Different natural compounds and polyphenols have been studied in the context of tendinitis, tendon tissue, and inflammation (Table 1). The chemical structures of some compounds are shown in Figure 1.

176]. Besides their anti-oxidant mechanisms, green tea polyphenols are able to stimulate recovery processes during tendinitis, as shown by the promotion of ECM components and glycosaminoglycans, among other recovery elements after Achilles tendinitis in rats, in combination with a glycine diet. In addition, the synthesis of collagen I as a crucial constituent of tendon was remarkably enhanced by green tea treatment. Simultaneously, inflammatory pathways were modulated in the form of decreased MMP-9 levels, which is important for the remodeling of tissue, whereas MMP-2 and IL-1β, both involved in the active remodeling process, remained elevated during green tea treatment, indicating the potential of green tea polyphenols to accelerate tendon tissue remodeling and the regeneration after tendinitis ^[23][24][132,177]. Altogether, several studies indicate that green tea extracts and EGCG represent promising agents when it comes to fighting ROS and inflammation-triggering stimuli, as well as inflammation itself in tendon tissue (Table 1). However, further research and clinical trials have to be conducted in the future for validation purposes.

Flavonoids and flavones (Figure 1) comprise a group of secondary metabolites that are present in a variety of plants, such as celery, parsley, red pepper, chamomile, mint or gingko bilboa, and citrus fruit, and are known to exhibit anti-inflammatory and associated properties in a wide range of chronic diseases ^{[61][62][63][64]}[178,179,180,181].

In an in vitro study model of rotator cuff-derived tenofibroblasts, the effect of flavonoid anthocyanin extracted from the black soybean (Glycine max (L.) MEER) as anti-oxidants was observed, thus reducing apoptosis in oxidation-stressed tenofibroblasts. Moreover, the suppression of activation of ERK1/2 and JNK accompanied by decreased ROS levels has been assumed to be an important mechanism in the effect of anthocyanins, as, in contrast, ERK1/2 and JAK were up-regulated in H₂O₂-induced apoptotic tenofibroblast cultures without anthocyanin treatment, indicating anthocyanins therapeutic potential in rotator cuff tendon that is exposed to oxidative stressors (Table 1) ^[27][133].

In previous research by Shang et al., eriocitrin, as another flavonoid derived from lemon and limes, was investigated for its potential as a bio-active reagent in tendon stem cells in vitro. Eriocitrin that has been described as the most potent anti-oxidant in citrus fruits was found to stimulate tendon stem cell proliferation and to enhance their migration activity, as an important feature of tissue healing and regeneration ^[28][65][66][147,182,183]. In addition, not only could pro-apoptotic caspase-3 activity be reduced in a concentration-dependent manner, but also the extent of scar formation, determined by scar-formation-related markers fibronectin and biglycan, could be markedly reduced in tenocyte stem cells when treated with eriocitrin, making it another promising plant-derived agent in tendinitis therapy (Table 1) ^[28][147].

In the context of estrogen deficiency, as experienced in menopause, which consequently promotes a loss of collagen and increases the risk of tendinopathies, the flavone and phyto-oestrogen genistein was investigated on collagen synthesis and Achilles tendon in ovariectomized rats in previous research ^[29][30][67][184,185,186]. Ramos et al. found evidence that genistein was able to prevent collagen loss in the Achilles tendon of rats in a postmenopausal state, underlining its potential for reducing tendinitis risk in women undergoing estrogen deficiency ^[29][184]. Moreover, it has been recently demonstrated that genistein improved functional features of Achilles tendon in estrogen-deficient rats, mostly by modulating proliferation-related gene expression (tenomodulin, proliferating cell nuclear antigen (Pcna)), as opposed to collagen remodeling (Table 1) ^[30][185]. However, further studies have to be conducted in the future to verify this hypothesis.

Icariin is the most abundant flavonoid in horny goat weed (Epimedium grandiflorum) and has been demonstrated to positively affect bone metabolism, regeneration, and density ^[68][69][187,188]. In a study by Ye et al., flavonoids have been shown to also support the healing and repair of tendon after rotator cuff reconstruction in rats in vivo, mainly by stimulating the synthesis of collagen type I and II. Moreover, the inhibition of bone loss and the promotion of osteogenesis and angiogenesis, as shown by vascular staining, clearly demonstrating enhanced CD31 (platelet endothelial cell adhesion molecule) and VEGF expression as a sign for intrinsic neovascularization around the tendon insertion site through icariin treatment, are assumed to be crucial components for tendon-bone healing (Table 1) ^[31][189]. On this background, icariin represents another flavonoid with therapeutic potential when it comes to tendinitis and tendon-associated issues, but still, cellular and molecular mechanisms have to be investigated in the future.

