International Journal of Molecular Medical Science, 2024, Vol.14 http://medscipublisher.com/index.php/ijmms © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. -
International Journal of Molecular Medical Science, 2024, Vol.14 http://medscipublisher.com/index.php/ijmms © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher, operated by Sophia Publishing Group (SPG), is an international Open Access publishing platform that publishes scientific journals in the field of life science. Sophia Publishing Group (SPG), founded in British Columbia of Canada, is a multilingual publisher. Publisher MedSci Publisher Edited by Editorial Team of International Journal of Molecular Medical Science Email: edit@ijmms.medscipublisher.com Website: http://medscipublisher.com/index.php/ijmms Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada International Journal of Molecular Medical Science (ISSN 1927-6656) is an open access, peer reviewed journal published online by MedSci Publisher. The journal publishes scientific articles like original research articles, case reports, review articles, editorials, short communications and correspondence of the high quality pertinent to all aspects of human biology, pathophysiology and molecular medical science, including genomics, transcriptomics, proteomics, metabolomics of disease therapy, clinical pharmacology, clinical biochemistry, vaccines, immunology, microbiology, epidemiology, aging, cancer biology, infectious diseases, neurological diseases and myopathies, stem cells and regenerative medicine, vascular and cardiovascular biology, as well as the important implications for human health and clinical practice research. All the articles published in International Journal of Molecular Medical Science are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
International Journal of Molecular Medical Science (online), 2024, Vol. 14, No. 5 ISSN 1927-6656 http://medscipublisher.com/index.php/ijmms © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Study on the Antitumor Effects and Molecular Mechanisms of Sanghuangporus Polysaccharides Haiyan Chen, Pengfei Hu, Li Liang, Ke Li, Binghui Liu, Liujing Zhou, Xinci Zheng International Journal of Molecular Medical Science, 2024, Vol. 14, No. 6, 324-341 Research on the Antioxidant and Immunomodulatory Effects of Lycium Bar-barum Polysaccharides and Their Molecular Mechanisms Jianhui Li International Journal of Molecular Medical Science, 2024, Vol. 14, No. 6, 342-354 The Role of Genetic Factors in Dementia Lin Mou, Lei Wu, Xinyu Fu, Bo Wang, Xu Wang, Xingjun Xiao International Journal of Molecular Medical Science, 2024, Vol. 14, No. 6, 355-368 The Integration of Holistic Approaches in Traditional Chinese Medicine and Micronutrient Research in Modern Nutrition Science: Theory and Application Zichao Chen, Haijuan Zhang International Journal of Molecular Medical Science, 2024, Vol. 14, No. 6, 369-379 Study on Individualized Dietary Therapy for Diabetes Based on Traditional Chinese Medicine (TCM) Constitution Identification Jing Zhang, Yeli Huang, Xiaolei Qi International Journal of Molecular Medical Science, 2024, Vol. 14, No. 6, 380-392
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 324 Research Insight Open Access Study on the Antitumor Effects and Molecular Mechanisms of Sanghuangporus Polysaccharides Haiyan Chen 1,2 , Pengfei Hu 3, Li Liang4, KeLi 1, Binghui Liu 1, Liujing Zhou1, Xinci Zheng1 1 College of Life Sciences, Changchun Sci-Tech University, Changchun, 130022, Heilongjiang, China; 2 College of Pharmacy, Changchun University of Chinese Medicine, Changchun, 130117, Heilongjiang, China; 3 Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130012, Heilongjiang, China; 4 School of Food Science and Technology, Jiangnan University, Wuxi, 214122, Jiangsu, China Corresponding author: 100361@cstu.edu.cn International Journal of Molecular Medical Science, 2024, Vol.14, No.6 doi: 10.5376/ijmms.2024.14.0033 Received: 14 Sep., 2024 Accepted: 22 Oct., 2024 Published: 06 Nov., 2024 Copyright © 2024 Chen et al., This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Chen H.Y., Hu P.F., Liang L., Li K., Liu B.H., Zhou L.J., and Zheng X.C., 2024, Study on the antitumor effects and molecular mechanisms of Sanghuangporus Polysaccharides, International Journal of Molecular Medical Science, 14(6): 324-341 (doi: 10.5376/ijmms.2024.14.0033) Abstract This study explores the antitumor effects and molecular mechanisms of Sanghuangporus polysaccharides. As the main active components of the traditional medicinal mushroom, Sanghuangporus polysaccharides exhibit significant antioxidant, immunomodulatory, and antitumor activities. They inhibit tumor growth by regulating the cell cycle, promoting apoptosis, and reducing cancer cell migration and invasion. Sanghuangporus polysaccharides exert antitumor effects by activating the p53 signaling pathway and down-regulating the expression of matrix metalloproteinases (MMPs). Additionally, their antioxidant properties help alleviate the side effects of chemotherapy and radiation therapy in cancer patients. Sanghuangporus polysaccharides can also be used for cancer prevention and adjuvant therapy, making them a promising natural therapeutic agent. Keywords Sanghuangporus polysaccharides; Antitumor effects; Apoptosis; Oxidative stress; Cancer therapy 1 Introduction Sanghuangporus, a traditional medicinal mushroom, has been utilized in Asia for nearly 2 000 years due to its various health benefits, including its potential anticancer properties (Wan et al., 2020; Wang et al., 2022b). Polysaccharides derived fromSanghuangporus have garnered significant attention for their biological activities, such as antioxidant, anti-aging, immunomodulatory, and particularly antitumor effects (Wang et al., 2022b; Zhou et al., 2023). Recent studies have demonstrated that these polysaccharides can inhibit tumor growth and induce apoptosis in cancer cells, although the precise molecular mechanisms remain to be fully elucidated (Chen and Huang, 2018; Wan et al., 2020). The increasing incidence of cancer and the severe side effects associated with conventional chemotherapy drugs underscore the