Polysaccharides of Cistanche deserticola Ma (CDPS), with high safety and low toxicity have been reported to possess anti-inflammatory, immunomodulatory, antioxidant, anti-aging, anti-osteoporosis, antidepressant, intestinal flora regulatory and hepatoprotective properties. Nevertheless, the effects of CDPS on inflammatory bowel disease (IBD) and its underlying mechanisms have never been reported. To estimate its therapeutic potential on IBD, the extracted CDPS were characterized via utilizing a series of chemical, spectroscopic, and instrumental analyses, and the protective effects and mechanisms of CDPS in colitis mice was investigated. Our results indicated that CDPS were identified as acidic heteropolysaccharides. CDPS alleviated dextran sodium sulfate-induced IBD mice characterized by decreasing disease activity index, improving colon length and body weight, restoring histopathological lesions, inhibiting the expression of pro-inflammatory cytokine (IL-6, IL-1β, TNF-α) and MPO activity, elevating the expression of anti-inflammatory cytokine (IL-10) in colon tissue. The findings manifested CDPS could mitigate the inflammation of colon. Simultaneously, CDPS inhibited the expression of genes and proteins associated with SRC/EGFR/PI3K/AKT signaling pathways, and reduced the diversity and abundance of harmful gut microbiota, including Helicobacter, Bacteroides and Colidextribacter, while descending the relative abundance of Lachnospiraceae_NK4A136_group at genus level. In summary, this work elucidated that CDPS alleviates IBD symptoms via mitigating the inflammation of colon, and modulating intestinal microbiota and SRC/EGFR/PI3K/AKT signaling pathways. It underscores the promise of CDPS as a functional food ingredient or preventive drugs for IBD.

The formation of mature mRNA is inseparable from the processing of RNA precursors and splicing by the spliceosome. The spliceosome is a multi‑protein complex composed of five small nuclear ribonucleoproteins. Elongation factor Tu GTP binding domain containing 2 (EFTUD2) is a component of spliceosome complex that is involved in the reorganization of the spliceosome complex, thereby promoting the removal of introns from precursor mRNA. Therefore, EFTUD2 can regulate embryonic development and innate immunity by modulating the splicing of various mRNAs. The mutations in EFTUD2 itself also lead to developmental defects and clinical manifestations in mandibulofacial dysostosis, the nervous system, the circulatory system, the digestive system and the reproductive system. Furthermore, the overexpression of EFTUD2 promotes the progression of hepatocellular carcinoma, breast cancer and colorectal cancer. The present review discussed the molecular mechanisms by which EFTUD2 exerts its physiological functions, focusing on EFTUD2 mutations and their corresponding clinical manifestations. It aimed to provide insight for the diagnosis and treatment of EFTUD2‑related diseases.

Inflammatory bowel disease (IBD) patients display genetic polymorphisms in toll-like receptor 4 (TLR4) genes, contributing to dysregulate enteric nervous system (ENS) circuits with increased levels of 5-HT and alteration of the neuroimmune crosstalk. In this study, we investigated the impact of TLR4 signalling on mouse ENS dysfunction caused by dextran sulphate sodium (DSS)-induced ileitis.

Male C57BL/6J (wild-type [WT]) and TLR4-/- mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and then were switched to 3-day regular drinking water. Histological analysis and proinflammatory cytokine mRNA levels were assessed in ileal samples. Gut motility was evaluated by changes in transit of a fluorescent-labelled marker and isometric neuromuscular responses of ileal full-thickness segments to receptor and non-receptor-mediated stimuli. Alterations in ENS architecture were assessed by confocal immunohistochemistry in longitudinal muscle-myenteric plexus whole-mount preparations.

In WT mice, DSS treatment caused delayed gastrointestinal transit, ileal myenteric neurodegeneration, reactive gliosis and release of proinflammatory cytokines. Enhanced cholinergic and tachykinergic excitatory tone, increased inducible nitric oxide synthase (iNOS)-mediated relaxation, and changes in 5-HT2A and 5-HT3 receptor-mediated responses were observed during ileitis in WT mice. TLR4 deficiency reversed most of the functional and morphological abnormalities.

Our results demonstrate that TLR4 activity influences the severity of ileitis, neuroglial plasticity, gut motility, and nitrergic and 5-HTergic neurotransmissions. The neuroimmune interaction between TLR4 and 5-HT observed in our study appears to be a potential pharmacological target to treat ENS dysfunction implicated in IBD onset/progression.

Programmed necrosis, a controlled cell death method that bypasses resistance mechanisms that render apoptosis ineffective, is a potential cancer treatment target. Due to their diverse biological activities and low side effects, natural products are being explored as modulators of programmed necrosis pathways. This review highlights the potential of natural compounds to target cancer cells while preserving healthy tissues and their interaction with essential programmed necrosis mechanisms like ferroptosis and necroptosis. Recent developments have identified various types of programmable necrosis, including necroptosis, ferroptosis, pyroptosis, proptosis, mitochondrial permeability transition-driven necrosis, and oncosis. Natural compounds are increasingly being utilized as a primary source of anti-cancer medications, providing new cancer treatments. This review demonstrates the molecular mechanisms behind lipid peroxidation, mixed lineage kinase domain-like protein, and receptor-interacting protein kinases (RIPK1 and RIPK3) inducing cell death. Recent research has identified natural compounds like polyphenols, alkaloids, and terpenoids that can modulate pathways and benefit preclinical cancer models. The review underscores the potential of natural compounds in developing innovative cancer treatments by integrating pharmacology and cellular signaling knowledge. Integrating natural compound studies and programmed necrosis research presents a promising avenue for oncologists to overcome treatment resistance. Natural compounds have shown potential in developing programmed necrosis as a novel cancer treatment approach, enhancing therapeutic effectiveness and minimizing side effects through preclinical research, pharmacology, and molecular biology.

