Iranian Journal of Pharmaceutical Research最新文献

Background: Mangrove ecosystems are rich in halotolerant microorganisms capable of synthesizing antimicrobial nanoparticles. Exploring these microorganisms for the development of novel antimicrobial agents is increasingly important, particularly given the escalating problem of multidrug resistance.

Objectives: This study aimed to confirm the biosynthesis of selenium nanoparticles (SeNPs) by the Kocuria strain Bm3, isolated from the Hera mangroves in Iran, and to evaluate the antimicrobial efficacy of SeNPs in combination with Chlorella vulgaris crude extract (C. vulgaris CE) against various bacterial strains.

Methods: The synthesized SeNPs were characterized with respect to morphology and size. Antimicrobial activity was assessed by measuring inhibition zones; minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined. Synergistic effects were calculated using the Fractional Inhibitory Concentration Index (ΣFIC). Additionally, cytotoxic effects on MCF-7 cell lines were evaluated.

Results: The combination of C. vulgaris CE and SeNPs significantly enhanced antibacterial activity against various strains, most notably a clinical isolate of Escherichia coli, which exhibited marked growth inhibition and reduced MIC values (P < 0.001). While Staphylococcus aureus did not demonstrate significant differences among treatments, Staphylococcus epidermidis and Staphylococcus saprophyticus showed improved sensitivity with the combination treatment, achieving substantial growth inhibition zones (P < 0.001). In contrast, the clinical isolate of Acinetobacter baumannii displayed potential resistance, with no growth inhibition observed when treated alone. The MTT assay revealed that C. vulgaris CE and SeNPs each exhibited low cytotoxicity individually, resulting in MCF-7 cell viability percentages of 49.75 ± 3.75% and 44.46 ± 4.26%, respectively; however, their combination significantly reduced cell viability to 29.36 ± 2.64% (P < 0.001).

Conclusions: The SeNPs synthesized by the Kocuria strain Bm3 significantly enhance the antimicrobial properties of C. vulgaris CE, indicating their potential as a therapeutic strategy against multidrug-resistant infections. Further investigation into their cytotoxic effects is warranted to evaluate safety and efficacy for clinical applications.

Background: Thyroid cancer is the most common endocrine malignancy, with aggressive subtypes frequently demonstrating resistance to conventional therapies. Bavachinin, a natural flavonoid derived from Psoralea corylifolia, has exhibited anti-cancer activity in various tumor models; however, its effects on thyroid cancer remain largely undefined.

Objectives: The aim of this study is to evaluate the anti-cancer activity of bavachinin in the papillary thyroid carcinoma TPC-1 cell line and elucidate its underlying molecular mechanisms.

Methods: TPC-1 cells were treated with bavachinin (5 - 20 μM) for 24 - 72 hours. Cell viability was assessed using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay); morphological changes were visualized by confocal microscopy. Migration and invasion were analyzed by wound-healing and Transwell assays, respectively. Cytokine secretion was measured using enzyme-linked immunosorbent assay (ELISA). Gene and protein expression levels of protein kinase B (AKT), mechanistic target of rapamycin (mTOR), extracellular signal-regulated kinase 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Apoptosis was confirmed by assessing the B-cell lymphoma-2-associated X protein (BAX)/B-cell lymphoma-2 (BCL-2) ratio and cleaved caspase-3 activity. All experiments were performed in triplicate, and data are presented as mean ± standard deviation (SD). Statistical significance was determined by one-way analysis of variance (ANOVA) followed by Tukey's post-hoc test (P < 0.05).

Results: Bavachinin significantly reduced cell viability, migration, and invasion in a dose-dependent manner (20 μM reduced viability by approximately 50% at 72 hours, P < 0.01). It suppressed the phosphorylation of AKT and ERK1/2, downregulated mTOR expression, and decreased secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Apoptosis was confirmed by an increased BAX/BCL-2 ratio and elevated cleaved caspase-3 levels.

Conclusions: Bavachinin exerts multi-targeted anti-cancer effects in thyroid carcinoma cells through dual inhibition of the phosphoinositide-3-kinase (PI3K)/AKT/mTOR and mitogen-activated protein kinase (MAPK)/ERK pathways, along with suppression of pro-inflammatory cytokines, culminating in apoptosis and impaired invasiveness.

Background: MicroRNAs (miRNAs) play key roles in colorectal cancer (CRC) progression and metastasis. miR-182-5p acts as an oncogenic metastamiR, frequently upregulated in cancers and promoting cell migration and invasion. In contrast, miR-203, miR-150-5p, and miR-139-5p function as tumor suppressors and are often downregulated in CRC.

Methods: Expression levels of these four miRNAs were quantified in three CRC cell lines using real-time polymerase chain reaction (RT-PCR). Functional assays, including cell viability, migration, and invasion, were conducted after silencing miR-182-5p or overexpressing the tumor-suppressive miRNAs through mimic transfection.

