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Implications of Glucagon-Like Peptide-1 Receptor Agonists in Otolaryngology - Head and Neck Surgery: A Review.
Ann Otol Rhinol Laryngol
Brady J Anderson, Douglas J Van Daele, Alexander D Claussen +2 more
The number of patients taking glucagon-like peptide-1 receptor agonists (GLP-1RAs) is increasing. Beyond diabetes and weight management, these medications have various effects within the head and neck with both beneficial and potentially adverse clinical implications. Delayed gastric emptying may contribute to reflux, chronic cough, and potential aspiration in the perioperative setting; as such, physicians should be aware of anesthetic guidelines (duration of pre-operative cessation, pre-operative fasting or liquid diet) to improve safety and avoid operative delay. GLP-1RAs have shown benefit in treating obstructive sleep apnea in those with obesity or overweight and may become increasingly relevant in multimodal treatment of sleep disorders. GLP-1 receptor signaling is involved in sinopulmonary inflammatory cascades and recent evidence suggests clinical implications for chronic sinusitis and olfactory disorders. Previously reported neuroprotective effects have led to investigation regarding potential benefit in neurotoxicity-associated hearing loss. Muscle atrophy with weight loss may contribute to a gaunt, aged appearance leading patients to seek facial rejuvenation, or to a patulous eustachian tube and changes in conductive hearing. Animal studies suggested an increased risk of thyroid cancer, but population studies have been inconclusive and will require long-term investigation to determine any causal relationship.
Tirzepatide-induced Weight Loss in Overweight or Obese Midlife Adults with and without Type 2 Diabetes: A Real-world Comparative Cohort Study.
J Midlife Health
Prabhat Kumar Agrawal, Shambo Samrat Samajdar, Ruchika Garg +5 more
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist, has demonstrated robust weight loss and glycemic benefits in randomized controlled trials. However, real-world data comparing its effectiveness and tolerability in obese adults with and without type 2 diabetes (T2D) are limited. The present study aimed to evaluate the real-world short-term effectiveness and safety of tirzepatide in promoting weight loss among obese or overweight adults with and without T2D.
Discovery of a High-Potency Balanced GLP-1/GIP Dual Agonist by Molecular Dynamics Evolution.
J Med Chem
Nan Zhang, Li Teng, Xiang Yu +4 more
HDM1005 (poterepatide), a novel highly potent GLP-1/GIP dual agonist, was engineered via computational alanine scanning and rational acylation design. Nonacylated HDM1005 (P001) showed stable receptor binding and higher affinity than nonacylated Tirzepatide in molecular dynamics simulations and MMGBSA calculation. Alanine scanning and steric clash analysis (radius of gyration) guided proper K24/28 acylation sites on P001. Optimized linker and acyl chain design at K24 precisely tuned bioactivity and extended long-acting performance (T1/2 ∼ 20.3-23.1 h vs Tirzepatide's 9.21 h in mice). HDM1005 exerted 3-fold more potent HbAlc reduction in db/db mice and superior weight loss in DIO mice (39.97% vs 34.47%) versus Tirzepatide, yielding enhanced metabolic benefits, plus preferential fat loss with lean mass preservation in obese mice. It exhibited a favorable safety profile with a NOAEL of 5 mg/kg. With enhanced receptor binding, extended pharmacodynamic activity, and superior efficacy, HDM1005 represents a potential best-in-class therapeutic agent for metabolic disorders.
GLP-1 Receptor Agonists, Fertility Restoration, and Reproductive Safety in Women of Reproductive Age: A Narrative Review.
