The living record of
peptide science.

Partly Substituting Whey for Collagen Peptide Supplementation Improves Neither Indices of Muscle Damage Nor Recovery of Functional Capacity During Eccentric Exercise Training in Fit Males.

Int J Sport Nutr Exerc Metab

Ruben Robberechts, Chiel Poffé, Noémie Ampe +2 more

Previous studies showed that collagen peptide supplementation along with resistance exercise enhance muscular recovery and function. Yet, the efficacy of collagen peptide supplementation in addition to standard nutritional practices in athletes remains unclear. Therefore, the objective of the study was to compare the effects of combined collagen peptide (20 g) and whey protein (25 g) supplementation with a similar daily protein dose (45 g) of whey protein alone on indices of muscle damage and recovery of muscular performance during eccentric exercise training. Young fit males participated in a 3-week training period involving unilateral eccentric exercises for the knee extensors. According to a double-blind, randomized, parallel-group design, before and after training, they received either whey protein (n = 11) or whey protein + collagen peptides (n = 11). Forty-eight hours after the first training session, maximal voluntary isometric and dynamic contraction of the knee extensors were transiently impaired by ∼10% (Ptime < .001) in whey protein and whey protein + collagen peptides, while creatine kinase levels were doubled in both groups (Ptime < .01). Furthermore, the training intervention improved countermovement jump performance and maximal voluntary dynamic contraction by respectively 8% and 10% (Ptime < .01) and increased serum procollagen type 1N-terminal peptide concentration by 10% (Ptime < .01). However, no differences were found for any of the outcomes between whey and whey protein + collagen peptides. In conclusion, substituting a portion of whey protein for collagen peptide, within a similar total protein dose, improved neither indices of eccentric muscle damage nor functional outcomes during eccentric training.

Excess dietary Lys reduces feed intake, stimulates jejunal CCK secretion and alters essential and non-essential blood AA profile in pigs.

J Anim Sci Biotechnol

Maximiliano Müller, Elout Van Liefferinge, Alan Tilbrook +2 more

Commercial diets are frequently formulated to meet or exceed nutrient levels including those of limiting essential amino acids (AA) covering potential individual variations within the herd. However, the provision of dietary excess of AA, such as Lys, may lead to reduced appetite and growth in pigs. The mechanisms modulating these responses have not been extensively investigated. This study evaluated the effect of Lys dietary excesses on performance and satiety biomarkers in post weaning pigs.

Satiety: a gut-brain-relationship.

J Physiol Sci

Ghinwa M Barakat, Wiam Ramadan, Ghaith Assi +1 more

Many hormones act on the hypothalamus to control hunger and satiety through various pathways closely associated with several factors. When food is present in the gastro intestinal (GI) tract, enteroendocrine cells (EECs) emit satiety signals such as cholecystokinin (CCK), glucagon like peptide-1 (GLP-1) and peptide YY (PYY), which can then communicate with the vagus nerve to control food intake. More specifically, satiety has been shown to be particularly affected by the GLP-1 hormone and its receptor agonists that have lately been acknowledged as a promising way to reduce weight. In addition, there is increasing evidence that normal flora is also involved in the peripheral, central, and reward system that impact satiety. Moreover, neurologic pathways control satiety through neurotransmitters. In this review, we discuss the different roles of each of the GLP-1 hormone and its agonist, gut microbiomes, as well as neurotransmitters and their interconnected relation in the regulation of body's satiety homeostasis.

Tau, ADNP, and sex.

Cytoskeleton (Hoboken)

Illana Gozes

With 50 years to the original discovery of Tau, I gave here my perspective, looking through the prism of activity-dependent neuroprotective protein (ADNP), and the influence of sex. My starting point was vasoactive intestinal peptide (VIP), a regulator of ADNP. I then moved to the original discovery of ADNP and its active neuroprotective site, NAP, drug candidate, davunetide. Tau-ADNP-NAP interactions were then explained with emphasis on sex and future translational medicine.

Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity.

Int J Mol Sci

Stjepan Eržen, Gašper Tonin, Dubravka Jurišić Eržen +1 more

Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from β-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.

The WMI Rat of Premature Cognitive Aging Presents Intrinsic Vulnerability to Oxidative Stress in Primary Neurons and Astrocytes Compared to Its Nearly Isogenic WLI Control.

