Oridonin: A Review of Its Pharmacology, Pharmacokinetics and Toxicity

Oridonin, as a natural terpenoids found in traditional Chinese herbal medicine Isodon rubescens (Hemsl.) H.Hara, is widely present in numerous Chinese medicine preparations. The purpose of this review focuses on providing the latest and comprehensive information on the pharmacology, pharmacokinetics and toxicity of oridonin, to excavate the therapeutic potential and explore promising ways to balance toxicity and efficacy of this natural compound. Information concerning oridonin was systematically collected from the authoritative internet database of PubMed, Elsevier, Web of Science, Wiley Online Library and Europe PMC applying a combination of keywords involving “pharmacology,” “pharmacokinetics,” and “toxicology”. New evidence shows that oridonin possesses a wide range of pharmacological properties, including anticancer, anti-inflammatory, hepatorenal activities as well as cardioprotective protective activities and so on. Although significant advancement has been witnessed in this field, some basic and intricate issues still exist such as the specific mechanism of oridonin against related diseases not being clear. Moreover, several lines of evidence indicated that oridonin may exhibit adverse effects, even toxicity under specific circumstances, which sparked intense debate and concern about security of oridonin. Based on the current progress, future research directions should emphasize on 1) investigating the interrelationship between concentration and pharmacological effects as well as toxicity, 2) reducing pharmacological toxicity, and 3) modifying the structure of oridonin—one of the pivotal approaches to strengthen pharmacological activity and bioavailability. We hope that this review can provide some inspiration for the research of oridonin in the future.


INTRODUCTION
, with the molecular formula of C 20 H 28 O 6 (Cheng et al., 2019), is a naturally occurring terpenoids that mainly exists in Isodon rubescens (Hemsl.) H.Hara (Figure 1; Yang I.-H. et al., 2017;Jian et al., 2019;Meng et al., 2019). In thousands of years of clinical practice, the Isodon rubescens (Hemsl.) H.Hara has been widely applied as central agent in classic traditional Chinese medicine (TCM) formulas with its efficacy of clearing away heat and detoxifying, boosting blood circulation and alleviating pain. Generally, I. rubescens (Hemsl.) H.Hara is frequently utilized in the treatment of acute and chronic pharyngitis, tonsillitis and bronchitis in clinic . As the main bioactive chemical component of I. rubescens (Hemsl.) H.Hara, in recent years, numerous achievements have been witnessed on the exploration of pharmacological effects of oridonin, such as antiinflammatory (Cummins et al., 2019;He et al., 2019), anti-cancer (Vasaturo et al., 2018;Jeon et al., 2019;Hu et al., 2020), antimicrobial , anti-sepsis , neuroprotection (Lin et al., 2019), immunoregulation (Guo et al., 2013) and so on. Consequently, to some extent, these rapid advancements in the discovery of the pharmacological activity of oridonin have provided extensive opportunities for the development of innovative disease strategies. On the other hand, there have been mounting reports concentrated on the adverse reactions of oridonin. Recent studies have shown that oridonin can cause suicidal erythrocyte death, induce the expression and activation of CYP2C and CYP3A family, and interfere with the early embryonic development of zebrafish. Under this background, thereby motivated, we herein to summarize the latest and comprehensive information on the pharmacology, toxicity and pharmacokinetics of oridonin, to excavate the potential of this natural active ingredient in the treatment of various diseases and furnish basic information for the rational and secure utilization of oridonin.