J Clin Med
Malak Moones Abedi, Mohamedanas Mohamedfaruk Patni, Arshiya Nasreen Bint Shajahan +8 more
Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for the management of obesity and type 2 diabetes, particularly among women of reproductive age. Emerging evidence suggests potential effects on ovulation, fertility, and pregnancy outcomes. This narrative review aims to synthesize current evidence on the reproductive safety of GLP-1RAs, with a focus on their implications for conception, unintended pregnancy, and maternal-fetal outcomes. Methods: A narrative literature review was conducted using PubMed and relevant bibliographic sources to identify studies published between 2020 and 2025. The search included clinical trials, observational studies, registry data, case reports, and selected preclinical evidence. Studies addressing reproductive outcomes, including ovulation, fertility, pregnancy exposure, and fetal safety, were included. Evidence was synthesized descriptively in accordance with recommended approaches for narrative reviews. Results: Available evidence indicates that GLP-1RAs may improve ovulatory function and menstrual regularity, particularly in women with obesity or polycystic ovary syndrome, potentially increasing the likelihood of conception. However, human data on pregnancy exposure remain limited. While current evidence does not consistently demonstrate a strong teratogenic signal, findings are based on small samples and heterogeneous study designs. Concerns persist regarding unintended pregnancies due to improved fertility and the absence of robust safety data during early gestation. Conclusions: GLP-1RAs present a complex clinical scenario in women of reproductive age, with potential benefits for metabolic and reproductive health but uncertain safety during pregnancy. Clinicians should exercise caution, provide appropriate contraceptive counseling, and carefully weigh the risks and benefits when prescribing these agents. Further large-scale, prospective studies are needed to clarify reproductive safety and inform evidence-based clinical guidelines.
Aggregation-driven expression of liraglutide precursors using engineered mini-tags in Escherichia coli.
Protein Sci
Pavan Reddy Regatti, Firdose Syed, Ramesh V Matur +1 more
Glucagon-like peptide-1 (GLP-1), a 31-amino acid incretin hormone, is widely used in the treatment of type 2 diabetes mellitus due to its glucose-dependent insulinotropic activity. However, its small size makes it highly prone to proteolytic degradation in microbial expression systems such as Escherichia coli, leading to reduced manufacturing yield. While fusion to cleavable protein tags can improve peptide stability during purification, excessively large tags often compromise the overall yield, especially when the target peptide is smaller than the fusion partner. To overcome this limitation, we have engineered 11 cleavable fusion tag constructs (LP1-LP11) for recombinant expression of Arg34-GLP-1(7-37) (liraglutide precursor) in E. coli. The 11 constructs differed only in the tags. The expression vector contained a T7 leader sequence, affinity tags (6×His/6×Arg), inclusion body tags (11-125 amino acids), and TEV protease cleavage sites. Among the 11 tags, LP8 with a compact 4.0 kDa tag achieved the highest expression, yielding 133 mg/L of fusion protein and a calculated liraglutide precursor yield of 60 mg/L based on mass fraction (45% of fusion mass), with an actual recovered yield of 14.6 mg/L after RP-HPLC purification, largely due to efficient inclusion body formation (>95% insolubility) and enhanced translational initiation driven by the T7 leader sequence. The purified peptide's identity and sequence integrity were confirmed by LC/MS analysis. The primary advantage of this approach is mass fraction optimization which focuses on minimizing fusion-tag mass to maximize yield relative to the tag size without compromising inclusion-body formation thereby providing a scalable and economical approach for GLP-1 analogs and potentially other peptide-based biopharmaceuticals.
Mitochondrial Dysfunction at the Intersection of CKM Syndrome: Molecular Mechanisms and Path-to-Target Therapies.
Int J Mol Sci
Yen-Jung Kuo, Li-Feng Chen, Yumay Chen +2 more
The American Heart Association (AHA) recently formalized cardiovascular-kidney-metabolic (CKM) syndrome to characterize the systemic interplay among cardiovascular failure, chronic kidney disease (CKD), and metabolic disturbances. Despite evolving clinical management, identifying a unifying cellular driver of this multi-organ deterioration remains a critical priority. This review explores the hypothesis that mitochondrial dysfunction serves as the fundamental pathological nexus of CKM syndrome, driving the progression from early-stage metabolic risk to end-stage organ failure. We synthesize evidence demonstrating how nutrient overload and lipotoxicity precipitate a vicious cycle of bioenergetic failure. In the cardiovascular system, ATP deficiency and impaired mitophagy lead to the structural remodeling observed in both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). In the kidney, the high mitochondrial density of proximal tubules renders them uniquely susceptible to oxidative stress and mitochondrial DNA (mtDNA) leakage, which subsequently triggers systemic inflammation. Furthermore, we analyze how established therapies-including sodium-glucose co-transporter 2 (SGLT2) inhibitors, Glucagon-like peptide-1 (GLP-1) receptor agonists, and non-steroidal mineralocorticoid receptor antagonists (MRAs)-exert organ-protective effects via mitochondrial mechanisms, promoting metabolic efficiency, reducing reactive oxygen species generation, stabilizing mitochondrial integrity, and promoting mitochondrial quality control processes. Finally, we review emerging mitochondrial-targeted strategies, such as mitoquinol, elamipretide and NAD+ boosters, which aim to restore the SIRT1-PGC-1 α signaling axis. Mitochondria function as the central engines of the CKM axis. A shift toward a mitocentric clinical model may enable earlier intervention and more precise targeting of the mechanisms driving organ crosstalk. Future success depends on multidisciplinary collaboration and the validation of mitochondrial biomarkers to advance precision medicine in CKM syndrome.