The polyphenolic flavonoid quercetin that is found in fruit and vegetables shows unique bio-active properties, such as anti-cancer, anti-inflammation, anti-oxidant, and anti-viral effects, which thus might play a role in health promotion and disease prevention, as well as in treatment ^[70][71][72][190,191,192]. Interestingly, previous studies have demonstrated that anti-oxidation methods reducing ROS could reduce the extent of tendon adhesion ^[73][74][193,194]. Furthermore, in a recent in vivo study by Liang et al., it has been demonstrated that quercetin treatment of rat tendon adhesion models can lead to increased anti-oxidant enzyme activity, as shown by enhanced levels of glutathione peroxidase and superoxide dismutase, while MDA levels were reduced in a concentration-dependent manner. In addition, histological analysis showed a lower extent of tendon adhesion in the rats treated with higher concentrations of quercetin, and no side effects or toxicity of quercetin therapy were observed ^[32][195].

Furthermore, Semis et al. found proof of quercetin exhibiting anti-inflammatory, anti-apoptotic, and anti-oxidant activity on rat tendon in vivo after collagenase-induced tendinitis. Moreover, inflammatory markers such as MMPs, ICAM-1, and STAT3 were activated by tendinitis induction, whereas all of them could be remarkably suppressed by quercetin administration, making it a promising agent for tendon damage protection ^[33][149]. In a study by Fu et al., quercetin has been investigated in combination with kaempferol and isorhamnetin as total flavones of sea buckthorn (Hippophae rhamnoides) for the healing of patellar tendon in rats. Within the study, it has been observed that the administration of the flavones not only improved the stress of healing tendons, especially at early stages, but also fiber alignment, collagen deposition, healing, and the recovery of the patellar tendon, suggesting that they could be effective for the improved recovery of tendon injuries (Table 1) ^[34][144].

Resveratrol (Figure 1) is a polyphenolic compound that is found in a variety of plants, including grapes, peanuts, or mulberries. It has been reported as a health-beneficial agent with pharmacological activity positively affecting inflammation, ROS, cancer, diabetes, obesity, and other chronic diseases ^{[75][76][77][78][79][80][81][82]}[117,128,196,197,198,199,200,201]. Moreover, resveratrol has been found to play a role in the modulation of a wide range of cellular mechanisms and pathways, including growth inhibition, proliferation and differentiation, apoptosis, and inflammation cascades ^{[35][37][83][84]}[14,62,71,202]. In addition, resveratrol, although its mode of action is not completely understood yet, is known to be a potent activator of Sirt-1; thus, it has a modulatory impact on the Sirt-1 signaling pathway ^[83][85][86][71,203,204] and acts as NF-κB inhibitor ^[87][88][89][101,205,206]. Furthermore, in the context of tendinitis, the potential of resveratrol to inhibit the NF-κB signaling pathway, induced by IL-1β and pro-inflammatory gene end products linked with it, has been observed in human tenocytes in vitro. Similarly, IL-1β-promoted PI3K activation has also been described to be suppressed in a dose-dependent manner by resveratrol treatment in tenocytes, comparable to the effects of PI3K inhibitors, suggesting PI3K as a main target signaling pathway of resveratrol in order to suppress NF-κB ^[37][14]. These anti-inflammatory effects of resveratrol in tenocytes are assumed to be partly associated with the linkage of Sirt-1 and scleraxis, as well as the deacetylation of NF-κB and PI3K ^[35][37][14,62]. In the same context, it has been demonstrated that resveratrol not only exhibited anti-inflammatory properties, but also stimulated the synthesis of collagens, tenomodulin, and tendon-specific transcription factor scleraxis, which is necessary for tissue vitality and regeneration ^[37][14]. The healing capabilities of resveratrol in tendon tissue have also been revealed in diabetic rats in vivo suffering from poor wound healing, following enhanced collagen production, vascular proliferation, and higher fibroblast density, which supported the healing process of Achilles tendinitis despite diabetic conditions ^[39][61]. Interestingly, in another in vitro study by Busch et al., the previously mentioned target of resveratrol, Sirt-1, was down-regulated in human tenocytes, leading to the expression of apoptotic proteins (Bax, caspase-3), the acetylation of p53 tumor suppressor Akt activation, and scleraxis suppression. Resveratrol could only inhibit IL-1β-induced NF-κB activation to down-regulate inflammatory mediators, such as COX-2 and MMP-9 in tenocytes, when Sirt-1 was expressed ^[35][62]. The role of Sirt-1 in association with resveratrol’s anti-inflammatory effects has also been demonstrated in an in vivo study by Poulsen et al. whereby resveratrol prevented dexamethasone-induced senescence of tenocytes triggered by Sirt-1 inhibition ^[36][207]. As glucocorticoids are known to promote tendon senescence and collagen attenuation, the effect of resveratrol to activate Sirt-1, thus inhibiting inflammatory and tendon degrading processes, despite glucocorticoid treatment, is of great potential ^[90][91][92][29,30,208].

