Search Results (2,310)

Background: Adhesion G protein-coupled receptor D1 (ADGRD1), formerly known as GPR133, has been implicated in tumor-associated signaling; however, its histology-specific clinicopathologic and prognostic significance in non-small cell lung cancer (NSCLC) remains incompletely characterized. Methods: Clinical and survival data from The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) and lung squamous cell carcinoma (TCGA-LUSC) cohorts were integrated with harmonized gene-expression data obtained from the Genomic Data Commons (GDC). ADGRD1 expression was dichotomized using a cohort-specific median cutoff and additionally analyzed as a continuous standardized variable. Clinicopathologic associations, Pearson correlations with prespecified subtype-associated genes, Kaplan–Meier survival analyses, and univariate and multivariable Cox proportional hazards regression analyses were performed. Benjamini–Hochberg false-discovery-rate correction was applied to molecular correlation analyses. Independent validation was performed using GSE30219 and GSE50081, followed by random-effects meta-analysis and proportional hazards sensitivity analyses. Results: High ADGRD1 expression was associated with favorable overall survival (OS) in LUAD in both univariate (HR = 0.542, 95% CI = 0.400–0.734, p < 0.001) and clinically adjusted Cox analyses (HR = 0.543, 95% CI = 0.398–0.740, p < 0.001). Continuous-expression analyses showed concordant results, and the association remained significant in an additional LUAD model incorporating EGFR mutation status (HR = 0.611, 95% CI = 0.391–0.956, p = 0.031). High ADGRD1 expression was also associated with favorable recurrence-free survival (RFS) in LUAD. In contrast, high ADGRD1 expression was associated with adverse OS in LUSC in both univariate (HR = 1.444, 95% CI = 1.099–1.898, p = 0.008) and clinically adjusted analyses (HR = 1.501, 95% CI = 1.137–1.982, p = 0.004), whereas RFS was not significantly different. After false-discovery-rate correction, ADGRD1 correlated positively with TP53 expression in LUAD and inversely with CDKN2A, SOX2, and PIK3CA in LUSC. Independent GEO validation supported the favorable LUAD association (pooled HR = 0.675, 95% CI = 0.538–0.847, p < 0.001), whereas the adverse LUSC association was not independently reproduced (pooled HR = 0.909, 95% CI = 0.686–1.204, p = 0.504). Conclusions: ADGRD1 shows histology-dependent prognostic associations in NSCLC. Its favorable association with survival in LUAD was robust across dichotomized and continuous analyses, multivariable adjustment, EGFR-mutation sensitivity analysis, and independent GEO cohorts. In contrast, the adverse association observed in TCGA-LUSC was not reproduced externally. These findings support further evaluation of ADGRD1 as a subtype-specific prognostic marker, particularly in LUAD. Full article

Triple-negative breast cancer (TNBC) is an aggressive and clinically heterogeneous breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression, limited targeted treatment options, early relapse, and frequent development of therapy resistance. Although TNBC often shows initial sensitivity to chemotherapy, durable responses are commonly undermined by the emergence of adaptive resistant cell states rather than solely by fixed genetic mutations. This review synthesizes the role of epigenetic plasticity as a central mechanism that enables TNBC cells to dynamically reprogram transcriptional identity, survive therapeutic stress, and transition between epithelial, mesenchymal, stem-like, immune-evasive, and drug-tolerant persister phenotypes. Key epigenetic mechanisms include aberrant DNA methylation, histone acetylation and methylation, BET/BRD4-dependent transcriptional regulation, EZH2-mediated repression, SWI/SNF-dependent chromatin remodeling, non-coding RNA networks, and three-dimensional genome reorganization. These processes regulate tumor suppressor silencing, DNA-damage repair, epithelial–mesenchymal plasticity, cancer stem-cell maintenance, metabolic adaptation, immune-checkpoint regulation, and minimal residual disease. The review also highlights the translational relevance of epigenetic biomarkers, including DNA methylation signatures, circulating epigenetic markers, chromatin-accessibility profiles, and single-cell epigenomic approaches for diagnosis, prognosis, therapy prediction, and monitoring resistance evolution. Finally, therapeutic strategies targeting epigenetic plasticity are discussed, including DNMT, HDAC, BET, EZH2, KDM, and LSD1 inhibitors, with emphasis on rational combination approaches involving chemotherapy, PARP inhibitors, immunotherapy, and metabolic targeting. Overall, epigenetic plasticity represents both a major driver of TNBC resistance and a therapeutically exploitable vulnerability, provided those future strategies account for tumor heterogeneity, adaptive cell-state transitions, biomarker-guided patient selection, and combination-based treatment design. Full article

