panax.JPGPnS has an obvious anti-inflammatory effect and its mechanisms are related to the inhibition of the Neu-[Ca2+]i level and PLA2 activity, and reduction of Din content.

Herbal medicines have traditionally played a major role in the management of diabetes in Asian countries for centuries. Panax notoginseng (Burk) F. H. Chen (Araliaceae) known as Tiánqī or san qi is a well-known medicinal herb in Asia for its long history of use in Chinese medicine. Qualified as ‘the miracle root for the preservation of life’, it has been used in China for 600 years, for treatment of various diseases. Panax notoginseng saponins (PNS) are the key active components. PNS have been widely used in China for treatment of cardiovascular diseases. However, scientific studies have shown a wide range of other pharmacological applications including anti-cancer, neuroprotective and anti-inflammatory agents, immunologic adjuvant and prevention of diabetes complications. Recently, hypoglycemic and anti-obesity properties of PNS have also been demonstrated. The present review highlights the effects of PNS on glucose production and absorption, and on inflammatory processes that seem to play an important role in the development of diabetes.

Notoginseng Radix et Rhizoma (Sanqi), the underground part of Panax notoginseng (Burk.) F. H. Chen (Araliaceae) is commonly used in Chinese medicine for treatment of haemorrhage, haemostasis, swelling, etc. The aerial part including leaves, flowers and fruits are also applied for similar functions. Triterpenoid saponins are considered to be responsible for the biological activities of Sanqi. Up to date, more than 100 saponins have been isolated from theroots, rhizomes, leaves, flowers and fruits of P. notoginseng. The reported saponins can be classified into protopanaxadiol (PPD), protopanaxatriol (PPT), C17 side-chain varied and other types, according to the skeletons of the aglycons. The present review summarizes the saponins isolated from P. notoginseng and their distribution in different medicinal organs, as well as the pharmacological actions on cardiovascular system.

Rutin (Figure (Figure3B),3B), a glycoside of quercetin, is found in many foods such as red wine, apples and onions. Panchal et al[99] first proved that rutin can decrease adiposity, improve insulin sensitivity, and reduce cardiac remodeling and liver injury in HFD rats[100]. Consistently, in a successive study, rutin effectively inhibited palmitate-induced macrophage activation and reduced liver fat by suppressing transcription of SREBP-1c and CD36 in the liver[101]. Recently, troxerutin was also shown to reduce liver steatosis and improve metabolic syndrome-related pathology in mice fed a high-fat diet, by suppressing oxidative stress-mediated NAD depletion and stimulating fat oxidation[99]. Other flavonoids, including pueraria[102], baicalein[103], luteolin[104], hydroxysafflor yellow A[105], genistein[106,107], silybin[108], isorhamnetin[109], iridin[110], naringin[111], shikonin[112], apigenin[113], kaempferol[114], myricetin[115], and pinocembrin[116] (Figure (Figure3C-P),3C-P), also play significant roles in the treatment of NAFLD.

Curcumin (Figure (Figure3R),3R), responsible for the yellow colour of the plant Curcuma Longa L, is extracted from curry and spice. Its antioxidant properties are widely studied in liver metabolism[132]. Curcumin has also been studied for NASH and metabolic pathologies. Leclercq et al[133] showed that curcumin improves liver injury by inhibiting nuclear factor-kappa B (NF-κB) activation, which in turn inhibits the expression of NF-κB target genes, including intercellular cell adhesion molecule-1, cyclooxygenase-2, and monocyte chemotactic protein 1. Vizzutti et al[134] later extended that curcumin can reduce alpha-smooth muscle actin a level in the NASH mice and can reduce the production of reactive oxygen species and tissue inhibitor of metalloproteinases-1 secreting activated hepatic stellate cells. While some dietary supplements containing curcumin are commercially available, it should be emphasized that case-reports and case series provide insufficient clinical evidence to draw firm conclusions. Polyphenols including techin-3-gallate[135], salvianolic acid B[136], anthocyanidin[137], ellagic acid[138] and cyanidin-3-glucoside[139] (Figure (Figure3S-W)3S-W) also play significant roles in the treatment of NAFLD.

Curcumin alleviates the severity of hepatic inflammation in experimental steatohepatitis induced by the MCD diet, an effect likely to be mediated via inhibition of NF-kB activation and dependent pro-inflammatory genes. The NF-kappaB pathway is one among several possible signalling pathways by which inflammation is recruited in experimental steatohepatitis.

Saponins are glycoside aglycones of three terpenoids or spirostane compounds, mainly found in terrestrial plants[147]. The primary active ingredients in many Chinese traditional herbs, such as Panax ginseng (C. A. Mey.), Polygala tenuifolia (Willd.), Glycyrrhiza uralensis (Fisch), and Platycodon grandiflorus (Jacq.) A. DC., are saponins. Some saponins also have anti-bacterial, anti-pyretic, and anti-cancer activities[148,149].

Dioscin (Figure (Figure4E)4E) is a natural steroid saponin widely found in various herbs[150]. Previous studies have demonstrated that dioscin has anti-tumor[151], anti-hyperlipidemic[152], and anti-fungal activities[153]. Studies have shown that dioscin can gradually reduce the weight, but not suppress appetite or increase physical activity in obese mice. Oral administration of dioscin reduces blood lipid levels, improves fat accumulation in the liver, decreases liver cholesterol and FA and triglyceride deposition through inhibition of FAS, promotes FA beta oxidation, reduces oxidative stress and inflammation, and regulates the MAPK signaling pathway and autophagy[154]. Other saponins such as ginsenoside Rb1[155], ginsenoside Rg1[156] and trillin[157] (Figure (Figure4F-H)4F-H) also play significant roles in the treatment of NAFLD.

Alkaloids are a group of nitrogenous organic compounds present in nature. They are widely found in dicotyledons. They have many pharmacological activities, such as anti-bacterial, anti-inflammatory, analgesic, anti-tumor, and anti-fungal actions[158,159]. A large number of studies have indicated that alkaloids have significant effects on NAFLD.

Berberine (Figure (Figure4I)4I) is isolated from the herb Coptis chinensis Franch. and widely used to treat diarrhea and other inflammatory diseases in China[160]. Recent studies have proved a new therapeutic function of berberine in metabolic disorders, including obesity and diabetes[161,162]. Berberine can be used as a cholesterol lowering drug, through a unique mechanism distinct from statins[163]. These studies suggested a potential therapeutic activity of berberine for NAFLD. Liver gene expression profile analysis showed that high fat diet induced hepatic steatosis in rats led to global changes in gene expression, and treatment with berberine reversed this process. Several modules of berberine-regulated genes, including abundant long non-coding RNAs (lncRNAs), were identified by bioinformatics analysis.