
==== Front
J Pharm Anal
J Pharm Anal
Journal of Pharmaceutical Analysis
2095-1779
2214-0883
Xi'an Jiaotong University

S2095-1779(24)00034-0
10.1016/j.jpha.2024.01.014
100946
Review Paper
Natural compounds improve diabetic nephropathy by regulating the TLR4 signaling pathway
Wu Jiabin 1
Li Ke 1
Zhou Muge
Gao Haoyang
Wang Wenhong 13595606803@163.com
∗∗
Xiao Weihua xiao_weihua@163.com
∗
Shanghai Key Lab of Human Performance, Shanghai University of Sport, Shanghai, 200438, China
∗ Corresponding author. xiao_weihua@163.com
∗∗ Corresponding author. 13595606803@163.com
1 Both authors contributed equally to this work.

06 2 2024
8 2024
06 2 2024
14 8 1009469 9 2023
12 12 2023
31 1 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Diabetic nephropathy (DN), a severe complication of diabetes, is widely recognized as a primary contributor to end-stage renal disease. Recent studies indicate that the inflammation triggered by Toll-like receptor 4 (TLR4) is of paramount importance in the onset and progression of DN. TLR4 can bind to various ligands, including exogenous ligands such as proteins and polysaccharides from bacteria or viruses, as well as endogenous ligands such as biglycan, fibrinogen, and hyaluronan. In DN, the expression or release of TLR4-related ligands is significantly elevated, resulting in excessive TLR4 activation and increased production of proinflammatory cytokines through downstream signaling pathways. This process is closely associated with the progression of DN. Natural compounds are biologically active products derived from natural sources that have advantages in the treatment of certain diseases. Various types of natural compounds, including alkaloids, flavonoids, polyphenols, terpenoids, glycosides, and polysaccharides, have demonstrated their ability to improve DN by affecting the TLR4 signaling pathway. In this review, we summarize the mechanism of action of TLR4 in DN and the natural compounds that can ameliorate DN by modulating the TLR4 signaling pathway. We specifically highlight the potential of compounds such as curcumin, paclitaxel, berberine, and ursolic acid to inhibit the TLR4 signaling pathway, which provides an important direction of research for the treatment of DN.

Graphical abstract

Image 1

Highlights

• TLR4 plays an important role in the development of diabetic nephropathy.

• TLR4-mediated signaling pathways can be affected by many natural compounds.

• Multiple natural compounds can improve diabetic nephropathy by affecting TLR4.

Keywords

Diabetic nephropathy
Toll-like receptor 4
Natural compounds
Inflammation
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pmc1 Introduction

Due to the increasing number of elderly individuals and changing ways of life, diabetes has emerged as a significant chronic illness on a global scale. As established through extensive surveys, diabetes affected over 500 million individuals worldwide in 2021, accounting for more than 10.5% of the adult population [1]. Chronic hyperglycemia can lead to various complications, among which diabetic nephropathy (DN) is a prevalent microvascular complication in diabetic patients. Approximately 30%–40% of patients diagnosed with either type 1 or type 2 diabetes will encounter DN and ultimately advance to end-stage renal disease [2]. DN has emerged as a subject of significant interest in the field of public health, thereby necessitating the exploration of innovative therapeutic approaches.

The latest research has elucidated the intricate pathophysiological mechanisms underlying DN, which involve multiple factors, such as inflammation, oxidative stress, autophagy, apoptosis, and mitochondrial dysfunction. These factors can act independently or in conjunction to inflict damage on the kidneys [3]. In recent times, there has been a growing emphasis on the inflammatory response observed in DN, presenting opportunities for the development of innovative therapeutic interventions targeting specific inflammatory mediators [4]. The innate immune response plays a pivotal role in promoting the inflammatory process and contributing to the onset of DN [5]. Toll-like receptors (TLRs), belonging to a class of pattern-recognition receptors present in the innate immune system, serve as the body's initial defense mechanism against pathogenic invasion, playing a crucial role in protecting against external threats. TLRs recognize specific ligands, including pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), triggering a series of signaling pathways that facilitate a rapid immune response and subsequent initiation of inflammation [6].

Toll-like receptor 4 (TLR4), among the initial members of TLR discovered and investigated, has been linked to the inflammatory mechanism in numerous DN patients [7]. TLR4 is present in diverse renal cells and experiences considerable upregulation in the context of diabetes [8]. The increased expression of TLR4 can activate multiple inflammatory pathways and stimulate the secretion of inflammatory cytokines, ultimately leading to kidney injury in individuals with diabetes.

Natural compounds are bioactive substances derived from natural sources that have therapeutic potential due to their antioxidant, anti-inflammatory, or antifibrotic properties [9]. Many studies have been conducted on the potential of natural compounds to alleviate DN by targeting the TLR4 signaling pathway. The main objective of this review is to provide a summary of the role of TLR4 in DN and discuss the natural compounds that have been found to regulate this pathway and have the potential to alleviate DN. This research is valuable because it offers new perspectives and insights into developing innovative treatments for DN.

2 Inflammatory pathogenesis of DN

DN is a clinical syndrome that is defined by the presence of persistent albuminuria and a gradual deterioration of kidney function [10]. It is considered as the most prevalent type of kidney disease among individuals with diabetes. The progression of DN is marked by several pathological changes, including mesangial cell expansion, glomerular basement membrane (GBM) thickening, glomerular hypertrophy, podocyte loss, glomerulosclerosis, and tubulointerstitial fibrosis. These changes contribute to water and sodium retention, increased blood pressure, proteinuria, and a decreased glomerular filtration rate [11]. Based on the most recent research, metabolic disorders, inflammation, oxidative stress, and changes in blood flow are considered as key factors in the onset and progression of DN [12]. An increasing amount of scientific literature supports the notion that inflammation plays a vital role in the pathological mechanisms underlying DN. Moreover, it is firmly established that the innate immune system, closely intertwined with the inflammatory response, significantly influences the development and progression of DN.

The innate immune pathogenesis of DN is complex and involves the interaction of multiple pathways. In diabetic patients, hyperglycemia, dyslipidemia, and advanced glycation end products (AGEs) can cause renal cell damage or death, releasing intracellular DAMPs into the extracellular milieu. Pattern recognition receptors (PRRS) recognize these DAMPs, which function as crucial “danger signals” [13]. Moreover, cell surface receptors associated with the complement system can be activated by AGEs [14]. Activation of these receptors induces an inflammatory response in renal cells, producing a variety of inflammatory mediators, such as cytokines, chemokines, and adhesion molecules [15]. Subsequently, these mediators can recruit and activate bone marrow-derived monocytes, which differentiate into inflammatory macrophages, leading to an inflammatory cascade response of macrophage infiltration and amplification in the kidney [16]. As various inflammation-related signaling pathways are activated, persistent chronic inflammation eventually leads to irreversible fibrosis and organ failure [17] (Fig. 1).Fig. 1 Inflammatory pathogenesis of diabetic nephropathy (DN). The release of damage-associated molecular patterns (DAMPs) by renal cells in the diabetic setting activates various inflammation-related signaling pathways leading to DN. AGEs: advanced glycation end products; PRRS: pattern recognition receptors; NF-κB: nuclear factor kappa-B; MAPK: mitogen-activated protein kinase; TGF-β: transforming growth factor-β; GBM: glomerular basement membrane.

