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Acromegaly and histopathology.

Vitam Horm

Gabriela A Caballero, Teresa Ribalta, Iban Aldecoa

Acromegaly is a chronic disorder caused by sustained excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), most commonly due to GH-secreting pituitary neuroendocrine tumors (PitNETs), mainly limited to Pit-1 expressing lineages. Histopathology remains central to diagnosis, prognosis, and treatment planning. Among GH-secreting or somatotroph neoplasms, densely and sparsely granulated are the most relevant clinicopathological subgroups, as they show distinct morphological, radiological, and clinical profiles. Risk assessment is refined by combining routine histology with immunohistochemistry (IHC), including lineage factors, proliferative markers, and somatostatin receptor (SSTR) subtypes, as well as selected molecular tests. Some assays, such as standardized evaluation of SSTR expression, still require further validation. Radiological signs of invasion complement tissue findings and contribute to practical grading systems. Optimal care requires a multidisciplinary approach that integrates endocrine evaluation, high-quality MRI, and expert neuropathology, essential not only for routine care but also for recognizing atypical presentations of acromegaly, such as pituitary hyperplasia, or ectopic growth hormone-releasing hormone (GHRH) or GH secretion. The integration of clinical, pathological, and molecular information provides the foundation for accurate diagnosis and personalized therapy in acromegaly.

Lycium barbarum polysaccharides as prebiotics prevent colorectal cancer liver metastasis in non-alcoholic fatty liver disease by modulating gut microbiota-FGF21-PI3K-AKT axis.

Front Pharmacol

Shuai Zhao, Zhenyao Tan, Jiaxin Suo +1 more

Colorectal cancer liver metastasis (CRLM) is the leading cause of death in colorectal cancer, and nonalcoholic fatty liver disease (NAFLD) promotes CRLM. Lycium barbarum polysaccharides (LBPs), bioactive metabolites of the traditional medicinal plant Lycium barbarum L, inhibit the progression of colorectal cancer and NAFLD by regulating gut microbiota composition. However, their roles in preventing CRLM under NAFLD conditions remain unclear. This study aimed to investigate the preventive effect of LBPs on liver metastasis of colorectal cancer in the context of NAFLD and explore its potential mechanisms.

CIMT combined with BoNT-A regenerates skeletal muscle and improves upper limb function through activating IGF-1/FGFR2 axis in hemiplegic cerebral palsy.

Exp Neurol

You Wang, Qihong Wu, Xiuying Zhao +16 more

Hemiplegic cerebral palsy (HCP) is a prevalent cause of pediatric motor disability. Constraint-induced movement therapy (CIMT), when combined with botulinum neurotoxin type A (BoNT-A), improves upper limb function and social participation in individuals with HCP. However, the mechanisms underlying the combined interventions remain unclear.

Cathelicidin Links Visceral Fat Accumulation and Coronary Artery Disease.

Circ J

Motoki Taniguchi, Akira Taruya, Chie Kitahara +20 more

Visceral fat (VF), particularly epicardial adipose tissue (EAT), plays a crucial role in the development of coronary artery disease (CAD). Cathelicidin (LL37) is an antimicrobial peptide involved in innate immunity and has been implicated in inflammatory processes. However, the relationship between VF accumulation, cathelicidin, and atherosclerosis remains unclear.

Tirzepatide mitigates atherosclerosis progression and modulates oxLDL-mediated proatherogenic effects in macrophages: evidence for M1/M2 homeostasis restoration.

