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Biomimetic Dynamics of Nanoscale Groove and Ridge Topography for Stem Cell Regulation.
Adv Mater
Hyunsik Hong, Dahee Kim, Hwapyung Jung +6 more
Native extracellular matrix exhibits multiscale groove and ridge structures that continuously change, such as collagen fibril-based nanogrooves in bone tissue, and regulate cellular responses. However, dynamic switching between groove and ridge nanostructures at the molecular level has not been demonstrated. Herein, materials capable of dynamic groove-ridge switching at tens-of-nanometers scale are developed by flexibly conjugating RGD-magnetically activatable nanoridges (MANs) to non-magnetic nanogrooves with independently tuned widths comparable to the sizes of integrin-presenting filopodia by modulating hydrophobicity in bicontinuous microemulsion, allowing for cyclic modulation of RGD accessibility and cellular adhesion. Nanogrooves with medium width restrict RGD accessibility in the "groove" state in which the RGD-MANs are buried, which is reversed by magnetically raising them to protrude and form the "ridge" state that fully exposes the RGDs. This reversibly stimulates integrin recruitment, focal adhesion complex assembly, mechanotransduction, and differentiation of stem cells in vivo. This is the first demonstration of molecular-level groove and ridge nanostructures that exhibit unprecedented switchability between groove and ridge nanostructures. Versatile tuning of the width, height, pitch, and shape of intricate nanogroove structures with remote manipulability can enlighten the understanding of molecular-scale cell-ligand interactions for stem cell engineering-based treatment of aging, injuries, and stress-related diseases.
From Gut to Brain: The roles of intestinal microbiota, immune system, and hormones in intestinal physiology and gut-brain-axis.
Mol Cell Endocrinol
Muhammad Talha Khan, Muhammad Zohair, Areeba Khan +3 more
The intestine plays numerous roles in the normal physiology of our body. Gut-brain axis (GBA) is a complex communication network linking the gastrointestinal (GI) tract and central nervous system (CNS). This bidirectional system integrates endocrine, neural, and immune signals, impacting host metabolism and cognition. The gut microbiota, a critical component of the GBA, significantly impacts gut hormones, neurotransmission, neural development, and other components of gut-brain-axis. The microbiota-gut-brain axis facilitates communication via metabolites such as short chain fatty acids (SCFAs), and neurotransmitters such as dopamine, γ-amino butyric acid (GABA) and serotonin. The microbiota influences gut peptide production, including ghrelin, glucagon like pepetide-1 (GLP-1), serotonin, and cholecystokinin (CCK), thereby modulating nutrient absorption and immune responses. Gut hormones such as ghrelin, CCK, GLP-1, gastric inhibitory peptide (GIP), serotonin (5-HT), neurotensin, peptide YY (PYY) and melatonin play key roles in the GBA. These hormones play several roles including modulation of appetite and satiety, metabolism of nutrients such as lipid and glucose, insulin and glucagon secretion, and influence on gut inflammation, mood, learning and cognition. The interaction between gut microbiota and these hormones underscores their role in maintaining gut-brain homeostasis. Dysbiosis, or microbial imbalance, is linked to altered stress responses, anxiety, and depressive behaviors, highlighting the therapeutic potential of microbiota modulation. Despite the significant roles of gut hormones and microbiota in the GBA, literature on their cellular and molecular mechanisms is limited, and often based on animal models. This review synthesizes current understanding of hormones secreted by the intestine, their physiological effects and the cellular and molecular mechanisms of action underlying these effects, with a focus on their roles in the GBA. By elucidating these complex relationships, the review aims to advance research and clinical applications, offering insights into gastrointestinal and systemic health.
Efficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials.
J Basic Clin Physiol Pharmacol
Saurav Misra, Ravi Kant Narayan, Manmeet Kaur
Obesity is a major public health issue linked to various health complications. Retatrutide, a triple agonist peptide targeting the glucagon receptor, GIP receptor, and GLP-1 receptor, shows promise in addressing this need.
