Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer.

Targeting ferroptosis, an iron-dependent form of regulated cell death triggered by the lethal overload of lipid peroxides, in cancer therapy is impeded by our limited understanding of the intersection of tumour's metabolic feature and ferroptosis vulnerability. In the present study, arginine is identified as a ferroptotic promoter using a metabolites library. This effect is mainly achieved through arginine's conversion to polyamines, which exerts their potent ferroptosis-promoting property in an H2O2-dependent manner. Notably, the expression of ornithine decarboxylase 1 (ODC1), the critical enzyme catalysing polyamine synthesis, is significantly activated by the ferroptosis signal--iron overload--through WNT/MYC signalling, as well as the subsequent elevated polyamine synthesis, thus forming a ferroptosis-iron overload-WNT/MYC-ODC1-polyamine-H2O2 positive feedback loop that amplifies ferroptosis. Meanwhile, we notice that ferroptotic cells release enhanced polyamine-containing extracellular vesicles into the microenvironment, thereby further sensitizing neighbouring cells to ferroptosis and accelerating the "spread" of ferroptosis in the tumour region. Besides, polyamine supplementation also sensitizes cancer cells or xenograft tumours to radiotherapy or chemotherapy through inducing ferroptosis. Considering that cancer cells are often characterized by elevated intracellular polyamine pools, our results indicate that polyamine metabolism exposes a targetable vulnerability to ferroptosis and represents an exciting opportunity for therapeutic strategies for cancer.

Active post-transcriptional regulation and ACLY-mediated acetyl-CoA synthesis as a pivotal target of Shuang-Huang-Sheng-Bai formula for lung adenocarcinoma treatment.

BACKGROUND: New therapeutic approaches are required to improve the outcomes of lung cancer (LC), a leading cause of cancer-related deaths worldwide. Chinese herbal medicine formulae widely used in China provide a unique opportunity for improving LC treatment, and the Shuang-Huang-Sheng-Bai (SHSB) formula is a typical example. However, the underlying mechanisms of action remains unclear. PURPOSE: This study aimed to confirm the efficacy of SHSB against lung adenocarcinoma (LUAD), which is a major histological type of LC, unveil the downstream targets of this formula, and assess the clinical relevance and biological roles of the newly identified target. METHODS: An experimental metastasis mouse model and a subcutaneous xenograft mouse model were used to evaluate the anti-cancer activity of SHSB. Multi-omics profiling of subcutaneous tumors and metabolomic profiling of sera were performed to identify downstream targets, especially the metabolic targets of SHSB. A clinical trial was conducted to verify the newly identified metabolic targets in patients. Next, the metabolites and enzymes engaged in the metabolic pathway targeted by SHSB were measured in clinical samples. Finally, routine molecular experiments were performed to decipher the biological functions of the metabolic pathways targeted by SHSB. RESULTS: Oral SHSB administration showed overt anti-LUAD efficacy as revealed by the extended overall survival of the metastasis model and impaired growth of implanted tumors in the subcutaneous xenograft model. Mechanistically, SHSB administration altered protein expression in the post-transcriptional layer and modified the metabolome of LUAD xenografts. Integrative analysis demonstrated that SHSB markedly inhibited acetyl-CoA synthesis in tumors by post-transcriptionally downregulating ATP-citrate lyase (ACLY). Consistently, our clinical trial showed that oral SHSB administration declined serum acetyl-CoA levels of patients with LC. Moreover, acetyl-CoA synthesis and ACLY expression were both augmented in clinical LUAD tissues of patients, and high intratumoral ACLY expression predicted a detrimental prognosis. Finally, we showed that ACLY-mediated acetyl-CoA synthesis is essential for LUAD cell growth by promoting G1/S transition and DNA replication. CONCLUSION: Limited downstream targets of SHSB for LC treatment have been reported in previous hypothesis-driven studies. In this study, we conducted a comprehensive multi-omics investigation and demonstrated that SHSB exerted its anti-LUAD efficacy by actively and post-transcriptionally modulating protein expression and particularly restraining ACLY-mediated acetyl-CoA synthesis.