Breast cancer remains one of the most common cancers in women, in which the majority of cases exhibit a hormone receptor-positive subtype. Although several treatment options are available for patients with this subtype, first-line therapies mainly rely on the patient’s sensitivity to endocrine therapy. Therapy resistance, which frequently develops over the treatment course, remains a key obstacle for clinical intervention. Efforts are currently underway to elucidate additional therapeutic targets to restore endocrine therapy sensitivity and treat hormone receptor-positive breast cancer. Here, we summarize work surrounding the sigma-2 receptor (σ2R) and its potential role in endocrine therapy resistance pathways, including PI3K-mTOR signaling and cholesterol metabolism. Although σ2R was pharmacologically characterized decades ago, its molecular identity remained elusive until 2017, when transmembrane protein 97 (TMEM97) was established as the sigma-2 receptor. TMEM97/σ2R is highly expressed in hormone receptor-positive breast cancer and its RNA expression levels are associated with endocrine resistance. High expression of TMEM97/σ2R elevates estrogen receptor activities and confers breast cancer cells with increased resistance to endocrine therapy via enhanced mTOR signaling. Given the role of TMEM97 in cholesterol homeostasis, understanding the connections between TMEM97/σ2R, breast cancer, and cholesterol regulation may reveal new pathways to aid in the development of targeted therapies. Evidence remains preclinical, and further investigation is needed to confirm hypothesized pathways involving TMEM97/σ2R in breast cancer endocrine resistance. Full article

Canine parvovirus 2 (CPV-2) is a major pathogen causing acute haemorrhagic enteritis and myocarditis in dogs. Since the discovery in the late 1970s, the original CPV-2 strain has evolved through VP2 mutations into new subtypes CPV-2a, 2b, and 2c. The viruses pose a persistent threat to canine health worldwide. This review summarizes the innate immunity evasion tactics employed by CPV-2, focusing on the interactions of various viral proteins and host signaling pathways. CPV-2 regulates the activation and inhibition of Toll-like receptors (TLRs), thereby influencing the downstream MyD88/TRIF signaling pathway and modulating the activation of NF-κB and interferons. CPV-2 exerts bidirectional regulation of apoptosis, thereby modulating host innate immune responses and promoting viral replication. CPV-2 employs multiple strategies to evade the humoral and adaptive immune systems, including evolutionary escape through rapid replication and the accumulation of mutations. Clarifying the key mechanisms underlying the defective TLR activation, the immunomodulatory functions of CPV proteins, and cross-species transmission of CPV-2 among animals and the potential zoonotic risk to humans can provide a crucial theoretical basis for precise virus control, understanding immune evasion, and assessing zoonotic risks, with significant value for both vaccine development and basic research. Full article

