Iranian Journal of Pharmaceutical Research最新文献

Context: Gastric cancer (GC) is a major global health burden, with drug resistance representing a critical barrier to effective treatment. Understanding the mechanisms underlying drug resistance and leveraging advanced technologies, such as artificial intelligence (AI), are essential for developing innovative therapeutic strategies.

Evidence acquisition: This review systematically examines the primary mechanisms of drug resistance in GC, organized into eight categories: Reduced drug uptake, enhanced drug efflux, impaired pro-drug activation or increased inactivation, molecular target alterations, enhanced DNA damage repair, imbalance in apoptotic regulation, tumor microenvironment modifications, and phenotypic changes. Additionally, the role of AI in addressing these challenges is explored, with a focus on omics-driven insights, pathway analysis, biomarker discovery, and modeling drug-response relationships.

Results: The review highlights the transformative potential of AI in advancing precision therapy for GC. Key applications include therapeutic stratification, optimization of drug combinations, adaptive therapy design, and integration with clinical workflows. Challenges such as data quality, model interpretability, and the need for interdisciplinary collaboration are identified, along with strategies to address these barriers. Future directions emphasize the development of explainable AI models, integration of multi-omics and real-time patient data, and AI-driven drug discovery targeting resistance pathways.

Conclusions: By bridging research and clinical practice, AI offers a promising path to more effective, personalized, and adaptive therapeutic strategies for GC. Overcoming existing challenges and leveraging AI's potential can significantly improve treatment outcomes and address the pressing issue of drug resistance in GC.

Background: To compare the effects of fentanyl combined with midazolam versus thiopental on serum levels of S100B in critically ill patients with brain injury.

Methods: Eighty-five patients who underwent neurosurgical interventions and required mechanical ventilation were included in the study. The Sequential Organ Failure Assessment (SOFA) score, duration of ventilation, length of intensive care unit (ICU) stay, and serum levels of S100B were measured and compared at baseline, day 3, and day 5 of the study.

Results: Seventy out of the 85 selected patients were randomized. There were no significant differences in the levels of S100B at admission (P = 0.7) and on day 3. However, on day 5, S100B levels were significantly lower in the thiopental group compared to the fentanyl plus midazolam group (P = 0.03). Although the duration of ventilation was shorter in the thiopental group, the difference was not statistically significant (P = 0.06). Additionally, the length of ICU stay was shorter for patients who received thiopental (214 hours vs. 209 hours, P = 0.4).

Conclusions: Our study demonstrated that both thiopental and fentanyl combined with midazolam could reduce S100B levels in patients with traumatic brain injuries. Furthermore, patients receiving thiopental experienced a shorter ICU stay and duration of ventilation.

Background: Chronic cerebral hypoperfusion (CCH), a pathophysiological state linked to vascular dementia and cognitive impairment, involves the NgR1/Lingo-1/p75 signaling complex implicated in neurodegenerative processes. Resveratrol (RES), a neuroprotective compound, was investigated for its potential to mitigate CCH-induced cognitive deficits by targeting this pathway.

Objectives: This study examined RES's ability to improve cognitive impairment in CCH by suppressing the NgR1/Lingo-1/p75 complex and downstream RhoA-ROCK2 signaling.

Methods: Rats were divided into five groups: Control, CCH + Ethanol (ETH), CCH, CCH + resveratrol (RES), and RES. Chronic cerebral hypoperfusion was induced via permanent bilateral carotid artery occlusion (2VO). Cognitive function was assessed using the Morris Water Maze (MWM). Hippocampal morphology in CA1, CA3, and dentate gyrus (DG) regions was analyzed via H&E staining. The expression levels of Lingo-1, NgR1, P75, RhoA, and ROCK2 signaling pathway were detected by western blot and quantitative real-time PCR (qRT-PCR).

