Iranian Journal of Basic Medical Sciences最新文献

Objectives: Ellagic acid (EA) is a natural polyphenol with anti-cancer, anti-oxidant, anti-inflammatory, antibacterial, and other effects. However, the role of EA in cerebral ischemia/reperfusion injury (CIRI) remains unclear. This study aims to investigate the neuroprotective effects of EA in CIRI.

Materials and methods: Forty male Wistar rats (260-300 g) were randomly divided into four groups with 10 rats per group: 1) Sham+Veh: Rats underwent I/R surgery, except that they were not inserted with thread plugs, and received solute treatment at the same time. 2) MCAO/R+Veh. 3) MCAO/R+EA: Rats were administered 200 mg/kg EA before undergoing MCAO. 4) MCAO/R+Nim: Rats were administered Nim before undergoing MCAO.

Results: Cerebral MCAO/R damaged brain tissue, elevated neurological deficit score (P<0.01), cerebral infarction volume (P<0.01), inflammatory cell infiltration (P<0.01), NLRP6, ASC, caspase-1 and GSDMD mRNA level (P<0.01 and P<0.001), NLRP6, caspase-1, GSDMD-N and IL-1β protein level (P<0.01 and P<0.001), and inflammatory cytokines in brain tissue (P<0.01). Prophylactic administration of EA also significantly improved brain tissue damage, reduced neurological deficit score (P<0.01), cerebral infarction volume (P<0.01), inflammatory cell number (P<0.05), NLRP6, caspase-1, GSDMD-N mRNA and protein level (P<0.05 and P<0.01), ASC mRNA level and IL-1β protein level (P<0.01), and IL-1β and IL-18 level in brain tissue (P<0.01) compared to positive control.

Conclusion: EA may serve as a potential drug for the treatment of brain I/R, which may exert an anti-inflammatory effect by inhibiting the activation of the inflammasome.

Objectives: To investigate the physicochemical properties, in vitro efficacy, and in vivo therapeutic potential of novel tree turmeric root and nano-hydroxyapatite (TRE@NHA) composites in mitigating chemotherapy-induced peripheral neuropathy (CIPN).

Materials and methods: TRE@NHA composites were synthesized and characterized using FTIR, XRD, TGA, and HRTEM. In vitro studies using PC12 cells assessed cytotoxicity, anti-inflammatory effects, and neuroprotective properties. An in vivo rat model of CIPN was established using paclitaxel (PTX). Behavioral assessments, histopathological analysis, and oxidative stress markers were evaluated in sciatic nerve tissues.

Results: TRE@NHA composites demonstrated successful integration of TRE into the NHA matrix. In vitro studies revealed significant anti-inflammatory and neuroprotective effects of TRE@NHA-2, particularly in suppressing cytokine production, enhancing cell viability, and mitigating oxidative stress. In vivo, TRE@NHA-2 effectively alleviated PTX-induced neuropathic pain, reduced neuronal damage, and exhibited potent antioxidant properties.

Conclusion: This study demonstrates the successful development and characterization of novel TRE@NHA composites. The findings strongly suggest that TRE@NHA-2 possesses promising therapeutic potential for mitigating CIPN due to its anti-inflammatory, antioxidant, and neuroprotective properties.

Objectives: This study aimed to engineer miR-216-overexpressing umbilical cord mesenchymal stem cells (UCMSCs) to generate miR-216-enriched UCMSC-derived exosomes (UCMSC-Exos) and evaluate their therapeutic potential in Spinal cord injury (SCI).

Materials and methods: miR-216 overexpression was achieved in UCMSCs, and exosomes were subsequently isolated. The biological effects of miR-216-overexpressing UCMSC-Exos (UCMSC-miR-216^OE-Exos) were assessed using in vitro migration, and tube formation assays with vascular endothelial cells. For in vivo evaluation, SCI mouse models were treated with either UCMSC-Exos or UCMSC-miR-216^OE-Exos. Functional recovery was measured using the BMS scores, while angiogenesis, neuronal apoptosis, and proinflammatory cytokine expression were analyzed through immunohistochemistry and molecular assays.

