Advances for pharmacological activities of Polygonum cuspidatum - A review

Abstract Context Polygonum cuspidatum Sieb. et Zucc (Polygonaceae), the root of which is included in the Chinese Pharmcopoeia under the name ‘Huzhang', has a long history as a medicinal plant and vegetable. Polygonum cuspidatum has been used in traditional Chinese medicine for the treatment of inflammation, hyperlipemia, etc. Objective This article reviews the pharmacological action and the clinical applications of Polygonum cuspidatum and its extracts, whether in vivo or in vitro. We also summarized the main phytochemical constituents and pharmacokinetics of Polygonum cuspidatum and its extracts. Methods The data were retrieved from major medical databases, such as CNKI, PubMed, and SinoMed, from 2014 to 2022. Polygonum cuspidatum, pharmacology, toxicity, clinical application, and pharmacokinetics were used as keywords. Results The rhizomes, leaves, and flowers of Polygonum cuspidatum have different phytochemical constituents. The plant contains flavonoids, anthraquinones, and stilbenes. Polygonum cuspidatum and the extracts have anti-inflammatory, antioxidation, anticancer, heart protection, and other pharmacological effects. It is used in the clinics to treat dizziness, headaches, traumatic injuries, and water and fire burns. Conclusions Polygonum cuspidatum has the potential to treat many diseases, such as arthritis, ulcerative colitis, asthma, and cardiac hypertrophy. It has a broad range of medicinal applications, but mainly focused on root medication; its aerial parts should receive more attention. Pharmacokinetics also need to be further investigated.


Introduction
Traditional Chinese medicine (TCM) has been used extensively for thousands of years, and the use of herbal medicinal products has been growing rapidly in many countries (Agbabiaka et al. 2018). For example, artemisinin and its derivatives, the most effective antimalarial drugs, are extracted from the sweet wormwood plant, Artemisia annua Linn (Compositae) . Numerous researchers have studied herbal medicine. An herbal medicine may have a variety of phytochemical constituents, each of which may have a different medicinal activity, so an herb can actually have a variety of therapeutic effects at the same time. Nowadays, people use herbal medicine alone or as a supplement to treat many diseases, such as cancer , cardiovascular , cerebrovascular, and nervous system diseases (Lu et al. 2020). Moreover, as the prevalence of TCM research increases worldwide, more pharmaceutical activities will be discovered (Acquaviva et al. 2021).
Polygonum cuspidatum Sieb. et Zucc (Polygonaceae) is a traditional Chinese herb that grows in Asia and North America. The roots of Polygonum cuspidatum (PC) are listed in the Pharmacopoeia of the People's Republic of China using the name of Huzhang. Resveratrol, polydatin, quercetin, emodin, and their derivatives are the primary active phytochemical components of PC. These phytochemical components of PC have undergone extensive research and are thought to be essential for PC's medicinal functions (Lachowicz and Oszmia nski 2019;. Moreover, PC has been known to have anti-inflammatory , antioxidant (Zeng et al. 2019), antiviral , antimicrobial , neuroprotective effects , etc. It is seen as a potential treatment for arthritis, ulcerative colitis , asthma (Zeng et al. 2019), cardiac hypertrophy (Ding W et al. 2014), etc. The main objective of this review is to provide a systematic elaboration of the therapeutic effects of PC on a variety of diseases, so as to promote the understanding of PC and the development PC-derived herbal medicinal products and supplements.
phytochemical constituents showed remarkable differences among different plant parts of PC. Stilbene compounds, such as resveratrol and polydatin, are the main active components in PC. Anthraquinone compounds mainly include emodin and its derivatives. Stilbene and anthraquinone compounds are more concentrated in the rhizomes than in other tissues, which may explain why the PC root is used in traditional Chinese medicine. Flavonoids are mainly found in the leaves and the stems, whereas polyphenols are more concentrated in the flowers . The root of the PC is most widely used in traditional Chinese medicine to clear away heat and toxic materials. The other plant parts, such as the leaves, are also used due to the health benefits of the phytochemicals contained. The root, leaves, flowers, rhizomes, and fibers of PC can all be used as medicinal proposes.