Background: Sparstolonin B (SsnB), a natural compound with anti-inflammatory and anti-proliferative properties, was investigated for its effects on cell viability, apoptosis, and inflammatory pathways in human colorectal cancer cells (HCT-116) and healthy human fibroblasts (BJ). Phorbol 12-myristate 13-acetate (PMA), a tumor promoter and inflammatory activator, was used to stimulate proliferation and inflammatory pathways. Methods: HCT-116 and BJ cells were treated with SsnB (3.125-50 μM) or PMA (1-10 nM) for 12-18 h. Cell viability was assessed using MTT analysis, while apoptosis was evaluated through cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and flow cytometry. Proliferation was analyzed through proliferating cell nuclear antigen (PCNA) staining. Toll-like receptor (TLR) signaling, cytokine expression, and sphingolipid levels were measured using immunofluorescence, enzyme-linked immunosorbent assay (ELISA), and mass spectrometry, respectively. Results: SsnB reduced HCT-116 cell viability in a dose- and time-dependent manner with minimal effects on BJ cells. SsnB (25 μM, 12 h) decreased HCT-116 viability 0.6-fold, while PMA (10 nM, 12 h) increased it 2-fold (p < 0.01). No significant change was observed in BJ cells. PCNA fluorescence staining increased 2-fold with PMA and decreased 0.4-fold with SsnB (p < 0.001). PMA upregulated TLR2 and TLR4 mRNA and protein levels, with MyD88, p-ERK, and pNF-κB fluorescence increasing 2.1-, 1.5-, and 1.7-fold, respectively (p < 0.001). PMA elevated TNF-α, IL-1β, and IL-6 levels (p < 0.01). SsnB suppressed PMA-induced effects and promoted apoptosis, increasing cleaved caspase-3 levels by 1.5-fold and TUNEL staining by 1.9-fold (p < 0.01). Flow cytometry confirmed a significant increase in early and late apoptotic cells in the SsnB group. SsnB also increased ceramide (C18, C20, C22, and C24) levels (1.3- to 2.5-fold, p < 0.01) while reducing PMA-induced S1P and C1P increases (p < 0.01). Conclusions: SsnB selectively inhibits proliferation, induces apoptosis, and modulates inflammatory and sphingolipid pathways in colorectal cancer cells, with minimal toxicity to healthy fibroblasts, supporting its potential as a targeted therapeutic agent.

Background: Gegen Qinlian Decoction (GQD), is used for intestinal disorders like ulcerative colitis, irritable bowel syndrome, and colorectal cancer. But the precise mechanisms underlying its anti-inflammatory and anti-tumor effects are not fully elucidated. Methods: Use network pharmacology to identify targets and pathways of GQD. In vivo (azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated colorectal cancer (CAC) mouse model) and in vitro (lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages) experiments were conducted to explore GQD's anti-inflammatory and anti-tumor effects. We monitored mouse body weight and disease activity index (DAI), and evaluated colon cancer tissues using hematoxylin and eosin staining. Expression of Ki67 and F4/80 was determined by immunohistochemistry analysis. The protein levels of TLR4 signaling pathway were assessed by western blotting analysis. Enzyme-linked immunosorbent assay measured IL-1β, IL-6, and TNF-α levels. Immunofluorescence (IF) staining visualized NF-κB and IRF3 translocation. Results: There were 18, 9, 24 and 77 active ingredients in the four herbs of GQD, respectively, targeting 435, 156, 485 and 691 genes. Through data platform analysis, it was concluded that there were 1104 target genes of GQD and 2022 target genes of CAC. Moreover, there were 99 intersecting genes between GQD and CAC. The core targets of GQD contained NFKB1, IL1B, IL6, TLR4, and TNF, and GQD reduced inflammation by inhibiting the TLR4 signaling pathway. In vivo experiment, GQD increased mouse body weight, lowered DAI scores, while also alleviating histopathological changes in the colon and decreasing the expressions of Ki67 and F4/80 in the AOM/DSS-induced mice. GQD reduced IL-1β, IL-6, and TNF-α levels in the serum and downregulated TLR4, MyD88, and phosphorylation of IκBα, P65, and IRF3 in the colon tissue from AOM/DSS-induced mice. In vitro, GQD suppressed pro-inflammatory cytokines and TLR4 signaling pathway in the LPS-induced RAW264.7 cells, and combined with TAK242, it further reduced the phosphorylation of IκBα, P65. Conclusions: GQD mitigated CAC by inhibiting the TLR4 signaling pathway, offering a potential therapeutic approach for CAC management.

An increasingly important role for gut microbiota in the initiation and progression of colorectal cancer (CRC) has been described. Even in the early stages of transformation, i.e., colorectal adenomas, changes in gut microbiota composition have been observed, and several bacterial species, such as pks+Escherichia coli and enterotoxigenic Bacteroides fragilis, have been proposed to drive colon tumorigenesis. In recent years, several strategies have been developed to study mucosa-associated microbiota (MAM), which is more closely associated with CRC development than lumen-associated microbiota (LAM) derived from fecal samples. This review summarizes the state of the art about the oncogenic actions of gut bacteria and compares the different sampling strategies to collect intestinal microbiota (feces, biopsies, swabs, brushes, and washing aspirates). In particular, this article recapitulates the current knowledge on MAM in colorectal adenomas and serrated polyps, since studying the intestinal microbiota associated with early-stage tumors can elucidate the molecular mechanisms underpinning CRC carcinogenesis.

Ulcerative colitis (UC) is a chronic intestinal disease characterized by spleen-lung qi deficiency and dampness-pathogenic obstruction. Although there are various treatment options available, patients frequently encounter significant drug-related side effects. Previous studies have shown the potential of Codonopsis Radix polysaccharides A (CPA) in treating UC, but their limited bioavailability has restricted their clinical use. Therefore, the objective of this study was to develop a novel formulation that can address the aforementioned limitations and assess its potential advantages.

We synthesized a negatively charged amphipathic prodrug called CPA-SA-DHA (CSD), which consists of CPA as the hydrophilic component, and succinic anhydride and docosahexaenoic acid as the hydrophobic segments. The CSD nanoparticles obtained had a particle size of 180.0 ± 3.2 nm, a negative zeta potential of -29.8 ± 5.3 mV, and a uniform shape with a PDI index of 0.230 ± 0.003. The interaction between positive and negative charges significantly increased the retention time of CSD nanoparticles in the colonic microenvironment. Furthermore, CSD nanoparticles demonstrated enhanced bioavailability in UC mice compared to CPA. Additionally, we observed that CSD nanoparticles exhibited therapeutic effects on DSS-induced UC mice by regulating the diversity and abundance of gut microbiota. This effect may be mediated by the inhibition of pro-inflammatory signaling pathways TLR4/NF-κB.