urgent need for alternative therapeutic agents with fewer adverse effects (Xie et al., 2020). Polysaccharides derived from Phellinus linteus exhibit a wide range of biological activities, with antitumor properties being particularly noteworthy. These polysaccharides have been shown to inhibit tumor growth and proliferation in various cancer cell lines. For instance, Sanghuangporus vaninii polysaccharides (SVP) have demonstrated modest anti-proliferative activity against HeLa, SHG-44, SMMC-7721, and MCF-7 cells. They effectively regulate the cell cycle, promote apoptosis, and reduce the migratory and invasive capacities of cancer cells. The antitumor mechanisms of these polysaccharides involve the activation of p53-related genes and the down-regulation of matrix metalloproteinase (MMP) expression, which are crucial for tumor suppression (Wan et al., 2020). Additionally, polysaccharides from Sanghuangporus Sanghuang have been found to possess antioxidant, anti-inflammatory, and antibacterial properties, further contributing to their therapeutic potential (Zhou et al., 2023; Liu et al., 2023b). This study aims to provide a comprehensive overview of the antitumor effects and molecular mechanisms of Sanghuangporus polysaccharides, discuses the traditional applications and medicinal value of Phellinus linteus, as well as the specific biological activities of its polysaccharides, seeks to elucidate the potential of these natural compounds in cancer therapy. This study reviews an analysis of the extraction, purification, and structural
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 325 characterization of these polysaccharides, as well as their specific antitumor mechanisms and broader biological activities. Through this study detailed examination, hopes to highlight the therapeutic potential of Sanghuangporus polysaccharides and their possible applications in modern medicine. 2 Basic Properties and Chemical Composition of Sanghuangporus Polysaccharides 2.1 Extraction and isolation of Sanghuangporus polysaccharides The extraction, isolation, and purification of polysaccharides form the basis for further research into their monosaccharide composition, molecular weight, primary structure, types and degrees of branching, configuration, biological activity, and structure-activity relationship. Sanghuangporus polysaccharides can be extracted using various methods, including hot water extraction and ultrasonic-assisted extraction. For instance, the optimal conditions for ultrasonic-assisted extraction from Sanghuangporus vaninii were found to be an extraction temperature of 60°C, an extraction time of 60 minutes, a solid-liquid ratio of 40 g/mL, and an ultrasonic power of 70 W, achieving an extraction rate of 1.41% (Liu et al., 2023b). Another method involves the use of a thermoseparating aqueous two-phase system (ATPS) based on ethylene oxide-propylene oxide (EOPO) copolymer and deep eutectic solvents (DES), which has shown high efficiency in extracting polysaccharides (Figure 1; Figure 2) (Gao et al., 2020; Wang et al., 2022a). Figure 1 Schematic illustration of preparation, structural elucidation, and bioactivity determination of the polysaccharides derived from the naturallymedicinal fungal resources Sanghuangporus (Adopted from Wang et al., 2022a)
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 326 Figure 2 The overall highlights discussed in this review (Adopted from Wang et al., 2022a) Purification and isolation of Sanghuangporus polysaccharides often involve gradient ethanol precipitation and chromatographic techniques. For example, five homogeneous monosaccharides were obtained by gradient ethanol precipitation followed by diethylaminoethyl-cellulose (DEAE) and Sephadex G-100 separation and purification (Liu et al., 2023b). High-speed counter-current chromatography (CCC) using an aqueous diphase solvent system has also been successfully employed for one-step separation of polysaccharides, minimizing chemical variation (Yin et al., 2012). The chemical structure of Sanghuangporus polysaccharides can be preliminarily identified using various analytical techniques. High-performance liquid chromatography (HPLC), ultraviolet (UV) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), Zeta potential analysis, and scanning electron microscopy (SEM) are commonly used to characterize the polysaccharides (Liu et al., 2023b). These techniques help in determining the monosaccharide composition, glycosidic linkages, and molecular weight distribution. 2.2 Chemical composition analysis of Sanghuangporus polysaccharides Sanghuangporus polysaccharides are composed of various monosaccharides, including glucose, galactose, mannose, xylose, arabinose, and rhamnose. These components contribute to the biological activities of the polysaccharides, such as antioxidant and anti-inflammatory effects (Liu et al., 2018; Liu et al., 2023b). The specific composition and structure can vary depending on the extraction and purification methods used (Table 1). The molecular weight of Sanghuangporus polysaccharides can vary significantly, and their structural complexity is revealed through techniques such as viscometry, osmometry, precipitation methods, HPLC, GPC, HPGPC, HPSEC, SEC-MALLS-RI, and HPSEC-MALLS-RI. For example, polysaccharides purified from Sanghuangporus fungi have an average molecular weight of 20.377 kDa (Zhang et al., 2023). Structural analysis indicates that the molecular weight of these polysaccharides ranges from 1 to 1×10⁶ kDa, and there is a correlation between molecular weight and the antioxidant capacity of the polysaccharides. Low-molecular-weight polysaccharides exhibit significantly better antioxidant and free radical scavenging abilities than high-molecular-weight polysaccharides, possibly due to the more active intramolecular hydrogen bonding of O-H and electron-donating substituents. Structural analysis using methylation and two-dimensional nuclear magnetic resonance (2D-NMR) techniques indicates that these polysaccharides typically consist of complex glycosidic linkages, including 1,4-linked α-D-pyran glucose residues with branching points (Figure 3) (Cheng et al., 2020a).
