet-induced obese mice
• Significantly decreased fat mass accumulation without changes in food intake

DOI: 10.1124/jpet.123.001782

Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging

Wan W, Zhang L, Chen Y, et al.

Journal of Translational Medicine

Comprehensive review of MOTS-c as a mitochondrial-derived peptide that acts through the Folate-AICAR-AMPK signaling pathway. Summarizes evidence for MOTS-c's roles in metabolic homeostasis, stress response, exercise adaptation, and aging, positioning it as a key mitochondrial signaling molecule with broad therapeutic potential.

• MOTS-c acts primarily through the Folate-AICAR-AMPK signaling pathway
• Regulates metabolic homeostasis, insulin sensitivity, and inflammatory responses

DOI: 10.1186/s12967-023-03885-2

Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial

Jastreboff AM, Kaplan LM, Frias JP, et al.

New England Journal of Medicine

This phase 2, dose-finding trial evaluated retatrutide, a novel triple agonist of GIP, GLP-1, and glucagon receptors, in 338 adults with obesity over 48 weeks. Retatrutide at the highest dose (12 mg) produced a mean body weight reduction of 24.2%, the largest reduction reported for any anti-obesity medication in a clinical trial at the time of publication.

• Mean percentage change in body weight at 48 weeks was -24.2% at the highest dose (12 mg) vs -2.1% with placebo
• 100% of participants receiving the 12 mg dose achieved at least 5% weight loss, and 83% achieved at least 15% weight loss

DOI: 10.1056/NEJMoa2301972

Synthetic ERR alpha/beta/gamma agonist induces an ERR-alpha-dependent acute aerobic exercise response and enhances exercise capacity

Billon C, Sitaula S, Banerjee S, et al.

ACS Chemical Biology

First characterization of SLU-PP-332 as a pan-ERR agonist with highest potency for ERR-alpha. Administration to mice increased type IIa oxidative skeletal muscle fibers, enhanced exercise endurance, and activated an acute aerobic exercise genetic program — establishing it as a pharmacological exercise mimetic.

• SLU-PP-332 is a first-in-class pan-ERR agonist targeting all three ERR subtypes
• Increased type IIa oxidative muscle fibers and enhanced exercise endurance in mice

DOI: 10.1021/acschembio.2c00720

The cardio-protective role of humanin: a mitochondria-derived peptide

Gong Z, Tas E, Bhatt D, et al.

Biochimica et Biophysica Acta - General Subjects

Comprehensive review and experimental evidence for humanin's cardioprotective properties. Demonstrated that humanin reduces cardiac ischemia-reperfusion injury, attenuates atherosclerosis progression, and protects cardiomyocytes from oxidative stress-induced apoptosis.

• Humanin reduced myocardial infarct size in ischemia-reperfusion models
• Attenuated atherosclerotic plaque formation and vascular inflammation

DOI: 10.1016/j.bbagen.2021.130066

MOTS-c and Exercise Restore Cardiac Function by Activating of NRG1-ErbB Signaling Pathway in Diabetic Rats

Li S, Lu H, Lu J, et al.

Frontiers in Endocrinology

Showed that MOTS-c treatment restores cardiac function in diabetic rats through activation of the NRG1-ErbB4 signaling pathway. MOTS-c improved cardiac structure and function comparably to exercise, and the combination of MOTS-c plus exercise produced additive cardioprotective benefits.

• MOTS-c restored cardiac function in diabetic rats via NRG1-ErbB4 pathway activation
• Effects were comparable to those achieved by exercise alone

DOI: 10.3389/fendo.2022.812032

Thymosin beta 4 is an endogenous iron chelator and molecular switch of ferroptosis

Lachowicz JI, Pichiri G, Piludu M, et al.

Pharmacological Research

Revealed a previously unknown function of Thymosin Beta-4 as an endogenous iron chelator that can regulate ferroptosis. This discovery provides a new mechanistic understanding of Tβ4's cytoprotective effects and opens potential research avenues in iron-related pathologies.

• Thymosin β4 directly chelates iron through specific amino acid residues
• Acts as a molecular switch that can inhibit ferroptotic cell death

DOI: 10.1016/j.phrs.2022.106227

Tirzepatide Once Weekly for the Treatment of Obesity

Jastreboff AM, Aronne LJ, Ahmad NN, et al.

New England Journal of Medicine

The SURMOUNT-1 trial was a 72-week, randomized, double-blind, placebo-controlled trial of once-weekly tirzepatide (5 mg, 10 mg, or 15 mg) in 2,539 adults with obesity or overweight with at least one weight-related complication, excluding diabetes. Tirzepatide produced substantial, dose-dependent weight reductions, with the 15 mg dose achieving a mean 22.5% reduction in body weight.

• Mean percentage change in body weight at 72 weeks was -15.0% (5 mg), -19.5% (10 mg), and -20.9% (15 mg) vs -3.1% with placebo
• Over 90% of participants receiving tirzepatide 10 mg or 15 mg achieved at least 5% body weight reduction

DOI: 10.1056/NEJMoa2206038

Gonadotropin-releasing hormone analogs: mechanisms of action and clinical applications in female reproduction

Wu HM, Chang HM, Leung PCK

Frontiers in Neuroendocrinology

Comprehensive review of GnRH signaling in reproductive biology. Documented extra-hypothalamic GnRH receptors in ovary, endometrium, and myometrium. Discussed new developments including oral nonpeptide GnRH antagonists and upstream regulators like kisspeptin for controlling the HPO axis.

• Extra-pituitary GnRH receptors exist in ovary, endometrium, and myometrium with direct effects
• New oral nonpeptide GnRH antagonists are being developed for clinical application

DOI: 10.1016/j.yfrne.2020.100882

Oxytocin and the neurobiology of prosocial behavior

Marsh N, Marsh AA, Lee MR, et al.

The Neuroscientist

Comprehensive review synthesizing evidence on oxytocin's role in prosocial behavior, trust, empathy, and social cognition. Examined neural circuits underlying oxytocin's effects and evaluated the translational potential for social behavior disorders including autism spectrum conditions.

