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Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
Free Radic Biol Med
Yiwei Feng, Zhijian Rao, Xu Tian +9 more
The mitochondrial open reading frame of 12S rRNA-c (MOTS-c) is a biologically active mitochondria-derived peptide. However, the relationship between MOTS-c, skeletal muscle mitochondrial function, and endurance exercise adaptations is unknown. Here, we tested indices such as maximal oxygen uptake and serum MOTS-c levels in marathon runners and sedentary subjects. In addition, we tested aerobic exercise capacity, skeletal muscle mitochondrial respiration rate, and serum MOTS-c levels in mice subjected to long-term endurance training groups and sedentary groups. Our results indicated a close association between serum MOTS-c levels and aerobic exercise capacity. Circulating MOTS-c levels are expected to be an important indicator for predicting aerobic exercise capacity and assessing body fat status, endurance training load, and physical function. More importantly, we found that endurance training may enhance the mitochondrial respiratory function of skeletal muscle by promoting the secretion of MOTS-c and activating the AMPK/PGC-1α pathway.
Effects and mechanisms of Apelin in treating central nervous system diseases.
Neuroscience
Zimeng Huang, Qing Liu, Qixuan Guo +3 more
Apelin, an endogenous ligand of G protein-coupled receptor APJ, is widely distributed in the central nervous system (CNS). It can be divided into such subtypes as Apelin-13, Apelin-17, and Apelin-36 as they have different amino acid structures. All Apelin is widely studied as an adipokine, showing a significant protective effect through regulating apoptosis, autophagy, oxidative stress, angiogenesis, inflammation, and other pathophysiological processes. As an adipokine, Apelin has been found to play a crucial role in cardiovascular disease development. In this paper, we reviewed the effects and mechanisms of Apelin in treating CNS diseases, such as neurotrauma, stroke, spinal cord injury, primary tumors, neurodegenerative diseases, psychiatric diseases, epilepsy, and pain.
Ligand Inter-Relation Analysis Via Graph Theory Predicts Macrophage Response.
Adv Mater
Nayeon Kang, Jangsun Hwang, Daun Jeong +23 more
Graph theory has been widely used to quantitatively analyze complex networks of molecules, materials, and cells. Analyzing the dynamic complex structure of extracellular matrix can predict cell-material interactions but has not yet been demonstrated. In this study, graph theory-based mathematical modeling of RGD ligand graph inter-relation is demonstrated by differentially cutting off RGD-to-RGD interlinkages with flexibly conjugated magnetic nanobars (MNBs) with tunable aspect ratio. The RGD-to-RGD interlinkages are less effectively cut off by MNBs with a lower aspect ratio, which decreases the shortest path while increasing the number of instances thereof, thereby augmenting RGD nano inter-relation. This facilitates integrin recruitment of macrophages and thus actin fiber assembly and vinculin expression, which mediates pro-regenerative polarization, involving myosin II, actin polymerization, and rho-associated protein kinase. Unidirectional pre-aligning or reversibly lifting highly elongated MNBs both increase RGD nano inter-relation, which promotes host macrophage adhesion and switches their polarization from pro-inflammatory to pro-regenerative phenotype. The latter approach produces nano-spaces through which macrophages can penetrate and establish RGD links thereunder. Using graph theory, this study presents the example of mathematically modeling the functionality of extracellular-matrix-mimetic materials, which can help elucidate complex dynamics of the interactions occurring between host cells and materials via versatile geometrical nano-engineering.
The mechanism of different orexin/hypocretin neuronal projections in wakefulness and sleep.
Brain Res
Nanxi Li, Lishan Huang, Bin Zhang +4 more
Since the discovery of orexin/hypocretin, numerous studies have accumulated evidence demonstrating its key role in various aspects of neuromodulation, including addiction, motivation, and arousal. This paper focuses on the projection of orexin neurons to specific target brain regions through distinct neural pathways to regulate sleep and arousal. We provide a detailed discussion of the projection mechanisms of orexin neurons to downstream neurons, particularly emphasizing their activation of monoaminergic and cholinergic neurons associated with arousal. Additionally, we briefly explore the immune response and inflammatory factors linked to the loss of orexin neurons. Our findings underscore the significance of understanding specific neural projections in the generation and maintenance of arousal, which could guide advancements in neuroscience and lead to new therapeutic opportunities for treating insomnia or narcolepsy.
