Iranian Journal of Basic Medical Sciences最新文献

Metabolic syndrome is a clustering of metabolic abnormalities and anthropometric factors that increase the risk of cardiovascular disease and type 2 diabetes mellitus. As the search for effective treatments intensifies, attention has turned towards natural substances with potential medicinal benefits. Among them, vanillic acid, a phenolic acid present in many plants, has attracted some attention due to its wide range of biological activities. This review aimed to provide an in-depth summary of the potential therapeutic use of vanillic acid in metabolic syndrome. The potential mechanisms of action of vanillic acid, including its anti-oxidant, anti-inflammatory, and hypolipidemic properties, are discussed. The effect of vanillic acid on glucose homeostasis, insulin sensitivity, and adipocyte activity is also addressed. The effect of vanillic acid on lipid metabolism, including the control of lipid synthesis, breakdown, and transport, is also reviewed. The emerging evidence for the beneficial effects of vanillic acid in animal models, in vitro studies, and preliminary clinical studies is also highlighted. The data suggests that vanillic acid has the potential to ameliorate metabolic syndrome. However, further preclinical and clinical research is needed to determine the specific mechanisms of action, appropriate dose, and subsequent advantages of vanillic acid. A more comprehensive understanding of the therapeutic potential of vanillic acid could pave the way for developing innovative techniques for preventing and treating metabolic syndrome and its implications.

Objectives: Adjuvants are some of the most important components used for vaccine formulation. In addition, the efficacy of vaccines is highly dependent on the nature of the adjuvants used. Therefore, new adjuvant formulations may help develop more potent vaccines. In the present study, the potency of an in-house and water-in-oil adjuvant (Yavar-70A) was compared with Montanide ISA 206 and Montanide ISA 266 in an HPV-16E7d vaccine model.

Materials and methods: Three HPV-16 E7d vaccines were formulated using three different adjuvants, Montanide ISA 206, Montanide ISA 266, and Yavar-70A, with standard protocols. Afterward, each formulation containing 10 μg of the E7d protein was administered thrice at two-week intervals to C57BL/6 mice. Serum levels of IFN-γ and IL-4 cytokines secreted from spleen cells, total IgG, and specific IgG1 and IgG2a isotypes were assessed using ELISA two weeks after the last immunization. Lymphocyte proliferative responses were also evaluated using the BrdU method.

Results: The results indicated that the vaccine formulated using the Yavar-70A adjuvant showed the highest lymphocyte proliferation responses compared with other groups and higher IFN-γ cytokine release compared with that formulated using Montanide ISA 206. However, the vaccine formulated using Montanide ISA 206 induced the highest total IgG responses compared with other groups. Importantly, the vaccine formulated using Yavar-70A decreased IL-4 secretion compared with other vaccinated groups.

Conclusion: The present study demonstrated that Yavar-70A induces cellular and humoral immunologic parameters against the HPV-16 E7d vaccine model comparable to commercialized oil-based adjuvants.

Objectives: Traumatic brain injury (TBI) is a significant cause of mortality and disability worldwide. TBI has been associated with factors such as oxidative stress, neuroinflammation, and apoptosis, which are believed to be mediated by the N-methyl-D-aspartate (NMDA)-type glutamate receptor. Two NMDA receptor antagonists, ketamine and memantine, have shown potential in mitigating the pathophysiological effects of TBI.

Materials and methods: To conduct the study, a controlled cortical impact model was used to induce TBI in rats. The rats with TBI were then divided into three groups: a group receiving only TBI, a group receiving TBI along with memantine, and a group receiving TBI along with ketamine. After 24 hr, the levels of oxidative stress markers (such as SOD, MDA, and total thiol) in the brain tissue were measured. Immunohistochemical staining was also performed seven days after TBI to assess the activation of glial cells and the TLR-4/NF-κB neuroinflammatory pathway.

Results: The results indicated that treatment with memantine led to a reduction in MDA levels and an increase in SOD and total thiol levels. Memantine also decreased astrogliosis and down-regulated the TLR-4/NF-κB pathway. On the other hand, ketamine increased the levels of anti-oxidant markers but did not significantly affect the MDA level. Additionally, ketamine decreased the expression of NF-κB seven days after TBI.