Int J Mol Sci

Adriana Ferreira, Aspen Harter, Sana Afreen +3 more

The primary neuronal and astrocyte culture described here is from the stress-hyperreactive Wistar Kyoto (WKY) More Immobile (WMI) rat with premature aging-related memory deficit, and its nearly isogenic control, the Less Immobile (WLI) strain. Primary WMI hippocampal neurons and cortical astrocytes are significantly more sensitive to oxidative stress (OS) generated by administration of H2O2 compared to WLI cells as measured by the trypan blue cell viability assay. Intrinsic genetic vulnerability is also suggested by the decreased gene expression in WMI neurons of catalase (Cat), and in WMI cortical astrocytes of insulin-like growth factor 2 (Igf2), synuclein gamma (Sncg) and glutathione peroxidase 2 (Gpx2) compared to WLI. The expressions of several mitochondrial genes are dramatically increased in response to H2O2 treatment in WLI, but not in WMI cortical astrocytes. We propose that the vulnerability of WMI neurons to OS is due to the genetic differences between the WLI and WMI. Furthermore, the upregulation of mitochondrial genes may be a compensatory response to the generation of free radicals by OS in the WLIs, and this mechanism is disturbed in the WMIs. Thus, this pilot study suggests intrinsic vulnerabilities in the WMI hippocampal neurons and cortical astrocytes, and affirm the efficacy of this bimodal in vitro screening system for finding novel drug targets to prevent oxidative damage in illnesses.

Enteric α-Defensin Contributes to Recovery of Radiation-Induced Intestinal Injury by Modulating Gut Microbiota and Fecal Metabolites.

Radiat Res

Jie Wu, Xi Ran, Tao Wang +5 more

The effect of ionizing radiation on the gastrointestinal tract is a common complication of abdominal and pelvic radiotherapy. However, the pathological features of radiation enteropathy and its effective medical intervention regimen is still a global challenge. Here, we explored the role and mechanism of enteric alpha-defensins (EαDs) in protecting against radiation enteropathy. To address this, we utilized EαDs-deficiency mice, in which the matrix metallopeptidase 7 to activate Paneth cell α-defensins was knockout (KO) mice, and the complementary wild-type (WT) control mice for this study. Remarkably, the KO mice were more susceptible to 5.0 Gy total-body irradiation, resulting in worse clinic scores and lower survival rate, compared with the wild-type mice. Histological examination indicated that the KO mice were subjected to slow recovery of intestinal villus and mucosa function, characterized by the reduced expression of TFF3, Glut1 and Muc2. In addition, compared with the wild-type controls, the KO mice experienced serious inflammation response in intestinal tissue, indicated by the remarkably increased expression level of IL-1β, IL-6 and IL-12. Using high-throughput sequencing analysis, we found that the intestinal bacterial community of the KO mice was more prone to dysbiosis than that of the WT mice, with significantly increased abundance of opportunistic pathogenic bacteria, such as Streptococcus sp. and Escherichia-Shigella sp., whereas remarkably decreased probiotics harboring Lactobacillus sp., Desulfovibrio sp. etc. Fecal metabolomics analysis indicated that the relative abundance of 31 metabolites arose significantly different between WT and KO mice on day 10 after radiation exposure. A subset of differential metabolites to regulate host metabolism and immunity, such as acetic acid, acetate, butanoic acid, was negatively correlated with the alteration of gut microbiota in the irradiated KO mice. This study provides new insight into EαDs contribution to the recovery of radiation-induced intestinal damage, and suggests a potential novel target to prevent the adverse effects of radiotherapy.

A Novel Leu-Enkephalin Prodrug Produces Pain-Relieving and Antidepressant Effects.

