Iranian Journal of Basic Medical Sciences最新文献

Objectives: Triple-negative breast cancer (TNBC), which affects 15-20% of cases, lacks targeted therapies and poses challenges in treatment. MicroRNAs (miRNAs) are potential biomarkers and therapeutic targets in breast cancer. To unravel its unique regulatory role, this study focused on miRNA microarray analysis, particularly miR-548F-3p, in TNBC samples.

Materials and methods: Using the GSE76275 dataset, gene expression profiles were analyzed using the Affymetrix Human Genome U133 Plus 2.0 Array. Differentially expressed genes (DEGs) were identified using robust preprocessing. Weighted gene co-expression network analysis (WGCNA) explored gene modules and identified hub genes co-expressed with miR-548F-3p. Functional enrichment and protein-protein interaction (PPI) network analyses were conducted. Survival analysis was used to assess the prognostic impact of the identified genes.

Results: The study found 224 up-regulated DEGs, with miR-548F-3p exhibiting significant down-regulation. MultimiR identified 400 genes that were targeted by miR-548F-3p. WGCNA revealed a blue co-expression module, with 356 genes targeted by miR-548F-3p. A Venn diagram identified common genes, including VANGL2, BRCC3, ANP32E, and ANLN. Functional enrichment highlighted crucial pathways in TNBC pathogenesis, including mitotic spindle organization, spindle assembly checkpoint signaling, cell cycle, and amino acid (serine) metabolism. PPI network analysis identified hub genes, including FOXM1, KIF23, and CDC20. VANGL2, BRCC3, ANP32E, and ANLN were significantly associated with patient outcomes in survival analysis.

Conclusion: This analysis highlighted TNBC's molecular landscape, emphasizing miR-548F-3p's regulatory role. The identified genes, VANGL2, BRCC3, ANP32E, and ANLN, offer insights into TNBC pathogenesis and potential therapeutic targets, laying the foundation for understanding their clinical implications in the intricate landscape of TNBC.

Objectives: The aim of this study is to investigate the possible role of the hippocampal BDNF-PI3K-AKT signaling pathway in the antidepressant-like activity of ellagic acid (EA) in mice.

Materials and methods: Male BALB/C mice were divided into 5 groups; vehicle (0.1 ml/day), sertraline (5mg/kg), EA (1 mg/kg), EA+BKM120 (PI3K inhibitor), EA+MK2206 (AKT inhibitor). EA, sertraline and vehicle were injected intraperitoneally for 14 days. Locomotor activity was determined by open field test. The tail suspension test was used to detect the antidepressant-like effect. After behavioral tests, hippocampal tissue was obtained and Western blot analyzes were performed for BDNF and pAKT1.

Results: Sertraline and EA provided a reduction in immobility time in the tail suspension test when compared with the control group. BKM120 and MK2206 administration reversed this effect of EA. No statistical difference was found between groups in terms of locomotor activity. EA treatment caused an increase in hippocampal BDNF and pAKT1 levels in mice. While inhibitory agent administrations did not affect the increase of BDNF induced by EA, MK2206 administration reversed the increase in pAKT1 observed with EA.

Conclusion: It has shown that EA has an antidepressant-like effect in mice without changing locomotor activity, and this effect may be mediated by the BDNF-PI3K-AKT signaling pathway.

Objectives: This experiment was carried out to investigate the protective effects of curcumin (CUR) on testicular damage induced by the valproic acid (VPA) administration.

Materials and methods: Male Wistar-Albino rats (n=28, 250-300 g) were randomly divided into four groups: Control (1 ml saline, oral), VPA (500 mg/kg, IP), CUR (200 mg/kg, oral), or VPA+CUR (500 mg/kg, VPA, IP plus 200 mg/kg CUR, oral). The treatments were applied for 14 days. Serum testosterone and testis [Janus kinases1 (JAK1), signal transducers and activators of transcription-3 (STAT-3), interleukin-6 (IL-6), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-18 (IL-18), and nuclear factor (NF)-κB)] samples were collected for biochemical analyses. Semen samples were subjected to microscopy for spermatological parameters. Testis tissue was also analyzed for histopathological and immunohistochemical methods.

