Open Access

Pharmacological profiles and therapeutic applications of pachymic acid (Review)

  • Authors:
    • Chunyong Wei
    • Hezhen Wang
    • Xun Sun
    • Zhixun Bai
    • Jing Wang
    • Guohui Bai
    • Qizheng Yao
    • Yingshu Xu
    • Lei Zhang
  • View Affiliations

  • Published online on: July 1, 2022     https://doi.org/10.3892/etm.2022.11484
  • Article Number: 547
  • Copyright: © Wei et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Poria cocos is a saprophytic fungus that grows in diverse species of Pinus. Its sclerotium, called fu‑ling or hoelen, has been used in various traditional Chinese medicines and health foods for thousands of years, and in several modern proprietary traditional Chinese medicinal products. It has extensive clinical indications, including sedative, diuretic, and tonic effects. Pachymic acid (PA) is the main lanostane‑type triterpenoid in Poria cocos. Evidence suggests that PA has various biological properties such as cytotoxic, anti‑inflammatory, antihyperglycemic, antiviral, antibacterial, sedative‑hypnotic, and anti‑ischemia/reperfusion activities. Although considerable advancements have been made, some fundamental and intricate issues remain unclear, such as the underlying mechanisms of PA. The present study aimed to summarize the biological properties and therapeutic potential of PA. The biosynthetic, pharmacokinetic, and metabolic pathways of PA, and its underlying mechanisms were also comprehensively summarized.

1. Introduction

Pachymic acid (PA), a lanostane-type triterpenoid, was first isolated and characterized from the sclerotium of Poria cocos (Fig. 1) in 1958(1). PA is mainly derived from the wood-rotting fungus Poria cocos (2-4), a saprophytic fungus that grows in diverse species of Pinus. Its sclerotium, known as fu-ling or hoelen, has been widely used as a health food and in traditional Chinese medicine with pharmacological properties, including sedative, diuretic, and tonic effects (5-7). Overall, >160 terpenoids have been identified in Poria cocos (8). As an important bioactive terpenoid, PA has been reported to exhibit numerous pharmacological effects, such as cytotoxic (9), anti-inflammatory (10), antihyperglycemic (11), antibacterial and antiviral (12), sedative-hypnotic (13) and anti-ischemia/reperfusion (14) effects. Thus, PA has potential for the treatment of various diseases. However, it is still in the preclinical development stage, possibly owing to limited in vivo data. To provide comprehensive data for further study, to the best of our knowledge, the current study systematically summarized the current progress in the research and development of PA for the first time, including its sources, structure and properties, pharmacological activities, and pharmacokinetics. It aimed to improve the current knowledge and development potential of PA, and improve its development for potential clinical applications.

PA was first discovered in the sclerotium of Poria cocos from which its name is derived (1). Since then, it has been observed as the active compound in several fungi, such as the sclerotium (15-24) and epidermis (25) of Poria cocos and the fruiting bodies of Fomitopsis nigra (26,27) and Fomitopsis pinicola (28,29), which are used in traditional medicine. In addition to fungi, PA is extracted from Heterosmilax chinensis (30), a traditional Chinese medicine used for the treatment of cancer. Zhu et al (31) reported a possible biosynthetic pathway from lanostane to PA (Fig. 2). PA is a white powder and highly insoluble in water (32). Therefore, the poor solubility of PA results in its low bioavailability in vivo, which may limit its further clinical applications. Cai et al (32) demonstrated that glycyrrhizin (a triterpenoid glycoside) increases the solubility of PA in an aqueous solution, thereby improving its bioavailability.

2. Pharmacological activities

Cytotoxic effect

At present, cancer is a major disease that seriously affects human health (33). Table I presents the cytotoxic effects and underlying molecular mechanisms of PA. PA has been reported to against various cancer cell lines, including colon cancer (16), leukemia (34), bladder cancer (35,36), nasopharyngeal carcinoma (37), prostate cancer (38), primary osteosarcoma (39), breast cancer (40,41), lung cancer (42,43), gastric cancer (44,45) and pancreatic cancer (46). Several molecular mechanisms are involved in this process.

Table I

Biological activities of PA.

Table I

Biological activities of PA.

