Iranian Journal of Pharmaceutical Research最新文献

Background: At present, regarding the optimal potential for prevention and treatment of cancer, medicinal plants have received more attention than before. Stachys lavandulifolia is one of the 34 Stachys species found in various regions such as Iran. Although effective secondary metabolites have been identified in several species of the Stachys genus, research on the anticancer effects of extracts of S. lavandulifolia is limited.

Methods: In the present study, different extracts of S. lavandulifolia (n-hexane, chloroform, ethyl acetate, ethanol, hydroethanol, and water) were acquired, and three human cancer cell lines (H1299, MCF-7, and A2780) were used to analyze their anticancer effects.

Results: The chloroform and ethyl acetate extracts provided the highest toxicity against A2780 and were fractioned into A-E and F-J, respectively. Fractions C and F resulted in reducing the mitochondrial membrane potential (MMP), while fractions C, E, F, and I led to an increase in the activity of the caspase-3 enzyme. Fractions B, C, and I increased the reactive oxygen species (ROS) in the A2780 cells.

Conclusions: Considering the reduction in MMP and the increase in caspase-9 by fraction C, it can be said that apoptosis is induced by the intrinsic pathway.

Background: Rosa rugosa polysaccharides (RRP), a principal active component derived from R. rugosa Thunb., exert immunomodulatory effects. However, their therapeutic application is limited by rapid metabolism, short duration of action, and low bioavailability.

Objectives: To optimize the preparation process of Rosa rugosa polysaccharide liposomes (RRPL) and evaluate their immune cell activation in vitro.

Methods: The RRPL were prepared using the reverse-phase evaporation method, with encapsulation efficiency (EE) as the primary evaluation criterion. An orthogonal test was employed to optimize the preparation parameters. Various characteristics of RRPL were assessed, including morphology, particle size, Polydispersity Index (PDI), zeta potential, cumulative release rate in vitro, and stability. The immunological effects of RRPL were evaluated through cellular assays involving mouse spleen lymphocytes, peritoneal macrophages, and bone marrow-derived dendritic cells (BMDCs).

Results: The RRPL demonstrated an EE of approximately 81.96%, an average drug loading (DL) capacity of 13.86%, a particle size of 124.00 nm, a PDI of 0.23, and a zeta potential of -12.97 mV. The formulated RRPL exhibited high EE and DL capacity, alongside favorable slow-release properties and stability. These enhancements led to improved drug bioavailability and prolonged duration of action. Furthermore, RRPL significantly promoted the proliferation of spleen lymphocytes; enhanced the phagocytic activity of peritoneal macrophages; increased the secretion of interleukin (IL)-6, IL-1β, and interferon (IFN)-γ; activated immature BMDCs; and induced the maturation of BMDCs, resulting in increased production of IL-12p70 and tumor necrosis factor (TNF)-α.

Conclusions: This study successfully developed RRPL that markedly enhance immune cell activation compared with RRP. These findings provide a theoretical foundation for further exploration and development of these liposomal formulations.

Background: Hypothyroidism is a major endocrine disorder characterized by the dysfunction of thyroid hormones.

Objectives: This study aimed to investigate the potential therapeutic effects of an oily extract derived from black walnut (Juglans nigra) kernels on methimazole-induced hypothyroidism in adult Wistar rats.

Methods: In this experimental study, hypothyroidism was induced by the oral administration of methimazole at a single dose of 25 mg/kg body weight. In this research, 40 adult male rats were used in five groups of eight, all of which were administered orally. At the end of the experimental period, blood samples were collected from the hearts of animals for the evaluation of oxidative stress and thyroid function parameters. Serum malondialdehyde (MDA) and nitric oxide (NO) levels were assessed as markers of oxidative stress, while catalase (CAT) and superoxide dismutase (SOD) enzyme activities were measured as indicators of antioxidant defense. Thyroid hormone levels [triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH)] were determined using ELISA-based assay kits. Statistical analysis was performed using one-way ANOVA followed by Tukey's post-hoc test.

Results: Black walnut kernel oil was found to contain essential fatty acids, various hydrocarbons, and phenolic compounds. Consequently, using treatment with black walnut kernel extract in hypothyroidism rats, the SOD and T4 levels were decreased in the methimazole-treated stress group in comparison with the control group (P > 0.05), while T3 and CAT levels were significantly decreased in the methimazole-treated stress group in comparison with the control group (P < 0.05). Furthermore, the TSH, Anti thyroid peroxidase (TPO), NO, and MDA levels were increased in the methimazole-treated stress group in comparison with the control group (P > 0.05).

Conclusions: Although the ethanolic extract of black walnut (J. nigra) led to an increase in T4 levels in hypothyroid rats, the change was not statistically significant, and T3 levels were significantly decreased. Therefore, the extract did not demonstrate a clear improvement in thyroid function.

Background: Thyroid cancer remains a significant global health concern, necessitating the development of more effective treatment strategies.

