Advances in Pharmacological and Pharmaceutical Sciences最新文献

Pollution from plastic waste has become an urgent issue, requiring solutions to prevent and mitigate diseases caused by plastic waste, particularly those involving nanoplastics (NP). This study specifically focused on investigating the exogenous antioxidant activity of three plant extracts: Mangifera foetida bark (MFB), Mangifera foetida leaves (MFL), and Cinnamomum burmanii leaves (CBL), to enhance the body's defense system and reduce the risk of Type II diabetes. Twenty-five rats (Rattus norvegicus) were randomly assigned to five groups: normal control, negative control, and three treatments that received different plant extracts (200 mg/kg of MFB, MFL, and CBL, respectively) after being exposed to 10 μL/kg NP for 30 days. According to confocal microscopy analysis, NPs were observed entering cells and localizing in the nucleolus more than in the cytoplasmic hepatocyte. This study found that the administration of the plant extract could reduce the level of the proapoptotic enzyme not through the intrinsic pathway but via the extrinsic pathway. Administration of MFB, MFL, and CBL could reduce Caspase-3 significantly (1.07 ± 0.05, 1.03 ± 0.08, 1.05 ± 0.10 ng/L, respectively). This effect is mediated by the upregulation of genes related to glycolipid metabolism, including AKT2, GLUT2, PI3K, FAS, PEPCK, and PK. Administration of MFL significantly upregulated the expression levels of AK2, GLUT2, PI3K, and PK genes compared to the negative control. Administration of CBL extract enhanced the percentage of normal hepatocytes and the diameter of the central vein and decreased the percentage of necrosis, swelling, and the number of Kupffer cells. All treatment groups showed a slight decrease in the level of SGOT and SGPT. Thus, plant extracts could be effective materials exhibiting exogenous antioxidant activity against NP, directly inhibiting proapoptotic signals and regulating glycolipid metabolism. These extracts could be further developed as a preventive or therapeutic strategy to address NP exposure in environmental and clinical settings.

Background: The U.S. Food and Drug Administration has approved disulfiram (DSF) as a treatment for alcoholism. DSF shows strong anxiolytic-like effects in mice without the side effects commonly associated with benzodiazepines. However, when combined with alcohol, oral administration exhibits side effects, such as headache and decreased body temperature, limiting its clinical use. We aimed to evaluate the effects of intranasal DSF administration. Methods: Male Wistar/ST rats were used. For intranasal formulation, DSF was encapsulated by 2-hydroxypropyl-β-cyclodextrin to form an inclusion complex. The DSF formulation exhibited a uniform particle size. The elevated plus maze (EPM) test was used to examine the anxiety-reducing effects of DSF. Ethanol (2000 mg/kg, p.o.) was administered 48 h after DSF. The body temperature was measured 2 h after ethanol administration. Subsequently, we collected blood and measured the blood acetaldehyde levels. Results: Intranasal DSF administration (1.5 mg/rat) significantly increased the time spent in the open arms of the EPM within 20 min of administration. Oral DSF administration of DSF (1000 mg/kg) significantly increased the time spent in the open arms of the EPM 30 min after administration. In contrast to the oral administration, the intranasal DSF administration did not reduce body temperature or increase the blood acetaldehyde levels. Conclusions: The intranasal DSF administration exhibited rapid and potent anxiolytic-like effects at lower doses than oral administration, without triggering the alcohol interactions observed upon oral administration. Hence, the intranasal DSF formulation may have potential clinical applications as a novel anxiolytic agent. Trial Registration: Japan Registry of Clinical Trials (jRCT): jRCTs031180183.