Arch Pharm Res

Mengjie Kang, HaoLin Ren, Yanru Zhen +10 more

Tirzepatide (TZP), a novel dual agonist of glucagon-like peptide (GLP)-1/glucose-dependent insulinotropic polypeptide (GIP) receptors (GLP-1R/GIPR), has been shown to reduce cardiovascular (CV) risk in patients with diabetes or obesity. This study investigated anti-atherosclerotic effects of TZP and the underlying mechanisms using apo E-/- mice and cultured macrophages. In the present study, apo E-/- mice were fed a high fat/high cholesterol (HF) diet with or without TZP treatment for 12 weeks. Atherosclerotic lesions, metabolic parameters, and M1/M2 macrophage homeostasis were assessed. In vitro, RAW264.7 and THP-1 macrophages were treated with oxLDL and TZP to evaluate foam cell formation, inflammation, and signaling pathways. The results showed that TZP significantly lowered body weight, plasma lipids, and atherosclerotic burden in vivo, and favorably modulated the expression of M1/M2 macrophage markers. ANCOVA suggested that the anti-atherosclerotic effect may be partially independent of metabolic improvements, although further studies are needed for confirmation. While these data support macrophage modulation as a key mechanism, other vascular cell types and plaque components likely contribute to the observed plaque-stabilizing effects. In vitro, TZP inhibited oxidized Low-density Lipoprotein (oxLDL)-induced cholesterol accumulation and foam cell formation, cluster of differentiation (CD) 36 expression and M1 inflammatory markers while promoting M2 markers. These effects were blocked by combined GLP-1R/GIPR antagonism and further confirmed in human THP-1 macrophages. Mechanistically, the anti-inflammatory effects and modulation of M1/M2 macrophage homeostasis by TZP were mediated via activating kruppel-like factor 4/the peroxisome proliferator-activated receptor γ pathway. Collectively, these findings indicate that TZP confers CV protection and anti-atherosclerotic benefits through both lipid-lowering dependent and independent mechanisms, highlighting its therapeutic potential for diabetic and obese patients who are at high risk of atherosclerotic CV diseases.

GLP-1 and dual GIP/GLP-1 agonists in obese patients with HFpEF: a systematic review and meta-analysis of RCTs.

BMC Cardiovasc Disord

Elhaitham Yasir Awad Musa, Amar Yasir Awad Musa

Saikosaponin D protects against isoproterenol-induced kidney injury in rats by regulating the intrarenal renin-angiotensin system.

Toxicol Appl Pharmacol

Xiaoli Yi, Shanshan Song, Huiru Yang +3 more

Saikosaponin D (SSD), a triterpene saponin isolated from Bupleurum falcatum, exhibits diverse pharmacological activities and has been shown to alleviate kidney-related diseases in rodent models. However, its effects on isoproterenol (ISO)-induced kidney injury and the underlying mechanisms have not been fully elucidated. Herein, SSD administration effectively mitigated ISO-induced kidney injury in Sprague-Dawley rats, as evidenced by improvements in renal function parameters (e.g., reduced plasma creatinine and blood urea nitrogen) and histopathological structure. Specifically, SSD significantly suppressed ISO-induced upregulation of inflammatory cytokines, fibrotic markers, and kidney injury biomarkers in renal tissues. SSD treatment downregulated renal expression of angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), reduced renal ACE activity and urinary angiotensin II (AngII) excretion, and upregulated renal angiotensin-converting enzyme 2 (ACE2) activity (without altering its expression) while increasing urinary angiotensin 1-7 (Ang1-7) excretion. Notably, no significant changes in plasma AngII or Ang1-7 concentrations were observed, indicating SSD specifically modulates the intrarenal renin-angiotensin system. Functional validation experiments showed that co-administration of SSD with the ACE inhibitor enalapril or AngII type 1 receptor (AT1R) antagonist losartan further potentiated its protective effects against ISO-induced kidney injury. In contrast, co-treatment with the ACE2 inhibitor MLN-4760 or Mas receptor (MasR) antagonist A779 completely abrogated SSD's renoprotective effects. In conclusion, our findings demonstrate that SSD exerts renoprotective effects against ISO-induced kidney injury by inhibiting renal fibrosis and inflammation. Mechanistically, SSD shifts the intrarenal RAS balance from the pro-inflammatory/fibrotic ACE/AngII/AT1R axis to the protective ACE2/Ang1-7/MasR axis, providing a novel therapeutic target for ISO-related kidney damage.

Serum malondialdehyde predicts mortality in patients with acute heart failure.

Redox Biol

Marija Pinterić, Iva Klobučar, Margarete Lechleitner +7 more

Acute heart failure (AHF) is associated with high short- and long-term mortality, and early identification of patients at highest risk remains challenging despite the use of established biomarkers and clinical risk scores. Oxidative stress plays a central role in the pathophysiology of AHF but has been insufficiently investigated as a prognostic target. This study aimed to evaluate the prognostic value of serum oxidative stress biomarkers for predicting short- and long-term mortality in AHF patients and to determine whether they improve risk stratification beyond established tools.

