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Copper Complexes with New Glycyl-l-histidyl-l-lysine-Hyaluronan Conjugates Show Antioxidant Properties and Osteogenic and Angiogenic Synergistic Effects.
Bioconjug Chem
Valentina Greco, Valeria Lanza, Barbara Tomasello +4 more
In recent years, hyaluronic acid (HA) and the natural tripeptide glycyl-l-histidyl-l-lysine (GHK), especially its copper(II) complex (GHK-Cu), individually have been shown to exert helpful properties for bone protection and regeneration. However, they are not strong enough to handle oxidative stress, hydrolytic attack, or environmental conditions. Being aware that conjugation chemistry has recently emerged as an appealing approach for generating new molecular entities capable of preserving the molecular integrity of their moieties or delaying their degradation, herein we present the synthesis of conjugates of HA with GHK (GHK-HA), at different loadings of the tripeptide. GHK-HA binds copper(II) ions and potentiates the chemical and biological properties of the two components in in vitro assays. The results highlight copper's role in promoting the expression and release of certain trophic, angiogenic, and osteogenic factors, including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), as well as bone morphogenetic protein-2 (BMP-2). The protective and regenerative activities of the metal ion are related to the translocation of its intracellular chaperones Copper Chaperone for Superoxide Dismutase (CCS) and Antioxidant-1 (Atox1) to the nucleus where they act as transcription factors.
The neurobiological impact of oxytocin in mental health disorders: a comprehensive review.
Ann Med Surg (Lond)
Ram Prasad Chaulagain, Yelona Shrestha, Harisharan Shrestha +2 more
Oxytocin, a neuropeptide, plays a significant role in modulating social behavior and has been widely studied for its potential impact on mental health disorders. This review examines the neurobiological mechanisms through which oxytocin influences mental health and its therapeutic potential in conditions such as autism spectrum disorder, schizophrenia, post-traumatic stress disorder, anxiety, and depression. Oxytocin enhances social bonding, trust, and empathy by modulating neural circuits linked to social interactions. Studies indicate that oxytocin's ability to regulate the hypothalamic-pituitary-adrenal axis plays a vital role in stress response and emotional regulation. Therapeutic applications, particularly intranasal administration of oxytocin, have shown promise in alleviating symptoms and improving patient outcomes. However, personalized approaches are essential to optimize treatment effectiveness. Despite its potential, challenges remain in understanding the mechanisms underlying its effects and identifying the patient populations that would benefit most from such therapies. Future research should focus on elucidating these mechanisms, exploring the long-term efficacy of oxytocin-based interventions, and advancing personalized medicine to maximize its clinical utility.
Tcf4 regulates secretory cell fate decisions in the small intestine and colon tumors: insights from transcriptomic, histological, and microbiome analyses.
Stem Cell Res Ther
Lucie Janeckova, Monika Stastna, Dusan Hrckulak +16 more
The canonical Wnt signaling pathway controls the continuous renewal of the intestinal epithelium and the specification of epithelial cell lineages. Tcf4, a nuclear mediator of Wnt signaling, is essential for the differentiation and maintenance of Paneth cells in the small intestine. Its deficiency is associated with reduced expression of key α-defensins, highlighting its role in host-microbe interactions. However, the exact function of Tcf4 in specifying the secretory lineage and its contribution to antimicrobial peptide production remain incompletely understood. Remarkably, α-defensin expression has also been detected in human colon adenomas, where aberrant Wnt signaling is a hallmark. This raises important questions: What is the role of these Paneth-like cells in tumor biology, and how does Tcf4 influence their identity and function?
Nutritional Interventions to Attenuate Quadriceps Muscle Deficits following Anterior Cruciate Ligament Injury and Reconstruction.