Conclusion: The findings suggest that NMDA receptor antagonists, such as ketamine and memantine, may have therapeutic effects on TBI by inhibiting oxidative stress and inflammatory responses.

Objectives: Increased nuclear factor (NF-kβ) and carbonyl stress due to decreased glyoxalase-1 activity (Glo-I) contribute significantly to insulin resistance and vascular complications. Therefore, we aimed to study the impact of the combination of thiamine and niacin on hepatic NF-kβ signaling, metabolic profile, and Glo-I activity in male rats with type-2 diabetes (T2DM).

Materials and methods: Forty male rats were divided equally into five groups: control, diabetic, diabetic treated with thiamine (180 mg/l in drinking water), niacin (180 mg/l), and a combination of both. The treated groups received the treatments daily in drinking water for two months. T2DM was induced using a combination of nicotinamide and alloxan. Metabolic profile and renal dysfunction parameters were assessed. Additionally, various glycation, oxidative stress, and inflammatory markers were measured.

Results: The treated group with both vitamins showed the lowest blood sugar and insulin resistance indices, cardiovascular indices, renal dysfunction parameters, hepatic NF-kβ expression, oxidative stress, inflammatory and glycation markers, and the highest anti-oxidant and anti-glycation markers, β cell activity, and insulin sensitivity. Thiamine exhibited more anti-inflammatory activity than niacin in diabetic rats, while niacin demonstrated stronger anti-oxidant activity (P<0.001).

Conclusion: The combined use of vitamins had a more beneficial impact on macro and microvascular complications in diabetes than each alone, attributed to their higher anti-oxidant, anti-inflammatory, and anti-glycation characteristics. The vitamins also had a more corrective effect on glucose-lipid metabolism, insulin sensitivity, and renal function through a stronger lowering effect on hepatic NF-kβ expression.

Objectives: For designing a suitable hydrogel, two crosslinked Alginate/ Carboxymethyl cellulose (Alg/CMC) hydrogel, using calcium chloride (Ca²⁺) and glutaraldehyde (GA) as crosslinking agents were synthesized and compared.

Materials and methods: All samples were characterized by Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), Blood compatibility (BC), Blood clotting index (BCI), weight loss (WL), water absorption (WA), pH, and Electrochemical Impedance Spectroscopy (EIS). Cell viability and cell migration were investigated using the MTT assay and the wound scratch test, respectively. Besides, the wound healing potential of prepared hydrogels was evaluated on the rat models with full-thickness skin excision. To further investigation, TGF β1, IGF-I, COL1, ACT-A (alfa-SMA), and GAPDH expression levels were also reported by RT-PCR.

Results: Water absorption and weight loss properties were compared between different crosslinker agents, and the most nontoxic crosslinker concentration was determined. We have shown that GA (20 µl/ml) and Ca²⁺ (50 or 75 mM) enhanced the physical stability of Alg-CMC hydrogel, and they are nontoxic and suitable crosslinkers for wound dressing applications. Although in vivo assessments indicated that the GA (20 µl/ml) had a cytotoxic effect on tissue repair, Ca²⁺ (75 mM) boosted the wound healing process. Further, RT-PCR results revealed that TGF β1, IGF-I, COL1, ACT-A (alfa-SMA), and GAPDH expression levels were increased in GA (20 µl/ml). Moreover, this trend is the opposite in the Ca²⁺ (75 mM) treatment groups.

Conclusion: This research shows that Ca²⁺ (75 mM) boosts tissue regeneration and wound healing process.

Objectives: Echinacoside (ECH) is an anti-fibrotic phenylethanoid glycoside derived from the Cistanche plant that protects against cardiac dysfunction by mitigating apoptosis, oxidative stress, and fibrosis. Nevertheless, ECH's precise function and mechanisms in addressing cardiac fibrosis are still not fully understood.

Materials and methods: In our current investigation, we induced cardiac fibrosis in mice by administering Angiotensin II (Ang II) and subsequently assessed the effects of ECH treatment four weeks post-fibrosis induction. Additionally, in an in vitro setting, we exposed cardiac fibroblasts (CFs) to Ang II to prove the anti-fibrotic mechanisms of ECH.

