Abstract
Nelumbo nucifera Gaertn (NNG), commonly known as sacred lotus or Indian lotus, has been extensively used in traditional medicine for its various pharmacological properties. Emerging research has focused on elucidating its potential as a therapeutic agent against cancer and other diseases. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating cellular processes such as cell growth, proliferation, and survival, and its dysregulation is implicated in various diseases, including cancer. This review examines the inhibitory effects of Nelumbo nucifera on the PI3K/AKT/mTOR pathway. We discuss the molecular components and functions of the PI3K/AKT/mTOR pathway, highlighting its significance in disease pathogenesis. The review compiles evidence from in vitro and in vivo studies demonstrating the ability of Nelumbo nucifera extracts (NNGE) and compounds to inhibit the PI3K/AKT/mTOR pathway. Additionally, it has pharmacological properties of NNG, including its anticancer, antidiabetic, antioxidant, and anti-inflammatory activities. Finally, we discuss the potential therapeutic applications of NNG-based interventions and outline future research directions in this promising field. Overall, this review underscores the therapeutic potential of NNG as an inhibitor of the PI3K/AKT/mTOR signaling pathway, suggesting avenues for the development of novel therapeutic strategies against cancer and other diseases.
Introduction
The lotus or Indian lotus has a rich history of traditional use in various cultures for its medicinal properties [1,2], with the increasing prevalence of diseases such as cancer, diabetes, and inflammatory conditions, there is a growing interest in exploring natural products for their therapeutic potential [3-6]. NNG, with its diverse phytochemical composition, has attracted attention as a potential source of bioactive compounds for the development of novel therapeutics [7]. The PI3K/AKT/mTOR signaling pathway is a key regulator of numerous cellular processes, including cell growth, proliferation, and survival [8,9]. Dysregulation of this pathway is implicated in the pathogenesis of various diseases, particularly cancer, where aberrant signaling contributes to tumor initiation, progression, and resistance to therapy. Consequently, targeting the PI3K/AKT/mTOR pathway has emerged as a promising strategy for the development of anticancer agents [10].
Given the importance of the PI3K/AKT/mTOR pathway in disease pathogenesis and the therapeutic potential of NNG, there is growing interest in investigating whether NNE and compounds can modulate this signaling cascade [11]. Several studies have reported inhibitory effects of NNG on the PI3K/AKT/mTOR pathway, suggesting its potential as a natural inhibitor of this critical signaling pathway [12].
In this review, we discuss the significance of the PI3K/AKT/mTOR pathway in cellular physiology and disease pathogenesis, with a focus on cancer [13]. Furthermore, we compile evidence from in vitro and in vivo studies investigating the inhibitory effects of NNG on the PI3K/AKT/mTOR pathway [13,14]. Additionally, we explore the pharmacological properties of NNG, including its anticancer, antidiabetic, antioxidant, and anti-inflammatory activities [15,16]. Finally, we discuss the potential therapeutic applications of NNG-based interventions and outline future research directions in this burgeoning field. Through this review article, we aim to provide insights into the therapeutic potential of NNG as an inhibitor of the PI3K/AKT/mTOR signaling pathway, thereby contributing to the development of novel therapeutic strategies for cancer and other diseases.
PI3K/AKT/mTOR Signaling Pathway: A Key Regulator in Cellular Processes
The signaling pathway is a central regulator of diverse cellular processes critical for homeostasis and adaptation to environmental cues. Activation of PI3K leads to the phosphorylation and activation of AKT, which in turn phosphorylates a plethora of downstream effectors involved in cell growth, proliferation, survival, metabolism, and motility [17]. One of the major effectors of AKT is mTOR, a master regulator of protein synthesis and cell growth. The PI3K/AKT/mTOR pathway integrates signals from growth factors, nutrients, and energy status, allowing cells to coordinate their responses accordingly [18,19]. Dysregulation of this pathway is implicated in various diseases, particularly cancer, where aberrant activation promotes oncogenesis and tumor progression [20]. Consequently, targeting components of the PI3K/AKT/mTOR pathway has emerged as a promising therapeutic strategy for cancer and other diseases characterized by dysregulated cell growth and proliferation [20].
