Uncaria tomentosa (Willd. ex Schult.) DC.: A Review on Chemical Constituents and Biological Activities

: Uncaria tomentosa (Willd. ex Schult.) DC. (Family: Rubiaceae), commonly known as cat’s claw, is a tropical medicinal vine originating at the Amazon rainforest and other areas of South and Central America. It has been traditionally used to treat asthma, abscesses, fever, urinary tract infections, viral infections, and wounds and found to be e ﬀ ective as an immune system rejuvenator, antioxidant, antimicrobial, and anti-inﬂammatory agent. U. tomentosa is rich in many phytoconstituents such as oxindole and indole alkaloids, glycosides, organic acids, proanthocyanidins, sterols, and triterpenes. Biological activities of U. tomentosa have been examined against various microorganisms and parasites, including pathogenic bacteria, viruses, and Plasmodium , Babesia and Theileria parasites. Several formulations of cat’s claw (e.g., tinctures, decoctions, capsules, extracts, and teas) are recently available in the market. The current review covers the chemical constituents, biological activities, pharmacokinetics, and toxic properties of U. tomentosa extracts. signaling pathway and change cytokine expression in the human acute monocytic leukemia cell line THP-1.


Introduction
Medicinal plants have been used for various therapeutic purposes from ancient times and they have also served as an important source for drug discovery [1][2][3]. A large proportion of the population living in developing countries in Asia and Africa depend on plant-based traditional medicines for

Traditional Uses
U. tomentosa bark and root have been traditionally used as a therapy in tropical South America for many conditions, like inflammations, cancer, gastric ulcers, arthritis, and infections. Moreover, it was documented to be used for blood purifications, after child delivery as a wash for wounds to allow skin healing, cleansing the kidneys, asthma, inhibition of several diseases, menstrual irregularity and hemorrhages, fevers, and possess a normalizing activity on body systems [20]. It also was used for the treatment of various ailments including abscesses, urinary tract infections, contraception, rheumatism, and weakness. Additionally, it was used as a treatment option for mental disorders (e.g., anxiety). Some indigenous people in America used the water stored in the stem to quench thirst, and as a restorative drink [21]. Few pharmacological effects of U. tomentosa have shown in Figure 1.

Antioxidant Activity
The antioxidant activities of U. tomentosa have been attributed to the existence of alkaloids, flavan-3-ol monomers, and polyphenols. The preclinical assessment revealed that the cat's claw defends toward various oxidative stresses, involving peroxynitrite that has been included in arthritis and other chronic inflammatory diseases along with inhibiting acute or chronic gastritis caused by high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) [22,23]. U. tomentosa aqueous extract was found to protect against oxidative stress in human erythrocytes and relieve chronic intestinal inflammation in rats caused by indomethacin [24,25]. Another study documented that hydroxybenzoic acids, proanthocyanidins acids hydroxycinnamic were responsible for potent radical scavenging and anti-inflammatory activities of the cat's claw [26,27]. In an in vitro experiment, U. tomentosa bark showed high antioxidant efficacy manifested by trolox equivalent antioxidant capacity, free radical diphenylpicrylhydrazyl capacity, superoxide radical scavenging activity, and peroxyl radical-trapping capacity. Moreover, it protected membrane lipids from the peroxidation caused by the iron/ascorbate system and was also evaluated by the formation of thiobarbituric acidreactive substances (TBARs) [26]. Another in vitro study revealed that the cat's claw prevented the inducible nitric oxide synthase (iNOS) gene expression caused by lipopolysaccharide, nitrite