From Regeneration to Analgesia: The Role of BPC-157 in Tissue Repair and Pain Management.

Int J Mol Sci

Claire Yuan, Ariana Demers, Victor Silva-Ortiz +7 more

Body Protective Compound-157 (BPC-157) is a synthetic pentadecapeptide derived from gastric proteins that has demonstrated notable reparative and anti-inflammatory properties across diverse preclinical models. Experimental evidence reveals that BPC-157 supports angiogenesis, collagen synthesis, fibroblast activity, and modulation of nitric oxide pathways, contributing to enhanced healing of muscle, tendon, ligament, bone, and gastrointestinal tissue. Studies also report reduced inflammatory cytokine activity, improved microvascular integrity, and beneficial effects on pain modulation through peripheral and dopaminergic mechanisms. Although animal data indicate favorable safety and pharmacokinetics, human research remains limited to small pilot studies investigating musculoskeletal pain, interstitial cystitis, and intravenous administration, all suggesting potential therapeutic value without reported major adverse effects. However, inconsistent preparation standards, limited clinical validation, and regulatory restrictions underscore the need for rigorous controlled trials. BPC-157 remains a promising candidate for regenerative medicine, yet comprehensive evaluation is required before clinical translation can be recommended.

Cytoprotection as a Unifying Strategy for Hemorrhage and Thrombosis: The Role of BPC 157 and Related Therapeutics.

Pharmaceuticals (Basel)

Predrag Sikiric, Ivan Barisic, Mario Udovicic +21 more

This review presents an innovative and timely exploration of how cytoprotection can serve as a cohesive therapeutic approach by which to address the hemorrhage-thrombosis paradox. Presenting counteraction of both hemorrhage and thrombosis as phase-dependent outcomes of vascular dysregulation, the manuscript synthesizes conceptual, experimental, and clinical evidence into a unified systems-level model focused on the stable gastric pentadecapeptide BPC 157, which acts as a cytoprotective mediator. In rodents, BPC 157 can simultaneously counteract hemorrhage and thrombosis without directly affecting the coagulation cascade (aggregometry, thromboelastometry). This cytoprotective framework (decreased hemorrhage, decreased thrombosis) stands with presentation of both hemorrhage and thrombosis in the wound, arrhythmias, and Virchow triad, and resolution of these disturbances. As proof of the concept (full cytoprotective effect), a vasoprotective cytoprotective mediator capable of bidirectional regulation, BPC 157, is effective for wound healing, arrhythmia control, and normalization of Virchow's triad (i.e., following major injuries, occlusion/occlusion-like syndromes). As a comparison from a cytoprotective (partial vs. full) standpoint, conventional agents-anticoagulants, antiplatelet drugs, and fibrinolytics-provide only partial protection by targeting isolated components of hemostasis. Beta blockers, calcium channel blockers, prostaglandins, NO modulators, ACE inhibitors, and statins each exert broader cytoprotective effects; however, these actions remain incomplete and context-dependent, typically unidirectional, dose-limited, or are achieved at the expense of opposing pathological risks. Contrarily, for BPC 157, decreased hemorrhage (including both anticoagulants and antiplatelet agents), decreased thrombosis, effective wound healing, arrhythmia control, and normalization of Virchow's triad involve preservation of endothelial integrity, normalization of microcirculation, modulation of the NO system, stabilization of hemostatic balance, and recruitment of adaptive collateral pathways. Nevertheless, reliance on preclinical models necessitates further clinical validation.

Growth Hormone-Releasing Peptide-6 (GHRP-6) Ameliorates Post-Infarct Ventricular Remodeling and Systolic Dysfunction in a Model of Permanent Coronary Ligation.

