Current molecular medicine最新文献

Objective: This study aimed to compare CD82 methylation patterns in peripheral blood among patients with rheumatoid arthritis [RA], inflammatory arthritis, and healthy controls [HC] and to assess their clinical associations with hypertension in RA.

Methods: In this cross-sectional study, CD82 methylation at positions 44596705- 44596865 on chromosome 11 was analyzed using targeted methylation techniques in peripheral blood from patients with RA, psoriatic arthritis [PsA], ankylosing spondylitis [AS], gout, and HC.

Results: CD82 cg22143324 methylation levels were significantly different between RA patients and healthy controls [P<0.0001], PsA [P=0.0281], and AS [P=0.0360]. In RA subgroups, individuals negative for both rheumatoid factor [RF] and cyclic citrullinated peptide [CCP] [RA-DN], as well as those positive for both [RA-DP], exhibited significantly different methylation levels compared to HC [P=0.0355 and P<0.0001, respectively]. ROC analysis indicated a promising diagnostic potential for CD82 cg22143324 methylation, especially with the TTT haplotype. Correlation analysis revealed significant associations between CD82 methylation and CCP levels, as well as hypertension in RA patients.

Conclusion: The analysis conducted revealed altered CD82 cg22143324 methylation in RA, with potential utility in distinguishing seronegative patients from healthy controls. An association between lower methylation levels and comorbid hypertension in RA patients was also observed, warranting further investigation.

Apoptosis is an established hallmark of cancer. In normal conditions, apoptosis is strictly controlled; however, when it is not properly managed, it causes several complications, including cancer progression and drug resistance. SMAC/ Diablo (SMAC) is a mitochondrial protein that is released into the cytosol upon activation of BAX/BAK channels with apoptotic signals. SMAC protein interacts and neutralizes inhibitors of apoptosis (IAP) proteins and initiates the caspase cascade, which leads to apoptosis. SMAC is downregulated in several types of cancer, which led to the design of small-molecule inhibitors known as SMAC mimetics as new cancer therapeutics, and some of these molecules are in the clinical phase. It has also been shown that a combination of SMAC with standard anti-cancer drugs could be beneficial to drug-resistant cancer. Despite being a pro-apoptotic protein, it has been found that SMAC/Diablo is overexpressed in several types of cancers like lung, breast, bladder, cervix, pancreas, prostate, and colon, as well as in melanoma and glioma, and in cancer cells. Recently, we have reported that the overexpression of SMAC in cancers is essential for cell and tumor growth due to non-apoptotic regulation of phospholipid synthesis. The current review is focused on apoptotic and non-apoptotic functions of SMAC and its role in drug resistance.

Background: Liver fibrosis is an important pathological feature of Wilson disease (WD). The miRNA-29b-3p level decreased in liver fibrosis, while the mechanism of miRNA-29b-3p in liver fibrosis has not been reported, and was elucidated in the work.

Methods: The miRNA-29b-3p levels were evaluated by q-PCR. The effect of miRNA- 29b-3p on the activity of hepatic stellate cells was detected by cell activity assay. The protein levels were checked by western blot. The interaction between miRNA-29b-3p and ULK1 mRNA with base complementary sequences was detected by double luciferase assay. The autophagosomes were observed by TEM. The cell fibrosis-like change was evaluated with an anti-α-smooth muscle actin (α-SMA) antibody by IF.

Results: The results showed that miRNA-29b-3p mimics down-regulated the α-SMA and Col1 protein levels, and miRNA-29b-3p inhibitors upregulated the α-SMA and Col1 protein levels. The dual-luciferase assay result revealed that miRNA-29b-3p interacted with ULK1. The miRNA-29b-3p mimics inhibited the protein expression of ULK1, beclin1, and LC3, whereas miRNA-29b-3p inhibitors promoted the protein expression of ULK1, beclin1, and LC3.

Conclusion: The miRNA-29b-3p blocked HSCs trans-differentiation into myofibroblasts by inhibiting autophagy, and further inhibiting liver fibrosis in WD.

Introduction: The antiviral effects of type I interferons [IFNs] on respiratory syncytial virus [RSV]-infected airway epithelial cells have been identified. We aim to further reveal the mechanism of stat3 and kruppel-associated box-associated protein 1 [KAP1] in RSV-infected airway epithelial cells.

Methods: Using the A549 cell line, we investigated the impact of RSV infection, KAP1 overexpression, and stat3 inhibition with Stattic. Cell counting kit 8 assay was used to determine the viability, and enzyme-linked immunosorbent assay was applied to measure the levels of IL-6, IL-8, IL-1β, IFN-α, and IFN-β. Viral replication was tested via plaque assay. Meanwhile, quantitative real-time reverse transcription polymerase chain reaction or/and western blot were applied to measure the expressions of p-stat3 and KAP1 in the cells.

