Effects of grain intervention on hypothalamic function and the metabolome of blood and milk in dairy cows.

BACKGROUND: The hypothalamus plays a crucial role in the health and productivity of dairy cows, yet studies on its functionality and its impact on peripheral circulation in these animals are relatively scarce, particularly regarding dietary interventions. Therefore, our study undertook a comprehensive analysis, incorporating both metabolomics and transcriptomics, to explore the effects of a grain-based diet on the functionality of the hypothalamus, as well as on blood and milk in dairy cows. RESULTS: The hypothalamic metabolome analysis revealed a significant reduction in prostaglandin E2 (PGE2) level as a prominent response to the grain-based diet introduction. Furthermore, the hypothalamic transcriptome profiling showed a notable upregulation in amino acid metabolism due to the grain-based diet. Conversely, the grain-based diet led to the downregulation of genes involved in the metabolic pathway from lecithin to PGE2, including phospholipase A2 (PLA2G4E, PLA2G2A, and PLA2G12B), cyclooxygenase-2 (COX2), and prostaglandin E synthase (PTGES). Additionally, the plasma metabolome analysis indicated a substantial decrease in the level of PGE2, along with a decline in adrenal steroid hormones (tetrahydrocortisol and pregnenolone) following the grain-based diet introduction. Analysis of the milk metabolome showed that the grain-based diet significantly increased uric acid level while notably decreasing PGE2 level. Importantly, PGE2 was identified as a critical metabolic marker in the hypothalamus, blood, and milk in response to grain intervention. Correlation analysis demonstrated a significant correlation among metabolic alterations in the hypothalamus, blood, and milk following the grain-based diet. CONCLUSIONS: Our findings suggest a potential link between hypothalamic changes and alterations in peripheral circulation resulting from the introduction of a grain-based diet.

Long-term hematopoietic transfer of the anti-cancer and lifespan-extending capabilities of a genetically engineered blood system by transplantation of bone marrow mononuclear cells.

A causal relationship exists among the aging process, organ decay and disfunction, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1K74R/K74R or Klf1(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/EKLF has been generated that possesses extended lifespan and healthy characteristics, including cancer resistance. We show that the healthy longevity characteristics of the Klf1(K74R) mice, as exemplified by their higher anti-cancer capability, are likely gender-, age-, and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1(K74R) mice, could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at a young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild-type NK cells. Targeted/global gene expression profiling analysis has identified changes in the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/blood system for long-term anti-cancer and, potentially, for anti-aging.

High-grain diet feeding alters ileal microbiota and disrupts bile acid metabolism in lactating dairy cows.

Bile acids (BAs) play an important role in the regulation of lipid metabolic homeostasis, but little is known about their metabolism in dairy cows fed a high-grain (HG) diet. In the present study, we examined the bacterial community, BA profile, and the FXR/FGF19 signaling pathway in the ileum and liver to investigate the gut microbe-BA metabolism interactions response to HG diet and the changes in the subsequent enterohepatic circulation of dairy cows. The results showed that the ileal bacterial community was altered, with an increase of Paraclostridium, Anaerobutyricum, Shuttleworthia, and Stomatobaculum in the relative abundance in the HG group. Moreover, real-time polymerase chain reaction (PCR) showed that the abundance of total bacteria and bacterial bile-salt hydrolase (BSH) genes was increased in the ileal digesta in the HG group. Meanwhile, HG feeding also decreased the total BA content in the digesta of jejunum and ileum and in feces. HG feeding altered the BA profile in the ileal digesta by increasing unconjugated BAs and decreasing conjugated BAs. In addition, the intestinal FXR/FGF19 signaling pathway was activated. The expression of CYP7A1 (cholesterol 7α-hydroxylase) was depressed, which inhibited BAs synthesis in the liver of cows fed HG. Overall, HG feeding altered the ileal bacterial community and BA profile, and activated FXR/FGF19 signaling pathway, resulting in a decrease of BA level in the ileal digesta via the inhibition of hepatic BA synthesis. The findings provided novel insights into understanding the relationship between gut microbiota and the homeostasis of BAs in dairy cows fed a HG diet.

