Glycosides as Potential Medicinal Components for Ulcerative Colitis: A Review

Ulcerative colitis (UC) is a chronic, non-specific disease of unknown etiology. The disease develops mainly in the rectum or colon, and the main clinical symptoms include abdominal pain, diarrhea, and purulent bloody stools, with a wide variation in severity. The specific causative factors and pathogenesis of the disease are not yet clear, but most scholars believe that the disease is caused by the interaction of genetic, environmental, infectious, immune, and intestinal flora factors. As for the treatment of UC, medications are commonly used in clinical practice, mainly including aminosalicylates, glucocorticoids, and immunosuppressive drugs. However, due to the many complications associated with conventional drug therapy and the tendency for UC to recur, there is an urgent need to discover new, safer, and more effective drugs. Natural compounds with biodiversity and chemical structure diversity from medicinal plants are the most reliable source for the development of new drug precursors. Evidence suggests that glycosides may reduce the development and progression of UC by modulating anti-inflammatory responses, inhibiting oxidative stress, suppressing abnormal immune responses, and regulating signal transduction. In this manuscript, we provide a review of the epidemiology of UC and the available drugs for disease prevention and treatment. In addition, we demonstrate the protective or therapeutic role of glycosides in UC and describe the possible mechanisms of action to provide a theoretical basis for preclinical studies in drug development.


Introduction
Inflammatory bowel disease is a chronic inflammatory disease of unknown etiology, including UC and Crohn's disease [1]. UC mainly involves the rectum and sigmoid colon, occurring mostly in the mucosal and submucosal layers of the colon and less frequently in the muscular layer, in continuous distribution and with slowly recurrent episodes [2]. The main clinical manifestations are abdominal pain, diarrhea, and purulent stools [3]. Some patients with UC may also have extra-intestinal involvement of joints, spine, bile ducts, skin, eyes, and mouth, resulting in a range of extra-intestinal symptoms. Eventually, complications such as acute peritonitis and intestinal perforation may occur, increasing the risk of hospitalization, surgery, and cancer [4,5].
As a chronic recurrent immune disease, UC is thought to result from the dysregulated expression of molecules involved in pro-and anti-inflammatory processes, often in association with other autoimmune diseases. Although the pathogenesis of epithelial damage due to an abnormal inflammatory response is unknown, it is speculated that its etiology may be related to factors such as diet, genetics, external environment, and intestinal flora [6,7]. UC has been reported to be particularly prevalent in Western developed countries and relatively uncommon in developing countries. However, changes in the standard of living

Epidemiology of UC
Epidemiological data show that there are significant geographical and ethnic differences in the incidence of UC, that it occurs in people aged 20-40 years, that it causes disability, and that it has a high rate of colon cancer [1,17,18]. The incidence of UC has reached 8.8-23.1/100,000 per year in North America; 0.6-24.3/100,000 per year in Europe; 7.3-17.4/100,000 per year in Oceania; and 2.03-17.8/100,000 per year in Asia [17]. Although the incidence of UC is much lower in developing countries such as Asia than in Western countries, the rate of increase in the incidence of UC is much higher than in Western countries [19], which is a relative reflection of the fact that the development of the disease is closely related to the social transformation of the country, the standard of living of the people, their ethnicity, and their dietary habits.
Surveys estimate that the direct and indirect costs associated with UC range from EUR 12.5 billion to EUR 29.1 billion in Europe and from USD 8.1 billion to USD 14.9 billion in the U.S. each year [20,21]. The root cause is also the fact that the exact pathogenesis of UC is not fully understood, and most of the available therapeutic drugs can only be used to alleviate the symptoms and are hardly curative. This not only adds to the national health care burden but also has a serious impact on the quality of life of patients and their families. In the 21st century, the prevalence of UC has also increased dramatically worldwide due to the proliferation of an aging population and the availability of early UC diagnosis [20]. Today, UC has been included as a global disease and has become a new world burden of disease.

Pharmacological Treatment of UC
The majority of patients are currently treated with medications, the choice of which is guided by the severity and progression of the disease [1]. In the course of UC development, drugs with low toxicity are generally chosen first, and if these do not provide the desired relief, other drugs with better results are chosen. The drugs shown in Table 1 have shown good results in clinical use for the treatment of UC, but these conventional drugs are mainly for single-target therapy, have limitations, and are associated with serious side effects.

