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Background: Colorectal cancer (CRC) is a major public health concern. Animal models play a crucial role in understanding the disease pathology and development of effective treatment strategies. Chemically induced CRC represents a cornerstone in animal model development; however, due to the presence of different animal species with different genetic backgrounds, it becomes mandatory to study the susceptibility of different mice species to CRC induction by different chemical entities such as 1,2-dimethylhydrazine (DMH). This study aimed to investigate the induction receptivity of two commonly used mice species, C57BL/6 and BALB/c, to DMH-induced CRC. Methods: Both mice species were exposed to weekly intraperitoneal injections of DMH at a dose of 20 mg/kg body weight for 15 consecutive weeks. The response to DMH was evaluated by monitoring body weight gain, daily food intake, and gastrointestinal symptoms. At the end of exposure, histopathology of distal colon dissected from both species was analyzed. Results: Results revealed that C57BL/6 had a higher response to DMH compared to BALB/c. A significant decrease in body weight gain concomitant with severe diarrhea was observed in C57BL/6 receiving DMH compared to their controls, without any difference in food intake. Histopathology of distal colon revealed aberrant crypt foci and loss of goblet cells in DMH-exposed C57BL/6 mice. On the other hand, BALB/c mice displayed a normal and intact colon, with a normal weight gain pattern, and without any gastrointestinal symptoms. Conclusion: In conclusion, C57BL/6 has a higher susceptibility toward chemical induction to CRC; therefore, it can be used to study CRC pathogenesis, prevention, and treatment. [ABSTRACT FROM AUTHOR]

Environmental chemicals and toxins are known to impact human health and contribute to cancer developments. Among these, genotoxins induce genetic mutations critical for cancer initiation. In the liver, proliferation serves not only as a compensatory mechanism for tissue repair but also as a potential risk factor for the progression of premalignant lesions. The role of Human Liver DnaJ-Like Protein (DNAJB4/HLJ1), a stress-responsive heat shock protein 40, in genotoxin-induced liver carcinogenesis remains unexplored. Using whole-genome transcriptomic analysis, we demonstrate that HLJ1 deficiency in mice results in altered gene signatures enriched in pathways associated with chemically induced liver cancer and IL-6/STAT3 signaling activation. Employing diethylnitrosamine (DEN) as a carcinogen, we further reveal that STAT3 and H2AX phosphorylation induced by short-term DEN treatment are amplified in HLJ1-deficient mice. In long-term DEN experiments, HLJ1 deletion enhances tumor proliferation and progression, accompanied by pronounced STAT3 phosphorylation in normal tissues rather than in tumor regions. The tumor-suppressive role of peritumoral HLJ1 is validated through the transplantation of HLJ1-wildtype B16F1 and LLC cancer cell lines into syngeneic HLJ1-deficient mice, which exhibits an augmented tumorigenic phenotype compared to wildtype controls. This study uncovers a previously unrecognized role of HLJ1 in suppressing liver carcinogenesis via the downregulation of STAT3 signaling in peritumoral normal cells. These findings suggest that HLJ1 reinforcement represents a promising strategy for liver cancer treatment and prevention. [ABSTRACT FROM AUTHOR]

Introduction: The striped hamster, often parasitized by ectoparasites in nature, is an ideal model for studying host-ectoparasite molecular interactions. Investigating the response to ectoparasites under laboratory conditions helps elucidate the mechanism of host adaptations to ectoparasite pressure. Methods: Using transcriptome sequencing, we analyzed gene expression in striped hamsters after short-term (3 days) and long-term (28 days) flea (Xenopsylla cheopis) parasitism. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Hub genes were pinpointed using protein-protein interaction (PPI) network analysis and the MCODE in Cytoscape. Gene Set Enrichment Analysis (GSEA) was used to further clarify the functional pathways of these hub genes. Validation of DEGs was performed via RT-qPCR. Additionally, the concentrations of reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were determined using specific enzyme-linked immunosorbent assay (ELISA) detection kits for hamsters. Results: GO analysis revealed that during early parasitism, hosts primarily responded to the ectoparasites by adjusting the expression of genes related to metabolic functions. As parasitism persisted, the immune response became prominent, activating various immune pathways against ectoparasites. KEGG analysis confirmed the ongoing roles of metabolism and immunity. Notably, the chemical carcinogenesis - reactive oxygen species pathway was upregulated during flea parasitism, with downregulation of hub genes ATP5MC1 and ATP5MC2, highlighting the importance of mitochondrial function in oxidative stress. ELISA findings revealed that on day 3, flea parasitism groups showed elevated ROS expression and reduced SOD and CAT levels compared to the control group. By day 28, only SOD expression showed a significant decrease in both parasitism groups. Conclusion: This study uncovered the dynamic changes in metabolism and immune responses of striped hamsters parasitized by Xenopsylla cheopis. Hosts adjust their physiological and immune states to optimize survival strategies during different ectoparasite stages, enhancing our understanding of host-ectoparasite interactions. This also paves the way for further research into how hosts regulate complex biological processes in response to ectoparasite challenges. [ABSTRACT FROM AUTHOR]

The optical properties of gold nanoparticles are widely investigated with interest in their application in photohyperthermia cancer treatments. Coating these nanoparticles with MCM-41 silica not only protects the gold nanoparticles but also has the potential for use as a nanocarrier, because of its textural properties. This nanocarrier allows the incorporation of drugs, such as methotrexate (MTX), for use in chemotherapy. Therefore, this nanoplatform shows promise for the treatment of cancer by photohyperthermia and chemotherapy, making the therapy more targeted and effective. This study aimed to investigate the incorporation and release of MTX from a nanoplatform of gold nanoparticles coated with MCM-41, which presents relevant properties for application in photohyperthermia treatments. The results showed that the proposed nanosystem has high cell viability and low cytotoxicity, indicating its potential for application in biological systems. Furthermore, our findings demonstrated that FITC-conjugated MCM-41 nanoparticles were internalized by the cells. Additionally, it was observed that nanomaterials containing MTX showed high cytotoxicity only to tumor cells and that these nanocarriers were taken up by cells, suggesting their specificity in cancer treatment. The synthesized nanocomposite shows promise for applications in cancer treatment through photohyperthermia and chemotherapy. [ABSTRACT FROM AUTHOR]

This study examined the effects of a 14-week combined exercise program on blood DNA methylation (DNAm) and its potential biological pathways in normal-weight, overweight, and obese older women. A total of 41 participants were assessed at baseline, 7 weeks, and 14 weeks into the training. Their whole-blood DNAm profiles were measured using the Infinitum MethylationEPIC BeadChip, alongside physical and biochemical health evaluations. The results showed notable health improvements, with decreases in blood pressure and cholesterol levels in the overweight and obese groups. Blood triglycerides were reduced only in the overweight group. Physical performance also improved across all groups. At 14 weeks, 1,043 differentially methylated positions (DMPs) were identified, affecting 744 genes. The genes were linked to biological processes, such as cellular metabolism, with significant pathway enrichment related to oxidative phosphorylation and chemical carcinogenesis. Additionally, the overweight group experienced significant reductions in methylation levels at eight lipogenesis-related genes. Protein EpiScore analysis revealed decreased levels of CCL11, VEGFA, and NTRK3 proteins at 14 weeks compared to baseline. Despite these significant molecular changes, there was no observable difference in DNAm age after the intervention. This study highlights how combined exercise can modify DNAm patterns in older women, particularly in lipogenesis-related genes, but suggests that further research is needed to understand the full implications for biological ageing. [ABSTRACT FROM AUTHOR]