Results: ECH treatment effectively reversed cardiac fibrosis in the mice model. ECH treatment significantly reduced the levels of fibrosis-related genes, such as α-SMA, Collagen I, and Collagen III (all, P<0.001). Moreover, it reduced the number of apoptotic cells and regulated the expression of apoptosis-related genes, such as BAX and BCL-2 (all, P<0.001). ECH treatment also positively affected serum levels of markers associated with cardiac fibrosis, including LDH, CK-MB, ANP, BNP, CTnl, and CTnT (all, P<0.001), in the in vivo experiments. In the in vitro studies, ECH pretreatment alleviated cardiac fibroblast apoptosis and reduced cell migration, collagen deposition, and MMP expression (all, P<0.001). In our in vivo and in vitro investigations, we observed that ECH treatment reversed the down-regulation of SIRT1 and up-regulation of IL-11 following cardiac fibrosis. The results suggest that the protective effects of ECH may involve regulating the SIRT1/IL-11 pathway.

Conclusion: ECH may protect against Ang II-induced cardiac fibrosis via the SIRT1/IL-11 pathway.

Objectives: To investigate the natural product sulforaphane (SFN) in protection of membranous nephropathy (MN) by inhibiting oxidative stress-associated podocyte pyroptosis.

Materials and methods: A passive Heymann nephritis (PHN) model was established and treated with SFN. Clinical manifestations were examined by testing 24-hr urine protein, albumin, total cholesterol, triglyceride, high-density and low-density lipoprotein levels. Podocyte injury was observed through glomerular ultrastructure and the expression of podocin and desmin. Intrarenal oxidative stress was evaluated through assessment of oxidative markers, including malondialdehyde, 8-isoprostane, and 8-hydroxydeoxyguanosine, and the activities of anti-oxidant enzymes, including total superoxide dismutase, catalase, and γ-glutamylcysteine synthetase. Podocyte and intrarenal pyroptosis were investigated by observing the localization of the GSDMD N-terminus (GSDMD(N)) in podocytes; the expression of pyroptosis signaling pathway, including GSDMD, NF-κB p65, p-NF-κB p65 (Ser536), NLRP3, ASC, caspase-1, IL-1β, and IL-18; and pyroptosis encounter Nrf2 in the glomeruli and kidney.

Results: SFN has a protective effect on MN, as reflected by alleviation of nephrotic syndrome, amelioration of podocyte foot process fusion, increased expression and normalization of podocin, and decreased expression of desmin in the glomeruli. Mechanistically, SFN relieved intrarenal oxidative stress, as indicated by decreased renal malondialdehyde, 8-isoprostane, and 8-hydroxydeoxyguanosine and increased activity of total superoxide dismutase, catalase, and γ-glutamylcysteine synthetase. SFN also inhibited podocyte and intrarenal pyroptosis, as revealed by decreased colocalization of GSDMD (N) with synaptopodin and ZO-1, decreased expression of pyroptosis signaling pathway, and increased expression of Nrf2 in the glomeruli and kidney.

Conclusion: SFN could alleviate MN by inhibiting oxidative stress-associated podocyte pyroptosis.

Objectives: Particulate matter 2.5 (PM2.5), particles with an aerodynamic diameter less than 2.5 µm, affect lung function and increase respiratory disease incidence and mortality rate. The molecular mechanism of lung injury and epithelial damage after PM2.5 exposure is not completely clear.

Materials and methods: Mouth-nose exposure of mice was performed with PM2.5 or neutral saline. In vitro experiments were conducted to investigate the role of the S100A9/AMPK pathway in PM2.5-mediated lung injury.

Results: PM2.5 exposure in mice caused lung epithelial damage, alveolar wall thickening, and alveolar wall structure destruction. The 16S rRNA sequencing results suggested that the microecology structure of lung tissue was altered after PM2.5 exposure. Proteomic sequencing was performed to explore the underlying mechanism, and 71 differentially expressed proteins were identified. KEGG database analysis of the up-regulated differential proteins revealed regulatory networks, including fat digestion and absorption, the AMPK signaling pathway, and the PPAR signaling pathway. Moreover, PM2.5 exposure in mice increased the level of S100A9 and ROS, leading to reduction of the ATP level. To achieve a sufficient energy supply by increasing fatty acid transfer and oxidation, activated AMPK up-regulates CD36 and CPT1, which leads to mitochondrial damage of PM2.5-exposed cells and injury or death of lung epithelial cells. siRNA-S100A9 and AMPK inhibitors significantly reduced the occurrence of cell damage.