Types Drugs Subjects Treated Side Effects References
Aminosalicylates Salazopyridine

5-Aminosalicylic acid
Olsalazine Mesalazine First-line drugs used to treat mild and moderate UC.
Long-term use can lead to drug resistance and may cause adverse effects such as damage to the blood, liver, kidney, and digestive tract and folic acid deficiency. [22,23] Glucocorticoids Prednisone Budesonide Beclomethasone Fluticasone propionate For acute and severe UC and mild patients who are intolerant or refractory to aminosalicylates.
Causes metabolic disorders, osteoporosis, etc. Long-term use can lead to drug dependence and irreversible complications. [24,25] Immunosuppressants Azathioprine Methotrexate Tacrolimus For the palliative treatment of hormone-dependent UC patients and severe cases that do not respond to steroids.
Hepatotoxic and nephrotoxic, may increase the risk of infection, and generally used clinically only as an adjunct. [26,27] Microbiological agents

Lactobacillus rhamnosus GG
For improving the symptoms of mild to moderate UC relapses.

Infliximab for Injection Tofacitinib
For patients with acute severe UC; for patients with severe UC where immunosuppressive drugs are ineffective or active UC with severe extraintestinal manifestations.
It is very effective for severe patients, but its use is limited due to its high price and side effects such as leukopenia, neutropenia, and allergy [30][31][32] Aminosalicylates are used to alleviate the disease by inhibiting the production of pro-inflammatory cytokines and oxygen free radicals, blocking neutrophil chemotaxis, and mast cell activation. These drugs are well tolerated by patients, but long-term use can lead to dizziness, headaches, and gastrointestinal adverse effects as well as blood disorders and male infertility as the dose increases over time [22,23]. Glucocorticoids are used for acute and severe UC as well as for mild cases that are intolerant to aminosalicylates or are refractory to treatment. Glucocorticoids can exert anti-inflammatory and immunosuppressive effects by interacting with their corresponding receptors or other nuclear transcription factors. Glucocorticoids have powerful anti-inflammatory effects but are associated with serious side effects, including metabolic disorders, osteoporosis, systemic perverse immune responses, and delayed wound healing [24,25]. For the palliative treatment of hormone-dependent UC patients, immunosuppressive drugs are used. These drugs have high hepatotoxicity and nephrotoxicity and are therefore usually used only in an adjuvant manner [26,27]. Microbial agents are used to improve mild to moderate UC symptoms by regulating the intestinal flora [28,29]. In addition, biologics can be used as appropriate in patients with acute severe UC or severe cases when immunosuppressants are ineffective, but their use is more limited due to their high cost and possible side effects such as leukocytopenia, neutropenia, and allergy [30][31][32]. This is why the search for natural products with abundant supplies and few side effects is of great interest to scholars at home and abroad.

Synopsis of Glycosides
Biologically active substances of natural origin are an important source of new drug discovery. In recent years and with improved techniques for the isolation of active ingredi-Molecules 2023, 28, 5210 4 of 33 ents from plants, many sugar-containing active ingredients from plants have been isolated and identified [33,34].
Glycosides are compounds formed when the hemiacetal hydroxyl group of a sugar loses a portion of water or other small molecules by coupling with a ligand to condense, and they consist of both a glycosyl group and aglycone [35][36][37][38][39]. There are many different ways of linking glycosides internally. According to the type of aglycone, glycosides can be classified into phenolic glycosides (e.g., salidroside 10), flavonoid glycosides (vitexin 6), terpenoid glycosides (asperuloside 13), etc. [40,41]. In addition, glycosides can be divided into primary glycosides (glycosides originally present in the plant) and secondary glycosides (hydrolysis or structural change of the primary glycosides) according to the form in which they exist in the organism.
Glycosides, the main form of sugar present in nature, have multiple pharmacological activities. For example, paeoniflorin 12, isolated from peony, has anti-inflammatory, antipyretic, anti-spasmodic and neuroprotective, and cerebral effects [42][43][44][45][46]. The polydatin 11, extracted from the rhizomes of Polygonum cuspidatum, has anti-inflammatory, oxidativestress-reducing, and apoptosis-inhibiting effects in ulcerative colitis [47]. The multiple pharmacological activities of glycosides are related to their structure-activity relationships [48]. The removal of hydroxyl groups from glycoside ligands as well as hydroxymethylation and the elimination of phenylpropenyl or phenylethyl all decrease the pharmacological activity, while the antioxidant activity is related to the number of unsaturated bonds, the number and position of phenolic hydroxyl groups, and the length of carbon chains [49]. In addition, glycosides have the characteristics of having multiple targets and mechanisms. For example, polydatin 11 regulates the HO-1/NQO1 signaling pathway through the AKT and Nrf2 pathways [50]. Paeoniflorin 12 inhibits ulcerative-colitis-related disease by targeting EGFL7 and has a protective effect on the TLR4/NF-κB signaling pathway [51].
Furthermore, the concept of glycoside drugs has been expanded from the general reference to glycoconjugate molecular drugs only to glycoside-based drugs. For example, digoxin is a representative glycosidic drug with cardiotonic effects [52]. In addition, since glycosides act mainly on the cell surface rather than inside the nucleus, they are characterized by relatively low toxic side effects and have a wide range of applications in the pharmaceutical and food fields, which are of greater importance from a medical point of view [53]. Currently, more and more scholars are turning their attention to glycoconjugates in the hope of discovering and developing new drugs with good activity for the benefit of mankind.

