Iranian Journal of Pharmaceutical Research最新文献

Background: Chronic pulmonary infections pose a significant health burden, with accumulating evidence suggesting their potential to trigger oncogenic transformation. However, the link between chronic bacterial pneumonia and early neoplastic changes remains poorly understood, particularly in juvenile lungs.

Objectives: The present study investigates how repeated Pseudomonas aeruginosa infection induces inflammation, oxidative stress, DNA damage, and oncogenic signaling in juvenile mice, and explores potential pharmacological targets to prevent long-term oncogenic consequences.

Methods: Juvenile BALB/c mice received intranasal challenges with P. aeruginosa on days 0, 5, and 10. Lung tissues were collected at baseline (day 0) and after the establishment of chronic infection (day 21) for all downstream analyses. Lung tissues were analyzed for inflammatory [factor-kappa B (NF-κB), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α)], oxidative [nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1)], and DNA damage (γH2AX) markers using Western blotting, quantitative real-time PCR (qPCR), and immunofluorescence microscopy. Cell viability was assessed using MTT assays, and wound healing capacity was evaluated through scratch assays. Oncogenic markers (Myc, Kras) were quantified by qPCR.

Results: Chronic P. aeruginosa infection led to persistent upregulation of inflammatory proteins (NF-κB, COX-2, TNF-α) and oxidative stress markers (Nrf2, HO-1) in lung tissues on day 21 compared to day 0. Increased γH2AX expression indicated DNA damage, although no significant DNA fragmentation was detected, suggesting sublethal, localized damage. Functionally, chronic infection resulted in a 35% reduction in cell viability and significantly delayed wound healing (60% closure compared to 90% in controls). Importantly, infected tissues displayed a 2.8-fold increase in Myc and a 2.5-fold increase in Kras mRNA levels, indicating early oncogenic signaling.

Conclusions: Chronic P. aeruginosa infection in juvenile mice induces a sustained inflammatory and oxidative response, leading to epithelial cell dysfunction and activation of oncogenic pathways. These findings highlight the need for early therapeutic intervention targeting inflammation and oxidative stress to mitigate malignant transformation risks associated with recurrent pediatric lung infections. Agents modulating NF-κB activity or enhancing antioxidant defenses, such as Nrf2 activators, may represent promising pharmacological strategies. Early intervention and monitoring of chronic lung infections in pediatric populations are essential to mitigate potential oncogenic risks.

Background: Antimicrobial resistance (AMR) is becoming a serious issue for global health, with predictions of up to 10 million deaths each year by 2050. Antimicrobial stewardship programs (ASPs), supported by WHO, CDC, and various health organizations, are designed to improve antibiotic use through guidelines and reviews.

Objectives: The present study examined adherence to national guidelines for broad-spectrum antibiotics in patients at Baqiyatallah Hospital in Tehran.

Methods: Between November 2024 and March 2025, researchers analyzed 120 hospitalized patients at Baqiyatallah Hospital who were prescribed specific broad-spectrum antibiotics, such as meropenem and vancomycin. They collected information about the patients, lab results, culture findings, and their antibiotic prescriptions.

Results: We found that only 33.3% of patients had a consult from infectious diseases (ID) specialists, and just 30% had their prescriptions reviewed by a pharmacist. Cultures were taken from 87.5% of patients. The ID specialists made continuation/discontinuation decisions in only 4 of 184 cases (2.2%).

Conclusions: Overall, the use of broad-spectrum antibiotics at this hospital often deviates from the recommended guidelines. Involvement from ID teams and routine checks by pharmacists were not utilized as much as needed. These results indicate a clear need to improve ASPs and increase the involvement of clinical pharmacists to encourage better antibiotic use.

Background: Reactive oxygen species (ROS)-mediated apoptosis of intestinal epithelial cells and tight junction (TJ) protein loss play critical roles in mycophenolic acid (MPA)-induced disruption of intestinal epithelial barrier function, yet no effective therapeutic strategies exist. Schisanhenol (Sal), a major component of the traditional Chinese medicine Wuzhi capsule, exhibits strong antioxidant activity.

Objectives: The present study aimed to investigate the protective efficacy and mechanisms of Sal against MPA-induced damage to the intestinal mechanical barrier.