Results: The VPA administration caused a 37% decrease in serum testosterone concentration and 5.32, 9.51, 2.44, and 3.68-fold increases in testicular tissue JAK1, STAT-3, IL-6, and MDA levels, respectively. There were also 50, 52, and 72% reductions in sperm motility, sperm viability, and the mean testicular biopsy score, respectively, accompanied by considerable degenerative changes and necrosis in seminiferous tubules in the VPA group. There is also an immune-positive reaction for IL-18 and NF-κB in only Leydig cells.

Conclusion: The CUR treatment may be beneficial in restoring testicular damage through antiinflammatory and anti-oxidant potential.

Objectives: This study aimed to evaluate the effects of pre-conditioning exercise on body lipid metabolism, leptin secretion, and the downstream pathways at the early stage of type 2 diabetes mellitus (T2DM).

Materials and methods: The T2DM model was established using an 8-week high-sugar, high-fat diet combined. The T2DM model was established using an 8-week high-sugar, high-fat diet combined with streptozocin (STZ) injection. Two exercise interventions, high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) were performed during the model-building process. One week following the STZ injection, rats were euthanized. Blood, gastrocnemius muscle, and epididymal fat pad were collected. Plasma leptin content was measured by ELISA. The expression of leptin-mRNA in epididymal adipose tissue was measured using RT-qPCR, and its protein expression was detected by a western blot. Leptin, leptin-R, and AMPK (AMP-activated protein kinase) - ACC (Acetyl-CoA carboxylase) expression in gastrocnemius muscle was also detected by western blot. Free fatty acids (FFA) and triglycerides (TG) contents in gastrocnemius muscle were measured using a biochemical assay.

Results: In the HIIT group, glucose tolerance and leptin receptor expression increased, as did the expression and phosphorylation of AMPK protein. At the early stage of T2DM, it increased significantly in the gastrocnemius muscle in the MICT group.

Conclusion: At the early stage of T2DM, pre-conditioning exercise in the form of HIIT was found to inhibit the leptin-mRNA expression in adipose tissue, suppress leptin synthesis, up-regulate AMPK-ACC signaling pathway, and promote lipid decomposition in skeletal muscle tissue. Pre-conditioning of MICT led to the accumulation of FFA and TG in skeletal muscle, likely due to exercise adaptation rather than ectopic deposition of lipids.

Objectives: Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that have vital roles in activating further immune responses. However, due to their tumor-induced diversity, we decided to examine ILCs, T cells, and the associated cytokines in mouse models of breast cancer.

Materials and methods: 4T1 and MC4-L2 cells were used to induce triple-negative and hormone-receptor-positive breast cancer, respectively. Tumor tissue was resected at early and late stages of tumor growth and used for further analysis. Total RNA was extracted and used in Real-Time PCR to analyze the expression of IFN-γ, IL-4, IL-10, IL-13, and IL-22. Tumor tissue was digested and used in a flow cytometric assay. H&E staining was used to examine the pathology of tumor progression.

Results: Both tumor models showed a notable increase in T-cell frequency at the early stage of tumor growth. However, as the tumors progressed, the frequency of T cells significantly decreased, while the ILC component exhibited a significant increase in tumor progression. Gene analysis indicated a significant increase in the inflammatory to anti-inflammatory cytokine ratio during tumor progression in the tumor model. In contrast, this ratio was considerably reduced in advanced MC4-L2 tumors. Both tumor models showed the development of invasive breast carcinoma and lung metastasis in advanced tumors.

Conclusion: Our study highlighted the expansion of ILCs during tumor progression in two distinct breast cancer models with different immunogenicity. These findings suggest that ILCs may actively modulate the tumor microenvironment during the advanced stage of tumor growth.

