Nobiletin Alleviated Epithelial-Mesenchymal Transition of Hepatocytes in Liver Fibrosis Based on Autophagy-Hippo/YAP Pathway.

SCOPE: The current researches indicated that the epithelial-mesenchymal transition (EMT) of hepatocytes plays a crucial role in the development of liver fibrosis. To date, there is a paucity of literature regarding the impact of nobiletin (NOB) on liver fibrosis. This study investigates the inhibitory effect of NOB on EMT in hepatocytes during the progression of liver fibrosis and its underlying mechanism. METHODS AND RESULTS: The findings demonstrated that NOB significantly suppresses liver fibrosis in carbon tetrachloride (CCl4 )-induced mice by reducing inflammation and fiber deposition in the liver. Moreover, NOB mitigates EMT in hepatocytes, concurrently alleviating inflammatory status and reducing the production of reactive oxygen species (ROS) generation. The comprehensive investigation reveals that the hepatoprotective effect of NOB in liver fibrosis is attributed to autophagy activation, as evidenced by a significant increase in LC3 II expression and p62 degradation upon NOB treatment. Additionally, NOB activates the Hippo/YAP pathway by downregulating YAP and its downstream targets in liver fibrosis, which is regulated by autophagy based on experiments with chloroquine (CQ), 3-methyladenine (3-MA), and siYAP intervention. CONCLUSION: Therefore, this study provides evidences that NOB can protect hepatocytes from undergoing EMT during liver fibrosis by inducing autophagy and subsequently modulating the Hippo/YAP pathway.

Isolation and characterization of a nephroprotective polysaccharide from Dendrobium chrysotoxum Lindl against LPS-induced acute kidney injury mice.

The structure and bioactivity of a novel polysaccharide from Dendrobium Chrysotoxum Lindl (DCP-1) were investigated. The crude polysaccharides of Dendrobium Chrysotoxum Lindl (DCP) were extracted by hot water extraction, and the protein was removed by enzymatic hydrolysis and Sevage. After purification, the chemical structure of polysaccharides was identified by infrared spectroscopy, methylation analysis and nuclear magnetic resonance spectroscopy. Then, a mouse model of acute kidney injury (AKI) was constructed using lipopolysaccharide (LPS), and pretreated with DCP. Structure characterization demonstrated that the number-average molecular weight and mass average molar mass of DCP-1 were 28.43 kDa and 15.00 kDa, respectively. DCP-1 mainly consisted of mannose (37.8 %) and glucose (55.6 %). The main linkage types of DCP-1 were contained 1,4-Linked Manp and 1,4-Linked Glcp. And DCP-1 was demonstrated to be an O-acetylglucomannan with ß-ᴅ-configuration in pyranoid form. Besides, the bioactivity of DCP was further investigated. The results showed that DCP exhibited notable anti-inflammatory activity in LPS-induced AKI mice. After treated with DCP, the creatinine (CREA) and urea nitrogen (BUN) in serum were successfully down-regulated in AKI mice. DCP treatment prevented the characteristic morphological changes of LPS-induced renal tubular injury. The results showed that DCP treatment significantly reduced the concentration of oxidative damage indicators (MDA, SOD) and the expression of inflammatory indices (TNF-α, IL-6, MCP-1, COX-2). In general, the newly extracted polysaccharide DCP showed excellent nephroprotective effect, which enabled it to be an ideal natural medicine for kidney diseases therapy.

Desymmetrization of Prochiral N-Pyrazolyl Maleimides via Organocatalyzed Asymmetric Michael Addition with Pyrazolones: Construction of Tri-N-Heterocyclic Scaffolds Bearing Both Central and Axial Chirality.

The desymmetrization of N-pyrazolyl maleimides was realized through an asymmetric Michael addition by using pyrazolones under mild conditions, leading to the formation of a tri-N-heterocyclic pyrazole-succinimide-pyrazolone assembly in high yields with excellent enantioselectivities (up to 99% yield, up to 99% ee). The use of a quinine-derived thiourea catalyst was essential for achieving stereocontrol of the vicinal quaternary-tertiary stereocenters together with the C-N chiral axis. Salient features of this protocol included a broad substrate scope, atom economy, mild conditions and simple operation. Moreover, a gram-scale experiment and derivatization of the product further illustrated the practicability and potential application value of this methodology.

Hypoglycemic Effect of Nobiletin via Gut Microbiota-Metabolism Axis on Hyperglycemic Mice.