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 327 Table 1 Structural analysis of Sanghuangporus polysaccharides (Li et al., 2022) Polysaccharide Name Isolation and Purification Method Molecular Weight/Da Monosaccharide Composition Reference SSEPS2 DEAE-Sepharose Fast Flow ion-exchange column and Sephacryl S-100 HR gel column 9.43×104 Mannose Cheng et al., 2020b PBF6 DEAE-Sepharose Fast Flow ion-exchange column and Sephacryl S-400 HR gel column 3.23×10⁵ Glucose Ge et al., 2013 PIP-1 DEAE-Sepharose Fast Flow ion-exchange column and Sepharose CL-4B gel column 8.12×105 Mannose, Glucose, and Galactose (2.41:87.74:3.86) Yuan et al., 2018 PLPS-1 DEAE-52 cellulose column and Sephadex G-100 gel column 2.5×10⁵ Glucose, Arabinose, Fucose, Galactose, and Xylose (21.964:1.336:1.182:1:1) Mei et al., 2015 PL-N1 DEAE-Sephadex A-25 column DEAE-Sephadex A-25 柱 3.43×108 Arabinose, Xylose, Glucose, and Galactose (4.0:6.7:1.3:1.0) Pei et al., 2015 PLP1-I DEAE-Sepharose Fast Flow ion-exchange column and Sephacryl S-400 HR gel column 2.9×108 Glucose and Galactose (8.9:1.0) Yuan et al., 2016a PRG DEAE cellulose column and Superdex-30 gel column 5.16×10³ Glucose Liu et al., 2015 PL-A11 DEAE-Sepharose Fast Flow ion-exchange column and Sephacryl S-400 HR gel column 1.38×104 Arabinose, Xylose, Mannose, and Glucose (1.1:1.3:1.0:6.6) Yuan et al., 2016b SSIPS1 DDEAE-Sepharose Fast Flow ion-exchange column and Sephacryl S-100 HR gel column 2.35×10⁴ Glucose and Galactose (94.8:5.2) Cheng et al., 2020a Figure 3 Molecular diagram
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 328 Sanghuangporus polysaccharides have shown potential antitumor effects. They can inhibit the levels of pro-inflammatory cytokines and promote anti-inflammatory cytokines, which may contribute to their antitumor activity (Liu et al., 2023b). Additionally, these polysaccharides have been found to downregulate genes involved in lipid accumulation, suggesting a role in lipid regulation therapy (Zhang et al., 2023). 2.3 Biological activities of Sanghuangporus polysaccharides Sanghuangporus polysaccharides exhibit significant antioxidant activity. They have been shown to scavenge superoxide anions and other free radicals, which helps in reducing oxidative stress (Liu et al., 2018; Liu et al., 2023b). The antioxidant properties are influenced by the specific monosaccharide composition and molecular weight of the polysaccharides. The immunomodulatory effects of Sanghuangporus polysaccharides include enhancing macrophage activity and modulating cytokine production. For example, certain fractions of Lycium barbarum polysaccharides, which share similar properties with Sanghuangporus polysaccharides, have been shown to enhance macrophage NO production and phagocytic capacity. These effects contribute to the overall immune-boosting properties of the polysaccharides. Preliminary studies have shown that Sanghuangporus polysaccharides possess antitumor potential. They can inhibit the proliferation of tumor cells and modulate immune responses to more effectively target cancer cells (Liu et al., 2023a; Zhang et al., 2023). Wei et al. (2016) studied the inhibitory effect of Sanghuangporus polysaccharides on liver cancer and found that the tumor mass in the experimental group treated with Sanghuangporus polysaccharides was reduced, and liver cancer cell necrosis was observed. Compared to anticancer drugs, Sanghuangporus polysaccharides demonstrated lower toxicity. Analysis of the antitumor mechanism suggested that Sanghuangporus polysaccharides might be related to immune regulation. Ying et al. (2017) found through research that polysaccharides from Sanghuangporus fruiting bodies exhibited better antitumor effects than those fromSanghuangporus mycelium. Additionally, the antitumor activity of mycelium polysaccharides gradually increased as the growth period extended. However, further research is still needed to fully understand the mechanisms behind these antitumor effects and to develop potential therapeutic applications. Sanghuangporus polysaccharides exhibit a range of biological activities, including antioxidant, immunomodulatory, and antitumor effects. Their chemical composition and structural characteristics play a crucial role in determining these activities, making them a promising area for research in therapeutic applications. 3 Inhibitory Effects of Sanghuangporus Polysaccharides on Tumor Cell Proliferation 3.1 Invitro studies Sanghuangporus polysaccharides have garnered significant attention for their antitumor potential in various in vitro studies. These polysaccharides can inhibit tumor cell proliferation and modulate immune responses to target cancer cells more effectively. For instance, polysaccharides isolated from Sanghuangporus vaninii (SVP) exhibited moderate antiproliferative activity against several cancer cell lines, including HeLa, SHG-44, SMMC-7721, and MCF-7 cells. In tumor cell inhibition experiments conducted in vitro, both crude polysaccharides and the purified SSP1 were shown to inhibit the proliferation of tumor cells such as HepG2, A549, MDA-MB-231, PC3, SGC-7901, and HCT-116 to varying degrees. Notably, SSP1 was more effective than the crude polysaccharides, with a significant difference (P<0.05) (Ying, 2023). Additionally, research has shown that SVP can modulate the cell cycle, promote apoptosis, and reduce the migration and invasion ability of MCF-7 cells (Figure 4) (Wan et al., 2020). Polysaccharides extracted fromPolygala tenuifolia Willd. (PTP) were found to induce apoptosis in S180 sarcoma cells, characterized by nuclear fragmentation, apoptotic body formation, and a decrease in mitochondrial membrane potential (Yu et al., 2021a). Cheng et al. (2020a) isolated a novel extracellular polysaccharide from the liquid culture of Sanghuangporus species, composed solely of mannose (Man), which featured 1,3-linked and 1,2-linked α-D-Manp units. The 1,2-linked α-D-Manp was substituted at the O-6 position with 1,6-linked
