Search Results (1,858)

Background/Objectives: The clinical management of ductal carcinoma in situ (DCIS) remains controversial due to its heterogeneous biological behavior and uncertain risk of progression. Standard treatment often includes surgery and radiotherapy, although the actual recurrence risk varies considerably among patients. This study aimed to evaluate recurrence patterns and associated clinicopathological factors in a large single-center cohort of patients with pure DCIS. Methods: We retrospectively analyzed 403 patients with histologically confirmed pure DCIS treated with breast-conserving surgery or mastectomy between 2016 and 2023. Clinical, imaging, pathological, and treatment-related variables were assessed. Descriptive and exploratory comparative analyses were performed between patients with and without ipsilateral recurrence. Results: A total of 417 lesions were analyzed, with 21 ipsilateral recurrences (5%) observed during follow-up. Among recurrent cases, 57% were non-invasive recurrent DCIS and 38% were invasive carcinomas. Most recurrences occurred in patients treated with breast-conserving surgery, and 52% of recurrent patients had not received adjuvant radiotherapy. All recurrent cases were estrogen receptor–positive at initial diagnosis, whereas none had received endocrine therapy. No clear association between recurrence patterns and tumor grade or tumor size emerged in this exploratory analysis. No distant metastases or disease-related deaths were observed during follow-up. Conclusions: Recurrence after treatment for pure DCIS was relatively uncommon and frequently non-invasive. Traditional clinicopathological variables alone appeared insufficient to consistently identify recurrence patterns in this cohort. These findings support the need for more individualized risk stratification approaches integrating clinical, imaging, and molecular factors in order to reduce potential overtreatment in selected patients with DCIS. Full article

Background and Objectives: Head and neck squamous cell carcinoma (HNSCC) is a biologically heterogeneous malignancy with variable clinical behavior and prognosis. Human papillomavirus (HPV)-associated tumors represent a distinct subgroup; however, data from Eastern European populations remain limited. This study aimed to evaluate the association between HPV DNA status and nodal involvement in a Bulgarian HNSCC cohort and to explore whether HPV genotype distribution is related to nodal involvement and therapeutic strategy. Materials and Methods: A prospective multicenter observational study with a cross-sectional analytical endpoint was conducted. Fifty patients with histologically confirmed HNSCC were included. Clinical and pathological data were collected, and HPV detection and genotyping were performed using molecular-based methods. Associations between HPV-related variables, nodal status (N0 vs. N+), and treatment strategy were evaluated using univariate tests. HPV status reflects DNA detection only and does not confirm transcriptionally active infection. Results: HPV DNA positivity was identified in 15/50 patients (30.0%). A higher proportion of nodal involvement was observed among HPV-positive patients compared with HPV-negative patients (46.7% vs. 17.1%, p = 0.040; crude OR = 4.23); however, this finding may be influenced by anatomical site distribution. In unadjusted analysis, HPV DNA positivity showed a relationship with nodal involvement (crude OR = 4.23; p = 0.040), although this should be interpreted cautiously. Multivariable analysis was not performed due to the limited number of outcome events. Differences in treatment allocation were observed between HPV-positive and HPV-negative patients; however, this finding may be confounded by anatomical site distribution and likely reflects differences in tumor localization rather than HPV-specific effects. Genotype analysis revealed heterogeneity, including multiple HPV types. Conclusions: HPV DNA positivity was observed in relation to nodal involvement in unadjusted analysis; however, this finding may be confounded by anatomical site and should be considered exploratory. Full article

Hypertrophic scars are characterized by excessive collagen deposition, fibrotic remodeling, and functional impairment. However, the ability of current models is limited in recapitulating human pathology. This study presents a novel approach using induced pluripotent stem cell-derived scar organoids to model hypertrophic scar characteristics in vitro. Following established protocols, human pluripotent stem cells were differentiated into skin organoids and induced fibrotic transformation by treatment with TGF-β1 (10 ng/mL) and hypoxia (5% O₂) from day 45 onward. Scar organoids exhibited significant contraction and increased collagen I deposition compared with skin organoids. Immunofluorescence analysis showed reduced LHX2 expression, indicating loss of hair follicle development, while collagen I expression was significantly elevated. Dark-field imaging revealed marked morphological divergence between skin and scar organoids. RNA sequencing revealed distinct transcriptomic profiles. Expression of hair follicle-associated gene families (KRT and KRTAP) was upregulated in scar organoids, whereas epidermal structure-related genes (KRT4, KRT7, CLDN7, and WNT7) were downregulated. These findings demonstrate that iPSC-derived scar organoids successfully recapitulate key features of human hypertrophic scars, including excessive collagen production, loss of skin appendage development, and contractile behavior. This platform offers potential for future applications in drug screening, precision medicine, and understanding the molecular mechanisms underlying scar formation. Full article