TNBS colitis induces architectural changes and alpha-synuclein overexpression in mouse distal colon: A morphological study.
Cell Tissue Res
Arianna Casini, Giorgio Vivacqua, Ludovica Ceci +16 more
Alpha-synuclein (α-syn) is widely expressed in presynaptic neuron terminals, and its structural alterations play an important role in the pathogenesis of Parkinson's disease (PD). Aggregated α-syn has been found in brain, in the peripheral nerves of the enteric nervous system (ENS) and in the intestinal neuroendocrine cells during synucleinopathies and inflammatory bowel disorders. In the present study, we evaluated the histomorphological features of murine colon with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, a common model of colitis. Thereafter, we investigated the expression of α-syn, Toll-like receptor 4 (TLR4), choline acetyltransferase (ChAT), vasoactive intestinal peptide (VIP), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), and calcitonin-like receptor (CALCR). Finally, we investigated the presence of phosphorylated α-syn (pS129 α-syn) aggregates and their relationship with inflammatory cells. Colon from TNBS mice showed an increase in inflammatory cells infiltrate and significative changes in the architecture of the intestinal mucosa. α-Syn expression was significantly higher in inflamed colon. VIP was increased in both the mucosa and muscularis externa of TNBS mice, while TH, CGRP, and CALCR were significantly reduced in TNBS mice. Amyloid aggregates of pS129 α-syn were detectable in the ENS, as in the macrophages around the glands of the mucosa correlating with the markers of inflammation. This study describes - for the first time - the altered expression of α-syn and the occurrence of amyloid α-syn aggregates in the inflammatory cells under colitis, supporting the critical role of bowel inflammation in synucleinopathies and the involvement of α-syn in IBD.
Mictlan-D3: A novel medium sized RGD-Disintegrin obtained from Crotalus mictlantecuhtli venom, in vitro tested against human breast Cancer and endothelial cells.
Toxicol In Vitro
E Rivas-Mercado, E Neri-Castro, V Zarzosa +4 more
Disintegrins are small non-enzymatic proteins present often at low concentration in the venom of viperid snakes. Isolated disintegrins are known for their lack of toxicity as well as their capacity to antagonize integrin receptors. Integrins are a major family of heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix (ECM) interactions. Integrins regulate key functions in cancer pathology and also tumor development. The aim of this study consisted in the isolation and characterization of disintegrins from rattlesnake new species Crotalus mictlantecuhtli venom. A disintegrin fraction obtained by RP-HPLC and named mictlan-D3, consist in two isoforms of 7439 and 7509 Da with 72 amino acid sequence containing the RGD binding motif. Mictlan-D3 inhibited MDA-MB-231 and HMEC-1 cell adhesion to laminin (LN), fibronectin (FN) and vitronectin (VN), highest inhibition was on MDA-MB-231 cell adhesion to LN by 81 % at 1 μM. The blockade of ⍺Vβ3 integrin was evaluated by wound healing migration assay. Mictlan-D3 inhibited MDA-MB-231 cell migration by 80 % and 38 % after 24 and 72 h of incubation respectively. HMEC-1 cell migration was inhibited by 67.6 % and 27.9 % after 24 and 72 h of incubation. Additionally, mictlan-D3. This work represent the first characterization of disintegrins from the Crotalus mictlantecuhtli venom.
Benchmark for Setting ACTH Cell Dosage in Clinical Regenerative Medicine for Post-Operative Hypopituitarism.
Diseases
Tatsuma Kondo, Hidetaka Suga, Kazuhito Takeuchi +6 more
Our objective is to develop hormone-producing pituitary cells that can function in the same manner as the human body and provide more effective treatments than current hormone replacement therapy. We have already established a technique for generating hypothalamic-pituitary organoids using feeder-free human pluripotent stem cells (hPSCs) and demonstrated their effectiveness in vivo through transplantation into hypopituitary mouse models. To prospectively determine the upper limit of transplanting adenohypophyseal cells into humans, we investigated the human maximum secretion capacity of adrenocorticotropic hormone (ACTH) and growth hormone (GH).
Enhanced Parkin-mediated mitophagy mitigates adverse left ventricular remodelling after myocardial infarction: role of PR-364.