Anti-Inflammatory Effects of Glycosides in a Model of UC
The establishment of a suitable animal model is important for the in-depth study of the pathomechanism of UC and preclinical drug screening. There are numerous methods to study animal models of UC, mainly including chemical, immunological, transgenic, or knockout genes [54], among which chemical stimulation models are most commonly used due to their simplicity and economic feasibility. Commonly used chemical induction agents include dextran sodium sulfate (DSS), trinitrobenzene sulfonic acid (TNBS), acetic acid, oxazolone (OXZ), dinitrochlorobenzene (DNCB), etc. Different modeling agents can be selected according to the needs of the experiment [55]. Among them, DSS-and TNBSinduced UC models are the more widely used animal models due to their simple modeling method, good reproducibility, and clinical symptoms and pathological changes that are extremely similar to those of human UC [56,57].
Under normal conditions, the intestine has an intact barrier function that prevents pathogenic antigens in the intestinal lumen from invading the organism and maintains its normal functioning. After modeling, the integrity of the colonic epithelial barrier is disrupted, which can increase the permeability of the intestinal mucosa, leading to increased expression of a range of inflammatory factors and triggering an inflammatory response [58].
In this review, we searched the literature on glycosides in the last decade by using PubMed, Google Scholar, and the Chinese National Knowledge Infrastructure database, from Molecules 2023, 28, 5210 5 of 33 which we selected 21 glycosides that were reported for their clear chemical structures, anti-inflammatory effects, or clear pharmacological mechanisms. We also classified these 21 glycosides with significant anti-inflammatory effects and summarized their roles in UC (Tables 2 and 3, Figure 1).
It has been documented that in DSS-induced colitis in mice, treatment with quercitrin 1 (1 and 5 mg/kg) improves histopathology and reduces biochemical parameters, inflammation, and bacterial translocation [59].
Another article showed that in TNBS-induced experimental colitis, quercitrin 1 (5 mg/kg) prevented early mesenteric vascular hyporesponsiveness by reducing NO overproduction by iNOS. Thus, the mesenteric vascular bed may be a new target for the prevention of UC [60].
In summary, quercitrin 1 has anti-inflammatory and protective effects on the intestinal mucosa in experimental colitis and may be used as an alternative treatment for inflammatory bowel disease. Its role in preventing bacterial translocation and preventing early mesenteric vascular hyporesponsiveness requires further studies to elucidate.
Baicalin 2 (30, 60, and 120 mg/kg) was able to dose-dependently improve the severity of experimental colitis by a mechanism that may be related to the inhibition of oxidative stress and regulation of a range of proteins associated with IEC apoptosis [63]. In addition, baicalein (20, 50, and 100 mg/kg) ameliorated DSS-induced colitis by activating NLRP6 inflammatory vesicles to promote mucus secretion by cupped cells through a mechanism associated with activation of the NLRP6/IL-18 pathway to promote cupped cell production in the mucosa [64].
There is also evidence that baicalin 2 (10 mL/kg) alleviates TNBS-induced colitis in mice concerning the balance between Th17 and Treg cells [65].
In summary, we found that baicalin 2 exerts powerful anti-inflammatory effects in UC treatment by mechanisms related to reducing the release of inflammatory factors, inhibiting oxidative stress and anti-apoptosis, modulating UC-related receptors, modulating immune cells, and regulating different signaling pathways. Thus, baicalin 2 may be a promising drug for UC, and its components may be important lead compounds for the development of novel UC-related chemical drugs.
In DSS-induced colitis in mice, hyperoside 3 (80 and 120 mg/kg) was able to exert a protective effect by inhibiting inflammation and apoptosis, the effect of which may be related to the activation of the Nrf2 signaling pathway [66].
These findings expand our understanding of the role of hyperoside 3 and may provide potential therapeutic targets for UC.
Another article clearly showed that mangiferin 4 (50 mg/kg) was able to exert a protective effect on DSS-induced acute colitis by inhibiting the NF-κB and MAPK signaling pathways [70].
The above results provide strong evidence for the use of mangiferin 4 in the treatment of human UC.
Studies have shown that in DSS-induced colitis mice, vitexin 6 (20 and 80 mg/kg) can combat colitis by inhibiting intestinal mucosal inflammation, maintaining intestinal barrier homeostasis, and remodeling the intestinal flora [72].
It has also been shown that vitexin 6 (40 and 80 mg/kg) not only alleviates DSSinduced colitis in mice but also protects against colitis-induced liver damage from inflammatory responses, which relies heavily on the inhibition of TLR4/NF-κB signaling pathway activation [73].
In summary, vitexin 6 was able to alleviate not only colitis but also colitis-induced liver injury, indicating multiple pharmacological activities of the drug.

