Plantamajoside: A potentially novel botanical agent for diabetes mellitus management

Abstract

Diabetes mellitus (DM) and its associated complications are metabolic disorders characterized by hyperglycemia, leading to high morbidity and reduced quality of life worldwide. This global healthcare problem imposes substantial personal and social burdens that warrant comprehensive and in-depth investigation. Plantamajoside (PMS), a naturally bioactive ingredient derived from the traditional Chinese medicinal herb Plantaginis Herba, exhibits a range of pharmacological properties, including anti-inflammatory, antioxidative, and antitumor effects, and has been traditionally utilized in clinical applications such as removing phlegm and clearing heat. However, the potential biological impact of PMS on DM remains largely unexplored. Recent research by Wang et al reported the therapeutic potential of PMS in type 2 DM (T2DM) and elucidated the underlying molecular mechanisms. Specifically, PMS mitigates endoplasmic reticulum stress and apoptosis of pancreatic β-cells by upregulating DnaJ heat shock protein family (Hsp40) member C1, thereby alleviating pancreatic β-cell damage and ameliorating T2DM progression. Given the novel and protective effect of PMS on pancreatic β-cells, this natural ingredient emerges as an innovative and promising therapeutic strategy for improving DM outcomes. PMS has been shown to modulate key signaling pathways involved in multiple types of regulated cell death (RCD), such as apoptosis and autophagy. Various forms of RCD, including apoptosis, ferroptosis, pyroptosis, autophagy, and PANoptosis, contribute to the pathogenesis of DM and its associated complications. There is significant potential for PMS to exert protective effects on β-cells against these forms of RCD and to provide a multitarget approach to DM therapy. Therefore, further exploration into whether PMS shields pancreatic β-cells from these types of RCD, coupled with elucidating the underlying molecular mechanisms, will facilitate the development of more effective therapeutic strategies for DM. Additionally, further investigation on PMS in conjunction with other therapeutic approaches is warranted to enhance therapeutic efficacy for DM.

Key Words: Diabetes mellitus; Pancreatic β-cells; Regulated cell death; Traditional Chinese medicine; Plantamajoside

Core Tip: Diabetes mellitus (DM) is a global health challenge impacting millions of lives, necessitating the urgent development of effective therapeutic agents. Wang et al observed that plantamajoside (PMS), a bioactive component derived from traditional Chinese medicine, alleviates pancreatic tissue damage and protects β-cells from apoptosis by upregulating DNAJC1. This research underscores the potential of PMS in DM treatment and suggests that other regulated cell death pathways may also be involved in DM progression as modulated by PMS. Further investigations are essential to elucidate the underlying mechanisms and to expand our understanding of PMS as a therapeutic agent for DM.

INTRODUCTION

Diabetes mellitus (DM), mainly encompassing type 1 DM (T1DM) and T2DM, is a group of complex, chronic metabolic disorders characterized by persistent hyperglycemia, resulting from absolute or relative insulin deficiency, insulin resistance, or both[1,2]. Chronic hyperglycemia progressively induces damage to multiple organs, ultimately contributing to devastating complications, including diabetic cardiomyopathy, neuropathy, nephropathy and retinopathy[2]. As is reported by International Diabetes Federation, approximately 6.7 million people died from DM in 2021[3]. DM has emerged as a significant public health challenge and economic burden worldwide due to its increasing prevalence, high morbidity, reduced quality of life and multiple severe complications[4,5]. Currently, glycemic control and the prevention or mitigation of DM-associated complications remain the mainstay of DM management. Despite significant advances in the development of DM therapies, a subset of individuals continues to exhibit poor therapeutic responses, and some drugs are associated with severe adverse effects[6-8]. Investigating the pathophysiological mechanisms underlying DM progression, along with identifying novel therapeutic strategies and drug candidates to enhance glycemic control and reduce DM complications, remains continuous efforts with considerable implications for both social and economic development worldwide.

