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Metabolic Dysfunction-Associated Steatotic Liver Disease in Adults: A Review.
JAMA
Herbert Tilg, Salvatore Petta, Norbert Stefan +1 more
Metabolic dysfunction-associated steatotic liver disease (MASLD) includes a range of liver conditions, progressing from isolated steatosis (characterized by fat accumulation in the liver without inflammation) to metabolic dysfunction-associated steatohepatitis (MASH), which involves fat accumulation and inflammation in the liver. The presence of MASLD is associated with increased morbidity and mortality due to liver-related complications, hepatocellular carcinoma, cardiovascular disease, and certain extrahepatic cancers.
Topics in Lung Disease: Pulmonary Hypertension.
FP Essent
Alexander Kaysin, Sunil Swami, Oluwatoni Aluko +1 more
Pulmonary hypertension is a complex progressive disorder characterized by elevated pulmonary artery pressure. Diagnosis requires early clinical suspicion based on symptoms such as exertional dyspnea, fatigue, syncope, and chest discomfort, with echocardiography as a first-line diagnostic study. Diagnosis is confirmed using right heart catheterization, with a mean pulmonary artery pressure of 20 mm Hg or more and pulmonary vascular resistance greater than 2 Wood units. Strategies for primary and secondary prevention include regular physical activity, tobacco cessation, weight management, immunizations, and family planning to minimize risks associated with pregnancy. Prevention and evidence-based control of hypertension, diabetes, and dyslipidemia are essential. Occupational and environmental exposures, including poor indoor and outdoor air quality, should be addressed. Advances in pharmacotherapy for pulmonary arterial hypertension that target the endothelin, prostacyclin, and nitric oxide pathways and activin receptor inhibition have improved outcomes. Endothelin receptor antagonists, prostacyclin analogues, and phosphodiesterase 5 inhibitors are key treatment options. Combination therapy is recommended for patients with moderate to severe disease, whereas parenteral prostanoids are indicated for advanced pulmonary arterial hypertension. Right-sided heart failure, a major complication, is managed with fluid manage-ment and diuretics, with lung transplant evaluation and palliative shunt procedures considered for refractory cases. Addressing nutrition and iron deficiency are important supportive measures.
The impact of growth hormone (GH) on immunosenescence: exploring the role of B and T cells.
Pituitary
Badra Bashir, Marcella van Hoolwerff, Fabian Benencia +4 more
Immunosenescence is a gradual decline in immune function, leading to increased susceptibility to infections and autoimmune conditions. Growth hormone (GH) has been shown to have an effect on both immune function and aging. In fact, the absence of GH-induced intracellular signaling can slow the aging process, as demonstrated by the longest-lived laboratory mouse (GH receptor gene disrupted or GHR-/- mice). Because GH receptors (GHR) are expressed in B and T cells, and these cells undergo age-related changes that impact immune function, we hypothesized that decreased GH action protects from immunosenescence. To validate this hypothesis, this study aimed to characterize differences in B cell and T cell populations within the lymphoid organs of aged female GHR-/- mice (24 months of age) compared to wild-type controls.
Evaluating methodological constraints in PET imaging of neuropeptide Y2 receptors with N-[11C]-methyl-(R)-JNJ-31020028 in brains of C57BL/6J mice.
EJNMMI Radiopharm Chem
Karsten Bamminger, Eduardo Felipe Alves Fernandes, Lena Zachhuber +7 more
The Neuropeptide Y (NPY) system regulates mood, stress, and feeding behavior and plays a central role in neuropsychiatric and metabolic disorders. It exerts its effects primarily through a family of G-protein-coupled NPY receptors (NPYR), comprising the Y1, Y2, Y4, and Y5 subtypes. Among these, the Y2 receptor (NPY2R) has emerged as a promising imaging target through its involvement in mood regulation, anxiety, and feeding behavior. This study evaluated the in vivo performance of the selective NPY2R antagonist PET tracer N-[11C]methyl-(R)-JNJ-31020028 in mice, focusing on tracer metabolism, brain uptake, and blood-brain barrier transport via P-glycoprotein (P-gp).
IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes.
Pharmacol Res
Andrew J Elmendorf, Mostafa Yousefian, Il-Man Kim +3 more
The epidemics of metabolic disease, in the form of obesity and type 2 diabetes, are a growing public health concern. However, incretin-based therapeutics have transformed our ability to address these diseases. While this current generation of incretin analogues show weight regain upon cessation of treatment, the amount of which can depend on the treatment and patient, iterative advancements may improve weight loss durability in the long term. In this review, we discuss the development of glucagon like peptide-1 receptor (GLP-1R) agonists and GLP-1R/ glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists, and how future generations will leverage this strategy. We focus our review on glucagon receptor (GCGR) agonism, which has recently been combined with both GLP-1R and GLP-1R/GIPR agonism to generate dual (e.g. survodutide, cotatutide, mazdutide, etc) and triple agonists (e.g. retatrutide, etc) for improved body weight loss via energy expenditure stimulation. We rely on largely pre-clinical evidence for action because clinical data is extremely limited for GCGR agonism. Herein, we review mechanisms by which glucagon receptor agonists act to increase energy expenditure. Finally, we discuss future improvements to incretin-based therapeutics, and how they can include strategies that target the GCGR. The purpose of this review is to discuss mechanisms by which GCGR agonism can reduce body weight and put them in the context of the combination with incretin receptor agonists. Mechanistic data has only currently been evaluated in preclinical rodent models and evidence for similar processes in humans is limited. We also provide perspectives about how treatments can improve for future advancement of obesity treatment.
The Roles of Incretin Hormones GIP and GLP-1 in Metabolic and Cardiovascular Health: A Comprehensive Review.
Int J Mol Sci
Dai Yamanouchi
The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) play central roles in metabolic and cardiovascular regulation. GLP-1 receptor agonists (GLP-1RAs) are established therapies for type 2 diabetes mellitus (T2DM) and obesity because of their insulinotropic effects, weight reduction, and proven cardiovascular benefit in trial level. In contrast, GIP was historically overlooked due to reduced β-cell responsiveness in T2DM. The development of dual GIP/GLP-1 receptor agonists has reshaped this view. Tirzepatide, the first-in-class co-agonist, an antidiabetic medication to treat type 2 diabetes and for weight loss, provides superior glycemic control and weight loss compared with selective GLP-1RAs in clinical trials, demonstrating synergistic actions between the two incretin pathways. This review summarizes key physiology, pathophysiology, and therapeutic evidence in incretin biology. We describe secretion patterns, receptor distributions, and distinct actions of GIP and GLP-1, as well as alterations in incretin signaling in T2DM and obesity. Cardiovascular protective mechanisms are outlined, including improvements in lipid metabolism, reductions in blood pressure, enhanced endothelial nitric oxide activity, suppression of macrophage inflammation, decreased foam-cell formation, and stabilization of atherosclerotic plaques. At the therapeutic level, emerging directions-such as dual and triple agonists-and unresolved questions regarding long-term vascular effects of GIP and the potential for genotype-guided incretin therapy are also discussed. Collectively, these findings highlight an emerging shift toward integrated incretin-axis modulation as a therapeutic strategy for metabolic and cardiovascular disease.
Identification of Pancreatic Neuroendocrine Tumor During Evaluation for Severe Valvulopathy in a Patient With a History of Lung Carcinoid Tumor: A Case Report.