Naringin 7
Naringin 7 is a flavonoid glycoside extracted from grapefruit, lime, and citrus seeds and has a variety of biological activities, including anti-inflammatory and antioxidant effects [118,119].
The above results suggest that naringin 7 may be a potentially effective drug candidate for UC and deserves further development and exploration.

Punicalagin 8
Punicalagin 8 is a polyphenolic active ingredient extracted from pomegranate, with anti-inflammatory, antioxidant, anti-apoptotic, and anti-proliferative biological activities [120][121][122][123]. It has been shown that in DNBS-induced colitis in rats, administration of punicalagin 8 (4 mg/kg) exhibited significant anti-inflammatory activity and improved inflammatory bowel disease in rats, which may be attributed to direct inhibition of the transcription factor NF-κB [76].
Punicalagin 8 has a significant anti-inflammatory effect on colitis and therefore could be a potential drug for the treatment of colitis, the mechanism of action of which needs to be further explored.

Curculigoside 9
Curculigoside 9 is a phenolic glycoside component of Curculigo orchioides Gaertn that has various pharmacological activities such as anti-inflammatory, antioxidant, antiosteoporotic, and neuroprotective effects [124][125][126][127]. It has been documented that curculigoside 9 (500 and 100 mg/kg) inhibits disease activity index, tissue damage, and cell death in DSS-induced colitis mice. It was also able to significantly reverse these alterations in irontoxicity characteristics such as iron overload, GSH depletion, ROS and MDA production, and reduced expression of SOD and GPX4 [77]. These findings suggest that curculigoside 9 prevents iron sagging in UC by inducing GPX4, suggesting it as a potential therapeutic agent for UC.
In conclusion, in addition to alleviating the symptoms of DSS-induced colitis in mice, curculigoside 9 was also able to reverse the altered iron toxicity profile, which also suggests that the drug's effects are diverse, while its mechanism requires further study.
It has been shown that salidroside 10 may exert a protective effect by reducing DSSinduced colonic tissue damage in mice through activation of the SIRT1/FoxOs pathway [78].
Additional data suggest that salidroside 10 protects against experimental colitis by reversing TREM1-associated macrophage pyroptosis and gut microbiota dysregulationderived Th17/Treg imbalance, suggesting a potential role for UC [79].
In summary, salidroside 10 offers new options as a treatment for UC and merits further drug development.
There is evidence that polydatin 11 (15,30, and 45 mg/kg) effectively reduce colonic oxidative stress and apoptosis. This effect may be mediated by the up-regulation of the Shh signaling pathway [47,80].
In addition, it has been shown that polydatin 11 inhibits intestinal inflammation and oxidative stress and maintains intestinal epithelial barrier integrity by mechanisms related to NF-κB, MAPK, and AKT/Nrf2/HO-1/NQO1 signaling pathways [50]. Interestingly, however, the authors did not indicate in their article the exact dose of polydatin 11 used in DSS-induced colitis in mice, which needs to be further mapped out.
In summary, polydatin 11 can exert anti-colitis effects through a variety of mechanisms, so we have reason to believe that polydatin may be a promising candidate for the treatment of UC.
It has been shown that continuous administration of paeoniflorin 12 (50 mg/kg) for 7 days significantly reduced the severity of DSS-induced colitis and led to a downregulation of the associated inflammatory parameters, suggesting that its beneficial effects may be related to blocking the activation of NF-κB and MAPK pathways [82]. In addition, we found that paeoniflorin 12 (3 g/kg) had a therapeutic effect on AOM/DSS-induced colitis-associated cancer mice by a mechanism associated with inhibition of TLR4/NF-κBmediated inflammatory responses and EGFL7 expression [51].
In summary, paeoniflorin 12 can play a role in the treatment of colitis-associated cancers in addition to its protective role in UC, suggesting a diversity of drug actions that merits further in-depth study.

