Iranian Journal of Basic Medical Sciences最新文献

Objectives: Insulin resistance (IR) is a critical component of metabolic syndrome, primarily linked to obesity. It contributes to impaired glucose metabolism, beta-cell dysfunction, and the onset of type 2 diabetes. This study aimed to develop a DNAsome nanocarrier designed for the targeted delivery of small interfering RNA (siRNA) to inhibit mRNA of Transforming growth factor beta-like Stimulated Clone 22 D4 (TSC22D4), thereby enhancing insulin sensitivity in hepatocytes.

Materials and methods: The DNAsome was constructed using Y-DNA building blocks derived from three distinct DNA oligonucleotides. Its structural characteristics were analyzed through atomic force microscopy (AFM). The functional efficacy of the DNAsome in delivering siRNA was evaluated by measuring its cellular uptake and ability to down-regulate TSC22D4 expression in HepG2 cells via real-time PCR. Additionally, the cytotoxicity and safety of both the DNAsome and the DNAsome-siRNA complexes were assessed using the MTT assay on HepG2 cells.

Results: Findings indicated successful fabrication of the DNAsome nanocarriers, although aggregation was observed at higher concentrations, yielding nanoparticle sizes between 116 and 740 nm. Real-time PCR results confirmed effective siRNA targeting, significant cellular uptake of the nanocomplexes, and successful silencing of TSC22D4 expression.

Conclusion: This study suggests that DNAsome-based siRNA delivery systems hold promise for improving insulin sensitivity and addressing IR associated with obesity and metabolic syndrome.

Objectives: Knee osteoarthritis (KOA) is a persistent degenerative disease affecting the joints, significantly reducing the quality of life for individuals afflicted. This study explores the therapeutic effects of total saponin Achranthes (TSA) on KOA rats and its underlying mechanism.

Materials and methods: Forty-eight rats were randomly assigned to six experimental groups: a blank control group, a model group, a sham-operated group, and a TSA treatment group (low, medium, and high dose), with eight rats in each group. The rats were treated continuously for four weeks. The degree of joint swelling was quantified, and the Lequesne MG score was evaluated. Network pharmacology approaches were employed to pinpoint potential TSA targets and related pathways for managing KOA. Additionally, histopathological examinations were conducted on the knee cartilage of the rats. Serum levels of TNF-α and IL-1β were assessed through the ELISA assay.

Results: The network pharmacology results indicate that TSA may effectively treat KOA through the MAPK and PI3K/Akt signaling pathways. Moreover, TSA significantly decreased the serum concentrations of pro-inflammatory cytokines such as TNF-α and IL-1β, and TSA down-regulated the P38 MAPK, PI3K/Akt, and NF-κB pathways, whereas the KOA model showed up-regulation. The treatment also significantly reduced MMP-9, MMP-13, and ADAMTS-5 protein levels.

Conclusion: TSA can potentially ameliorate inflammation, safeguard knee cartilage tissue, and alleviate symptoms of KOA by inhibiting the MAPK/Akt/NF-κB signaling pathway.

Obesity remains a significant worldwide health concern, and further research into other strategies, including herbal weight-loss medications, is necessary. By reviewing clinical trials, this study aims to evaluate the effectiveness of herbal medicines for weight loss or obesity. A comprehensive search was conducted using multiple databases. Clinical trials evaluating the effects of herbal medicines on weight loss or obesity management were included. Relevant data, such as study design, intervention details, and outcome measures, were extracted and analyzed. The use of herbal medicines exhibited varying efficacy in promoting weight loss or managing obesity. Some herbal interventions significantly reduced body weight, body mass index (BMI), and waist circumference. Notably, these interventions led to decreases in fasting blood glucose (FBG) and homeostatic model assessment of insulin resistance (HOMA-IR), regulating insulin levels while increasing levels of catalase (CAT) and glutathione (GSH). Additionally, reductions in inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-α) were observed, indicating a potential anti-inflammatory effect. Mechanisms of action included appetite regulation, fat oxidation, increased satiety, enhanced insulin sensitivity, and modulation of lipid metabolism. However, it is important to note that these herbal interventions' efficacy and safety profiles may vary among different population groups. The findings suggest that certain herbal medicines hold promise as adjunctive therapies for weight loss and obesity management. However, comprehensive and targeted research efforts are warranted to determine these herbal interventions' optimal use, dosages, and long-term effects in specific population subgroups.

