Pathophysiology

Background: Zika virus (ZIKV), a mosquito-borne flavivirus, is associated with congenital malformations and neuroinflammatory disorders, highlighting the need to identify host factors that shape infection outcomes. Macrophages, key targets and reservoirs of ZIKV, orchestrate both antiviral and inflammatory responses. Methods: Vitamin D (VitD) has emerged as a potent immunomodulator that enhances macrophage antimicrobial activity and regulates inflammation. To investigate how VitD shapes macrophage responses to ZIKV, we reanalyzed publicly available RNA-seq and miRNA-seq datasets from monocyte-derived macrophages (MDMs) of four donors, differentiated with or without VitD and subsequently infected with ZIKV. Results: Differential expression analysis identified long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs integrated into competing endogenous RNA (ceRNA) networks. In VitD-conditioned and ZIKV-infected MDMs, 65 lncRNAs and 23 miRNAs were significantly modulated. Notably, lncRNAs such as HSD11B1-AS1, Lnc-FOSL2, SPIRE-AS1, and PCAT7 were predicted to regulate immune and metabolic genes, including G0S2, FOSL2, PRELID3A, and FBP1. Among the miRNAs, let-7a and miR-494 were downregulated, while miR-146a, miR-708, and miR-378 were upregulated, all of which have been previously implicated in antiviral immunity. Functional enrichment analysis revealed pathways linked to metabolism, stress responses, and cell migration. ceRNA network analysis suggested that SOX2-OT and SLC9A3-AS1 may act as molecular sponges, modulating regulatory axes relevant to immune control and viral response. Conclusions: Despite limitations in sample size and experimental validation, this study provides an exploratory map of ncRNA–mRNA networks shaped by VitD during ZIKV infection, highlighting candidate molecules and pathways for further studies on host–virus interactions and VitD-mediated immune regulation. Full article

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, with amyloid beta oligomers (AβOs) emerging as the most neurotoxic species and acting as early triggers of cellular alterations. Before the appearance of other protein aggregates, AβOs disrupt the dynamics and stability of the neuronal cytoskeleton, a structure essential for maintaining neuronal morphology, axonal transport, and synaptic plasticity. Experimental evidence demonstrates that AβOs promote microtubule disassembly, Tau hyperphosphorylation, reduced kinesin levels, impaired axonal transport, and alterations in actin dynamics through the LIMK–cofilin signaling pathway. In addition, increased levels of neurofilament light chain have been identified as an early biomarker of axonal damage. Notably, these cytoskeletal disturbances arise in the absence of extensive neuronal death, underscoring the cytoskeleton as a critical early target in AD pathogenesis. In this review, we analyze cytoskeletal alterations induced by AβOs in neurons and discuss how these changes may contribute to disrupted neuronal communication, a defining early hallmark of AD pathology. Full article

Background/Objectives: Although tissue inhibitors of metalloproteinases (TIMPs) are key regulators in breast cancer, their differential expression, clinical relevance, and molecular roles remain unclear. This study aimed to compare the expression patterns of the four TIMPs in breast cancer and evaluate their molecular interactions and associated pathways through an integrated bioinformatic analysis. Methods: The expression of TIMPs and their correlations with MMPs were analyzed using the TCGA PanCancer, cBioPortal, and GEO datasets. Associations between TIMP expression and overall survival were assessed in the TCGA Breast Invasive Carcinoma PanCancer cohort. Pathway enrichment analysis was performed using GO, KEGG, and DAVID. The relationships between immune cell infiltration, stromal cells, and TIMP expression were assessed using the EPIC algorithm. Statistical analyses were performed using R. Results: TIMP1 was the only inhibitor overexpressed in breast tumors and showed significant associations with the Luminal B, HER2, TNBC, and normal-like subtypes, along with a modest increase across stages. TIMP2, TIMP3, and TIMP4 were downregulated in tumors. High expression of TIMP1 and TIMP4 correlated with better overall survival. TIMP1-associated genes were enriched in NF-kappa and PI3K–Akt signaling and actin cytoskeleton components. TIMP2 was linked to Hedgehog and MAPK pathways and actin-related elements. TIMP3 correlated with Hedgehog and PI3K–Akt signaling, DNA damage response, and membrane components. TIMP4 was associated with VEGF, MAPK, PI3K–Akt, DNA damage pathways, and actin organization. TIMP2 showed strong positive correlations with MMP2 and MMP14, while TIMP4 showed negative correlations with MMP1 and MMP9. Interestingly, we found a strong positive correlation between TIMP2 and TIMP3 with ADAM12, as well as between TIMP2 and TIMP3 with ADAM10, and negative correlations with ADAM15. The differential expression of TIMPs favors greater infiltration of immune cells related to tumor progression and poor prognosis in breast cancer patients. Conclusions: TIMPs display contrasting expression profiles and distinct pathway associations in breast cancer. TIMP1 emerges as the only consistently overexpressed inhibitor, while TIMP4 appears as a promising prognostic marker with unique MMP correlations that may influence tumor behaviors. Full article

