Acute necrotizing encephalopathy (ANE) secondary to influenza infection is characterized by fulminant neurological deterioration and a high mortality rate. The underlying mechanisms remain unclear, and specific treatments are currently lacking. Therefore, understanding the pathogenesis and identifying diagnostic and therapeutic targets for influenza-induced ANE are crucial. Peripheral blood samples were collected from two groups: influenza-infected patients without ANE (mild) and influenza infection with ANE patients (severe). Differentially expressed genes (DEG) were identified through microRNA sequencing analysis, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The expression levels of the four specific miRNAs were validated using qRT-PCR. In the severe group, 24 genes were up-regulated, and 67 genes were down-regulated compared to the mild group. The expression levels of hsa-miR-1290, hsa-miR-4657, has-miR-1231, and hsa-miR-342-3p were validated by qRT-PCR, and the levels of has-miR-4657 and hsamiR- 342-3p showed significant differences between severe and mild groups. GO analysis demonstrated that the DEGs were predominantly involved in the positive regulation of cellular processes, intracellular anatomical structure, and protein binding. KEGG pathway analysis revealed that DEGs were mainly enriched in calcium signaling pathway and axon guidance. The down-regulated hsa-miR-4657 and hsa-miR-342-3p might be associated with the development of ANE in pediatric patients with influenza by regulation of calcium pathways and axon guidance.

The Lin28 protein is well known for its role in inhibiting the biogenesis of microRNAs (miRNAs) that belong to the let-7 family. The Lin28 and let-7 axes are associated with several types of cancers. It is imperative to understand the underlying mechanism to treat these cancers in a more efficient way. In this study, we employed all-atom molecular dynamics simulation as a research tool to investigate the interaction formed between Lin28 and the precursor element of let-7d, one of the 12 members of the let-7 family. By constructing systems of an intact sequence length of preE-let-7d, our simulations suggest that both the loop region of the hairpin structure and the GGAG sequence can form stable interactions with the cold shock domain (CSD) and zinc knuckle domain (ZKD) regions of the protein, respectively. The system, by deleting the nucleotides GGAG at the 3' terminal, indicates that the loop region is more responsible for its ability in bypassing the binding and repression of Lin28. Additionally, using let-7c-2, which can bypass Lin28 regulation, as a template, we constructed systems with mutated loop region sequences in miRNAs and tested their stabilities. Our simulation results coincide well with experimental observations. Based on both simulation results and statistical analysis from two databases, we hypothesized that two factors, namely, the interaction between terminal nucleotides and the ring tension originating from the middle nucleotides, can significantly influence their stabilities. Systems combining strong and weak terminal interactions with large and small ring tensions were recruited to validate our hypothesis. Our findings offer a new perspective and shed light on strategies for designing sequences to regulate the interactions formed between proteins and hairpin structures.

Verify whether Onconstatin M receptor (OSMR) plays a regulatory role in the growth of glioblastoma (GBM) and explore its specific regulatory mechanism.

In vitro investigations were carried out using OSMR knockdown and treatment with JAK agonist Butyzamide (JAKa). Evaluate cell proliferation rate through CCK-8; Colony formation experiment to detect cell proliferation; Transwell experiment evaluates cell invasion; Cell scratch assay to detect cell migration; WB detects the expression levels of pathway related proteins JAK, p-JAK, STAT3, p-STAT3, and CCL-2; Flow cytometry analysis of apoptosis rate, cell cycle arrest rate, and proportion of M2 macrophages; RT-qPCR was implemented to identify the expression of M2 polarization factors CD206, CD163 and IL-10 in macrophages. In the in vivo experiment, SF188 cells were subcutaneously injected into mice's right sides and divided into two groups: those with knocked down OSMR or those without. The knocked down OSMR group was divided into subgroups treated with DMSO containing or not containing JAKa. Subsequently, the tumor volume and weight of the mice were measured. RT-qPCR was utilized to assess the level of M2 polarization-related components in tumor tissues, while flow cytometry was employed to determine the M2 polarization ratio of macrophages in tumor tissues.

Knocking down OSMR dramatically reduces tumor cell proliferation, invasion, and migration, accelerates cell death and cell cycle arrest, and lowers JAK and STAT3 phosphorylation as well as CCL-2 expression levels, all while decreasing the fraction of M2 macrophages. Furthermore, knocking down OSMR drastically lowered tumor development and M2 polarization levels of monocytes in tumor tissue. JAKa reversed the inhibitory effect of OSMR knockdown on GBM malignant development and macrophage M2 polarization in both in vitro and in vivo studies.

OSMR promotes the JAK/STAT3 signaling pathway, which promotes malignant glioblastoma growth and macrophages M2 polarization.

Doxorubicin is a crucial chemotherapy used in the treatment of triple-negative breast cancer (TNBC) patients, but elevated doxorubicin doses may induce therapeutic resistance. To overcome this limitation, we have previously established a photodynamic therapeutic (PDT)-like strategy that irradiates doxorubicin-treated cells with a low-power nonionizing blue LED device. This combined treatment increases the production of reactive oxygen species to promote cell death, consequently enabling reduced doxorubicin dosages. Yet, precisely determining the molecular mechanisms that drive this outcome is still required for advancing such PDT-like approach. Here, we aimed to correlate the expression of the inflammatory markers NF-κB, IL-8, IL-6, and IL-1β with the survival of TNBC cells submitted to our PDT-like protocol. Our results show that NF-κB/p65 nuclear levels were enhanced in MDA-MB-231 cells treated with doxorubicin and blue LED. Moreover, this PDT-like strategy increased IL-6 mRNA levels in MDA-MB-231 cells. IL-1β and IL-8 mRNA were upregulated in samples incubated with doxorubicin regardless of concomitant irradiation with blue LED. These results show that our PDT-like protocol is effective in elevating inflammatory signals, shedding light on the molecular mechanisms that underlie the efficacy of this innovative anticancer therapeutic approach.