Methods: Caco-2 cells were exposed to MPA (10 μM), Sal (5, 10, and 25 μM), or ML385 (2 μM) for 24 hours. Cell viability was measured via a Cell Counting Kit-8 (CCK-8) assay. The expression of apoptosis-related and TJ proteins was evaluated through Western blot analysis. Flow cytometry was used to quantify the percentage of apoptotic Caco-2 cells. Immunofluorescence assays were performed to assess the localization of TJ proteins. Intracellular ROS levels were measured using H2DCFDA staining. Oxidative and antioxidative biomarker levels were quantified using specific assay kits.

Results: Sal significantly increased the viability of MPA-treated cells. It also upregulated Bcl-2 expression and reduced apoptosis. Furthermore, Sal increased the expression of the TJ proteins ZO-1 and occludin. Additionally, Sal upregulated the MPA-mediated decrease in Nrf2/HO-1 expression, reduced intracellular ROS accumulation, and increased the levels of antioxidants, including SOD, CAT, and GSH. However, ML385 partially abrogated the protective effects of Sal.

Conclusions: Schisanhenol alleviates MPA-induced intestinal mechanical barrier damage via modulation of the Nrf2 signaling pathway, highlighting its antioxidant and antiapoptotic properties.

Background: Colorectal cancer (CRC) often develops resistance to oxaliplatin (L-OHP), a key chemotherapeutic agent. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment are implicated in chemoresistance, but their role in L-OHP resistance via interleukin-6 (IL-6) secretion remains unclear.

Objectives: The presnt study investigated how CAFs contribute to L-OHP resistance in CRC, focusing on IL-6 secretion and its impact on cancer cell survival.

Methods: NIH3T3 fibroblasts were co-cultured with murine (CT26) or human (DLD1) colon cancer cells and treated with L-OHP. The supernatant IL-6 levels were measured by enzyme-linked immunosorbent assay (ELISA). Indirect co-culture using Transwell chambers was employed to separate CAF and tumor cell effects. Conditioned media (CM) from both cell types were collected and analyzed for IL-6. Cytotoxicity assays were conducted to assess the survival of L-OHP-treated CT26 cells in the presence of CAF-derived CM, with or without an IL-6-neutralizing antibody.

Results: Co-culture significantly increased IL-6 secretion, which was further amplified by L-OHP. The IL-6 levels in CAF-derived CM were approximately 3.5-fold higher than in tumor cell-derived CM. The CAF-derived CM improved the survival of L-OHP-treated CT26 cells, an effect reversed by IL-6-neutralizing antibodies. Furthermore, adding exogenous IL-6 to tumor cell-derived CM also enhanced survival. Similar IL-6 upregulation in cisplatin-treated CAFs suggests a broader role in platinum-based resistance.

Conclusions: The CAFs promote L-OHP resistance in CRC through IL-6 secretion, enhancing cancer cell survival. Therefore, targeting CAFs and IL-6 signaling may help overcome chemoresistance in CRC.

Background: Opioid abuse is a global crisis, with diamorphine being one of the most dangerous substances of abuse. Diamorphine is a major contributor to addiction and social issues.

Objectives: This study aimed to investigate the impact of different doses of diamorphine on spatial learning and memory by examining its effects on brain mitochondria function.

Methods: Four groups of nine rats were selected to receive diamorphine at doses of 1, 5, and 10 mg/kg, while one group received diamorphine solvent at a dose of 1 mL/kg. All treatments were given twice a day at 12-hour intervals for 10 days. The animals' memory performance was assessed using the Morris Water Maze test. Additionally, tests were conducted to measure ADP/ATP levels, mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), lipid peroxidation (LPO), and antioxidant function, including total thiol groups measurement (TTM), and ferric reducing antioxidant power (FRAP).

Results: The results indicated that diamorphine at doses of 5 and 10 mg/kg significantly disrupted learning and spatial memory, as evidenced by changes in latency (P < 0.0001), distance (P < 0.0001), and time spent in the target quadrant (P < 0.0001). Diamorphine also negatively impacted mitochondrial function parameters, such as ROS levels (P < 0.0001), MMP (P < 0.0001), mitochondrial swelling (P < 0.0001), and ADP/ATP ratio (P < 0.0001). Furthermore, brain antioxidant capacity was compromised (P < 0.0001).

