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A rare case report of familial glucocorticoid deficiency type 4 (GCCD4) with dilated cardiomyopathy: a 3-year follow-up study.

Transl Pediatr

Zeli Xun, Yan'an Du, Ting Zhao +1 more

Familial glucocorticoid deficiency type 4 (GCCD4), caused by nicotinamide nucleotide transhydrogenase (NNT) gene mutations, represents a rare multisystem disorder with poorly characterized cardiac manifestations.

Characterization of membrane-interaction mechanisms of proteins using vacuum-ultraviolet circular dichroism spectroscopy.

Chirality

Munehiro Kumashiro, Koichi Matsuo

Protein-membrane interactions play an important role in various biological phenomena, such as material transport, demyelinating diseases, and antimicrobial activity. We combined vacuum-ultraviolet circular dichroism (VUVCD) spectroscopy with theoretical (e.g., molecular dynamics and neural networks) and polarization experimental (e.g., linear dichroism and fluorescence anisotropy) methods to characterize the membrane interaction mechanisms of three soluble proteins (or peptides). α1 -Acid glycoprotein has the drug-binding ability, but the combination of VUVCD and neural-network method revealed that the membrane interaction causes the extension of helix in the N-terminal region, which reduces the binding ability. Myelin basic protein (MBP) is an essential component of the myelin sheath with a multi-layered structure. Molecular dynamics simulations using a VUVCD-guided system showed that MBP forms two amphiphilic and three non-amphiphilic helices as membrane interaction sites. These multivalent interactions may allow MBP to interact with two opposing membrane leaflets, contributing to the formation of a multi-layered myelin structure. The antimicrobial peptide magainin 2 interacts with the bacterial membrane, causing damage to its structure. VUVCD analysis revealed that the M2 peptides assemble in the membrane and turn into oligomers with a β-strand structure. Linear dichroism and fluorescence anisotropy suggested that the oligomers are inserted into the hydrophobic core of the membrane, disrupting the bacterial membrane. Overall, our findings demonstrate that VUVCD and its combination with theoretical and polarization experimental methods pave the way for unraveling the molecular mechanisms of biological phenomena related to protein-membrane interactions.

Antimicrobial Peptides (AMPs) Are Not Increased in Asymptomatic Bacteriuria in Healthy Older Adult Patients.

J Am Geriatr Soc

Katherine M Hunold, Andrew Schwaderer, Julie A Stephens +8 more

Antimicrobial peptides have demonstrated promise as biomarkers for urinary tract infection (UTI) in older adults (age ≥ 65 years). However, it is unknown if urinary AMP levels also increase in asymptomatic bacteriuria. Our objective was to determine if AMP levels vary between older adult patients with and without asymptomatic bacteriuria.

Body Weight Support Treadmill Training Combined With Sciatic Nerve Electrical Stimulation Ameliorating Motor Function by Enhancing PI3K/Akt Proteins Expression via BDNF/TrkB Signaling Pathway in Rats with Spinal Cord Injury.

World Neurosurg

Qingqin Xu, Zhen Li, Junhong Su +5 more

To investigate the effects of body weight support treadmill training (BWSTT) and sciatic nerve electrical stimulation (SNES) on motor function recovery in spinal cord injury (SCI) rats and its possible mechanism.

Cholinergic neurons in the dorsal nucleus of the vagus nerve are involved in the mechanism of action of electroacupuncture at HT7 in a mouse model of chronic heart failure.

Acupunct Med

Shi-Yue Wang, Hao-Sheng Wu, Sheng-Bing Wu +1 more

To investigate the role and mechanism of the dorsal motor nucleus of the vagus nerve (DMV) in the effects of electroacupuncture (EA) at HT7 in a mouse model of chronic heart failure (CHF).

Multi-omics approach identifies PI3 as a biomarker for disease severity and hyper-keratinization in psoriasis.

J Dermatol Sci

Jingwen Deng, Emmerik Leijten, Yongzhan Zhu +11 more

Psoriasis is an immune-mediated inflammatory skin disease. Psoriasis severity evaluation is important for clinicians in the assessment of disease severity and subsequent clinical decision making. However, no objective biomarker is available for accurately evaluating disease severity in psoriasis.

Semaglutide alleviates ovarian ferroptosis in polycystic ovary syndrome and is associated with reduced GPX4 promoter hypermethylation.