Results: Chronic cerebral hypoperfusion rats showed elevated protein expression of Lingo-1, p75, RhoA, and ROCK2, though NgR1 remained unchanged. The RES treatment significantly reduced these protein levels. Similarly, mRNA levels of all five targets increased in CCH, but RES notably lowered Lingo-1 and NgR1 expression. The MWM tests revealed RES improved spatial learning and memory deficits in 2VO rats. H&E staining demonstrated RES's neuroprotective effects, preserving hippocampal neuron integrity.

Conclusions: Resveratrol alleviates CCH-induced cognitive impairment by downregulating the Lingo-1/NgR1/p75 signaling axis and inhibiting RhoA-ROCK2 pathways. These findings highlight RES's potential as a therapeutic agent for vascular cognitive impairment associated with chronic hypoperfusion.

Background: Alzheimer's disease (AD) is characterized by cholinergic dysfunction and oxidative stress, creating a need for the development of new therapeutic agents. Traditional Chinese medicine (TCM) compounds, such as hainanolidol and norwogonin, have shown potential neuroprotective activity.

Objectives: This study investigates the inhibitory action of these compounds on cholinesterase enzymes and their possible therapeutic application in an AD-like rat model generated by lead acetate (PbAc), a well-known neurotoxicant that mimics AD-associated oxidative damage and cognitive decline.

Methods: The cholinesterase inhibitory activity of nine TCM compounds was assessed in vitro against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with donepezil and tacrine as controls. Hainanolidol and norwogonin, identified as the most potent inhibitors, were further evaluated in a PbAc-induced AD rat model to assess their neuroprotective effects. Oxidative stress biomarkers malondialdehyde (MDA), glutathione (GSH), cholinesterase activity, and in silico molecular interactions were analyzed, including docking studies, molecular dynamics (MD) simulations, and ADME-toxicity profiling.

Results: Hainanolidol and norwogonin showed strong nanomolar-range inhibition of both AChE and BuChE, with considerable IC₅₀ values superior to those of standard inhibitors. In the PbAc-induced AD model, both compounds significantly reduced MDA levels and increased GSH levels, indicating oxidative stress mitigation.The level of cholinesterase activity inhibition was as effective as, or more effective than, the suppression achieved by standard treatments, particularly regarding AChE, thus suggesting enhanced therapeutic potential compared to donepezil. Molecular docking and MD simulations confirmed stable binding interactions with key catalytic residues of AChE and BuChE, reinforcing their inhibitory mechanisms. ADME-toxicity analysis further demonstrated favorable pharmacokinetics and safety profiles.

Conclusions: This study concludes that both hainanolidol and norwogonin are worthy of being regarded as dual cholinesterase inhibitors with antioxidant properties, which may serve as alternative therapeutics for AD. The use of PbAc as an AD model underscores the role of environmental neurotoxins in disease pathogenesis, offering insights into novel intervention strategies. Advanced preclinical and clinical studies are needed for further validation.

Background: Cancer is a deadly and multifaceted disease that poses a significant challenge to treatment due to its heterogeneity and ability to adapt and evolve. Despite advancements in research and medicine, the development of effective treatment options remains a major obstacle in the battle against cancer. Manganese oxide (MnO) and iron (III) oxide (Fe₂O₃) nanoparticles (NPs) are increasingly used for numerous new applications in modern industrial sectors. However, the toxic and treatment impact of MnO and Fe₂O₃ NPs has not been clearly elucidated on human cell lines at the cellular and molecular levels.

Objectives: This study aimed to assess the potential cytotoxic effect of combining infrared (IR) laser therapy with MnO and Fe₂O₃ nanoparticles on breast and colorectal cancer cells for cancer treatment.

Methods: We treated the cancer cells with MnO and Fe₂O₃ NPs and then exposed them to IR radiation for 6, 12, 24, 48, and 72 hours to investigate the effectiveness of this cancer treatment approach. To evaluate cytotoxicity, we conducted assessments on Skbr3 and HT29 cancer cells, both individually and in combination, using various methods.

