Associated Targets of the Antioxidant Cardioprotection of <i>Ganoderma lucidum</i> in Diabetic Cardiomyopathy by Using Open Targets Platform: A Systematic Review

Shaher, Fahmi; Qiu, Hongbin; Wang, Shuqiu; Hu, Yu; Wang, Weiqun; Zhang, Yu; Wei, Yao; AL-ward, Hisham; Abdulghani, Mahfoudh A. M.; Alenezi, Sattam Khulaif; Baldi, Salem; Zhou, Shaobo

doi:https://doi.org/10.1155/2020/7136075

BioMed Research International

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Abstract Introduction Methods Results Discussion Abbreviations Conflicts of Interest Authors’ Contributions Acknowledgments Supplementary Materials References Copyright Related Articles

Review Article | Open Access

Volume 2020 | Article ID 7136075 | https://doi.org/10.1155/2020/7136075

Associated Targets of the Antioxidant Cardioprotection of Ganoderma lucidum in Diabetic Cardiomyopathy by Using Open Targets Platform: A Systematic Review

Fahmi Shaher,¹Hongbin Qiu,¹Shuqiu Wang,¹Yu Hu,¹Weiqun Wang,²Yu Zhang,³Yao Wei,¹Hisham AL-ward,⁴Mahfoudh A. M. Abdulghani,⁵Sattam Khulaif Alenezi,⁵Salem Baldi,⁶and Shaobo Zhou⁷

Academic Editor: Miroslav Pohanka

Received12 Apr 2020

Revised05 Jun 2020

Accepted09 Jun 2020

Published25 Jul 2020

Abstract

Even with substantial advances in cardiovascular therapy, the morbidity and mortality rates of diabetic cardiomyopathy (DCM) continually increase. Hence, a feasible therapeutic approach is urgently needed. Objectives. This work is aimed at systemically reviewing literature and addressing cell targets in DCM through the possible cardioprotection of G. lucidum through its antioxidant effects by using the Open Targets Platform (OTP) website. Methods. The OTP website version of 19.11 was accessed in December 2019 to identify the studies in DCM involving G. lucidum. Results. Among the 157 cell targets associated with DCM, the mammalian target of rapamycin (mTOR) was shared by all evidence, drug, and text mining data with 0.08 score association. mTOR also had the highest score association 0.1 with autophagy in DCM. Among the 1731 studies of indexed PubMed articles on G. lucidum published between 1985 and 2019, 33 addressed the antioxidant effects of G. lucidum and its molecular signal pathways involving oxidative stress and therefore were included in the current work. Conclusion. mTOR is one of the targets by DCM and can be inhibited by the antioxidative properties of G. lucidum directly via scavenging radicals and indirectly via modulating mTOR signal pathways such as Wnt signaling pathway, Erk1/2 signaling, and NF-κB pathways.

1. Introduction

Cardiovascular complications are associated with diabetes and lead to high mortality [1, 2]. Diabetic cardiomyopathy (DCM) is one of the main causes of heart injury and death in patients with diabetes. A total of 1.6 million deaths worldwide are directly attributed to diabetes every year [3]. Independent of coronary artery disease, DCM has increased prevalence during the last two decades and is experienced by 55% of patients with diabetes [4]. With diabetes being a global epidemic, the number of patients with DCM has increased. For the last two decades, the number of people with diabetes worldwide has increased from 151 million in 2000 to 425 million in 2017 and is estimated to increase to 629 million by 2045 [5]. The risk of developing DCM is higher for patients with diabetes than that for those without diabetes [6] and increases 2 to 4 times for those with more than a 10-year span of diabetes [7, 8]. Once DCM has developed, reducing its morbidity and mortality is difficult even with pharmacological improvement in terms of regulating blood glucose and insulin sensitivity. Clinical and preclinical investigations have examined the complexity of the pathophysiological consequences of DCM.