Cureus
Zhan Rong, Cassie Liu, Christopher Loh +4 more
A 36-year-old man with a history of resected typical lung carcinoid tumor and bicuspid aortic valve presented with acute decompensated heart failure. Workup revealed severe mitral valvulopathy and incidentally identified an enhancing pancreatic head mass with additional lesions on imaging. Liver biopsy was benign, while endoscopic ultrasound-guided biopsy of the pancreatic mass showed a well-differentiated, WHO grade 1 pancreatic neuroendocrine tumor (NET) positive for chromogranin, synaptophysin, and CD56, with Ki-67 < 3%. Serum 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A were elevated. Positron emission tomography (PET)-DOTATATE demonstrated somatostatin receptor-avid lesions in the pancreas, liver, bone, and lymph nodes, consistent with metastatic neuroendocrine neoplasm. The patient underwent aortic valve replacement followed by long-acting octreotide therapy. Concurrent duodenal biopsies revealed celiac disease, and his gastrointestinal symptoms improved with a gluten-free diet. This case represents an exceptionally rare scenario of pancreatic neuroendocrine tumor in a patient with prior lung carcinoid tumor and raises the critical question of pancreatic metastasis versus a second primary NET in the absence of hereditary syndromes. It underscores the need for heightened vigilance for second primary malignancies (SPMs) and atypical metastatic patterns in patients with a history of NETs and highlights the importance of multidisciplinary evaluation for accurate classification and optimal management.
Acupuncture ameliorates diet-induced obesity via the vagal-GLP-1-ARC circuit: neural mechanism of anorexigenic action.
Chin Med
Yanan Yang, Yuwei Shao, Jun Tian +7 more
Electroacupuncture (EA) has demonstrated efficacy in ameliorating obesity through its marked appetite-suppressing effects. This study aims to elucidate the peripheral-central communication mechanism underlying EA's appetite inhibition mediated by the "vagal afferent fiber-nucleus tractus solitarius (NTS)-hypothalamic arcuate nucleus (ARC)" neural circuit.
Convergent state-control of endogenous opioid analgesia.
bioRxiv
Blake A Kimmey, Lindsay Ejoh, Lily Shangloo +13 more
Pain is a dynamic and nonlinear experience shaped by injury and contextual factors, including expectations of future pain or relief1. While μ opioid receptors are central to the analgesic effects of opioid drugs, the endogenous opioid neurocircuitry underlying pain and placebo analgesia remains poorly understood. The ventrolateral column of the posterior periaqueductal gray is a critical hub for nociception and endogenous analgesia mediated by opioid signaling2. However, significant gaps remain in understanding the cell-type identities, the sub-second neural dynamics involved in pain modulation, the role of endogenous peptide neuromodulators, and the contextual factors influencing these processes. Using spatial mapping with single-nuclei RNA sequencing of pain-active neurons projecting to distinct long-range brain targets, alongside cell type-specific and activity-dependent genetic tools for in vivo optical recordings and modulation of neural activity and opioid peptide release, we identified a functional dichotomy in the ventrolateral periaqueductal gray. Neurons expressing μ opioid receptors encode active nociceptive states, whereas enkephalin-releasing neurons drive pain relief during recovery from injury, in response to learned fear predictions, and during placebo analgesia. Finally, by leveraging the functional effects of placebo analgesia, we used direct optogenetic activation of vlPAG enkephalin neurons to drive opioid peptide release, resulting in a robust reduction in pain. These findings show that diverse need states converge on a shared midbrain circuit that releases endogenous opioids with high spatiotemporal precision to suppress nociceptive activity and promote analgesia.
Haploinsufficiency of Sox2 causes fewer GnRH neurons and delayed puberty in mice.
