Medicine and Pharmacology

Abstract: Background: Physical inactivity in older adults affects physical function, cognition, and social well-being. Rhodiola rosea, an adaptogenic herb, reported to improve endurance, reduce fatigue, and support mental health; however, clinical evidence in physically inactive older adults remains limited. Methods: This randomized, multicenter, double-blind, placebo-controlled study evaluated the efficacy and safety of Rhodiola rosea extract (RhoSera®) in 140 physically inactive adults aged 55 to 75 years, with early symptoms of muscle weakness or loss of muscle mass. The participants were equally randomized into two groups and observed for 12 weeks. Results: Compared with placebo, the Rhodiola rosea extract group showed improvements in anthropometric parameters, including waist and hip circumference, skinfold thickness, fat mass, muscle mass, lean body mass, and BMI. Improvements were also observed in handgrip strength, ASMI, balance, and postural stability, alongside reduced fatigue and stress, improved mood, and enhanced motivation for physical activity. Functional performance improved in the chair stand test, six-minute walk test, and gait speed. Conclusion: Rhodiola rosea extract is a safe and effective way to improve body composition, physical performance, and overall well-being in physically inactive older adults. These benefits may help preserve functional independence, mobility, and quality of life as people age.

Abstract: Background: Body composition may be a relevant determinant of metabolic and functional vulnerability in patients with colorectal cancer. This study aimed to investigate the association between different therapeutic strategies and body composition parameters. Methods: An observational, analytical, cross-sectional study was conducted in adult patients with colorectal adenocarcinoma undergoing active oncological management at Hospital Universitario de Badajoz, Spain, consecutively recruited between February 1, 2024, and June 20, 2024. Nutritional status was assessed using the Patient-Generated Subjective Global Assessment (PG-SGA), and body composition was evaluated by multifrequency bioelectrical impedance analysis (BIA). Fat mass, fat-free mass, skeletal muscle mass, bone mass, protein mass, total body water, visceral fat, and basal metabolic rate were assessed. Patients were stratified according to treatment modality: surgery alone, FOREST protocol, neoadjuvant chemotherapy, adjuvant chemotherapy, and combined neoadjuvant-adjuvant chemotherapy. Between-group differences were assessed using one-way ANOVA, with additional Kruskal-Wallis tests performed as nonparametric sensitivity analyses for departures from normality. Statistical significance was set at p<0.05. Results: A total of 91 patients were included, with a mean age of 64.97±9.92 years; 56 (61.5%) were men. Significant differences between treatment modalities were observed in bone mass (p=0.023), protein mass (p=0.002), skeletal muscle mass (p=0.022), fat-free mass (p=0.022), and basal metabolic rate (p=0.039). Patients receiving adjuvant chemotherapy alone exhibited the lowest values for protein mass, skeletal muscle mass, fat-free mass, and basal metabolic rate, whereas those receiving combined neoadjuvant-adjuvant chemotherapy showed the highest values. No significant differences were observed in the remaining body composition parameters. Conclusions: Body composition parameters differed across therapeutic groups, particularly in parameters related to skeletal muscle mass and physiological reserve. These findings support incorporating body composition assessment into comprehensive clinical and nutritional evaluation. However, the cross-sectional design precludes determining whether the observed differences reflect treatment-related changes or pre-existing differences between therapeutic groups. In particular, the higher muscle-related values observed in the combined neoadjuvant-adjuvant group should not be interpreted as evidence of preservation or improvement of physiological reserve. Prospective longitudinal studies are warranted to determine changes in body composition over the course of treatment and their relationship with treatment-related toxicity and clinical outcomes.

Abstract: Anabolic resistance, a reduced muscle protein synthetic response to protein or exercise, is reported in older adults and in people with obesity and insulin resistance. Yet it is still measured with one readout: the increment in muscle protein synthesis over a few hours after a single dose. This review makes four contributions. First, it identifies five impasses: single doses confound sensitivity with maximal responsiveness; most of an ingested meal goes untracked; breakdown is rarely measured; individual reproducibility is unknown; and acute responses are not validated predictors of muscle mass. Second, it proposes amino acid metabolic flexibility as a disposal framework in which an attenuated response can arise through four routes: reduced delivery, impaired sensing and translation, competing oxidative disposal, and impaired antiproteolysis. Third, it treats exercise as a probe as well as a stimulus, because whether prior exercise corrects a deficit helps to locate it. Fourth, applying the framework to aging and obesity-related insulin resistance suggests that similar synthetic phenotypes arise through different routes and yields a testable hypothesis: that insulin resistance diverts absorbed amino acids toward oxidation. A multidomain, repeated-measures design to test these predictions is outlined.

