Gastrointestinal filling, distension, and contraction subject the gut wall to dynamic mechanical loads. Interstitial cells of Cajal (ICC) help generate electrical slow waves, but the mechanisms coupling mechanical stimuli to pacemaker activity remain incompletely defined. This focused narrative review distinguishes currents recorded in identified ICC from candidate mechanisms and indirect epithelial, neural, and smooth-muscle pathways. In isolated human jejunal ICC, perfusion shear enhances a NaV1.5-associated Na+ current; its recruitment by physiological wall loading and contribution to propulsion in vivo remain unknown. Hypotonic swelling evokes a volume-sensitive Cl− current in cultured murine ICC without identifying the channel protein. ANO1 couples intracellular Ca2+ signals to depolarization. Piezo1 and TRPM7 are candidates for mechanical signaling in native gastrointestinal ICC, whereas Piezo2 has established epithelial and sensory-neuronal functions. Within the electrically coupled network of smooth muscle cells, ICC, and platelet-derived growth factor receptor α-positive cells, these responses may alter contraction timing and coordination. Clinical studies link ICC abnormalities and SCN5A channel dysfunction to motor disorders, but do not establish a causal ICC-specific mechanical defect. Translation requires experiments connecting controlled loading, currents in identified cells, and organ-level motor outcomes.
Background/Objectives: Advanced heart failure (HF) carries a high symptom burden and mortality, and identifying the right time for palliative and advanced-therapy discussions remains difficult. We systematically reviewed the prognostic value of serological biomarkers, echocardiographic indices, and patient-reported outcomes (PROs) in advanced HF. Methods: PubMed, Scopus, Web of Science, and the Cochrane Library were searched on 1 June 2026 for studies published within the prior 10 years, following PRISMA 2020 (PROSPERO CRD420261505929). Risk of bias was assessed with the Newcastle–Ottawa Scale and certainty of evidence with GRADE. Hazard ratios (HRs) for all-cause mortality were pooled with random-effects models within pathophysiologically defined serological subgroups; markers with opposing prognostic directions were synthesized narratively. Results: Of 3866 records, 37 studies (approximately 31,849 patients) were included; 29 (78%) were at low risk of bias. The pooled HR was 1.35 (95% CI 1.06–1.74; k = 4; I2 = 92%) for neurohormonal/congestive markers; exploratory two-study estimates were 1.75 (1.50–2.04; I2 = 6%) for renal/cardiorenal and 2.17 (0.85–5.52; I2 = 86%) for inflammatory-nutritional markers. GRADE certainty was Low for the renal/cardiorenal estimate and Very Low for the other two, and funnel-plot asymmetry suggested small-study effects. Echocardiographic and PRO markers were individually associated with prognosis but showed opposing directions within outcome categories and were not pooled. Conclusions: Serological, echocardiographic, and patient-reported markers each carry prognostic information in advanced HF, but the pooled estimates are exploratory. Most studies assessed mortality or hospitalization rather than palliative or advanced-therapy decisions; relevance to such decisions is interpretive and requires prospective confirmation.
Background/Objectives: Reserpine depletes vesicular monoamine stores and can affect both monoaminergic neurotransmission and cardiovascular physiology. This study investigated the effects of citalopram and ticagrelor on myocardial oxidative/nitrosative status, cardiac injury biomarkers, histopathological alterations, and NF-κB/Nrf2- and apoptosis-related protein immunoreactivity in reserpine-treated rats. Methods: Forty-eight adult male Wistar albino rats were randomly assigned to six groups (n = 8/group): sham control (SH), reserpine (RES), ticagrelor (TIC), citalopram (CIT), reserpine + ticagrelor (RES + TIC), and reserpine + citalopram (RES + CIT). Reserpine (0.2 mg/kg/day, intraperitoneally) was administered for 14 days, while ticagrelor (30 mg/kg/day) and citalopram (10 mg/kg/day) were administered by oral gavage from days 5 to 14. Cardiac MDA, NOx, and GSH; serum CK-MB and cTnT; myocardial histopathology; and NF-κB, Nrf2, Bax, Bcl-2, and cleaved caspase-3 immunoreactivity were evaluated. Results: Reserpine increased cardiac MDA and NOx levels and decreased GSH levels compared with the SH group. Ticagrelor significantly reduced MDA levels, whereas citalopram did not. Both treatments significantly reduced NOx levels and increased GSH levels compared with the RES group. Reserpine increased serum CK-MB and cTnT levels compared with the SH group. Both citalopram and ticagrelor significantly reduced CK-MB levels relative to the RES group. In contrast, a significant reduction in cTnT was observed only in the RES + TIC group; however, cTnT levels in this group remained significantly higher than those in the SH group. Histopathological assessment revealed that both treatments significantly reduced interstitial edema and inflammatory cell infiltration, but not cardiomyocyte degeneration or vascular congestion. Both treatments significantly reduced NF-κB, Bax, and cleaved caspase-3 immunoreactivity compared with the RES group. Nrf2 immunoreactivity was significantly increased only in the RES + CIT group, whereas both treatments significantly increased Bcl-2 immunoreactivity. Conclusions: Reserpine exposure was associated with myocardial oxidative/nitrosative imbalance, increased circulating cardiac injury biomarkers, histopathological alterations, and changes in inflammatory, antioxidant, and apoptosis-associated protein immunoreactivity. Both citalopram and ticagrelor reduced CK-MB levels, whereas a significant reduction in cTnT was observed only with ticagrelor, and cTnT remained elevated relative to the sham control group. Treatment-associated responses also differed for MDA and Nrf2 immunoreactivity. These findings indicate that the two treatments were associated with distinct response patterns across the measured outcomes and do not establish equivalent effects on all myocardial injury markers or demonstrate the underlying mechanisms.