Mol Pharm

Lukas Hohenwarter, Ernest Puil, Elham Rouhollahi +8 more

Persistent pain is a significant healthcare problem with limited treatment options. The high incidence of comorbid chronic pain and depression significantly reduces life quality and complicates the treatment of both conditions. Antidepressants are less effective for pain and depression than for depression alone and they induce severe side effects. Opioids are highly efficacious analgesics, but rapid development of tolerance, dependence, and debilitating side effects limit their efficacy and safe use. Leucine-enkephalin (Leu-ENK), the endogenous delta opioid receptor agonist, controls pain and mood and produces potent analgesia with reduced adverse effects compared to conventional opioids. High proteolytic instability, however, makes Leu-ENK ineffective after systemic administration and limits its clinical usefulness. KK-103, a Leu-ENK prodrug, was developed to overcome these limitations of Leu-ENK via markedly increased plasma stability in mice. We showed rapid and substantially increased systemic adsorption and blood plasma exposure of KK-103 compared to Leu-ENK. We also observed brain uptake of radiolabeled KK-103 after systemic administration, indicating a central effect of KK-103. We then established KK-103's prolonged antinociceptive efficacy in the ramped hot plate and formalin test. In both models, KK-103 produced a comparable dose to the maximum antinociceptive-effect relationship. The pain-alleviating effect of KK-103 primarily resulted from activating the delta opioid receptor after the likely conversion of KK-103 to Leu-ENK in vivo. Finally, KK-103 produced an antidepressant-like activity comparable to the antidepressant desipramine, but with minimal gastrointestinal inhibition and no incidence of sedation.

Comprehensive Review of the Safety and Efficacy of Thymosin Alpha 1 in Human Clinical Trials.

Altern Ther Health Med

Elliot Dinetz, Edwin Lee

This study aims to assess the safety and efficacy of Thymosin Alpha 1 (Tα1) through a comprehensive narrative review of clinical studies involving over 11 000 human subjects in more than 30 trials. The focus was on Tα1's application in COVID-19, autoimmune conditions, and cancer treatment, with implications for future considerations.

A Neurofilament-L reporter cell line for the quantification of early neuronal differentiation: A Bioassay for neurotrophic activities.

Heliyon

Lisa-Franziska Seidl, Stefan Winter, Ludwig Aigner +1 more

Neurotrophic activity constitutes a crucial factor in the recovery from neurological injuries and is impaired in neurodegenerative disorders. Preclinical studies of neurotrophic factors to improve outcome of neurodegenerative diseases have yielded promising results. However, due to the complexity of these therapies, the clinical translation of this approach was so far not successful and more feasible treatments with neurotrophic activity may be promising alternatives. Therefore, highly sensitive and robust assays for compound screening are required.

Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males.

J Mol Neurosci

Jospeh Levine, Alexandra Lobyntseva, Shula Shazman +2 more

Activity-dependent neuroprotective protein (ADNP) is essential for neurodevelopment and de novo mutations in ADNP cause the ADNP syndrome. From brain pathologies point of view, tauopathy has been demonstrated at a young age, implying stunted development coupled with early/accelerated neurodegeneration. Given potential genotype-phenotype differences and age-dependency, we have assessed here a cohort of 15 individuals (1-27-year-old), using 1-3 longitudinal parent (caretaker) interview/s (Vineland 3 questionnaire) over several years. Our results indicated developmental delays, or even developmental arrests, coupled with potential spurts of development at early ages. Severe outcomes correlated with the truncating high impact mutation, in other words, the remaining mutated protein length as well as with the tested individual age, corroborating the hypothesis of developmental delays coupled with accelerated aging. A significant correlation was noted between mutated protein length and communication, implying a high impact of ADNP on communicative skills. Additionally, correlations were discovered between the two previously described epi-genetic signatures in ADNP emphasizing aberrant acquisition of motor behaviors, with truncating mutations around the nuclear localization signal being mostly affected. Finally, all individuals seem to acquire an age equivalent of 1-6 years, requiring disease modification treatment, such as the ADNP-derived drug candidate, NAP (davunetide), which has recently shown efficacy in women suffering from the neurodegenerative disorder, progressive supranuclear palsy (PSP), a late-onset tauopathy.

Erythropoietic protoporphyria and afamelanotide: a patient's perspective.

Clin Exp Dermatol

Marese O'Reilly, Vicky A McGuire, Robert S Dawe

A model of subcutaneous pramlintide pharmacokinetics and its effect on gastric emptying: Proof-of-concept based on populational data.