Clinical studies in patients with DCM reported that the pathological remodeling of the heart, which is characterized by left ventricular concentric hypertrophy and perivascular and interstitial fibrosis commencing to diastolic dysfunction and extended contraction and relaxation [9, 10], shortens ventricular ejection and increases wall stiffness [11, 12]. The influence of the diabetic condition on heart and cardiomyocyte function has been experimentally evaluated.

DCM and cardiac dysfunction are initiated in diabetic-induced experimental animals from 2 to 12 weeks [13]. Streptozotocin-induced diabetes in mice leads to the morphological changes of heart tissues, interstitial collagen deposition, cardiac hypertrophy, fibrosis, and remarkable elevation of paracrine of angiotensin II level in myocardium and NADPH oxidase activities, which are considered the primary source of free radicals in the cardiomyocytes of diabetic heart [14]. Connective tissue growth factor mediates cardiac fibrosis in diabetes [13, 15]. In diabetic mice with cardiomyopathy, the expression of sarcoplasmic reticulum calcium ATPase and [Ca⁺²] ion transient is reduced [16]. Sarcoplasmic reticulum calcium ATPase is a primary cardiac isoform of calcium pump transporting calcium from cytoplasm to sarcoplasmic reticulum during diastolic relaxation [17].

Even with substantial advances in cardiovascular therapy, diabetic morbidity and mortality rate are continually increasing, and a feasible therapeutic approach for DCM is still lacking. Exploring the medication targets for DCM may further identify novel drugs and improve specific therapies for DCM. Therapeutic targets for DCM with natural resources are considered as one of the main reservoirs for drug discovery. Therefore, novel therapeutics for a range of targets must be developed to prevent DCM progression. This study identifies molecular target involvement and its association with DCM by using the Open Targets Platform (OTP) website established by Biogen, EMBL European Bioinformatics Institute, GlaxoSmithKline, and Wellcome Trust Sanger Institute. The OTP provides comprehensive and up-to-date data for drug molecular targets associated with relative diseases. Oxidative stress (OS) may be a key factor in the molecular and cellular mechanisms of diabetes-induced DCM [18]. Hence, targeting OS-related processes could be a promising therapeutic strategy for DCM.

Ganoderma (G.) lucidum, which is known in Chinese as “Lingzhi,” is a medicinal mushroom commonly used as a Chinese herbal medicine and the main ingredient in many conventional combinations or dietary supplements [19]. This name has been proposed by Petter Adolf Karsten from England in the late 19^th century and has been applied in various places such as Asia, Africa, Oceania, and Europe [20]. Lingzhi has been widely cultivated in China and has a long history as a traditional Chinese medicine. Chinese G. lucidum exhibits high variability of basidioma morphology and more or less consistency in its microscopic characters, e.g., short clavate cutis elements, Bovista-type ligative hyphae, and strongly echinulated basidiospores [21]. G. lucidum also contains various bioactive compounds, such as flavonoids, ganoderic acid, phenolics, and polysaccharides [21], that can treat many chronic diseases including diabetes and its complications by counteracting OS. Preclinical studies reported the beneficial effects of G. lucidum against OS-induced diseases, its liver protection against CCl₄-induced OS [22], skin protection against croton oil-induced lipid peroxidation in mice [23], and thymus and spleen protection against 5-fluorouracil-induced OS in mice [21]. This systematic review is aimed at discussing the potential cell targets and cardioprotective pathway of G. lucidum based on preclinical and clinical investigations.

2. Methods

The OTP website version 19.11 (OTP V 19.11) was used to prioritize and identify the targets associated with DCM. The OTP provides score and rank target-disease associations and integrates evidence from six resources, including genetics, genomics, transcriptomics, drugs, animal models, and scientific literature [24, 25]. Two main steps of searching were performed in December 2019. In the first step, the term “diabetic cardiomyopathy” was used, and all the targets associated with DCM were listed according to available evidence recorded through bioinformatic processing, including data evidence of drug, text mining, genetic association, somatic mutation, pathways and signals, RNA signal, and animal model. The resulting targets with the highest association with DCM from the first step were used to further search for evidence on G. lucidum cardioprotection.