Short-term effects of dietary selenium on lactating sows to improve litter performance, milk composition and tissue selenium retention in piglets.

OBJECTIVE: This study was conducted to evaluate the short-term effects of dietary selenium supplementation on lactating sows on the physiological response, litter performance, milk composition, and tissue selenium retention in piglets when selenium was provided by different sources and at different levels in a lactation diet. METHODS: A total of 48 multiparous sows (Yorkshire×Landrace) with average body weight, backfat thickness, and parity were assigned to one of the four treatments with 12 sows per treatment using a 2×2 factorial arrangement in a completely randomized design. Inorganic or organic Se sources were added to the diet at 0.30 ppm and 0.50 ppm Se. Treatments were as follows: i) IS30, basal diet + inorganic Se 0.30 ppm; ii) IS50, basal diet + inorganic Se 0.50 ppm; iii) OS30, basal diet + organic Se 0.30 ppm; and iv) OS50: basal diet + organic Se 0.50 ppm. RESULTS: At Day 21 of lactation, a high tendency of litter weight (p = 0.08) and litter weight gain (p = 0.09) were observed when sows were fed an organic Se source. The milk Se concentration in the organic Se treatment was higher than that in the inorganic Se treatment at Day 21 of lactation (p<0.05). The serum Se concentrations of sows and piglets at Day 21 of lactation were significantly higher when lactating sows were fed organic Se instead of inorganic Se (p<0.01). During the suckling period, the kidney and muscle Se concentrations of piglets at Day 21 of lactation were significantly higher when the sow dietary Se source was organic (p<0.05). Liver Se concentrations were affected by Se source and level (p<0.05). This also resulted in an interaction response at 21 days of lactation (p<0.05). CONCLUSION: The supplementation of dietary organic Se in a lactating diet could improve sow feed consumption, piglet performance, milk Se level, and the Se status of sows and piglets.

Network pharmacology analysis of the mechanism of Huisheng oral liquid in the treatment of lung cancer.

Background: To study the active ingredient and possible mechanism of Huisheng oral liquid in the treatment of lung cancer by network pharmacology. Methods: The active ingredient and drug targets of Huisheng oral liquid were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID), and lung cancer targets were screened using the Gene Expression Omnibus (GEO) database. The drug targets of the effective components of Huisheng oral liquid were matched with disease targets and the obtained intersecting targets were imported into the Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) database to construct a protein-protein interaction (PPI) network. R software and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database were used for Gene Ontology (GO) and KEGG enrichment analyses, and Cytoscape software was used to construct a Huisheng oral liquid component target-lung cancer target network. The function and pathway of the therapeutic target of Huisheng oral liquid for lung cancer were analyzed. Results: A total of 1,376 differentially expressed genes (DEGs) of lung cancer were obtained, and 185 potential effective components of Huisheng oral liquid in the treatment of lung cancer were obtained, including quercetin, luteolin, kaempferol, and baicalein. There were 36 intersecting targets between Huisheng oral liquid and lung cancer, and the key targets for lung cancer treatment were CDKN1A, CCNB1, MDM2, CDK1, ErbB2, E2F1, EGFR, etc. Huisheng oral liquid mainly regulates the p53 signaling pathway. Conclusions: The mechanism of Huisheng oral liquid in the treatment of lung cancer is mainly reflected in regulating tumor cell apoptosis, inhibiting angiogenesis, and improving immunity.

Koumine regulates macrophage M1/M2 polarization via TSPO, alleviating sepsis-associated liver injury in mice.