Comput Methods Programs Biomed

Clara Furió-Novejarque, Iván Sala-Mira, José-Luis Díez +1 more

Pramlintide, an amylin analog, has been coming up as an agent in type 1 diabetes dual-hormone therapies (insulin/pramlintide). Since pramlintide slows down gastric emptying, it allows for easing glucose control and reducing the burden of meal announcements. Pre-clinical in silico evaluations are a key step in the development of any closed-loop strategy. However, mathematical models are needed, and pramlintide models in the literature are scarce. This work proposes a proof-of-concept pramlintide model, describing its subcutaneous pharmacokinetics (PK) and its effect on gastric emptying (PD). The model is validated with published populational (clinical) data. The model development is divided into three stages: intravenous PK, subcutaneous PK, and PD modeling. In each stage, a set of model structures are proposed, and their performance is assessed using the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC). In order to evaluate the modulation of the rate of gastric emptying, a literature meal model was used. The final pramlintide model comprises four compartments and a function that modulates gastric emptying depending on plasma pramlintide. Results show an appropriate fit for the data. Some aspects are left as open questions due to the lack of specific data (e.g., the influence of meal composition on the pramlintide effect). Moreover, further validation with individual data is necessary to propose a virtual cohort of patients.

Therapeutic applications of thymosin peptides: a patent landscape 2018-present.

Expert Opin Ther Pat

Michael Quagliata, Anna Maria Papini, Paolo Rovero

Thymosins are small proteins found mainly in the thymus. They are involved in several biological processes, including immunoregulation, angiogenesis, and anti-inflammatory activity. Due to these multiple activities, thymosins are widely used as therapeutics. In fact, these peptides have shown interesting results in the treatment of eye disorders, anticancer therapy, and dysregulated immune disorders.

Cerebrolysin provides effective protection on high glucose-induced neuropathy in cultured rat dorsal root ganglion neurons.

J Recept Signal Transduct Res

Ugur Yazar, Ali Rıza Guvercin, Mahindokht Rouhikia +4 more

Cerebrolysin, an endogenous peptide with neuroprotective and neurotrophic properties, indicated to be beneficial on diabetic neuropathy by preliminary clinical and experimental studies but without evidence on central or peripheral action. Dorsal root ganglion (DRG) neurons, based on involvement of pain sensation in both health and disease as first relay centers for transmission and processing of peripheral nociceptive sensory signals, was used to investigate possible effects of Cerebrolysin on high glucose-induced neuropathy, as model. DRG's were obtained from adult rats and the isolated neurons were seeded on E-Plate®'s equipped with gold microelectrodes, and incubated in culture media in a CO2 incubator at 37 C. DRGs were exposed to high glucose (50 mM) in the absence and presence of different concentrations of Cerebrolysin ® (2-40 mg/ml). Cell index (derived from cell viability and neurite outgrowth) was recorded with Real-Time Cell Analyzer and was used as primary outcome measure. High glucose-induced cellular neuropathy and neuroprotective effects of Cerebrolysin was evaluated from area under the curve (AUC) of cell index-time graphs. Exposure of DRG neurons to high glucose caused a rapid and persistent decrease in the mean AUC values compared to normoglycemic controls. Co-treatment with Cerebrolysin (40 mg/ml) attenuated this high glucose-induced effect in a concentration-dependent manner. In normoglycemic conditions, treatment with Cerebrolysin caused a dose-dependent increase in the mean AUC values. Cerebrolysin treatment resulted in maintenance of the functional integrity, survival, and promotion of neurite outgrowth of the cultured DRG neurons exposed to high glucose, indicating involvement of peripheral sensory neurons.

Heterogeneous treatment effects of Cerebrolysin as an early add-on to reperfusion therapy: post hoc analysis of the CEREHETIS trial.