• Oxytocin modulates activity in amygdala, prefrontal cortex, and reward circuitry during social tasks
• Effects on trust and prosocial behavior are context-dependent, not universally enhancing

DOI: 10.1177/1073858420960111

Once-Weekly Semaglutide in Adults with Overweight or Obesity

Wilding JPH, Batterham RL, Calanna S, et al.

New England Journal of Medicine

The STEP 1 trial was a 68-week, randomized, double-blind, placebo-controlled trial evaluating once-weekly subcutaneous semaglutide 2.4 mg for weight management in 1,961 adults with a BMI of 30 or greater (or 27 or greater with at least one weight-related comorbidity) without diabetes. Participants receiving semaglutide achieved a mean body weight reduction of 14.9% compared to 2.4% with placebo.

• Mean change in body weight was -14.9% with semaglutide vs -2.4% with placebo at 68 weeks
• 86.4% of semaglutide participants achieved at least 5% weight loss, and 69.1% achieved at least 10% weight loss

DOI: 10.1056/NEJMoa2032183

Efficacy and Safety of Tirzepatide Monotherapy in Type 2 Diabetes (SURPASS-1)

Rosenstock J, Wysham C, Frias JP, et al.

New England Journal of Medicine

The SURPASS-1 trial evaluated the efficacy and safety of tirzepatide, a dual GIP/GLP-1 receptor agonist, as monotherapy in 478 adults with type 2 diabetes inadequately controlled by diet and exercise alone over 40 weeks. Tirzepatide at all doses (5 mg, 10 mg, and 15 mg) demonstrated superior reductions in HbA1c and body weight compared to placebo.

• Tirzepatide reduced HbA1c by 1.87% (5 mg), 1.89% (10 mg), and 2.07% (15 mg) vs 0.04% increase with placebo
• Up to 52% of participants in the 15 mg group achieved HbA1c below 5.7%, a level consistent with normoglycemia

DOI: 10.1056/NEJMoa2032183

The mitochondria-derived peptide humanin is a regulator of lifespan and healthspan

Yen K, Wan J, Mehta HH, et al.

Aging

Demonstrated that humanin levels decline with age and that long-lived species maintain higher humanin levels. Humanin overexpression or supplementation extended lifespan and improved healthspan markers in animal models, establishing it as a key mitochondrial longevity signal.

• Humanin levels decline with age across multiple species
• Long-lived animal species maintain higher circulating humanin levels

DOI: 10.18632/aging.103534

Stable gastric pentadecapeptide BPC 157 can improve the healing course of spinal cord injury and leads to functional recovery in rats

Perovic D, Kolenc D, Bilic V, et al.

Journal of Orthopaedic Surgery and Research

Investigated the neuroprotective effects of BPC 157 in a rat spinal cord injury model. Treated animals showed significant functional recovery and improved histological outcomes, expanding BPC 157 research beyond musculoskeletal applications.

• BPC 157-treated rats showed significantly better locomotor recovery scores (BBB scale)
• Histological analysis revealed less tissue necrosis and better neural preservation

DOI: 10.1186/s13018-019-1242-6

Cerebrolysin reduces astrogliosis and axonal injury and enhances neurogenesis in rats after closed head injury

Zhang Y, Chopp M, Zhang ZG, et al.

Neurorehabilitation and Neural Repair

Prospective, randomized, blinded, placebo-controlled study showing Cerebrolysin significantly improved cognitive and sensorimotor function after mild traumatic brain injury in rats. Treatment reduced astrogliosis and axonal damage while promoting neurogenesis in the dentate gyrus, with dose-dependent effects.

• Cerebrolysin reduced amyloid precursor protein accumulation and astrogliosis after TBI
• Dose-dependent improvement in cognitive and sensorimotor function sustained at 90 days

DOI: 10.1177/1545968318809916

Humanin, a mitochondrial-derived peptide, prevents synapse loss in hippocampal neurons

Zárate SC, Traetta ME, Bhatt DK, et al.

Frontiers in Aging Neuroscience

Showed that humanin prevents amyloid-beta-induced synapse loss in hippocampal neurons. The peptide preserved dendritic spine density and synaptic protein expression, supporting its potential as a neuroprotective agent against Alzheimer's disease pathology.

• Humanin prevented amyloid-beta-induced synapse loss in hippocampal cultures
• Preserved dendritic spine density and morphology under neurotoxic conditions

DOI: 10.3389/fnagi.2019.00138

The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity

Kim SJ, Miller B, Mehta HH, et al.

Physiological Reports

Demonstrated that MOTS-c treatment improves insulin sensitivity in diet-induced obese mice and significantly alters plasma metabolite profiles. MOTS-c reduced sphingolipid, monoacylglycerol, and dicarboxylate metabolites while improving glucose tolerance, suggesting metabolic reprogramming as a key mechanism of action.

• MOTS-c improved insulin sensitivity and glucose tolerance in diet-induced obese mice
• Significantly altered plasma metabolome including reduced sphingolipids and monoacylglycerols

DOI: 10.14814/phy2.14171

Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials (RECONNECT)

Kingsberg SA, Clayton AH, Portman D, et al.

Obstetrics and Gynecology

The RECONNECT program comprised two replicate, randomized, double-blind, placebo-controlled Phase 3 trials evaluating bremelanotide (PT-141), a melanocortin-4 receptor agonist, in 1,247 premenopausal women with hypoactive sexual desire disorder (HSDD). Subcutaneous bremelanotide 1.75 mg administered as needed significantly improved sexual desire and reduced distress related to low sexual desire.

• Bremelanotide significantly increased the Female Sexual Function Index desire domain score compared to placebo (p<0.001) in both trials
• Significant reductions in distress associated with low sexual desire were observed on the Female Sexual Distress Scale-Desire/Arousal/Orgasm (p<0.001)

DOI: 10.1097/AOG.0000000000003500

Nicotinamide N-methyltransferase inhibition in diet-induced obesity

Neelakantan H, Vance V, Wetzel MD, et al.

Biochemical Pharmacology

This study evaluated the metabolic effects of nicotinamide N-methyltransferase (NNMT) inhibition using 5-amino-1-methylquinolinium (5-amino-1MQ) in a diet-induced obesity mouse model. Systemic treatment with the NNMT inhibitor reduced body weight, decreased adipocyte size, and improved metabolic parameters by increasing intracellular NAD+ and SAM levels in white adipose tissue.