The Epstein-Barr virus (EBV) encoded tegument protein BSRF1 plays a significant role in the processes of viral maturation and release, however, it's not clear whether BSRF1 is involved in the modulation of host innate immunity. In this study, we demonstrated that BSRF1 can inhibit interferon β (IFN-β) production by downregulating nuclear factor kappa B (NF-κB) activity and subsequently reducing the yield of inflammatory cytokines, thereby facilitating viral replication. Dual luciferase reporter assays indicated that BSRF1 may inhibit NF-κB signaling at the level of IKK or between IKK and p65, while co-immunoprecipitation experiments revealed its association with multiple critical host adaptor proteins. Mechanistically, BSRF1 hinders the phosphorylation of IκBα at Ser32/36 and K48-linked polyubiquitination, thereby preventing proteasome-mediated degradation of IκBα by disrupting the assembly of the regulatory subunits within the IKK complex. Although BSRF1 interacts with p65 and its N-terminal domain, it does not alter the formation of the p65/p50 heterodimer. Instead, it prevents the nuclear translocation of p65 by inhibiting the dissociation of IκBα from the NF-κB dimer. Collectively, these findings suggested that BSRF1 assists EBV's evasion of host innate immune system by inhibiting the antiviral response to IFN-β through the NF-κB signaling pathway, potentially contributing to the virus's ability to establish persistent infection and its association with tumorigenesis.

Background: Breast cancer (BrCa) patients with tumors expressing high interleukin-6 (IL6) levels have poor clinical outcomes. In BrCa, altered occupancy of CCCTC-binding factor (CTCF) within its DNA binding sites deregulates the expression of its targeted genes. In this study, we investigated whether CTCF contributes to the altered IL6 expression in BrCa. Methods/Results: We performed CTCF gain- and loss-of-function assays in BrCa cell lines and observed an inverse correlation between CTCF and IL6 expression levels. To understand how CTCF negatively regulates IL6 gene expression, we performed luciferase gene reporter assays, site-directed mutagenesis assays, and chromatin immunoprecipitation assays. Our findings revealed that CTCF interacted with the IL6 promoter, a form of regulation disrupted in a CpG methylation-independent fashion in MDA-MB-231 and Tamoxifen-resistant MCF7 cells. Data from TCGA and GEO databases allowed us to explore the clinical implications of our results. An inverse correlation between CTCF and IL6 expression levels was seen in disease-free survival BrCa patients but not in patients who experienced cancer recurrence. Conclusions: Our findings provide evidence that the CTCF-mediated negative regulation of the IL6 gene is lost in highly tumorigenic BrCa cells.

The Flinders sensitive line (FSL) rat is an accepted rodent model for depression that presents with strong face, construct, and predictive validity, thereby making it suitable to investigate novel antidepressant mechanisms. Despite the translatability of this model, available literature on this model has not been reviewed for more than ten years. The PubMed, ScienceDirect and Web of Science databases were searched for relevant articles between 2013 and 2024, with keywords relating to the Flinders line rat, and all findings relevant to treatment naïve animals, included. Following screening, 77 studies were included and used to create behavioral reference standards and calculate FSL favor ratios for the various behavioral parameters. The GRADE and SYRCLE risk of bias tools were used to scale the quality of these studies. Based on these results, FSL rats display reliable and reproducible depressive-like behavior in the forced swim test, together with hyperlocomotor activity across various behavioral tests. Despite reports of increased anhedonia, anxiety-like behavior, and cognitive dysfunction, the reviewed findings indicate that these parameters are comparable between strains. For the various neuro- and biological constructs, oxidative stress, energy production, and glutamatergic, noradrenergic and serotonergic neurotransmission received the most support for strain differences. Taken together, the FSL remains a reliable, popular, and translatable rodent model of depression, with strong face and construct validity. As for predictive validity, similar review approaches should be considered to establish whether the mentioned behavioral aspects and neurochemical constructs may be more sensitive (or resistant) to certain antidepressant strategies.

Breast cancer (BC) is a health concern worldwide and is often accompanied by depressive symptoms in patients. In BC, elevated interleukin-6 (IL-6) levels contribute to an inflammatory signature linked to cancer stem cell (CSC) stemness and depressive behaviors. Bioactive food components, such as berberine (BBR), have preventative effects against BC by targeting CSCs.

This study aimed to investigate the effects of BBR on breast CSC proliferation, on levels of specific micro (mi)RNAs and IL-6 in vitro and in vivo, and in alleviating depressive-like behaviors in mice with BC.

Mammosphere formation assays were conducted by treating murine 4T1 and human MDA-MB-231 BC cell lines with BBR. qPCR analysis of miRNAs miR-let-7c and miR-34a-5p was performed on 4T1 CSCs exposed to BBR. BBR was administered orally to female BALB/c, followed by injection with mammary carcinoma cells to induce BC. Behavioral tests were conducted to assess depressive-like behaviors. Tumor tissues were collected for ex vivo mammosphere assays, miRNA expression analysis, and IL-6 detection by ELISA. Serum was also collected for IL-6 analysis.

BBR treatment inhibited mammosphere formation and proliferation of CSCs derived from 4T1 and MDA-MB-231 cell lines. Quantification of mammosphere formation showed a significant decrease in both cell lines at 75 μM BBR (4T1: P < 0.001; MDA-MB-231: P < 0.0001). BBR upregulated the expression of miRNAs miR-let-7c and miR-34a in both cell lines, with miR-34a showing a significant increase (P < 0.001) and let-7c showing a significant increase (P < 0.05) in expression. In vivo, oral administration of BBR reduced mammosphere formation in breast tumor tissues (P < 0.0001) and elevated expression of miR-145 and miR-34a, with both showing significant upregulation (P < 0.0001), indicating its potential tumor-suppressive effects. BBR treatment resulted in a significant decrease in serum IL-6 levels (P < 0.05), suggesting anti-inflammatory properties, while the IL-6 in tumor tissue did not show significant changes (P > 0.05). However, no significant differences were observed in depressive-like behaviors between control and treatment groups.

BBR may have the potential to be used as an "Epi-Natural Compound" to prevent cancer by reducing inflammation and affecting epigenetics.

Osteosarcoma, a highly aggressive malignancy with a generally poor prognosis, is characterized by tumor cells' ability to evade immune responses and resist treatment. The nuclear transcription factor NF-κB signaling pathway is crucial in regulating inflammatory and immune reactions. It occupies a central position in the development of the osteosarcoma tumor microenvironment. This research aimed to explore how NF-κB influences the recruitment and polarization of tumor-associated macrophages and myeloid-derived suppressor cells, both of which contribute to immunosuppression. Furthermore, NF-κB facilitates immune surveillance evasion in osteosarcoma cells by altering the expression of immune checkpoint molecules, such as PD-L1. It also enhances tumor cell resistance to chemotherapy and radiotherapy by activating anti-apoptotic signaling pathways and exacerbating treatment-induced inflammation. Potential therapeutic approaches include using NF-κB inhibitors, possibly in combination with immune checkpoint inhibitors, to overcome tumor cell resistance mechanisms and reshape antitumor immune responses. A thorough examination of NF-κB's role in osteosarcoma development is expected to yield novel clinical treatment strategies, and significantly improve patient prognosis by targeting this key signaling pathway.