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 329 α-D-Manp residues and terminal α-D-Manp residues, demonstrating potential antitumor activity against HepG2 and MCF-7 cell growth in vitro. Figure 4 A series of antitumor mechanism pathways for SVP in MCF-7 cells (Adopted from Wan et al., 2020) Ganoderma atrum polysaccharide (PSG-1) also showed antitumor effects by inhibiting tumor growth and inducing apoptosis in tumor cells. The treatment with PSG-1 resulted in increased cAMP and PKA activities, which are crucial for the apoptotic pathway (Zhang et al., 2014a). Similarly, polysaccharides from Lentinus edodes (SLNT1 and JLNT1) demonstrated significant antitumor effects by inducing apoptosis in H22-bearing mice (Wang et al., 2013). 3.2 Molecular mechanisms of cell cycle regulation The molecular mechanisms underlying the antitumor effects of Sanghuangporus polysaccharides involve several pathways. SVP from Sanghuangporus vaninii was found to enhance the activation of p53-related genes and down-regulate matrix metalloproteinase (MMP) expression, which are critical for cell cycle regulation and apoptosis (Wan et al., 2020). The PTP from Polygala tenuifolia Willd. induced apoptosis through the FAS/FAS-L-mediated death receptor pathway, increasing the ratio of BAX to Bcl-2, promoting cytochrome c release, and activating caspase-9 and -3 (Yu et al., 2021a). Ganoderma atrum polysaccharide (PSG-1) activated the cAMP-PKA signaling pathway while down-regulating the Ca(2+)/PKC signal pathway, leading to apoptosis in tumor cells (Zhang et al., 2014a). Another study on PSG-1 revealed that it induced apoptosis via the mitochondria-mediated pathway, involving the loss of mitochondrial membrane potential, cytochrome c release, and activation of caspases (Zhang et al., 2014b). Furthermore, polysaccharides from Tetrastigma Hemsleyanum (SYQ-PA) were shown to inhibit breast cancer by reprogramming tumor-associated macrophages through the PPARγ signaling pathway, promoting M1 macrophage polarization and inhibiting cancer cell proliferation (Liu et al., 2023a). 3.3 Invivo experimental studies In vivo studies have further confirmed the antitumor efficacy of Sanghuangporus polysaccharides. For example, SVP from Sanghuangporus vaninii significantly inhibited tumor growth in MCF-7 xenograft models by promoting apoptosis and reducing tumor invasiveness (Wan et al., 2020). Polysaccharides from Polygala tenuifolia Willd. (PTP) demonstrated antitumor activity in S180 tumor-bearing mice by inducing apoptosis and enhancing immune responses, such as increased NK cell activity and cytokine production (Yu et al., 2021a). Ganoderma atrum polysaccharide (PSG-1) showed potent antitumor effects in CT26 tumor-bearing mice by inducing apoptosis and boosting the immune system, as evidenced by increased lymphocyte proliferation and cytokine levels (Zhang et al., 2014b). Similarly, polysaccharides from Lentinus edodes (SLNT1 and JLNT1) significantly inhibited tumor growth in H22-bearing mice by enhancing immune responses and inducing apoptosis (Wang et al., 2013).
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 330 Polysaccharides from Actinidia eriantha roots (AEP) also exhibited significant antitumor activity in mouse models by promoting splenocyte proliferation, NK cell activity, and cytokine production, thereby enhancing the immune response (Xu et al., 2009). Additionally, polysaccharides fromPanax japonicus (PSPJ) repressed H22 tumor growth in vivo by modulating immune responses and reducing immunosuppressive factors in tumor-associated macrophages (Shu et al., 2018). Sanghuangporus polysaccharides exhibit potent antitumor effects through various mechanisms, including cell cycle regulation, apoptosis induction, and immune modulation. These findings highlight the potential of Sanghuangporus polysaccharides as natural therapeutic agents for cancer treatment. 4 Mechanisms of Sanghuangporus Polysaccharides-Induced Tumor Cell Apoptosis 4.1 Methods for detecting apoptosis To investigate the antitumor effects of Sanghuangporus polysaccharides, various methods are employed to detect apoptosis in cancer cells. Common techniques include the Cell Counting Kit-8 (CCK-8) assay, which measures cell viability, and Hoechst staining, which identifies apoptotic cells by their characteristic nuclear morphology (Figure 5) (Ding et al., 2020). Flow cytometry is another critical method used to analyze cell cycle distribution and quantify apoptotic cells by detecting sub-G1 peaks (Cao et al., 2010). Additionally, TUNEL assay and PI staining are utilized to confirm DNA fragmentation and other morphological changes associated with apoptosis (Song et al., 2014; Chen, 2024). Figure 5 Inhibitory effects of Sargassum fusiforme polysaccharide (SFPS) on the growth of human erythroleukemia (HEL) cells and human embryonic lung (MRC-5) cells relative to DMEM-treated control cultures (Adopted from Ding et al., 2020) Image caption: Data are presented as the mean ± SD (n=5). HEL cells and MRC-5 cells were incubated with (A) SFPS I, (B) SFPS II, and (C) SFPS III (10~100 μg·mL−1) for 24 h. (D) IC50 values for the inhibition of HEL cell viability by different purified components of SFPS. Cell viability was measured using CCK-8 and MTT assays (Adopted from Ding et al., 2020) Western blot analysis is frequently used to detect the expression of apoptosis-related proteins, providing insights into the molecular mechanisms underlying apoptosis (Cao et al., 2010; Bie et al., 2020). Real-time quantitative polymerase chain reaction (qPCR) is employed to measure the mRNA levels of genes involved in apoptosis, offering a comprehensive understanding of gene regulation during the apoptotic process (Ding et al., 2020; Xu et al., 2021). 4.2 Study of apoptotic signaling pathways Sanghuangporus polysaccharides induce apoptosis through multiple signaling pathways. One of the primary pathways is the intrinsic mitochondrial pathway, which involves the disruption of mitochondrial membrane potential and the release of cytochrome c into the cytoplasm. This pathway is characterized by the activation of