To explore the medication rules of traditional Chinese medicine (TCM) and mechanism of action of hub herb pairs for treating insomnia. Totally 104 prescriptions were statistically analyzed. The association rule algorithm was applied to mine the hub herb pairs. Network pharmacology was utilized to analyze the mechanism of the hub herb pairs, while molecular docking was applied to simulate the interaction between receptors and herb molecules, thereby predicting their binding affinities. The most frequently used herbs in TCM prescriptions for treating insomnia included Semen Ziziphi Spinosae , Radix Glycyrrhizae , Radix et Rhizoma Ginseng , and Poria cum Radix Pini. Among them, the most commonly used were the supplementing herbs, followed by heat-clearing, mind-calming, and exterior-releasing ones, with their properties of warm and cold, flavors of sweet, Pungent, and bitter, and meridian tropisms of liver, lungs, spleen, kidneys, heart, and stomach. The hub herb pairs based on the association rules included Radix Astragali - Radix et Rhizoma Ginseng , Rhizoma Chuanxiong - Radix Glycyrrhizae , Seman Platycladi - Semen Ziziphi Spinosae , Pericarpium Citri Reticulatae - Radix Glycyrrhizae , Radix Polygalae - Semen Ziziphi Spinosae , and Radix Astragali - Semen Ziziphi Spinosae. Network pharmacology revealed that the cAMP signaling pathway might play a key role in treating insomnia synergistically with HIF-1 signaling pathway, prolactin signaling pathway, chemical carcinogenesis receptor activation, and PI3K-Akt signaling pathway. Molecular docking indicated that there was good binding between the active ingredients of the hub herb pairs and the hub targets. This study identified six hub herb pairs for treating insomnia in TCM. These hub herb pairs may synergistically treat insomnia with HIF-1 signaling pathway, prolactin signaling pathway, chemical carcinogenesis receptor activation, and PI3K-Akt signaling pathway through the cAMP signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) have been identified as playing an integral role in the development of bladder cancer (BC). However, the mechanism by which circRNAs operate in the chemical carcinogenesis of BC remains unclear. Methods: To explore this mechanism, we used RNA high-throughput sequencing to identify differentially expressed circRNA in bladder epithelial cells and chemically induced malignant transformed BC cells. Subsequently, in vitro experiments were conducted to investigate the biological function and molecular mechanism of circLMBR1 in BC. Finally, animal experiments were conducted to examine the clinical relevance of circLMBR1 in vivo. Results: Our profiling of circular RNA expression during cellular malignant transformation induced by chemical carcinogens identified a subset of circRNAs associated with cell transformation. We verified that the expression of circLMBR1 in bladder epithelial malignant transformed cells was decreased compared with control cells, as well as in BC tissues and bladder cell lines. Furthermore, circLMBR1 was seen to inhibit the proliferation, invasion, and migration of BC cells both in vitro and in vivo. Mechanistically, circLMBR1 was found to exert its antitumor effect by binding to the protein ALDH1A3. Conclusions: Our findings have revealed that circLMBR1 inhibits the progression of BC cells by binding to ALDH1A3 and upregulating its expression. As such, circLMBR1 serves as a promising predictor of BC and may provide a novel therapeutic target for the treatment of BC.

Detrimental side effects of drugs like doxorubicin, which can cause cardiotoxicity, pose barriers for preventing cancer progression, or treating cancer early through molecular interception. Extracellular vesicles (EVs) are valued for their potential as biomarkers of human health, chemical and molecular carcinogenesis, and therapeutics to treat disease at the cellular level. EVs are released both during normal growth and in response to toxicity and cellular death, playing key roles in cellular communication. Consequently, EVs may hold promise as precision biomarkers and therapeutics to prevent or offset damaging off-target effects of chemotherapeutics. EVs have promise as biomarkers of impending cardiotoxicity induced by chemotherapies and as cardioprotective therapeutic agents. However, EVs can also mediate cardiotoxic cues, depending on the identity and past events of their parent cells. Understanding how EVs mediate signaling is critical toward implementing EVs as therapeutic agents to mitigate cardiotoxic effects of chemotherapies. For example, it remains unclear how mixtures of EV populations from cells exposed to toxins or undergoing different stages of cell death contribute to signaling across cardiac tissues. Here, we present our perspective on the outlook of EVs as future clinical tools to mitigate chemotherapy-induced cardiotoxicity, both as biomarkers of impending cardiotoxicity and as cardioprotective agents. Also, we discuss how heterogeneous mixtures of EVs and transient exposures to toxicants may add complexity to predicting outcomes of exogenously applied EVs. Elucidating how EV cargo and signaling properties change during dynamic cellular events may aid precision prevention of cardiotoxicity in anticancer treatments and development of safer chemotherapeutics. [ABSTRACT FROM AUTHOR]

Centrosomes are the major microtubule organizing centers of animal cells. Supernumerary centrosomes are a common feature of human tumors and associated with karyotype abnormalities and aggressive disease, but whether they are cause or consequence of cancer remains controversial. Here, we analyzed the consequences of centrosome amplification by generating transgenic mice in which centrosome numbers can be increased by overexpression of the structural centrosome protein STIL. We show that STIL overexpression induces centrosome amplification and aneuploidy, leading to senescence, apoptosis, and impaired proliferation in mouse embryonic fibroblasts, and microcephaly with increased perinatal lethality and shortened lifespan in mice. Importantly, both overall tumor formation in mice with constitutive, global STIL overexpression and chemical skin carcinogenesis in animals with inducible, skin-specific STIL overexpression were reduced, an effect that was not rescued by concomitant interference with p53 function. These results suggest that supernumerary centrosomes impair proliferation in vitro as well as in vivo, resulting in reduced lifespan and delayed spontaneous as well as carcinogen-induced tumor formation. Author summary: Already at the beginning of the last century, Theodor Boveri suggested that supernumerary centrosomes might be a cause of cancer via the generation of abnormal mitotic spindles and subsequent chromosome missegregation. In the meantime, centrosome amplification has been observed in most tumor types and is viewed as a "hallmark" of cancer cells. However, studies on tumor formation in mice by overexpression of PLK4, the principal kinase regulating centrosome duplication, led to ambiguous results, as some but not all models resulted in increased tumorigenesis. In this study, we generated transgenic mice, which overexpress the structural centrosome protein STIL. Similar to PLK4, overexpression of STIL caused centrosome amplification and aneuploidy in mouse cells. Our analyses revealed that powerful mechanisms lead to the elimination of cells with extra centrosomes and/or aneuploidy by impaired proliferation, senescence and apoptosis, thereby delaying both spontaneous tumor formation and chemical skin carcinogenesis, and explaining the reduced life span of STIL-transgenic mice. [ABSTRACT FROM AUTHOR]