Pharmacological activities
Anti-inflammation effect Ethanol extract of PC (100, 200, 400 mg/kg) could prevent colon length shortening and tissue damage, and reduce the levels of inflammatory cytokines in serum of ulcerative colitis mice including interleukin 1b (IL-1b), IL-6, and tumor necrosis factor a (TNF-a). Ethanol extract of PC exerted the above therapeutic effect by regulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) signal pathway. Researchers discovered that polydatin, resveratrol, and emodin were the primary antiinflammatory phytochemical components in PC ethanol extract ). Emodin-8-O-b-D-glucoside (50, 100, 200 lmol/ L), derived from the alcohol extract of PC, could reduce the lipopolysaccharide (LPS) induced inflammation of murine macrophage cell. The above study showed that emodin-8-O-b-Dglucoside had significant inhibitory effects on IL-6, IL-1b, and monocyte chemotactic protein-1 (MCP-1) . Resveratrol and polydatin in PC could also inhibit the releasing of IL-6 and nitric oxide (NO) in the murine macrophage cell inflammatory model in another study, and this effect was related to the suppression on NF-jB and Janus kinase/signal transducer and activator of transcription (STAT) signaling pathway Sun et al. 2015). Meanwhile, resveratrol could reduce inflammation by downregulating miR-155 and suppressing of cytokine signaling 1 (SOCS1) (Ma et al. 2017; Figure 1(a)).
In vitro, polydatin (15 lg/mL) could reduce the level of IL-1b and TNF-a in human monocytic cells gouty inflammation model and inhibit the expression of pro-inflammatory proteins including toll-like receptor 2 (TLR2), TLR4, and NF-jB (Zhu et al. 2017). In addition, polydatin (20 lmol/L) could also restrain the expression and secretion of MCP-1 in preadipocytes, then inhibited the proliferation and differentiation of preadipocytes. These results indicated that polydatin might treat obesity by regulating the inflammatory (Zheng et al. 2017). Li, Maimai et al. (2019) revealed that polydatin (20, 40, 80 mg/kg) could diminish the infiltration of inflammatory cells in the uterine tissue of endometritis mouse. The protective effect of polydatin might associated with the inhibitory effect on the expression of TNF-a, IL-1b, and IL-6, then suppressed the activation of NF-jB (Li, Maimai et al. 2019). In the mouse mastitis model induced by Staphylococcus, polydatin (15, 30, 45 mg/kg) could suppress the activation of the p38 mitogen-activated protein kinase (MAPK)/ NF-jB signal pathway, thereby inhibiting the inflammation in breast tissue and reducing tissue damage .
In vivo experiments showed that PC possessed the potential to treat arthritis (Figure 1(b)). PC could improve synovitis injury in collagen-induced arthritis (CIA) rats by regulating the peroxisome proliferator-activated receptor c (PPARc)/NF-jB signal pathway . In acute gouty arthritis (AGA) mouse model, ethanol extract of PC (90, 180, 360 mg/kg) could inhibit the production of IL-1b and TNF-a in the ankle cavity in a dose-dependent manner. Its mechanism might be ethanol extract of PC could regulate the expression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)/apoptosis-associated speck-like protein (ASC)/caspase-1 signaling at gene and protein levels . Researchers found that the crude extract of PC (65, 130, 260 mg/kg) could also improve synovitis symptoms and reduce acute ankle joint swelling in AGA rats. This study further found that this therapeutic effect might be attributed to stilbene and anthraquinone in the crude extract of PC (Ren et al. 2016). In rats with rheumatoid arthritis (RA), polydatin (40, 80, 160 mg/kg) was found to reduce blood levels of TNF-and IL-1 and reduce joint inflammation. This antiinflammatory effect of polydatin was likely to involve the inhibition of the Wnt/b-catenin signaling pathway (Zeng et al. 2018). In the CIA model, emodin could also alleviate RA by inhibiting synovium inflammation of the knee joint and promoting neovascularization. This effect might be related to emodin could suppress the TNF-a-hypoxia-inducible factor 1a (HIF-1a)-inducible nitric oxide synthase (iNOs)-NO signaling pathway Pan, Wang et al. 2019). In addition, emodin could also alleviate the symptoms of RA rats by up-regulating Bax and Bcl-2 expression (Jin et al. 2018). 8-O-b-Glucopyranoside, another quinone compound extracted from the root of PC was found to significantly inhibit the proliferation of fibroblast-like synoviocyte and improve the foot swelling of CIA rats, therefore having therapeutic effects on arthritis (Geng et al. 2018).
The combination of PC and other drugs also showed remarkable anti-inflammatory effects. The combination of PC and Cinnamomum cassia Presl (Lauraceae) (Guizhi) alleviated symptoms and played a therapeutic role in rats with AGA. These two Chinese herbs could decrease the expression of pro-inflammatory genes including TLR2, TLR4, and myeloid differentiation factor 88 (MyD88), and reduce the level of IL-1b in the blood of AGA rats Cheng and Jiang 2017).  found that PC ointment, an external medicine made in China, could reduce tissue inflammation caused by calcium extravasation. The effect was better than the classical medicine of magnesium sulfate . Studies on the anti-inflammatory effects of PC and its extracts are listed in Table 1.