Background/Objectives: Male breast cancer (MBC) is a rare malignancy accounting for less than 1% of all breast cancers, and current treatment recommendations are largely extrapolated from studies in women. We aimed to evaluate the clinicopathological characteristics, treatment patterns, survival outcomes, and prognostic factors of male breast cancer patients treated at a tertiary referral center. Methods: We retrospectively reviewed 45 patients with histopathologically confirmed MBC treated between January 2015 and July 2025. Demographic, clinicopathological, treatment, and follow-up data were collected from institutional records. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method, and potential prognostic factors were analyzed using univariate Cox proportional hazards regression. Results: The median age at diagnosis was 60 years, and invasive ductal carcinoma was the predominant histological subtype (95.6%). Estrogen and progesterone receptor positivity were observed in 93.0% and 95.2% of patients, respectively, while HER2 positivity was identified in 26.8%. Modified radical mastectomy was performed in 95.6% of patients, adjuvant endocrine therapy in 88.9%, chemotherapy in 73.3%, and radiotherapy in 64.4%. After a median follow-up of 84 months (range, 1–125 months), the estimated 5-year OS and DFS rates were 85.3% and 68.4%, respectively. No locoregional recurrence was observed in the entire cohort; all recurrences were distant metastases. None of the evaluated clinicopathological variables demonstrated a statistically significant association with OS or DFS. Conclusions: This single-center experience demonstrates favorable long-term survival and no observed locoregional recurrence in a contemporary cohort of patients with male breast cancer. These real-world findings are consistent with current treatment strategies and provide additional evidence regarding the management of this rare disease. Larger multicenter collaborative studies are needed to establish robust prognostic models and generate male-specific evidence to further optimize clinical management. Full article

OX40 (TNFRSF4) is a costimulatory T-cell receptor and OX40 agonists are in clinical development, yet its role in small cell lung cancer (SCLC) is still to be characterised. We analysed the discovery cohort (n = 77, 48 events), GSE60052 (n = 79 tumours; 48 with survival), GDSC1+GDSC2 (61 SCLC cell lines, 542 drugs) and human SCLC single-cell atlas (77,143 cells from primary and metastatic sites, 20 donors), using Cox models, FDR-controlled correlation, nested-model comparison and deconvolution. High TNFRSF4 showed a non-significant protective trend (pooled HR = 0.86 per SD, 0.68–1.10, p = 0.23); a nominal cutpoint did not survive correction for cutpoint search (p = 0.25). No drug reached FDR < 0.05 among 658 tests, including platinum agents and etoposide. TNFRSF4 tracked immune infiltration (13-gene score ρ = 0.76, p = 3 × 10⁻¹⁶) and was detected in 17.6% of T cells versus 1.03% of malignant cells in all 20 donors. OX40 was enriched in the POU2F3/SCLC-P subtype (p = 0.033), persisting after immune adjustment (β = 1.32, p = 0.011) but not replicating independently (p = 0.10). Adding TNFRSF4 to clinical-plus-immune models provided no meaningful discrimination gain (ΔC-index ≤ 0.005). Power was limited to HR ≥ 1.50 harmful or HR ≤ 0.67 protective, so the observed trend is undetectable at this size. Bulk OX40 therefore primarily reflects immune infiltration, and its SCLC-P association is a hypothesis for prospective testing. Full article