These findings confirm the potential of CSD nanoparticles as a promising treatment option for UC.

Appropriate host-microbiota interactions are essential for maintaining intestinal homeostasis; hence, an imbalance in these interactions leads to inflammation-associated intestinal diseases. Toll-like receptors (TLRs) recognize microbial ligands and play a key role in host-microbe interactions in health and disease. TLR13 has a well-established function in enhancing host defenses against pathogenic bacteria. However, its role in maintaining intestinal homeostasis and controlling colitis-associated colon cancer (CAC) is largely unknown. This study aimed to investigate the involvement of TLR13-mediated signaling in intestinal homeostasis and colonic tumorigenesis using ex vivo cell and in vivo CAC animal model. Tlr13-deficient mice were prone to dextran sodium sulfate (DSS)-induced colitis. During the early stages of the CAC regimen (AOM/DSS-treated), Tlr13 deficiency led to severe ulcerative colitis. Moreover, Tlr13-deficient mice exhibited increased intestinal permeability, as evidenced by elevated levels of fluorescein isothiocyanate (FITC)-dextran, endotoxins, and bacterial translocation. Enhanced cell survival and proliferation of colonic intestinal cells were observed in Tlr13-deficient mice. A transcriptome analysis revealed that Tlr13 deficiency is associated with substantial changes in gene expression profile of colonic tumor tissue. Tlr13-deficient mice were more susceptible to CAC, with increased production of interleukin (IL)-6, IL-12, and TNF-α cytokines and enhanced STAT3, NF-κB, and MAPK signaling in colon tissues. These findings suggest that TLR13 plays a protective role in maintaining intestinal homeostasis and controlling CAC. Our study provides a novel perspective on intestinal health via TLR13-mediated signaling, which is crucial for deciphering the role of host-microbiota interactions in health and disease.

Chronic intestinal inflammation and neo-angiogenesis are interconnected in colorectal carcinoma (CRC) pathogenesis. Molecules reducing inflammation and angiogenesis hold promise for CRC prevention and treatment. N-Palmitoyl-d-glucosamine (PGA), a natural glycolipid analog with anti-inflammatory properties, has shown efficacy against acute colitis. Micronized PGA (mPGA) formulations exhibit superior anti-inflammatory activity. This study investigates the in vivo anti-angiogenic and protective effects of mPGA in a mouse model of colitis-associated CRC induced by azoxymethane/dextran sodium sulfate (AOM/DSS). CRC was induced in C57BL/6J mice using intraperitoneal azoxymethane followed by three cycles of 2.5% dextran sodium sulfate (DSS) in drinking water. Mice were treated with mPGA (30-150 mg/kg) with or without the PPARα inhibitor MK886 (10 mg/kg). At Day 70 post-azoxymethane injection, mice underwent anesthetized endoscopic colon evaluation. Post-mortem analysis of tumorigenesis and angiogenesis was performed using histological, immunohistochemical, and immunoblotting techniques. mPGA improved disease progression and survival rates in a dose- and PPARα-dependent manner in AOM/DSS-exposed mice. It reduced polyp formation, decreased pro-angiogenic CD31, pro-proliferative Ki67, and pro-inflammatory TLR4 expression levels, and inhibited VEGF and MMP-9 secretion by disrupting the pAkt/mTOR/HIF1α pathway. mPGA increased colon PEA levels, restoring anti-tumoral PPARα and wtp53 protein expression. Given its lack of toxicity, mPGA shows potential as a nutritional intervention to counteract inflammation-related angiogenesis in CRC.

Colorectal cancer (CRC) is highly prevalent, accounting for approximately one-tenth of cancer cases and deaths globally. It stands as the second most deadly and third most common cancer type. Although the gut microbiota has been implicated in CRC carcinogenesis for the last several decades, it remains one of the least understood risk factors for CRC development, as the gut microbiota is highly diverse and variable. Many studies have uncovered unique microbial signatures in CRC patients compared with healthy matched controls, with variations dependent on patient age, disease stage, and location. In addition, mechanistic studies revealed that tumor-associated bacteria produce diverse metabolites, proteins, and macromolecules during tumor development and progression in the colon, which impact both cancer cells and immune cells. Here, we summarize microbiota's role in tumor development and progression, then we discuss how the metabolic alterations in CRC tumor cells, immune cells, and the tumor microenvironment result in the reprogramming of activation, differentiation, functions, and phenotypes of immune cells within the tumor. Tumor-associated microbiota also undergoes metabolic adaptation to survive within the tumor environment, leading to immune evasion, accumulation of mutations, and impairment of immune cells. Finally, we conclude with a discussion on the interplay between gut microbiota, immunometabolism, and CRC, highlighting a complex interaction that influences cancer development, progression, and cancer therapy efficacy.

Epithelial homeostasis is fundamental for the physiological functions of colon tissue. Dysregulation of colon epithelial structure leads to abnormal immune responses and diseases such as inflammatory bowel disease. In this work we found long non-coding RNA DANCR was a novel regulator to colon epithelial homeostasis. Silencing DANCR resulted in decreased expression of epithelial barrier proteins and enhanced susceptibility to TNFα stimulation, which was accompanied by hyperactivation of the NF-κB pathway. Mechanistical studies revealed DANCR modulated the expression of a protein methyltransferase SET7 to suppress responses to TNFα, as well as the activity of NF-κB pathway. In summary, DANCR regulated colon epithelial homeostasis through modulating the TNFα/NF-κB axis. These findings cast light on the discovery of novel regulators to colon epithelial homeostasis and added new evidence to the physiological functions of DANCR.