Front Pharmacol

Mikhail N Kalinin, Dina R Khasanova

Background: There has been intensive research into enhancing the effects of reperfusion therapy to mitigate hemorrhagic transformation (HT) in stroke patients. Using neuroprotective agents alongside intravenous thrombolysis (IVT) appears a promising approach. Cerebrolysin is one of the candidates since it consists of neuropeptides mimicking the action of neurotrophic factors on brain protection and repair. Objectives: We looked at treatment effects of Cerebrolysin as an early add-on to IVT in stroke patients with varying HT risk. Methods: It was post hoc analysis of the CEREHETIS trial (ISRCTN87656744). Patients with middle cerebral artery infarction (n = 238) were selected from the intention-to-treat population. To stratify participants according to their HT risk, the DRAGON, SEDAN and HTI scores were computed for each eligible subject using on-admission data. The study endpoints were any and symptomatic HT, and functional outcome measured with the modified Rankin Scale (mRS) on day 90. Favorable functional outcome (FFO) was defined as an mRS ≤2. The performance of each stratification tool was estimated with regression approaches. Heterogeneous treatment effect analysis was conducted using techniques of meta-analysis and the matching-smoothing method. Results: The HTI score outperformed other tools in terms of HT risk stratification. Heterogeneity of Cerebrolysin treatment effects was moderate (I2, 35.8%-56.7%; H2, 1.56-2.31) and mild (I2, 10.9%; H2, 1.12) for symptomatic and any HT, respectively. A significant positive impact of Cerebrolysin on HT and functional outcome was observed in the moderate (HTI = 1) and high (HTI ≥2) HT risk patients, but it was neutral in those with the low (HTI = 0) risk. In particular, there was a steady decline in the rate of symptomatic (HTI = 0 vs. HTI = 4: by 4.3%, p = 0.077 vs. 21.1%, p < 0.001) and any HT (HTI = 0 vs. HTI = 4: by 1.2%, p = 0.737 vs. 32.7%, p < 0.001). Likewise, an mRS score reduction (HTI = 0 vs. HTI = 4: by 1.8%, p = 0.903 vs. 126%, p < 0.001) with a reciprocal increase of the fraction of FFO patients (HTI = 0 vs. HTI = 4: by 1.2% p = 0.757 vs. 35.5%, p < 0.001) was found. Conclusion: Clinically meaningful heterogeneity of Cerebrolysin treatment effects on HT and functional outcome was established in stroke patients. The beneficial effects were significant in those whose estimated on-admission HT risk was either moderate or high.

Role of thymosin α1 in restoring immune response in immunological nonresponders living with HIV.

BMC Infect Dis

Chaoyu Chen, Jiangrong Wang, Jingna Xun +6 more

Immunological nonresponders (INRs) living with HIV are at increased risk of co-infection and multiple tumors, with no effective strategy currently available to restore their T-cell immune response. This study aimed to explore the safety and efficacy of thymosin α1 in reconstituting the immune response in INRs.

Circulating Growth Differentiation Factors 11 and 8, Their Antagonists Follistatin and Follistatin-Like-3, and Risk of Heart Failure in Elders.

J Gerontol A Biol Sci Med Sci

Jorge R Kizer, Sheena Patel, Peter Ganz +9 more

Heterochronic parabiosis has identified growth differentiation factor (GDF)-11 as a potential means of cardiac rejuvenation, but findings have been inconsistent. A major barrier has been lack of assay specificity for GDF-11 and its homolog GDF-8.

Catechol chitosan coated dual-loaded liposomes based on oxidation and saccharification mechanisms for enhancing skin anti-aging effects.

Int J Biol Macromol

Xinying Wang, Linlin Lv, Tongyan Liu +3 more

Skin aging has become a major urgent problem to be solved. Evidence reveals that oxidation and glycosylation are two dominant inducements of aging. Resveratrol (RES) with outstanding anti-oxidant effect and carnosine (CAR) with superb anti-glycation property were selected as two model drugs to evaluate the feasibility of their synergistic anti-aging effect. RES and CAR at the most desired mass ratio, supplying the most superior synergistic anti-aging effects were further encapsulated in liposomes (LP), which were separately coated with chitosan (CS) and catechol chitosan (Cat-CS) to increase the transdermal penetration. Their anti-aging efficacy was explored in human skin fibroblast (HSF) and human immortalized keratinocytes (HaCaT) cells, as well as the back skin of guinea pigs. Herein, RES and CAR at the mass ratio of 2:1 exhibited the most ideal synergistic anti-aging effect. The constructed liposomes have been shown to possess excellent fundamental properties and sustained-release properties. The aging-related indicator levels in the two cells and guinea pigs were obviously improved for the RES + CAR@Cat-CS-LP group. Additionally, skin appearance, tissue morphology, and collagen content were visibly improved, indicating its perfect anti-aging effect. In conclusion, RES + CAR@Cat-CS-LP is expected to be exploited as a potential anti-aging drug delivery system.

First-time orgasm in a young man with lifelong anorgasmia after flibanserin use: a case report.

Sex Med

Gal Saffati, Taher Naeem, Basil Kaaki +1 more

Anorgasmia is a poorly understood phenomenon defined as either a lifelong or acquired consistent inability to achieve ejaculation. Despite the prevalence of anorgasmia, there is currently no established treatment for the condition.