Anti-Inflammatory Activity
According to the literature, oridonin can markedly inhibit experimental autoimmune neuritis (EAN) by lessening local inflammatory reaction and increasing the proportion of immune regulating macrophages in the peripheral nerves possibly by the pathway of Notch, which indicates that it can be developed as a potential therapeutic agent for human Guillain-Barre syndrome (GBS) and neuropathies . Moreover, the employment of oridonin enables to relieve carrageenan-induced pleurisy through activating the KEAP-1/ Nrf2 pathway and suppressing the TXNIP/NLRP3 and NF-κB pathway in the model of BALB/c mice. These specific manifestations includes reducing lung injury scores, releasing of cytokines, neutrophil infiltration, exudating volume and the exudate protein concentration, decreasing the levels of oxidative stress markers . Recently, researcher relies on the fact that oridonin itself can act as a protective agent against LPS-induced inflammatory response, which the specific mechanisms involve in ROS accumulation, JNK activation, nuclear translocation of NF-κB . Oridonin also inhibits autophagy and survival in rheumatoid arthritis fibroblast-like synoviocytes (He et al., 2020). In addition, oridonin can also resist a series of inflammatory reactions including LPS-induced inflammation in human gingival fibroblasts , IL-1β-induced inflammation in human osteoarthritis chondrocytes (Jia et al., 2019) and LPSinduced endometritis . These findings indicate that oridonin may be served as a potential therapeutic agent for a variety of inflammatory related diseases. A great deal of immune cells including T cells plays an important role in the process of inflammation. In recent years, studies on anti-inflammatory effect of oridonin based on immune response have gradually increased. Research showed that it alleviated the colitis induced by trinitrobenzene sulfonic acid as represented by a decrease in colonic interferon-/inteleukin-17 secretion and a consumption in splenic Th1/Th17 cells and effector memory CD4(+) T cells . In addition, oridonin inhibited inflammatory graft rejection by depleting a great number of T cells in spleen and peripheral blood (Guo et al., 2013).

Anticancer Activity
The efficacy of mainstay cancer therapies such as cytotoxics and radiation, has reached a plateau in the treatment of multiple cancers. In this regard, there is an urgent sense that ameliorations must now come from fresh approaches. In recent years, continuous attention is also shifting to the development of natural anti-tumor agents. Oridonin has a variety of documented anti-cancer activities such as its ability to against gastric cancer , oral cancer , nasopharyngeal carcinoma (Liu et al., 2021), esophageal cancer , ovarian cancer (Dong et al., 2018), leukemia Zhang D. et al., 2019), and myeloma , etc. Its main mechanism involves in inhibiting proliferation (Hao et al., 2016), inducing apoptosis (Gu et al., 2015;Clayton et al., 2016;Qing et al., 2016;Xu et al., 2016) and autophagy (Tiwari et al., 2015;Yao et al., 2017), suppressing migration and invasion , reversing drug resistance (Kadioglu et al., 2018)] and so on.
As documented in literature, utilization of oridonin increased the level of E-cadherin and ALP, reduced the vimentin, phospho-FAK levels, snail, slug, and LDH in human small cell lung cancer cell line H1688 with concentration of 2.5, 5, 10, 20, and 40 µM for 24 and 48 h in vitro. Of course, the author also confirmed the antilung cancer effect of oridonin in the model of BALB/c nude mice . Another study on the anti-lung cancer of oridonin proved that, oridonin sensitized cisplatin-induced apoptosis via AMPK/Akt/mTOR-dependent autophagosome accumulation in A549 Cells (Yang et al., 2019a). Moreover, it augmented the radiosensitivity of lung cancer cells by upregulating Bax and down-regulating Bcl-2 , underpinned radiation-induced cell death by accelerating DNA damage in non-small cell lung cells (Park et al., 2018) and promoted G 2 /M arrest in A549 cells by facilitating ATM (Zheng et al., 2017). In the aspect of anti-breast cancer, oridonin could synergistically enhance the anti-tumor effect of doxorubicin on aggressive breast cancer by promoting apoptosis and anti-angiogenesis . Besides, this compound could inhibit angiogenesis and EMT related to VEGF-A , block Notch signaling pathway to inhibit the growth and metastasis of breast cancer (Xia et al., 2017), and induce autophagy to promote apoptosis (Li and Yang, 2015). In addition to its above anti-tumor effects, there is growing evidences that oridonin exhibits other anti-tumor activities such as colorectal cancer , pancreatic cancer , gallbladder cancer , prostate cancer (Lu et al., 2017) and so on. Given that pathway defects have been recognized by most chemotherapies, oridonin may be a logical botanical for future researches of tumor adjuvant therapy. Figure 2 gives the antitumor mechanism of oridonin.