Biological effectsDetailsCell lines/ModelDoseApplication(Refs.)
Cytotoxic effectInhibit proliferation with an IC50 value of 29.1 µM and inhibit DNA topoisomerase I and IIColon HT-29 cells20-100 µMIn vitro(16)
 A novel RXR-specific agonist and induces differentiation of HL-60 cells with an EC50 value of 6.7±0.37 µMLeukemia HL-60 cells100 µMIn vitro(34)
 Inhibit proliferation and induce apoptosis via mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathwayBladder T24 cells5-30 µMIn vitro(35)
 Inhibit proliferation and induce apoptosis via ROS generation, mitochondrial- mediated intrinsic pathway, and DR5- mediated extrinsic pathwayBladder EJ cells2.5-30 µMIn vitro(36)
 Inhibit proliferation, induce apoptosis, and upregulate the levels of PARP, p-ATM, p-ATR, p-Chk-1, p-Chk-2, and p-histone H2A.XNasopharyngeal carcinoma CNE-1, CNE-2 cells10-30 µMIn vitro(37)
 Inhibit proliferation and induce apoptosis through mitochondria dysfunction by decreasing the phosphorylation of Bad and Bcl-2, and activating caspases-9 and -3Prostate DU145 cells10-40 µg/mlIn vitro(38)
 Inhibit proliferation, and induce PTEN and caspase 3/7-dependent apoptosisPrimary osteosarcoma cells10-50 µg/mlIn vitro(39)
 An activator of PKM2 and an inhibitor of HK2, decrease glucose uptake and lactate production, and induce mitochondrial dysfunction, ATP depletion, and ROS generationBreast SK-BR-3 cells10-100 µMIn vitro(40)
 Inhibit proliferation with an IC50 value of 2.13±0.24 µg/ml, induce cell cycle arrest and apoptosis through mitochondria-related and death receptor-mediated pathwayBreast MDA- MB-231 cells1-5 µMIn vitro(41)
 Inhibit the proliferation, induce apoptosis, and disrupt mitochondrial membrane potential, decrease IL-1β-induced activation of cPLA2 and COX-2 via inhibition of MAPK and the NF-κB signaling pathwayLung A549 cells1-200 µMIn vitro(42)
 Inhibit proliferation, induce apoptosis, cell cycle arrest and ROS generation, and suppress tumor growthLung NCI-H23, NCI-H460 cells Nude mice bearing NCI-H23 xenograft tumors20-180 µM 10-60 mg/kgIn vitro In vivo(43)
 Inhibit proliferation, induce cell cycle arrest, apoptosis, and ROS generation via upregulation of Bax, cytochrome c and caspase 3, and suppress tumor growthGastric SGC7901 cells Nude mice bearing20-80 µMIn vitro(44)
 SGC-7901 xenograft tumors10-60 mg/kgIn vivo 
 Inhibit proliferation, induce apoptosis via regulating the expression levels of apoptosis-related proteins and suppressing the mitochondrial capacity, and suppress tumor growthGastric SGC-7901, MKN-49P cells15-240 µMIn vitro(45)
 Nude mice bearing SGC-7901 and MKN-49P xenograft tumors15-60 mg/kgIn vivo 
 Induce apoptosis and ER stress by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and p-eIF2α, and suppress the tumor growthPancreatic PANC-1, MIA paca-2 cells Nude mice bearing MIA paca-2 xenograft tumors15-30 µMIn vitro(46)
 25-50 mg/kgIn vivo 
 Inhibit the promotion of skin tumor formation by TPA in DMBA-treated miceICR mice0.2 µM/mouseIn vivo(47)
 Have no cytotoxicity but enhance the cytotoxicity of vincristineEpidermoid carcinoma KBV200 cells12.5-25 µg/mlIn vitro(48)
 Sensitize cancer cells to radiation therapy in vitro and in vivo by upregulating Bax through HIF1αGastric SGC-7901, MKN-49P cells Nude mice bearing SGC-7901 and MKN-49P xenograft tumors60 µMIn vitro(49)
 60 mg/kgIn vivo 
Anti-invasive effectInhibit proliferation, migration, invasion and adhesion ability, and induce cell cycle arrest involving AKT and ERK signaling pathwaysGallbladder GBC-SD cells10-50 µg/mlIn vitro(50)
 Inhibit proliferation, induce cell cycle arrest and suppress migration and invasion via decreasing β-catenin and COX-2 expression and increasing E-cadherin expressionOvarian HO-8910 cells0.5-2 µMIn vitro(51)
 Inhibit proliferation and cell invasion by suppressing NF-κB-dependent MMP-9 expressionBreast MDA-MB-231 and MCF-7 cells2.5-40 µMIn vitro(52)
 Inhibit migration and invasion via suppressing the phosphorylation of PITPNM3Breast MDA-MB-231 cells10-40 µg/mlIn vitro(53)
 Inhibit proliferation with an IC50 value of 0.26 µM and suppress invasion by downregulating MMP-7 expressionPancreatic bxpc-3 cells0.125-25 µMIn vitro(54)
Anti-inflammatory effectRestore AH Plus-damaged cell viability and ALP activity, suppress secretion of NO, TNF-a and IL-1β, reduce ROS formation and NF-κB translocationMC-3T3 E1 cells15 µMIn vitro(26)
 Inhibit inflammatory effect, induce odontoblast differentiation through increasing HO-1 expression, show cytoprotection and mineralization, suppress NF-κB translocation and induce Nrf2 translocationHuman dental pulp cells15 µMIn vitro(27)
 Inhibit the activity of phospholipase A2 with an IC50 value of 2.897 mMPhospholipase A20.5-4 mMIn vitro(56)
 Inhibit leukotriene B4 releaseHuman leukocytes100 µMIn vitro(57)
 Reduce LPS-induced apoptosis, attenuate LPS-induced increased mRNA expression levels of IL1, IL6 and TNFα, and inhibit LPS-induced apoptosis via ERK1/2 and p38 pathwaysH9c2 cells0.125-5 µMIn vitro(58)
 Inhibit TPA-induced mouse ear edema with an ID50 value of 4.7x10-3 µM/earMouse 1x10-2-1x10-4 mg/earIn vivo(59)
 Inhibit TPA-induced mouse ear edema with an ID50 value of 0.044 mg/earMouse-In vivo(60)
 Inhibit serotonin-induced mouse paw edema, TPA-induced mouse ear swelling and PLA2-induced mouse paw edemaSwiss mice0.5 mg/ear and 50 mg/kgIn vivo(61)
 Reduce intravesical IL-1, IL-6 and LDH levels, downregulate TNF-α and upregulate TP53 proteinsICR mice20-40 mg/kgIn vivo(62)
 Improve the survival of septic rats and attenuate CLP-induced acute lung injury, downregulate the serum levels of TNF-a, IL-1β and IL-6, decrease malondialdehyde and myeloperoxidase contents and increase SOD levelWistar rats1-10 mg/kgIn vivo(63)
 Alleviate LPS-induced lung injury, relieve LPS-inflammation such as TNF-α, IL-6, MCP-1 and IL-1β, reduce cell numbers in the BALF, inhibit LPS-induced cell apoptosis and suppress NF-κB and MAPK signaling pathwaysRats10-20 mg/kgIn vivo(64)
 Decrease the kidney index, drop the contents of Cre and BUN, inhibit the renal inflammation via reducing the levels of TNF-α, IL-6 and iNOS and enhance the expression of Nrf2 and HO-1SD rats5-5 mg/kgIn vivo(65)
 Ameliorate renal injury markers, improve renal inflammation, restore renal klotho levels and ameliorate renal Wnt/β-catenin signaling, improve renal tissue structure, and ameliorate renal fibrosis in doxorubicin-induced nephropathyWistar albino rats10 mg/kgIn vivo(66)
Antihyperglycemic effectInduce GLUT4 expression, stimulate GLUT4 redistribution from intracellular vesicles to the plasma membrane, increase the phosphorylation of IRS-1, AKT and AMPK, induce triglyceride accumulation and inhibit lipolysis3T3-L1 cells0.01-1 µMIn vitro(67)
 Increase glucose uptake by 50%3T3-L1 cells5 µMIn vitro(68)
 Decrease blood glucose levels in streptozocin-treated mice via enhanced insulin sensitivity irrespective of PPAR-γDb/db mice1-10 mg/kgIn vivo(69)
Antibacterial and antiviral effectsExhibit inhibitory effecton the SARS- CoV-2 3CL hydrolytic enzyme with an IC50 value of 18.607 µMMpro protease10-50 µMIn vitro(12)
 Inhibit EBV-EA activation induced by TPARaji cells-In vitro(17)
 Inhibit the biofilm formation of E. coliE. coli32-256 µg/mlIn vitro(70)
Sedative-hypnotic effectSuppress locomotion activity, prolong sleeping time, and enhance hypnotic effect in pentobarbital-treated mice via chloride channel activation and GABA- ergic mechanismsICR mice1-5 mg/kgIn vivo(13)
 Increase total sleep time and non-rapid eye movement sleep and reduce numbers of sleep/wake cyclesSD rats5 mg/kgIn vivo(72)
Anti-ischemia/ reperfusion injuryIncrease cerebral blood flow, reduce infarct volume and brain water content and decrease neuronal damage and neuronal apoptosis via upregulation of p-PTEN, p-PDK1, p-Akt and p-BAD, and downregulation of cleaved caspase protein expressionSD rats12.5-100 mg/kgIn vivo(14)
 Exhibit protective effect on ischemia-reperfusion induced acute kidney injury through inhibition of ferroptosis, activation of NRF2, and upregulation of the expression of the downstream ferroptosis related proteins, GPX4, SLC7A11 and HO1C57BL/6 mice5-20 mg/kgIn vivo(74)
Other pharmacological effectsSuppress 5-HT-stimulated inward current and inhibit I5-HT in Xenopus oocytes expressing human 5-HT3A receptor with an IC50 value of 5.5±0.6 µMXenopus oocytes0.1-100 µMIn vitro(75)
 Inhibit IACh in oocytes expressing nicotinic type α3β4 acetylcholine channel receptors with an IC50 value of 24.9 µM, via a concentration dependent and reversible mannerXenopus oocytes3-300 µMIn vitro(76)
 Decrease allograft rejection, protect PBLs from apoptosis involving stabilization of the mitochondrial transmembrane potential, and reduce the percentage of CD8+ lymphocyteSD rats1-10 mg/kgIn vivo(77)
 Induce autophagy via upregulation of the LC3-II, Beclin 1 and Atg7 expression levels, and negative modulation of IGF-1 signaling pathwayWI-38 cells1-4 µMIn vitro(78)
 Reduce the cytotoxicity of root canal sealersL929 cells300 mg/mlIn vitro(79)
 Maintain the physiochemical properties of AH Plus sealer, reduce the flow, film thickness and setting time of AH Plus and improve the sealing ability of the modified sealer with timeAh plus0.5%In vitro(80)
 Inhibit KLK5 protease activity with an IC50 value of 5.9 µMHuman kallikrein 51-100 µMIn vitro(81)
 Decrease free fatty acid-induced increase in intracellular triglyceride levels and induce the phosphorylation of AMPKHepatoma hepg2 cells0.63-1.25 µMIn vitro(82)
 Improve the abnormal metabolism, increase the potential of GV oocytes, reduce the number of abnormal MII oocytes and damaged embryos, downregulate the expression ofovarian- related genes in ovarian tissue and pro- inflammatory cytokines in adipose tissueICR mice50 mg/kgIn vivo(83)
 Reverse right ventricular hypertrophy and pulmonary vascular remodeling, suppress proliferation and induce apoptosis in hypoxia-induced pulmonary artery smooth muscle cells, downregulate the peroxy- related factor expressionSD rats5 mg/kgIn vivo(84)
 Demonstrates improvements in weight and kidney damage, and lower fasting blood glucose, Scr, BUN, U-Pro, p-AKT, p-PI3K levels and higher SOD activityC57BL/6J mice50 mg/kgIn vivo(85)
 PA alone or as an adjuvant therapy with losartan lower serum BNP and improve systolic function and cardiac fiber diameter via suppressing miR-24 and preserving cardiac junctophilin-2Albino rats10 mg/kgIn vivo(86)
 Ameliorates doxorubicin-induced renal injury via regulation of serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho, TNF-α, IL-6 and IL-1βWistar albino rats10 mg/kgIn vivo(66)

