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Concerted actions by MMPs, ADAMTS and serine proteases during remodeling of the cartilage callus into bone during osseointegration of hip implants.
Bone Rep
Jean Cassuto, Agnetha Folestad, Jan Göthlin +2 more
Although the number of patients undergoing total hip arthroplasty is constantly on the rise, we only have limited knowledge of the molecular mechanisms necessary for successful osseointegration of implants or the reasons why some fail. Understanding the spatiotemporal characteristics of signaling pathways involved in bone healing of implants is therefore of particular importance for our ability to identify factors causing implants to fail. The current study investigated the role of three families of proteases, i.e. MMPs (matrix metalloproteinases), ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and serine proteases, as well as their endogenous inhibitors during osseointegration of hip implants that have endured two decades of use without clinical or radiological signs of loosening.
Kisspeptin signaling in astrocytes modulates the reproductive axis.
J Clin Invest
Encarnacion Torres, Giuliana Pellegrino, Melissa Granados-Rodríguez +23 more
Reproduction is safeguarded by multiple, often cooperative, regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation. Protein-protein interaction and ontology analyses of hypothalamic proteomic profiles after kisspeptin stimulation revealed that glial/astrocyte markers are regulated by kisspeptin in mice. This glial-kisspeptin pathway was validated by the demonstrated expression of Kiss1r in mouse astrocytes in vivo and astrocyte cultures from humans, rats, and mice, where kisspeptin activated canonical intracellular signaling-pathways. Cellular coexpression of Kiss1r with the astrocyte markers GFAP and S100-β occurred in different brain regions, with higher percentage in Kiss1- and GnRH-enriched areas. Conditional ablation of Kiss1r in GFAP-positive cells in the G-KiR-KO mouse altered gene expression of key factors in PGE2 synthesis in astrocytes and perturbed astrocyte-GnRH neuronal appositions, as well as LH responses to kisspeptin and LH pulsatility, as surrogate marker of GnRH secretion. G-KiR-KO mice also displayed changes in reproductive responses to metabolic stress induced by high-fat diet, affecting female pubertal onset, estrous cyclicity, and LH-secretory profiles. Our data unveil a nonneuronal pathway for kisspeptin actions in astrocytes, which cooperates in fine-tuning the reproductive axis and its responses to metabolic stress.
Quality of life in children with erythropoietic protoporphyria: a case-control study.
J Dermatol
Louisa G Kluijver, Debby Wensink, Margreet A E M Wagenmakers +4 more
Erythropoietic protoporphyria (EPP) is an inherited metabolic disease that causes painful phototoxic reactions, starting in childhood. Studies have shown a reduced quality of life (QoL) in adults with EPP, however, data on children with the disease are lacking. Since treatment for EPP is currently not registered for children, knowledge about their QoL is of crucial importance. In this prospective, case-control study, we included children from the Netherlands and Belgium diagnosed with EPP and matched to healthy controls. Previously collected EPP quality of life (EPP-QoL) data from matched adults with EPP were used. QoL scores, utilizing the Pediatric Quality of Life Inventory (PedsQL) and the disease-specific EPP-QoL, were collected. Scores range from 0 to 100, with higher scores indicating a higher QoL. Non-parametric tests were used to compare groups. A total of 15 cases, 13 matched healthy control children, and 15 matched adults with EPP were included. Children with EPP exhibited lower median scores in the PedsQL in both physical (cases: 87.5 (interquartile range [IQR] 77.7-96.1), controls: 99.2 [IQR 94.9-100.0], p = 0.03) and social (cases: 77.5 [IQR 69.4-86.3], controls: 97.5 [IQR 78.8-100.0], p = 0.04) domains compared to healthy children, although these differences were not statistically significant after correcting for multiple testing. The overall median EPP-QoL score for children was similar to adults with EPP (children: 44.4 [IQR 25.0-54.2], adults: 45.8 [IQR 25.7-68.1], p = 0.68). However, within the EPP-QoL subdomain on QoL, children were found to have significantly lower median scores (children: 16.7 [IQR 0.0-33.3], adults: 33.3 [IQR 33.3-62.5], p < 0.01). In conclusion, children with EPP experience a reduced QoL compared to both healthy children and adults with EPP. Ensuring treatment availability for this patient group is crucial for improving their QoL. We advocate the inclusion of children in safety and efficacy studies, to ensure availability of treatment in the future.
