Phytochemistry and Biological Activities of Poria

Poria is a common Traditional Chinese Medicine in clinic. In recent years, the chemical and pharmacological studies of Poria have made great progress, triterpenes and polysaccharides have been isolated, and various types of compounds containing lipids, octanoic acids, fatty acids, and trace elements have been found. In this paper, we reviewed the literature, summarized the main compound types, and reviewed in detail their pharmacological effects in antitumor, immunomodulatory, effects on kidney, hepatoprotective activity, effects on blood sugar, antioxidant effects, anti-inflammatory effects, effects on the gut, antidepressant, and so on, and also categorized the compounds with the same or similar pharmacological effects to provide a reference for the in-depth study of the material basis of the pharmacological effect, quality standards, and pharmacological activity of Poria.


Polysaccharides.
Polysaccharides account for 70%∼90% of the dry weight of Poria, and until now, 35 kinds of PAC from Poria have been reported (Table 2) [63]. Many scholars have found that the physicochemical properties and biological activities of polysaccharides would change to a certain extent after the chemical modification or the introduction of some specific chemical groups [64], which are taken as one efficient way to treat some human diseases [65][66][67].

Bioactivity of Poria
In this paper, articles related to the pharmacological activity of Poria after 2011 were selected as references. And its pharmacological effects are summarized (Table 3).

Antitumor Action.
e antitumor effect of Poria has been attracting many researchers for a long time. Many studies found that triterpenes and polysaccharides in Poria had obvious antitumor activity, especially to the colon cancer cells, lung adenocarcinoma cells, kidney cancer cells, human prostate cancer cells, cervical cancer cells, and human breast cancer cells.

e Antitumor Effect of Poria
Triterpenes. Lin proved that total triterpenes of Poria had a significant inhibitory effect on the RKO cell line by inducing apoptosis through caspase 9 and caspase 3 activated by the combination of Cyt C and Apaf-1 [68]. Triterpenes from Poria could inhibit the proliferation of the A549 cell line by increasing the protein expression levels of Nrf2, GST, and NQO1 [69]. PA induced apoptosis of human renal cell carcinoma 786-0 cell line by inhibiting the activation of the Wnt signaling pathway [70]. PA could inhibit the expression of trim29 mRNA, activate caspase-9, and inhibit the expression of cyclin D1, which indicated that PA could induce apoptosis of Caski cells through inhibition [71]. Jiang found that PA could promote the apoptosis of human breast cancer MDA-MB-231 cells by enhancing the activity of caspase and the expression of cleaved PARP [72]. Poria ethanol extract could induce apoptosis by decreasing the expression of Bcl-2 and increasing the expression of Bax, increasing the content of cytoplasm, the active forms of cleaved caspase-9 and caspase-3, and cleaved PARP, which proved that pachymic acid had an inhibitory effect on MDA-MB-231 cells. Poria ethanol extract treatment alleviated the damage to the liver and normalized the serum levels of ALT and AST in mice compared with the mice with cisplatin treatment [73]. e study showed that PA could induce apoptosis of SGC-7901 cells by inactivating the JAK2/STAT3 signaling pathway, which proved that PA was a potential bioactive substance for the treatment of gastric cancer [74]. PA could induce caspase 3-mediated apoptosis of HOS and primary osteosarcoma cells by increasing PTEN expression and inhibiting Akt activation [75].

e Antitumor Effect of PAC.
Tang proved that PAC could inhibit the phosphorylation of the ERK signaling pathway by downregulating the expression of p-ERK1/2, which indicated that PAC could inhibit the proliferation and promote apoptosis of HeLa cells [52]. Lin et al. demonstrated that FMGP inhibited the migration of lung cancer CL1-5 cells by downregulating TGFβRI expression and simultaneously decreasing the phosphorylation levels of FAK and Akt [53]. CMP3 induced HepG2 cell apoptosis through two pathways. e first pathway was to promote HepG2 cell apoptosis by upregulating the release of pro-apoptotic proteins Bax, Caspase-3, p53, and cyto C. e other pathway was to upregulate the expression of Fas, FasL, and FADD mRNA, and promote the expression of caspase-3, caspase-8, and caspase-9 [54]. PPSW-1 and Sul-W-1 inhibit the migration of MDA-MB-231 cells by inhibiting SATB1 gen [56].
In summary, Poria plays an antitumor role mainly by inhibiting tumor cell proliferation, inducing cell apoptosis, and inhibiting tumor cell metastasis.