BACKGROUND: Translocator protein (TSPO) is an 18-kDa transmembrane protein found primarily in the mitochondrial outer membrane, and it is implicated in inflammatory responses, such as cytokine release. Koumine (KM) is an indole alkaloid extracted from Gelsemium elegans Benth. It has been reported to be a high-affinity ligand of TSPO and to exert anti-inflammatory and immunomodulatory effects in our recent studies. However, the protective effect of KM on sepsis-associated liver injury (SALI) and its mechanisms are unknown. PURPOSE: To explore the role of TSPO in SALI and then further explore the protective effect and mechanism of KM on SALI. METHODS: The effect of KM on the survival rate of septic mice was confirmed in mouse models of caecal ligation and puncture (CLP)-induced and lipopolysaccharide (LPS)-induced sepsis. The protective effect of KM on CLP-induced SALI was comprehensively evaluated by observing the morphology of the mouse liver and measuring liver injury markers. The serum cytokine content was detected in mice by flow cytometry. Macrophage polarization in the liver was examined using western blotting. TSPO knockout mice were used to explore the role of TSPO in sepsis liver injury and verify the protective effect of KM on sepsis liver injury through TSPO. RESULTS: KM significantly improved the survival rate of both LPS- and CLP-induced sepsis in mice. KM has a significant liver protective effect on CLP-induced sepsis in mice. KM treatment ameliorated liver ischaemia, improved liver pathological injuries, and decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and proinflammatory cytokines in serum. Western blotting results showed that KM inhibited M1 polarization of macrophages and promoted M2 polarization. In TSPO knockout mice, we found that TSPO knockout can improve the survival rate of septic mice, ameliorate liver ischaemia, improve liver pathological injuries, and decrease the levels of ALT, AST, and LDH. In addition, TSPO knockout inhibits the M1 polarization of macrophages in the liver of septic mice and promotes M2 polarization and the serum levels of proinflammatory cytokines. Interestingly, in TSPO knockout septic mice, these protective effects of KM were no longer effective. CONCLUSIONS: We report for the first time that TSPO plays a critical role in sepsis-associated liver injury by regulating the polarization of liver macrophages and reducing the inflammatory response. KM, a TSPO ligand, is a potentially desirable candidate for the treatment of SALI that may regulate macrophage M1/M2 polarization through TSPO in the liver.

Network pharmacological analysis and molecular docking of Huangqin-Baizhu herb pair in the treatment of threatened abortion.

BACKGROUND: The incidence of threatened abortion (TA) is increasing due to poor diet and living habits, which brings great pressure to pregnant women and their families. Huangqin-Baizhu herb pair recorded in ancient books of traditional Chinese medicine has been widely used in the treatment of TA with remarkable effect. In this study, we will use the network pharmacology method to predict the target and mechanism of Huangqin-Baizhu herb pair. METHODS: Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform database was used to screen the active components of Huangqin-Baizhu herb pair. Pubchem and Swiss Target Prediction databases were used to predict the action targets. Genecards, OMIM, and Drugbank databases were used to predict the related targets of TA. The intersection of drug target and disease target was selected and the intersection genes were uploaded to STRING database to construct protein-protein interaction network and conduct module analysis. Metascape database was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, which was imported into Cytoscape software to construct component-pathway-gene network and finally verified by molecular docking. Ethical approval and informed consent of patients are not required because the data used in this study is publicly available and does not involve individual patient data or privacy. RESULTS: The main active components of the herb pair are baicalein, flavanone, and norwogonin, etc. The main targets are AKT1, VEGFA, STAT3, MAPK1, SRC, etc. Cluster module analysis shows that the targets are related to cell metabolism, immune regulation and hormone level regulation. There were 2073, 3169, and 161 KEGG pathways involved in the biological processes, cell components, and molecular functions of Gene Ontology analysis, respectively. The main KEGG pathways involved in the intervention were HIF1 signaling pathway, PI3K-Akt signaling pathway, and Rap1 signaling pathway. Molecular docking showed that the main active components of the herb pair were well combined with the key targets. CONCLUSIONS: In this study, 42 active components, 152 potential targets and 11 key targets of Huangqin-Baizhu herb pair for the treatment of TA were revealed, participating in multiple signaling pathways such as PI3K-Akt, providing a theoretical basis for further experimental research.