[i] RXR, retinoid X receptor; ROS, reactive oxygen species; p-, phosphorylated; DR5, death receptor 5; PARP, poly (ADP-ribose) polymerases; ATM, ataxia telangiectasia mutated protein; ATR, ataxia telangiectasia-mutated and Rad3-related kinase; Chk, checkpoint kinase 1; PTEN, phosphatase and tensin homolog; PKM2, pyruvate kinase muscle isozyme; HK2, hexokinase 2; cPLA2, cytosolic phospholipase A2; COX-2, cyclooxygenase 2; ER, endoplasmic reticulum; XBP-1s, X-box-binding protein-1s; ATF4, activating transcription factor 4; Hsp70, heat shock protein 70; CHOP, C/EBP homologous protein; eIF2α, eukaryotic initiation factor-2α; TPA, 12-O-tetradecanoylphorbol-13-acetate; DMBA, 7,12-dimethylbenz[a]anthracene; HIF1α, hypoxia-inducible factor 1α; MMP, matrix metalloproteinase; PITPNM3, membrane-associated phosphatidylinositol transfer protein 3; ALP, alkaline phosphatase; NO, nitric oxide; Nrf2, nuclear factor erythroid 2-related factor 2; LPS, lipopolysaccharise; LDH, lactate dehydrogenase; CLP, cecal ligation and puncture; SOD, superoxide dismutase; BALF, bronchoalveolar lavage fluid; Cre, creatine; BUN, blood urea nitrogen; iNOS, inducible nitric oxide synthase; HO-1, heme oxygenase 1; GLUT4, glucose transporter type 4; IRS-1, insulin receptor substrate-1; PPAR-γ, peroxisome proliferator-activated receptor-γ; PDK1, pyruvate dehydrogenase kinase 1; BAD, Bcl-2-associated death promoter; GPX4, glutathione peroxidase 4; SLC7A11, solute carrier family 7 member 11; PBL, peripheral blood lymphocyte; BNP, B-type natriuretic peptide; miR, microRNA.

Notably, PA has been demonstrated to be a novel retinoid X receptor (RXR)-specific agonist that induces the differentiation of leukemia HL-60 cells (34). Moreover, it displays antiproliferative activity against SK-BR-3 cells by specifically activating pyruvate kinase muscle isozyme M2 (PKM2), inhibiting hexokinase 2 (HK2), and decreasing glucose uptake and lactate production (40). PA can inhibit the proliferation of several cancer cell lines by downregulating the expression of CDK1, CDK2, CDK4 and cyclin E to block cell cycle arrest, including in MDA-MB-231, SGC-7901 and MKN-49P cells (41,44,45). Apoptosis also plays an important role in PA's cytotoxicity. PA induces apoptosis in various cancer cells, including bladder EJ cells, breast SK-BR-3 cells, pancreatic PANC-1 cells, MIA paca-2 cells and prostate DU145 cells, through the generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress, upregulation of cleaved caspase-3,-8 and -9, cleaved poly (ADP-ribose) polymerases, Bax and Bad, phosphorylated (p)-ataxia telangiectasia mutated protein, p-ataxia telangiectasia-mutated and Rad3-related kinase, p-checkpoint kinase 1, p-histone H2A.X, X-box-binding protein-1s, activating transcription factor 4 (ATF4), heat shock protein 70, C/EBP homologous protein and p-eukaryotic initiation factor-2α and downregulation of Bcl-2 and B-cell lymphoma-extra large (36,37,38,44,46).

Studies on animal models have further demonstrated the in vivo anticancer activities of PA. For example, Kaminaga et al (47) revealed that PA suppresses the promotion of skin tumor formation by 12-O-tetradecanoylphorbol-13-acetate (TPA) in 7,12-dimethylbenz[a]anthracene-treated mice. Ma et al (43) demonstrated that PA significantly inhibits the growth of NCI-H23 xenograft tumors by inhibiting cell proliferation and inducing apoptosis without causing toxicity. Sun and Xia (44) reported that PA significantly suppresses the growth of SGC-7901 tumors in nude mice. In addition, PA pretreatment before animal xenograft model construction resulted in a significant decrease in tumor volume and weight (45). In addition, PA pretreatment increased xenograft survival and median times in vivo. This suggested that cancer cells pretreated with PA possessed weaker tumorigenicity and lethality. In a study by Cheng et al (46), PA was demonstrated to significantly inhibit MIA PaCa-2 tumor growth via the induction of apoptosis and the expression of ER stress-related proteins in tumor tissues; in addition, no major toxicity is observed in animals treated with 25 mg/kg PA. However, some toxic effects have been observed in mice treated with 50 mg/kg PA, including obvious pathological changes in the liver, kidney and spleen. Moreover, PA also demonstrates a sensitization effect. For example, Shan et al (48) reported that PA has no cytotoxicity at a concentration of 12.5 µg/ml, but does significantly enhance vincristine-induced cytotoxicity in drug-resistant KBV200 cells. PA was revealed to sensitize SGC-7901 and MKN-49P cells to radiation therapy by upregulating Bax under hypoxic conditions in vitro and in vivo (49).

Anti-invasion effect

In addition to its cytotoxic effect, PA also has an anti-invasion effect (Table I). It was reported to inhibit the invasion and adhesion ability of GBC-SD cells by affecting the ERK and AKT signaling pathways (50), HO-8910 cells by decreasing β-catenin and COX-2 expression and increasing E-cadherin expression (51), MDA-MB-231 cells via suppression of NF-κB-dependent MMP-9 expression and phosphorylation of membrane-associated phosphatidylinositol transfer protein 3 (52,53), and BxPc-3 cells via downregulation of MMP-7 expression (54).

Anti-inflammatory effect

Inflammation underlies numerous physiological and pathological processes involved in numerous diseases such as cancer, obesity and cardiovascular diseases (55). A number of studies have reported that PA has anti-inflammatory effects, and its mechanisms of action have been partially identified (Table I). Cuéllar et al (56) demonstrated that PA exhibits inhibitory activity against phospholipase A2 in vitro. PA has been observed to inhibit leukotriene B4 release, which is involved in chronic inflammation of skin pathologies (57). In addition, PA reduces lipopolysaccharide (LPS)-induced apoptosis, attenuates LPS-induced increases in mRNA expression levels of IL-1, IL-6 and TNF-α and inhibits LPS-induced apoptosis via the ERK1/2 and p38 pathways in H9c2 cells (58). Moreover, PA has been reported to inhibit inflammation in oral cells. For example, Kim et al (26) demonstrated that PA restores resin sealer AH Plus-damaged cell viability and alkaline phosphatase activity, suppresses the secretion of nitric oxide, TNF-α and IL-1β and reduces ROS formation and NF-κB translocation in MC-3T3 E1 cells. In addition, this study demonstrated that PA inhibits inflammation and induces odontoblast differentiation by increasing heme oxygenase 1 (HO-1) expression, suppressing NF-κB translocation and inducing nuclear factor erythroid 2-related factor 2 (Nrf2) translocation in human dental pulp cells (27). Furthermore, PA has been observed to inhibit TPA-induced mouse ear edema and phospholipase A2-induced mouse paw edema in vivo (59-61). Feng et al (62) revealed that, in animal models, PA reduces intravesical IL-1, IL-6 and lactate dehydrogenase levels, downregulates TNF-α and upregulates TP53 proteins in bladder samples. In cecal ligation and puncture (CLP)-induced septic rats, PA increases the survival of rats and attenuates CLP-induced acute lung injury by downregulating the serum levels of TNF-α, IL-1β and IL-6, decreasing malondialdehyde and myeloperoxidase levels and increasing superoxide dismutase levels (63). Gui et al (64) reported that PA alleviates LPS-induced lung injury by relieving LPS-inflammation, such as TNF-α, IL-6, monocyte chemoattractant protein 1 and IL-1β, reducing cell numbers in bronchoalveolar lavage fluid, and inhibiting LPS-induced apoptosis. Additionally, PA ameliorates renal injury in vivo by inhibiting renal inflammation, reducing the levels of TNF-α, IL-6 and inducible nitric oxide synthase, enhancing the expression of Nrf2 and HO-1, and preventing renal Wnt/β-catenin signaling (65,66).

Antihyperglycemic effect

Previously, several studies reported that PA has a significant antihyperglycaemic effect (67-69) (Table I). For example, Huang et al (67) revealed that PA induces glucose transporter type 4 (GLUT4) expression, stimulates GLUT4 redistribution from intracellular vesicles to the plasma membrane by upregulating the insulin-independent AMPK and insulin receptor substrate-1-PI3K-AKT pathways and induces triglyceride accumulation. Similarly, Chen et al (68) revealed that PA increases the glucose uptake by 50% in 3T3-L1 cells. PA has been further observed to decrease blood glucose levels in streptozocin-treated mice by enhancing insulin sensitivity irrespective of peroxisome proliferator-activated receptor-γ (69).