The Effect of Chronic Endurance Exercise on Serum Levels of MOTS-c and Humanin in Professional Athletes.
Rev Cardiovasc Med
Maha Alser, Manjunath Ramanjaneya, Najeha Rizwana Anwardeen +7 more
Humanin and the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) are mitochondrial encoded peptides involved in energy metabolism, cytoprotection, longevity, insulin sensitivity and their expression decrease with age. Levels of these molecules have been shown to respond to acute exercise, however little is known about their modulation under different chronic exercise conditions. In this study, we aim to compare levels of Humanin and MOTS-c in non-athletes vs professional (moderate and high endurance) athletes.
Exploring the central region of amylin and its analogs aggregation: the influence of metal ions and residue substitutions.
Front Chem
Mawadda Alghrably, Giulia Bennici, Gabriela Szczupaj +7 more
Human amylin (hIAPP) is found in the form of amyloid deposits within the pancreatic cells of nearly all patients diagnosed with type 2 diabetes mellitus (T2DM). However, rat amylin (rIAPP) and pramlintide - hIAPP analogs - are both non-toxic and non-amyloidogenic. Their primary sequences exhibit only slight variations in a few amino acid residues, primarily concentrated in the central region, spanning residues 20 to 29. This inspired us to study this fragment and investigate the impact on the aggregation properties of substituting residues within the central region of amylin and its analogs. Six fragments derived from amylin have undergone comprehensive testing against various metal ions by implementing a range of analytical techniques, including Nuclear Magnetic Resonance (NMR) spectroscopy, Thioflavin T (ThT) assays, Atomic Force Microscopy (AFM), and cytotoxicity assays. These methodologies serve to provide a thorough understanding of how the substitutions and interactions with metal ions impact the aggregation behavior of amylin and its analogs.
Behavioral and transcriptional effects of carnosine in the central ring ganglia of the pond snail Lymnaea stagnalis.
J Neurosci Res
Veronica Rivi, Giuseppe Caruso, Filippo Caraci +6 more
Carnosine is a naturally occurring endogenous dipeptide with well-recognized anti-inflammatory, antioxidant, and neuroprotective effects at the central nervous system level. To date, very few studies have been focused on the ability of carnosine to rescue and/or enhance memory. Here, we used a well-known invertebrate model system, the pond snail Lymnaea stagnalis, and a well-studied associative learning procedure, operant conditioning of aerial respiration, to investigate the ability of carnosine to enhance long-term memory (LTM) formation and reverse memory obstruction caused by an immune challenge (i.e., lipopolysaccharide [LPS] injection). Exposing snails to 1 mM carnosine for 1 h before training in addition to enhancing memory formation resulted in a significant upregulation of the expression levels of key neuroplasticity genes (i.e., glutamate ionotropic receptor N-methyl-d-aspartate [NMDA]-type subunit 1-LymGRIN1, and the transcription factor cAMP-response element-binding protein 1-LymCREB1) in snails' central ring ganglia. Moreover, pre-exposure to 1 mM carnosine before an LPS injection reversed the memory deficit brought about by inflammation, by preventing the upregulation of key targets for immune and stress response (i.e., Toll-like receptor 4-LymTLR4, molluscan defense molecule-LymMDM, heat shock protein 70-LymHSP70). Our data are thus consistent with the hypothesis that carnosine can have positive benefits on cognitive ability and be able to reverse memory aversive states induced by neuroinflammation.
Harnessing the melanocortin system in the control of food intake and glucose homeostasis.