Genome-Wide Analysis of the HDAC Gene Family and Its Functional Characterization at Low Temperatures in Tartary Buckwheat (Fagopyrum tataricum).

Histone deacetylases (HDACs), widely found in various types of eukaryotic cells, play crucial roles in biological process, including the biotic and abiotic stress responses in plants. However, no research on the HDACs of Fagopyrum tataricum has been reported. Here, 14 putative FtHDAC genes were identified and annotated in Fagopyrum tataricum. Their gene structure, motif composition, cis-acting elements, phylogenetic relationships, protein structure, alternative splicing events, subcellular localization and gene expression pattern were investigated. The gene structure showed FtHDACs were classified into three subfamilies. The promoter analysis revealed the presence of various cis-acting elements responsible for hormone, abiotic stress and developmental regulation for the specific induction of FtHDACs. Two duplication events were identified in FtHDA6-1, FtHDA6-2, and FtHDA19. The expression patterns of FtHDACs showed their correlation with the flavonoid synthesis pathway genes. In addition, alternative splicing, mRNA enrichment profiles and transgenic analysis showed the potential role of FtHDACs in cold responses. Our study characterized FtHDACs, providing a candidate gene family for agricultural breeding and crop improvement.

Effects of mixed selenium sources on the physiological responses and blood profiles of lactating sows and tissue concentration of their progeny.

OBJECTIVE: This study was conducted to investigate the effects of selenium benefits on the physiological responses, litter performance, blood profiles and milk composition of lactating sows and tissue concentration of their progeny when mixed form of selenium was provided in a lactation diet. METHODS: A total of 45 multiparous sows (Yorkshire×Landrace) with similar body weight, backfat thickness, and parity were assigned to one of three treatments with 15 sows per treatment in a completely randomized design. Organic and inorganic selenium were mixed and added to the diet at 0.15 ppm and 0.25 ppm, respectively. A non-Se-fortified corn-soybean meal basal diet served as a negative control. Treatments were as follows: i) Control: corn-soybean meal based diet, ii) ISOS15: control+ inorganic Se 0.15 ppm+organic Se 0.15 ppm, iii) ISOS25: control+inorganic Se 0.25 ppm+organic Se 0.25 ppm. RESULTS: Serum selenium concentrations of sows and piglets were increased by the supplemental Se mixture at 7 days of lactation compared with the control (p<0.01, respectively). The kidney and muscle selenium concentrations of piglets were increased by the supplemental Se mixture at 21 days of lactation compared with the control (p = 0.03; p = 0.04, respectively). CONCLUSION: Consequently, supplementation with mixed inorganic and organic selenium in a lactating diet could improve the selenium status of sows and piglets; no differences were observed among the mixing levels.

Effects of selenium source and level on the physiological response, reproductive performance, serum Se level and milk composition in gestating sows.

OBJECTIVE: This study was conducted to evaluate the effects of selenium (Se) source and level on the physiological response, reproductive performance, serum Se level, and milk composition in gestating sows. METHODS: A total of 54 multiparous sows (Yorkshire×Landrace) with average body weight (BW), backfat thickness (BF), and parity were assigned to one of five treatments with 10 or 11 sows per treatment using a 2×2 factorial arrangement with one additional treatment in a completely randomized design. Inorganic or organic Se (IS or OS) sources were added to the diet at 0.30 ppm and 0.50 ppm Se. A non-Se-fortified corn-soybean meal basal diet served as a negative control. Treatments were as follows: i) Control: corn-soybean based diet, ii) IS30: control+inorganic Se 0.30 ppm, iii) IS50: control+inorganic Se 0.50 ppm, iv) OS30: control+ organic Se ppm, and v) OS50: control+organic Se 0.50 ppm. RESULTS: At day 21 of lactation, piglet weight and weight gain in the OS treatments were higher than those in the IS treatments (p<0.05). Meanwhile, adding 0.5 ppm Se also resulted in the same significant differences in piglet BW and weight gain (p<0.05). Colostrum and milk Se concentrations increased (p<0.05) with Se level for both Se sources but were greater when sows were fed organic Se (p<0.05). Except for 24 hours postpartum, the Se concentrations were higher when sows were fed organic Se (p<0.05). Sow serum Se content was greater as Se levels increased from 0.3 ppm to 0.5 ppm at day 110 of gestation, 24 hours postpartum and day 21 of lactation (p<0.05). The pig serum Se concentration increased as the dietary Se level increased (p<0.05) and was higher when the sow dietary Se source was organic (p<0.05). Organic Se 0.5 ppm also had the highest serum Se level at two measured points (p<0.05). CONCLUSION: Consequently, supplementation with organic Se or 0.5 ppm Se in a gestating diet could improve piglet performance, the Se status of sows and piglets and milk composition, but organic Se at 0.5 ppm is optimal.