Prolonged psychological stress is closely associated with cancer due to its role in promoting the release of stress hormones through the sustained activation of the sympathetic-adrenal-medullary system. These hormones interact with receptors on inflammatory cells, leading to the activation of key signaling pathways, including the transcription factors signal transducer and activator of transcription 3 (STAT-3) and kappa-light-chain-enhancer of activated B cells (NF-κB). These factors drive the production of pro-inflammatory substances, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which can influence the initiation and progression of cancer.

This article aims to summarize how the chronic inflammatory environment induced by chronic stress promotes the initiation, progression, and invasion of cancer. By enhancing our understanding of the complex mechanisms through which stress contributes to cancer, we hope to identify new targets for cancer prevention and treatment.

Chronic stress establishes an inflammatory microenvironment by activating STAT-3 and NF-κB in inflammatory cells. This ongoing inflammation further enhances the activity of these transcription factors, which serve multiple roles: they act as pro-inflammatory agents in inflammatory cells, maintaining chronic inflammation; as oncogenic transcription factors in premalignant cells, promoting cancer initiation; and as pro-differentiation transcription factors in tumor-infiltrating immune cells, facilitating cancer progression. Additionally, the impact of chronic stress varies among different cancer types and individual responses to stress, highlighting the complexity of stress-related cancer mechanisms. Ultimately, this dynamic interplay creates a feedback loop involving IL-6, STAT-3, and TNF-α-NF-κB within the tumor microenvironment, mediating the intricate interactions between inflammation, immunity, and cancer.

Noncoding RNAs (ncRNAs) play critical roles in essential cell fate decisions. However, the exact molecular mechanisms underlying ncRNA-mediated bistable switches remain elusive and controversial. In recent years, systematic mathematical and quantitative experimental analyses have made significant contributions to elucidating the molecular mechanisms of controlling ncRNA-mediated cell fate decision processes. In this chapter, we review and summarize the general framework of mathematical modeling of ncRNA in a pedagogical way and the application of this general framework to real biological processes. We discuss the emerging properties resulting from the reciprocal regulation between mRNA, miRNA, and competing endogenous mRNA (ceRNA). We also explore the efforts within the synthetic biology approach to understand the fundamental design principles underlying cell fate decisions. Both the positive feedback loops between ncRNAs and transcription factors and the emerging properties from the miRNA-mRNA reciprocal regulation enable bistable switches to direct cell fate decisions.

Chronic obstructive pulmonary disease (COPD) will become the fourth largest cause of death of chronic diseases in the world in 2030. The incidence of COPD ranked top among chronic diseases in the world. At present, there is a lack of simple and effective drugs for the treatment of COPD and for slowing the progression of the disease. The application of vitamin D as a drug in clinical treatment has been a research hotspot. In this study, we investigated the correlation between serum 25-hydroxyvitamin D (25(OH)D), inflammatory markers, and T lymphocytes with the severity of COPD and its effect on the risk of acute exacerbation.

In this study, we recruited hospital inpatients and outpatient clinic patients with COPD. Their levels of 25(OH)D, inflammatory markers, and T lymphocytes were assessed. We built a nomogram model to evaluate the risk of acute exacerbation of COPD.

The inflammatory mediators were higher in patients with acute exacerbation of COPD (AECOPD) than those in patients with COPD, but 25(OH)D showed the opposite phenomenon. In logistic regression analysis, high levels of neutrophil-lymphocyte ratio, C-reactive protein, and partial pressure of carbon dioxide and low levels of vitamin D, partial pressure of oxygen, and forced expiratory volume in the first as a percentage of predicted were regarded as independent risk factors for AECOPD. These variables were used for the construction of the nomogram model. The AUCs of the model were 0.971 (95% CI, 0.952-0.989), and 0.981 (95% CI, 0.959-1.000) in the training and testing set respectively, demonstrating that the model exhibited high accuracy for the prediction of the risk of acute exacerbation of COPD. The calibration curve of the nomogram found a high degree of consistency between the expected and actual values. The decision curve analysis and clinical impact curve indicated that the nomogram has clinical applicable for patients with COPD.

A considerable percentage of patients with COPD were found to have insufficient vitamin D levels. Patients with AECOPD reported more symptoms than those with COPD. The variables neutrophil-lymphocyte ratio, C-reactive protein, partial pressure of carbon dioxide, 25(OH)D, partial pressure of oxygen, and forced expiratory volume in the first as a percentage of predicted can be used for the prediction of AECOPD. Accordingly, this study provided experimental rationales for the role of 25(OH)D in the prevention and the potential anti-inflammatory mechanisms involved in the control of the COPD process.

Alveolar macrophages (AMs) are the first line of defence against pathogens that initiate an inflammatory response in the lungs and exhibit a strong affinity for surfactant protein A (SP-A). Extracellular vesicles (EVs) have emerged as a promising drug delivery platform due to their minimal cytotoxicity. However, precise targeting of specific cell types and the rapid lysosomal degradation of EVs within recipient cells remain persistent challenges.

In this study, we explored the biological significance of SP-A-EVs as novel drug delivery systems for combating lung inflammation. We first verified that respiratory EVs express SP-A receptor (SP-R210), facilitating the conjugation of SP-A with EVs. The delivery efficiency, cellular internalisation pathways and therapeutic effects were evaluated using an in vivo mouse model.

SP-A-EVs were robustly internalised into AMs both in vitro and in vivo. Furthermore, our investigation revealed that the toll-like receptor 4-mediated endocytosis pathway was employed for the uptake of SP-A-EVs, significantly delaying their degradation compared with natural EVs, which primarily followed the conventional lysosomal degradation pathway within AMs. In a functional study, we successfully loaded anti-inflammatory microRNA (let-7b) into SP-A-EVs, leading to the suppression of AM activation and the alleviation of lung inflammation induced by lipopolysaccharide.