Eur Heart J
Lizhuo Ai, Juliana de Freitas Germano, Chengqun Huang +15 more
Almost 30% of survivors of myocardial infarction (MI) develop heart failure (HF), in part due to damage caused by the accumulation of dysfunctional mitochondria. Organelle quality control through Parkin-mediated mitochondrial autophagy (mitophagy) is known to play a role in mediating protection against HF damage post-ischaemic injury and remodelling of the subsequent deteriorated myocardium.
Pharmacological inhibition of histamine N-methyltransferase extends wakefulness and suppresses cataplexy in a mouse model of narcolepsy.
Sleep
Fumito Naganuma, Birkan Girgin, Anne Bernadette S Agu +7 more
Histamine, a neurotransmitter, plays a predominant role in maintaining wakefulness. Furthermore, our previous studies showed that histamine N-methyltransferase (HNMT), a histamine-metabolizing enzyme, is important for regulating brain histamine concentration. However, the effects of pharmacological HNMT inhibition on mouse behavior, including the sleep-wake cycle and cataplexy, in a mouse model of narcolepsy have not yet been investigated. In the present study, we investigated the effects of metoprine, an HNMT inhibitor with high blood-brain barrier permeability, in wild-type (WT) and orexin-deficient (OxKO) narcoleptic mice. Metoprine increased brain histamine concentration in a time- and dose-dependent manner without affecting peripheral histamine concentrations. Behavioral tests showed that metoprine increased locomotor activity in both novel and familiar environments, but did not alter anxiety-like behavior. Sleep analysis showed that metoprine increased wakefulness and decreased non-rapid eye movement (NREM) sleep through the activation of the histamine H1 receptor (H1R) in WT mice. In contrast, the reduction of rapid eye movement (REM) sleep by metoprine occurred independent of H1R. In OxKO mice, metoprine was found to prolong wakefulness and robustly suppress cataplexy. In addition, metoprine has a greater therapeutic effect on cataplexy than pitolisant, which induces histamine release in the brain and has been approved for patients with narcolepsy. These data demonstrate that HNMT inhibition has a strong effect on wakefulness, demonstrating therapeutic potential against cataplexy in narcolepsy.
Postmortem study of adrenomedullin and cortisol in femoral serum and pericardial fluid related to acute pulmonary edema.
Int J Legal Med
Daniel Martínez-Jiménez, Juan Pedro Hernández Del Rincón, Maria Sabater-Molina +4 more
Currently, various tools aid in determining the cause of death and the circumstances surrounding it. Thanatochemistry is one such method that provides insights into the physiopathological mechanisms of death and the behavior of specific biomarkers in different body fluids postmortem. Certain biomarkers, characterized by their stability and specificity to vital tissues like the lungs, are associated with mechanisms contributing to death, such as acute pulmonary edema (APE). This study aims to analyze the behavior of midregional pro-adrenomedullin (MR-proADM) and cortisol levels, measured in pericardial fluid and femoral serum, in relation to the severity of APE, categorized according to specific criteria. Samples were collected from a total of 92 corpses (77 males, 15 females) with a mean age of 56.7 ± 15.2 years. The severity of APE associated with the deaths was classified into three groups: slight or absent (n = 7; 8.6%), medium or moderate (n = 16; 19.8%), and intense (n = 58;71.6%).The determination of MR-proADM and cortisol levels was conducted using ELISA kits and an Immunoassay Analyzer, respectively. Our results reveal a significant increase in MR-proADM concentration with the severity of APE. Furthermore, a correlation was established between cortisol and MR-proADM concentrations in both pericardial fluid and femoral serum samples. This indicates that the severity of APE influences the production of ADM, regardless of the specific underlying pathophysiological mechanisms. Cortisol values were also found to be higher in the intense APE group compared to the moderate group.This study contributes to our understanding of the relationship between MR-proADM and cortisol, and the severity of APE, shedding light on potential applications in postmortem investigations.
Objective and subjective appetite measures: high versus low eating frequency in a randomized crossover clinical trial.
Obesity (Silver Spring)
Xiaochen Zhang, Martine Perrigue, Jeannette M Schenk +4 more
The objective of this study was to examine objective (ghrelin and peptide YY [PYY]) and subjective appetite measures following 21-day high and low eating frequency (EF) interventions among healthy adults.
Ageing-related modification of sleep and breathing in orexin-knockout narcoleptic mice.