Objectives: Hydatid cysts are typically treated with albendazole. Nevertheless, this drug has side effects and limited bioavailability. In this study, we aimed to explore a nanoemulsion of black seed oil to enhance the therapeutic efficacy of albendazole in mice with hydatid cysts.

Materials and methods: The size of the prepared nanoemulsions was characterized using a Zetasizer analyzer. Additionally, the stability of the nanoemulsions was assessed after 45 days. MTT assay was used to compare the cytotoxicity of free albendazole, nanoemulsion containing albendazole, and nanoemulsion without albendazole. Furthermore, infected mice were treated with these preparations, euthanized, and subjected to autopsy examination. Cysts obtained from mice were examined for histopathological features.

Results: ALB-NE (albendazole-loaded nanoemulsion) DLS results were obtained from black seed oil. Freshly prepared ALB-NE showed (d50 = 170 nm), PDI: 0.323, ALB-NE after 45 days storage at 25 ºC were (d50 = 92.4 nm), and ALB-NE after 45 days storage at 45 ºC revealed (d50 = 118 nm). The cytotoxicity of albendazole was reduced when loaded into the nanoemulsion. Moreover, the group treated with nanoemulsion containing albendazole showed a significant decrease in size and number of cysts compared to those receiving free albendazole or nanoemulsion without the drug. Additionally, after 60 days, the nanoemulsion containing albendazole showed 100% survival, while the survival rate was 50% for free albendazole, 75% for nanoemulsion without albendazole, and 37.5% for PBS.

Conclusion: The nanoemulsion containing albendazole can be a promising treatment for hydatid cysts.

Objectives: Epigallocatechin gallate (EGCG) exhibits various biological effects, including antiviral, anti-inflammatory, cardioprotective, and lipid-regulating properties. This study aims to investigate the therapeutic effects and mechanisms of EGCG in spinal cord injury (SCI).

Materials and methods: The bioinformatic databases were used to screen therapeutic target genes for drugs against SCI. Component-Target-Disease networks were constructed with Cytoscape software, and inter-target interactions were analyzed using the String database. Additionally, KEGG pathway enrichment analyses were conducted on the identified target genes. SCI was evaluated by detecting inflammation-related factors, H&E staining, and immunohistochemistry. Furthermore, ROS and JC1 staining were performed on HT22 cells subjected to various treatments. Molecular mechanisms were investigated using western blot and qRT-PCR analyses.

Results: Forty-four overlapping genes were identified as potential targets, with HMOX1, GPX-4, and HIF-1A emerging as central hub genes. Key pathways associated with these targets included Ferroptosis and HIF-1 signaling. In vivo studies demonstrated that EGCG effectively promotes motor function recovery and reduces the expression of proteins and genes such as IL-1β, IL-6, HIF-1α, and 4HNE. In vitro experiments showed that EGCG decreases ROS and intracellular lipid ROS levels in HT22 cells while increasing GPX-4 and HMOX1 expression to inhibit ferroptosis and HIF-1 signaling pathways.

Conclusion: Our findings reveal a significant new mechanism by which EGCG can reduce SCI through the inhibition of ferroptosis, facilitated by the activation of HMOX1 expression and the down-regulation of the HIF-1 signaling pathway. This suggests its potential as a therapeutic option for this condition.

Objectives: Cardiac fibroblast (CF) proliferation and activation drive cardiac fibrosis and heart failure. Dapagliflozin (DAPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, ameliorates diabetic cardiomyopathy (DCM). We investigated whether DAPA exerts anti-fibrotic and cardioprotective effects on DCM by directly suppressing CF proliferation and activation independent of SGLT2 inhibition.