Neuropeptide Y neurons surrounding the locus coeruleus inhibit noradrenergic system activity to reduce anxiety.
Sci Adv
Danai Riga, Karlijn L Kooij, Kelly Rademakers +3 more
Adaptive responses to challenging environments depend on optimal function of the locus coeruleus (LC), the brain's main source of noradrenaline and primary mediator of the initial stress response. Combining functional circuit dissection and causal in vivo interventions in mice, we here investigate a built-in peptidergic regulatory system that restricts LC noradrenergic output. In particular, we characterize a population of neuropeptide Y (NPY)-expressing neurons surrounding LC noradrenergic cells. We show that this peri-LCNPY population exerts neuromodulatory inhibitory control over the LC via NPY-Y1R signaling. Under naïve conditions, this results in bidirectional control of anxiety-like behaviors. Stressful experiences recruit peri-LCNPY neurons, leading to local NPY release in vivo, whereas enhanced peri-LCNPY neuronal activity curbs anxiety after stress. Together, we establish a causal role for peri-LCNPY-mediated neuromodulation of the LC in the regulation of anxiety, providing mechanistic insights into the endogenous systems underlying adaptive responses to adversity.
Upper-gastrointestinal tract metabolite profile regulates glycaemic and satiety responses to meals with contrasting structure: a pilot study.
Nat Metab
Mingzhu Cai, Shilpa Tejpal, Martina Tashkova +12 more
Dietary interventions to combat non-communicable diseases focus on optimizing food intake but overlook the influence of food structure. Here, we investigate how food structure influences digestion. In a randomized crossover study, ten healthy participants were fitted with nasoenteric tubes that allow simultaneous gastric and duodenal sampling, before consuming iso-nutrient chickpea meals with contrasting cellular structures. The primary outcome is gut hormone response. Secondary outcomes are intestinal content analysis, blood glucose and insulin response, subjective appetite changes and ad libitum energy intake. We show that the 'Broken' and 'Intact' cell structures of meals result in different digestive and metabolomic profiles, leading to distinct postprandial gut hormones, glycaemia and satiety responses. 'Broken' meal structure elicits higher glucose-dependent insulinotropic peptide, glucagon-like peptide-1 and blood glycaemia, driven by high starch digestibility and a sharp rise in gastric maltose within 30 min. 'Intact' meal structure produces a prolonged release of glucagon-like peptide-1 and peptide-YY, elevated duodenal amino acids and undigested starch at 120 min. This work highlights how food structure alters upper gastrointestinal nutrient-sensing hormones, providing insights into the adverse effects of modern diets on obesity and type 2 diabetes. ISRCTN registration: ISRCTN18097249.
One Case of Sudden Isolated Adrenocorticotropic Hormone (ACTH) Deficiency Diagnosed Based on Repeated Hypoglycemic Attacks.
Cureus
Tomohide Sato
Our patient is a 28-year-old male who was being treated by a local doctor for Hashimoto's thyroiditis. Four days prior to admission, nausea and diarrhea appeared, and it gradually became difficult for him to eat. The night before admission, his level of consciousness decreased (Japan Coma Scale (JCS) II-20), and he was rushed to the hospital. His other vital signs were stable. After completing a detailed examination, the cause was diagnosed as hypoglycemia with a blood glucose level of 21 mg/dl. After the administration of glucose, he regained consciousness and became alert, allowing him to return home, with the expectation that he would return to the hospital for a follow-up visit at a later date. However, an altered consciousness (JCS I-3) appeared again the next morning. Similar to the previous day, the cause of the altered consciousness was determined to be hypoglycemia. After making a detailed inpatient examination, his early morning fasting serum cortisol level was found to be less than 0.1 μg/dL, and his blood adrenocorticotropic hormone (ACTH) was 3.1 pg/mL, thus indicating decreases in both. After performing rapid ACTH testing, almost no increase in the serum cortisol levels was observed after 30 minutes and 60 minutes following ACTH administration, thus suggesting the presence of adrenal insufficiency. According to a contrast-enhanced CT of the abdomen, atrophy of both adrenal glands was observed; however, there was no macroadenoma or the like according to the contrast-enhanced MRI of the brain. Based on the results of the ACTH continuous load test, triple anterior pituitary stimulation test with corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH), growth hormone-releasing peptide-2 (GHRP-2) load test, and insulin hypoglycemic load test, no abnormalities were found in his pituitary functions other than ACTH-cortisol, and no history of trauma or adenoma lesions, leading to a diagnosis of a sudden isolated ACTH deficiency. The patient has remained stable with no hypoglycemic episodes since treatment with hydrocortisone was initiated. Based on the fact that isolated ACTH deficiency is often associated with a complication of autoimmune endocrine disease, an autoimmune mechanism has been speculated. Although the disease is rare, it is an important disease that affects the quality of life (QOL) of patients, and it should therefore be considered when making a differential diagnosis.