J Sleep Res
Stefano Bastianini, Sara Alvente, Chiara Berteotti +5 more
Narcolepsy type-1 (NT1) is a lifelong sleep disease, characterised by impairment of the orexinergic system, with a typical onset during adolescence and young adulthood. Since the wake-sleep cycle physiologically changes with ageing, this study aims to compare sleep patterns between orexin-knockout (KO) and wild type (WT) control mice at different ages. Four groups of age-matched female KO and WT mice (16 weeks of age: 8 KO-YO and 9 WT-YO mice; 87 weeks of age: 13 KO-OLD and 12 WT-OLD mice) were implanted with electrodes for discriminating wakefulness, rapid-eye-movement sleep (REMS), and non-REMS (NREMS). Mice were recorded for 48 h in their home cages and for 7 more hours into a plethysmographic chamber to characterise their sleep-breathing pattern. Regardless of orexin deficiency, OLD mice spent less time awake and had fragmentation of this behavioural state showing more bouts of shorter length than YO mice. OLD mice also had more NREMS bouts and less frequent NREMS apneas than YO mice. Regardless of age, KO mice showed cataplexy-like episodes and shorter REMS latency than WT controls and had a faster breathing rate and an increased minute ventilation during REMS. KO mice also had more wakefulness, NREMS and REMS bouts, and a shorter mean length of wakefulness bouts than WT controls. Our experiment indicated that the lack of orexins as well as ageing importantly modulate the sleep and breathing phenotype in mice. The narcoleptic phenotype caused by orexin deficiency in female mice was substantially preserved with ageing.
Pharmacotherapy of Hypoactive Sexual Desire Disorder in Premenopausal Women.
Ann Pharmacother
Donna Barakeh, Hadil Mdaihly, Lamis R Karaoui
This review aims to provide an overview of pharmacologic management for hypoactive sexual desire disorder (HSDD) in premenopausal women, with a focus on available agents.
[Astragaloside IV regulates Snail1 lactylation and acetylation to mediate macrophage polarization and improve myocardial infarction].
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi
Shaopeng Chen, Rudian Kang, Xinbao Hong +1 more
Objective To investigate the impact of Astragaloside-IV (AS-IV) on the progression of myocardial infarction (MI) through macrophage-dependent mechanisms by regulating Snail1 lactylation and acetylation, as well as the transforming growth factor β (TGF-β) pathway. Methods Oxygen glucose deprivation (OGD) was used to establish an in vitro myocardial ischemia model in rat cardiomyocytes (H9c2), which were then treated with AS-IV. Cell viability was assessed using CCK-8, apoptosis was evaluated by flow cytometry, and LDH levels were measured to assess cellular damage. RAW246.7 cells were treated with LPS, and lactate levels in the supernatant were measured using ELISA, while expression of macrophage phenotype markers was evaluated using Western blot. RAW246.7 cell-conditioned medium (CM) was co-cultured with H9c2 cells to assess the protective effects of AS-IV on macrophage CM-mediated H9c2 damage. RAW246.7 cells were induced to differentiate into M1-like macrophages using LPS (100 ng/mL) + IFN-γ (20 ng/mL), and Snail1 was overexpressed in M1 macrophages. Transfected M1 macrophage CM was co-cultured with H9c2 cells to validate the mechanisms of AS-IV in MI. An MI rat model was established by ligation of the left anterior descending coronary artery (LAD), and was treated with AS-IV. Cardiac function, myocardial cell apoptosis, and cardiac tissue pathology were studied using echocardiography, TUNEL, and HE staining, respectively. Results Compared to the OGD group, AS-IV treatment promoted cell viability, reduced apoptosis and decreased LDH release. LPS upregulated lactate levels in the supernatant of RAW246.7 cell cultures and induced polarization of RAW246.7 cells to the M1 phenotype. AS-IV attenuated the damaging effects of RAW246.7 cell CM on H9c2 cells . Overexpression of Snail1 in M1 macrophages weakened the protective effects of AS-IV on H9c2 cells . In vivo study, results showed that, compared to the MI group, AS-IV treatment reduced lactate levels in the hearts of MI rats, improved cardiac function and myocardial injury and attenuated myocardial cell apoptosis. Conclusion AS-IV inhibits TGF-β pathway activation through the suppression of Snail1 lactylation and acetylation in a macrophage-dependent manner, thereby mitigating myocardial cell damage following MI.
Topically applied GHK as an anti-wrinkle peptide: Advantages, problems and prospective.