Endocrinology
Jessica Cassin, Geneva A Dunn, Ryan D Nguyen +7 more
Mutations in the SOX2 gene have been previously linked to a syndromic form of isolated hypogonadotropic hypogonadism, with additional ocular and neurodevelopmental phenotypes. Recently, we reported a functional role for SOX2 in hypothalamic kisspeptin-expressing neurons and established a mechanistic relationship between SOX2 heterozygous variants and isolated hypogonadotropic hypogonadism. To further test the role of Sox2 in the hypothalamic-pituitary-gonadal axis, we generated mice with a whole-body heterozygous knockout of Sox2 (Sox2WT/KO). We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2WT/KO mice compared to wild-ype (WT) controls. In females, fertility was also compromised, with fewer estrous cycles and a significant delay in time to first litter of Sox2WT/KO dams compared to WT controls. Circulating levels of gonadotropins were normal in both male and female Sox2WT/KO mice, suggesting a functional pituitary. Finally, we assessed the number of kisspeptin and GnRH neurons and found that Sox2WT/KO mice do not differ from controls in the number of kisspeptin neurons but have significantly fewer GnRH neurons. This deficit occurs before birth, as by embryonic day 15.5, there are already fewer GnRH neurons in the Sox2WT/KO mice. Using luciferase assays, we determined that Sox2 increases expression of GnRH in vitro; thus, the decrease in GnRH-expressing neurons in vivo is likely the result of Sox2 haploinsufficiency. Together, these data further substantiate a critical role for SOX2 in the hypothalamic-pituitary-gonadal axis via effects on GnRH neuron development and, therefore, pubertal timing and reproductive function.
Microbiota modulation by a human Paneth cell α-defensin fragment protects against DSS-induced colitis.
iScience
Erica Bonazzi, Fuhua Hao, Andrew D Patterson +3 more
The gastrointestinal tract hosts a diverse microbial community, named the intestinal microbiota, which plays a vital role in gut health. Host defense peptides (HDPs), such as defensins, help regulate interactions between the host and its microbiota. Dysfunction in HDPs expression has been associated with a greater risk of inflammatory bowel diseases (IBDs), while some HDPs may positively shape the gut environment. Human alpha defensin 5 (HD5) can be cleaved by intestinal enzymes into bioactive fragments such as HD51-9. In this study, we screened various HDPs (LL-37, hBD2, HD5, and HD51-9) for their modulatory effects on healthy human microbiotas in vitro and found distinct, donor-specific effects, with HD51-9 showing the strongest functional impact. Testing HD51-9 in a mouse colitis model revealed potent and microbiota-dependent protection against DSS-induced inflammation, partly through the beneficial of mucus-microbiota interactions. These findings highlight the potential of HDPs, especially HD51-9, in modulating gut microbiota and treating intestinal inflammation.
Bio-Adrenomedullin Predicts Death and Major Adverse Cardiovascular Events in Cardiac Amyloidosis: A Cross-Continental Multicenter Study.
J Am Heart Assoc
Maximilian L Müller, Fabian Knebel, Katrin Hahn +10 more
Bio-ADM (bioactive adrenomedullin) is a vasoactive peptide hormone that predicts clinical outcomes in heart failure-the main driver of adverse outcomes in cardiac amyloidosis (CA). This prospective observational study sought to assess the prognostic role of bio-ADM in CA.
Growth hormone-releasing peptide 6 (GHRP-6) hydrogel for acute kidney injury therapy via metabolic regulation.
J Nanobiotechnology
Xiaotong Zhao, Kai Pan, Rui Li +8 more
Renal tubular epithelial cells (TECs), which are highly susceptible to injury during acute kidney injury (AKI), have notable regenerative effects on renal recovery after AKI. AKI-driven metabolic reprogramming of TECs plays a critical role in determining whether kidneys recover functionally or develop fibrosis. Targeting the metabolism of TECs offers valuable insights into AKI treatment. Growth hormone-releasing hormone (GHRH) and its analog GHRH peptide (GHRP) play beneficial roles in the field of regenerative medicine. Here, we designed a self-assembling GHRP-6 peptide hydrogel, and we hypothesized that this hydrogel could reprogram the metabolism of TECs, further enhancing recovery from AKI. Metabolomic sequencing analysis revealed that spermidine, L-glutamine, and acetyl-CoA, which are involved in amino acid and fatty acid metabolism, were highly enriched in a mouse model of AKI treated with the GHRP-6 hydrogel. Further study revealed that GHRP-6 hydrogel treatment enhanced the survival of TECs in the ischemic microenvironment by activating the mTOR-P70 pathway. In conclusion, GHRP-6 hydrogel treatment has beneficial therapeutic effects on AKI through the targeting of metabolic reprogramming, which offers a novel therapeutic strategy to protect TECs in AKI treatment.