High-throughput transcriptomics (HTTr) is increasingly being used to identify molecular targets of chemicals that can be linked to adverse outcomes. Cell proliferation (CP) is an important key event in chemical carcinogenesis. Here, we describe the construction and characterization of a gene expression biomarker that is predictive of the CP status in human and rodent tissues. The biomarker was constructed from 30 genes known to be increased in expression in prostate cancers relative to surrounding tissues and in cycling human MCF-7 cells after estrogen receptor (ER) agonist exposure. Using a large compendium of gene expression profiles to test utility, the biomarker could identify increases in CP in (i) 308 out of 367 tumor vs. normal surrounding tissue comparisons from 6 human organs, (ii) MCF-7 cells after activation of ER, (iii) after partial hepatectomy in mice and rats, and (iv) the livers of mice and rats after exposure to nongenotoxic hepatocarcinogens. The biomarker identified suppression of CP (i) under conditions of p53 activation by DNA damaging agents in human cells, (ii) in human A549 lung cells exposed to therapeutic anticancer kinase inhibitors (dasatinib, nilotnib), and (iii) in the mouse liver when comparing high levels of CP at birth to the low background levels in the adult. The responses using the biomarker were similar to those observed using conventional markers of CP including PCNA, Ki67, and BrdU labeling. The CP biomarker will be a useful tool for interpretation of HTTr data streams to identify CP status after exposure to chemicals in human cells or in rodent tissues. [ABSTRACT FROM AUTHOR]

Purpose: Radiation cystitis (RC) is a complex and common complication after radiotherapy for pelvic cancer. Icariside II (ICAII) is a flavonoid compound extracted from Epimedium, a traditional Chinese medicine, with various pharmacological activities. The aim of the present study was to investigate the cysto-protective effects of ICAII in RC rats and its possible mechanisms. Materials and Methods: A rat model of induced radiation cystitis using pelvic X-ray irradiation was used, and bladder function was assessed by bladder volume and bladder leakage point pressure (LPP) after ICAII treatment. HE and Masson stains were used to assess the histopathological changes in the bladder. IL-6, TNF-α, IL-10, IL-4 and IL-1β were measured by ELISA to assess the level of inflammation. The gene-level changes in ICAII-treated RC were observed by transcriptome sequencing, and then the potential targets of action and biological mechanisms were explored by PPI, GO and KEGG enrichment analysis of the differentially expressed genes. Finally, the predicted targets of action were experimentally validated using immunohistochemistry, RT–qPCR, molecular docking and CETSA. Results: ICAII significantly increased bladder volume and the LPP, ameliorated pathological damage to bladder tissues, decreased the levels of IL-6, TNF-α, and IL-1β, and increased the levels of IL-10 and IL-4 in radiation-injured rats. A total of 90 differentially expressed genes were obtained by transcriptome sequencing, and PPI analysis identified H3F3C, ISG15, SPP1, and LCN2 as possible potential targets of action. GO and KEGG analyses revealed that these differentially expressed genes were mainly enriched in the pathways metabolism of xenobiotics by cytochrome P450, arachidonic acid metabolism, Staphylococcus aureus infection and chemical carcinogenesis - reactive oxygen species. Experimental validation showed that ICAII could significantly increase the expression of H3F3C and ISG15 and inhibit the expression of SPP1 and LCN2. ICAII binds well to H3F3C, ISG15, SPP1 and LCN2, with the best binding ability to H3F3C. Furthermore, ICAII inhibited the protein degradation of H3F3C in bladder epithelial cells. Conclusions: ICAII may alleviate the bladder inflammatory response and inhibit the fibrosis process of bladder tissues through the regulation of H3F3C, ISG15, SPP1, and LCN2 targets and has a protective effect on the bladder of radioinjured rats. In particular, H3F3C may be one of the most promising therapeutic targets. [ABSTRACT FROM AUTHOR]

Pregnane X receptor (PXR) is a xenobiotic-sensing nuclear receptor that plays a key role in drug metabolism. Recently, PXR was found to attenuate the development of liver cancer by suppressing epithelial-mesenchymal transition (EMT) in liver cancer cells in a mouse model of two-stage chemical carcinogenesis. To elucidate the role of PXR in the EMT of liver cancer cells, we focused on its role in hepatic stellate cells (HSCs), which are components of the tumor microenvironment in hepatocellular carcinoma (HCC). Human HSC-derived LX-2 cells stably expressed destabilization domain (DD)-fused human PXR (hPXR-LX2 cells). Human HCC-derived HepG2 cells were transfected with the EMT marker VIM promoter-regulated reporter plasmid and co-cultured with hPXR-LX2 cells or treated with hPXR-LX2-derived conditioned medium (CM). Co-culture or CM treatment increased reporter activity in HepG2 cells. This induction was attenuated upon PXR acti- vation in hPXR-LX2 cells by treatment with the DD-stabilizing chemical Shield-1 and the human PXR ligand rifampicin. PXR activation in hPXR-LX2 cells exhibited inhibition of TGF-β1-induced transdifferentiation, supported by observations of morphological changes and protein or mRNA levels of the transdifferentiation markers COL1A1 and FN1. PXR activation in hPXR-LX2 cells also attenuated the mRNA levels of the key trans- differentiation factor, POSTN. Treatment of hPXR-LX2 cells with recombinant POSTN restored the PXR-mediated suppression of transdifferentiation. Reporter assays with the POSTN promoter showed that PXR inhibited the NF-κB-mediated transcription of POSTN. Consequently, PXR activation in HSCs is expected to inhibit transdifferentiation by down-regulating POSTN expression, thereby suppressing EMT of liver cancer cells. [ABSTRACT FROM AUTHOR]

Prostate cancer is a very common cancer in men, affecting approximately 1.40 million men worldwide in 2020. To improve the quality of life and survival of both animals and humans, effective therapeutic approaches have been developed and evaluated using animal models. The rat model of prostate cancer induced by a multi-step protocol that consists of a sequential administration of flutamide, followed by testosterone propionate, then the administration of Nmethyl-N-nitrosourea, and finally subcutaneous implantation of tubes filled with crystalline testosterone, is one of the most frequently used for prostate cancer research. However, the lack of standardization in procedures for prostate cancer induction, sample collection, and analysis represents a challenge for researchers. To address this issue, we aim to provide investigators with a detailed, step-by-step guide to implementing a rat model of prostate cancer, based on our extensive experience in this field. First, we briefly review the prostate cancer-induced protocols found in the literature, then we provide a detailed description of the prostate cancer rat model implemented by our team. After, we explore the rats' prostate monitoring during the experiment protocol through imaging modalities, such as ultrasonography, computed tomography, and magnetic resonance imaging. We also describe animal welfare monitoring based on a table of humane endpoints, as well as data collection, such as biological variables and prostate samples. In sum, this article will ensure the quality of results and enable their comparison among different researchers using this rat model. [ABSTRACT FROM AUTHOR]

AbstractBenzene exposure is known to cause serious damage to the human hematopoietic system. However, recent studies have found that chronic benzene exposure may also cause neurological damage, but there were few studies in this issue. The aim of this study was to investigate the mechanism of damage to the central nervous system (CNS) by chronic benzene exposure with a multi-omics analysis. We established a chronic benzene exposure model in C57BL/6J mice by gavage of benzene-corn oil suspension, identified the differentially expressed proteins (DEPs) and differentially expressed genes (DEGs) in mice brain using 4D Label-free proteomic and RNA-seq transcriptomic. We observed that the benzene exposure mice had a significant loss of body weight, reduction in complete blood counts, abnormally high MRI signals in brain white matter, as well as extensive brain edema and neural demyelination. 162 DEPs were identified by the proteome, including 98 up-regulated and 64 down-regulated proteins. KEGG pathway analysis of DEPs showed that they were mainly involved in the neuro-related signaling pathways such as metabolic pathways, pathways of neurodegeneration, chemical carcinogenesis, Alzheimer disease, and autophagy. EPHX1, GSTM1, and LIMK1 were identified as important candidate DEGs/DEPs by integrated proteomic and transcriptomic analyses. We further performed multiple validation of the above DEGs/DEPs using fluorescence quantitative PCR (qPCR), parallel reaction monitoring (PRM), immunohistochemistry, and immunoblotting to confirm the reliability of the multi-omics study. The functions of these DEGs/DEPs were further explored and analyzed, providing a theoretical basis for the mechanism of nerve damage caused by benzene exposure. [ABSTRACT FROM AUTHOR]