Pharmaceuticals (Basel)

Linlin Wang, Arielis Rodriguez-Ulloa, Jorge Berlanga-Acosta +7 more

Background/Objective: GHRP-6 is a GH secretagogue hexapeptide with expanding and promising cardioprotective effects. Having determined 0.4 mg/kg as the minimum effective dose for enhancing inotropy based on echocardiographic parameters in healthy rats, we implemented a non-reperfusion myocardial infarct model, with its consequent left ventricle wall thinning and ballooning, via permanent left descending coronary artery ligation. Methods: Rats were assigned to three groups: sham-operated/normal rats, infarcted + saline-treated control rats, and infarcted + GHRP-6-administration rats. Treatments were initiated post-surgery and continued for 7 days. On day 7, the animals were echocardiographically and histologically evaluated. For mitochondrial proteomic analysis, an additional 12 healthy rats were used. Six animals received GHRP-6 or normal saline and were observed for 6 h after the inoculation. Results: Here, we show that GHRP-6 attenuated myocardial tissue demise, reduced myocardial interstitial fibrosis/scarring, and integrally improved left ventricle physiology. The proteomic analysis indicated that the GHRP-6 cardioprotective effects may be theoretically mediated by the concerted upregulation of proteins/pathways involved in fatty acid beta-oxidation, apoptosis prevention pathways, antioxidant defenses, and mitochondrial metabolic reprogramming. Conclusions: GHRP-6 is a potent cardioprotective candidate attenuating morphological and functional outcomes caused by late ischemia.

Myrtenol from Lavender Essential Oil Possesses Neuroprotective Effects and Promotes Neurite Outgrowth by Potentially Targeting TrkA and IGF-1R in PC12 Cells.

Int J Mol Sci

Ting Jiang, Lan Xiang, Jianhua Qi

Alzheimer's disease (AD) is a prevalent chronic neurodegenerative disorder; the progression of this disease is driven by cellular determinants such as oxidative stress and dysregulated neurotrophic signaling. Lavender essential oil is traditionally used in aromatherapy for neuronal regulation and neuroprotection, suggesting its potential neuroprotective effects for chronic neurodegenerative disorders like AD. However, the key active constituents responsible for its benefits and the specific molecular pharmacological mechanisms remain unclear. In this study, we isolated myrtenol from lavender essential oil under the guidance of activity evaluation. Its neuroprotective effects were evaluated in PC12 cells via neurite outgrowth, anti-Aβ/H2O2 cytotoxicity, and antioxidant assays. Targets and pathways were explored using inhibitor experiments, cell thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and Western blot. Myrtenol significantly induced neurite outgrowth in PC12 cells and effectively mitigated cytotoxicity and oxidative stress damage induced by Aβ25-35 and H2O2. Mechanistic studies revealed that myrtenol's effects are associated with the modulation of tyrosine kinase receptor A (TrkA) and insulin-like growth factor-1 receptor (IGF-1R), activating phospholipase C (PLC)/protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways to jointly mediate neuroprotection effects against the pathology of AD. This study demonstrates that myrtenol as a highly active component of lavender essential oil possesses NGF-like neuritogenic activity and neuroprotective effects. It provides a foundation for understanding the cellular mechanisms of myrtenol as a small-molecule lead for further investigation in neurodegeneration-related research.

Satellite Glial Cells in Peripheral Nerve Injury and Regeneration.

Biomedicines

Linjia Hu, Haimin Lu, Yufan Shen +4 more

Satellite glial cells (SGCs) are morphologically unique peripheral glial cells that surround neuronal somas in sensory, sympathetic, and parasympathetic ganglia. Satellite glial cells communicate with neurons that they ensheathe and form a distinct structural and functional unit. Following peripheral nerve injury, satellite glial cells undergo remarkable morphological changes, including gliosis, and help regulate the microenvironment surrounding neuronal somas. The expression of many satellite glial cell markers such as glial fibrillary acidic protein (GFAP) and connexin-43, pro-inflammatory cytokines, and growth factors in satellite glial cells is altered in these cells. Injury responses of satellite glial cells, particularly the activation of peroxisome proliferator-activated receptor α (PPARα), contribute to enhanced axonal regeneration. Targeting satellite glial cells may therefore offer novel therapeutic strategies for the treatment of peripheral nerve injury.

Review of the Pathology of Muscle in Amyotrophic Lateral Sclerosis.