Background: Neuroinflammation and gut–brain axis (GBX) dysregulation are key pathological drivers of stress-related neuropsychiatric disorders. Zhi-Zi-Chi Decoction (ZZCD), a classic Traditional Chinese Medicine (TCM) formula, has been clinically used to alleviate mental disturbances via the TCM principle of “clearing heat and relieving restlessness.” Still, its modern neuroprotective mechanisms, especially its links to gut microbiota and central signaling pathways, remain incompletely elucidated. Purpose: This study aimed to systematically investigate the therapeutic effects of ZZCD on chronic restraint stress (CRS)-induced neurodysfunction in mice and clarify its mechanisms from the perspectives of TCM theory, material basis, gut microbiota–metabolite axis, and central signaling pathways. Method: CRS mice were treated with ZZCD or protocatechuic acid. Behavioral tests evaluated depression- and anxiety-like behaviors. UHPLC-Q-TOF/MS identified ZZCD’s chemical constituents; 16S rRNA sequencing and untargeted metabolomics analyzed gut microbiota and metabolite changes. Western blot, immunofluorescence, and proteomics examined neuroinflammation, microglial polarization, and signaling pathway activity (PI3K/Akt/mTOR, AMPK). Results: ZZCD reversed CRS-induced depression- and anxiety-like behaviors and suppressed neuroinflammation. Mechanistically, UHPLC-Q-TOF/MS identified 424 ZZCD constituents, with prenol lipids, organooxygen compounds, and flavonoids as the most abundant. ZZCD reversed CRS-induced imbalance in gut microbiota, reducing pro-inflammatory Prevotella and enriching beneficial Lactobacillus, and mediated the enrichment of the prebiotic metabolite PCA in colonic and serum samples, which crossed the blood–brain barrier (BBB) to exert neuroprotection. Additionally, ZZCD and PCA normalized the PI3K/Akt/mTOR pathway and activated AMPK, promoting M2 microglial polarization and restoring synaptic plasticity. Conclusions: ZZCD exerts antidepressant effects by a gut-microbiota-dependent modulation of PCA-PI3K/Akt/mTOR and AMPK dual axes that converts microglia from M1 to M2, providing ethnopharmacological evidence and a mechanistic rationale for its clinical application in major depressive disorder. Full article