Antioxidant effect
The radical scavenging capacity and oxygen radical absorbance capacity assays indicated that the leaf of PC had the strongest antioxidant capacity, followed by the root and stem (Lachowicz and Oszmia nski 2019). The supercritical carbon dioxide liquid extract of PC (10, 20, 50, 100, 250 mg/mL) could scavenge 1,1diphenyl-2-picrylhydrazyl radical in a concentration-dependent manner. When the concentration was raised to 250 mg/mL, this PC extract had a remarkable capacity for ferric reduction (Lee et al. 2015). In vitro experiments revealed that 70% ethanol, ethyl acetate, and butanol extracts of PC strongly inhibited the production of reactive oxygen species by the enzyme xanthine oxidase (Sun, Zhao et al. 2014;. In vitro experiments showed that polydatin (50, 100 lmol/L) could prevent the apoptosis of human umbilical vein endothelial cells (HUVEC) induced by methylglyoxal via inhibiting oxidative stress and maintaining mitochondrial function (Pang et al. 2017). In an adriamycin-induced oxidative stress cardiomyopathy rat model, both polydatin and resveratrol (200 lmol/kg) could significantly promote the activities of total superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) in plasma and increase the content of GSH in myocardial tissue. These enzymes can prevent excessive levels of reactive oxygen species (ROS) and oxidative stress response in the body . Polydatin (0.2 g/kg) could also increase the level of SOD in the serum of atherosclerotic mice, ultimately improving the morphology of atherosclerotic vascular tissue and relieving lipid deposition (Hu et al. 2016). In the ovalbumin-induced asthmatic mice model, polydatin could increase the activity of SOD and CAT in bronchoalveolar lavage fluid and decrease the content of ROS and malondialdehyde (MDA). The mechanism might be related to activating the p38 MAPK/nuclear factor E2related factor 2 (Nrf2) signal pathway (Zhao, Jiang et al. 2018;Zeng et al. 2019). Researchers found that polydatin could also reduce the ROS content in the fat tissue of the retrobulbar of Graves' orbitopathy mice model by stimulating the Kelch like-ECH-associated protein 1 (Keap1)/Nrf2 pathway in orbital fibroblasts . The stimulation of PC on Keap1/Nrf2 could also reduce the ROS level in the liver tissue of rats with fructose-induced liver injury and inhibit fatty liver degeneration (Zhao, Yu et al. 2018). Figure 2 depicts the primary mechanisms of PC's antioxidant effect. Studies on the antioxidant effects of PC and its extracts are listed in Table 2.