Hepatorenal Protective Activity
With the deepening of the research, the hepatorenal protective activity of oridonin has been gradually recognized. In a report on the research of LPS/D-galactosamine-induced acute liver injury in mice, oridonin was used as a compound known to be effective at improving the survival rate, alleviating histopathological abnormalities, and suppressing plasma aminotransferases, which the mechanisms may involve in the suppression of proapoptotic cytokine TNF-α and JNK-associated pro-apoptotic signaling (Deng et al., 2017). Oridonin also ameliorated carbon tetrachloride-induced liver fibrosis in mice through inhibiting the NLRP3 inflammasome (Liu D.-L. et al., 2020). Mouse immortalized stellate cell line JS1 treated with oridonin at the concentration of 5, 10, and 15 µM showed that it significantly impede posttranslational modifications of IRAK4 in the TLR4 signaling pathway . In addition, the inhibition of LPS induced apoptosis promoting cytokines IL-1 β, IL-6, and MCP-1, as well as ICAM-1 and VCAM-1 observed in LX-2 cells also appear to be able to validate the protective effect of oridonin on liver (Cummins et al., 2018). In terms of kidney protection, oridonin alleviated IRI-induced kidney injury by suppressing inflammatory response of macrophages through AKT-related pathways (Yan et al., 2020). Furthermore, oridonin at the concentrations of 2.5, 5, 10, and 20 µM managed to alleviate albuminuria, improve renal function and attenuate renal histopathological injury, hinder inflammatory cytokine production, down-regulate TLR4 expression and inhibit NF-κB and p38-MAPK activation, with the effects augmented as the dose increased . These studies may provide a new recognition of natural medicine for the treatment of liver and kidney diseases.

Cardioprotective Activity
Diseases associated with cardiovascular diseases are an increasing problem in most parts of the world and, as with many other problems of today, are becoming more and more urgent for people all over the world. Therefore, a reasonable and effective strategy and approach is now essential to fight against this malady. As reported by researches in recent years, oridonin exhibited beneficial influences on cardiovascular disease. In a FIGURE 2 | The antitumor mechanism of oridonin.
Frontiers in Pharmacology | www.frontiersin.org July 2021 | Volume 12 | Article 645824 myocardial ischemia-reperfusion injury mouse models, downregulation of oxidative stress and NLRP3 inflammation has been shown to mitigative effect of oridonin to myocardial ischemia reperfusion injury . Similar results have been verified by researchers from the perspective of metabonomics . Oxidative stress, which has a critical link with the development of cardiac hypertrophy and heart failure, can reportedly be inhibited by oridonin via mitigating pressure overload-induced cardiac hypertrophy and fibrosis, preserving heart function, enhancing myocardial autophagy in pressureoverloaded hearts and angiotensin II-stimulated cardiomyocytes . In the respect of inhibition for vascular inflammation, oridonin could reduce the endothelial-leukocyte adhesion and leukocyte transmigration, inhibit the expression of TNF-α-induced endothelial adhesion molecules, suppress the penetration of the leukocyte, suppress the TNF-α-activated MAPK and Nuclear factor kappa B (NF-κB) activation, as described in the literature .

Lung Protective Activity
In recent years, oridonin, isolated from the plants of the genus rubescens, has shown great potential in lung protection due to its antioxidant and anti-inflammatory effects. Oxidative stress and the resulting inflammation are significant pathological processes in acute lung injury (ALI). According to the literature, oridonin can exert protective effects on LPS-induced ALI through Nrf2independent anti-inflammatory and Nrf2-dependent antioxidative activities (Yang et al., 2019b). It also protects against chemical induced pulmonary fibrosis. Research shows that it could markedly suppress the mRNA and protein expression of α-SMA and COL1A1 in TGF-b1-induced MRC-5 cells as well as undermine pathological changes, such as alveolar space collapse, emphysema, and infiltration of inflammatory cells induced by BLM (Fu et al., 2018). Immune regulation disorder and persistent inflammatory injury are important mechanisms of ventilatorinduced lung injury (VILI). As research has shown, oridonin can reduce VILI by blocking the interaction between NEK7 and NLRP3 and halting the activation of NLRP3 inflammatory bodies . In addition, post-exposure treatment with oridonin was able to ameliorate lung pathology, attenuate lung edema, abate MDA and TNF-α, and elevate GSH and IL-10 in the lung, which indicate that it can defend the lung against hyperoxia-induced injury in the model of mice (Liu et al., 2017).