Background: AMP-activated protein kinase (AMPK) acts as a key energy sensor that negatively regulates skeletal muscle mass. Zinc is an essential trace element that is required for myogenic differentiation and protein synthesis, while zinc deficiency has been associated with muscle atrophy in vivo. However, how zinc status modulates AMPK activation itself or alters downstream responses to AMPK signaling in muscle cells remains unclear. Methods: C2C12 myotubes were cultured under zinc-depleted (ZnD), zinc-sufficient (20 μM; Zn20), or zinc-supplemented (40 μM; Zn40) conditions. AMPK was activated by AICAR, and zinc status–dependent responses were evaluated using molecular and morphological analyses. Results: AICAR increased intracellular zinc levels in Zn20 and Zn40 but not in ZnD. Zinc transporter expression exhibited gene-specific regulation: Zip3 was upregulated across all zinc conditions, Zip14 was significantly induced in ZnD and Zn40, and Zip10 was selectively upregulated in Zn40. AICAR induced myotube atrophy in all groups; however, the reduction in myotube diameter was significantly greater under zinc-depleted conditions. Zinc depletion was associated with transcriptional upregulation of FoxO1, FoxO3, Atrogin-1, and MuRF1 in response to AICAR, while AMPK activation and suppression of S6K1 phosphorylation occurred to a similar extent regardless of zinc status. Conclusions: These findings indicate that zinc availability does not alter AMPK activation itself but modulates downstream atrophic responses to AMPK signaling. Under conditions of AMPK activation, adequate zinc availability is accompanied by increased intracellular zinc levels and stress-responsive ZIP regulation, which may limit excessive atrophic gene induction, whereas zinc depletion increases susceptibility to AMPK-induced atrophic responses in skeletal muscle cells. Full article

Background/Objectives: Cannabis use has a particularly high prevalence in individuals with psychotic disorders. Although cannabis use is generally associated with cognitive impairments in the general population, its impact on cognition in psychosis remains controversial. This study aimed to investigate the association between cannabis use and cognitive performance in a cohort of individuals affected by psychotic disorders. Methods: A total of 105 inpatients with psychotic disorders (mean age: 40.3 years; 34 females) were recruited from the University Hospital Center “Mother Teresa” in Tirana. Data collection included socio-demographic and clinical variables. Cognitive functioning was evaluated using the Montreal Cognitive Assessment (MoCA), while psychopathology was assessed with the Brief Negative Symptom Scale (BNSS), the Calgary Depression Scale for Schizophrenia (CDSS), the Psychotic Symptom Rating Scales (PSYRATS), and the Scale for the Assessment of Thought, Language, and Communication (TLC). Results: Cannabis users (CU) were more frequently male, younger, and exhibited an earlier onset of psychosis compared to non-users (No-CU). Importantly, CU demonstrated higher MoCA scores, with the most favorable outcomes observed among daily users. Conclusions: Contrary to the prevailing assumption that cannabis use exacerbates cognitive decline, our findings indicate an unexpected association between cannabis use and preserved cognitive functioning in psychosis. These results underscore the need to consider dosage, frequency, and cannabinoid composition (THC/CBD ratio) when interpreting cannabis-related cognitive outcomes in psychotic disorders. Full article