SCOPE: Prediabetes and diabetes are major public health problems worldwide without specific cure currently. Gut microbes have been recognized as one of the vital therapeutic targets for diabetes. The exploration that nobiletin (NOB) whether affects gut microbes provides a scientific basis for its application. METHODS AND RESULTS: A hyperglycemia animal model is established using high-fat-fed ApoE-/- mice. After 24 weeks of NOB intervention, the level of fasting blood glucose (FBG), glucose tolerance, insulin resistance, and glycosylated serum protein (GSP) are measured. Pancreas integrity is observed by hematoxylin-eosin (HE) staining and transmission electron microscopy. 16s RNA sequencing and untargeted metabolomics are to determine the changes of intestinal microbial composition and metabolic pathways. The levels of FBG and GSP in hyperglycemic mice are effectively reduced. The secretory function of pancreas is improved. Meanwhile, NOB treatment restored the gut microbial composition and affected metabolic function. Furthermore, NOB treatment regulates the metabolic disorder mainly through lipid metabolism, amino acid metabolism, and Secondary bile acid metabolism, etc. In addition, it is possibly existed mutual promotion between microbe and metabolites. CONCLUSION: NOB probably plays a vital role in the hypoglycemic effect and pancreatic islets protection by improving microbiota composition and gut metabolism.

The biological regulatory activities of Flammulina velutipes polysaccharide in mice intestinal microbiota, immune repertoire and heart transcriptome.

The effects of a novel Flammulina velutipes polysaccharide (FVP) on intestinal microbiota, immune repertoire and heart transcriptome were investigated in this study. The results showed that FVP treatment could effectively regulate the abundance of colonic microbiota. And FVP exhibited obvious immunoregulatory effect by influencing V gene and J gene fragments usage on TCRα chain. The usage frequency of TRBV1, TRBJ1-6 and TRBJ1-5 were significantly altered, and 41 V-J pairs were identified with obvious difference after FVP treatment. Furthermore, the mRNA of mice heart was analyzed by transcriptome assay. Total 525 genes and 1587 mRNA were significantly changed after FVP treatment. KEGG annotation indicated that the up-regulated mRNA was enriched in 17 pathways including adherens junction, mTOR signaling pathway, insulin signaling pathway, mitophagy, tight junction, PPAR signaling pathway and TNF signaling pathway, etc. Meanwhile, the down-regulated mRNA was gathered in AMPK signaling pathway, metabolism of xenobiotics by cytochrome P450, apelin signaling pathway, PPAR signaling pathway, PI3K-Akt signaling pathway, insulin signaling pathway, cardiac muscle contraction, adrenergic signaling in cardiomyocytes, Fc gamma R-mediated phagocytosis, etc. The great potential exhibited by FVP could make it an ideal candidate as complementary medicine or functional food for promotion of health.

Free-recall benefit, inhomogeneity and between-item interference in working memory.

We investigated visual working memory (VWM) with a whole-report task, where participants were asked to sequentially recall all the items in an order either chosen by themselves (free recall) or randomly chosen by the computer (forced recall). Comparisons between free and forced recalls helped us understand important but largely neglected aspects of VWM, such as inhomogeneity (different levels of precision) and between-item interference. One unique part of our task was the introduction of a separate item-selection stage before each recall, during which participants located the next item to recall. Their mouse trajectory was recorded and served as a dynamic measure of between-item interference over time. We found a free-recall benefit: the overall precision of all items is higher in free recall than in forced recall. Meanwhile, during item-selection, free recall is associated with faster localization of the target and less interference from the other items in memory. We also found evidence for inhomogeneity and discuss the connection of inhomogeneity and between-item interference to the free-recall benefit.

PINK1/Parkin-mediated mitophagy inhibits warangalone-induced mitochondrial apoptosis in breast cancer cells.

Breast cancer is the most common malignancy in women all around the world, especially in many countries in Asia. However, antitumor drugs with unique curative effects and low toxic side-effects have not been found yet. Warangalone is an isoflavone extracted from the Cudrania tricuspidata fruit, and is reported to possess anti-inflammatory and anti-cancer activity. The purpose of this study was to determine the effects of warangalone on breast cancer cells. In this study, we found that warangalone decreased the viability of breast cancer cells by increasing the generation of reactive oxygen species (ROS) resulting in mitochondrial damage and decreased mitochondrial membrane potential (MMP). Warangalone induced mitochondrial apoptosis by increasing the BAX/BCL-2 ratio. Warangalone activated mitophagy via upregulation of PINK1 and Parkin expression and co-localization. The combination of warangalone and autophagy inhibitors or PINK1 siRNA increased the degree of cell apoptosis compared to treatment with warangalone alone. Warangalone damages mitochondria via ROS, thereby triggering PINK1/Parkin-mediated mitophagy and inducing mitochondrial apoptosis. However, autophagy/mitophagy protects against warangalone-induced mitochondrial apoptosis. A combination of warangalone and autophagy/mitophagy inhibitors may be a potential treatment for breast cancer.