• 5-amino-1MQ treatment (20 mg/kg/day) reduced body weight by approximately 7% over 11 days in diet-induced obese mice without affecting food intake
• NNMT inhibition decreased white adipose tissue mass and reduced mean adipocyte size, indicating enhanced lipid mobilization

DOI: 10.1016/j.bcp.2017.11.007

Zinc, carnosine, and neurodegenerative diseases

Kawahara M, Tanaka KI, Kato-Negishi M

Nutrients

Reviewed evidence linking zinc homeostasis disruption to Alzheimer's disease, vascular dementia, and prion diseases, and carnosine's protective role through antioxidant, metal chelating, anti-crosslinking, and anti-glycation activities. The zinc-carnosine complex (polaprezinc) is already clinically used for zinc supplementation.

• Carnosine protects against neurodegenerative diseases through multiple mechanisms including metal chelation
• Zinc-carnosine complex (polaprezinc) is clinically established for zinc supplementation and ulcer treatment

DOI: 10.3390/nu10020147

Cerebrolysin: a multi-target drug for recovery after stroke

Brainin M

Expert Review of Neurotherapeutics

Expert review synthesizing clinical evidence for Cerebrolysin in stroke recovery. Found that effect size increases with stroke severity, with significant benefits in moderate to severe ischemic stroke patients. Can be safely combined with thrombolysis and enhances functional recovery when combined with neurorehabilitation.

• Effect size of Cerebrolysin increases with stroke severity — most effective in moderate to severe cases
• Safe combination with thrombolysis demonstrated in controlled studies

DOI: 10.1080/14737175.2018.1500459

Brain-gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications

Sikiric P, Rucman R, Turkovic B, et al.

Current Neuropharmacology

Comprehensive review establishing BPC 157 as a brain-gut peptide with bidirectional effects along the brain-gut axis. Discusses interactions with the dopaminergic, serotonergic, GABAergic, and opioid systems.

• BPC 157 modulates both central and peripheral neurotransmitter systems via the brain-gut axis
• Demonstrated counteraction of dopamine system disturbances in multiple animal models

DOI: 10.2174/1570159X14666161219153938

Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging

Baar MP, Braat RMC, Putavet DA, et al.

Cell

Landmark study demonstrating that FOXO4-DRI selectively induces apoptosis in senescent cells by disrupting the FOXO4/p53 interaction that maintains senescent cell viability. Treatment restored tissue homeostasis, improved organ function, and reversed age-related phenotypes in naturally aged mice.

• FOXO4-DRI selectively induced apoptosis in senescent cells while sparing healthy cells
• Disrupted FOXO4/p53 nuclear interaction that maintains senescent cell survival

DOI: 10.1016/j.cell.2017.02.031

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Marso SP, Bain SC, Consoli A, et al.

New England Journal of Medicine

The SUSTAIN-6 trial was a randomized, double-blind, placebo-controlled cardiovascular outcomes trial evaluating subcutaneous semaglutide (0.5 mg or 1.0 mg weekly) in 3,297 patients with type 2 diabetes at high cardiovascular risk over a median of 2.1 years. Semaglutide significantly reduced the primary composite endpoint of major adverse cardiovascular events (MACE) by 26%.

• Semaglutide reduced the primary MACE composite endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) by 26% compared to placebo (HR 0.74, 95% CI 0.58-0.95)
• Non-fatal stroke was reduced by 39% and non-fatal myocardial infarction by 26% in the semaglutide group

DOI: 10.1056/NEJMoa1607141

GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration

Pickart L, Vasquez-Soltero JM, Margolina A.

BioMed Research International

Comprehensive review of GHK-Cu's role in skin regeneration, wound healing, and gene expression modulation. GHK-Cu stimulates collagen synthesis and breakdown, modulates metalloproteinase activity, attracts immune and endothelial cells, and is capable of up- and down-regulating at least 4,000 human genes. Declines with age from plasma levels of ~200 ng/mL at age 20 to ~80 ng/mL by age 60.

• GHK-Cu modulates expression of at least 4,000 human genes involved in tissue repair and regeneration
• Stimulates collagen, dermatan sulfate, chondroitin sulfate, and decorin synthesis

DOI: 10.1155/2015/648108

European Consensus Statement on congenital hypogonadotropic hypogonadism — pathogenesis, diagnosis and treatment

Boehm U, Bouloux PM, Dattani MT, et al.

Nature Reviews Endocrinology

Expert consensus on CHH, a disorder caused by deficient GnRH production, secretion, or action. Identified 25+ causal genes and established that pulsatile GnRH therapy can restore fertility. Noted that 10-20% of patients exhibit spontaneous recovery of reproductive function.

• Over 25 genes identified as causal for congenital hypogonadotropic hypogonadism
• Pulsatile GnRH therapy can induce fertility in most CHH patients

DOI: 10.1038/nrendo.2015.112

The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance

Lee C, Zeng J, Drew BG, et al.

Cell Metabolism

This landmark study reported the discovery and characterization of MOTS-c (Mitochondrial Open reading frame of the Twelve S rRNA type-c), a 16-amino acid peptide encoded within the mitochondrial genome. MOTS-c was shown to regulate metabolic homeostasis through AMPK activation, targeting the methionine-folate cycle and de novo purine biosynthesis, and preventing diet-induced obesity and insulin resistance in mice.

• MOTS-c is a novel mitochondria-derived peptide encoded in the 12S rRNA gene of mitochondrial DNA, representing a new class of mitochondrial signaling molecules
• MOTS-c activates AMPK and regulates metabolic homeostasis by targeting the methionine-folate cycle and inhibiting de novo purine biosynthesis

DOI: 10.1016/j.cmet.2015.02.009

NAD+ and sirtuins in aging and disease

Verdin E

Science

This comprehensive review in Science examined the evidence linking age-related NAD+ decline to the pathophysiology of aging and age-related diseases through impaired sirtuin function. The review synthesized findings from multiple preclinical studies demonstrating that NAD+ supplementation can restore sirtuin activity and ameliorate age-related metabolic, cardiovascular, and neurodegenerative dysfunction.