Bile acids plays an important role in regulating lipids metabolism in animals and human. Dairy cows fed high-grain (HG) diet generally suffer abnormal lipids metabolism. However, if there is a relationship between the bile acids metabolism and abnormal lipids metabolism in dairy cows fed HG diet is unclear. This study found that HG diet altered the bacterial community and bile aids composition in the ileum of dairy cows. HG also activated the FXR/FGF19 signaling pathway in the ileum, and inhibited the bile acid synthesis in the liver, which might be the reason for the reduced level of bile acid in the digesta of small intestine. The reduced bile acid level in the small intestine might affect the digestion and absorption of the dietary lipids in dairy cows fed HG diet.

Correlation between Polyphenol Contents and Antioxidant Activities in Different Echinacea Purpurea Varieties.

OBJECTIVE: Polyphenols are complex compounds containing multiple phenolic hydroxyl groups. They are widely distributed in plants and have antioxidant activities. Whether the antioxidant activities of the cultivated varieties of Echinacea are similar to or better than those of the wild ones and the relationship between the accumulation of polyphenols and their antioxidant activities are still not clear. METHODS: Folin-Ciocalteu method, high performance liquid chromatography (HPLC), 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, ferric ion reducing antioxidant power (FRAP) assay, 2,2'-azino-bis(3-ethylbenzothiazoline-6)-sulfonic acid (ABTS) radical scavenging assay, and Fe2+ chelating ability assay were used, respectively, to detect the total polyphenols and 5 kinds of caffeic acid derivatives (chicoric acid, caffeic acid, caftaric acid, chlorogenic acid, and 1,5-dicaffeoylquinic acid) in the roots, stems, leaves, and flowers, and the antioxidant activities of 3 varieties of Echinacea: E. purpurea L., cultivar E. purpurea 'Aloha', and E. purpurea 'White Swan'. RESULTS: E. purpurea L. had the highest contents of total polyphenols, 5 caffeic acid derivatives and antioxidant activities, followed by E. purpurea 'White Swan' and E. purpurea 'Aloha', respectively. E. purpurea 'White Swan' had the strongest ability to remove the DPPH, ABTS•+ and free radicals, and to chelate Fe2+; E. purpurea L. had the strongest ability to reduce FRAP. The correlation analyses revealed that the contents of total polyphenols and caffeic acid derivatives of E. purpurea L. and E. purpurea 'White Swan' were correlated with their antioxidant activities. CONCLUSION: E. purpurea L. was the most appropriate material for the development of medicinal plants. E. purpurea 'White Swan' could be used as a substitute for E. purpurea L. in terms of its antioxidant activity.

Inhibitory effect of ß-escin on Zika virus infection through the interruption of viral binding, replication, and stability.

ß-Escin is a mixture of triterpenoid saponins extracted from horse chestnut seeds that have diverse pharmacological activities, including anti-inflammation, anti-edematous, venotonic, and antiviral effects. In the clinical setting, ß-escin is primarily used to treat venous insufficiency and blunt trauma injuries. The anti-Zika virus (ZIKV) activity of ß-escin has not been explored. This study investigated the antiviral efficacy of ß-escin on ZIKV and dengue virus (DENV) in vitro and then elucidated the underlying mechanism. The inhibitory effects of ß-escin on viral RNA synthesis, protein levels, and infection ability were determined using qRT-PCR, Western blotting, and immunofluorescence assays, respectively. To further characterize how ß-escin interferes with the viral life cycle, the time-of-addition experiment was performed. An inactivation assay was performed to determine whether ß-escin affects ZIKV virion stability. To broaden these findings, the antiviral effects of ß-escin on different DENV serotypes were assessed using dose-inhibition and time-of-addition assays. The results showed that ß-escin exhibits anti-ZIKV activity by decreasing viral RNA levels, protein expression, progeny yield, and virion stability. ß-Escin inhibited ZIKV infection by disrupting viral binding and replication. Furthermore, ß-escin demonstrated antiviral activities against four DENV serotypes in a Vero cell model and prophylactic protection against ZIKV and DENV infections.

Generalized Brewster angle-enhanced photonic spin Hall effect in an all-dielectric metasurface.

