Licochalcone A alleviates abnormal glucolipid metabolism and restores energy homeostasis in diet-induced diabetic mice.

Licochalcone A (LCA) is a bioactive chalcone compound identified in licorice. This study aimed to investigate the effects of LCA on glucolipid metabolism and energy homeostasis, as well as the underlying mechanisms. Blood glucose levels, oral glucose tolerance, serum parameters, and histopathology were examined in high-fat-high-glucose diet (HFD)-induced diabetic mice, with metformin as a positive control. Additionally, changes in key markers related to glucolipid metabolism and mitochondrial function were analyzed to comprehensively assess LCA's effects on metabolism. The results showed that LCA alleviated metabolic abnormalities in HFD-induced diabetic mice, which were manifested by suppression of lipogenesis, promotion of lipolysis, reduction of hepatic steatosis, increase in hepatic glycogenesis, and decrease in gluconeogenesis. In addition, LCA restored energy homeostasis by promoting mitochondrial biogenesis, enhancing mitophagy, and reducing adenosine triphosphate production. Mechanistically, the metabolic benefits of LCA were associated with the downregulation of mammalian target of rapamycin complex 1 and activation of adenosine monophosphate-activated protein kinase, the two central regulators of metabolism. This study demonstrates that LCA can alleviate abnormal glucolipid metabolism and restore energy balance in diet-induced diabetic mice, highlighting its therapeutical potential for the treatment of diabetes.

Cytosolic and Nucleosolic Calcium-Regulated Molecular Networks in Response to Long-Term Treatment with Abscisic Acid and Methyl Jasmonate in Arabidopsis thaliana.

Calcium acts as a universal secondary messenger that transfers developmental cues and stress signals for gene expression and adaptive growth. A prior study showed that abiotic stresses induce mutually independent cytosolic Ca2+ ([Ca2+]cyt) and nucleosolic Ca2+ ([Ca2+]nuc) increases in Arabidopsis thaliana root cells. However, gene expression networks deciphering [Ca2+]cyt and [Ca2+]nuc signalling pathways remain elusive. Here, using transgenic A. thaliana to selectively impair abscisic acid (ABA)- or methyl jasmonate (MeJA)-induced [Ca2+]cyt and [Ca2+]nuc increases, we identified [Ca2+]cyt- and [Ca2+]nuc-regulated ABA- or MeJA-responsive genes with a genome oligo-array. Gene co-expression network analysis revealed four Ca2+ signal-decoding genes, CAM1, CIPK8, GAD1, and CPN20, as hub genes co-expressed with Ca2+-regulated hormone-responsive genes and hormone signalling genes. Luciferase complementation imaging assays showed interactions among CAM1, CIPK8, and GAD1; they also showed interactions with several proteins encoded by Ca2+-regulated hormone-responsive genes. Furthermore, CAM1 and CIPK8 were required for MeJA-induced stomatal closure; they were associated with ABA-inhibited seed germination. Quantitative reverse transcription polymerase chain reaction analysis showed the unique expression pattern of [Ca2+]-regulated hormone-responsive genes in cam1, cipk8, and gad1. This comprehensive understanding of distinct Ca2+ and hormonal signalling will allow the application of approaches to uncover novel molecular foundations for responses to developmental and stress signals in plants.

Shenlian (SL) Decoction, a Traditional Chinese Medicine Compound, May Ameliorate Blood Glucose via Mediating the Gut Microbiota in db/db Mice.

Shenlian (SL) decoction is a herbal formula composed of Coptis and ginseng, of which berberine and ginsenoside are the main constituents. Even though SL decoction is widely used in treating diabetes in China, the mechanism of its antidiabetes function still needs further study. Gut microbiota disorder is one of the important factors that cause diabetes. To explore the effect of SL decoction on intestinal microbiota, gut microbiota of mice was analyzed by sequencing the gut bacterial 16S rRNA V3+V4 region and metagenomics. In this study, results demonstrated that SL decoction had a better hypoglycemic effect and ß cell protection effect than either ginseng or Coptis chinensis. Alpha diversity analysis showed that all interventions with ginseng, Coptis, and SL decoction could reverse the increased diversity and richness of gut microbiota in db/db mice. PCoA analysis showed oral SL decoction significantly alters gut microbiota composition in db/db mice. 395 OTUs showed significant differences after SL treatment, of which 37 OTUs enriched by SL decoction showed a significant negative correlation with FBG, and 204 OTUs decreased by SL decoction showed a significant positive correlation with FBG. Results of KEGG analysis and metagenomic sequencing showed that SL decoction could reduce the Prevotellaceae, Rikenellaceae, and Helicobacteraceae, which were related to lipopolysaccharide biosynthesis, riboflavin metabolism, and peroxisome, respectively. It could also upregulate the abundance of Bacteroidaceae, which contributed to the metabolism of starch and sucrose as well as pentose-glucuronate interconversions. In the species level, SL decoction significantly upregulates the relative abundance of Bacteroides_acidifaciens which showed a significant negative correlation with FBG and was reported to be a potential agent for modulating metabolic disorders such as diabetes and obesity. In conclusion, SL decoction was effective in hypoglycemia and its mechanism may be related to regulating gut microbiota via upregulating Bacteroides_acidifaciens.

