The living record of
peptide science.

Retraction: The role of thymosin beta 4 on odontogenic differentiation in human dental pulp cells.

PLoS One

Oxytocin's social and stress-regulatory effects in children with autism and intellectual disability: a protocol for a randomized placebo-controlled trial.

BMC Psychiatry

G Ricchiuti, A Taillieu, E Tuerlinckx +5 more

Oxytocin is increasingly considered as a new pharmacological option for mitigating social difficulties and regulating stress in autism spectrum disorder. However, in prior trials, autistic individuals with co-occurring intellectual disability (ID) have largely been overlooked, despite their high prevalence, poorer outcome, and the enhanced need but reduced availability of therapeutic interventions. Prior studies have also overlooked the importance of standardizing the context in which oxytocin is administered, rendering outcomes from prior trials inconclusive.

Multifunctionality and Possible Medical Application of the BPC 157 Peptide-Literature and Patent Review.

Pharmaceuticals (Basel)

Michalina Józwiak, Marta Bauer, Wojciech Kamysz +1 more

BPC 157, known as the "Body Protection Compound", is a pentadecapeptide isolated from human gastric juice that demonstrated its pleiotropic beneficial effects in various preclinical models mimicking medical conditions, such as tissue injury, inflammatory bowel disease, or even CNS disorders. Unlike many other drugs, BPC 157 has a desirable safety profile, since only a few side effects have been reported following its administration. Nevertheless, this compound was temporarily banned by the World Anti-Doping Agency (WADA) in 2022 (it is not currently listed as banned by the WADA). However, it has not been approved for use in standard medicine by the FDA and other global regulatory authorities due to the absence of sufficient and comprehensive clinical studies confirming its health benefits in humans. In this review, we summarize information on the biological activities of BPC 157, with particular reference to its mechanism of action and probable toxicity. This generated the attention of experts, as BPC 157 has been offered for sale on many websites. We also present recent interest in BPC 157 as reflected in a number of patent applications and granted patents.

The intricate relationship between circadian rhythms and gastrointestinal peptides in obesity.

Peptides

Filipe M Ribeiro, Luiz Arnaldo, Lana P Milhomem +2 more

There are different molecular pathways that regulate appetite, particularly the role of the hypothalamus, circadian rhythms, and gastrointestinal peptides. The hypothalamus integrates signals from orexigenic peptides like neuropeptide Y (NPY) and agouti-related protein (AgRP), which stimulate appetite, and anorexigenic peptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which promote satiety. These signals are influenced by peripheral hormones like leptin, ghrelin, insulin, and cortisol, as well as gut peptides including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK). The circadian rhythm, regulated by proteins like circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), modulates the secretion of these peptides, aligning feeding behaviors with the sleep-wake cycle. In obesity, these regulatory systems are disrupted, leading to leptin resistance, increased ghrelin sensitivity, and altered gut peptide secretion. This results in heightened appetite and impaired satiety, contributing to overeating and metabolic dysfunction. Additionally, circadian disruptions further impair metabolic processes, exacerbating obesity. The present article underscores the importance of understanding the molecular interplay between circadian rhythms and gastrointestinal peptides, particularly in the context of obesity. While some molecular interactions, such as the regulation of GLP-1 and PYY by reverberation of circadian rhythm α (REV-ERBα) and retinoic acid-related orphan receptor α (RORα), are well-established, clinical studies are scarce. Future research is expected to explore these pathways in obesity management, especially with the rise of incretin-based treatments like semaglutide. A deeper understanding of hypothalamic molecular mechanisms could lead to novel pharmacological and non-pharmacological therapies for obesity.

Toward effective oxytocin interventions in autism: Overcoming challenges and harnessing opportunities.