Results: The findings indicate that despite the inherent toxicity of NPs and IR laser radiation on cancer cells, the utilization of MnO and Fe₂O₃ NPs in conjunction with IR laser radiation treatment had the highest cytotoxic impact on cancer cells.

Conclusions: These findings suggest that using MnO and Fe₂O₃ NPs in combination with IR laser therapy has great potential as an effective method for reducing the population of cancer cells.This revision maintains the original content while ensuring clarity and adherence to the AMA style guidelines.

Background: Vancomycin is commonly used in intensive care units (ICUs), but its optimal dosage in patients with acute kidney injury (AKI) remains uncertain. This study aimed to evaluate vancomycin's pharmacokinetic and pharmacodynamic (PK/PD) properties, therapeutic target attainment area under the curve/minimum inhibitory concentration (AUC/MIC ≥ 400) under two dosage regimens, and the need for dosage adjustments in AKI.

Objectives: The primary objective was to assess the proportion of patients achieving a therapeutic AUC/MIC ratio of 400 - 600 mg.h/L and to analyze PK/PD parameters, including volume of distribution (Vd), half-life (T½), and elimination constant (K). The secondary objective was to evaluate kidney function decline, the requirement for renal replacement therapy (RRT), and mortality rates.

Methods: A single-blind randomized clinical trial (IRCT20130917014693N16) was conducted at Loghman Hakim Hospital, Tehran, Iran. Patients over 18 years of age who received at least four doses of vancomycin and developed AKI were included in the study. Eligible patients were randomly allocated into either the intervention or control groups. The intervention group received vancomycin without any dose adjustment, while the control group's vancomycin dose was adjusted based on daily vancomycin clearance, following the standard protocol in our ICU. Daily serum creatinine, vancomycin peak and trough levels, and clinical outcomes were monitored.

Results: Twenty patients were included in the study. There were no significant differences in baseline data between the two groups. Among the 20 patients, the mean AUC/MIC was higher in the intervention group (345.80 ± 31.95) compared to the control group (251.43 ± 83.10, P = 0.005), although the therapeutic target was not achieved in either group. Despite the lower AUC in the control group, mortality rates, AKI progression, and the need for hemodialysis were comparable between groups (P = 0.29).

Conclusions: Full-dose vancomycin increases the likelihood of achieving PD targets like AUC/MIC in AKI patients. Larger studies are warranted to confirm these findings.

Background: Artemisia biennis is a weed of several crops, but some valuable biological effects have been reported from its various extracts.

Objectives: The present phytochemical study was carried out on the dichloromethane (DCM) extract of the aerial parts of A. biennis. The prominent cytotoxic and antifungal activities of this extract were previously reported.

Methods: The DCM extract was fractionated using vacuum-liquid chromatography (VLC). The selected fractions were purified by VLC and semi-preparative high-performance liquid chromatography (HPLC). The structures of the isolated compounds were characterized by comprehensive spectroscopic analyses.

Results: Two acetylenic metabolites [(E)-en-yn-dicycloether, (Z)-en-yn-dicycloether], and a 2-phenoxychromone derivative (6-demethoxy-4'-O-methylcapillarisin) were isolated from the DCM extract of A. biennis aerial parts.

Conclusions: These two acetylenic metabolites have exhibited various effects on biological systems. The results of this study are in accordance with the reported cytotoxic and antifungal activities of the DCM extract of A. biennis. The chemotaxonomic significance of the isolated compounds is also notable.

Background: Acinetobacter baumannii-induced nosocomial pneumonia and its associated biofilm infections pose significant clinical challenges due to high rates of antibiotic resistance. Traditional antibiotic treatments encounter numerous obstacles, making antimicrobial peptides (AMPs) a promising alternative for controlling such pathogens. The emergence of multidrug-resistant strains necessitates the exploration of innovative therapeutic strategies.

Objectives: We recently designed a novel hybrid peptide, M-PEX12, which exhibits antimicrobial activity and low toxicity in vitro. To confirm its therapeutic potential, we evaluated it in both in vitro and in vivo settings.