Fig. 1

3 TLR4 introduction

TLRs are a group of receptors that recognize patterns in the innate immune system [18]. Activation of these receptors can occur through endogenous ligands, resulting in noninfectious inflammation [19], or exogenous ligands, which trigger the innate immune defense against pathogenic infections [20]. TLR4, the initial TLR-related protein identified in humans [21], is located on the surface of cells and is a vital member of the TLR family. It performs a pivotal function in signaling immune and inflammatory responses within the body.

3.1 TLR4 structure and distribution

TLR4, a transmembrane receptor of type 1, comprises three sections: the domain located outside the cell, the domain spanning the cell membrane, and the domain situated within the cell [22]. The extracellular domain functions to identify various ligands through its leucine-rich repeat units, thereby playing a critical role in ligand recognition by TLR4. Alterations in the spatial configuration of this domain can affect the detection of PAMPs and DAMPs. The intracellular domain of TLR4 demonstrates exceptional conservation, exhibiting significant similarity to the intracellular region of the interleukin (IL)-1 receptor (IL-1R), and consequently, it is commonly denoted as the Toll-interleukin 1 receptor (TIR) region [23]. Within the TIR domain is a homologous region comprising three conserved cassettes that play a crucial role in signaling. When TLR4 binds to its specific ligand, it initiates signal transduction from the TIR region and this leads to the recruitment of downstream signaling molecules, which are involved in the inflammatory cascade [24].

TLR4 is found in various cell types and is widely distributed. It is present not only in macrophages and dendritic cells, which are innate immune cells, but also in adaptive immune cells such as B and T cells [25,26]. In the kidney, TLR4 is expressed in endothelial cells, tubular epithelial cells, and glomerular mesangial cells [27,28]. Furthermore, TLR4 expression has been observed in podocytes [29].

3.2 Ligands of TLR4

Exogenous PAMPs and endogenous danger signal DAMPs are two types of molecules that play important roles in innate immunity [30]. PAMPs are essential functional components of microorganisms that enable host cells to distinguish themselves from nonself cells and activate signaling pathways associated with innate immunity [31]. DAMPs, on the other hand, are substances released into the intercellular or blood circulation after tissues or cells are stimulated by factors such as injury and infection [32]. Both PAMPs and DAMPs can be recognized as ligands by TLR4, triggering an immune response.

A variety of endogenous and exogenous ligands associated with TLR4 have been identified and reported, such as lipopolysaccharides (LPS) from Gram-negative bacterial cell walls and low-density lipoproteins that can transport cholesterol [33,34]. Some of these ligands play a role in the development of DN, which occurs under conditions such as hyperglycemia, hypoxia, and dyslipidemia [35]. These conditions cause the upregulation of expression and release of several endogenous ligands of TLR4. These ligands include proteins such as high mobility group box 1 (HMGB1) [36], biglycan [37], heat shock protein (HSP) 60 [38], HSP70 [39], and S100 calcium-binding protein A8 (S100A8) [40]. Additionally, the degradation or accumulation of components of extracellular matrix (ECM) remodeling, such as fibronectin [41], hyaluronan [42], and heparan sulfate [43], are also ligands of TLR4. The interaction between these ligands and TLR4 activates a downstream signaling pathway, facilitating the inflammatory response.

3.3 TLR4 signaling pathway

The TLR4 signaling pathway is activated upon binding to ligands, leading to the induction of immune-inflammatory responses. However, it is important to note that the relevant signaling pathways are quite complex. Current studies suggest that TLR4 is involved in two major signaling pathways that induce immune inflammatory responses: the myeloid differentiation factor 88 (MyD88)-dependent pathway and the MyD88-independent pathway [44,45] (Fig. 2).Fig. 2 The Toll-like receptor 4 (TLR4) signaling pathway. TLR4 induces an immune-inflammatory response through two major signaling pathways: the myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways. TIRAP: Toll-interleukin 1 receptor (TIR) domain-containing adapter protein; IRAK4: interleukin (IL)-1 receptor-associated kinase 4; TRAF6: tumor necrosis factor receptor-associated factor 6; MAPK: mitogen-activated protein kinase; IKK: inhibitory kappa B kinase; IκB: inhibitory kappa B; NF-κB: nuclear factor kappa-B; AP-1: activator protein-1; TRIF: TIR domain-containing adaptor inducing interferon (IFN)-β; TRAM: TRIF-related adaptor molecule; RIP1: RIP1: receptor-interacting protein-1; TBK1: TRAF family member-associated NF-κB activator (TANK)-binding kinase 1; IRF3: IFN regulatory factor 3.

Fig. 2

3.3.1 The MyD88-dependent pathway

The pathway known as the MyD88-dependent mechanism encompasses two adaptor proteins, MyD88 and TIR domain-containing adapter protein (TIRAP). These proteins bind to the TIR domain found within the cytoplasmic region of TLR4. Through this interaction, IL-1 receptor-associated kinase 4 (IRAK4) is recruited and activated. Consequently, IRAK4 phosphorylates IRAK1 and recruits tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) [46]. Subsequently, the IRAK1-TRAF6 complex is formed, facilitating the activation of downstream inhibitory kappa B kinase (IKK) and mitogen-activated protein kinase (MAPK) pathways [47]. IKK functions as an enzyme complex composed of IKKα and IKKβ, serving alongside a regulatory subunit known as nuclear factor kappa-B (NF-κB) essential modulator or IKKγ. The primary role of IKK involves phosphorylating inhibitory kappa B (IκB) proteins, leading to their degradation. Consequently, this degradation enables the translocation of NF-κB, a transcription factor, into the nucleus [48]. The NF-κB family of transcription factors comprises five members: p65 (REL-A), REL-B, c-REL, p50, and p52. These members possess the ability to interact with each other, forming distinct heterodimers or homodimers. Among these combinations, the p65/p50 heterodimer is the most commonly activated [49]. In the absence of stimulation, IκB inhibits NF-κB activity within the cytoplasm. However, upon TLR4 activation, IKK phosphorylates and leads to the degradation of IκB, liberating the p65 heterodimer [50]. Consequently, the p65 heterodimer translocates into the nucleus and initiates the regulation of various inflammation-related genes, including cytokines, chemokines, and other effectors of innate immune responses [51]. An alternative pathway involves the activation of MAPK by TLR4, resulting in phosphorylation of activator protein-1 (AP-1), a transcription factor. This phosphorylation enables AP-1 to translocate into the nucleus, where it regulates the expression of diverse inflammation-related genes [52].

3.3.2 The MyD88-independent pathway

The pathway that is independent of MyD88 involves the recruitment and activation of TRAF3 through the TIR domain-containing adaptor inducing interferon (IFN)-β (TRIF) and TRIF-related adaptor molecule (TRAM). This activation results in the activation of TRAF family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1) and IKKε, which phosphorylate IFN regulatory factor 3 and stimulate the production of IFN-β [53,54]. Moreover, TRIF and TRAM can interact with either receptor-interacting protein-1 (RIP1) or TRAF6 to enhance MAPK signaling and activate NF-κB [55].