Results: qPCR analysis confirmed successful miR-216 overexpression in UCMSCs and their derived exosomes. In vitro, UCMSC-miR-216^OE-Exos significantly enhanced endothelial cell migration and tube formation compared to control UCMSC-Exos. In vivo, both UCMSC-Exos and UCMSC-miR-216^OE-Exos improved BMS scores, promoted angiogenesis, and reduced neuronal apoptosis and proinflammatory cytokine expression in SCI mice. Notably, UCMSC-miR-216^OE-Exos demonstrated superior therapeutic effects, including greater improvements in functional recovery, enhanced angiogenic responses, and more pronounced reductions in neuronal apoptosis and inflammation compared to control UCMSC-Exos. Additionally, in vitro experiments revealed that PTEN expression was down-regulated, and the AKT pathway was activated following treatment with UCMSC-miR-216^OE-Exos.

Conclusion: These findings demonstrate that miR-216-overexpressing UCMSC-Exos exhibits enhanced therapeutic efficacy in promoting angiogenesis, reducing inflammation and neuronal apoptosis, and improving functional recovery after SCI. This study demonstrates the promise of miR-216-enriched exosomes as a novel cell-free therapeutic approach for SCI, paving the way for clinical translation through their biologically translatable mechanisms.

Objectives: This research aimed to investigate the effect of 2 types of exercise on apoptosis, neurogenesis, and angiogenesis factors in the penumbra area of stroke during the rehabilitation period after stroke.

Materials and methods: A transient distal middle cerebral artery occlusion (td-MCAO) model was used to induce stroke and after that, the animals were randomly divided into three groups: stroke, stroke + continuous exercise with increasing duration (CTID), and stroke + exercise with increasing intensity (CTII). At 24 hr spost-stroke , MRA, neurological deficit, and behavioral tests were conducted, and also continuous exercises were conducted for five consecutive days, Finally, MRI and behavioral tests were performed, and 24 hr after that, tissue separation and blood sampling were performed to evaluate plasma irisin, Extracellular Signal-Regulated Kinases 1 and 2 (ERK1/2) / cAMP Response Element-Binding Protein (CREB) / 90 kDa Ribosomal S6 Kinase (P90RSK) pathway, Vascular Endothelial Growth Factor (VEGF) / Vascular Endothelial Growth Factor Receptor 2 (VEGF-R2), and Brain-Derived Neurotrophic Factor (BDNF) / Tropomyosin Receptor Kinase B (TrKB) levels. for statistical analysis, one-way and two-way ANOVA tests were used at the significance level of P<0.05.

Results: Both training models reduced the volume of stroke and neurological defects compared to the stroke group (P<0.05), while the amounts of irisin and CREB in the CTID group increased significantly compared to the CTII and stroke groups (P<0.01). VEGFR2 values in training groups increased significantly compared to the stroke group (P<0.05) but in the CTII group, VEGFR2 values increased significantly compared to the CTID group (P<0.05).

Conclusion: The findings of the present study showed it seems that doing exercises with moderate intensities and gradually increasing the duration of exercise in the acute phase after stroke can be considered a suitable treatment in future research.

Objectives: Diabetes increases the risk of heart disease and stroke, primarily through endothelial cell dysfunction and vascular damage. These vascular complications are partly due to defects in endothelial progenitor cells (EPCs). This study explores the efficacy of pharmacological priming of bone marrow EPCs (BMEPCs) with Deferoxamine (DFO), a hypoxia mimetic agent, in restoring dysregulated angiogenic pathways in streptozotocin (STZ)-induced mice with type-1 diabetes (T1D).

Materials and methods: BMEPCs were isolated from both normal and STZ-induced mice with T1D. The effects of an optimal concentration of DFO (80 µM) on the viability, proliferation, and tubulogenesis of EPCs were assessed. Furthermore, the probable beneficial effects of the conditioned medium from EPCs treated in the presence and absence of DFO were examined in mice (T1D) wound healing models.

