Pharmacological Reports最新文献

Cerebrovascular diseases are highly lethal and disabling events. Stroke is most commonly modeled using focal ischemia, of which middle cerebral artery occlusion (MCAO) is widely employed. Reproducible and reliable animal models are crucial for studying the pathophysiology of diseases and the evaluation of therapeutic candidates. However, despite showing efficacy in experimental studies, neuroprotective approaches have failed to translate into clinical benefit so far. A key measure to improve preclinical stroke research is the inclusion of functional endpoints intended to cover a wide range of parameters. The selection of appropriate tests is a critical issue and a challenging task, given the many variables to be considered. These variables include the experimental species, strain, sex, age, occlusion method and duration, infarct size and location, and degree of collateral irrigation, operational costs, among others. The focus of this review is on the behavioral tests most commonly used to identify neurological alterations associated with sensorimotor deficits following transient cerebral ischemia in rats and mice. Commonly used tests include the neurological score, the adhesive removal test, the hanging wire test, the corner test, the cylinder test, and the rotarod test. Functional endpoints must be included in preclinical testing, including sensorimotor and cognitive function, given the variable recovery rates of specific neurological functions. Importantly, screening for sensorimotor function prior to cognitive testing ensures accurate conclusions and helps identify the best specific conditions with minimal confounding by neurological abnormalities. Behavioral outcomes allow assessment of the severity, persistence, or recovery of post-ischemic injury over time.

Anthracyclines are cornerstone agents in oncology, yet their cardiotoxic effects may do more than inflict damage-they may uncover latent cardiac vulnerabilities. This mini-review examines anthracycline-induced mitochondrial stress as a potential diagnostic stressor that exposes subclinical impairments in cardiomyocyte energetics and quality control. We focus on receptor-mediated mitophagy, particularly the TRDMT1-BNIP3 epitranscriptomic axis, which enables organelle clearance independently of membrane depolarization, and the canonical PINK1-Parkin pathway, highlighting their distinct and sometimes context-dependent roles. Unlike the canonical PINK1-Parkin pathway, which is typically activated by mitochondrial depolarization, the TRDMT1-BNIP3 axis may better reflect early adaptive responses to specific cellular stresses. We summarize emerging evidence from iPSC-derived cardiomyocytes, animal models, and molecular imaging studies, suggesting that mitochondrial dysfunction precedes overt systolic decline. We propose that doxorubicin-induced effects on mitophagy pathways may serve as a functional indicator of mitochondrial reserve, providing a basis for risk stratification and targeted cardioprotection. Reframing cardiotoxicity as a measurable biological signal-not only as injury-could improve early detection of heart failure susceptibility by revealing these hidden vulnerabilities. These insights are hypothesis-generating and require further clinical validation before implementation in diagnostic frameworks.

The treatment methods for ischemic stroke (IS) are currently limited, posing a significant challenge to global healthcare. Tissue-type plasminogen activator remains the only effective drug for IS, yet its use is restricted by narrow therapeutic windows and potential complications, limiting its benefits to a small fraction of patients. Magnolol, the primary bioactive compound extracted from the bark of Magnolia officinalis, a traditional Chinese medicinal herb, has demonstrated promising neuroprotective properties in IS models. This review synthesizes recent findings regarding the neuroprotective effects of magnolol in IS models. It highlights its advantages across various protective mechanisms, including antioxidant activity, anti-inflammatory effects, inhibition of autophagy, prevention of cell death, protection of the blood-brain barrier, and promotion of neuronal survival. By elucidating these mechanisms, this review highlights the therapeutic potential of magnolol in IS and provides a theoretical foundation for future experimental and clinical studies.

Vascular smooth muscle cells (SMCs) are pivotal in regulating vascular tone and integrity. Their dysregulation significantly contributes to the pathophysiology of cardiovascular ailments, including atherosclerosis, blood pressure, and vascular remodeling. Curcumin, a polyphenol with a natural origin in turmeric, exhibits promising therapeutic properties due to its remarkable anti-inflammatory, antioxidant, and antiproliferative characteristics. This review aims to assess the effects of curcumin on vascular SMC behavior, encompassing its impact on proliferation, migration, phenotypic switching, and extracellular matrix remodeling. The underlying molecular mechanisms are highlighted, particularly curcumin's modulation of signaling pathways such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and nuclear transcription factor E2-related factor-2 (Nrf2) signaling pathways, as well as its ability to decrease oxidative stress and inflammatory cytokine generation. Furthermore, we evaluate the implications of the results for vascular health and disease, emphasizing curcumin's potential to prevent or mitigate atherosclerosis, restenosis, and hypertension. Despite promising preclinical evidence, challenges related to curcumin's bioavailability and clinical translation remain.

