A Novel Ultrafiltrate Extract of Propolis Exerts Anti-inflammatory Activity through Metabolic Rewiring.

Thousands of years ago, humans started to use propolis because of its medicinal properties, and modern science has successfully identified several bioactive molecules within this resinous bee product. However, a natural propolis extract which has been removed the adhesive glue and preserved propolis bioactive compounds is urgently needed to maximise the therapeutic opportunities. In this study, a novel ultrafiltrate fraction from Brazilian green propolis, termed P30K, was demonstrated with anti-inflammatory properties, both in vitro and in vivo. Total flavonoids and total phenolic acids content in P30K were 244.6 mg/g and 275.8 mg/g respectively, while the IC50 value of inhibition of cyclooxygenase-2 (COX-2) was 8.30 µg/mL. The anti-inflammatory activity of P30K was furtherly corroborated in experimental models of lipopolysaccharides (LPS)-induced acute liver and lung injury. Mechanistically, integrated GC-MS and LC-MS based serum metabolomics analysis revealed that P30K modulated citrate cycle (TCA), pyruvate, glyoxylate and dicarboxylate metabolism pathways to inhibit secretion of pro-inflammatory cytokines. Results of network pharmacology and molecular docking suggested that P30K targeted catechol-O-methyltransferases (COMT), 11ß-hydroxysteroid dehydrogenases (HSD11B1), and monoamine oxidases (MAOA and MAOB) to promote cellular metabolomic rewiring. Collectively, our work reveals P30K as an efficient therapeutic agent against inflammatory conditions and its efficacy is related to metabolic rewiring.

Membrane-Based Preparation Process and Antioxidant and Anti-AGEs Activities of a Novel Propolis Ultrafiltrate.

Propolis is one functional supplement with hundreds of years of usage. However, it's rarely consumed directly for its resinous property. Herein, a pre-treated process which can remove the impurity while preserve its bioactivities is needed to maximise its therapeutic opportunities. In the present study, a membrane-based ultrafiltration process was developed on a KM1812-NF experimental instrument. Using Brazilian green propolis as testing material, all experimental steps and parameters were sequentially optimized. In addition, a mathematical model was developed to fit the process. As a result, the optimum solvent was 60 % ethanol adjusted to pH 8-9, while the optimum MWCO (molecular weight cut-off) value of membrane was 30 KDa. The membrane filtration dynamic model fitted with the function y=(ax+b)/(1+cx+dx2 ). The resulting propolis ultrafiltrate from Brazilian green propolis, termed P30K, contains the similar profile of flavonoids and phenolic acids as raw propolis. Meanwhile, the ORAC (oxygen radical absorbance capacity) value of P30K is 11429.45±1557.58 µM TE/g and the IC50 value of inhibition of fluorescent AGEs (advanced glycation end products) formation is 0.064 mg/mL. Our work provides an innovative alternative process for extraction of active compounds from propolis and reveals P30K as an efficient therapeutic antioxidant.

MKL-1 suppresses ferroptosis by activating system Xc- and increasing glutathione synthesis.

Chemotherapy is a standard method in traditional treatment for gastric cancer. It is well known that the anti-tumor effects of chemotherapy are achieved mainly through the direct killing of cancer cells via apoptosis. However, chemotherapy often fails due to drug resistance. Therefore, non-apoptotic cell death induction by ferroptosis has recently been proposed as a new therapeutic modality to ablate cancer. In this study, we determined the role of MKL-1 in ferroptosis. In vitro and in vivo experiments showed that inhibition of MKL-1 expression significantly enhanced cell sensitivity to ferroptosis-inducing agents. It functions by targeting system Xc- to affect the synthesis of GSH in cells. Therefore, we developed an exosome-based therapeutic approach targeting MKL-1, which provides a novel insight into the treatment of gastric cancer.

The role of lncRNA SNHG14 in gastric cancer: enhancing tumor cell proliferation and migration, and mechanisms of CDH2 expression.

LncRNAs are a class of non-coding RNAs that play an important role in regulating gene expression. However, their specific molecular mechanisms in gastric carcinogenesis and metastasis need further exploration. TCGA data showed that the expression of MFGE8, which was closely related to survival, was significantly positively correlated with lncRNA SNHG14. And moreover, the results of high-throughput sequencing and qRT-PCR showed that lncRNA SNHG14 was significantly elevated in gastric cancer. Further, in vitro functional realization showed that lncRNA SNHG14 overexpression significantly increased gastric cancer's proliferation, invasion and migration. Animal experiments also showed that lncRNA SNHG14 overexpression promoted tumorigenesis and metastasis in vivo. Mechanistically, MFGE8 activates the expression of lncRNA SNHG14, which activates the cellular EMT by stabilizing CDH2. Our study suggests that lncRNA SNHG14 could be a potential target for gastric cancer therapy.