A Review on the Potential Role of Humanin Peptide and its Analogs in the Regulation of Autophagy Pathways for Therapeutic Application in Metabolic Disorders.
Protein Pept Lett
Hira Moin, Rizwan Ashraf, Batool Butt +3 more
Autophagy is a self-eating cellular process in which the cell breaks down worn-out organelles, damaged/defective proteins, and toxins. Impaired autophagy is a significant factor in the development of various metabolic disorders, along with oxidative stress, inflammation, mitochondrial and endoplasmic reticulum dysfunction. These disorders pose a significant health and economic burden on the global human population, owing to their steadily rising prevalence. Therefore, modulating the expression of proteins involved in the autophagy-related pathways can be a promising avenue for curbing the development and progression of these disorders. Humanin (HN) is a 24-amino acid mitochondrial-derived peptide. It possesses anti-oxidant, anti-inflammatory, and pro-apoptotic properties. The analogs of HN can be generated by replacing specific amino acids in the polypeptide chain, thereby functionally modifying the peptide. Among these, humanin- glycine (HNG) is the most widely studied analog in both in vivo and in vitro disease models. It is far more potent than HN, with a potency that is 1000 times greater. To the best of our knowledge, this review is the first to discuss and examine the available evidence regarding the potential involvement of HN or its analogs in regulating autophagy pathways. The review primarily highlights that HN is an autophagy inducer, which can promote cell survival in the presence of metabolic and oxidative stress, particularly the HNG analog. Future research is imperative to comprehensively evaluate the effects of HN and its analogs on autophagy. Further investigations are needed to correlate its levels with various autophagic markers in different metabolic diseases, offering the potential for groundbreaking discoveries in understanding disease mechanisms and developing novel therapeutic strategies.
Cholecystokinin and gastrin-releasing peptide differentially inhibit appetite of rainbow trout.
Gen Comp Endocrinol
Antti Forsman, Elisabeth Jönsson, Björn Thrandur Björnsson +2 more
The appetite in fish is a multifaceted phenomenon that comprises specialized interactions between brain and peripheral signals, and as a result, appetite is either stimulated or inhibited. Cholecystokinin (Cck) and gastrin-releasing peptide (Grp) are two postprandially released gastrointestinal peptide hormones that affect feed intake in fish. As the stimulatory or inhibitory effects of hormones can vary in duration and strength, making the nature of hormone effects dynamic, we modelled the dynamics of Cck and Grp using a direct, non-stressful approach. Fish were hormonally treated through an intraperitoneal cannula and feed intake was monitored for 12 h post-injection using a self-feeder system. Cck and Grp decreased feed intake in a dose-dependent manner, hormone-specific both in terms of magnitude and duration. Cck had an immediate inhibitory effect on feed intake, which lasted two-three hours, whereas the immediate inhibitory effect of Grp lasted for the entire 12-hour observation period. The data suggest that Cck acts as a short-term satiety signal in rainbow trout, while Grp acts as a longer-term appetite suppressor.
ELABELA Ameliorates Atherosclerosis Through Restoring the M1/M2 Macrophage Balance in ApoE-/- Mice.