For more than a century, pathology has served as a cornerstone of modern medicine, relying primarily on static microscopic assessment of tissue morphology—such as H&E staining—which remains the “gold standard” for disease diagnosis. However, this conventional paradigm provides only a snapshot of disease states and often fails to capture their dynamic evolution and complex functional mechanisms. Moreover, animal models are constrained by marked interspecies differences, creating a persistent gap in translational research. To overcome these limitations, we propose the concept of New Pathophysiology, a research framework that transcends purely morphological descriptions and aims to resolve functional dynamics in real time. This approach integrates Organ-on-a-Chip (OOC) technology, multi-omics analyses, and artificial intelligence to reconstruct the entire course of disease initiation and to enable personalized medicine. In this review, we first outline the foundations and limitations of traditional pathology and animal models. We then systematically summarize more than one hundred existing OOC disease models across multiple organs—including the kidney, liver, and brain. Finally, we elaborate on how OOC technologies are reshaping the study of key pathological processes such as inflammation, metabolic dysregulation, and fibrosis by converting them into dynamic, mechanistic disease models, and we propose future perspectives in the field. This review adopts a relatively uncommon classification strategy based on pathological mechanisms (mechanism-based), rather than organ-based categorization, allowing readers to recognize shared principles underlying different diseases. Moreover, the focus of this work is not on emphasizing iteration or replacement of existing approaches, but on preserving past achievements from a historical perspective, with an emphasis on overcoming current limitations and enabling new advances. Full article

Objectives: The molecular characterization of male breast cancer (MaBC) has long been understudied, primarily due to its rare occurrence. Clinical management of MaBC remains profoundly challenging, with current therapeutic strategies largely extrapolated from female breast cancer protocols. Methods: Through panel-based sequencing targeting BRCA1, BRCA2, and PALB2 variants, we delineated the genomic landscape of 96 MaBC cases. Subsequent whole-exome sequencing (WES) of 84 BRCA1/2- and PALB2-mutation-negative MaBC patients, compared against 4480 healthy controls, revealed compelling findings. Results: Pathogenic variants in BRCA1/2 and PALB2 were identified in 14.6% (14/96) of MaBC cases, with BRCA2 mutations predominating at 12.5% (n = 12). Notably, one patient harbored the BRCA1 c.4015G > T stop-gained mutation, while another exhibited the PALB2 c.481_482dupGA alteration. Our analysis further uncovered 170 pathogenic/likely pathogenic mutations, with RAD50, DMD, ARSA, and ABCC6 demonstrating recurrent mutations in MaBC. Conclusions: As the inaugural germline genomic investigation of MaBC in a Han Chinese population, this work reveals clinically actionable alterations with diagnostic and therapeutic implications. These discoveries not only advance our understanding of MaBC’s molecular architecture but also underscore the critical need for dedicated research into this malignancy. Full article

Hepatocellular carcinoma (HCC) is the main type of liver cancer and one of the malignancies with the highest mortality rates worldwide. HCC is associated with diverse etiological factors including alcohol use, viral infections, fatty liver disease, and liver cirrhosis (a major risk factor for HCC). Unfortunately, many patients are diagnosed at advanced stages of the disease and receive palliative treatment only. Therefore, early markers of HCC and novel therapeutic approaches are urgently needed. The endocannabinoid system is involved in various physiological processes such as motor coordination, emotional control, learning and memory, neuronal development, antinociception, and immunological processes. Interestingly, endocannabinoids modulate signaling pathways involved in cell survival, proliferation, apoptosis, autophagy, and immune response. Consistently, several cannabinoids have demonstrated potential antitumor properties in experimental models. The participation of metabotropic and ionotropic cannabinoid receptors in the biological effects of cannabinoids has been extensively described. In addition, cannabinoids interact with other targets, including several ion channels. Notably, several ion channels targeted by cannabinoids are involved in inflammation, proliferation, and apoptosis in liver diseases, including HCC. In this literature review, we describe and discuss both the endocannabinoid system and exogenous phytocannabinoids, such as cannabidiol and Δ⁹-tetrahydrocannabinol, along with their canonical receptors, as well as the cannabidiol-targeted ion channels and their role in liver cancer and its preceding liver diseases. The cannabidiol-ion channel association is an extraordinary opportunity in liver cancer prevention and therapy, with potential implications for several environments that are for the benefit of cancer patients, including sociocultural, public health, and economic systems. Full article