Conclusions: This study on the mechanisms of brain damage induced by diamorphine showed that the harm arises from the impairment of mitochondrial function. This impairment leads to the generation of ROS, reduced antioxidant capacity, decreased MMP, and an elevated ADP/ATP ratio.

Background: Cervical cancer is among the most prevalent malignancies affecting women globally. This study examines the anti-tumor effects and mechanisms of Hedyotis diffusa Willd (HDW), a traditional Chinese medicinal herb, on cervical cancer.

Methods: The effects of HDW on the proliferation and migration of SiHa and CaSki cells were evaluated through in vitro assays. Additionally, the anti-tumor activity of HDW was assessed in vivo using a xenograft mouse model. To further explore its potential mechanisms, the effects of HDW on apoptosis, the cell cycle, and the IL-17/NF-κB signaling pathway were analyzed.

Results: In vitro, HDW dose-dependently reduced the proliferation, colony formation, and migration of SiHa and CaSki cervical cancer cells (P < 0.01). It induced apoptosis by modulating the expression of BCL2, BAX, caspase 3, and cleaved-caspase 3, and caused S-phase cell cycle arrest through suppression of CDK2 and cyclin A (P < 0.05 or P < 0.01). Hedyotis diffusa Willd also inhibited the IL-17/NF-κB signaling pathway by reducing IL-17A and phosphorylated NF-κB p65 expression (P < 0.05 or P < 0.01). In vivo, HDW significantly inhibited tumor growth in a xenograft mouse model (n = 5), with no signs of systemic toxicity, as demonstrated by stable body weight.

Conclusions: These findings suggest that HDW exerts its anti-tumor effects by inducing apoptosis, causing cell cycle arrest, and inhibiting the IL-17/NF-κB signaling pathway, highlighting its potential as a promising therapeutic candidate for cervical cancer.

Background: Arctium lappa L. is a well-known medicinal herb recognized for its anti-inflammatory and antioxidant properties, which have been shown to be beneficial in the treatment of various diseases.

Objectives: The present study aimed to explore the protective effects of the hydroalcoholic extract of A. lappa root in complete Freund's adjuvant (CFA)-induced arthritis in rats.

Methods: Arthritis was induced in Sprague-Dawley rats through a single subcutaneous CFA injection into the right hind paws. After induction, the animals were orally administered A. lappa at doses of 200 and 400 mg/kg, or prednisolone (as a reference drug), for a duration of 30 days. Blood and ankle joint samples were collected for analysis. The anti-arthritic effects were assessed through nociceptive behavioral tests, paw edema, body weight measurements, serum concentrations of tumor necrosis factor-α (TNF-α), nitric oxide (NO), glutathione (GSH), superoxide dismutase (SOD) activity, and histopathological evaluations.

Results: The A. lappa root extract significantly improved body weight and reduced thermal hyperalgesia, as well as decreased paw edema in a dose-dependent manner (P < 0.001). Furthermore, A. lappa reduced inflammatory cytokines and increased antioxidant defenses in the serum of all treated rats (P < 0.05 to P < 0.001). Histologically, A. lappa notably restored the ankle joint architecture compared to untreated arthritic rats (P < 0.05 to P < 0.001).

Conclusions: The results suggest that A. lappa has significant anti-arthritic potential by reducing inflammatory cytokines and enhancing serum antioxidant levels, which supports its traditional use in the management of joint diseases.

Background: Acinetobacter baumannii is a hospital-acquired opportunistic pathogen, with biofilm formation playing a crucial role in its multidrug resistance. Given the rise in antibiotic resistance, herbal medicines, including peppermint (Mentha piperita), have gained attention for their potential antibacterial properties.

Objectives: This study aimed to evaluate the inhibitory effects of peppermint extract on biofilm formation in A. baumannii strains isolated from clinical samples.