THERAPEUTIC POTENTIAL OF PLANTAMAJOSIDE IN DISEASES

Traditional Chinese medicine (TCM), one of the oldest traditional medical systems around the world, has been practiced in China for thousands of years and emphasizes the balance of Yin and Yang while minimizing side effects[9,10]. TCM is gaining increasing attention worldwide and has been officially incorporated into the 11^th version of International Statistical Classification of Diseases and Related Health Problems. From ancient archives to a formal endorsement by the World Health Organization as a recognized global healthcare system, TCM has established itself as a complementary and alternative medicine within the Western medical system and remains irreplaceable in the prevention and treatment of multiple diseases[11-13]. Plantamajoside (PMS), a naturally bioactive ingredient derived from the traditional Chinese medicinal herb Plantaginis Herba and related species, exhibits diverse pharmacological properties, including anti-inflammatory[14], antioxidant[15], antitumor[16], antifibrotic[17] and antimicrobial effects[18]. Growing evidence indicates that PMS exerts distinct bioactivities through various signaling pathways, presenting significant potential as a therapeutic agent (Table 1)[14,15,17,19-30]. For example, PMS has been shown to attenuate cardiac fibrosis via specifically binding with the receptor for advanced glycation end products (RAGE) to suppress the advanced glycation end products-activated RAGE/autophagy/endothelial-to-mesenchymal transition pathway, suggesting that PMS serves as an effective antifibrotic agent and a promising therapeutic candidate for chronic heart failure[19]. PMS also abates interleukin 1 beta-stimulated extracellular matrix degeneration and inflammatory responses by suppressing the nuclear factor kappa B and mitogen-activated protein kinase signaling pathways, thereby alleviating osteoarthritis progression, highlighting its potential as a therapeutic candidate for osteoarthritis[20]. In addition, the safety of PMS was verified in an oral toxicity study[31]. Considering the versatility, safety, and availability for industrial synthesis[32], PMS represents a potential drug candidate that warrants further exploration in the treatment of various diseases. PMS reportedly possesses antiglycation activity, suggesting its potential relevance to DM[23]. Nevertheless, the therapeutic involvement of PMS in DM and the underlying mechanism is poorly studied, necessitating further investigation.

Table 1 Current bioactivities of plantamajoside in various diseases[14,15,17,19-30].

Bioactivities	Mechanism of action	Specific diseases	Ref.
Antioxidative	Scavenge free radicals, reduce oxidative stress and decrease activities of SOD, catalase, and GSH-Px	Acute myocardial infarction	Zeng et al[15]; Choi et al[21]; Amakura et al[22]
Anti-inflammation	Inhibit PI3K/AKT signaling pathway and pro-inflammatory factors, such as COX-2, iNOS, IL-6, NO, IL-8, and TNF-α	Osteoarthritis, pulmonary inflammation	Liu et al[14]; Lin et al[20]; Wu et al[23]
Antifibrosis	Suppress the fibrotic process and downregulate fibrosis-related factors, such as α-SMA, TGF-β, and Col1α1	Cardiac fibrosis, liver fibrosis	Wang and Yan[17]; Zhang et al[19]
Antitumor	Inhibit the growth and invasion of various tumor cells and induce apoptosis	Cervical cancer, hepatocellular carcinoma	Yin et al[24]; Zou et al[25]
Antimicrobial	Inhibit the growth of bacteria, fungi and virus via disrupting metabolic processes and inhibiting the formation of aggregates and biofilms	Bacterial infections, fungal infections, viral infections	Zhakipbekov et al[26]; Chen et al[27]
Neuroprotective	Reduce neurons death, inhibit microglia polarization, alleviate substantia nigra damage	Acute spinal cord injury, Alzheimer’s disease, Parkinson’s disease	Darwish et al[28]; Guo et al[29]; Živković et al[30]

α-SMA: Alpha smooth muscle actin; Col1a1: Collagen type 1 alpha 1 chain; GSH-Px: Glutathione peroxidase; COX-2: Cyclooxygenase 2; IL: Interleukin; iNOS: Inducible nitric oxide synthase; NO: Nitric oxide; PI3K: Phosphoinositide 3-kinase; SOD: Superoxide dismutase; TGF-β: Transforming growth factor beta; TNF-α: Tumor necrosis factor alpha.

DIVERSE TYPES OF REGULATED CELL DEATH IN PANCREATIC B-CELLS ARE ASSOCIATED WITH DM

Pancreatic β-cells, located in the islets of the Langerhans, are essential for insulin production and secretion. Defects in the function or number of these cells can ultimately contribute to the progression of T1DM and T2DM[33-35]. A plethora of evidence shows that multiple forms of regulated cell death (RCD) in pancreatic β-cells, such as apoptosis, ferroptosis, pyroptosis and autophagy, are closely involved in the initiation and progression of DM and its complications[36,37] (Figure 1). Inhibition of β-cell death represents a promising therapeutic approach for DM. Thus, elucidating the various models of RCD in β-cells and the specific pathways involved is beneficial for developing effective strategies to enhance the survival and functionality of these cells, improving the outcomes of β-cell-based therapies.