Materials and methods: CFs were isolated from mouse hearts. Mouse cardiac function and fibrosis were investigated using histological analysis, western blotting, and echocardiography. Additionally, genetic loss-of-function studies were conducted in vitro by small interfering RNA silencing and in vivo by lentivirus-mediated gene knockdown.

Results: Compared with high-glucose-treated neonatal rat CFs, genetic loss-of-function of signal transducer and activator of transcription 3 (STAT3) or pretreatment with DAPA dramatically inhibited STAT3 phosphorylation and Yin Yang 1 (YY1) nuclear translocation, alleviated CF proliferation and activation, and reduced fibrosis. In diabetic db/db mice, administration of DAPA remarkably ameliorated diabetes-induced STAT3 activation, YY1 nuclear translocation, CF proliferation and activation, and reduced cardiac fibrosis and dysfunction. These in vitro and in vivo effects of DAPA were ameliorated by colivelin TFA, a potent activator of STAT3. Intriguingly, knockdown of SGLT2 did not have an inhibitory effect on CF proliferation and activation in db/db mice.

Conclusion: DAPA reduces cardiac fibrosis and DCM. This may, at least in part, be attributable to the repression of the STAT3-YY1 signaling axis-mediated CF proliferation and activation, independent of SGLT2 inhibition.

Objectives: Embryonic implantation is a complex and poorly understood process in which numerous cellular, hormonal, and molecular factors play critical roles. Infections in this process can result in pregnancy failure, such as implantation failure, infertility, and spontaneous abortion. Antibiotic use is necessary for infections. However, antibiotic use in pregnancy and the effect of the drug used on implantation are also conditions that must be considered. The implantation site is highly sensitive to lipopolysaccharide (LPS) and tumor necrosis factor (TNF)α, both of which can induce embryonic resorption. This study aimed to determine the effect of azithromycin (AZIT) on implantation failure, an important factor in early embryonic loss caused by LPS, by evaluating TNFα, interleukin (IL)-10, IL-2, and leukemia inhibitory factor (LIF) mRNA expressions in uterine tissue.

Materials and methods: The study involved twenty-six female rats, divided into four groups: Control, Sham, LPS, and LPS+AZIT. Lipopolysaccharide was administered intravenously on the 5th day of pregnancy in the LPS and LPS+AZIT groups. AZIT was administered intraperitoneally in the LPS+AZIT group simultaneously with LPS. TNFα, IL-10, IL-2, and LIF mRNA expressions were evaluated in uterine tissue three hours post-LPS administration.

Results: Lipopolysaccharide administration increased the expression of TNFα and IL-2 and decreased the expression of LIF. AZIT prevented the LPS-induced increase in TNFα and IL-2 mRNA expression and the decrease in LIF mRNA expression, all of which are involved in implantation failure.

Conclusion: AZIT may support the continuation of pregnancy by preventing the cytokine imbalance caused by infection at implantation.

Objectives: This study aimed to investigate whether vericiguat exerts a protective effect against myocardial ischemia-reperfusion injury (MIRI) by inhibiting toll-like receptor 4 (TLR4) and c-Jun N-terminal kinases (JNK) activation and whether heat shock protein 90 (HSP90) mediates these effects.

Materials and methods: A total of 120 male mice were randomly divided into six groups: sham, ischemia/reperfusion (I/R group), VPreC (vericiguat, 3 mg/kg, administered intravenously 12 hr before ligation), VPreC+HSP90 inhibitor geldanamycin (GA) (geldanamycin, 1 mg/kg, injected intraperitoneally 30 min before ligation), VPostC (vericiguat, 3 mg/kg, administered intravenously ten minutes before reperfusion), and VPostC+GA (geldanamycin, 1 mg/kg, injected intraperitoneally 20 min before reperfusion). The remaining five groups were subjected to 30 min of ischemia followed by two hours of reperfusion. The sizes of myocardial infarction, rates of cardiomyocyte apoptosis, and levels of myocardial markers were measured. In addition, the protein expressions of HSP90, TLR4, JNK, BAX, and B-lymphoblastoma-2 (Bcl-2) were detected, along with the mRNA levels of inflammatory factors.