Asperuloside 13
Asperuloside 13 is a terpenoid extracted from Rubiaceae, Eucommiaceae, and other plants. Recent pharmacological studies have shown that asperuloside 13 has a variety of pharmacological activities that are anti-inflammatory, antioxidant, and immunomodulatory [141]. There is evidence that asperuloside 13 (125 and 0.5 mg/kg) may improve DSS-induced colitis in mice by alleviating inflammation and oxidative stress, activating the Nrf2/HO-1 signaling pathway, and limiting the NF-κB signaling pathway [85].
The above indicates that the drug is characterized by multiple pharmacological mechanisms and predicts a potential application of asperuloside 13 in the treatment of UC.
In summary, pedunculoside 14 has a good therapeutic effect on UC and may be a potential natural product for the treatment of UC.
Furthermore, in TNBS-induced experimental colitis, glycyrrhizin 15 (100 mg/kg) was able to modulate the intestinal inflammatory response by regulating the subtle balance of T cells [89].
In conclusion, glycyrrhizin 15 can play a significant anti-inflammatory role in experimental colitis, and its mechanism is related to inhibiting the expression of inflammatory factors, alleviating oxidative stress, up-regulating PPARγ activity, and regulating the ex-pression of immune cells. This provides strong evidence for glycyrrhizin 15 as a new potential therapeutic agent.
Gentiopicroside 17 (50, 100, and 200 mg/kg) may exert anti-inflammatory effects on DSS-induced acute colitis by inhibiting the expression of inflammatory factors, suggesting a possible therapeutic potential in the treatment of colitis, but its exact mechanism of action needs further study [91].
Ginsenoside Rg1 18 (200 mg/kg) significantly improved DSS-induced colonic injury and colonic inflammation in mice, which may be related to the regulation of intestinal flora [92].
The ability of convallatoxin 20 (50 and 150 µg/kg) to ameliorate DSS-induced inflammation in colitis by activating PPARγ and inhibiting NF-κB suggests that it may be a promising compound for the treatment of UC [94].

Aloin A 21
Aloin A 21 is an anthraquinone glycoside extracted from the secretion of Aloe vera leaves and has anti-inflammatory, anti-bacterial, antioxidant, anti-viral, and anti-cancer pharmacological effects [168]. Aloin A 21 (25 and 50 mg/kg) can prevent DSS-induced colitis by enhancing intestinal barrier function through inhibition of the Notch signaling pathway [95].

Suppressing Inflammatory Responses
Excessive production of inflammatory factors and mediators such as TNF-α, IL-1, IL-6, COX-2, and iNOS in the intestine can dominate and perpetuate the inflammatory response [91]. In addition, ICAM-1 acts as a glycoprotein that mediates cell-cell and cell-extracellular matrix adhesion and is proportional to the severity of the inflammatory response when UC occurs [169].
All the glycosides in Table 3 exerted anti-inflammatory effects by inhibiting the expression of inflammatory factors and mediators in the colonic tissues of UC mice to varying degrees. Therefore, the study of the effects of drugs on inflammation-related factors and mediators is important for the treatment of UC.

Reduction of Oxidative Stress
Oxidative stress is thought to be one of the etiologies involved in inflammatory bowel disease. Excessive oxidative reactions can upset the balance of redox reactions in the colonic mucosa and cause intestinal damage. Whereas antioxidant enzymes are markers for scavenging free radicals generated by oxidative stress, drugs can alleviate the intestinal oxidative stress state in UC by increasing their expression levels [170].
All the glycosides in Table 3 were able to reduce intestinal pathological damage and improve clinical symptoms of UC by modulating the expression of different antioxidant enzymes (Figure 2). The ability of convallatoxin 20 (50 and 150 μg/kg) to ameliorate DSS-induced inflammation in colitis by activating PPARγ and inhibiting NF-κB suggests that it may be a promising compound for the treatment of UC [94].

Aloin A 21
Aloin A 21 is an anthraquinone glycoside extracted from the secretion of Aloe vera leaves and has anti-inflammatory, anti-bacterial, antioxidant, anti-viral, and anti-cancer pharmacological effects [168]. Aloin A 21 (25 and 50 mg/kg) can prevent DSS-induced colitis by enhancing intestinal barrier function through inhibition of the Notch signaling pathway [95].

Suppressing Inflammatory Responses
Excessive production of inflammatory factors and mediators such as TNF-α, IL-1, IL-6, COX-2, and iNOS in the intestine can dominate and perpetuate the inflammatory response [91]. In addition, ICAM-1 acts as a glycoprotein that mediates cell-cell and cellextracellular matrix adhesion and is proportional to the severity of the inflammatory response when UC occurs [169].
All the glycosides in Table 3 exerted anti-inflammatory effects by inhibiting the expression of inflammatory factors and mediators in the colonic tissues of UC mice to varying degrees. Therefore, the study of the effects of drugs on inflammation-related factors and mediators is important for the treatment of UC.

Reduction of Oxidative Stress
Oxidative stress is thought to be one of the etiologies involved in inflammatory bowel disease. Excessive oxidative reactions can upset the balance of redox reactions in the colonic mucosa and cause intestinal damage. Whereas antioxidant enzymes are markers for scavenging free radicals generated by oxidative stress, drugs can alleviate the intestinal oxidative stress state in UC by increasing their expression levels [170].
All the glycosides in Table 3 were able to reduce intestinal pathological damage and improve clinical symptoms of UC by modulating the expression of different antioxidant enzymes (Figure 2).

Figure 2.
Glycosides and oxidative stress. All glycosides produced relief of UC by inhibited oxidative stress.