Peptides
Patrick Swan, Brett Johnson, Carel W le Roux +1 more
The central and peripheral melanocortin system, comprising of five receptors and their endogenous ligands, is responsible for a wide array of physiological functions such as skin pigmentation, sexual function and development, and inflammation. A growing body of both clinical and pre-clinical research is demonstrating the relevance of this system in metabolic health. Disruption of hypothalamic melanocortin signalling is the most common cause of monogenic obesity in humans. Setmelanotide, an FDA-approved analogue of alpha-melanocyte stimulating hormone (α-MSH) that functions by restoring central melanocortin signalling, has proven to be a potent pharmacological tool in the treatment of syndromic obesity. As the first effective therapy targeting the melanocortin system to treat metabolic disorders, its approval has sparked research to further harness the links between these melanocortin receptors and metabolic processes. Here, we outline the structure of the central and peripheral melanocortin system, discuss its critical role in the regulation of food intake, and review promising targets that may hold potential to treat metabolic disorders in humans.
Calcitonin gene-related peptide and intermedin induce phosphorylation of p44/42 MAPK in primary human lymphatic endothelial cells in vitro.
Cell Signal
Shirin R Hasan, Dimitrios Manolis, Ewan Stephenson +3 more
Calcitonin gene-related peptide (CGRP) and adrenomedullin 2/intermedin (AM2/IMD) play important roles in several pathologies, including cardiovascular disease, migraine and cancer. The efficacy of drugs targeting CGRP signalling axis for the treatment of migraine patients is sometimes offset by side effects (e.g. inflammation and microvascular complications, including aberrant neovascularisation in the skin). Recent studies using animal models implicate CGRP in lymphangiogenesis and lymphatic vessel function. However, whether CGRP or AM2/IMD can act directly on lymphatic endothelial cells is unknown. Here, we found that CGRP and AM2/IMD induced p44/42 MAPK phosphorylation in a time- and dose-dependent manner in primary human dermal lymphatic endothelial cells (HDLEC) in vitro, and thus directly affected these cells. These new findings reveal CGRP and AM2/IMD as novel regulators of LEC biology and warrant further investigation of their roles in the context of pathologies associated with lymphatic function in the skin and other organs, and therapies targeting CGRP signalling axis.
Life-Threatening Anaphylaxis due to Cerebrolysin®.
Case Rep Neurol Med
Helmut Trimmel, Wolfgang Tauber, Martin Zikeli
In this case report, we describe a well-documented, severe anaphylactic reaction after intravenous administration of cerebrolysin, a neurotrophic agent derived from highly purified porcine brain tissue, consisting of peptides and free amino acids. Cerebrolysin has been in use for decades, in various neurological diseases, but especially stroke and traumatic brain injury, with the aim of enhancing cognitive performance. After administration of cerebrolysin to an 85-year-old male patient suffering from subacute stroke, he developed a fulminant anaphylactic reaction. Following institutional standards, vital functions were quickly restored. The anaphylactic reaction was clearly confirmed by laboratory tests. To date, only rare cases of anaphylaxis due to cerebrolysin have been published in the literature. The current report is intended to raise awareness for the possibility of such a reaction, given the widespread use of cerebrolysin in several indications in mostly critical patients. The case shows how a completely unexpected life-threatening situation can be successfully treated by targeted measures, if the situation is recognized quickly. In light of this event, we consider pathophysiology of allergic reactions and treatment guidelines.
Supplementation of Vitamin D3 and Fructooligosaccharides Downregulates Intestinal Defensins and Reduces the Species Abundance of Romboutsia ilealis in C57BL/6J Mice.
