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Research advances in the diagnosis and treatment of MASLD/MASH.
Ann Med
Dekai Wang, Jinxian Miao, Lihua Zhang +1 more
Background: The global increase in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) and its progression to Metabolic Dysfunction-Associated Steatohepatitis (MASH) pose significant public health challenges. Objective: To review key research advancements in the diagnosis and treatment of MASLD/MASH over the past two decades. Methods: This article synthesizes recent findings on diagnostic and therapeutic strategies for MASLD/MASH, focusing on non-invasive diagnostic tools and emerging pharmacological treatments. Results: Non-invasive diagnostic techniques, including high-resolution CT, MRI, FIB-4 index, and FAST score, have enhanced early detection and diagnostic accuracy. Treatment strategies encompass pharmaceuticals such as THR-β agonists, FXR agonists, PPAR agonists, GLP-1 receptor agonists, and SGLT2 inhibitors, alongside lifestyle interventions like dietary changes, weight management, and exercise. Surgical options, including gastric bypass and liver transplantation, are effective, particularly for obese and advanced MASH patients. However, challenges remain in standardizing treatment protocols, validating long-term efficacy, and addressing patient-specific factors. Conclusion: MASLD/MASH treatment has advanced significantly with new diagnostic tools and therapies. Future research should focus on personalized approaches, long-term treatment outcomes, and multidisciplinary collaboration to improve patient care and treatment efficacy.
Narcolepsy type 1 following immune checkpoint inhibitor therapy for metastatic melanoma.
BMJ Case Rep
Aiden Cushnahan, Su Hii, Kirk Kee +2 more
Narcolepsy is a rare disorder of central hypersomnolence which is often under-recognised owing to a variable clinical phenotype. Narcolepsy type 1 (NT1) is caused by loss of hypothalamic hypocretin (orexin) secreting neurons, which function to maintain wakefulness. There is strong evidence that NT1 is an immune-mediated disorder associated with the class II human leucocyte antigen DQB1*06:02 allele. Immune checkpoint inhibitors have revolutionised the treatment of many cancers; however, through their mechanism of action, they are associated with immune-related adverse effects. We describe a complex case of NT1 following ipilimumab and nivolumab exposure for management of metastatic melanoma.
Revitalizing mitochondrial quality control: targeting mitochondria-derived vesicles in Parkinson's disease.
Biochem Pharmacol
Jimna Mohamed Ameer, Sneha Mary Alexander, K Navya +2 more
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the midbrain substantia nigra, resulting in debilitating motor and non-motor symptoms. No disease modifying therapy is currently available for PD patients. Mounting evidence implicates impaired mitochondrial quality control (MQC) as a central driver of PD pathogenesis. MQC maintains mitochondrial integrity and function through coordinated mechanisms such as mitochondrial biogenesis, dynamics, mitophagy, the ubiquitin-proteasome system, and the formation of mitochondria-derived vesicles (MDVs). MDVs are small vesicular structures that selectively sequester and transport damaged mitochondrial components to lysosomes for degradation, representing a rapid and localized quality control pathway distinct from mitophagy. Beyond their degradative role, MDVs also participate in inter-organelle signalling and intercellular communication, suggesting a broader influence on neuronal homeostasis. Disruption of MDV biogenesis, trafficking, or clearance has been emerging as a key contributor of mitochondrial dysfunction and neurodegeneration in PD. This review synthesizes current understanding of MDV biology, its integration within the MQC network, role in PD pathogenesis and explores how targeting MDV pathways may offer novel diagnostic and therapeutic strategies to modify disease progression in PD.
Weight Loss With GLP-1 Agonists in Nondiabetic Adults: Systematic Review and Network Meta-Analysis.
Obesity (Silver Spring)
Michael Lim, Pooja Gokhale, Akwasi Akosah +1 more
Two glucagon-like peptide-1 receptor agonists (GLP-1 RAs) (semaglutide and liraglutide) and one dual agonist (tirzepatide) are FDA-approved for weight loss in adults with obesity without type 2 diabetes mellitus. This systematic review and network meta-analysis aims to compare the efficacy of these agents against each other.