Results: RSV infection repressed the viability, upregulated p-stat3 and KAP1 expressions, elevated levels of inflammation-related factors [IL-6, IL-8, IL-1β], and type I IFN immune response-associated factors [IFN-α, IFN-β], and promoted viral replication in A549 cells. Stattic attenuated the promoting effect of RSV on inflammation-related factors and viral replication, but enhanced its impact on IFN-α and IFN-β levels in the cells. More importantly, KAP1 overexpression reversed the effects of Stattic on viability, inflammation [IL-6, IL-8, IL-1β], type I IFN immune response [IFN-α, IFN-β], and viral replication in RSV-infected A549 cells.

Conclusion: Our findings unveil the pivotal role of stat3 inhibition in potentiating type I IFN-mediated antiviral responses against RSV in lung epithelial cells, revealing KAP1 as a potential therapeutic target for combating respiratory viral infections.

Background: Mesenchymal stem cell-derived conditioned medium (MSCCM) contains bioactive factors that provide neuroprotection in cases of cerebral ischemia-reperfusion (IR) injury. This study aimed to compare the therapeutic potential of rat adipose-derived MSC-CM (rAD-MSC-CM) and chicken embryo liver-derived MSC-CM (cLD-MSC-CM) following global cerebral IR injury in male rats.

Material and methods: We harvested rAD-MSC-CM from the adipose tissue surrounding the epididymis of Wistar rats and cLD-MSC-CM from the liver tissue of 10- day-old chicken embryos. To induce global cerebral ischemia, we utilized a four-vessel occlusion (4VO) model in rats. After inducing ischemia, the conditioned media were administered via intravenous injection 30 minutes post-reperfusion. We evaluated the cognitive and non-cognitive functions of the animals using standard behavioral tests. Additionally, we assessed blood-brain barrier (BBB) permeability, brain water content (BWC), oxidative-antioxidative status, and conducted histopathological analyses of the hippocampal tissue in the IR rats.

Results: Our findings demonstrated that treatment with both rAD-MSC-CM and cLDMSC- CM significantly improved memory function, reduced anxiety- and depressionlike behaviors, and enhanced exploratory activities. These behavioral improvements correlated with decreased BBB permeability and BWC, reduced oxidative stress, and mitigated histopathological changes in the hippocampal tissue.

Conclusion: Our findings suggest that both rAD-MSC-CM and cLD-MSC-CM offer protective benefits against IR injury, likely owing to their antioxidant properties.

Background: Prior research has displayed that the dysregulation of miR- 9-5p is related to cerebral ischemia-reperfusion (I/R) injury. However, the underlying neuroprotective mechanism of miR-9-5p in cerebral I/R injury has not been clarified.

Materials and methods: The cerebral I/R injury was simulated by oxygen-glucose deprivation/reperfusion (OGD/R) model that was constructed in human SH-SY5Y cells. Changes in reactive oxygen species (ROS) and superoxide dismutase (SOD) levels were detected with the commercial kits. ELISA assay was applied for measuring the expressions of inflammatory cytokines. Western blot was used for testing the protein levels. Cell apoptosis was measured by TUNEL assay.

Results: MiR-9-5p expression was dramatically decreased, while NADPH oxidase 4 (NOX4) expression was significantly increased in SH-SY5Y cells under OGD/R operation. MiR-9-5p over-expression dramatically inhibited OGD/R-induced oxidative stress, inflammation, and apoptosis in SH-SY5Y cells. Mechanistically, results from luciferase reporter assay demonstrated that NOX4 was a target of miR-9-5p, and NOX4 over-expression partially reversed the effects of miR-9-5p mimic on oxidative stress, inflammation, and apoptosis in OGD/R SH-SY5Y cells.

Conclusion: MiR-9-5p over-expression suppressed oxidative stress, inflammation, and apoptosis in cerebral I/R injury by targeting NOX4, suggesting that miR-9-5p might be a new anti-inflammatory and anti-oxidative modulator in cerebral I/R injury.

Background: Gastric cancer (GC) remains one of the most common malignancies and the third cause of cancer-related deaths worldwide. Non-coding RNAs (ncRNAs), including microRNAs and long ncRNAs, can contribute to the pathogenesis and progression of GC and therefore could be its potent diagnostic and prognostic biomarkers. The aim of our work was to estimate the expression of PROX1- AS1 (Prospero Homeobox 1 Antisense RNA 1) and miR-647 (microRNA-647) in GC and investigate their potential interaction and clinical significance.

Methods: The study included tumor and adjacent non-tumor tissues from 110 GC patients and plasma samples from 65 GC patients; 38 sectional normal gastric tissue samples and 49 plasma samples of healthy donors were included as controls. Expression levels of both ncRNAs were quantified in all samples by using real-time polymerase chain reaction (RT-PCR) and their possible correlations with the clinical and pathological characteristics of patients were analyzed. A potential inverse correlation between PROХ1-AS1 and miR-647 expression was addressed by in vitro experiments in a panel of cancer cell lines.