Methods: M-PEX12 was evaluated using time-kill kinetics, thermal stability, reactive oxygen species (ROS) generation, biofilm inhibition assays, scanning electron microscopy (SEM), cytotoxicity tests, and virulence gene expression analysis. Its in vivo activity against A. baumannii was also assessed in an animal model.

Results: The time-kill kinetics assay indicated that exposure to M-PEX12 at 1x minimum inhibitory concentration (MIC) (33/154) and 2x MIC resulted in over 95% reduction in bacterial populations within 30 minutes. Notably, the bacteria did not develop resistance to increased temperatures. M-PEX12 effectively disrupted biofilm formation at various concentrations. Field emission SEM revealed significant ultrastructural deformities in A. baumannii cell walls. Treatment with M-PEX12 increased production of intracellular ROS and decreased cell viability in a concentration-dependent manner. Cytotoxicity assays showed no significant effect on HEK293 cell viability. Additionally, expression levels of omp33, csuE, bfmR, and ompA were significantly reduced. The antimicrobial efficacy of M-PEX12 was confirmed in vivo.

Conclusions: M-PEX12 exhibited significant antimicrobial activity and low toxicity in a mouse model, suggesting its potential as a treatment for drug-resistant bacterial infections.

Background: Liver cancer is increasing in different parts of the world and is the fourth leading cause of cancer death globally.

Objectives: The present study aims to synthesize and analyze the characterization of gold nanoparticles (AuNPs) synthesized by Cichorium intybus extract and evaluate their antioxidant and cellular toxicity activity against liver cancer cells (HepG2).

Methods: The synthesized AuNPs were characterized using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and fourier-transform infrared spectroscopy (FTIR). The antioxidant activity of the nanoparticles was assessed using the DPPH test, and their cytotoxicity activity was analyzed using the MTT method.

Results: The results indicate that the AuNPs are crystalline materials with a particle size of less than 100 nm, with a mean particle size of 23.94 nm. The FTIR study reveals the presence of biochemical groups that act as reducing factors. The results demonstrate that antioxidant activity increases with concentration, with 87% inhibition of DPPH free radical scavenging observed at 250 µg/mL. Cell toxicity results in liver cancer cell lines (HepG2) demonstrated significant cytotoxicity in a time- and dose-dependent manner. The percentage of cell viability at a concentration of 1000 µg/ml after 24, 48, and 72 hours was determined to be 45%, 51%, and 22%, respectively.

Conclusions: The present study revealed the simple cost-effective and environmentally friendly method that could be employed from food to pharmaceutical industries.

Background: Hepatic ischemia-reperfusion injury (HIRI) significantly affects the prognosis of liver surgery, such as hepatocellular carcinoma resection and liver transplantation. However, the pathogenesis of HIRI has not been fully elucidated, and prevention and treatment strategies remain challenging.

Methods: A mouse model of HIRI was established, and schisandrin B (Sch B) was used to intervene in HIRI. The effect of Sch B on HIRI was assessed using hematoxylin and eosin (HE) staining, quantitative polymerase chain reaction (qPCR), Western blot (WB), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA).

Results: The expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of the HIRI mouse model was significantly increased, indicating the successful construction of the HIRI mouse model. In the Sch B intervention group, serum ALT and AST levels were significantly decreased. Hematoxylin and eosin staining and qPCR results demonstrated that Sch B could reduce HIRI in mice. The qPCR and immunohistochemistry showed that Sch B reduced HIRI in mice by decreasing the expression of autophagy-related factors Beclin-1 and LC3-II.

Conclusions: Additionally, qPCR and immunohistochemical results indicated that Sch B reduced HIRI by decreasing the expression of autophagy-related factors (Beclin-1 and LC3-II) and hepatocyte damage-related factors (caspase-3, caspase-9, and Bax), thereby reducing HIRI in mice. The results of electron microscopy, immunohistochemistry, and qPCR confirmed that Sch B could reduce autophagy and alleviate HIRI.