The enhancement of the photonic spin Hall effect (PSHE) is usually limited at horizontally polarized incidence and around the nonadjustable Brewster angle. In this Letter, a flexible method for enhancing the reflective PSHE with tunable incident angle under both vertically (V) and horizontally (H) polarized light has been theoretically explored. By using the multipole decomposition method, the variable generalized Brewster angle (GBA) is proven to be obtained under both V- and H-polarized light at different wavelengths in the all-dielectric metasurface. Then, owing to the large ratio of Fresnel coefficients at the GBA, the enhancement of PSHE in this Letter can not only be available for both V- and H-polarization, but also achieved at widely tunable incident angle and different operating wavelengths in the same metasurface. This work provides a simple method to achieve the flexible enhancement of PSHE and offers a novel way for designing a functional spin-based photonic device.

Total Synthesis of (±)- and (-)-Daphnillonin B.

The first total synthesis of (±)- and (-)-daphnillonin B, a daphnicyclidin-type alkaloid with a new [7-6-5-7-5-5] A/B/C/D/E/F hexacyclic core, has been achieved. The [6-5-7] B/C/D ring system was efficiently and diastereoselectively constructed via a mild type I intramolecular [5+2] cycloaddition, followed by a Grubbs II catalyst-catalyzed radical cyclization. The [5-5] fused E/F ring system was synthesized via a diastereoselective intramolecular Pauson-Khand reaction. Notably, the synthetically challenging [7-6-5-7-5-5] hexacyclic core was reassembled by a unique Wagner-Meerwein-type rearrangement from the [6-6-5-7-5-5] hexacyclic framework found in calyciphylline A-type Daphniphyllum alkaloids.

Effects of high-grain diet feeding on fatty acid profiles in milk, blood, muscle, and adipose tissue, and transcriptional expression of lipid-related genes in muscle and adipose tissue of dairy cows.

BACKGROUND: High-grain (HG) diets affect lipid metabolism in the liver and mammary tissue of dairy cows, but its effects on muscle and adipose tissue have not been wide evaluated. Thus, the aim of this study is to clarify this issue. METHODS: Twelve Holstein cows were randomly divided into two groups: conventional diet group (CON, n = 6) and the HG diet group (n = 6). On day 7 of week 4, rumen fluid was sampled to measure pH, milk was sampled to measure components, and blood was sampled to measure biochemical parameters and fatty acid composition. After the experiment, cows were slaughtered to collect muscle and adipose tissue for fatty acid composition and transcriptome analysis. RESULTS: HG feeding decreased the ruminal pH, milk's fat content and long-chain fatty acid proportion (P < 0.05) and increased the proportion of short- and medium-chain fatty acids in the milk (P < 0.05) as compared with CON diets. The concentrations of blood cholesterol, low-density lipoprotein, and polyunsaturated fatty acids in the HG cows were lower than those in CON cows (P < 0.05). In muscle tissue, HG feeding tended to increase the triacylglycerol (TG) concentration (P < 0.10). Transcriptome analysis revealed changes in the biosynthesis of the unsaturated fatty acids pathway, the regulation of lipolysis in the adipocytes pathway, and the PPAR signalling pathway. In adipose tissue, HG feeding increased the concentration of TG and decreased the concentration of C18:1 cis9 (P < 0.05). At the transcriptome level, the fatty acid biosynthesis pathway, linoleic acid metabolism pathway, and PPAR signalling pathway were activated. CONCLUSION: HG feeding leads to subacute rumen acidosis and a decreased milk fat content. The fatty acid profiles in the milk and plasma of dairy cows were changed by HG feeding. In muscle and adipose tissue, HG feeding increased TG concentration and up-regulated the expression of genes related to adipogenesis, while down-regulated the expression of genes related to lipid transport. These results complement our knowledge of the fatty acid composition of muscle and adipose tissue in dairy cows and expand our understanding of the mechanisms by which HG diets affect lipid metabolism in muscle and adipose tissue.

Supplemental Clostridium butyricum modulates lipid metabolism by reshaping the gut microbiota composition and bile acid profile in IUGR suckling piglets.