Primary cilia regulate GLP-1 signaling in pancreatic β cells.
Mol Metab
Isabella Melena, Jeong Hun Jo, Shannon E Townsend +5 more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are mainstay therapies for diabetes and obesity, acting in part by enhancing glucose-dependent insulin secretion. While the primary cilium is a known signaling compartment for certain G-protein coupled receptors (GPCRs), its role in the β-cell response to incretins remains undefined. Here, we show that primary cilia are essential for full GLP-1R signaling. Loss of β-cell cilia in mouse and human islets severely impaired GLP-1-potentiated insulin secretion, an effect preceded by blunted whole-cell cAMP and Ca2+ responses. Immunofluorescence and immunogold scanning electron microscopy revealed endogenous GLP-1R localized to the primary cilium. Adenylyl cyclase immunostaining was also enriched within cilia, and targeted inhibition of ciliary PKA reduced insulin secretion. Critically, disrupting ciliary GPCR trafficking via Tulp3 knockdown - while preserving cilia structure - recapitulated the signaling and secretory deficits, demonstrating a specific requirement for the ciliary receptor pool. These findings establish the primary cilium as a non-redundant signaling compartment for GLP-1R and uncover a new layer of subcellular organization in incretin action in β cells.
Neuropeptide Y Receptor Modulators in Gut Physiology and Therapy.
Curr Protein Pept Sci
Kalyani R Thombre, Nikita D Rahangdale, Krishna Radheshyam Gupta +1 more
Gut-brain communication depends on neuropeptides and hormones, and the Neuropeptide Y (NPY) family, which includes NPY, Peptide YY (PYY), and Pancreatic Polypeptide (PP), plays an important role. These peptides also affect gastrointestinal (GI) motility, secretion, nutrient uptake, and intestinal development. Diseases, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastroparesis, and obesity, are attributed to disruptions in this signaling axis. In this review, the physiological and pathological functions of NPY and its receptor subtypes (Y1, Y2, Y4, Y5) in the GI tract, the therapeutic potential of Pharmacological and natural modulators of this pathway are evaluated.
Chicoric acid enhanced brain cholesterol efflux and reduced Aβ pathology via LXR-ABCA1 signaling in Alzheimer's models.
Neurotherapeutics
Daiyue Li, Yu Zhang, Ruonan Wang +6 more
Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways.
MOTS-c primes adrenal cortex metabolism without directly driving steroidogenesis.
Folia Histochem Cytobiol
Malgorzata Blatkiewicz, Kacper Kaminski, Marta Sobalska-Kwapis +4 more
Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c), a 16-amino acid mitochondrial-derived peptide, regulates cellular metabolism through AMPK and mTOR signaling and exerts protective effects across multiple endocrine tissues. However, its role in adrenal physiology remains unexplored. We hypothesized that MOTS-c establishes "steroidogenic readiness" by priming metabolic pathways rather than directly activating hormone synthesis.
Synergistic effects through targeting the PI3K and IGFR pathways in treating lung cancer carrying activation alterations along the PI3K pathway.
Transl Oncol
Mohamed Abd El-Salam, Wu Chen, Yan Tang +9 more
Alterations in the PI3K/AKT pathway occur in over 60 % of lung squamous cell carcinoma and approximately 20 % of lung adenocarcinoma, driving tumor progression and therapeutic resistance. While PI3K-targeted therapies suppress proliferation in PIK3CA-mutant non-small cell lung cancer (NSCLC), their clinical impact is limited due to compensatory activation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling. This study aimed to determine whether dual blockade of PI3K and IR/IGF-1R signaling could overcome this adaptive resistance.
Mitochondrial transfer as a therapeutic target for peripheral neuropathy.