Exploring the relationship between osteoporosis and polycystic ovary syndrome based on bioinformatics.

BACKGROUND: In recent years, clinical studies have found that there is a close relationship between osteoporosis and polycystic ovary syndrome. However, there are few literature on the pathogenesis of osteoporosis and polycystic ovary syndrome. In order to clarify their common pathogenic mechanism and provide potential targets for drugs to regulate them at the same time, bioinformatics methods are used to explore, so as to provide a new direction for the study of the relationship between diseases in the future. METHODS: To screen the targets of osteoporosis and polycystic ovary syndrome by Genecards, Online Mendelian Inheritance in Man databases and Therapeutic Target Database to take the intersection of the two mappings and upload the intersection targets to the STRING database to construct protein-protein interaction network; to screen the core targets by degree value and import them to Metascape database for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis; and finally, to construct the visualization network of core targets and pathways by Cytoscape software. Ethical approval and informed consent of patients are not required because the data used in this study is publicly available and does not involve individual patient data or privacy. RESULTS: The core targets of polycystic ovary syndrome and osteoporosis were insulin gene, insulin-like growth factor 1, CTNNB1, serine/threonine kinase 1, signal transducer and activator of transcription 3, LEP, etc. The biological processes involved include the regulation of protein phosphorylation, cell proliferation and differentiation, hormone endocrine, reproductive system and skeletal system. The related pathways were concentrated in Foxo signaling pathway, HTLV-I infection, PI3K-AKT signaling pathway, MAPK signaling pathway and AGE-RAGE signaling pathway in diabetic complications. CONCLUSIONS: There is a close relationship between osteoporosis and polycystic ovary syndrome in terms of target and molecular mechanism. This study used bioinformatics to clarify their targets and mechanisms, providing potential targets for drugs to regulate both diseases simultaneously and providing new directions to explore the relationship between the diseases.

Multi-View Random-Walk Graph Regularization Low-Rank Representation for Cancer Clustering and Differentially Expressed Gene Selection.

Cancer genome data generally consists of multiple views from different sources. These views provide different levels of information about gene activity, as well as more comprehensive cancer information. The low-rank representation (LRR) method, as a powerful subspace clustering method, has been extended and applied in cancer data research. Although the multi-view learning methods based on low rank representation have achieved good results in cancer multi-omics analysis because they fully consider the consistency and complementarity between views, these methods have some shortcomings in mining the potential local geometry of data. In view of this, this paper proposes a new method named Multi-view Random-walk Graph regularization Low-Rank Representation (MRGLRR) to comprehensively analyze multi-view genomics data. This method uses multi-view model to find the common centroid of view. By constructing a joint affinity matrix to learn the low-rank subspace representation of multiple sets of data, the hidden information of each view is fully obtained. In addition, this method introduces random walk graph regularization constraint to obtain more accurate similarity between samples. Different from the traditional graph regularization constraint, after constructing the KNN graph, we use the random walk algorithm to obtain the weight matrix. The random walk algorithm can retain more local geometric information and better learn the topological structure of the data. What's more, a feature gene selection strategy suitable for multi-view model is proposed to find more differentially expressed genes with research value. Experimental results show that our method is better than other representative methods in terms of clustering and feature gene selection for cancer multi-omics data.