J Mol Histol

Yaling Zhang, Daojuan Wang, Xiaosa Si +4 more

Polycystic ovary syndrome (PCOS) is associated with ovarian granulosa cell dysfunction. Ferroptosis, a regulated cell death driven by lipid peroxidation, represents a novel pathological mechanism. Hypermethylation of the glutathione peroxidase 4 (GPX4) promoter may contribute to its suppression. While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve metabolic features of PCOS, their direct effects on ovarian ferroptosis and the underlying epigenetic mechanisms are unclear. To explore the therapeutic potential of GLP-1RAs across PCOS phenotypes, we employed a hyperandrogenism-induced rat model and a letrozole plus high-fat diet mouse model, treating them with exenatide or semaglutide, respectively. Phenotypic assessment included estrous cycle monitoring, ovarian histology, and serum hormone profiling. Ferroptosis was evaluated using a multi-parametric approach, including iron deposition (Perls' staining), lipid peroxidation (MDA), redox status (GSH/GSSG), ultrastructural analysis (TEM), and expression of key regulators. The methylation status of the GPX4 promoter was analyzed by methylation-specific PCR (MSP) and bisulfite sequencing (BSP), alongside the expression of related epigenetic modifiers (DNMTs, TET1). In vitro studies using DHT-stimulated primary granulosa cells further validated the semaglutide effects. GLP-1 RA exenatide alleviated the polycystic ovarian morphology in rats with PCOS, semaglutide treatment not only alleviated PCOS phenotypes but also reversed ovarian ferroptosis markers, restored GPX4 expression, and reduced the GPX4 promoter hypermethylation and DNMTs levels, with efficacy comparable to 5-azacytidine. In vitro, semaglutide corrected DHT-induced GPX4 hypermethylation and ferroptosis in granulosa cells. This study demonstrates that semaglutide alleviates PCOS phenotypes and reverses ovarian granulosa cell ferroptosis. These beneficial effects may be related to the alleviation of GPX4 promoter hypermethylation. Our findings extend the therapeutic rationale for semaglutide in PCOS beyond metabolic benefits, suggesting potential direct ovarian protection via epigenetic modulation.

Identification of intranasal oxytocin plasma proteome signatures.

Endocrine

Lauren Breithaupt, Stephanie G Harshman, Patrick M Botros +10 more

Oral Use of Collagen Supplements in Dermatology.

Acta Dermatovenerol Croat

Vanda Haralović, Ines Sjerobabski Masnec

Collagen is a crucial protein found in bones, muscles, skin, and tendons that provides strength and elasticity to tissues. It is obtained from sources such as marine organisms, cows, pigs, and chickens and is widely used in medicine and cosmetics. Hydrolyzed collagen peptides in the form of powder or liquid are typically used in food supplements. Marine collagen, produced from fish skin, is considered a high-quality source of collagen in food supplements. Research suggests that supplementation of hydrolyzed collagen improves skin hydration, elasticity, and collagen content. UV radiation, aging, and environmental toxins lead to the breakdown of collagen, causing wrinkles, dryness, and reduced elasticity. Excessive sun exposure should be avoided to boost collagen production. However, collagen supplementation has potential risks, including allergies and product quality. Oral supplements based on hydrolyzed collagen show promising results for the health and well-being of the skin, especially when sourced from marine collagen.

Low factor XI activity in heart failure: A Potential marker of disease severity?

Kardiol Pol

Mahmoud Mansour, Makxim Kagarlyk, Eias Massalha +6 more

Advanced heart failure (HF) is characterized by progressive cardiac remodeling and recurrent episodes of decompensation, highlighting the need for biomarkers reflecting disease severity. Coagulation factor XI (FXI), beyond its established role in hemostasis, may influence inflammatory and remodeling pathways in the heart, but its relevance in advanced HF remains unclear.

Insulin receptor trafficking and interactions in muscle cells.

J Endocr Soc

Haoning Howard Cen, Aurora J Mattison, Alireza Omidi +7 more

Insulin action is critical for energy homeostasis and its dysfunction in muscle cells is associated with type 2 diabetes. Insulin receptor (INSR) internalization and cell-surface dynamics at rest and during insulin exposure are incompletely understood in muscle cells.

