Pharmacological Reports最新文献

Background: Separation and encapsulation provide a practical and effective strategy for the targeted delivery of bioactive components in formulation technologies. This study aimed to develop an inorganic Pickering-mediated formulation, Solcumin™, for food-derived tetrahydrocurcumin (THC), and to evaluate its long-term storage stability and in vitro bioactivity.

Methods: In this study, we investigated the application of inorganic Pickering-mediated techniques to encapsulate food-derived bioactive compounds. Solcumin™ was industrially produced and subjected to physicochemical analysis, stability testing in distilled water over 8 weeks at 25 °C, and in vitro bioactivity assessment, including antioxidant (DPPH, ABTS), cytotoxicity (HDFn cells), and anti-inflammatory (NO, IL-6) assays.

Results: Solcumin™ contained 11.5% tetrahydrocurcumin (THC) and exhibited excellent stability in distilled water, retaining 85% of its initial THC content after 8 weeks of storage at 25°C, while effectively preventing leaching and oxidation. Furthermore, Solcumin™ demonstrated notable anti-inflammatory activity, inhibiting nitric oxide (NO) production by approximately 89.11% and reducing interleukin-6 (IL-6) expression in a dose-dependent manner. It also exhibited antioxidant activity, as indicated by radical scavenging activity in both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays at a concentration of 100 µg/mL.

Conclusions: To the best of our knowledge, this is the first study to report the development of biomineralization-based Solcumin™ and evaluate its in vitro bioactivity.

Background: The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular antioxidant response, playing an important role in protecting neurons from ischemic injury. The hippocampus exhibits region-specific vulnerability to ischemia, with CA1 neurons being highly susceptible, while CA2-3 and dentate gyrus (DG) neurons demonstrate greater resistance. Our previous work revealed higher basal and post-ischemia/reperfusion (I/R) Nrf2 activity in the resistant CA2-3,DG region compared to CA1. This study aimed to identify potential Nrf2-regulated genes that contribute to this regional neuroprotection in a gerbil model of global cerebral ischemia.

Methods: We used a combined computational and experimental approach. By utilizing the mouse Hipposeq database and Nrf2 target gene lists from the GSEA Molecular Signatures Database, we identified 15 candidate genes with predicted roles in the CA2-3,DG stress response. Quantitative real time-PCR and Western blot analysis were then used to validate expression patterns in the gerbil hippocampus following I/R.

Results: The analysis confirmed distinct expression patterns. Although some genes, including MPP3, RET, and SHISA2, showed higher basal expression in CA2-3,DG, they were unexpectedly downregulated after I/R. In contrast, others, such as AIFM2, BRIP1, and CAMK1, were specifically upregulated in this region. Furthermore, some (GPC1) showed delayed upregulation or showed altered protein levels despite unchanged mRNA expression (FZD7, STC2).

Conclusions: These results emphasize the regional and time-dependent regulation of gene expression in the hippocampus after I/R. The identified up- and downregulated genes represent novel molecular targets whose pharmacological modulation could enhance endogenous neuroprotective pathways, revealing new therapeutic avenues for stroke.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to permanent damage to the central and peripheral motor neurons. Currently, there is no effective treatment for ALS, and therapy focuses solely on slowing the progression of the disease. Recent studies show that gut microbiota plays an important role in the development of neurodegenerative diseases. Altered gut microbiota has also been found in ALS. These changes have prompted the search for alternative forms of ALS treatment, focusing on changing the microbial composition of the gut. It has been noted that diet, probiotics, prebiotics and vitamins can all influence the course of ALS. Another interesting issue is fecal microbiota transplantation, which is already used in the treatment of certain intestinal diseases and could potentially be useful in the treatment of ALS. This review summarizes current knowledge on the impact of gut microbiota on the neurodegenerative process in ALS, with particular emphasis on the role of diet and probiotics. It also discusses potential mechanisms and highlights future research directions in this emerging field.

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.