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 331 caspase-9 and caspase-3, leading to the execution of apoptosis (Cao et al., 2010; Wu et al., 2014). The intrinsic pathway is often regulated by the balance between pro-apoptotic (e.g., Bax) and anti-apoptotic (e.g., Bcl-2) proteins (Figure 6) (Cui et al., 2016; Wan et al., 2020). Figure 6 Mechanism diagram of cell apoptosis signaling pathway Another significant pathway is the extrinsic death receptor pathway, which involves the binding of ligands to death receptors such as FAS, leading to the activation of caspase-8 and subsequent activation of downstream caspases (Yu et al., 2020). This pathway can also interact with the intrinsic pathway through the cleavage of Bid, a pro-apoptotic Bcl-2 family member, linking the two apoptotic mechanisms (Carneiro and El-Deiry, 2020). Additionally, Sanghuangporus polysaccharides have been shown to modulate other signaling pathways, such as the PI3K/AKT and MAPK pathways. These pathways play crucial roles in cell survival and proliferation, and their inhibition can promote apoptosis. For instance, the polysaccharide from Grifola frondosa (GFP-A) was found to inhibit the PI3K/AKT pathway and activate the MAPK pathway, leading to increased apoptosis in HT-29 cells (Bie et al., 2020). Similarly, the AMPK/PI3K/mTOR pathway is involved in the regulation of apoptosis and autophagy, with polysaccharides from Pleurotus nebrodensis (PN50G) shown to activate AMPK and inhibit PI3K/AKT, promoting apoptosis in A549 cells (Cui et al., 2016). 4.3 Expression of apoptosis-related genes and proteins The expression of apoptosis-related genes and proteins is a critical aspect of understanding the molecular mechanisms of Sanghuangporus polysaccharides-induced apoptosis. Key genes involved in the intrinsic pathway include Bax, Bcl-2, and caspases. Studies have shown that treatment with Sanghuangporus polysaccharides leads to the upregulation of Bax and downregulation of Bcl-2, promoting the release of cytochrome c and activation of caspase-9 and caspase-3 (Wu et al., 2014; Wan et al., 2020). This regulation of gene expression is crucial for the initiation and execution of apoptosis. In the extrinsic pathway, the expression of death receptors such as FAS and their ligands (FAS-L) is upregulated, leading to the activation of caspase-8 and subsequent apoptosis (Yu et al., 2020). The interaction between the intrinsic and extrinsic pathways is further evidenced by the cleavage of Bid, linking the two apoptotic mechanisms (Song et al., 2014).
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 332 Moreover, the modulation of other signaling pathways also affects the expression of apoptosis-related genes and proteins. For example, the inhibition of the PI3K/AKT pathway by GFP-A results in decreased expression of anti-apoptotic proteins and increased expression of pro-apoptotic proteins, enhancing apoptosis in HT-29 cells (Bie et al., 2020). Similarly, the activation of AMPK and inhibition of mTOR by PN50G leads to changes in the expression of proteins involved in cell cycle regulation and apoptosis, promoting cell death in A549 cells (Cui et al., 2016). Sanghuangporus polysaccharides induce tumor cell apoptosis through multiple mechanisms, involving the intrinsic and extrinsic pathways, as well as the modulation of other signaling pathways. The detection of apoptosis, study of signaling pathways, and analysis of gene and protein expression provide a comprehensive understanding of the molecular mechanisms underlying the antitumor effects of Sanghuangporus polysaccharides. These findings highlight the potential of Sanghuangporus polysaccharides as promising agents for cancer therapy. 5 Antioxidant Stress Effects of Sanghuangporus Polysaccharides and Their Antitumor Mechanisms 5.1 Relationship between oxidative stress and tumor development Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify these reactive intermediates, plays a crucial role in the development and progression of tumors. Excessive ROS can damage cellular components, including DNA, proteins, and lipids, leading to mutations and genomic instability, which are hallmarks of cancer. The persistent oxidative environment promotes oncogenic signaling pathways, such as those involving NF-κB and HIF, which further drive tumorigenesis by enhancing cell proliferation, survival, and angiogenesis (Jiao et al., 2016). Moreover, oxidative stress can modulate the tumor microenvironment, making it more conducive to cancer progression. For instance, ROS can activate stromal cells and immune cells within the tumor microenvironment, leading to the secretion of pro-inflammatory cytokines and growth factors that support tumor growth and metastasis (Jiao et al., 2016). Therefore, targeting oxidative stress and its associated pathways presents a promising strategy for cancer prevention and therapy. 5.2 Analysis of antioxidant activity of Sanghuangporus polysaccharides Sanghuangporus polysaccharides have demonstrated significant antioxidant activities, which are pivotal in their antitumor effects. These polysaccharides can scavenge various free radicals, including DPPH, superoxide, and hydroxyl radicals, thereby reducing oxidative stress within the body (Shao et al., 2014; Wang et al., 2018). The antioxidant potential of Sanghuangporus polysaccharides is dose-dependent, with higher concentrations exhibiting greater free radical scavenging abilities (Wang et al., 2018). In addition to direct free radical scavenging, Sanghuangporus polysaccharides can enhance the body's endogenous antioxidant defense systems. For example, they have been shown to upregulate the expression of antioxidant enzymes such as superoxide dismutase (SOD) and catalase, which play critical roles in neutralizing ROS (Wang et al., 2018). This dual mechanism of action-direct scavenging of free radicals and boosting endogenous antioxidant defenses-makes Sanghuangporus polysaccharides potent agents against oxidative stress. 5.3 Mechanisms of tumor inhibition by Sanghuangporus polysaccharides through antioxidant stress Sanghuangporus polysaccharides inhibit tumor growth through multiple mechanisms, primarily by mitigating oxidative stress. By reducing ROS levels, these polysaccharides prevent the oxidative damage to DNA, proteins, and lipids that can lead to mutations and cancer progression. This reduction in oxidative stress also disrupts the oncogenic signaling pathways that are often activated by ROS, such as the NF-κB and HIF pathways, thereby inhibiting tumor cell proliferation and survival (Jiao et al., 2016). Furthermore, Sanghuangporus polysaccharides can induce apoptosis in tumor cells by modulating the expression of apoptosis-related genes. For instance, they have been shown to enhance the activation of p53-related genes, which are crucial for the induction of apoptosis in cancer cells (Wan et al., 2020). This activation leads to the downregulation of anti-apoptotic proteins like Bcl-2 and the upregulation of pro-apoptotic proteins like Bax,