This systematic review on the antioxidant activity of G. lucidum was described as follows. Abstracts published from 1985 to July 2019 were reported as guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [26] (Figure 1). The key terms used were G. lucidum and spore of G. lucidum. In this step, the studies were divided into seven 5-year periods to easily read and select related abstracts. The search was limited to studies published in English and Chinese languages. Inclusion criteria were as follows: studies must focus on (1) G. lucidum and its (2) antioxidant, antidiabetic, and cardioprotective activities. Exclusion criteria were as follows: studies focusing on (1) mushrooms other than G. lucidum and (2) not related to its antioxidant activities such as the botanical and genetic studies of G. lucidum.

3. Results

3.1. Targets Associated with DCM in Diabetes Integrated by OTP

3.1.1. DCM and Its Associated Targets

A total of 309 targets were associated with DCM based on evidence from drug and text mining data with overall association scores from 0.004 to 0.177 (Table 1, supplementary file (available here)). Among the selected drug data, only two targets, namely, carnitine palmitoyltransferase 1B (CPT1B) and 2 (CPT2) were associated with DCM with 0.1 score association. A total of 306 targets were identified from text mining. Only the mechanistic target of rapamycin kinase (mTOR) was common in both types of data. A total of 309 targets were expressed in 32 tissue organs including the heart and were involved in 19 pathway types (Table 2, supplementary file (available here)). Among these 309 targets, 155 were expressed in the heart tissues with overall association scores ranging from 0.007 to 0.177 (Table 1). Among the 19 pathways, 4 targets were included in autophagy (Table 2), namely, mTOR, beclin 1 (BECN1), parkin RBR E3 ubiquitin protein ligase (PRKN), and voltage-dependent anion channel 1 (VDAC1) with scores of 0.1, 0.06, 0.05, and 0.03, respectively.

mTOR was further investigated, and its association with heart diseases ranged from 0.0004 to 0.8588, which is the overall association score for 49 subtypes of heart diseases. mTOR had 0.1 and 0.8 overall association scores with DCM and hypertrophic cardiomyopathy, respectively (Table 3).

mTOR is a serine/threonine-protein kinase playing as a central regulator of cellular metabolism, growth, and survival in response to hormone growth factor [27], nutrients, energy, and stress signals [28, 29]. According to UniPort, mTOR can be found in different subcellular locations including the membranes of endoplasmic reticulum, Golgi apparatus, outer mitochondrion, microsome, and lysosome; lysosome, cytoplasm, nucleus, and PML nuclear body. The RNA and protein expression levels of mTOR are present in several organs including the heart, e.g., the medium RNA and high protein levels of mTOR are expressed in the left ventricle, atrium, and coronary artery but not in the heart muscles (Figure 2).

3.1.2. Evidence on the Cardioprotection of G. lucidum

A total of 1731 articles were identified (Figure 3) and further divided into seven 5-year time periods. The first period ranged from 1985 to 1989, and the last period ranged from August 2018 to August 2019 (Figure 1). These articles were reviewed in the following three phases. First, 1571 articles remained after the duplicated ones were removed. Second, articles that did not satisfy the inclusion criteria based solely on their titles (remaining 1399 articles) and abstracts (remaining 59 articles) were excluded. Lastly, the remaining articles were scanned, and those that did not meet our inclusion criteria were excluded. After the initial screening of titles and abstracts, the 59 remaining articles were screened for the second time by two individual reviewers. Inclusion of full articles was agreed upon by two reviewers prior to data extraction. Finally, 33 studies were considered eligible for the review (Figure 2). In this section, the collected pieces of evidence were divided into two main parts, namely, the in vivo antioxidant of G. lucidum (14 studies, Table 4), in which the in vivo effect of antioxidant on the parameters related to OS was discussed, and the in vitro antioxidant of G. lucidum (19 studies, Table 5), in which the in vitro effect of antioxidant activities and possible molecular mechanisms was elaborated.