Antiviral and antibacterial effects

As presented in Table I, PA displays inhibitory effects on the SARS-CoV-2 3CL hydrolytic enzyme in vitro, with an IC50 value of 18.607 µM (12). Akihisa et al (17) demonstrated that PA exhibits antiviral activity against Epstein-Barr virus early antigen-induced TPA in Raji cells, with an IC50 value of 286 mol ratio/32 pmol TPA. In addition, PA at concentrations ranging from 32 to 256 µg/ml demonstrate antibacterial activity against Escherichia coli by inhibiting biofilm formation (70).

Sedative-hypnotic effect

Poria cocos is used in traditional Chinese medicine to treat various sleep disorders, such as insomnia (71). As presented in Table I, PA at a dose of 5 mg/kg suppresses locomotor activity, prolongs sleep time and enhances hypnotic effects in pentobarbital-treated mice via chloride channel activation and GABA-ergic mechanisms (13). Their subsequent study further indicated that PA increases total sleep time and non-rapid eye movement sleep, and reduces the number of sleep/wake cycles and wakefulness (72). To the best of our knowledge, no lanostane-type triterpenoids have been reported to show sedative-hypnotic effects, except for PA.

Anti-ischemia/reperfusion injury

Ischemia/reperfusion injury is a serious clinical problem that causes several diseases, including myocardial hibernation and cerebral dysfunction (73). Pang et al (14) reported that PA exhibits neuroprotective effects on brain ischemia/reperfusion injury in vivo by increasing cerebral blood flow, reducing infarct volume and brain water content and decreasing neuronal damage and apoptosis. Jiang et al (74) revealed that PA exhibits a dose-dependent protective effect on ischemia-reperfusion-induced acute kidney injury in vivo through the inhibition of ferroptosis in the kidneys, activation of Nrf2 and upregulation of the expression of the downstream ferroptosis-related proteins, glutathione peroxidase 4, solute carrier family 7 member 11 and HO1. These studies indicate that PA has the potential to treat ischemia/reperfusion injury (Table I).

Other pharmacological effects

As presented in Table I, PA has been revealed to have several other pharmacological effects. Specifically, it suppresses 5-hydroxytryptamine (5-HT)-stimulated inward currents, and inhibits 5-HT-stimulated inward current in Xenopus oocytes expressing the human 5-HT3A receptor. It also inhibits the acetylcholine-induced inward current in oocytes expressing nicotinic type α3β4 acetylcholine channel receptors (75,76). PA decreases allograft rejection in rats, protects peripheral blood lymphocytes from apoptosis by stabilizing the mitochondrial transmembrane potential and reduces the percentage of CD8+ lymphocytes (77). Lee and Kim (78) reported that PA could induce WI-38 cell autophagy to delay the aging process. Furthermore, PA can reduce the cytotoxicity of root canal sealers (79), maintain the physiochemical properties of AH Plus sealer, reduce the flow, film thickness and setting time of AH Plus, and improve the sealing ability of the modified sealer over time (80). PA has been revealed to affect the skin barrier function via inhibition of KLK5 protease activity (81) and to ameliorate hepatic steatosis by decreasing the free fatty acid-induced increase in intracellular triglyceride levels (82). Fu et al (83) reported that PA can protect oocytes by improving abnormal metabolism, increasing the potential of GV oocytes and reducing the number of abnormal metaphase II oocytes and damaged embryos in mice with polycystic ovary syndrome. Recently, He et al (84) demonstrated that PA significantly reverses right ventricular hypertrophy and pulmonary vascular remodeling, suppresses proliferation, induces apoptosis in hypoxia-induced pulmonary artery smooth muscle cells, downregulates the expression of peroxy-related factors and upregulates the expression levels of antioxidant-related factors. PA can protect against kidney injury in mice with diabetic nephropathy by inhibiting the PI3K/AKT pathway (85). PA alone or as adjuvant therapy with losartan can lower serum B-type natriuretic peptide and improve systolic function and cardiac fiber diameter to attenuate doxorubicin-induced heart failure in vivo (86). Moreover, PA ameliorates doxorubicin-induced renal injury by regulating of serum cystatin-C, urine albumin/creatinine ratio, renal podocin and klotho content, TNF-α, IL-6 and IL-1β (66).

3. Pharmacokinetics

Several analytical methods have been reported for the determination of PA in vitro and in vivo. The pharmacokinetic properties of PA, including its absorption, distribution, metabolism and excretion are summarized in Table II. Using the LC-ESI-MSn method, Ling et al (87) reported that seven out of 34 compounds in the extract of Poria cocos can be detected in rat urine after oral administration, whereas only PA can be detected in rat urine and plasma. In vitro determination of PA, using Caco-2 cell monolayers as an intestinal epithelial cell model with reversed-phase-high performance liquid chromatography, revealed that PA is transported through the Caco-2 cell monolayer in a concentration-dependent manner, and that the Papp values of PA are (9.50±2.20)10-7 cm/sec from the apical (AP) side to the basolateral (BL) side, and (11.30±5.90)10-7 cm/sec from the BL side to the AP side, respectively.

Table II

Pharmacokinetic information of PA.

Table II

Pharmacokinetic information of PA.

ModelDoseAdministration methodQuantitative methodDetails(Refs.)
SD rats200 mg/kg (Poria cocos extract)Oral gavageLC-ESI-MSn methodPA is the only one detected both in rat urine and plasma(87)
Caco-2 cells10-50 µMMixed systemRP-HPLC methodPA is transported through the Caco-2 cell monolayer in a concentration-dependent manner and the Papp values of PA are (9.50±2.20)10-7 cm/sec from AP side to BL side, and (11.30±5.90)10-7 cm/sec from BL side to AP side, respectively(88)
SD rats30 mg/kgIntravenous administrationHPLC method t1/2 =8.79±6.80 h; CL=0.53±0.28 l/h; AUC0-∞=18.90±9.39 µg h/ml; MRT0-∞=12.58±9.95 h(89)
Wistar rats10 mg/kgOral administrationLC-MS/MS method t1/2β=4.96±1.33 h; AUC0-∞=1466.9±361.7 ng h/ml; CL=6.82±1.73 l/h(90)
SD rats12.3 mg/kgOral administrationUPLC-Q- Orbi-trap MS method t1/2z=11.51±9.90 h; AUC0-∞=336.29±161.99 ng h/ml; CL=45.07±73.64 l/h(91)
Human liver microsomes100 µMMixed systemHPLC methodInhibit CYP3A4, 2E1, and 2C9 in a concentration-dependent manner, with IC50 values of 15.04, 27.95 and 24.22 µM, respectively(92)
SD rats5 mg/kgOral administrationLC-MS/MS methodIncrease AUC and t1/2, decrease CL, enhance metabolic stability, and inhibit transport of bavachin via the inhibition of CYP2C9 and P-gp(93)

[i] PA, pachymic acid; AP, apical; BL, basolateral; CL, clearance; t1/2, half-life; CYP3A4, cytochrome P450 3A4; CYP2E1, cytochrome P450 2E1; CYP2C9, cytochrome P450 2C9; AUC, area under the curve; P-gp, P-glycoprotein.

In addition to the passive diffusion of PA, ATP partially participates in its transport (88). After sublingual vein injection of PA at a dose of 30 mg/kg, the pharmacokinetic parameters in rat plasma were obtained using HPLC with half-life (t1/2) at 8.79±6.80 h, clearance (CL) at 0.53±0.28 l/h, area under the curve (AUC)0-∞ at 18.90±9.39 µg h/ml and mean residence time0-∞ at 12.58±9.95 h (89). Following oral administration of PA (10 mg/kg), the main pharmacokinetic parameters in rat plasma using liquid chromatography tandem mass spectrometry (MS) were elimination half-life at 4.96±1.33 h, AUC0-∞ at 1466.9±361.7 ng h/ml and CL at 6.82±1.73 l/h (90). Determination of PA (12.3 mg/kg) in rats after oral administration using UPLC-Q-Orbi-trap MS demonstrated that the pharmacokinetic parameters were terminal half-life at 11.51±9.90 h, AUC0-∞ at 336.29±161.99 ng h/ml and CL at 45.07±73.64 L/h. PA is mainly distributed in the intestine and stomach and is considered to be further converted into other molecules in vivo (91). In addition, treatment of human liver microsomes with PA (100 µM) demonstrated that PA inhibits cytochrome P450 (CYP)3A4, 2E1 and 2C9, with IC50 values of 15.04, 27.95 and 24.22 µM, respectively, indicating potential drug-drug interactions (92). Moreover, after oral administration of PA (5 mg/kg) in rats, Zhang et al (93) indicated that PA increases the AUC and t1/2, decreases CL, enhances metabolic stability and further inhibits transport of natural flavonoid bavachin via regulation of CYP2C9 and P-glycoprotein.