Results: The miR-182-5p was significantly overexpressed and positively correlated with metastatic potential, while miR-203, miR-150-5p, and miR-139-5p were downregulated and inversely associated with metastatic traits. Modulation of these miRNAs reduced CRC cell viability, migration, and invasion. Mechanistically, miR-182-5p enhanced metastasis via ANLN and PDE4D regulation, whereas miR-203, miR-150-5p, and miR-139-5p suppressed metastasis through PDE4D, NEGR1, and ATP11A pathways, respectively.

Conclusions: These results highlight the opposing roles of miR-182-5p and the tumor-suppressive miRNAs in CRC metastasis and suggest their potential as biomarkers and therapeutic targets.

Background: Herb-drug interactions (HDIs) have garnered significant attention in recent years.

Objectives: To investigate the effects of acacetin on the pharmacokinetics of diazepam both in vivo and in vitro.

Methods: Rat liver microsomes (RLMs) were incubated with diazepam and acacetin to determine the half-maximal inhibitory concentration (IC₅₀) and inhibition constant (Ki) values of acacetin, as well as to evaluate its inhibitory effect on diazepam metabolism in vitro. For the in vivo experiment, twelve male Sprague-Dawley rats were randomly allocated into two groups (n = 6) and received either 50 mg/kg acacetin or vehicle for two weeks. Subsequently, diazepam (10 mg/kg) was administered to each rat. Blood samples (300 μL) were collected from the tail vein at 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, and 8 hours post-administration. The plasma concentrations of diazepam and its metabolites were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

Results: The IC₅₀ values for temazepam and nordiazepam in RLMs were 2.065 μM and 5.2 μM, respectively. The Ki values for temazepam and nordazepam demonstrated that acacetin inhibits diazepam metabolism in vitro. In vivo, pretreatment with acacetin increased the area under the curve (AUC) and maximum plasma concentration (Cmax) of diazepam, while significantly decreasing its apparent clearance (CLz/F, P < 0.05). The AUC values for temazepam and nordiazepam decreased, whereas their CLz/F values increased significantly (P < 0.05). PyMOL simulations indicated that acacetin and diazepam share the same cytochrome P450 3A4 (CYP3A4) or cytochrome P450 2C19 (CYP2C19) binding pocket, suggesting that acacetin inhibits diazepam metabolism via competitive inhibition.

Conclusions: Acacetin significantly altered the pharmacokinetics of diazepam both in vivo and in vitro, indicating a potential interaction between acacetin and diazepam. Therefore, the concomitant use of acacetin and diazepam in clinical practice should be approached with caution.

Background: Long noncoding RNA (lncRNA) hox transcript antisense intergenic RNA (HOTAIR) is implicated in the progression of gastric cancer (GC) by promoting the microRNA-217 (miR-217)-glypican-5 (GPC5) axis. Quercetin (QCT), a well-known flavonoid, has demonstrated anticancer effects against various malignancies, including GC. However, the impact of QCT on HOTAIR expression and its downstream mediators remains unclear.

Objectives: This study aimed to elucidate the antitumor mechanisms of QCT and its regulatory effects on the HOTAIR/miR-217/GPC5 axis in AGS and MKN-45 GC cell lines.

Methods: Cellular viability, apoptosis, cell cycle progression, invasion, and oxidative stress markers were assessed using the MTT assay, annexin V-FITC/PI staining, real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and spectrophotometry. Expression levels of HOTAIR, miR-217, and GPC5 were quantified.

Results: The QCT significantly downregulated HOTAIR and GPC5 while upregulating miR-217 in both cell lines (P < 0.001). The QCT induced dose-dependent apoptosis and cell cycle arrest, and reduced invasion through upregulation of TP53/PTEN (P < 0.05). Oxidative stress modulation displayed lineage-specific differences, with a marked reduction in malondialdehyde (MDA) in MKN-45 cells (P = 0.013). AGS cells exhibited greater sensitivity to QCT than MKN-45 cells.

Conclusions: These findings highlight QCT's ability to inhibit GC progression via the HOTAIR/miR-217/GPC5 axis, with molecular heterogeneity influencing therapeutic response. The QCT emerges as a promising candidate for further investigation as a multifaceted agent against GC, though validation in preclinical models is necessary.

Background: The trans-signaling pathway mediated by soluble interleukin-6 receptor (IL-6R) plays a crucial role in the pathogenesis of chronic inflammatory diseases, autoimmune disorders, and various cancers.

Objectives: The present study aimed to model amino acid residues 121 to 300 of the IL-6R and to predict the effect of this selected fragment on reducing its interaction with glycoprotein 130 (gp130) using molecular docking.

Methods: The engineered selected sequence interleukin-6 receptor (seIL-6R) was designed to diminish interaction with gp130. Physicochemical parameters were evaluated using the ProtParam tool. Structural modeling and prediction were performed using AlphaFold. Molecular docking was conducted using ClusPro. Subsequently, the seIL-6R gene was recombinantly expressed in the Chinese hamster ovary (CHO)-K1 cell line. The expression of recombinant seIL-6R was evaluated by Western blotting, and its secondary structure was examined by Fourier transform infrared (FTIR) spectroscopy.