Antioxidant Activity
The antioxidant activities of U. tomentosa have been attributed to the existence of alkaloids, flavan-3-ol monomers, and polyphenols. The preclinical assessment revealed that the cat's claw defends toward various oxidative stresses, involving peroxynitrite that has been included in arthritis and other chronic inflammatory diseases along with inhibiting acute or chronic gastritis caused by high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) [22,23]. U. tomentosa aqueous extract was found to protect against oxidative stress in human erythrocytes and relieve chronic intestinal inflammation in rats caused by indomethacin [24,25]. Another study documented that hydroxybenzoic acids, proanthocyanidins acids hydroxycinnamic were responsible for potent radical scavenging and anti-inflammatory activities of the cat's claw [26,27]. In an in vitro experiment, U. tomentosa bark showed high antioxidant efficacy manifested by trolox equivalent antioxidant capacity, free radical diphenylpicrylhydrazyl capacity, superoxide radical scavenging activity, and peroxyl radical-trapping capacity. Moreover, it protected membrane lipids from the peroxidation caused by the iron/ascorbate system and was also evaluated by the formation of thiobarbituric acid-reactive substances (TBARs) [26]. Another in vitro study revealed that the cat's claw prevented the inducible nitric oxide synthase (iNOS) gene expression caused by lipopolysaccharide, nitrite formation, cell death, and the NF-kappaB activation. Cat's claw possessed a cytoprotective effect due to its ability to interact with the injurious oxidant, therefore, it may act on regulating cell death [22].

Anti-Neoplastic Activity
Cat's claw was supposed to have antitumor and immunostimulatory effects because of its oxindole alkaloids content [10,23,28]. U. tomentosa extracts were found to have antiproliferative efficacy against SW620 colon adenocarcinoma, MCF7 breast cancer, and AGS gastric cells [19]. Interestingly, several studies suggested the antiproliferative effect of U. tomentosa against several cancer cell lines, namely cervical carcinoma, osteosarcoma, and breast cancer. For instance, an in vitro study reported that U. tomentosa hot water extract prevents inflammatory responses as well as tumor cell proliferation by inhibiting the transcriptional regulator nuclear factor kappa beta (NF-κB) activation without interfering with interleukin-2 (IL-2) production or IL-2 receptor signaling [29]. Cheng et al. [30] documented the antiproliferative effect of cat's claw extracts against several cell lines, including glioma, premyelocytic leukemia, MCF7 breast cancer, acute lymphoblastic leukaemia, and neuroblastoma.

Anti-Inflammatory Activity
Recently, POA isolated from U. tomentosa extract has been documented to enhance the lymphocyte proliferation-regulating factor released from human endothelial cells; however, TOA was found to reduce POA activity on these cells in a dose-related manner [22,31]. Additionally, U. tomentosa stem bark extracts have been revealed to stimulate the in vitro production of IL-6 and IL-1 in rat alveolar and lipopolysaccharide-stimulated macrophages in a dose-related manner and its suppressive activities on cancer cell multiplication appear to be due to apoptosis induction [18,32]. Moreover, Xiao et al. [33] examined the hypotensive efficacy of isorhynchophylline in rats and dogs, whereas Xiang et al. [34] documented the ability of rhynchophylline to suppress rabbit and rat platelet accumulation ex vivo. Additionally, the anti-inflammatory activity of the standardized aqueous extract of U. tomentosa (AC 11 of U. tomentosa extract) was attributed to NF-κB inhibition [35]. Recently, several studies reported the antioxidant, anti-neoplastic and immunomodulant activities of the alkaloids isolated from the cat's claw [36][37][38]. For instance, Lopes et al. [39] revealed that U. tomentosa extract encourages the myeloid precursor's proliferation by increasing serum colony-stimulating growth factors (CSFs). Moreover, in vivo studies demonstrated the effectiveness of aqueous U. tomentosa extract on leukocyte counts in healthy animals and doxorubicin-induced neutropenia [23,40,41]. Interestingly, Cisneros et al. [42] reported that lung inflammation was reduced in all mice treated with U. tomentosa bark extract. Additionally, Dreifuss et al. [19] examined the in vivo anti-inflammatory efficacy of quinovic acid glycoside separated from the aqueous cat's claw extracts.