Objectives: Migraine, a serious neurological disease that affects millions of people worldwide, is one of the most considerable burdens on the healthcare system and has significant economic implications. Even though various treatment methods are available, including medication, lifestyle changes, and behavioral therapy, many migraine sufferers do not receive adequate relief or experience intolerable side effects. Hence, the present review aims to evaluate the nanoformulation regarding migraine therapy.

Materials and methods: Between 2005 and 2024, specific keywords were used to search several databases, such as Pubmed, Google Scholar, and Scopus.

Results: The nanoformulation field is an increasing field within nanotechnology that offers new solutions for treating migraine, including improving drug delivery, increasing therapeutic efficacy, and minimizing side effects. By combining nanoscale materials with therapeutic agents, nanoformulations can enhance bioavailability, sustain drug release, deliver targeted drugs, and penetrate the Blood-Brain Barrier (BBB) more efficiently. Nanoformulation has the potential to be a useful tool for migraine therapy. However, several challenges still need to be overcome, such as the BBB penetration, safety and biocompatibility of the product, manufacturing, and scalability reproducibility to pass regulatory approval and affordability. To overcome these challenges, research efforts should be focused on developing innovative techniques to penetrate the BBB, target specific migraine pathways, incorporate personalized medicine approaches, and develop nanotechnology-based diagnostics.

Conclusion: A nanotechnology-based approach aims to revolutionize migraine therapy, improving patient outcomes and living standards by offering personalized and precise treatments.

Objectives: Exploring the role of VDAC1 in hepatocyte apoptosis during acute liver injury induced by obstructive jaundice.

Materials and methods: Animal and cell models were established to investigate possible mechanisms during acute liver injury induced by OJ. Blood was collected for liver function assessment. H&E and TEM were employed to observe pathological changes in the liver tissues. Flow cytometry was used to measure the hepatocyte apoptosis. The mitochondrial MPTP assay was employed to assess the mitochondrial function of hepatocytes. IHC, western blot, and qRT-PCR were employed to determine the expression levels of VDAC1. Then, VDAC-siRNA was used to establish a knockdown model. Flow cytometry was used again to measure hepatocyte apoptosis following VDAC1 knockdown.

Results: The serum of rats in the OJ group exhibited a significant increase in liver function. Irregular tissue structure and mitochondrial morphology were observed in the liver tissues of OJ rats. A significant increase in mitochondrial permeability in hepatocytes. The expression levels of VDAC1 were significantly increased in the liver tissue of OJ rats. They were also significantly increased in the hepatocytes, primarily within mitochondrial membranes, determined by western blot in vivo and in vitro. Significant increases in the rates of hepatocyte apoptosis, particularly early apoptosis, were observed in the OJ groups. However, there was a reverse in the rates of hepatocyte apoptosis after knockdown regulation of VDAC1 only within the cells of the OJ group.

Conclusion: The up-regulation of VDAC in liver injury caused by obstructive jaundice may lead to increased early apoptosis of hepatocytes.

Objectives: COTI-2, an innovative oral homocysteine, has shown promising antitumor results on multiple types of cancer. However, its effects in treating bladder cancer (BCa) and the underlying molecular mechanisms have not been elucidated. The present study aimed to explore the antitumor effects of COTI-2 on BCa and the potential mechanisms.

Materials and methods: BCa cell lines, including the 5637 and T24 cell lines, were treated with COTI-2 at concentrations of 0.5 and 1 μM, respectively. Cell Counting Kit (CCK)-8 assay, colony formation assay, apoptosis assay, and transwell migration and invasion assay were conducted to evaluate the antitumor effects of COTI-2 on BCa cells. Western blotting, H&E, immunohistochemical staining, and immunofluorescence analysis were performed to investigate the underlying mechanisms. Moreover, a xenograft model in nude mice using T24 cells was generated to determine the antitumor activities of COTI-2 in vivo.