Telmisartan reduces systemic inflammation and alters the renin-angiotensin system in mild COVID-19.
Sci Rep
Angela Lu, Melissa Agsalda-Garcia, Weiyuan Hu +14 more
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a respiratory viral infection that disrupts renin angiotensin system (RAS) peptide metabolism by downregulating angiotensin converting enzyme-II (ACE2), leading to accumulation of pro-inflammatory angiotensin II (AngII). We posit that angiotensin receptor blockers (ARBs) like telmisartan (TEM) can activate the pro-resolving arm of RAS (MasR/ACE2/Ang1-7), reducing lung inflammation in COVID-19 patients. In this randomized, double-blinded, placebo-controlled pilot clinical trial, outpatient SARS-CoV-2-infected study participants received either 40 mg TEM or placebo once daily. Plasma inflammatory biomarker levels revealed a reduction in global systemic inflammation with TEM treatment, corresponding with an increase in MasR. We corroborated these clinical findings with in vitro analysis. A549-ACE2 lung epithelial cells treated with TEM showed increased ACE2 and MasR, as well as decreased angiotensin II receptor type I (AT1R) and angiotensin II receptor type II (AT2R) expression levels. Additionally, AngII peptide levels decreased, while Ang(1-9) and Ang(1-7) increased. TEM treatment at physiologically achievable concentration reduced SARS-CoV-2 viral load. Taken collectively, these results show TEM mediated activation of the Ang(1-7)/MasR/ACE2 pro-resolving arm of RAS, which activates anti-inflammatory events that reduce global inflammation. These findings support the use of ARBs like TEM in mitigating COVID-19 driven alterations in RAS.
A narrative review on tirzepatide's therapeutic potential in glycemic control and cardioprotection.
Ann Med Surg (Lond)
Mrudula Thiriveedi, Francis Sto Domingo, Hannah Yates +4 more
Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, represents a new class of incretin-based therapy for type 2 diabetes mellitus (T2DM), obesity, and related comorbidities. This narrative review synthesizes evidence from the SURPASS, SURMOUNT, and SUMMIT clinical trial programs. Across studies, tirzepatide reduced glycated hemoglobin (HbA1c) by up to 2.5% and body weight by more than 20%. It also improved cardiovascular risk factors (blood pressure, lipids, inflammation) and has demonstrated benefits in patients with heart failure with preserved ejection fraction (HFpEF) and obstructive sleep apnea (OSA), with reductions in the apnea-hypopnea index (AHI) and heart failure hospitalizations. Its safety profile is consistent with that of GLP-1 receptor agonists (GLP-1 RAs), although gastrointestinal side effects, gallbladder events, and thyroid cancer signals warrant monitoring. Ethical concerns related to off-label use, weight regain after discontinuation, and barriers to real-world access remain active issues. Ongoing outcome trials and real-world data will clarify its long-term role and potential integration into future clinical guidelines.
Genetic inactivation of the CRF1 receptor eliminates age-linked elevation of hippocampal 11β-hydroxysteroid dehydrogenase type 1 activity in female mice.
