BMC Pharmacology & Toxicology最新文献

Background: Tremors and rigid muscles are symptoms of Parkinson's disease (PD), which affects about 1% of the global population.

Purpose: To investigate the integrated therapeutic benefits of the phytopharmaceutical berberine and mucoadhesive nanoliposomes, administered via the nose-to-brain route, to enhance bioavailability, facilitate blood-brain barrier penetration, and augment efficacy against neurodegenerative progression in Parkinson's disease (PD).

Study design: This study aimed to develop and characterize chitosan-decorated liposomes (chitosomes) loaded with berberine (BER) for targeted brain delivery via the intranasal route.

Methods: In vitro characterization of BER loaded chitosomes was conducted including measurement of particle size, zeta potential, EE % and in vitro drug release. The optimized formulation was intranasally administered in rats with rotenone-induced PD animal model, motor function and coordination were investigated besides testing the levels of different biomarkers and histopathological examination.

Results: The prepared chitosomes had a particle size of 312 nm, zeta potential of 34 mV, and high encapsulation efficiency (89.3%) and sustained drug release. In vivo assessments conducted in a rotenone-induced PD animal model revealed notable improvements in motor function and coordination. Biochemical evaluations showed that BER chitosomes reduced α-synuclein by 49% and raised dopamine levels by 55% as compared to the model group. Additionally, BER chitosomes significantly decreased oxidative stress markers by a 67% decrease in NF-κB levels and a one-fold increase in Nrf2. Histological examination showed a noticeable reduction in neuronal degeneration and Lewy body formation.

Conclusion: Our findings imply that BER chitosomes are a viable intranasal delivery tool for the efficient treatment of PD due to their enhanced bioavailability. and greater nasal mucosa penetration.

Background: Cancer has become a global health threat with increasing incidence & mortality rates, and despite significant advancements in diagnostics and therapeutics, they limited for aggressive cancers like pancreatic ductal adenocarcinoma (PDAC). To note, KRAS-mutated PDAC is very frequent and limited by potent therapeutics due to their aggressiveness. Drug repurposing has become a potent strategy due to cost-effective, established safety & toxicity profiles. Sitagliptin and Linagliptin are Dipeptidyl Peptidase-4 (DPP-4) inhibitors, which are being used to manage Type 2 Diabetes Mellitus (T2DM). Recent studies have indicated that they have the potential to induce apoptotic-mediated cell death in cancer.

Methods: In the current study, we examined the therapeutic potential of these DPP-4 inhibitors in proliferation, wound healing, and colony formation, ROS induction, DNA fragmentation, apoptosis induction, and regulation of gene expression in KRAS G12C-mutated MIA PaCa-2 & KRAS G12D-mutated PANC-1 PDAC cells. Additionally, the network pharmacology, Gene Ontology (GO) & KEGG pathways enrichment were also studied for DPP-4 inhibitors in PDAC.

Results: The results indicated that both drugs inhibited the proliferation, migration, & colony formation; elevated intracellular ROS levels; induced DNA fragmentation, regulated MAPK & apoptosis-related gene expression, and induced apoptosis confirmed by flow cytometry. In addition, the network pharmacology analysis supported that the identified hub genes plays a role in apoptosis.

Conclusions: Overall, we report that Sitagliptin and Linagliptin have significant anticancer potential towards KRAS-mutated PDAC. Furthermore, we recommend repurposing of more drugs to examine their anti-cancer potential towards these aggressive cancers and to overcome clinical resistance in the near future.

Background: Fluconazole (FCZ), a triazole antifungal agent, is routinely used in the treatment of various Candida infections, including oropharyngeal, esophageal, vulvovaginal candidiasis, candidemia, and disseminated candidiasis. Despite its broad safety profile, superior efficacy, and favorable pharmacokinetics, resistance to FCZ is an increasing clinical challenge. Zinc undecylenate (ZU), derived from castor oil, is an established topical antifungal agent with additional dermatological protective and immunoendocrinological properties. Combining these two pharmacotherapeutic agents presents a promising approach to overcoming fungal resistance, preventing biofilm formation, and reducing recurrence rates.

Methods: In this study, powdered ZU was condensed with powdered FCZ using low-pressure radiofrequency plasma (LPRFP). This plasma-assisted approach enabled the creation of a compound with sequential antifungal mechanisms. The condensed FCZ-ZU product was characterized and validated using nuclear magnetic resonance (NMR), optical emission spectrometry (OES), scanning electron microscopy (SEM), zeta potential, and particle size analyses. Statistical significance was determined using zeta potential and particle size data, with results evaluated at a threshold of p < 0.0001.