Inhibitory Effects of Nelumbo nucifera Gaertn on PI3K/AKT/mTOR Signaling Pathway
Several studies have demonstrated the inhibitory effects of NNG on the PI3K/AKT/mTOR signaling pathway [21]. Extracts and bioactive compounds from NNG have been shown to suppress the activation of PI3K, AKT, and mTOR, thereby inhibiting downstream signaling cascades involved in cell proliferation, survival, and metastasis [22]. Mechanistic studies have revealed that NNG exerts its inhibitory effects through various mechanisms, including modulation of protein expression, inhibition of kinase activity, and induction of apoptosis. These findings highlight the potential of NNG as a natural inhibitor of the PI3K/AKT/mTOR pathway for therapeutic intervention in cancer and other diseases [23].
Evidence from in vitro studies
In vitro, studies have provided compelling evidence for the inhibitory effects of NNG on the PI3K/AKT/mTOR signaling pathway. Cell-based assays utilizing cancer cell lines have shown that NNE and compounds attenuate the phosphorylation and activation of key signaling molecules within this pathway, including PI3K, AKT, and mTOR [24,25]. Furthermore, treatment with NNG has been associated with inhibition of downstream effectors involved in cell proliferation, such as ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1] [26]. These findings suggest that NNG exerts its inhibitory effects on the PI3K/AKT/mTOR pathway at multiple levels, making it a promising candidate for further investigation as a natural inhibitor of this signaling cascade in cancer therapy.
Evidence from in vivo studies
In vivo studies have provided compelling evidence for the inhibitory effects of NNG on the PI3K/AKT/mTOR signaling pathway [27]. Animal models, including xenograft models and transgenic mouse models of cancer, have demonstrated that administration of Nelumbo nucifera Gaertn extracts, or bioactive compounds inhibits tumor growth and metastasis through modulation of the PI3K/AKT/mTOR pathway [28]. These studies have shown reduced phosphorylation levels of key signaling molecules, including PI3K, AKT, and mTOR, in tumour tissues following NNG treatment. Additionally, downstream effectors of this pathway involved in cell proliferation, survival, and angiogenesis are downregulated upon NNG administration [29]. These findings underscore the therapeutic potential of NNG as a natural inhibitor of the PI3K/AKT/mTOR pathway in cancer treatment.
Mechanistic insights into the inhibition
Mechanistic insights into the inhibition of the PI3K/AKT/mTOR signaling pathway by NNG involve multiple cellular processes and molecular interactions. Some key mechanisms include:
Modulation of protein expression: NNGE and compounds have been shown to downregulate the expression of key components of the PI3K/AKT/mTOR pathway, including PI3K, AKT, and mTOR. This downregulation can occur at the transcriptional or post-translational level, leading to reduced activation of downstream signaling cascades [30].
Inhibition of kinase activity: NNG compounds may directly inhibit the kinase activity of PI3K, AKT, or mTOR, thereby preventing their phosphorylation and activation. By interfering with the catalytic activity of these kinases, NNG disrupts the transmission of proliferative and survival signals within the cell [25].
Induction of apoptosis: NNG has been reported to induce apoptosis, or programmed cell death, in cancer cells. This process may be mediated, in part, by the inhibition of the PI3K/AKT/mTOR pathway, as activation of this pathway is often associated with the suppression of apoptosis [23]. By blocking PI3K/AKT/mTOR signaling, NNG promotes apoptosis and inhibits cancer cell survival.
Regulation of downstream effectors: NNG can modulate the activity of downstream effectors of the PI3K/AKT/mTOR pathway, such as S6K and eukaryotic translation initiation factor 4EBP1. By regulating the activity of these effectors, NNG influences processes such as protein synthesis, cell growth, and proliferation [31]. Overall, these mechanistic insights into the inhibition of the PI3K/AKT/mTOR pathway by NNG provide a comprehensive understanding of its anticancer properties and pave the way for the development of novel therapeutic interventions targeting this critical signaling cascade.