Anti-Apoptosis
The Bcl-2 protein family consists of Bcl-2, Bcl-xL, and Bax. In animal models, overexpression of Bcl-2 attenuates joint damage in animals, while overproduction of Bax promotes apoptosis.
In addition, Bcl-2 blocks the release of cytochrome c and down-regulates caspase activity. Caspase-3 is a central molecule in apoptosis, and its activation is regulated by a series of signal transduction cascades. Moreover, caspase-9 can be activated through the Bcl-2/Bax-ratio-mediated apoptotic pathway [83].
Studies have shown that salidroside 10 and polydatin 11 inhibit apoptosis in colon cells by down-regulating the expression of Bax, caspase-3, and cleaved-caspase-3 and up-regulating the expression of Bcl-2 [47,78]. Paeoniflorin 12, baicalin 2, and hyperoside 3 can also inhibit colon cell apoptosis by down-regulating Bax expression. Aloin A 21 also inhibited apoptosis in colon cells by down-regulating cleaved-caspase-3 expression [95]. This suggests that apoptosis plays a role in the pathogenesis of UC [63,66,83] (Figure 3). activity. Caspase-3 is a central molecule in apoptosis, and its activation is regulated by a series of signal transduction cascades. Moreover, caspase-9 can be activated through the Bcl-2/Bax-ratio-mediated apoptotic pathway [83].

Regulation of Impaired Intestinal Epithelial Barrier Function
The mucus proteins secreted by the cupulae cover the intestinal epithelium to form a dense mucin network that forms the first barrier in the intestinal lumen [171]. In addition, the tight junction (TJ) is the most important component of the intestinal epithelial barrier and is a complex of claudins and occludin proteins, peripheral membrane protein family ZOs, and other proteins. Abnormal expression of TJ can increase the permeability of the intestinal epithelial barrier, leading to the entry of pathogenic antigens such as bacteria into the mucosa and blood circulation, causing inflammation [172].

Regulation of Impaired Intestinal Epithelial Barrier Function
The mucus proteins secreted by the cupulae cover the intestinal epithelium to form a dense mucin network that forms the first barrier in the intestinal lumen [171]. In addition, the tight junction (TJ) is the most important component of the intestinal epithelial barrier and is a complex of claudins and occludin proteins, peripheral membrane protein family ZOs, and other proteins. Abnormal expression of TJ can increase the permeability of the intestinal epithelial barrier, leading to the entry of pathogenic antigens such as bacteria into the mucosa and blood circulation, causing inflammation [172].

Regulation of Immune Cells
CD4 + T cells can differentiate into Th1, Th2, Th17, and Treg cells in response to different cytokine stimuli [173]. Previous studies have shown that the pro-inflammatory effects of Th17 cells can be antagonized by Treg cells, producing the anti-inflammatory cytokines IL-10 and TGF-β [174]. Conversely, Treg can alleviate colitis by down-regulating Th1 and Th17 through IL-10 and TGF-β [175]. In addition, differentiation of both Treg and

Regulation of Immune Cells
CD4 + T cells can differentiate into Th1, Th2, Th17, and Treg cells in response to different cytokine stimuli [173]. Previous studies have shown that the pro-inflammatory effects of Th17 cells can be antagonized by Treg cells, producing the anti-inflammatory cytokines IL-10 and TGF-β [174]. Conversely, Treg can alleviate colitis by down-regulating Th1 and Th17 through IL-10 and TGF-β [175]. In addition, differentiation of both Treg and Th17 cells requires TGF-β to induce Foxp3 and RORγt. Already-differentiated Treg cells stimulated by IL-6 can inhibit Foxp3 expression and release IL-17, which in turn induces cell differentiation into Th17 cells [176]. Th17/Treg cells remain in balance under normal conditions, and once imbalanced, especially when Th17 cells are overrepresented, they can be reduced to Th17 cells. In particular, an excessive increase in Th17 cells can lead to intestinal mucosal damage and inflammatory bowel disease. Therefore, maintaining the homeostasis of Th17/Treg cells is important to prevent the development of UC.
Paeoniflorin 12 and vitexin 6 can exert anti-inflammatory effects by reducing TLR4 expression and blocking the TLR4/NF-κB signaling pathway [51,73]. Baicalin 2 can reduce the expression of TLR2, TLR4, and TLR9 and inhibit NF-κB by blocking MyD88 signaling activation, thus inhibiting the production of inflammatory factors and exerting a protective effect [61] (Figure 6). TLRs are recognition factors that initiate inflammatory responses and immune responses. When activated, they bridle MyD88 protein for signaling and promoting the expression of related inflammatory factors, exacerbating intestinal inflammation. Previous studies have demonstrated that the TLRs/MyD88/NF-κB signaling pathway plays an important role in UC [51,61,73].
Paeoniflorin 12 and vitexin 6 can exert anti-inflammatory effects by reducing TLR4 expression and blocking the TLR4/NF-κB signaling pathway [51,73]. Baicalin 2 can reduce the expression of TLR2, TLR4, and TLR9 and inhibit NF-κB by blocking MyD88 signaling activation, thus inhibiting the production of inflammatory factors and exerting a protective effect [61] (Figure 6). PPARr is a member of the nuclear receptor superfamily, most of which are liganddependent transcriptional activators. The anti-inflammatory activity of activated PPARγ is mediated through inhibition of NF-κB activity, leading to a reduction in the expression of inflammatory factors and exerting anti-inflammatory effects [88,94].
Glycyrrhizin 15, convallatoxin 20, and naringin 7 were all able to inhibit the expression of NF-κB and other inflammatory factors by increasing the expression of PPARγ, thereby reducing colonic mucosal inflammation and improving experimental colitis [74,88,94] ( Figure 6).