Results: The plasma-condensed FCZ-ZU compound demonstrated distinct physicochemical properties compared to the parent FCZ and ZU powders. Characterization confirmed the structural modification and condensation process, while particle size and zeta potential analyses indicated significant differences, supporting the creation of a novel compound (p < 0.0001). The sequential mechanism of action between FCZ and ZU suggested enhanced antifungal efficacy, reduced likelihood of resistance development, and inhibition of biofilm formation.

Conclusions: This study successfully demonstrated, for the first time, the plasma-assisted condensation of FCZ with ZU into a single antifungal preparation. The novel compound has the potential to shorten treatment duration, prevent relapse, and overcome resistance in persistent and recurrent mycosis infections. The findings highlight LPRFP as a promising method for combining multiple pharmacotherapeutic agents into innovative formulations with enhanced clinical potential.

Background: Inflammation and oxidative stress strongly contribute to the pathophysiology of acute respiratory distress syndrome (ARDS), which is a life-threatening pulmonary disease. Zinc oxide/berberine nanoparticles (ZnO/Ber-NPs) have been shown to have a protective effect against COVID-19 because of their antioxidant, anti-inflammatory, and antiviral properties. Hence, this study aimed to investigate the therapeutic action of ZnO/Ber NPs against ARDS. ARDS was induced by a combination of lipopolysaccharides and nicotine (LPS + Nt).

Methods: Male mice were induced with LPS + Nt alternately for 14 days and then orally administered berberine (Ber) (1.24 mg/kg), ZnO NPs (2.06 mg/kg), a ZnO NP + Ber mixture (3.3 mg/kg), or ZnO/Ber NPs (3.3 mg/kg). Assessment of (1) prooxidant and antioxidant (enzymatic and nonenzymatic) parameters, (2) inflammatory and anti-inflammatory markers (TNF-α, IL-1β, IFN-ɣ, NF-kB and IL-10), (3) lung lesion parameters, triggering receptor expressed on myeloid cells-1 (TREM-1), myeloperoxidase enzyme (MPO) and angiotensin-converting enzyme-2 (ACE II), (4) and apoptotic markers (Bax and p53) were performed via standardized methods. In addition, ZnO, Ber, and ZnO/Ber NPs were examined for their bioactivities against the following proteins GPx, code: 2R37, SOD protein, code: 1PL4, ACE2 protein, code: 6M1D, TREM1 protein, code: 1Q8M and MPO protein, code: 6WYZ.

Results: The results demonstrated that LPS + Nt administration significantly elevated oxidative stress, proinflammatory, lung lesion, and proapoptotic parameters while reducing antioxidant and ACE II levels in the lung. Treatments, especially ZnO/Ber NPs, significantly attenuated the oxidative stress and inflammation associated with ARDS, as indicated by the restoration of antioxidant enzyme activities, decreased lipid peroxidation, and proinflammatory TNF-α and IFN-ɣ levels. ZnO/Ber NPs significantly decreased TREM-1 and MPO in association with elevated ACE II. In addition, ZnO/Ber NPs decreased the expression of apoptotic markers and decreased the number of alveolar inflammatory infiltrates to the minimal score. Molecular docking analysis revealed that ZnO/Ber NPs showed the strongest binding with all tested receptors.

Conclusion: ZnO/Ber NPs exhibit antioxidant, anti-apoptotic, and anti-inflammatory effects and act as therapeutic candidates against ARDS.

The liver has a tremendous regeneration potential, yet chronic liver injury poses a life-threatening condition if not managed appropriately. Apocynin, an NADPH oxidase inhibitor, has been a central focus of attention in recent years due to its significant antioxidant/anti-inflammatory potentials. In this study, we evaluated the acute toxicity and hepatoprotective effects of Apocynin against thioacetamide (TAA)-induced liver fibrosis in rats. Liver fibrosis was induced by 200 mg/kg TAA three times/week for two months, along with treatment with distilled water (positive control), silymarin (reference, 50 mg/kg), or apocynin (50 and 100 mg/kg/day). Hepatic tissues were screened for histopathological, biochemical, and immunohistochemical changes, while hepatic homogenate was examined for the antioxidant contents (catalase, CAT; superoxide dismutase, SOD) and MDA levels. Apocynin treatment showed significant hepatoprotective effects against TAA-hepatotoxicity, evidenced by reduced hepatic tissue alterations with a slight fibroplasia, reduction of hepatomegaly, less hepatic nodules/necrosis, and recovered hepatic function. Additionally, apocynin administration reduced oxidative stress by lowering pro-oxidants (MDA) and up-regulating antioxidants (SOD and CAT). Furthermore, the anti-apoptotic and anti-fibrotic effects of apocynin were confirmed by reduced pro-apoptotic P53 proteins and β-catenin (tissue proliferation/aggregation enhancer). Apocynin treatment ameliorated ECM generation (lowered collagen bundles/fibrous septa) and reduced inflammatory (less TNf-α and IL-6 cytokines) mediators, all of which restored liver functional parameters (ALT, AST, ALP, and albumin). Apocynin attenuated TAA-mediated liver fibrosis by its modulatory potentials on several cytoprotective mechanisms associated with the oxidative stress/inflammation, making it a viable therapeutic source for liver fibrosis.