These findings underscore the potential of SP-A-EVs as highly effective drug delivery systems for targeted therapeutics in lung-related disorders, capitalising on the strong affinity between AMs and SP-A and the modulation of cellular internalisation.

'Epigenetics' is the process by which distinct cell types or cell states are inherited through multiple cell divisions. 'Epigenomics' refers to DNA-associated physical and functional entities including histone modifications and DNA methylation, not concepts of inheritance. Conflating epigenetics and epigenomics is confusing and causes misunderstanding of a fundamental biological process.

Lin28A and Lin28B are paralogous RNA-binding proteins that play fundamental roles in development and cancer by regulating the microRNA family of tumor suppressor Let-7. Although Lin28A and Lin28B share some functional similarities with Let-7 inhibitors, they also have distinct expression patterns and biological functions. Increasing evidence indicates that Lin28A and Lin28B differentially impact cancer stem cell properties, epithelial-mesenchymal transition, metabolic reprogramming, and other hallmarks of cancer. Therefore, it is important to understand the overexpression of Lin28A and Lin28B paralogs in specific cancer contexts. In this review, we summarize the main similarities and differences between Lin28A and Lin28B, their implications in different cellular processes, and their role in different types of cancer. In addition, we provide evidence of other specific targets of each lin28 paralog, as well as the lncRNAs and miRNAs that promote or inhibit its expression, and how this impacts cancer development and progression.

Breast cancer (BC) is the most frequently diagnosed malignancy among women. It is characterized by a high level of heterogeneity that emerges from the interaction of several cellular and soluble components in the tumor microenvironment (TME), such as cytokines, tumor cells and tumor-associated immune cells. Tumor necrosis factor (TNF) receptor 2 (TNFR2) appears to play a significant role in microenvironmental regulation, tumor progression, immune evasion, drug resistance, and metastasis of many types of cancer, including BC. However, the significance of TNFR2 in BC biology is not fully understood. This review provides an overview of TNFR2 biology, detailing its activation and its interactions with important signaling pathways in the TME (e.g., NF-κB, MAPK, and PI3K/Akt pathways). We discuss potential therapeutic strategies targeting TNFR2, with the aim of enhancing the antitumor immune response to BC. This review provides insights into role of TNFR2 as a major immune checkpoint for the future treatment of patients with BC.

Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation of damaged organelles and proteins. However, the late onset of diseases suggests that compensatory quality control mechanisms may be engaged to delay the deleterious effects induced by compromised autophagy. Neurons expressing common familial Parkinson's disease (PD)-associated mutations in LRRK2 kinase exhibit defective autophagy. Here, we demonstrate that both primary murine neurons and human iPSC-derived neurons harboring pathogenic LRRK2 upregulate the secretion of extracellular vesicles. We used unbiased proteomics to characterize the secretome of LRRK2G2019S neurons and found that autophagic cargos including mitochondrial proteins were enriched. Based on these observations, we hypothesized that autophagosomes are rerouted toward secretion when cell-autonomous degradation is compromised, likely to mediate clearance of undegraded cellular waste. Immunoblotting confirmed the release of autophagic cargos and immunocytochemistry demonstrated that secretory autophagy was upregulated in LRRK2G2019S neurons. We also found that LRRK2G2019S neurons upregulate the release of exosomes containing miRNAs. Live-cell imaging confirmed that this upregulation of exosomal release was dependent on hyperactive LRRK2 activity, while pharmacological experiments indicate that this release staves off apoptosis. Finally, we show that markers of both vesicle populations are upregulated in plasma from mice expressing pathogenic LRRK2. In sum, we find that neurons expressing pathogenic LRRK2 upregulate the compensatory release of secreted autophagosomes and exosomes, to mediate waste disposal and transcellular communication, respectively. We propose that this increased secretion contributes to the maintenance of cellular homeostasis, delaying neurodegenerative disease progression over the short term while potentially contributing to increased neuroinflammation over the longer term.

Viral infections in humans often cause excessive inflammation. In some viral infections, inflammation can be serious and even fatal, while in other infections it can promote viral clearance. Viruses can escape from the host immune system via regulating inflammatory pathways, thus worsening the illness. MicroRNAs (miRNAs) are tiny non-coding RNA molecules expressed within diverse tissues as well as cells and are engaged in different normal pathological and physiological pathways. Emerging proof suggests that miRNAs can impact innate and adaptive immunity, inflammatory responses, cell invasion, and the progression of viral infections. We discuss some intriguing new findings in the current work, focusing on the impacts of different miRNAs on host inflammatory responses and virus-mediated inflammation. A better understanding of dysregulated miRNAs in viral infections could improve the identification, prevention, and treatment of several serious diseases.

Endometriosis is a debilitating, chronic inflammatory disease affecting approximately 10% of reproductive-age women worldwide with no cure. While macrophages have been intrinsically linked to the pathophysiology of endometriosis, targeting them therapeutically has been extremely challenging due to their high heterogeneity and because these disease-associated macrophages (DAMs) can be either pathogenic or protective. Here, we report identification of pathogenic macrophages characterized by TET3 overexpression in human endometriosis lesions. We show that factors from the disease microenvironment upregulated TET3 expression, transforming macrophages into pathogenic DAMs. TET3 overexpression stimulated proinflammatory cytokine production via a feedback mechanism involving inhibition of let-7 miRNA expression. Remarkably, these cells relied on TET3 overexpression for survival and hence were vulnerable to TET3 knockdown. We demonstrated that Bobcat339, a synthetic cytosine derivative, triggered TET3 degradation in both human and mouse macrophages. This degradation was dependent on a von Hippel-Lindau (VHL) E3 ubiquitin ligase whose expression was also upregulated in TET3-overexpressing macrophages. Furthermore, depleting TET3-overexpressing macrophages either through myeloid-specific Tet3 ablation or using Bobcat339 strongly inhibited endometriosis progression in mice. Our results defined TET3-overexpressing macrophages as key pathogenic contributors to and attractive therapeutic targets for endometriosis. Our findings may also be applicable to other chronic inflammatory diseases where DAMs have important roles.

Immune stressors, such as lipopolysaccharides (LPS), profoundly affect microbiota balance, leading to gut dysbiosis. This imbalance disrupts the metabolic phenotype and structural integrity of the gut, increasing intestinal permeability. During puberty, a critical surge in estrogen levels is crucial for mammary gland development. However, inflammation originating from the gut in this period may interfere with this development, potentially heightening breast cancer risk later. The long-term effects of pubertal inflammation on mammary development and breast cancer risk are underexplored. Such episodes can dysregulate cytokine levels and microRNA expression, altering mammary cell gene expression, and predisposing them to tumorigenesis.