3.4 Role of TLR4 in DN

TLR4, the first discovered and most extensively studied TLR, has been implicated in the development of various renal diseases, such as acute kidney injury [56], renal ischemia-reperfusion injury [57], and glomerulonephritis [58]. In the perpetuation of inflammation in DN, TLR4 plays a crucial role [59]. Within the diabetic environment, the expression of TLR4 and its ligands in the kidney greatly increases due to hyperglycemia, dyslipidemia, and hypoxia. This, in turn, promotes the progression of inflammation. In a mouse model of DN, Kim et al. [60] demonstrated that the upregulation of HMGB1, an endogenous ligand of TLR4, in glomerular and tubular epithelial cells resulted in heightened NF-κB activity. Similarly, Kaur et al. [61] discovered that high glucose (HG) levels stimulated the secretion of TLR4, NF-κB, IL-6, transforming growth factor-β (TGF-β), and monocyte chemotactic protein-1 (MCP-1) from glomerular mesangial cells. This suggests that TLR4 may have a close association with abnormal glomerular mesangial cell function and the development of inflammation. Similarly, Takata et al. [62] found that hyperglycemia in diabetic patients resulted in increased TLR4 protein expression in glomerular capillary endothelial cells. In the diabetic setting, cytokines produced by glomerular endothelial cells through the TLR4 signaling pathway may enable the production of ECM proteins by mesangial cells. In addition to its close association with glomeruli, TLR4 expression is also significantly activated in podocytes in a HG environment. This activation is accompanied by an upregulation of downstream cytokines (TNF-α), chemokines (MCP-1 and C−X−C motif chemokine 10 (CXCL10)), and profibrotic proteins (TGF-β and fibronectin), suggesting that TLR4 activation in the diabetic kidney may contribute to inflammation, podocyte injury, and interstitial fibrosis [63]. Furthermore, Lin et al. [64] observed increased TLR4 expression in the renal tubules of DN patients, along with the upregulation of endogenous ligand HMGB1 levels and downstream IL-6 and MCP-1 expressions in proximal tubular cells, suggesting a role for the TLR4-mediated pathway in eliciting tubulointerstitial inflammation. Mudaliar et al. [65] similarly discovered that HG stimulation increased TLR4 expression and HMGB1 release in the proximal tubule, resulting in an inflammatory response.

These studies suggest that the amplified expression of TLR4 in the kidneys of individuals with diabetes significantly contributes to kidney damage, a conclusion supported by additional investigations into the inhibition of TLR4. In their study, Lin et al. [66] observed that the application of the inhibitor CRX-526, which blocks TLR4, had a beneficial effect on the kidneys of mice with DN that lacked endothelial nitric oxide synthase. Cha et al. [67] conducted research that demonstrated the nephroprotective properties of the TLR4 signaling pathway inhibitor GIT27 in a mouse model of DN. This intervention effectively alleviated insulin resistance, as well as inducing mechanisms combating glomerulosclerosis. Furthermore, Jialal et al. [68] presented evidence indicating that the knockout of the TLR4 gene led to the downregulation of renal inflammation, fibrosis, and podocytopathy in mice with DN.

In summary, TLR4 in renal cells is significantly upregulated in the diabetic setting, thereby participating in the development and progression of DN through various mechanisms, including inflammation, while the use of TLR4 antagonists, TLR4 signaling pathway inhibitors, and knockdown of TLR4 genes is protective of the kidney in the diabetic setting. This suggests that TLR4 can be a molecular target for DN treatment (Fig. 3).Fig. 3 The role of Toll-like receptor 4 (TLR4) in diabetic nephropathy (DN). In DN, the expression of TLR4 with related ligands is significantly upregulated in renal cells, and the expression of related inflammatory factors is increased, leading to renal injury. GBM: glomerular basement membrane; HMGB1: high mobility group box 1; MCP-1: monocyte chemotactic protein-1; TNF-α: tumor necrosis factor-α; TGF-β: transforming growth factor-β; CXCL10: C−X−C motif chemokine 10; IL-6: interleukin-6.

Fig. 3

4 Natural compounds improve DN by regulating the TLR4 signaling pathway

Natural compounds can positively impact human health by influencing the expression of different cytokines, offering potential therapeutic benefits [69]. In the treatment of DN, numerous natural compounds show promise by modulating inflammation [70]. One significant mechanism by which natural compounds exhibit anti-inflammatory effects is through the regulation of TLR4-related signaling pathways [71], thereby opening up new possibilities for therapeutics. This review will focus on several natural compounds that can enhance the therapeutic effects of DN by modulating the TLR4 signaling pathway. We have summarized them in Fig. 4 and Table S1 [[72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102]].Fig. 4 Natural compounds that improve diabetic nephropathy (DN) by modulating the Toll-like receptor 4 (TLR4) signaling pathway. DMDD: 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione.

Fig. 4

4.1 Alkaloids

Alkaloids are a group of natural compounds primarily composed of basic nitrogen atoms. They are predominantly found in plants and serve as active ingredients in numerous herbal medicines [103]. Alkaloids possess significant antitumor, anti-inflammatory, antibacterial, antiviral, and antidiabetic properties, making them valuable for treating DN [104,105].

4.1.1 Berberine

Berberine, an isoquinoline alkaloid, is derived from plants such as Coptidis rhizome and Berberis. It possesses various pharmacological activities [106], including anti-inflammatory [107], antioxidant [108,109], antitumor [110], antiarrhythmic, hypolipidemic, and hypoglycemic effects [111]. Berberine has a well-established history of clinical use supported by research for treating different diseases [112]. In recent studies, it has been found that berberine has displayed protective effects on the kidneys in cases of DN [113]. Zhu et al. [72] discovered that berberine effectively suppressed the activation of the TLR4/NF-κB inflammatory signaling pathway in both DN rats and podocytes treated with HG. Specifically, berberine successfully reduced the expression and secretion of various inflammatory factors, such as TNF-α, IL-1β, IL-6, and MCP-1, both in the renal cortex and throughout the body. Furthermore, it inhibited the expression of proteins associated with the TLR4/NF-κB pathway, including TLR4, p65, and IκBα. These actions led to a decrease in podocyte apoptosis, thickening of the glomerular basement membrane, and an enhancement in renal function. Consequently, it alleviated podocyte injury in models of DN.

4.1.2 Matrine

Matrine, a natural alkaloid isolated from Sophora flavescens Ait., exhibits a wide range of pharmacological effects, including anticancer [114], antiviral [115], anti-inflammatory [116], and anti-aging effects [117]. It has been extensively studied in various types of tumors, heart disease, spondylitis, and acute kidney injury in humans [118]. Matrine improves cardiac function by affecting TLR4-related inflammatory pathways [119]. In addition, matrine inhibits the release of HMGB1 from glomerular podocytes in an HG environment and prevents its binding to TLR4. The activation of NF-κB signaling and the production of proinflammatory factors such as IL-1β, IL-6, and TNF-α are effectively hindered by this action. As a result, the damage and inflammatory response of the podocytes is ultimately decreased. These findings suggest the therapeutic potential of matrine in treating DN [73].