Inorganic arsenical compounds, such as arsenic trioxide (ATO), are toxic environmental contaminants that occur widely in soil, water, and biological systems. Besides, zinc oxide nanoparticles (ZNPs) have been recently incorporated in various industrial and medicinal applications. Thus, their co-existence in the environment could widely occur. This study examined the potential protective activity of gallic acid (GA, 20 mg/kg b. wt) against the harmful impacts of 60-day co-exposure to ATO (8 mg ATO/kg b. wt) and ZNPs (100 mg ZNPs/kg b. wt) on the kidneys of rats. The results indicated that ZNPs and/or ATO exposure resulted in increased serum levels of markers associated with renal damage, an imbalance in electrolytes (sodium, potassium, and calcium), diminished levels of antioxidant enzymes in the kidneys, and an increased malondialdehyde (MDA) concentration. Furthermore, ZNPs and/or ATO co-exposed rats demonstrated markedly increased levels of renal zinc (Zn) and arsenic (As), accompanied by pronounced histopathological alterations, including interstitial nephritis, renal tubular necrosis, and vascular wall thickening. Immunohistochemical analysis revealed that exposure to ZNPs and/or ATO reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while increasing that of heat shock protein 90 (HSP90) in kidney tissues. Co-exposure to ZNPs and ATO produced more pronounced alterations, including increased serum uric acid and creatinine, decreased sodium levels, reduced renal GPx activity, increased MDA content, greater renal accumulation of As and Zn, and diminished Nrf2 expression, compared with individual exposures, suggesting additive toxic effects. However, GA notably reduced renal tissue damage, oxidative stress, and disturbances in renal function and electrolyte balance in rats co-exposed to ZNPs and ATO. Conclusively, the study found that exposure to ZNPs and ATO, especially when combined, was toxic to the kidneys, leading to impaired renal function through increased oxidative stress and disrupted electrolyte balance. However, GA effectively protected kidney health at the administered doses by counteracting these effects through its antioxidant properties and by modulating cellular defense mechanisms involving Nrf2 and HSP90.

Background: Topiramate (TPM) is a sulfamate-substituted monosaccharide known for its wide-ranging effects on epilepsy, neuropathic pain, and migraines. However, its precise influence on plasmalemmal ionic currents, including their magnitude and gating kinetics, remains uncertain. Therefore, a reassessment of the regulatory effect of TPM on ionic currents in electrically excitable cells is warranted.

Methods: With the aid of patch clamp technology, we investigated the effects of TPM on the amplitude, gating, and hysteresis of plasmalemmal ionic currents from GH₃ lactotrophs.

Results: We observed that TPM exhibited a concentration-dependent inhibition of both transient (I_Na(T)) and late (I_Na(L)) components of I_Na, activated by brief depolarizing stimuli. At low concentration, TPM did not show any noticeable effect on I_Na(T); however, it was effective in reducing I_Na(L) amplitude. TPM caused a leftward shift in the midpoint of the steady-state inactivation curve of I_Na(T) without altering the gating charge. Importantly, the overall current density versus voltage relationship of I_Na(T) remained unaltered during TPM exposure. Intriguingly, the reduction in I_Na(T) induced by TPM could not be reversed by subsequent additions of flumazenil or chlorotoxin. Furthermore, TPM suppressed the density of the hyperpolarization-activated cation current (I_h). Simultaneously, the activation time course of I_h slowed in the presence of TPM. Moreover, TPM exposure decreased the hysteretic strength activated by double triangular ramp voltage, a change partially reversed by oxaliplatin. In current-clamp potential recordings, spontaneous action potentials were susceptible to suppression in the presence of TPM.

Conclusions: Collectively, these findings strongly suggest that TPM's effects on I_Na and I_h have the potential to impact the functional activities and electrical behaviors of excitable cells.