Antimicrobial, Antiprotozoal and Antiviral Activities
The previous study documented the antimicrobial effect of U. tomentosa bark extracts against several morphological forms of Borrelia burgdorferi and respiratory pathogens namely Enterococcus faecalis, Pseudomonas aeruginosa and Staphylococcus aureus and this activity were attributed to the presence of proanthocyanidins, including dimers and oligomers up to undecamers [43]. U. tomentosa showed remarkable antifungal efficacy against various anidulafungin, terbinafine and fluconazole-resistant non-albicans species [44]. The antiprotozoal activity has been recently documented by Batiha et al. [45] against Babesia and Theileria parasites and this efficacy was attributed to its ability to digest harmful microorganisms. In addition to that, it has been documented to treat many parasites except Giardia. Therefore, U. tomentosa could be a good complementary antiprotozoal herb [11,45]. The antiviral activity of quinovic acid glycosides has been demonstrated in vitro against vesicular stomatitis, ribonucleic acid (RNA), a minus-strand RNA virus, and rhinovirus 1B [25]. Caon et al. [46] assessed the in vitro antiherpetic activity of hydroethanolic U. tomentosa extract, as well as the purified fractions of oxindole alkaloids and quinovic acid glycosides against herpes simplex virus (HSV) infections as well as the protective activity of these preparations on UV-induced DNA damage.

Immunomodulatory Activity
Smith et al. [47] reported that the POA isolated from U. tomentosa extracts improved the cellular immune system, while the TOA suppressed this immunostimulating effect of this POA in vitro. Another in vitro study showed the effect of different cat's claw extracts and mixtures of alkaloids in modulating the immunobiochemical pathways enhanced by interferon-gamma [48]. Notably, in vivo experiments revealed that U. tomentosa extracts exhibited immunomodulatory activity indirectly and promoted a higher provide of myeloid progenitors in the bone marrow as a result of the release of biologically active cytokines (e.g., CSFs, IL-6, and IL-1) [49]. Moreover, Allen-Hall et al. [50] documented that U. tomentosa extracts prevented the mitogen-activated protein kinases (MAPK) signaling pathway and change cytokine expression in the human acute monocytic leukemia cell line THP-1.

Cardiovascular Activity
Hirsutine isolated from U. rhynchophylla extract was found to decrease intracellular calcium concentrations in rat aortas by inhibiting the calcium channels and effecting calcium stores [51]. Moreover, it showed a vasodilated, negative chronotropic, and antiarrhythmic effect. TOA namely corynoxeine, isocorynoxiene, rhynchophylline, and isorhynchophylline exhibited a Ca 2+ channel blocking effect, which resulted in low blood pressure and may affect the central nervous system [52].

Anti-Alzheimer's Disease (AD) Activity
U. tomentosa is reported to act as a strong medicinal extract eliminator of Aβ plaques and it is considered as a potential plant for Alzheimer's Disease (AD) therapy. This activity was attributed to the fact that U. tomentosa contains newly identified polyphenolic components namely specific proanthocyanidins that possess both "plaque and tangle" reducing and inhibitory effects. Proanthocyanidin B2 (epicatechin-4β-8-epicatechin) is one major cat's claw-identified specific polyphenol that markedly diminished the brain plaque load and enhanced short-term memory in younger and older Aβ precursor protein (APP) transgenic mice "plaque-producing". Moreover, proanthocyanidin B2 has been shown to be a strong inhibitor of the brain inflammation as evidenced by a decrease in astrocytosis and gliosis in TASD-41 transgenic mice [53]. List of some of POA and TOA alkaloids along with their structures and biological activities are provided in Table 1. purified fractions of oxindole alkaloids and quinovic acid glycosides against herpes simplex virus (HSV) infections as well as the protective activity of these preparations on UV-induced DNA damage.

Immunomodulatory Activity
Smith et al. [47] reported that the POA isolated from U. tomentosa extracts improved the cellular immune system, while the TOA suppressed this immunostimulating effect of this POA in vitro. Another in vitro study showed the effect of different cat's claw extracts and mixtures of alkaloids in modulating the immunobiochemical pathways enhanced by interferon-gamma [48]. Notably, in vivo experiments revealed that U. tomentosa extracts exhibited immunomodulatory activity indirectly and promoted a higher provide of myeloid progenitors in the bone marrow as a result of the release of biologically active cytokines (e.g., CSFs, IL-6, and IL-1) [49]. Moreover, Allen-Hall et al. [50] documented that U. tomentosa extracts prevented the mitogen-activated protein kinases (MAPK) signaling pathway and change cytokine expression in the human acute monocytic leukemia cell line THP-1.

