Journal of Biomedical Research最新文献

The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer (PCa) as well as to elucidate biological mechanisms underlying the associations. We first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify risk-associated circRNAs by using the MiOncoCirc database. We then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls, and identified circHIBADH rs11973492 T>C as a significant risk-associated variant (odds ratio = 1.20, 95% confidence interval: 1.08-1.34, P = 7.06 × 10 ^-4) in a dominant genetic model, which altered the secondary structure of the corresponding RNA chain. In the in silico analysis, we found that circHIBADH sponged and silenced 21 RNA-binding proteins (RBPs) enriched in the RNA splicing pathway, among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house (four tissue samples) and publicly available single-cell transcriptomes. Additionally, we demonstrated that HNRNPA1 influenced hallmarks including MYC target, DNA repair, and E2F target signaling pathways, thereby promoting carcinogenesis. In conclusion, genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1, playing an oncogenic role in PCa.

Ischemia-reperfusion injury (IRI) remains an unavoidable challenge in liver surgery, with macrophages playing a critical role in its pathogenesis. However, the mechanisms by which macrophages regulate the pathogenesis of IRI are not well understood. Through a target-guided screening approach, we identified a small 3 kDa peptide (SjDX5-271) from various schistosome egg-derived peptides that induced M2 macrophage polarization. SjDX5-271 treatment protected mice against liver IRI by promoting M2 macrophage polarization, and this protective effect was abrogated when the macrophages were depleted. Transcriptomic sequencing showed that the TLR signaling pathway was significantly inhibited in macrophages from the SjDX5-271 treatment group. We further identified that SjDX5-271 promoted M2 macrophage polarization by inhibiting the TLR4/MyD88/NF-κB signaling pathway and alleviated hepatic inflammation in liver IRI. Collectively, SjDX5-271 exhibited some promising therapeutic effects in IRI and represented a novel therapeutic approach, potentially applicable to other immune-related diseases. The current study demonstrates the potential of new biologics from the parasite, enhances our understanding of host-parasite interplay, and provides a blueprint for future therapies for immune-related diseases.

Tumor vaccines are a promising avenue in cancer immunotherapy. Despite the progress in targeting specific immune epitopes, tumor cells lacking these epitopes can evade the treatment. Here, we aimed to construct an efficient in situ tumor vaccine called Vac-SM, utilizing shikonin (SKN) to induce immunogenic cell death (ICD) and Mycobacterium smegmatis as an immune adjuvant to enhance in situ tumor vaccine efficacy. SKN showed a dose-dependent and time-dependent cytotoxic effect on the tumor cell line and induced ICD in tumor cells as evidenced by the CCK-8 assay and the detection of the expression of relevant indicators, respectively. Compared with the control group, the in situ Vac-SM injection in mouse subcutaneous metastatic tumors significantly inhibited tumor growth and distant tumor metastasis, while also improving survival rates. Mycobacterium smegmatis effectively induced maturation and activation of bone marrow-derived dendritic cells (DCs), and in vivo tumor-draining lymph nodes showed an increased maturation of DCs and a higher proportion of effector memory T-cell subsets with the Vac-SM treatment, based on flow cytometry analysis results. Collectively, the Vac-SM vaccine effectively induces ICD, improves antigen presentation by DCs, activates a specific systemic antitumor T-cell immune response, exhibits a favorable safety profile, and holds the promise for clinical translation for local tumor immunotherapy.

Bladder cancer (BC) is the tenth most prevalent malignancy globally, presenting significant clinical and societal challenges because of its high incidence, rapid progression, and frequent recurrence. Presently, cystoscopy and urine cytology serve as the established diagnostic methods for BC. However, their efficacy is limited by their invasive nature and low sensitivity. Therefore, the development of highly specific biomarkers and effective non-invasive detection strategies is imperative for achieving a precise and timely diagnosis of BC, as well as for facilitating an optimal tumor treatment and an improved prognosis. microRNAs (miRNAs), short noncoding RNA molecules spanning around 20-25 nucleotides, are implicated in the regulation of diverse carcinogenic pathways. Substantially altered miRNAs form robust functional regulatory networks that exert a notable influence on the tumorigenesis and progression of BC. Investigations into aberrant miRNAs derived from blood, urine, or extracellular vesicles indicate their potential roles as diagnostic biomarkers and prognostic indicators in BC, enabling miRNAs to monitor the progression and predict the recurrence of the disease. Simultaneously, the investigation centered on miRNA as a potential therapeutic agent presents a novel approach for the treatment of BC. This review comprehensively analyzes biological roles of miRNAs in tumorigenesis and progression, and systematically summarizes their potential as diagnostic and prognostic biomarkers, as well as therapeutic targets for BC. Additionally, we evaluate the progress made in laboratory techniques within this field and discuss the prospects.