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 333 thereby promoting cell death in tumor cells. Additionally, Sanghuangporus polysaccharides can arrest the cell cycle at specific phases, such as the G0/G1 and S phases, further inhibiting tumor cell proliferation (Shao et al., 2014). Another key mechanism by which Sanghuangporus polysaccharides exert their antitumor effects is through the regulation of the tumor microenvironment. These polysaccharides can modify the immune landscape within tumors, promoting the infiltration and activation of immune cells that target cancer cells. For instance, polysaccharide components such as SSP1 were extracted and isolated from Sanghuangporus derived from mulberry and analyzed for their structure and monosaccharide composition. Network pharmacology and molecular docking analysis revealed that SSP1 might inhibit HepG2 tumor cells through core targets such as VEGFA and AR. These polysaccharides can also enhance the activity of macrophages and T cells, which is crucial for initiating an effective antitumor immune response. This immunomodulatory effect is partially mediated by the antioxidant properties of Sanghuangporus polysaccharides, which reduce the immunosuppressive effects of oxidative stress in the tumor microenvironment (Yu et al., 2021b). Sanghuangporus polysaccharides inhibit tumor growth through a multifaceted approach that involves reducing oxidative stress, inducing apoptosis, arresting the cell cycle, and modulating the tumor microenvironment. These combined actions make Sanghuangporus polysaccharides promising candidates for cancer therapy, particularly in strategies aimed at targeting oxidative stress and enhancing immune responses against tumors. 6 Combined Application of Sanghuangporus Polysaccharides with Conventional Antitumor Drugs 6.1 Antitumor effects of combined drug therapy Sanghuangporus polysaccharides, as the main active components of the medicinal fungus Sanghuangporus, have been shown to effectively inhibit tumor growth and metastasis and induce apoptosis in tumor cells. Additionally, when used in combination with conventional chemotherapy drugs, Sanghuangporus polysaccharides can enhance antitumor effects. The mechanisms involved include modulating immune responses and directly acting on tumor cells, which can improve the efficacy of traditional chemotherapy, leading to better treatment outcomes and reduced side effects. For example, polysaccharides extracted from Sanghuangporus vaninii (SVP) have demonstrated the ability to inhibit tumor cell proliferation, induce apoptosis, and reduce the migration and invasion of cancer cells, particularly in breast cancer models (Wan et al., 2020). When combined with conventional chemotherapy drugs, these polysaccharides enhance antitumor effects by modulating the tumor microenvironment and boosting immune responses (Wang et al., 2022b; Li et al., 2023). Studies have shown that natural polysaccharides, including those fromSanghuangporus, can significantly increase the efficacy of chemotherapy drugs such as cisplatin in ovarian cancer by inhibiting cell proliferation, inducing apoptosis, and enhancing immunomodulatory activities (Wang et al., 2022b). This synergistic effect not only improves the antitumor efficacy but also helps in mitigating the adverse effects commonly associated with chemotherapy, making the treatment more tolerable for patients. 6.2 Molecular mechanisms of combined drug therapy The molecular mechanisms underlying the enhanced antitumor effects of combined therapy involving Sanghuangporus polysaccharides and conventional drugs are multifaceted. One of the key mechanisms is the activation of the p53 signaling pathway, which plays a crucial role in regulating cell cycle arrest and apoptosis. SVP, for example, has been shown to enhance the activation of p53-related genes and down-regulate matrix metalloproteinase (MMP) expression, thereby inhibiting tumor growth and metastasis (Wan et al., 2020). Additionally, polysaccharides can modulate the tumor microenvironment by enhancing the immune response. They activate both non-specific and specific immune responses, leading to the inhibition of tumor proliferation and metastasis (Figure 7) (Ying and Hao, 2023). Polysaccharides also improve the delivery and efficacy of chemotherapy drugs through the use of stimulus-responsive nanomedicines, which allow for controlled drug