Background: Schizophrenia is a mental disorder with multifactorial etiology including positive, negative and cognitive symptoms. Nitric oxide (NO֗)-related biochemical pathways significantly contribute to the disease's pathophysiology and subsequent antipsychotic treatment. Recently, metabotropic glutamatergic (mGlu) or muscarinic (M) receptors have been considered as potent antipsychotics with the potential to reverse cognitive symptoms. The aim of this study was to investigate how selected mGlu or muscarinic receptor ligands regulate the most important aspects of NO֗-related neurotransmission.

Methods: In this study, MK-801-the tool compound that induces schizophrenia-related changes-was used alone or with mGlu or muscarinic receptor ligands. Positive allosteric modulators (PAM) of mGlu₂ (LY487379), mGlu₅ (CDPPB), M₁ (VU0357017) and M₄ (VU0152100) receptors were administered. cGMP levels, superoxide dismutase (SOD) activity, nitrite and GLT-1 s-nitrosilation processes were investigated in mouse brain and plasma samples, while oxidative stress was measured in vitro with the use of mouse or human astrocytic cell lines.

Results: MK-801 did not change cGMP levels, while a decrease was observed in mice treated with VU0357017 or LY487379 in parallel. Increased SOD activity was observed in the cortex of MK-801-treated mice, and the compounds, with the exception of CDPPB, prevented this effect. The investigated compounds also prevented an MK-801-induced increase in plasma nitrite levels. GLT-1 protein was decreased after MK-801 treatment which was not evident in mice administered with muscarinic or mGlu ligands. GLT-1 S-nitrosilation was increased in all groups. In vitro studies revealed the potency of these compounds in counteracting MK-801-induced oxidative stress.

Conclusions: The present data confirm that both mGlu and muscarinic receptor ligands may exert antipsychotic effects through biochemical pathways regulated by NO֗, in particular by decreasing oxidative stress indicators.

Background: Alendronate (ALN), a nitrogen-containing bisphosphonate (NBP), augments proinflammatory cytokine production by mouse macrophage-like cells incubated with ligands of Toll-like receptor (TLR) 2 and TLR4. The present study investigated whether ALN augments the production of interferon (IFN)-β, which has anti-viral activity.

Methods: Mouse macrophage-like J774.1 cells were pretreated with or without ALN and then incubated with or without lipid A, a TLR4 ligand. Levels of secreted mouse IFN-β were measured by enzyme-linked immunosorbent assay (ELISA). Expression of interferon regulatory factor (IRF)-5, cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), retinoic acid-inducible gene-I (RIG-I), downstream of kinase (DOK) 3, caspase-11, Nur77, laminB1, and β-actin was analyzed by Western blot analysis. Cell viability was evaluated by measuring the reduction of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) to formazan by living cells.

Results: Pretreatment with ALN significantly augmented lipid A-induced IFN-β production and nuclear IRF-5 expression in J774.1 cells. In addition, treatment with ALN upregulated the expression of cGAS, RIG-I, and DOK3. Pretreatment of J774.1 cells with RU.521, a cGAS inhibitor, inhibited ALN-augmented IFN-β production, IRF-5 activation, and caspase-11 expression. Similar results were shown in the pretreatment of cells with another inhibitor, G140. RIG012, a RIG-I antagonist, also suppressed ALN-augmented lipid A-induced IFN-β production. Furthermore, pretreatment with ALN significantly upregulated lipid A-induced Nur77 expression, which was also inhibited by RU.521.

Conclusion: These results suggest that pretreatment with ALN augments lipid A-induced IFN-β production by J774.1 cells via the upregulation of cGAS expression.

Background: Polyphenols have garnered significant interest because of their potential health benefits, but their bioavailability is limited. According to recent studies, in vivo metabolites of phenol compounds may mediate their biological activity, potentially countering systemic oxidation and inflammation and therefore reducing multi-organ dysfunction associated with gut microbiota alterations. This pre-clinical study aims to characterize a novel formulation, enhancing metabolite bioavailability, ensuring long-term stability, and employing sustainable production methods. Our research provides the first evidence of the presence of these metabolites in the blood plasma of animals receiving different Bergamot polyphenols fraction (BPF) formulations.

Methods: Male Sprague-Dawley were used throughout the study. The animals were subdivided into three groups of six animals each receiving 50 mg/kg of BPF standard (BPF), 50 mg/kg of Bergamot polyphenols fraction micronized (BPFmicro), and 50 mg/kgof Bergamot polyphenols fraction encapsulation (BPFencap), respectively, by oral gavage. Blood samples were collected, and plasma was prepared with a specific protocol and analysed for the presence of primary and secondary metabolites through ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS).

Results: UHPLC-MS/MS analysis showed significantly higher plasma concentrations of naringin and its metabolites in the BPFencap group compared to the BPF standard and BPFmicro groups at all time points. In comparison to BPF, plasma Area Under Curve (AUC) analysis of metabolites revealed substantially elevated values for the BPFencap group and substantially reduced values for the BPFmicro group.

Conclusion: While BPFmicro greatly increased bioavailability, the improvement was only temporary, highlighting a stability problem. The bioavailability and stability of metabolites are significantly improved over time by the new BPFencap formulation (micronized BPF in hybrid phospholipid systems with citrus albedo fibers).