J Am Heart Assoc
Le Tang, Xiaoli Yi, Wenting Tan +10 more
Atherosclerosis is a progressive arterial disease characterized by chronic inflammation and plaque formation in blood vessel walls. ELABELA, an endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), has multiple pharmacological activities for protecting the cardiovascular system. This study aimed to determine the potential antiatherosclerotic effect of ELABELA and reveal the underlying mechanisms.
Endogenous and exogenous oxytocin modulate interpersonal motor resonance in autism: A context-dependent and person-specific approach.
Autism
Jellina Prinsen, Kaat Alaerts
Understanding and interpreting non-verbal actions are critical components of social cognition, which are often challenging for autistic individuals. Oxytocin, a neuropeptide known to modulate social behavior and enhance the salience of social stimuli, is being explored as a therapeutic option for improving social mirroring. However, its effects are mediated by context- and person-dependent factors. This study examines the impact of a single intranasal dose of oxytocin (24 IU) on interpersonal motor resonance in young adult men with and without autism. Neurophysiological assessments of corticomotor excitability were performed using transcranial magnetic stimulation while participants observed real-time hand movements displayed by an experimenter demonstrating varying social intent (i.e. showing direct vs averted gaze). While no overall effect of oxytocin on interpersonal motor resonance was observed across groups, person-specific factors significantly influenced outcomes. In the autism group, individuals with higher endogenous oxytocin levels exhibited greater motor resonance during action observation. Autistic individuals with heightened social difficulties or avoidant attachment styles showed enhanced motor resonance following oxytocin administration. These findings highlight the nuanced role of both endogenous and exogenous oxytocin in shaping neurophysiological motor resonance and emphasize the importance of individual variability in assessing oxytocin's therapeutic potential for addressing social challenges in autism.Lay abstractThis study explores how oxytocin, a hormone that influences social behaviors, affects the ability to interpret and respond to non-verbal cues, particularly in autistic adults. Understanding others' actions and intentions, often guided by observing body language and eye contact, is a critical part of social interaction. Autistic individuals frequently face challenges in these areas. Using a safe, non-invasive brain stimulation technique, the study measured participants' brain responses as they observed real-time hand movements paired with the interaction partner's direct eye contact or averted gaze. Participants included young autistic and non-autistic adult men who received a placebo and a single dose of oxytocin via nasal spray. Results showed no overall differences between the two groups in their brain responses to these movements. However, in the autism group, several factors significantly influenced the effects of oxytocin. Participants with higher natural oxytocin levels or those who reported greater social challenges showed stronger responses after oxytocin administration, particularly when observing hand movements combined with direct gaze. These findings suggest that oxytocin may enhance social understanding in autistic individuals, especially for those experiencing greater difficulties. This highlights the potential of personalized approaches when considering oxytocin as a therapeutic option to improve social interactions.
Tunable Integrin-Ligand Coupling Strength Modulates Cellular Adaptive Mechanosensing.
Nano Lett
Zheng Zhang, Xiaoxi Liu, Baoyong Sha +10 more
Cells sense and respond to the matrix by exerting traction force through binding of integrins to an integrin-specific ligand. Here, Arg-Gly-Asp (RGD) peptide is covalently conjugated to the double-stranded DNA (dsDNA) and stem-loop DNA (slDNA) tethers with a tension tolerance of 43pN and immobilized on a PEG substrate. Unlike dsDNA, which is ruptured under high tension, leading to the removal of RGD, slDNA remains bound even when ruptured. Our results suggest that cells adapt their adhesion state by modulating actin filament polymerization and cofilin phosphorylation, effectively balancing the talin conformation to prevent dsDNA rupture and maintain normal adhesion. This phenomenon, termed integrin-ligand coupling strength, mediated cellular adaptive mechanosensing. Furthermore, we demonstrate that positive durotaxis can shift to negative durotaxis, depending on the integrin-ligand coupling strength. This study highlights the significance of the coupling strength in cell-extracellular matrix (ECM) interactions and offers new insights into designing biomaterials with tunable adhesive properties for cell-based applications.