J Psychopharmacol

Grazia Ricchiuti, Elise Tuerlinckx, Aymara Taillieu +4 more

Intranasal administration of oxytocin is emerging as a potential pharmacological option for mitigating social difficulties and regulating stress in autism spectrum disorder. However, initial single-dose and multiple-dose trials showed mixed results, with some demonstrating improvements in social and repetitive behavior and others showing no benefit over placebo. This perspective aims to elucidate factors contributing to this variability and to highlight pitfalls and opportunities in the field. We identified two major factors: design-related elements and individual participant characteristics. Pertaining to design-related elements, optimal dosing regimens have yet to be established, but appear to favor moderate intervention durations (i.e., 4-6 weeks) with intermittent and intermediate dosing (i.e., 24-32 IU every other day). Also, the context of the intervention seems crucial, as enhanced outcomes are mainly observed when oxytocin administration is paired with a socially stimulating and supporting environment. In addition, more adequate outcome measures have to be established to effectively assess oxytocin's impact, including behavioral scales and objective biophysiological markers tapping into stress and neurophysiological regulation. Future research should also account for individual participant differences in biological sex, developmental stage and cognitive and adaptive functioning, and incorporate (epi)genetic screening to identify responders. Overall, refining study designs and personalizing intervention protocols are essential for optimizing oxytocin's prosocial and anxiolytic effect in autism.

[Effect of neurofeedback training on relative α variant score monitored by bedside continuous electroencephalography and optic nerve sheath diameter evaluated by ultrasound in patients with ischemic hypoxic encephalopathy].

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue

Jie Sun, Jian Wan

To approach the evaluation of relative α variant score monitored by bedside continuous electroencephalography and optic nerve sheath diameter (ONSD) evaluated by ultrasound in patients with ischemic hypoxic encephalopathy, and to observe the effect of neurofeedback training on brain function.

Optimal dose of oxytocin to improve social impairments and repetitive behaviors in autism spectrum disorders: meta-analysis and dose-response meta-analysis of randomized controlled trials.

Front Psychiatry

Yingying Zhang, Xiaolu Zhang, Linghong Huang

Social impairments and repetitive behaviors are at the core symptoms of autism spectrum disorder (ASD). Intranasal administration of the neuropeptide oxytocin (OXT) is a promising treatment. However, there have been inconsistencies in the effects of OXT on social impairments and repetitive behaviors.

Importance of integrin transmembrane helical interactions for antagonistic versus agonistic ligand behavior: Consequences for medical applications.

Bioorg Chem

Ute Reuning, Vincenzo Maria D'Amore, Kairbaan Hodivala-Dilke +2 more

Integrins are well-characterized receptors involved in cell adhesion and signaling. With six approved drugs, they are recognized as valuable therapeutic targets. Here, we explore potential activation mechanisms that may clarify the agonist versus antagonist behavior of integrin ligands. The reorganization of the transmembrane domain (TMD) in the integrin receptor, forming homooligomers within focal adhesions, could be key to the understanding of the agonistic properties of integrin ligands at substoichiometric concentrations. This has significant implications for medical applications. While we focus on the RGD peptide-recognizing integrin subfamily, we propose that these mechanistic insights may also apply to other integrin subtypes. For application of integrin ligands in medicine it is essential to consider this mechanism and its consequences for affinity and bioavailability.

Effects of Oral Xylitol, Sucrose, and Acesulfame Potassium on Total Energy Intake During a Subsequent ad libitum Test Meal: A Randomized, Controlled, Crossover Trial in Healthy Humans.

Nutrients

Emilie Flad, Anita Altstädt, Christoph Beglinger +4 more

Xylitol, a natural low-caloric bulk sweetener, is increasingly used as a sugar alternative due to its low-glycemic and low-insulinemic properties. The aim was to investigate the effect of orally administered xylitol, sucrose, and acesulfame potassium (ace-K) on energy intake during a subsequent ad libitum test meal.

Synthesis and biological evaluation of new dual APN/NEP inhibitors as potent analgesics.