Exposure to blast waves without kinetic, penetrating, thermal, or toxic components causes a distinct form of traumatic brain injury, termed primary blast-induced TBI (pbTBI). Clinical manifestations of pbTBI span a wide spectrum, ranging from life-threatening intracranial hemorrhage, hyperemia, and delayed cerebral edema to mild and transient neurological symptoms without detectable structural abnormalities on routine imaging. At the mild end of the spectrum, symptoms after a single exposure may resolve quickly, yet repeated exposures—even at very low levels, termed “subconcussive”—can develop into post-concussive syndrome (PCS) or persistent post-concussive symptoms (PPCS) in a subset of individuals. Despite extensive studies, the molecular pathobiology linking primary blast exposure to delayed and sometimes chronic neurobehavioral deficits remains incompletely understood. A mechanistic framework connecting blast-wave physics to biomechanics to biological vulnerability may therefore help define exposure hazards, interpret clinical symptomatology, and guide diagnostic and therapeutic development. This review summarizes the physics of primary blast waves, the resulting biomechanical responses, and candidate biological substrates, emphasizing structures and interfaces with distinct acoustic impedances across anatomical, tissue, cellular, and molecular scales. We synthesize evidence supporting the hypothesis that the cerebral vasculature and endothelial cells represent critically vulnerable substrates of primary blast-wave injury, in part because the vascular tree constitutes the brain’s largest and most widely distributed interface between compartments with different acoustic impedances. Across experimental and human studies, endothelial stress, vascular injury, and downstream neuroinflammation emerge as convergent molecular responses to primary blast exposure. Temporal dynamics are central to understanding pbTBI because many blast-induced processes unfold in sequential phases. These observations support conceptualizing pbTBI as a condition characterized by prominent cerebrovascular injury of varying severity with secondary consequences for neuronal signaling, network function, and behavior. Within this framework, cerebrovascular and neurovascular unit (NVU) dysfunction provides a parsimonious bridge between primary blast-wave exposure and chronic symptom trajectories, where vascular pathology may offer more accessible therapeutic targets than neuronal injury. Key knowledge gaps include identifying which physical component(s) of the blast are most injurious, establishing biologically meaningful dose–response relationships at molecular and physiological levels, and defining windows of vulnerability during recovery that are relevant to repeated exposures. Addressing these gaps is essential for refining safety protocols, improving diagnostic specificity through mechanism-informed biomarkers, and developing evidence-based molecular and vascular therapeutic targets for pbTBI-associated conditions. Progress will require integrating waveform-aware dosimetry with longitudinal physiological and molecular monitoring across both preclinical and human cohorts. Such integration offers a practical path toward translating blast physics into actionable medical guidance for prevention, triage, and recovery management. Full article

Background: Uterine sarcomas are rare, heterogeneous malignancies with distinct pathological behaviors. This study aimed to identify clinicopathological characteristics, prognostic risk factors, and potential therapeutic targets to enhance clinical management. Methods: A retrospective analysis was conducted on 148 patients with uterine sarcoma treated at Peking University People’s Hospital between 1996 and 2025. Clinical outcomes, pathological subtypes, and immunohistochemical profiles were assessed. Additionally, bioinformatics analyses from RNA bulk sequencing of GEO datasets (GSE87581, GSE85383, GSE222045 and GSE64763) were performed to elucidate molecular characteristics across subtypes. Results: The most prevalent subtypes were uterine leiomyosarcoma (uLMS; 38.5%) and low-grade endometrial stromal sarcoma (LG-ESS; 29.7%). The 5-year recurrence rate was 50.5%, with frequent metastases to the pelvis and lungs. LG-ESS demonstrated the most favorable 5-year survival rate (90.3%), significantly higher than that of uLMS (61.8%) and undifferentiated uterine sarcoma (50.0%). Multivariate analysis identified histological subtype, stage, and coagulative necrosis as independent prognostic factors for overall and progression-free survival. Transcriptomic profiling revealed immunosuppression (CSF1R/CSF3R expression) in high-grade ESS, while uLMS exhibited activation of cell cycle and homologous recombination pathways. Conclusions: Histological subtype, stage, and coagulative necrosis were critical prognostic factors in uterine sarcoma. The findings suggest that vigilant pulmonary surveillance and further investigation into tailored therapeutic strategies may be warranted-including endocrine therapy for hormone-receptor-positive tumors, immunotherapy for high-grade ESS, and PARP inhibitors for uLMS. However, these hypotheses require thorough preclinical and clinical validation. Additionally, caution should be exercised to avoid overtreatment of chemotherapy in early-stage uLMS. Full article

