Pharmacological Reports最新文献

Background: Recent preclinical studies have shown sex-dependent antidepressant-like responses of cannabidiol in adolescence, which were dependent on biological sex, early-life stress, and dose. In particular, cannabidiol (10 mg/kg) induced acute and sustained antidepressant-like responses in adolescent male rats, while it lacked efficacy in females. This follow-up study aimed at further characterizing cannabidiol's effects in adolescence, in an attempt to overcome female unresponsiveness, while also evaluating its long-term safety profile in adulthood.

Methods: Groups of adolescent rats of both sexes were treated (ip) with cannabidiol (10, 30, 60 mg/kg) or vehicle (1 ml/kg) for 7 days. Acute (30 min post-injection) and repeated (24 h post-treatment) antidepressant-like responses were measured in the forced-swim test. Brains were collected to evaluate several neurochemical correlates in the hippocampus (CBR1, CBR2, BDNF, and cell proliferation) after adolescent cannabidiol exposure (acute and repeated). Some rats were left undisturbed until adulthood, when long-term effects on cognition were measured in the Barnes maze (short- and long-term memory) or affective-like responses in the forced-swim test. Data was analyzed with two-way ANOVAs (independent variables: sex and treatment).

Results: While the dose of 10 mg/kg of cannabidiol induced antidepressant-like effects in adolescent rats, higher doses had no effect in adolescent rats of both sexes. No changes were observed in any of the hippocampal neuroplasticity markers evaluated. Adolescent cannabidiol exposure did not induce long-term changes in cognitive performance or affective-like behavior.

Conclusions: Overall, our data suggest that adolescent cannabidiol treatment produces dose-dependent antidepressant-like effects of moderate magnitude without compromising long-term cognition in rats.

Background: Naltrexone is an opioid receptor antagonist that can modulate reward processing in opposite directions depending on the dose. Whether naltrexone similarly affects motivation remains unexplored. This study investigates the effects of naltrexone on behavioral measures of motivation and search for potential mechanisms, including the endogenous opioid pathway dependent on proopiomelanocortin (POMC).

Methods: Male Sprague Dawley rats received naltrexone (0.01, 0.1, or 1 mg/kg, ip) for two weeks. During this period, rats were tested daily using a progressive ratio schedule of reinforcement (PR) test and effort-based choice (EBC) that address motivational vigor, directedness, and effort-based decision-making. After tests, the hypothalami were collected for proteomic analysis using data-independent acquisition (DIA).

Results: Low-dose naltrexone (0.01 mg/kg; LDN) transiently increased PR response vigor without altering decision-making in EBC. At 0.1 mg/kg, but not at the high dose of 1 mg/kg, it impaired effort-based decision-making and goal-directedness. Proteomic analysis correlated LDN with the downregulation of a growth hormone (GH) pathway and altered G protein-coupled receptors (GPCR) signaling. Naltrexone's intermediate dose predominantly impacted proteins involved in neural growth, while the 1 mg/kg dose affected proteins related to gene regulation.

Conclusions: Different doses of naltrexone had varying effects on motivational measures and the rat's hypothalamic proteome. Naltrexone 0.1 mg/kg impaired motivational directedness and effort-based decision-making that corresponds to reduced reward signaling due to opioid blockade. In contrast, LDN enhanced vigor, but only early in the treatment. Naltrexone had no effects on the POMC-dependent endogenous opioid pathway, suggesting that a different mechanism underlies its motivational effects.

Background: Propofol-remifentanil-dexmedetomidine-based total intravenous anesthesia is widely utilized in clinical practice. However, maintaining safety during the sleep-wake transition and ensuring hemodynamic stability continues to pose significant challenges. This study aimed to investigate the impact of genes that are expressed specifically in orexinergic neurons on interindividual variability in the time to loss of consciousness (LOC), time to wake, and cardiovascular fluctuations.

Methods: A total of 250 patients were included in the study. Gene polymorphisms were detected using the Agena Bioscience MassARRAY system. Anesthesia induction began with propofol and was maintained with propofol and remifentanil. Dexmedetomidine was administered before anesthesia induction. The time to LOC, time to wake, heart rate (HR), and mean arterial pressure (MAP) were documented.

Results: HCRTR2 (Hypocretin receptor 2) rs2292040 and rs76380807 were significantly associated with the time to LOC, and HCRTR2 rs7774031 was correlated with the time to wake. HCRTR2 rs3122162, rs3122169, and rs74296544 were correlated with HR fluctuations, and HCRTR1 (Hypocretin receptor 1) rs2176807, rs2271933, rs871634, and HCRTR2 rs74296544 were associated with MAP fluctuations. Multiple linear regression analysis revealed that the Target-controlled infusion (TCI) plasma concentration (Cp) of propofol > 4 µg ml^- 1 at the time of LOC and dexmedetomidine were influencing factors for the time to LOC, whereas HCRTR2 rs7774031 influenced the time to wake. Baseline HR, baseline MAP, dexmedetomidine, HCRTR2 rs3122162, and HCRTR1 rs2176807 were predictive factors for cardiovascular susceptibility. The predictive models for the time to LOC, time to wake, mean HR, and mean MAP fluctuations accounted for 41.89%, 3.36%, 35.56%, and 47.41% of variations, respectively.

