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Evaluating the Effect of Cerebrolysin as an Adjuvant to Standard Therapy in Patients with Acute Ischemic Stroke: A Prospective Observational Study.
Medicina (Kaunas)
Geetha Kandasamy, Vijayakumar Arumugam, Khalid Orayj +4 more
Background and Objectives: Acute ischemic stroke is a major cause of disability and mortality. Cerebrolysin, a neuropeptide with neuroprotective and neurotrophic properties, may enhance post-stroke recovery. This study evaluated the impact of adding Cerebrolysin to standard therapy on clinical outcomes in patients with acute ischemic stroke. Materials and Methods: This non-randomized prospective observational study included 143 adults with acute ischemic stroke at Kovai Medical Center and Hospital, Coimbatore (April 2016-May 2018). Participants were divided into two groups: the standard therapy group (n = 70) and the adjuvant therapy group (n = 73), which received Cerebrolysin (30 mL IV daily for 14 days) in addition to standard care. Stroke severity and functional outcomes were evaluated using the National Institutes of Health Stroke Scale (NIHSS) and Barthel Index (BI) at baseline and Day 14. A p < 0.05 was considered statistically significant. Results: Stroke severity improved in both groups, but the adjuvant group demonstrated significantly greater reductions in NIHSS scores from 9.90 ± 2.90 to 3.40 ± 1.40 compared to the standard group, which improved from 10.10 ± 2.80 to 4.80 ± 1.30 (t = 6.19, p < 0.001). Additionally, 43.84% of patients in the adjuvant group shifted to minor stroke severity versus 25.71% in the standard group. Both groups showed significant improvements across all domains of the BI, which assesses activities of daily living (ADL); however, the gains were consistently greater in the adjuvant group (p < 0.001). A higher proportion of patients in the Cerebrolysin group achieved slight dependency (38.36%) or full independence (16.44%), compared to 20% and 5.71% in the standard group, respectively. Conclusions: This prospective observational study suggests that adding Cerebrolysin to standard therapy was associated with greater neurological recovery and functional independence in acute ischemic stroke patients. However, the short follow-up, single-center setting, and lack of randomization limit generalizability. Larger multicenter randomized trials with longer follow-up are needed to confirm these findings.
Orexin and Lifestyle Habits: A Meaningful Connection Among Nutrition, Physical Activity, and Sleep Pattern in Health and Diseases.
Int J Mol Sci
Ersilia Nigro, Francesca Argentino, Giuseppe Musumeci +1 more
Orexin is a neuropeptide produced in the hypothalamus that plays a key role in regulating slee-wake cycles, energy metabolism, feeding behavior, and physical activity. It exists in two forms, orexin-A and orexin-B, which bind to G protein-coupled receptors OX1R and OX2R with differing affinities. Orexin signaling is widespread in the brain and extends to peripheral tissues, including adipose tissue. Its involvement in hypothalamic and extrahypothalamic circuits suggests a broad role in homeostatic regulation. Dysfunctions in the orexinergic system are implicated in neurodegenerative diseases such as Alzheimer's, Parkinson's, and multiple sclerosis, particularly through mechanisms involving sleep disturbances and neuroinflammation. This study examines how orexin influences neural circuits related to arousal, motivation, and motor control. It also explores how physical activity stimulates orexin release, enhancing neuroplasticity and cognitive resilience. In addition, orexin's role in reward-related feeding, genetic susceptibility to obesity, and brown adipose tissue thermogenesis is discussed. Overall, the orexinergic system represents a vital neurochemical link between physical activity, metabolism, and cognitive health. Although many of its mechanisms remain to be clarified, its central role in integrating energy balance and behavioral responses makes it a promising target for future therapeutic strategies.
ACE2/Ang(1-7)/MasR axis exerts protective effects on lung ischemia/reperfusion injury via NF-κB-dependent mitochondrial adaptation and epithelial cell pyroptosis.
