Iranian Journal of Pharmaceutical Research最新文献

Background: Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes.

Objectives: The objective of the study is to identify key genes and cellular mechanisms driving DFU pathogenesis and healing using multi-omics integration.

Methods: We used differential expression analysis and weighted co-expression network analysis (WGCNA) to identify key genes in DFU. We constructed protein-protein interaction (PPI) networks through STRING and Cytoscape. Support vector machine-recursive feature elimination (SVM-RFE) was used to screen out potential diagnostic biomarkers. Single-cell transcriptomic analysis detected differences in the cellular landscape, and intercellular communication analysis deciphered the key intercellular signaling pathway.

Results: We first found 388 differentially expressed genes that are closely related to DFU (fold change > 2 and WGCNA-derived module significantly correlated with DFU, R = 0.78). We further constructed a PPI network and identified 15 hub genes and 10 diagnostic biomarkers (including FGF7) for DFU. FGF7 is lowly expressed in DFU and enriched in stromal cells and fibroblasts in DFU, and participates in the immune microenvironment of DFU. FGF7-FGFR1 is the main pathway for intercellular communication involving fibroblasts and stromal cells in the healing process of DFU.

Conclusions: These results provide an in-depth understanding of the multifactorial mechanisms underlying DFU progression and healing, offering a theoretical basis for optimizing clinical treatment.

Background: The global human immunodeficiency virus HIV/AIDS pandemic persists without complete eradication. Developing a safe and effective vaccine remains the most promising approach, but ongoing clinical trials have been unsuccessful due to the vaccines' inability to stimulate robust immunity.

Objectives: The present research endeavor proposes an innovative therapeutic vaccine by employing immunoinformatics strategies. Herein, we aimed to compare the efficiency of the whole sequence of Tat^{(exons 1 + 2)} with its first exon^{(exon 1)} in a fusion vaccine construct harboring the whole sequence of the Nef protein [i.e., Nef-Tat^{(exons 1 + 2)} and Nef-Tat^{(exon 1)} fusion proteins] using in silico studies.

Methods: First, the secondary structures of both fusion proteins were predicted. Then, 3D models of the constructs were refined, and their physicochemical properties were determined. After analysis of toxicity, allergenicity, and antigenicity of constructs, the formation of ligand (constructs)-receptor (TLR-2 to TLR-5, and TLR-7 to TLR-9) complexes was examined using the ClusPro and HDOCK servers, and the highest scores of docking analysis were used for molecular dynamics (MDs) simulation. Finally, the JCat server was applied for codon optimization.

Results: Our results indicated that both protein constructs were antigenic, non-allergenic, and capable of eliciting adaptive immune responses. The average values of radius of gyration (Rg) for Nef-Tat^{(exon 1)} and Nef-Tat^{(exons 1+2)} with TLR-4 were 1.74 and 1.90, respectively. Therefore, both constructs were stable. Moreover, the Nef-Tat^{(exon 1)} construct could significantly activate both T- and B-cells as compared to the Nef-Tat^{(exons 1+2)}. Indeed, inclusion of the second exon of Tat^{(exon 2)} did not enhance the immunogenicity of the Nef protein.

Conclusions: Generally, immunoinformatics studies showed the importance of Tat exon 1 in HIV-1 fusion vaccine design.

Background: Streptococcus equi subsp. S. zooepidemicus is a notable producer of hyaluronic acid (HA), a natural polysaccharide widely utilized in the pharmaceutical, cosmetic, and food industries due to its unique properties.

Objectives: This study focuses on strain optimization and the purification of HA. The key goals include reducing hyaluronidase activity, which degrades HA, eliminating beta-hemolytic traits, and developing a purification process that significantly minimizes organic solvent consumption to lower costs and reduce environmental impact.

Methods: UV-induced physical mutagenesis and chemical mutagenesis utilizing nitrous acid and N-methyl-N'-nitro-N-nitrosoguanidine (NTG) were employed to generate mutant strains with diminished hyaluronidase activity and beta-hemolytic properties. Following strain optimization, an efficient downstream process was implemented, focusing on pre-treatment methods involving pH and temperature adjustments, followed by ultrafiltration and phenol acetate treatment.