Emerging evidence reveal that tumor-associated bacteria (TAB) can facilitate the initiation and progression of multiple types of cancer. Recent work has emphasized the significant role of intestinal microbiota, particularly bacteria, plays in affecting responses to chemo- and immuno-therapies. Hence, it seems feasible to improve cancer treatment outcomes by targeting intestinal bacteria. While considering variable richness of the intestinal microbiota and diverse components among individuals, direct manipulating the gut microbiota is complicated in clinic. Tumor initiation and progression requires the gut microbiota-derived metabolites to contact and reprogram neoplastic cells. Hence, directly targeting tumor-associated bacteria metabolites may have the potential to provide alternative and innovative strategies to bypass the gut microbiota for cancer therapy. As such, there are great opportunities to explore holistic approaches that incorporates TAB-derived metabolites and related metabolic signals modulation for cancer therapy. In this review, we will focus on key opportunistic areas by targeting TAB-derived metabolites and related metabolic signals, but not bacteria itself, for cancer treatment, and elucidate future challenges that need to be addressed in this emerging field.

Toll-like receptor 4 (TLR4) is pivotal as an innate immune receptor, playing a critical role in mediating neuropathic pain and drug addiction through its regulation of the neuroinflammatory response. The nonclassical (+)-opioid isomers represent a unique subset of TLR4 antagonists known for their effective blood-brain barrier permeability. Despite growing interest in the structure-activity relationship of these (+)-opioid-based TLR4 antagonists, the specific impact of heteroatoms on their TLR4 antagonistic activities has not been fully explored. This study investigated the influence of the hydroxyl group at C14 in six (+)-opioid TLR4 antagonists (1-6) using wet-lab experiments and in silico simulations. The corresponding C14-deoxy derivatives (7-12) were synthesized, and upon comparison with their corresponding counterparts (1-6), it was discovered that their TLR4 antagonistic activities were significantly diminished. Molecular dynamics simulations showed that the (+)-opioid TLR4 antagonists (1-6) possessed more negative binding free energies to the TLR4 coreceptor MD2, which was responsible for ligand recognition. This was primarily attributed to the formation of a hydrogen bond between the hydroxyl group at the C-14 position of the antagonists (1-6) and the R90 residue of MD2 during the binding process. Such an interaction facilitated the entry and subsequent binding of these molecules within the MD2 cavity. In contrast, the C14-deoxy derivatives (7-12), lacking the hydroxyl group at the C-14 position, missed this crucial hydrogen bond interaction with the R90 residue of MD2, leading to their egression from the MD2 cavity during simulations. This study underscores the significant role of the C14 hydroxyl moiety in enhancing the effectiveness of (+)-opioid TLR4 antagonists, which provides insightful guidance for designing future (+)-isomer opioid-derived TLR4 antagonists.

Colorectal cancer (CRC) ranks third in both the incidence and mortality rates among male and female cancers, and it is the leading digestive system cancer. Due to the inter- and intratumor heterogeneity of cancer, the TNM system is insufficient for predicting prognosis, necessitating the use of molecular biomarkers for prognostic prediction. Toll-like receptors (TLRs) have been associated with CRC survival rates. This study focused on the investigation of the role and potential value of TLRs in CRC genotyping to aid in immunotherapy for CRC patients.

Differential gene expression analysis was performed on CRC transcriptomic data from The Cancer Genome Atlas database. TLRs were referred from the literature, and their intersection with differentially expressed genes (DEGs) in CRC yielded TLR-DEGs. The expression patterns of TLR-DEGs were predicted using the STRING website, and copy number variations of TLR-DEGs were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted on TLR-DEGs. ConsensusClusterPlus R package was used for clustering CRC patients, and ESTIMATE and GSEAbase were employed to analyze immune characteristics of different subtypes. Immune phenotyping scores and tumor immune dysfunction and exclusion scores were evaluated. DEGs of different subtypes were analyzed, followed by GO and KEGG enrichment analyses, the protein-protein interaction (PPI) network analysis, and further selection of hub genes. The sensitivity of drugs was assessed using the identified hub genes.

We identified 37 TLR-DEGs, and the PPI analysis revealed their coexpression, although they were distributed on different chromosomes. Enrichment analyses indicated that the 37 TLR-DEGs were linked to cancer cell immune response. Based on these TLR-DEGs, CRC patients were classified into three subtypes. Cluster2 exhibited lower survival rates and higher immune infiltration levels and predicted poorer response to immune checkpoint inhibitor therapy. The intersection of DEGs from cluster2 and cluster1 with DEGs from cluster2 and cluster3 yielded a set of 426 commonly shared DEGs. Enrichment analyses revealed that these shared DEGs might regulate immune cell viability. Eight common hub genes for different subtypes were further identified to predict drug-related correlations.

The developed TLR genotyping was used to predict the survival status and tumor microenvironment of CRC, providing a foundation for understanding the molecular mechanisms of TLR signaling and deepening its clinical significance.

The toll-like receptor 4 (TLR4) signaling pathway constitutes an intricate network of protein interactions primarily involved in inflammation and cancer. This pathway triggers intracellular signaling cascades, modulating transcription factors that regulate gene expression related to immunity and malignancy. Previous studies showed that colon cancer patients with low TLR4 expression exhibit extended survival times and the TLR4 signaling pathway holds a significant role in CRC pathogenesis. In recent years, traditional Chinese medicines (TCMs) have garnered substantial attention as an alternative therapeutic modality for CRC, primarily due to their multifaceted composition and ability to target multiple pathways. Emerging evidence indicates that specific TCM products, such as andrographolide, rosmarinic acid, baicalin, etc., have the potential to impede CRC development through the TLR4 signaling pathway. Here, we review the role and biochemical processes of the TLR4 signaling pathway in CRC, and natural products from TCMs affecting the TLR4 pathway. This review sheds light on potential treatment strategies utilizing natural TLR4 inhibitors for CRC, which contributes to the advancement of research and accelerates their clinical integration into CRC treatment.

The link between inflammation and cancer is well documented and colonic inflammation caused by inflammatory bowel disease (IBD) is thought to be a high-risk factor for the development of colorectal cancer (CRC). The complex crosstalk between epithelial and inflammatory cells is thought to underlie the progression from inflammation to cancer. The present review collates and summarises recent advances in the understanding of the pathogenesis of IBD-associated CRC (IBD-CRC), including the oncogenic mechanisms of the main inflammatory signalling pathways and genetic alterations induced by oxidative stress during colonic inflammation, and discusses the crosstalk between the tumour microenvironment, intestinal flora and host immune factors during inflammatory oncogenesis in colitis-associated CRC. In addition, the therapeutic implications of anti-inflammatory therapy for IBD-CRC were discussed, intending to provide new insight into improve clinical practice.