Abstract: This article offers a pragmatic, evidence-based approach to optimal nutrition for adults and athletes seeking to enhance their strength, endurance, and recovery. We begin with key concepts related to a clean, anti-inflammatory eating pattern of whole and minimally processed foods, with special attention to protein (muscle protein synthesis), carbohydrates, fats, and fiber. Ergogenic supplements are presented as an adjunct to, not a substitute for, healthy eating, emphasizing caffeine, creatine, nitrates, polyphenols, beta-alanine, added protein, and omega-3 fatty acids. We conclude with considerations for masters, endurance, and strength athletes and show how nutrition and supplements synergize with other pillars of optimum human performance (e.g., restorative sleep). Our goal is to emphasize principles over practice and evidence over myths, thereby enhancing the ability of all individuals, regardless of athletic ability, to embrace healthy habits that help them be and perform their best.

Abstract: For a century, the study of human body weight regulation has been dominated by the Energy Balance Model (EBM) and challenged by the Carbohydrate-Insulin Model (CIM). Both frameworks, however, rely on the indirect conversion of mass to energy, introducing propagated uncertainties and theoretical stalemates. The Eagle Project proposes a paradigm shift: direct mass accounting. By conducting feeding experiments in state-of-the-art whole-room metabolic chambers capable of continuous measurement for up to seven days, we will quantify every gram of mass entering and leaving the human body (food, beverages, O₂, CO₂, urine, feces, sweat). This extended duration eliminates the need for mathematical extrapolations. Furthermore, the project will integrate comprehensive, high-frequency blood sampling to map the full endocrine and metabolic response against physical mass fluxes. Committed to radical transparency, all raw data will be published in near real-time via preprints, free of paywalls and embargoes. The Eagle Project is not merely an experiment – it is a global, collaborative effort to resolve the metabolic stalemate and establish a new, physically rigorous foundation for nutritional science.

Abstract: Substance use disorder (SUD) is a chronic, treatable condition with wide-ranging effects on health and functioning, and recovery involves restoring the biological, psychological, and social systems affected by substance use. Diet influences many biological and behavioral processes relevant to recovery, yet nutrition remains largely absent from SUD care, and existing research has focused primarily on nutrient deficiencies and overall diet quality rather than food processing. In this Perspective, we propose that early recovery represents a critical nutritional transition during which ultra-processed food (UPF) intake may influence recovery trajectories and long-term health. After the acute withdrawal phase, appetite and energy intake often increase, but diet quality frequently remains poor. Limited evidence, largely from alcohol use disorder, suggests that UPFs contribute a substantial proportion of total energy intake during early abstinence. We examine how UPF intake may influence four recovery-relevant domains affected by chronic substance use: neurobehavioral function, cardiometabolic health, gut-immune interactions, and affective well-being. We also discuss structural, clinical, workforce, and evidentiary barriers to integrating nutrition into SUD care, including challenges in dietary assessment, limited treatment reach, and food-access constraints, particularly in rural settings. At the same time, emerging opportunities in policy, patient engagement, digital health, and food-is-medicine initiatives may support greater integration of nutrition into recovery care. Although direct evidence remains limited and no trial has evaluated UPF reduction as an adjunct to SUD treatment, the biological plausibility, observed dietary patterns, and broader health implications warrant investigation. We conclude by outlining research priorities, including improved assessment of UPF exposure, prospective cohorts beginning at treatment entry, and intervention trials extending beyond discharge, to determine whether reducing UPF intake can support recovery and long-term health.