Results: The expression of PROX1-AS1 and miR-647 was not significantly different in tissues of GC patients and sectional normal gastric tissue samples. However, they have demonstrated a negative correlation both in the tumor and the adjacent nontumor tissue of GC patients. PROX1-AS1 expression was significantly decreased in GC tissues, whereas the miR-647 expression was increased. The expression of the ncRNAs was associated with clinical and pathological characteristics of GC patients. The overexpression of miR-647 led to a significant decrease in PROX1-AS1 expression in five cancer cell lines, including the GC cell line SNU-1.

Conclusion: We have demonstrated a negative correlation between PROX1-AS1 and miR-647 in both GC tissues and the cancer cell lines. In addition, expression of both ncRNAs was associated with the primary tumor size. Therefore, these ncRNAs might have potential prognostic value.

Background: The Orthoflavivirus zikaense (ZIKV), a member of the Flaviviridae family, has been associated with severe neurological issues, particularly microcephaly, due to its ability to infect neural progenitor cells. This study investigates the mRNA expression of cytokines involved in the inflammatory response during ZIKV infection in Mesocricetus auratus. The research aims to understand the immune response to ZIKV in the context of sexual transmission.

Methods: The study utilized hamsters of the species Mesocricetus auratus, divided into four groups: three infected with ZIKV and one control group. The animals were euthanized according to ethical guidelines, and renal tissues were collected. Total RNA was extracted and quantified, and both viral load and cytokine mRNA levels were measured using RT-qPCR. The study targeted cytokines such as TNF-A, RIG-I, RANTES, MDA5, IFN-A, and IFN-B. Statistical analysis was performed using Jamovi v 1.6.

Results: The study found that the viral load peaked between 3 and 5 days postinfection and then significantly decreased. The expression of cytokine mRNAs showed distinct patterns, with peaks and declines at various time points post-infection. These patterns differed between male and female subgroups. Pearson correlation analysis revealed negative correlations between mRNA expression and days post-infection in most groups.

Conclusion: The study concludes that ZIKV infection in hamsters induces a robust inflammatory response in the kidneys, with dynamic cytokine expression profiles that could serve as markers for monitoring infection and related pathologies. Genderspecific immune responses highlight the complexity of ZIKV pathogenesis, suggesting potential therapeutic targets for Zika-related complications.

Hemolysis is a major challenge in the screening and validation of serum or plasma miRNA biomarkers for human diseases. Over the past decade, numerous studies have focused on hemolysis detection at both the pre-analytical and postanalytical stages to minimize bias in miRNA quantification. Both conventional and advanced hemolysis determination methods have played important roles in quality control in hemolysis assessment and risk prediction during the plasma or serum miRNA quantification process. This review discusses the advantages of these methods and provides an interactive summary of prior knowledge on hemolysissensitive miRNAs and their potential applications in disease diagnosis. Furthermore, the review highlights the advancements in machine learning technologies that enhance classifier predictions and hemolysis risk model evaluations, particularly during the post-analytical stage. Finally, it discusses the ongoing development, standardization, and potential applications of these approaches, which will contribute to a more comprehensive and interpretable framework for the discovery and validation of plasma or serum miRNA biomarkers.

Atherosclerosis (AS) is a chronic inflammatory disease closely associated with endothelial dysfunction and oxidative stress. The NOD-like receptor protein 3 (NLRP3) inflammasome, a key regulator of inflammatory responses, can exacerbate the progression of AS when activated. Growing evidence suggests that exercise, as a non-pharmacological intervention, can alleviate the progression of AS by modulating the activity of NLRP3 inflammasome. This review discusses how exercise influences the development of AS through the regulation of NLRP3 inflammasome and the underlying molecular mechanism. This study introduces the structure and activation mechanisms of NLRP3 inflammasome, as well as its role in AS. And summarizes how exercise can ameliorate endothelial dysfunction, regulate lipid metabolism, and suppress oxidative stress and inflammation by affecting the expression and activity of NLRP3 inflammasome, thereby exerting a beneficial impact on AS. Additionally, we explore the effects of exercise on the downstream inflammatory cytokines of NLRP3 inflammasome and how this regulation could help to slow the progression of AS. These findings underscore the therapeutic relevance of exercise in the prevention and treatment of AS. It provides new insights into the role of exercise interventions in the management of AS and lays a theoretical foundation for the development of innovative treatment strategies for cardiovascular disease. Given that the NLRP3 inflammatome plays an important role in the pathogenesis and treatment of AS, exercise therapy strategies targeting the NLRP3 inflammatome will help promote the development of precision medicine for AS.