Immune
Regulation. Poria also has immunological activity in vitro and in vivo. Triterpenes and polysaccharides from Poria were found with extensive immunomodulatory effects and could improve the immune function of the body. Xie et al. study showed that total triterpenes of Poria could reduce the metabolic activity of spleen cells in mice stimulated by LPS and Con A and reduce the levels of IgG, IgM, IL-2, and IFN-c. Total triterpenes can reduce the levels of serum hemolysin and IL-4 in humoral immune response model mice. e spleen index was decreased in high doses (400 mg/kg) and medium doses (200 mg/kg), indicating that total triterpenes had inhibitory effects on the immune function of mice in vitro and in vivo [76]. Wang et al. study showed that S-CMP could significantly reduce the content of MDA and significantly increase the titer of serum hemolysin antibody and the production of spleen antibody. is Poriacosones A [26] Journal of Chemistry 3  Journal of Chemistry Journal of Chemistry 5     Journal of Chemistry indicated that S-CMP had a good immune activity [57]. e results of TIAN showed that Poria polysaccharide could exert immunomodulatory activity through TLR4/TRAF6/ NF-κB signaling pathway [77]. Pu et al. found that Poria polysaccharide could exert immunomodulatory effects in Ca 2+ /PKC/p38/NF-κB signaling pathway [78]. All of the above studies confirm that Poria played an immunological regulatory role through various ways, which can lay a solid foundation for subsequent studies on immunity and benefit the exploitation of potential clinical application value.

Effects on Kidney.
Studies have found that Poria can effectively resist renal injury, and the protection of diabetic nephropathy is a research hotspot. Li et al. study found that Poria polysaccharide treatment group could reduce serum IL-6 and TGR-β1 in DN rats (P < 0.01), reduce inflammatory infiltration, and protect kidney tissue to a certain extent [79]. Wu et al. experiment showed that Poria polysaccharides could reduce hepatocyte apoptosis and inflammatory stress by inhibiting the NF-κB pathway, which indicated that Poria polysaccharides had a protective effect on acetaminophen-induced liver injury in mice [80]. Another experiment showed that WRP could enhance the antioxidant level by increasing superoxide dismutase and glutathione peroxidase and significantly reducing malondialdehyde level in mice kidney tissue. Another experiment showed that WRP could significantly reduce malondialdehyde level and enhance the antioxidant level of the body through increasing superoxide dismutase and glutathione peroxidase in kidney tissue of type 2 diabetic mice, and reduce the expression of the Bax gene in kidney tissue and reduce the apoptosis of renal tissue cells [58]. Zhang et al. experiment showed that WRP could inhibit the expression of the Bax gene in kidney tissue of type 2 diabetic mice and reduce the apoptosis of renal tissue cells. e mechanism of action still needs further study [81]. PPC could increase uric acid excretion by upregulating rOAT1 expression and downregulating rURAT1 expression. It was proved that PPC had anti-hyperuricemia activity [59].
Chen et al. study showed that Poricoic acid ZC (115), Poricoic acid ZD (116), and Poricoic acid ZE (69) could prevent tubulointerstitial fibrosis by blocking the interaction between TGFbR1 and Smad3, selectively inhibiting TGFβ1 and vaso-induced Smad3 phosphorylation [82]. Another of their experiments found that Poricoic acid ZG (117) and Poricoic acid ZH (20) could reduce renal fibrosis by inhibiting the TGF-β/Smad pathway [83]. e above triterpenes were isolated for the first time and their activities were explored.
Studies showed that Poria had diuretic effect. e results of Yong et al. showed that poricoic acid A (94) had a significant diuretic effect on rats with water retention. e results showed that the urine volume of the poricoic acid A group was greater than the spironolactone group in the first hour, indicating that the effect of poricoic acid A was good for the diuretic effect. Reabsorption of electrolyte Na + and water increases urination [84]. Ni et al. selected triterpenoids extracted from Poria as ligands and selected three aquaporins AQP1, 4, 5 as target proteins. e results of screening with software and molecular docking showed that methyl dehydroabietate had a strong binding activity with AQP1, 4, and 5, respectively. It was speculated that dehydroabietic acid methyl ester (137) could be the active substance of Poria for diuresis and spleen strengthening, which provided a reference for the follow-up study of active ingredients [85]. Intravenous injection of Poria aqueous extract (1.5 g/kg)  S-CMP S-CMP (at 100, 200 mg/kg) showed immunoactivity in BALB/c mice - [57] Poria polysaccharide Poria polysaccharide has immunomodulatory activity in vivo (at 200 mg/kg) and in vitro (at 200 g/mL) Immunoregulatory activity is exerted through TLR4/TRAF6/NF-κB signaling pathway in vitro and in vivo [77] Poria polysaccharide Poria polysaccharide had immunomodulatory activity in vitro (at 200 μg/mL) Immunoregulatory activity is exerted through Ca 2+ /PKC/p38/NF-κB signaling pathway in macrophages [78] Journal of Chemistry 13 Pachymaran Pachymaran can prevent renal interstitial fibrosis in rats with type 2 diabetic nephropathy in vivo at doses of 3, 6, and 12 mg/kg, respectively - [81] PPC In vivo, PPC at 2 g/kg has antihyperuricemia activity Uric acid excretion was increased by upregulating rOAT1 expression and downregulating rURAT1 expression [59] Poricoic acid ZC, Poricoic acid ZD, and Poricoic acid ZE Poricoic acid ZC, poricoic acid ZD, and Poricoic acid ZE can prevent tubulointerstitial fibrosis in vivo (at 10 mg/kg) and in vitro (at 10 μM) By inhibiting the activation of the Wnt/β-catenin pathway and blocking Smad3 phosphorylation, renal tubulointerstitial fibrosis was reduced [82] Poricoic acid ZG and Poricoic acid ZH