Sports Med
Miriam J Smith, Nolan J Hoffman, Argell J San Jose +2 more
Following anterior cruciate ligament (ACL) injury, quadriceps muscle atrophy persists despite rehabilitation, leading to loss of lower limb strength, osteoarthritis, poor knee joint health and reduced quality of life. However, the molecular mechanisms responsible for these deficits in hypertrophic adaptations within the quadriceps muscle following ACL injury and reconstruction are poorly understood. While resistance exercise training stimulates skeletal muscle hypertrophy, attenuation of these hypertrophic pathways can hinder rehabilitation following ACL injury and reconstruction, and ultimately lead to skeletal muscle atrophy that persists beyond ACL reconstruction, similar to disuse atrophy. Numerous studies have documented beneficial roles of nutritional support, including nutritional supplementation, in maintaining and/or increasing muscle mass. There are three main mechanisms by which nutritional supplementation may attenuate muscle atrophy and promote hypertrophy: (1) by directly affecting muscle protein synthetic machinery; (2) indirectly increasing an individual's ability to work harder; and/or (3) directly affecting satellite cell proliferation and differentiation. We propose that nutritional support may enhance rehabilitative responses to exercise training and positively impact molecular machinery underlying muscle hypertrophy. As one of the fastest growing knee injuries worldwide, a better understanding of the potential mechanisms involved in quadriceps muscle deficits following ACL injury and reconstruction, and potential benefits of nutritional support, are required to help restore quadriceps muscle mass and/or strength. This review discusses our current understanding of the molecular mechanisms involved in muscle hypertrophy and disuse atrophy, and how nutritional supplements may leverage these pathways to maximise recovery from ACL injury and reconstruction.
Appetite-related Gut Hormone Responses to Feeding Across the Life Course.
J Endocr Soc
Adrian Holliday, Katy Horner, Kelsie O Johnson +2 more
Appetite-related hormones are secreted from the gut, signaling the presence of nutrients. Such signaling allows for cross-talk between the gut and the appetite-control regions of the brain, influencing appetite and food intake. As nutritional requirements change throughout the life course, it is perhaps unsurprising that appetite and eating behavior are not constant. Changes in appetite-related gut hormones may underpin these alterations in appetite and eating. In this article, we review evidence of how the release of appetite-related gut hormones changes throughout the life course and how this impacts appetite and eating behaviour. We focus on hormones for which there is the strongest evidence of impact on appetite, food intake, and body weight: the anorexigenic glucagon like peptide-1, peptide tyrosine tyrosine, and cholecystokinin, and the orexigenic ghrelin. We consider hormone concentrations, particularly in response to feeding, from the very early days of life, through childhood and adolescence, where responses may reflect energy requirements to support growth and development. We discuss the period of adulthood and midlife, with a particular focus on sex differences and the effect of menstruation, pregnancy, and menopause, as well as the potential influence of appetite-related gut hormones on body composition and weight status. We then discuss recent advancements in our understanding of how unfavorable changes in appetite-related gut hormone responses to feeding in later life may contribute to undernutrition and a detrimental aging trajectory. Finally, we briefly highlight priorities for future research.
Exogenous oral application of PYY and exendin-4 impacts upon taste-related behavior and taste perception in wild-type mice.
Neuropharmacology
Satya Iyer, Jean-Pierre Montmayeur, Sergei Zolotukhin +1 more
Several gut peptides have been implicated in feeding and body mass accumulation. Glucagon-like peptide 1 (GLP-1) and peptide tyrosine-tyrosine (PYY) have been shown to mediate satiety and reduce food intake. While systemic administration of such peptides has been explored as a therapy for metabolic disease, the effects of these hormones on taste signaling should also be considered given the importance of taste to feeding decisions and considering the fact that components of these signaling systems are expressed in cells of the peripheral gustatory system. We previously demonstrated that genetic disruption of PYY signaling in mice can impact on taste responsiveness and feeding and that viral expression of PYY in the salivary glands of PYY knockout mice can rescue responsiveness. The present work uses adeno-associated virus-mediated salivary gland treatment with both GLP-1 receptor agonist exendin-4 and/or PYY encoding vectors to explore the effect of stimulating these orally present signaling systems on taste-related behavioral responsiveness in male wild-type mice with intact peptide signaling systems. Results showed a significant effect of salivary gland treatment on responsiveness to multiple taste qualities. Data gathered from taste bud cells in vitro suggest that these peptides directly influence the responsiveness of these primary sensory cells. Collectively, these findings show that taste perception can be modulated by the exogenous application of satiety peptides in wild-type mice and suggest that the taste bud is a promising substrate for food intake modulation.
Ghrelin-LEAP2 interactions along the stomach-liver axis.