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 334 release and targeted delivery to the tumor site (Li et al., 2023). This targeted approach not only maximizes the therapeutic effects but also minimizes systemic toxicity. Figure 7 Anti-tumor mechanism of natural polysaccharides (Adopted from Ying and Hao, 2023) Image caption: Polysaccharides not only induce apoptosis by directly acting on tumor cells, but also inhibit the occurrence and development of tumors by acting on tumor microenvironment (TME); Among them, (A) indicates that natural polysaccharides promote the expression of cytokines such as IL-2, IFN-γ and IL-12, inhibit the expression of cytokines such as IL-4, IL-5, IL-10 and IL-13, resluting in promoting the differentiation of Th0 cells into Th1 cells, which have anti-tumor effect. What’s more, natural polysaccharides activate DC cells, allowing them to function normally in antigen presentation; (B) indicates that polysaccharide reduces the concentration of cytokines such as IL-6, IL-10, COX-2 and TGF-β in TME, so as to promote the differentiation of M1 macrophages,which play an anti-tumor role; (C) indicates that polysaccharides down regulate the expression of VEGF and so inhibit tumor related angiogenesis; (D) shows the direct anti-tumor effect of natural polysaccharides: cell cycle arrest and inducing apoptosis (Adopted from Ying and Hao, 2023) Chemical modifications of polysaccharides, such as sulfation, phosphorylation, and selenylation, have been shown to further enhance their antitumor activities and improve their physicochemical properties, such as water solubility and molecular weight (Xie et al., 2020; Li et al., 2021). These modifications can lead to more effective interactions with conventional chemotherapy drugs, resulting in a more robust antitumor response. 6.3 Clinical prospects of combined therapy The clinical prospects of combining Sanghuangporus polysaccharides with conventional antitumor drugs are highly promising. The synergistic effects observed in preclinical studies suggest that such combinations could lead to more effective and less toxic cancer treatments. Polysaccharides' ability to enhance the efficacy of chemotherapy drugs while reducing their side effects makes them attractive candidates for adjuvant therapy in clinical settings (Chen and Huang, 2018; Yang et al., 2021). Moreover, the use of polysaccharides in combination with other therapeutic modalities, such as immunotherapy, photodynamic therapy, and photothermal therapy, has shown potential in preclinical studies. These combination
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 335 strategies can lead to improved antitumor efficacy by targeting multiple pathways and mechanisms involved in tumor growth and progression (Li et al., 2023). The broad application prospects of polysaccharides are further supported by their non-toxic nature and ability to enhance the quality of life for cancer patients. As more efficient polysaccharides with antitumor activities are discovered, their integration into clinical practice is expected to grow, providing new avenues for cancer treatment (Yang et al., 2021). The combined application of Sanghuangporus polysaccharides with conventional antitumor drugs holds significant potential for improving cancer treatment outcomes. The synergistic effects, molecular mechanisms, and clinical prospects discussed herein highlight the importance of further research and development in this area to fully realize the therapeutic benefits of such combinations. 7 Potential of Sanghuangporus Polysaccharides in Cancer Prevention 7.1 Anti-inflammatory and immunomodulatory effects of Sanghuangporus polysaccharides Sanghuangporus polysaccharides have demonstrated significant anti-inflammatory and immunomodulatory effects, which are crucial in cancer prevention. These polysaccharides can modulate the immune system by enhancing the activity of various immune cells, such as lymphocytes and myeloid cells, thereby boosting the body's natural defense mechanisms against cancerous cells (Ren et al., 2020). The immunomodulatory activities of these polysaccharides are attributed to their ability to stimulate both innate and adaptive immune responses, which are essential for identifying and eliminating tumor cells (Ramberg et al., 2010; Ren et al., 2020). Moreover, the anti-inflammatory properties of Sanghuangporus polysaccharides help in reducing chronic inflammation, a known risk factor for cancer development. Chronic inflammation can lead to DNA damage, promote tumor growth, and create an environment conducive to cancer progression. By mitigating inflammation, Sanghuangporus polysaccharides can potentially lower the risk of cancer initiation and progression (Wang et al., 2022b; Pradhan et al., 2023). These combined anti-inflammatory and immunomodulatory effects make Sanghuangporus polysaccharides a promising candidate for cancer prevention strategies. 7.2 Application of Sanghuangporus polysaccharides in early cancer prevention The application of Sanghuangporus polysaccharides in early cancer prevention is supported by their ability to inhibit tumor growth and induce apoptosis in cancer cells. Studies have shown that these polysaccharides can regulate cell cycle progression, promote apoptosis, and reduce the migratory and invasive capacities of cancer cells. For instance, polysaccharides from Sanghuangporus vaninii have been found to activate the p53 signaling pathway, which plays a critical role in controlling cell proliferation and apoptosis in breast cancer cells (Wan et al., 2020). This suggests that Sanghuangporus polysaccharides can be effective in preventing the early stages of cancer by targeting and eliminating abnormal cells before they develop into malignant tumors. Additionally, the antioxidant properties of Sanghuangporus polysaccharides contribute to their cancer-preventive effects. Antioxidants neutralize free radicals, which can cause oxidative stress and DNA damage, leading to cancer. By scavenging these free radicals, Sanghuangporus polysaccharides help protect cells from oxidative damage and reduce the likelihood of cancer development (Wang et al., 2022b; Pradhan et al., 2023). These properties highlight the potential of Sanghuangporus polysaccharides as a natural and effective means of early cancer prevention. 7.3 Application of Sanghuangporus polysaccharides in dietary supplements The incorporation of Sanghuangporus polysaccharides into dietary supplements offers a practical approach to harness their cancer-preventive properties. As dietary supplements, these polysaccharides can be consumed regularly to provide continuous support to the immune system and maintain overall health. The safety and tolerability of polysaccharides from various sources, including Sanghuangporus, have been well-documented, making them suitable for long-term use as dietary supplements (Ramberg et al., 2010; Li et al., 2021).