Anticancer effect
In vivo experiments showed that PC (300 mg/kg) could inhibit osteosarcoma cell growth. PC could initiate apoptosis and S-phase cell cycle arrest in osteosarcoma cells through impeding protein kinase B (AKT)/extracellular signal-regulated protein kinase (ERK)/epidermal growth factor receptor (EGFR) pathway . Crude extract of PC (25, 50, 100, 200, 400 lg/ mL) could inhibit the activity of human breast cancer cells and ovarian cancer cells, as well as promote cancer cell apoptosis in a dose and time-dependent manner, with IC 50 (50% of the maximum inhibitory concentration) values of 31.18 ± 1.95 lg/mL and 28.12 ± 1.07 lg/mL, respectively (Pan, Shi et al. 2019). PC ethanol extract (50, 100, 150, 200 lg/mL) could also suppress the cell viability of cisplatin-resistant human oral cancer cells in vitro and promote cancer cell apoptosis through the endogenous pathway (caspase-3/9) (Wang, Horng et al. 2019). In vitro experiments showed that when the concentration was higher than 25 mg/mL, supercritical carbon dioxide liquid extract of PC could significantly inhibit tyrosinase activity in melanoma cells. This PC extract might lower the amount of melanin in melanoma cells when the concentration reached 50 mg/mL. Moreover, this PC extract could also induce the release of TNF-a from human monocytic after 48 h of culture. TNF-a is a kind of inflammatory/killing cytokine, and such immune stimulation might promote PC extract's antitumor activity (Lee et al. 2015).
In vivo experiments showed that polydatin (50 mg/kg) could restrain the growth of human laryngeal cancer cells transplanted into nude mice and diminish the tumor weight by 40%. Researchers found that polydatin could inhibit the proliferation of cancer cells by suppressing the activation of the platelet-derived growth factor (PDGF)/AKT signaling pathway in a dose-dependent manner . Polydatin could also induce the S-phase arrest of human acute monocytic leukemia cell line THP-1 dosedependently and inhibit the proliferation of cancer cells. The mechanism might regulate Bcl-2, Bax, cyclin A, and cyclin D1 expression . Moreover, polydatin could also inhibit the proliferation of leukemia cell line K562 by regulating the AKT/mammalian target of rapamycin (mTOR)/P70S6K signaling pathway ). In addition to these cancer cells, in vitro experiments also showed that polydatin could inhibit the growth of cervical cancer (Pan et al. 2017), lung cancer (Sun and Ye 2019), and breast cancer Feng et al. 2019).
Resveratrol also showed a prominent anticancer effect. It could down-regulate Bcl-2 protein and up-regulate the expression of Bax protein, and induce human liver carcinoma cells into phase S and promote apoptosis ). In addition, resveratrol could also inhibit the growth of the human gastric adenocarcinoma cells and arrest the cancer cells at the G0/G1 stage (Jing et al. 2016). Emodin (20 lmol/L) could inhibit the expression of transforming growth factor b2 (TGF-b2) and reduce the cell viability and colony formation of human ovarian cancer cells. This effect of emodin was mediated by activating forkhead box protein D3 (FoxD3) and miR-199a (Song et al. 2018). Rhein, an anthraquinone compound that can be isolated from PC, was found to suppress tumors in vitro by interfering with Pin1/c-Jun interaction (Cho et al. 2017). Moreover, rhein could also reverse the adriamycin resistance in the hepatoma cell line in a dose-dependent manner and increase adriamycin in the cells. Moreover, 20 lmol/L rhein could enhance the sensitivity to adriamycin of the hepatoma cell line by 7.24 times ). These studies may provide a new direction for the treatment of drug resistance in cancer cells.
Resveratrol-4-O-D-(2 0 -galloyl)-glucopyranoside is one of the active compounds isolated from PC. Xie et al. (2014) revealed that this compound could inhibit the activity of human hepatoma cells and slow tumor growth in mice transplanted with hepatoma cells. The mechanisms included the regulation of the c-Jun-N-terminal kinase (JNK)/ERK signaling pathway, and this effect was dose-and time-dependent . Another active compound in the ethyl acetate (EtOAc) extract of PC, 2-ethoxystypandron, could also restrain the cell growth of human hepatoma cells in a dosedependent manner. This effect of 2-ethoxystypandron was linked to its inhibition of STAT3 signaling and the induction of hepatoma cell cycle arrest ). 2-Methoxystypandron, another EtOAc extract of the PC roots was found to be an inhibitor of JAK2 and IjB kinase. 2-Methoxystypandron could also inhibit the activation of STAT3 induced by IL-6 and suppress the growth of cervical cancer cells. Even a concentration of 10 lmol/L could completely inhibit the growth of cancer cells (Kuang et al. 2014). 2-Methoxy-6-acetyl-7-methyljuglone, the active component of PC, could significantly reduce the proliferation of 16 types of cancer cell lines in vitro, and its IC 50 value was less than 5.5 lmol/ L . Studies on the anticancer effects of PC and its extracts are listed in Table 3.