Osteoinductive activity of bisdemethoxycurcumin and its synergistic protective effect with human amniotic mesenchymal stem cells against ovariectomy-induced osteoporosis mouse model.

Osteoporosis is a common disease characterized by skeletal fragility and microarchitectural deterioration. However, existing conventional drugs exhibit limited efficacy and can elicit severe adverse effects; moreover, and novel stem cell-based therapies have not exhibited sufficient therapeutic efficacy. Our hypothesis is that an appropriate osteogenic inducer may improve their therapeutic efficacy. In this study, we found that bisdemethoxycurcumin (BDMC) stimulates the differentiation of human amniotic mesenchymal stem cells (hAMSCs) into osteoblasts without inducing cytotoxicity. Here BDMC enhances calcium deposition in hAMSCs, while promoting the expression of early and late markers of osteoblast differentiation, including ALP, runt-related transcription factor 2, osterix, COL1-α1, osteocalcin, and osteopontin at the transcriptional and translational levels. Mechanistically, BDMC was found to activate the JAK2/STAT3 pathway; whereas AG490 (JAK2/STAT3 pathway inhibitor) inhibited BDMC functioning. Subsequently, we found that the combinatorial therapy of BDMC and hAMSC had a positive synergistic effect on osteoporotic mouse model induced by bilateral ovariectomy, including inhibiting bone loss and bone resorption and improving bone micro-architecture. Moreover, BDMC inhibited production of the bone resorption markers C-terminal telopeptide of type I collagen, and tartrate resistant acid phosphatase, while promoting serum levels of bone formation markers OCN, and procollagen I N-terminal propeptide. BDMC also improved liver and kidney function in osteoporotic mouse model. Collectively, BDMC improved osteoporosis by enhancing hAMSC osteogenesis and exhibited a protective effect on liver and kidney function in an osteoporotic mouse model. Hence, BDMC may serve as an effective adjuvant, and combined therapy with hAMSCs is a promising new approach toward osteoporosis treatment.

Ethanol supernatant extracts of Gynura procumbens could treat nanodiethylnitrosamine-induced mouse liver cancer by interfering with inflammatory factors for the tumor microenvironment.

ETHNOPHARMACOLOGICAL RELEVANCE: Gynura procumbens (Lour.) Merr, (Family Asteraceae), which serves as both medicine and food in traditional ethnic medicine, has the effects of diminishing inflammation, relieving cough, reducing blood glucose and lipids levels, mitigating hepatotoxicity, and can be used for liver cancer prevention and treatment. AIM OF THE STUDY: To explore how the ethanol extract of Gynura procumbens stems (EEGS) can effectively intervene in the tumor microenvironment, it is necessary to study the mechanism of EEGS on the chemical toxicant nanodiethylnitrosamine (nanoDEN) that induces liver cancer. MATERIALS AND METHODS: EEGS contains large quantities of caffeoylquinic acid (CAC) and non-caffeoylquinic acid (n-CAC), which can be separated by high-performance liquid chromatography. The liver cancer model that was induced by the chemical toxin, nanoDEN, was used to clarify the effective mechanism for tumor intervention of the EEGS and its active ingredients. RESULTS: (1) after interventions with the four drugs on liver cancer, the tumor nodules were obviously reduced and inflammation levels improved. (2) The immunohistochemical staining results showed that both the EEGS and its active ingredients could significantly reverse the abnormal changes in inflammation, proliferation, aging and hypoxia-related proteins in mouse liver tissues that were caused by nanoDEN. (3) Real-time PCR results showed that compared with the nanoDEN group, the expression levels of inflammatory, fatty, and fibrosis-related factors in each group after drug intervention were decreased. (4) The transmission electron microscopy measurements showed that the EEGS significantly reversed the nanostructure changes in hepatocytes that were induced by nanoDEN. CONCLUSION: The EEGS component of Gynura procumbens is effective in preventing and treating liver cancer by interfering with the inflammatory microenvironment during oncogenesis induced by nanoDEN.