Bioorg Chem

Naining Zhang, Xinyue Wang, Chengchun Zhu +8 more

An alternative approach for the management of acute and chronic pains involves prolonging the half-life of endogenous opiates, such as enkephalins that are released in response to nociceptive stimuli. This can be achieved through the inhibition of enzymatic pathways responsible for the hydrolysis of these peptides, particularly targeting Aminopeptidase N (APN) and Neutral Endopeptidase (NEP). In this study, we designed and synthesized a series of dual enkephalinase inhibitors (DENKIs) targeting both APN and NEP as novel analgesic treatments. Notably, SDUY812, SDUY816 and SDUY817 exhibited potent inhibition of APN activity with IC50 values of 0.38 µM, 0.68 µM and 0.29 µM, respectively, whereas their IC50 values against NEP were 6.9 µM, 6.9 µM and 7.4 µM, separately. In in-vivo antinociceptive assays, SDUY816 and SDUY817 demonstrated superior analgesic efficacy compared to Thiorphan and Bestatin in mice models of acute, inflammatory and neuropathic pains with jumping latencies exceeding 100 s and withdrawal thresholds more than 0.13 g. Moreover, the analgesic activity of these inhibitors was significantly diminished by a potent opioid antagonist, naloxone, indicating the contribution of opioid receptors to the robust analgesic properties of these newly developed DENKIs. In addition, SDUY816 and SDUY817 exerted the analgesic activity in a concentration- and time-dependent manner with SDUY816 possessing acceptable pharmacokinetic properties (t1/2 = 4.02 h and F = 27 %) and low toxicity. These findings provide alternative analgesic therapeutics that are potentially devoid of opioid-associated side effects.

Expanded-access use of elamipretide in a newborn with Barth syndrome: a case report.

Eur Heart J Case Rep

Laura Ortmann, Danita Velasco, Jason Cole

Barth syndrome (BTHS) is a rare genetic disease, with no approved curative therapies, characterized by abnormally developed cardiolipin, resulting in mitochondrial dysfunction. Cardiomyopathy, a common clinical manifestation of BTHS, often appears in infancy. Elamipretide, an investigational drug that binds to cardiolipin on the inner mitochondrial membrane, leads to improved membrane stability, enhanced adenosine triphosphate production, and reduced reactive oxygen species. This patient case aims to further support elamipretide's role in treating BTHS infants.

The Possible Roles of β-alanine and L-carnosine in Anti-aging.

Curr Med Chem

Amin Gasmi, Pavan Kumar Mujawdiya, Roman Lysiuk +9 more

β-alanine (BA), being a non-proteinogenic amino acid, is an important constituent of L-carnosine (LC), which is necessary for maintaining the muscle buffering capacity and preventing a loss of muscle mass associated with aging effects. BA is also very important for normal human metabolism due to the formation of a part of pantothenate, which is incorporated into coenzyme A. BA is synthesized in the liver, and its combination with histidine results in the formation of LC, which accumulates in the muscles and brain tissues and has a well-defined physiological role as a good buffer for the pH range of muscles that caused its rapidly increased popularity as ergogenic support to sports performance. The main antioxidant mechanisms of LC include reactive oxygen species (ROS) scavenging and chelation of metal ions. With age, the buffering capacity of muscles also declines due to reduced concentration of LC and sarcopenia. Moreover, LC acts as an antiglycation agent, ultimately reducing the development of degenerative diseases. LC has an anti-inflammatory effect in autoimmune diseases such as osteoarthritis. As histidine is always present in the human body in higher concentrations than BA, humans have to get BA from dietary sources to support the required amount of this critical constituent to supply the necessary amount of LC synthesis. Also, BA has other beneficial effects, such as preventing skin aging and intestinal damage, improving the stress-- fighting capability of the muscle cells, and managing an age-related decline in memory and learning. In this review, the results of a detailed analysis of the role and various beneficial properties of BA and LC from the anti-aging perspective are presented.

Role of RGD-binding Integrins in ovarian cancer progression, metastasis and response to therapy.

Integr Biol (Camb)