Structural and functional changes of the intestinal barrier, as a consequence of a number of (epi)genetic and environmental causes, have a main role in penetrations of pathogens and toxic agents, and lead to the development of inflammation-related pathological conditions, not only at the level of the GI tract but also in other extra-digestive tissues and organs. Anthocyanins (ACNs), a subclass of polyphenols belonging to the flavonoid group, are well known for their health-promoting properties and are widely distributed in the human diet. There is large evidence about the correlation between the human intake of ACN-rich products and a reduction of intestinal inflammation and dysfunction. Our review describes the more recent advances in the knowledge of cellular and molecular mechanisms through which ACNs can modulate the main mechanisms involved in intestinal dysfunction and inflammation, in particular the inhibition of the NF-κB, JNK, MAPK, STAT3, and TLR4 proinflammatory pathways, the upregulation of the Nrf2 transcription factor and the expression of tight junction proteins and mucins.

Due to the health emergency created by SARS-CoV-2, the virus that causes the COVID-19 disease, the rapid implementation of a new vaccine technology was necessary. mRNA vaccines, being one of the cutting-edge new technologies, attracted significant interest and offered a lot of hope. The potential of these vaccines in preventing admission to hospitals and serious illness in people with comorbidities has recently been called into question due to the vaccines' rapidly waning immunity. Mounting evidence indicates that these vaccines, like many others, do not generate sterilizing immunity, leaving people vulnerable to recurrent infections. Additionally, it has been discovered that the mRNA vaccines inhibit essential immunological pathways, thus impairing early interferon signaling. Within the framework of COVID-19 vaccination, this inhibition ensures an appropriate spike protein synthesis and a reduced immune activation. Evidence is provided that adding 100 % of N1-methyl-pseudouridine (m1Ψ) to the mRNA vaccine in a melanoma model stimulated cancer growth and metastasis, while non-modified mRNA vaccines induced opposite results, thus suggesting that COVID-19 mRNA vaccines could aid cancer development. Based on this compelling evidence, we suggest that future clinical trials for cancers or infectious diseases should not use mRNA vaccines with a 100 % m1Ψ modification, but rather ones with the lower percentage of m1Ψ modification to avoid immune suppression.

Abnormalities in dopamine function might be related to psychiatric disorders such as schizophrenia. Even at the same concentration, dopamine exerts opposite effects on information processing in the prefrontal cortex depending on independent dopamine release modes known as tonic and phasic releases. This duality of dopamine prevents a blanket interpretation of the implications of dopamine abnormalities for diseases on the basis of absolute dopamine levels. Moreover, the mechanisms underlying the mode-specific dopamine abnormalities are not clearly understood. Here, I show that the two modes of dopamine release in the prefrontal cortex of a schizophrenia-like model are disrupted by different mechanisms. In the schizophrenia-like model established by perinatal exposure to inflammatory cytokine, epidermal growth factor, tonic release was enhanced and phasic release was decreased in the prefrontal cortex. I examined the activity of dopamine neurons in the ventral tegmental area (VTA), which sends dopamine projections to the prefrontal cortex, under anaesthesia. The activation of VTA dopamine neurons during excitatory stimulation (local application of glutamate or N-methyl-d-aspartic acid [NMDA]), which is associated with phasic activity, was blunt in this model. Dopaminergic neuronal activity in the resting state related to tonic release was increased by disinhibition of the dopamine neurons due to the impairment of 5HT2 (5HT2A) receptor-regulated GABAergic inputs. Moreover, chronic administration of risperidone ameliorated this disinhibition of dopaminergic neurons. These results provide an idea about the mechanism of dopamine disturbance in schizophrenia and may be informative in explaining the effects of atypical antipsychotics as distinct from those of typical drugs.

The study aimed to evaluate the impact of tobacco use on the composition and functions of the oral microbiome in healthy adult humans.

We conducted a systematic search on PubMed, Web of Science, and Cinhal databases for literature published until 15 December 2023, to identify studies that have evaluated the oral microbiome with culture-independent next-generation techniques comparing the oral microbiome of tobacco users and non-users. The search followed the PECO format. The outcomes included changes in microbial diversity and abundance of microbial taxa. The quality assessment was performed using the Newcastle-Ottawa Scale (NOS) (PROSPERO ID CRD42022340151).

Out of 2,435 articles screened, 36 articles satisfied the eligibility criteria and were selected for full-text review. Despite differences in design, quality, and population characteristics, most studies reported an increase in bacterial diversity and richness in tobacco users. The most notable bacterial taxa enriched in users were Fusobacteria and Actinobacteria at the phylum level and Streptococcus, Prevotella, and Veillonella at the genus level. At the functional level, more similarities could be noted; amino acid metabolism and xenobiotic biodegradation pathways were increased in tobacco users compared to non-users. Most of the studies were of good quality on the NOS scale.

Tobacco smoking influences oral microbial community harmony, and it shows a definitive shift towards a proinflammatory milieu. Heterogeneities were detected due to sampling and other methodological differences, emphasizing the need for greater quality research using standardized methods and reporting.

CRD42022340151.

Cell surface markers are most widely used in the study of cancer stem cells (CSCs). However, cell surface markers that are safely and stably expressed in CSCs have yet to be identified. Colonic CSCs express leukocyte CD14. CD14 binding to the ligand lipopolysaccharide (LPS) is involved in the inflammatory response via the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88) signaling pathway. TLR4 and MyD88 have been reported to promote the proliferation, metastasis and tumorigenicity of colon cancer cells, which is consistent with the characteristics of CSCs. In the present study, the proposed experimental method to detect cell proliferation, metastasis and tumorigenesis was used to confirm that, under LPS stimulation, CD14 promoted the proliferation, migration and tumorigenesis of colonic CSCs via the TLR4/MyD88 signaling pathway. Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine assays were used to assess the proliferation and migration of the cells. Colony formation and nude mouse xenograft assays were used to assess the capacity of cells to form tumors. Using western blotting and reverse transcription-quantitative PCR, the mRNA and protein levels of CD14, TLR4 and MyD88 were examined. It was confirmed that CD14 promoted the proliferation, metastasis and tumorigenesis of colon CSCs in response to LPS stimulation via the TLR4/MyD88 signaling pathway, and CD14+ colon cancer cells were successfully isolated and sorted. According to the results of proliferation assay, it was determined that CD14 regulated the LPS-induced proliferation of colon CSCs. CD14, TLR4 and MyD88 protein and mRNA expression was upregulated in colon CSCs in response to LPS stimulation. This indicates a potential novel target for colon CSC-related studies.