Jujuboside B Inhibits the Proliferation of Breast Cancer Cell Lines by Inducing Apoptosis and Autophagy.

Jujuboside B (JB) is one of the main biologically active ingredients extracted from Zizyphi Spinosi Semen (ZSS), a widely used traditional Chinese medicine for treating insomnia and anxiety. Breast cancer is the most common cancer and the second leading cause of cancer-related death in women worldwide. The purpose of this study was to examine whether JB could prevent breast cancer and its underlying mechanism. First, we reported that JB induced apoptosis and autophagy in MDA-MB-231 and MCF-7 human breast cancer cell lines. Further mechanistic studies have revealed that JB-induced apoptosis was mediated by NOXA in both two cell lines. Moreover, the AMPK signaling pathway plays an important role in JB-induced autophagy in MCF-7. To confirm the anti-breast cancer effect of JB, the interaction of JB-induced apoptosis and autophagy was investigated by both pharmacological and genetic approaches. Results indicated that autophagy played a pro-survival role in attenuating apoptosis. Further in vivo study showed that JB significantly suppressed the growth of MDA-MB-231 and MCF-7 xenografts. In conclusion, our findings indicate that JB exerts its anti-breast cancer effect in association with the induction of apoptosis and autophagy.

Ameliorative Effects of Peptides Derived from Oyster (Crassostrea gigas) on Immunomodulatory Function and Gut Microbiota Structure in Cyclophosphamide-Treated Mice.

The intestinal flora is recognized as a significant contributor to the immune system. In this research, the protective effects of oyster peptides on immune regulation and intestinal microbiota were investigated in mice treated with cyclophosphamide. The results showed that oyster peptides restored the indexes of thymus, spleen and liver, stimulated cytokines secretion and promoted the relative mRNA levels of Th1/Th2 cytokines (IL-2, IFN-γ, IL-4 and IL-10). The mRNA levels of Occludin, Claudin-1, ZO-1, and Mucin-2 were up-regulated, and the NF-κB signaling pathway was also activated after oyster peptides administration. Furthermore, oyster peptides treatment reduced the proportion of Firmicutes/Bacteroidetes, increased the relative abundance of Alistipes, Lactobacillus, Rikenell and the content of short-chain fatty acids, and reversed the composition of intestinal microflora similar to that of normal mice. In conclusion, oyster peptides effectively ameliorated cyclophosphamide-induced intestinal damage and modified gut microbiota structure in mice, and might be utilized as a beneficial ingredient in functional foods for immune regulation.

Prevalence of the methylenetetrahydrofolate reductase 677C>T polymorphism in the pregnant women of Yunnan Province, China.

Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene can result in a reduced ability to utilize folic acid. The MTHFR 677C>T polymorphism in particular has been linked to both birth defects and pregnancy-associated diseases. This study aimed to evaluate the prevalence of the MTHFR 677C>T mutation among pregnant women in Yunnan Province so as to collect baseline data that may be utilized to guide folic acid supplementation efforts and to support related disease prevention programs. We retrospectively reviewed 3387 pregnant women from Yunnan Province. The MTHFR 677C>T polymorphism was identified using polymerase chain reaction (PCR) and DNA sequencing. In total, 1350 (39.9%) subjects were homozygous for the C allele (CC), 1540 (45.4%) subjects were heterozygous (CT), and 497 (14.7%) subjects were homozygous for the T allele (TT). The MTHFR 677C>T polymorphism was found to be present within the studied population, with ∼60% of these patients being either heterozygous or homozygous for the mutant allele and with an overall T allele frequency of 0.37. The frequency of the T allele was significantly higher among pregnant women with complications relative to women with healthy pregnancies, particularly among women <30 years old. As such, the maternal MTHFR 677C>T polymorphism may be a genetic risk factor associated with pregnancy complications and may help identify pregnant women at a high risk of such complications.

GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC1 signaling.