Insulin-like growth factor 1 receptor (IGF1R)-dependent signaling regulates blastocyst formation during early embryonic development.

Front Cell Dev Biol

Chi-Hun Park, Young-Hee Jeoung, JiTao Wang +1 more

Insulin-like growth factor 1 (IGF1) signaling is a conserved regulator of embryonic growth and survival. However, the specific role of IGF1 signaling mediated by its cognate receptor IGF1R during mammalian preimplantation development remains unclear and unexplored. In this study, we employed both genetic ablation using cytidine deaminase base editors and pharmacological inhibition to assess the role of IGF1R in porcine early embryonic development. Embryos lacking IGF1R advanced through early cleavage divisions and progressed to blastocyst formation; however, they displayed delayed blastocyst development and significantly increased apoptosis. Lineage segregation was largely unperturbed. Exogenous IGF-1 supplementation did not ameliorate developmental impairments in IGF1R-knockout embryos and instead exacerbated apoptotic responses when receptor signaling was compromised. Collectively, these results establish that IGF1R signaling is dispensable for cell fate specification but is crucial for regulating blastocyst growth dynamics and embryonic viability.

Glucagon-like peptide-1 agonists in children with obesity and type 2 diabetes. an umbrella review.

Front Endocrinol (Lausanne)

Hyder Mirghani, Laila Albishi, Sawsan Mohmmad Alblewi

Obesity and type 2 diabetes mellitus (Type 2 DM) are rising at an alarming rate among children and adolescents. This population often exhibits suboptimal glycemic control and diabetes-related complications. Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) have emerged as a promising therapeutic option for pediatric patients due to their beneficial effects on weight reduction and glycemic regulation. Literature on this important issue is scarce. We aimed to assess the effects of GLP-1 agonists on body weight, HbA1c, body mass index z (BMI z), and systolic blood pressure (SBP). Additionally, we discussed adverse events and hypoglycemia.

Baseline metabolite profiles predict the glucose-lowering efficacy of exenatide in patients with type 2 diabetes.

Metabol Open

Yunyi Le, Jin Yang, Qi Wu +6 more

Individual heterogeneity in the glucose-lowering response to glucagon-like peptide-1 receptor agonists (GLP-1RAs), including exenatide, limits efficient treatment selection for type 2 diabetes mellitus (T2DM). This study assessed whether baseline clinical characteristics together with serum metabolomic features could predict the glucose-lowering efficacy of exenatide.

[Obesity: novel pharmacological treatments].

Dtsch Med Wochenschr

Jochen Seufert

Obesity is currently considered as adiposity based chronic disease with BMI as therapeutic target for prevention of obesity associated complications. For treatment of obesity, a stepwise approach is recommended including multifactorial basal therapy with nutrition counseling, exercise training and behavior modification. Further steps comprise adjuvant pharmacological treatment and bariatric surgery. With the development of incretin based medications that activate GLP-1 and GIP receptors for increase in satiety, an impressive improvement in effectivity of obesity medications is observed. Licensed substances in Germany include the GLP-1 receptor agonists liraglutide and semaglutide, and the GLP-1/GIP receptor coagonist tirzepatide. Trial data reveal weight losses of on average 7.5 kg after 160 weeks for liraglutide, up to 17.4 kg after 68 weeks for semaglutide, and up to 22.5 kg after 72 weeks for tirzepatide. In addition, semaglutide demonstrated positive results in cardiovascular outcome trials. The weight reducing effects of incretin based substances are close to those achieved by bariatric interventions, therefore closing the gap between lifestyle intervention and bariatric surgery.

Crosstalk between alcohol use disorder and obesity: two sides of the same coin?