Although the p21-activated kinase 2 (PAK2) is an essential serine/threonine protein kinase, its role in lung squamous cell carcinoma (LUSC) progression has yet to be fully understood. We analyzed PAK2 mRNA levels and DNA copy numbers as well as protein levels by quantitative real-time PCR and immunohistochemical staining, respectively, in human LUSC tissues and adjacent normal tissues. Then, we used colony formation assays, cell counting kit-8 assays, matrigel invasion assays, wound healing assays and xenograft models in nude mice to investigate the functions of PAK2 in LUSC progression. We demonstrated that the mRNA levels, DNA copy numbers, and protein levels of PAK2 were up-regulated in human LUSC tissues than in adjacent normal tissues. In addition, a higher PAK2 expression was correlated with a poorer prognosis in LUSC patients. In the in vitro study, we found that PAK2 promoted cell growth, migration, invasion, EMT process, and cell morphology regulation in LUSC cells. Furthermore, PAK2 enhanced tumor cell proliferation, migration, and invasion by regulating actin dynamics through the LIMK1/cofilin signaling. Our findings implicated that the PAK2/LIMK1/cofilin signaling pathway is likely a potential clinical marker and therapeutic target for LUSC.

Acute lung injury (ALI) linked to sepsis has a high mortality rate, with limited treatment options available. In recent studies, medical ozone has shown promising results in alleviating inflammation and infection. Here, we aimed to evaluate the therapeutic potential of medical ozone in sepsis-induced ALI using a mouse model, measuring behavioral assessments, lung function, and blood flow. Western blot was used to quantify the levels of protein. In vitro, experiments on BMDM cells examine the impact of AMPK inhibitors and agonists on phagocytic activity. Results indicate that medical ozone can enhance the survival rate, ameliorate lung injury, and improve lung function and limb microcirculation in mice with ALI. Notably, it inhibits NETs formation, a crucial player in ALI development. Medical ozone also counteracts elevated TF, MMP-9, and IL-1β levels. In ALI mice, the effects of ozone are nullified and BMDMs exhibit impaired engulfment of NETs following Sr-a1 knockout. Under normal physiological conditions, the use of an AMPK antagonist produces similar effects to Sr-a1 knockout, significantly inhibiting the phagocytosis of NETs by BMDMs. On the contrary, AMPK agonists enhance this phagocytic process. In conclusion, medical ozone can alleviate sepsis-induced lung injury via the AMPK/SR-A1 pathway, thereby enhancing phagocytosis of NETs by macrophages.

Reliable molecular biomarkers to predict fertility remain scarce. The current study explored the potential of testis-specific circBOULE RNAs as biomarkers for male infertility and sperm quality. Using RT-PCR and RT-qPCR assays, we identified seven circular RNAs from the human BOULE gene in human sperm. We found that sperm circEx3-6 RNA exhibited a significantly decreased expression in asthenozoospermia while circEx2-6 and circEx2-7 expression decreased in teratozoospermia, compared with the controls. Furthermore, circEx2-6 expression exhibited a negative correlation with sperm DNA Fragmentation Index (DFI), and circEx2-7 levels were correlated with both fertilization and cleavage rates involving assisted reproductive technologies. Further functional analyses in a transgenic fly model lent support for the roles of circBOULE RNAs in sperm development and human fertility. Collectively, our findings support that sperm circBOULE RNAs may serve as diagnostic biomarkers for assessing sperm motility and DNA quality. Hence clinical application and significance of sperm circular RNAs in assisted reproductive technologies warrant further investigation.

