Pharmacological Reports最新文献

Background: Central nervous system (CNS) tumors, including gliomas, are among the most aggressive cancers, with glioblastoma multiforme (GBM) being the most common and lethal. This study explores the potential of multidrug repositioning as a modern chemotherapy strategy for GBM cell lines. It combines the standard GBM chemotherapeutic temozolomide (TMZ) with olaparib (OLA) and oxaliplatin (OXA), both repurposed from other cancer types. Most experimental drug therapy studies focus on just one or two selected high-grade GBM cell lines, but in this study, four such cell lines were used.

Methods: Glioblastoma (GBM) cell lines U118 MG, H4, U251 MG and U87 MG were treated for 72 h with oxaliplatin (OXA, 50-200 µM), olaparib (OLA, 1-100 µM), or temozolomide (TMZ, 10-100 µM). Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) assay. Half-maximal inhibitory concentration (IC₅₀) values were calculated using GraphPad Prism 8. A human fibroblast line (hFib) from a healthy donor was used as a control. The type of cell death following the above treatments was analysed using a fluorescence-based Apoptotic, Necrotic & Healthy Cells Quantification Kit.

Results: The combination of OLA, OXA, and TMZ significantly reduced cell viability and survival, inducing apoptosis/necrosis more effectively than TMZ alone. These synergistic effects alter glioblastoma metabolism, promote apoptosis, and enhance antitumor activity in vitro.

Conclusions: The proposed multidrug repositioning chemotherapy produced a therapeutic effect at lower doses, suggesting that it is potentially a safer and more effective treatment option.

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, characterized by debilitating motor and non-motor symptoms. Its complex pathogenesis involves dopaminergic neuron degeneration, α-synuclein aggregation, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Current symptomatic treatments offer limited symptom improvement, highlighting the urgent need for new strategies, including lifestyle modifications. The ketogenic diet (KD), a dietary approach that shifts the body's primary energy source from glucose to ketone bodies (KBs) like β-hydroxybutyrate (β-HB), has demonstrated significant therapeutic potential. This review explores KD as a promising, multifaceted intervention for PD. The potential beneficial impact of KD on PD stems from several key mechanisms. β-HB exhibits potent anti-inflammatory properties, reducing pro-inflammatory cytokines and microglial activation by inhibiting pathways such as NF-κB and NLRP3 inflammasome. The diet also improves mitochondrial function by enhancing electron transport chain activity and increasing ATP synthesis, which is crucial given the mitochondrial deficits observed in PD. Furthermore, KBs directly alleviate oxidative stress through enhanced antioxidant defenses. KD offers neuroprotection for dopaminergic neurons, provides an alternative fuel source to the brain, and optimizes cerebral glucose metabolism. It also boosts levels of essential neurotrophic factors, including brain-derived neurotrophic factor (BDNF). Beyond direct neurological effects, KD may enhance levodopa efficacy by improving its bioavailability and appears to play a crucial role in modulating gut microbiota dysbiosis, a frequently observed and potentially contributing factor in PD. While further research is essential, the comprehensive effects of KD on PD-related pathophysiology position it as a promising non-pharmacological strategy.

Background: Colorectal cancer (CRC) remains a major global health challenge, with increasing incidence, particularly among individuals under 50 years of age. Cathelicidin LL-37, a multifunctional antimicrobial peptide, has shown promise in cancer treatment, particularly for its anti-inflammatory effects.

Methods: Using in vitro and in vivo models, we investigated the anticancer potential of KR-12 amide, the shortest active fragment of LL-37, and its short-chain fatty acid (SCFA)-modified derivatives (acetyl-, propionyl-, and butyryl-KR-12-NH₂). Peptides were synthesized by Fmoc solid-phase synthesis and purified by RP-HPLC. Their cytotoxicity was assessed in colon cancer HT-29 and normal colon epithelial CCD 841 CoN cell lines using MTT viability assays. In vivo efficacy was evaluated in a mouse (male Balb/C mice) azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated colorectal cancer (CACRC). Tumor burden was quantified by macroscopic and histological scoring, while inflammation was assessed through myeloperoxidase activity, ELISA-based cytokine profiling (IL-1β, IL-6, TNF-α), and microscopic evaluation of colon architecture.

Results: For all tested compounds, except KR-12-NH₂ modified with butyric acid, the concentrations needed for 50% growth inhibition were lower for colon cancer cell line HT-29 than for healthy colon epithelial cells CCD 841 CoN. The IC₅₀ values for KR-12 amide and propionyl-KR-12-NH₂ against HT-29 cells were 236.7 µM and 309.0 µM, respectively, compared with 347.3 µM and 422.1 µM for CCD 841 CoN cells. In the AOM/DSS-induced murine model, rectal administration of KR-12-NH₂ and propionyl-KR-12-NH₂ significantly reduced total tumor number compared with AOM/DSS-only animals (p = 0.02 and p = 0.03, respectively), accompanied by lower macroscopic (both p < 0.001) and microscopic disease scores (p = 0.005 and p = 0.01). Both compounds also significantly decreased proinflammatory cytokines: rectal KR-12-NH₂ lowered IL-6 levels (p = 0.05), while rectal propionyl-KR-12-NH₂ reduced IL-6 (p = 0.02) and TNF-α (p = 0.01).

Conclusions: These findings provide a foundation for further investigation of cathelicidin derivatives in colorectal cancer therapy.

Treatment-resistant depression (TRD) continues to pose a major challenge in clinical practice, as a large proportion of patients fail to achieve remission despite multiple antidepressant drugs. Growing evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, together with epigenetic alterations, neuroinflammation, and kynurenine pathway metabolism, plays a central role in the pathophysiology of TRD. Particularly, prolonged stress-induced glucocorticoid receptor (GR) resistance, persistent hypercortisolaemia, and elevated pro-inflammatory cytokines contribute to neurotoxicity, hippocampal atrophy, and impaired neuroplasticity, aggravating depressive symptoms and reducing treatment response. Additionally, dysregulated tryptophan metabolism and the shift towards neurotoxic kynurenine metabolites further impair neuronal function and resulting in TRD. This review integrates recent findings on the complex interplay between HPA axis dysfunction, neuroimmune responses, and metabolic disturbances in TRD while highlighting novel therapeutic avenues such as ketamine, GR modulators, and anti-inflammatory agents. Further, disruption in the blood-brain barrier as one of the mechanisms of TRD was also reviewed. A deeper understanding of these mechanisms will enable the development of personalized treatment strategies to enhance clinical outcomes for TRD patients.

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.