Proteoglycan Extracted from Ganoderma lucidum Ameliorated Diabetes-Induced Muscle Atrophy via the AMPK/SIRT1 Pathway In Vivo and In Vitro.

Muscle atrophy often occurs in type 2 diabetes (T2D) and leads to an increase in physical disability and insulin resistance. However, there are very few studies that have investigated potential natural products used for this condition. In this study, we demonstrated that FYGL (Fudan-Yueyang-G. lucidum), a proteoglycan extracted from Ganoderma lucidum, ameliorated muscle atrophy in rat and mouse models of diabetes. Histopathological analysis of muscle revealed that oral administration of FYGL significantly prevented reduction of the cross-sectional area of muscle fibers and overexpression of muscle atrophic factors in diabetic rats and mice. Muscle RNA-seq analysis in vivo indicated that FYGL regulated genes related to myogenesis, muscle atrophy, and oxidative phosphorylation. Also, FYGL activated AMPK in vivo. Furthermore, the underlying molecular mechanisms were studied in palmitate-induced C2C12 muscle cells using immunofluorescence staining and Western blotting, which revealed that FYGL inhibited muscle atrophy by stimulating ATP production and activating the AMPK/SIRT1 pathway, thus promoting oxidative metabolism. This result rationalized the in vivo findings. These results suggest FYGL as a promising functional food ingredient for the prevention of T2D-induced muscle atrophy.

Balancing adipocyte production and lipid metabolism to treat obesity-induced diabetes with a novel proteoglycan from Ganoderma lucidum.

Obesity is often accompanied by metabolic disorder and insulin resistance, resulting in type 2 diabetes. Based on previous findings, FYGL, a natural hyperbranched proteoglycan extracted from the G. lucidum fruiting body, can decrease blood glucose and reduce body weight in diabetic mice. In this article, the underlying mechanism of FYGL in ameliorating obesity-induced diabetes was further investigated both in vivo and in vitro. FYGL upregulated expression of metabolic genes related to fatty acid biosynthesis, fatty acid ß-oxidation and thermogenesis; downregulated the expression of insulin resistance-related genes; and significantly increased the number of beige adipocytes in db/db mice. In addition, FYGL inhibited preadipocyte differentiation of 3T3-L1 cells by increasing the expression of FABP-4. FYGL not only promoted fatty acid synthesis but also more significantly promoted triglyceride degradation and metabolism by activating the AMPK signalling pathway, therefore preventing fat accumulation, balancing adipocyte production and lipid metabolism, and regulating metabolic disorders and unhealthy obesity. FYGL could be used as a promising pharmacological agent for the treatment of metabolic disorder-related obesity.

Effects of a Ganoderma lucidum Proteoglycan on Type 2 Diabetic Rats and the Recovery of Rat Pancreatic Islets.

Type 2 diabetes (T2D) results from both insulin resistance and pancreatic ß-cell dysfunction. A natural proteoglycan extracted from Ganoderma lucidum, namely, FYGL, has been demonstrated to be capable of ameliorating insulin resistance in previous work. In this work, a T2D rat model induced by streptozocin (STZ) and a high-fat diet was used to investigate the effects of FYGL on pancreatic functions, and the transcriptomics of the rat pancreas was used to investigate the biological processes (BP) and signal pathways influenced by FYGL on the gene basis. Furthermore, the results of transcriptomics were verified both by histopathological analyses and protein expression. The studies showed that FYGL positively regulated T2D-related BP and signaling pathways and recovered the pancreatic function, therefore ameliorating hyperglycemia and hyperlipidemia in vivo. Importantly, the recovery of the pancreatic function suggested a crucial strategy to radically treat T2D.

Manganese and cobalt bimetallic-doped Prussian blue analogs as a bifunctional electrocatalyst for zinc-air batteries.

Zinc-air battery is a novel safe and environment-friendly energy storage device, but the noble-metal electrocatalysts at the air electrode urge people to search for new substitutes. Herein, different ratios of manganese (Mn) and cobalt (Co) are doped into the iron Prussian blue analogs (PBAs) and used as bifunctional electrocatalysts. The Mn1.33Co0.67-PBA shows the outstanding electrocatalytic properties that the half-wave potential is 0.79 V, the Ej=10 of OER is 1.54 V, and the ΔE is as low as 0.75 V, which is superior to that of Pt/C + RuO2 system (0.78 V). Benefiting from the bimetallic-doping advantage, the Mn1.33Co0.67-PBA has good stability in alkaline solutions. Besides, the Mn1.33Co0.67-PBA was assembled into ZAB, possessing a high maximum power density of 161 mW cm-2 and a large specific capacity of 617 mAh g-1, as well as excellent cycle stability. The as-prepared bimetallic-doped PBA has the potential for applications in the energy storage and conversion field.

The thermodynamic and kinetic mechanisms of a Ganoderma lucidum proteoglycan inhibiting hIAPP amyloidosis.

Ganoderma lucidum is a valuable medicinal herbal which has been reported to prevent type 2 diabetes (T2D). A natural hyperbranched proteoglycan extracted from Ganoderma lucidum, namely, FYGL, has been demonstrated to inhibit the amyloidosis of human islet amyloid polypeptide (hIAPP) previously by our lab. However, the effective active components and the mechanisms of FYGL in inhibiting hIAPP amyloidosis are unknown. To identify the effective active components, different components from FYGL were isolated: the polysaccharide FYGL-1, the proteoglycans of FYGL-2 and FYGL-3. We further separated and sequenced the protein moieties of FYGL-2 and FYGL-3, namely, FYGL-2-P and FYGL-3-P, respectively, and compared their abilities to inhibit hIAPP amyloidosis, and systematically explored the inhibitory mechanisms by spectroscopy, microscopy and molecular dynamic simulation methods. Results showed that the protein moieties of FYGL played essential roles in inhibiting hIAPP amyloidosis. The strong, specific, and enthalpy-driven interaction by π-π stacking and electrostatic forces between hIAPP and FYGL-3-P dramatically inhibited hIAPP amyloidosis. These results suggested that FYGL-3-P had enormous potential to prevent hIAPP misfolding-induced diabetes and structurally helped researchers to seek or design inhibitors against polypeptide amyloidosis.