4.2 Flavonoids

Flavonoids are a family of compounds formed by two benzene rings interconnected by three carbon atoms that are widely found in plants. Flavonoids are now recognized as essential ingredients in various nutraceuticals and pharmaceutical applications due to their antioxidant, anti-inflammatory, and anticancer properties [120]. Additionally, certain flavonoids have shown the potential to improve renal function in individuals with DN through their influence on the TLR4 signaling pathway.

4.2.1 Baicalin

Baicalin, a flavonoid derived from the root of Scutellaria baicalensis, has been discovered to possess anti-inflammatory [121], antioxidant [122], and antifibrotic activities [123]. It is frequently utilized in traditional Chinese medicine and pharmacological studies [124]. Researchers have shown that baicalin has the ability to increase the expression of microRNA-124 (miR-124), which specifically targets TLR4 in the proximal tubular epithelial cells of DN mice. This action ultimately inhibits the TLR4/NF-κB signaling pathway, leading to the suppression of inflammatory factors as well as the expression of type IV collagen and fibronectin in HG-stimulated human kidney 2 cells [74]. The results of these investigations suggest that baicalin offers a promising outlook as a potential therapeutic agent for preventing and managing DN through modulation of the miR-124/TLR4/NF-κB pathway.

4.2.2 Icariin

Icariin, a flavonoid derived from the leaves and stems of Herba epimedii, exhibits various pharmacological effects, including neuroprotective, cardioprotective, antiosteoporotic, anti-inflammatory, antioxidative stress, antidepressant, and antitumor activities [125]. In a study conducted by Qi et al. [75], it was demonstrated that icariin significantly ameliorated pathological damage in diabetic kidneys by directly inhibiting the activation of TLR4, reducing the phosphorylation of NF-κB p65, leading to a reduction in the expression of proinflammatory cytokines, such as TNF-α and IL-6, and ultimately exerting a protective effect on the kidneys of streptozotocin (STZ)-induced DN mice.

4.2.3 Astilbin

Astilbin, a flavonoid compound, is an active natural substance that can be commonly found in various herbs, including the rhizome of Smilax China L. (Smilaceae). Extensive research conducted on astilbin has revealed its numerous beneficial properties, such as its ability to display anti-inflammatory and immunoregulatory activities [126]. In the context of DN, astilbin has demonstrated its effectiveness in protecting human proximal tubular epithelial cells against autophagy and apoptosis induced by HG through the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway [127]. A notable study by Chen et al. [76] demonstrated that astilbin has the ability to directly inhibit the expression levels of factors related to the NF-κB signaling pathway in glomerular thylakoid HBZY-1 cells under HG conditions. These factors include TLR4, MyD88, IκBα, p65, and other NF-κB signaling pathway-related factors. The inhibition of these factors leads to a reduction in the secretion of inflammatory cytokines, specifically IL-6 and TNF-α. The decrease in inflammatory cytokines ultimately leads to the attenuation of inflammatory responses and the inhibition of excessive accumulation of ECM. Consequently, astilbin protects at the cellular level for the treatment of DN. These results suggest that astilbin can be used as a novel therapeutic agent for DN by inhibiting the TLR4/MyD88/NF-κB signaling pathway.

4.2.4 Puerarin

Puerarin, a bioactive isoflavone glucoside extracted from Pueraria lobata [128], has been extensively studied for its various biological activities, such as its anti-inflammatory and antioxidant effects [129,130]. It has shown promising results in the treatment of DN, with studies demonstrating its ability to alleviate DN through mechanisms such as affecting podocyte autophagy [131], attenuating oxidative stress [132], and modulating apoptotic pathways [133]. Additionally, puerarin can ameliorate DN by inhibiting the overexpression of miRNA-140-5p. A significant correlation between miRNA-140-5p and TLR4 was demonstrated, with puerarin exerting an indirect impact on the TLR4/MyD88/NF-κB signaling pathway through the modulation of miRNA-140-5p. Consequently, this modulation influences the synthesis of proinflammatory cytokines such as TNF-α and IL-6 as well as the ensuing inflammatory reaction, reducing renal fibrosis and inflammatory injury of renal tissue [77].

4.3 Polyphenols

Phenolic compounds, a class of chemicals with aromatic rings and hydroxyl groups, are naturally abundant and known for their remarkable anti-inflammatory and antioxidant properties [134]. There is increasing evidence to suggest that polyphenols could significantly impact the treatment of DN [135]. These compounds effectively regulate the TLR4 signaling cascade response, leading to an improvement in DN.

4.3.1 Curcumin

Curcumin, a polyphenolic compound extracted from the roots of the Curcuma longa plant, exhibits a range of medicinal properties. These properties include anti-inflammatory, antioxidant, atherosclerotic, and anticancer effects [136]. According to the available research, curcumin may inhibit TLR4 and exert therapeutic effects in inflammatory, infectious, and immune-related diseases [137]. Sun et al. [78] demonstrated that the administration of curcumin diminishes the phosphorylation level of caveolin-1 at the Tyr14 position in renal tissues in a DN model induced by STZ. This reduction in caveolin-1 phosphorylation leads to the suppression of TLR4 activation and the subsequent NF-κB signaling pathway, ultimately resulting in the mitigation of the renal inflammatory response and fibrosis. Furthermore, these findings were further validated through in vitro experiments using podocytes treated with HG, in which curcumin caused a decrease in the expression levels of proinflammatory cytokines (such as IL-6 and TNF-α), TLR4, and caveolin-1 phosphorylation at the Tyr14 position. These outcomes signify that curcumin effectively hinders the TLR4/NF-κB signaling pathway by reversing the phosphorylation of caveolin-1 at the Tyr14 position, ultimately leading to the amelioration of DN.

4.3.2 Secoisolariciresinol diglucoside

Secoisolariciresinol diglucoside is a polyphenolic compound extracted from flaxseed [138]. It is well known for its positive effects on various health conditions, such as inflammation, oxidative stress, urinary system disorders, tumor progression, atherosclerosis, and diabetes [139]. Due to these beneficial properties, secoisolariciresinol diglucoside has the potential to be a natural treatment option for DN. One study demonstrated that secoisolariciresinol diglucoside has a significant impact on the expression level of HSP70, which is the endogenous ligand for TLR4, in renal tissues. This leads to the inhibition of the TLR4/NF-κB signaling pathway, resulting in decreased levels of proinflammatory factors such as IL-6, TNF-α, and IL-1β, as well as ECM components such as collagen I and fibronectin. Consequently, it effectively reduces renal inflammation and fibrosis. Researchers also found that this effect can be reversed by using an HSP70-specific inhibitor. These findings suggest that secoisolariciresinol diglucoside has the potential to improve DN by inhibiting the TLR4/NF-κB signaling pathway through the upregulation of HSP70 [79].