Peucedanum decursivum (Miq.) Maxim (P. decursivum) is a traditional Chinese medicinal plant with pharmacological effects such as anti-inflammatory and anti-tumor effects, the root of which is widely used as medicine. Determining the spatial distribution and pharmacological mechanisms of metabolites is necessary when studying the effective substances of medicinal plants. As a means of obtaining spatial distribution information of metabolites, mass spectrometry imaging has high sensitivity and allows for molecule visualization. In this study, matrix-assisted laser desorption mass spectrometry (MALDI-TOF-MSI) and network pharmacology were used for the first time to visually study the spatial distribution and anti-inflammatory mechanism of coumarins, which are metabolites of P. decursivum, to determine their tissue localization and mechanism of action. A total of 27 coumarins were identified by MALDI-TOF-MSI, which mainly concentrated in the cortex, periderm, and phloem of the root of P. decursivum. Network pharmacology studies have identified key targets for the anti-inflammatory effect of P. decursivum, such as TNF, PTGS2, and PRAKA. GO enrichment and KEGG pathway analyses indicated that coumarins in P. decursivum mainly participated in biological processes such as inflammatory response, positive regulation of protein kinase B signaling, chemical carcinogenesis receptor activation, pathways in cancer, and other biological pathways. The molecular docking results indicated that there was good binding between components and targets. This study provides a basis for understanding the spatial distribution and anti-inflammatory mechanism of coumarins in P. decursivum. [ABSTRACT FROM AUTHOR]

It is necessary to verify whether nail fold capillaroscopy can be utilized for the early detection of breast cancer. To establish this technology, an animal model was developed, utilizing mice for nail fold observations. Nail fold capillaroscopy revealed a human-like anatomical pattern and facilitated the observation of cellular movement within blood vessels. Injection of MCF-7 or mammary fibroblasts in mice allowed the observation of cellular vibrations using motion microscopy from nail fold. We have named this technology 'capillary cell motion microscopy.' Intriguingly, we were able to identify distinct cellular vibrations in the MCF-7 group. Moreover, evaluating its effectiveness in mice with chemically induced cancer revealed higher sensitivity (81%-85%) compared to conventional methods (45%-68%). Capillary cell motion microscopy, operating at 0.5–1.5 Hz, provided clear distinction of tumor cells and demonstrated potential applicability in human subjects. While condition adjustments may be necessary, this method holds promise for noninvasive breast cancer detection through nail fold observations. [ABSTRACT FROM AUTHOR]

Organochlorine pesticides (OCPs) are a class of environmentally persistent and bioaccumulative pollutants. Among these, β-hexachlorocyclohexane (β-HCH) is a byproduct of lindane synthesis, one of the most worldwide widespread pesticides. β-HCH cellular mechanisms inducing chemical carcinogenesis correspond to many of those inducing chemoresistance, in particular, by the activation of signal transducer and activator of transcription 3 (STAT3) signaling pathways. For this purpose, four cell lines, representative of breast, lung, prostate, and hepatocellular cancers, were treated with β-HCH, specific tyrosine kinase inhibitors (TKIs), and a STAT3 inhibitor. All cell samples were analyzed by a viability assay, immunoblotting analysis, a wound-healing assay, and a colony formation assay. The results show that β-HCH reduces the efficacy of TKIs. The STAT3 protein, in this context, plays a central role. In fact, by inhibiting its activity, the efficacy of the anticancer drug is restored. Furthermore, this manuscript aimed to draw the attention of the scientific and socio-healthcare community to the issue of prolonged exposure to contaminants and their impact on drug efficacy. [ABSTRACT FROM AUTHOR]

In order to obtain models of gliomas of varying degrees of malignancy, we performed morphological and molecular genetic study of a tissue strain of glioma 10-17-2 (Astrid-17) obtained by intracranial passaging of tumor fragments of chemically induced rat brain tumor, and a cell strain isolated from it. More or less pronounced changes in the expression levels of Mki67, Trp53, Vegfa, and Gfap genes in the tissue and cell strain of glioma 10-17-2 (Astrid-17) compared with intact brain tissue were shown. The tissue model of glioma 10-17-2 (Astrid-17) according to the studied characteristics shows features of grade 3-4 astrocytoma and the cellular model — grade 2-3 astrocytoma. [ABSTRACT FROM AUTHOR]

The editorial in "Frontiers in Oncology" discusses the importance of precision medicine and cancer prevention through insights in molecular and chemical carcinogenesis. It emphasizes the need for a comprehensive approach to understand cancer's diverse manifestations and mechanisms. The research topic explores biological targets, biomarkers, and early mechanisms of carcinogenesis to inform precision prevention strategies and reduce cancer health disparities. The articles highlight the significance of integrating mechanistic and epidemiological data-driven approaches to advance cancer research and prevention efforts. [Extracted from the article]

Introduction: Betanin (C24H26N2O13) is safe to use as food additives approved by the FDA with anti-inflammatory and anticancer effects in many types of cancer cell lines. The current experiment was designed to test the chemotherapeutic effect of the combination of betanin with the standard chemotherapeutic agent, capecitabine, against chemically induced colon cancer in mice. Methods: Bioinformatic approachwas designed to get information about the possible mechanisms through which the drugs may control cancer development. Five groups of mice were assigned as, (i) saline, (ii) colon cancer, (iii) betanin, (iv) capecitabine and (v) betanin/capecitabine. Drugs were given orally for a period of six weeks. Colon tissues were separated and used for biological assays and histopathology. Results: In addition, the mRNA expression of TNF-a (4.58-fold), NFκB (5.33-fold), IL-1β (4.99-fold), cyclin D1 (4.07-fold), and IL-6 (3.55-fold) and protein levels showed several folds increases versus the saline group. Tumor histopathology scores in the colon cancer group (including cryptic distortion and hyperplasia) staining demonstrated poor mucin content (33% of the saline group). These pathologic manifestations were reduced remarkably in betanin/capecitabine group. Conclusion: Collectively, our findings demonstrated the usefulness of betanin/capecitabine combination in targeting colon cancer and highlighted that betanin is a promising adjuvant therapy to capecitabine in treating colon cancer patients. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by abnormal accumulation of extracellular matrix (ECM) due to dysregulated expression of various RNAs in pulmonary fibroblasts. This study utilized RNA-seq data meta-analysis to explore the regulatory network of hub long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) in IPF fibroblasts. The meta-analysis unveiled 584 differentially expressed mRNAs (DEmRNA) and 75 differentially expressed lncRNAs (DElncRNA) in lung fibroblasts from IPF. Among these, BCL6, EFNB1, EPHB2, FOXO1, FOXO3, GNAI1, IRF4, PIK3R1, and RXRA were identified as hub mRNAs, while AC008708.1, AC091806.1, AL442071.1, FAM111A-DT, and LINC01989 were designated as hub lncRNAs. Functional characterization revealed involvement in TGF-β, PI3K, FOXO, and MAPK signaling pathways. Additionally, this study identified regulatory interactions between sequences of hub mRNAs and lncRNAs. In summary, the findings suggest that AC008708.1, AC091806.1, FAM111A-DT, LINC01989, and AL442071.1 lncRNAs can regulate BCL6, EFNB1, EPHB2, FOXO1, FOXO3, GNAI1, IRF4, PIK3R1, and RXRA mRNAs in fibroblasts bearing IPF and contribute to fibrosis by modulating crucial signaling pathways such as FoxO signaling, chemical carcinogenesis, longevity regulatory pathways, non-small cell lung cancer, and AMPK signaling pathways. [ABSTRACT FROM AUTHOR]