Results: COTI-2 highly inhibited the proliferation of BCa cell lines, including 5637 and T24 cells, and induced their apoptosis. Moreover, it efficiently suppressed the migration and invasion of BCa cells. Additionally, the subcutaneous xenograft model in nude mice showed that COTI-2 treatment inhibited the tumor growth of BCa by inducing its apoptosis in vivo. We also found that COTI-2 promoted apoptosis in BCa cells, presumably through activating the AMPK/mTOR pathway.

Conclusion: Our data suggest that COTI-2 effectively reduces the malignancy of BCa, probably by inducing apoptosis via the AMPK/mTOR signaling pathway. These data highlight the potential of COTI-2 as a therapeutic agent for the treatment of BCa.

Glioblastoma multiforme (GBM) presents a significant challenge in oncology due to its highly aggressive nature and inherent resistance to conventional therapeutic interventions. Vortioxetine, a novel antidepressant, exhibits anticancer abilities and can traverse the blood-brain barrier. In this study, the antitumor effect and mechanism of vortioxetine on GBM cells were investigated. Cell proliferation in GBM cells was assessed using the CCK8 and colony formation assays. Flow cytometry, western blot, and wound healing assay were used to study the mechanisms of vortioxetine. mCherry-GFP-LC3B and confocal microscopy were used to evaluate autophagic activity. RNA sequencing uses the capabilities of high-throughput sequencing methods to provide insight into the transcriptome of cells. Vortioxetine significantly inhibited the proliferation of GBM cells by inducing G1/G0 phase cell cycle arrest. Meanwhile, it also reduced the migratory capabilities of GBM cells. Furthermore, it promoted apoptotic cell death in GBM cells. In addition, it promoted autophagy in GBM cells, and autophagy inhibitors markedly enhanced its antiproliferative activities. Vortioxetine could down-regulate the expressions of PI3K and Akt, which were related to the occurrence and development of GBM. Our findings support the potential of vortioxetine as a novel therapeutic agent for GBM treatment. Vortioxetine exhibits anti-GBM activity via the PI3K-Akt signaling pathway. Meanwhile, our findings reveal autophagy inhibitors as an effective sensitizer for vortioxetine, offering new strategies for treating GBM.

Objectives: Due to its low toxicity and high absorbance in the range of 650 to 900 nm, indocyanine green (ICG) has garnered significant attention for its applications in photodynamic therapy (PDT) and photothermal therapy (PTT). However, its tendency to aggregate in aqueous environments limits its efficacy in both in vitro and in vivo applications. Encapsulating ICG in a biocompatible nanomicelle can improve its aqueous stability and photophysical properties. The present study investigated the synergistic effect of ICG-loaded nanomicelles upon irradiation by an 808-nm laser on Leishmania major (L. major) parasites.

Materials and methods: Initially, a nanomicelle comprised ICG was synthesized and characterized. Then, the temperature increase during irradiation and promastigote viability were evaluated in vitro. Subsequently, the prepared samples' in vitro dark toxicity and phototoxicity were assessed via the MTS assay. Finally, the in vivo antileishmanial efficacy of the ICG-loaded nanomicelles formulation was investigated in BALB/c mice.

Results: The absorbance of ICG-loaded nanomicelles at 808 nm was more than 2 times greater than Free-ICG. Also, the prepared formulation exhibited a mean diameter of ~25 nm and a zeta potential of -2.3 ± 1 mV. The combination of ICG-loaded nanomicelles and 808 nm laser with a power density of 2.5 W cm^-2 led to a significant reduction in the survival rate of promastigotes and lesion size of infected mice compared to control groups.

Conclusion: The PDT/PTT mediated by ICG-loaded nanomicelles can be considered a promising and efficient therapeutic method for L. major, as it is inexpensive, safe, and easy to implement.