Trends Mol Med
Junlin Wei, Fang Wang
Satellite glial cells transfer mitochondria to sensory neurons via myosin 10-dependent tunneling nanotubes. Ji et al. show that this transfer is impaired in diabetic neuropathy, causing energy failure. Restoring it via cell or mitochondrial transplantation alleviates pain and promotes nerve regeneration, revealing a new therapeutic strategy for peripheral neuropathy.
Childhood Obesity and Cardiac Risk in Youth: Emerging Challenges Toward 2050.
Clin Nutr ESPEN
Nikunja Kishor Mishra
Pediatric obesity is increasing at an alarming rate, affecting over 381 million children worldwide and emerging as a critical public health issue. According to World Health Organization (WHO) 2016, 40% of adults are overweight and 13% are obese, highlighting obesity's persistence throughout life. Childhood obesity significantly heightens the risk of adult obesity and cardiovascular diseases (CVD) such as atherosclerosis and coronary artery disease, potentially leading to a global health crisis by 2050. Genetic predispositions identified through genome-wide association studies (GWAS) contribute to elevated body mass index (BMI), yet lifestyle factors reduced physical activity, prolonged screen time, and consumption of high-calorie, low-nutrient foods remain key drivers. This study aim is to explore the Real-world data (RWD) on childhood obesity from major countries, prevalence, risk factors, and cardiovascular consequences of pediatric obesity, evaluating public health initiatives, lifestyle interventions, and therapeutic strategies to address this growing concern. Data collected from PubMed, Scopus, and Springer databases reveal that childhood obesity is closely linked to hypertension, dysglycemia, dyslipidemia, and other cardiovascular disorders (heart attack, arrhythmias and stroke). The WHO Global Action Plan on Physical Activity 2018-2030 (GAPPA) emphasizes urgent preventive measures. Current management strategies include lifestyle modification, pharmacotherapy, and bariatric surgery. Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide and liraglutide are effective for weight management but commonly cause gastrointestinal adverse effects. The SURMOUNT-5 trial demonstrated superior weight-loss outcomes with tirzepatide, with a similar gastrointestinal safety profile. Emerging therapies including cagrilintide plus semaglutide, oral agents such as orforglipron and danuglipron, and the triagonist retatrutide may improve adherence and accessibility; however, these agents remain investigational and are currently under clinical evaluation. Despite promising advancements, gene therapy for pediatric obesity remains in the experimental phase. Overall, addressing childhood obesity requires multifaceted interventions combining public health initiatives, behavioral changes, and novel therapeutic strategies to mitigate cardiovascular risks and promote sustainable health outcomes.
Disparities in GLP-1 and GIP responses to small intestinal glucose infusion in individuals with well- and poorly-controlled type 2 diabetes.
Diabetes Res Clin Pract
Yixuan Sun, Cong Xie, Michelle Bound +6 more
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are key regulators of glucose homeostasis in health and type 2 diabetes (T2D). Whether their secretion is influenced by antecedent glycaemic control in T2D remains unclear. This study compared GLP-1 and GIP responses to intraduodenal glucose infusion between individuals with well- and poorly-controlled T2D.
Maternal Nutrition and Hypothalamic Programming of Offspring Metabolic Health.
J Nutr
Smita Mall, Busayo Oladun, Min-Hyun Kim
The hypothalamus plays a central role in regulating metabolism by integrating hormonal and nutrient-derived signals to maintain energy homeostasis across the life span. Maternal nutritional status during critical windows of development is a major environmental factor that can permanently alter this regulation. Both maternal overnutrition and undernutrition have been shown to disturb circulating leptin, insulin, and glucagon-like peptide-1 (GLP-1), and to disrupt the normal development of hypothalamic nuclei implicated in energy balance. Experimental and clinical studies indicate that these insults miswire proopiomelanocortin (POMC) and neuropeptide Y/ agouti-related peptide (NPY/AgRP) pathways, alter leptin and insulin receptor signaling, trigger neuroinflammation, glial and vascular changes, and are accompanied by enduring epigenetic alterations, including DNA methylation and chromatin remodelling at genes such as Pomc, Npy, Mc4r, Lepr and Insr. Together, these adaptations establish new set points for appetite, energy expenditure, and glucose regulation, thereby increasing the lifelong risk of obesity and type 2 diabetes in the offspring. In this narrative review, we synthesize evidence from animal models and human studies linking maternal nutrition to hypothalamic programming via leptin, insulin, and GLP-1. We also highlight major gaps, including limited data on GLP-1 in maternal undernutrition, the specific role of individual micronutrients, and the timing and reversibility of hypothalamic programming, to inform future mechanistic, translational, and preventive research.
