Pharmacological Reports最新文献

Background: Statin usage has increased significantly in India due to the very high incidence of dyslipidemia, however, approximately 18% of the population is at risk for statin-induced myopathy. Hence, we conducted a population-level screening for pharmacogenetic determinants of statin therapy, particularly Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) and ATP-binding cassette sub-family G member 2 (ABCG2).

Materials and methods: Whole exome sequencing was performed in 2180 subjects, and the variant data were segregated further into diplotypes and phenotypes.

Results: SLCO1B1 normal function was observed in 81% of subjects (diplotypes: 1/*1, *1/*14, *1/*20, *1/*37, and *37/*37). Increased SLCO1B1 function was observed in 8% of the population (diplotypes: *14/*14 and *20/*20). Decreased function of SLCO1B1 (*1/*15) was observed in 5% of the population. Poor function of SLCO1B1 was observed in 6% of the population (diplotypes: *5/*5 and *15/*15). About 81.46% of subjects displayed normal ABCG2 function, while 17.34% had decreased and 1.19% had poor function. Combined SLCO1B1/ABCG2 functional defects were observed in 7.4% of subjects. Two rare SLCO1B1 variants in SLCO1B1 i.e., rs201722521 and rs71581988, were reported to affect the binding affinity of certain statins. The SLCO1B1 C-C-C-A-A-A haplotype was associated with a 2.22-fold risk for hyperbilirubinemia (95% CI: 1.13-4.36, p = 0.02). Rosuvastatin's daily dose of up to 10 mg is well tolerated across the different SLCO1B1 functionality groups.

Conclusions: This study demonstrates that 11% of our population exhibit decreased or poor function of SLCO1B1 and 7.4% exhibit decreased or poor function of both SLCO1B1 and ABCG2, necessitating adjustments in daily statin doses to minimize the risk for statin-induced myopathy.

The temporal stability of ligand-receptor complexes is increasingly acknowledged as a critical factor in drug discovery, influencing both efficacy and pharmacodynamics. Although the relationship between the duration of compound action and complex stability can be traced back to Paul Ehrlich's 19th-century doctrine Corpora non agunt nisi fixata, its significance has gained renewed attention in recent years. This review comprehensively examines the concept of residence time (RT). We first summarize key ligand binding models (lock-and-key, induced-fit, and conformational selection) and delve into various perspectives on how RT impacts functional outcomes. Furthermore, we discuss experimental methods for measuring RT, highlighting both radioligand and non-radioligand approaches. The growing interest in RT has spurred advancements in computational techniques, particularly molecular dynamics simulations, which utilize diverse strategies to observe dissociation events. We outline these molecular dynamics-based methods, their theoretical foundations, and provide examples of their application in assessing RT. Finally, we highlight molecular determinants of prolonged RT, focusing primarily on G protein-coupled receptors (GPCRs) while also incorporating relevant data from other receptor classes.

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.