Background/Objectives: The Rho^P23H/WT mouse line is a commonly used model to study rhodopsin P23H-associated autosomal dominant retinitis pigmentosa. Previous studies in Rho^P23H/WT mice have largely focused on retinal changes occurring at one month of age and later, and have indicated a compensatory thickening of inner retinal layers in response to rod degeneration. However, the effect of disease processes during early postnatal retinal development remains understudied. Methods: In this study, we investigated the retinal response to rod dysfunction during early postnatal developmental ages P8–P24 in our novel Rho^P23H/WT reporter line, RhoP23H.GFP, which expresses green fluorescent protein (GFP) exclusively in cone photoreceptors. Results: Histological analysis revealed no significant difference in retinal thickness in RhoP23H.GFP mice compared to healthy controls at the ages investigated. RhoP23H.GFP retinas initially exhibited a greater mislocalization of rhodopsin to the rod cell bodies at P12, though this mislocalization normalized to wildtype by P24. Most notably, flow cytometry revealed significantly increased cone photoreceptor numbers in P12 (61%), P16 (48%), and P24 (40%) RhoP23H.GFP mice compared to wildtype controls, indicating a possible compensatory response of cone photoreceptors to rod dysfunction. Additionally, cone morphology appeared altered in diseased cones. Conclusions: Our results suggest that cones may undergo a developmental compensatory adaptation in response to rod dysfunction, providing new insights into early disease mechanisms of retinitis pigmentosa. Full article

Objective: To assess whether chronic rhinosinusitis (CRS) severity is associated with obstructive sleep apnea (OSA) in adult people with cystic fibrosis (pwCF). Methods: We conducted a retrospective single-center study of 44 adults with CF who underwent overnight polysomnography (PSG), Epworth Sleepiness Scale (ESS) assessment, and sinus computed tomography (CT). CRS severity was quantified using the Lund–Mackay score (LMS) and the main nasal cavity score (MNCS). OSA was defined by Apnea–Hypopnea Index (AHI) thresholds per American Academy of Sleep Medicine criteria. Results: Participants had a mean age of 31.1 ± 8.4 years and a mean percent predicted FEV1 of 51.8 ± 15.7. Sinus CT showed radiological evidence of CRS in all participants. Mean AHI was 5.3 ± 4.4/h; 48% had AHI ≥ 5/h. There were no significant differences between pwCF with and without OSA in age, sex, BMI, lung function, total sleep time, sleep efficiency, or ESS score (all p > 0.05). Mean LMS and MNCS did not differ between OSA and non-OSA groups (both p > 0.05), and neither score correlated with PSG parameters or ESS (all p > 0.05). Receiver operating characteristic (ROC) analysis demonstrated low discriminative ability of LMS and MNCS for predicting OSA (AUCs < 0.70, p < 0.05). Conclusions: In this cohort of adults with CF, CT-based CRS severity was not associated with OSA. Given the substantial prevalence of OSA observed, PSG screening should be considered irrespective of CRS severity. Full article

Introduction: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS) that leads to demyelination of CNS neurons and is influenced by genetic, environmental, and lifestyle factors, including diet and obesity. Methods: This review aims to analyze at the molecular level the relationship between obesity, as a chronic inflammatory condition, and the pathophysiology of MS, as a chronic autoimmune inflammatory disease, in order to understand the complex links between obesity and MS through a search of the PubMed and Google Scholar databases. Discussion: Chronic inflammation and OS are interconnected processes, causing a toxic state, which contributes to the development of CNS neuroinflammation and neuronal damage, resulting in neuronal demyelination and the onset of MS. Adipose tissue is a complex endocrine organ; in addition to being a lipid storage organ, it secretes cytokines and adipokines, which are involved in the regulation of hormones, metabolism, inflammation, and whole-body homeostasis. Obesity triggers chronic low-grade inflammation, disruption of the blood–brain barrier (BBB) and brain metabolism, infiltration of the CNS by immune cells, production of ROS, and generation of oxidative stress (OS). Anti-inflammatory and pro-inflammatory adipokines are also implicated in MS and obesity. Conclusions: Obesity affects MS through common underlying mechanisms and seems to be a modifiable risk factor. Antioxidant and anti-inflammatory compounds with multi-functional characteristics could be additional tools to slow the progression of MS and its promotion through obesity while also offering potential treatment options for both conditions via their multi-targeting characteristics. Full article