Cardiovascular Activity
Hirsutine isolated from U. rhynchophylla extract was found to decrease intracellular calcium concentrations in rat aortas by inhibiting the calcium channels and effecting calcium stores [51]. Moreover, it showed a vasodilated, negative chronotropic, and antiarrhythmic effect. TOA namely corynoxeine, isocorynoxiene, rhynchophylline, and isorhynchophylline exhibited a Ca 2+ channel blocking effect, which resulted in low blood pressure and may affect the central nervous system [52].

Anti-Alzheimer's Disease (AD) Activity
U. tomentosa is reported to act as a strong medicinal extract eliminator of Aβ plaques and it is considered as a potential plant for Alzheimer's Disease (AD) therapy. This activity was attributed to the fact that U. tomentosa contains newly identified polyphenolic components namely specific proanthocyanidins that possess both "plaque and tangle" reducing and inhibitory effects. Proanthocyanidin B2 (epicatechin-4β-8-epicatechin) is one major cat's claw-identified specific polyphenol that markedly diminished the brain plaque load and enhanced short-term memory in younger and older Aβ precursor protein (APP) transgenic mice "plaque-producing". Moreover, proanthocyanidin B2 has been shown to be a strong inhibitor of the brain inflammation as evidenced by a decrease in astrocytosis and gliosis in TASD-41 transgenic mice [53]. List of some of POA and TOA alkaloids along with their structures and biological activities are provided in Table 1. Appl. Sci. 2020, 10, x FOR PEER REVIEW 5 of 12 purified fractions of oxindole alkaloids and quinovic acid glycosides against herpes simplex virus (HSV) infections as well as the protective activity of these preparations on UV-induced DNA damage.

Immunomodulatory Activity
Smith et al. [47] reported that the POA isolated from U. tomentosa extracts improved the cellular immune system, while the TOA suppressed this immunostimulating effect of this POA in vitro. Another in vitro study showed the effect of different cat's claw extracts and mixtures of alkaloids in modulating the immunobiochemical pathways enhanced by interferon-gamma [48]. Notably, in vivo experiments revealed that U. tomentosa extracts exhibited immunomodulatory activity indirectly and promoted a higher provide of myeloid progenitors in the bone marrow as a result of the release of biologically active cytokines (e.g., CSFs, IL-6, and IL-1) [49]. Moreover, Allen-Hall et al. [50] documented that U. tomentosa extracts prevented the mitogen-activated protein kinases (MAPK) signaling pathway and change cytokine expression in the human acute monocytic leukemia cell line THP-1.

Cardiovascular Activity
Hirsutine isolated from U. rhynchophylla extract was found to decrease intracellular calcium concentrations in rat aortas by inhibiting the calcium channels and effecting calcium stores [51]. Moreover, it showed a vasodilated, negative chronotropic, and antiarrhythmic effect. TOA namely corynoxeine, isocorynoxiene, rhynchophylline, and isorhynchophylline exhibited a Ca 2+ channel blocking effect, which resulted in low blood pressure and may affect the central nervous system [52].

Reported Side Effects
The American Herbal Products Association (AHPA) classified cat's claw as a class-4 safety rating, although, it was known traditionally to be safe and nontoxic, indicating the lack of scientific data for herb safety consideration [31]. Previous reports noted several adverse effects after administration of high doses of cat's claw including nausea, acute renal failure, slow heart rate, stomach discomfort, hormonal effects, diarrhea, hepatotoxicity, decrease progesterone and estrogen levels, neuropathy [58,59], and increased risk of bleeding when administered with blood thinner agents such as warfarin, therefore, patients may be recommended to stop cat's claw administration before surgeries [31,60,61]. Signs of allergic reactions including swelling of face, lips, tongue, or throat, difficulty breathing, and hives have been observed [62]. Additionally, acute renal failure was noticed in systemic lupus erythematosus patients after the daily administration of four capsules of the cat's claw [31,63,64].