Vipin Ranga, Tikam Chand Dakal, Pawan Kumar Maurya +3 more

Integrins are transmembrane receptors that play a crucial role in cell adhesion and signaling by connecting the extracellular environment to the intracellular cytoskeleton. After binding with specific ligands in the extracellular matrix (ECM), integrins undergo conformational changes that transmit signals across the cell membrane. The integrin-mediated bidirectional signaling triggers various cellular responses, such as changes in cell shape, migration and proliferation. Irregular integrin expression and activity are closely linked to tumor initiation, angiogenesis, cell motility, invasion, and metastasis. Thus, understanding the intricate regulatory mechanism is essential for slowing cancer progression and preventing carcinogenesis. Among the four classes of integrins, the arginine-glycine-aspartic acid (RGD)-binding integrins stand out as the most crucial integrin receptor subfamily in cancer and its metastasis. Dysregulation of almost all RGD-binding integrins promotes ECM degradation in ovarian cancer, resulting in ovarian carcinoma progression and resistance to therapy. Preclinical studies have demonstrated that targeting these integrins with therapeutic antibodies and ligands, such as RGD-containing peptides and their derivatives, can enhance the precision of these therapeutic agents in treating ovarian cancer. Therefore, the development of novel therapeutic agents is essential for treating ovarian cancer. This review mainly discusses genes and their importance across different ovarian cancer subtypes, the involvement of RGD motif-containing ECM proteins in integrin-mediated signaling in ovarian carcinoma, ongoing, completed, partially completed, and unsuccessful clinical trials of therapeutic agents, as well as existing limitations and challenges, advancements made so far, potential strategies, and directions for future research in the field. Insight Box Integrin-mediated signaling regulates cell migration, proliferation and differentiation. Dysregulated integrin expression and activity promote tumor growth and dissemination. Thus, a proper understanding of this complex regulatory mechanism is essential to delay cancer progression and prevent carcinogenesis. Notably, integrins binding to RGD motifs play an important role in tumor initiation, evolution, and metastasis. Preclinical studies have demonstrated that therapeutic agents, such as antibodies and small molecules with RGD motifs, target RGD-binding integrins and disrupt their interactions with the ECM, thereby inhibiting ovarian cancer proliferation and migration. Altogether, this review highlights the potential of RGD-binding integrins in providing new insights into the progression and metastasis of ovarian cancer and how these integrins have been utilized to develop effective treatment plans.

Plasma concentration of gastrointestinal hormones and subjective appetite ratings after diet or bariatric surgery: 1-year results from the DISGAP study.

Int J Obes (Lond)

Marthe Isaksen Aukan, Jens Frederik Rehfeld, Jens Juul Holst +1 more

Long-term weight loss outcomes are contrasting between bariatric surgery and dietary restriction alone. This is the first study to investigate changes in gastrointestinal (GI) hormones involved in appetite regulation, and subjective appetite feelings, at 1-year follow-up, after initial weight loss induced by a very-low energy (VLED) alone (controls), or with bariatric surgery.

Endothelial insulin resistance induced by adrenomedullin mediates obesity-associated diabetes.

Science

Haaglim Cho, Chien-Cheng Lai, Rémy Bonnavion +11 more

Insulin resistance is a hallmark of obesity-associated type 2 diabetes. Insulin's actions go beyond metabolic cells and also involve blood vessels, where insulin increases capillary blood flow and delivery of insulin and nutrients. We show that adrenomedullin, whose plasma levels are increased in obese humans and mice, inhibited insulin signaling in human endothelial cells through protein-tyrosine phosphatase 1B-mediated dephosphorylation of the insulin receptor. In obese mice lacking the endothelial adrenomedullin receptor, insulin-induced endothelial nitric oxide-synthase activation and skeletal muscle perfusion were increased. Treating mice with adrenomedullin mimicked the effect of obesity and induced endothelial and systemic insulin resistance. Endothelial loss or blockade of the adrenomedullin receptor improved obesity-induced insulin resistance. These findings identify a mechanism underlying obesity-induced systemic insulin resistance and suggest approaches to treat obesity-associated type 2 diabetes.

Food-Derived Tripeptide-Copper Self-Healing Hydrogel for Infected Wound Healing.

Biomater Res

Han Chen, Pu Yang, Ping Xue +5 more

The field of infected wound management continues to face challenges, and traditional methods used to cope with wounds include debridement, gauze coverage, medication, and others. Currently, synthetic and natural biomaterials are readily available today, enabling the creation of new wound dressings that substantially enhance wound healing. Considerable attention is being paid to hydrogels based on natural materials, which have good biocompatibility and degradability properties, while exhibiting higher similarity to natural extracellular matrix as compared to synthetic materials. In this study, we extracted the active ingredients of oxidized konjac glucomannan (OKGM) and fresh egg white (EW) from 2 foods, konjac, and egg, respectively, and formed a self-repairing hydrogel based on the cross-linking of a Schiff base. Subsequently, a natural active peptide, glycyl-l-histidyl-l-lysine-Cu (GHK-Cu), was loaded, and an all-natural composite hydrogel dressing, EW/OKGM@GHK-Cu (GEK), was developed. The GEK hydrogel, exhibiting both antibacterial and anti-inflammatory properties, plays a hemostatic role by adhering to tissues and promoting neovascularization and serves as an optimal dressing for skin regeneration. Taken together, GEK hydrogel dressings derived from natural food sources therefore constitute an efficient and cost-effective strategy for managing infected wound healing and have significant potential for clinical application and transformation.