Inhibition of Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptors (NLRs)
NOD-like receptor protein 3 (NLRP3) inflammasomes in NLRs are important regulators of intestinal homeostasis. Previous studies have shown that NLRP3 can improve experimental colitis by down-regulating IL-1β levels, and therefore, NLRP3 inflammasome is essential in the pathogenesis of UC.
Studies have shown that naringin 7 can exert anti-UC effects by down-regulating the expression of NLRP3 inflammasome [74]. Furthermore, in LPS-induced macrophages RAW264.7, salidroside 10 was similarly able to exert anti-inflammatory effects by downregulating NLRP3 inflammasome excitation and apoptosis [79] (Figure 6). 6.7. Regulating Signal Transduction 6.7.1. Inhibition of the NF-κB Pathway Activation of NF-κB is a key step in the activation and proliferation of the inflammatory response in enteritis [51]. As a heterodimer complex of (p50/p65), NF-κB is regulated by IκB and IKK. Activated in response to external stimuli, IKKs phosphorylates the inhibitory IκB protein. Activated NF-KB is then transferred to the nucleus, where it binds to target DNA elements and encodes multiple inflammatory mediators.

Inhibition of the MAPK Pathway
The MAPK family consists of three main members: JNK, p38MAPK, and ERK [86]. ERK is mainly activated by mitogen. p38MAPK can induce the expression of inflammatory factors such as TNF-α, ILs, and IFN-γ as well as COX-2 by mediating the activation of NF-κB [177]. JNK phosphorylates the transcription factor c-JNK and induces the production of related inflammatory factors that trigger UC. In addition, JNK activates the transcription factor STAT3 and the non-transcription factor Bcl-2, which play an important role in the development of UC [178].

Inhibition of the Nrf2/HO-1 Pathway
The transcription factor Nrf2 is the most important transcription factor against oxidative stress and maintains mucosal homeostasis by inhibiting the production of excess ROS. When activated, Nrf2 is phosphorylated, leading to increased expression of antioxidant genes such as SOD, NQO1, CAT, GSH-Px, and HO-1 [50,85].
Asperuloside 13 can reduce DSS-induced oxidative stress and inflammation in mouse colon tissue by activating the Nrf2/HO-1 signaling pathway; increasing the expression of Nrf2, HO-1, and NQO-1 proteins; and down-regulating p65 levels [85]. Hyperoside 3 was also able to ameliorate the inflammatory response and apoptosis in experimental colitis by activating the Nrf2 signaling pathway [66]. In vitro, experiments have also shown that polydatin 11 can exert anti-inflammatory effects by inhibiting MAPK and NF-κB inflammatory signaling pathways and activating AKT/Nrf2/HO-1/NQO1 signaling pathway [50] (Figure 6).

Inhibition of Other Related Pathways
The pathogenesis of UC also involves the JAK-STAT, PI3K/AKT, Notch, and Shh pathways. Through in vivo and vitro experiments of UC, polydatin 11 was able to specifically block the JAK/STAT3 signaling pathway and inhibit the differentiation of Th17 cells to improve intestinal inflammation [81]. In TNBS-induced colitis, baicalin 2 was able to play a protective role in colitis by inhibiting the PI3K/AKT pathway [62]. Astragaloside IV 16 and aloin A 21 can effectively inhibit DSS-induced inflammatory damage in colon tissue by inhibiting the Notch signaling pathway and reconstructing the colonic mucosa [90,95]. Oxidative stress and epithelial cell apoptosis in the gastrointestinal tract are associated with the Shh pathway, and polydatin 11 may inhibit experimental colitis by modulating the Shh signaling pathway [47].