The Impact of Alternate-Day Fasting on the Salivary Gland Ductal Compartments and the Differentiation Potential of Keratin 5+ Salivary Gland Progenitor Cells in an Induced Mouse Model of Sjögren's-like Hyposalivation.
Int J Mol Sci
Dongfang Li, Shoko Onodera, Qing Yu +1 more
Intermittent fasting confers protection in diverse diseases through various mechanisms, including the clearance of senescent and pathogenic cells, modulation of tissue inflammation and enhancement of stem/progenitor cell niche and functionality. Our previous study demonstrated the beneficial impact of alternate-day fasting (ADF) on xerostomia and sialadenitis, along with an improvement in salivary gland ductal compartments, where salivary gland progenitor cells reside, in non-obese diabetic mice, a spontaneous model of Sjögren's syndrome (SS). In the present study, we induced SS-associated hyposalivation in KRT5CreERT2; R26tdTomato lineage tracing mice by immunizing them with submandibular gland proteins from wild-type C57BL/6 mice. ADF alleviated salivary gland hypofunction, which was accompanied by decreased expression of the senescent cell marker p16INK4a, reduced protein levels of anti-apoptotic proteins BCL-2, BCL-XL, and MCL-1, and attenuated NLRP3 inflammasome activity in the submandibular glands, particularly within the ductal compartments, of this inducible model. Furthermore, immunofluorescence staining of submandibular gland sections revealed the expression of the acinar cell marker aquaporin 5 in a small subset of Keratin 5+ cells in 2 of 9 mice that were subjected to ADF, whereas no such cells were detected in the control mice. Taken together, these findings indicate that ADF favorably modulates the salivary gland progenitor cell niche, potentially by promoting apoptosis-mediated senescent cell clearance, suppressing NLRP3 inflammasome signaling, and promoting Keratin 5+ progenitor cell-derived acinar cell replenishment, thereby contributing to the structural and functional restoration of damaged salivary glands in autoimmune exocrinopathy.
Phagocytosis deficient glia display phagosome processing defects and macrophage recruitment to the brain of adult Drosophila melanogaster.
bioRxiv
Guangmei Liu, Iqra Amin, Cheng Yang Shi +1 more
Efficient clearance of dying cells is essential for brain homeostasis, yet how partial defects in phagocytic processing affect neuroimmune interactions during aging remains unclear. In the adult Drosophila brain, glia function as professional phagocytes through the conserved engulfment receptor Draper (Drpr). Here, we show that glial loss of Drpr does not completely eliminate phagocytosis but instead leads to persistent, age-dependent inefficiency in corpse degradation. Using a genetically encoded pH-sensitive reporter to visualize acidified phagocytic compartments, we find that drpr -deficient glia retain residual engulfment activity but progressively accumulate enlarged, incompletely degraded phagocytic cargo. This chronic clearance defect coincides with altered immune dynamics at the central nervous system periphery, including increased recruitment and adhesion of peripheral hemocytes at the blood-brain barrier (BBB), without overt BBB disruption. Notably, hemocytes at the brain surface can phagocytose glial material in a Drpr-dependent manner, revealing a form of barrier-associated "border clearance". Together, these findings demonstrate that inefficient corpse degradation is sufficient to reshape neuroimmune interactions during aging.
Natural killer cell immunotherapy reverses lung fibrosis by eliminating senescent fibroblasts.
