Iranian Journal of Basic Medical Sciences最新文献

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: 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.

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: Cisplatin (DDP) resistance remains a primary cause of chemotherapy failure and recurrence of non-small cell lung cancer (NSCLC). Abnormal high microsomal glutathione transferase 1 (MGST1) expression has been found in DDP-resistant NSCLC cells. This study aimed to explore the function and mechanism of MGST1 in DDP resistance of NSCLC cells.

Materials and methods: The expression levels of target molecules were assessed by quantitative real-time polymerase chain reaction (RT-qPCR) and western blotting. Cell proliferation was evaluated by cell counting kit-8 (CCK-8) and colony formation assays. Ferroptosis was determined by malondialdehyde (MDA), glutathione (GSH), Fe²⁺, and reactive oxygen species (ROS) levels. The interaction between proteins was confirmed by Co-immunoprecipitation (Co-IP). The effect of MGST1 on DDP resistance was evaluated using the tumor xenograft assay in vivo. Immunohistochemical staining was performed to measure Ki-67 and p-H2A.X expression in tumor tissues.

Results: MGST1 expression was higher, while arachidonate lipoxygenase 5 (ALOX5) expression was lower in DDP-resistant NSCLC patients and cells. MGST1 ablation sensitized NSCLC cells to DDP therapy through inducing ferroptosis. MGST1 protein directly interacted with ALOX5 protein to restrain ALOX5-triggered ferroptosis. Ferroptosis inhibitor or sh-ALOX5 reversed the promotive effect of MGST1 silencing on the DDP sensitivity of NSCLC cells. Finally, MGST1 depletion sensitized NSCLC cells to DDP therapy in nude mice in vivo.

Conclusion: MGST1 high expression contributed to DDP resistance of NSCLC cells by inhibiting ALOX5-induced ferroptosis. Our results provide a potential therapeutic target for overcoming DDP resistance in NSCLC patients.

Objectives: While ketone bodies are not the main heart fuel, exercise may increase their uptake. Objectives: 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).

Materials and methods: 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.

Results: 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.

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

Cancers are extremely dynamic diseases that can actively cause refractorines to be gained from applied therapies, which is why they are at the forefront of deaths worldwide. In this literature review, we covered the most recent and important discoveries regarding the influence of human microbiota, including tumor bacteriome, on the development and treatment of cancer. Advances in research on microbial communities have enabled us to discover the role of the human microbiome in the development and course of this disease, helping us understand neoplasms better and design new potential therapies. As we show through our findings, by immunomodulation and the secretion of certain chemical substances, the correct bacteriome of the intestinal tract, respiratory system, or skin can protect humans against cancer development and help during the treatment process. Bacteria also reside inside tumors, forming part of the tumor microenvironment (TME), where they interact with immunological and cancer cells in many complex ways. Some bacteria, such as Pseudomonas aeruginosa or Akkermansia muciniphila, can stimulate anticancer cell-mediated immune responses or even directly lead to cancer cell death. We also present the clinical possibilities of using some live, usually modified bacteria to develop bacteriotherapies. Modifying the gut microbiome to stimulate standard treatment is also important. Research on the microbiome and cancer remains a challenging topic in microbiology, having a great potential for advancements in cancer therapy in the future, and is continuously becoming a more and more popular field of research, as shown by our statistical analysis of PubMed data.

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.