Isoliquiritigenin alleviates diabetic symptoms via activating AMPK and inhibiting mTORC1 signaling in diet-induced diabetic mice.

PURPOSE: To determine the effects of isoliquiritigenin (ISL), a chalcone compound isolated from licorice, on type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: 8-week-old C7BL/6 mice were used to establish the T2DM animal model by feeding with high-fat-high-glucose diet (HFD) combined with intraperitoneal injection of streptozotocin. The animals were treated with ISL for 3 weeks. Blood glucose levels, oral glucose tolerance, and insulin tolerance were examined, serum parameters were determined, histologic sections were prepared, activities of enzymes related to glucolipid metabolism were analyzed, and the mitochondrial function was investigated to evaluate effects of ISL on metabolism. The underlying mechanisms of ISL alleviating insulin resistance and restoring metabolic homeostasis were analyzed in HepG2 and INS-1 cells. RESULTS: ISL exhibits a potent activity in relieving hyperglycemia of type 2 diabetic mice. It alleviates insulin resistance and restores metabolic homeostasis without obvious adversary effects in HFD-induced diabetic mice. The metabolic benefits of ISL treatment include promoting hepatic glycogenesis, inhibiting hepatic lipogenesis, reducing hepatic steatosis, and sensitizing insulin signaling. Mechanistically, ISL activates adenosine monophosphate-activated protein kinase (AMPK) and inhibits mammalian target of rapamycin complex 1 (mTORC1). It also suppresses mitochondrial function and reduces ATP production. CONCLUSION: Our findings demonstrate that ISL is able to significantly reduce blood glucose level and alleviate insulin resistance without obvious side effects in diabetic mice, hence uncovering a great potential of ISL as a novel drug candidate in prevention and treatment of T2DM.

ARPI, ß-AS, and UGE regulate glycyrrhizin biosynthesis in Glycyrrhiza uralensis hairy roots.

KEY MESSAGE: ARPI, ß-AS, and UGE were cloned from G. uralensis and their regulatory effects on glycyrrhizin biosynthesis were investigated. ß-AS and UGE but not ARPI positively regulate the biosynthesis of glycyrrhizin. Glycyrrhiza uralensis Fisch. has been used to treat respiratory, gastric, and liver diseases since ancient China. The most important and widely studied active component in G. uralensis is glycyrrhizin (GC). Our pervious RNA-Seq study shows that GC biosynthesis is regulated by multiple biosynthetic pathways. In this study, three target genes, ARPI, ß-AS, and UGE from different pathways were selected and their regulatory effects on GC biosynthesis were investigated using G. uralensis hairy roots. Our data show that hairy roots knocking out ARPI or UGE died soon after induction, indicating that the genes are essential for the growth of G. uralensis hairy roots. Hairy roots with ß-AS knocked out grew healthily. However, they failed to produce GC, suggesting that ß-AS is required for triterpenoid skeleton formation. Conversely, overexpression of UGE or ß-AS significantly increased the GC content, whereas overexpression of ARPI had no obvious effects on GC accumulation in G. uralensis hairy roots. Our findings demonstrate that ß-AS and UGE positively regulate the biosynthesis of GC.

Self-assembled peptido-nanomicelles as an engineered formulation for synergy-enhanced combinational SDT, PDT and chemotherapy to nasopharyngeal carcinoma.

A formulation of self-assembled peptido-nanomicelles has been developed for a combinational treatment of SDT, PDT and chemotherapy to nasopharyngeal carcinoma. In vitro cellular tests and in vivo mice therapy proved effective for targeted tumor growth inhibition. These merits provided a novel approach to non-invasive cancer treatments.

Multifunctional nanocapsules on a seesaw balancing sonodynamic and photodynamic therapies against superficial malignant tumors by effective immune-enhancement.

The effective strategy to treat superficial malignant tumors is challenging due to the complexed mechanisms for tumor growth inhibition. The proposed immune-enhancement and immune response activation pathways rely on the direct and massive implementation of therapeutic agents. In this manuscript, an alternative route has been developed to apply the multifunctional peptide amphiphile-Rose Bengal (RB) nanocapsules for noninvasive sonodynamic and photodynamic therapies in association with the targeted immune enhancement to tumor proliferation. The nanocapsules proved better RB loading capacity, comparable reactive oxygen species generation and improved B16 and HeLa cell killing capability. The proof-of-principle in-vivo nude mice therapy studies with routine blood examinations and cytokine analysis validated their effectiveness for tumor cell elimination, and a direct tumor vasculature damage for efficacious lesion necrosis, positive prognosis with minimized side-effects. This state-of-the-art strategy provides a promising route to merge tumor enhancement and tumor response activation methodologies, and is expected to be universalized for a broad spectra of cancer diseases.