Endocr J
Katsuya Sakai, Yuki Nakazato, Yuki Shiimura +2 more
Ghrelin produced in the stomach promotes food intake and GH secretion, and acts as an anabolic peptide during starvation. Ghrelin binds to the growth hormone secretagogue receptor, a G protein-coupled receptor (GPCR), whose high-resolution complex structures have been determined in the apo state and when bound to an antagonist. Anamorelin, a low-molecular-weight ghrelin agonist, has been launched in Japan for the treatment of cancer cachexia, and its therapeutic potential has attracted attention due to the various biological activities of ghrelin. In 2019, liver-expressed antimicrobial peptide (LEAP2), initially discovered as an antimicrobial peptide produced in the liver, was identified to be upregulated in the stomach of diet-induced obese mice after vertical sleeve gastrectomy. LEAP2 binds to the GHSR and antagonizes ghrelin's activities. The serum concentrations of human LEAP2 are positively correlated with body mass index, body fat accumulation, and fasting serum concentrations of glucose and triglyceride. Serum LEAP2 elevated and ghrelin reduced in obesity. Ghrelin and LEAP2 regulate body weight, food intake, and GH and blood glucose concentrations, and other physiological phenomena through their interactions with the same receptor, GHSR.
New studies with stable gastric pentadecapeptide protecting gastrointestinal tract. significance of counteraction of vascular and multiorgan failure of occlusion/occlusion-like syndrome in cytoprotection/organoprotection.
Inflammopharmacology
Predrag Sikiric, Marko Sever, Ivan Krezic +19 more
Since the early 1990s, when Robert's and Szabo's cytoprotection concept had already been more than one decade old, but still not implemented in therapy, we suggest the stable gastric pentadecapeptide BPC 157 as the most relevant mediator of the cytoprotection concept. Consequently, it can translate stomach and gastrointestinal mucosal maintenance, epithelium, and endothelium cell protection to the therapy of other tissue healing (organoprotection), easily applicable, as native and stable in human gastric juice for more than 24 h. These overwhelm current clinical evidence (i.e., ulcerative colitis, phase II, no side effects, and no lethal dose (LD1) in toxicology studies), as BPC 157 therapy effectively combined various tissue healing and lesions counteraction. BPC 157 cytoprotection relevance and vascular recovery, activation of collateral pathways, membrane stabilizer, eye therapy, wound healing capability, brain-gut and gut-brain functioning, tumor cachexia counteraction, muscle, tendon, ligament, and bone disturbances counteraction, and the heart disturbances, myocardial infarction, heart failure, pulmonary hypertension, arrhythmias, and thrombosis counteraction appeared in the recent reviews. Here, as concept resolution, we review the counteraction of advanced Virchow triad circumstances by activation of the collateral rescuing pathways, depending on injury, activated azygos vein direct blood flow delivery, to counteract occlusion/occlusion-like syndromes starting with the context of alcohol-stomach lesions. Counteraction of major vessel failure (congested inferior caval vein and superior mesenteric vein, collapsed azygos vein, collapsed abdominal aorta) includes counteraction of the brain (intracerebral and intraventricular hemorrhage), heart (congestion, severe arrhythmias), lung (hemorrhage), and congestion and lesions in the liver, kidney, and gastrointestinal tract, intracranial (superior sagittal sinus), portal and caval hypertension, aortal hypotension, and thrombosis, peripherally and centrally.
The Application and Molecular Mechanisms of Mitochondria-Targeted Antioxidants in Chemotherapy-Induced Cardiac Injury.
Curr Issues Mol Biol
Chih-Jen Liu, Lu-Kai Wang, Fu-Ming Tsai
Chemotherapeutic agents play a crucial role in cancer treatment. However, their use is often associated with significant adverse effects, particularly cardiotoxicity. Drugs such as anthracyclines (e.g., doxorubicin) and platinum-based agents (e.g., cisplatin) cause mitochondrial damage, which is one of the main mechanisms underlying cardiotoxicity. These drugs induce oxidative stress, leading to an increase in reactive oxygen species (ROS), which in turn damage the mitochondria in cardiomyocytes, resulting in impaired cardiac function and heart failure. Mitochondria-targeted antioxidants (MTAs) have emerged as a promising cardioprotective strategy, offering a potential solution. These agents efficiently scavenge ROS within the mitochondria, protecting cardiomyocytes from oxidative damage. Recent studies have shown that MTAs, such as elamipretide, SkQ1, CoQ10, and melatonin, significantly mitigate chemotherapy-induced cardiotoxicity. These antioxidants not only reduce oxidative damage but also help maintain mitochondrial structure and function, stabilize mitochondrial membrane potential, and prevent excessive opening of the mitochondrial permeability transition pore, thus preventing apoptosis and cardiac dysfunction. In this review, we integrate recent findings to elucidate the mechanisms of chemotherapy-induced cardiotoxicity and highlight the substantial therapeutic potential of MTAs in reducing chemotherapy-induced heart damage. These agents are expected to offer safer and more effective treatment options for cancer patients in clinical practice.