Int Immunopharmacol
Yin Chen, Liang Guo, Juan Shen +2 more
Mitochondrial dysfunction and pyroptosis of epithelial cells are main contributors to the pathological process of lung ischemia/reperfusion (I/R) injury. Angiotensin-converting enzyme 2 (ACE2) has been implicated in suppressing lung injury. Accordingly, this study investigated whether ACE2 could attenuate mitochondrial dysfunction and pyroptosis after lung I/R injury.
β-Caryophyllene's potential modulation of the renin-angiotensin system: Implications for anosmia and neuroinflammation in the olfactory circuitry.
Int Immunopharmacol
Hugo Alejandro Espinoza-Gutiérrez, Sofía Cecilia López-Salido, Mario Eduardo Flores-Soto +3 more
The sense of smell perceives odorants via the olfactory circuitry. Sense of smell is essential for multiple species, while its loss in humans (Anosmia) has been described in COVID-19, Parkinson's and Alzheimer's diseases, where neuroinflammation is a common denominator. Olfactory circuitry is proximal to the respiratory tract, therefore, is susceptible to foreign particles intromission that trigger neuroinflammation. The brain Renin-Angiotensin System (RAS) influence neuroinflammation through its counter-regulatory axes: The pro-inflammatory Renin/(Pro)Renin Receptor ((P)RR) axis and the anti-inflammatory Angiotensin-Converting Enzyme 2 (ACE2)/Angiotensin-(1-7) (Ang-(1-7))/Mas Receptor (MasR) axis. Certain phytochemicals with angiotensinergic activity may improve neuroinflammation. Among these, β-Caryophyllene, stands out for its bicyclic sesquiterpenoid structure and its activity toward multiple targets, including the Cannabinoid Receptor 2 and the peripheral ACE2/Ang-(1-7)/MasR axis. It is still unknown whether β-Caryophyllene affects the brain RAS, especially in vulnerable regions to neuroinflammation, like the olfactory circuitry. This study aims to explore the angiotensinergic effect of β-Caryophyllene on anosmia and the neuroinflammation of the olfactory circuitry. Male BALB/c mice were intranasally administered with lipopolysaccharide and orally treated with β-Caryophyllene for seven days. Multiple parameters concerning RAS, olfaction, neuroinflammation, cell death and stress were evaluated. Results demonstrate that β-Caryophyllene improved anosmia, increased ACE2 and Ang-(1-7) levels, reduced pro-inflammatory cytokines as well as reduced corticosterone levels and cell death. Molecular docking showed favorable interactions between β-Caryophyllene and ACE2. Therefore, β-Caryophyllene could be useful against anosmia and neuroinflammation due to the possible regulation of the RAS.
Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.
Diseases
Mainak Bardhan, Ayush Anand, Amaan Javed +10 more
Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.
Engineered basement membrane mimetic hydrogels to study mammary epithelial morphogenesis and invasion.
Sci Adv
Jane A Baude, Megan D Li, Sabrina M Jackson +3 more
Reconstituted basement membrane products, like Matrigel, suffer from variability and xenogenic contaminants, hindering three-dimensional cell culture models. To overcome these challenges, we developed engineered basement membranes (eBMs) using peptide-conjugated alginate hydrogels with independently tunable mechanics. Ile-Lys-Val-Ala-Val (IKVAV)-modified eBMs, with fast stress relaxation and low stiffness, supported normal mammary acinus formation. Both increased stiffness and slow relaxation were required to induce invasion in IKVAV-modified eBMs, differing from the invasive phenotype observed in Arg-Gly-Asp (RGD)-modified eBMs regardless of the mechanical properties. Mechanistic studies revealed the balance of β1 and β4 integrin signaling, hemidesmosome formation, and laminin production were influenced by eBM properties. Inhibiting focal adhesion kinase or hemidesmosome signaling disrupted acinus formation in IKVAV-modified eBMs. This defined, xenogenic-free eBM system offers a modular platform for tissue engineering and disease modeling.
Dual PET Imaging with [68Ga]Ga-DOTA-TOC and [18F]FDG to Localize Neuroendocrine Tumors of Unknown Origin.
