Deciphering the impact of circRNA-mediated autophagy on tumor therapeutic resistance: a novel perspective.

Cancer therapeutic resistance remains a significant challenge in the pursuit of effective treatment strategies. Circular RNAs (circRNAs), a class of non-coding RNAs, have recently emerged as key regulators of various biological processes, including cancer progression and drug resistance. This review highlights the emerging role of circRNAs-mediated autophagy in cancer therapeutic resistance, a cellular process that plays a dual role in cancer by promoting both cell survival and death. Increasing evidence suggests that circRNAs can modulate autophagy pathways, thereby influencing the response of cancer cells to therapeutic agents. In this context, the intricate interplay between circRNAs, autophagy, and therapeutic resistance is explored. Various mechanisms are discussed through which circRNAs can impact autophagy, including direct interactions with autophagy-related genes, modulation of signaling pathways, and cross-talk with other non-coding RNAs. Furthermore, the review delves into specific examples of how circRNA-mediated autophagy regulation can contribute to resistance against chemotherapy and radiotherapy. Understanding these intricate molecular interactions provides valuable insights into potential strategies for overcoming therapeutic resistance in cancer. Exploiting circRNAs as therapeutic targets or utilizing them as diagnostic and predictive biomarkers opens new avenues for developing personalized treatment approaches. In summary, this review underscores the importance of circRNA-mediated autophagy in cancer therapeutic resistance and proposes future directions for research in this exciting and rapidly evolving field.

Decreased GDF9 and BMP15 in follicle fluid and granulosa cells and outcomes of IVF-ET among young patients with low prognosis.

PURPOSE: To analyze the level of growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) in follicle fluid (FF) and granulosa cells (GCs) derived from young patients with low prognosis for in vitro fertilization and embryo transfer (IVF-ET) treatment. METHODS: A prospective cohort study was carried out by enrolling 52 young patients with low prognosis according to the POSEIDON classification group 3 (low prognosis group) and 51 young patients with normal ovarian reserve (control group). The concentration of the GDF9 and BMP15 proteins in FF was determined by enzyme-linked immunosorbent assay. The mRNA level of the GDF9 and BMP15 in the GCs was measured by quantitative real-time PCR. RESULTS: The concentration of GDF9 (1026.72 ± 159.12 pg/mL vs. 1298.06 ± 185.41 pg/mL) and BMP15 (685.23 ± 143.91 pg/mL vs. 794.37 ± 81.79 pg/mL) in FF and the mRNA level of GDF9 and BMP15 in the GCs and the live birth rate per treatment cycle started (30.77% vs. 50.98%) and oocytes retrieved (4.25 ± 1.91 vs.12.04 ± 4.24) were significantly lower, whereas the canceled cycle rate was significantly higher (9.62% vs. 0) in the low prognosis group compared with the control group (P < 0.05). The expression of GDF9 and BMP15 in the ovary was positively correlated with live birth (P < 0.05). CONCLUSION: The expression of GDF9 and BMP15 in the ovary was decreased in young patients with low prognosis accompanied by a poorer outcome of IVF-ET treatment. TRIAL REGISTRATION: ChiCTR1800016107 (Chinese Clinical Trial Registry), May 11, 2018. ( http://www.chictr.org.cn/edit.aspx?pid=27216&htm=4 ).

Mutual regulation between N6-methyladenosine (m6A) modification and circular RNAs in cancer: impacts on therapeutic resistance.

The resistance of tumor cells to therapy severely impairs the efficacy of treatment, leading to recurrence and metastasis of various cancers. Clarifying the underlying mechanisms of therapeutic resistance may provide new strategies for overcoming cancer resistance. N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotes, and is involved in the regulation of RNA splicing, translation, transport, degradation, stability and processing, thus affecting several physiological processes and cancer progression. As a novel type of multifunctional non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been demonstrated to play vital roles in anticancer therapy. Currently, accumulating studies have revealed the mutual regulation of m6A modification and circRNAs, and their interaction can further influence the sensitivity of cancer treatment. In this review, we mainly summarized the recent advances of m6A modification and circRNAs in the modulation of cancer therapeutic resistance, as well as their interplay and potential mechanisms, providing promising insights and future directions in reversal of therapeutic resistance in cancer.