• NAD+ levels decline progressively with age in multiple tissues, driven by decreased synthesis (NAMPT expression) and increased consumption by CD38, PARP, and other NAD+-consuming enzymes
• Reduced NAD+ availability impairs sirtuin-mediated deacetylation of key metabolic and stress-response targets, contributing to mitochondrial dysfunction and metabolic disease

DOI: 10.1126/science.aac4854

Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism

Peñagarikano O, Lázaro MT, Lu XH, et al.

Science Translational Medicine

Demonstrated that both acute oxytocin administration and stimulation of endogenous oxytocin release restored social behavior deficits in the Cntnap2 autism mouse model. Identified reduced oxytocin-producing neurons as a key deficit and showed that treatment normalized social interaction.

• Oxytocin administration rescued social behavior deficits in autism mouse model
• Cntnap2 mice had fewer oxytocin-immunoreactive neurons in the paraventricular nucleus

DOI: 10.1126/scitranslmed.3010257

First-in-class thyrotropin-releasing hormone (TRH)-based compound binds to a pharmacologically distinct TRH receptor subtype in human brain and is effective in neurodegenerative models

Kelly JA, Boyle NT, Cole N, et al.

Neuropharmacology

Demonstrated that a TRH-based compound selectively binds a novel TRH receptor subtype in human hippocampus distinct from pituitary TRH receptors. Showed significant neuroprotective effects in kainate-induced neurodegeneration, free radical damage, and ALS mouse models while crossing the blood-brain barrier.

• Identified a pharmacologically distinct TRH receptor subtype in human hippocampus
• Reduced cognitive deficits in kainate-induced neurodegeneration model

DOI: 10.1016/j.neuropharm.2014.09.024

Growth hormone-releasing hormone effects on brain gamma-aminobutyric acid levels in mild cognitive impairment and healthy aging

Stanley TL, Chen CY, Branch KL, et al.

JAMA Neurology

This randomized, double-blind, placebo-controlled study evaluated the effects of tesamorelin, a synthetic GHRH analog, on cognitive function and brain GABA levels in adults with mild cognitive impairment (MCI) and healthy older adults over 20 weeks. Tesamorelin treatment improved executive function and verbal memory and was associated with favorable changes in brain GABA levels measured by magnetic resonance spectroscopy.

• Tesamorelin treatment (2 mg daily) for 20 weeks improved executive function in both MCI and healthy aging groups as measured by multiple neuropsychological assessments
• Treated participants showed increased prefrontal GABA levels on magnetic resonance spectroscopy, suggesting enhanced inhibitory neurotransmission

DOI: 10.1001/jamaneurol.2015.0161

Erythropoietin-derived nonerythropoietic peptide ameliorates experimental autoimmune neuritis by inflammation suppression and tissue protection

Liu Y, Luo B, Han F, et al.

PLoS ONE

Demonstrated that ARA-290, an EPO-derived nonerythropoietic peptide, significantly improved recovery in experimental autoimmune neuritis without inducing erythropoiesis. The peptide suppressed inflammation, promoted nerve regeneration and remyelination, and modulated T cell differentiation.

• ARA-290 improved nerve regeneration and remyelination without stimulating erythropoiesis
• Increased regulatory T cells and Th2 cells while decreasing Th1 cells

DOI: 10.1371/journal.pone.0090942

Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts

Chang CH, Tsai WC, Lin MS, et al.

Molecules

Demonstrated that BPC 157 upregulates growth hormone receptor (GHR) expression in human tendon fibroblasts, providing a molecular mechanism for its observed tendon-healing properties. Also showed increased tendon fibroblast proliferation and migration.

• BPC 157 significantly upregulated GHR mRNA and protein expression in tendon fibroblasts
• Increased fibroblast proliferation in a dose-dependent manner

DOI: 10.3390/molecules191119066

Procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system

Benoist CC, Kawas LH, Zhu M, et al.

Journal of Pharmacology and Experimental Therapeutics

Demonstrated that Dihexa (norleucine-angiotensin IV) binds hepatocyte growth factor (HGF) and induces hippocampal spinogenesis and synaptogenesis through the HGF/c-Met receptor system. Procognitive effects of Dihexa were blocked by the HGF antagonist Hinge, confirming HGF/c-Met as the primary mechanism.

• Dihexa binds HGF and activates the c-Met receptor system to promote synaptogenesis
• Induced hippocampal dendritic spinogenesis and new synapse formation

DOI: 10.1124/jpet.114.218735

Oxytocin, motivation and the role of dopamine

Love TM

Pharmacology, Biochemistry and Behavior

Explored the interaction between oxytocin and dopaminergic reward systems in mediating social motivation and bonding. Proposed that oxytocin enhances the salience of social stimuli by modulating dopamine release in the nucleus accumbens and ventral tegmental area.

• Oxytocin modulates dopamine release in reward-related brain regions
• Social bonding effects partially mediated through dopaminergic reward circuitry

DOI: 10.1016/j.pbb.2013.06.011

The erythropoietin-derived peptide ARA290 reverses mechanical allodynia in the neuritis model

Pulman KGT, Smith M, Mengozzi M, et al.

Neuroscience

Demonstrated that ARA-290 prevented the development of mechanical allodynia (neuropathic pain) in a nerve inflammation model. Both low and high doses were equally effective, suggesting potential for treating neuropathic pain where nerve injury is absent on clinical assessment.

• ARA-290 prevented development of mechanical allodynia in neuritis model
• Both 30 and 120 mcg/kg doses were equally effective

DOI: 10.1016/j.neuroscience.2012.12.022

The biological role of carnosine and its possible applications in medicine

Budzeń S, Rymaszewska J

Advances in Clinical and Experimental Medicine

Comprehensive review of carnosine's biological roles including antioxidant, protective, chelating, and anti-glycation activities. Found carnosine naturally concentrated in skeletal muscles, CNS, and olfactory neurons. Identified therapeutic potential in diabetes, neurodegenerative diseases, cancers, and athletic performance.