Nutrients
Tyler Hanson, Ethan Constantine, Zack Nobles +4 more
The activation of the vitamin D receptor (VDR) in the ileum has been shown to regulate Paneth cell-specific defensins, a large family of antimicrobial peptides; hence, this may serve as a potential mechanism to maintain intestinal homeostasis. Previously, we have demonstrated that a combination of vitamin D3 (VD) and fructooligosaccharides (FOSs) upregulates colonic Vdr in mice. Here, we aim to examine the effect of VD, alone or in combination with FOSs, on intestinal barrier integrity and the secretion of antimicrobial peptides, as well as the gut microbial community. Male and female C57BL/6J mice at 6 weeks old were randomized into three groups to receive the following dietary regimens (n = 10/sex/group) for 8 weeks: (1) standard AIN-93G control diet (CTR), (2) CTR + 5000 IU vitamin D3 (VD), and (3) VD + 5% fructooligosaccharides (VF). VD and VF differentially regulated the mRNA expressions of tight junction proteins in the colon and ileum. VF suppressed the upregulation of colonic ZO-1 and occludin, which was induced by VD supplementation alone. In the ileum, occludin but not ZO-1 was upregulated 20-fold in the VF-treated mice. While VD did not alter the mRNA expressions of Vdr and defensins in the ileum, these targets were downregulated by VF. Microbial analysis further reveals a shift of microbial beta diversity and a reduction in Romboutsia ilealis, a pathobiont, in VF-treated mice. Though the implications of these phenotypical and microbial changes remain to be determined, the administration of FOSs in the presence of VD may serve as an effective dietary intervention for maintaining intestinal homeostasis.
Endogenous opiates and behavior: 2023.
Peptides
Richard J Bodnar
This paper is the forty-sixth consecutive installment of the annual anthological review of research concerning the endogenous opioid system, summarizing articles published during 2023 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides and receptors as well as effects of opioid/opiate agonists and antagonists. The review is subdivided into the following specific topics: molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors (1), the roles of these opioid peptides and receptors in pain and analgesia in animals (2) and humans (3), opioid-sensitive and opioid-insensitive effects of nonopioid analgesics (4), opioid peptide and receptor involvement in tolerance and dependence (5), stress and social status (6), learning and memory (7), eating and drinking (8), drug and alcohol abuse (9), sexual activity and hormones, pregnancy, development and endocrinology (10), mental illness and mood (11), seizures and neurologic disorders (12), electrical-related activity and neurophysiology (13), general activity and locomotion (14), gastrointestinal, renal and hepatic functions (15), cardiovascular responses (16), respiration and thermoregulation (17), and immunological responses (18).
Ghrelin Improves Glucolipotoxicity-Induced Pancreatic β-Cellular Dysfunction and Apoptosis by Inhibiting Endoplasmic Reticulum Stress-Induced IRE1/JNK Pathway.
Discov Med
Xin-Ying Li, Chun-Rong Zhong, Jin-Chan Wu +2 more
Glucose and fatty acid overload-induced glucolipid toxicity of pancreatic β-cells is associated with the development of diabetes. Endoplasmic reticulum stress (ERS) plays an essential role in this process. Ghrelin, a peptide secreted by the pancreas, negatively correlates with oxidative stress. The study aimed to investigate ghrelin's role in glycolipid-induced β-cell dysfunction and its possible mechanism.
Biologically active adrenomedullin as a marker for residual congestion and early rehospitalization in patients hospitalized for acute heart failure: Data from STRONG-HF.
Eur J Heart Fail
Geert Voordes, Beth Davison, Jan Biegus +30 more
Biologically active adrenomedullin (bio-ADM) is a promising marker of residual congestion. The STRONG-HF trial showed that high-intensity care (HIC) of guideline-directed medical therapy (GDMT) improved congestion and clinical outcomes in heart failure (HF) patients. The association between bio-ADM, decongestion, outcomes and the effect size of HIC of GDMT remains to be elucidated.
Mitochondrial-derived peptides and exercise.