Chemical agents can cause cancer in animals by damaging their DNA, mutating their genes, and modifying their epigenetic signatures. Carcinogen-induced preclinical cancer models are useful for understanding carcinogen-induced human cancers, as they can reproduce the diversity and complexity of tumor types, as well as the interactions with the host environment. However, these models also have some drawbacks that limit their applicability and validity. For instance, some chemicals may be more effective or toxic in animals than in humans, and the tumors may differ in their genetics and phenotypes. Some chemicals may also affect normal cells and tissues, such as by causing oxidative stress, inflammation, and cell death, which may alter the tumor behavior and response to therapy. Furthermore, some chemicals may have variable effects depending on the exposure conditions, such as dose, route, and duration, as well as the animal characteristics, such as genetics and hormones. Therefore, these models should be carefully chosen, validated, and standardized, and the results should be cautiously interpreted and compared with other models. This review covers the main features of chemically induced cancer models, such as genetic and epigenetic changes, tumor environment, angiogenesis, invasion and metastasis, and immune response. We also address the pros and cons of these models and the current and future challenges for their improvement. This review offers a comprehensive overview of the state of the art of carcinogen-induced cancer models and provides new perspectives for cancer research. [ABSTRACT FROM AUTHOR]

Skin cancer and other skin-related inflammatory pathologies are rising due to heightened exposure to environmental pollutants and carcinogens. In this context, natural products and repurposed compounds hold promise as novel therapeutic and preventive agents. Strengthening the skin's antioxidant defense mechanisms is pivotal in neutralizing reactive oxygen species (ROS) and mitigating oxidative stress. Sunset Yellow (SY) exhibits immunomodulatory characteristics, evidenced by its capacity to partially inhibit the secretion of proinflammatory cytokines, regulate immune cell populations, and modulate the activation of lymphocytes. This study aimed to investigate the antioxidant and anti-genotoxic properties of SY using in-silico, in vitro, and physiochemical test systems, and to further explore its potential role in 7,12-dimethylbenz(a) anthracene (DMBA)/ 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis. In vitro experiments showed that pre-treatment of SY significantly enhanced the cell viability of HaCaT cells when exposed to tertiary-Butyl Hydrogen Peroxide (tBHP). This increase was accompanied by reduced ROS levels, restoration of mitochondrial membrane potential, and notable reduction in DNA damage in (SY + tBHP) treated cells. Mechanistic investigations using DPPH chemical antioxidant activity test and potentiometric titrations confirmed SY's antioxidant properties, with a standard reduction potential ( E o ) of 0.211 V. Remarkably, evaluating the effect of topical application of SY in DMBA/TPA-induced two-step skin carcinogenesis model revealed dose-dependent decreases in tumor latency, incidence, yield, and burden over 21-weeks. Furthermore, computational analysis and experimental validations identified GSK3β, KEAP1 and EGFR as putative molecular targets of SY. Collectively, our findings reveal that SY enhances cellular antioxidant defenses, exhibits anti-genotoxic effects, and functions as a promising chemopreventive agent. [ABSTRACT FROM AUTHOR]

Adenocarcinoma of the bladder is a rare urinary bladder carcinoma with limited therapy options due to lack of molecular characterization. Here, we aimed to reveal the mutational and transcriptomic landscapes of adenocarcinoma of the bladder and assess any relationship with prognosis. Between February 2015 and June 2021, a total of 23 patients with adenocarcinoma of the bladder were enrolled. These included 16 patients with primary bladder adenocarcinomas and seven patients with urachal adenocarcinoma. Whole exome sequencing (16 patients), whole genome sequencing (16 patients), bulk RNA sequencing (RNA‐seq) (19 patients), and single‐cell RNA‐seq (5 patients) were conducted for the specimens. Correlation analysis, survival analysis, and t‐tests were also performed. Prevalent T>A substitutions were observed among somatic mutations, and major trinucleotide contexts included 5'‐CTC‐3' and 5'‐CTG‐3'. This pattern was mainly contributed by COSMIC signature 22 related to chemical carcinogen exposure (probably aristolochic acid), which has not been reported in bladder adenocarcinoma. Moreover, genes with copy number changes were also enriched in the KEGG term 'chemical carcinogenesis'. Transcriptomic analysis suggested high immune cell infiltration and luminal‐like features in the majority of samples. Interestingly, a small fraction of samples with an APOBEC‐derived mutational signature exhibited a higher risk of disease progression compared with samples with only a chemical carcinogen‐related signature, confirming the molecular and prognostic heterogeneity of bladder adenocarcinoma. This study presents mutational and transcriptomic landscapes of bladder adenocarcinoma, and indicates that a chemical carcinogen‐related mutational signature may be related to a better prognosis compared with an APOBEC signature in adenocarcinoma of the bladder. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide. Late-stage detection, ineffective treatments, and tumor recurrence contribute to the low survival rate of the HCC. Conventional chemotherapeutic drugs, like doxorubicin (DOX), are associated with severe side effects, limited effectiveness, and tumor resistance. To improve therapeutic outcomes and minimize these drawbacks, combination therapy with natural drugs is being researched. Herein, we assessed the antitumor efficacy of Ceiba pentandra ethyl acetate extract alone and in combination with DOX against diethylnitrosamine (DENA)-induced HCC in rats. Our in vivo study significantly revealed improvement in the liver-function biochemical markers (ALT, AST, GGT, and ALP), the tumor marker (AFP-L3), and the histopathological features of the treated groups. A UHPLC-Q-TOF-MS/MS analysis of the Ceiba pentandra ethyl acetate extract enabled the identification of fifty phytomolecules. Among these are the dietary flavonoids known to have anticancer, anti-inflammatory, and antioxidant qualities: protocatechuic acid, procyanidin B2, epicatechin, rutin, quercitrin, quercetin, kaempferol, naringenin, and apigenin. Our findings highlight C. pentandra as an affordable source of phytochemicals with possible chemosensitizing effects, which could be an intriguing candidate for the development of liver cancer therapy, particularly in combination with chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