4.3.3 Ellagic acid

Ellagic acid, an organic compound found naturally in various soft fruits, nuts, and other plant tissues, exhibits multiple biological characteristics, including its ability to act as an antioxidant, anti-inflammatory agent, and anticancer compound [[140], [141], [142]]. Additionally, it shows great promise in terms of preventing and treating chronic diseases [143]. Studies have shown that ellagic acid effectively suppresses the release of HMGB1 in DN mice, hinders the specific interaction between TLR4 and HMGB1, and subsequently inhibits the phosphorylation and transcriptional activation of downstream signaling molecules such as IRAK4, TRAF6, IKK-β, and NF-κB through the MyD88-dependent pathway. This mechanism ultimately reduces oxidative stress levels and decreases the production of inflammatory factors in renal tissues. These findings suggest that ellagic acid possesses the capability to protect kidney function by impeding the HMGB1/TLR4/NF-κB pathway [80].

4.3.4 Tilianin

Tilianin, an extracted polyphenol flavonoid found in Dracocephalum moldavica L., is a naturally occurring compound. Its various properties include antioxidant, anti-inflammatory, and antidiabetic effects [[144], [145], [146]]. Over the past few years, tilianin has been widely recognized as a prominent natural compound. Its remarkable anti-inflammatory capacity has significantly contributed to its role in treating diabetes-related diseases [147]. Studies in diabetic rats have revealed that tilianin reduces the expression and activation of TLR4 in the kidney, thereby blocking its binding to MyD88, which in turn inhibits the activation of signaling molecules such as MyD88, TRAF6, IκBα, p38MAPK, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 2 (ERK2), and positively affects diabetes-induced renal dysfunction by its anti-inflammatory effects. In addition, tilianin has been shown to regulate oxidative stress by inhibiting nuclear factor erythroid 2-related factor 2-Kelch-like epichlorohydrin (ECH)-associated protein 1 (Nrf2-Keap1), which, together with the inhibition of the inflammatory pathway TLR4/MAPK/NF-κB, protects renal function in diabetic rats [81].

4.3.5 P-coumaric acid

P-coumaric acid is a phenolic compound commonly found in plants, either in free or conjugated form, with significant anti-inflammatory [148], antioxidant [149], and antidiabetic activities [150]. Several studies have demonstrated that P-coumaric acid exerts nephroprotective effects through multiple pathways [151,152]. In DN, P-coumaric acid plays a role in improving renal function through its effects on lipid metabolism [153], oxidative stress [154], and inflammation. According to a study by Zabad et al. [82], P-coumaric acid has been found to reduce TLR4 expression, increase superoxide dismutase activity, and decrease malondialdehyde content. This helps restore the oxidative/antioxidant balance in mice with DN. This compound also inhibits NF-κB activation and reduces the levels of renal IL-6 and TGF-β1, thereby preventing inflammation and collagen deposition.

4.4 Terpenoids

Terpenoids, derived from isoprene, are a group of compounds found in plants, fungi, algae, and sponges [155]. They exhibit diverse physicochemical properties and biological activities, making them promising candidates for managing DN [156].

4.4.1 Ursolic acid

Ursolic acid, a natural pentacyclic triterpene compound, is found in various medicinal plants, such as Mirabilis jalapa and Ligustrum lucidum Ait.. In recent years, this compound has gained significant attention due to its diverse clinical pharmacological effects, including anti-inflammatory, antitumor, and antifibrotic properties [[157], [158], [159]]. Ursolic acid significantly reduced the protein expression of TLR4, MyD88, and NF-κB in DN mice, inhibited the activation of the TLR4/NF-κB signaling pathway, reduced the levels of proinflammatory factors such as TNF-α, IL-1β, IL-6, and IL-18 in the kidneys, and attenuated the inflammatory response. Inhibitors of TLR4 can significantly reverse this effect, suggesting that ursolic acid can directly act on TLR4 to alleviate DN [83].

4.4.2 Artesunate

Artesunate is an artemisinin derivative extracted from the Chinese herb Artemisia annua, which is widely used clinically for the treatment of malaria and other diseases because of its significant antimalarial, antiviral, antitumor, and anti-inflammatory pharmacological effects [[160], [161], [162], [163]]. According to recent scientific research, the compound artesunate can hinder the activation of the TLR4/NF-κB signaling pathway. This is achieved by diminishing the expression of key proteins involved in this pathway, such as TLR4, MyD88, and NF-κB, as shown within a rat mesangial cell line induced by HG. Consequently, the activation of nucleotide-binding, oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) inflammatory vesicles is mitigated. Additionally, artesunate can decrease the levels of IL-1β and IL-6 in rat mesangial cell lines. This reduction effectively ameliorates both intracellular and extracellular inflammatory responses, oxidative stress, and ECM deposition [84].

4.4.3 Glycyrrhizin

Researchers have conducted extensive studies on glycyrrhizin, a triterpene compound attached to glycol, which is derived from the root of the Glycyrrhiza glabra plant, commonly known as licorice. This compound has gained attention for its potential anti-inflammatory, antioxidant, and antitumor properties [164]. Furthermore, in the field of diabetes, glycyrrhizin has been recognized for its significant medicinal value. It has been shown to inhibit the activity of the cytokine HMGB1, reduce the expression levels of receptor for AGE (RAGE) and TLR4, decrease the phosphorylation levels of ERK and p38 MAPK, block the translocation of NF-κB from the cytoplasm to the nucleus, and ameliorate renal injury and the inflammatory response in diabetic rats [165]. In addition, the role of glycyrrhizin in inhibiting the overexpression of HMGB1, TLR4, and NF-κB was also demonstrated in another diabetes experiment [85]. HMGB1, an endogenous ligand of TLR4, is known to be elevated in the diabetic environment and it triggers inflammation upon binding to TLR4 [166]. This suggests that glycyrrhizin indirectly modulates TLR4 through HMGB1, thereby regulating inflammation in DN.

4.4.4 Oleanolic acid

Oleanolic acid, a pentacyclic triterpenoid commonly found in plants, has gained significant attention for its various biological activities, including its anti-inflammatory, antioxidant, hypolipidemic, and hypoglycemic effects [167]. Studies have demonstrated that oleanolic acid can alleviate inflammation and oxidative damage in diabetic mice by exerting a hypoglycemic effect [168]. In DN, oleanolic acid has been found to reduce endoplasmic reticulum stress and oxidative stress, thereby ameliorating renal fibrosis [169]. Additionally, the administration of oleanolic acid effectively mitigated lipid accumulation in the kidneys and improved renal structural abnormalities in diabetic rats. Following the intervention of oleanolic acid in the renal tissue of diabetic rats, there was a significant increase in the expression levels of nephrin, adenosine monophosphate (AMP)-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Conversely, the expression levels of cluster of differentiation 68 (CD68), collagen-IV, TLR4, NF-κB, and TGF-β1 were reduced. These findings provide evidence of the potential of oleanolic acid to alleviate kidney injury in diabetic rats by modulating the AMPK/PGC-1α and TLR4/NF-κB signaling pathways [86].