J Neuroendocrinol
Julie Brossaud, Alessandro Piccin, Angelo Contarino +1 more
Glucocorticoids are produced through activation of the hypothalamic-pituitary-adrenal (HPA) axis, initiated by the release of corticotropin-releasing factor (CRF) from the hypothalamus. CRF acts through two receptor subtypes, CRF1 and CRF2. However, the specific contributions of CRF1 and CRF2 receptors to age-related changes in brain glucocorticoid activity remain largely unexplored. In certain tissues, including the hippocampus, glucocorticoid signaling is further amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates inactive glucocorticoid metabolites into their active form. Notably, prior research investigating the role of hippocampal 11β-HSD1 in aging has focused exclusively on male subjects. In this study, we used genetic mouse models lacking functional CRF1 or CRF2 receptors to investigate their respective roles in regulating hippocampal 11β-HSD1 activity and glucocorticoid levels across age and sex. Mice of both sexes at 6 and 18 months of age were analyzed. Hippocampal 11β-HSD1 activity was assessed by measuring the ratio of corticosterone to dehydrocorticosterone using mass spectrometry in tissue extracts from CRF1 and CRF2 wild-type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β-HSD1 activity increases with age in female CRF1 WT and HET mice but not in CRF1 KO females. In contrast, aged males exhibit elevated 11β-HSD1 activity regardless of CRF1 genotype. In CRF1 males, the age-related increase in hippocampal 11β-HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF1 females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF1 deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF1 deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF2 mice show an age-dependent increase in hippocampal 11β-HSD1 activity, which is not altered by CRF2 deficiency. Moreover, CRF2 deficiency results in increased plasma corticosterone in female, but not in male, mice. Overall, our findings reveal that hippocampal 11β-HSD1 activity increases with age in both sexes. In females, this increase is dependent on the presence of functional CRF1 receptors. In contrast, males exhibit age-related increases in 11β-HSD1 activity independent of CRF1 function. These findings underscore the importance of considering sex as a biological variable when developing therapeutic strategies targeting 11β-HSD1 to mitigate age-related memory decline.
BMP9-mediated regulation of endothelin-1 requires integrated SMAD1/5 and SMAD2/3 signaling.
bioRxiv
Jana Bagarova, Shreya Sangam, Luca Troncone +8 more
BMP9 is a pleiotropic growth factor cytokine with diverse roles in vascular development, homeostasis and disease. BMP9 regulates a broad array of vasoactive molecules that mediate endothelial and mural cell function, including ET-1, a potent vasoconstrictor, regulator of cell growth and fibrosis, and therapeutic target for pulmonary arterial hypertension (PAH). Consistent with its pleiotropic activities, BMP9 is unique in being able to recruit both BMP-responsive SMAD1/5/9 and TGFβ-responsive SMAD2/3 signaling effectors in endothelial cells, however, the physiologic significance of activating both pathways remains incompletely defined. We investigated the role of SMAD1/5/9 vs. SMAD2/3 signaling in BMP9-mediated regulation of ET-1, using primary and immortalized human and murine microvascular endothelial cells, with conditional knockout, small molecule inhibitor and siRNA strategies. BMP9-mediated expression of ET-1 requires coordinated activation of SMAD1/5/9 and SMAD2/3 effector pathways, both downstream of BMPR2, ALK1, and ENG. Analysis of the ET-1 promoter revealed that BMP9 requires, in addition to a SMAD3/4 binding site sufficient for TGFβ1-mediated transcription, a novel putative SMAD1/5 binding motif. BMP9-mediated regulation of endothelial ET-1 requires coordinated activation of both SMAD1/5 and SMAD2/3 downstream of ALK1, integrated at the promoter level, representing a non-canonical signaling motif linking BMP9 to a critical effector of vascular tone and remodeling in PAH and related vascular syndromes.
Thymosin β4-derived peptides alleviate neuroinflammation and neurite atrophy in both in vitro models and in vivo 5 × FAD mice: A potential therapy for memory improvement in Alzheimer's disease.