Curr Oncol
Ali Zaidi, Pavithraa Ravi, Ingrid Bloise +8 more
Neuroendocrine tumors of unknown primary (CUP-NET) present a diagnostic challenge when conventional imaging fails to localize the primary tumor. This study aimed to evaluate the diagnostic value of concurrent [68Ga]Ga-DOTA-TOC and [18F]FDG PET/CT imaging in localizing primary tumors in patients with histologically confirmed CUP-NET. Thirty-four patients underwent both imaging modalities as part of a prospective imaging protocol after negative conventional imaging or [111In]In-octreotide scintigraphy. Primary tumor detection rates were assessed, and imaging characteristics compared between the two modalities. The overall localization rate was 58.9% (20/34). Of these, 90% (18/20) of primary tumors were identified solely by [68Ga]Ga-DOTA-TOC PET/CT, with the remaining two visualized by both modalities. [18F]FDG PET/CT did not independently localize any primary tumors. Identified primaries were limited to grade 1 (60%) or grade 2 (40%) tumors, predominantly in the small intestine (95%). Among localized cases, 45% (9/20) underwent surgical resection and 15% (3/20) became eligible for peptide receptor radionuclide therapy. [68Ga]Ga-DOTA-TOC PET/CT demonstrated superior detection of metastatic lesions compared to [18F]FDG PET/CT (97.1% vs. 70.6%, p = 0.006). No significant survival differences were observed between patients with localized versus non-localized primaries. These findings support the value of [68Ga]Ga-DOTA-TOC PET/CT for identifying primary tumors in CUP-NET. Further research is warranted to explore the role of [18F]FDG PET/CT in high-grade NETs.
Thymosin α1 Combined With 2HRZE/4HR Regimen as a Potential Treatment of Pulmonary Tuberculosis: An Analysis of Immune Function, Pulmonary Function and Inflammatory Response.
Br J Hosp Med (Lond)
Guofeng Wu, Xuelian Sun
Aims/Background Immunotherapy plays a critical role in the clinical treatment of tuberculosis, an infectious disease caused by Mycobacterium tuberculosis, in which immune damage promotes the occurrence and development of the disease. This study aimed to investigate the efficacy of thymosin α1 combined with the 2HRZE/4HR (2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 4 months of isoniazid and rifampin) in the treatment of pulmonary tuberculosis and its effect on immune function and inflammatory factors. Methods A retrospective analysis was conducted on 106 pulmonary tuberculosis patients treated between October 2022 and June 2024. The patients were divided into two groups based on their treatment regimens: the control group (n = 47) received the 2HRZE/4HR treatment, while the observation group (n = 59) received thymosin α1 in addition to the 2HRZE/4HR treatment. All patients underwent a 6-month treatment course. Clinical efficacy was evaluated 6 months after treatment based on clinical symptoms and sputum smear results. The study compared foci resorption rates, cavity closure rates, and changes in pulmonary function indices, immune function indices, and inflammatory factor levels before and after treatment between the two groups. Adverse reactions were also recorded and analyzed. Results The total effective rate and the rate of foci resorption and cavity closure of the observation group were higher than the control group (p < 0.05). After 6 months of treatment, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC, and peak expiratory flow (PEF) of the observation group were higher compared to the control group (p < 0.05). Compared with the control group, the observation group exhibited lower mRNA expression of T-cell immunoglobulin mucin-1 (TIM-1) and TIM-3; reduced levels of immunoglobulin E (IgE), sputum supernatant, serum interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-α); but higher interferon-gamma (IFN-γ) levels (p < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (p > 0.05). Conclusion Thymosin α1 combined with the 2HRZE/4HR regimen holds promise as an effective treatment of pulmonary tuberculosis by improving immune function and pulmonary function of patients while attenuating the inflammatory response.
Dosing strategies for β-alanine supplementation in strength and power performance: a systematic review.