This study hypothesizes that prebiotics, specifically Lentinula edodes Cultured Extract (AHCC), can counteract LPS's adverse effects. Using BALB/c mice, an acute LPS dose was administered at puberty, and breast cancer predisposition was assessed at 13 weeks. Cytokine and tumor-related microRNA levels, tumor development, and cancer stem cells were explored through immunoassays and qRT-PCR.

Results show that LPS induces lasting effects on cytokine and microRNA expression in mammary glands and tumors. AHCC modulates cytokine expression, including IL-1β, IL-17A/F, and IL-23, and mitigates LPS-induced IL-6 in mammary glands. It also regulates microRNA expression linked to tumor progression and suppression, particularly counteracting the upregulation of oncogenic miR-21, miR-92, and miR-155. Although AHCC slightly alters some tumor-suppressive microRNAs, these changes are modest, highlighting a complex regulatory role that warrants further study.

These findings underscore the potential of dietary interventions like AHCC to mitigate pubertal LPS-induced inflammation on mammary gland development and tumor formation, suggesting a preventive strategy against breast cancer.

Cancer stem cells (CSCs) are a class of cells with self-renewal and multi-directional differentiation potential, which are present in most tumors, particularly in aggressive tumors, and perform a pivotal role in recurrence and metastasis and are expected to be one of the important targets for tumor therapy. Studies of tumor metabolism in recent years have found that the metabolic characteristics of CSCs are distinct from those of differentiated tumor cells, which are unique to CSCs and contribute to the maintenance of the stemness characteristics of CSCs. Moreover, these altered metabolic profiles can drive the transformation between CSCs and non-CSCs, implying that these metabolic alterations are important markers for CSCs to play their biological roles. The identification of metabolic changes in CSCs and their metabolic plasticity mechanisms may provide some new opportunities for tumor therapy. In this paper, we review the metabolism-related mechanisms of CSCs in order to provide a theoretical basis for their potential application in tumor therapy.

The coronavirus disease 2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to a huge mortality rate and imposed significant costs on the health system, causing severe damage to the cells of different organs such as the heart. However, the exact details and mechanisms behind this damage are not clarified. Therefore, we aimed to identify the cell and molecular mechanism behind the heart damage caused by SARS-Cov-2 infection.

RNA-seq data for COVID-19 patients' hearts was analyzed to obtain differentially expressed genes (DEGs) and differentially expressed ferroptosis-related genes (DEFRGs). Then, DEFRGs were used for analyzing GO and KEGG enrichment, and perdition of metabolites and drugs. we also constructed a PPI network and identified hub genes and functional modules for the DEFRGs. Subsequently, the hub genes were validated using two independent RNA-seq datasets. Finally, the miRNA-gene interaction networks were predicted in addition to a miRNA-TF co-regulatory network, and important miRNAs and transcription factors (TFs) were highlighted.

We found ferroptosis transcriptomic alterations within the hearts of COVID-19 patients. The enrichment analyses suggested the involvement of DEFRGs in the citrate cycle pathway, ferroptosis, carbon metabolism, amino acid biosynthesis, and response to oxidative stress. IL6, CDH1, AR, EGR1, SIRT3, GPT2, VDR, PCK2, VDR, and MUC1 were identified as the ferroptosis-related hub genes. The important miRNAs and TFs were miR-124-3P, miR-26b-5p, miR-183-5p, miR-34a-5p and miR-155-5p; EGR1, AR, IL6, HNF4A, SRC, EZH2, PPARA, and VDR.

These results provide a useful context and a cellular snapshot of how ferroptosis affects cardiomyocytes (CMs) in COVID-19 patients' hearts. Besides, suppressing ferroptosis seems to be a beneficial therapeutic approach to mitigate heart damage in COVID-19.

Despite unprecedented survival in patients with glioblastoma (GB), the aggressive primary brain cancer remains largely incurable and its mechanisms of treatment resistance have gained particular attention. The cytokine interleukin 6 (IL-6) and its receptor weave through the hallmarks of malignant gliomas and may represent a key vulnerability to GB. Known for activating the STAT3 pathway in autocrine fashion, IL-6 is amplified in GB and has been recognized as a negative biomarker for GB prognosis, rendering it a putative target of novel GB therapies. While it has been recognized as a biologically active component of GB for three decades only with concurrent advances in understanding of complementary immunotherapy has the concept of targeting IL-6 for a human clinical trial gained scientific footing.

Several studies have reported the relationship between LIN28A gene polymorphisms (rs3811463 T > C and rs34787247 G > A) and cancer susceptibility, but the results are inconsistent and need further clarification. The current study aimed to evaluate their relationship and also to explore the relationship between LIN28A gene expression and immune infiltration, tumor stage, survival prognosis, and drug sensitivity in pan-cancer. The meta-analysis and data mining were completed by STATA software and the GSCA platform, respectively. The meta-analysis showed that the rs3811463 polymorphism was not associated with cancer susceptibility, while the rs34787247 polymorphism was associated with cancer susceptibility in the Chinese population [AA vs. GG: Odd Ratio (OR)=1.98, 95% Confidence Interval (CI)=1.35-2.89, PZ<0.001; GA vs. GG: OR = 1.17, 95%CI= 1.01-1.36, PZ=0.04; (AA + GA) vs. GG: OR = 1.24, 95%CI = 1.07-1.43, PZ=0.004; AA vs. (GA + GG): OR = 1.90, 95%CI = 1.30- 2.78, PZ=0.001; A vs. G: OR = 1.27, 95%CI = 1.12-1.44, PZ<0.001]. LIN28A gene expression was associated not only with immune infiltration, pathological stage, and survival prognosis of certain cancers, but also with sensitivity to multiple anticancer drugs, such as cisplatin, pazopanib, olaparib, and selumetinib. In conclusion, the current study suggested that the rs34787247 G > A polymorphism might be used as a cancer risk marker in the Chinese population, and LIN28A might serve as a prognostic marker and therapeutic target for certain cancers.