Toxicity evaluation
NNG, bioactive compounds involve comprehensive assessment methodologies to determine their potential adverse effects on human health. A review of existing literature on the bioactive compounds presents in NNG, including studies on their pharmacological properties, toxicological profiles, and potential adverse effects [32].
Chemical analysis: Analyze the chemical composition of the bioactive compounds extracted from NNG to identify their specific constituents and concentrations.
In vitro studies: Perform in vitro experiments to assess the cytotoxicity, genotoxicity, and mutagenicity of the bioactive compounds using cell culture models and biochemical assays [33].
Animal studies: Conduct acute and sub chronic toxicity studies in laboratory animals to evaluate the effects of the bioactive compounds on various organ systems, including the liver, kidneys, and nervous system [34].
Dose-response analysis: Determine the dose-response relationship of the bioactive compounds to establish the minimum toxic dose and identify potential dose-dependent effects.
Safety pharmacology: Evaluate the effects of the bioactive compounds on cardiovascular, respiratory, and central nervous system functions to assess their potential for causing adverse physiological effects.
Metabolism and pharmacokinetics: Investigate the metabolism, distribution, and elimination of the bioactive compounds in vivo to understand their bioavailability and potential for accumulation in tissues.
Ecotoxicology: Assess the potential environmental impact of NNG bioactive compounds through studies on their persistence, bioaccumulation, and toxicity to non-target organisms in aquatic and terrestrial ecosystems.
Risk assessment: Integrate the findings from toxicity studies to conduct a risk assessment and determine the safe exposure levels of the bioactive compounds for human consumption or use in pharmaceuticals or cosmetics [35,36].
The potential toxicity concerns regarding bioactive compounds from NNG are,
Alkaloids: Such as nuciferine and aporphine, which may have psychoactive effects and could potentially lead to toxicity if consumed in large quantities [37].
Cyanogenic Glycosides: Some parts of the lotus plant may contain cyanogenic glycosides, which can release cyanide upon metabolism, posing a risk of toxicity if ingested in significant amounts [38].
Tannins: Lotus seeds and leaves contain tannins, which in excess amounts may lead to gastrointestinal irritation, inhibition of digestive enzymes, and interference with nutrient absorption [39].
Oxalates: Lotus roots and leaves contain oxalates, which can contribute to the formation of kidney stones in susceptible individuals if consumed excessively [40].
Pesticide residues: Depending on cultivation practices, lotus plants may accumulate pesticide residues, which could pose health risks if not properly regulated and controlled [41].
Figure 1: PI3K/AKT/mTOR signaling pathway.
Pharmacological Properties of Nelumbo nucifera Gaertn Extracts and Compounds
NNG exhibits a wide range of pharmacological properties attributed to its diverse phytochemical composition. Extracts and compounds derived from NNG demonstrate potent anticancer activity, inhibiting tumor growth, metastasis, and angiogenesis through modulation of various signaling pathways, including PI3K/AKT/mTOR. Additionally, NNG exhibits antidiabetic properties by enhancing insulin sensitivity, regulating glucose metabolism, and protecting pancreatic beta cells [30,42,43]. Its antioxidant activity scavenges free radicals, reducing oxidative stress and inflammation implicated in numerous diseases [44,45]. Furthermore, NNG demonstrates anti-inflammatory effects by inhibiting pro-inflammatory mediators and cytokines, alleviating symptoms of inflammatory conditions [46,47]. Other pharmacological properties include hepatoprotective, neuroprotective, and cardioprotective effects, contributing to their potential in the treatment of liver diseases, neurodegenerative disorders, and cardiovascular diseases, respectively [48,49]. Overall, NNG emerges as a promising source of bioactive compounds with multifaceted pharmacological properties, holding potential for the development of therapeutic agents against cancer, diabetes, inflammation, and various other diseases.