Abstract: Objective: The current Chinese catalogue of medicinal and edible substances applies a “safety–history” criterion that decides whether a substance may be admitted, but it cannot state how strong its cold–hot nature bias is after admission, where its boundaries lie relative to everyday foods and medicines, or how it should be used according to individual constitution. This study constructs an operational scoring framework that uses cold–hot nature bias as a single coordinate axis, is fully rule-disclosed and reproducibly computable, and can be extrapolated to plant-derived substances that lie outside the frozen reference tables. Methods: We propose the Bias Continuum Framework (BCF; methodological framework V1), in which foods and medicines are defined as intervals on a continuum of [−10, +10], indexed by the nature bias score B (positive = warm/hot, negative = cool/cold, zero = neutral). B is computed from three measurable dimensions—environmental habits (40%), metabolic characteristics (40%), and growth cycle (20%)—under a publicly specified operational scoring rule. Two cut-offs partition the continuum into three zones: |B|≤3, the low-bias (food-nourishment dominant) zone; 3<|B|≤6, the moderate-bias (medicine–food homology) zone; and |B|>6, the high-bias (medicine dominant) zone. The three-dimensional rules and weights were frozen and published on an international preprint platform in 2025, and no rule was retroactively changed for any substance in the present calibration. The 106 national catalogue substances were scored item by item and reported by evidence tier (L1/L2/L3a/L3b/R). Validation followed an ascending staircase: in-system consistency (60 typical foods/herbs), extrapolation of the frozen rules to 19 off-catalogue foodstuffs, and a “predict-before-check” blind prediction on 15 exotic crops and new-resource foods outside the reference tables, supplemented by a cut-off grid sensitivity analysis. Results: The 106 substances were classified as 41 low-bias (38.7%), 50 moderate-bias (47.2%), and 15 high-bias (14.2%), a unimodal distribution that bulges in the middle and tapers at both ends. All 30 everyday foods fell in the low-bias zone, and 28 of 30 recognised strongly biased herbs fell in the high-bias zone, with zero food–medicine diagonal misclassification. Of the 19 off-catalogue foodstuffs, 17 were low-bias and 2 (winter melon B=−3.2, bitter melon B=−3.3) crossed into the lower edge of the moderate-bias zone. The three-zone structure remained stable for α∈[2.5, 3.5] and β∈[5.5, 6.5]. B correlated strongly with the rank of Pharmacopoeia natures (Spearman ρ=0.910, n=106, P<0.001; ρ=0.938 in the high-confidence subset), and the plant-derived score span within a single Pharmacopoeia nature label reached about 6.9 points (the four natures govern direction rather than intensity). All 15 high-bias substances were supported by high-confidence evidence (L1/L2); a leave-one-class-out sensitivity analysis that removed all L3b and animal-source (R) entries left the high-bias membership unchanged (0% change). In the blind prediction, 13 of 15 exotic crops agreed in cold–hot direction with public reports; the two exceptions (guarana, cacao) were both rich in caffeine and theobromine (excitatory methylxanthines), precisely exposing a coverage gap of the frozen rule in the metabolic dimension. None of the 15 fell in the high-bias zone, reproducing the general pattern that everyday foods cluster in the low-bias zone. Conclusions: The BCF is a reproducible, calibratable, and extrapolatable operational scoring tool that complements rather than replaces the current catalogue: the catalogue governs legality and safety (whether a substance may be admitted or traded), whereas the continuum governs cold–hot displacement and adaptation constraints (how it should be used by constitution, dose, and frequency). The B score measures the direction and intensity of cold–hot bias and is not a direct measure of therapeutic efficacy or toxicity. Because its three-dimensional inputs are botanical measurable parameters independent of classical texts, the framework is, by design, able to compute cold–hot direction and zone membership for exotic crops and new-resource foods “for which botanical data exist but no classical textual record does”; until independent-criterion validation is completed, such results remain “values computed under the frozen rules.” The two blind-prediction reversals (the methylxanthine gap) constitute preliminary evidence of the framework’s falsifiability. Independent-scorer blind replication (inter-rater reliability) and modern pharmacological criterion association have been registered as subsequent validations.

Abstract: The calorie is a unit of heat, not a measurement of metabolism. It is treated as a primary, measurable quantity. This paper argues that it is neither primary nor a measurement of anything the body does. The calorie was derived from 19th-century thermodynamics and imported into biology by Atwater and colleagues. It is a derived abstraction that has been reified into an ontological entity – a ghost in the machine of metabolic research. Human metabolism does not process calories. It processes mass. The body lacks calorie receptors; it regulates behavior through mass-based signals: nutrient concentration, gastric distension, hormonal feedback. The measurement chain that converts food mass into bomb calorimetry heat, then into metabolizable calories, and finally back into predicted body mass is an epistemological dead end. It introduces avoidable assumptions and obscures the stoichiometric reality of tissue accretion and loss. The Mass Balance Model (MBM) offers a direct alternative. It tracks atoms in grams, bypassing the calorie entirely. The calorie served its purpose in the 19th century. It is time for nutrition science to abandon it and adopt a mass-based ontology. The body counts grams. It is time for the science to count them too.