As a key factor in tumorigenesis, progression, recurrence and metastasis, the biological properties, metabolic adaptations and immune escape mechanisms of CSCs are the focus of current oncological research. CSCs possess self-renewal, multidirectional differentiation and tumorigenicity, and their mechanisms of action can be elucidated by the clonal evolution, hierarchical model and the dynamic CSCs model, of which the dynamic model is widely recognized due to its better explanation of the function and origin of CSCs. The origin hypothesis of CSCs involves cell-cell fusion, horizontal gene transfer, genomic instability and microenvironmental regulation, which together shape the diversity of CSCs. In terms of classification, CSCs include primary CSCs (pri-CSCs), precancerous stem cells (pre-CSCs), migratory CSCs (mig-CSCs), and chemo-radiotherapy-resistant CSCs (cr-CSCs and rr-CSCs), with each type playing a specific role in tumor progression. Surface markers of CSCs, such as CD24, CD34, CD44, CD90, CD133, CD166, EpCAM, and LGR5, offer the possibility of identifying, isolating, and targeting CSCs, but the instability and heterogeneity of their expression increase the difficulty of treatment. CSCs have adapted to their survival needs through metabolic reprogramming, showing the ability to flexibly switch between glycolysis and oxidative phosphorylation (OXPHOS), as well as adjustments to amino acid and lipid metabolism. The Warburg effect typifies their metabolic profiles, and altered glutamine and fatty acid metabolism further contributes to the rapid proliferation and survival of CSCs. CSCs are able to maintain their stemness by regulating the metabolic networks to maintain their stemness characteristics, enhance antioxidant defences, and adapt to therapeutic stress. Immune escape is another strategy for CSCs to maintain their survival, and CSCs can effectively evade immune surveillance through mechanisms such as up-regulating PD-L1 expression and promoting the formation of an immunosuppressive microenvironment. Together, these properties reveal the multidimensional complexity of CSCs, underscoring the importance of a deeper understanding of the biology of CSCs for the development of more effective tumor therapeutic strategies. In the future, therapies targeting CSCs will focus on precise identification of surface markers, intervention of metabolic pathways, and overcoming immune escape, with the aim of improving the relevance and efficacy of cancer treatments, and ultimately improving patient prognosis.

Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.

Activation of vascular smooth muscle cell inflammation is recognised as an important early driver of vascular disease. We have previously identified the let-7 miRNA family as important regulators of inflammation in in vitro and in vivo models of atherosclerosis. Here we investigated a dual statin/let-7d-5p miRNA combination therapy approach to target human aortic SMC (HAoSMC) activation and inflammation.

In vitro studies using primary HAoSMCs were performed to investigate the effects of let-7d-5p miRNA overexpression and inhibition. HAoSMCs were treated with combinations of the inflammatory cytokine tumor necrosis factor-α (TNF-α), and atorvastatin or lovastatin. HAoSMC Bulk RNA-seq transcriptomics of HAoSMCs revealed downstream regulatory networks modulated by let-7d-5p miRNA overexpression and statins. Proteome profiler cytokine array, Western blotting and quantitative PCR analyses were performed on HAoSMCs to validate key findings.

Let-7d-5p overexpression significantly attenuated TNF-α-induced upregulation of IL-6, ICAM1, VCAM1, CCL2, CD68, MYOCD gene expression in HAoSMCs (p<0.05). Statins (atorvastatin, lovastatin) significantly attenuated inflammatory gene expression and upregulated Let-7d levels in HAoSMCs (p<0.05). Bulk RNA-seq analysis of a dual Let-7d-5p overexpression/statin therapy in HAoSMCs revealed that let-7d-5p activation and statins converge on key inflammatory pathways (IL-6, IL-1β, TNF-α, IFN-γ). Let-7d-5p overexpression led to reduced expression of the ox-LDL receptor OLR1, and this was associated with lower ox-LDL uptake in HAoSMCs. In silico analysis of smooth muscle cell phenotypic switching shows that overexpression of let-7d-5p in HAoSMCs maintains a contractile phenotype.

Targeting the Let-7 network alongside statins can modulate HAoSMC activation and attenuate key inflammatory pathway signals.

The RNA-binding proteins LIN28A and LIN28B contribute to a variety of developmental biological processes. Dysregulation of Lin28A and Lin28B expression is associated with numerous types of tumors. This study demonstrates that Lin28A overexpression in the mouse nephrons leads to severe inflammation and kidney damage rather than to tumorigenesis. Notably, Lin28A overexpression causes inflammation only when expressed in nephrons, but not in the stromal cells of the kidneys, highlighting its cell context-dependent nature. The nephron-specific Lin28A-induced inflammatory response differs from previously described Lin28B-mediated inflammatory feedback loops as it is IL-6 independent. Instead, it is associated with the rapid upregulation of cytokines like Cxcl1 and Ccl2. These findings suggest that the pathophysiological effects of Lin28A overexpression extend beyond cell transformation. Our transgenic mouse model offers a valuable tool for advancing our understanding of the pathophysiology of acute kidney injury, where inflammation is a key factor.

Cancer represents a major global health burden, prompting continuous research for effective therapeutic strategies. Natural compounds derived from plants have emerged as potential strategies for preventing cancer and treatment because of their inherent pharmacological properties. This comprehensive review aimed to evaluate the therapeutic potential of five key natural compounds: apigenin, quercetin, piperine, curcumin, and resveratrol in cancer prevention and therapy. By examining their molecular mechanisms and preclinical evidence, this review seeks to elucidate their role as potential adjuvants or stand-alone therapies in cancer management. The exploration of natural compounds as cancer therapeutics offers several advantages, including low toxicity, wide availability, and compatibility with conventional chemotherapeutic agents. We highlighted the current understanding of their anticancer mechanisms and clinical applications for advancing personalized cancer care to improve patient outcomes. We discussed the empirical findings from in vitro, in vivo, and clinical studies reporting biological activity and therapeutic efficacy in antioxidant, immunomodulatory, anti-carcinogenic, and chemo-sensitizing modes. Innovative delivery systems and personalized treatment approaches may further enhance their bioavailability and therapeutic utility in a synergistic approach with chemo- and radiotherapeutic disease management. This review underscores the importance of natural compounds in cancer prevention and treatment, promoting a multidisciplinary approach to the development of innovative therapeutic strategies.