Results: The selected mutant, designated as S. equi subsp. S. zooepidemicus K12, maintained stable mutation characteristics over 15 generations. The HA yield of the selected mutant showed an increase of 85.7%, rising from 0.42 g/L in the wild type to 0.78 g/L. According to gel permeation chromatography, the average molecular weight (Mw) of HA increased from 6.7 × 10⁴ Da to 1.2 × 10⁵ Da. Our purification strategy achieved a recovery rate of 72% with approximately 0.3% protein impurities, meeting European Pharmacopoeia (EP) standards. Additionally, organic solvent consumption was reduced by at least 25-fold compared to conventional methods.

Conclusions: The study presents an integrated approach to HA production, encompassing strain improvement and purification. It addresses key challenges in the manufacturing of streptococcal HA and contributes to the development of more efficient and environmentally friendly purification methods, ultimately resulting in high-purity HA.

Context: Uterine disorders are among the most prevalent gynecological problems in women. Persian Medicine (PM) has long provided herbal approaches for managing such conditions, based on temperament theory and humoral balance.

Objectives: This study aimed to identify medicinal plants used in PM for the treatment of uterine disorders and to assess their pharmacological evidence.

Methods: A literature review of classical PM texts, including Makhzan al-Adwiyyah and Taqwim al-Abdan, was conducted to extract herbs recommended for uterine ailments. Plant names, traditional indications, and temperament properties were documented. Modern pharmacological evidence for each plant was then retrieved from scientific databases (PubMed, Scopus, Web of Science).

Results: A total of 97 plant species belonging to 39 botanical families were identified. Most herbs exhibited hot and dry temperaments, aligning with the PM view that uterine disorders are linked to cold-moist imbalances. Common traditional indications included dysmenorrhea, endometrial inflammation, discharge, and cold uterus. In this study, the pharmacological findings for 10 key species, including Nigella sativa, Crocus sativus, and Vitex agnus-castus, were summarized.

Conclusions: Several PM herbs show promising potential for treating uterine disorders and align with modern pharmacological mechanisms. These findings provide a basis for further research and may support the development of evidence-based herbal therapies for women's reproductive health. Among the most frequently cited species, Foeniculum vulgare, V. agnus-castus, and N. sativa exhibit promising pharmacological activity, have shown potential uterotonic effects, and may support menstrual regulation, relieve uterine pain, and help modulate hormonal balance. The findings of this review may support the design of novel plant-based interventions in reproductive medicine, guided by both traditional knowledge and modern scientific evidence.

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic inflammation, as well as metabolic and reproductive dysfunction. While insulin resistance affects many tissues, ovarian tissue exhibits insulin hypersensitivity, which promotes androgen excess and worsens PCOS symptoms. The kynurenine pathway (KP), a major route of tryptophan metabolism regulated by indoleamine 2,3-dioxygenase (IDO), is implicated in ovarian dysfunction in PCOS.

Objectives: To investigate the effects of IDO inhibition on ovarian morphology and insulin signaling in a PCOS rat model, evaluating its potential as a therapeutic approach compared to metformin.

Methods: Twenty-four female rats were randomly assigned to four groups: Control, PCOS, 1-methyltryptophan (1-MT, IDO inhibitor) (10 mg/kg), and metformin (100 mg/kg). The PCOS was induced by subcutaneous testosterone injections at 21 days of age. Outcomes measured included luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio, ovarian weight, follicle and corpus luteum counts, granulosa and theca layer thickness, fasting blood glucose, and ovarian expression of insulin receptor substrate 1 (IRS-1) and phosphoinositide 3-kinase (PI3K).

Results: The results indicated that both treatments, 1-MT and metformin, significantly reduced the LH/FSH ratio, with metformin showing a more substantial effect. Additionally, 1-MT increased ovarian weight and the number of healthy follicles (HFs), unlike metformin. Both treatments increased the number of corpora lutea (CL), indicating restored ovulation. The IRS-1 expression decreased with both treatments, whereas PI3K levels remained unchanged.

Conclusions: The IDO inhibition by 1-MT improves ovarian function and hormonal balance in PCOS more effectively than metformin, likely by reducing inflammation and modulating insulin signaling. These findings support 1-MT as a promising therapeutic candidate for PCOS management and improving ovarian function. However, these results are from a short-term animal study, and further clinical trials are necessary to assess long-term efficacy and safety.