BACKGROUND: Intrauterine growth restriction (IUGR) can cause lipid disorders in infants and have long-term adverse effects on their growth and development. Clostridium butyricum (C. butyricum), a kind of emerging probiotics, has been reported to effectively attenuate lipid metabolism dysfunctions. Therefore, the objective of this study was to investigate the effects of C. butyricum supplementation on hepatic lipid disorders in IUGR suckling piglets. METHODS: Sixteen IUGR and eight normal birth weight (NBW) neonatal male piglets were used in this study. From d 3 to d 24, in addition to drinking milk, the eight NBW piglets (NBW-CON group, n = 8) and eight IUGR piglets (IUGR-CON group, n = 8) were given 10 mL sterile saline once a day, while the remaining IUGR piglets (IUGR-CB group, n = 8) were orally administered C. butyricum at a dose of 2 × 108 colony-forming units (CFU)/kg body weight (suspended in 10 mL sterile saline) at the same frequency. RESULTS: The IUGR-CON piglets exhibited restricted growth, impaired hepatic morphology, disordered lipid metabolism, increased abundance of opportunistic pathogens and altered ileum and liver bile acid (BA) profiles. However, C. butyricum supplementation reshaped the gut microbiota of the IUGR-CB piglets, characterized by a decreased abundance of opportunistic pathogens in the ileum, including Streptococcus and Enterococcus. The decrease in these bile salt hydrolase (BSH)-producing microbes increased the content of conjugated BAs, which could be transported to the liver and function as signaling molecules to activate liver X receptor α (LXRα) and farnesoid X receptor (FXR). This activation effectively accelerated the synthesis and oxidation of fatty acids and down-regulated the total cholesterol level by decreasing the synthesis and promoting the efflux of cholesterol. As a result, the growth performance and morphological structure of the liver improved in the IUGR piglets. CONCLUSION: These results indicate that C. butyricum supplementation in IUGR suckling piglets could decrease the abundance of BSH-producing microbes (Streptococcus and Enterococcus). This decrease altered the ileum and liver BA profiles and consequently activated the expression of hepatic LXRα and FXR. The activation of these two signaling molecules could effectively normalize the lipid metabolism and improve the growth performance of IUGR suckling piglets.

The gastrointestinal microbiome in dairy cattle is constrained by the deterministic driver of the region and the modified effect of diet.

BACKGROUND: Dairy cattle (Bos taurus), especially Holstein cows, which are the highest-producing dairy animals and are widely bred to provide milk products to humans, rely critically on their associated gastrointestinal tract (GIT) microbiota to digest plant feed. However, the region-specific taxonomic composition and function of the GIT microbiome in dairy cattle and the mechanistic basis for the diet-induced effects remain to be elucidated.  RESULTS: We collected 120 digesta samples from 10 GIT regions of 12 Holstein cows fed forage- and grain-based diets and characterized their GIT microbiome via functional shotgun metagenomics and the resolution of metagenome-assembled genomes. Our results demonstrated that the GIT microbiome was mainly partitioned into three distinct clusters, four-chambered stomach, small intestine, and large intestine. Moreover, we found that the four-chambered stomach microbiome with the highest diversity had a strong ability to degrade recalcitrant polysaccharide substrates, underpinned by the prevalence of potential cellulosome--producing and plant-derived polysaccharide utilization loci-encoding consortia. In contrast, the post-gastric intestinal microbiome orchestrated alternative fermentation pathways to adapt to nutrient availability and energy acquisition. Diet shifts selectively modified the metabolic cascades of the microbiome in specific GIT regions, evidenced by the loss of fiber-degrading taxa and increased hydrogen sinks in propionate after grain introduction. CONCLUSIONS: Our findings provide new insights into GIT microbial organization and function in dairy cattle by GIT regions and diet regimes, which offers clues for improving animal production and health in the future. Video Abstract.

Genome-centric investigation of bile acid metabolizing microbiota of dairy cows and associated diet-induced functional implications.