Background/Objectives: Ki-67 is a cell proliferation marker which is tightly coupled to the cell cycle. Its importance stems from the information it provides on prognosis, response to therapy, and clinical outcomes in several tumors. However, several gaps regarding its use should be addressed before it can be used as a standard-of-care test in cancer management. Methods: A structured literature search of articles was conducted using PubMed to evaluate Ki-67 for its prognostic value across human cancers. The primary areas of interest were immunohistochemistry (IHC) methods, the impact of Ki-67 index variability on clinical judgment, and the potential for standardizing evaluation provided by AI-powered tools and automated digital image analysis (DIA). Results: In different cancers, Ki-67 overexpression is related to worse clinicopathological characteristics, shorter overall survival, and higher tumor burden. Increased Ki-67 expression in breast cancer was associated with higher risk of recurrence in the ER-positive, HER2-negative subtypes. Similarly, in prostate cancer, higher Ki-67 scores correlated well with higher Gleason scores and early biochemical relapse. In lung cancer, Ki-67 levels were found to be higher in the later stages, in metastatic disease, and in patients with poor survival. However, the cut-off values varied widely (5–50%). Conclusions: The Ki-67 index is a promising biomarker, which, with some refinements, may prove to be an invaluable tool in the management of malignant tumors. Future studies should therefore be directed towards reducing variability by increasing standardization and establishing standardized, tumor-specific cut-off values.
Diabetic retinopathy (DR) is a progressive neurovascular complication of diabetes driven by interconnected metabolic stress, oxidative injury, inflammation, vascular dysfunction, regulated cell death, and neurodegeneration. Quercetin, a naturally occurring flavonol, has attracted increasing interest because its pharmacological actions overlap with multiple pathogenic processes involved in DR. Experimental evidence suggests that quercetin may modulate glucose-related metabolic stress, enhance endogenous antioxidant defenses, suppress NF-κB-centered inflammatory signaling and VEGF-associated angiogenesis, regulate apoptosis, autophagy, and ferroptosis, and support neurotrophic signaling. However, these mechanistic advantages have not yet translated into clinical application. Poor aqueous solubility, chemical instability, extensive metabolism, low systemic bioavailability, and limited posterior-segment exposure create a substantial gap between pharmacological activity and therapeutically meaningful retinal concentrations. To address these limitations, lipid nanoparticles, targeted and stimulus-responsive liposomes, hydrogel-based depot systems, nanomicelles, metallic nanostructures and nanozymes, and structurally optimized quercetin derivatives have been investigated to improve drug stability, retinal accumulation, and sustained or responsive release. Importantly, the current evidence remains predominantly preclinical, and findings from non-diabetic ocular models should be distinguished from direct evidence obtained in diabetic retinal models. This review therefore critically integrates the molecular pharmacology of quercetin with its pharmacokinetic limitations and emerging retinal delivery strategies, with particular emphasis on evidence relevance, retinal exposure, treatment durability, safety, and translational feasibility. Future studies should prioritize direct retinal pharmacokinetic assessment, mechanism-linked efficacy in clinically relevant diabetic models, repeated-dose ocular and systemic safety, and comparison or combination with established therapies. Such an evidence-based development framework will be essential to determine whether quercetin-based strategies can progress from multi-target experimental pharmacology to clinically meaningful intervention in DR.