Background: Infantile hemangiomas (IH) are the most prevalent benign vascular tumors diagnosed in the pediatric population. Propranolol, a nonselective beta-adrenergic receptor antagonist, is the first-line treatment for IH. In this study, we aimed to assess the changes in plasma levels of HIF-1α, MMP-2, MMP-9, and TIMP-1 in patients with IH before and after one month of propranolol treatment.

Methods: Twenty children with IH and sixteen control subjects, admitted to the Department of Pediatric Surgery and Urology for elective inguinal hernia surgery, were included in this study. Blood plasma samples were obtained twice from the IH group (before and one month after initiating propranolol treatment) and once from the healthy control group.

Results: Patients treated with propranolol exhibited higher levels of MMP-2 both before (p = 0.0008) and after (p = 0.0006) treatment compared to the control group. The control group had higher levels of MMP-9 than the study group before propranolol treatment (p = 0.0267), but MMP-9 levels increased significantly after propranolol treatment in the study group (p = 0.0281). Plasma levels of TIMP-1 were considerably higher in the study group both before (p = 0.0097) and after (p = 0.0013) propranolol treatment compared to the control group. Additionally, HIF-1α levels were higher in the study group and showed an upward trend following propranolol treatment compared to the control group (p = 0.0114).

Conclusions: This study provides insight into the plasma levels of MMP-2, MMP-9, TIMP-1, and HIF-1α involved in the involution of infantile hemangiomas during the early stage of propranolol treatment.

Background: The use of immune-modifying biological agents has markedly changed the clinical course and the management of inflammatory bowel diseases (IBDs). Active post-marketing surveillance programs are essential for the early recognition of both expected and unexpected adverse events (AEs), providing a powerful tool for better defining the safety profiles of biologics in a real-world setting.

Methods: Patients diagnosed with IBDs and treated with biologic drugs at two gastroenterology units in Calabria, Italy, were monitored during the period from 2023 to 2024. AEs and drug switches or swaps were recorded. The primary objective was to assess the safety profile of biological therapies in real-world practice, as measured by the occurrence of AEs. Secondary objectives focused on assessing treatment effectiveness by monitoring rates of therapeutic ineffectiveness and rigorously analyzing necessary modifications to therapy (swaps/switches) in response to treatment failure.

Results: A total of 214 patients were enrolled, including 85 with Crohn's disease (CD) and 120 with ulcerative colitis (UC). Among biologics, vedolizumab (VDZ) was the most prescribed drug (50.3%), followed by ustekinumab (UST, 33.6%). Among biosimilars, infliximab (IFX) was the most administered (70%), followed by adalimumab (ADA) (63.3%). 96 patients experienced AEs, though no serious adverse events (SAEs) were reported. The highest number of AEs was reported with VDZ (n = 31; 32.3%), followed by IFX (n = 22, 23.0%), ADA and UST (n = 17, 17.7%), and golimumab (GOL) (n = 7; 7.3%). The biological drugs associated with the fewest AEs were upadacitinib (UPA) and tofacitinib (TFC) (n = 1; 1.0%).

Conclusions: This study confirms the importance of pharmacovigilance in monitoring the safety of biologics in IBDs. The results offer useful insights into the actual use of monoclonals in gastroenterology and support more targeted prescribing.

Clinical trial number: Not applicable.

Background: Recombinant granulocyte colony-stimulating factor (G-CSF) is the most commonly used agent for treating neutropenia and mobilizing hematopoietic stem cells (HSCs) for transplantation. However, some patients do not respond effectively to the currently used mobilization protocols. To address this, new therapeutic approaches are needed. A potential strategy is pharmacological induction of endogenous mobilizing factors via cobalt protoporphyrin IX (CoPP). CoPP mobilizes HSCs and granulocytes by increasing endogenous G-CSF, though optimal dosing and potential side effects remain unclear. Our study aimed to optimize CoPP dosing and timing, and assess its safety in mobilizing cells from bone marrow to blood.

Methods: Mice were treated with different doses of CoPP, and blood cell counts, cytokine concentrations, and organ damage markers were evaluated at various time points after injection.

Results: Our results show that CoPP exerts a dose-dependent mobilizing effect, with the highest G-CSF levels and number of mobilized leukocytes observed in mice treated with 10 mg/kg of CoPP. While there were no severe adverse effects, there were mild fluctuations in markers of organ function, including a reduction in blood urea nitrogen (BUN) and glucose levels during the five days of administration. Additionally, although most parameters normalized within 30 days, the decrease in BUN persisted. Mice experienced short-term weight loss following CoPP administration, but they regained their initial weight within two weeks.

Conclusions: This study demonstrates that CoPP mobilizes cells from the bone marrow to the blood in a dose-dependent manner, with mild side effects, including temporary changes in biochemical markers and a sustained reduction in BUN levels.