Mol Psychiatry

Lorenzo Leggio, Mehdi Farokhnia, Paul J Kenny +2 more

Investigating similarities and differences between alcohol use disorder (AUD) and obesity is important because both AUD and obesity are public health concerns and share neurobiological and periphery-brain mechanisms. Furthermore, AUD and obesity often present with similar medical consequences related to organ damage, including liver and cardiovascular diseases. There is also growing evidence of changes in alcohol drinking in people who undergo bariatric surgery for obesity. In this non-systematic critical review, we identified relevant articles through PubMed searches, previous knowledge, and recursive reference searching. A librarian also used PubMed and Google Scholar for additional relevant articles, using terms such as alcohol, metabolic disorders, obesity, glucagon-like peptide-1 (GLP-1), bariatric surgery, and gut-brain axis. We provide an overview of the neurobiological, pathophysiological, neuroimaging, and clinical features related to the overlap and crosstalk between AUD and obesity. We also provide a summary of the currently approved medications for obesity and those for AUD and note the potential for some of these medications to work for both disorders. Specific to the latter point, we place emphasis on GLP-1 therapies, given their recent approval for weight loss and the growing evidence suggesting their potential efficacy for AUD and other addictions. We further review studies of the relationship between bariatric surgery and AUD and discuss potential mechanisms and future directions. In summary, studying the overlap between obesity and AUD may shed light on the mechanisms underlying the development and maintenance of both diseases. This knowledge, in turn, may help identify new therapeutic targets for AUD, and possibly comorbid obesity and/or other metabolic disorders.

Real-world observational study on pulmonary arterial hypertension: Italian cohort treated with macitentan and/or selexipag as a part of a combination treatment (INSPECTIO).

Vascul Pharmacol

Michele D'Alto, Laura Scelsi, Livio Giuliani +17 more

Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Combination therapy targeting multiple pathways has been shown to improve clinical outcomes.

Non-specific Protein and Peptide Antibacterial Factors of Mammals.

Protein J

Pavel Levashov, Ilia Zaitsev, Sergei Zaitsev +1 more

The review summarises the basic information on non-specific factors of mammals that potentially have antimicrobial action. A comparison of previously known factors with the latest literature data is carried out. The following peptide and protein factors are considered: lysozymes, transferrins, interferons, interleukin-2, antimicrobial peptides (defensins, cathelicidins, histatins) and protective glycoproteins (mucins, lectins). These major antibacterial factors perform regulatory functions in the immune system, and some are also able to resist viral and fungal infections or oncological pathologies. The study of the internal antibacterial factors of mammals and the mechanisms of their activation is of great importance for the fight against bacterial infections, including antibiotic-resistant ones. This knowledge is necessary for the development of new approaches to the treatment of humans and farm animals.

Structural determinants of glycosaminoglycan oligosaccharides as LL-37 inhibitors in breast cancer.

Glycobiology

Chloe Le Fournis, Martyna Maszota-Zieleniak, Adam Kulesza +6 more

The human antimicrobial peptide LL-37 exerts a dual role in cancer, promoting tumor progression in breast carcinoma by stimulating calcium influx and enhancing cell migration. Its interactions with glycosaminoglycans (GAGs) provide an attractive therapeutic avenue for intervention. In this study, we investigated the ability of structurally distinct GAG oligosaccharides to inhibit LL-37-mediated responses in MDA-MB-231 breast cancer cells. Functional assays were performed to evaluate membrane depolarization, intracellular calcium mobilization, and migration capacity. When applied at a 1:1 stoichiometric ratio with LL-37, heparin emerged as the most effective inhibitor. This inhibitory activity required a minimum oligosaccharide length of 18 monosaccharide units and was strongly dependent on the degree of sulfation. Heparin displayed significantly higher efficacy than either chondroitin sulfate or dermatan sulfate. Binding studies using microscale thermophoresis demonstrated nanomolar affinity of LL-37 for heparin, whereas interactions with chondroitin and dermatan sulfate were weaker. Complementary molecular dynamics simulations reinforced these findings by highlighting the predominant role of electrostatic interactions in stabilizing LL-37/GAG complexes and by providing atomistic models of the binding interfaces. Binding studies on a heparin-derived synthetic oligosaccharide array revealed that, apart from the degree of sulfation, structural components in heparin contribute to its affinity for LL-37. Collectively, our results suggest that the structural optimization of GAG mimetics may represent a promising targeted strategy to block LL-37-driven tumor progression.

SIRT3-dependent enhancement of apelinergic signaling mediates the cardioprotective effects of late-life high-intensity interval training.

J Physiol Sci

Qiaowei Li, Yanmei Song, Qin Liu +4 more

Deficiency in apelinergic signaling (APJ/Apelin) has been shown to accelerate cardiac aging. Given our observation that high-intensity interval training (HIIT) upregulates APJ and Apelin in aged mouse hearts, this study aimed to investigate whether apelinergic signaling mediates the cardioprotective effects of exercise.