Tanshinone IIA prevents acetaminophen-induced nephrotoxicity through the activation of the Nrf2-Mrp2/4 pathway in mice.

It's known that APAP overdose often leads to hepatotoxicity and nephrotoxicity. In the present study, we investigated the preventative effect of Tan IIA on APAP-induced nephrotoxicity. Mice were orally administrated with Tan IIA (10 or 30 mg/kg/day) for 1 week and subsequently gavaged with 200 mg/kg of APAP. Tan IIA reduced APAP-induced nephrotoxicity as evidenced by histopathological evaluation and serum creatinine levels. Tan IIA pretreatment promoted the efflux of the toxic intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI), thus reduced its injury to mouse kidney. After Tan IIA pretreatment, a remarkable increase in mRNA and protein expression of Nrf2 and its target genes Mrp2 and Mrp4 was observed in Nrf2+/+ mice kidneys, however, no obvious change of Mrp2 and Mrp4 mRNA and protein expression was detected in Nrf2-/- mice kidneys. HK-2 cells were used for exploring the roles of Tan IIA in the Nrf2-MRPs pathway in vitro. Consistently, Tan IIA up-regulated the Nrf2-MRPs pathway and promoted the nuclear Nrf2 accumulation in HK-2 cells. Collectively, our findings suggested that Tan IIA facilitated the clearance of toxic intermediate metabolite NAPQI from the kidney through upregulation of the Nrf2-MRP2/4 pathway, thereby, performing preventive effects against APAP-induced nephrotoxicity.

Regulatory roles of phytochemicals on circular RNAs in cancer and other chronic diseases.

As novel non-coding RNAs (ncRNAs), circular RNAs (circRNAs) play an essential role in the pathogenesis of many chronic diseases, and the regulation of these functional molecules has become a research hotspot gradually. Within the past decade, phytochemicals were reported to regulate the expression of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in various chronic diseases, and more recently, most studies focus on the regulatory roles of phytochemicals on circRNAs. Abnormal expression of circRNAs has been identified in chronic diseases like cancer, heart failure, depression and atherosclerosis, and numerous studies have revealed the modulation of circRNAs by phytochemicals including berberine, celastrol, cinnamaldehyde, curcumin, et al. The expression of circRNAs, such as circSATB2 and circFOXM1, were modulated by phytochemicals, and these regulations further affected cell proliferation, apoptosis, migration, invasion, autophagy, chemosensitivity, radiosensitivity and other biological processes. Mechanismly, the circRNAs mainly functioned as miRNA sponge, subsequently affecting miRNA-mediated regulation of target genes and related cell signaling pathways. In this review, we summarized the impact of phytochemicals on circRNAs expression and biological function, and discussed the mechanisms underlying phytochemicals regulating circRNAs in cancer and other chronic diseases.

A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin.

Microtubules composed of α/ß tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.

Pharmacokinetic properties of wogonin and its herb-drug interactions with docetaxel in rats with mammary tumors.

Docetaxel, frequently used for the treatment of breast cancer, is mainly metabolized via hepatic cytochrome P450 (CYP) 3A in humans and is also a substrate of P-glycoprotein (P-gp). Wogonin has been shown to be able to modulate the activities of CYPs and P-gp, and it could serve as an adjuvant chemotherapeutic agent. However, the impacts of co-administration of wogonin and docetaxel on their pharmacokinetics have not been studied because of a lack of an analytical method for their simultaneous measurement. In the present study, we established an HPLC-MS/MS method for simultaneous measurement of wogonin and docetaxel in rat plasma, and it was then utilized to explore the pharmacokinetics of wogonin and the herb-drug interactions between wogonin and docetaxel after their combined administration in rats with mammary tumors. The rats received 10, 20 and 40 mg/kg wogonin via oral administration, with or without docetaxel intravenously administered at 10 mg/kg, and the plasma concentrations of wogonin and docetaxel were measured using the established and validated HPLC-MS/MS method. The Cmax and AUC0-t of wogonin were proportionally increased in the dose range from 10 to 40 mg/kg, suggesting a linear pharmacokinetics of wogonin. Moreover, the Cmax and AUC0-t of docetaxel and the AUC0-t of wogonin were increased after co-administration (p < 0.05), indicating increased in vivo exposures of both wogonin and docetaxel, which might lead to an increase in not only therapeutic but also toxic effects. Thus the alterations of pharmacokinetics should be taken into consideration when wogonin and docetaxel are co-administered.