Abstract: Aim: The Oral Frailty Diet (OF Diet) has been implemented since 2022 as a safe initial meal option for elderly patients on emergency admission, addressing risks of malnutrition,dysphagia, choking, and aspiration. However, the prevalence of oral frailty and dysphagia among elderly emergency admissions is unclear, and the suitability of the OF Diet against patients’ actual swallowing abilities has not been systematically assessed. Therefore, we aimed to evaluate the impact the OF Diet on swallowing function and dietary intake in elderly patients (≥70 years) on emergency admission. Methods: This retrospective study included 478 patients aged ≥70 years on emergency admission between October 2022 and December 2024. Patients were divided into OF Diet (n=108) and non-OF Diet (n=370) groups. Assessments included meal texture at admission and after modification, swallowing function (Seirei Swallowing Questionnaire), and dietary intake. Results: Initial meal provision comprised 53% regular diet and 23% OF Diet. The OF Diet group had a higher rate of suspected dysphagia on admission (p&lt;0.0001). While the non-OF Diet group showed significant deterioration in meal texture from admission to modification (p&lt;0.0001), the OF Diet group showed stable textures. A linear mixed model revealed significant main effects of the OF Diet (F=19.71, p&lt;0.0001) on swallowing scores. The OF Diet group also demonstrated significantly lower dietary intake &lt;30% (12.0% vs. 21.4%, p=0.0308). Conclusions: Implementation of the OF Diet enables safe initial meal provision for elderly patients on emergency admission who are at high risk of dysphagia, thereby improving dietary intake without negatively affecting swallowing function.

Abstract: The International Society of Sports Nutrition (ISSN) has published two documents on diet and body weight regulation: a position stand on diets for body weight reduction (Aragon et al., 2026) and a review of common questions and misconceptions about diets (Antonio et al., 2026). Both are thorough, evidence-based, and practically useful for their intended audience of coaches, athletes, and sports nutrition practitioners. Yet both contain the same category error at their foundation. The position stand calls the caloric deficit “axiomatic” – but a derived quantity cannot be an axiom. The review invokes the First Law of Thermodynamics as justification for the energy balance framework – but the First Law concerns energy, not mass, and says nothing about whether mass is primary or derived. In both documents, the same structural pattern appears: mass phenomena described in energy language, with logical contradictions following directly from the mismatch. This commentary presents the clearest contradictions from each document, with formal analyses derived from the energy balance framework’s own premises. The error is structural, not incidental. Both documents are already mass-based. Neither has yet named itself as one.

Abstract: Background/Objectives: Associations between the Dietary Inflammatory Index (DII) and cardiovascular disease (CVD) in the National Health and Nutrition Examination Survey (NHANES) have usually relied on selected cycles, short-term recalls, and prevalent disease. This study examined the association’s consistency across survey periods, its dependence on recall measurement error, and reverse causation. Methods: Adults aged ≥20 years in NHANES 2005–2018 with two 24 h recalls (n = 30,579) were analyzed with survey-weighted logistic regression of self-reported CVD on a 27-parameter DII. Pre-specified analyses were an equivalence test of 2005–2010 versus 2011–2018, regression calibration using the replicate recall, restrictions for post-diagnosis dietary change, and survey-weighted Cox models for mortality through 2019 in 27,239 adults free of CVD. Results: Each 1-unit higher DII was associated with higher odds of CVD (odds ratio [OR] 1.09, 95% CI 1.03–1.15). Period-specific ORs were 1.09 and 1.08, but equivalence within ±10% was not established (interaction-model ratio of ORs per SD 0.94, 90% CI 0.85–1.04). After calibration, ORs per unit of usual DII were 1.17 (1.07–1.27) for the two-day mean and 1.20 (1.10–1.31) for day one. Excluding special diets or restricting to diagnoses within 5 or 10 years did not attenuate the association. Hazard ratios were 1.09 (0.98–1.21) for CVD mortality and 1.09 (1.04–1.14) for all-cause mortality. Post hoc, cycle-specific estimates showed no evidence of heterogeneity, and each DII unit was associated with 13% higher serum C-reactive protein. Conclusions: The DII–CVD association was modest, similar across survey periods and recall strategies, and larger after correction for recall error; restriction analyses did not indicate that post-diagnosis dietary change created it, and the CVD mortality estimate was concordant but imprecise. Formal equivalence across periods, a CVD mortality association, and causation were not established.