Bioimpacts
Seyedeh Maryam Mortazavi, Seyyed Ali Mohammadi Vadoud, Hamid Reza Moghimi
Peptides are promising and attractive anti-wrinkle active ingredients, amongst which glycyl-histidyl-lysine peptide (GHK) is one of the most broadly promoted peptide for topical application. This simple sequence of amino acid residues not only has the capability of tissue regeneration and the enhancement of collagen and glycosaminoglycans synthesis but also is able to increase nerve outgrowth and angiogenesis. Consequently, GHK has several properties, from wound healing to prevention/reduction wrinkles. GHK-Cu and Pal-GHK are metal complex and palmitoylated derivatives of GHK, respectively. Although GHK-Cu and Pal-GHK are widely used in anti-wrinkle products available on the cosmetic market, the published information on their skin permeability, effectiveness, physicochemical properties and so on is insufficient.
Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity.
Adv Drug Deliv Rev
Artur Galushkin, Illana Gozes
In this review we examine the neuroprotective potential of NAP (davunetide), a small peptide derived from Activity-Dependent Neuroprotective Protein (ADNP), in the context of neurodevelopmental and neurodegenerative disorders. ADNP, a protein essential for brain development and function, is associated with tauopathy-related diseases, such as Alzheimer's Disease (AD), and circadian rhythm regulation. NAP enhances microtubule stability and prevents tauopathy. In preclinical studies, NAP shows promise in improving cognitive performance and correcting behavioral deficits in different models. Clinical studies on NAP (davunetide) administered via intranasal delivery have demonstrated its safety, favorable bioavailability, and potential efficacy in improving cognitive function, making it a viable therapeutic option. In the pure tauopathy, progressive supranuclear palsy, NAP (davunetide) significantly slowed disease progression in women in a phase II-III clinical trial. Additionally, the complex interactions between ADNP, associated pathways, and circadian regulation and the extensive NAP compensation upon ADNP deficiency attest to further clinical development. Thus, NAP is an example of a reductionist approach in drug delivery, replacing/enhancing the critical large ADNP-related pathways including dysregulated microtubules and tauopathy with a small brain bioavailable investigational drug, davunetide.
Unraveling the relationship between inflammation and cluster headache.
Front Neurol
Yu-Wen Wang, Xu-Hong Yang, Xin-Hui Zheng +4 more
Cluster headache (CH) is often referred to as the 'suicide headache.' Existing research suggests that the activation of the trigeminal-vascular system, increased sensitivity of nerve fibers, and the release and interaction of various neuropeptides and inflammatory mediators may contribute to neurogenic inflammation, which serves as a crucial pathophysiological basis for the development of CH. Additionally, some neuropeptides can modulate neuronal activity related to pain transmission and may increase pain perception by sensitizing central nerves. This review discusses the neuropeptides and inflammatory mediators associated with CH neuroinflammation, focusing on calcitonin gene-related peptide (CGRP), inflammatory cytokines and related signaling pathways, nitric oxide (NO), pituitary adenylate cyclase-activating peptide 38 (PACAP-38), and vasoactive intestinal peptide (VIP), incorporating both preclinical and clinical evidence to provide new insights into potential therapeutic targets for CH.
GH-Releasing Hormone Neurons Regulate the Hypothalamic-Pituitary-Somatotropic Axis via Short-Loop Negative Feedback.
Endocrinology
Daniela O Gusmao, Maria E de Sousa, Ligia M M de Sousa +5 more
Growth hormone (GH)-releasing hormone (GHRH) neurons are master regulators of GH secretion. However, the role of these cells in controlling pituitary GH secretion through short-loop negative feedback has not yet been fully clarified. Thus, GHRH-specific GH receptor (GHR) knockout (GHRHΔGHR) mice were generated, and possible consequences on GH secretion and body growth were determined. Approximately 60% of arcuate nucleus GHRH neurons exhibited GH-induced STAT5 phosphorylation, a marker of GHR-expressing cells. This response was practically eliminated in GHRHΔGHR mice. GHR ablation in GHRH-expressing cells increased body weight, lean mass, and naso-anal length in male and female mice without affecting fat mass. The higher body growth of GHRHΔGHR mice was associated with increases in GH secretion, mainly via higher pulsatile GH secretion and GH pulse amplitude. GHRHΔGHR female mice also showed increased GH pulse frequency and basal (non-pulsatile) secretion compared to control females. Liver Igf1 expression was increased only in GHRHΔGHR male mice. Mice carrying ablation of the insulin-like growth factor-1 (IGF-1) receptor (IGF1R) or both GHR and IGF1R in GHRH-expressing cells were generated. The increases in body growth and serum IGF-1 levels were significantly higher in GHRHΔGHR/IGF1R mice compared to GHRHΔGHR mice but similar to levels observed in GHRHΔIGF1R mice. Electrophysiological experiments showed no acute changes in the activity of GHRH neurons after GH or IGF-1 exposure. In conclusion, GH feeds back on GHRH cells to control the hypothalamic-pituitary-somatotropic axis. However, IGF1R signaling prevails over GHR as the primary signal sensed by GHRH neurons to regulate GH secretion.