Background: Metabotropic glutamate receptor subtype 5 (mGluR5) is a promising therapeutic target for a range of neuropsychiatric disorders, and [¹⁸F]FPEB is a PET radioligand developed for imaging central mGluR5 receptor availability. This study aimed to determine the biodistribution, kinetic characteristics, and radiation dosimetry of [¹⁸F]FPEB in healthy Asian subjects and to evaluate the feasibility of reference tissue models as alternatives to conventional blood-based kinetic modeling. Methods: Five healthy Asian male volunteers underwent whole-body and dynamic brain PET imaging following administration of [¹⁸F]FPEB. Radiation dosimetry was estimated using OLINDA/EXM software. Tracer kinetics were analyzed using both blood-based compartmental models and reference tissue models to derive regional binding potentials (BPND) and volumes of distribution. Model performance was assessed using the Akaike Information Criterion (AIC). Results: The mean whole-body effective radiation dose was 0.703 mSv/mCi, with the gallbladder identified as the critical organ receiving the highest absorbed dose (5.63 mGy/mCi). Brain time–activity curves demonstrated the highest tracer uptake in the nucleus accumbens, followed by the cingulate gyrus, putamen, and insula, with moderate uptake in the thalamus and globus pallidus and the lowest uptake in the brainstem and cerebellum. Using the simplified reference tissue models (SRTM/SRTM2), the highest BPND values were observed in the nucleus accumbens, followed by the cingulate gyrus, putamen, and insula. In contrast, two-tissue compartment models (2TCM/2TCM-C) showed the highest BPND values in the hippocampus, followed by the amygdala, nucleus accumbens, and caudate nucleus. Although differences were observed in the absolute BPND values and regional ranking, both modeling approaches identified similar brain regions with high mGluR5 binding. Conclusions: [¹⁸F]FPEB demonstrated a favorable radiation dosimetry profile and supports the feasibility of reference tissue models for BPND estimation in healthy Asian subjects. These findings provide preliminary baseline data, although validation in larger cohorts is needed to confirm the pharmacokinetic characteristics and modeling approach. Full article

Immunohistochemistry (IHC) of ER, PR, HER2, and Ki67 are established prognostic and predictive markers in breast cancer. Gene expression assays such as PAM50 and Oncotype DX are increasingly used for molecular subtyping and recurrence risk calculation. The APIS Breast Cancer Subtyping Kit (BCSK) quantitatively measures the mRNA expression of these markers (ER, PR, HER2, and Ki67) and includes a novel four-gene BCSK Proliferation Signature (PS) designed for subtype classification and risk stratification. This exploratory retrospective cohort study compares the BCSK with established molecular assays in an age-stratified cohort. We aimed to compare BCSK subtype classification in distinguishing Luminal A versus Luminal B subtypes with IHC and with PAM50. We have also aimed to assess correlations between the BCSK PS and the Oncotype DX Recurrence Score (RS) as well as the PAM50 Risk of Recurrence (ROR) score in patients stratified by age (<65 versus ≥65 years). Formalin-fixed, paraffin-embedded (FFPE) tumor specimens from 59 patients with ER+/HER2− breast cancer (33 < 65 years, 26 ≥ 65 years), diagnosed between 2020 and 2022 at the Cantonal Hospital Baselland and University Hospital Basel, were analyzed using IHC, BCSK, and PAM50 (Prosigna^®). All patients received adjuvant therapy and had ODx scores available. Patient, disease and treatment characteristics were compared between age groups using the Fisher exact test. We assessed concordance in luminal subtype classification across IHC, BCSK, and PAM50 assays pairwise and stratified by age groups descriptively. We used Spearman’s rank correlation to examine associations between BCSK PS, RS, and ROR. Differences between age groups regarding PS were analyzed using the Mann–Whitney U test. In the ≥65-year cohort, subtype classification concordance between the BCSK and PAM50 was higher (84.6%) than in those aged <65-years (60.6%). In patients aged <65 years, the PS was significantly correlated with both RS (ρ = 0.5745, p < 0.0005) and ROR (ρ = 0.391, p = 0.024), whereas RS and ROR were not significantly correlated. In patients ≥65 years, PS correlated significantly with ROR (ρ = 0.603, p = 0.001), while there were no significant correlations between PS and RS (ρ = 0.134, p = 0.514) and between RS and ROR (ρ = 0.149, p = 0.466). Median PS values did not significantly differ between age groups (0.589 versus 0.602, p = 0.97). In this exploratory retrospective age-stratified analysis, the BCSK demonstrated descriptive concordance with PAM50 subtype classifications, especially in patients aged ≥65 years. PS showed significant but moderate correlation with the established molecular recurrence scores RS and ROR, however these differed across age groups. Our findings should be considered hypothesis-generating because this study did not include outcome metrics and was based on a relatively small cohort. Larger prospective studies incorporating clinical outcomes are necessary to determine the diagnostic and prognostic utility as well as comparative cost-effectiveness of the BCSK and its utility across age groups. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor with limited therapeutic options and extremely poor prognosis. Aberrant activation of the receptor tyrosine kinase MET drives tumor progression, therapeutic resistance, and reduced survival, particularly in the mesenchymal GBM subtype. Given its crucial role in GBM recurrence and progression, we investigated the mechanisms of resistance to MET inhibition using patient-derived glioma-initiating cells (GICs) and orthotopic xenograft mouse models. GICs were treated with the MET inhibitor crizotinib to elucidate the mechanism of adaptive resistance. Prolonged MET inhibition induced a senescent-like phenotype in GICs, associated with downregulation of BNIP3, a mitochondrial protein regulating mitophagy. We showed that BNIP3 downregulation led to activation of mTOR signaling, promoting cellular survival and adaptive resistance. Combining crizotinib with the mTOR inhibitor everolimus effectively suppressed mTOR activity, reduced cell viability, and induced mitochondrial alterations, apoptosis, and necroptosis. In orthotopic GBM xenograft models, combined MET and mTOR inhibition significantly prolonged survival compared with single-agent treatments. Notably, sequential treatment—crizotinib followed by everolimus—further enhanced therapeutic efficacy. These effects were achieved without significant weight loss, supporting tolerability of the treatment regimen. Our findings identify the BNIP3-mTOR axis as a critical mediator of resistance to MET inhibition and demonstrate that combined inhibition of MET and mTOR exhibits significant synergy against GBM. Full article