Abstract: Background: Fruits and vegetables vary in flavor, texture and nutrient composition, but consumer impressions of historical deterioration are often conflated with nutritional inadequacy. Objective: To critically examine genetic, agronomic and postharvest determinants of produce quality and their implications for childhood dietary diversity. Methods: A narrative synthesis began with the preceding manuscript's bibliography and used targeted retrieval and bibliographic verification through 12 October 2026. Crop studies, sensory experiments, pediatric studies, evidence syntheses and World Health Organization guidance were interpreted according to design and population. No exhaustive screening or meta-analysis was conducted. Synthesis: Evidence across strawberries, melons, citrus, pome and stone fruits, tomatoes, carrots and brassicas supports crop-specific variability associated with genotype, production conditions, maturity, storage and preparation. Flavor differences do not establish a universal decline in nutrient content. Historical food-composition comparisons have substantial comparability limitations. Child studies support evaluating preparation and eating context, but adult preference and food-chemistry findings cannot directly establish sustained pediatric intake. Plate color is a useful educational cue to variety, not a validated measure of nutritional adequacy. The author's prior clinical work is integrated as a conceptual clinical perspective, with its preprint and conference-abstract status explicitly identified. Conclusions: Childhood nutrition assessment should connect food properties with actual intake, whole-diet adequacy, feeding skills and documented medical needs. Studies linking characterized produce to repeated child consumption are needed; the proposed clinical integration requires validation.

Abstract: A recent analytical paper by Arencibia-Albite demonstrates that the energy balance model (EBM) is internally inconsistent. The proof does not rely on any empirical dataset. The argument is that EBM’s own equations require energy balance and body weight stability to be simultaneous equilibrium states. That equilibrium requires stable fat mass and fat-free mass. Stable fat-free mass requires nitrogen balance. Nitrogen balance is impossible given obligatory nitrogen losses. The model cannot simultaneously satisfy its own equilibrium conditions. This commentary explains the proof for a general nutrition science audience, situates it within the broader critique of the energy balance framework, and discusses its implications for research and practice. The proof is analytical, not empirical. It shows that the model’s equations do not close. This does not mean that energy is irrelevant. It means that energy balance alone cannot describe body weight regulation. Mass balance offers a more complete description. The clinical implication is direct: when patients fail to lose weight despite adherence to caloric restriction, the failure may lie in the framework, not in the patient.

Abstract: Background/Objectives: Sodium-glucose cotransporter 2 (SGLT2) inhibitors share a renal mechanism but differ in SGLT1 selectivity, off-target activity and licensed indications. We compared exposure-adjusted reporting of suspected adverse reactions for canagliflozin, dapagliflozin, empagliflozin and ertugliflozin and examined whether differences between them are consistent with molecule-specific pharmacology. Methods: UK Yellow Card reaction entries for 2021–2025 were related to English NHS general practice and estimated hospital prescribed items for the same 60 months. Rates were calculated with exact Poisson intervals, reporting rate ratios (RRRs) versus dapagliflozin with Poisson regression and Holm adjustment, and annual trends with quasi-Poisson regression; within-class disproportionality was also calculated without a prescribing denominator. Results: The analysis included 8789 reaction entries and 52.19 million items. Total reporting rates were 125.47, 188.83, 143.53 and 213.64 per million items, respectively. Ketoacidosis and ketosis reporting was higher for canagliflozin (RRR 2.45, 95% CI 2.02–2.95) and empagliflozin (1.93, 1.69–2.19), as was euglycaemic ketoacidosis reporting, and peripheral tissue injury reporting was higher for canagliflozin (2.80, 1.63–4.64). Amputation reporting was higher for canagliflozin (3.69, 1.14–10.61) but not after adjustment, and 2.68 for lower-limb terms. Within the class, the entry-level ketoacidosis reporting odds ratio for canagliflozin was 3.10 (2.53–3.80). Ketoacidosis reporting declined by 32.0% per year for dapagliflozin and by 24.4% for empagliflozin. Conclusions: Higher ketoacidosis and peripheral tissue injury reporting for canagliflozin is compatible with its lower SGLT2 selectivity, but equally with population or reporting differences, which these data cannot separate. Empagliflozin does not fit a selectivity explanation. These are reporting rates, not incidence estimates.

