Iranian Journal of Basic Medical Sciences
Volume:28 Issue: 1, Jan 2025

Gliomas are the most common lethal tumors of the brain associated with a poor prognosis and increased resistance to chemo-radiotherapy. Circular RNAs (circRNAs), newly identified noncoding RNAs, have appeared as critical regulators of therapeutic resistance among multiple cancers and gliomas. Since circRNAs are aberrantly expressed in glioma and may act as promoters or inhibitors of therapeutic resistance, we categorized alterations of these specific RNAs expression in therapy resistant-glioma in three different classes, including chemoresistance, radioresistance, and glioma stem cell (GSC)-regulation. circRNAs act as competing endogenous RNA, sponging target microRNA and consequently affecting the expression of genes related to glioma tumorigenesis and resistance. By doing so, circRNAs can modulate the critical cellular pathways and processes regulating glioma resistance, including DNA repair pathways, GSC, epithelial-mesenchymal transition, apoptosis, and autophagy. Considering the poor survival and increased resistance to currently approved treatments for glioma, it is crucial to increase the knowledge of the resistance regulatory effects of circRNAs and their underlying molecular mechanisms. Herein, we conducted a comprehensive search and discussed the existing knowledge regarding the important role eof circRNAs in the emergence of resistance to therapeutic interventions in glioma. This knowledge may serve as a basis for enhancing the effectiveness of glioma therapeutic strategies.

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.

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

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.

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

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).

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.

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.

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.

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.

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.

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. 

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.

Anemoside B4 (AB4) is a multifunctional compound with anti-inflammatory, anti-apoptotic, antioxidant, antiviral, and autophagy-enhancing effects. However, the role of AB4 in cerebral ischemia/reperfusion injury (CIRI) remains obscure. This experiment aims to investigate the pharmacological effects of AB4 in CIRI.

In vivo, eighty male SD rats were randomly divided into five groups: sham, MCAO/R, LD group (2.5 mg/kg), MD group (5 mg/kg), and HD group (10 mg/kg). The rats in sham and MCAO/R groups were given equal volumes of normal saline. In vitro, PC12 cells were divided into five groups: normal, OGD/R, OGD/R+AB4 (50 μM), OGD/R+AB4 (100 μM), and OGD/R+AB4 (200 μM). The cells were treated with hypoxia and hypoglycemia for 1.5 hr and reoxygenation for 24 hr.

In vivo, TTC and neurological scoring tests indicated that AB4 favors promoting the recovery of the brain. The histopathologic study of the brain tissues revealed that AB4 inhibited the damage of neuron cells. The TUNEL assay found that AB4 could improve cell apoptosis and prevent the brain from injury. In vitro, the data showed that AB4 inhibited cell damage and prevented PC12 cells from OGD/R injury, reduced IL-1β content, and increased the IL-10 level. AB4 could inhibit apoptosis of PC12 cells, down-regulate Caspase 12 and BAX expression, and up-regulate Bcl-2 expression.

AB4 played a protective role in CIRI and could be a promising active ingredient against ischemia stroke.

Soybeans have various positive effects on health, including anti-inflammatory and preventing kidney damage. There is concern regarding the phytoestrogen content due to the high isoflavone content in soybeans. Various forms of soybean processing have been tried; in this study, the hydrolysis method will be used to obtain the active substance Arginine-Glycine-Aspartate (RGD) tripeptide in soybean protein hydrolyzed by bromelain (SPHB). The research aimed to determine the characteristics and influence of SPHB on kidney function, inflammation, body weight, and estrogen in male Wistar rats induced by gentamicin.

Soybeans (Glycine max) are hydrolyzed using the proteolytic enzyme Bromelain from pineapples. The proteomics was investigated using Liquid-Chromatography Mass Spectroscopy Tandem (LC-MS/MS). SPHB in three doses would be tested for 28 days on male Wistar rats induced by gentamicin. The parameters measured were body weight, high-sensitive cell reactive protein (hs-CRP) levels, urea, creatinine, and estrogen levels.