Hypothyroidism is a common endocrine disorder that requires medical intervention by the administration of hormone replacement therapy: levothyroxine-a drug recognized as a NTI drug. Generic levothyroxine formulations can be considered as an economic alternative; however, bioequivalence problem has been encountered between various available levothyroxine formulations; thus, generic substitution is considered controversial. Dissolution testing is often used to assess the bioequivalence. The dissolution of levothyroxine from four pharmaceutical formulations: Euthyrox (old and new formulations), Eltroxin, and generic levothyroxine Sandoz was studied using a sensitive anion-exchange HPLC method. Dissolution profiles were compared using model-dependent and model-independent approaches. Results showed that there is significant difference between the formulations confirmed by the similarity (f ₁) and dissimilarity (f ₂) factors. All formulations showed variable and pH-dependent dissolution behaviors where at pH 1.2, the highest dissolution (almost 100%) is achieved. The drug-release kinetics model for each formulation varied depending on the dissolution media; where no unique kinetic model can be used to describe the release of levothyroxine from the tablets. The revealed variations in the in vitro dissolution profiles of the four formulations could be due to excipient variability from one brand to another affecting oral absorption and bioavailability and may be the reason behind bioequivalence problems between various formulations.

Riparin A is a synthetic compound with established antidepressant and anxiolytic properties. Given its therapeutic potential and the crucial roles of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and the GluN2B subunit of the N-methyl-D-aspartate (NMDA) receptor in the pathophysiology and treatment of depression, this study aimed to evaluate the effects of Riparin A on the expression of these neurotrophic factors and receptor subunit in the hippocampus and cortex of rats subjected to the chronic unpredictable mild stress (CUMS) model of depression. Using RT-qPCR, we observed that Riparin A significantly upregulated BDNF and VEGF mRNA levels while downregulating GluN2B expression, remarkably on the hippocampal area. Furthermore, ELISA assays revealed that Riparin A modulated neuroinflammation by reducing proinflammatory cytokines TNF-α and IL-1β while increasing anti-inflammatory cytokines IL-4 and IL-10. These findings support the antidepressant properties of Riparin A and shed light on its underlying mechanisms, reinforcing the interplay between neurotrophic and inflammatory pathways in pathophysiology of depression and its treatment.

Type 2 diabetes mellitus is closely linked with obesity and associated metabolic dysfunctions, including insulin resistance, dyslipidemia, and chronic inflammation. Pentacyclic triterpene acids (PTAs) derived from Cecropia angustifolia are promising bioactive compounds that may help mitigate these disorders. This study investigated the effects of a PTA-rich fraction on metabolic disruptions in cellular and diet-induced obesity mouse models. Prediabetic C57BL/6J mice fed on high-fat diet (HFD) for 8 weeks exhibited typical metabolic abnormalities, such as increased body weight, glucose intolerance, hyperinsulinemia, and dyslipidemia, which served as a baseline for assessing PTA efficacy. 8-week treatment with C. angustifolia PTAs showed significant improvement in glucose metabolism, enhancing insulin sensitivity and glucose tolerance and reducing plasma insulin levels. Although PTAs did not alter body weight or lipid profiles in HFD-fed mice in a sacha inchi oil (SIO) vehicle, they effectively prevented further weight gain, especially with intraperitoneal administration. Interestingly, we found that SIO, used as PTA solubilizer, yielded similar hypoglycemic and anti-inflammatory outcomes, and coadministration did not yield additive or synergistic effects. Furthermore, both PTAs and SIO demonstrated in vitro anti-inflammatory activity by downregulating proinflammatory gene expression, and no adverse liver, kidney, and pancreas toxicity was observed. In conclusion, PTAs from Cecropia angustifolia and SIO present potential as nontoxic, bioactive agents for modulating carbohydrate metabolism and inflammation in obesity-related conditions, although further studies are warranted to optimize dosing and investigate SIO's standalone therapeutic potential.