3.2. In Vivo Antioxidant Activity and Protective Effect of G. lucidum

According to 10 in vivo experimental studies, G. lucidum has antioxidant activities and protects against OS through four main factors in different tissues, such as the heart, liver, thymus, spleen, eyes, and skeletal muscles, and by regulating chemical-level OS parameters in blood circulation (Table 4). G. lucidum exhibits its antioxidant effects by increasing the antioxidant enzymes and inhibiting the enzymes involved in OS. G. lucidum also increases the activities of superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), mitochondrial succinate dehydrogenase (SDH), and Mn-SOD and reduces glutathione (GSH) levels. By contrast, G. lucidum decreases the activities of nitric oxide synthase (NOS), cytochrome P450 2E1 (CYP2E1), xanthine oxidase (XOD), and myeloperoxidase (MPO). G. lucidum also significantly decreases lipid peroxidation levels, advanced oxidation protein products (AOPPs), and malondialdehyde (MDA) levels.

The first factor is the four toxic substances, including CCl₄-induced oxidative stress (OS) in the liver, croton oil produced OS in the skin through inflammation, N-methyl-N-nitrosourea (MNU) causing retinal photoreceptor cell lesions in the eyes, and 5-fluorouracil-induced OS in the thymus and spleen of mice. Oral administration of G. lucidum polysaccharides (GLPs) represses free radical lipid peroxidation induced by CCl₄ to reduce the enzyme activities of NOS and CYP2E1. Significant inhibition of NOS and CYP2E1 activities and MDA and IL-1β levels was noted in liver tissues, and depleted levels of interleukin- (IL-) 1β, IL-18, IL-6, and tumor necrosis factor-α were found in serum. In CCl₄-induced liver damage, highly reactive trichloromethyl free radicals are generated by the cytochrome P450 isozymes (P450s) of the endoplasmic reticulum [22]. Topical administration of G. lucidum ethanol extract inhibits the croton oil-induced lipid peroxidation in the skin of mice [23]. Ganoderma spore lipid (GSL) shows a protective effect on MNU-induced retina injury by inhibiting the related apoptosis to modulate the expression levels of Bax, Bcl-xl, and caspase-3 [30]. GLPs also exhibit an antioxidant effect in 5-fluorouracil-induced OS and improve SOD, an intracellular compound that protects against oxidative processes initiated by superoxide anion and GPx contents in the spleen and thymus of mice [31].

The second factor creates conditions in biological systems that can induce OS, such as exercise-like exhaustive swimming, which is OS induced in skeletal muscles, and a carotid artery ligation, which disturbs the flow-induced OS level of manganese-dependent superoxide dismutase (Mn-SOD) in blood vessels. GLPs show protective effects against comprehensive swimming-induced OS by improving the activities of antioxidant enzymes (SOD, GPx, and CAT) and decreasing the MDA levels in the skeletal muscle of mice [32]. Oral ganoderma triterpenoids (GTs) protect against disturbed flow-induced OS through carotid artery ligation, which leads to chronic OS and inflammation that are features of early atherogenesis in mice, and by preventing neointimal thickening 2 weeks after ligation. Early atherogenesis includes neointimal hyperplasia and endothelial dysfunction due to flow turbulence in the ligated artery as induced by OS. GTs alleviate OS and restore the atheroresistent status of endothelium by inhibiting endothelin-1 induction, von Willebrand factor, and monocyte chemoattractant protein-1 after 3-day ligation as atherogenic factors [33]. Inflammatory cytokines, OS-induced endothelial dysfunction, and chronic OS contribute to endothelial impairment and induces atherogenesis.