Sci Transl Med
Wolfgang Merkt, Lea Rodon, Franca S Deicher +29 more
Impaired immune clearance of senescent fibroblasts is a putative driver of pulmonary fibrosis. Exhausted natural killer (NK) cells have been implicated in this process, yet the underlying immune evasion mechanisms remain poorly understood. Using single-cell RNA sequencing (scRNA-seq) and spectral flow cytometry, we identified natural killer group 2 member A (NKG2A) as the predominant inhibitory checkpoint receptor expressed on NK cells in fibrotic lung diseases. Mechanistic in vitro coculture studies showed that NK cell suppression was mediated by senescent fibroblasts expressing human leukocyte antigen-E (HLA-E), the high-affinity ligand for NKG2A. scRNA-seq analysis of lungs from patients with idiopathic pulmonary fibrosis (IPF) further identified selective HLA-E expression in senescent HAS1+ fibroblast subsets. Further, spatial transcriptomics and multiplex immunofluorescence of patient lungs demonstrated that HLA-E+ fibroblasts were positioned at the periphery of fibroblast foci adjacent to NKG2A+ NK cells, establishing an immune-privileged niche. In contrast, extracellular matrix-producing myofibroblasts at the core of fibrotic foci lacked HLA-E and exhibited minimal NK engagement. In vivo, therapeutic blockade of NKG2A restored NK cell function, promoted clearance of senescent fibroblasts, and promoted fibrosis resolution in the bleomycin-induced mouse model. Monalizumab, a clinical-grade NKG2A inhibitor, reactivated patient-derived NK cells and enhanced lysis of human senescent fibroblasts in vitro. Together, these findings uncover a spatially restricted immune checkpoint axis that allows senescent fibroblasts to evade immune NK surveillance. Targeting the HLA-E/NKG2A axis represents a promising therapeutic strategy to restore NK cell-mediated immune clearance of senescent fibroblasts and reverse pulmonary fibrosis.
Mechanical aging of tire microplastics enhances the bioavailability of pre-adsorbed 17β‑estradiol in goldfish.
J Hazard Mater
Wenwen Song, Yiyu Wu, Zhuanxi Luo +3 more
Tire microplastics (TMPs) are emerging contaminants in aquatic environments, posing ecological risks from both their ingredients and adsorbed pollutants. However, the transformation of TMPs by mechanical forces on wet-road surfaces and its effects on the carrier behavior of TMPs remain poorly understood. Here, we employed wet ball-milling to simulate mechanical TMP aging after rainfall by repeated TMP-road surface friction. The mechanical aging significantly increased the proportion of fine particles (1-10 μm) from 6.4% to 73.1%, accompanied by a change from dense, compact structures into loosely aggregated particles. In vitro desorption experiments showed that the aging enhanced the release of 14C-labeled 17β-estradiol (E2) pre-adsorbed onto the TMPs in simulated fish digestive fluids. This enhancement was likely due to shortened intraparticle diffusion pathways, leading to increased bioavailability. Goldfish exposure experiments revealed that the aged TMPs modulated the absorption, distribution, and clearance of E2 in vivo, promoting its intestinal release while delaying its hepatic accumulation, thereby altering the temporal response of the estrogen-responsive biomarker vitellogenin. Our findings indicate that mechanical aging under wet-road conditions not only refines TMP particles and alters their structure, but also increases their environmental risks as carriers of low-molecular-weight organic pollutants.
From Healthy to Heart Failure in 24 Hours: Defining the upper limit of exercise induced cardiac fatigue.
J Appl Physiol (1985)
Stephen J Foulkes, Mitchell Anderson, Kristel Janssens +7 more
This study sought to investigate the cardiac consequences of undertaking 12- and 24-hours of intense cycling as part of two successful world record-setting attempts in a former professional ultra-endurance athlete (12-hour attempt: March 2017, aged 41 yrs; 24-hour attempt: March 2018, aged 42 years). The athlete was comprehensively evaluated prior to- and at several timepoints following both attempts using cardiac imaging (echocardiography, rest and exercise cardiac magnetic resonance imaging, CMR), cardiac biomarkers (B-type natriuretic peptide, BNP; cardiac troponin-I, cTnI) and clinical evaluation. Following the 12-hour attempt, the athlete was physically exhausted but demonstrated no signs of respiratory distress or heart failure. Immediately post-attempt, BNP (166 ng/L) and cTnI (64 ng/L) were moderately increased, while left- (LV) and right-ventricular (RV) strain (LV: -12.2%; RV: -13.4%) and ejection fraction (LV: 43% RV: 43%) were moderately reduced. However, all parameters recovered within 14-days of the attempt. Following the 24-hour attempt, the athlete was in acute respiratory distress and showed signs of acute pulmonary edema. This coincided with pronounced biomarker elevations (BNP: 561 ng/L; cTnI: 394 ng/L) and marked reductions in myocardial strain (LV: -14.2%; RV: -13.8%) and bi-ventricular ejection fraction (LV: 37%; RV: 32%). Cardiac function only partially recovered 18-days post-attempt but had completely normalized by 5-months post-attempt. Overall, these findings provide the most definitive illustration of an exercise dose threshold that resulted in acute heart failure in a highly trained endurance athlete. The absence of persistent myocardial injury highlights the resilience of the heart to acute stress.