Alpha-mangostin (α-M), a xanthone derivative with known antioxidative properties, has demonstrated a protective effect on neurons under oxidative stress, a key factor in the pathogenesis of Parkinson's disease (PD). However, its impact on mitochondrial integrity and autophagy in PD remains insufficiently understood. Therefore, the present study aimed to investigate the role of α-M in regulating defective mitochondrial proteins and its influence on the mTOR pathway, both of which are critical in the regulation of autophagy. This study investigated the effects of α-M pretreatment on 1-methyl-4-phenylpyridinium (MPP⁺)-induced neurotoxicity in SH-SY5Y dopaminergic neurons. MPP⁺, a mitochondrial complex I inhibitor, significantly reduced the expression of mitochondrial proteins NDUFS3 and TIMM23, induced mitochondrial damage, and triggered excessive autophagy, as evidenced by elevated LC3-II/LC3-I ratio and phospho-Beclin-1 expression. These changes were accompanied by dysregulation of the mTOR signaling pathway, including increased phosphorylation of mTOR and suppression of its downstream effector p70S6K. α-M pretreatment restored NDUFS3 and TIMM23 levels, preserved mitochondrial morphology and membrane potential, and reduced autophagy activation by mitigating MPP⁺-induced LC3B accumulation and Beclin-1 activation. Additionally, α-M restored balance in the mTOR signaling pathway by reducing mTOR phosphorylation and restoring p70S6K activity, counteracting the autophagic dysregulation caused by MPP⁺. Importantly, α-M exhibited no toxicity under normal conditions, indicating its protective effects are context-dependent and activated only during cellular stress. These findings highlight the potential of α-M as a therapeutic agent for PD, providing neuroprotection through its targeted modulation of mitochondrial proteins and mTOR signaling that regulates autophagy.

In Morocco, Dittrichia viscosa L. has long been used to treat a variety of illnesses. The objective of this work was to comprehensively evaluate the essential oil (EO) derived from D. viscosa essential oil (DVEO) for its antibacterial, antidiabetic, and antioxidant effects and to confirm the in vitro results using in silico approaches. The chemical composition of DVEO was investigated using gas chromatography-mass spectrometry (GC-MS). The antioxidant ability was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and the β-carotene bleaching inhibitory activity. To assess the antibacterial potential, disc diffusion and in vitro microdilution were employed. The antidiabetic potential of DVEO was further investigated in this study by evaluating its inhibitory effects on α-amylase and α-glucosidase enzymes. The molecular docking was employed to support the experimental findings by modeling interactions between key DVEO compounds and relevant protein targets. Pharmacokinetics and toxicity were evaluated and predicted for these compounds. GC-MS analysis revealed that Shyobunol constituted over 40% of the DVEO composition. In the β-carotene and DPPH tests, DVEO exhibited a notable antioxidant effect, with IC₅₀ values of 28.93 ± 0.37 μg/mL and 759.44 ± 4.35 μg/mL, respectively, compared with standard antioxidant BHT (19.23 ± 0.53 μg/mL). The EO also demonstrated strong antibacterial activity, especially against Staphylococcus aureus (inhibitory zone [IZ] = 17.11 ± 1.11 mm) and Bacillus subtilis (IZ = 22.05 ± 0.98 mm). By inhibiting intestinal α-glucosidase and pancreatic α-amylase, the DVEO had IC₅₀ values of 0.341 ± 0.11 mg/mL and 0.361 ± 0.04 mg/mL. The IC₅₀ was determined to be between 0.281 and 0.401 mg/mL based on replicate experiments. Molecular docking simulations indicated that DVEO constituents interact favorably with the active sites of key enzymes, reinforcing their potential biological relevance. Several compounds also displayed favorable physicochemical, pharmacokinetic, and toxicity profiles, supporting their role as potent therapy candidates. These findings highlight DVEO as a valuable source of bioactive molecules with potential applications in drug discovery and development.