Conclusions: Genetic variants of HCRTR1 and HCRTR2 may affect sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia.

Inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, pulmonary sarcoidosis, and interstitial lung diseases (ILDs), represent a significant cause of morbidity and mortality globally. These conditions are characterized by chronic inflammation and tissue damage, leading to substantial respiratory compromise and impairing quality of life. This review aims to provide a comprehensive overview of pathogenesis, clinical features, and diagnostic approaches for inflammatory lung diseases, emphasizing their shared and distinct characteristics. The review synthesizes current literature on the genetic predisposition, environmental exposures, and immune responses involved in the development and progression of inflammatory lung diseases. It also examines the classification and staging of these conditions to highlight the importance of accurate diagnosis and effective management. Key findings include the complex interplay of numerous factors that contribute to disease development and progression, as well as an analysis of classification and staging systems that support clinical practice. By elucidating the underlying mechanisms and clinical features of inflammatory lung diseases, this review aims to inform the development of novel therapeutic strategies and enhance patient outcomes.

Adult stem cells residing in the body's tissues are responsible for the regeneration and replacement of old cells by new ones, thanks to their ability to differentiate. Scientific research increasingly focuses on the regeneration processes associated with these cells and the ability to modulate the microenvironment in which they are located. The modulatory effect can occur through direct interactions of stem cells with other cells or through their paracrine activity by releasing biologically active substances. For the nervous system, neural stem/progenitor cells are located in the subgranular zone in the hippocampal dentate gyrus and the subventricular zone around the lateral ventricles. This type of cell, in addition to giving rise to new neurons depending on the physiological state of the body, is also involved in the modulation of the niche in which they are found. This process plays a particular role in inflammation associated with many neurodegenerative diseases, which is connected with increased activity of the immune system cells. In this review article, we wanted to present the biologically active factors found in the neural stem/progenitor cells' secretome, which are key factors that can contribute physiologically to the silencing of inflammatory processes.

Treatment for oral squamous cell carcinoma (OSCC) has seen the rise of receptor tyrosine kinase inhibitors (RTKIs). However, their therapeutic effectiveness is severely limited by the emergence of resistance. Epidermal growth factor receptor (EGFR)-independent survival pathways, extracellular vesicle (EV)-mediated drug sequestration, lysosomal exocytosis, and metabolic reprogramming mediated by METTL1 (methyltransferase-like protein 1) are some of the molecular and cellular mechanisms that underlie RTKI resistance in OSCC. In this line, specific resistance methods are carefully studied, including the signaling processes involving SHP2, the different ways ErbB2 and AKT, and features related to tumor stemness. Additionally, the interaction between resistance and the tumor microenvironment (TME), namely via EVs and modified angiogenic signaling, is emphasized. Novel therapy approaches are put forth to address these issues. The effectiveness of treatment may be improved by combination treatments that include RTKIs with other medications, such as mTOR inhibitors, chemotherapy, radiation, and immunotherapies. Innovative nanotechnology-based strategies, such as exosome-based drug carriers and liposomal drug delivery systems, provide encouraging answers for overcoming resistance and enhancing precise targeting. Furthermore, phytochemicals and herbal remedies are investigated as supplementary approaches to enhance RTKI responses. Despite the potential of these approaches, obstacles, including resolving tumor heterogeneity, limiting off-target effects, and improving delivery methods, continue to be major obstacles to clinical use. To inform personalized medicine strategies, future studies should concentrate on finding predictive biomarkers and conducting thorough preclinical validation. By integrating emerging therapies and addressing these limitations, this work provides a comprehensive foundation for advancing the management of OSCC and improving patient outcomes.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with endothelial dysfunction, which may also compromise the microcirculation within ocular tissues. This prospective study evaluated associations between radial peripapillary capillary (RPC) vessel density (VD) and systemic treatment, age, hypoxia, D-dimer, and interleukin-6 (IL-6) levels in patients recovering from coronavirus disease 2019 (COVID-19) related pneumonia.

Methods: Sixty-three individuals who were admitted to the hospital due to COVID-19 bilateral pneumonia underwent ophthalmic examination two months post-discharge. RPC VD was measured using optical coherence tomography angiography. Associations with age, arterial hypertension, and systemic treatment (dexamethasone, remdesivir, and oxygen therapy), oxygen saturation, D-dimer, and IL-6 levels were evaluated. The control group comprised 43 control participants with no history of COVID-19 who attended routine ophthalmic examinations.

Results: No ophthalmic abnormalities were detected. RPC VD did not differ significantly with hypertension or systemic treatment with dexamethasone and remdesivir. However, patients receiving oxygen therapy had higher RPC VD. A borderline inverse correlation was observed between inferior RPC VD and age. There were no correlations between RPC VD and oxygen saturation. Significant inverse correlations were found between nasal RPC and mean RPC with D-dimer levels and between inferior RPC VD and IL-6 levels. No significant differences in RPC parameters were observed when comparing the COVID-19 group with controls.