Speech Therapy Combined With Cerebrolysin in Enhancing Nonfluent Aphasia Recovery After Acute Ischemic Stroke: ESCAS Randomized Pilot Study.
Stroke
Volker Homberg, Dragoș Cătălin Jianu, Adina Stan +7 more
Stroke-induced aphasia significantly impacts communication and quality of life. Despite the standard treatment being speech and language therapy, outcomes vary, highlighting the need for additional therapies. Cerebrolysin, a neuroprotective and neurotrophic agent, has shown potential in stroke management. This study addresses the notable gap in research about the combined use of Cerebrolysin and speech therapy, evaluating their synergistic potential in the treatment of aphasia.
Treatment Advances in Vitiligo: An Updated Review.
Dermatol Pract Concept
Ishrat Binti Ismail, Yasmeen Jabeen Bhat, Mohd Shurjeel Ul Islam
Vitiligo is a common disorder of depigmentation caused by the progressive destruction of melanocytes that affects the skin, hair, and mucous membranes, clinically presenting as depigmented macules and leukotrichia. This condition, affecting millions of people worldwide, has a significant psychosocial burden on patients' quality of life, particularly in relation to skin colour. The etiopathogenesis of this disorder is obscure, but multiple factors contribute to the loss of melanocytes in the skin, like oxidative stress, inflammation, genetics, and autoimmunity. The treatment of vitiligo has been challenging over the past years, but recent developments in understanding the etiopathogenesis of the disease have paved the way for the development of more effective and promising therapeutic treatment options.
Peptide pharmacology: Pioneering interventions for alcohol use disorder.
Prog Mol Biol Transl Sci
Ramkumar Katturajan, Sabina Evan Prince, Abilash Valsala Gopalakrishnan
Alcohol use disorder (AUD) is a substantial public health issue, with few treatment choices and a high social cost. This review investigates the possibility of peptide pharmacology as a new treatment for AUD. Peptides, or short chains of amino acids, provide specific manipulation of neuronal pathways involved in addiction, such as the opioid, corticotropin-releasing factor (CRF), neuropeptide Y (NPY), and glutamate systems. Preclinical research has shown that peptide-based therapies can reduce alcohol intake, demand, and relapse in animal models of AUD. Opioid peptides like β-endorphin and enkephalins affect alcohol reward processing by interacting with µ, ∂, and κ opioid receptors. CRF peptides reduce stress-induced alcohol-seeking behavior by targeting the dysregulated CRF system. NPY and associated peptides reduce cravings and anxiety by regulating stress and emotional processing. Peptide-based therapies have strong translational potential, as evidenced by early clinical trial results. There are also challenges in converting preclinical discoveries into clinical practice, such as establishing the safety, tolerability, and effectiveness of peptide therapies in humans. Future initiatives include identifying new peptide targets, optimizing pharmacokinetics, and incorporating peptide-based therapies into established therapy methods. Overall, peptide pharmacology represents a potential prospect in AUD therapy, as it provides tailored therapies that address the complex neurobiological pathways that underpin addiction.
Ghrelin promotes neurologic recovery and neurogenesis in the chronic phase after experimental stroke.
Neurol Res Pract
Carolin Beuker, Ulrike Schreiner, Jan-Kolja Strecker +6 more
The neuroprotective and proangiogenic potential of ghrelin in acute ischemic stroke has been demonstrated in experimental studies. However, the transferability of these results is limited as ghrelin was administered either before or very early after stroke onset and follow-up was limited to the first days after stroke. The aim of this study was therefore to close and extend this knowledge gap. To this end, we investigated the effect of ghrelin in two different translational animal models, one investigating acute and one investigating long-term structural and functional recovery after experimental stroke.
Are post-exercise plasma glucose elevations involved in exercise-induced appetite suppression?