Rising drug resistance undermines current anti-influenza virus therapies. Although targeting the hemagglutinin (HA)–sialic acid receptor interaction is a promising strategy, progress is impeded by the lack of subtype-independent screening models. Herein, we established a fluorescence-based cell high-throughput model using fluorescein isothiocyanate-conjugated Sambucus Nigra Lectin (FITC-SNA) as a stable HA surrogate and α-2,6-sialyltransferase (ST6GAL1)-overexpressing MDCK cells to mimic the HA–receptor interface. This platform was designed to serve as an efficient primary screening tool to rapidly filter large compound libraries for potential binders to the receptor-binding interface. Screening 10,000 compounds identified Obatoclax Mesylate and Ethylparaben as primary hits. Both exhibited broad-spectrum HA inhibition activity, validating the model’s capability to identify compounds interfering with viral attachment. Further cellular antiviral assays revealed cytotoxicity for both compounds, resulting in low selectivity indexes (SIs), indicating that while these molecules effectively target the interaction site, they require substantial structural optimization for therapeutic use. Molecular docking confirmed their binding to type A H1N1, H3N2, and B/Victoria HA proteins, while ADMET predictions highlighted specific structural optimization needs to mitigate toxicity. In conclusion, this subtype-independent, highly specific high-throughput screening (HTS) model provides an efficient and reliable platform for early-stage influenza drug discovery and lead compound development. Full article

Background/Objectives: Serum cancer antigen 15.3 (CA 15.3) is frequently measured in advanced breast cancer, but its prognostic significance after adjusting for established clinical factors remains incompletely characterized in Latin American populations. We evaluated the association of baseline CA 15.3 with metastatic burden and overall survival (OS) in hormone receptor-positive/HER2-negative advanced breast cancer and descriptively explored baseline/follow-up patterns. Methods: We retrospectively evaluated 127 women treated at a Peruvian public oncology institution between 2018 and 2024, with CA 15.3 levels ≥32.4 U/mL being considered elevated. Baseline associations were assessed using multivariable logistic regression, and OS was evaluated using Kaplan–Meier estimates and Cox proportional hazards regression adjusted for age, ECOG performance status, de novo versus recurrent disease, luminal subtype, first-line treatment, number of metastatic sites, and metastatic site. Results: Baseline CA 15.3 was elevated in 41/127 patients (32.3%) and was independently associated with postmenopausal status (OR: 3.27; 95% CI, 1.33–9.03; p = 0.014) and ≥2 metastatic sites (OR: 2.72; 95% CI, 1.24–6.10; p = 0.013). Median OS was 55 months (95% CI, 43–78), while elevated baseline CA 15.3 was associated with shorter OS (41 vs. 65 months; log-rank p = 0.024) and remained independently associated with shorter OS after multivariable adjustment (adjusted HR: 3.42; 95% CI, 1.63–7.19; p = 0.001). Conclusions: Elevated baseline CA 15.3 was associated with greater metastatic burden and shorter OS, and baseline/follow-up patterns were exploratory because the sampling was not standardized. Thus, CA 15.3 should be interpreted as an adjunct to clinical and radiological assessment. Full article