Although the importance of bile acid (BA)-related microbial strains and enzymes is increasingly recognized for monogastric animals, a lack of knowledge about BA metabolism in dairy cows limits functional applications aimed at the targeted modulation of microbe-host interactions for animal production and health. In the present study, 108 content samples from six intestinal regions of dairy cows were used for shotgun metagenomic sequencing. Overall, 372 high-quality metagenome-assembled genomes (MAGs) were involved in BA deconjugation, oxidation, and dehydroxylation pathways. Furthermore, the BA-metabolizing microbiome predominately occurred in the large intestine, resulting in the accumulation of secondary unconjugated BAs. Comparative genomic analysis revealed that the bile salt hydrolase (BSH)-carrying microbial populations managed with the selective environment of the dairy cow intestine by adopting numerous host mucin glycan-degrading abilities. A sequence similarity network analysis classified 439 BSH homologs into 12 clusters and identified different clusters with diverse evolution, taxonomy, signal peptides, and ecological niches. Our omics data further revealed that the strains of Firmicutes bacterium CAG-110 processed the increased abundance of BSHs from Cluster 1, coinciding with the changes in the colon cholic acid concentration after grain introduction, and were intricately related to intestinal inflammation. This study is the first to use a genome-centric approach and whole intestine-targeted metabolomics to reveal microbial BA metabolism and its diet-induced functional implications in dairy cows. These findings provide insight into the manipulation of intestinal microorganisms for improving host health.

An advanced systems biology framework of feature engineering for cold tolerance genes discovery from integrated omics and non-omics data in soybean.

Soybean is sensitive to low temperatures during the crop growing season. An urgent demand for breeding cold-tolerant cultivars to alleviate the production loss is apparent to cope with this scenario. Cold-tolerant trait is a complex and quantitative trait controlled by multiple genes, environmental factors, and their interaction. In this study, we proposed an advanced systems biology framework of feature engineering for the discovery of cold tolerance genes (CTgenes) from integrated omics and non-omics (OnO) data in soybean. An integrative pipeline was introduced for feature selection and feature extraction from different layers in the integrated OnO data using data ensemble methods and the non-parameter random forest prioritization to minimize uncertainties and false positives for accuracy improvement of results. In total, 44, 143, and 45 CTgenes were identified in short-, mid-, and long-term cold treatment, respectively, from the corresponding gene-pool. These CTgenes outperformed the remaining genes, the random genes, and the other candidate genes identified by other approaches in an independent RNA-seq database. Furthermore, we applied pathway enrichment and crosstalk network analyses to uncover relevant physiological pathways with the discovery of underlying cold tolerance in hormone- and defense-related modules. Our CTgenes were validated by using 55 SNP genotype data of 56 soybean samples in cold tolerance experiments. This suggests that the CTgenes identified from our proposed systematic framework can effectively distinguish cold-resistant and cold-sensitive lines. It is an important advancement in the soybean cold-stress response. The proposed pipelines provide an alternative solution to biomarker discovery, module discovery, and sample classification underlying a particular trait in plants in a robust and efficient way.

How do microplastics adsorb metals? A preliminary study under simulated wetland conditions.

Microplastics (MPs) are widely detected in wetlands as emerging pollutants of global concern. Co-occurrence of MPs and trace metals in wetlands is common and the vector effects of MPs on other environmental pollutants have been increasingly reported. However, the interaction of different MPs and trace metals under environmentally realistic conditions is not well understood. Here, we investigated the adsorption capacity of MPs for metals under simulated conditions of Poyang Lake wetlands in Jiang Xi, China, a Ramsar site of international importance for conservation and sustainable use. ICP-MS was used to quantify the amount of adsorbed metals onto different types of MPs. SEM-EDS and micro-FTIR were used to examine the morphological and chemical characteristics of MPs before and after metal adsorption. The influence of internal (polymer types and particle sizes of MPs) and external factors (water pH values, organic matters, ion strength, and sediment) on metal adsorption was systematically investigated. Metal adsorption equilibrium was most achieved at 72 h. The adsorption capacity of MP types to metal ions tended to decrease as PP > PE > PS, and the amount of adsorbed metals decreased as Cu > Pb > Cd. The amount of adsorbed metals generally decreased with the increase of particle size of MPs. With the increase of water pH and K+ strength, the adsorption of metals by MPs showed an increasing and then decreasing trend; the adsorption capacity of MPs increased with the increase of fulvic acid. Under the simulated sedimentary conditions, the adsorption of different metals by MPs also tended to be Cu > Pb > Cd, which was mainly determined by metal concentrations in the sediments collected in situ. The results of this study improve our understanding of metal-MP interaction under simulated environmental conditions, shedding new light on the environmental behavior of MPs and metals in wetlands.