Neuroprotection effect
The main components of PC have shown significant neuroprotective effects in many neurological diseases. Polynapstilbene B, resveratrol, (-)-epicatechin, procyanidin B 2, 3-O-gallate, and 2 0 -O-galloyl-peceid were isolated from PC. These components could significantly relieve the damage of PC12 cells caused by rotenone at 10 lmol/L in vitro, among which resveratrol had the most potent inhibitory effect (71.7%) . Studies observed that physcion 8-O-b-glucopyranoside, isolated from PC, could alleviate the symptoms of dementia rats and reduce the increase in escape time of dementia rats in Morris water maze by 44.8% .
The chronic and unpredictable mild stress (CUMS) rat model was established to investigate the effect of resveratrol on depression. Long-term use of resveratrol could significantly prevent behavioral changes induced by CUMS, such as spatial learning and memory disorders ). In addition, resveratrol could up-regulate the cAMP-response element-binding protein (CREB) and brain derived neurotrophic factor (BDNF) and modulate the mRNA levels of Bcl-2 and Bax in the hippocampus of CUMS rats (Wang, Xie et al. 2016;Shen et al. 2018). Resveratrol also had an antidepressant effect by regulating serum corticosterone levels. When trans-resveratrol was combined with piperine, a bioavailability enhancer, the minimum effective dose of trans-resveratrol could be reduced to 20 mg/kg Xu et al. 2016). In addition to alleviating symptoms of depression, resveratrol (10, 100 nmol/L) significantly reduced hypoxia-induced degradation of IjB-a, phosphorylation of p65 NF-jB protein, ERK1/2, and JNK, thereby inhibiting microglial activation (Zhang, Yuan et al. 2015).

Hepatoprotective effect
Continuous gavage of PC water extract (80, 160 mg/kg) for 11 weeks could decrease liver lipid accumulation in fructose-fed rats with metabolic syndrome by targeting the Keap1/Nrf2 pathway (Zhao, Chen et al. 2022). In addition, polydatin (50, 100 mg/ kg) could also reduce alanine transaminase and aspartate aminotransferase in serum of mice with alcohol induced hepatic injury (Koneru et al. 2017). Furthermore, polydatin (6.25 mg/mL) could alleviate hepatic steatosis in zebrafish larvae induced by ethanol. This effect of polydatin might correlate with the improvement of  ethanol and fat metabolism, inhibition of oxidative stress and DNA damage (Lai et al. 2018).

Cardioprotective effect
Ding W et al. (2014) have found that polydatin is essential in preventing pressure overload-induced cardiac hypertrophy and heart failure. The mechanism might be polydatin could inhibit the Ca 2þ -calcineurin pathway without affecting myocardial contractility (Ding W et al. 2014). Furthermore, trans-polydatin could also decrease the expression of angiotensin, inhibit the activity of renin and angiotensin-converting enzyme, and protect against myocardial ischemia injury (Ming et al. 2017). This suggested that PC might be a new cardiac protective drug.

Blood vessel protective effect
The extracts of PC root (100, 350 mg/kg) could inhibit the increase of retinal vascular permeability in diabetic rats, suggesting that oral administration might help to suppress the development of retinopathy in diabetic patients (Sohn et al. 2016). In vitro, it was shown that polydatin (1, 3, 10 lmol/L) could restore abnormal vasodilation induced by high glucose levels in a dosedependent manner. When the concentration of polydatin was 10 lmol/L, it could recover vascular endothelial function to the same level as the normal glucose group. The effect of polydatin was related to activating the PPAR protein-NO pathway . Researchers discovered that quercetin (0.1, 0.5, 1 lmol/L) could protect human brain microvascular endothelial cells injured from hypoxia and reoxygenation. Regulating the Keap1/Nrf2 pathway and endoplasmic reticulum stress might be important for the protective effect of quercetin. Such effects suggest that quercetin may protect small vessels and thus be a potential treatment for cerebral small vessel disease .