4.4.5 Dandelion sterol

Dandelion sterol is a pentacyclic triterpenoid compound, which is one of the main active components isolated from the traditional Chinese medicinal herb dandelion (Taraxacium official). It has anti-inflammatory [170], antioxidant [171], and antitumor [172] effects. Previous studies have demonstrated that dandelion sterol exhibits antioxidant effects in diabetes [173], regulates the expression of TLR4 [174], and provides some protective effects on the kidneys [175]. In a study conducted by Tian et al. [87], it was discovered that dandelion sterols have the ability to enhance the expression of miR-140-5p in kidneys affected by DN. This enhanced expression of miR-140-5p ultimately leads to the inhibition of its target gene, TLR4, and subsequently inhibits the downstream NF-κB p65 signaling pathway. As a result of this inhibition, the secretion of various inflammatory factors, such as TNF-α, IL-1β, and IL-6, is reduced, ultimately resulting in the attenuation of both the inflammatory response and oxidative stress within the kidneys affected by DN.

4.4.6 Paclitaxel

Paclitaxel is a diterpenoid derived from the bark of the Taxus brevifolia tree [176]. It is currently a widely utilized natural anticancer agent with broad-spectrum effectiveness and low toxicity in treating different types of cancers [177]. Moreover, research has demonstrated the positive influence of paclitaxel on ameliorating renal fibrosis in diabetic mice [178]. According to research conducted by Son et al. [88], the utilization of paclitaxel can improve podocyte damage by alleviating endoplasmic reticulum stress, oxidative stress, inflammation, and fibrosis. Moreover, paclitaxel also plays a role in impacting the inflammatory response through the inhibition of inflammatory cytokines such as MCP-1, TNF-α, TNF-R2, and TLR4. This discovery emphasizes the potential therapeutic use of paclitaxel in the treatment of DN podocyte injury.

4.4.7 Oridonin

Oridonin, a renowned diterpenoid compound derived from the Chinese herb Rabdosia rubescens, has been extensively studied for its diverse pharmacological activities. These activities include antitumor, antibacterial, anti-inflammatory, and anti-aging properties [179]. Recent research has focused on the potential of oridonin to protect the kidney by modulating inflammation-related pathways such as the TLR4 signaling pathway [180,181]. In a study concerning DN, it was observed that oridonin suppressed the expression of TLR4 and inhibited the phosphorylation of IκBα, p65, and p38. Moreover, the DNA binding activity of NF-κB was substantially reduced. These notable outcomes suggest that the potential of oridonin to shield against diabetes-induced renal injury may arise from its anti-inflammatory properties and its ability to regulate the TLR4/p38-MAPK and TLR4/NF-κB signaling pathways [89].

4.5 Glycosides

Glycosides are composed of glucose entities bound to glycosides, which serve as the active ingredients in numerous traditional Chinese medicines. These compounds possess various pharmacological activities and demonstrate effective anti-inflammatory and antifibrotic properties [182]. Research indicates that certain glycosides can be utilized in the treatment of DN by influencing the TLR4 signaling pathway, which is associated with the inflammatory response.

4.5.1 Dioscin

Dioscin, a steroidal saponin, is derived from various vegetables and herbs and showcases properties of both anti-inflammation and antioxidants, making it a compound with great therapeutic potential [183,184]. Numerous studies have indicated that dioscin holds promise in the treatment of metabolic disorders, cancer, inflammation, and infection [185]. In the scope of DN, dioscin exhibits inhibitory effects against oxidative stress and apoptosis, improving both the quantity and quality of mitochondria [186]. Additionally, it possesses the ability to decrease the release of inflammatory cytokines, rendering the TLR4/NF-κB pathway inactive, thus relieving inflammation and enhancing kidney function. Conversely, experiments with TLR4-deficient mice revealed that the protective impacts of dioscin on renal function and the inflammatory response were hindered, implying that dioscin improves renal function through the TLR4 pathway [90].

4.5.2 Polydatin

Polydatin is a glycoside compound of resveratrol extracted from Polygonum cuspidatum that has excellent anti-inflammatory, antioxidant, and antifibrotic effects [187]. Studies have shown that polydatin may have a potential therapeutic role in various renal diseases, including acute kidney injury [188], lupus nephritis [189], and hyperuricemia [190]. In DN, polydatin reduces IκBα phosphorylation, p65 phosphorylation, and TLR4 protein levels, decreases the production of the inflammatory factors IL-1β, IL-6, and MCP-1, and inhibits the development of renal fibrosis and inflammatory responses. This effect can be observed simultaneously in vitro and in vivo, demonstrating that the nephroprotective effect of polydatin is, in part, attributable to the downregulation of the TLR4/NF-κB signaling pathway [91].

4.5.3 Paeoniflorin

Paeoniflorin, which is the key component of the paeony glycosides obtained from the dried root of Paeonia lactiflora Pall., a traditional Chinese herbal medicine from the Ranunculaceae plant family, has been discovered to possess noteworthy anti-inflammatory [191], immunomodulatory [192], and antioxidant effects [193]. In the context of DN, Zhang et al. [194] conducted a study revealing that paeoniflorin effectively hindered the activation of macrophages by repressing the expression of TLR4 signaling. Shao et al. [92] also found that paeoniflorin intervention and knockdown of TLR4 significantly downregulated CD68 expression and reduced macrophage activation and M1-type macrophage polarization, whereas paeoniflorin treatment was further found to inhibit the expression of MyD88-dependent and MyD88-independent downstream signaling pathways in the TLR4 knockdown group, which was accompanied by a decrease in the expression of TNF-α, IL-1β, MCP-1, and inducible nitric oxide synthase. This suggests that paeoniflorin can improve DN by affecting macrophages by inhibiting TLR4.

4.5.4 Catalpol

Catalpol, a compound derived from the roots of Rehmannia glutinosa, has exhibited diverse pharmacological properties, including antioxidant, anti-inflammatory, antiapoptotic, and antifibrotic effects [195]. It holds promise as a potential therapeutic agent for the treatment of diabetic conditions. Several studies have indicated that catalpol possesses a nephroprotective effect, which is closely associated with the reduction of proteinuria and injury to podocytes [196,197]. The mechanism of action behind this protective effect involves the suppression of reactive oxygen species production by inhibiting the enzyme nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX-4). In addition, catalpol can significantly downregulate the expression of TLR4 and MyD88, thus preventing IκBα phosphorylation and degradation and inhibiting NF-κB transnucleation and the activation of inflammatory responses. Catalpol also inhibits the p38 MAPK/NF-κB signaling pathway [93]. Collectively, these actions contribute to the safeguarding of renal function.

4.5.5 Picroside II

Picroside II, a glycoside belonging to the iridoid class, is present in the roots of Picrorhiza scrophulariiflora. It displays a diverse range of pharmacological activities. These activities encompass the reduction of oxidative stress [198], the inhibition of apoptosis [199], and the downregulation of inflammatory factor expression [200]. Picroside II has demonstrated its effectiveness in alleviating inflammation in various inflammatory disorders through distinct signal transduction pathways. In the context of DN, picroside II demonstrated its ability to suppress the expression of TLR4 and phosphorylated p65 and IκBα in renal tissues. Consequently, it resulted in the upregulation of IκBα expression while concurrently inhibiting the production of MCP-1, IL-1β, IL-6, and TNF-α. As a result, these findings suggest that picroside II has the potential to disrupt the signaling cascades of the TLR4/NF-κB pathway, effectively curtailing inflammatory responses and safeguarding against kidney injury in mice [94].