Moreover, in a recently conducted study, polydatin, a derivate of resveratrol, was found to exhibit anti-glycation effects in rat tail tendon in vitro. Glycation leads to AGE formation that causes molecular cross-linking of collagen, making it develop resistance to MMPs, leading to strongly reduced collagen turnover, in turn making collagen and tendon less flexible, and increasing the risk of tendinitis. AGE formation has been found to be accelerated by ROS; hence, resveratrol as a plant-derived anti-oxidant could be a potential natural anti-glycation agent for diabetes and could help to prevent diabetes accompanying disorders, such as tendinitis (Table 1) ^[38][209].

Avocado and soybean unsaponifiables (ASUs) are made of oils extracted from fruit and seeds of avocado and soybean that exhibit active anti-inflammatory properties; thus, they are recommended as supplementary treatment in inflammation-linked chronic diseases, such as osteoarthritis (OA) ^{[40][41][42][43]}[153,154,155,156]. In a recent study by Grzanna et al., the effects of ASU have been examined in IL-1β-induced inflammation horse tenocytes. ASUs were concomitantly administered with glucosamine (GLU) and chondroitin sulfate (CS), because this mixture has been used in osteoarthritis joint-inflammation therapy before. As a result of the study, it has been demonstrated that ASU was able to significantly suppress IL-1β-induced inflammation and to reduce COX-2 and prostaglandin E2 expression, indicating that ASU can act as a potential treatment agent in tendon-associated inflammation for combination therapy with GLU and CS (Table 1) ^[1][157]. However, because of the small number of studies conducted with ASU in the context of tendinitis, these results must be considered as an only vague hint of ASU’s potential in tendinitis treatment and further research has to be carried out.

Bromelain is a natural complex of proteolytic enzymes that are derived from fruit or stem of the Ananas cosmosus (pineapple). It has been used as another phytopharmaceutical in folk medicine for centuries due to its anti-inflammatory, anti-cancer, immune-modulating, as well as anti-thrombotic properties, to name just a few, as well as its safety for administration ^[44][45][46][158,159,160]. In musculoskeletal injuries or disorders, it is also known to reduce acute pain and swelling ^[7][161]. In a study by Aiyegbusi et al., the effects of aqueous extracts of different parts of the pineapple plant were investigated on tenocyte proliferation in rats in vivo after crush injury of the Achilles tendon. In addition, the tendon malondialdehyde (MDA) level, which is a marker of oxidative stress, was analyzed ^[7][47][161,162]. Finally, the extracts of pineapple flesh and bark were found to promote the proliferation of tenoblasts, comparable to untreated tendon, whereas leaves and core extracts negatively affected the proliferation of tenocytes. Using the pineapple flesh extract, even the MDA level in tendon could be alleviated, suggesting that the anti-oxidant properties of the pineapple are located in its flesh, while both flesh and bark showed the potential to promote tendon regeneration and injury healing by promoting tenoblast proliferation ^[7][161]. The proliferation-stimulating properties of bromelain in tendon were supported by further studies in rats, arguably due to the role for reactive oxygen species (ROS), or, on the other hand, the increased expression of platelet activating factor (PAF) by modulating the cytokine system, leading to the proliferation of tenoblasts ^[8][9][130,163].

Curcuminoids (Figure 1) describe a group of bio-active nutraceutical compounds found in the rhizome of turmeric (Curcuma longa) that exhibit considerable inflammation-protective and anti-oxidant properties and have a long history in traditional Ayurvedic and Chinese medicine ^{[48][49][50][51][52]}[34,35,164,165,166].

Curcumin is the most abundant polyphenolic compound found in the group of curcuminoids that gives turmeric its characteristic intensive yellow colour ^[53][167]. Due to its multiple health-beneficial effects in a wide range of chronic diseases, including rheumatoid arthritis (RA), OA, cancer, neurological, cardiovascular or respiratory disorders, it has reached a lot of attention as an anti-inflammatory agent in therapy ^{[49][53][54][55][56]}[35,54,111,127,167]. As a well-known curcuminoid, curcumin has also been widely investigated in the context of tendon and tendinitis in several studies, where it was proven to stimulate tendon vitality and regeneration ^{[13][14][15][16][17][18][19][57]}[10,64,131,146,168,169,170,171]. For instance, in previous in vitro research using human tenocyte cultures, it was found that curcumin was able to suppress NF-κB activation triggered by IL-1β through inhibition of IκBα and NF-κB -dependent pro-inflammatory COX-2 and matrix metalloproteinases (MMPs) as well as Bcl-2, Bcl-xL and TRFA-1 that are involved in apoptosis. Moreover, it was demonstrated that these effects were at least partly executed by down-regulation of PI3K/Akt signaling promoted by curcumin, suggesting the polyphenol as an effective treatment option for tendinitis as well as for prophylaxis by its modulation of pro-inflammatory NF-κB signaling ^[13][10]. The strong anti-inflammatory effect of curcumin was also found in a recent in vivo study by Chen et al., demonstrating the down-regulation of pro-inflammatory ROS, TNF-α, IL-1β and MMPs in rats during curcumin treatment in the form of curcumin/Mg²⁺ hydrogels as well ^[19][146].