Purpose: Vitamin D3 deficiency is a global health concern affecting millions. However, its lipophilicity and poor water solubility limit its pharmaceutical applications. This study aims to improve the solubility of vitamin D3 by forming an inclusion complex with Captisol® (β-cyclodextrin sulfobutyl ether sodium salt) and developing a mouth-dissolving film (MDF) for its delivery. Methods: The inclusion complex was prepared using a green, microwave-assisted method and characterized via molecular docking, phase-solubility studies, drug loading, and FTIR spectroscopy. The optimized complex was incorporated into MDFs which was further evaluated for their physicochemical and mechanical properties and sensory aspects. Results: Molecular docking confirmed a high binding affinity (-10.7 K·mol^-1) between vitamin D3 and Captisol®. The optimum stoichiometric ratio of vitamin D3 and Captisol® was 2:1 confirmed by the solubility curve, drug loading, and FTIR. The complex was incorporated into MDFs prepared using polyvinyl alcohol as a film former and Tween 80 as a plasticizer. The optimized films demonstrated desirable physicochemical and mechanical properties, rapid disintegration (36 s) and dissolution (complete release within the first 5 min), and excellent content uniformity (98.8%). Sensory evaluation revealed high acceptability, although improvements in the film's color and flavor were suggested. Conclusion: This study establishes a novel, eco-friendly approach to enhance the solubility and patient-friendly delivery of vitamin D3.

Lung cancer is the second most common type of cancer and the leading cause of cancer-related deaths worldwide. Some chemotherapeutic agents, such as curcumin and gemcitabine, have low bioavailability due to their hydrophobicity or the need for specialized transporters. This limits their cytotoxic potential against tumor cells but can be addressed through nanoencapsulation. This study evaluated the effects of nanometric encapsulation of curcumin and gemcitabine in chitosan, a biocompatible polymer, on the A549 lung cancer cell line and B16F10 murine melanoma cells. The chemical properties of the synthesized nanoparticles were characterized using UV-vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM). The nanoparticles ranged in size from 180 to 197 nm, with a positive surface charge between 11.8 and 16.3 mV. Cytotoxicity assays were conducted on the A549 and B16F10 cell lines, along with morphological analyses of apoptosis and flow cytometry to assess cell death mechanisms. Compared to the free drugs, the nanometric encapsulation of curcumin and gemcitabine did not always enhance the cytotoxic effects, but it did induce pronounced apoptosis in the lung cancer cells. These findings suggest that this approach could optimize drug delivery, reduce the required doses, and minimize side effects, thereby improving the overall efficacy of lung cancer treatment.

Ardisia polycephala, Iresine herbstii, and Oenanthe javanica are commonly used to nourish women's blood and treat reproductive system diseases, according to Thai Traditional Medicine (TTM) scriptures. This study explores the biological activities of these herbs as documented in TTMs. Both water and ethanol extracts of the three herbs were examined for their antioxidant activities using DPPH, FRAP, and NO assays. Additionally, their antiestrogen and cytotoxic effects were investigated, focusing on breast cancer cell lines (T47D and MCF-7). Chemical analysis was conducted using the GC-MS technique, with reference data obtained from the National Institute of Standards and Technology (NIST) library. All herbs demonstrated good antioxidant activity. The water extract of Ardisia polycephala (AP^∗∗) exhibited the highest activity in the DPPH assay (EC₅₀ = 7.09 ± 1.47 μg/mL), which correlated with the FRAP results (358.52 ± 1.07 mg Trolox equivalent per gram). The ethanol extract of Oenanthe javanica (OJ^∗) specifically showed cytotoxicity against both T47D and MCF-7 cell lines (IC₅₀ = 38.06 ± 1.52 and 39.93 ± 0.36 μg/mL, respectively) and demonstrated antiestrogen activity by inhibiting the growth of T47D cells by 99% at 1.3 μg/mL when stimulated with 100 pM estradiol. GC-MS analysis identified numerous compounds that support the observed biological activities, including antioxidant and cytotoxic effects. In summary, the three herbs demonstrated antioxidant, cytotoxic, and antiestrogen activities consistent with the chemical compounds identified in the GC-MS analysis. These findings suggest the potential use of these herbs in future breast cancer treatments.