Results: DFO (80 µM) increased cell viability, proliferation, and tubulogenesis. EPCs isolated from diabetic mice showed significant impairments in the expression of HIF-1α, VEGF, and SDF-1 proteins compared to controls. DFO-preconditioning significantly enhanced protein expression of these genes. The conditioned medium from diabetic EPCs treated with DFO had a substantially greater favorable effect on wound healing in diabetic mice, connected with elevated levels of HIF-1α, VEGF, phosphorylated Tie2/Tie2, and Ang1.

Conclusion: DFO reactivates proliferation and restores the impaired angiogenic properties of EPCs from diabetic mice by stabilizing HIF-1α and VEGF. Additionally, DFO enhanced the pro-angiogenic activity in the EPC-secretome, leading to improved wound healing. This improvement is attributed to the dual activation of HIF-1α /VEGF and Ang-1/Tie2 pathways, which are crucial for initiating and maturing new blood vessels.

Objectives: The present study investigated the protective effect of melittin (MEL) against bleomycin (BLM)- induced pulmonary fibrosis (PF) in mice and the mechanism underlying this effect.

Materials and methods: A mouse model of PF was established by intratracheal injection of 3.5 mg/kg BLM. Twenty-four hours after the model was established, the mice in the treatment groups were intraperitoneally injected with MEL, and specimens were collected 28 days later. The body weight, survival rate, and pulmonary index (PI) of the mice were determined. Haematoxylin and eosin (HE) staining, Masson's trichrome staining, immunohistochemical staining, kit assays, and Western blot (WB) analysis were performed.

Results: Our study indicated that MEL significantly increased the body weight and survival rate, reduced PI, and improved lung histopathology in mice. In addition, MEL inhibited epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Attenuated mitochondrial damage and reduced oxidative stress (OS) were also observed in MEL-treated mice. We further showed that MEL inhibited the TGF-β1/Smad2/3 pathway and activated the AMPK/SIRT1/PGC-1α pathway.

Conclusion: MEL is a promising future therapeutic agent for PF. Its multifaceted and complex mechanism of action inhibits both EMT and ECM production by modulating the TGF-β1/Smad2/3 pathway. It also improves mitochondrial function and reduces OS at least partially through the activation of the AMPK/SIRT1/PGC-1α signaling pathway.

Objectives: Acetaminophen (APAP)-mediated liver injury poses a significant public health concern. Curcuma xanthorrhiza extract (CXE) has been traditionally used for its hepatoprotective properties. This research aimed to assess the hepatoprotective effects of CXE in APAP-mediated hepatotoxicity by investigating the modulatory effects of CXE on key biomarkers, including Interleukin (IL), namely, (IL-6), IL-10, IL-1β, Nitric Oxide (NO), Lactate Dehydrogenase (LDH), and the genes expression related to apoptosis-like Caspase-3 (Casp-3), Casp-9, and genes related to liver metabolic c-Jun N-terminal Kinase (JNK), in APAP-mediated HepG2 cells.

Materials and methods: APAP-induced HepG2 cells were treated with different concentrations of CXE. IL-6, IL-10, IL were measured using an Enzyme-linked Immunosorbent Assay (ELISA) and NO, LDH were measured using colorimetric assay. Gene expression was analyzed using quantitative Real-Time Reverse Transcription (qRT-PCR).

Results: CXE significantly reduced IL-1β and IL-6 levels, enhanced IL-10 production, and attenuated NO levels in APAP-mediated hepatotoxicity. CXE also suppressed the expression of Casp-9, Casp-3, JNK, and LDH levels. The study presented a concentration-dependent response, with 125 μg/ml CXE exhibiting the most pronounced effects. CXE effectively modulated immune responses, decreased oxidative stress, and inhibited apoptotic and inflammatory pathways in APAP-mediated hepatotoxic cells.

Conclusion: These studies highlight the CXE potential as a therapeutic candidate for liver disorders, particularly in drug-mediated liver injury.

