Dongjin Pan

Glucose-regulated protein 78 (GRP78), a molecular chaperone, is overexpressed in patients suffering from obesity, fatty liver, hyperlipidemia and diabetes. GRP78, therefore, can be not only a biomarker to predict the progression and prognosis of obesity and metabolic diseases but also a potential therapeutic target for anti-obesity treatment. In this paper, GRP78 inhibitors targeting its ATPase domain have been reviewed. Small molecules and proteins that directly bind GRP78 have been described. Putative mechanisms of GRP78 in regulating lipid metabolism were also summarized so as to investigate the role of GRP78 in obesity and other related diseases and provide a theoretical basis for the development and design of anti-obesity drugs targeting GRP78.

Phycocyanin (PC) is a pigment-protein complex. It has been reported that PC exerts anti-colorectal cancer activities, although the underlying mechanism has not been fully elucidated. In the present study, azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mice were orally administrated with PC, followed by microbiota and transcriptomic analyses to investigate the effects of PC on colitis-associated cancer (CAC). Our results indicated that PC ameliorated AOM/DSS induced inflammation. PC treatment significantly reduced the number of colorectal tumors and inhibited proliferation of epithelial cell in CAC mice. Moreover, PC reduced the relative abundance of Firmicutes, Deferribacteres, Proteobacteria and Epsilonbacteraeota at phylum level. Transcriptomic analysis showed that the expression of genes involved in the intestinal barrier were altered upon PC administration, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed the IL-17 signaling pathway was affected by PC treatment. The study demonstrated the protective therapeutic action of PC on CAC.

Obesity is among the most serious public health problems worldwide, with few safe pharmaceutical interventions. Natural products have become an important source of potential anti-obesity therapeutics. Dihydromyricetin (DHM) exerts antidiabetic effects. The biochemical target of DHM, however, has been unknown. It is crucial to identify the biochemical target of DHM for elucidating its physiological function and therapeutic value. The objective of this study was to identify the biochemical target of DHM. An abundant antiadipogenic flavanonol was extracted from the herbal plant Ampelopsis grossedentata through bioassay-guided fractionation and characterized with high-resolution LC-MS and ¹H and ¹³C nuclear magnetic resonance. Antiadipogenic experiments were done with mouse 3T3-L1 preadipocytes. A biochemical target of the chemical of interest was identified with drug affinity responsive target stability assay. Direct interactions between the chemical of interest and the protein target in vitro were predicted with molecular docking and subsequently confirmed with surface plasmon resonance. Expression levels of peroxisome proliferator-activated receptor γ (PPARγ), which is associated with 78-kDa glucose-regulated protein (GRP78), were measured with real-time qPCR. DHM was isolated, purified, and structurally characterized. Cellular studies showed that DHM notably reduced intracellular oil droplet formation in 3T3-L1 cells with a median effective concentration of 294 μM (i.e., 94 μg/mL). DHM targeted the ATP binding site of GRP78, which is associated with adipogenesis. An equilibrium dissociation constant between DHM and GRP78 was 21.8 μM. In 3T3-L1 cells upon treatment with DHM at 50 μM (i.e., 16 μg/mL), the expression level of PPARγ was downregulated to 53.9% of the solvent vehicle control's level. DHM targets GRP78 in vitro. DHM is able to reduce lipid droplet formation in 3T3-L1 cells through a mode of action that is plausibly associated with direct interactions between GRP78 and DHM, which is a step forward in determining potential applications of DHM as an anti-obesity agent.