Int J Mol Sci

Matthew Katz, Thomas Robertson, Shyuan T Ngo +4 more

In amyotrophic lateral sclerosis (ALS), a central event is the withdrawal of the motor nerve terminal from its target muscle. Whether this defect is driven by faults in the motor neuron or faults that originate within the muscle remains an area of investigation. In this review, we focus on the pathological abnormalities that are found in skeletal muscle, focusing, when possible, on human ALS, with support from ALS animal models. We begin with an overview of skeletal muscle, including a review of muscle fiber type, motor units and the neuromuscular synapse. Next, we provide a description of the clinical and biomarker changes that occur in the muscles of patients with ALS. We provide an extensive account of the histopathological changes that are evident in ALS muscle, such as fiber type grouping, muscle inflammation, protein misfolding, mitochondrial dysfunction, and alterations in neuromuscular junctions and muscle satellite cells. Our review then concludes with an update of metabolic and molecular-genetic changes that are found in ALS muscle. The evidence shows that muscle can be an additional target for therapy in ALS, in combination with therapies targeting neurons and glia within the central nervous system (CNS).

Single-Cell RNA-Sequencing Reveals Cachectic Satellite Cell Population in Muscle of Male Mice With Cancer Cachexia.

J Cachexia Sarcopenia Muscle

Alex Brown, Nicolás Collao, Aisha Saleh +3 more

Cancer cachexia leads to decreases in body mass, lean mass and fat mass, decreased therapeutic potential and ~20% of cancer-related deaths. While several studies have demonstrated changes to components of the muscle microenvironment with cancer cachexia, none have comprehensively assessed changes to cellular dynamics across the duration of cachexia development.

Peripheral Oxidation-Inflammation and Immunosenescence in Triple-Transgenic Mice for Alzheimer's Disease (3xTg-AD) at Early Neuropathological Stages of Disease and Decrease of Immune Impairment by Voluntary Exercise.

Biomolecules

Mónica De la Fuente, Antonio Garrido, Carmen Vida +2 more

Inflammatory-oxidative stress generated by immune cells plays an important role in aging and in age-related neurodegenerative disorders such as Alzheimer's disease (AD). Triple-transgenic mice for AD (3xTg-AD) are a suitable model for mimicking this disease in an age-dependent manner. We previously showed that peritoneal leukocyte functions and their redox-inflammatory state are altered early in female 3xTg-AD mice, which exhibit premature aging compared to non-transgenic (NTg) animals. However, their characteristics at 9 months of age, when they present an early neuropathological state, and the sex differences are not known. Here, we analyzed several spleen and thymus leukocyte functions (chemotaxis, natural killer activity, and lymphoproliferation in response to mitogens), pro-inflammatory (IL-1B, TNF-alpha) and anti-inflammatory (IL-10) released cytokine concentrations, and redox parameters (glutathione concentrations and glutathione peroxidase, glutathione reductase, and xanthine oxidase activities) in male and female 3xTg-AD mice compared to age-matched controls. We also analyzed the effects of voluntary physical exercise on immune functions. Our results show that 9-month-old male and female 3xTg-AD mice have worse immune functions, redox state, and inflammation than NTg counterparts. Physical exercise improves immune function. Thus, accelerated aging reflected by peripheral immunosenescence and oxidation-inflammation in 3xTg-AD mice precedes hallmark neuropathology, and exercise can slow down AD progression.

Real-World Weight-Loss Outcomes in Weight-Reduced Patients Treated With Tirzepatide.

Obesity (Silver Spring)

Sarah R Barenbaum, Ariel Gonzalez, Zoe Verzani +2 more

This study compared weight-loss outcomes in patients prescribed tirzepatide by weight-loss status and assessed results among patients transitioning from semaglutide.

Resistant and Refractory Obesity: The Complexity of Anti-Obesity Therapy Failure.