Metabolic Benefits vs. Cardiovascular Uncertainty: A Critical Review of GLP-1 Receptor Agonists in Type 1 Diabetes.
Int J Mol Sci
Elżbieta Wójcik-Sosnowska, Adrianna Tabeau, Agnieszka Pawlik +2 more
Type 1 diabetes (T1DM) is associated with elevated cardiovascular (CV) risk, often exacerbated by the rising prevalence of obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce CV risk in type 2 diabetes, but their role in T1DM is less well-defined. This umbrella review synthesizes evidence from systematic reviews, meta-analyses, and Mendelian Randomization (MR) studies to evaluate the metabolic efficacy and safety of GLP-1 RAs in T1DM. Adjunctive therapy, particularly with liraglutide and exenatide, was associated with clinically meaningful weight reduction (mean difference: -4.35 kg to -5.1 kg) and lower total daily insulin doses. HbA1c reductions were statistically significant but modest (0.2-0.3%), with no improvement in Time in Range. Secondary benefits included lower systolic blood pressure. Safety data were mixed: the risk of severe hypoglycemia was not increased, whereas Time Below Range and gastrointestinal adverse events were more frequent. Evidence on diabetic ketoacidosis (DKA) was inconsistent across studies. Overall, GLP-1 RAs improve weight and reduce insulin requirements in T1DM, potentially mitigating indirect CV risk factors; however their direct cardiovascular benefits remain unproven in the absence of dedicated outcome trials.
Brca1 heterozygosity leads to hepatic steatosis in male and female mice despite sexually dimorphic effects on systemic metabolism.
bioRxiv
Sailesh Palikhe, Linlan Qiao, Caleb Kutz +9 more
Carrying a germline mutation in BRCA1 is associated with an increased risk of several cancers, including breast and ovarian. Our recent work has demonstrated that obesity is associated with elevated levels of DNA damage in breast glands in this high-risk population. BRCA1 is a canonical tumor suppressor gene primarily recognized for its role in DNA damage repair, yet emerging evidence suggests broader functions in metabolic regulation. To determine whether heterozygous loss of Brca1 , as seen in individuals who carry a germline mutation, modifies susceptibility to diet-induced metabolic dysfunction in a sex-dependent manner, we subjected wild-type (WT) and Brca1 +/- mice of both sexes to a high-fat diet (HFD) and performed longitudinal metabolic phenotyping. Female Brca1 +/- mice exhibited pronounced obesity, increased adiposity, hyperinsulinemia, and impaired glucose tolerance. In contrast, male Brca1 +/- mice showed modest resistance to HFD-induced weight gain and displayed improved glucose tolerance compared to WT controls. Notably, Brca1 heterozygosity led to more severe hepatic steatosis with HFD, indicating a shared susceptibility to liver lipid accumulation despite divergent systemic outcomes. In females, steatosis was associated with reduced mitochondrial respiratory complex IV activity and transcriptional remodeling that favored lipid storage. Treatment with the dual GLP⍰1/GIP receptor agonist tirzepatide ameliorated systemic metabolic dysfunction and hepatic steatosis in HFD-fed female Brca1 +/- mice. These findings identify Brca1 heterozygosity as a modifier of metabolic disease risk, expanding BRCA1 biology beyond tumor suppression.
Acupuncture plus wet cupping therapy for post stroke depression: a randomized controlled trial.
Front Psychiatry
Dong Li, Hang Gao, Jin Li +4 more
To explore the preliminary clinical efficacy and safety of acupuncture plus wet cupping on post-stroke depression (PSD) and to investigate its potential associations with changes in the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory factors.