As presented in Fig. 3, three metabolic pathways are proposed for PA (87). It may undergo loss of H2O + CO2 to generate fragment M1, which is converted to fragment M2 by the loss of C3H6, and forms fragment M3 via the loss of CH3COOH (87). A very low-abundance ion had been detected in the fragment M4 spectra via the loss of C8H14 from M3(87). Finally, PA is converted to fragment M5 via dehydration (87).

4. Conclusions

PA can be obtained from a number of natural sources, and has attracted great attention owing to its various pharmacological activities in the potential treatment of several diseases. In addition, progress has been made in exploring the pharmacological profiles and underlying molecular mechanisms of PA. In particular, PA has been demonstrated to be a novel RXR-specific agonist and can induce the differentiation of leukaemia HL-60 cells (34). In addition, PA has been demonstrated to be an activator of PKM2 and an inhibitor of HK2, and can inhibit the proliferation of breast cancer SK-BR-3 cells (40). It demonstrates significant anti-inflammatory effects by inhibiting the activity of PLA2(56). To the best of our knowledge, no lanostane-type triterpenoids have been reported to show sedative-hypnotic effects, except PA (72).

Although considerable progress has been made in previous years regarding PA, tremendous challenges still lie ahead owing to the shortcomings of its low content in nature, complex structure, physical and chemical properties and pharmacokinetic profiles. Its low content in nature hinders further investigation and clinical applications. For example, the percentage of PA in Poria cocos crude extract was 0.053‰ (69). The bioavailability of PA is relatively low due to its poor water solubility after oral administration. Regarding intravenous administration, the dissolution of PA is complex (89). Mixed solubilizers, including DMSO, PEG-400 and 1, 2-propylene glycol are used to solubilize PA in physiological saline, which may increase the risk of side effects and adverse reactions (89).

A limited amount of research on the pharmacological activity, underlying molecular mechanisms and other new biological effects of PA warrants further investigation (8). Investigators use different methods including experimental animals (in vivo), tissue and cell cultures (in vitro) in order to investigate novel therapies of human diseases (94). The mentioned procedures have their own advantages and disadvantages. In vitro models are used in biomedical fields for the advantages of low cost, efficiency and ease of quantification (94). The disadvantage of in vitro methods is they are usually conducted on cell lines. Although animal models (in vivo) provide some drawbacks such as high cost, inefficiency and a difference in biokinetics parameters in comparison with humans, they are more credible compared with in vitro tests (95). The majority of studies are focused on in vitro experiments (Table I); hence, it is necessary to validate the in vivo effectiveness and efficacy of PA, such as its anticancer and anti-inflammatory effects in different animal models. In addition to the above challenges, another critical concern is the safety assessment of PA (46). The main natural source of PA is Poria cocos, which is homologous to medicine and food (22). Evidence suggests that PA may be toxic in vivo (46). However, at present, the toxicity and relationship between dose and toxicity remains unaddressed.

To address these challenges, five strategies and suggestions aimed at enhancing the development and clinical application of PA are proposed in the present review. First, it is necessary to improve the efficiency of PA separation or efficiently prepare PA via chemistry and biocatalytic technologies. Second, the adoption of appropriate pharmaceutical or chemical methods would improve bioavailability. For example, some suitable formulation technologies (solid dispersion and micronization), chemical modifications with water-solubilizing groups, and PA derivatives designed as prodrugs or prepared in the form of sodium salts could be adopted to improve solubility and bioavailability. Third, regarding the stage of current research on the pharmacology and molecular mechanism of PA, further investigation of the in vivo effectiveness and efficiency of PA should be performed. Fourth, special pharmacological profiles of PA, such as its sedative-hypnotic effect, should be given more attention, as no other lanostane-type triterpenoids have been reported to exhibit a sedative-hypnotic effect (13,72). Fifth, novel PA derivatives library for exploring more promising candidates with higher pharmacological activities and improved drug-like properties should be performed. PA has a 33-carbon skeleton with five available sites at the C-3, C-8, C-16, C-21, and C-24 positions for modification (Fig. 1), which might promote the synthesis of novel molecules with higher potency and selectivity, fewer side effects and gradual expansion of the scope of patent protection. At present, to the best of our knowledge, only one study has reported the synthesis of novel PA derivatives with in vitro pharmacological evaluation (96). Finally, more attention should be paid to investigating the toxicity and underlying mechanism of PA in animals, and drug-drug interactions, to elucidate the relationship between dosage and toxic effects and decrease or avoid side effects. Although the awareness of PA has grown in recent years, it is necessary to further investigate its safety, efficacy, mechanism and pharmacokinetics.

Overall, the present review focused on comprehensive research on the biological properties and therapeutic potential of PA, and will be beneficial for the development and utilization of PA in the future.

Acknowledgements

Not applicable.

Funding

Funding: This work was financially supported by the National Natural Science Foundation of China (grant no. 81860622), Department of Science and Technology of Zunyi City [grant no. (2020)293] and Education and Teaching Reform Program of Zunyi Medical University (grant no. ZYK38).

Availability of data and materials

Not applicable.

Authors' contributions

CW, HW, XS and JW carried out the literature search, summarized data and wrote the paper. GB, YX and LZ reviewed and edited the manuscript and analyzed the manuscript contents. QY contributed to manuscript reviewing and design of tables and figures. LZ and ZB revised the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Li J, Wang Y, Xue J, Wang P and Shi S: Dietary exposure risk assessment of flonicamid and its effect on constituents after application in lonicerae japonicae flos. Chem Pharm Bull (Tokyo). 66:608–611. 2018.PubMed/NCBI View Article : Google Scholar

2 

Shingu T, Tai T and Akahori A: A lanostane triterpenoid from Poria cocos. Phytochemistry. 31:2548–2549. 1992.

3 

Zheng Y and Yang XW: Two new lanostane triterpenoids from Poria cocos. J Asian Nat Prod Res. 10:323–328. 2008.PubMed/NCBI View Article : Google Scholar

4 

Dong HJ, Xue ZZ, Geng YL, Wang X and Yang B: Lanostane triterpenes isolated from epidermis of Poria cocos. Phytochem Lett. 22:102–106. 2017.

5 

Ríos JL: Chemical constituents and pharmacological properties of Poria cocos. Planta Med. 77:681–691. 2011.PubMed/NCBI View Article : Google Scholar

6 

Zhao YY, Feng YL, Du X, Xi ZH, Cheng XL and Wei F: Diuretic activity of the ethanol and aqueous extracts of the surface layer of Poria cocos in rat. J Ethnopharmacol. 144:775–778. 2012.PubMed/NCBI View Article : Google Scholar

7 

Nie A, Chao Y, Zhang X, Jia W, Zhou Z and Zhu C: Phytochemistry and pharmacological activities of WolfiPoria cocos (FA Wolf) Ryvarden & Gilb. Front Pharmacol. 11(505249)2020.PubMed/NCBI View Article : Google Scholar

8 

Liu J, Tian J, Zhou L, Meng L, Chen S, Ma C, Wang J, Liu Z, Li C and Kang W: Phytochemistry and Biological Activities of Poria. J Chem. 2021(6659775)2021.

9 

Lai KH, Lu MC, Du YC, El-Shazly M, Wu TY, Hsu YM, Henz A, Yang JC, Backlund A, Chang FR and Wu YC: Cytotoxic Lanostanoids from Poria cocos. J Nat Prod. 79:2805–2813. 2016.PubMed/NCBI View Article : Google Scholar

10 

Taofiq O, Martins A, Barreiro MF and Ferreira ICFR: Anti-inflammatory potential of mushroom extracts and isolated metabolites. Trends Food Sci Tech. 50:193–210. 2016.

11 

Tang X, Chen J and Shen X: The signaling pathway for regulation of glucose transporter 4 and its application in drug devel-opment. Sci Sin Chim. 42:1760–1773. 2012.