Methods: A total of 25 A. baumannii strains were isolated from clinical samples at the Faculty of Allied Medical Sciences, Tehran. Their biofilm-forming ability and antibiotic susceptibility against nine antibiotics were assessed using the disk diffusion method. The antibacterial activity of peppermint extract was evaluated by well diffusion, with its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) compared to ciprofloxacin. Synergistic effects between the extract and ciprofloxacin were analyzed, followed by a time-kill assay. Polymerase chain reaction (PCR) was used to detect the presence of PgaA and AbaI genes linked to biofilm formation.

Results: The study found that 88% of A. baumannii strains exhibited strong biofilm formation. Peppermint extract effectively inhibited biofilm formation, with MIC values ranging from 1.5 to 6 mg/mL (mean MIC: 3.75 ± 1.38 mg/mL) and MBC values equivalent to their respective MIC concentrations. For ciprofloxacin, the MIC for all samples was greater than 2048 mg/mL. No significant synergistic effect was observed between peppermint extract and ciprofloxacin. Both PgaA (involved in biofilm matrix synthesis) and AbaI (quorum sensing-related autoinducer synthase) genes were present in all tested strains.

Conclusions: Peppermint extract demonstrates biofilm-inhibitory properties against A. baumannii, suggesting its potential as an alternative therapeutic approach for combating biofilm-associated infections.

Background: Acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells, resulting in acute hypoxemic respiratory failure. Minocycline, a tetracycline antibiotic, is known to have excellent anti-inflammatory activity.

Objectives: The present study aims to reveal the protective effect and potential mechanism of the anti-inflammatory effects of minocycline on lipopolysaccharide (LPS)-induced ALI in mice and A549 cells.

Methods: We investigated the role of minocycline in ALI mice and inflammation-induced damage to alveolar epithelial cells using various experimental approaches, including histological staining, enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR, flow cytometry, western blot analysis, and other relevant assays.

Results: Pre-treatment with minocycline effectively attenuated LPS-induced ALI in vivo by inhibiting inflammation and oxidative damage, improving pathological changes in the lungs, alleviating pulmonary edema and protein exudation, and suppressing neutrophil aggregation. In vitro, minocycline suppressed the inflammatory response of human alveolar epithelial A549 cells, as evidenced by the inhibition of inflammatory cytokine and oxidative damage biomarker expression, reduction in intracellular reactive oxygen species (ROS) production, alleviation of mitochondrial damage, and inhibition of cell apoptosis. Subsequent mechanistic studies revealed that the protective effects of minocycline against ALI may be attributed to its suppression of poly (ADP-ribose) polymerase-1 (PARP-1) and histone deacetylase 3 (HDAC3) expression.

Conclusions: In conclusion, our study presents minocycline as a potential candidate for ALI therapy and provides an experimental foundation for investigating its anti-inflammatory mechanisms in the treatment of ALI. Further therapeutic value awaits verification in clinical and preclinical studies.

Background: As a prevalent neurodegenerative illness, Parkinson's disease (PD) is associated with serious disability and reduced quality of patients' lives. Therefore, finding new adjuvant treatment approaches that can improve patients' quality of life is crucial.

Objectives: This study evaluated the impacts of cannabidiol (CBD) on the PC12 cell line and elucidated its mechanism of action, emphasizing the antioxidant pathway.

Methods: First, CBD was extracted from the hemp plant. Then, the cells were treated with CBD at different dosages. After treatment, the cells were exposed to 6-HODA, and cell viability and apoptosis, reactive oxygen species (ROS) content, total antioxidant capacity, lipid peroxidation, super oxide dismutase (SOD) and GSH levels, as well as the Nrf2, Bax, Bcl-2, and Casp3 genes' expressions were measured.

Results: Cannabidiol augmented the cell viability and decreased the apoptosis rates of 6-HODA-exposed PC12 cells. Also, pretreatment of PC12 cells with CBD was associated with decreases in ROS and malondialdehyde (MDA) contents, and an improvement in total antioxidant capacity and SOD and GSH activities were also seen. In addition, CBD overexpressed Nrf2 and Bcl-2 genes in 6-HODA-exposed PC12 cells and, on the other hand, prevented the upregulation of Bax and Casp3.

Conclusions: Overall, it was concluded that CBD has neuroprotective impacts against 6-HODA-induced neurotoxicity via the Nrf2 signal transduction pathway.