Figure 1 Plantamajoside: A potentially novel botanical agent for diabetes mellitus management. Multiple forms of regulated cell death (RCD) in pancreatic β-cells, including apoptosis, pyroptosis, ferroptosis and autophagy, are closely involved in the initiation and progression of diabetes mellitus (DM). Plantamajoside may mitigate DM progression through protecting β-cells from various RCD. The schematic model was plotted with BioRender (https: //www.biorender.com). TCM: Traditional Chinese medicine.

Apoptosis is a form of RCD characterized by cellular shrinkage, plasma membrane blebbing, and nuclear fragmentation, and is a multifactorial process implicated in numerous physiological and pathological conditions[38,39]. In DM, β-cell apoptosis is modulated via the activation of intrinsic or extrinsic pathways. Mechanistically, intrinsic pathways are triggered in response to various cellular stresses, including hyperglycemia, free fatty acids, cytokines and endoplasmic reticulum stress, and are marked by mitochondrial dysfunction as well as the activation of proapoptotic B-cell lymphoma-2 (Bcl-2) family members[40-42]. Extrinsic pathways are regulated by the formation of a death-inducing signaling complex[43,44]. Both pathways can initiate distinct caspases, leading to β-cell apoptosis and islet damage, thereby driving progression of DM[45].

Ferroptosis, a type of RCD driven by iron-dependent lipid peroxidation, exhibits considerable heterogeneity in morphology and underlying biological mechanisms compared with classical forms of RCD[46,47]. The morphological alterations are distinguished by abnormally shrunken mitochondria with diminished cristae and condensed membrane density. Ferroptosis is strongly associated with various pathological conditions such as neurodegenerative disorders, ischemic injury, and tumors[48,49]. Numerous studies have shown that ferroptosis plays significant roles in the pathophysiology and pathogenesis of DM and its complications. For instance, chronic arsenic exposure can induce β-cell ferroptosis and inflammation via the glutathione peroxidase 4/Ager/p65 axis, consequently leading to islet dysfunction and onset of DM[50-52]. Quercetin, a bioactive flavonoid with therapeutic potential for T2DM management, can protect β-cells from ferroptosis by inhibiting iron deposition and reducing lipid peroxidation[53].

Pyroptosis, a caspase-dependent form of pro-inflammatory RCD, is distinguished by multiple features including cytoplasmic swelling, pore membrane formation, chromatin concentration and inflammatory responses[54,55]. This process is predominantly triggered by inflammasomes (especially nucleotide-binding oligomerization domain-like receptor protein 3 [NLRP3] inflammasomes) and executed by gasdermin (GSDM) family members, particularly GSDMD. It plays significant roles in various physiological and pathological processes, including DM and its complications[56-58]. Accumulating evidence has indicated that inhibiting β-cell pyroptosis is becoming a promising therapeutic strategy for DM[59]. For example, several agents such as salidroside (a primary ingredient of the traditional herbal medicine Rhodiola species)[60] and vitamin D[61], can protect β-cells against pyroptosis by suppressing the NLRP3/GSDMD pathway, thereby mitigating progression of DM.

Autophagy is an evolutionarily conserved and lysosome-dependent catabolic process characterized by the lysosomal degradation of cellular components, followed by recycling of proteins and organelles to preserve intracellular homeostasis. This process is initiated by the formation of autophagosomes, which subsequently fuse with lysosomes to facilitate degradation of cellular cargoes[62,63]. Autophagy typically serves as one of the major quality control mechanisms in cells; however, abnormal autophagic flux usually contributes to cell death and is involved in the pathogenesis of various diseases[64,65]. In DM, β-cell autophagy exerts a double-edged effect. On the one hand, autophagy is indispensable for maintaining the architecture and function of β-cells via preserving the functions of mitochondria and endoplasmic reticulum[66]. On the other hand, dysregulated autophagy may contribute to progressive β-cell failure with consequently impaired insulin secretion and aggravated DM[67].