Background: Traditional Chinese medicines (TCMs) offer a comprehensive approach to managing malignant tumors.

Objectives: The present study aims to predict the high-frequency herbs, core components, and core targets for liver cancer treatment through data mining and network pharmacology.

Methods: The "traditional Chinese Medicine - active components - target - disease" network was established using Cytoscape to identify core components. A protein-protein interaction (PPI) network was constructed using the STRING database, and Cytoscape was used for network topological analysis to identify the core targets. Subsequently, molecular docking was performed using AutoDock Vina and PyMOL to calculate binding energies of core components with core targets. Furthermore, in vitro experiments explored quercetin's impact on liver cancer cell migration, apoptosis, and protein expression.

Results: A total of 50 high-frequency drugs were selected. Among these, Atractylodes macrocephala koidz, Astragalus membranaceus, Scutellaria barbata, and Cremastra appendiculata were high-frequency drugs for invigorating qi and heat-clearing in liver cancer treatment. There were 226 common targets of herbal medicine for liver cancer treatment. Based on the degree value, beta-sitosterol, kaempferol, stigmasterol, and luteolin potentially represented core components. Eight key targets, including JUN, MAPK1, RELA, TNF, ESR1, IL-6, TP53, and FOS, were screened out, which were involved in 417 entries and 159 pathways. Molecular docking verified a strong binding affinity of the key compounds to the core targets. In vitro experiments showed that quercetin induced apoptosis and inhibited migration activity of HepG2 cells in a dose-dependent manner by affecting the expression levels of p-c-Jun/c-Jun and c-Fos proteins.

Conclusions: This study provides a foundational basis for future clinical application of TCMs in liver cancer treatment.

Background: Chronic cerebral hypoperfusion (CCH) is a key contributor to vascular dementia (VaD) and Alzheimer's disease. Resveratrol (RSV), a polyphenol with potential neuroprotective properties, may mitigate CCH-induced neuronal damage, but its mechanisms remain unclear.

Objectives: This study investigated RSV's effects on memory enhancement through synaptogenesis and apoptosis inhibition in the hippocampus in a rat CCH model.

Methods: Forty male rats were randomly divided into four groups: Sham, 2-VO (bilateral carotid artery occlusion), 2-VO+RSV (2.5 mg/kg), and 2-VO+RSV (5 mg/kg). Initial group sizes (n = 10 each) were maintained by replacing deceased animals (2-VO: 7, 2-VO+RSV2.5: 4, 2-VO+RSV5: 6 deaths). The RSV was administered via intraperitoneal injection (ip) for 35 days post-surgery. Cognitive function was assessed using Morris water maze (MWM) and shuttle box tests. Hippocampal mRNA/protein levels of B-cell lymphoma 2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase-3, Ras homolog family member A (RhoA), Rho-associated coiled-coil containing protein kinase 2 (ROCK2), calcium/calmodulin-dependent protein kinase II alpha (CaMKII-α), and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B) were measured.

Results: The RSV (5 mg/kg) significantly improved spatial memory in the MWM. Also, RSV at doses of 2.5 and 5 mg/kg significantly increased the entrance latency to the dark compartment (P < 0.05 and P < 0.01 vs 2-VO, respectively). There was a downregulation of pro-apoptotic markers (Bax, Caspase-3) and Rho/ROCK gene expressions, and an upregulation of anti-apoptotic Bcl-2 gene expression and synaptic proteins (CaMKII-α, NMDAR2B) after RSV treatment. The RSV at 5 mg/kg significantly reduced the Bax/Bcl-2 ratio compared to the 2-VO group.

Conclusions: The RSV protects against CCH-induced neuronal damage by inhibiting apoptosis and enhancing synaptic plasticity. These findings highlight RSV's therapeutic potential for vascular cognitive impairment.

Context: Vancomycin is an important antibiotic with a glycopeptide structure, effective against gram-positive bacterial infections through the inhibition of bacterial cell wall biosynthesis. It is indicated for the treatment of serious complicated skin, bloodstream, lower respiratory tract, bone, and joint infections. Primarily administered intravascularly, vancomycin shows negligible oral bioavailability. This review discusses the mechanism of action and toxicity of vancomycin, along with resistance issues and the mechanisms involved.