Conclusions: Hypertension or systemic treatment had no significant effect on RCP VD. However, VD in specific RPC areas correlated inversely with D-dimer and IL-6 levels, highlighting the need for monitoring peripapillary microvasculature for potential long-term ocular effects of COVID-19.

Background: Major Depressive Disorder (MDD) is a prevalent condition characterized by alterations in different biological systems including inflammatory and antioxidant pathways. Antidepressants seem to rebalance biological abnormalities. In this short communication, we report differences in a set of biomarkers between drug-free patients and those who benefited from response to antidepressant monotherapy.

Methods: A sample of patients affected by MDD (N = 38) was recruited at the inpatient and outpatient clinic of Policlinico Hospital in Milan: 26 responders and 12 drug-free subjects. The two groups of patients were compared by χ2 tests and analyses of variance, respectively, for qualitative and continuous variables. Correlation analyses were performed to evaluate the relationship between rating scale scores (severity of MDD) and biological parameters.

Results: Drug-free patients (compared to the counterpart) had a higher number of previous suicide attempts (p < 0.01), lower levels of plasmatic proteins (p < 0.01), albumin (p = 0.02), and total cholesterol (p = 0.02), but higher plasma levels of dehydroepiandrosterone sulfate (DHEAs) (p = 0.02), adrenocorticotropic hormone (ACTH) (p < 0.01) and angiotensin converting enzyme (ACE) (p = 0.02).

Conclusions: The results of the present study suggest that the severity of MDD is associated with more prominent biological changes, and antidepressants might mitigate these abnormalities. Future studies with larger samples are needed to confirm these preliminary findings.

Background: Different immune/inflammatory molecules play key roles in the development of inflammatory diseases, including chronic obstructive pulmonary disease (COPD). Thyroid hormones (THs) participate in immune/inflammatory reactions and may play a role in COPD. The main TH metabolism reactions are dependent on iodothyronine deiodinase (DIO). Accumulating evidence also supports the role of cytokines in TH metabolism-related factors. This cross-sectional, observational study investigated the levels of DIO and proinflammatory cytokines and their correlations with stable COPD.

Methods: A total of 55 participants, comprising 25 patients diagnosed with stable COPD and 30 control patients, were enrolled in this study. Cytokine and DIO levels were measured using commercially available human enzyme-linked immunosorbent assay (ELISA) kits from R&D Systems and My BioSource.

Results: Increased levels of DIO1-3 and interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-ɑ, and interferon (IFN)-ɣ were found. Correlation analysis revealed several significant correlations, including interdependence between DIO and cytokine levels, with strong correlations between DIO2 and IFN-ɣ levels and an association between the above protein levels and clinical data. The levels of DIO 1-3 and cytokines (IL-6, TNF-α, and IFN-γ) all showed a positive relationship with COPD relative risk, suggesting that higher levels of DIO and cytokines may influence COPD biology.

Conclusions: Findings from our novel study indicate that DIO and proinflammatory cytokines are possibly involved in the mechanisms underlying processes related to COPD, including immune-endocrine interaction. These can be discussed for further evaluation in COPD-related studies with more precise diagnostic and therapeutic monitoring of all confounding factors and a larger cohort.

Background: At the end of 2024, Polish infectious disease specialists observed a sharp increase in influenza hospitalizations, raising concerns about potential underlying causes. This study aimed to analyze differences in patient characteristics, disease progression, and outcomes among individuals hospitalized for influenza in January 2025 compared to January 2024.

Methods: We conducted an exploratory retrospective comparative study across leading infectious disease units in Poland, evaluating demographic data, clinical presentations, treatment regimens, and outcomes of hospitalized influenza patients from both periods. Key variables included influenza type, age, sex distribution, symptom profile, oxygen saturation, inflammatory markers, presence of co-infections, and type of treatment.

Results: Hospitalizations surged by 630% in January 2025, with in-hospital mortality nearly quadrupling to 10.7%. Despite this, patients from both periods had comparable demographic and clinical admission profiles. Most were treated with oseltamivir (though its use was below 90%), and most required antibiotics for bacterial co-infections. Unsurprisingly, the vast majority of hospitalized patients (97%) and non-survivors (93%) in 2025 were unvaccinated. Among non-survivors in 2025, all were infected with influenza A, were older, had higher rates of chronic peripheral circulatory failure, chronic kidney disease, and immunodeficiency, and exhibited more severe inflammatory responses, lower oxygen saturation, and a higher prevalence of dyspnea.

Conclusion: The observed surge likely reflects a post-pandemic phenomenon in a vulnerable, aging, comorbid, and largely unvaccinated population. The findings highlight the urgent need for enhanced influenza vaccination strategies in high-risk groups in Poland, as well as the importance of maintaining continuous antiviral availability throughout the epidemic season. Further research encompassing full-season comparisons and incorporating virological, immunological, and health system factors are warranted to better understand the drivers of such surges and guide future preparedness efforts.