Mitochondrial Cardiolipin-Targeted Tetrapeptide, SS-31, Exerts Neuroprotective Effects Within In Vitro and In Vivo Models of Spinal Cord Injury.
Int J Mol Sci
Baylen Ravenscraft, Do-Hun Lee, Heqiao Dai +5 more
Spinal cord injury (SCI) affects millions globally, leading to severe motor and sensory deficits with no effective clinical treatment. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a critical role in bioenergetics and apoptosis. Emerging evidence suggests that CL alterations contribute to secondary SCI pathology, but their precise role and underlying mechanisms remain fully understudied. In this study, we investigated the protective effects of SS-31 on CL alteration, neuronal death, tissue damage, and behavioral recovery after SCI using both in vitro and in vivo models, lipidomics analysis, histological evaluation, and behavioral assessments. In vitro investigations used primary spinal cord neuron cultures, challenged with either rotenone or glutamatergic excitotoxicity, with protective capabilities measured via cell death assays and neurite morphological analysis. In vivo investigations used female adult C57Bl/6 mice, challenged with a contusive SCI. The results showed that SS-31 reduced rotenone- and glutamate-induced mitochondrial dysfunction and neuronal death in a dose-dependent manner in vitro. Additionally, SS-31 attenuated rotenone- and glutamate-induced neurite degeneration in vitro. Lipidomics analysis revealed a reduction in CL at 24 h post-SCI in adult mice, which was attenuated by SS-31 in a dose-dependent manner. Consistent with this effect, SS-31 improved behavioral recovery after SCI in adult mice, although it had no significant effect on tissue damage. These findings suggest that CL alteration may play a key role in the pathogenesis of SCI, at least in the C57BL/6 mouse, and as such could be an attractive therapeutic target for ameliorating secondary SCI.
Growth Hormone-Releasing Hormone Antagonists Increase Radiosensitivity in Non-Small Cell Lung Cancer Cells.
Int J Mol Sci
Iacopo Gesmundo, Francesca Pedrolli, Francesca Romana Giglioli +15 more
Growth hormone-releasing hormone (GHRH) antagonists exert antitumor functions in different experimental cancers. However, their role in combination with radiotherapy in non-small cell lung cancer (NSCLC) remains unknown. Therefore, we investigated the radiosensitizing effect of GHRH antagonists in NSCLC. A549 and H522 NSCLC cell lines were exposed to ionizing radiation (IR) and GHRH antagonists MIA-602 and MIA-690, either individually or in combination. Cell viability and proliferation were evaluated by MTT, BrdU, flow cytofluorimetry, and clonogenic assays; gene and protein expression, signaling pathways, and apoptosis were analyzed by real-time PCR, Western blot, annexin staining, and caspase-3 assay. GHRH antagonists showed antitumor effects alone and potentiated IR-induced inhibition of cell viability and proliferation. The combination of MIA-690 and IR decreased the expression of GHRH receptor, its oncogenic splice variant 1, and IGF1 mRNA levels. Additionally, cell cycle inhibitors and proapoptotic markers were upregulated, whereas cyclins, oncogenic MYC, and the antiapoptotic protein Bcl-2 were downregulated. Radioresistance was prevented by MIA-690, which also blunted epithelial-mesenchymal transition by enhancing E-cadherin and reducing mesenchymal, oxidative, and proangiogenic effectors. Finally, both MIA-602 and MIA-690 enhanced radiosensitivity in primary human NSCLC cells. These findings highlight the potential of GHRH antagonists as radiosensitizers in NSCLC treatment.