SPHB has a low molecular weight (LMW) of 10 kDa and contains RGD in the lunasin sequence. SPHB showed no effect on body weight (P>0.05). The impact of SPHB on hs-CRP, urea, and creatinine showed differences significantly from the positive control, especially SPHB at a dose of 112 mg/day (P<0.01). Meanwhile, SPHB has almost no effect on estrogen levels.

The administration of SPHB with LMW and contains lunasin showed decreased inflammation and kidney function parameters but did not affect body weight and estrogen levels in induced gentamicin Wistar rats.

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.

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.  

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.

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.

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.

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.

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).

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

While ketone bodies are not the main heart fuel, exercise may increase their uptake. This study aimed to investigate the effect of 6-week endurance training and Pyruvate dehydrogenase kinase 4 )PDK4( inhibition on ketone bodies metabolism in the heart of diabetic rats with emphasis on the role of Peroxisome proliferator-activated receptor-gamma coactivator PGC-1alpha (PGC-1α).

Sixty male Wistar rats were divided into eight groups: healthy control group (CONT), endurance training group (TRA), diabetic group (DM), DM + EX group, Dichloroacetate (DCA) group, DM + DCA group, TRA + DCA group, and DM + TRA + DCA group. Diabetes was induced using streptozotocin (STZ). The animals in training groups ran on the treadmill for six weeks (30–50 min running at 20–30 m/min). After the training period, molecular markers for mitochondrial biogenesis and ketone metabolism were assessed in the heart. Circulating ß-hydroxybutyrate (ßOHB) and Acetylacetonate (AcAc) levels were also measured. 

Our results showed that 6-week endurance training increased the cardiac expression of PGC-1α, 3-oxoacid CoA-transferase 1 (OXCT1), and Acetyl-CoA Acetyltransferase 1 (ACAT1) and reduced beta-hydroxybutyrate dehydrogenase1 (BDH1) expression (P≤0.05). In addition, exercise and DCA usage significantly decreased PDK4 gene expression, ßOHB, and AcAc blood levels (P≤0.05). Furthermore, the combination of 6-week endurance training and DCA supplementation led to more reduction in PDFK4 gene expression, ßOHB, and AcAc blood levels. 

Six-week endurance training and DCA supplementation could safely improve ketone body metabolism in the heart, ultimately reducing hyperketonemia/ketoacidosis in diabetic rats.

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

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. 

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.

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

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).

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.

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).  

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.

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.

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.

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.

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.

Plinabulin, a marine-derived anticancer drug targeting microtubules, exhibits anti-cancer effects on glioblastoma cells. However, its therapeutic potential, specifically for glioblastoma treatment, remains underexplored. This study aims to elucidate the mechanisms by which plinabulin exerts its effects on glioblastoma cells.

Using the SRB and colony formation assay to observe the effect of plinabulin on glioblastoma cell viability. Wound healing and transwell migration assay were used to test the effect of plinabulin on glioblastoma cell metastatic potential. Crucial target genes were identified through RNA sequencing and bioinformatics analysis. Protein levels were evaluated in a concentration-dependent manner using western blot analysis.

Plinabulin suppressed glioblastoma cell proliferation by causing cell cycle G2/M phase arrest and inhibited migration. The IC50 values were 22.20 nM in A172 cells and 20.55 nM in T98G cells. Plinabulin reduced AKT and mTOR phosphorylation. Combined with the AKT/mTOR inhibitors LY294002 and rapamycin, plinabulin decreased p-mTOR and EGFR protein levels and increased cleaved-PARP levels. Plinabulin induces autophagy, and using an autophagy inhibitor enhances plinabulin-induced cell apoptosis. This suggests that plinabulin might trigger cytoprotective autophagy in glioblastoma cells. These findings indicate that plinabulin hinders glioblastoma growth and induces protective autophagy via the PI3K/AKT/mTOR pathway. Additionally, plinabulin combined with erlotinib showed greater cytotoxic efficacy than either drug alone in glioblastoma cells in vitro.

Our study provides new insights into the efficacy of plinabulin against glioblastoma and highlights the potential clinical utility of combining plinabulin with EGFR inhibitors as a chemotherapy strategy.

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.

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.

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.

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

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.

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.

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.

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