Int J Mol Sci

Michał Nicze, Maciej Borówka, Adrianna Dec +3 more

Pharmacotherapy is a key component of obesity management, yet treatment failure remains a prevalent challenge in clinical practice. Such failure may present as insufficient pharmacological response, early discontinuation, or post-treatment weight regain, underscoring the discrepancy between clinical trial efficacy and real-world outcomes. The effectiveness of anti-obesity medications (AOMs) is influenced by psychiatric comorbidities, including depression, anxiety, and disordered eating patterns, as well as environmental and socioeconomic factors such as limited healthcare access, weight-related stigma, and high medication costs. Individual characteristics, including physical activity, body composition, visceral adiposity, and microbiome profile, further modulate treatment outcomes. Pharmacokinetic and pharmacotherapeutic limitations such as drug-phenotype mismatch, route of administration, suboptimal formulations, and exposure to counterfeit products also compromise efficacy. No less important are genetic and immunological factors, comprising pharmacogenomic variants of both incretin and melanocortin receptors along with antidrug antibodies (ADAs), which may constitute therapy resistance. Concomitant medications and comorbid endocrine disorders can additionally attenuate weight-loss effects. The objective of this review is to characterize the multifactorial nature of resistance and refractoriness to anti-obesity therapy, and the importance of identifying pretreatment predictive factors for recognizing individuals at risk of inadequate or lack of response, thereby enabling personalized management strategies and improving long-term clinical outcomes, particularly in "difficult-to-treat" patients.

GLP-1 Receptor Agonists at the Crossroads of Circadian Biology, Sleep, and Metabolic Disease.

Int J Mol Sci

Ayush Gandhi, Ei Moe Phyu, Kwame Koom-Dadzie +2 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes and obesity, yet their actions extend beyond glycemic control and weight loss. This narrative review synthesizes current preclinical and clinical evidence examining the bidirectional relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and circadian biology. A structured literature search was conducted in PubMed using combinations of the terms 'GLP-1,' 'circadian,' 'chronobiology,' 'sleep,' 'obesity,' and 'type 2 diabetes' through January 2026. Accumulating evidence indicates that GLP-1 physiology is closely coupled to circadian timing systems and sleep-wake regulation. In this narrative review, we synthesize emerging data that reframe GLP-1RAs as chronometabolic modulators, acting at the intersection of metabolism, circadian biology, and sleep. We review circadian control of GLP-1 secretion by intestinal L-cells, emphasizing the role of core clock genes and the vulnerability of incretin rhythms to circadian misalignment from shift work, nocturnal light exposure, and sleep loss. We then examine GLP-1 receptor signaling within central and peripheral clock networks, including feedback effects on hypothalamic and hepatic circadian regulation. Emerging data suggest that GLP-1 signaling is under circadian regulation and may, in turn, influence central and peripheral clock systems. Comparative discussion of semaglutide, liraglutide, and tirzepatide highlights agent-specific pharmacokinetics and emerging clinical data linking GLP-1RA therapy to sleep outcomes, particularly obstructive sleep apnea. Finally, we outline translational opportunities for chronotherapy and precision medicine, positioning GLP-1RAs as integrative tools for metabolic and sleep-related disease rather than purely weight-centric therapies. We propose that GLP-1 receptor agonists may function as chronometabolic modulators, with potential implications for personalized chronopharmacological strategies in metabolic disease.

New Drugs on the Block: Dietary Management and Nutritional Considerations During the Use of Anti-Obesity Medication.

Nutrients

Eleni C Pardali, Kalliopi K Gkouskou, Christos Cholevas +4 more

Incretin-based pharmacotherapy has rapidly transformed obesity management. However, despite its efficacy, gastrointestinal (GI) adverse events (AEs) are common and represent a major driver of treatment discontinuation. Symptoms such as nausea, vomiting, acid reflux, diarrhea, and constipation, not only impair the quality of life, but also compromise adherence, thereby limiting the real-world effectiveness of these agents. Targeted nutritional strategies may play a pivotal role in mitigating these symptoms and supporting sustained treatment. However, most clinical trials have relied on generalized lifestyle advice combined with hypocaloric dietary prescriptions, with limited integration of structured, mechanism-based nutritional counseling tailored to the physiological actions of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs. Consequently, practical guidance for clinicians and dietitians remains fragmented. The present review synthesizes the available evidence on GI AEs associated with incretin-based therapies and examines whether structured, targeted nutritional management can meaningfully reduce symptom burden. We also outline key monitoring strategies and focus on important clinical aspects for physicians and dietitians, aiming to optimize patient outcomes. In addition, we provide detailed information on the spectrum of GI AEs to guide effective management and limit intolerance. By bridging pharmacology with applied clinical nutrition, we aim to provide a pragmatic framework for improving tolerability, sustaining adherence, and translating trial efficacy into durable real-world effectiveness.