Cell membranes exhibit specific structural and chirality properties influencing their biological behavior and functionality. Artemia salina endothelial-like cell membranes, structurally simpler, provide insights into fundamental cellular structures, whereas human endothelial cell membranes represent complex, specialized tissues essential for understanding advanced vascular functions. This study aims to compare the structural and chiral properties of Artemia salina endothelial-like cell membranes and human endothelial cell membranes through computational molecular-level modeling, evaluating potential histological and biological implications. Membrane models for Artemia salina and human endothelial cells were developed using Protein Data Bank (PDB) structures. Computational descriptors, including radius of gyration (Rg), solvent-accessible surface area (SASA), geometric asymmetry index (GAI), chiral moment (CM), fractal dimension (FD), and additional chirality indices (SOC, HCI, ACI, CAI, ME, RDF) were calculated to assess membrane complexity, structural asymmetry, and chirality. Significant structural divergences between Artemia salina and human endothelial membranes were identified. Artemia membranes exhibited lower values of Rg, SASA, and chirality metrics, indicating simpler, more symmetrical structures. In contrast, human endothelial membranes displayed elevated structural complexity, pronounced asymmetry, higher chirality indices, and more significant structural heterogeneity, consistent with their specialized physiological functions. Principal Component Analysis (PCA) further highlighted clear structural clustering distinctions between the two models. The comparative analysis underscores fundamental structural and functional divergences between Artemia salina and human endothelial cell membranes. Artemia membranes represent simplified, uniform cellular arrangements optimized for fundamental physiological roles, while human endothelial membranes exhibit complex architectures, structural specialization, and significant chirality essential for dynamic vascular functionalities. These computational descriptors offer potential diagnostic biomarkers for evaluating endothelial functionality and pathological states. Full article

Background: Traumatic brain injury (TBI) affects millions of individuals annually and remains a major global cause of neurological disability and death. Tau protein hyperphosphorylation, particularly in its cis conformation, is a major pathological hallmark contributing to neurodegeneration following TBI. Single-chain variable fragments (scFvs), despite their diagnostic potential, suffer from rapid renal clearance and short circulation half-lives, which limit their in vivo performance. PEGylation is therefore employed to prolong systemic circulation and improve the pharmacokinetic behavior of scFvs, enabling more effective brain retention and target engagement. Methods: In this study, we utilized a previously validated anti-cis p-tau scFv antibody fragment, radiolabeled with technetium-99m tricarbonyl (^99mTc(CO)₃), as a diagnostic tracer to detect tau pathology in TBI rat models. The antibody was conjugated with polyethylene glycol (PEG, 20 kDa); PEGylation efficiency was determined by quantifying the products on SDS-PAGE, and the products were subsequently radiolabeled. Results: Radiochemical purity (RCP) was ~95.4% for the non-PEGylated tracer (^99mTc-AININ20) and ~92.7% for the PEGylated form (^99mTc-AININ20-PEG), with both showing >90% radiochemical purity consistently. Upon systemic administration, PEGylated scFv was able to cross the blood–brain barrier (BBB) and selectively accumulated in injured regions, as confirmed by single-photon emission computed tomography (SPECT) imaging. Both PEGylated and non-PEGylated scFv tracers showed significantly higher brain uptake in TBI rats compared to healthy controls (p < 0.0001). At 24 h, the PEGylated form exhibited a significantly higher brain signal than the non-PEGylated version (p < 0.0001), indicating improved tracer retention. Biodistribution analysis at 2 h post-injection showed significantly reduced renal clearance for the PEGylated tracer and increased hepatic uptake compared to the non-PEGylated form. At 24 h, in vivo imaging confirmed sustained brain retention, highlighting improved pharmacokinetics and imaging potential. Conclusions: These results support PEGylated scFv as a promising SPECT imaging agent for early detection of tauopathy in TBI, offering enhanced brain retention and improved pharmacokinetics. Full article

Polygonatum kingianum (PK), a plant with established medicinal and nutritional applications, has shown potential neuroprotective activity in Alzheimer’s disease (AD). Nevertheless, the effects of its major bioactive fractions remain unclear. This study examined the neuroprotective effects of PK polysaccharides (PKPs) and saponins (PKSs) using an AlCl₃-induced zebrafish model. Chemical analyses revealed that PKP was dominated by a low-molecular-weight fraction (1890 Da, 83.8%), whereas LC-MS analysis detected 13 tentatively identified steroidal saponins within PKS, including diosgenin. Furthermore, behavioral assessments demonstrated that both PKP and PKS improved locomotor and cognitive functions. PKP exhibited a stronger effect on the cholinergic system; its acetylcholinesterase (AChE) inhibitory activity at 60 μg/mL was comparable to that of donepezil under the experimental conditions. Histopathological analysis indicated that PKP showed a stronger effect in reducing neuronal apoptosis, resulting in a 68% reduction in the number of apoptotic cells. Conversely, PKS displayed a greater effect on amyloid pathology, reducing amyloid-beta (Aβ) aggregation by 62%. These findings suggest that PKP and PKS showed different neuroprotective profiles in the zebrafish model. Specifically, PKP was more closely associated with cholinergic regulation and neuronal survival, whereas PKS showed a stronger effect on Aβ aggregation. This study provides experimental support for the potential use of PK-derived fractions as food-derived bioactive components for alleviating AD-related pathological changes. Full article