Despite advances in breast cancer treatment, there remains a need for local management of noninvasive, low-grade ductal carcinoma in situ (DCIS). These focal lesions are well suited for local intraductal treatment. Intraductal administration supported target site drug retention, improved efficacy, and reduced systemic exposure. Here, we used a poly(N-isopropyl acrylamide, pNIPAM) nanoparticle delivery system loaded with cytotoxic piplartine and an MAPKAP Kinase 2 inhibitor (YARA) for this purpose. For tumor environment targeting, a collagen-binding peptide SILY (RRANAALKAGELYKSILYGSG-hydrazide) was attached to pNIPAM nanoparticles, and the nanoparticle diameter, zeta potential, drug loading, and release were assessed. The system was evaluated for cytotoxicity in a 2D cell culture and 3D spheroids. In vivo efficacy was evaluated using a chemical carcinogenesis model in female Sprague–Dawley rats. Nanoparticle delivery significantly reduced the IC50 of piplartine (4.9 times) compared to the drug in solution. The combination of piplartine and YARA in nanoparticles further reduced the piplartine IC50 (~15 times). Treatment with these nanoparticles decreased the in vivo tumor incidence (5.2 times). Notably, the concentration of piplartine in mammary glands treated with nanoparticles (35.3 ± 22.4 μg/mL) was substantially higher than in plasma (0.7 ± 0.05 μg/mL), demonstrating targeted drug retention. These results indicate that our nanocarrier system effectively reduced tumor development with low systemic exposure. [ABSTRACT FROM AUTHOR]

Frameworks have been developed to standardize the assessment of carcinogenic potential in the pharmaceutical and agrochemical industries, building upon decades of research. Carcinogenicity is also evaluated during the safety evaluation of food substances, using a comprehensive approach unique to each substance. To better understand these approaches, a retrospective assessment was conducted on the publicly available database of substances notified to the United States Food and Drug Administration (US FDA) as being Generally Recognized As Safe (GRAS). The data contained within these GRAS notifications (GRNs) were reviewed for the methods used to evaluate carcinogenic potential (genotoxicity studies, 2-year bioassays, other pre-clinical animal studies) to identify patterns that could provide an understanding of how this assessment has been conducted for different categories of food substances. While different approaches to the safety evaluation were required to adapt to the unique food substances, the data in all notifications supported the conclusion of safety. The evaluation of food substances for carcinogenic potential must consider all available data, including identifying the need for when more data must be generated to support an evaluation. Due to the complexity of substances used in food, ranging from defined chemical entities to minimally processed agricultural commodities to live microorganisms, the approach to conducting the safety evaluation of food substances must be able to adapt to the most relevant scientifically supported approach. This paper illustrates the data commonly used to support the safety of different types of food substances and proposes an approach familiar to other product sectors. [ABSTRACT FROM AUTHOR]

Per- and poly-fluoroalkyl substances (PFAS) exhibit high persistence in the environment and accumulate within the human body, warranting a thorough assessment of their toxicity. In this study, we exposed mice (male C57BL/6J mice aged 8 weeks) to a composite of nine PFAS, encompassing both long-chain PFAS (e.g., perfluorooctanoic acid and perfluorooctanesulfonic acid) and short-chain PFAS (e.g., perfluorobutanoic acid and perfluorobutanesulfonic acid). The exposure concentrations of PFAS were equivalent to the estimated daily human intake in the composition reported (1 µg/L (sum of the nine compounds), representing the maximum reported exposure concentration). Histological examination revealed hepatocyte vacuolization and irregular hepatocyte cord arrangement, indicating that exposure to low levels of the PFAS mixture causes morphological changes in liver tissues. Transcriptome analysis revealed that PFAS exposure mainly altered a group of genes related to metabolism and chemical carcinogenesis. Machine learning analysis of the liver metabolome showed a typical concentration-independent alteration upon PFAS exposure, with the annotation of substances such as glutathione and 5-aminovaleric acid. This study demonstrates that daily exposure to PFAS leads to morphological changes in liver tissues and alters the expression of metabolism- and cancer-related genes as well as phospholipid metabolism. [ABSTRACT FROM AUTHOR]

Environmental carcinogens exert their carcinogenic effects by forming DNA adducts. This type of DNA damage can also be formed endogenously as a result of, e.g., oxidative damage. Unrepaired DNA adducts may induce mutations in critical genes, leading to the initiation of chemical carcinogenesis. Therefore, detection, identification, and quantification of DNA adducts is essential for cancer risk assessment. Over the last 50 years, the major DNA adducts formed by different classes of environmental carcinogens were characterized. With the development of techniques such as 32P-postlabeling, their measurement was implemented into molecular epidemiology. Advances in liquid chromatography-tandem mass spectrometry (LC-MS) made the measurement of adducts more precise and allowed to gain knowledge about their identity and structures. Therefore, these new techniques opened the way to DNA adductomics, the "omics" approach investigating DNA adducts comprehensively, similarly to proteomics. This review presents the historical perspective of DNA adducts research and the emerging field of adductomics. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a major global health concern, representing one of the leading causes of cancer-related deaths. Despite various treatment options, the prognosis for HCC patients remains poor, emphasizing the need for a deeper understanding of the factors contributing to HCC development. This study investigates the role of poly(ADP-ribosyl)ation in hepatocyte maturation and its impact on hepatobiliary carcinogenesis. A conditional Parg knockout mouse model was employed, utilizing Cre recombinase under the albumin promoter to target Parg depletion specifically in hepatocytes. The disruption of the poly(ADP-ribosyl)ating pathway in hepatocytes affects the early postnatal liver development. The inability of hepatocytes to finish the late maturation step that occurs early after birth causes intensive apoptosis and acute inflammation, resulting in hypertrophic liver tissue with enlarged hepatocytes. Regeneration nodes with proliferative hepatocytes eventually replace the liver tissue and successfully fulfill the liver function. However, early developmental changes predispose these types of liver to develop pathologies, including with a malignant nature, later in life. In a chemically induced liver cancer model, Parg-depleted livers displayed a higher tendency for hepatocellular carcinoma development. This study underscores the critical role of the poly(ADP-ribosyl)ating pathway in hepatocyte maturation and highlights its involvement in liver pathologies and hepatobiliary carcinogenesis. Understanding these processes may provide valuable insights into liver biology and liver-related diseases, including cancer. [ABSTRACT FROM AUTHOR]

In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of several cancer hallmark pathways such as MAPK, mTOR and integrin/ILK/actin, affecting epithelial and stromal colonic cells. Importantly, an independent analysis of protein arrays of human colon tumors colonized with SGG showed up-regulation of PI3K/Akt/mTOR and MAPK pathways, providing clinical relevance to our findings. To test SGG's capacity to induce pre-cancerous transformation of the murine colonic epithelium, we grew ex vivo organoids which revealed unusual structures with compact morphology. Taken together, our results demonstrate the oncogenic role of SGG UCN34 in a murine model of CRC associated with activation of multiple cancer-related signaling pathways. [ABSTRACT FROM AUTHOR]

We examine the use of the truncated singular value decomposition and Tikhonov regularization in standard form to address ill-posed least squares problems Ax = b that frequently arise in molecular mechanics force field parameter optimization. We illustrate these approaches by applying them to dihedral parameter optimization of genotoxic polycyclic aromatic hydrocarbon-DNA adducts that are of interest in the study of chemical carcinogenesis. Utilizing the discrete Picard condition and/or a well-defined gap in the singular value spectrum when A has a well-determined numerical rank, we are able to systematically determine truncation and in turn regularization parameters that are correspondingly used to produce truncated and regularized solutions to the ill-posed least squares problem at hand. These solutions in turn result in optimized force field dihedral terms that accurately parameterize the torsional energy landscape. As the solutions produced by this approach are unique, it has the advantage of avoiding the multiple iterations and guess and check work often required to optimize molecular mechanics force field parameters. [ABSTRACT FROM AUTHOR]