J Int Soc Sports Nutr
Si-Wei Ong, Wei-Ling Chen, Kuei-Yu Chien +1 more
β-alanine is a well-established ergogenic aid that enhances muscle carnosine levels and buffering capacity during high-intensity efforts. However, its role in improving strength and power performance remains inconsistent across the literature. This systematic review investigates whether dosing strategy, rather than duration alone, is the critical determinant of efficacy in resistance-trained populations.
Kinetics of adrenomedullin pathway activation in a porcine sepsis model and a human cohort of sepsis and septic shock.
Sci Rep
Christoph Thiele, Yulia Ilina, Paul Kaufmann +7 more
Sepsis is a life-threatening condition characterized by endothelial dysfunction. The peptide hormone adrenomedullin (ADM) plays a key role in sepsis owing to its potent vasodilatory effects, ability to maintain vascular integrity, and critical role in modulating immune responses and reducing inflammation. To gain its biological activity, the inactive ADM precursor (ADM-Gly) is converted into its active form (bio-ADM) by peptidylglycine α-amidating monooxygenase (PAM). Here, we present hourly resolved kinetics of ADM activation during early sepsis onset in a porcine model and analyze the AdrenOSS-1 human cohort data to assess biomarker changes in advanced sepsis progression. The porcine model data showed that both bio-ADM and ADM-Gly mean concentrations rose within the first two hours post-induction, preceding measurable sepsis onset, with a greater increase in ADM-Gly (260.8 ± 92.0 pg/mL) compared to bio-ADM (28.0 ± 12.9 pg/mL). PAM activity increased at 6 h (39.3 ± 10.5 Units), accompanied by a rise in the bio-ADM/ADM-Gly ratio. AdrenOSS-1 study revealed that ICU sepsis patients had higher ADM-Gly (121.5 pg/mL [IQR: 44.4-284.1]) and PAM activity (23.5 Units [IQR: 17.7-32.7]) than controls. Elevated ADM-Gly (> 730 pg/mL) and PAM activity (> 35.1 Units) were associated with increased 28-day mortality, with non-survivors exhibiting higher ADM-Gly (603.5 pg/mL [IQR: 131.1-1443]) and PAM activity (28.3 Units [IQR: 19.0-45.1]) than survivors. This study provides novel insights into the dynamics of adrenomedullin (ADM) homeostasis during sepsis progression, highlighting the critical interplay between its glycine-extended precursor (ADM-Gly), fully active form (bio-ADM), and the amidating enzyme PAM. The findings demonstrate that early and significant elevations in ADM-Gly, accompanied by delayed PAM activity, result in incomplete ADM amidation, compromising endothelial barrier function. Elevated ADM-Gly and PAM activity were associated with increased sepsis severity and 28-day mortality, while a higher bio-ADM/ADM-Gly ratio was linked to improved survival. These results underscore the potential of ADM-Gly, bio-ADM, and PAM as biomarkers for sepsis severity and prognosis, and support therapeutic strategies aimed at enhancing PAM activity to restore endothelial integrity and improve patient outcomes in sepsis.
TSG attenuated NAFLD and facilitated weight loss in HFD-fed mice via activating the RUNX1/FGF21 signaling axis.