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 336 Dietary polysaccharides have been shown to exert significant immunomodulatory effects in both animal and human studies, enhancing immune function and potentially improving the body's ability to fight off cancerous cells. For example, glucan extracts from mushrooms have been found to improve survival and immune function in cancer patients, suggesting that similar benefits could be achieved with Sanghuangporus polysaccharides (Ramberg et al., 2010). Furthermore, the use of these polysaccharides as dietary supplements can provide additional health benefits, such as improved gut health and reduced inflammation, which are important for overall well-being and cancer prevention (Wang et al., 2022b; Pradhan et al., 2023). Sanghuangporus polysaccharides hold great potential in cancer prevention through their anti-inflammatory, immunomodulatory, and antioxidant properties. Their application in early cancer prevention and as dietary supplements offers a promising strategy for reducing cancer risk and promoting health. Continued research and development of Sanghuangporus polysaccharides will further elucidate their mechanisms of action and optimize their use in cancer prevention and health maintenance. 8 Future Research Directions and Challenges 8.1 In-depth research on molecular mechanisms of Sanghuangporus polysaccharides The molecular mechanisms underlying the antitumor effects of Sanghuangporus polysaccharides remain an area ripe for exploration. Current studies have shown that these polysaccharides can regulate cell cycles, promote apoptosis, and reduce the migratory and invasive capacities of cancer cells. For instance, Sanghuangporus vaninii polysaccharides (SVP) have been found to activate p53-related genes and down-regulate matrix metalloproteinase (MMP) expression, thereby inhibiting tumor growth and metastasis in breast cancer cells (Wan et al., 2020). However, the precise molecular pathways and interactions involved are not fully understood. Future research should focus on elucidating these mechanisms through advanced molecular biology techniques such as transcriptomics, proteomics, and metabolomics. Additionally, the role of structural modifications of polysaccharides, such as sulfation and phosphorylation, in enhancing their antitumor activity should be investigated (Huang and Huang, 2017). Understanding these mechanisms will provide a solid foundation for developing more effective Sanghuangporus polysaccharide-based therapies. 8.2 Challenges in developing Sanghuangporus polysaccharides as antitumor drugs Despite the promising antitumor properties of Sanghuangporus polysaccharides, several challenges hinder their development into clinically viable drugs. One major challenge is the variability in polysaccharide composition and bioactivity due to differences in extraction methods, sources, and strains of Sanghuangporus (Wang et al., 2022b; Wang and Huang, 2024). Standardizing the extraction and purification processes is crucial to ensure consistent quality and efficacy. Another challenge is the limited understanding of the pharmacokinetics and bioavailability of these polysaccharides in the human body. Studies have shown that polysaccharides can have significant antitumor effects in vitro and in animal models, but their effectiveness in humans remains to be validated through clinical trials (Zhao et al., 2021). Additionally, the potential side effects and toxicity of long-term use of Sanghuangporus polysaccharides need to be thoroughly assessed. Addressing these challenges requires a multidisciplinary approach involving pharmacologists, biochemists, and clinical researchers. 8.3 Clinical application prospects of Sanghuangporus polysaccharides The clinical application of Sanghuangporus polysaccharides holds great promise, particularly in the field of oncology. Their ability to enhance immune function, as demonstrated by the increased secretion of cytokines such as IL-2, IL-6, and IFN-γ, positions them as potential adjuvants in cancer therapy (Zhu et al., 2023). Moreover, the antioxidant and anti-inflammatory properties of these polysaccharides could help mitigate the side effects of conventional cancer treatments such as chemotherapy and radiation therapy. Clinical trials are essential to validate the efficacy and safety of Sanghuangporus polysaccharides in human patients. For example, a meta-analysis of Grifola frondosa polysaccharides has shown significant tumor inhibition and immune enhancement in preclinical studies, suggesting a potential for similar outcomes with Sanghuangporus polysaccharides (Zhao et al., 2021). Furthermore, the integration of Sanghuangporus polysaccharides into functional foods and dietary supplements could provide a preventive approach to cancer, leveraging their health-promoting properties
International Journal of Molecular Medical Science, 2024, Vol.14, No.6, 324-341 http://medscipublisher.com/index.php/ijmms 337 (Wang et al., 2022b). However, rigorous clinical studies and regulatory approvals are necessary to translate these prospects into reality. While Sanghuangporus polysaccharides exhibit significant antitumor potential, further research is needed to fully understand their molecular mechanisms, overcome development challenges, and realize their clinical application. Collaborative efforts across various scientific disciplines will be key to unlocking the therapeutic potential of these natural compounds. 9 Concluding Remarks The studies on Sanghuangporus polysaccharides have demonstrated significant antitumor effects across various cancer models. Specifically, Sanghuangporus vaninii polysaccharides (SVP) have shown to inhibit tumor proliferation, regulate the cell cycle, promote apoptosis, and reduce the migratory and invasive capacities of cancer cells, particularly in breast cancer MCF-7 cells. The mechanism involves the activation of p53-related genes and down-regulation of MMP expression. Additionally, polysaccharides from other sources, such as Grifola frondosa and Actinidia eriantha, have also exhibited potent antitumor activities by enhancing immune responses and inducing apoptosis in tumor cells. The structural characterization of these polysaccharides reveals that their antitumor efficacy is closely related to their specific molecular compositions and structural features. The research on Sanghuangporus polysaccharides has significantly contributed to the understanding of natural polysaccharides as potential antitumor agents. These studies have provided insights into the molecular mechanisms underlying the antitumor effects of these polysaccharides, highlighting their ability to modulate key signaling pathways, such as the p53 pathway, and to enhance immuneresponses. Furthermore, the structural analysis of these polysaccharides has elucidated the relationship between their molecular structure and biological activity, paving the way for the development of more effective polysaccharide-based therapies. The findings also underscore the potential of Sanghuangporus polysaccharides as functional foods and nutraceuticals with health-promoting properties. The promising antitumor effects of Sanghuangporus polysaccharides suggest their potential application in cancer therapy. Future research should focus on clinical trials to validate the efficacy and safety of these polysaccharides in human subjects. Additionally, the structural modification of polysaccharides could further enhance their antitumor activity, offering new avenues for the development of novel anticancer drugs. The immunomodulatory properties of these polysaccharides also indicate their potential use in combination therapies to boost the immune response in cancer patients. Moreover, the antioxidant and anti-inflammatory activities of Sanghuangporus polysaccharides highlight their potential in the prevention and treatment of other diseases, such as ulcerative colitis, thereby broadening their therapeutic applications. By advancing our understanding of the antitumor mechanisms and therapeutic potential of Sanghuangporus polysaccharides, these studies lay the groundwork for future research and development in the field of natural product-based cancer therapies. Acknowledgments Thank you to the anonymous peer review for providing targeted revision suggestions for the manuscript. Funding This research was fiinded by agrant from Changchun Sci-Tech University Youth Fund Project 2024ZD001. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Bie N., Han L., Wang Y., Wang X., and Wang C., 2020, A polysaccharide from Grifola frondosa fruit body induces HT-29 cells apoptosis by PI3K/AKT-MAPKs and NF-κB-pathway, International Journal of Biological Macromolecules, 147: 79-88. https://doi.org/10.1016/j.ijbiomac.2020.01.062
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