Appl Physiol Nutr Metab
Derek P D Bornath, Seth F McCarthy, Jessica A L Tucker +3 more
Changes in glucose and insulin are potentially involved in the appetite-regulatory effects of exercise considering their role post-prandially. The purpose of this study was to examine whether glucose and insulin play a role in post-exercise appetite regulation. Twelve participants (M = 8; 26 ± 5 years) completed 3 experimental sessions in a systematically rotated randomized crossover design: (1) no-exercise control (CTRL); (2) moderate-intensity continuous training (MICT; 30 min, 70% maximal oxygen consumption (V̇O2max)); and (3) sprint interval training (SIT; 4 × 30 s "all-out" sprints, interspersed with 4 min rest). Plasma glucose, insulin, acylated ghrelin, active peptide tyrosine tyrosine (PYY), active glucagon-like peptide-1 (GLP-1), and overall appetite perceptions were measured pre-exercise, 0, 30, 60, and 120 min post-exercise. Energy intake was recorded the day before, of, and after experimental sessions. Glucose was elevated 0 min post-exercise (p < 0.097, d > 0.52) compared to CTRL with no differences between exercise bouts. Acylated ghrelin was suppressed by MICT (60, 120 min) and SIT (0, 30, 60, 120 min; p < 0.080, d > 0.56) compared to CTRL, while also suppressed in SIT compared to MICT at 30, 60, 120 min (p < 0.026, d > 0.74). GLP-1 was elevated following MICT (0, 30, and 60 min) and SIT (60 min; p < 0.094, d > 0.53) compared to CTRL and following MICT compared to SIT (0 min; p = 0.005, d = 1.03). Overall appetite was suppressed by SIT post-exercise (p < 0.058, d > 0.61) compared to CTRL and MICT, and by MICT 0 min post-exercise compared to CTRL (p = 0.036, d = 0.71). There were no exercise effects on insulin, PYY, or free-living energy intake (p > 0.217, ηp 2 < 0.130). Glucose and insulin do not appear to play a role in exercise-induced appetite suppression.
Evaluating the Effectiveness of Pegbelfermin in MASH-Associated Hepatic Fibrosis A Meta-Analysis and Systematic Review of Randomized Controlled Trials.
JGH Open
Muhammad Shahzil, Fariha Hasan, Syeda Kanza Kazmi +8 more
Metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of fatty liver disease, is characterized by liver inflammation and fibrosis, with an emerging interest in fibroblast growth factor (FGF)-21 analogs, particularly pegbelfermin (PGBF). This study evaluates the efficacy and safety of PGBF in treating MASH-associated hepatic fibrosis.
Gap in Sexual Dysfunction Management Between Male and Female Patients Seen in Primary Care: An Observational Study.
J Gen Intern Med
Elizabeth E Stanley, Elizabeth Pfoh, Laura Lipold +1 more
Female sexual dysfunction (FSD), defined as clinically distressing problems with desire, arousal, orgasm, or pain, affects 12% of US women. Despite availability of medications for FSD, primary care physicians (PCPs) report feeling underprepared to manage it. In contrast, erectile dysfunction (ED) is frequently treated in primary care.
Amelioration of Glutamate-induced Toxicity by a New Thyrotropin-releasing Hormone (TRH) Analogue PYR-l-(2,5-Dibromo)-His-l-ProNH2.
Ann Neurosci
Mallikarjuna R Sunkara, Jitendra N Singh, C L Meena +3 more
Glutamate has been implicated in the pathophysiology of central nervous system diseases, including stroke.
German Cohort Observational Study to Investigate the Short- and Long-Term Safety and Clinical Effectiveness of Afamelanotide 16 mg (SCENESSE) in Patients With Erythropoietic Protoporphyria (EPP).
Photodermatol Photoimmunol Photomed
Bernhard Homey, Kathrin Schelonke, Carla Marie Schlegel +10 more
Afamelanotide 16 mg (SCENESSE) is the first approved treatment for erythropoietic protoporphyria (EPP). EPP is a rare autosomal recessive inherited disorder of the haem biosynthesis pathway, where patients experience severe and debilitating acute phototoxicity. It affects at least one in 140,000 of the European population. A postauthorisation safety study (PASS) and a disease registry were imposed as conditions of the European marketing authorisation.
Current priorities in research on metabolic-associated fatty liver disease based on the results of EASL - 2024.
Pol Merkur Lekarski
Leonid L Pinsky, Mykola V Khaitovych, Olga A Golubovska +1 more
Aim: To systematize and comprehensively analyze scientific sources and studies on metabolic-associated steatotic liver disease (MASLD) based on materials from the European Congress of the European Association for the Study of the Liver (EASL - 2024)..
Genome-wide RNA sequencing analysis reveals that IGF-2 attenuates memory decline, oxidative stress and amyloid plaques in an Alzheimer's disease mouse model (AD) by activating the PI3K/AKT/CREB signaling pathway.
Int Psychogeriatr
Lei Xia, Xiangyu Zhu, Ying Zhao +5 more
Alzheimer's Disease (AD), characterized by deficits in memory and cognition and by behavioral impairment, is a progressive neurodegenerative disorder that influences more than 47 million people worldwide. Currently, no available drug is able to stop AD progression. Therefore, novel therapeutic strategies need to be investigated.