Visualization of relative 11β-hydroxylase (CYP11B1) activity in human cortisol-producing adrenocortical adenoma (CPA) using mass spectrometry imaging-based enzyme histochemistry.
Anal Bioanal Chem
Erika Nagano, Masamichi Fujita, Hironobu Umakoshi +6 more
Enzymes play essential roles in numerous biochemical reactions, making it necessary to evaluate both their localization and activity. While conventional enzyme activity detection methods require specific antibodies and colorimetric reactions for each target compound, a recent method using mass spectrometry imaging enables the visualization of enzyme distribution and activity by applying substrates directly to tissue sections and detecting the resulting enzyme reaction products generated on these sections. Notably, the 11β-hydroxylase (CYP11B1, EC 1.14.15.4) reaction plays a key role in stress response, metabolism, and immune function regulation. Consequently, the regulation of CYP11B1 activity can significantly impact these physiological processes, enabling improved drug development. Therefore, controlling this enzyme activity will facilitate the development of new therapies for related diseases. This study investigated a method for visualizing the distribution and relative activity of CYP11B1 in cortisol-producing adrenocortical adenoma (CPA) tissue sections derived from patients with mild autonomous cortisol secretion (MACS). By optimizing key parameters such as the substrate and coenzyme concentrations, together with reaction times, the method successfully revealed the relative CYP11B1 activity in human MACS. Additionally, visualization was achieved in aldosterone-producing adrenocortical adenoma (APA) derived from patients with primary aldosteronism and in non-functioning adrenal adenoma (NFA) derived from patients with adrenal cortical adenoma. The relative CYP11B1 activities of CPA, APA, and NFA samples obtained in this study correlated with the clinical information and were consistent with the previously reported cortisol, adrenocorticotropic hormone, and dexamethasone suppression test profiles in blood and urine, thereby validating the proposed method.
Cyclical ectopic Cushing's syndrome due to a mediastinal neuroendocrine tumor: a case-based review.
Ir J Med Sci
Carolina Peixe, Marta Vaz Lopes, Mariana de Griné Severino +2 more
Cyclical Cushing's syndrome (CCS) is an uncommon form of endogenous hypercortisolism characterized by alternating periods of cortisol excess and remission. Its intermittent nature delays diagnosis and localization of the adrenocorticotropic hormone (ACTH) source and complicates therapeutic decision-making.
Early ingestive experience with a high-fat diet tunes satiation and nutrient-specific appetitive behaviors.
bioRxiv
Meaghan McCoy, Ciorana Roman-Ortiz, Jason Perez +2 more
Overconsumption of foods rich in fats, sugars, and calories is a major contributing factor to increased risk for cardiometabolic disease. Ingestive experience with these foods can begin early in children, yet there is limited understanding of the impact of early life nutrition on the development of vagal afferent neurons necessary for coordinating appetitive and satiating behaviors. To this end, mice reared on a chow diet (control) were compared to those reared on a high-fat diet (HFD EARLY ). We demonstrate that the vagally-mediated satiation response to cholecystokinin (CCK) does not mature until adolescence in chow-reared mice. However, HFD EARLY exposure triggers a precocious maturation of this response, accompanied by transcriptomic changes in the nodose ganglion. Durable changes in appetitive behaviors were also evident in adult HFD EARLY mice, which consumed more lipid than control mice. Behavioral analyses point to alterations in orosensory integration and enhanced appetition in adult HFD EARLY mice, establishing nutrient exposure as a significant contributor to vagal circuit maturation and function.
Roflumilast Enhances Liraglutide's Atrial Natriuretic Peptide-Dependent Suppression of Adrenal Aldosterone Secretion.