Multifunctional Biodegradable Prussian Blue Analogue for Synergetic Photothermal/Photodynamic/Chemodynamic Therapy and Intrinsic Tumor Metastasis Inhibition.

To date, various Prussian blue analogues (PBAs) have been prepared for biomedical applications due to their unique structural advantages. However, the safety and effectiveness of tumor treatment still need further exploration. This contribution reports a facile synthesis of PBA with superior tumor synergetic therapeutic effects and a detailed mechanistic evaluation of their intrinsic tumor metastasis inhibition activity. The as-synthesized PBA has a uniform cube structure with a diameter of approximately 220 nm and shows high near-infrared light (NIR) photoreactivity, photothermal conversion efficiency (41.44%), and photodynamic effect. Additionally, PBA could lead to a chemodynamic effect, which is caused by the Fenton reaction and ferroptosis. The combined therapy strategy of PBA exhibits notable tumor ablation properties due to photothermal therapy (PTT)/photodynamic therapy (PDT)/chemodynamic therapy (CDT) effects without obvious toxicity in vivo. The PBA has also shown potential as a contrast agent for magnetic resonance imaging (MRI) and photoacoustic (PA) imaging. More importantly, careful investigations reveal that PBA displays excellent biodegradation and anti-metastasis properties. Further exploration of the PBA implies that its underlying mechanism of intrinsic tumor metastasis inhibition activity can be attributed to the modulation of epithelial-mesenchymal transition (EMT) expression. The considerable potential exhibited by the as-synthesized PBA makes it an ideal candidate as a synergetic therapeutic agent for tumor treatment.

Flammulina velutipes polysaccharide improves C57BL/6 mice gut health through regulation of intestine microbial metabolic activity.

Flammulina velutipes polysaccharides (FVP) can improve gut health through gut microbiota and metabolism regulation. In this study, the 28-days fed experiment was used to investigate gut microbime and metabolic profiling induced by FVP. After treatment, intestinal tissue section showed the higher villus height and villus height/crypt depth (V/C) value in FVP-treated group. The 16 s rRNA gene sequencing revealed microbiota composition alteration caused by FVP, as the Firmicutes phylum increased while Bacteroidetes phylum slightly decreased. The metabolic profiling was detected by LC/MS and results showed 56 and 99 compounds were dramatically changed after FVP treatment in positive and negative ion mode, respectively. Annotation in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways displayed the adjustment of energy metabolism, amino acid metabolism, nucleotide metabolism and other related basic pathways after FVP treatment. Our study suggested that FVP can be developed as a dietary supplement for intestine health promotion.

Exploring the Preventive Effect and Mechanism of Senile Sarcopenia Based on "Gut-Muscle Axis".

Age-related sarcopenia probably leads to chronic systemic inflammation and plays a vital role in the development of the complications of the disease. Gut microbiota, an environmental factor, is the medium of nutritional support to muscle cells, having significant impact on sarcopenia. Consequently, a significant amount of studies explored and showed the presence of gut microbiome-muscle axis (gut-muscle axis for short), which was possibly considered as the disease interventional target of age-related sarcopenia. However, a variety of nutrients probably affect the changes of the gut-muscle axis so as to affect the healthy balance of skeletal muscle. Therefore, it is necessary to study the mechanism of intestinal-muscle axis, and nutrients play a role in the treatment of senile sarcopenia through this mechanism. This review summarizes the available literature on mechanisms and specific pathways of gut-muscle axis and discusses the potential role and therapeutic feasibility of gut microbiota in age-related sarcopenia to understand the development of age-related sarcopenia and figure out the novel perspective of the potential therapeutic interventional targets.

Injectable Hydrogel-Based Nanocomposites for Cardiovascular Diseases.

Cardiovascular diseases (CVDs), including a series of pathological disorders, severely affect millions of people all over the world. To address this issue, several potential therapies have been developed for treating CVDs, including injectable hydrogels as a minimally invasive method. However, the utilization of injectable hydrogel is a bit restricted recently owing to some limitations, such as transporting the therapeutic agent more accurately to the target site and prolonging their retention locally. This review focuses on the advances in injectable hydrogels for CVD, detailing the types of injectable hydrogels (natural or synthetic), especially that complexed with stem cells, cytokines, nano-chemical particles, exosomes, genetic material including DNA or RNA, etc. Moreover, we summarized the mainly prominent mechanism, based on which injectable hydrogel present excellent treating effect of cardiovascular repair. All in all, it is hopefully that injectable hydrogel-based nanocomposites would be a potential candidate through cardiac repair in CVDs treatment.