Suicidal behavior includes completed suicides and suicide attempts, which reflect different risk profiles and require joint analysis. In the Republic of Kazakhstan, recent data that simultaneously assess temporal trends, regional heterogeneity, and the probability of a fatal outcome remain limited. This study aimed to comprehensively assess the dynamics of completed suicides and suicide attempts in the Republic of Kazakhstan in 2023–2024, describe regional and age differences, and identify factors associated with a higher likelihood of completed suicide versus an attempt. A nationwide retrospective population-based observational study was conducted using anonymized officially registered data on suicidal behavior in Kazakhstan for 2023–2024. All registered episodes were included (n = 15,478), including completed suicides (n = 7102) and attempts (n = 8376). Age strata were 5–14, 15–24, 25–34, 35–44, 45–54, 55–64, 65–74, and 75+. Rates per 100,000 population, the attempt-to-completed ratio, and the proportion of completed suicides among all episodes were calculated. Associations were assessed using odds ratios (ORs) with 95% confidence intervals (reference group: 15–24 years) and the Cochran–Armitage χ² test for trend (p < 0.05). In 2024 versus 2023, the number of completed suicides decreased from 3694 to 3408 (−7.7%), and attempts from 4340 to 4036 (−7.0%). Among minors, completed cases decreased (−14.2%), while attempts increased (+20.5%). The completed suicide rate declined from 18.6 to 17.2 per 100,000, and the attempt rate from 21.9 to 20.4 per 100,000. Across regions in 2024, completed suicide rates ranged from 11.7 to 28.8 per 100,000, attempt rates from 5.0 to 46.5 per 100,000, and the attempt-to-completed ratio from 0.3 to 3.6. Age showed a stable lethality gradient, with the proportion of completed suicides among all episodes increasing from 26.4% (15–24) to 67.7% (75+). The risk of completed suicide versus an attempt was highest in the 75+ group (OR = 5.86; 95% CI 5.15–6.67; p < 0.001) and increased sharply after age 45. In 2024, the likelihood of a fatal outcome was significantly higher for episodes with unestablished circumstances (OR = 2.29; 95% CI 2.08–2.52; p < 0.001) and severe somatic diseases (OR = 2.64; 95% CI 1.91–3.65; p < 0.001), whereas family/relationship conflicts were more common among attempts (e.g., conflict with parents OR = 0.12; 95% CI 0.06–0.21; p < 0.001). Similar patterns were observed in 2023 (unestablished circumstances OR = 1.92; severe somatic diseases OR = 2.22; conflict with parents OR = 0.17; all p < 0.001). In 2023–2024, Kazakhstan showed a decline in registered completed suicides and attempts; however, the structure of suicidal behavior is becoming more complex. Attempts among minors are increasing, high regional heterogeneity persists, and there is a pronounced age-related increase in the probability of a fatal outcome, especially after age 45. Prevention priorities should include targeted measures for older age groups and patients with severe somatic pathology, strengthening programs for early identification and support of minors, and improving the quality of registration and interagency analysis of the circumstances of fatal outcomes. Full article