Background/Objectives: Metabolic syndrome (MetS) conditions lead to structural and functional alterations in cardiomyocytes, microvasculature, and extracellular matrix (ECM), leading to myocardial fibrosis and impaired diastolic function. Cardiac lymphatic vessels (LVs) are increasingly recognized as key regulators of myocardial homeostasis, yet their response to MetS remains poorly understood. Therefore, we aimed to investigate transcriptional changes in cardiac lymphatic endothelial cells (LECs) in db/db mice, a well-established model of MetS. Methods: Using flow cytometry-sorted LECs and RT-PCR, we analyzed mRNA expression of genes involved in lymphangiogenesis, metabolism, mechanotransduction, immune cell trafficking, and ECM interactions. Results: Our findings show the transcriptional plasticity of cardiac LECs in response to MetS. Conclusions: Although our study is limited by the lack of protein-level validation and functional assays, our approach provides a broader interpretative framework and identifies potential directions for future research, including functional studies and pathway-specific investigations of the identified genes to assess their impact on lymphatic flow and cardiac function. Understanding LEC responses to metabolic stress may uncover novel therapeutic targets for heart failure associated with MetS. Full article

Background: Menopause, a critical period during a woman’s life, is characterized by various changes, including disturbances in their oxidative balance and circadian rhythm. Currently, the gut microbiome is suggested as an important participant in these processes. Methods: This study involved 96 menopausal women. Their sleep quality was assessed using three questionnaires: the Insomnia Severity Index (ISI), the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS). The GSH and GSTP1 contents in the serum were measured by means of immunoassay methods, while the composition of the gut microbiome was determined via molecular genetic methods. Results: E. coli, K. oxytoca, S. aureus, Enterobacter spp., Shigella spp., Streptococcus spp., Prevotella spp., and M. stadmanae were found to correlate with the GSH content in different sleep groups, while the presence of K. oxytoca, S. aureus, Enterococcus spp., K. pneumoniae, and M. stadmanae is also important for the GSH level in several of these groups. F. prausnitzii, S. aureus, P. micra, Acinetobacter spp., and E. rectale are associated with GSTP1 concentration in various sleep groups, while the presence of F. nucleatum and P. micra is also relevant for the GSTP1 content in some of these groups. Conclusions: Thus, in menopausal women, the composition and structure of the gut microbiota are associated with sleep disorders. GSH and GSTP1 are associated with some gut microbiome markers in menopausal women, but these relationships differ in different sleep disorders. Full article

Background: Obstructive sleep apnea (OSA) is a heterogeneous disorder traditionally classified and stratified by the apnea–hypopnea index (AHI), which fails to capture variability in symptom burden, comorbid associations, and treatment responses. Clinical phenotyping has emerged as a promising strategy to improve disease characterization and management over the last decade. Methods: We conducted a narrative literature review of studies published between January 2014 and December 2022 that used cluster analysis to define OSA phenotypes in adults with moderate-to-severe disease (AHI ≥ 15 events/h). Eligible studies employed validated questionnaires, symptom reporting, and comorbidity profiling to identify subgroups. Findings were summarized across diverse populations, with emphasis on phenotype reproducibility, comorbidity associations, and treatment implications. Results: Across international cohorts, three reproducible symptom-based phenotypes were consistently identified: excessively sleepy (ES), disturbed sleep (DS), and minimally symptomatic (MS). Additional subtypes, such as upper airway dominant (UA) and moderately sleepy (MoS), were described in larger cohorts. Phenotypes differed in demographic profiles, comorbidity burden, and treatment adherence. ES patients exhibited the greatest symptom burden, higher cardiovascular risk, and better adherence to positive airway pressure (PAP) therapy, with significant symptomatic improvement. DS patients frequently reported insomnia symptoms, showed modest PAP-related gains, and may benefit from adjunctive insomnia-targeted interventions. MS patients, despite low symptom burden, often carried substantial comorbidity risk, specifically buildup of OSA-related cardiovascular risk. Conclusions: Symptom-based OSA phenotypes are reproducible across diverse populations and provide clinically meaningful insights beyond AHI. They allow for improved risk stratification, highlight gaps in detection of minimally symptomatic patients, and inform personalized treatment strategies. Integrating phenotyping into clinical practice has the potential to enhance diagnostic accuracy, optimize therapeutic outcomes, and refine cardiovascular risk prediction in OSA. Full article