Comparative study of Nelumbo nucifera Gaertn
Herbal extracts from Nelumbo nucifera have been traditionally used for their various pharmacological properties, including antioxidant, anti-inflammatory, and anticancer effects. Studies suggest that compounds such as flavonoids, alkaloids, and phenolic acids present in Nelumbo nucifera may exert therapeutic effects through the modulation of signaling pathways (e.g., NF-κB, MAPK), and inhibition of cell proliferation and angiogenesis [50]. The PI3K/AKT/mTOR pathway, leading to inhibition of downstream signaling cascades involved in cell growth, survival, and metabolism. By blocking these pathways, synthetic inhibitors exert anticancer effects and may also have therapeutic potential in other diseases [51].
Potential Therapeutic Applications and Future Perspectives
The diverse pharmacological properties of NNG suggest its potential therapeutic applications across a spectrum of diseases. Future research could focus on elucidating the specific mechanisms underlying its effects and optimizing formulations for enhanced bioavailability and efficacy. Additionally, clinical studies are warranted to validate its therapeutic potential in humans. With its demonstrated efficacy against cancer, diabetes, inflammation, and other conditions, NNG holds promise as a valuable source of natural therapeutics for improving human health and well-being [52,53].
Development of Nelumbo nucifera-based therapeutics
The development of NNG-based therapeutics involves several key steps. First, comprehensive phytochemical profiling and identification of bioactive compounds are essential to understand the therapeutic potential of this plant. Subsequently, preclinical studies, including in vitro and in vivo experiments, elucidate the pharmacological mechanisms and efficacy of NNGE or isolated compounds [54]. Formulation development aims to optimize delivery systems for enhanced bioavailability and stability. Clinical trials assess safety, tolerability, and efficacy in human subjects, paving the way for regulatory approval and commercialization. Additionally, ongoing research may explore synergistic combinations with conventional therapies or other natural compounds to maximize therapeutic outcomes [55].
Challenges and opportunities in translational research
Challenges in translational research of NNG-based therapeutics include standardization of extracts, ensuring reproducibility, and addressing potential herb-drug interactions [56]. Moreover, elucidating optimal dosage regimens and identifying biomarkers for patient stratification is critical [57]. Opportunities lie in harnessing advanced analytical techniques for phytochemical characterization and employing innovative drug delivery systems for improved efficacy [58]. Collaboration between academia, industry, and regulatory bodies facilitates the translation of preclinical findings into clinically viable therapies. Additionally, exploring traditional knowledge and integrating complementary approaches can enrich the development of NNG-based therapeutics.
Future directions for studying the therapeutic potential of Nelumbo nucifera Gaertn
Future directions for studying the therapeutic potential of NNG involve several avenues of investigation. Firstly, further elucidation of the underlying molecular mechanisms and signaling pathways involved in its pharmacological effects is essential [59]. Advanced omics technologies can provide valuable insights into the global effects of NNG on cellular processes. Additionally, research should focus on identifying specific bioactive compounds responsible for their therapeutic activities and optimizing their extraction and purification methods. Furthermore, exploring novel applications, such as combination therapies or targeted delivery systems, can enhance the efficacy and clinical relevance of NNG-based interventions [3,60]. Finally, large-scale clinical trials are needed to validate its safety and efficacy for various diseases, paving the way for its integration into mainstream healthcare practices.
Conclusion
In conclusion, NNGE exhibits significant inhibitory potential against the PI3K/AKT/mTOR signaling pathway, highlighting its promising role as a natural inhibitor in the treatment of cancer and other diseases. Through modulation of key components within this pathway, NNGE disrupts cellular processes involved in proliferation, survival, and metastasis. Mechanistic insights reveal its multifaceted actions, including modulation of protein expression, inhibition of kinase activity, and induction of apoptosis. However, further research is warranted to fully elucidate its therapeutic mechanisms and optimize its clinical applications. Overall, NNGE represents a valuable resource for the development of novel therapeutic interventions targeting the PI3K/AKT/mTOR pathway.
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