Acta Pharmacol Sin
Zhen-Lin Huang, Shao-Bo Zhang, Shang-Fu Xu +5 more
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by steatosis in hepatocytes and is now becoming the major cause of liver-related mortality. Fibroblast growth factor 21 (FGF21) is an endocrine hormone mainly secreted by the liver, which can bind to its receptor (FGFR) and co-receptor beta klotho (KLB) to form a receptor complex, exerting its lipid-lowering function. 2,3,5,4'-Tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG), a natural compound isolated from Polygonum multiflorum Thunb, has shown excellent activity in lowering lipid content and efficacy in improving NAFLD. In this study we investigated whether FGF21 was implicated in the therapeutic effect of TSG in NAFLD mice. NAFLD was induced in mice by feeding with a high-fat diet (HFD) for 12 weeks, and treated with TSG (20, 40 mg·kg-1·d-1, i.g.) during the last 4 weeks. We showed that TSG treatment significantly alleviated NAFLD in HFD-fed mice evidenced by reduced hepatic triglyceride (TG) and non-esterified fatty acids (NEFA), diminished lipid droplets and decreased NAFLD activity score (NAS) in liver tissues. We demonstrated that TSG treatment significantly increased the mRNA and protein levels of FGF21 in vitro and in vivo, and reduced lipid accumulation in both the liver and adipose tissues. Transcriptomics analysis revealed that TSG treatment significantly increased the nuclear translocation of a transcription factor RUNX1. Knockdown of Runx1 in HFD-fed mice eliminated the efficacy of TSG in alleviating NAFLD, reducing hepatic lipid accumulation and regulating FGF21 signaling pathway in liver and adipose tissues. In conclusion, TSG alleviates NAFLD by enhancing the FGF21-mediated lipid metabolism in a RUNX1-dependent manner.
The impact of mitokine MOTS-c administration on the soleus muscle of rats subjected to a 7-day hindlimb suspension.
J Muscle Res Cell Motil
Daria A Sidorenko, Irina D Lvova, Sergey A Tyganov +2 more
The aim of the study was to investigate the effect of MOTS-c on the key functional alterations in the rat soleus muscle during 7-day unloading - the transformation of slow fibers into fast ones, atrophy and increased fatigue. We daily intraperitoneally injected male Wistar rats with a short mitochondrial peptide MOTS-c during 7-day unloading of their hind limbs. After the end of the experiment, we conducted an ex vivo fatigue test of soleus muscle and showed that the MOTS-c administration prevents increased fatigue during 7-day hind limb unloading. Also, using immunohistochemical analysis, we showed that MOTS-c prevents the transformation of slow fibers into fast ones, mitigates the slow muscle atrophy fibers (but not fast ones) of the soleus muscle. In the group receiving MOTS-c, the decrease in Akt and GSK3β phosphorylation was prevented, and the 18 S and 28 S rRNA levels were at the control level. The ubiquitin ligases MuRF and Atrogin-1 mRNA were also reduced compared to the hindlimb unloading group with placebo. In addition, MOTS-c prevented a decrease in the expression of a few mitochondrial biogenesis parameters and the level of ACC phosphorylation (AMPK target). Thus, the MOTS-C injections during hind limb unloading lead to the normalization of several protein synthesis and degradation processes and support the expression of genes that ensure muscle resistance to fatigue.
Saving muscle while losing weight: A vital strategy for sustainable results while on glucagon-like peptide-1 related drugs.
World J Diabetes
Maja Cigrovski Berkovic, Lana Ruzic, Vjekoslav Cigrovski +1 more
Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications, with cardiovascular disease being a leading cause of mortality. Losing 5%-10% of body weight is considered clinically significant for improving health. This weight loss can be achieved through pharmacotherapy, including glucagon-like peptide 1 (GLP-1) receptor agonists, GLP-1/glucose-dependent insulinotropic peptide dual receptor agonists, and GLP-1/glucose-dependent insulinotropic peptide/glucagon triple receptor agonists (such as semaglutide, tirzepatide, and retatrutide, respectively). While much of the weight loss comes from fat mass, these treatments also result in the loss of lean mass, including muscle. This loss of muscle may contribute to difficulties in maintaining weight over the long term and can lead to sarcopenia. Therefore, the focus of new anti-obesity treatments should be primarily on reducing fat mass while minimizing the loss of muscle mass, ideally promoting muscle gain. Research focusing on human myocytes has identified more than 600 myokines associated with muscle contraction, which may play a crucial role in preserving both muscle mass and function. We explored the potential of new anti-obesity agents and their combinations with incretin-based therapies to achieve these outcomes. Further studies are needed to better understand the functional implications of lean mass expansion during weight loss and weight maintenance programs.