The third factor in OS includes diseases such as type II diabetes mellitus (DM) and cancer. In type II DM, the beneficial effects of G. lucidum on abnormal heart and testis and epididymal cells of rats with streptozotocin-induced type II DM were evaluated. GLPs improve the myocardial ultrastructure by reducing MDA, activating antioxidant enzymes (GSH-Px, CAT, SOD, and NO) in cardiac tissues, and reducing lipid peroxidation in type II DM rats [34]. G. lucidum spores protect the testis of rats with type II DM by substantially increasing the mitochondrial SDH and decreasing the activities of XOD and MPO [35]. G. lucidum spores protect epididymal cells and counteract their apoptosis that damages the mitochondria and disequilibrium of calcium homeostasis by reducing the amount of mitochondrial cytoplasm cytochrome C in type II DM rats [36]. GLP administration enhances the immunity and antioxidant activities in N-methyl-N9-nitro-nitrosoguanidine-induced gastric cancer in Wistar rats. GLP remarkably reduces the levels of serum IL-6 and TNF-α and increases the levels of serum IL-2, IL-4, and IL-10. In addition, GLP improves the levels of SOD, CAT, and GSH-Px in serum and gastric tissues [37].

The fourth factor involved in OS is aging. G. lucidum administration ameliorates the age-related decline of antioxidant status in aged mice, substantially elevates the activities of GST, Mn-SOD, GPx, and CAT, and reduces GSH. By contrast, lipid peroxidation, AOPP, and reactive oxygen species (ROS) are reduced [38] (Table 4).

3.3. In Vitro Antioxidant of G. lucidum and Its Possible Pathway

Chemical antioxidant tests consistently revealed the free radical scavenging activity of G. lucidum. Twelve studies reported the scavenging activity of G. lucidum for different free radicals including 2,2-diphenylpicrylhydrazyl radical (DPPH^⋅), 2,2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) radical (ABTS^⋅+), hydroxyl radical (HO^⋅), and hydrogen peroxide radicals (H₂O₂) [39–49] (Table 5). G. lucidum also inhibits lipid peroxidation [23, 49]. In some studies, G. lucidum protects against DNA damage [41, 42, 50]. The results of chemical antioxidant tests regarding the antioxidant properties of G. lucidum are also in agreement with the cell-based antioxidant assays. G. lucidum shows free radical scavenging activity for H₂O₂ in RAW264.7 cells incubated with G. lucidum lipopolysaccharide and protects against H₂O₂-induced cell death [48]. G. lucidum also hinders sphingomyelinase activity in incubated RAW264.7 cells with lipopolysaccharide [51]. In addition, G. lucidum prevents lipid peroxidation in two cell models, namely, WBCs incubated with lipopolysaccharide to induce OS [39] and hepatocytes incubated with CCl₄ to induce OS [52]. In both cell models, G. lucidum showed protection by elevating the antioxidant enzyme activity (SOD, GPx, and GR) and improving the GSH level. Moreover, G. lucidum protects macrophages in human monocytic cells incubated with lipopolysaccharide to stimulate NO production [53].

Wnt, Erk1/2, and NF-κB are the possible signaling pathways of G. lucidum that support its antioxidant and protective effects. A pancreatic cell study suggested β-catenin in the Wnt signaling pathway as a target of ganoderic acid A, thus leading to cell protection and effective scavenging of ROS [54]. The Wnt signaling pathways transfer the signals from extracellular to intercellular and are stimulated by the Wnt protein binding to the cytoplasmic family receptor, which occurs in downstream cell signaling and controls the transcription of genes. In the canonical Wnt pathway, β-catenin accumulates in the cytoplasm and is further translocated into the nucleus, and this phenomenon is widely recognized as a regulation marker of fat and glucose metabolism and β-catenin/Wnt signaling involved in insulin secretion [54]. In 2006, Thyagarajan and his colleagues mentioned that G. lucidum modulates Erk1/2 signaling and transcription factors AP-1 and NF-κB and downregulates c-Fos, whose expression can be induced by OS as the result of the inhibited OS-induced invasive behavior of breast cancer cells. A high H₂O₂ concentration (5 mM) can stimulate Erk1/2 signaling in MCF-7 cells [55].