Abstract: The DiAL Health Pilot Trial is a well-designed study that measures body mass, fat mass, fat-free mass, and food intake using state-of-the-art methods. Yet its analysis converts these mass measurements into energy equivalents and uses energy as the primary variable. This commentary identifies three loci of energy derivation in the protocol: the weight-loss nomograms, the CR adherence quantification (Equation 1), and the calorie prescription itself. A concrete numerical example shows that energy-based and mass-based analyses can produce divergent results for the same participant. The energy balance equation is mathematically underdetermined with respect to growth composition: one equation, two unknowns. The mass measurements are not. The TRE arm of the trial is not affected by the same issue, because its adherence metric is time-based rather than energy-based. This makes the CR analysis an isolated case rather than a general problem with the trial. A mass-balance analysis would preserve the information that the energy conversion discards, and would produce adherence metrics directly interpretable in the units actually measured. The argument is not that the DiAL Health trial is flawed. It is that the analytical framework it inherited contains a detour that is no longer necessary given the measurements the trial already performs.

Abstract: Behavioral and sensory research on food intake has long treated energy content as if it were a directly perceptible property of food. Organisms are said to “detect,” “evaluate,” or “compensate for” calories. This language imports an energy-centric ontology into a sensory system that has no access to energy as such. There are no receptors for the joule or the kilocalorie. Taste, smell, texture, oral processing, and gastric distension respond to molecular identity, physical mass, volume, and structure. Post-ingestive signals report molecular identity and concentration, not energy content. Energy is a derived quantity that can be associated with sensory patterns through learning, but it is not sensed directly. The present commentary argues that this category error – a derived property treated as a perceptible one – has shaped experimental design, interpretation, and vocabulary in the behavioral literature, and that restoring mass to primacy brings the psychology of appetite into register with the physics and physiology of mass balance.

Abstract: Worldwide, consumption of ultra-processed foods (UPFs) is increasing in parallel with a rising incidence of obesity, type 2 diabetes, cardiovascular disease, kidney disease, and related cardiometabolic complications. Among the many features of UPFs that may drive these outcomes, industrial thermal processing is a defining characteristic that promotes the formation of advanced glycation end products (AGEs) and other food neo-contaminants, including acrylamide, furan, 5-hydroxymethylfurfural, heterocyclic amines, polycyclic aromatic hydrocarbons, 3-monochloropropane-1,2-diol, and glycidol. This review evaluates the hypothesis that AGEs and thermally generated neo-contaminants contribute significantly to the metabolic and toxicological effects of UPFs. After formation in food, these compounds may be partially absorbed in the gastrointestinal tract and act systemically, promoting tissue injury through protein cross-linking, oxidative stress, inflammation, endothelial dysfunction, and activation of the receptor for advanced glycation end products (RAGE). Several high-temperature neo-contaminants are linked to carcinogenicity, hepatotoxicity, neurotoxicity, and reproductive toxicity, while emerging evidence also implicates them in insulin resistance, adipogenesis, β-cell dysfunction, and cardiovascular risk. Overall, the evidence supports a biologically plausible link between thermal processing, AGE and neo-contaminant burden, and cardiometabolic disease, although the strength of evidence varies by compound. Improved exposure assessment, standardized analytical methods, mechanistic studies, and intervention trials are needed to define dose–response relationships and to determine whether reformulation and lower-temperature, moisture-rich cooking can reduce risk while maintaining food safety and acceptability.