Fatty acid-binding proteins (FABPs) are a family of intracellular lipid chaperones that transport fatty acids and other hydrophobic molecules, playing essential roles in cellular lipid metabolism, signaling, and brain function. Within the central nervous system, FABP3, FABP5, and FABP7 facilitate the trafficking of long-chain polyunsaturated fatty acids and endocannabinoids, thereby modulating key regulatory pathways including the endocannabinoid system (ECS), peroxisome proliferator-activated receptor (PPAR) signaling, and dopaminergic neurotransmission. Peripherally, FABP1 and FABP4 contribute to hepatic drug metabolism, kidney excretion, and inflammatory processes in both tissues, with implications for the pharmacokinetics of substances of abuse. This narrative review synthesizes the current literature on FABPs and their involvement in substance use and addiction-related behaviors. Evidence from transgenic knockout models, pharmacological inhibition studies, and adeno-associated virus vector approaches demonstrates that manipulation of FABP subtypes can alter reward-related behaviors across multiple substances, including THC, ethanol, nicotine, and cocaine. Reduction or knockout of FABP7 alters THC metabolite levels in a sex-dependent manner. FABP3 shows involvement with dopamine receptor expression; however, interaction between FABP3 modulation and specific substances has sparsely been investigated. FABP5 has vastly diverging interactions with addictive behavior and appears to be substance dependent, as downregulation reduces cocaine self-administration, but knockout enhances nicotine conditioned place preference (CPP) and increases brain uptake of THC. Combined deletion of FABP5 and 7 additionally reduces cocaine CPP and reinstatement, while showing promising decreases in ethanol consumption paradigms. FABPs may be a potential therapeutic target for treating substance use disorders and underlying reward deficiency mechanisms underlying addiction and further research is required to elucidate specific mechanistic effects and eliminate potential adverse consequences of chronic FABP modulation. Full article

Endocannabinoid receptors of the CB1 subtype are the most abundant G-protein-coupled receptors in the central nervous system, where they strongly regulate neurotransmitter release. The effects of the activation of these receptors by exogenously applied agonists have also been described in the peripheral nervous system, particularly at neuromuscular junctions (NMJs). However, the physiological role of these receptors at NMJs has not been demonstrated. We have shown that blockade of CB1 receptors at the NMJs of newborn or young mice increases the quantal content of end-plate potentials, as well as their decay time constant. Neither effect of CB1 receptor blockade is observed if postsynaptic muscle acetylcholine receptors are partially blocked. Thus, CB1 receptors may be involved in maintaining synaptic homeostasis. Importantly, the effect of CB1 receptor blockade on quantal content is potentiated by blockade of the enzyme butyrylcholinesterase. Therefore, butyrylcholinesterase may be considered a component of the extracellular degradation system for endocannabinoids. Full article