Antiviral effect
Procyanidin c-13,3 0 ,3 00 -tri-O-gallate was isolated from the ethanol extract of PC and could activate the transcription of HIV-1 in a concentration and time-dependent manner. This suggested that procyanidin c-13,3 0 ,3 00 -tri-O-gallate could be combined with highly active antiretroviral therapy to eliminate inactive potential HIV . The aqueous extract of PC, with resveratrol and emodin as the most effective active compounds,  was found to inhibit the replication of the H1N1 influenza virus in vitro, with an IC 50 value of 312 g/mL . Both the ethanol and aqueous extracts of PC were able to inhibit 3chymotrypsin-like (3CL) protease and prevent the interaction between spike-protein and angiotensin-converting enzyme II, which in turn prevented the entry of SARS-CoV-2 wild-type and omicron pseudotyped viruses into intact zebrafish larvae. The researchers further found that among the 9 major phytochemical constituents in these PC extracts, only gallic acid significantly inhibited viral entry into HEK293T cells in a dose-dependent manner, with an IC 50 value of 23.5 lmol/L (Lin et al. 2022).
Other studies have shown that EtOAc extract from the root of PC (12.5 lg/mL) could suppress the expression of Epstein-Barr virus lytic proteins and transcriptional genes, and the transcriptional inhibition rates of lytic genes BRLF1 and BZLF1 are 95.29% and 95.31%, respectively (Yiu et al. 2014). Orthoquin, a natural product extracted from the root of PC, could react with oxygen to produce singlet oxygen and shortlived reactive oxygen species. These oxygen species can damage large molecules such as proteins, lipids, and nucleic acids near the virus, then inhibit viral replication. Orthoquin could inhibit herpes simplex virus infection in a light-dependent manner (Monjo et al. 2018). Resveratrol (30 g/mL) and polydatin (200 g/ mL) were both shown to have anti-human enterovirus-71 properties in vitro and to be able to protect rhabdosarcoma cells. Compared to polydatin, resveratrol exhibited a stronger antiviral effect .

Antibacterial and antifungal effects
Different extracts from PC have extraordinary bacteriostatic effects. The methanol extract of PC root could significantly suppress the activity of bacterial neuraminidase and alleviate the symptoms of the host. In particular, the active ingredient emodin-1-O-b-D-glucopyranoside in PC extract demonstrated a robust inhibitory effect on activity of bacterial neuraminidase at a low concentration (IC 50 ¼ 0.43 lmol/L) (Uddin et al. 2016). The ethanol extract of PC had inhibitory effects on Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa, with minimum inhibitory concentration (MIC) values of 100, 50, and 100 lg/mL. This effect of PC extract suggested that it can treat bacterial infection caused by snakebite (Liu, Nielsen et al. 2014). The ethyl ether fraction of PC also showed a broad antimicrobial spectrum against the tested clinical drug-resistant isolates, with the MIC between 0.2 $ 1.63 mg/mL, which was 3 to 10 times more effective than crude PC extract. The ethyl ether fraction of PC at 2 times the MIC could completely kill 3 Â 10 5 CFU/mL Staphylococcus aureus within 1 h (Su et al. 2015). In addition, the ethyl ether fraction of PC had anti-methicillin-resistant Staphylococcus aureus activity, as it could destroy the integrity of bacterial cell walls and cell membranes. It was found that emodin (32 g/mL) was the main component of ethyl ether fraction of PC to reduce the activities of the methicillin-resistant Staphylococcus aureus. Emodin could inhibit the expression of biofilm-related genes, reduce the release of extracellular DNA, and thus inhibit the formation of Staphylococcus aureus biofilm in a dose-dependent manner (Cao et al. 2015). Moreover, the extracts of PC could also be used as a chemical stabilizer that binds to the surface of silver nanoparticles to enhance their antibacterial effect (Sun, Qu et al. 2014).