New cardiovascular biomarkers in patients with advanced cancer - A prospective study comparing MR-proADM, MR-proANP, copeptin, high-sensitivity troponin T and NT-proBNP.
Eur J Heart Fail
Markus S Anker, Laura C Lück, Muhammad Shahzeb Khan +16 more
Traditional cardiovascular (CV) biomarkers (high-sensitivity troponinT [hsTnT] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) are important to monitor cancer patients' cardiac function and to assess prognosis. Newer CV biomarkers (mid-regional pro-adrenomedullin [MR-proADM], C-terminal pro-arginine vasopressin [copeptin], and mid-regional pro-atrial natriuretic peptide [MR-proANP]) might outperform traditional biomarkers.
Amylin: emergent therapeutic opportunities in overweight, obesity and diabetes mellitus.
Nat Rev Endocrinol
Christopher S Walker, Jacqueline F Aitken, Greeshma Vazhoor Amarsingh +2 more
The identification of amylin as a glucoregulatory peptide hormone with roles in meal-ending satiation sparked a surge of experimental development, which culminated in the amylin mimetic drug pramlintide. Pramlintide was approved by the FDA in 2005 for the treatment of type 1 diabetes mellitus and insulin-requiring type 2 diabetes, and was also explored as a novel anti-obesity treatment. Despite this exciting potential, efforts to develop an amylin-based anti-obesity therapeutic stalled owing to challenges around dosage frequency, safety and formulation. Generally, anti-obesity therapies have displayed modest efficacy and mixed safety profiles, leaving a clear unmet clinical need that requires addressing. Advances in peptide chemistry have reinvigorated the amylin field by enabling the manufacture of effective new amylin-based molecules, resulting in therapeutics that are now on the cusp of approval. At present, there are growing concerns around GLP1 receptor agonist-based therapeutics, in particular their association with loss of lean body mass. Additionally, treatment of patients with overweight or obesity without associated comorbidities is increasingly common. The widespread pharmacotherapy of otherwise healthy populations with overweight or obesity with the goal of improving future health requires further regulatory and ethical consideration. This Review describes how amylin controls energy homeostasis and provides a current overview of amylin-based therapeutic development.
Exogenous [Pyr1]apelin-13 prevents bupivacaine-induced cardiotoxicity via the apelin (APJ) receptor.
Clin Toxicol (Phila)
Chaoxing Chen, Shishi Zhao, Zhengjie Chen +11 more
Abnormal energy metabolism is an important mechanism in the development of bupivacaine-induced cardiotoxicity. Apelin, a peptide derived from adipocytes, plays a pivotal role in both energy metabolism and the regulation of the cardiovascular system, thereby potentially linking it to bupivacaine-induced cardiotoxicity.
Random forest and Shapley Additive exPlanations predict oxytocin targeted effects on brain functional networks involved in salience and sensorimotor processing, in a randomized clinical trial in autism.
Neuropsychopharmacology
Elissar Andari, Kaundinya Gopinath, Erin O'Leary +7 more
Intranasal oxytocin (IN-OXT) has shown some promises in rescuing social deficits in autism spectrum disorder (ASD) as well as some inconsistencies in long-term trials. We conducted a target engagement study to study the precise effects of different doses of IN-OXT on brain resting-state functional connectivity (rsFC) in ASD. We examined the effects of varying doses of IN-OXT (0 IU, 8 IU, 24 IU, 48 IU) on rsFC in a double-blind, placebo-controlled, within-subject design in 30 male adults with ASD and 17 neurotypical controls (NT) receiving placebo. Random forest analysis was used to classify individuals as ASD or NT. Shapely Additive explanations values were calculated to rank brain functional networks by level of contribution to ASD deficits and to evaluate IN-OXT dose effects. The model predicted ASD diagnosis with an AUC of 94%. Hypoconnectivity between salience/empathy and visual networks, and hyperconnectivity between reward and sensorimotor networks and theory of mind networks were among the strongest predictors of ASD deficits. IN-OXT had a dose-dependent effect on rescuing both deficits described above. Overall, 48 IU dose was more effective, and 24 IU dose was more effective in those who have lower DNA OXT receptor methylation and lower severity of clinical symptoms. Higher doses of OXT might be necessary to enhance empathic responses, and ASD individuals with less support needs and with a preserved OXT system might benefit most from OXT treatment. Applying machine learning approaches in OXT research can provide data-driven unbiased results that can inform future clinical trials.