Methods: This study investigated the therapeutic potential of valproic acid (VA) and retinoic acid (RA), both as single agents and in combination with conventional chemotherapeutics etoposide (Et) and epirubicin (Ep), using in vitro models of thyroid cancer. The research employed two representative cell lines: B-CPAP (poorly differentiated thyroid carcinoma) and SW-1736 (anaplastic thyroid carcinoma). Through comprehensive experimental approaches, including MTT viability assays, flow cytometry-based apoptosis and cell cycle analysis, and scratch wound migration assays, we systematically evaluated the compounds' effects.

Results: The results revealed distinct pharmacological profiles: The RA demonstrated superior cytotoxicity with significantly lower IC₅₀ values (3.01 µg/mL for B-CPAP and 1.83 µg/mL for SW) compared to VA (407.29 µg/mL and 584.32 µg/mL, respectively). Importantly, RA exhibited strong synergistic effects when combined with Et/Ep [Combination Index (CI) < 1], while VA showed primarily additive or antagonistic interactions (CI ≥ 1). Mechanistically, RA combined with low-dose Et/Ep (1/5 IC₅₀) significantly enhanced early apoptosis rates (P < 0.05) and induced S-phase cell cycle arrest, effects not observed with VA combinations. In migration assays, RA completely inhibited cancer cell movement (100% inhibition), outperforming VA's partial inhibition (40 - 70%).

Conclusions: These findings collectively demonstrate RA's potent anticancer activity and its ability to synergize with conventional chemotherapeutics, highlighting its potential as a promising candidate for combination therapy in thyroid cancer treatment. The study provides compelling preclinical evidence supporting further investigation of RA-based therapeutic strategies through advanced preclinical studies and clinical trials.

Background: The cellular mesenchymal-epithelial transition (c-Met) receptor, a member of the receptor tyrosine kinase family, is a novel therapeutic target for treating many cancers, including stomach cancer. Overexpression of c-Met and/or high levels of hepatocyte growth factor (HGF) correlate with poor prognosis. Statins, as LDL-lowering agents, are exploited to obtain anti-cancer effects via a wide range of pleiotropic effects.

Objectives: The present study aimed to discover the most effective statin as a c-Met signaling inhibitor through computational and experimental approaches.

Methods: Two main computational approaches, i.e., machine learning (ML) model and molecular dynamics (MDs) simulation, were followed by cytotoxicity, flow cytometric analysis, and western blot assay on AGS and MKN-45 gastric cancer cells.

Results: The machine learning section was founded on developing tree-based classification algorithms to predict the biological activities of the proposed statin structures as c-Met receptor inhibitors. In the second step, molecular docking and MD simulation were utilized to estimate the biomolecular interactions. The proposed classification models reveal that all structures have more than 200 nM biological activities. Machine learning led the experiment to find fluvastatin and pitavastatin as the two compounds with the highest inhibitory effects. In cell-based assays, both tested statins exhibited cytotoxicity and induced apoptosis, accompanied by sub-G1 accumulation in gastric cancer cells. However, no significant reduction in c-Met phosphorylation was observed by western blot.

Conclusions: No relation between the statins' inhibitory effect and the c-Met pathway on cancerous cells could be reported.

Background: Targeted therapy with small molecule inhibitors (SMIs) has been considered a highly effective therapeutic strategy for chronic lymphocytic leukemia (CLL). However, there is little information on the detailed mechanisms and association of SMIs with immune evasion mechanisms.

Objectives: This study examined the effects of signaling pathway inhibitors ibrutinib, idelalisib, duvelisib, and venetoclax on the expression of immune checkpoint ligands: Programmed death ligand 1 (PD-L1), galectin-9 (Gal-9), cluster of differentiation (CD)200, CD155, and herpes virus entry mediator (HVEM) in CLL leukemic cells.

Methods: Leukemic cells were isolated from fifteen CLL patients using the magnetic activated cell sorting method, confirmed by flow cytometry, and then cultured and treated with different SMIs for 72 hours. The optimal doses of the applied SMIs for in-vitro treatment were determined by MTT assay. The mRNA expression was measured by real-time PCR assay using β-actin as a housekeeping gene.

Results: The purity of isolated CLL leukemic cells was determined to be more than 97%, as confirmed by dual-color flow cytometry. Based on the IC₅₀ results obtained from the MTT assay, the optimal doses of 5, 15.03, 1.07 μM, and 0.5 nM were determined for ibrutinib, idelalisib, duvelisib, and venetoclax, respectively. None of the SMI drugs showed changes in PD-L1 expression levels compared to the untreated group. Additionally, the level of Gal-9 mRNA expression was slightly decreased in all treated groups. The expression level of CD155 was downregulated only after treatment with venetoclax, and an upregulation was observed in the other treated groups. Finally, ibrutinib and idelalisib indicated a mild non-significant upregulation in HVEM gene expression.

Conclusions: Altogether, the treatment of leukemic cells with different SMIs in this study indicated increased or decreased variations in the expression level of immune checkpoint inhibitory ligands in CLL. Therefore, these mechanisms should be considered for further treatment approaches, especially for combinational strategies.