The main pathogenic factor leading to cardiac remodeling and heart failure is myocardial fibrosis. Recent research indicates that microRNAs are essential for the progress of cardiac fibrosis. Myocardial fibrosis is considered to be alleviated through the bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), which does this by blocking the transforming growth factor β1 (TGF-β1) signaling pathway. Here, this study sought to elucidate the post-transcriptional regulation of miR-19a-3p on BAMBI and its role in TGF-β1-induced cardiac fibroblast activation. Transverse aortic constriction (TAC) caused both myocardial interstitial and perivascular collagen deposition. RT-PCR showed that miR-19a-3p was upregulated in the myocardial tissue of cardiac fibrosis, and TGF-β1 induced an increase of miR-19a-3p expression in cardiac fibroblasts. The dual-luciferase reporter test and qRT-PCR confirmed that miR-19a-3p directly combined with BAMBI mRNA 3'UTR, thus reduced BAMBI expression, which diminished the capability of BAMBI to inhibit TGF-β1. Furthermore, miR-19a-3p mimic increased the activation of TGF-β1/SMAD2/3 pathway signaling, which supported cardiac fibroblast activation, which blocked by overexpression of BAMBI. These findings imply that miR-19a-3p enhances the activation of TGF-β1/SMAD2/3 by inhibiting BAMBI, further boosting the activation of cardiac fibroblasts, and may thus offer a novel strategy to tackling myocardial fibrosis.

Circadian clock plays a vital role in the pathological progression of cardiovascular disease (CVD). Our previous studies showed that acrolein, an environmental pollutant, promoted atherosclerosis by reducing CLOCK/BMAL1 and disturbing circadian rhythm. Whereas, intermittent fasting (IF), a diet pattern, was able to ameliorate acrolein-induced atherosclerosis. In vivo, mice were fed acrolein 3 mg/kg/day via drinking water and IF for 18h (0:00-18:00). We observed that IF decreased acrolein-accelerated the formation of aortic lesion in ApoE ^-/- mice. Up-regulation of NF-κB, IL-1β and TNF-α levels were found in liver and heart tissue upon acrolein exposure, while was down-regulated by IF. Interestingly, IF treatment exhibited higher AMPK, p-AMPK and SIRT1and lower MAPK expression which was caused by acrolein. Besides, circadian genes Clock/ Bmal1 expression were suppressed and disturbed treated with acrolein, while were reversed by IF. Furthermore, consistent with that in vivo, short-term starvation as a fasting cell model in vitro could improve the disorders of CLOCK/BMAL1 and raised SIRT1 via regulating AMPK, as well as ROS-MAPK induced by acrolein. In conclusion, we demonstrated that IF repressed ROS-MAPK while activated AMPK to elevate the expression of circadian clock genes to ameliorate acrolein-induced atherogenesis, which shed a novel light to prevent cardiovascular diseases.

Inflammation plays a crucial role in the initiation and progression of sepsis, and it also induces alterations in brain neurotransmission, thereby contributing to the development of sepsis-associated encephalopathy (SAE). Parvalbumin (PV) interneurons are pivotal contributors to cognitive processes in various central dysfunctions including SAE. Oxytocin, known for its ability to augment the firing rate of gamma-aminobutyric acid (GABA)ergic interneurons and directly stimulate inhibitory interneurons to enhance the tonic inhibition of pyramidal neurons, has prompted an investigation into its potential effects on cognitive dysfunction in SAE. In the current study, we administered intranasal oxytocin to the SAE mice induced by lipopolysaccharide (LPS). Behavioral assessments, including open field, Y-maze, and fear conditioning, were used to evaluate cognitive performance. Golgi staining revealed hippocampal synaptic deterioration, local field potential recordings showed weakened gamma oscillations, and immunofluorescence analysis demonstrated decreased PV expression in the cornu ammonis 1 (CA1) region of the hippocampus following LPS treatment, which was alleviated by oxytocin. Furthermore, immunofluorescence staining of PV co-localization with vesicular glutamate transporter 1 or vesicular GABA transporter indicated a balanced excitation/inhibition effect of neurotransmitters on PV interneurons after oxytocin administration in the SAE mice, leading to improved cognitive function. In conclusion, cognitive function improved after oxytocin treatment. The number of PV neurons in the hippocampal CA1 region and the balance of excitatory/inhibitory synaptic transmission on PV interneurons, as well as changes in local field potential gamma oscillations in the hippocampal CA1 region, may represent its specific mechanisms.