Results: Evaluation of the physicochemical parameters of the recombinant seIL-6R protein demonstrated improved stability and solubility, along with a reduced molecular weight (20.6 kDa). Molecular docking results indicated reduced binding of seIL-6R to gp130. Expression of the recombinant seIL-6R protein was confirmed by Western blotting. Furthermore, FTIR spectroscopy revealed that the secondary structure of seIL-6R was preserved and consistent with predicted structural models.

Conclusions: This engineered protein has potential for further investigation as a promising and cost-effective therapeutic agent targeting IL-6-related pathologies.

Background: Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney, with clear cell renal cell carcinoma (ccRCC) representing its predominant subtype. Despite significant advances in targeted and immune therapies, treatment resistance and recurrence continue to pose major challenges, underscoring the urgent need for novel therapeutic strategies. Jing-Si Herbal Tea (JSHT), a traditional Chinese medicine (TCM) formulation, has demonstrated anti-tumor, anti-inflammatory, and antioxidant properties; however, its mechanisms of action in kidney disease and cancer remain poorly understood.

Methods: Human proximal tubule epithelial (HK-2) cells were treated with various concentrations of JSHT (0%, 4%, and 8%) for 24 and 48 hours. Cell viability was assessed using the WST-1 assay. The expression levels of cleaved-caspase 3, glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) were analyzed by western blotting and quantified relative to β-actin.

Results: The JSHT significantly reduced HK-2 cell viability in a time- and concentration-dependent manner. Treatment with JSHT resulted in upregulation of cleaved-caspase 3, indicating activation of apoptosis, while concurrently downregulating GPX4 and SLC7A11, which are key regulators of ferroptosis resistance. These findings demonstrate that JSHT induces two forms of regulated cell death - ferroptosis and apoptosis - in renal epithelial cells.

Conclusions: The JSHT exhibits antiproliferative effects in HK-2 cells by promoting apoptosis and sensitizing cells to ferroptosis through suppression of GPX4 and SLC7A11. These results provide preliminary mechanistic insights into the effects of JSHT and indicate its potential relevance for future research in RCC. However, validation in RCC-specific models and in vivo systems is necessary. A notable limitation of this study is the use of a non-cancerous renal cell line; thus, the in vitro findings may not fully recapitulate tumor biology. Future studies employing RCC cell lines, patient-derived tumor models, and in vivo validation are warranted to elucidate the therapeutic potential of JSHT as a complementary approach for RCC management.

Background: Alveolar macrophages (AMs) play a pivotal role in the initiation, resolution, and tissue repair processes of pulmonary inflammatory diseases. The regulation of poly (ADP-ribose) polymerase-1 (PARP-1) is closely associated with inflammatory mechanisms, including the expression of inflammatory mediators, macrophage polarization, and mitochondrial damage. Tanshinone IIA, the primary active component of the Chinese herb Salvia miltiorrhiza Bge., exhibits potent anti-inflammatory activity.

Objectives: This study aims to elucidate the mechanism by which tanshinone IIA inhibits macrophage polarization, attenuates the inflammatory response, and prevents mitochondrial damage through regulation of the PARP-1 signaling pathway.

Methods: We investigated the effects of tanshinone IIA on macrophage polarization, inhibition of inflammation and oxidative stress, and protection against mitochondrial damage via the PARP-1 signaling pathway using various experimental approaches, including enzyme-linked immunosorbent assay (ELISA), flow cytometry, western blot analysis, molecular docking, and molecular dynamics (MD) simulation studies.

Results: Compared with the model group, tanshinone IIA significantly inhibited the phosphorylation and activation of nuclear factor kappa B (NF-κB, P < 0.05) in AMs by modulating PARP-1 (P < 0.05). This modulation led to suppression of NLRP3 inflammasome activation (P < 0.05 versus the model group), ultimately inhibiting the release of inflammatory mediators such as nitric oxide (NO), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α, P < 0.05). Simultaneously, tanshinone IIA suppressed cellular oxidative stress via the Nrf2/heme oxygenase-1 (HO-1) pathway (P < 0.05 versus the model group), resulting in decreased reactive oxygen species (ROS) release (P < 0.05) and reduced mitochondrial MitoSOX production (P < 0.05). By regulating PARP-1, tanshinone IIA also effectively inhibited mitochondrial damage (compared with the model group, JC-1 decreased and mitochondrial permeability transition (MPTP) increased, P < 0.05) and M1 polarization of AMs induced by lipopolysaccharide [LPS; expression of CD86, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) decreased; arginase-1 (ARG-1) and CD206 increased, P < 0.05]. Furthermore, it efficiently modulated signaling pathways involved in mitochondrial fission and fusion [optic atrophy 1 (OPA1), dynamin-related protein 1 (DRP1)] (P < 0.05).

Conclusions: These findings suggest that the therapeutic effects of tanshinone IIA on pulmonary inflammation are closely related to its ability to inhibit inflammatory damage and oxidative stress, regulate AM polarization, and alleviate mitochondrial damage in AMs through modulation of the PARP-1 pathway.