Biochim Biophys Acta Gen Subj
Jonathan S T Woodhead, Troy L Merry
Acute exercise, and in particular aerobic exercise, increases skeletal muscle energy demand causing mitochondrial stress, and mitochondrial-related adaptations which are a hallmark of exercise training. Given that mitochondria are central players in the exercise response, it is imperative that they have networks that can communicate their status both intra- and inter-cellularly. Peptides encoded by short open-reading frames within mitochondrial DNA, mitochondrial-derived peptides (MDPs), have been suggested to form a newly recognised branch of this retrograde signalling cascade that contribute to coordinating the adaptive response to regular exercise. Here we summarise the recent evidence that acute high intensity exercise in humans can increase concentrations of the MDPs humanin and MOTS-c in skeletal muscle and plasma, and speculate on the mechanisms controlling MDP responses to exercise stress. Evidence that exercise training results in chronic changes in MDP expression within tissues and the circulation is conflicting and may depend on the mode, duration, intensity of training plan and participant characteristics. Further research is required to define the effect of these variables on MDPs and to determine whether MDPs other than MOTS-c have exercise mimetic properties. MOTS-c treatment of young and aged mice improves exercise capacity/performance and leads to adaptions that are similar to that of being physically active (weight loss, increased antioxidant capacity and improved insulin sensitivity), however, studies utilising a MOTS-c inactivating genetic variant or combination of exercise + MOTS-c treatment in mice suggest that there are distinct and overlapping pathways through which exercise and MOTS-c evoke metabolic benefits. Overall, MOTS-c, and potentially other MDPs, may be exercise-sensitive myokines and further work is required to define inter- and intra-tissue targets in an exercise context.
Cardio-protective role of Humanin in myocardial ischemia-reperfusion.
Biochim Biophys Acta Gen Subj
Zhenwei Gong, Eric Goetzman, Radhika H Muzumdar
Mitochondria-derived peptides (MDPs) are bioactive peptides encoded by and secreted from the mitochondria. To date, a few MDPs including humanin, MOTS-c and SHLP1-6, and their diverse biological functions have been identified. The first and most studied MDP is humanin, a 24-amino-acid poly peptide. It was first identified in 2001 in the surviving neurons of patient with Alzheimer's disease, and since then has been well characterized for its neuro-protective effect through inhibition of apoptosis. Over the past two decades, humanin has been reported to play critical roles in aging as well as multiple diseases including metabolic disorders, cardiovascular diseases, and autoimmune disease. Humanin has been shown to modulate multiple biological processes including autophagy, ER stress, cellular metabolism, oxidative stress, and inflammation. A role for humanin has been shown in a wide range of cardiovascular diseases, such as coronary heart disease, atherosclerosis, and myocardial fibrosis. In this minireview, we will summarize the literature demonstrating a role for humanin in cardio-protection following myocardial ischemia-reperfusion induced injury and the potential mechanisms that mediate it.
Synthesis and characterization of novel ssDNA X-aptamers targeting Growth Hormone Releasing Hormone (GHRH).
PLoS One
Burcu Ayhan-Sahin, Zeynep-Elif Apaydın, Pınar Obakan-Yerlikaya +2 more
Growth Hormone Releasing Hormone (GHRH), 44 amino acids containing hypothalamic hormone, retains the biological activity by its first 29 amino acids. GHRH (NH2 1-29) peptide antagonists inhibit the growth of prostate, breast, ovarian, renal, gastric, pancreatic cancer in vitro and in vivo. Aptamers, single-strand RNA, or DNA oligonucleotides are capable of binding to target molecules with high affinity. Our aim in this study is to synthesize and select X-aptamers against both GHRH NH2 (1-29) and GHRH NH2 (1-44) and demonstrate synthesized aptamers' target binding activity as well as serum stability.
Supramolecular Nanofibrils Formed by Coassembly of Clinically Approved Drugs for Tumor Photothermal Immunotherapy.