4.6 Polysaccharides

Natural polysaccharides are macromolecules that occur naturally in plants, fungi, and algae. These polysaccharides have been found to exhibit diverse and significant biological activities, such as antitumor, antioxidant, and antidiabetic effects [201]. In the search for treatments for DN, several natural polysaccharides have shown promising therapeutic potential, largely due to their ability to modulate TLR4.

4.6.1 Sanziguben polysaccharides

Sanziguben is a prescription compound created from a combination of four traditional Chinese herbs: Gynostemma pentaphyllum (Thunb.) Makino, Chinese Rosa laevigata Michx, Schisandra chinensis Fructus, and Phyllanthus emblica and Fructus. The Sanzigube formula contains abundant polysaccharides, which have been shown to possess anti-inflammatory properties and provide benefits to kidney function in mice with DN induced by a combination of a high-fat diet and low-dose STZ [202]. This polysaccharide was found to modulate the intestinal microbiota, reduce the abundance of Gram-negative bacteria (Aspergillus phylum, Klebsiella, and Shigella), and decrease LPS levels in DN mice. In addition, it inhibited the expression levels of TLR4, phospho-NF-κB p65, NLRP3, IL-18, and IL-1β, suggesting that Sanziguben polysaccharides can ameliorate DN by inhibiting LPS, a ligand of TLR4 [95].

4.6.2 Grifola frondosa polysaccharides

Grifola frondosa polysaccharides, the primary bioactive component of Grifola frondosa, a medicinal fungus known for its antitumor, antioxidant, and immunomodulatory properties [[203], [204], [205]], hold significant clinical and research potential. Research has demonstrated that Grifola frondosa polysaccharide could effectively improve glucose tolerance and insulin sensitivity, as well as directly inhibit the expression of TLR4 and reduce HG-induced renal tubular epithelial cell levels of p-p65 and p-IκBα. The alleviation of pathological changes in the early diabetic kidney through the inhibition of the activation of the TLR4/NF-κB signaling pathway suggests that it may provide a new therapeutic strategy for DN treatment [96].

4.6.3 Bupleurum polysaccharides

Bupleurum polysaccharides, derived from the roots of the medicinal plant Bupleurum, are bioactive compounds known for their anti-inflammatory and antioxidant properties [206]. These polysaccharides have shown potential benefits for diabetes by protecting pancreatic β-cells and hepatocytes from damage and dysfunction [207]. Additionally, research has revealed that Bupleurum polysaccharides regulate TLR4 expression to improve inflammation [208]. In a diabetic mouse model with renal injury induced by STZ, Bupleurum polysaccharide treatment significantly inhibited TLR4 and HMGB1 overexpression and significantly reduced NF-κB activity and the levels of the inflammatory cytokines IL-6 and TNF-α by inhibiting the activity of the HMGB1-TLR4 signaling pathway [97].

4.6.4 Cordyceps cicadae polysaccharides

Cordyceps cicadae polysaccharides are natural active components found in the insect pathogenic fungus Cordyceps cicadae. In recent years, these polysaccharides have gained attention due to their remarkable anti-inflammatory [209], antioxidant [210], and anti-aging properties [211]. They play a significant role in some metabolic diseases [212]. Studies have shown that Cordyceps cicadae polysaccharides regulate dysbiosis of intestinal flora by increasing the relative abundance and proliferative capacity of probiotics, reducing the LPS-induced TLR4/NF-κB inflammatory signaling pathway, inhibiting TGF-β1-induced fibroblast activation brought about by a reduction in the proinflammatory cytokines IL-1β, IL-6, and TNF-α, and protecting renal function [98].

4.6.5 Siraitia grosvenorii polysaccharides

Siraitia grosvenorii is a medicinal plant renowned for its pleasant, refreshing, and nonharmful flavor. It is widely utilized in treating ailments such as laryngitis, bronchitis, and gastrointestinal disorders [213]. From this remarkable plant, a polysaccharide can be extracted, possessing remarkable antioxidant properties [214], anticancer effects [215], and an ability to lower blood sugar levels [216]. Research has demonstrated that polysaccharides derived from Siraitia grosvenorii exhibit renoprotective properties against DN. Additionally, they possess the ability to hinder the activation of the TLR4/NF-κB pathway by reducing the messenger RNA (mRNA) and protein expression of TLR4 and NF-κB. As a result, the inflammatory response in a mouse model of DN was alleviated. Moreover, Siraitia grosvenorii polysaccharides contributed to the mitigation of oxidative stress in the same DN mouse model. This was accomplished by augmenting the production of superoxide dismutase and diminishing the production of cytokines (IL-6 and TNF-α) and malondialdehyde [99].

4.7 Others

In addition to the aforementioned natural compounds, other compounds, such as melatonin, umbelliferone, and 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD), also have positive effects on DN by modulating the TLR4-related signaling pathway.

4.7.1 Melatonin

Melatonin, a compound secreted by the pineal gland, is also found in the leaves, fruits, and seeds of plants. It possesses various biological activities, including antioxidant [217], anti-inflammatory [218], and antitumor properties [219]. This significant compound is widely utilized in the treatment of diverse diseases, such as cancer, neurodegenerative diseases, and cardiovascular diseases [220]. Numerous studies have demonstrated that melatonin can improve DN by targeting inflammation [221], oxidative stress [222], and mitochondrial autophagy [223]. In a study investigating the effects of melatonin on renal inflammation and fibrosis in DN, melatonin significantly reduced the expression of TLR4 and NF-κB and inhibited the nuclear translocation of the NF-κB p65 subunit in HG-treated thylakoid cells, suggesting that melatonin inhibits HG-mediated activation of TLR4 and NF-κB and downregulates the inflammatory genes that targets through the TLR4 signaling pathway. In addition, melatonin negatively regulates the TGF-β1/drosophila mothers against decapentaplegic (Smad3) pathway to control renal fibrosis in DN [100]. These findings suggest that melatonin, by influencing TLR4, can be considered as a natural compound for the treatment of DN.

4.7.2 Umbelliferone

Umbelliferone, a natural product of the coumarin family, possesses several properties, including antibacterial, antioxidant, and anti-inflammatory effects [224]. It exerts its antidiabetic effect by modulating glucolipid metabolism and inflammation [225,226]. Moreover, umbelliferone treatment has been found to reduce renal damage caused by diabetes [227]. One study demonstrated that umbelliferone has the potential to ameliorate the histopathological changes in kidneys affected by diabetes. Umbelliferone reduced the levels of podocin and CD2-associated protein, which are molecules associated with the transition between epithelial and mesenchymal states. Moreover, umbelliferone inhibited the expression of TLR2, TLR4, and MyD88, as well as the activation of NF-κB. Furthermore, it significantly decreased the levels of other inflammatory molecules, including TNF-α, IL-6, and IL-1β. These findings suggest that umbelliferone may enhance renal function by modulating inflammatory responses and pathways associated with TLR4 [101].

4.7.3 DMDD

DMDD is a monomeric compound derived from the roots of Averrhoa carambola L.. It has been recently discovered to possess significant antidiabetic activity and the ability to inhibit the progression of DN [228]. DMDD exerts its effects by modulating glucolipid metabolism and antifibrosis, thereby attenuating the development and progression of DN. During this process, the protein expression of TLR4, TGF-β1, and Smad2/3 were downregulated by DMDD treatment. This downregulation aligns with the molecular mechanism observed in TLR4 knockdown, indicating the significant involvement of the TLR4/TGF-β signaling pathway in this particular process [102].