Intelligent Fall-Risk Assessment Based on Gait Stability and Symmetry Among Older Adults Using Tri-Axial Accelerometry.

This study aimed to use the k-nearest neighbor (kNN) algorithm, which combines gait stability and symmetry derived from a normalized cross-correlation (NCC) analysis of acceleration signals from the bilateral ankles of older adults, to assess fall risk. Fifteen non-fallers and 12 recurrent fallers without clinically significant musculoskeletal and neurological diseases participated in the study. Sex, body mass index, previous falls, and the results of the 10 m walking test (10 MWT) were recorded. The acceleration of the five gait cycles from the midsection of each 10 MWT was used to calculate the unilateral NCC coefficients for gait stability and bilateral NCC coefficients for gait symmetry, and then kNN was applied for classifying non-fallers and recurrent fallers. The duration of the 10 MWT was longer among recurrent fallers than it was among non-fallers (p < 0.05). Since the gait signals were acquired from tri-axial accelerometry, the kNN F1 scores with the x-axis components were 92% for non-fallers and 89% for recurrent fallers, and the root sum of squares (RSS) of the signals was 95% for non-fallers and 94% for recurrent fallers. The kNN classification on gait stability and symmetry revealed good accuracy in terms of distinguishing non-fallers and recurrent fallers. Specifically, it was concluded that the RSS-based NCC coefficients can serve as effective gait features to assess the risk of falls.

Cabozantinib promotes erythroid differentiation in K562 erythroleukemia cells through global changes in gene expression and JNK activation.

Cabozantinib is a potent tyrosine kinase inhibitor with multiple targets including MET, VEGFR2, RET, KIT, and FLT3. Cabozantinib is widely used for the treatment of medullary thyroid cancer and renal cell carcinoma. We recently suggested cabozantinib as a potential therapeutic alternative for acute myeloid leukemia (AML) patients with FLT3-internal tandem duplication (FLT3-ITD). Here, we report that cabozantinib can promote differentiation in erythroid leukemia cells. We found that K562 erythroid leukemia cells treated with 1 µM cabozantinib for 72 h underwent erythroid lineage differentiation. Transcriptomic analysis revealed that various pathways associated with heme biosynthesis, hemoglobin production, and GATA1 targets were upregulated, whereas cell survival pathways were downregulated. Further examination revealed that cabozantinib-induced erythroid differentiation is at least in part regulated by JNK activation and phosphorylation. Levels of phosphorylated BCR-ABL, AKT, STAT5, ERK, and p38 also decreased following cabozantinib treatment. Therefore, we indicate that cabozantinib has dual functions. First, it induces K562 cell differentiation toward the erythroid lineage by upregulating heme biosynthesis, globin synthesis, and erythroid-associated reactions. Second, cabozantinib inhibits K562 cell proliferation by inhibiting the phosphorylation of BCR-ABL and the downstream MAPK, PI3K-AKT, and JAK-STAT signaling pathways.

An improved crystal embedding method of fetal lung duct casting specimen and its application / 解剖学报

Objective To improve the success rate of crystal embedding of human (animal) pipeline cast specimens for long-term preservation and application of cast specimens better. Methods The selection of embedding mold, specimen fixation, adjustment of the proportion of glue, grinding and polishing were improved, and a crystal embedding model of a fetal lung duct cast specimen was made to explore and optimize the simple and efficient production process of a crystal-embedded human (animal) pipeline casting specimen. Results The crystal model produced after the improvement had great transparency, beautiful shape, no bubbles, and no mold branches broken. The distribution and running of the casted branches of the fetal lung of the crystal model could be observed clearly in the embedded middle fetal lung through any angle and orientation, which was consistent with the cast specimens before embedding, and had a strong sense of three-dimensional space. Conclusion The improved process is better for embedding human (animal) pipeline casting specimens, which is conducive to long-term preservation. It is better for clinical anatomy teaching and exhibition in life science museum.