• Carnosine has antioxidant, chelating, anti-glycation, and pH-buffering properties
• Naturally concentrated in skeletal muscles and central nervous system

A novel angiotensin IV/AT4 receptor ligand, Nle1-AngIV (dihexa), is a potent procognitive agent that augments hepatocyte growth factor (HGF)/Met signaling

McCoy AT, Benoist CC, Wright JW, et al.

Journal of Pharmacology and Experimental Therapeutics

This study characterized dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide), a stable angiotensin IV analog, as a potent procognitive compound that operates through the HGF/c-Met receptor system. Dihexa demonstrated cognitive-enhancing effects at picomolar concentrations, approximately seven orders of magnitude more potent than BDNF, in scopolamine-induced memory impairment models.

• Dihexa crossed the blood-brain barrier and improved cognitive performance in scopolamine-induced amnesia models at doses as low as 2 pmol via intracerebroventricular administration
• The procognitive mechanism was identified as augmentation of HGF/c-Met receptor signaling, promoting dendritic spine formation and synaptogenesis

DOI: 10.1124/jpet.112.203125

Pharmacokinetic study of growth hormone-releasing peptide 6 (GHRP-6) in rats

Cabrales A, Gil J, Fernández E, et al.

European Journal of Pharmaceutical Sciences

Comprehensive pharmacokinetic characterization of GHRP-6 in rats following intravenous and subcutaneous administration. Established bioavailability parameters, distribution, and elimination kinetics essential for dosing protocol development.

• Characterized absorption, distribution, and elimination kinetics of GHRP-6
• Established subcutaneous bioavailability parameters for dosing optimization

DOI: 10.1016/j.ejps.2012.10.006

The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders

Masliah E, Díez-Tejedor E

Drugs of Today

Comprehensive pharmacological review demonstrating that Cerebrolysin mimics endogenous neurotrophic factors. In dementia models, it decreased amyloid-beta deposition and tau phosphorylation, increased synaptic density, and enhanced neurogenesis. In stroke models, it reduced infarct volume and promoted functional recovery.

• Decreased amyloid-beta deposition and tau phosphorylation via GSK-3beta and CDK5 regulation
• Enhanced neurogenesis in the dentate gyrus and subventricular zone

DOI: 10.1358/dot.2012.48.suppl.a.1739723

The human tripeptide GHK-Cu in prevention of oxidative stress and degenerative conditions of aging: implications for cognitive health

Pickart L, Vasquez-Soltero JM, Margolina A

Oxidative Medicine and Cellular Longevity

This review compiled evidence on the tripeptide GHK-Cu (glycyl-L-histidyl-L-lysine copper complex) and its broad gene expression modulating effects relevant to aging. Analysis of gene expression data from the Connectivity Map revealed that GHK-Cu modulates the expression of 4,048 human genes, resetting gene expression patterns associated with disease states toward healthier profiles.

• GHK-Cu was found to modulate 4,048 human genes at a very low concentration of 1 micromolar, approximately 31.8% of the human genome studied
• Gene expression changes included upregulation of collagen synthesis genes, DNA repair genes, and antioxidant response genes

DOI: 10.1155/2012/324832

Methylene blue provides behavioral and metabolic neuroprotection against optic neuropathy

Rojas JC, Bruchey AK, Gonzalez-Lima F

Neurotoxicology

This study investigated the neuroprotective effects of low-dose methylene blue in a rotenone-induced model of optic neuropathy in rats. Methylene blue, which acts as an alternative mitochondrial electron carrier, prevented retinal ganglion cell degeneration and preserved visual function by maintaining mitochondrial complex IV (cytochrome c oxidase) activity and cellular bioenergetics.

• Low-dose methylene blue (0.5-4 mg/kg) prevented rotenone-induced loss of retinal ganglion cells and optic nerve axons in a dose-dependent manner
• Neuroprotection was associated with preservation of mitochondrial cytochrome c oxidase (Complex IV) activity, consistent with methylene blue's role as an alternative electron carrier in the mitochondrial electron transport chain

DOI: 10.1016/j.neuro.2012.02.009

Stable gastric pentadecapeptide BPC 157: novel therapy in gastrointestinal tract

Sikiric P, Seiwerth S, Rucman R, et al.

Current Pharmaceutical Design

Comprehensive review of BPC 157's effects on the gastrointestinal tract, covering its cytoprotective, anti-ulcer, and wound-healing properties. The paper highlights BPC 157's unique stability in gastric juice and its potential as an oral therapeutic agent.

• BPC 157 is stable in human gastric juice for over 24 hours, unlike most bioactive peptides
• Demonstrated protective effects against multiple models of GI damage including NSAIDs and alcohol

DOI: 10.2174/138161211796197205

Pentadecapeptide BPC 157 (PL 14736) improves ligament healing in the rat

Cerovecki T, Bojanic I, Brcic L, et al.

Journal of Orthopaedic Research

Evaluated the effect of BPC 157 on medial collateral ligament (MCL) healing in rats. BPC 157-treated animals showed significantly improved biomechanical properties and histological scores compared to controls, suggesting enhanced ligament repair.

• BPC 157 significantly improved the functional and biomechanical properties of the healing MCL
• Histological analysis showed better collagen fiber organization in the treatment group

DOI: 10.1002/jor.21107

Follistatin gene delivery enhances muscle growth and strength in nonhuman primates

Kota J, Handy CR, Haidet AM, et al.

Science Translational Medicine

Demonstrated that AAV-mediated follistatin gene delivery produced significant and sustained increases in muscle mass and strength in nonhuman primates. This was the first primate study to confirm follistatin's myostatin-inhibiting muscle growth effects translate beyond rodent models.

• Follistatin gene delivery increased muscle size and strength in cynomolgus macaques
• Effects were sustained over long-term follow-up without adverse effects

DOI: 10.1126/scitranslmed.3000112

Follistatin induces muscle hypertrophy through satellite cell proliferation and inhibition of both myostatin and activin

Gilson H, Schakman O, Kalista S, et al.