The Glymphatic System and Meningeal Lymphatics: Current Understandings and Future Perspectives.
MedComm (2020)
Hangzhe Sun, Haonan Fan, Yuhang Zhou +6 more
The central nervous system (CNS) maintains homeostasis and immune surveillance through a recently defined brain-wide clearance network: the glymphatic-lymphatic axis. This system couples the intramural glymphatic pathway, responsible for convective fluid transport and parenchymal waste removal, with the meningeal lymphatic vessels (MLVs), which serve as the critical efferent route to the peripheral immune system. This review delineates the structural and functional foundations of each component, their regulatory dynamics, including the roles of sleep and aging, and their synergistic interplay in maintaining fluid balance, clearing metabolic waste, and facilitating neuroimmune communication. Mounting evidence identifies the dysfunction of this integrated axis as a common pathological mechanism across a spectrum of neurological disorders. We highlight its pivotal role in three key paradigms: acute injury (stroke), chronic proteinopathy (Alzheimer's disease, AD), and autoimmune dysregulation (multiple sclerosis, MS), where impaired clearance and maladaptive immune responses are central, recurring themes. The review critically evaluates emerging translational strategies aimed at therapeutically modulating this axis, including pharmacological targets (VEGF-C, Piezo1 agonists), noninvasive neuromodulation (photo-biomodulation, PBM), and surgical interventions (lymphaticovenous anastomosis, LVA). This synthesis positions the glymphatic-lymphatic axis as a fundamental physiological network and a pivotal target for novel interventions, outlining key future research directions in neurology.
Cellular senescence: Between protection and pathologies.
J Physiol Pharmacol
I Klak, A Ptak-Belowska, G Krzysiek-Maczka
Cellular senescence is a stable and irreversible state of proliferative arrest triggered by diverse stressors, inclh3uding DNA damage, oncogenic signaling, oxidative stress, and metabolic imbalance. Once regarded as a culture artifact, senescence is now recognized as a fundamental biological program that governs tissue homeostasis, development, aging, and disease. Based on its origin, senescence can be divided into two principal categories: damage-induced, encompassing replicative, oncogene-induced, and therapy-induced forms, and developmentally programmed, which orchestrates tissue patterning and remodeling during embryogenesis. These processes converge on the activation of p53/p21 and p16/RB tumor suppressor axes, sustained DNA damage response (DDR), and the establishment of the senescence-associated secretory phenotype (SASP). Acute senescence serves beneficial roles in tumor suppression, wound healing, and embryonic morphogenesis by transiently activating SASP-mediated immune clearance. However, persistent senescence becomes detrimental, promoting chronic inflammation, tissue dysfunction, and cancer progression. Within the tumor microenvironment, chronic SASP signaling driven by nuclear factor kB (NF-κB), CCAAT/enhancer-binding protein beta (C/EBPβ), and Signal Transducer and Activator of Transcription 3 (STAT3) fosters epithelial-to-mesenchymal transition (EMT), invasion, and therapy resistance. Therapy-induced senescence (TIS) often leads to polyploidization and the emergence of polyploid giant cancer cells (PGCCs) that can escape arrest, regenerate proliferative progeny, and drive tumor relapses. Thus, senescence represents a biological paradox: a protective, transient process that maintains tissue integrity but, when unresolved, transforms into a driver of aging and malignancy. Understanding the molecular determinants, distinguishing beneficial from pathological senescence is crucial for developing targeted senotherapies.