In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, and 59 healthy controls. Before treatment, saliva samples were obtained from all participants, and the content of VEGF and cytokines in saliva was determined by an enzyme-linked immunosorbent assay, as well as the content of amino acids by high-performance liquid chromatography. It was found that VEGF was positively correlated with the level of pro-inflammatory cytokines IL-1β (r = 0.6367), IL-6 (r = 0.3813), IL-8 (r = 0.4370), and IL-18 (r = 0.4184). Weak correlations were shown for MCP-1 (r = 0.2663) and TNF-α (r = 0.2817). For the first time, we demonstrated changes in the concentration of VEGF and related cytokines in saliva in different molecular biological subtypes of breast cancer depending on the stage of the disease, differentiation, proliferation, and metastasis to the lymph nodes. A correlation was established between the expression of VEGF and the content of aspartic acid (r = -0.3050), citrulline (r = -0.2914), and tryptophan (r = 0.3382) in saliva. It has been suggested that aspartic acid and citrulline influence the expression of VEGF via the synthesis of the signaling molecule NO, and then tryptophan ensures tolerance of the immune system to tumor cells.

PdPt nanosheets decorated on SnS2 nanosheets (i.e., PdPt@SnS2 NSs) were fabricated for a novel electrochemiluminescence (ECL) biosensor for ultrasensitive detection of miRNA-21 based on catalytic hairpin assembly (CHA) cycles. The PdPt@SnS2 NSs serve as both the main luminophore and a highly effective coreaction accelerator in the ECL biosensor. In the CHA cycles, more miRNA-21 is captured, and the performance of the ECL biosensor is improved. When miRNA-21 is present, the hairpin chain DNA1 (i.e., H1) is opened, and the ferrocene (Fc)-modified hairpin chain DNA2 (i.e., Fc-H2) hybridizes with as-opened H1 by replacing miRNA-21 to stimulate CHA cycles of miRNA-21. During the CHA cycles, Fc-H2 quenches the ECL signal to monitor miRNA-21. As a result, the ECL biosensor shows ultrasensitive and highly selective detection of miRNA-21 from 1 aM to 1 nM with a detection limit (LOD) of 0.02 aM. In addition, the ECL biosensor exhibits excellent practicality for miRNA-21 detection in human serum samples.

Many types of gynecological cancer (GC) are often silent until they reach an advanced stage, and are therefore often diagnosed too late for effective treatment. Hence, there is a real need for more efficient diagnosis and treatment for patients with GC. During recent years, researchers have increasingly studied the impact of microRNAs cancer development, leading to a number of applications in detection and treatment. MicroRNAs are a particular group of tiny RNA molecules that regulate regular gene expression by affecting the translation process. The downregulation of numerous miRNAs has been observed in human malignancies. Let-7 is an example of a miRNA that controls cellular processes as well as signaling cascades to affect post-transcriptional gene expression. Recent research supports the hypothesis that enhancing let-7 expression in those cancers where it is downregulated may be a potential treatment option. Exosomes are tiny vesicles that move through body fluids and can include components like miRNAs (including let-7) that are important for communication between cells. Studies proved that exosomes are able to enhance tumor growth, angiogenesis, chemoresistance, metastasis, and immune evasion, thus suggesting their importance in GC management.

L-Tryptophan (L-Trp), an essential amino acid, is the only amino acid whose level is regulated specifically by immune signals. Most proportions of Trp are catabolized via the kynurenine (Kyn) pathway (KP) which has evolved to align the food availability and environmental stimulation with the host pathophysiology and behavior. Especially, the KP plays an indispensable role in balancing the immune activation and tolerance in response to pathogens.

In this review, we elucidate the underlying immunological regulatory network of Trp and its KP-dependent catabolites in the pathophysiological conditions by participating in multiple signaling pathways. Furthermore, the KP-based regulatory roles, biomarkers, and therapeutic strategies in pathologically immune disorders are summarized covering from acute to chronic infection and inflammation.

The immunosuppressive effects dominate the functions of KP induced-Trp depletion and KP-produced metabolites during infection and inflammation. However, the extending minor branches from the KP are not confined to the immune tolerance, instead they go forward to various functions according to the specific condition. Nevertheless, persistent efforts should be made before the clinical use of KP-based strategies to monitor and cure infectious and inflammatory diseases.

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

Muscular atrophy is a complex catabolic condition that develops due to several inflammatory-related disorders, resulting in muscle loss. Tumor necrosis factor alpha (TNF-α) is believed to be one of the leading factors that drive inflammatory response and its progression. Until now, the link between inflammation and muscle wasting has been thoroughly investigated, and the non-coding RNA machinery is a potential connection between the candidates. This study aimed to identify specific miRNAs for muscular atrophy induced by TNF-α in the C2C12 murine myotube model. The difference in expression of fourteen known miRNAs and two newly identified miRNAs was recorded by next-generation sequencing between normal muscle cells and treated myotubes. After validation, we confirmed the difference in the expression of one novel murine miRNA (nov-mmu-miRNA-1) under different TNF-α-inducing conditions. Functional bioinformatic analyses of nov-mmu-miRNA-1 revealed the potential association with inflammation and muscle atrophy. Our results suggest that nov-mmu-miRNA-1 may trigger inflammation and muscle wasting by the downregulation of LIN28A/B, an anti-inflammatory factor in the let-7 family. Therefore, TNF-α is involved in muscle atrophy through the modulation of the miRNA cellular machinery. Here, we describe for the first time and propose a mechanism for the newly discovered miRNA, nov-mmu-miRNA-1, which may regulate inflammation and promote muscle atrophy.

Studies have identified genes and molecular pathways regulating cancer metastasis. However, it remains largely unknown whether metastatic potentials of cancer cells from different lineage types are driven by the same or different gene networks. Here, we aim to address this question through integrative analyses of 493 human cancer cells' transcriptomic profiles and their metastatic potentials in vivo. Using an unsupervised approach and considering both gene coexpression and protein-protein interaction networks, we identify different gene networks associated with various biological pathways (i.e. inflammation, cell cycle, and RNA translation), the expression of which are correlated with metastatic potentials across subsets of lineage types. By developing a regularized random forest regression model, we show that the combination of the gene module features expressed in the native cancer cells can predict their metastatic potentials with an overall Pearson correlation coefficient of 0.90. By analyzing transcriptomic profile data from cancer patients, we show that these networks are conserved in vivo and contribute to cancer aggressiveness. The intrinsic expression levels of these networks are correlated with drug sensitivity. Altogether, our study provides novel comparative insights into cancer cells' intrinsic gene networks mediating metastatic potentials across different lineage types, and our results can potentially be useful for designing personalized treatments for metastatic cancers.