HIF-1α-induced autophagy contributes to cisplatin resistance in ovarian cancer cells.

In this study, the viability and apoptosis of ovarian cancer cell line OVCAR-3 were assessed using MTT and flow cytometry analysis. GFP-tagged LC3 plasmid transfection was utilized to demonstrate the occurrence of autophagy. The expression of HIF-1α, Beclin1, LC3 and ß-actin were determined with Western blot analysis. We found that hypoxia could inhibit cisplatin induced apoptosis in OVCAR-3 cells and enhance the chemoresistance to cisplatin. Furthermore, GFP-tagged LC3 plasmid transfection and western blot were used to demonstrate that hypoxia induced chemoresistance of OVCAR-3 cells to cisplatin is related to HIF-1α-induced autophagy. All these findings suggest that the cisplatin resistance of ovarian cancer cells is associated with HIF-1α-induced autophagy.

Anti-Tumor Effects of Atractylenolide-I on Human Ovarian Cancer Cells.

BACKGROUND The aim of this study was to investigate the effects of Atractylenolide-I (AT-I), a naturally occurring sesquiterpene lactone isolated from Atractylodes macrocephala Koidz, on human ovarian cancer cells. MATERIAL AND METHODS The viability and anchorage-independent growth of ovarian cancer cells were evaluated using MTT and colony formation assay, respectively. Cell cycle and apoptosis were detected with flow cytometry analysis. The level of cyclin B1 and CDK1 was measured using qPCR and ELISA analysis. The expression of Bax, cleaved caspase-9, cleaved caspase-3, cytochrome c, AIF, and Bcl-2, and phosphorylation level of PI3K, AKT, and mTOR were determined with Western blot analysis. RESULTS AT-I decreased the cell viability and suppressed anchorage-independent growth of A2780 cells. Cell cycle was arrested in G2/M phase transition by AT-I treatment, which was related to decreased expression of cyclin B1 and CDK1 in a dose-dependent manner. In addition, the treatment induced apoptosis, as shown by up-regulation of Bax, cleaved caspase-9, cleaved caspase-3, and cytosolic release of cytochrome c and AIF, and down-regulation of Bcl-2, in a dose-dependent manner. Then, the effects of AT-I on PI3K/Akt/mTOR pathways were examined to further investigate the underlying anti-cancer mechanism of AT-I, and the results showed that treatment with AT-I significantly decreased the phosphorylation level of PI3K, Akt, and mTOR. CONCLUSIONS This study demonstrated that AT-I induced cell cycle arrest and apoptosis through inhibition of PI3K/Akt/mTOR pathway in ovarian cancer cells. These results suggest that AT-I might be a potential therapeutic agent in the treatment of ovarian cancer.

Chemopreventive effects of atractylenolide-III on mammary tumorigenesis via activation of the Nrf2/ARE pathway through autophagic degradation of Keap1.

The incidence of breast cancer is increasing annually, making it a major health threat for women. Chemoprevention using natural, dietary, or synthetic products has emerged as a promising approach to address this growing burden. Atractylenolide-III (AT-III), a sesquiterpenoid present in various medicinal herbs, has demonstrated potential therapeutic effects against several diseases, including tumors, nonalcoholic fatty liver disease, and cerebral ischemic injury. However, its impact on breast cancer chemoprevention remains unexplored. In this study, we used an N-methyl-N-nitrosourea (NMU)-induced rat breast cancer model and 17ß-estradiol (E2)-treated MCF-10A cells to evaluate the chemopreventive potential of AT-III on mammary tumorigenesis. AT-III inhibited mammary tumor progression, evidenced by reduced tumor volume and multiplicity, prolonged tumor latency, and the reversal of NMU-induced weight loss. Furthermore, AT-III suppressed NMU-induced inflammation and oxidative stress through the Nrf2/ARE pathway in breast cancer tissues. In vitro, AT-III effectively suppressed E2-induced anchorage-independent growth and cell migration in MCF-10A cells. Nrf2 knockdown attenuated the protective effects of AT-III, highlighting the pivotal role of Nrf2 in AT-III-mediated suppression of tumorigenesis. The mechanism involves the induction of Nrf2 expression by AT-III through the autophagic degradation of Kelch-like ECH-associated protein 1 (Keap1). Overall, the results of this study indicate that AT-III is a promising candidate for breast cancer chemoprevention and provide valuable insights into its molecular interactions and signaling pathways.