Immunosuppressant Drugs
Theoretically, it was believed that POA isolated from cat's claw possesses an immunostimulatory effect, therefore, it is contraindicated to be used with immunosuppressant drugs including cyclosporine, azathioprine, daclizumab, basiliximab, mycophenolate, muromonab-CD3, tacrolimus, sirolimus, corticosteroids, prednisone, or other chemotherapeutic drugs recommended for autoimmune disease treatment or after organ transplantation [39,62].

Anticoagulants
Cat's claw contains TOA that increased risk of bleeding when administered with aspirin, anticoagulant drugs such as warfarin or heparin, NSAIDs such as ibuprofen and naproxen, antiplatelet drugs like clopidogrel due to rhynchophylline inhibitory efficacy on platelet aggregation, therefore, patients may be recommended to stop cat's claw administration before surgeries [31,61].

Diuretics
Cat's claw has a diuretic effect, so it is contraindicated to be used with other diuretics, as they act by the same mechanism and thus increases the risk of electrolyte imbalance. Moreover, it may interact with hormonal drugs, cholesterol-lowering drugs, and drugs that affect the kidney [65].

Antihypertensive Drugs
Hirsutine extracted from cat's claw was reported to have a hypotensive effect, therefore it is not recommended to be used to hypotensive people or those administering antihypertensive drugs (e.g., casein protein, coenzyme Q-10 (ubiquinone), fish oil, L-arginine, Lycium, or stinging nettle) due to rhynchophylline and isorhynchophylline hypotensive effects as it may reduce the blood pressure to be too low [33].

Cytochrome P450 Substrates
Cat's claw prevents the microsomal CYP 3A4 activity, and thus, increased the serum levels of drugs that are metabolized by CYP 3A4 suchlike nonnucleoside reverse-transcriptase inhibitors, cyclosporine, and some benzodiazepines and increased the serious adverse effects of these drugs [66]. Moreover, the cat's claw may interact with allergic drugs like fexofenadine, anti-cancer agents as paclitaxel, antifungals like ketoconazole, antiviral drugs, and oral contraceptives [67].

Drug Safety
Based on the possible safety data, U. tomentosa extracts appears to be safe when administered to several cases of inflammation. Cat's claw safety has not been documented in breastfeeding and pregnant women, or children under three years of age because of insufficient safety research [31,64].

Recommended Doses
The typical and recommended dose of U. tomentosa is one gram given two to three times daily. A standardized extract attributed to specific chemotype of this species consisting of less than 0.5% oxindole alkaloids and 8% to 10% carboxy alkyl esters has been used in doses of 250 to 300 mg in several clinical studies [68,69]. In rats, it was determined that the average lethal dose for a single dose of water extract from U. tomentosa is higher than 8 g/kg. In humans, no toxic symptoms were noticed with frequent administration of 350 mg/day for 6 successive weeks [18,70,71]. Tinctures, decoctions, capsules, extracts, and teas are recently prepared from the cat's claw. For instance, 250-1000 mg capsule is taken orally in divided doses per day [31], while in a decoction, up to 25 g of raw bark has been used, although this based on traditional management practices. Although U. tomentosa is commercially applicable in skin formulation, its typical dose has not yet been documented [31].

Conclusions
The existing review investigates the medicinal activities and all phytochemical molecules extracted from U. tomentosa. U. tomentosa (cat's claw) is used in the tradition medicine as a treatment option against wide range of health problems, including immune system deficiencies, neurodegenerative disorders, cancer, chronic fatigue syndrome, Crohn's disease, digestive complaints, parasitic and microbial infections, kidney cleanser, inflammatory problems, irritable and leaky bowel syndrome. Moreover, U. tomentosa has many phytochemical molecules that are attributed to its therapeutic activities and exist in different degrees in the herb. U. tomentosa acts as an effective natural herbal extract eliminator of Aβ protein "plaques". Thence, U. tomentosa could be a potential herb for AD treatment. Although these medicinal properties, the cat's claw shows several adverse effects such as nausea, acute renal failure, stomach discomfort, hormonal effects, diarrhea, hepatotoxicity, neuropathy and it is contraindicated to be used with anticoagulants, antihypertensive, and immunosuppressant drugs.

Conflicts of Interest:
The authors declare no conflict of interest.