Tardive dyskinesia (TD) is a persistent hyperkinetic movement disorder associated with prolonged dopamine D2 receptor blockade, particularly during chronic haloperidol (HP) exposure. Emerging evidence suggests that TD-like pathology is sustained by an interconnected redox–mitochondrial–inflammatory network within striatal circuits; however, the regulatory architecture of this network remains incompletely defined. Hyperoside (HS), a flavonol glycoside with cytoprotective properties, has been implicated in cellular stress-response modulation, yet its role in antipsychotic-induced motor dysfunction remains unclear. In this study, a six-group mechanistic design was employed in which rats received HP (1 mg/kg, i.p., 21 days) to induce TD-like orofacial dyskinesia (OD), quantified by vacuous chewing movements (VCMs) and tongue protrusions (TPs). HS (30 mg/kg, i.p.) was administered alone or in combination with HP, with or without pharmacological inhibition of nuclear factor erythroid 2–related factor 2 (Nrf2) using ML385. HP exposure induced progressive dyskinetic behavior accompanied by oxidative and nitrosative stress, mitochondrial dysfunction, increased pro-inflammatory cytokines, and elevated caspase-3 activity in the striatum. HS significantly attenuated behavioral abnormalities while restoring redox balance, preserving mitochondrial enzyme activities, and reducing inflammatory and apoptotic signaling. Notably, Nrf2 inhibition intensified molecular pathology without proportionally worsening behavioral outcomes, indicating a dissociation between biochemical vulnerability and overt motor expression. Furthermore, ML385 markedly attenuated HS-mediated protection across multiple endpoints. Collectively, these findings support a potential protective role for Nrf2-related regulatory mechanisms in limiting network destabilization in TD-like pathology, while highlighting the importance of integrated stress-response pathways in modulating disease progression. Full article

Background: Cang-ai volatile oil (CAVO) is a traditional Chinese medicine with properties that soothe the liver and alleviate depression. CAVO is widely utilized in the field of antidepressant research and has surfaced as a possible treatment for depression. Depression is a common affective disorder and effective treatment methods are still limited. CAVO is effective in treating depression; however, the exact mechanism is still unclear. This study aimed to explore the likely mechanism by which CAVO reduces symptoms of depression in rats exposed to chronic unpredictable mild stress (CUMS). Methods: We established a CUMS model in Sprague–Dawley rats and administered CAVO via nebulization to evaluate its therapeutic effect. Behavioral and histology tests were conducted to evaluate brain tissue damage. We utilized metabolomics combined with proteomics to analyze the effects of CAVO. We then assessed molecular validation to further clarify the molecular mechanism of its activity. Results: In CUMS model rats, inhaling aerosolized CAVO reduced brain pathology and depression-like behaviors. CAVO changed serum levels of inflammatory cytokines and neurotrophic factors. Biomarkers linked to CAVO’s antidepressant effects were found via metabolomics. Functional analyses highlighted key molecular players such as TrkB, and CREB, and a close association with the antidepressant action of CAVO was confirmed. Conclusions: This study reveals that CAVO reduces depression-like behaviors in CUMS rats by regulating the NT/Trk signaling pathway. These results demonstrate CAVO’s therapeutic potential and lay the groundwork for future studies and the creation of depressive treatments. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. Its main pathological features are extracellular plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. The Aβ hypothesis proposes that Aβ accumulation is a key driver of AD, influencing tau pathology, neuroinflammation, and neurodegeneration. However, therapies that reduce Aβ have shown limited clinical benefits. This suggests that the mechanisms underlying peptide-mediated modulation of AD pathology are much more complex. Both Aβ and tau undergo various post-translational modifications (PTMs) that affect their structure, aggregation, and toxicity. In addition, these abnormal proteins are not efficiently cleared in AD, indicating dysfunction of the protein quality control (PQC) system that maintains proteostasis. Such abnormal PTMs and impaired PQC likely work together to drive disease progression, which may explain the limited success of Aβ-reduction therapies. In this review, we describe how major PTMs, including phosphorylation, ubiquitination, acetylation, glycosylation, and oxidation, regulate the pathological behavior of Aβ and tau. We also discuss the role of the PQC systems in the pathology of AD. We propose that dysregulation of PTMs and PQC constitutes a convergent mechanism underlying AD pathogenesis. Therapeutic strategies targeting these processes may provide more effective and sustained disease modification than approaches focused solely on Aβ reduction. Full article