12 

Wu Z, Chen X, Ni W, Zhou D, Chai S, Ye W, Zhang Z, Guo Y, Ren L and Zeng Y: The inhibition of Mpro, the primary protease of COVID-19, by Poria cocos and its active compounds: A network pharmacology and molecular docking study. RSC Adv. 11:11821–11843. 2021.PubMed/NCBI View Article : Google Scholar

13 

Shah VK, Choi JJ, Han JY, Lee MK, Hong JT and Oh KW: Pachymic acid enhances pentobarbital-induced sleeping be-haviors via GABAA-ergic systems in mice. Biomol Ther (Seoul). 22:314–320. 2014.PubMed/NCBI View Article : Google Scholar

14 

Pang Y, Zhu S and Pei H: Pachymic acid protects against cerebral ischemia/reperfusion injury by the PI3K/Akt signaling pathway. Metab Brain Dis. 35:673–680. 2020.PubMed/NCBI View Article : Google Scholar

15 

Tai T, Shingu T, Kikuchi T, Tezuka Y and Akahori A: Isolation of lanostane-type triterpene acids having an acetoxyl group from sclerotia of Poria cocos. Phytochemistry. 40:225–231. 1995.

16 

Li G, Xu ML, Lee CS, Woo MH, Chang HW and Son JK: Cytotoxicity and DNA topoisomerases inhibitory activity of constituents from the sclerotium of Poria cocos. Arch Pharm Res. 27:829–833. 2004.PubMed/NCBI View Article : Google Scholar

17 

Akihisa T, Nakamura Y, Tokuda H, Uchiyama E, Suzuki T, Kimura Y, Uchikura K and Nishino H: Triterpene acids from Poria cocos and their anti-tumor-promoting effects. J Nat Prod. 70:948–953. 2007.PubMed/NCBI View Article : Google Scholar

18 

Zhou L, Zhang Y, Gapter LA, Ling H, Agarwal R and Ng KY: Cytotoxic and anti-oxidant activities of lanostane-type triterpenes isolated from Poria cocos. Chem Pharm Bull (Tokyo). 56:1459–1462. 2008.PubMed/NCBI View Article : Google Scholar

19 

Cai TG and Cai Y: Triterpenes from the fungus Poria cocos and their inhibitory activity on nitric oxide production in mouse macrophages via blockade of activating protein-1 pathway. Chem Biodivers. 8:2135–2143. 2011.PubMed/NCBI View Article : Google Scholar

20 

Yang H, Shen Y, Chen B, Jia X and Cai B: RP-HPLC-DAD determination of six triterpenes in a herbal tonic hoelen. J Liq Chromatogr Relat Technol. 34:1772–1782. 2011.

21 

Li S, Wang Z, Gu R, Zhao Y, Huang W, Wang Z and Xiao W: A new epidioxy-tetracyclic triterpenoid from Poria cocos Wolf. Nat Prod Res. 30:1712–1717. 2016.PubMed/NCBI View Article : Google Scholar

22 

Li M, Wang GZ, Nie L and Shen JY: Study on the content comparison of pachymic acid from different medicinal parts of Poria cocos (Schw.) Wolf. Lishizhen Med Mater Med Res. 26:2858–2860. 2015.

23 

Fu M, Wang L, Wang X, Deng B, Hu X and Zou J: Determination of the five main terpenoids in different tissues of WolfiPoria cocos. Molecules. 23(1839)2018.PubMed/NCBI View Article : Google Scholar

24 

Yang PF, Hua T, Wang D, Zhao ZW, Xi GL and Chen ZF: Phytochemical and chemotaxonomic study of Poria cocos (Schw.) Wolf. Biochem Syst Ecol. 83:54–56. 2019.

25 

Jiang TT, Ding LF, Nie W, Wang LY, Lei T, Wu XD and Zhao QS: Tetranorlanostane and lanostane triterpenoids with cytotoxic activity from the epidermis of Poria cocos. Chem Biodivers. 18(e2100196)2021.PubMed/NCBI View Article : Google Scholar

26 

Kim TG, Lee YH, Lee NH, Bhattarai G, Lee IK, Yun BS and Yi HK: The antioxidant property of pachymic acid improves bone disturbance against AH Plus-induced inflammation in MC-3T3 E1 cells. J Endod. 39:461–466. 2013.PubMed/NCBI View Article : Google Scholar

27 

Lee YH, Lee NH, Bhattarai G, Kim GE, Lee IK, Yun BS, Hwang PH and Yi HK: Anti-inflammatory effect of pachymic acid promotes odontoblastic differentiation via HO-1 in dental pulp cells. Oral Dis. 19:193–199. 2013.PubMed/NCBI View Article : Google Scholar

28 

Keller AC, Maillard MP and Hostettmann K: Antimicrobial steroids from the fungus Fomitopsis pinicola. Phytochemistry. 41:1041–1046. 1996.PubMed/NCBI View Article : Google Scholar

29 

Kuo PC, Tai SH, Hung CC, Hwang TL, Kuo LM, Lam SH, Cheng KC, Kuo DH, Hung HY and Wu TS: Anti-inflammatory triterpenoids from the fruiting bodies of Fomitopsis pinicola. Bioorg Chem. 108(104562)2021.PubMed/NCBI View Article : Google Scholar

30 

Ma J, Liu J, Lu CW and Cai DF: Pachymic acid modified carbon nanoparticles reduced angiogenesis via inhibition of MMP-3. Int J Clin Exp Pathol. 8:5464–5470. 2015.PubMed/NCBI

31 

Zhu W, Liu Y, Tang J, Liu H, Jing N, Li F, Xu R and Shu S: Functional analysis of sterol O-Acyltransferase involved in the biosynthetic pathway of pachymic acid in WolfiPoria cocos. Molecules. 27(143)2021.PubMed/NCBI View Article : Google Scholar

32 

Cai SY, Lv SW, Wang YH, Guo YY and Li YJ: Solubility and Apparent Oil/Water Partition Coefficient of Glycyrrhizin and Pachymic Acid. Inf Tradit Chin Med. 29:118–121. 2012.(In Chinese).

33 

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.PubMed/NCBI View Article : Google Scholar

34 

Xu H, Wang Y, Zhao J, Jurutka PW, Huang D, Liu L, Zhang L, Wang S, Chen Y and Cheng S: Triterpenes from Poria cocos are revealed as potential retinoid X receptor selective agonists based on cell and in silico evidence. Chem Biol Drug Des. 95:493–502. 2020.PubMed/NCBI View Article : Google Scholar

35 

Jeong JW, Baek JY, Kim KD, Choi YH and Lee JD: Induction of apoptosis by pachymic acid in T24 human bladder cancer cells. J Life Sci. 25:93–100. 2015.

36 

Jeong JW, Lee WS, Go SI, Nagappan A, Baek JY, Lee JD, Park C, Kim GY, Kim HJ, Kim GS, et al: Pachymic acid induces apoptosis of EJ bladder cancer cells by DR5 up-regulation, ROS generation, modulation of Bcl-2 and IAP family members. Phytother Res. 29:1516–1524. 2015.PubMed/NCBI View Article : Google Scholar

37 

Zhang YH, Zhang Y, Li XY, Feng XD, Jian W and Li RQ: Antitumor activity of the pachymic acid in nasopharyngeal carcinoma cells. Ultrastruct Pathol. 41:245–251. 2017.PubMed/NCBI View Article : Google Scholar

38 

Gapter L, Wang Z, Glinski J and Ng KY: Induction of apoptosis in prostate cancer cells by pachymic acid from Poria cocos. Biochem Biophys Res Commun. 332:1153–1161. 2005.PubMed/NCBI View Article : Google Scholar

39 

Wen H, Wu Z, Hu H, Wu Y, Yang G, Lu J, Yang G, Guo G and Dong Q: The anti-tumor effect of pachymic acid on osteosarcoma cells by inducing PTEN and Caspase 3/7-dependent apoptosis. J Nat Med. 72:57–63. 2018.PubMed/NCBI View Article : Google Scholar

40 

Miao G, Han J, Zhang J, Wu Y and Tong G: Targeting pyruvate kinase M2 and Hexokinase II, pachymic acid impairs glucose metabolism and induces mitochondrial apoptosis. Biol Pharm Bull. 42:123–129. 2019.PubMed/NCBI View Article : Google Scholar

41 

Jiang Y and Fan L: Evaluation of anticancer activities of Poria cocos ethanol extract in breast cancer: In vivo and in vitro, identification and mechanism. J Ethnopharmacol. 257(112851)2020.PubMed/NCBI View Article : Google Scholar