Gastric cancer is one of the malignant tumors with a high incidence and high mortality rate worldwide. The current treatment modalities for gastric cancer are surgery, chemotherapy and targeted therapy. However, the 5-year survival rate of gastric cancer patients is still less than 30%. The main reason for the low survival rate of gastric cancer patients is that most cases are already at an advanced disease stage when first diagnosed, with tumor metastasis, tumor heterogeneity and resistance to radiotherapy. TCGA data showed that the expression of MFGE8, which was closely related to survival, was significantly positively correlated with lncRNA SNHG14.We found that lncRNA SNHG14 expression was significantly elevated in gastric cancer by high-throughput sequencing. It was further confirmed in vitro and in vivo that overexpression of lncRNA SNHG14 promoted the proliferation and migration ability of gastric cancer. Mechanistically, lncRNA SNHG14 played an oncogene role by promoting CDH2 expression to activate EMT in tumor cells.

MiR-205-5p/GGCT Attenuates Growth and Metastasis of Papillary Thyroid Cancer by Regulating CD44.

Papillary thyroid cancer (PTC) remains the most common endocrine malignancy, despite marked achieves in recent decades, and the mechanisms underlying the pathogenesis and progression for PTC are incompletely elucidated. Accumulating evidence show that γ-glutamylcyclotransferase (GGCT), an enzyme participating in glutathione homeostasis and is elevated in multiple types of tumors, represents an attractive therapeutic target. Using bioinformatics, immunohistochemistry, qRT-PCR, and Western blot assays, we found that GGCT expression was upregulated in PTC and correlated with more aggressive clinicopathological characteristics and worse prognosis. GGCT knockdown inhibited the growth and metastasis ability of PTC cells both in vitro and in vivo and reduced the expression of mesenchymal markers (N-cadherin, CD44, MMP2, and MMP9) while increasing epithelial marker (E-cadherin) in PTC cells. We confirmed binding of microRNA-205-5p (miR-205-5p) on the 3'-UTR regions of GGCT by dual-luciferase reporter assay and RNA-RNA pull-down assay. Delivery of miR-205-5p reversed the pro-malignant capacity of GGCT both in vitro and in vivo. Lastly, we found that GGCT interacted with and stabilized CD44 in PTC cells by co-immunoprecipitation and immunohistochemistry assays. Our findings illustrate a novel signaling pathway, miR-205-5p/GGCT/CD44, that involves in the carcinogenesis and progression of PTC. Development of miR-205-mimics or GGCT inhibitors as potential therapeutics for PTC may have remarkable applications.

A High-Fat High-Fructose Diet Dysregulates the Homeostatic Crosstalk Between Gut Microbiome, Metabolome, and Immunity in an Experimental Model of Obesity.

SCOPE: Ample evidence supports the prominent role of gut-liver axis in perpetuating pathological networks of high-fat high-fructose (HFF) diet induced metabolic disorders, however, the molecular mechanisms are still not fully understood. Herein, this study aims to present a holistic delineation and scientific explanation for the crosstalk between the gut and liver, including the potential mediators involved in orchestrating the metabolic and immune systems. METHODS AND RESULTS: An experimental obesity-associated metaflammation rat model is induced with a HFF diet. An integrative multi-omics analysis is then performed. Following the clues illustrated by the multi-omics discoveries, putative pathways are subsequently validated by RT-qPCR and Western blotting. HFF diet leads to obese phenotypes in rats, as well as histopathological changes. Integrated omics analysis shows that there exists a strong interdependence among gut microbiota composition, intestinal metabolites, and innate immunity regulation in the liver. Some carboxylic acids may contribute to gut-liver communication. Moreover, activation of the hepatic LPS-TLR4 pathway in obesity is confirmed. CONCLUSION: HFF-intake disturbs gut flora homeostasis. Crosstalk between gut microbiota and innate immune system mediates hepatic metaflammation in obese rats, associated with LPS-TLR4 signaling pathway activation. Moreover, α-hydroxyisobutyric acid and some other organic acids may play a role as messengers in the liver-gut axis.

Gut microbiota alterations and health status in aging adults: From correlation to causation.

The deterioration of tissue structure and decline in physiological function during aging are accompanied by alterations to the gut microbiota. The elderly has higher risks of various diseases and chronic diseases. However, inter-individual differences are more apparent in elderly than younger, and a proportion of individuals have a delayed onset or even avoid developing chronic diseases. This difference in health status is influenced by both heredity and Lifestyle and environmental factors. During the process of aging, the gut microbiota is also affected by the external environment, and provides a buffer to external challenge, and thus the gut microbiota reflects an individual's personal experience. Moreover, the immune system undergoes a series of changes with age, which are related to chronic inflammation in the elderly. The formation, maturation and senescence of the intestinal immune system is closely related to the gut microbiota. Additionally, changes in the gut microbiota of elderly individuals may modulate the immune system, which may in turn affect health status. Herein, we summarize the correlations between the gut microbiota with individual health status in the elderly and explore the related mechanisms, which may provide a basis to maintain or enhance the health of the elderly though interventions targeting the gut microbiota.