Int J Mol Sci
Ariana Hosseini, Alexis J M'Sadoques, Renee A Stoicovy +7 more
Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. GLP-1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3'-5'-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various effects mainly via protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). Cardiac GLP-1R has been reported to induce atrial natriuretic peptide (ANP) secretion via Epac2, while ANP is known to inhibit aldosterone secretion from adrenocortical zona glomerulosa (AZG) cells. Herein, we tested the effects of the GLP-1R agonist liraglutide on ANP secretion in H9c2 cardiomyocytes and on angiotensin II (AngII)-induced aldosterone secretion. We also examined whether phosphodiesterase (PDE)-4 inhibition with roflumilast could potentiate liraglutide's effects. We found that liraglutide stimulated ANP secretion from H9c2 cardiomyocytes, an effect potentiated by roflumilast but blocked by AC inhibition. Epac inhibition with ESI-09 also significantly reduced liraglutide-dependent ANP secretion in H9c2 cardiomyocytes. Moreover, application of medium from liraglutide-treated H9c2 cardiomyocytes, but not from control cardiomyocytes, led to suppression of AngII-dependent aldosterone secretion from H295R cells. This effect was blocked by cyclic guanosine monophosphate (cGMP)-dependent protein kinase inhibition (an effector of ANP) in H295R cells, while direct application of liraglutide to these cells failed to suppress AngII-induced aldosterone secretion. Again, aldosterone suppression was more potent when medium from liraglutide plus roflumilast-treated cardiomyocytes was applied to H295R cells. Taken together, these results suggest that roflumilast enhances the adrenocortical aldosterone suppression induced by GLP-1R agonists via cardiac GLP-1R/cAMP/Epac-dependent ANP secretion. Given the cardio-toxic effects of elevated aldosterone levels in the context of various heart diseases, such as post-myocardial infarction heart failure, combination of a GLP-1R agonist drug with a PDE4 inhibitor drug may be more advantageous than either agent alone in treatment of certain cardiovascular diseases.
Modulation of Bovine Muscle Satellite Cells Myogenesis by Paracrine Fibroblast-Derived Signaling in Three-Dimensional Spinner Flask Culture System.
Int J Biochem Cell Biol
Karolina Zygmunt, Katarzyna Piórkowska, Julia Adamiak +1 more
Studies examining the paracrine effect of fibroblasts on the myogenesis of bovine muscle satellite cells (MuSCs) have confirmed their stimulating effect on proliferation and early differentiation. However, traditional two-dimensional (2D) cell culture models fail to accurately represent the complexity of in vivo muscle tissue. This study aims to investigate the paracrine effect of fibroblasts on myogenesis in a three-dimensional (3D) cell culture model. Cells were cultured in monoculture and co-culture with fibroblasts in a spinner flask using gelatin microcarriers, Cultishper, which maximizes the growth surface area for adherent cells. Then, muscle cells from the co-culture were sorted by the FACS method based on negative expression of CD90, a fibroblast-associated marker. The progress of myogenesis was assessed based on qPCR analysis for selected muscle markers and at the protein level for skeletal myosin. Fluorescent staining and luminescent metabolic assays were performed to control culture conditions. The obtained results revealed up-regulation of genes involved in cell activation and proliferation (PAX7, MYF5, and MYOD) and differentiation (MYOG, EGR1, and MYH). Metabolism analyses did not show changes between mono- and co-culture conditions. To summarize, fibroblasts through paracrine signaling promote early differentiation of MuSCs and potentially proliferation, which provides valuable insights for the advancement of cultured meat production.
Phage satellites induced by virulent phages are mobilized by natural competence leading to phage resistance in a new host.
Nat Commun
Carlee Morency, Geneviève M Rousseau, Zacharie Morneau +1 more
A phage satellite (PS) typically resides within repeat regions (attL and attR sites) of a bacterial genome. Its genome ranges from 7 to 20-kb and includes genes encoding an integrase along with regulatory and DNA replication functions. However, it lacks genes associated with viral structural proteins. Streptococcus thermophilus (S.t.) is extensively used to produce yogurt and specialty cheeses. Intriguingly, the majority of S.t. strains harbor a PS while very few possess a complete prophage, suggesting that PSs may confer advantages to their hosts. In this study, we showed that PSs of S.t. can excise from the bacterial chromosome, at a very low rate, without any phage interaction. Furthermore, we found that they can also be induced by virulent phages. By leveraging CRISPR-Cas9, we selected S.t. cells devoid of any PS (delta-PS strain). Then, we mobilized a PS from one strain to a delta-PS strain, using only natural competence, bypassing the need for a helper phage. The resulting strain exhibited increased resistance to virulent phages. Through the isolation of phage mutants escaping the resistance phenotype, we pinpointed a specific phage protein responsible for the induction of a PS. Lastly, we demonstrated that a PS can be significantly induced by a virulent phage, which, in turn, greatly promote their transfer and specific integration into new cells through natural competence. Our study introduces a novel natural approach to develop phage-resistant strains.