The prognosis of patients with kidney renal clear cell carcinoma (KIRC), a life-threatening condition, is poor. Immunogenic cell death (ICD) induces regulated cell death via immunogenic signal secretion and exposure. ICD induces regulated cell death through immunogenic signal secretion and exposure. ICD plays an essential role in tumorigenesis, however, the role of ICD in KIRC remains unclear.

This study examined the expression levels of 34 ICD-related genes in The Cancer Genome Atlas (TCGA) data set. Signature genes linked to KIRC survival were identified using Cox regression. Next, a prognostic risk model (RM) was built. Subsequently, the KIRC patients were divided into low- and high-risk groups. Kaplan-Meier curves and receiver operating characteristic (ROC) curves were plotted. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were carried out to investigate the possible role of differential gene expression between the two groups. The immune microenvironment (IME) was assessed using Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression, CIBERSORT, and single-sample gene-set enrichment analysis algorithms. An enrichment analysis was used to determine the biological significance of these regulatory networks we conducted. The relationship between immune checkpoint gene expression and risk score, and the relationship between treatment outcome and gene expression were assessed using correlation analyses.

We developed a KIRC RM based on five ICD-related genes (i.e., FOXP3, IFNB1, IL6, LY96, and TLR4), which were identified as the prognostic signature genes. Using the TCGA data set, we conducted a survival analysis and found that the 3-year RM had an area under the curve (AUC) of 0.735, which validated the reliability of the signature. Similarly, using the International Cancer Genome Consortium (ICGC) data set, we found that the 3-year RM had an AUC of 0.732.

A RM based on five ICD-related genes was built to predict the prognosis of KIRC patients. This RM predicted patient prognosis and reflected the tumor IME of KIRC patients. Thus, this RM could be used to promote individualized treatments and provide potential novel targets for immunotherapy.

Amorphous silica nanoparticles (ASNP) are among the nanomaterials that are produced in large quantities. ASNP have been present for a long time in several fast-moving consumer products, several of which imply exposure of the gastrointestinal tract, such as toothpastes, food additives, drug excipients, and carriers. Consolidated use and experimental evidence have consistently pointed to the very low acute toxicity and limited absorption of ASNP. However, slow absorption implies prolonged exposure of the intestinal epithelium to ASNP, with documented effects on intestinal permeability and immune gut homeostasis. These effects could explain the hepatic toxicity observed after oral administration of ASNP in animals. More recently, the role of microbiota in these and other ASNP effects has attracted increasing interest in parallel with the recognition of the role of microbiota in a variety of conditions. Although evidence for nanomaterial effects on microbiota is particularly abundant for materials endowed with bactericidal activities, a growing body of recent experimental data indicates that ASNPs also modify microbiota. The implications of these effects are recounted in this contribution, along with a discussion of the more important open issues and recommendations for future research.

Patients suffering from inflammatory bowel disease (IBD) face a two to three-fold higher risk of developing colorectal cancer (CRC) compared to the general population. In recent years, significant progress has been made in comprehending the natural history of IBD-associated CRC (IBD-CRC) and refining its treatment strategies. The decreased incidence of IBD-CRC can be attributed to improved therapeutic management of inflammation, advancements in endoscopy, and early detection of precancerous lesions via surveillance programs. Advanced imaging technologies have made previously undetectable dysplasia visible in most cases, allowing for a much more precise and detailed examination of the mucosa. Additionally, new tools have facilitated the endoscopic resection (ER) of visible lesions in IBD. Particularly, the key to effectively manage colitis-associated colorectal neoplasia (CAN) is to first identify it and subsequently guarantee a complete ER in order to avoid surgery and opt for continuing surveillance. Advanced ER techniques for CAN include endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and hybrid ESD-EMR (h-ESD). This narrative review aims to consolidate the current literature on IBD-CRC, providing an overview of advanced techniques for ER of CAN in IBD, with a particular emphasis on the impact of ESD on the long-term outcomes of IBD patients.

Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.

Cancer is an outcome of various disrupted or dysregulated metabolic processes like apoptosis, growth, and self-cell transformation. Human anatomy harbors trillions of microbes, and these microbes actively influence all kinds of human metabolic activities, including the human immune response. The immune system which inherently acts as a sentinel against microbes, curiously tolerates and even maintains a distinct normal microflora in our body. This emphasizes the evolutionarily significant role of microbiota in shaping our adaptive immune system and even potentiating its function in chronic ailments like cancers. Microbes interact with the host immune cells and play a part in cancer progression or regression by modulating immune cells, producing immunosuppressants, virulence factors, and genotoxins.

An expanding plethora of studies suggest and support the evidence of microbiome impacting cancer etiology. Several studies also indicate that the microbiome can supplement various cancer therapies, increasing their efficacy. The present review discusses the relationship between bacterial and viral microbiota with cancer, discussing different carcinogenic mechanisms influenced by prokaryotes with special emphasis on their immunomodulatory axis. It also elucidates the potential of the microbiome in transforming the efficacy of immunotherapeutic treatments.

This review offers a thorough overview of the complex interaction between the human immune system and the microbiome and its impact on the development of cancer. The microbiome affects the immune responses as well as progression of tumor transformation, hence microbiome-based therapies can vastly improve the effectiveness of cancer immunotherapies. Individual variations of the microbiome and its dynamic variability in every individual impacts the immune modulation and cancer progression. Therefore, further research is required to understand these underlying processes in detail, so as to design better microbiome-immune system axis in the treatment of cancer.

The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin-protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING-type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3-deficient mice in an azoxymethane/dextran sulphate sodium-induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll-like receptor 4 (TLR4)-mediated inflammation through ubiquitination-dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation-mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.