Characterization of a Tumor-Microenvironment-Relevant Gene Set Based on Tumor Severity in Colon Cancer and Evaluation of Its Potential for Dihydroartemisinin Targeting.

Colon cancer (COAD) is a leading cause of cancer mortality in the world. Most patients with COAD die as a result of cancer cell metastasis. However, the mechanisms underlying the metastatic phenotype of COAD remain unclear. Instead, particular features of the tumor microenvironment (TME) could predict adverse outcomes including metastasis in patients with COAD, and the role of TME in governing COAD progression is undeniable. Therefore, exploring the role of TME in COAD may help us better understand the molecular mechanisms behind COAD progression which may improve clinical outcomes and quality of patients. Here, we identified a Specific TME Regulatory Network including AEBP1, BGN, POST, and FAP (STMERN) that is highly involved in clinical outcomes of patients with COAD. Comprehensive in silico analysis of our study revealed that the STMERN is highly correlated with the severity of COAD. Meanwhile, our results reveal that the STMERN might be associated with immune infiltration in COAD. Importantly, we show that dihydroartemisinin (DHA) potentially interacts with the STMERN. We suggest that DHA might contribute to immune infiltration through regulating the STMERN in COAD. Taken together, our data provide a set of biomarkers of progression and poor prognosis in COAD. These findings could have potential prognostic and therapeutic implications in the progression of COAD.

Potent and orally active purine-based fetal hemoglobin inducers for treating ß-thalassemia and sickle cell disease.

Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe ß-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as ß-thalassemia and SCD.

Anti-glioblastoma Activity of Kaempferol via Programmed Cell Death Induction: Involvement of Autophagy and Pyroptosis.

Glioblastoma is one of the most common and lethal intracranial malignant, and is still lack of ideal treatments. Kaempferol is a major nutrient found in various edible plants, which has exhibited the potential for the treatment of glioblastoma. However, the specific anti-glioma mechanism of kaempferol is yet to be studied. Herein, we aim to explore the mechanisms underlying the anti-glioma activity of kaempferol. Our results demonstrated that kaempferol suppresses glioma cell proliferation in vitro and inhibits tumor growth in vivo. Moreover, kaempferol raises ROS and decreases mitochondrial membrane potential in glioma cells. The high levels of ROS induce autophagy then ultimately trigger the pyroptosis of glioma cells. Interestingly, when we used 3-MA to inhibit autophagy, we found that the cleaved form of GSDME was also decreased, suggesting that kaempferol induces pyroptosis through regulating autophagy in glioma cells. In conclusion, this study revealed kaempferol possesses good anti-glioma activity by inducing ROS, and subsequently leads to autophagy and pyroptosis, highlighting its clinical potentials as a natural nutrient against glioblastoma.

Harringtonine Inhibits Zika Virus Infection through Multiple Mechanisms.

Mosquito-borne Zika virus (ZIKV) is a Flavivirus that came under intense study from 2014 to 2016 for its well-known ability to cause congenital microcephaly in fetuses and neurological Guillain-Barré disease in adults. Substantial research on screening antiviral agents against ZIKV and preventing ZIKV infection are globally underway, but Food and Drug Administration (FDA)-approved treatments are not available yet. Compounds from Chinese medicinal herbs may offer an opportunity for potential therapies for anti-ZIKV infection. In this study, we evaluated the antiviral efficacy of harringtonine against ZIKV. Harringtonine possessed anti-ZIKV properties against the binding, entry, replication, and release stage through the virus life cycle. In addition, harringtonine have strong virucidal effects in ZIKV and exhibited prophylaxis antiviral ability prior ZIKV infection. The antiviral activity also observed in the treatment against Japanese encephalitis reporter virus (RP9-GFP strain). Overall, this study demonstrated that harringtonine would be a favorable potential candidate for the development of anti-ZIKV infection therapies.