Neuroprotective Activity
Oridonin produced a conspicuous effect of neuroprotective in PC12 and N2a cells by rescuing IR, reducing the autophagosome formation and synaptic loss and ameliorating cognitive dysfunction, halting IRinduced synaptic deficits . In the Aβ 1-42 -induced mouse model of Alzheimer's disease (AD), oridonin sharply rescues synaptic loss induced by Aβ 1-42 , lessens the alterations in dendritic structure and spine density, augment PSD-95 and promotes mitochondrial activity . The neuropathological characteristics of AD are amyloid aggregation, tau phosphorylation, and neuroinflammation. A study indicates that different routes of administration of oridonin severely attenuated-amyloid deposition, plaque-associated APP expression and microglial activation, which suggest that this natural terpenoid might be considered a prospective therapeutic agent for human neurodegenerative diseases such as AD . Furthermore, available data suggest the potentiality of oridonin to attenuate Aβ 1-42 -induced neuroinflammation and inhibit NF-κB pathway .

Other Pharmacological Activities
Several lines of evidence suggest oridonin exerts its potential role of amelioration lupus-like symptoms through suppressing BAFF expression, improving serological and clinical manifestations of SLE, lessening proteinuria levels, diminishing production of specific auto-antibodies . Besides, oridonin exerted its protective effects against hydrogen peroxide-induced damage by altering the profiles of mRNA in human dermal fibroblasts (Lee et al., 2013). In the treatment of respiratory diseases, oridonin could lessen protein quantification in bronchoalveolar lavage fluid and the lung W/D ratio, mitigate inflammation and suppress the injuries, as well as abate the TNF-α, IL-6 . Oridonin could also decrease the OVA-induced airway hyper-responsiveness and eosinophil number, and suppress the eosinophilia and mucus production, which confirms its great prospect in the treatment of asthma (Wang S. et al., 2016). In addition, oridonin could effectively ameliorate inflammation-induced bone loss in the model of mice by inhibiting DC-STAMP expression (Zou et al., 2020), halt the growth of methicillin-resistant Staphylococcus aureus (MRSA) (Yuan et al., 2019), mitigate visceral hyperalgesia in a rat model of postinflammatory irritable bowel syndrome (Zang et al., 2016), and augment gamma-globin expression in erythroid precursors from patients (Guo et al., 2020). Due to the extensive biological effects of oridonin, its application in aquaculture has been gradually discovered in recent years. As reported in the literature, oridonin could improve the antioxidant capacity of arbor acres broilers liver, as evidenced by the decrease in MDA and the increase in total SOD activities and mRNA expression levels of the liver antioxidant genes (Zheng, et al., 2016). Adding oridonin to the diet of arbor acres broilers could significantly improve the immune response induced by Salmonella and protect the intestinal health (Wu et al., 2018a), increase the relative weights of spleen and bursa, number of proliferation peripheral blood T and B lymphocytes, the phagocytic rate of neutrophils, as well as the IL-2, IL-4, and TNF-α (Wu et al., 2018a). In addition, oridonin could also interfere with the effects of Salmonella pullorum on immune cells and Th1/Th2 balance of spleen in arbor acres broilers (Wu et al., 2018b). As discussed above, oridonin is a natural active compound with therapeutic potential for dozens of diseases. Additional details on the pharmacological activities of oridonin were depicted as in Table 1.