Int Immunopharmacol
Haiyan Ou, Ruiye Chen, Longjian Zhou +3 more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder defined by neuroinflammation, neurite atrophy, and cognitive decline. This study explored the therapeutic potential of Thymosin β4 (Tβ4)-derived peptides (TB500 and Ac-SDKP) in mitigating AD-related neuropathology. Using the 5 × FAD mouse model and established in vitro AD cell systems, we evaluated the neuroprotective and anti-inflammatory effects of these peptides. In Aβ25-35-treated HT22 cells and primary cortical neurons, TB500 and Ac-SDKP significantly attenuated neurite atrophy, restored cell viability, and modulated the expression of apoptosis-related genes. In BV2 microglia assays, the peptides exhibited robust anti-inflammatory effects, as shown by suppressing lipopolysaccharide (LPS)-induced nitric oxide (NO) production, reducing expression of pro-inflammatory cytokines, and inhibiting M1 microglial polarization. In 5 × FAD mice, TB500 and Ac-SDKP ameliorated cognitive impairments, as evidenced by improved performance in the Morris water maze and novel object recognition tests. Immunohistochemical analyses revealed markedly reduced glial activation and neuronal apoptosis in treated mice. Notably, the peptides restored axonal density in the perirhinal cortex and attenuated β-amyloid (Aβ) plaque-associated dystrophic neurites, though hippocampal Aβ burden remained unchanged. Transcriptomic profiling identified critical regulatory genes, including forkhead box B2 (Foxb2) and olfactory receptor, family 2, subfamily K, member 2 (Or2k2), and linked their neuroprotective effects to the modulation of apoptosis and synaptic plasticity. Collectively, TB500 and Ac-SDKP exert multi-targeted efficacy against AD pathology by enhancing neuronal survival, suppressing neuroinflammation, and promoting axonal regeneration, thereby emerging as promising candidates for AD intervention.
Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions.
J Am Acad Orthop Surg Glob Res Rev
Omar F Rahman, Steven J Lee, William A Seeds
Therapeutic peptides are emerging as promising adjuncts in the management of orthopaedic injuries, grounded in their ability to modulate molecular signaling networks central to cellular medicine. By acting on key pathways such as PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK, peptides exert influence over tissue regeneration, inflammation resolution, and neuromuscular recovery. Wound-healing peptides such as BPC-157, TB-500, and GHK-Cu promote angiogenesis, integrin-mediated extracellular matrix remodeling, and fibroblast activation, whereas growth hormone secretagogues like ipamorelin, CJC-1295, tesamorelin, sermorelin, and AOD-9604 activate IGF-1 signaling and satellite cell repair. Recovery-enhancing agents such as epithalon, delta sleep-inducing peptide, and pinealon target circadian and mitochondrial regulators, and neuroactive peptides like selank, semax, and dihexa enhance brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity. Although preclinical studies are promising, there is a current lack of clinical trials. This review integrates current mechanistic insights with orthopaedic relevance, emphasizing safety, efficacy, and future directions for responsible integration into musculoskeletal care.
Psilocybin induces sex- and context-specific recruitment of the stress axis.
Curr Biol
Sarah Gibson Cook, Stephanie Lee, Emma Ference +7 more
Following decades of prohibition, psychedelic drugs have reemerged as promising therapeutics for stress-related conditions, including depression and post-traumatic stress disorder. Still, their impact on stress-related brain regions and the hypothalamic-pituitary-adrenal (HPA) axis remains unclear. This work explores the acute effects of psilocybin on the primary regulators of the HPA axis: corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). Here, using blood plasma measurements and in vivo single-fiber photometry, we demonstrate that psilocybin induces robust activation of the HPA axis via CRHPVN neurons, with more pronounced responses observed in female mice and a reliance on serotonergic 5-HT2A and 5-HT2C receptors. Ex vivo electrophysiology indicates that the 5-HT2A-receptor-mediated effects involve dual mechanisms: direct post-synaptic depolarization of CRHPVN neurons and increased presynaptic glutamate release. Our findings also reveal that psilocybin alters how CRHPVN neurons react to environmental changes, resulting in a surprising decrease in activity that contrasts with typical elevated stress responses. This context-specific modulation may be a key mechanism underlying the therapeutic potential of psychedelics to recalibrate maladaptive stress reactivity. Our findings emphasize the interplay between the serotonergic and stress systems and support the considerable influence of contextual factors, i.e., "setting," on the psychedelic experience. This study provides the first real-time in vivo evidence of neuronal activation of the stress system following psilocybin administration and has significant implications for optimizing the therapeutic efficacy of psychedelic-assisted therapy.