Hypofractionated radiotherapy combined with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor, and thymosin-α1 in advanced metastatic solid tumors: a multicenter Phase II clinical trial.

Cancer Immunol Immunother

Jiamin Yu, Li Yin, Wenjie Guo +13 more

This multicenter Phase II clinical study assessed the efficacy and safety of hypofractionated radiotherapy (HFRT) in combination with a PD-1 inhibitor, granulocyte macrophage-colony stimulating factor (GM-CSF), and thymosin-α1 in patients with heavily treated metastatic solid tumors.

A temperature-responsive dual-hormone foam nanoengine improves rectal absorptivity of insulin-pramlintide for diabetes treatment.

Sci Adv

Shujun Feng, Yu Zhang, Chunyuan Hou +4 more

Despite the therapeutic benefits of insulin-pramlintide dual-hormone therapy in diabetes, its application potential has been limited due to a lack of efficient delivery routes. Here, we developed a temperature-responsive dual-hormone foam nanoengine (HormFoam) and combined it with a customized spraying device to further construct an in situ foam-generating system for improving the rectal bioavailability of dual-hormone therapy. To support rapid clinical translation, a continuous microfluidic preparation for HormFoam was proposed, including the power unit of perfluorocarbon nanodroplets and the pharmaceutical components Pluronic F127-functionalized liposomal insulin and pramlintide. We found that HormFoam could consistently generate foams to drive drugs forward after rectal administration, which enhanced intestinal distribution and mucosa absorption, leading to systemic codelivery of insulin-pramlintide. HormFoam reproduced the physiology of endocrine pancreas for glycemic control and induced body weight loss while reversing metabolic disorders in diabetic mice with good biosafety. Therefore, HormFoam represents a state-of-the-art dual-hormone regimen with the potential to address unmet needs in diabetes management.

Stable Gastric Pentadecapeptide BPC 157 as Therapy After Surgical Detachment of the Quadriceps Muscle from Its Attachments for Muscle-to-Bone Reattachment in Rats.

Pharmaceutics

Danijel Matek, Irena Matek, Eva Staresinic +17 more

This is a novel rat study using native peptide therapy, focused on reversing quadriceps muscle-to-bone detachment to reattachment and stable gastric pentadecapeptide BPC 157 per-oral therapy for shared muscle healing and function restoration.

Changes in Locomotor Activity Observed During Acute Nicotine Withdrawal Can Be Attenuated by Ghrelin and GHRP-6 in Rats.

Biomedicines

Jázmin Ayman, András Buzás, Roberta Dochnal +3 more

Background/Objectives: Ghrelin and growth hormone-releasing peptide 6 (GHRP-6) are peptides which can stimulate GH release, acting through the same receptor. Ghrelin and its receptor have been involved in reward sensation and addiction induced by natural and artificial drugs, including nicotine. The present study aimed to investigate the impacts of ghrelin and GHRP-6 on the horizontal and vertical activity in rats exposed to chronic nicotine treatment followed by acute nicotine withdrawal. Methods: Male and female Wistar rats were exposed daily to intraperitoneal (ip) injection with 2 mg/kg nicotine or saline solution for 7 days, twice a day (at 8:00 and at 20:00). In parallel, the rats were exposed daily to an intracerebroventricular (icv) injection with 1 μg/2 μL ghrelin or 1 μg/2 μL GHRP-6 or saline solution for 7 days, once a day (at 8:00). On the morning of the eighth day (12 h after the last ip administration) and the ninth day (24 h after the last ip administration), the horizontal and vertical activity were monitored in a conducta system. Results: On the eighth day, in nicotine-treated rats a significant hyperactivity was observed, that was reduced significantly by ghrelin and GHRP-6. On the ninth day, in nicotine-treated rats a significant hypoactivity was assessed that was reversed significantly by ghrelin and GHRP-6. Conclusions: Based on the present results, the changes in horizontal and vertical activity observed after 12 and 24 h of nicotine withdrawal can be attenuated by ghrelin and GHRP-6.