Background: Excessive and prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause hepatotoxicity. However, prevention and treatment of this complication remain challenging.

Objectives: This study investigated the potential of the hydroalcoholic extract of Dracocephalum kotschyi (HEDK) in inhibiting diclofenac (DIC)-induced hepatotoxicity in rats.

Methods: Forty-two male Wistar rats were divided into six groups: Control group, DIC group, DIC+HEDK group in three different doses, and DIC+silymarin (SLY) group. The rats were treated for 7 days. Then, by inducing anesthesia, collecting blood from the heart, and isolating the liver, the effects of HEDK were evaluated by measuring the liver enzymes, antioxidant enzymes (using the calorimetric method), and inflammatory factors (using the RT-PCR method). Histopathological changes of the liver were also studied.

Results: The DIC significantly increased the levels of enzymes in the liver, such as ALT, AST, and ALP, lipid oxidation product, malondialdehyde (MDA), and cytokines, interleukin 1 beta (IL-1β), tumor necrosis factor α (TNF-α), NOD-like receptor protein 3 (NLRP3), and high-mobility group box 1 (HMGB1). It also decreased the levels of oxidative stress factors, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Treatment with HEDK improved the liver's biochemical parameters and significantly reduced the inflammatory cytokines. With the reduction of MDA, antioxidant enzymes also increased. The liver's histological study showed the ameliorating effects of HEDK.

Conclusions: The HEDK provided significant protection against DIC-induced toxicity due to its antioxidant effects and inhibition of inflammatory factors.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with sorafenib being a key treatment option. However, resistance to sorafenib often develops, limiting its effectiveness. Celastrol, a phytochemical derived from Tripterygium wilfordii, has shown potential in enhancing anti-tumor drug efficacy, but concerns about toxicity and clinical applicability remain.

Objectives: This study investigated whether celastrol at plasma-achievable concentrations could modulate sorafenib resistance in HCC cells in-vitro.

Methods: Cytotoxicity experiments were conducted using MTT assays to assess the effects of celastrol and sorafenib on HCC cells and normal hepatocytes. Immunofluorescence (IF) and ELISA assays were employed to measure IL-6 expression and secretion in HCC cells. Bioinformatics analyses were performed on publicly available gene expression data to identify pathways associated with sorafenib resistance. Conditioned media (CM) from treated cells were used to evaluate the impact of celastrol on sorafenib sensitivity in untreated HCC cells.

Results: High concentrations of celastrol enhanced sorafenib's inhibitory effects on HCC cells but also increased cytotoxicity in normal hepatocytes. Low concentrations of celastrol mitigated sorafenib-induced tumor cell inhibition but reversed acquired sorafenib resistance without increasing cytotoxicity in normal hepatocytes. The reversal of resistance by low-dose celastrol was associated with the inhibition of sorafenib-induced IL-6 secretion. The CM from tumor cells treated with low-dose celastrol plus sorafenib increased the sensitivity of untreated tumor cells to sorafenib, an effect reversed by the addition of exogenous IL-6 or by using IL-6-neutralizing antibodies.

Conclusions: Low-dose celastrol can reverse sorafenib resistance in HCC cells by inhibiting sorafenib-induced IL-6 secretion, without increasing hepatotoxicity.

Background: Pharmacy services in public hospitals are crucial for improving patients' health and effectively managing diseases. Previously, these services were limited to dispensing medications and counseling; they have now expanded to include a more integrated, patient-centered approach that actively supports clinical decisions and enhances treatment outcomes.

Objectives: This study aims to identify and explore the pharmacy services provided in Erbil's public hospitals, highlighting the primary challenges encountered and the strategies employed to address them.

Methods: An exploratory sequential mixed-methods approach was employed, combining qualitative and quantitative data collection methods. The qualitative phase consisted of semi-structured, in-depth, face-to-face interviews with nine pharmacy heads in Erbil's public hospitals, which were analyzed using Braun and Clarke's six-step method to identify themes. This phase was followed by a quantitative phase, which involved a structured, closed-ended questionnaire distributed to 250 pharmacy staff, with the data analyzed using SPSS 24.

Results: In the qualitative phase, five main themes emerged, identifying the state of pharmacy services and the significant challenges that directly impact the quality of care, including frequent drug shortages (N = 9), staffing shortages (N = 5), technological limitations (N = 8), and regulatory challenges (N = 9). In the quantitative phase, data from 212 completed questionnaires revealed the range of pharmacy services provided by public hospitals, including medication dispensing (88.2%), counseling (42.85%), inventory management (72.64%), and clinical services (48.11%), as well as the challenges faced in delivering these services effectively. Therefore, systematic strategies are needed to overcome these barriers.

Conclusions: The findings of this study indicate that the provision of pharmacy services within Erbil's public hospitals faces numerous challenges, indicating the need for increased investments in public hospitals, improved regulatory support, and the adoption of technological resources, all of which are essential for the advancement of pharmacy services and the improvement of patient outcomes.