Conclusion: These results may help to clarify biomarkers and specific mechanisms of lung tissue injury induced by PM2.5 exposure.

Objectives: Ischemia/reperfusion (IR)-induced ventricular arrhythmia, which mainly occurs after the opening of coronary artery occlusion, poses a clinical problem. This study aims to investigate the effectiveness of pretreatment with coenzyme Q₁₀ (CoQ₁₀) in combination with mitochondrial transplantation on IR-induced ventricular arrhythmias in aged rats.

Materials and methods: Myocardial IR induction was performed by left anterior descending coronary artery occlusion for 30 min, followed by re-opening for 24 hr. CoQ₁₀ was administered intraperitoneally at a dosage of 10 mg/kg/day for two weeks before inducing IR. At the start of reperfusion, 500 µl of the respiration buffer containing 6×10⁶±5×10⁵ mitochondria/ml of respiration buffer harvested from the pectorals major muscle of young donor rats were injected intramyocardially. To investigate arrhythmias, the heart's electrical activity during ischemia and the first 30 min of reperfusion were recorded by electrocardiogram. After 24 hr of reperfusion, cardiac histopathological changes, creatine kinase-MB, nitric oxide metabolites (NOx), oxidative stress markers (malondialdehyde, total anti-oxidant, superoxide dismutase, and glutathione peroxidase), and the expression of genes regulating mitochondrial fission/fusion were measured.

Results: Pretreatment with CoQ₁₀ in combination with mitochondrial transplantation reduced ventricular arrhythmias, cardiac histopathological changes, and creatine kinase-MB levels. Simultaneously, this combined therapeutic approach increased myocardial NOx levels, fostering an improved oxidative balance. It also triggered the down-regulation of mitochondrial fission genes, coupled with the up-regulation of mitochondrial fusion genes.

Conclusion: The combination of CoQ₁₀ and mitochondrial transplantation demonstrated a notable anti-arrhythmic effect by elevating NOx levels, reducing oxidative stress, and improving mitochondrial fission/fusion in aged rats with myocardial IRI.

Objectives: LOXL2, known as Lysyl oxidase-like 2, is classified as a lysyl oxidase (LOX) family member. However, its role and mechanism in endometrial cancer (EC) are unknown. Therefore, we aimed to investigate the potential role and mechanism of LOXL2 in EC.

Materials and methods: The levels of LOXL2 expression in EC tissues and normal adjacent tissues were evaluated by immunohistochemically (IHC) labeling. Following the dye application, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Transwell methodologies were executed to evaluate the effects of LOXL2 inhibition and up-regulation on the growth, programmed cell death, migration, and susceptibility to iron-dependent cell death of EC. Moreover, protein analysis through Western blotting and gene expression analysis using Real-time quantitative PCR (RT-qPCR) was employed to measure the levels of pertinent biomarkers.

Results: LOXL2 is highly expressed in both EC tissues and serum in vivo. Silencing LOXL2 reduced EC cell proliferation and migration while increasing apoptosis in vitro. LOXL2 silencing increased the ferroptosis-related proteins Solute Carrier Family 7 Member 11 (SLC7A11) and Ferritin Heavy Chain 1 (FTH1) while decreasing Glutathione Peroxidase 4 (GPX4) (both, P<0.001). Additionally, LOXL2 silencing reduced the p-PI3K and p-Akt protein expression, while LOXL2 overexpression (OE-LOXL2) elevated the p-PI3K and p-Akt protein expression (both, P<0.001). Additionally, LOXL2 silencing increases SLC7A11 and FTH1 while decreasing GPX4 (both P<0.001). LOXL2 overexpression has the opposite effect. However, the LY294002 inhibitor restores SLC7A11 and FTH1 expression while decreasing GPX4 (P<0.001).

Conclusion: Our research demonstrated that LOXL2 might protect EC via phosphorylation by activating the PI3K/AKT pathway.