Abstract:

Background/Objectives: Betanidin glycosides (betacyanins) are plant dietary pigments with reported significant benefits on human health. Betacyanin research has largely focused on betanin common in some plant foods like beets, amaranth, quinoa, cacti fruits , whereas the biological properties of structurally diverse gomphrenin derivatives remain insufficiently characterized. Gomphrenin-type betacyanins dietary source is predominantly Malabar spinach (Basella alba L.) but its health-promoting and disease preventing properties remain understudied. This study investigated whether differences in the composition of gomphrenin-rich preparations influence their effects on inflammatory and oxidative cellular responses. Methods: Betacyanin-rich preparations were obtained from Basella alba f. rubra fruits and Gomphrena globosa L. flowers using chromatographic purification. Their betacyanin profiles were characterized by LC-DAD-ESI-MS and total betacyanin contents were determined spectrophotometrically. The biological effects of crude and purified preparations (1–100 μg/mL) were evaluated in Caco-2 intestinal epithelial cells and human polymorphonuclear neutrophils (PMN). IL-8 secretion in Caco-2 cells, TNF-α, IL-8, and IL-1β secretion in LPS-stimulated PMN, ROS generation in f-MLP-stimulated PMN, and cell viability were assessed. Results: Purification resulted in preparations with markedly different betacyanin profiles. The gomphrenin-enriched BE₂ contained 312 ± 83 mg/g total betacyanins, whereas the acylated-betacyanin-enriched BE₃ contained 188 ± 12 mg/g and was dominated by globosin and other hydroxycinnamoyl derivatives. Despite its lower total betacyanin content, BE₃ displayed stronger inhibition of TNF-α, IL-8, and IL-1β secretion than BE₂; at 100 μg/mL, these cytokine levels were 39.17%, 44.61%, and 58.93% of the LPS control, respectively. All preparations reduced IL-8 secretion in Caco-2 cells by more than 50% at the highest concentration and the Basella preparations effectively suppressed neutrophil ROS generation. No significant cytotoxicity was observed. Conclusions: The biological activity of betalain-rich preparations was not determined by total betacyanin content alone but was associated with their qualitative pigment composition and broader chemical matrix. The stronger anti-inflammatory activity of the acylated-betacyanin-enriched preparation highlights hydroxycinnamoylated gomphrenins as candidates for further investigation, while the complex nature of the preparations warrants further studies to determine the contribution of individual pigments to the observed biological effects.

Abstract: Nutraceuticals are evaluated as though efficacy were a stable ingredient property, although net value may vary with exercise stimulus, exposure schedule, recovery pressure, athlete state, and prioritized outcome. This structured narrative review integrates exercise-adaptation biology, pe-riodized sports nutrition, training-load and recovery models, precision nutrition, and human evi-dence for sport-relevant interventions. Searches of PubMed/MEDLINE, Web of Science, and Scopus were updated through August 2026 and supplemented by citation tracking. General efficacy was separated from direct evidence of timing, context, or state modification. Nutraceutical Periodiza-tion for eXercise (NPX) is an allocation layer applied only after safety, legality, product quality, and plausible efficacy are established. It defines four non-sequential functional win-dows—performance exploitation, adaptation-permissive signaling, restoration, and resili-ence—and separates intervention strategy, training context, athlete state, and outcome hierarchy. Four falsifiable propositions test context modification, temporal allocation, bottleneck/state de-pendence, and whole-policy utility. Despite limited direct evidence for most allocation rules, NPX converts compound-specific efficacy into prospectively testable decisions. Targeted allocation may improve athlete-centered outcomes or preserve them with fewer exposures, lower burden, or less harm than standardized evidence-based use. Prospective interaction and policy trials are needed to establish the value and boundaries of these rules.

Abstract: Type 2 diabetes mellitus (T2DM), a global metabolic disease, is fundamentally characterized by a vicious cycle of chronic low-grade inflammation and metabolic dysregulation. The complement system, a key effector of innate immunity, has recently been recognized as deeply involved in initiating and amplifying metabolic inflammation. Although current studies have revealed critical roles of complement components in pancreatic β-cell damage, insulin resistance, and adipose tissue inflammation, the interactive network between complement and metabolic inflammation in T2DM microvascular and macrovascular complications remains incompletely understood, and complement-targeted therapies still face specificity and safety challenges. This review systematically summarizes the molecular crosstalk between complement components and metabolic inflammation in T2DM and its complications, focusing on complement-mediated β-cell apoptosis, suppression of insulin signaling, adipose tissue macrophage polarization, and renal and vascular endothelial injury. We also discuss the prospects of complement-targeted drug development and barriers to clinical translation, aiming to offer new insights for precision treatment of T2DM and its complications.