Genes That Associated with Action of ACTH-like Peptides with Neuroprotective Potential in Rat Brain Regions with Different Degrees of Ischemic Damage.
Int J Mol Sci
Ivan B Filippenkov, Yana Yu Shpetko, Daria A Ales +9 more
In the treatment of ischemic stroke, an innovative approach is the use of neuroprotective compounds. Natural peptides, including adrenocorticotropic hormone (ACTH), can serve as the basis for such drugs. Previously, a significant effect of non-hormonal ACTH(4-7)PGP (Semax) and ACTH(6-9)PGP peptides on the functions of the nervous system was shown. Also, while using RNA-Seq, we firstly revealed differentially expressed genes (DEGs) that associated with peptides in the penumbra-associated region of the frontal cortex (FC) of rats at 24 h after transient middle cerebral artery occlusion (tMCAO) model. Peptides significantly reduced profile disturbances caused by ischemia for almost two-thousand DEGs in FC related to the neurotransmitter and inflammatory response. Here, we studied how peptides affected the expression of genes in the striatum with an ischemic focus, predominantly. The same animals from which we previously acquired FC were used to collect striatum samples. Peptides generated fewer DEGs in the striatum than in the FC. Both peptides tended to normalize the profile of disturbances caused by ischemia for hundreds of DEGs, whereas 152 genes showed an even more affected profile in the striatum under ACTH(6-9)PGP action. These DEGs were associated with inflammation, predominantly. About hundred genes were overlapped between both peptides in both tissues and were associated with neuroactive ligand-receptor interaction, predominantly. Thus, genes that are associated with the ACTH-like peptide action in rat brain regions with varying levels of ischemia injury were identified. Moreover, differential spatial regulation of the ischemia process in the rat brain at the transcriptome levels was discovered under peptides with different ACTH structures. We suppose that our results may be useful for selecting more effective neuroprotective drug structures in accordance with their specific tissue/damage therapeutic impact.
Naturally Occurring Angiotensin Peptides Enhance the SARS-CoV-2 Spike Protein Binding to Its Receptors.
Int J Mol Sci
Katelin X Oliveira, Fariha E Bablu, Emily S Gonzales +2 more
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus Disease 2019 (COVID-19), utilizes its spike protein to infect host cells. In addition to angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1), AXL acts as a spike protein receptor and mediates infection, especially in respiratory cells with low ACE2 expression. Angiotensin II (1-8) can be cleaved into shorter peptides within the biological system. Antibody-based binding assays showed that angiotensin II causes a two-fold increase in the binding between the spike protein and AXL, but not ACE2 or NRP1. While a longer peptide, angiotensin I (1-10), did not affect the spike-AXL binding, shorter lengths of angiotensin peptides exhibited enhancing effects. The C-terminal deletions of angiotensin II to angiotensin (1-7) or angiotensin (1-6) resulted in peptides with enhanced activity toward spike-AXL binding with a similar capacity as angiotensin II. In contrast, the N-terminal deletions of angiotensin II to angiotensin III (2-8) or angiotensin IV (3-8) as well as the N-terminal deletions of angiotensin (1-7) to angiotensin (2-7) or angiotensin (5-7) produced peptides with a more potent ability to enhance spike-AXL binding (2.7-fold increase with angiotensin IV). When valine was substituted for tyrosine at position 4 in angiotensin II or when tyrosine at position 4 was phosphorylated, spike-AXL binding was increased, suggesting that modifications to tyrosine trigger enhancement. Angiotensin IV also enhances spike protein binding to ACE2 and NRP1. Thus, angiotensin peptides may contribute to COVID-19 pathogenesis by enhancing spike protein binding and thus serve as therapeutic targets.