Objectives: One of the leading causes of endometriosis is the return of menstrual blood flow into the pelvic cavity and the establishment of menstrual blood mesenchymal stem cells (MenSCs) outside the uterus. MenSCs from endometriosis patients (E-MenSCs) and healthy women have been shown to vary in terms of surface markers and gene expression, which may suggest the involvement of these cells in the development and expansion of ectopic lesions. This study aimed to investigate the effects of beta-catenin signaling inhibitor C-82 and naringenin as PI3K signaling pathway inhibitors on E-MenSCs to modulate their gene expression and functional pattern.

Materials and methods: Briefly, E-MenSCs isolated by density-gradient centrifugation were treated with C-82 and naringenin, and the genes and pathways related to inflammation, proliferation, and survival were evaluated. E-MenSCs showed increased early apoptosis and decreased levels of ROS, IL-6 and IL-8, ER, α-SMA, and Ki-67 protein expression.

Results: Our results shed light on the function of C-82 and naringenin in modulating E-MenSCs.

Conclusion: However, more research is needed to analyze the precise effects of small molecule C-82 and naringenin on endometriosis.

Objectives: Isoflavone Daidzein (DDZ) has emerged as a promising alternative to hormone replacement therapy (HRT) for ameliorating estrogen deficiency (ED). However, the stereological and molecular mechanism of its effects in the OVX-hippocampus are unclear. We studied the impact of DDZ on stereological changes, estrogen receptor (ERs) expression, BDNF, GSK-3β, and inflammatory and apoptosis-related genes in the hippocampus of ovariectomized rats, compared to 17β-estradiol (E2).

Materials and methods: OVX rats were treated with DDZ or E2. The stereological analysis assessed the total volume and number of pyramidal and granular neurons in the hippocampus CA1 and DG subregions. Expression of proinflammatory cytokines, apoptotic-related genes, ERs, and BDNF genes was evaluated using Real-Time PCR, and the GSK-3β phosphorylation level was measured by western blot analysis.

Results: DDZ has effectively increased the volume and total number of pyramidal neurons in the CA1 region, the expression of ERα, ERβ, BDNF, and Bcl-2 genes, and the phosphorylation rate of GSK-3β protein. However, the effect of DDZ on the DG region, ERα, and BDNF genes was not significant in comparison with E2; DDZ significantly suppressed the expression of TNF-α, IL-6, and the Bax/Bcl2 ratio compared with OVX rats.

Conclusion: DDZ effectively reversed the stereological changes in the CA1 region by stimulating BDNF gene expression, increasing the phosphorylation ratio of the GSK-3β protein, and modulating inflammatory and apoptotic pathways. Although its effects on the DG region, BDNF, and ERα molecules were less significant than E2, DDZ could still be a promising candidate for ameliorating ED.

Objectives: Substrate engineering is one of the attractive fields of changing cell behavior and fate, especially for stem cell (SC) therapies. The SC pool is an essential factor in transplantation outcomes. Here, the objective was to preserve the stemness of the cornea's limbal epithelial stem cell (LESC) using naturally biomimicking corneal cell topography.

Materials and methods: A cell-imprinted substrate was prepared using the natural topography of rabbit cornea's LESC. The LESC cells were characterized by immunostaining (ABCG2 and Cytokeratin-12), then re-cultivated on a topography mold (imprinted PDMS), on FLAT PDMS (without any pattern), and the control group (tissue culture plate). Ultimately, an alkaline burn model was created on a rabbit's cornea, and the effectiveness of cell-imprinted molds as implants for healing corneal wounds was examined in vivo.

Results: The in vitro results showed that imprinted PDMS kept LESC cells in a state of stemness with high expression of ∆NP63 and ABCG2 genes (stemness-associated genes) compared to the other two groups and low Cytokeratin-3 and -12 expression (as differentiation-related genes). In vivo studies showed a more significant number of cells and the expression of the ABCG2 gene in the imprinted PDMS group. In contrast, higher expressions of the ∆Np63 gene and more stratification were observed in the control group (no treatment). Histological studies showed that the imprinted PDMS group had normal morphology with fully organized collagens.

Conclusion: The results of LESC cultured on imprinted PDMS suggested that LESC cell imprinting could be an excellent substrate for LESC expansion and preserve their stemness for cell therapy.