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Phenobarbital (PB) is an archetypal substance used as a mouse hepatocellular carcinoma (HCC) promotor in established experimental protocols. Our previous results showed CAR is the essential factor for PB induced HCC promotion. Subsequent studies suggested Gadd45β, which is induced by PB through CAR activation, is collaborating with CAR to repress TNF-α induced cell death. Here, we used Gadd45β null mice (Gadd45β KO) treated with N-diethylnitrosamine (DEN) at 5 weeks of age and kept the mice with PB supplemented drinking water from 7 to 57 weeks old. Compared with wild type mice, Gadd45β KO mice developed no HCC in the PB treated group. Increases in liver weight were more prominent in wild type mice than KO mice. Microarray analysis of mRNA derived from mouse livers found multiple genes specifically up or down regulated in wild type mice but not null mice in DEN + PB groups. Further qPCR analysis confirmed two genes, Tgfbr2 and irisin/Fndc5, were up-regulated in PB treated wild type mice but no significant increase was observed in Gadd45β KO mice. We focused on these two genes because previous reports showed that hepatic Irisin/Fndc5 expression was significantly higher in HCC patients and that irisin binds to TGF-β receptor complex that includes TGFBR2 subunit. Our results revealed irisin peptide in cell culture media increased the growth rate of mouse hepatocyte-derived AML12 cells. Microarray analysis revealed that irisinregulated genes in AML12 cells showed a significant association with the genes in the TGF-β pathway. Expression of irisin/Fndc5 and Tgfbr2 induced growth of human HCC cell line HepG2. Thus, Gadd45β plays an indispensable role in mouse HCC development regulating the irisin/Fndc5 and Tgfbr2 genes. [ABSTRACT FROM AUTHOR]

In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of several cancer hallmark pathways such as MAPK, mTOR and integrin/ILK/actin, affecting epithelial and stromal colonic cells. Importantly, an independent analysis of protein arrays of human colon tumors colonized with SGG showed up-regulation of PI3K/Akt/mTOR and MAPK pathways, providing clinical relevance to our findings. To test SGG's capacity to induce pre-cancerous transformation of the murine colonic epithelium, we grew ex vivo organoids which revealed unusual structures with compact morphology. Taken together, our results demonstrate the oncogenic role of SGG UCN34 in a murine model of CRC associated with activation of multiple cancer-related signaling pathways. [ABSTRACT FROM AUTHOR]

In contrast to genotoxic carcinogens, there are currently no internationally agreed upon regulatory tools for identifying non-genotoxic carcinogens of human relevance. The rodent cancer bioassay is only used in certain regulatory sectors and is criticized for its limited predictive power for human cancer risk. Cancer is due to genetic errors occurring in single cells. The risk of cancer is higher when there is an increase in the number of errors per replication (genotoxic agents) or in the number of replications (cell proliferation-inducing agents). The default regulatory approach for genotoxic agents whereby no threshold is set is reasonably conservative. However, non-genotoxic carcinogens cannot be regulated in the same way since increased cell proliferation has a clear threshold. An integrated approach for the testing and assessment (IATA) of non-genotoxic carcinogens is under development at the OECD, considering learnings from the regulatory assessment of data-rich substances such as agrochemicals. The aim is to achieve an endorsed IATA that predicts human cancer better than the rodent cancer bioassay, using methodologies that equally or better protect human health and are superior from the view of animal welfare/efficiency. This paper describes the technical opportunities available to assess cell proliferation as the central gateway of an IATA for non-genotoxic carcinogenicity. [ABSTRACT FROM AUTHOR]

Because of its chemical versatility and abundance in nature, aluminium is employed in a myriad of frequently used products - including cosmetics and food additives - and applications - drinking water purification procedures being an example. Despite what its widespread use might suggest, aluminium's harmlessness is a matter of debate in the scientific community. In this article we trace the lines of a growing questioning about the potential mutagenic effects of this metal, due to the data produced over the recent years, and with an eye to the discussions currently underway in this regard between the scientific community, industry, and regulatory bodies. [ABSTRACT FROM AUTHOR]

[Objectives] The paper was to explore the mechanism of capsicum (Capsicum annuum L.) in treating type 2 diabetes mellitus (T2DM) and search for new targets. [Methods] The active ingredients of capsicum were queried from TCMSP database to obtain the corresponding target proteins. The related targets of T2DM were screened from GeneCards database, and the target intersection of active ingredients of capsicum and diabetes mellitus was obtained via Venny software. The protein-protein interaction (PPI) network of the compounds was constructed using STRING database, and the GO bio-function and KEGG pathway enrichment were further analyzed using Metascape database. [ Results] Through TCMSP database query and conditional screening, 14 candidate active molecules, 93 potential targets and 225 related pathways were obtained. [Conclusions] The results of GO and KEGG enrichment analysis show that the main active ingredients of capsicum play a role in the treatment of T2DM by regulating cancer pathways, chemical carcinogenesis--receptor activation, proteoglycans in cancer, and prostate cancer pathways, 'which will provide an important theoretical basis for subsequent research. [ABSTRACT FROM AUTHOR]

Non-melanoma skin cancer (NMSC) is the most common cancer in Caucasians worldwide. We investigated the pathophysiological role of MIF and its homolog D-DT in UVB- and chemically induced NMSC using Mif−/−, D-dt−/− and Mif−/−/D-dt−/− mice on a hairless SKH1 background. Knockout of both cytokines showed similar attenuating effects on inflammation after acute UVB irradiation and tumor formation during chronic UVB irradiation, without additive protective effects noted in double knockout mice, indicating that both cytokines activate a similar signaling threshold. In contrast, genetic deletion of Mif and D-dt had no major effects on chemically induced skin tumors. To get insight into the contributing mechanisms, we used an in vitro 3D skin model with incorporated macrophages. Application of recombinant MIF and D-DT led to an accumulation of macrophages within the epidermal part that could be reversed by selective inhibitors of MIF and D-DT pathways. In summary, our data indicate that MIF and D-DT contribute to the development and progression of UVB- but not chemically induced NMSC, a role at least partially accounted by effects of both cytokines on epidermal macrophage accumulation. These data highlight that MIF and D-DT are both potential therapeutic targets for the prevention of photocarcinogenesis but not chemical carcinogenesis. [ABSTRACT FROM AUTHOR]

Inflammatory Bowel diseases (IBDs) constitute a complex panel of disorders characterized with chronic inflammation affecting the alimentary canal along with extra intestinal manifestations. Its exact etiology is still unknown; however, it seems to be the result of uncharacterized environmental insults in the intestine and their immunological consequences along with dysbiosis, in genetically predisposed individuals. It was the main target of our team since 2002 to explore the etiology of IBD and the related role of bacteria. For almost two decades, our laboratory, among others, has been involved in the reciprocal interaction between the host gastrointestinal lining and the homing microbiota. In the first decade, the attention of scientists focused on the possible role of enteropathogenic E. coli and its relationship to the mechanistic pathways involved in IBD induced in both rats and mice by chemicals like Iodoacetamide, Dextran Sodium Sulfate, Trinitrobenzene, thus linking microbial alteration to IBD pathology. A thorough characterization of the various models was the focus of research in addition to exploring how to establish an active homeostatic composition of the commensal microbiota, including its wide diversity by restoration of gut microbiota by probiotics and moving from dysbiosis to eubiosis. In the last six years and in order to effectively translate such findings into clinical practice, it was critical to explore their relationship to colorectal cancer CRC both in solid tumors and chemically induced CRC. It was also critical to explore the degree of intestinal dysbiosis and linking to IBD, CRC and diabetes. Remarkably, the active mechanistic pathways were proposed as well as the role of microbiota or bacterial metabolites involved. This review covers two decades of investigations in our laboratory and sheds light on the different aspects of the relationship between microbiota and IBD with an emphasis on dysbiosis, probiotics and the multiple mechanistic pathways involved. [ABSTRACT FROM AUTHOR]