Sex effect on disease characteristics in patients with narcolepsy type 1.
Sleep
Lucie Barateau, Fabio Pizza, Emanuela Postiglione +7 more
Narcolepsy type 1 (NT1) is a rare sleep disorder caused by orexin/hypocretin (Hcrt-1) deficiency, equally prevalent in women and men. Sex differences have been reported in animal models, particularly regarding cataplexy. Whether these differences can be transposed to humans remains unclear. We studied the sex effect on the characteristics of the disease in a large population of patients with NT1 in drug-free conditions.
Tβ4-Engineered ADSC Extracellular Vesicles Rescue Cell Senescence Through Separable Microneedle Patches for Diabetic Wound Healing.
Adv Sci (Weinh)
Youjun Ding, Jinglin Wang, Jiaye Li +5 more
Microneedles loaded with bioactive substances have demonstrated efficacy in wound healing, while their application in the elderly chronic wounds, aggravated by cellular senescence, is still a significant challenge. Here, a novel therapeutic strategy is presented utilizing Thymosin β4 (Tβ4)-modified adipose-derived stem cell extracellular vesicles (ADSC-EVs) delivered via separable microneedle patches (MN@EVsTβ4). The therapeutic EVsTβ4 are derived from ADSCs that overexpress Tβ4, a factor that reverses cellular senescence. Leveraging the drug-loading and release properties of gelatin methacryloyl and poly(ethylene glycol) diacrylate, EVsTβ4 are encapsulated within the tips of the microneedles. Notably, the soluble hyaluronic acid base layer dissolves rapidly and separates from the tips upon exudate absorption, enabling a sustained release of EVsTβ4. Subsequently, it is demonstrated its ability to mitigate senescence and improve function via the PTEN/PI3K/AKT pathway. Furthermore, MN@EVsTβ4 patches showed significant efficacy in reversing senescence and promoting wound healing in diabetic wound models. Thus, the engineered ADSC-EVs, combined with separable microneedle patches, represent a promising bioengineering strategy for clinical wound management.
Role of the renin-angiotensin pathway in epilepsy: a strategy for its management by drug repurposing.
Mol Biol Rep
Rakesh Bagle, Shubham Teli, Bhushan Khombare +1 more
Epilepsy is a neurological disorder characterised by aberrant synchronised neuronal activity in the brain and affects millions of people globally. The renin-angiotensin system (RAS) has been implicated in epilepsy pathophysiology, with angiotensin receptors playing pivotal role in seizure modulation and neuroprotection. This review explores the angiotensin-epilepsy axis, and elaborates upon the role of angiotensin receptors (AT-1, AT-2, AT-4, and Mas) in the CNS. AT-1 receptor stimulation is related to neuroinflammation, oxidative stress, and propagation of seizures, whereas their blockade by angiotensin receptor blockers (ARBs) demonstrated anticonvulsant and neuroprotective effects in preclinical model. AT-2 receptor activation down-regulates pro-inflammatory cytokines & protects the blood-brain barrier and induces neuronal survival and differentiation. They also interact with the AT-4 receptor identified as insulin-regulated amino peptidase (IRAP), a receptor that is implicated in its neuroinflammatory modulation, oxidative stress, and excitotoxicity. Against this background, the Mas receptor was recognized as the receptor for angiotensin-(1-7), leading to vasodilator, anti-inflammatory and anti-oxidant effects that oppose angiotensin II actions. This intricate interplay between these receptors and ligands accompanies the dynamic regulation of neurotransmitters, neuroinflammation, and neuroprotection in epileptic seizures. The role of the RAS in epilepsy may present new therapeutic targets in addressing this devastating disorder, especially in patients with coexisting cardiovascular illnesses.