The role of circular RNAs in regulating resistance to cancer immunotherapy: mechanisms and implications.

Cancer immunotherapy has rapidly transformed cancer treatment, yet resistance remains a significant hurdle, limiting its efficacy in many patients. Circular RNAs (circRNAs), a novel class of non-coding RNAs, have emerged as pivotal regulators of gene expression and cellular processes. Increasing evidence indicates their involvement in modulating resistance to cancer immunotherapy. Notably, certain circRNAs function as miRNA sponges or interact with proteins, influencing the expression of immune-related genes, including crucial immune checkpoint molecules. This, in turn, shapes the tumor microenvironment and significantly impacts the response to immunotherapy. In this comprehensive review, we explore the evolving role of circRNAs in orchestrating resistance to cancer immunotherapy, with a specific focus on their mechanisms in influencing immune checkpoint gene expression. Additionally, we underscore the potential of circRNAs as promising therapeutic targets to augment the effectiveness of cancer immunotherapy. Understanding the role of circRNAs in cancer immunotherapy resistance could contribute to the development of new therapeutic strategies to overcome resistance and improve patient outcomes.

Exploring the potential of Huangqin Tang in breast cancer treatment using network pharmacological analysis and experimental verification.

AIMS OF THIS STUDY: This study aims to investigate the potential of Huangqin Tang (HQT), a traditional Chinese medicine formulation, in the treatment of breast cancer (BC) through a comprehensive approach integrating network pharmacology, molecular docking, and experimental validation. METHODS: Chemical composition and target information of HQT were collected using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Disease-related target genes were obtained from the GeneCards database. Network pharmacological analysis, including construction of compound-disease-target networks and protein-protein interaction networks, was performed. Molecular docking simulations were conducted to evaluate the binding affinity between HQT components and key targets. Experimental validation was carried out using cell viability assays, clone formation assays, flow cytometry, Western blotting, and pathway analysis. RESULTS: A total of 210 candidate targets were identified. Network analysis revealed STAT3, AKT1, MAPK3 etc. as central targets. Enrichment analysis suggested HQT may exert anti-tumor effects through regulating lipid metabolism and inflammation related pathways. Molecular docking showed that the key compounds baicalein, wogonin, kaempferol and quercetin all bound effectively to MAPK1. The binding of baicalein to IL6 and naringenin to TNF-α was also relatively stable. The experimental results demonstrated that HQT effectively inhibited the proliferation of breast cancer cells, with IC50 values of 2.334 mg/mL and 1.749 mg/mL in MCF-7 cells at 24 h and 48 h, and IC50 values of 1.286 mg/mL and 1.496 mg/mL in MDA-MB-231 cells at 24 h and 48 h, respectively. Furthermore, HQT induced cell cycle arrest at the G2/M phase in breast cancer cells and downregulated the expression of related proteins including CDK1, Cyclin B1, CDK2, and Cyclin E. Additionally, HQT promoted apoptosis in breast cancer cells by upregulating the expression of Bak and CC-3, while downregulating the expression of Bcl-2. Notably, HQT also exhibited regulatory effects on the HIF-1 signaling pathway. CONCLUSIONS: This study provides insights into the potential multi-component and multi-target mechanisms of HQT against BC, suggesting it may achieve therapeutic effects through regulating inflammatory response and cancer-related pathways via the identified active compounds and targets. The findings highlight the importance of integrating traditional medicine with modern approaches for the development of novel cancer therapies.

NKG2D knockdown improves hypoxic-ischemic brain damage by inhibiting neuroinflammation in neonatal mice.

Hypoxic-ischemic brain damage (HIBD) is a leading cause of neonatal death and neurological dysfunction. Neuroinflammation is identified as one of the crucial pathological mechanisms after HIBD, and natural killer group 2 member D (NKG2D) is reported to be implicated in the pathogenesis of immunoinflammatory diseases. However, the role of NKG2D in neonatal HIBD is seldomly investigated. In this study, a neonatal mice model of HIBD was induced, and the role of the NKG2D in neuroinflammation and brain injury was explored by intracerebroventricular injection of lentivirus to knockdown NKG2D in neonatal mice with HIBD. The results showed that a significant increase in NKG2D protein level in the brain of neonatal mice with HIBD. The NKG2D knockdown in the brain significantly alleviated cerebral infarction, neurobehavioral deficits, and neuronal loss in neuronal HIBD. Moreover, the neuroprotective effect of NKG2D knockdown was associated with inhibition of the activation of microglia and astrocytes, expression of NKG2D ligands (NKG2DLs) and DAP10, and the nuclear translocation of NF-κB p65. Our findings reveal NKG2D knockdown may exert anti-inflammatory and neuroprotective effects in the neonatal mice with HIBD through downregulation of NKG2D/NKG2DLs/DAP10/NF-κB pathway. These results suggest that NKG2D may be a potential target for the treatment of neonatal HIBD.

Unraveling the future: Innovative design strategies and emerging challenges in HER2-targeted tyrosine kinase inhibitors for cancer therapy.

Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor-like protein with tyrosine kinase activity that plays a vital role in processes such as cell proliferation, differentiation, and angiogenesis. The degree of malignancy of different cancers, notably breast cancer, is strongly associated with HER2 amplification, overexpression, and mutation. Currently, widely used clinical HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, have several drawbacks, including susceptibility to drug resistance caused by HER2 mutations and adverse effects from insufficient HER2 selectivity. To address these issues, it is essential to create innovative HER2 TKIs with enhanced safety, effectiveness against mutations, and high selectivity. Typically, SPH5030 has advanced to phase I clinical trials for its strong suppression of four HER2 mutations. This review discusses the latest research progress in HER2 TKIs, with a focus on the structural optimization process and structure-activity relationship analysis. In particular, this study highlights promising design strategies to address these challenges, providing insightful information and inspiration for future development in this field.

QBT improved cognitive dysfunction in rats with vascular dementia by regulating the Nrf2/xCT/GPX4 and NLRP3/Caspase-1/GSDMD pathways to inhibit ferroptosis and pyroptosis of neurons.

BACKGROUND: The novel phthalein component QBT, extracted from Ligusticum chuanxiong, shows promising biological activity against cerebrovascular diseases. This study focused on ferroptosis and pyroptosis to explore the effects of QBT on nerve injury, cognitive dysfunction, and related mechanisms in a rat model of vascular dementia (VaD). METHODS: We established a rat model of VaD and administered QBT as a treatment. Cognitive dysfunction in VaD rats was evaluated using novel object recognition and Morris water maze tests. Neuronal damage and loss in the brain tissues of VaD rats were assessed with Nissl staining and immunofluorescence. Furthermore, we investigated the neuroprotective mechanisms of QBT by modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/cystine-glutamate antiporter (xCT)/glutathione peroxidase 4 (GPX4) and Nod-like receptor family pyrin domain-containing 3 (NLRP3)/cysteine-requiring aspartate protease-1 (Caspase-1)/Gasdermin D (GSDMD) pathways to inhibit ferroptosis and pyroptosis both in vivo and in vitro. RESULTS: Our findings indicated that QBT significantly ameliorated neuronal damage and cognitive dysfunction in VaD rats. Additionally, QBT reversed abnormal changes associated with ferroptosis and pyroptosis in the brains of VaD rats, concurrently up-regulating the Nrf2/xCT/GPX4 pathway and down-regulating the NLRP3/Caspase-1/GSDMD pathway to inhibit ferroptosis and pyroptosis in neuronal cells, thereby exerting a neuroprotective role. CONCLUSION: In summary, QBT effectively mitigated neuronal damage and cognitive dysfunction in VaD rats, demonstrating a neuroprotective effect by inhibiting ferroptosis and pyroptosis in neuronal cells. This study offers a novel perspective and theoretical foundation for the future development of drugs targeting VaD.

Wogonin Diminishes Radioresistance of Breast Cancer via Inhibition of the Nrf2/HIF-1[Formula: see text] Pathway.

Radiotherapy plays a crucial role in the multimodal treatment of breast cancer. However, radioresistance poses a significant challenge to its effectiveness, hindering successful cancer therapy. Emerging evidence indicates that Nrf2 and HIF-1[Formula: see text] are critical regulators of cellular anti-oxidant responses and that their overexpression significantly promotes radioresistance. Wogonin (WG), the primary component isolated from Scutellaria baicalensis, exhibits potential antitumor and reversal of multidrug resistance activities. Nevertheless, the role of WG in radioresistance remains unclear. This study aims to explore the effects of WG on the radioresistance of breast cancer. Our results indicate that Nrf2 and HIF-1[Formula: see text] overexpression was observed in breast cancer tissues and was correlated with the histological grading of the disease. Radiation further increased the levels of Nrf2 and HIF-1[Formula: see text] in breast cancer cells. However, WG demonstrated the ability to induce cell apoptosis and reverse radioresistance by inhibiting the Nrf2/HIF-1[Formula: see text] pathway. These effects were also confirmed in xenograft mice models. Mechanistically, WG enhanced the level of the Nrf2 inhibitor Keap1 through reducing CpG methylation in the promoter region of the Keap1 gene. Consequently, the Nrf2/HIF-1[Formula: see text] pathway, along with the Nrf2- and HIF-1[Formula: see text]-dependent protective responses, were suppressed. Taken together, our findings demonstrate that WG can epigenetically regulate the Keap1 gene, inhibit the Nrf2/HIF-1[Formula: see text] pathway, induce apoptosis in breast cancer cells, and diminish acquired radioresistance. This study offers potential strategies to overcome the limitations of current radiotherapy for breast cancer.

Modulation of Xiongdanjiuxin pills on the gut-liver axis in high-fat diet rats.

AIM: Xiongdanjiuxin pill (XP) is a traditional Chinese medicine formula for the prevention and treatment of hyperlipidemia (HLP) and related complications. In this study, the gut-liver axis was used as the breakthrough point to analyze the therapeutic effect and potential mechanism of XP on HLP model rats and related complications. MAIN METHODS: We used high-fat diet (HFD) to establish the HLP model of rats and treated them with XP. The 16S rRNA sequencing method was used to explore the effect of XP on the gut microbiota of HFD rats, and the effects of XP on ileum pathology, intestinal barrier and circulatory inflammation in HFD rats were also investigated. We further explored the molecular mechanism of XP treating liver inflammation in rats with HFD by regulating toll-like receptor 4 (TLR4) signaling. KEY FINDINGS: We found that XP could regulate the imbalance of gut microbiota in HFD rats, and up-regulate the expression of tight junction protein in intestinal epithelium of HFD rats, thereby improving the intestinal barrier damage and intestinal inflammatory response. In addition, XP could significantly reduce the levels of inflammatory cytokines in HFD rats, and inhibit TLR4 signaling pathway, thereby reducing liver inflammation in HFD rats. SIGNIFICANCE: XP can effectively improve the imbalance of gut-liver axis in hyperlipidemic rats and alleviate the inflammatory damage of liver. Its mechanism may be related to regulating the disorder of gut microbiota and inhibiting TLR4 signal pathway, so as to achieve the therapeutic effect on hyperlipidemic fatty liver in rats.

Dietary phytochemicals targeting Nrf2 for chemoprevention in breast cancer.