Background/Objectives: No effective intervention currently exists for non-compressible pulmonary injury, especially in a prehospital setting. Visco-liquids like trisilanol i-octyl POSS could remedy this. POSS resists hemorrhage and activates clotting; this can be augmented with kaolin (22.5%; PK) or chitin (10%; PC). Methods: We tested the efficacy of POSS, PK, and PC in treating incisional lung wounds in swine (39 ± 1 kg; n = 10). An incisional wound was made in the lung via a left thoracotomy, allowed to bleed freely for 30 s, and then no treatment (UNT), gauze with compression (GC), or POSS, PK, or PC was applied (1.5 mL). Each treatment was applied once per animal for a total of 5 wounds. Wounds were observed for 10 min for hemostasis and pneumostasis; GC treatments were assessed at 3 min intervals. Results: POSS and PC produced hemostasis in 8 of 10 wounds; GC: 7 (all significant from UNT); PK: 5 and UNT: 1. PK was not different from any group. POSS (2 ± 0.3 min) and PC (1.4 ± 0.4 min) clotted more quickly than GC (8 ± 3 min); PK was intermediate (3.8 ± 2 min) and not different from any other group. Pneumostasis was achieved in all POSS, PC, and PK, and only after hemostasis in the GC group. Conclusions: Because both POSS and PC provided quick and lasting hemorrhage and pneumatic control in this model, without need for compression, these results support the concept that these types of liquid POSS compounds could prove to be efficacious in prehospital treatment of non-compressible trauma wounds. Full article

Cancer remains a leading global cause of morbidity and mortality. Modifiable lifestyle factors, including avoidance of tobacco use and excessive ultraviolet radiation, healthy dietary patterns, regular physical activity, and weight management, play key roles in prevention and care. This narrative review synthesizes evidence on lifestyle-based interventions influencing cancer risk, treatment tolerance, and survivorship. A literature search was conducted in PubMed and Scopus, supplemented by manual screening via Google Scholar. The time frame (2001–2025) was selected to reflect evidence produced within the modern era of molecular oncology and contemporary lifestyle medicine research. Eligible publications addressed carcinogen exposure (tobacco, alcohol, ultraviolet radiation), diet and nutritional strategies, physical activity, sedentary behavior, obesity, metabolic health, complementary therapies, and cancer outcomes. Evidence indicates that reducing exposure to tobacco and ultraviolet radiation remains central to cancer prevention. Adherence to predominantly plant-based diets, regular physical activity, and maintenance of healthy body weight are consistently associated with lower incidence of several cancers, including breast, colorectal, and liver cancer. Nutritional strategies such as caloric restriction, ketogenic diets, and fasting-mimicking diets show promise in improving treatment efficacy and quality of life. Complementary and mind–body therapies may alleviate treatment-related symptoms, although high-quality evidence on long-term safety and effectiveness is limited. Integrating lifestyle medicine into oncology offers a cost-effective, sustainable strategy to reduce cancer burden and enhance survivorship. Comprehensive programs combining carcinogen avoidance, dietary regulation, structured exercise, and effective radiation risk mitigation may extend healthspan, improve treatment tolerance, and help prevent recurrence. Full article