The importance of microbiota in developing and treating diseases, including lung cancer (LC), is becoming increasingly recognized. Studies have shown differences in microorganism populations in the upper and lower respiratory tracts of patients with lung cancer compared to healthy individuals, indicating a link between dysbiosis and lung cancer. However, it is not only important to identify "which bacteria are present" but also to understand "how" they affect lung carcinogenesis. The interactions between the host and lung microbiota are complex, and our knowledge of this relationship is limited. This review presents research findings on the bacterial lung microbiota and discusses the mechanisms by which lung-dwelling microorganisms may directly or indirectly contribute to the development of lung cancer. These mechanisms include influences on the host immune system regulation and the local immune microenvironment, the regulation of oncogenic signaling pathways in epithelial cells (causing cell cycle disorders, mutagenesis, and DNA damage), and lastly, the MAMPs-mediated path involving the effects of bacteriocins, TLRs signaling induction, and TNF release. A better understanding of lung microbiota's role in lung tumor pathology could lead to identifying new diagnostic and therapeutic biomarkers and developing personalized therapeutic management for lung cancer patients.

Progressive up-regulation of β-catenin signaling is very common in the transformation of colorectal epithelium to colorectal cancer (CRC). Practical measures for opposing such signaling hence have potential for preventing or slowing such transformation. cAMP/PKA activity in colon epithelium, as stimulated by COX-2-generated prostaglandins and β2-adrenergic signaling, boosts β-catenin activity, whereas cGMP/PKG signaling has the opposite effect. Bacterial generation of short-chain fatty acids (as supported by unrefined high-carbohydrate diets, berberine, and probiotics), dietary calcium, daily aspirin, antioxidants opposing cox-2 induction, and nicotine avoidance, can suppress cAMP production in colonic epithelium, whereas cGMP can be boosted via linaclotides, PDE5 inhibitors such as sildenafil or icariin, and likely high-dose biotin. Selective activation of estrogen receptor-β by soy isoflavones, support of adequate vitamin D receptor activity with UV exposure or supplemental vitamin D, and inhibition of CK2 activity with flavanols such as quercetin, can also oppose β-catenin signaling in colorectal epithelium. Secondary bile acids, the colonic production of which can be diminished by low-fat diets and berberine, can up-regulate β-catenin activity by down-regulating farnesoid X receptor expression. Stimulation of PI3K/Akt via insulin, IGF-I, TLR4, and EGFR receptors boosts β-catenin levels via inhibition of glycogen synthase-3β; plant-based diets can down-regulate insulin and IGF-I levels, exercise training and leanness can keep insulin low, anthocyanins and their key metabolite ferulic acid have potential for opposing TLR4 signaling, and silibinin is a direct antagonist for EGFR. Partially hydrolyzed phytate can oppose growth factor-mediated down-regulation of β-catenin by inhibiting Akt activation. Multifactorial strategies for safely opposing β-catenin signaling can be complemented with measures that diminish colonic mutagenesis and DNA hypomethylation - such as avoidance of heme-rich meat and charred or processed meats, consumption of phase II-inductive foods and nutraceuticals (e.g., Crucifera), and assurance of adequate folate status.

Bacteroides fragilis, one of the potential next-generation probiotics, but its protective mechanism is not yet known. We aimed to characterize the anti-inflammatory effect of B. fragilisATCC25285 and to elucidate its mechanism through in vivo and in vitro experiments. An in vitro model of inflammation by induction of colonic cells with TNF-a, and co-cultured with B. fragilis to detect cell viability, apoptosis and invasive capacity. Furthermore, critical proteins of the TLR/NF-κB pathway and the inflammatory cytokines were measured. For animal trials, C57BL/6 J male mice were orally administered B. fragilis or PBS once daily for 21 days. Colitis was induced by drinking 2.5% DSS from days 0 to 7. The mice were weighed daily and rectal bleeding, stool condition and blood in the stool were recorded. We found that B. fragilis treatment alone was harmless and had no effect on cell viability or apoptosis. While predictably TNF-α decreased cell viability and increased apoptosis, B. fragilis attenuated this deterioration. The NF-κB pathway and inflammatory cytokines IL-6 and IL-1β activated by TNF-α were also blocked by B. fragilis. Notably, the metabolic supernatant of B. fragilis also has an anti-inflammatory effect. Animal studies showed that live B. fragilis rather than dead strain ameliorated DSS-induced colitis, as evidenced by weight loss, shortened colon length and enhanced barrier function. The colonic tissue levels of inflammatory cytokines (TNF-α, IL-1β, IL-6) were decreased and IL-10 was increased as a result of B. fragilis administration. In conclusion, B. fragilis ATCC25285 exhibited anti-inflammatory effects whether in vivo or in vitro, and it may be a potential probiotic agent for improving colitis.

The endoplasmic reticulum (ER) is a multifunctional organelle playing a vital role in maintaining cell homeostasis, and disruptions to its functions can have detrimental effects on cells. Dysregulated ER stress and the unfolded protein response (UPR) have been linked to various human diseases. For example, ER stress and the activation of the UPR signaling pathways in intestinal epithelial cells can either exacerbate or alleviate the severity of inflammatory bowel disease (IBD), contingent on the degree and conditions of activation. Our recent studies have shown that EPICERTIN, a recombinant variant of the cholera toxin B subunit containing an ER retention motif, can induce a protective UPR in colon epithelial cells, subsequently promoting epithelial restitution and mucosal healing in IBD models. These findings support the idea that compounds modulating UPR may be promising pharmaceutical candidates for the treatment of the disease. In this review, we summarize our current understanding of the ER stress and UPR in IBD, focusing on their roles in maintaining cell homeostasis, dysregulation, and disease pathogenesis. Additionally, we discuss therapeutic strategies that promote the cytoprotection of colon epithelial cells and reduce inflammation via pharmacological manipulation of the UPR.