Poricoic acid ZG and poricoic acid ZH (at 10 μM) can inhibit renal fibrosis in vitro
Attenuate renal fibrosis via a Wnt/ β-catenin pathway and targeted phosphorylation of smad3 signaling [83] Poricoic acid A Poricoic acid A (at 5, 10, 20 mg/kg) has diuretic activity in vivo - [84] Dehydroabietic acid methyl ester e authors found that methyl dehydroabietic acid may be the diuretic substance of Poria - [85] Poria aqueous extract In vivo, Poria aqueous extract can increase the urine volume of rabbits - [86] Hepatoprotective activity

Poria polysaccharides
Effects of Poria polysaccharides on liver protection against acetaminopheninjured hepatocytes in vitro (at 200 and 400 mg/kg) and in vivo (at 20 and 40 g/L) rough the molecular mechanisms of reducing hepatocellular inflammatory stress and Hsp90 bioactivity [87] Carboxymethyl pachyman Carboxymethyl pachyman in vivo (at 50 mg/kg) can alleviate liver injury of CT26 mice induced by 5-FU Hepatoprotective activity through regulation of NF-κB, Nrf2-ARE and MAPK/P38/JNK pathways [88] Effects on blood sugar

Pachymic acid
In vitro pachymic acid (at 1 μM) can increase glucose uptake in 3T3-L1 adipocytes Hypoglycemic activity through regulation of PI3K and AMPK pathways [89] WRP WRP (at 200 mg/kg) had hypoglycemic effects on NIDDM mice in vitro - [90] Insoluble polysaccharide Insoluble polysaccharide (at 1.0 g/kg and 0.5 g/kg) can improve the symptoms of hyperglycemia in ob/ob mice in vivo Hypoglycemic activity through regulation of intestinal flora [91] 14 Journal of Chemistry − and there was an agent-activity relationship. When the sample concentration was 4.5 mg/mL, the scavenging rates of OH and·O 2 − were 79% and 84.2%, respectively, which indicated that the sample had a certain antioxidant activity.

Hepatoprotective Activity. Wu et al. research demonstrated that
Poria polysaccharides could reduce the inflammatory stress of liver cells and the biological activity of HSP90, which proved that Poria polysaccharides had a liver protective effect against acetaminophen-damaged liver cells [87]. Wang et al. found that carboxymethyl pachyman could reduce liver injury of CT26 mice by regulating NF-κB, Nrf2-ARE, and MAPK/P38/JNK pathways [88].