Background: Memantine, an uncompetitive and voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist, is clinically established for moderate-to-severe Alzheimer’s disease. Its pharmacodynamic profile, low-to-moderate affinity, rapid open-channel block, and strong voltage dependency allows selective inhibition of pathological NMDA overactivation while preserving physiological neurotransmission. Increasing evidence shows that these same mechanistic principles operate in the peripheral nervous system, where NMDA receptors contribute to excitotoxicity, oxidative stress, neuroinflammation, and maladaptive nociceptive signaling. Purpose: To synthesize emerging preclinical and clinical evidence demonstrating memantine’s modulatory and neuroprotective actions in peripheral neurons and glia and to outline implications for drug repurposing across neurology, pain medicine, oncology, supportive care, and ophthalmology. Methodology: A narrative integration of mechanistic studies, in vivo preclinical models, and heterogeneous clinical trials evaluating memantine’s effects on peripheral sensory neurons, autonomic neurons, Schwann cells, retinal ganglion cells, and neuromuscular junction physiology. Evidence was examined across conditions involving excitotoxicity, oxidative injury, mitochondrial dysfunction, apoptotic signaling, neuroinflammation, and neuropathic pain amplification. Results: Memantine consistently attenuates peripheral excitotoxic calcium influx, suppresses NOX-2–mediated ROS generation, stabilizes mitochondrial membrane potential, modulates Bax/Bcl-2 signaling, and reduces neuroinflammatory cytokine activity. It also inhibits dorsal horn wind-up selectively under neuropathic conditions. These convergent mechanisms yield protective effects across chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathy, traumatic nerve injury, phantom limb pain, retinal ganglion cell excitotoxicity, and organophosphate-induced neuromuscular toxicity. Clinical evidence includes improved multimodal neuropathy outcomes in diabetic neuropathy when combined with gabapentin, reduced phantom limb pain prevalence and intensity at six months, and a five-fold reduction in post-mastectomy neuropathic pain with pre-emptive administration. Conclusions: Memantine should be conceptually reframed as a system-wide neuroprotective agent with substantial translational potential beyond the CNS. Priorities for future development include NR2B-selective peripheral NMDA antagonists, peripherally restricted formulations, single-cell transcriptomic mapping of peripheral NMDA receptor subtypes, and adequately powered PNS-specific randomized trials. Full article

Background: Norepinephrine is commonly used during acute burn resuscitation to maintain adequate perfusion pressure. However, its effects, together with the burn-induced catecholamine surge, on arterial α₁-adrenergic receptors (α₁-AR) remain unclear. This study examined whether burn injury and continuous norepinephrine infusion alter arterial α₁-AR subtype expression at the transcriptional and protein levels. Methods: Sprague–Dawley rats were randomized to full-thickness scald burn involving 25% total body surface area with continuous intravenous norepinephrine or sodium chloride (NaCl) infusion, sham injury with norepinephrine infusion, or untreated controls. Mean arterial pressure (MAP) was measured at baseline and before euthanasia (six or 24 h). Aorta, carotid, and renal arteries were collected for analysis of α₁-AR subtypes (Adra1a, Adra1b, and Adra1d) using quantitative PCR (qPCR) and immunohistochemistry (IHC). Results: Norepinephrine efficiently increased MAP in sham animals. In burned animals with norepinephrine, MAP increased at six hours (+10.6 mmHg) but fell below baseline at 24 h (−6.4 mmHg). Burned animals given NaCl had persistently lower MAP than those given norepinephrine, at six hours (−19.1 mmHg) and 24 h (−21.1 mmHg). qPCR demonstrated significant downregulation of Adra1b in the renal artery across all groups compared to control (7.8–16.4-fold, p < 0.001). Overall, changes in protein expression across different vascular beds and receptor subtypes were inconsistent. Conclusions: Norepinephrine increased MAP in both sham and burned animals, confirming the drug’s efficacy. Burn injury and sustained norepinephrine exposure were associated with early, vessel-specific alterations in α₁-AR mRNA expression. The absence of consistent protein-level changes within 24 h suggests a delay in receptor expression on protein level. Full article