Background: Myocardial ischemia/reperfusion injury (MIRI) remains a major limitation to effective cardioprotection. Chikusetsusaponin IVa (CS-IVa) has shown promising cardioprotective activity; however, its pharmacokinetic behavior and exposure–response relationship under MIRI pathological conditions remain insufficiently characterized. This study aimed to evaluate the disease-state-related pharmacokinetics of CS-IVa in MIRI rats and to explore its concentration–effect relationship using a revised descriptive PK framework. Methods: A rat MIRI model was established by ligation and reperfusion of the left anterior descending coronary artery. The cardioprotective effects of CS-IVa were evaluated using echocardiography, hemodynamic parameters, myocardial infarct size, histopathological examination, and biochemical markers of myocardial injury and oxidative stress. Plasma CS-IVa concentrations were quantified by UHPLC-MS/MS over 0–24 h after administration. Non-compartmental pharmacokinetic parameters were statistically compared between normal and MIRI rats. To address model reliability and parameter identifiability, candidate PK models with different structural assumptions and weighting schemes were systematically re-evaluated. The selected descriptive PK model was further assessed using the leave-one-rat-out robustness analysis. An exploratory exposure–response analysis was performed using CK-MB as the longitudinal PD endpoint, and a Ke0 sensitivity analysis was conducted to evaluate the robustness of the downstream effect-compartment interpretation. Data-driven models were retained only as supplementary exploratory predictive analyses. Results: CS-IVa improved cardiac function; reduced myocardial infarct size; attenuated histopathological injury; decreased serum CK-MB, cTnI, LDH and plasma MDA levels; and restored SOD activity in MIRI rats. In normal rats, systemic exposure to CS-IVa increased with dose escalation. Compared with normal rats at 15 mg/kg, MIRI rats showed markedly altered pharmacokinetic behavior, including reduced C_max and AUC, delayed T_max, shortened apparent half-life, and increased apparent volume of distribution. After systematic model re-evaluation, a one-compartment model with first-order absorption, no lag time, and unweighted fitting was selected as the revised working descriptive PK model, providing a better balance between model fit, parameter stability, and parsimony. The leave-one-rat-out analysis supported the robustness of this revised model. The exploratory concentration–effect analysis revealed a temporal dissociation between plasma CS-IVa exposure and CK-MB response, suggesting a delayed pharmacodynamic response. Ke0 sensitivity analysis indicated that effect-compartment-based PD fitting was sensitive to Ke0 selection; accordingly, the exposure–response analysis is interpreted as exploratory rather than as a definitive mechanistic PK/PD model. Conclusions: CS-IVa exerted cardioprotective effects in MIRI rats, while MIRI markedly altered its overall pharmacokinetic behavior. The revised analysis supports disease-state-related PK changes and an exploratory exposure–response delay between plasma CS-IVa exposure and CK-MB response. These findings provide a pharmacokinetic basis for understanding CS-IVa under MIRI pathological conditions; however, further studies incorporating individual-level PD endpoints, tissue distribution data, and clinically relevant formulations are needed before translational dosing recommendations can be made. Full article

The hypothalamic–pituitary–somatotropic (HPS) axis, which includes growth hormone (GH) and insulin-like growth factor 1 (IGF-1), is one of three endocrine systems that show a decline in hormone concentration with age. Among the hypothalamic hormones involved in the aging process, GH-releasing hormone (GHRH) and somatostatin (SST) are most affected, resulting in several age-related changes. The pathophysiology of GH decline in the aging process is unclear, specifically, whether it results from decreased GHRH or increased SST levels. Similarly, it is not known whether quantitative changes in hypothalamic peptides (including SST) precede or follow age-related pathological behavioral changes. SST is produced mainly by cells of the central nervous system (CNS) and the gastrointestinal (GI) tract, which are functionally interconnected systems that undergo significant changes during aging. The physical changes in the aging organism are considered physiological, and experimental evidence indicates that a large proportion of these changes are the result of declining hormonal activity (including the SST system). It is particularly important to understand the role of SST in diseases of old age, which affect both cognitive processes and memory (e.g., Alzheimer’s and Parkinson’s diseases) and the proper functioning of the GI tract and pancreas (e.g., obesity, type 2 diabetes mellitus, and colorectal cancer). This narrative review discusses systemic and peripheral changes in SST production and secretion observed in aging individuals and their potential association with selected diseases of old age, especially CNS and GI tract diseases. Understanding the role of SST expression with age will enable the better application of this neuropeptide in the diagnosis and treatment of diseases of old age (including cancers). Full article