Other pharmacological effects
The water extract of PC (100, 250 mg/kg) significantly reduced the corneal irregular score and increased the volume of tears after extra orbital lacrimal gland resection in dry-eye rats. Park et al. (2018) have proved that this effect of PC extract might be related to the increased expression of mucin-4 and the inhibition of oxidative stress and inflammation (Park et al. 2018). PC and its extracts also have a strong regulatory effect on carbohydrate and lipid metabolism. The a-glucosidase and protein-tyrosine phosphatase 1B (PTP1B) were essential in insulin metabolism. In vitro, it was found that the crude EtOAc extract of PC could inhibit the activity of a-glucosidase and PTP1B, with IC 50 values of 8.33 ± 1.42 and 16.21 ± 0.38 lg/mL, respectively . Ethanol extract from the root of PC (100, 350 mg/kg) could inhibit the expansion and proliferation of glomerular mesangial matrix in diabetic rats, thus preventing diabetic nephropathy (Sohn et al. 2014).
In addition, resveratrol (20, 50, 100 lmol/L) could up-regulate the expression of type II collagen in superficial chondrocytes and middle chondrocytes, indicating that it could be used in the treatment of arthritis (Maepa et al. 2016). In a clinical test, the plant was found to have the ability to inhibit platelet aggregation. When healthy subjects took a supplement (80 mL) containing 10% resveratrol, the platelet aggregation induced by the plateletactivating factor could be suppressed significantly (Gavriil et al. 2019). The inhibitory effect of polydatin on angiogenesis allowed it to be used to treat angiogenesis-related diseases, including retinopathy, rheumatoid arthritis, and psoriasis . Emodin is considered as a potential therapeutic drug for lung cancer induced-cachexia, because feeding with emodin-enriched PC extract (2% of feed supplement) could increase the weight and reduce gastrocnemius muscle atrophy of A549 tumor-bearing BALB/c-nu mice. In vivo and in vitro mechanism research showed that emodin in this PC extract could inhibited transcription factor 4 (TCF4)-TWIST1 (a bHLH-domain-containing transcription factor) interaction, then suppress parathyroid hormone-related protein (PTHrP) expression (Fang et al. 2022).

Summary of pharmacologic effects
PC has been prescribed for medicinal purposes for thousands of years in China. In addition to anti-inflammatory, antioxidative, anticancer, and neuroprotective properties, PC and its phytochemical constituents had protective effects on the heart, kidney, liver, and other organs. PC can be a valuable alternative to various diseases, including inflammation, cancer, cognitive impairments, depression, fatty liver disease, and diabetes. Identifying the best therapeutic effect of one or more phytochemical constituents of PC and analyzing its mechanisms of action would help with the development of PC-related medicines. In addition, the above studies on the pharmacological activities of PC and its phytochemical constituents were all animal or cell experiments, and the therapeutic effects and safety need to be verified in future clinical studies.

Clinical application
This review summarized the dosage and compatibility of PC in prescriptions of past dynasties and found that the effective dosage of PC mainly was between 10 g and 30 g. When the dosage was 30 g, it primarily removes dampness and jaundice, clears heat, and helps with body detoxification; when the dosage was greater than 10-90 g, it promotes blood circulation and dredged channels. The most commonly drugs compatible to be used with PC supplements were blood-activating and stasis-dissolving drugs, heat-clearing drugs, blood-enriching drugs, Qi-tonic drugs, and water-dampening drugs , which were used to treat severe moldy sugarcane poisoning, cirrhosis ascites, carotid atherosclerosis, etc. In addition, PC could also be made into a tincture to treat burns or made into an ointment to assist in the treatment of periappendiceal abscess (Liu, Zheng et al. 2014;Xia and Yang 2014;Li, Bei et al. 2016;Chen et al. 2018). Compatible drugs and appropriate dosage for different diseases should be carefully selected when clinicians prescribe the medicine.
The information on proprietary Chinese medicines with PC as the main component in the State Drug Administration (https://www.nmpa.gov.cn) was also queried. The results included Huzhangye capsules (approval number: Z20026314), Huzhangfanshi liniments (approval number: Z20025342), Huzhangshangtong tincture (approval number: Z20025395), Compound Huzhang tablets (approval number: Z45022334), Compound Rhizoma Polygoni Cuspidati burn oil (approval number: Z10920021), and Compound paracetamol and chlorphenamine maleate capsules (approval number: H13023540). Huzhangye capsules were used to treat dizziness, headaches, and other symptoms related to hypertension (Zhao 2016). It was safe and effective in treating primary hypertension with liver Yang hyperactivity when used in combination with nifedipine. Its antihypertensive mechanism might be related to the protection of vascular endothelial cells (Ding and Gao 2021). Experimental findings also indicated that Huzhangye capsules were more effective in improving the symptoms of benign paroxysmal positional vertigo when combined with manual reduction . Compound Huzhang tablets could clear heat and remove phlegm, relieve coughs and asthma; it could also be used to prevent liver damage from psychotropic drugs . Compound paracetamol and chlorphenamine maleate capsules, which was made according to the principle of combining Chinese and western medicine to treat cold, contain acetaminophen, chlorpheniramine maleate, and PC. Huzhangshangtong tincture, Huzhangfanshi liniments, and Compound Rhizoma Polygoni Cuspidati burn oil are all external drugs. Huzhangshangtong tincture was used to treat traumatic injuries (Liu 2016), and the latter two were used to treat mild water and fire burns (Liu et al. 2012).