Butyrolactone I (BTL-I), a butenolide compound isolated from land or marine-derived fungi, has been reported to show diverse activities. To further study the pharmaceutical potential of BTL-I, transcriptome and bioinformatics analysis of BTL-I treated HepG2 cells were taken. BTL-I was revealed with lipid metabolism regulatory activity and confirmed by increasing the mRNA expression of related genes, such as LXRα and its target gene UGT1A1. However, the obvious chemical carcinogenesis of BTL-I was also disclosed. BTL-I could significantly increase the mRNA and protein levels of oncogenes such as CYP1A1. Molecular docking of BTL-I and its analogs were performed to understand the active or toxic effects. Although BTL-I showed attractive activities, enough attention must be paid to its adverse effects in its further development. [ABSTRACT FROM AUTHOR]

Five million non-melanoma skin cancers occur globally each year, and it is one of the most common malignant cancers. The dysregulation of the endocannabinoid system, particularly cannabinoid receptor 2 (CB2), is implicated in skin cancer development, progression, and metastasis. Comparing wildtype (WT) to systemic CB2 knockout (CB2-/-) mice, we performed a spontaneous cancer study in one-year old mice, and subsequently used the multi-stage chemical carcinogenesis model, wherein cancer is initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). We found that aging CB2-/- mice have an increased incidence of spontaneous cancerous and precancerous skin lesions compared to their WT counterparts. In the DMBA/TPA model, CB2-/- developed more and larger papillomas, had decreased spontaneous regression of papillomas, and displayed an altered systemic immune profile, including upregulated CD4+ T cells and dendritic cells, compared to WT mice. Immune cell infiltration in the tumor microenvironment was generally low for both genotypes, although a trend of higher myeloid-derived suppressor cells was observed in the CB2-/- mice. CB2 expression in carcinogen-exposed skin was significantly higher compared to naïve skin in WT mice, suggesting a role of CB2 on keratinocytes. Taken together, our data show that endogenous CB2 activation plays an anti-tumorigenic role in non-melanoma skin carcinogenesis, potentially via an immune-mediated response involving the alteration of T cells and myeloid cells coupled with the modulation of keratinocyte activity. [ABSTRACT FROM AUTHOR]

Because of its chemical versatility and abundance in nature, aluminium is employed in a myriad of frequently used products - including cosmetics and food additives - and applications – drinking water purification procedures being an example. Despite what its widespread use might suggest, aluminium’s harmlessness is a matter of debate in the scientific community. In this article we trace the lines of a growing questioning about the potential mutagenic effects of this metal, due to the data produced over the recent years, and with an eye to the discussions currently underway in this regard between the scientific community, industry, and regulatory bodies.

Post-translational modifications (PTMs) regulate all aspects of protein function. Therefore, upstream regulators of PTMs, such as kinases, acetyltransferases, or methyltransferases, are potential therapeutic targets for human diseases, including cancer. To date, multiple inhibitors and/or agonists of these PTM upstream regulators are in clinical use, while others are still in development. However, these upstream regulators control not only the PTMs of disease-related target proteins but also other disease-irrelevant substrate proteins. Thus, nontargeted perturbing activities may introduce unwanted offtarget toxicity issues that limit the use of these drugs in successful clinical applications. Therefore, alternative drugs that solely regulate a specific PTM of the disease-relevant protein target may provide a more precise effect in treating disease with relatively low side effects. To this end, chemically induced proximity has recently emerged as a powerful research tool, and several chemical inducers of proximity (CIPs) have been used to target and regulate protein ubiquitination, phosphorylation, acetylation, and glycosylation. These CIPs have a high potential to be translated into clinical drugs and several examples such as PROTACs and MGDs are now in clinical trials. Hence, more CIPs need to be developed to cover all types of PTMs, such as methylation and palmitoylation, thus providing a full spectrum of tools to regulate protein PTM in basic research and also in clinical application for effective cancer treatment. [ABSTRACT FROM AUTHOR]

It is well‐documented that pro‐inflammatory cytokines and inflammation play a significant role in the expansion of cancer disease. Gallic acid (GA), a natural compound, and metformin (Met), a synthetic drug exhibit potent anticancer potential via the distinct molecular mechanism. However, whether both these compounds can act synergistically to preclude and treat cancer is still unknown. This prompted us to scrutinize, the synergism between GA and Met, and that of a new co‐drug synthesizing of GA and Met (GA‐Met) and investigated the chemo‐protective effect against breast cancer with possible intervention of cytokines. In vivo studies were based on chemical carcinogenesis, challenging breast tissue by dimethylbenz[α]anthracene (DMBA). Tumour incidence, tumour burden, pro‐inflammatory cytokines in serum, breast, hepatic tissue, macroscopically and histological analysis of mammary tumours were carried out and estimated. GA, Met and GA‐Met co‐drug exhibited the inhibition of cell proliferation; higher reduction of cell proliferation was observed by GA‐Met. The inhibitory effect of GA‐Met was linked to cell cycle arrest at G0/G1 phase, along with induction of apoptosis and accumulation in the sub‐G1 phase. GA‐Met significantly inhibited the cytokines production along with protection against DMBA‐induced hyperplasia. Taken altogether, the current result suggests that GA‐Met co‐drug endows a safe and protective effect against cancer metastasis and can possibly use for the treatment of human breast cancer. [ABSTRACT FROM AUTHOR]

Pentachlorophenol (PCP) is a ubiquitous environmental contaminant commonly existing as its sodium salt (NaPCP), which enters the human body primarily through long term but low-level dietary exposure. PCP contributes to chemical carcinogenesis and teratogenesis. In this study, the probabilistic risk of dietary exposure to PCP in Guangzhou citizens was investigated. In total, 923 food samples in the categories of pork, livestock (beef and lamb), poultry, offal, eggs, and freshwater fish (considered to be relatively susceptible to PCP contamination) were collected from various markets in Guangzhou and tested for PCP. Probabilistic risk assessment model calculations for PCP dietary exposure and margin of exposure (MOE) values were performed using @RISK software, based on a Monte Carlo simulation with 10,000 iterations. The overall detection rate of PCP (above 1 μg kg−1, the detection limit) was 19.9% (184/923), with an average of 7.9 μg kg−1. The highest rate of PCP detection, 28.2%, was in livestock (beef and lamb). The MOE value for dietary PCP exposure in general Guangzhou residents averaged 400, which was far below 5,000 (the borderline for judging a health risk). The lowest MOE value, 190, was observed in the 3- to-6-year old population and indicates a significant risk. In conclusion, this study suggests that PCP exposure in Guangzhou residents is of considerable health risk, especially for the pre-school young children. [ABSTRACT FROM AUTHOR]