Mounting evidence has demonstrated that other types of RCD, including necroptosis, PANoptosis as well as cuproptosis, play crucial roles in the pathogenesis of numerous diseases, including DM[68-70]. Hyperglycemia has been shown to induce β-cell necroptosis by promoting the formation of necrosome complexes, which consist of receptor-interacting protein kinase 1, receptor-interacting protein kinase 2 and mixed lineage kinase domain-like protein, resulting in cell swelling and membrane disruption[4]. Moreover, impaired copper metabolism has been reported in T2DM, highlighting the potential significance of cuproptosis, a recently identified copper-dependent form of RCD, in the progression of DM[71]. Given the significance of RCD in β-cells in the pathogenesis of DM and its complications, further research is required to elucidate the precise mechanisms underlying these RCD processes, the crosstalk between different types of RCD, and therapeutic potential of targeting RCD in DM.

PMS IS A POTENTIALLY BOTANICAL AGENT FOR DM MANAGEMENT

Although PMS has been demonstrated to possess the capacity to mitigate multiple diseases via different pathways, its potential roles in DM remain poorly understood. In a previous study[72], the researchers revealed that PMS upregulated the expression of DnaJ heat shock protein family (Hsp40) member C1 (DNAJC1), a molecule associated with endoplasmic reticulum stress, thereby enhancing its interaction with the molecular chaperone glucose-regulated protein 78. This interaction subsequently alleviates the unfolded protein response and endoplasmic reticulum stress. As a result, PMS downregulates the expression of proapoptotic proteins B-cell lymphoma 2 (Bcl-2)-associated X protein and cytochrome c, while upregulating the antiapoptotic molecule Bcl-2 to inhibit β-cell apoptosis, ultimately alleviating β-cell damage and ameliorating T2DM progression[72]. Given the novel and protective effects of PMS on β-cells and its modulation of DNAJC1 in these cells, a mechanism that has never been extensively explored, these findings provide innovative mechanistic insights into DM pathogenesis, and highlight PMS as a promising therapeutic candidate for DM. However, the underlying mechanisms through which PMS modulates DNAJC1 remain unclear. Moreover, it remains to be determined whether PMS inhibits β-cell apoptosis through other molecules or pathways. Considering that PMS has been shown to modulate key signaling pathways involved in various types of RCD, such as apoptosis and autophagy[16,73], PMS holds significant potential to protect β-cells from other forms of RCD, including apoptosis, ferroptosis, pyroptosis and autophagy (Figure 1). Therefore, further exploration into whether PMS shields pancreatic β-cells from these types of RCD, coupled with unraveling the underlying molecular mechanisms, will provide a deeper understanding of how PMS may influence pancreatic β-cell survival under stress conditions and facilitate the advancement of more effective therapeutic strategies for DM. Given that glycosides generally exhibit low oral bioavailability, future structural modifications of PMS analogs should focus on improving their pharmacokinetic properties, particularly enhancing oral absorption, to facilitate drug development.

CONCLUSION

RCD of pancreatic β-cells plays a pivotal role in the onset and progression of DM, as the loss of functional β-cells leads to impaired insulin secretion and disrupted glucose homeostasis. Targeting RCD of β-cells has therefore emerged as a promising therapeutic strategy for DM. PMS, a bioactive compound derived from TCM, is characterized by its versatility, safety and suitability for industrial synthesis, exhibiting diverse pharmacological properties through multiple pathways, such as inhibiting autophagy and apoptosis in different diseases. Although current research on the regulation of RCD such as ferroptosis, PANoptosis, and cuproptosis by PMS in DM is limited, the ongoing investigation is highly likely to uncover additional RCD pathways influenced by PMS. By specifically targeting the RCD of β-cells, PMS presents a potentially novel therapeutic strategy with a multitarget approach for improving DM management. However, there is still a lack of large-scale clinical trials assessing the effects of PMS in humans, and much of the existing preclinical data remains preliminary. While the molecular mechanisms discussed in the aforementioned research appear promising, the translation of PMS from bench to bedside remains a significant challenge, further investigation is warranted to comprehensively elucidate PMS pharmacological effects and evaluate its clinical applications.

ACKNOWLEDGEMENTS

We would like to express our sincere appreciation to Xiong ZJ for his expert advice and guidance on this manuscript.