Results: Vericiguat significantly reduced I/R-induced myocardial infarct size, apoptosis rate, and myocardial marker release. Alongside these positive effects, there was an increase in HSP90 and Bcl-2 expression, as well as a decrease in TLR4, JNK, BAX expression, and inflammatory factor levels. However, the HSP90 inhibitor GA reversed these protective and anti-inflammatory effects.

Conclusion: HSP90 mediates the cardioprotective effects of vericiguat, potentially by inhibiting TLR4, JNK activation, and inflammatory responses.

Objectives: To investigate the therapeutic potential of Ficus carica leaf extract (FCLE) against high-fat diet (HFD) coupled with isoproterenol-induced cardiac injury in a rat model that mimics myocardial infarction.

Materials and methods: HPLC was performed to check the phytochemical composition of FCLE. Analysis of the drug-likeness of phytochemicals and molecular docking was conducted. Four groups of rats were allocated as negative control (NC), positive control (PC), standard (STD), and FCLE treatment groups. After the experiment, serum samples were collected to carry out biochemical analyses. Histopathological assessments of the heart and aorta tissues were performed. The heart tissue gene expression analysis was conducted.

Results: : Four active compounds were identified in HPLC. Drug-likeness analysis of bioactive phytochemical compounds from FCLE indicated no violations of Lipinski's and Veber's rules, except for one compound. Quercetin and chlorogenic acid exhibited high affinity for Duox1 and Keap1 (<-8 kcal/mol). FCLE demonstrated a significant reduction in Troponin I (P<0.01), CK-MB (P<0.001), triglycerides (P<0.001), total cholesterol (P<0.001), LDL-C (P<0.001), MDA (P<0.001), and NO (P<0.0001) alongside significant increases in HDL-C (P<0.01), SOD (P<0.001), and CAT (P<0.0001) when compared to PC. FCLE treatment significantly (P<0.0001) down-regulated gene expressions of Duox1, Duoxa1, Duoxa2, Bax, and Bad, whereas the expressions of Nfe2l2, Nrf1, and Bcl2 were significantly (P<0.0001) up-regulated when compared with PC.

Conclusion: Our results suggest that FCLE mitigates cardiac injury by modulating oxidative stress and apoptosis through dual oxidases, the Nrf2/Keap1 pathway, and related apoptotic signaling cascades.

Objectives: Colistin is a crucial antibiotic for multidrug-resistant Gram-negative bacterial infections, but its nephrotoxicity limits clinical use. Trans sodium crocetinate (TSC), a synthetic crocetin derivative, exhibits anti-oxidative, antiapoptotic, and renal-protective effects. This study investigated whether TSC could alleviate colistin-induced cytotoxicity in HEK-293 cells, a human renal epithelial model.

Materials and methods: HEK-293 cells were pretreated with varying TSC concentrations for 24 hr, followed by 200 µM colistin for another 24 hr. Cell viability was measured via MTT assay, and reactive oxygen species (ROS) levels were quantified using DCFH-DA fluorescence. Apoptotic markers (Bax, Bcl-2, caspase-3) and autophagy-related proteins (LC3, Beclin-1) were analyzed by western blotting.

Results: Colistin reduced HEK-293 cell viability by 50%, increased ROS by 43%, and elevated autophagy markers (LC3, Beclin-1) by 50%. The Bax/Bcl-2 ratio rose by 50%, and cleaved caspase-3 increased by 33% compared to controls. However, TSC pretreatment significantly attenuated these effects: viability improved by 35%, ROS decreased by 50%, and the Bax/Bcl-2 ratio dropped by 50%. Additionally, TSC reduced Bax (40%), cleaved caspase-3 (55%), LC3 (35%), and Beclin-1 (45%) levels compared to colistin-only treatment.

Conclusion: These findings suggest that TSC protects HEK-293 cells from colistin-induced toxicity by reducing oxidative stress, suppressing apoptosis, and modulating autophagy. Thus, TSC may serve as a potential adjunct therapy to mitigate colistin-associated nephrotoxicity.