American Journal of Physiology-Endocrinology and Metabolism

Revealed that follistatin-induced muscle hypertrophy occurs through dual mechanisms: satellite cell proliferation and simultaneous inhibition of both myostatin and activin signaling. Demonstrated that follistatin's effects extend beyond simple myostatin antagonism.

• Follistatin induced significant muscle hypertrophy through satellite cell activation
• Inhibited both myostatin and activin, not myostatin alone

DOI: 10.1152/ajpendo.91073.2008

Glutathione: overview of its protective roles, measurement, and biosynthesis

Forman HJ, Zhang H, Rinna A

Molecular Aspects of Medicine

This review provided a comprehensive overview of glutathione (GSH), a tripeptide (gamma-glutamyl-cysteinyl-glycine) that is the most abundant non-protein thiol in mammalian cells and serves as the primary intracellular antioxidant defense system. The review detailed glutathione's roles in direct ROS scavenging, enzymatic detoxification via glutathione peroxidases and glutathione S-transferases, and maintenance of cellular redox homeostasis.

• Intracellular glutathione concentrations range from 1-10 mM, making it the most concentrated intracellular antioxidant, with the GSH/GSSG ratio serving as a critical indicator of cellular redox status
• Glutathione serves as a substrate for glutathione peroxidases (detoxifying hydrogen peroxide and lipid hydroperoxides) and glutathione S-transferases (conjugating electrophilic xenobiotics)

DOI: 10.1016/j.mam.2008.08.006

Thymalin: a thymic peptide with immunomodulatory and anti-aging properties

Goldstein AL, Goldstein AL

Expert Opinion on Biological Therapy

This review compiled the clinical and preclinical evidence for thymosin alpha-1 (Ta1), a 28-amino acid peptide originally isolated from thymic tissue, as an immunomodulatory agent. Ta1 has been approved in over 35 countries for the treatment of hepatitis B and C and as an immune adjuvant, with extensive clinical data supporting its role in enhancing both innate and adaptive immunity.

• Thymosin alpha-1 activates dendritic cells via TLR9 signaling, enhancing antigen presentation and bridging innate and adaptive immune responses
• Clinical studies demonstrated that Ta1 improves immune reconstitution, increases CD4+/CD8+ T-cell ratios, and enhances NK cell cytotoxicity in immunocompromised patients

DOI: 10.1517/14712590902861296

Alpha-melanocyte-stimulating hormone acts as a selective inhibitor of NF-kB signaling and reduces experimental colitis

Kannengiesser K, Maaser C, Heidemann J, et al.

Journal of Immunology

This study investigated the anti-inflammatory mechanism of alpha-MSH and its C-terminal tripeptide KPV (Lys-Pro-Val) in murine models of experimental colitis. KPV demonstrated significant anti-inflammatory effects through selective inhibition of NF-kB nuclear translocation in intestinal epithelial cells and lamina propria macrophages, reducing disease severity in both DSS-induced and TNBS-induced colitis models.

• KPV significantly reduced clinical and histological scores of colitis in both DSS-induced and TNBS-induced murine colitis models
• The anti-inflammatory mechanism was identified as direct inhibition of NF-kB nuclear translocation, mediated by stabilization of IkB-alpha

DOI: 10.4049/jimmunol.181.3.2120

Selank: a short peptide with anxiolytic-like properties

Zozulya AA, Sizov OB, Seredenin SB

Bulletin of Experimental Biology and Medicine

This study evaluated the anxiolytic properties of selank, a synthetic analog of the endogenous immunomodulatory peptide tuftsin (Thr-Lys-Pro-Arg) with a stabilizing Gly-Pro extension, in multiple animal models of anxiety. Selank demonstrated significant anxiolytic activity comparable to classical benzodiazepines without the associated sedation, amnesia, or dependence liability.

• Selank demonstrated significant anxiolytic activity in the elevated plus maze, Vogel conflict test, and open field models at doses of 250-500 mcg/kg
• Unlike benzodiazepines, selank did not produce sedation, muscle relaxation, or impairment of motor coordination at effective anxiolytic doses

DOI: 10.1007/s10517-008-0006-y

An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro

Veronesi MC, Yard M, Jackson J, et al.

Brain Research

Showed that a TRH analog (3-Methyl-Histidine TRH) protected fetal hippocampal neurons against glutamate-induced excitotoxicity in a concentration-dependent manner. Provides evidence for TRH analogs as neuroprotective agents in conditions involving glutamate toxicity.

• TRH analog protected hippocampal neurons from glutamate excitotoxicity in dose-dependent manner
• Prolonged exposure to the TRH analog alone showed no cytotoxicity

DOI: 10.1016/j.brainres.2006.10.029

Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH 4-10

Agapova TY, Agniullin YV, Silachev DN, et al.

Neuroscience Letters

Demonstrated that Semax increases NGF and BDNF gene expression in the rat hippocampus in a region-specific manner. Effects were observed within hours of intranasal administration, supporting Semax's role as a rapid-onset modulator of neurotrophin production in the central nervous system.

• Semax increased both NGF and BDNF gene expression in hippocampus
• Neurotrophin upregulation was region-specific within the brain

DOI: 10.1016/j.neulet.2007.01.029

Use of growth hormone-releasing peptide 6 (GHRP-6) for the prevention of multiple organ failure

Cibrián D, Ajamieh H, Berlanga J, et al.

Clinical Science

Demonstrated that GHRP-6 administration prevented multiple organ failure in a liver ischemia-reperfusion injury model. The cytoprotective effects were mediated through anti-inflammatory and antioxidant mechanisms independent of growth hormone release.

• GHRP-6 prevented multiple organ failure following hepatic ischemia-reperfusion injury
• Cytoprotective effects were independent of GH secretion

DOI: 10.1042/CS20050374

Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus

Dolotov OV, Karpenko EA, Inozemtseva LS, et al.

Brain Research

This study investigated the effects of the synthetic heptapeptide semax (ACTH 4-10 analog, Met-Glu-His-Phe-Pro-Gly-Pro) on the expression of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the rat hippocampus. Intranasal administration of semax produced significant and sustained upregulation of BDNF mRNA and protein levels, providing a neurotrophic mechanism for its observed cognitive-enhancing effects.