Neuroinflammation in stroke-A review of implications for precision immunomodulation.
Neuroscience
Tatyana Zharikova, Elizaveta Petrova, Igor Makarov +3 more
Stroke remains a leading cause of mortality and long-term disability worldwide, and secondary injury mechanisms-particularly neuroinflammation-continue to limit functional recovery despite advances in reperfusion therapies. Post-stroke neuroinflammation is not a static or uniformly deleterious process but a temporally evolving and spatially heterogeneous continuum shaped by cellular transcriptional plasticity, metabolic reprogramming, and systemic modifiers such as aging and comorbidities. Across hyperacute, acute, subacute, and chronic phases, microglia, astrocytes, and neurovascular unit components undergo dynamic state transitions that may either exacerbate neuronal injury or promote debris clearance, angiogenesis, synaptic remodeling, and circuit reorganization. Emerging transcriptomic and spatial profiling studies challenge simplified polarization frameworks and highlight the need for multidimensional models of immune activation. We propose a precision-based framework in which neuroinflammation is interpreted through the integration of temporal dynamics, cellular heterogeneity, and responsiveness to rehabilitation. Within this context, the concept of an "immune window" underscores the importance of aligning immunomodulatory interventions with phase-specific inflammatory states to enhance neuroplasticity without suppressing reparative signaling. Although targeted strategies-including cytokine inhibition, metabolic reprogramming, gene-editing approaches, and biomarker-guided stratification-show mechanistic promise, translational progress has been limited by model heterogeneity, blood-brain barrier constraints, safety concerns, and insufficient validation in aged and comorbid populations. Future advances will depend on biomarker-driven patient stratification, phase-informed trial design, and integration of immunomodulation with reperfusion and rehabilitation. Rather than indiscriminate suppression, calibrated and context-aware immunoregulation may represent the most rational path forward in optimizing stroke recovery.
Comparative Proteomic Analysis of the Secretome of Control and BRAF/MEK Inhibitor-Resistant Melanoma Cells.
J Proteome Res
Aleksandra Simiczyjew, Magdalena Surman, Magdalena Kot +2 more
Treatment based on BRAF/MEK kinase inhibitors is one of the most commonly used methods in advanced melanoma therapy, but patients often develop resistance to treatment. Treatment-resistant cells can affect other cancer cells and the tumor microenvironment through the factors that they secrete. Therefore, this study aimed to examine the protein composition of the secretome of cells resistant to vemurafenib (a BRAF inhibitor) and cobimetinib (a MEK inhibitor) and to compare it with that of nonresistant cells. Proteomic analysis, followed by gene ontology (GO) analysis, identified many differences in resistant melanoma cells' secretomes compared to controls (nonresistant). Many proteins upregulated in resistant melanoma cells compared to their nonresistant variants were directly related to cancer progression and associated with cell adhesion, actin cytoskeleton, matrix organization, proteolysis, and drug resistance. Proteins secreted by resistant melanoma cells can undoubtedly influence the surrounding microenvironment in a way that promotes the formation of a pro-tumor niche. Among the proteins secreted in significantly higher amounts by resistant cells (compared to the control group), which may be potential biomarkers or therapeutic targets in melanoma, plasminogen activator inhibitor 1, thymosin beta-4, clusterin, interleukin-6, superoxide dismutase, and selected matrix metalloproteinases can be distinguished.