Interaction and Inhibition of a Ganoderma lucidum Proteoglycan on PTP1B Activity for Anti-diabetes.

Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and an effective target for the treatment of type 2 diabetes (T2D). A natural hyperbranched proteoglycan extracted from Ganoderma lucidum, namely, Fudan-Yueyang G. Lucidum (FYGL), was demonstrated capable of inhibiting the activity of PTP1B. Here, to identify the effective active components of FYGL, three different components, the polysaccharide FYGL-1, proteoglycans FYGL-2, and FYGL-3, were isolated from FYGL, and then, the protein moiety of FYGL-3 was further separated, namely, FYGL-3-P. Their abilities to enhance the glucose uptake in cells and inhibit the activity of PTP1B were compared. The inhibitory mechanisms were systematically explored by spectroscopic methods and MD simulations. The results showed that FYGL-3 and FYGL-3-P significantly enhanced the insulin-provoked glucose uptake in insulin-resistant HepG2 cells, detected by the glucose oxidase method. Also, the FYGL-3-P protein moiety in FYGL played an essential role in inhibiting the activity of PTP1B. A strong, enthalpy-driven, and multitargeted interaction by electrostatic forces between PTP1B and FYGL-3-P dramatically inhibited the catalytic activity of PTP1B. These results provided deep insights into the molecular mechanisms of FYGL inhibiting the activity of PTP1B and structurally helped researchers seek natural PTP1B inhibitors.

Distinction of chiral penicillamine using metal-ion coupled cyclodextrin complex as chiral selector by trapped ion mobility-mass spectrometry and a structure investigation of the complexes.

Penicillamine (Pen) is a common chiral drug that is obtained from penicillin. Between the two enantiomers of Pen, only D-Pen can be used to treat cystinuria and rheumatoid arthritis while L-Pen is toxic. Therefore, it requires great efforts for the research of the rigorous analysis and distinction of the two enantiomers. The non-covalent combination of chiral molecules and chiral selectors (CSs) has been proved as a unique strategy for chiral distinction by ion mobility spectrometry in coupling with -mss spectrometry (IM-MS). Here, we developed a simple method to distinguish D, L-Pen by using special CSs for IM-MS separation. The CSs utilized here include cyclodextrins (CD) and linear chain oligosaccharides plus metal ions. We found that non-covalent complexes [Pen+ß-CD + Li]+ could be easily formed by electrospray ionization of the mixture of the solution, and the chirality of Pen could be effectively recognized by measuring their mobilities due to the different collision cross collision sections of [D-Pen+ß-CD + Li]+ and [L-Pen+ß-CD + Li]+. A detailed analysis of [Pen+ß-CD + Li]+ was then conducted by the optical rotation measurements and NMR experiments to reveal their structural differences. Furthermore, DFT calculation showed the differences of molecular conformation between the complexes. The results provide a new powerful method for fast analysis and recognition of chirality of Pen compounds by IM-MS.

Effect of Transition-Metal Ions on the Conformation of Encephalin Investigated by Hydrogen/Deuterium Exchange and Theoretical Calculations.

We have studied the effects of different 3d orbitals in divalent transition-metal ions [G2+ = Mn2+ (d5), Fe2+ (d6), Co2+ (d7), Ni2+ (d8), Cu2+ (d9), or Zn2+ (d10)] on the conformations of leucine encephalin (LE) and methionine encephalin (ME) in the gas phase using hydrogen/deuterium exchange mass spectrometry (HDX-MS) and theoretical calculations at the molecular level. The HDX-MS reveals a 1:1 stoichiometric monovalent complex of [LE/ME + G - H]+ and observed that the different HDX reactivities follow the trend Fe2+ < Co2+ < Ni2+ < Mn2+ < Cu2+ ≈ Zn2+ and that [ME + Mn/Cu/Zn - H]+ > [LE + Mn/Cu/Zn - H]+, while [LE + Fe/Co/Ni - H]+ > [ME + Fe/Co/Ni - H]+. We cross-correlated the collision-induced dissociation energies of the complexes with the HDX results and found that the more stable the complex, the harder it is for it to undergo HDX. Furthermore, we used theoretical calculations to optimize the favorable conformations of the complexes and found the same interaction structure of G2+ coordination with the five carbonyl oxygens of LE/ME that have different bond lengths. Finally, we calculated the proton affinity (PA) values of the optimized complexes in order to interpret the HDX observations that the higher the PA values, the more difficult it is for the complex to undergo HDX. Overall, both the experiments and the theoretical calculations show that the six metal ions have different effects on the LE/ME conformation, with the low-energy stability of the G2+ 3d orbitals corresponding to more dramatic effects on the LE/ME conformation. In addition, the hardness of the ionic acid corresponding to the fully filled Mn2+ and half-filled Zn2+ orbitals also contributes strongly to the coordination effect; the conformation effect of Fe2+/Co2+/Ni2+ on LE is greater than that on ME, whereas the conformation effect of Mn2+/Cu2+/Zn2+ on ME is greater than that on LE.