Effects on Blood
Sugar. Sun et al. proved that pachymic acid could stimulate glucose uptake in 3T3-L1 adipocytes by enhancing GLUT4 expression and transport [89]. Not only that, PAC could also reduce blood glucose in diabetic rats [90]. Sun (47), polyporenic acid C (53), 3βhydroxylanosta-7,9(11),24-trien-21-oic acid (39), and trametenolic acid (3). ese compounds could downregulate the expression of COX-2 and PGE2 by inhibiting the production of NO and the expression of iNOS in RAW264.7 cells stimulated by LPS; poricoic acid A exerted the highest anti-inhibitory activity and reduced PGE2 levels via downregulation of COX-2 protein expression, indicating that they had anti-inflammatory activities [93]. Qin's study found that PA could inhibit TNF-α induced oxidative stress and inhibit apoptosis of SH-SY5Y cells by inhibiting ERK/ Nrf2 pathway [94]. Coriacoic acid A (131), Coriacoic acid B (73), dehydroeburic acid (46), acetyl eburicoic acid (19), and Poricoic acid C (97) could inhibit NO production, among which the  [104] activities of Poricoic acid C were the strongest. Its mechanism was to exert anti-inflammatory activity by downregulating NF-kappaB to inhibit the expression of iNOS and COX-2. Coriacoic acid A and Coriacoic acid B were isolated for the first time and found to have anti-inflammatory activity for the first time [30]. CMP33 (35) could inhibit the release of NO, IL-1β, IL-6, and TNF-α in RAW264.7 macrophages stimulated by LPS, indicating that PPS had anti-inflammatory activity [51]. Liang et al. found that Poria polysaccharide could inhibit the activation of IL-33/ST2 signaling pathway, reduce the activation of UC, inhibit the expression of inflammatory factors, and reduce the infiltration degree of colitis, which indicated that Poria polysaccharide had an obvious therapeutic effect on ulcerative colitis [95].
3.8. Effects on the Gut. Studies showed that Poria had a protective effect on the intestinal tract. 16α-hydroxytrametenolic acid (6) could improve intestinal barrier function through glucocorticoid receptor-mediated PI3K/ Akt/NF-κB pathway, suggesting that 16α-hydroxytrametenolic acid could strengthen the intestinal barrier [96]. Xiao et al. study showed that the alcohol extract of Poria could inhibit intestinal contraction in vitro by blocking the M receptor and regulate intestinal peristalsis function, which provided a new theoretical basis for the treatment of diarrhea type IBS [97]. Zou showed that watersoluble polysaccharides could increase the relative content of probiotic bacteria and decrease the relative content of pathogenic bacteria to regulate the change of intestinal flora structure caused by cis-uranium, and water-soluble polysaccharides could also reduce the intestinal damage caused by cis-uranium by regulating the disturbance of metabolic pathways such as lipid metabolism, amino acid metabolism, and purine metabolism [16]. e experimental results of Song et al. showed that Poria powder exerted a regulatory effect on intestinal flora by significantly increasing the level of intestinal bifidobacteria in mice [98].
3.9. Antidepressant. Poria has antidepressant activity. Zhang et al. study demonstrated that sulfated pachymaran had antidepressant-like effects in rats, which may be mediated by enhancing GluR1 receptor function and upregulating the protein expression of p-CREB and BDNF in the hippocampus [61]. Zhang et al. experiments showed that the resting time of animals treated with 300 mg/kg PCWPW and PCWPS was also significantly shortened (P < 0.001), suggesting that PCWPW and PCWPS have antidepressant effects. PCWPs had a good protective effect on H 2 O 2 -induced cell death in vitro. Its neuroprotective effect could reduce nerve damage in patients with depression [62].

Conclusion and Prospect
In recent years, many researches have been conducted on the extracts of Poria and their multiple biological activities. Poricoic acid A (95), for example, not only showed its impact on the tyrosinase activity but also has a diuretic effect. ese active compounds have enormous potential to be developed to treat some diseases with multi-targets safely and effectively. In this paper, both the chemical composition and biological activity of Poria were discussed in detail to provide abundant theoretical guidance for the further development of Poria as a potential medicinal and edible resource.

Conflicts of Interest
e authors declare no conflicts of interest.