Nobiletin Triggers Reactive Oxygen Species-Mediated Pyroptosis through Regulating Autophagy in Ovarian Cancer Cells.

Ovarian cancer is one of the most serious female malignancies worldwide. Despite intensive efforts being made to overcome ovarian cancer, there still remain limited optional treatments for this disease. Nobiletin, a prospective food-derived phytochemical extracted from citrus fruits, has recently been reported to suppress ovarian cancer cells, but the role of pyroptosis in ovarian carcinoma with nobiletin still remains unknown. In this study, we aim to explore the effect of nobiletin on ovarian carcinoma and further expound the underlying mechanisms of nobiletin-induced ovarian cancer cell death. Our results showed that nobiletin could significantly inhibit cell proliferation, induce DNA damage, and also lead to apoptosis by increasing the cleaved poly (ADP-ribose) polymerase (PARP) level of human ovarian cancer cells (HOCCs) in a dose-dependent manner. Moreover, we revealed that nobiletin decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) generation and autophagy of HOCCs, contributing to gasdermin D-/gasdermin E-mediated pyroptosis. Taken together, nobiletin as a functional food ingredient represents a promising new anti-ovarian cancer candidate that could induce apoptosis and trigger ROS-mediated pyroptosis through regulating autophagy in ovarian cancer cells.

Comparison of various anthropometric indices in predicting abdominal obesity in Chinese children: a cross-sectional study.

BACKGROUND: Former evidence regarding reference values of abdominal fat percentage (AFP) and optimal anthropometric indicators in predicting abdominal obesity measured by dual-energy X-ray absorptiometry (DXA) scan in Chinese children were scarce. METHODS: A total of 452 Chinese children aged 6-9 years were included in this cross-sectional study. Abdominal fat and lean mass were measured by a DXA scan, and AFP were calculated. Anthropometric indicators including body mass index (BMI), chest circumference (CC), waist circumference (WC) and hip circumference (HC) were measured, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR) was also calculated. RESULTS: By defining abdominal obesity as those with an AFP ≥ 85th percentile, the cutoffs values are 24.80, 30.29, 31.58, 31.86% in boys, and 25.02, 30.32, 31.66, 31.79% in girls, for children aged 6, 7, 8, and 9 years old, respectively. All anthropometric indicators were independently and positively associated with AFP (P all < 0.01). In girls, BMI was found to be the optimal predictors of childhood abdominal obesity. The values of area under curves (AUCs) were significantly higher (P all < 0.05) than other anthropometric indicators, except for WHtR (AUCs value: 0.886). However, in boys, WHtR instead of BMI, provided the largest AUCs value (0.922) in predicting abdominal obesity, followed by BMI ((AUCs value: 0.913). CONCLUSION: This study provides reference values of AFP measured by DXA in Chinese children aged 6-9 years. BMI and WHtR tend to be the optimal anthropometric indicators in predicting abdominal obesity in Chinese girls and boys, respectively.

Enhanced visible-light photocatalytic activity and photostability of Ag3PO4/Bi2WO6 heterostructures toward organic pollutant degradation and plasmonic Z-scheme mechanism.

Novel Ag3PO4/Bi2WO6 heterostructured materials with enhanced visible-light catalytic performance were successfully synthesized by assembly combined with a hydrothermal treatment. The microstructures, morphologies, and optical properties of the prepared samples were characterized by multiple techniques. The irregular Ag3PO4 nanospheres dispersed on the surface of Bi2WO6 nanoflakes, and their catalytic performances were evaluated via the degradation of organic pollutants including rhodamine B (RB), methylene blue (MB), crystal violet (CV), methyl orange (MO), and phenol (Phen) under visible-light irradiation. The resulting Ag3PO4/Bi2WO6 heterostructured materials displayed higher photocatalytic activity than that of either pure Bi2WO6 or Ag3PO4. The enhanced photocatalytic activity was due to the good formation of heterostructures, which could not only broaden the spectral response range to visible light but also effectively promoted the charge separation. Meanwhile, the reasonable photoreactive plasmonic Z-scheme mechanism was carefully investigated on the basic of the reactive species scavenging tests, photoelectrochemical experiments, and photoluminescence (PL) spectrum. In addition, the excellent photostability of Ag3PO4/Bi2WO6 was obtained, which Ag formed at the early photocatalytic reaction acted as the charge transmission-bridge to restrain the further photoreduction of Ag3PO4.