Conclusions and Outlook
A large number of review papers discuss the possible application of various extracts from natural products as well as pure biologically active substances in medicine [179][180][181][182].
Pure bioactive substances include synthetic drugs and pure natural substances. The decisive factor for the dominance of pure bioactive substances in modern medicine is the ease of drug administration and clinical pharmacological evaluation. Synthetic drugs have been widely used in clinical practice, but there are many side effects as well as resistance and drug-induced diseases; in addition, the development cycle of synthetic drugs is long, the investment is large, and the enterprises often cannot bear it.
With the progress of science, people's awareness of self-care is enhanced, the understanding of natural medicine is deepened, and the desire to return to nature is rising, so the demand for natural medicine is increasing [183].
Natural products are the largest pool of biologically active substances on Earth [179]. The bioactive compounds derived from natural products, especially medicinal plants, have emerged as new treatments for a variety of diseases. Natural products with biodiversity and chemical diversity, especially higher plants, will always be the most reliable source of leads for the development of new drugs [13]. In addition, the success rate of the development of new drugs by synthetic substances is extremely low, while the success rate of the development of new drugs by natural products from plants is much higher, the development time is greatly shortened, and the financial and human investment is also reduced accordingly.
Despite the great potential of natural products in the treatment of diseases, there are other issues that need to be addressed, such as the extraction, isolation, and standardization of derived compounds as well as their effective treatment modalities. In addition, some natural ingredients have low activity, a narrow antibacterial spectrum, strong drug resistance, poor stability, or serious side effects, and the corresponding technology should be used for structural modification to overcome their defects. Therefore, much research is needed before any natural product can be used as a treatment [13].
The extraction of active ingredients from natural products is an important source of new drug discovery. Understanding the mechanism of action of drugs helps to obtain the best clinical treatment drugs. This manuscript reviews 21 glycosides with relatively clear anti-inflammatory effects and mechanisms of action to provide new insights and ideas for the discovery of new drugs for the treatment of UC.
Glycosides have a wide range of pharmacological effects, including antioxidant, analgesic, antipyretic, anti-hypertensive, anti-tumor, and neuroprotective effects in addition to anti-inflammatory effects [71,[113][114][115][116][117]. In this review, we found that glycosides can improve UC symptoms and play a role in the prevention and treatment of UC by inhibiting inflammatory response, reducing oxidative stress and anti-apoptosis, inhibiting abnormal immune response, and regulating signal pathway transduction (Figure 7). The glycosides in this review mainly include flavonoids, phenols, terpenes, etc., which can exert anti-inflammatory effects by inhibiting the expression of inflammatory-related factors and reducing oxidative stress. The main mechanisms include NF-κB, MAPK inflammatory signaling pathways, and the Nrf2/HO-1 signaling pathway. Astragaloside IV 16 and aloin A 21 can inhibit the colonic inflammatory response by modulating the Notch signaling pathway. Polydatin 11 was also able to reduce the inflammatory response by acting on JAK/STAT3 and Shh signaling pathways. Baicalin 2 can play a protective role in colitis by inhibiting the PI3K/AKT pathway. In addition, the intestinal flora also plays an important role in the pathogenesis of UC, but there are few studies on glycosides in this regard, which need further study. Meanwhile, glycosides are also worthy of further study in the prevention and treatment of UC-related carcinogenesis. modulating the Notch signaling pathway. Polydatin 11 was also able to reduce the inflammatory response by acting on JAK/STAT3 and Shh signaling pathways. Baicalin 2 can play a protective role in colitis by inhibiting the PI3K/AKT pathway. In addition, the intestinal flora also plays an important role in the pathogenesis of UC, but there are few studies on glycosides in this regard, which need further study. Meanwhile, glycosides are also worthy of further study in the prevention and treatment of UC-related carcinogenesis.  UC is a complex disease, and although we have identified a strong relationship between glycosides and UC, there are still many issues to be resolved. Firstly, oral bioavailability is poor, and glycosides must be hydrolyzed by intestinal enzymes or microflora before they can be absorbed. Secondly, glycosides are unstable and readily hydrolyzed by acids, bases, and enzymes. It has been found that only 10-15% of the glycosides are absorbed in the small intestine, with the remaining glycosides being metabolized by microorganisms in the large intestine to form small molecules, so it is doubtful whether it is the broken-down glycosides and their metabolites or the original glycoside molecules that work in the body [184][185][186]. Thirdly, the side effects of glycosides and the pharmacological control of UC complications are not fully understood.
In summary, these glycosides are valuable candidates for the prevention and treatment of UC even taking into account the problems mentioned above. Therefore, it is urgent to study the pharmacokinetic characteristics of natural-product-isolated glycosides and establish their dose-pharmacology-toxicology relationship. Further clinical studies are essential to prove the effective role of glycosides in the prevention and treatment of UC. Therefore, future research must explore the targets and molecular mechanisms of glycosides, combine laboratory anti-UC studies with clinical practice, test the reliability of glycosides against UC, and promote their use in the practical prevention and treatment of UC.

Data Availability Statement:
The data that support the findings of this study are available from the corresponding author upon reasonable request.

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