Background and aims: This study aimed to determine whether neuromuscular electrical stimulation (NMES) combined with nutritional counseling promotes an increase in thigh muscle thickness (MT), as well as to assess changes in the relationship between MT and intracellular water (ICW). Body composition methods such as ultrasound may overestimate muscle mass, depending on the context, because they cannot distinguish the contractile protein component from body fluids, including intra- and extracellular water. Methods: A pilot randomized parallel trial was conducted with 25 hospitalized patients with unselected cancer, who were divided into two groups: NMES + Diet and Diet. Both groups received nutritional counseling, but only one group received NMES. NMES was applied bilaterally to the origin and insertion points of the quadriceps twice daily, with a 3 h interval between sessions, for 7 consecutive days. MT and ICW were measured before and after the intervention. Food consumption was assessed using a 24 h dietary recall at baseline and at the end of the study to quantify and adjust macronutrient intake during the intervention. Results: Both treatment groups (Diet × NMES + Diet) showed similar dropout rates which means participants in the more intensive treatment did not quit more frequently, once intervention with NMES was feasible and well tolerated. In addition, both groups showed a reduction in carbohydrate intake (p = 0.012) and an increase in leucine intake (p < 0.001) post-intervention. The increase in leucine intake was significantly greater in the NMES + Diet group (p < 0.001), and the reduction in carbohydrate intake was also greater in this group (p = 0.012). In the delta analysis, the NMES + Diet group showed an increase in thigh MT, whereas the Diet group experienced a decrease (Diet group: ∆ = −2.53 ± 3.73 mm vs. NMES + Diet group: ∆ = 2.09 ± 2.27 mm, p = 0.001). Moreover, the MT/ICW ratio was higher in the NMES + Diet group post-intervention (Diet group: ∆ = −0.15 ± 0.19 mm/L vs. NMES + Diet group: ∆ = 0.11 ± 0.09 mm/L, p < 0.001), while no significant difference in ICW was observed between groups. Conclusions: short-term intervention combining nutritional counseling with NMES increased thigh MT and the MT/ICW ratio, possibly due to NMES-induced extracellular water expansion. Full article

Objectives: This study investigates the effects of resveratrol on systemic inflammatory, oxidative, and metabolic responses in a rat model that combines surgical trauma with prior exposure to Single Prolonged Stress (SPS), an established experimental protocol for modeling post-traumatic stress disorder (PTSD). Methods: Male Wistar rats (n = 21) were randomly assigned to three groups: (I) control (polyvinylpyrrolidone, PVP), (II) SPS + laparotomy + PVP), and (III) SPS + laparotomy + resveratrol. Resveratrol (5 mg/kg of body weight/day) or vehicle was administered intragastrically for seven days. Serum concentrations of cortisol, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), glucose, insulin, lipid fractions, and thiobarbituric acid–reactive substances (TBA-RS) were determined by enzyme-linked immunosorbent assay and spectrophotometric methods. Insulin resistance was assessed using the homeostatic model assessment of insulin resistance (HOMA-IR) index. Results: Combined SPS and surgical trauma induced a pronounced systemic inflammatory response characterized by elevated cortisol (+138%), TNF-α (+83%), IL-6 (+465%), and ceruloplasmin (+71%), as well as hyperglycemia, hyperinsulinemia, increased HOMA-IR, and atherogenic dyslipidemia with reduced high-density lipoprotein cholesterol (HDL-CH; −64%), elevated triglycerides (TGs; +216%), and very low-density lipoprotein cholesterol (VLDL-CH; +218%). Marked activation of lipid peroxidation was observed, as indicated by increased TBA-RS levels before and after incubation. Resveratrol administration significantly decreased cortisol (−45%), TNF-α (−47%), and IL-6 (−85%), normalized the IL-10/IL-6 ratio, and reduced ceruloplasmin levels (−13%). The compound improved insulin sensitivity (HOMA-IR −50%), elevated HDL-CH (+115%), and lowered TGs and VLDL-CH (−44%). It also attenuated both basal and inducible lipid peroxidation (TBA-RS −11% and −13%), indicating restoration of antioxidant capacity. Conclusions: Thus, resveratrol effectively counteracts the neuroendocrine, inflammatory, and metabolic disturbances induced by combined PTSD-like stress and surgical trauma. Full article