5 Role of molecular structures in the regulation of the TLR4 signaling pathway

The relationship between structure and activity is a crucial research focus when investigating the effects of natural compounds on DN, particularly in their role in regulating the TLR4 signaling pathway. Although the structure-activity relationship of these compounds with TLR4 has not been directly studied in DN models, it is noteworthy that molecular docking experiments have explored the structural interactions between compounds such as curcumin, paclitaxel, berberine, and ursolic acid, as well as their derivatives, with TLR4.

TLR4 is a horseshoe-shaped protein consisting of 839 amino acids that form a heterodimer with myeloid differentiation factor 2 (MD2). The ligand binding site of the TLR4/MD2 complex consists of two antiparallel β-sheets, resulting in the formation of a spacious hydrophobic cavity in MD2. LPS is able to bind to the hydrophobic cavity by utilizing its lipid chains, which are predominantly enclosed within the MD2 structure [229]. By their 1,3-diketone configuration, curcumin and its analogs have the capability to occupy the hydrophobic binding cavity of MD2, thereby obstructing the LPS binding site. This interaction involves important modes of interaction with MD2, such as hydrogen bonding, and engaging residues Arg90, Glu92, and Tyr102, thereby reducing the activation of the downstream signaling pathway [230]. Paclitaxel also inhibits TLR4 signaling by binding to MD2, primarily through hydrophobic interactions. It closely interacts with hydrophobic side-chain residues such as Ile61, Phe76, Leu78, Phe119, and Phe151 in the MD2 pocket [231]. In addition, due to its small molecular size, berberine can directly bind to MD2 through the hydrophobic surface, and the more berberine molecules enter the lumen, the lower the chance for LPS to bind to MD2, suggesting that MD2 preferentially binds to berberine over LPS [232]. This high affinity for TLR4 is related to the ability of berberine to form hydrogen bonds with Thr174, Asn204, and Val203 of the TLR4 A chain and to form close hydrophobic interactions with the Asn204 and Gln202 residues of the TLR4 A chain [233]. Ursolic acid binds to the active pocket region of MD2, specifically to the binding sites of Ile52, Leu78, Ile80, Phe121, and Tyr131, resulting in a conformational change in TLR4 and reducing the activity of the TLR4–MD2 complex [234].

These intricate intermolecular interactions emphasize the significance of incorporating molecular structures into the design of innovative anti-inflammatory approaches. By carefully analyzing the activity and structure of compounds, we can not only improve our understanding of how natural compounds affect the function of TLR4 in DN but also generate innovative research ideas for the development of new drugs for DN treatment.

6 Conclusion and future perspectives

Inflammation plays a vital role in the development of DN. TLR4, an essential member of the PPRS family within the innate immune system, acts as a crucial regulator of the inflammatory response in DN. In DN, the occurrence of cellular damage is triggered by contributing factors such as hyperglycemia, hyperlipidemia, and hypertension. Consequently, these factors result in the generation of multiple endogenous ligands, which encompass HMGB1, fibronectin, hyaluronan, and heparan sulfate. The interaction between these ligands and TLR4 instigates the discharge of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, thus activating the inflammatory response. This cascade subsequently leads to varying levels of renal structure and functional impairment experienced by DN patients.

Natural compounds, as a class of active molecules possessing anti-inflammatory properties, can ameliorate DN by modulating ligands associated with TLR4 or by directly acting on TLR4 and its downstream signaling pathways. In this paper, several classes of natural compounds, including alkaloids, flavonoids, polyphenols, terpenoids, glycosides, and polysaccharides, which show potential inhibitory effects on TLR4, were reviewed, providing a scientific basis for the development of novel therapeutic agents. Among these compounds, those molecules that show significant therapeutic effects against DN, bind to TLR4, and have a good basis for drug development should be prioritized. For example, curcumin is considered as an important candidate molecule for the development of anti-inflammatory drugs due to the similarity of its ketocarbonyl structure to that of fluoroquinolone antibiotics. Paclitaxel is currently used mainly as an anticancer drug, but it has also been shown to affect innate immune activation through the TLR4-MD2 pathway, and direct evidence of its binding to MD2 has been demonstrated in vitro. As a widely studied natural compound, berberine has promising applications in drug development for the treatment of DN. Exploration of the therapeutic activity of ursolic acid and its synthetic derivatives has also been favored by researchers, and the conformational relationships of these analogs have been explored to some extent, with great potential for medicinal ursolic acid. In addition to these compounds, there are other natural compounds whose binding relationship with TLR4 has yet to be discovered, although they have also been shown to ameliorate DN by affecting the TLR4-related signaling pathway. For example, glycyrrhizin, an HMGB1 inhibitor, shows great therapeutic potential. Polydatin also holds great promise in the field of drug discovery due to its structural similarity to resveratrol. The conformational relationship of these compounds with TLR4 needs to be further investigated in the future to provide a more comprehensive scientific basis for natural drug discovery in DN.

Although natural compounds have shown potential in improving DN through TLR4 in animal models and cellular experiments, there are significant challenges in translating them into clinical applications. These compounds may have issues with structural instability, poor solubility, low bioavailability, and unknown side effects. Therefore, the development of new drugs requires a comprehensive evaluation and optimization of these properties. However, with our increasing understanding of the pharmacological mechanisms of natural compounds and the regulatory role of TLR4 in the innate immune response, along with advancements in research on novel delivery systems such as nanoparticles, it is expected that more clinical trials utilizing natural compounds for the treatment of DN via the TLR4 pathway will emerge in the future.

CRediT author statement

Jiabin Wu: Conceptualization, Data curation, Writing - Original draft preparation; Ke Li: Conceptualization, Data curation, Writing - Reviewing and Editing; Muge Zhou and Haoyang Gao: Writing - Reviewing and Editing, Investigation; Wenhong Wang: Supervision, Project administration, Writing - Reviewing and Editing; Weihua Xiao: Funding acquisition, Project administration, Supervision, Writing - Reviewing and Editing.

Declaration of competing interest

The authors declare that there are no conflicts of interest.

Appendix A Supplementary data

The following is the Supplementary data to this article:Multimedia component 1

Multimedia component 1

Acknowledgments

This study was sponsored by the 10.13039/501100001809 National Natural Science Foundation of China (Grant No.: 32371185 ), the Shanghai Science and Technology Plan Project, China (Project No.: 23010504200), the “Shuguang Program” (Program No.: 20SG50) funded by 10.13039/501100003024 Shanghai Education Development Foundation and Shanghai Municipale Education Commission, China, the Shanghai Talent Development Fund, China (Grant No.: 2020125 ), the Key Lab of Exercise and Health Sciences of Ministry of Education (Shanghai University of Sport, China) (Grant No.: 2022KF001 ), and the Shanghai Key Lab of Human Performance (Shanghai University of Sport, China) (Grant No.: 11DZ2261100 ).

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.jpha.2024.01.014.
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