Evidence acquisition: We covered updated literature regarding various delivery systems for vancomycin, including nanoparticles, nanofibers, microparticles, liposomes, and hydrogels. Their antimicrobial evaluations and significant results are presented, alongside summaries of attempts for vancomycin oral delivery. The main issues of vancomycin, such as poor physicochemical properties (high molecular mass and aqueous solubility), poor oral bioavailability, minimum inhibitory concentration (MIC) creep, emergence of resistance, and high tendency to accumulate in the kidneys, can be addressed using novel drug delivery systems.

Results and conclusions: We summarized a range of novel drug delivery systems that have been investigated for enhancing the efficacy of vancomycin. The data collected here could be used as a guide for fabricating proper carriers for vancomycin delivery and selecting appropriate antimicrobial tests. Further in-depth studies on the mechanisms by which nanoparticles overcome resistance and enhance drug efficacy may pave the way for designing more effective systems.

Background: Plant-based pain-relieving formulations have garnered attention in drug discovery, particularly those with a traditional background, often considered essential remedies for communities that rely on plant-based therapies for pain relief.

Objectives: This study aimed to develop and evaluate a semisolid nanoemulsion using Piper nigrum L. (black pepper) fruit essential oil, known for its analgesic properties, as the active ingredient.

Methods: A topical nanoemulsion was prepared under standard conditions using black pepper essential oil, emulsifiers, and excipients. Various combinations of Span 80 and Tween 80 were screened to achieve the desired hydrophilic-lipophilic balance (HLB) value. Among the several formulations prepared, a nanoemulsion sample was selected for detailed analytical and pharmaceutical evaluations. Gas chromatography with flame ionization detection (GC/FID) was used to identify and quantify major chemical constituents of the essential oil and the formulated nanoemulsion.

Results: An optimized combination of Span 80 and Tween 80, with an HLB of 11, contributed significantly to the physical stability of the formulations. A concentration of 2.7% P. nigrum essential oil in the nanoemulsion containing 3793.33 ± 222.75 µg/mL of caryophyllene, the major bioactive monoterpene, rendered a stable and acceptable nanoemulsion product. The nanoemulsion formulation ST42 was declared to have a viscosity of 1.8 MPa.s, ST mix (Span 80/Tween 80, 1.5:2.5), and a ratio of surfactant/essential oil (40:60), demonstrated optimal consistency and physical stability. The zeta potential (Z) of the optimized formulation ST42 was found to be close to neutral (-8.12 ± 2.0 mV), minimizing potential tissue irritation. The nanoemulsion was ultimately validated using a modified homogenization technique to improve droplet size, stability, and rheological characteristics.

Conclusions: The formulated black pepper nanoemulsion successfully passed key pharmaceutical quality tests, indicating its potential as a natural topical pain-relieving agent. Further in vivo studies and subsequent clinical trials may lead to the development of a plant-based product for managing neuropathic pain.

Background: Cancer is regarded as one of the most significant health concerns in the world. Hepatocellular carcinoma (HCC) is a malignancy with high incidence and mortality rates and can lead to death. Cyclooxygenase (COX)-2 is responsible for the development of various cancers, including HCC. Therefore, the use of COX-2 inhibitors can help in the prevention and treatment of cancer.

Objectives: The present study aimed to synthesize and examine the effect of imidazolium [1,2-a] piperidinium (4cl-A) and benzo [d] imidazo [1,2-b] thiazolium (1-naphtyl-C) compounds as COX-2 inhibitors on the rat model of HCC.

Methods: Animals were randomly assigned to control and HCC induction groups. The study duration was 15 weeks. The HCC was induced using DEN (200 mg/kg, ip) at a single dose and 2-AAF (dietary, 0.02% w/w, for 2 weeks). After 15 weeks, the investigation focused on mitochondrial toxicity parameters. One-way and two-way ANOVA statistical tests were used to analyze the data.

Results: The results showed that 4cl-A and 1-naphtyl-C can reduce mitochondrial activity, increase the level of free radicals (ROS), collapse in mitochondrial membrane potential (MMP), cause swelling of mitochondria, and release cytochrome c from HCC mitochondria. While this effect was not observed in healthy mitochondria.

Conclusions: The results of the study indicate that these COX-2 inhibitors, along with selected drugs, can help in the treatment of HCC. However, more clinical studies should be conducted.