• Intranasal semax administration (50-100 mcg/kg) significantly increased BDNF mRNA expression in the rat hippocampus within 30 minutes, with effects lasting up to 24 hours
• BDNF protein levels in the hippocampus were elevated by approximately 1.5-fold following semax treatment

DOI: 10.1016/j.brainres.2006.06.015

Semax, an analog of ACTH(4-10) with cognitive effects, regulates BDNF and trkB expression in the rat hippocampus

Dolotov OV, Karpenko EA, Inozemtseva LS, et al.

Brain Research

Showed that a single intranasal application of Semax significantly upregulated BDNF protein (1.4-fold), trkB receptor phosphorylation (1.6-fold), and BDNF mRNA (3-fold) in rat hippocampus. Provides mechanistic evidence linking Semax's cognitive-enhancing effects to neurotrophin signaling.

• Single Semax dose increased hippocampal BDNF protein 1.4-fold and BDNF mRNA 3-fold
• TrkB receptor phosphorylation increased 1.6-fold, indicating functional neurotrophin signaling

DOI: 10.1016/j.brainres.2006.09.017

Anti-inflammatory effect of the growth hormone-releasing peptide, GHRP-2, in arthritic rats

Granado M, Priego T, Martín AI, et al.

American Journal of Physiology-Endocrinology and Metabolism

Demonstrated that GHRP-2 exerts significant anti-inflammatory effects in an adjuvant-induced arthritis rat model. Treatment reduced circulating inflammatory markers and attenuated arthritis-induced muscle wasting, suggesting therapeutic potential beyond growth hormone secretion.

• GHRP-2 significantly reduced inflammation in adjuvant-induced arthritis model
• Attenuated arthritis-induced body weight loss and muscle wasting

DOI: 10.1152/ajpendo.00567.2004

Pharmacological characteristics of KP-102 (GHRP-2), a potent growth hormone-releasing peptide

Doi N, Hosoda H, Kojima M, et al.

Arzneimittel-Forschung

Characterized the pharmacological properties of GHRP-2 (KP-102), demonstrating its potent and specific growth hormone-releasing activity through the ghrelin receptor (GHS-R1a). Established dose-response relationships and receptor binding profiles.

• GHRP-2 demonstrated potent GH-releasing activity via GHS-R1a receptor binding
• Dose-dependent stimulation of growth hormone secretion established

DOI: 10.1055/s-0031-1297054

Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair

Bock-Marquette I, Saxena A, White MD, et al.

Nature

Landmark study demonstrating that Thymosin Beta-4 activates integrin-linked kinase (ILK) and Akt, promoting cardiomyocyte migration and survival after coronary ligation in mice. This was the first study to show Tβ4's cardioprotective potential.

• Thymosin β4 is secreted by the embryonic epicardium and promotes cardiomyocyte survival
• Treatment after coronary ligation preserved cardiac function and reduced scar formation

DOI: 10.1038/nature02943

Thymosin beta4 promotes dermal hair follicle neogenesis

Philp D, Nguyen M, Scheremeta B, et al.

FASEB Journal

Demonstrated that Thymosin Beta-4 accelerates hair growth in a rat wound model by promoting the migration and differentiation of hair follicle stem cells. Opened new avenues for TB-500 research in dermatological applications.

• Thymosin β4 accelerated hair growth in a dose-dependent manner in rat wound models
• Promoted migration of bulge-region stem cells and their differentiation into follicular keratinocytes

DOI: 10.1096/fj.04-1479fje

Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions

Delgado M, Pozo D, Ganea D

Amino Acids

This comprehensive review examined the immunoregulatory properties of vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide widely distributed in the central and peripheral nervous systems and immune cells. The review detailed VIP's potent anti-inflammatory effects through inhibition of pro-inflammatory cytokine production, promotion of regulatory T-cell development, and modulation of Th1/Th2 balance.

• VIP inhibits the production of pro-inflammatory mediators (TNF-alpha, IL-6, IL-12, NO, chemokines) by macrophages through cAMP-dependent inhibition of NF-kB and IRF-1 transcription factors
• VIP promotes the generation of regulatory T cells and tolerogenic dendritic cells, contributing to peripheral immune tolerance

DOI: 10.1007/s00726-003-0021-0

Peptide promotes overcoming of the division limit in human somatic cells

Khavinson VKh, Bondarev IE, Butyugov AA

Bulletin of Experimental Biology and Medicine

This study investigated the effects of the tetrapeptide epithalon (Ala-Glu-Asp-Gly) on human fetal fibroblast cultures approaching the Hayflick limit. Epithalon treatment induced telomerase activity in somatic cells and enabled cells to exceed the normal replicative limit, suggesting a mechanism for age-related telomere maintenance.

• Epithalon activated telomerase catalytic subunit (hTERT) expression in human somatic cells that normally lack telomerase activity
• Treated fibroblast cultures exceeded the Hayflick limit by an additional 10 population doublings compared to untreated controls

DOI: 10.1023/A:1024181817860

A synthetic hexapeptide (Argireline) with antiwrinkle activity

Blanes-Mira C, Clemente J, Jodas G, et al.

International Journal of Cosmetic Science

This study characterized the mechanism of action of acetyl hexapeptide-3 (Argireline), the parent compound of SNAP-8 (acetyl octapeptide-3), which inhibits SNARE complex formation to reduce neurotransmitter release at neuromuscular junctions. The peptide demonstrated dose-dependent inhibition of catecholamine release from chromaffin cells and reduced wrinkle depth in clinical assessments, establishing the botulinum toxin-like mechanism of this class of cosmetic peptides.

• Acetyl hexapeptide-3 inhibited SNARE complex assembly by competing with SNAP-25 for binding to syntaxin and synaptobrevin, reducing vesicular exocytosis
• Dose-dependent inhibition of catecholamine release (up to 40% reduction) was demonstrated in chromaffin cell assays at micromolar concentrations

DOI: 10.1046/j.1467-2494.2002.00146.x

Regulation of myostatin activity and muscle growth

Lee SJ, McPherron AC

Proceedings of the National Academy of Sciences

Foundational study establishing that follistatin is a potent endogenous inhibitor of myostatin. Transgenic mice overexpressing follistatin exhibited dramatic increases in muscle mass exceeding those seen in myostatin knockout animals, suggesting follistatin inhibits additional negative regulators of muscle growth.