CD4+CD25+Foxp3+ regulatory T cells (Tregs), a vital component of the immune system, are responsible for maintaining immune homeostasis and preventing excessive immune responses. This review explores the signaling pathways of the cytokines that regulate Treg cells, including transforming growth factor beta (TGF-β), interleukin (IL)-2, IL-10, and IL-35, which foster the differentiation and enhance the immunosuppressive capabilities of Tregs. It also examines how, conversely, signals mediated by IL-6 and tumor necrosis factor -alpha (TNF-α) can undermine Treg suppressive functions or even drive their reprogramming into effector T cells. The B7 family comprises indispensable co-stimulators for T cell activation. Among its members, this review focuses on the capacity of CTLA-4 and PD-1 to regulate the differentiation, function, and survival of Tregs. As Tregs play an essential role in maintaining immune homeostasis, their dysfunction contributes to the pathogenesis of autoimmune diseases. This review delves into the potential of employing Treg-based immunotherapy for the treatment of autoimmune diseases, transplant rejection, and cancer. By shedding light on these topics, this article aims to enhance our understanding of the regulation of Tregs by cytokines and their therapeutic potential for various pathological conditions.

Although cancer initiation and progression are generally associated with the accumulation of somatic mutations1,2, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility3-6, suggesting that genetic mechanisms might not be the only drivers of malignant transformation7. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK-STAT signalling pathway and zfh1, the fly homologue of the ZEB1 oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.

Probiotics play a crucial role in immunomodulation by regulating dendritic cell (DC) maturation and inducing tolerogenic DCs. Akkermansia muciniphila affects inflammatory response by elevating inhibitory cytokines. We aimed to evaluate whether Akkermansia muciniphila and its outer membrane vesicles (OMVs) affect microRNA-155, microRNA-146a, microRNA-34a, and let-7i expression of inflammatory and anti-inflammatory pathways. Peripheral blood mononuclear cells (PBMCs) were isolated from the healthy volunteers. To produce DCs, monocytes were cultivated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). DCs were allocated into six subgroups: DC + Lipopolysaccharide (LPS), DC + dexamethasone, DC + A. muciniphila (MOI 100, 50), DC + OMVs (50 µg/ml), and DC + PBS. The surface expression of human leukocyte antigen-antigen D related (HLA-DR), CD86, CD80, CD83, CD11c, and CD14 was examined using flow cytometry, and the expression of microRNAs was assessed using qRT-PCR, and the levels of IL-12 and IL-10 were measured using ELISA. A. muciniphila (MOIs 50, 100) could significantly decrease IL-12 levels relative to the LPS group. The IL-10 levels were decreased in the DC + LPS group than the DC + dexamethasone group. Treatment with A. muciniphila (MOI 100) and OMVs could elevate the concentrations of IL-10. DC treatment with LPS led to a significant increment in the expression of microRNA-155, microRNA-34a, and microRNA-146a. The expression of these microRNAs was reversed by A. muciniphilia and its OMVs treatment. Let-7i increased in treatment groups compared to the DC + LPS group. A. muciniphilia (MOI 50) had a substantial effect on the expression of HLA-DR, CD80, and CD83 on DCs. Therefore, DCs treatment with A. muciniphila led to induce tolerogenic DCs and the production of anti-inflammatory IL-10.

Chromatin structure is regulated through posttranslational modifications of histone variants that modulate transcription. Although highly homologous, histone variants display unique amino acid sequences associated with specific functions. Abnormal incorporation of histone variants contributes to cancer initiation, therapy resistance, and metastasis. This study reports that, among its biologic functions, histone H3.1 serves as a chromatin redox sensor that is engaged by mitochondrial H2O2. In breast cancer cells, the oxidation of H3.1Cys96 promotes its eviction and replacement by H3.3 in specific promoters. We also report that this process facilitates the opening of silenced chromatin domains and transcriptional activation of epithelial-to-mesenchymal genes associated with cell plasticity. Scavenging nuclear H2O2 or amino acid substitution of H3.1(C96S) suppresses plasticity, restores sensitivity to chemotherapy, and induces remission of metastatic lesions. Hence, it appears that increased levels of H2O2 produced by mitochondria of breast cancer cells directly promote redox-regulated H3.1-dependent chromatin remodeling involved in chemoresistance and metastasis.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most globally devastating viruses threatening the swine industry worldwide. Substantial advancements have been achieved in recent years towards comprehending the pathogenesis of PRRSV infection and the host response, involving both innate and adaptive immune responses. Not only a multitude of host proteins actively participate in intricate interactions with viral proteins, but microRNAs (miRNAs) also play a pivotal role in the host response to PRRSV infection. If a PRRSV-host interaction at the protein level is conceptualized as the front line of the battle between pathogens and host cells, then their fight at the RNA level resembles the hidden front line. miRNAs are endogenous small non-coding RNAs of approximately 20-25 nucleotides (nt) that primarily regulate the degradation or translation inhibition of target genes by binding to the 3'-untranslated regions (UTRs). Insights into the roles played by viral proteins and miRNAs in the host response can enhance our comprehensive understanding of the pathogenesis of PRRSV infection. The intricate interplay between viral proteins and cellular targets during PRRSV infection has been extensively explored. This review predominantly centers on the contemporary understanding of the host response to PRRSV infection at the RNA level, in particular, focusing on the twenty-six miRNAs that affect viral replication and the innate immune response.

Originally discovered in C. elegans, LIN28 is an evolutionarily conserved zinc finger RNA-binding protein (RBP) that post-transcriptionally regulates genes involved in developmental timing, stem cell programming, and oncogenesis. LIN28 acts via two distinct mechanisms. It blocks the biogenesis of the lethal-7 (let-7) microRNA (miRNA) family, and also directly binds messenger RNA (mRNA) targets, such as IGF-2 mRNA, and alters downstream splicing and translation events. This review focuses on the molecular mechanism of LIN28 repression of let-7 and current strategies to overcome this blockade for the purpose of cancer therapy. We highlight the value of the LIN28/let-7 pathway as a drug target, as multiple oncogenic proteins that the pathway regulates are considered undruggable due to their inaccessible cellular location and lack of cavities for small molecule binding.