PHARMACOKINETICS
In the process of innovative agent development, pharmacokinetic research has become a pivotal part of preclinical and clinical research of drugs. It not only plays a supporting role in drug toxicity or clinical research, but also contributes to optimize the Frontiers in Pharmacology | www.frontiersin.org July 2021 | Volume 12 | Article 645824    screening of candidate agents, which provides a novel approach to study modern pharmacotherapy (Sun et al., 2020a). Up to now, benefited from the continuous emergence of novel analytical techniques, researchers have investigated the pharmacokinetic parameters of oridonin in vivo by means of MS-MS , LC-MS-MS Jin et al., 2015) and other analytical methods with rats (Jian et al., 2007) and rabbits (Mei et al., 2008), which partially interpreted the kinds of events related to the efficacy and toxicity of relevant herbal preparations in which this constituent is used. Following rat oral administration of Herba Isodi Rubescentis extract containing oridonin (1.68 mg/kg), the pharmacokinetic parameters in rat plasma were obtained with the method of LC-MS-MS, revealing AUC0-t at 78.45 ± 33.83 ng/ml/h and AUC (0-infinity) at 79.29 ± 34.26 ng/ml/h, t 1/2 at 0.19 ± 0.05 h, T max at 0.69 ± 0.13 h, C max at 164.51 ± 58.42 ng/ml (Ma et al., 2013). Determination of oridonin (40 mg/kg) in rat plasma after intragastrical administration with determination of LC-MS-MS suggested that it mainly metabolized in liver, and acquired main pharmacokinetic parameters, such as t 1/2 at 10.88 ± 4.38 h, T max at 1.00 ± 0.12 h, C max at 146.9 ± 10.17 ng/ml, AUC(0-t) at 1.31 ± 0.29 mg h/L. At the same time, this project also told us that verapamil could substantially alter the pharmacokinetic profile of oridonin in rats, as well as it might exert these effects via elevating the absorption of this terpenoid compound by suppressing the activity of P-gp, or through hindering the metabolism of it in rat liver . Figure 3 shows the main metabolites of oridonin.
A strategy of using ultra-high-performance liquid chromatography-Triple/time-of-flight mass spectrometry (UPLC-Triple-TOF-MS/MS) to identify metabolites and evaluate the in vitro metabolic profile of oridonin corroborate that, oridonin is universally metabolized in vitro, which the metabolic pathway mainly consists of dehydration, hydroxylation, di-hydroxylation, hydrogenation, decarboxylation, and ketone formation. Meanwhile, 16 metabolites of I-and IIphase were identified (Ma Y. et al., 2016). Another similar study also indicated that 16 phase I and 2 phase II metabolites were detected after oral administration of oridonin in rats, and the main biotransformation pathways of oridonin were reduction, oxidation, dehydroxylation and glucuronic acid coupling . In addition, the treatment of HepaRG cells with oridonin at concentration of 1, 5, 10, and 20 µM demonstrated that oridonin induced the mRNA and protein expression and enzyme activity of CYP450s, especially on the CYP3A4 and CYP2C9 (Zhang Y. W. et al., 2018). Besides, studies have also shown that oridonin could induce the expression of human CYP3A4 mRNA and protein through pregnane X receptormediated (PXR) pathway. Notably, there is no effect on the expression of PXR-nnRNA and protein (Zhang Y.-w. et al., 2014). In the aspect of interaction between oridonin and blood protein, it could bind to human serum albumin (HAS) through hydrogen bonding and van der Waals force, and induce conformational changes of HSA, thus affecting its biological function as carrier protein. The research provides an accurate and full basic data for clarifying the binding mechanism of oridonin with HSA and is beneficial for comprehending its  In vivo Wu et al. (2018c) Frontiers in Pharmacology | www.frontiersin.org July 2021 | Volume 12 | Article 645824 activity on protein function and biological activity in vivo during blood transportation process . Other pharmacokinetic studies on oridonin are shown in Table 2.

TOXICITY
When evaluating the efficacy of ingredients, the toxicity and safety of them should be considered particularly (Sun et al., 2020b). For a long time, traditional Chinese medicine (TCM) is well known for its safety. But in recent years, the adverse reactions have been reported frequently. Being a diterpenoids compound broadly distributed in medicinal plants, oridonin has an extensive range of pharmacological activities. However, several lines of evidence indicated that oridonin may exhibit adverse effects, even toxicity under specific circumstances, which sparked intense debate and concern about security of oridonin. As discussed above, it was discovered that oridonin showed antitumor activity on small cell Frontiers in Pharmacology | www.frontiersin.org July 2021 | Volume 12 | Article 645824 9 lung cancer (SCLC), but at the same time, HE staining revealed a certain degree of cytotoxicity in hepatic tissue after treatment with oridonin (10 mg/kg) . In addition, intervention of oridonin induced abnormalities in zebrafish, such as uninflated swim bladder and pericardial congestion at an EC 50 of 411.94 mg/L in vitro, as well as it also decreased the body length of zebrafish. In this article, researcher relied on the fact that the downregulation of VEGFR3 gene expression probably be related to the occurrence of abnormalities following oridonin exposure during embryonic development (Tian et al., 2019). A 48 h exposure to oridonin (P25 µM) sharply augmented cytosolic Ca2 + concentration, potentiated formation of ceramide, and then triggered suicidal death of erythrocytes (Jilani et al., 2011).
On the other hand, some reports suggested that oridonin could induce the expression and activation of CYP2C and CYP3A family (Zhang Y. W. et al., 2018), and appeared to be a potential risk to herb-drug interactions as a result of its induction effects on drug processing genes expression and activation (Zhang Y.-w. et al., 2014). Therefore, these reports suggested that we should pay attention to the safety issues caused by the combination of oridonin in clinical practice. Generally speaking, there are few adverse reports on the safety of oridonin, but the lack of reports does not mean that there are no such potential risks. In view of this, it is particularly important to explore the mechanisms responsible for the adverse risk of oridonin under particular circumstances. Other toxicity researches of oridonin are shown in Table 3.