Pharmacokinetics
Most of the current pharmacokinetic studies on PC focused on its active ingredients. This review discussed the pharmacokinetic studies of four richest ingredients in PC. Resveratrol was characterized by low solubility and high intestinal permeability, with a plasma bioavailability of about 1% after oral administration. Glucuronides and monosulfates were the main metabolites in plasma Briskey and Rao 2020;Zhang et al. 2021). After oral administration, resveratrol was swiftly metabolized in the liver and intestine, mostly into sulfate conjugates and glucuronides, and excreted through the urine (Honari et al. 2019). It has also been reported that the above metabolites could be converted back to resveratrol by intestinal microbes ). Polydatin, a glucose derivative of resveratrol, was mainly metabolized to resveratrol in the small intestine and liver, then metabolized to glucuronidation forms, but polydatin could still be detected in plasma and urine (Lou et al. 2021;Montanari et al. 2021;Sunsong et al. 2021). Animal experiments showed the mutual transformation between polydatin and resveratrol in rats after oral administration of polydatin and resveratrol at the same dosages, respectively .
After oral administration of PC, emodin also rapidly underwent phase II metabolism to form its glucuronide. The parent form of emodin was of low concentration in the body, which was only detectable in the liver and the brain (Di et al. 2015;Dong et al. 2016). A study in mice showed that plasma glucuronidated emodin peaked 1 h after intragastric administration of emodin and was eliminated within 12 h. Female mice appeared to metabolize emodin faster than male mice (Sougiannis et al. 2021). Studies have shown that quercetin was present in a conjugated form whose primary form was glycoside in human blood after a single oral dose (Li, Yao et al. 2016). After oral administration of 200 mg of quercetin, the C max and T max were 2.3 ± 1.5 mg/mL and 0.7 ± 0.3 h, respectively (Batiha et al. 2020). Quercetin aglycones were absorbed in the small intestine mainly through passive diffusion and transported by organic anion transport peptides, followed by methylation, vulcanization, and glucuronidation in the small intestine and liver (Li, Yao et al. 2016). After metabolized by the liver, it could enter the circulation or be metabolized by the kidney and finally excreted from urine (Guo and Bruno 2015;Li, Yao et al. 2016).
In general, the primary components of PC were rapidly metabolized by the small intestine and liver after entering the body. More studies should be carried out on improving drug solubility, controlling drug release, preventing drug degradation, changing the means of administration, and preventing metabolism for enhancing the bioavailability of drugs.

Conclusions and future perspectives
PC has been used in the clinical practice for thousands of years and has extensive pharmacological activities. This review summarized its phytochemical constituents, pharmacological actions, the clinical application, and pharmacokinetics. PC and its main components have a wide range of pharmacological activities and are used for antipyretic, antibacterial, anticancer, cardiovascular and cerebrovascular protection, etc. It could be an effective therapeutic drug for various related diseases, such as arthritis, ulcerative colitis, asthma, and cardiac hypertrophy. PC can exert its therapeutic effects on a variety of systems and pathways since it contains a variety of phytochemical ingredients.
The synergistic therapeutic effect of the main phytochemical constituents in PC and the herb-drug interaction should also be further explored, which can guide the clinical drug use and standardized drug preparation. Many active ingredients that come from the roots of PC have been studied. The phytochemical constituents and pharmacological effects of flowers or leaves have been less studied, which limits the clinical use of PC. In the future, more research on other parts of PC should also be done to expand the understanding of PC.
Pharmacokinetic studies showed that the poor bioavailability of PC and its main phytochemical constituents affected its medicinal properties. Contemporary technology should be used to develop biological preparations of compounds with improved bioavailability and tested them in animals or even humans for early application in the clinical treatment. Although PC has been reported to be nephrotoxic in some cases, its contributions to the clinical treatment are undeniable. With more research being done on PC, its pharmacological effects and safety will be better known, allowing for more widespread therapeutic application of these plants.

Disclosure statement
No potential conflict of interest was reported by the author(s).