Intestinal epithelial cells (IECs) perform several physiological and metabolic functions at the epithelial barrier. IECs also play an important role in defining the overall immune functions at the mucosal region. Pattern recognition receptors (PRRs) on the cell surface and in other cellular compartments enable them to sense the presence of microbes and microbial products in the intestinal lumen. IECs are thus at the crossroads of mediating a bidirectional interaction between the microbial population and the immune cells present at the intestinal mucosa. This communication between the microbial population, the IECs and the underlying immune cells has a profound impact on the overall health of the host. In this review, we focus on the various PRRs present in different cellular compartments of IECs and discuss the recent developments in the understanding of their role in microbial recognition. Microbial recognition and signaling at the epithelial barrier have implications in the maintenance of intestinal homeostasis, epithelial barrier function, maintenance of commensals, and the overall tolerogenic function of PRRs in the gut mucosa. We also highlight the role of an aberrant microbial sensing at the epithelial barrier in the pathogenesis of inflammatory bowel disease (IBD) and the development of colorectal cancer.

Monensin is an ionophore antibiotic isolated from Streptomyces cinnamonensis with very strong antibacterial and antiparasitic effects. Although monensin is known to exhibit anticancer activity in different cancer types, there are a very limited number of studies on its anti-inflammatory effects in colorectal cancer (CRC) cells. The aim of this study was to investigate the TLR4/IRF3-mediated antiproliferative and anti-inflammatory effects of monensin in colorectal cancer cells. The dose- and time-dependent antiproliferative activity of monensin in colorectal cancer cells was determined by XTT method and its effects on mRNA expression changes of Toll-like receptors and IRF3 genes were determined by RT-PCR. TLR4 and Interferon Regulatory Factor 3 (IRF3) protein expression was evaluated by immunofluorescence method. TLR4 and type 1 interferon (IRF) levels were also evaluated by ELISA. IC₅₀ value of monensin in HT29 cells was determined as 10.7082 µM at 48 h and 12.6288 µM at 48th for HCT116 cells. Monensin treatment decreased TLR4 and TLR7 and IRF3 mRNA expression in CRC cells. Monensin treatment decreased the expression level of IRF3 induced by LPS. Our study demonstrates for the first time the TLR4/IRF3-mediated anti-inflammatory effects of monensin in colorectal cancer cells. Further studies on the effects of monensin on TLR receptors in colorectal cancer cells are needed.

Toll-like receptors (TLRs) are key components of the innate immune system and serve as a crucial link between innate and acquired immunity. In addition to immune function, TLRs are involved in other important pathological processes, including tumorigenesis. TLRs have dual regulatory effects on tumor immunity by activating nuclear factor κ-B signaling pathways, which induce tumor immune evasion or enhance the antitumor immune response. Therefore, TLRs have become a popular target for cancer prevention and treatment, and TLR agonists and antagonists offer considerable potential for drug development. The TLR7 agonist imiquimod (1) has been approved by the U.S. Food and Drug Administration as a treatment for malignant skin cancer. Herein, the structure, signaling pathways, and function of the TLR family are summarized, and the structure-activity relationships associated with TLR selective and multitarget modulators and their potential application in tumor therapy are systematically discussed.

Excessive activation of Toll-like receptor (TLR) signaling pathways and the circulating endotoxin are key players in the pathogenesis of many acute and chronic inflammatory diseases. Regulation of TLR-mediated inflammatory responses by bioactive nanodevices represents a promising strategy for treating these diseases. In searching for novel, clinically applicable nanodevices with potent TLR inhibitory activities, three types of hexapeptide-modified nano-hybrids with different cores of phospholipid nanomicelles, liposomes, and poly(lactic-co-glycolic acid) nanoparticles are constructed. Interestingly, only the peptide-modified lipid-core nanomicelles (M-P12) display potent TLR inhibitory activities. Further mechanistic studies disclose that lipid-core nanomicelles have a generic property to bind to and scavenge lipophilic TLR ligands including lipopolysaccharide to block the ligand-receptor interaction and down-regulate the TLR signaling extracellularly. In addition, the peptide modification enables M-P12 a unique capability to modulate endosomal acidification upon being endocytosed into macrophages, which subsequently regulates the endosomal TLR signal transduction. In an acute lung injury mouse model, intratracheal administration of M-P12 can effectively target lung macrophages and reduce lung inflammation and injuries. This work defines a dual mechanism of action of the peptide-modified lipid-core nanomicelles in regulating TLR signaling, and provides new strategies for the development of therapeutic nanodevices for treating inflammatory diseases.

Toll-like receptors (TLRs) are indispensable for the activation, maintenance and halting of immune responses. TLRs can mediate inflammation by recognizing molecular patterns in microbes (pathogen-associated molecular patterns: PAMPs) and endogenous ligands (danger-associated molecular patterns: DAMPs) released by injured or dead cells. For this reason, TLR ligands have attracted much attention in recent years in many cancer vaccines, alone or in combination with immunotherapy, chemotherapy and radiotherapy (RT). TLRs have been shown to play controversial roles in cancer, depending on various factors that can mediate tumor progression or apoptosis. Several TLR agonists have reached clinical trials and are being evaluated in combination with standard of care therapies, including RT. Despite their prolific and central role in mediating immune responses, the role of TLRs in cancer, particularly in response to radiation, remains poorly understood. Radiation is recognized as either a direct stimulant of TLR pathways, or indirectly through the damage it causes to target cells that subsequently activate TLRs. These effects can mediate pro-tumoral and anti-tumoral effects depending on various factors such as radiation dose and fractionation, as well as host genomic features. In this review, we examine how TLR signaling affects tumor response to RT, and we provide a framework for the design of TLR-based therapies with RT.

Long noncoding RNAs (lncRNAs) are emerging players in cancer and they entail potential as prognostic biomarkers or therapeutic targets. Earlier studies have identified somatic mutations in lncRNAs that are associated with tumor relapse after therapy, but the underlying mechanisms behind these associations remain unknown. Given the relevance of secondary structure for the function of some lncRNAs, some of these mutations may have a functional impact through structural disturbance. Here, we examined the potential structural and functional impact of a novel A > G point mutation in NEAT1 that has been recurrently observed in tumors of colorectal cancer patients experiencing relapse after treatment. Here, we used the nextPARS structural probing approach to provide first empirical evidence that this mutation alters NEAT1 structure. We further evaluated the potential effects of this structural alteration using computational tools and found that this mutation likely alters the binding propensities of several NEAT1-interacting miRNAs. Differential expression analysis on these miRNA networks shows upregulation of Vimentin, consistent with previous findings. We propose a hybrid pipeline that can be used to explore the potential functional effects of lncRNA somatic mutations.

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune-inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors.