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Triple-negative breast cancer (TNBC) has been clearly recognized as a heterogeneous tumor with the worst prognosis among the subtypes of breast cancer (BC). The advent and application of current small-molecule drugs for treating TNBC, as well as other novel inhibitors, among others, have made treatment options for TNBC more selective. However, there are still problems, such as poor patient tolerance, large administration doses, high dosing frequency, and toxic side effects, necessitating the development of more efficient and less toxic treatment strategies. High expression of Nrf2, a vital antioxidant transcription factor, often promotes tumor progression, and it is also one of the most effective targets in BC therapy. We found that in MDA-MB-231 cells and SUM159 cells, brusatol (BRU) combined with polydatin (PD) could significantly inhibit cell proliferation in vitro, significantly downregulate the expression of Nrf2 protein as well as the expression of downstream related target genes Heme Oxygenase-1 (HO-1) and NAD(P)H dehydrogenase, quinone 1 (NQO1), and promote reactive oxygen species (ROS) levels to further strengthen the anti-tumor effect. Furthermore, we discovered in our in vivo experiments that by reducing the drug dosage three times, we could significantly reduce tumor cell growth while avoiding toxic side effects, providing a treatment method with greater clinical application value for TNBC treatment. [ABSTRACT FROM AUTHOR]

Confusoside (CF), a major chemical compound in the leaves of Anneslea fragrans Wall., is a dihydrochalcone glycoside with excellent antioxidant and anti-inflammatory effects. However, the hepatoprotective effect of CF has not been described. This study aimed to explore the hepatoprotective effect of CF against acetaminophen (APAP)-induced hepatic injury in HepG2 cells. First, the potential hepatoprotective effect mechanisms of CF were predicted by network pharmacology and were thought to involve reducing inflammation and inhibiting apoptosis. Target proteins (phosphatidylinositol3-kinase (PI3K) and caspase-3 (CASP3)) were found via molecular docking analysis. To verify the predicted results, an analysis of biological indicators was performed using commercial kits and Western blotting. The results showed that CF significantly decreased the levels of liver injury biomarkers (ALT, AST, and LDH), strongly inhibited the production of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the NO level via inhibiting the activation of the NF-κB signaling pathway, and markedly regulated the expression levels of Bcl2, Bax, and cleaved-CASP3/9 proteins by activating the PI3K-CASP3 apoptosis pathway. The results demonstrated that CF has a therapeutic effect on APAP-induced liver injury by inhibiting intracellular inflammation and cell apoptosis, indicating that CF may be used as a potential reagent for the prevention and treatment of APAP-induced liver injury. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC) is a chronic, relapsing, and nonspecific inflammatory bowel disease (IBD). Phillygenin (PHI), a natural bioactive ingredient, isolated from Forsythiae Fructus, exhibits anti-inflammatory, anti-oxidative, and hepatoprotective activities. However, few reports provide direct evidence on the efficacy of PHI in improving colitis mice. The present study elucidated that the symptoms of DSS-induced colitis mice were alleviated after PHI administration, including body weight loss, the disease activity index, colon length shortening, colonic pathological damage, splenomegaly, and hepatomegaly. PHI treatment improved the intestinal mucosal barrier by protecting goblet cells, promoting gene expressions of Clca1, Slc26a3, and Aqp8, increasing tight junction proteins (TJs), and reducing epithelial cell apoptosis. In addition, the levels of oxidative stress (MPO, SOD, and MDA) and inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-10) were reversed by PHI in colitis mice. According to transcriptome and network pharmacology analysis, inflammatory pathway might be an important mechanism for PHI to improve colitis. Western blotting displayed that the PHI inhibited the activation of tyrosine kinase Src mediated by TLR4, and then reduced the phosphorylation of downstream proteins p38, JNK, and NF-κB in colitis mice. In summary, our results suggested that PHI might be an appropriate and effective drug candidate to protect colitis. [ABSTRACT FROM AUTHOR]

Atraric acid (AA) is derived from lichens and is widely used in perfumes for its desirable scent. It has been reported as having anti-inflammatory and antioxidant activity. Hyperpigmentation is the underlying cause of a variety of dermatological diseases that have a significant impact on patients' quality of life and are frequently difficult to treat. This study aimed to explore the inhibitory effects of AA on hyperpigmentation in vitro and in vivo and its potential molecular mechanisms. The cytological results revealed that at a dose of 250 μM, AA may reduce melanin content and tyrosinase levels without causing cytotoxicity. Furthermore, the expression of melanocortin-1 receptor (MC1R), phosphorylated protein kinase A (pPKA) and phosphorylated cAMP response element binding protein (pCREB) were downregulated in AA-administrated cells. In vivo, histological analysis showed that AA could inhibit melanin production and tyrosinase activity, and 3% AA had the best activity, with almost no side effects. Furthermore, the results of Western blot analysis and RT-PCR suggested that AA may suppress the mRNA transcription of microphthalmia-associated transcription factor (MITF) protein and tyrosine protease by decreasing the expression of MC1R, consequently decreasing the phosphorylation of PKA and CREB. Finally, the MC1R inhibitor MSG606 verified the hypothesis that AA suppresses melanin formation by downregulating the PKA/CREB/MITF signaling pathway. Taken together, our study offers valuable information for the development of AA as a possible ingredient in skin-lightening cosmeceuticals and hyperpigmentation inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: CircRNAs: as molecules involved in gene regulation, have become a new research hotspot in the non-coding RNA field. CircRNAs show tissue- or developmental stage-specific patterns of expression and can influence the expression levels of their parental genes. Recent studies have documented the potential biological roles of circRNAs in the growth, development, reproduction and health of humans and animals. Tongue sole (Cynoglossus semilaevis) is a marine flatfish that is an economically important farmed species in China. The commercial aquaculture of tongue sole has developed in the last few years because wild resources have decreased. Reproduction is regulated by brain-pituitary-gonad-liver axis which limits the development of artificial tongue sole culture. However, the roles of circRNAs in the ovarian development and maturation of tongue sole has never been reported. The identification of the potential functions of circRNAs provides a foundation for understanding the genetic mechanisms that regulate oocyte growth and maturation, which will allow the efficiency of tongue sole reproduction to be improved. Moreover, our findings extend the knowledge about a new type of endogenous RNA involved in regulating the ovarian development and maturation of tongue sole. CircRNAs are novel endogenous non-coding small RNAs involved in the regulation of multiple biological processes. However, little is known regarding circRNAs in ovarian development and maturation of fish. Our study, for the first time, provides the genome-wide overview of the types and relative abundances of circRNAs in tongue sole tissues during three ovarian developmental stages. We detected 6790 circRNAs in the brain, 5712 in the pituitary gland, 4937 in the ovary and 4160 in the liver. Some circRNAs exhibit tissue-specific expression, and qRT-PCR largely confirmed 6 differentially expressed (DE) circRNAs. Gene Ontology and KEGG pathway analyses of DE mRNAs were performed. Some DE circRNA parental genes were closely associated with biological processes in key signalling pathways and may play essential roles in ovarian development and maturation. We found that the selected circRNAs were involved in 10 pathways. RNase R digestion experiment and Sanger sequencing verified that the circRNA had a ring structure and was RNase R resistant. qRT-PCR results largely confirmed differential circRNA expression patterns from the RNA-seq data. These findings indicate that circRNAs are widespread in terms of present in production-related tissues of tongue sole with potentially important regulatory roles in ovarian development and maturation. [ABSTRACT FROM AUTHOR]

Ferroptosis is an iron-dependent mode of cell death associated with the occurrence and development of age-related neurodegenerative diseases. Currently, there are no effective drugs available to prevent or treat these aging-related neurodegenerative diseases. Vitamin D (VD) is an antioxidant and immunomodulator, but its relationship with ferroptosis in aging-related neurodegenerative diseases has not been extensively studied. In this study, we aimed to investigate the role of VD in learning and memory in aging mice. To examine whether VD protects aging hippocampal neurons, we used physiologically active 1,25(OH)2D3. We established aging models in vivo (C57BL/6 mice) and in vitro (HT22 cells) using D-galactose (D-gal). The results demonstrated that VD could improve learning and memory in mice aged via the use of D-gal, and it reduced damage to hippocampal neurons. VD could regulate ferroptosis-related proteins (increasing GPX4 expression and decreasing ACSL4 and ALOX15 protein expression levels), increasing GSH levels, reducing MDA and intracellular and mitochondrial ROS levels, as well as total iron and Fe2+ levels, and improving mitochondrial morphology, thereby alleviating ferroptosis in aging hippocampal neurons. Additionally, VD activated the VDR/Nrf2/HO-1 signaling pathway, thereby inhibiting ferroptosis. Notably, when the VDR was knocked down, VD lost its ability to activate Nrf2. Consequently, inhibiting Nrf2 decreased the protective effect of VD against ferroptosis in aged hippocampal neurons. In summary, VD activates the Nrf2/HO-1 signaling pathway through the VDR, effectively preventing ferroptosis induced by aging in hippocampal neurons. [ABSTRACT FROM AUTHOR]

Transcriptome sequencing showed that syndecan-3 (SDC3) was differentially expressed in high-fat and low-fat mammary epithelial cells of Chinese Holstein cows. Previous studies found that SDC3 plays an important role in inflammatory diseases and virus infection. However, those studies did not confirm whether or not the functional gene SDC3, which plays an important role in regulating milk fat metabolism, has an effect on susceptibility to breast tissue diseases. Therefore, we studied the effects of SDC3 on milk lipid metabolism and inflammation in bovine mammary epithelial cells (BMECs) and further explored the common regulatory pathway of SDC3 in both. The overexpression of SDC3 increased the contents of triglycerides and cholesterol, reduced the content of non-esterified fatty acids, inhibited the expression of inflammatory factors (IL-6, IL-1β, TNF-α and COX-2), and reduced the production of ROS in BMECs. However, silenced SDC3 had the opposite effect. Further exploring the mechanisms of SDC3, we found that SDC3 upregulated the expression of peroxisome proliferator-activated receptor gamma (PPARG) through the AMPK/SIRT1 signal pathway to promote milk fat synthesis. It also regulated the activation of the NF-κB pathway through the AMPK/SIRT1 signal pathway, reducing the expression of inflammatory factors and ROS production, thus inhibiting the inflammatory response of BMECs. Nuclear factor kappa B subunit 1 (NF-κB p50) was an important target of SDC3 in this process. To sum up, our results showed that SDC3 coregulated milk fat metabolism and inflammation through the AMPK/SIRT1 signaling pathway. This study laid a foundation for the comprehensive evaluation of breeding value based on multi-effect functional genes in dairy cow molecular breeding. [ABSTRACT FROM AUTHOR]

Naturally occurring polyphenols are believed to have beneficial effects in the prevention and treatment of a myriad of disorders due to their anti-inflammatory, antioxidant, antineoplastic, cytotoxic, and immunomodulatory activities documented in a large body of literature. In the era of molecular medicine and targeted therapy, there is a growing interest in characterizing the molecular mechanisms by which polyphenol compounds interact with multiple protein targets and signaling pathways that regulate key cellular processes under both normal and pathological conditions. Numerous studies suggest that natural polyphenols have chemopreventive and/or chemotherapeutic properties against different types of cancer by acting through different molecular mechanisms. The present review summarizes recent preclinical studies on the applications of bioactive polyphenols in lung cancer therapy, with an emphasis on the molecular mechanisms that underlie the therapeutic effects of major polyphenols on lung cancer. We also discuss the potential of the polyphenol-based combination therapy as an attractive therapeutic strategy against lung cancer. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) plays crucial roles in plant development and defence response. Reactive oxygen species (ROS) are produced during normal plant growth, and high ROS concentrations can change the antioxidant status of cells, leading to spontaneous cell death. In addition, ROS function as signalling molecules to improve plant stress tolerance, and they induce PCD under different conditions. This review describes the mechanisms underlying plant PCD, the key functions of mitochondria and chloroplasts in PCD, and the relationship between mitochondria and chloroplasts during PCD. Additionally, the review discusses the factors that regulate PCD. Most importantly, in this review, we summarise the sites of production of ROS and discuss the roles of ROS that not only trigger multiple signalling pathways leading to PCD but also participate in the execution of PCD, highlighting the importance of ROS in PCD. [ABSTRACT FROM AUTHOR]

The tomato is a research model for fruit-ripening, however, its fruit-ripening mechanism still needs more extensive and in-depth exploration. Here, using TMT and LC-MS, the proteome and phosphoproteome of AC++ (wild type) and rin (ripening-inhibitor) mutant fruits were studied to investigate the translation and post-translational regulation mechanisms of tomato fruit-ripening. A total of 6141 proteins and 4011 phosphorylation sites contained quantitative information. One-hundred proteins were identified in both omics' profiles, which were mainly found in ethylene biosynthesis and signal transduction, photosynthesis regulation, carotenoid and flavonoid biosynthesis, chlorophyll degradation, ribosomal subunit expression changes, MAPK pathway, transcription factors and kinases. The affected protein levels were correlated with their corresponding gene transcript levels, such as NAC-NOR, MADS-RIN, IMA, TAGL1, MADS-MC and TDR4. Changes in the phosphorylation levels of NAC-NOR and IMA were involved in the regulation of tomato fruit-ripening. Although photosynthesis was inhibited, there were diverse primary and secondary metabolic pathways, such as glycolysis, fatty acid metabolism, vitamin metabolism and isoprenoid biosynthesis, regulated by phosphorylation. These data constitute a map of protein—protein phosphorylation in the regulation of tomato fruit-ripening, which lays the foundation for future in-depth study of the sophisticated molecular mechanisms of fruit-ripening and provide guidance for molecular breeding. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (PNET) remain an unmet clinical need. In this study, we show that targeting both nicotinamide phosphoribosyltransferase (NAMPT) and p21-activated kinase 4 (PAK4) could become a synthetic lethal strategy for PNET. The expression of PAK4 and NAMPT was found to be higher in PNET tissue compared to normal cells. PAK4-NAMPT dual RNAi suppressed proliferation of PNET cell lines. Treatment with KPT-9274 (currently in a Phase I trial or analogs, PF3758309 (the PAK4 selective inhibitor) or FK866 (the NAMPT inhibitor)) suppressed the growth of PNET cell lines and synergized with the mammalian target of rapamycin (mTOR) inhibitors everolimus and INK-128. Molecular analysis of the combination treatment showed down-regulation of known everolimus resistance drivers. KPT-9274 suppressed NAD pool and ATP levels in PNET cell lines. Metabolomic profiling showed a statistically significant alteration in cellular energetic pathways. KPT-9274 given orally at 150 mg/kg 5 days/week for 4 weeks dramatically reduced PNET sub-cutaneous tumor growth. Residual tumor analysis demonstrated target engagement in vivo and recapitulated in vitro results. Our investigations demonstrate that PAK4 and NAMPT are two viable therapeutic targets in the difficult to treat PNET that warrant further clinical investigation. [ABSTRACT FROM AUTHOR]