In addition to its antioxidant activities, G. lucidum also exhibits an anti-inflammatory property and modulates the immune system. It can reverse LPS-induced inflammation by downregulating inflammatory mediators such as NF-κB, thus substantially inhibiting NOS and reducing NO level [39]. G. lucidum also modulates the immune system byregulating cytokine production in RAW264.7 macrophages [56, 57]. Moreover, it increases the formation of autophagosomes and controls proteins (Vps34, beclin 1, LC3-I, LC3-II, and p62) that induce autophagy in a gastric adenocarcinoma cell line. G. lucidum increases the cellular levels of LC3-II and decreases the cellular levels of p62 (Table 5).

4. Discussion

Among the 155 targets associated with DCM, mTOR, CPT1B, and CPT2 have the highest association. mTOR acts as a core regulator of cellular metabolism, growth, and survival in response to hormone growth factors, nutrients, energy, and stress signals. An animal study confirmed that streptozotocin-induced diabetes increases mTOR levels in rats [58]. mTOR can be found in different cellular locations including membrane, cytoplasm, and nucleus and different cellular organs (mitochondria, Golgi, and endoplasmic reticulum) and therefore is involved directly or indirectly in regulating the phosphorylation of at least 800 proteins (OPT.V19.11). mTOR functions through two distinct signaling complexes of mTORC1 and mTORC2 [59]. When activated, mTORC1 upregulates protein synthesis by phosphorylating the key regulators of mRNA translation and ribosome synthesis. mTORC1 also regulates protein synthesis [29], lipid synthesis [60], and mitochondrial biogenesis and stimulates the pyrimidine biosynthesis pathway through acute and delayed regulations. In acute regulation, mTORC1 stimulates pyrimidine biosynthesis through the ribosomal protein S6 kinase B1-mediated phosphorylation of biosynthetic enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase; these enzymes catalyze the first three steps in de novo pyrimidine synthesis [61]. In delayed regulation, mTORC1 stimulates pyrimidine biosynthesis through the transcriptional enhancement of the pentose phosphate pathway, which produces 5-phosphoribosyl-1-pyrophosphate, an allosteric activator of pyrimidine biosynthesis enzyme at a later step in the synthesis. In addition, mTORC1 regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through the phosphorylation and inhibition of MAF1 protein, a RNA polymerase III-repressor. When nutrients are available and mTOR kinase is active, MAF1 is hyperphosphorylated, and RNA polymerase III is engaged in the transcription [62]. Stress-induced MAF1 dephosphorylation resulted in nuclear localization, increased targeting of gene-bound RNA polymerase III, and decreased transcriptional readout [63, 64]. Moreover, mTORC1 is involved in the negative feedback regulation of autophagy on upstream growth factor signaling during microtubule regulation [64–66].

mTORC2 regulates other cellular processes such as survival and organization of cytoskeleton, actin cytoskeleton [67], osteoclastogenesis, and circadian clock function. In a pressure-overloaded male mouse heart, mTORC2 maintains a contractile function [68]. In brown adipose tissues, mTOR complex 2 has a role in β3-adrenoceptor-stimulated glucose uptake by stimulating the translocation of newly synthesized GLUT1 to the plasma membrane, thereby increasing the glucose uptake [69]. mTOR complex 2 regulates the proper turnover of insulin receptor substrate-1 [70].