Expression of irisin in the porcine pituitary gland during the oestrous cycle and early pregnancy: the role of GnRH, gonadotropins, and insulin.
Reprod Fertil Dev
Barbara Zarzecka, Kamil Dobrzyn, Marta Kiezun +6 more
Context Metabolic status significantly affects female reproductive function, with both excess and deficiency of body fat negatively affecting fertility. Irisin, a hormone secreted by muscle and fat tissue, is linked to metabolism and reproduction, but its role in the pituitary gland remains unclear. Aims This study investigated the expression of irisin and its receptor (integrin αV/β5) in the anterior (AP) and posterior (PP) lobes of the porcine pituitary during the oestrous cycle and early pregnancy. We hypothesised that they are localised in specific pituitary cell types and that gonadotropin-releasing hormone (GnRH), luteinising hormone (LH), follicle-stimulating hormone (FSH), and insulin modulate irisin expression and secretion by AP cells. Methods The expression of irisin and integrin αV/β5 was analysed using quantitative real-time polymerase chain reaction (qPCR) and western blotting. Immunofluorescence was used to determine colocalisation with pituitary hormones. AP cells were cultured in vitro and treated with GnRH, LH, FSH, or insulin to assess their effects on irisin protein concentrations and secretion. Key results Irisin and its receptor were expressed in both AP and PP lobes and colocalised with all major trophic cell types. Their expression varied depending on the reproductive stage. GnRH, LH, FSH, and insulin inhibited irisin secretion by AP cells during the luteal phase, whereas only insulin had an effect during the follicular phase. Conclusions Irisin and its receptor are expressed in a hormone-dependent manner and localise to specific pituitary cell types, suggesting intra-pituitary regulatory roles. Implications These findings indicated that irisin may act as a local modulator of pituitary function and reproductive hormone regulation, linking metabolic and reproductive health.
Tirzepatide for metabolic dysfunction-associated steatohepatitis: results from phase II clinical trials and perspectives.
Expert Opin Investig Drugs
Stefano Fiorucci, Ginevra Urbani
Tirzepatide is a once-weekly injectable dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. GIP and GLP-1 are incretins promoting insulin release from pancreatic β-cells. Results from clinical trials have confirmed that tirzepatide exerts favorable effects on glucose metabolism and insulin resistance, reduces food intake and has been approved for the treatment of adults with type 2 diabetes, and who are overweight/obese or who have weight-related comorbidities.
Identification of alexamorelin consumption biomarkers using human hepatocyte incubations and high-resolution mass spectrometry.
J Anal Toxicol
Elizabeth Pobee, Gloria Daziani, Prince S Gameli +3 more
Alexamorelin is a synthetic peptide and growth hormone secretagogue (GHS) with potential performance-enhancing properties, making its use and abuse a topic of interest in clinical research and doping monitoring. Alexamorelin mimics the natural peptide hormone ghrelin by binding to the GHS type 1a receptor (GHS-R1a) in the pituitary gland, thereby promoting endogenous growth hormone release. Identifying alexamorelin and/or its metabolite biomarkers is crucial for effective doping controls. The purpose of this study was to determine and characterize biomarkers associated with alexamorelin intake. In silico metabolite predictions were performed using GLORYx freeware, and in vitro incubations were conducted with pooled human hepatocytes from 10 donors. Samples were analysed using liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS), with data processed through Thermo Scientific's Compound Discoverer. GLORYx predicted 21 single-reaction metabolites. N-Acetylation was identified as the primary transformation, with the highest probability score (98%), and occurring either at the C-terminal Ala or the N-terminal Lys. Other predicted transformations included N-oxidation, hydroxylation, amide hydrolysis, oxidative deamination, and phase II N-glucuronidation, with probability scores below 40%. All these transformations were predicted to occur at the two C-terminal (Ala or His) or N-terminal (d-Phe or Lys) amino acids. After 3 h of incubation with hepatocytes, only one metabolite (known as examorelin or hexarelin) was detected, resulting from the C-terminal cleavage of the Ala amino acid; this metabolic reaction is mediated by a carboxypeptidase. The alexamorelin signal decreased approximately 150-fold after 3 h, indicating significant hepatic metabolism. However, examorelin itself is a commercially available GHS secretagogue, and thus, it is not specific to alexamorelin consumption. Detecting alexamorelin remains critical to documenting its use.