42 

Ling H, Jia X, Zhang Y, Gapter LA, Lim YS, Agarwal R and Ng KY: Pachymic acid inhibits cell growth and modulates arachidonic acid metabolism in nonsmall cell lung cancer A549 cells. Mol Carcinog. 49:271–282. 2010.PubMed/NCBI View Article : Google Scholar

43 

Ma J, Liu J, Lu C and Cai D: Pachymic acid induces apoptosis via activating ROS-dependent JNK and ER stress pathways in lung cancer cells. Cancer Cell Int. 15(78)2015.PubMed/NCBI View Article : Google Scholar

44 

Sun KX and Xia HW: Pachymic acid inhibits growth and induces cell cycle arrest and apoptosis in gastric cancer SGC-7901 cells. Oncol Lett. 16:2517–2524. 2018.PubMed/NCBI View Article : Google Scholar

45 

Lu C, Ma J and Cai D: Pachymic acid inhibits the tumorigenicity of gastric cancer cells by the mitochondrial pathway. Anticancer Drugs. 28:170–179. 2017.PubMed/NCBI View Article : Google Scholar

46 

Cheng S, Swanson K, Eliaz I, McClintick JN, Sandusky GE and Sliva D: Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress. PLoS One. 10(e0122270)2015.PubMed/NCBI View Article : Google Scholar

47 

Kaminaga T, Yasukawa K, Kanno H, Tai T, Nunoura Y and Takido M: Inhibitory effects of lanostane-type triterpene acids, the components of Poria cocos, on tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. Oncology. 53:382–385. 1996.PubMed/NCBI View Article : Google Scholar

48 

Shan H, Qinglin Z, Fengjun X, Yuxin L, Xiaochen C and Yuan H: Reversal of multidrug resistance of KBV200 cells by triterpenoids isolated from Poria cocos. Planta Med. 78:428–433. 2012.PubMed/NCBI View Article : Google Scholar

49 

Lu C, Cai D and Ma J: Pachymic acid sensitizes gastric cancer cells to radiation therapy by upregulating bax through hypoxia. Am J Chin Med. 46:875–890. 2018.PubMed/NCBI View Article : Google Scholar

50 

Chen Y, Lian P, Liu Y and Xu K: Pachymic acid inhibits tumorigenesis in gallbladder carcinoma cells. Int J Clin Exp Med. 8:17781–17788. 2015.PubMed/NCBI

51 

Gao AH, Zhang L, Chen X, Chen Y, Xu ZZ, Liu YN and Zhang H: Inhibition of ovarian cancer proliferation and invasion by pachymic acid. Int J Clin Exp Pathol. 8:2235–2241. 2015.PubMed/NCBI

52 

Ling H, Zhang Y, Ng KY and Chew EH: Pachymic acid impairs breast cancer cell invasion by suppressing nuclear factor-κB-dependent matrix metalloproteinase-9 expression. Breast Cancer Res Treat. 126:609–620. 2011.PubMed/NCBI View Article : Google Scholar

53 

Hong R, Shen MH, Xie XH and Ruan SM: Inhibition of breast cancer metastasis via PITPNM3 by pachymic acid. Asian Pac J Cancer Prev. 13:1877–1880. 2012.PubMed/NCBI View Article : Google Scholar

54 

Cheng S, Eliaz I, Lin J, Thyagarajan-Sahu A and Sliva D: Triterpenes from Poria cocos suppress growth and invasiveness of pancreatic cancer cells through the downregulation of MMP-7. Int J Oncol. 42:1869–1874. 2013.PubMed/NCBI View Article : Google Scholar

55 

Medzhitov R: Origin and physiological roles of inflammation. Nature. 454:428–435. 2008.PubMed/NCBI View Article : Google Scholar

56 

Cuéllar MJ, Giner RM, Recio MC, Just MJ, Máñez S and Ríos JL: Two fungal lanostane derivatives as phospholipase A2 inhibitors. J Nat Prod. 59:977–979. 1996.PubMed/NCBI View Article : Google Scholar

57 

Prieto JM, Recio MC, Giner RM, Máñez S, Giner-Larza EM and Ríos JL: Influence of traditional Chinese anti-inflammatory medicinal plants on leukocyte and platelet functions. J Pharm Pharmacol. 55:1275–1282. 2003.PubMed/NCBI View Article : Google Scholar

58 

Li FF, Yuan Y, Liu Y, Wu QQ, Jiao R, Yang Z, Zhou MQ and Tang QZ: Pachymic acid protects H9c2 cardiomyocytes from lipopolysaccharide-induced inflammation and apoptosis by inhibiting the extracellular signal-regulated kinase 1/2 and p38 pathways. Mol Med Rep. 12:2807–2813. 2015.PubMed/NCBI View Article : Google Scholar

59 

Cuélla MJ, Giner RM, Recio MC, Just MJ, Mañez S and Rios JL: Effect of the basidiomycete Poria cocos on experimental dermatitis and other inflammatory conditions. Chem Pharm Bull (Tokyo). 45:492–494. 1997.PubMed/NCBI View Article : Google Scholar

60 

Yasukawa K, Kaminaga T, Kitanaka S, Tai T, Nunoura Y, Natori S and Takido M: 3beta-p-Hydroxybenzoyldehydrotumulosic acid from Poria cocos, and its anti-inflammatory effect. Phytochemistry. 48:1357–1360. 1998.PubMed/NCBI View Article : Google Scholar

61 

Giner EM, Máñez S, Recio MC, Giner RM, Cerdá-Nicolás M and Ríos JL: In vivo studies on the anti-inflammatory activity of pachymic and dehydrotumulosic acids. Planta Med. 66:221–227. 2000.PubMed/NCBI View Article : Google Scholar

62 

Feng Z, Shi H, Liang B, Ge T, Cai M, Liu F, Huang K, Wen J, Chen Q and Ge B: Bioinformatics and experimental findings reveal the therapeutic actions and targets of pachymic acid against cystitis glandularis. Biofactors. 47:665–673. 2021.PubMed/NCBI View Article : Google Scholar

63 

Li JY, Wu HX and Yang G: Pachymic acid improves survival and attenuates acute lung injury in septic rats induced by cecal ligation and puncture. Eur Rev Med Pharmacol Sci. 21:1904–1910. 2017.PubMed/NCBI

64 

Gui Y, Sun L, Liu R and Luo J: Pachymic acid inhibits inflammation and cell apoptosis in lipopolysaccharide (LPS)-induced rat model with pneumonia by regulating NF-κB and MAPK pathways. Allergol Immunopathol (Madr). 49:87–93. 2021.PubMed/NCBI View Article : Google Scholar

65 

Cai ZY, Sheng ZX and Yao H: Pachymic acid ameliorates sepsis-induced acute kidney injury by suppressing inflammation and activating the Nrf2/HO-1 pathway in rats. Eur Rev Med Pharmacol Sci. 21:1924–1931. 2017.PubMed/NCBI

66 

Younis NN, Mohamed HE, Shaheen MA, Abdelghafour AM and Hammad SK: Potential therapeutic efficacy of pachymic acid in chronic kidney disease induced in rats: Role of Wnt/β-catenin/renin-angiotensin axis. J Pharm Pharmacol. 74:112–123. 2022.PubMed/NCBI View Article : Google Scholar

67 

Huang YC, Chang WL, Huang SF, Lin CY, Lin HC and Chang TC: Pachymic acid stimulates glucose uptake through enhanced GLUT4 expression and translocation. Eur J Pharmacol. 648:39–49. 2010.PubMed/NCBI View Article : Google Scholar

68 

Chen B, Zhang J, Han J, Zhao R, Bao L, Huang Y and Liu H: Lanostane triterpenoids with glucose-uptake-stimulatory activity from peels of the cultivated edible mushroom Wolfi Poria cocos. J Agric Food Chem. 67:7348–7364. 2019.PubMed/NCBI View Article : Google Scholar

69 

Li TH, Hou CC, Chang CL and Yang WC: Anti-Hyperglycemic properties of crude extract and triterpenes from Poria cocos. Evid. Based Complement. Alternat Med. 2011(128402)2011.PubMed/NCBI View Article : Google Scholar

70 

Yang Z, Du R, Chang A, Zhang J and Li Q: The in vitro anti-biofilm activity of the etoac extract of Poria cocos against Escherichia coli. Asian J Pharma Res Deve. 1:152–156. 2013.