Breast cancer accounts for 11.7% of all newly diagnosed cancer cases and has become the leading cause of cancer worldwide. Currently, more effective and less toxic chemopreventive strategies for breast cancer are urgently needed. Notably, naturally occurring dietary phytochemical compounds, such as curcumin and resveratrol, are generally considered to be the most promising breast cancer preventive agents. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a key regulatory role in the expression of multiple antioxidant and anti-inflammatory enzymes, which can effectively suppress the excessive accumulation of carcinogens and their metabolites. Therefore, modulation of Nrf2 by dietary phytochemicals appears to be a promising approach for breast cancer prevention, which further removes excessive carcinogenic metabolites by inducing Phase II cytoprotective enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase 1 (NQO1). In this review, we summarize recently published findings on the prevention of breast cancer with potential natural phytochemical compounds targeting Nrf2, as well as a mechanistic discussion of Nrf2 activation and its contribution in inhibiting breast cancer carcinogenesis. The epigenetic regulation of Nrf2 by phytochemicals is also explored.

Dietary Phytochemicals Targeting Nrf2 to Enhance the Radiosensitivity of Cancer.

Nowadays, cancer has become the second leading cause of death worldwide. Radiotherapy (RT) is the mainstay in management of carcinoma; however, overcoming radioresistance remains a great challenge to successfully treat cancer. Nrf2 is a key transcription factor that is responsible for maintaining cellular redox homeostasis. Activation of Nrf2 signaling pathway could upregulate multifarious antioxidant and detoxifying enzymes, further scavenging excessive reactive oxygen species (ROS). Despite its cytoprotective roles in normal cells, it could also alleviate oxidative stress and DNA damage caused by RT in cancer cells, thus promoting cancer cell survival. Accumulating evidence indicates that overactivation of Nrf2 is associated with radioresistance; therefore, targeting Nrf2 is a promising strategy to enhance radiosensitivity. Dietary phytochemicals coming from natural products are characterized by low cost, low toxicity, and general availability. Numerous phytochemicals are reported to regulate Nrf2 and intensify the killing capability of RT through diverse mechanisms, including promoting oxidative stress, proapoptosis, and proautophagy as well as inhibiting Nrf2-mediated cytoprotective genes expression. This review summarizes recent advances in radiosensitizing effects of dietary phytochemicals by targeting Nrf2 and discusses the underlying mechanisms, including N6-methyladenosine (m6A) modification of Nrf2 mediated by phytochemicals in cancer.

Upregulation of circ_0008812 and circ_0001583 predicts poor prognosis and promotes breast cancer proliferation.

Background: Accumulating evidence suggests that circular RNAs (circRNAs) are highly correlated with tumor progression and pathogenesis in breast cancer. Whereas, their regulatory roles and corresponding mechanisms in breast cancer are still not exhaustive. Thus, we intended to establish circRNA-mediated competive endogenous RNA (ceRNA) network to uncover the possible roles and clinical implications of circRNAs in breast cancer. Methods: Microarray and RNA-sequencing (RNA-seq) data were download from GEO and TCGA database to screen for differentially expressed RNAs (DEcircRNAs, DEmiRNAs, DEmRNAs) in breast cancer. By implementing online databases, we established ceRNA networks, performed gene set enrichment analysis, constructed protein-protein interaction (PPI) networks, and assessed the expression levels and prognostic significance of hub genes. Subsequently, we explored the functions of prognosis-related genes and constructed gene-drug interaction networks. Finally, the functional roles of DEcircRNAs in breast cancer were revealed via MTT and colony formation assay. Results: Based on the identified 8 DEcircRNAs, 25 miRNAs and 216 mRNAs, a ceRNA regulatory network was established. Further analysis revealed that prominent enrichments were transcription factor binding, transforming growth factor-beta (TGF-ß) and Apelin signaling pathway etc. PPI network and survival curves analysis showed that elevated levels of hub genes (RACGAP1 and KPNA2) were associated with poorer prognosis. They were found to be positively relevant to cell cycle and proliferation. Then a prognostic sub-network of ceRNA was constructed, consisting of 2 circRNAs, 4 miRNAs and 2 mRNAs. The gene-drug interaction network showed that numerous drugs could regulate the expression of these two prognosis-related genes. Functional experiments showed that depletion of circ_0008812 and circ_0001583 could significantly inhibit the proliferation of MCF-7 cells. Conclusion: Our study constructed 4 prognostic regulatory axes that are significantly correlated with tumor prognosis in breast cancer patients, and uncover the roles of circ_0008812 and circ_0001583 in breast cancer, providing a new perspective into the molecular mechanisms of breast cancer pathogenesis.