Efficacy of thymosin α1 for sepsis: a systematic review and meta-analysis of randomized controlled trials.
Front Cell Infect Microbiol
Bin Gu, Yu Zhou, Yao Nie +8 more
Despite advances in understanding sepsis pathophysiology and extensive research, few treatments effectively target its underlying immune dysfunction. Thymosin α1 (Tα1) shows promise as an immunomodulator, but its impact on sepsis remains unclear.
Beyond satiety: unraveling the complex roles of POMC neurons in behavior and metabolism.
Rev Endocr Metab Disord
Victor Jouque, Cristina Miralpeix, Antonio J López-Gambero +3 more
Hypothalamic pro-opiomelanocortin (POMC) neurons are classically viewed as mediators of satiety, acting in response to metabolic and hormonal cues and in opposition to Agouti-related protein (AgRP) neurons to maintain energy balance. This model, centered on the appetite-suppressant effects of the POMC-derived neuropeptide α-melanocyte-stimulating hormone (α-MSH) through its activation of melanocortin-4 receptors (MC4R), has shaped our understanding of feeding and body weight regulation for decades. However, recent discoveries have challenged and expanded this traditional view, revealing that POMC neurons are not a uniform population dedicated solely to satiety control. Single-cell transcriptomic analyses have revealed striking molecular heterogeneity, reflected in distinct anatomical distributions, receptor expression profiles, electrophysiological properties, and projection patterns - all supporting the idea of functional specialization within this neuronal population. In this review, we propose a conceptual framework that integrates POMC neuronal heterogeneity with the regulation of appetite, metabolic physiology, and behavior beyond feeding. We highlight emerging evidence showing that discrete POMC neuronal subpopulations respond to specific combinations of interoceptive and environmental cues to orchestrate diverse adaptive responses. This perspective underscores the developmental plasticity and functional versatility of POMC neurons, offering new insights into the mechanisms of obesity and potentially paving the way for novel targeted therapeutic strategies.
FGF21 deletion mildly exacerbates hepatic dysfunction in GAN diet and alcohol fed rats.
NPJ Metab Health Dis
Peter Aldiss, Malte Hasle Nielsen, Hayley Burm +4 more
Fibroblast growth factor 21 (FGF21) analogues are in clinical development as treatments for metabolic and alcohol-associated liver disease. The aim of this study was to characterize the first FGF21 knockout (KO) rat line to validate its utility as a translational animal model that recapitulates human disease. We generated an FGF21 KO rat model and exposed 6-month-old WT and KO rats to either chow (n = 8 per genotype) or the obesogenic GAN (Gubra Amylin NASH) diet (n = 16 per genotype) for 12 weeks. Lack of endogenous FGF21 increased plasma transaminases, liver weight, and total levels of liver TG in GAN-fed FGF21 KO rats. FGF21 KO had no impact on body weight, glycaemic traits, or MASH histological endpoints, including hepatic steatosis, NAS score, lobular inflammation, ballooning degeneration, fibrosis stage, or the liver transcriptome. Finally, we demonstrate that endogenous FGF21 does not regulate drinking behaviour in rats.
Regeneration or Risk? A Narrative Review of BPC-157 for Musculoskeletal Healing.
Curr Rev Musculoskelet Med
Flynn P McGuire, Riley Martinez, Annika Lenz +2 more
This scoping review aims to evaluate the molecular mechanisms, therapeutic potential, and safety concerns of Body Protective Compound-157 (BPC-157) in the context of musculoskeletal healing. Given the compound’s increasing availability, popularity, and its regulatory controversies, we sought to assess the breadth and quality of preclinical and clinical data supporting its use in musculoskeletal medicine.