71 

Singh A and Zhao K: Treatment of insomnia with traditional Chinese herbal medicine. Int Rev Neurobiol. 135:97–115. 2017.PubMed/NCBI View Article : Google Scholar

72 

Shah VK, Na SS, Chong MS, Woo JH, Kwon YO, Lee MK and Oh KW: Poria cocos ethanol extract and its active constituent, pachymic acid, modulate sleep architectures via activation of GABAA-ergic transmission in rats. J Biomed Res. 16:84–92. 2015.

73 

Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, Li CY and Li CJ: Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem. 46:1650–1667. 2018.PubMed/NCBI View Article : Google Scholar

74 

Jiang GP, Liao YJ, Huang LL, Zeng XJ and Liao XH: Effects and molecular mechanism of pachymic acid on ferroptosis in renal ischemia reperfusion injury. Mol Med Rep. 23(63)2021.PubMed/NCBI View Article : Google Scholar

75 

Lee JH, Lee YJ, Shin JK, Nam JW, Nah SY, Kim SH, Jeong JH, Kim Y, Shin M, Hong M, et al: Effects of triterpenoids from Poria cocos Wolf on the serotonin type 3A receptor-mediated ion current in Xenopus oocytes. Eur J Pharmacol. 615:27–32. 2009.PubMed/NCBI View Article : Google Scholar

76 

Eom S, Kim YS, Lee SB, Noh S, Yeom HD, Bae H and Lee JH: Molecular determinants of α3β4 nicotinic acetylcholine receptors inhibition by triterpenoids. Biol Pharm Bull. 41:65–72. 2018.PubMed/NCBI View Article : Google Scholar

77 

Zhang F, Zhang XF, Wang BC, Liu HY, Li CY, Liu ZH, Zhang GW, Lü H, Chi C and Wang F: Pachymic acid, a novel compound for anti-rejection: Effect in rats following cardiac allograft transplantation. Chin Med J (Engl). 122:2898–2902. 2009.PubMed/NCBI

78 

Lee SG and Kim MM: Pachymic acid promotes induction of autophagy related to IGF-1 signaling pathway in WI-38 cells. Phytomedicine. 36:82–87. 2017.PubMed/NCBI View Article : Google Scholar

79 

Arun S, Sampath V, Mahalaxmi S and Rajkumar K: A comparative evaluation of the effect of the addition of pachymic acid on the cytotoxicity of 4 different root canal sealers-an in vitro study. J Endod. 43:96–99. 2017.PubMed/NCBI View Article : Google Scholar

80 

Kamalakannan Preethi O, Sampath V, Ravikumar N and Mahalaxmi S: Comparative evaluation of physicochemical properties and apical sealing ability of a resin sealer modified with Pachymic Acid. Eur Endod J. 5:23–27. 2020.PubMed/NCBI View Article : Google Scholar

81 

Matsubara Y, Matsumoto T, Koseki J, Kaneko A, Aiba S and Yamasaki K: Inhibition of human kallikrein 5 protease by triterpenoids from natural sources. Molecules. 22(1829)2017.PubMed/NCBI View Article : Google Scholar

82 

Kim JH, Sim HA, Jung DY, Lim EY, Kim YT, Kim BJ and Jung MH: Poria cocus Wolf extract ameliorates hepatic steatosis through regulation of lipid metabolism, inhibition of ER stress, and activation of autophagy via AMPK activation. Int J Mol Sci. 20(4801)2019.PubMed/NCBI View Article : Google Scholar

83 

Fu XP, Xu L, Fu BB, Wei KN, Liu Y, Liao BQ, He SW, Wang YL, Chen MH, Lin YH, et al: Pachymic acid protects oocyte by improving the ovarian microenvironment in polycystic ovary syndrome mice. Biol Reprod. 103:1085–1098. 2020.PubMed/NCBI View Article : Google Scholar

84 

He Y, Zhong JH, Wei XD, Huang CY, Peng PL, Yao J, Song XS, Fan WL and Li GC: Pachymic acid ameliorates pulmonary hypertension by regulating Nrf2-Keap1-ARE pathway. Curr Med Sci. 42:56–67. 2022.PubMed/NCBI View Article : Google Scholar

85 

Li W, Wang C, Zhang M, Yuan Y, Zhang Z, Liu X, Zhang F and Wu Y: Pachymic acid protects against kidney injury in mice with diabetic nephropathy by inhibiting the PI3K/AKT pathway. Trop J Pharm Res. 20:2539–2544. 2021.

86 

Younis NN, Salama A, Shaheen MA and Eissa RG: Pachymic acid attenuated doxorubicin-induced heart failure by suppressing miR-24 and preserving cardiac junctophilin-2 in rats. Int J Mol Sci. 22(10710)2021.PubMed/NCBI View Article : Google Scholar

87 

Ling Y, Chen M, Wang K, Sun Z, Li Z, Wu B and Huang C: Systematic screening and characterization of the major bioactive components of Poria cocos and their metabolites in rats by LC-ESI-MS(n). Biomed Chromatogr. 26:1109–1117. 2012.PubMed/NCBI View Article : Google Scholar

88 

Zheng Y and Yang XW: Absorption and transport of pachymic acid in the human intestinal cell line Caco-2 monolayers. Zhong Xi Yi Jie He Xue Bao. 6:704–710. 2008.PubMed/NCBI View Article : Google Scholar

89 

Alatengqimuge Y, Yang XW, Zheng Y, Ma L and Lu W: LC analysis and pharmacokinetic study of pachymic acid after intravenous administration to rats. Chroma. 67:807–811. 2008.

90 

Wang FY, Lv WS and Han L: Determination and pharmacokinetic study of pachymic acid by LC-MS/MS. Biol Pharm Bull. 38:1337–1344. 2015.PubMed/NCBI View Article : Google Scholar

91 

Zhang J, Guo H, Yan F, Yuan S, Li S, Zhu P, Chen W, Peng C and Peng D: An UPLC-Q-Orbitrap method for pharmacokinetics and tissue distribution of four triterpenoids in rats after oral administration of Poria cocos ethanol extracts. J Pharm Biomed Anal. 203(114237)2021.PubMed/NCBI View Article : Google Scholar

92 

Ding B, Ji X, Sun X, Zhang T and Mu S: In vitro effect of pachymic acid on the activity of Cytochrome P450 enzymes. Xenobiotica. 50:913–918. 2020.PubMed/NCBI View Article : Google Scholar

93 

Zhang J, Liu L, Li H and Zhang B: Pharmacokinetic study on the interaction between pachymic acid and bavachin and its potential mechanism. Pharm Biol. 59:1256–1259. 2021.PubMed/NCBI View Article : Google Scholar

94 

Staton CA, Reed MW and Brown NJ: A critical analysis of current in vitro and in vivo angiogenesis assays. Int J Exp Path. 90:195–221. 2009.PubMed/NCBI View Article : Google Scholar

95 

Saeidnia S, Manayi A and Abdollahi M: From in vitro experiments to in vivo and clinical studies; pros and cons. Curr Drug Discov Technol. 12:218–224. 2015.PubMed/NCBI View Article : Google Scholar

96 

Wang P, She G, Yang Y, Li Q, Zhang H, Liu J, Cao Y, Xu X and Lei H: Synthesis and biological evaluation of new ligustrazine derivatives as anti-tumor agents. Molecules. 17:4972–4985. 2012.PubMed/NCBI View Article : Google Scholar

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September-2022
Volume 24 Issue 3

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Spandidos Publications style
Wei C, Wang H, Sun X, Bai Z, Wang J, Bai G, Yao Q, Xu Y and Zhang L: Pharmacological profiles and therapeutic applications of pachymic acid (Review). Exp Ther Med 24: 547, 2022
APA
Wei, C., Wang, H., Sun, X., Bai, Z., Wang, J., Bai, G. ... Zhang, L. (2022). Pharmacological profiles and therapeutic applications of pachymic acid (Review). Experimental and Therapeutic Medicine, 24, 547. https://doi.org/10.3892/etm.2022.11484
MLA
Wei, C., Wang, H., Sun, X., Bai, Z., Wang, J., Bai, G., Yao, Q., Xu, Y., Zhang, L."Pharmacological profiles and therapeutic applications of pachymic acid (Review)". Experimental and Therapeutic Medicine 24.3 (2022): 547.
Chicago
Wei, C., Wang, H., Sun, X., Bai, Z., Wang, J., Bai, G., Yao, Q., Xu, Y., Zhang, L."Pharmacological profiles and therapeutic applications of pachymic acid (Review)". Experimental and Therapeutic Medicine 24, no. 3 (2022): 547. https://doi.org/10.3892/etm.2022.11484