Centriolar satellites regulate CEP350 mRNA localization and centrosome amplification.
bioRxiv
Abraham Martinez, Chad G Pearson
Messenger RNAs (mRNAs) accumulate at centrosomes in mitosis and interphase, yet the mechanisms governing their localization and the functional significance of centrosomal localization remain poorly understood. Here, we investigate the regulation and function of the centrosome-localized mRNA, CEP350 . We find that CEP350 mRNA localizes to centrosomes during S phase via the centriolar satellite protein CEP131 and the RNA binding protein (RBP) Unkempt (UNK), in a microtubule (MT)-dependent manner. CEP131 and UNK stabilize CEP350 mRNA to maintain CEP350 mRNA steady-state levels. Furthermore, CEP131 and UNK promote normal CEP350 protein levels at centrosomes. CEP350 is required for PLK4-induced centriole overduplication but is less important for canonical centriole duplication. Moreover, CEP131, UNK, and CEP350 are important for centrosome amplification in triple-negative breast cancer cells. Together, these findings reveal a centriolar satellite-RBP pathway regulating CEP350 mRNA localization to centrosomes.
Plant-derived exosome-like vesicles enhance exercise-induced muscle recovery and sleep quality.
Nutr Res
Emrah Aykora, Damla Aykora
Exercise-induced muscular stress triggers a complex cascade of adaptive responses, including micro-injury, inflammation, activation of satellite cells, mitochondrial remodeling, and myofibrillar repair. The efficiency of recovery processes is crucial for athletic performance, especially among elite athletes, where rapid restoration of muscle function, reduction of inflammation, and improved sleep quality influence training results. Beyond traditional recovery methods, EVs and, more recently, plant-derived exosome-like nanovesicles (PELNs) have emerged as promising bioactive mediators of intercellular communication and tissue regeneration. PELNs contain various biomolecules such as lipids, proteins, small RNAs, and plant-specific metabolites that may affect oxidative stress, inflammatory signaling, and cellular repair pathways. While most research has focused on mammalian or cell-line sources, growing evidence indicates that PELNs may improve muscle regeneration and recovery through cellular modulation and enhanced sleep-related recovery. Notably, PELNs represent a multi-target strategy that may simultaneously modulate neuroendocrine pathways involved in sleep regulation and metabolic-inflammatory mechanisms governing skeletal muscle repair. By influencing circadian rhythm signaling, mitochondrial dynamics, and redox homeostasis, PELNs may bridge the sleep-muscle recovery axis, an emerging concept in exercise physiology. This dual regulatory capacity distinguishes PELNs from conventional recovery interventions and highlights their innovative and translational potential in sports science. This review aims to compile current evidence linking PELNs to exercise-induced muscle recovery, highlighting potential mechanisms, including the regulation of inflammatory and redox balance, microRNA-driven signaling, and neurometabolic adaptation. By combining insights from exercise physiology and molecular regenerative biology, we propose that PELNs offer a natural approach to enhancing recovery and performance in athletes.
Semaglutide as a potential tool in pre-lung transplant weight loss optimization.
JCEM Case Rep
Roshaneh Ali, Holly Keyt, Carolina Solis-Herrera +1 more
Patients with end-stage lung disease go through an extensive screening process prior to transplant. Obesity and uncontrolled type 2 diabetes mellitus (T2DM) are unfavorable risk factors that lead to poor outcomes. We present the case of a 69-year-old man with stage IV chronic obstructive pulmonary disease (COPD) on chronic oxygen, T2DM on insulin, and class II obesity (reference range, body mass index [BMI], 35.0-39.9) who underwent pre-lung transplant evaluation. He had a BMI of 38.05, surpassing the institutional transplant eligibility criteria of BMI <32. The patient was initiated on semaglutide for weight loss. After 6 months, the patient's BMI decreased to 30.5, losing 25 kg and qualifying him for transplant. However, given substantial improvements in respiratory status, the pre-lung transplant committee deferred waitlisting. After 16 months of treatment, the patient lost a total of 35.17 kg, his forced vital capacity improved from 44% to 82%, and he was weaned off oxygen. Chronic hypoxia and corticosteroids make weight management challenging for COPD patients. This case demonstrates the use of semaglutide for rapid weight loss and improved respiratory function in patients with end-stage lung disease, emphasizing its emerging potential in pre-lung transplant optimization.