Adv Mater
Shukun Li, Wenjia Zhang, Ruirui Xing +3 more
Pancreatic cancer, one of the most lethal malignancies, compromises the performance of traditional therapeutic regimens in the clinic because of stromal resistance to systemic drug delivery and poor prognosis caused by tumor metastasis. Therefore, a biocompatible therapeutic paradigm that can effectively inhibit pancreatic tumor growth while simultaneously eliminating tumor metastasis is urgently needed. Herein, supramolecular nanofibrils are fabricated through coassembly of clinically approved immunomodulatory thymopentin and near-infrared indocyanine green for localized photothermal immunotherapy of pancreatic tumors. The resulting long-range ordered fibrous nanodrugs show improved photophysical capabilities for fluorescence imaging and photothermal conversion and significantly promote the proliferation and differentiation of antitumor immune cells. Hence, the integration of rapid photothermal therapy and moderate immunomodulation for inhibiting tumor growth and eliminating tumor metastasis is promising. The utilization of clinically approved molecules to construct nanodrugs administered via localized injection amplifies the complementary photothermal immunotherapeutic effects of the components, creating opportunities for clinical translation as a treatment for pancreatic cancer.
Molecular Changes Implicate Angiogenesis and Arterial Remodeling in Systemic Sclerosis-Associated and Idiopathic Pulmonary Hypertension.
Arterioscler Thromb Vasc Biol
Yuechen Zhou, Tracy Tabib, Mengqi Huang +6 more
Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension). Investigation of transcriptomic alterations in vascular populations is critical to elucidating cellular mechanisms underlying pathobiology of SSc-associated and idiopathic PH.
QEEG indices in traumatic brain injury - insights from the CAPTAIN RTMS trial.
J Med Life
Verişezan Roşu Olivia, Diana Chira, Vlad-Florin Chelaru +4 more
This secondary analysis of the CAPTAIN-RTMS trial data focused on the significance of quantitative electroencephalography (qEEG) indices as indicators of recovery in patients with traumatic brain injury (TBI). By focusing on the delta alpha ratio (DAR), delta theta/alpha beta ratio (DTABR), and theta beta ratio (TBR), this study explored the shifts in brainwave activity as a response to an integrative treatment regimen of repetitive transcranial magnetic stimulation (rTMS) combined with the neurotrophic agent Cerebrolysin. Findings revealed significant increases in DAR and DTABR, suggesting changes in neurophysiological dynamics after treatment. However, variations in TBR were inconclusive in providing clear electrophysiological insights. These results indicate that further research is necessary to describe and understand the underlying mechanisms of brain recovery and to develop refined treatment frameworks for patients with TBI.
Understanding the Interplay Between Premenstrual Dysphoric Disorder (PMDD) and Female Sexual Dysfunction (FSD).
Cureus
Mahati Gollapudi, Angelica Thomas, Angelina Yogarajah +8 more
Premenstrual dysphoric disorder (PMDD) is a severe variant of premenstrual syndrome (PMS), categorized as a mood disorder due to marked symptoms of depression and anxiety, compounded with severe physical symptoms. Female sexual dysfunction (FSD) can manifest as low libido, difficulty achieving sexual pleasure, and dyspareunia, causing functional and psychological distress. PMDD and FSD are globally prevalent conditions with postulated biological, psychological, and social associations between them. Nevertheless, sexual dysfunction in PMDD is an important aspect of women's health that has been understudied and has notable methodological limitations. In this narrative review, we summarize the existing literature on sexual function in women with PMDD and PMS, specify the distinctions between PMDD and other general symptoms of PMS, highlight the significance of understanding sexual dysfunction in the female population, and outline some available therapeutic options. Studies show that women frequently experience debilitating sexual distress during the premenstrual phase; however, there is an essential need to formulate standardized tools for definite diagnosis. Selective serotonin re-uptake inhibitors (SSRIs) and combined oral contraceptive pills (COCPs) are approved medications for PMDD, while flibanserin and bremelanotide are effective in treating FSD. However, the potential effects of these treatment modalities on the two comorbid conditions render them inconclusive. Awareness of PMDD and FSD among clinicians and society can allow the implementation of targeted interventions to alleviate the suffering of women and enhance their quality of life.