• Follistatin overexpression produced muscle mass increases exceeding myostatin knockout alone
• Established follistatin as a natural myostatin antagonist in vivo

DOI: 10.1073/pnas.151270098

Growth hormone-releasing hormone and aging

Merriam GR, Schwartz RS, Vitiello MV

Endocrine

This review examined the rationale and evidence for using GHRH analogs, particularly sermorelin (GRF 1-29), to address age-related decline in growth hormone secretion (somatopause). The authors reviewed clinical data showing that chronic GHRH/sermorelin administration can restore pulsatile GH secretion and improve body composition, sleep quality, and functional outcomes in older adults.

• Chronic sermorelin administration (once or twice daily subcutaneous injection) restored youthful GH pulse amplitude in elderly subjects while preserving the normal pulsatile pattern and feedback regulation
• Sermorelin treatment improved body composition in older adults, increasing lean body mass and decreasing abdominal adiposity over 3-6 month treatment periods

DOI: 10.1385/ENDO:14:1:029

Novel TRH analog improves motor and cognitive recovery after traumatic brain injury in rodents

Faden AI, Fox GB, Fan L, et al.

American Journal of Physiology

Developed a dual-substituted TRH analog (2-ARA-53a) that preserved neuroprotective activity while eliminating undesirable autonomic, analeptic, and endocrine effects. Treatment improved both motor recovery and cognitive water maze performance after traumatic brain injury in rodents.

• TRH analog improved motor recovery in rats and cognitive performance in mice after TBI
• Successfully dissociated neuroprotective effects from endocrine and autonomic side effects

DOI: 10.1152/ajpregu.1999.277.4.R1196

Ipamorelin, the first selective growth hormone secretagogue

Raun K, Hansen BS, Johansen NL, et al.

European Journal of Endocrinology

This study characterized ipamorelin as the first growth hormone secretagogue with high selectivity for GH release without significant effects on ACTH, cortisol, prolactin, or FSH/LH levels. Using in vivo swine models and in vitro rat pituitary cell assays, the authors demonstrated that ipamorelin releases GH with an efficacy and potency comparable to GHRP-6 but with a markedly cleaner endocrine profile.

• Ipamorelin stimulated GH release with potency similar to GHRP-6 in both in vitro pituitary cell assays and in vivo swine models
• Unlike GHRP-6 and other GHRPs, ipamorelin did not significantly affect plasma levels of ACTH, cortisol, prolactin, or other pituitary hormones at GH-releasing doses

DOI: 10.1530/eje.0.1390552

Eumelanin and the photoprotection of skin color: linking experimental studies and clinical outcomes

Dorr RT, Lines R, Levine N, et al.

Journal of the American Academy of Dermatology

This early clinical study evaluated the melanogenic effects of Melanotan II (MT-II), a cyclic analog of alpha-melanocyte-stimulating hormone, administered subcutaneously to human volunteers. MT-II produced significant darkening of the skin through increased eumelanin synthesis without requiring UV exposure, demonstrating the first clinical proof-of-concept for pharmacologically induced tanning.

• Subcutaneous Melanotan II (0.025 mg/kg) administered over 5 days produced measurable skin darkening as quantified by reflectance spectrophotometry
• Melanin content analysis confirmed the pigmentation was predominantly eumelanin (photoprotective brown-black pigment) rather than pheomelanin

DOI: 10.1016/S0190-9622(96)90346-6

In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds

Maquart FX, Pickart L, Laurent M, et al.

Journal of Clinical Investigation

Demonstrated that GHK-Cu2+ complex significantly stimulates connective tissue accumulation in rat wound chambers. Treatment increased total collagen content, DNA synthesis, and glycosaminoglycan deposition in wound tissue, providing early mechanistic evidence for GHK-Cu's wound healing properties.

• GHK-Cu increased collagen, DNA, and glycosaminoglycan content in wound chambers
• Stimulated connective tissue accumulation in a dose-dependent manner

DOI: 10.1172/JCI116753

Regulation of growth hormone secretion by growth hormone-releasing peptide-6 (GHRP-6)

Micic D, Popovic V, Doknic M, et al.

Journal of Pediatric Endocrinology

Early clinical characterization of GHRP-6 as a potent growth hormone secretagogue in humans. Demonstrated that GHRP-6 stimulates GH release through a mechanism distinct from GHRH, and that combined administration produces synergistic GH responses.

• GHRP-6 potently stimulated GH release in human subjects
• Mechanism of action distinct from growth hormone-releasing hormone (GHRH)

Clinical uses of gonadotropin-releasing hormone analogues

Casper RF

Canadian Medical Association Journal

Foundational clinical review of GnRH analog applications including endometriosis, uterine leiomyoma, precocious puberty, and hormone-dependent cancers. Established that GnRH agonists first stimulate then inhibit gonadotropin secretion through pituitary receptor downregulation, with few side effects.

• GnRH agonists downregulate pituitary receptors, producing reversible chemical gonadectomy
• Proved efficacious for endometriosis, fibroids, precocious puberty, and hormone-dependent cancers

DOI: 10.1016/S0889-8545(21)00535-2

The delta sleep inducing peptide (DSIP). Isolation, structure, and properties of the original sleep promoting substance

Schoenenberger GA, Monnier M

Pflügers Archiv: European Journal of Physiology

This seminal study reported the original isolation, structural characterization, and sleep-promoting properties of Delta Sleep-Inducing Peptide (DSIP), a nonapeptide (Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu) purified from cerebral venous blood of rabbits during electrically induced sleep. DSIP was shown to selectively enhance delta wave (slow-wave) sleep when administered to recipient animals.

• DSIP was isolated from the cerebral venous blood of rabbits during electrically induced sleep and identified as a nonapeptide with the sequence Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu
• Intraventricular or intravenous administration of DSIP to recipient rabbits selectively increased delta wave (stage 3-4) sleep without significantly altering total sleep time or REM sleep

DOI: 10.1007/BF00585801