In addition, in a study by Sajithlal et al. investigating the preventive and therapeutic potential of curcumin in tail tendon of diabetic rats, it has been demonstrated that curcumin treatment significantly reduced oxidative stress by the suppression of lipid peroxidation and even more, prevented increased accumulation of advanced glycation end products and collagen crosslinking in tendon as an issue coming along with diabetes ^[14][168]. In another study, of diabetic rats similar observations were made using tetrahydro-curcumin (a metabolite of curcumin) for treatment ^[20][172], showing curcumins potential in tendon-associated therapy as an effective anti-oxidant ^[14][20][168,172]. Besides its anti-inflammatory effects, curcumin has also been proven in vitro (human tenocytes) and in vivo (rats) to help in tendon regeneration and healing by promoting collagen I and II synthesis ^[13][17][10,170] and their organization as filaments enhancing tendons biomechanical traits ^[15][64] as well as by suppressing the peritendinous adhesion of inflammatory products ^[16][169]. Moreover, curcumin has been shown to prevent tendon calcification in rats as a common issue of late-stage tendinitis due to aberrant tendon stem and progenitor cells osteogenic differentiation triggered by inflammation, by promoting tenogenesis while suppressing osteogenesis at the respective pathological sites ^[18][131], as summarized in Table 1.

Besides curcumin, another bio-active compound of turmeric, namely calebin A, has been recently investigated in in vitro tendinitis study models by our group. Within oneur study, calebin A was demonstrated with the ability to suppress inflammatory conditions in tenocytes by inhibiting the NF-κB signaling pathway and its associated gene end products, such as COX-2, MMP-9, and caspase-3, which are responsible for matrix degrading and apoptotic processes, leading to tissue inflammation and degeneration. By suppressing these catabolic events, calebin A helps in inflammation protection and tendon regeneration, which was shown by an increased expression of tendon-specific transcription factor scleraxis, tenomodulin, as well as collagen I. The down-regulation of NF-κB with the simultaneous up-regulation of tenogenic scleraxis indicates a multi-modulatory effect of calebin A in tendinitis by targeting the NF-κB–scleraxis axis (Table 1) ^[12][36].

Therefore, calebin A represents another powerful nutraceutical with great potential in tendinitis therapy, as well as in its prevention. However, further studies are needed to examine the full potential of the natural compound calebin A in fighting inflammatory and degrading processes in tendinitis ^[12][36].

Epigallocatechin gallate (Figure 1), as the most abundant polyphenol component of green tea, has been shown to be beneficial in many different diseases, including cancer, the metabolic syndrome, and neurodegenerative disorders, because of its anti-oxidant and anti-inflammatory characteristics ^[58][59][60][173,174,175]. These effects were also found in a study investigating human tendon-derived fibroblasts in vitro, in which EGCG administration suppressed IL-1β-stimulated collagenase and stromelysin, as well as the expression of MMPs, and simultaneously reduced the stimulation of p54/JNK/SAPK phosphorylation. Altogether, these outcomes suggest ECM breakdown as an important target for EGCG and other green tea polyphenols, thus proposing a potential target for EGCG therapy in tendon injury ^[21][148]. In addition to that, green tea extract has also been shown to remarkably reduce glycation, i.e., the resulting formation of advanced glycation end products (AGE), as well as crosslink collagen in the tail tendon of diabetic rats. These outcomes demonstrate the therapeutic potential of green tea extracts in treating diabetes-related tendon glycation, since the formation of glycation and AGE in tendon finally leads to impaired tendon turnover, making it even more vulnerable to tendinitis ^[22][145]. Furthermore, in an in vivo study by Rutter et al., it has been demonstrated that green tea polyphenols could prevent collagen aging markers from rising and to even delay collagen crosslinking by anti-oxidant mechanisms in rats, further supporting green tea extract as a promising anti-glycation agent. These effects could be even enhanced by the concomitant supplementation of vitamin C and E ^[25][