Lung cancer (LC) is a leading cause of cancer-related deaths worldwide. Its rapid growth requires hyperactive catabolism of principal metabolic fuels. It is unclear whether fructose, an abundant sugar in current diets, is essential for LC. We demonstrated that, under the condition of coexistence of metabolic fuels in the body, fructose was readily used by LC cells in vivo as a glucose alternative via upregulating GLUT5, a major fructose transporter encoded by solute carrier family 2 member 5 (SLC2A5). Metabolomic profiling coupled with isotope tracing demonstrated that incorporated fructose was catabolized to fuel fatty acid synthesis and palmitoleic acid generation in particular to expedite LC growth in vivo. Both in vitro and in vivo supplement of palmitoleic acid could restore impaired LC propagation caused by SLC2A5 deletion. Furthermore, molecular mechanism investigation revealed that GLUT5-mediated fructose utilization was required to suppress AMPK and consequently activate mTORC1 activity to promote LC growth. As such, pharmacological blockade of in vivo fructose utilization using a GLUT5 inhibitor remarkably curtailed LC growth. Together, this study underscores the importance of in vivo fructose utilization mediated by GLUT5 in governing LC growth and highlights a promising strategy to treat LC by targeting GLUT5 to eliminate those fructose-addicted neoplastic cells.

Z-ligustilide and n-Butylidenephthalide Isolated from the Aerial Parts of Angelica tenuissima Inhibit Lipid Accumulation In Vitro and In Vivo.

Abnormal lipid metabolism, such as increased fatty acid uptake and esterification, is associated with nonalcoholic fatty liver disease (NAFLD). The aqueous extract of the aerial part of Angelica tenuissima Nakai (ATX) inhibited high-fat diet-induced hepatic steatosis in mice as well as oleic acid-induced neutral lipid accumulation in HepG2 cells. ATX decreased the mRNA and protein levels of CD36 and diglyceride acyltransferase 2 (DGAT2), the maturation of sterol regulatory element-binding proteins (SREBP), and the expression of the lipogenic target genes fasn and scd1. The ATX components, Z-ligustilide and n-butylidenephthalide, inhibited the expression of FATP5 and DGAT2 and thus oleic acid-induced lipid accumulation in HepG2 cells. These results suggest that ATX and its active components Z-ligustilide and n-butylidenephthalide inhibit fatty acid uptake and esterification in mice and have potential as therapeutics for NAFLD.

An ethyl acetate fraction of Artemisia capillaris (ACE-63) induced apoptosis and anti-angiogenesis via inhibition of PI3K/AKT signaling in hepatocellular carcinoma.

In cancer treatment, herbal medicines may be a good choice because of the reduced risk of adverse side effects. Artemisia capillaris has been recognized as a promising candidate due to its hepatoprotective effects. Herein, we investigated whether A. capillaris-derived fraction (ACE-63) could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. In this study, ACE-63 effectively inhibited the growth and proliferation of HCC cells. ACE-63 induced apoptosis, as observed using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, which was accompanied with increases in cleaved Poly (ADP-ribose) polymerase (PARP) and caspase-3 in HCC cells. Additionally, the pro-apoptotic effect of ACE-63 was demonstrated by a decrease in the expression of the X-linked inhibitor of apoptosis protein (XIAP) and survivin via a loss of mitochondrial membrane potential. In an ex vivo model, ACE-63 significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of cleaved caspase-3 and DNA fragmentation. In addition, ACE-63 decreased the expression of hypoxia-inducible factor-1α and vascular endothelial growth factor and inhibited tube formation of human umbilical vein endothelial cells. A mechanistic study revealed that ACE-63 effectively suppressed the PI3K/AKT/mTOR signaling pathways, which were observed as a target signaling by phosphokinase array. Taken together, our findings demonstrate that ACE-63 could not only efficiently induce apoptosis but also inhibit the growth/angiogenesis of human HCC cells by blocking the PI3K/AKT/mTOR signaling pathway, suggesting that ACE-63 may be a new chemotherapeutic candidate against HCC.