SUMMARY AND OUTLOOKS
Oridonin exists in considerable number of traditional herbal medicines and possesses salient medicinal value. Numerous researches have exhibited that it can regulate a variety of gene and protein expression such as ALP, IL-6, TNF-α, Bcl-2, caspase-3, PGE2, etc. It also shows extensive effects in the regulation of NF-κB, PI3K/Akt/mTOR, and ERK1/2 signaling pathways. This review summarized the mechanism by which oridonin is utilized to treat related diseases (as shown in Table 1) and the related parameters of the pharmacokinetics (as shown in Table 2), as well as security problems in clinical practice (as shown in Table 3). However, there are some issues that need further clarification in future research.  Although oridonin has been proved to possess assorted pharmacological activities in vivo and in vitro, the specific mechanism of its biological activity has not been fully expounded. Hence, it is severely significant to further excavate the mechanism of pharmacological activity at molecular level.
Additionally, as described herein, it has shown prominent adverse effects, even toxicity under specific circumstances in vitro and in vivo. Hence, the conduction of essential investigations and comprehensive strategies to strike the balance between toxicological safety and therapeutic efficacy, as well as the establishment of an all-round research on the effect of dosage on pharmacological activity and toxicity, is highly demanded in this field.
As described herein, oridonin has shown prominent adverse effects, even toxicity under specific circumstances in vitro and in vivo. It showed hepatotoxicity and hepatoprotective effects, which the pair of pharmacological activities seems to be a paradox. However, through the analysis, it is found that this is mainly related to the concentration of oridonin and the time of administration. Long-term administration and high dose administration may cause liver damage. Therefore, it is necessary to further investigate the effects of the concentration of oridonin on pharmacological effects and toxicity. On the other hand, according to the chemical structure of oridonin, it may react covalently with the sulfhydryl group of some proteins, which can partly explain the reason of adverse reactions even toxicity of oridonin in specific environment. In addition, based on the analysis of the existing literatures, we think that the current researches are focus more on the toxicity of oridonin itself. Nevertheless, the toxic process of oridonin metabolites is still unknown. These aspects can be further interpreted in future. Therefore, in view of the above reasons for the safety of oridonin, we suggest that the conduction of essential investigations and comprehensive strategies to strike the balance between toxicological safety and therapeutic efficacy are necessary, as well as the establishment of an all-round research on the effect of dosage on pharmacological activity and toxicity, is highly demanded in this field.
In recent years, structural modification of oridonin, including 1) the derivatization of hydroxyl groups, 2) modification of A-ring, 3) modification of the enone system, and 4) the transformation and derivatization of the framework structure, has been conducted in order to ameliorate the activity and amplify their application scope . In the past decades, great progress has been made in structure activity relationship and mechanism of action studies of oridonin for the treatment of malignant tumor and other diseases ( Figure 4). The structure and activity relation studies based on these new derivatives have tremendously contributed to the comprehension of their mechanism of actions and molecular targets.
According to the above literatures, we deeply realized that an increasing number of reports indicate that oridonin has miscellaneous positive pharmacological activities. However, on the whole, the oridonin's specific mechanism related various diseases still remain to be clarified. On the other hand, although this natural active ingredient can positively influence the disease process by regulating multiple signal pathways or targets, it is only utilized as adjuvant agents in clinical practice, and rarely applied in the treatment of specific diseases. Therefore, in consideration of the current scattered research, detailed mechanism of oridonin in the treatment of specific diseases should be systematically integrated in the future.

AUTHOR CONTRIBUTIONS
XL and QH contributed to the conception and design of the study. XL, WM, and C-TZ organized the database, performed the statistical analysis, and wrote the first draft of the manuscript. XX and QH contributed to the manuscript revision. All authors read and approved the submitted version.