G. lucidum exhibits cardiac protection via its antioxidant properties through OS modulation. This systemic review of 33 studies has documented its antioxidant activities. At the molecular and cellular levels, OS is a key in diabetes-induced DCM [18]. The antioxidant effects of G. lucidum are facilitated by increasing the antioxidant enzymes and inhibiting the enzymes involved in OS [33–35, 38]. G. lucidum consistently shows free radical scavenging activity against several free radicals including DPPH^⋅, ABTS^⋅+, HO^⋅, and H₂O₂. As confirmed by the in vitro (chemical and cell-based) antioxidant tests, G. lucidum inhibits lipid peroxidation and protects against DNA damage.

G. lucidum modulates several signal pathways including Erk1/2, NF-κB, and Wnt. Its antioxidant activity protects against inflammation and directly modulates immunity through scavenging radicals and through the oxidative signal pathways, thereby protecting the cells. These effects of G. lucidum may contribute to its positive influence on DCM.

DM is a state of persistent inflammation that upregulates mTOR at different levels of the myocardium, thereby influencing several signal pathways. The elevation of cellular cAMP levels disrupts phosphodiesterase-Rheb interaction, increases Rheb-mTOR interaction, and consequently leads to mTOR1 activation. Phosphodiesterase binds with Rheb and thereby inhibits the latter’s ability to activate mTOR [71]. Heart myocardium responds to high blood glucose by adapting its energy metabolism and using only fatty acids as a substrate, thus increasing OS through the upregulation of NADPH-oxidases, NO synthases [72], and reversible oxidative modifications for myocardial titin elastic protein [73]. mTOR upregulation and oxidative modification alter titin-based stiffness and titin isoform composition, thereby impairing myocardium contractility. The PI3K-Akt-mTOR kinase axis regulates the composition of titin isoform [73]. OS decreases NO levels, leading to the impairment of the NO-soluble guanylate cyclase- (sGC-) cyclic guanosine monophosphate- (cGMP-) protein kinase G (PKG) pathway, an important regulator of cardiac contractility [72]. Chronic intrude accumulation to high free fatty acids downregulates PPAR-α and impairs mTOR-PPAR-α, thereby causing mitochondrial dysfunction in rodent cardiomyocytes and further deteriorating cardiac function through the inhibition of fatty acid oxidation and increase in intracellular fat accumulation. PPAR-α is involved in the upregulation of carnitine palmitoyltransferase I, which increases the uptake of long-chain fatty acid in the mitochondria and facilitates the beta-oxidation of fatty acids. mTOR-PPAR-α axis modification can lead to inflammation [74] and immune dysfunction [75]. mTOR upregulation leads to the impaired response to adrenergic stimulation in DCM mice and further reduces heart contractility [58]. mTOR inhibition improves contractility via the chronic administration of PDE inhibitor in animals and patients with diabetes [76] and restores the impaired response to adrenergic stimulation in DCM mice [58]. G. lucidum shows its effects via several signal pathways such as Wnt, Erk1/2, and NF-κB pathway and consequently reduces the upregulated mTOR and its effects. mTOR is the main target of G. lucidum, and this finding supports its antioxidant and cardioprotective effects. G. lucidum inhibits the Wnt pathway [54] and may decrease the activity of mTOR via the Wnt/GSk/mTOR signal pathway. A pathologically stressed heart reactivates the Wnt signal pathway, which is modulated during left ventricular remodeling [77]. In heart cells, the Wnt pathway plays a role in the release of intracellular Ca²⁺ whose accumulation activates several Ca⁺²-sensitive proteins, fat and glucose metabolism, and cell fate decisions, such as renewal, differentiation, and apoptosis. Wnt dysregulation has an important role in cardiac diseases such as hypertrophy and fibrosis [78]. The Wnt pathway is important in the response to heart injuries leading to adverse effects on the heart [79] and is integrated with bioenergetic status to control mTOR activity [80]. Wnt is activated in late-stage inflammation of heart tissue [81]. G. lucidum suppresses Erk1/2 signaling [55] and consequently reduces the mTOR level. Erk1/2 signaling inhibits the TSC1/2 complex, which is the downregulator of mTOR, and thus activates mTOR [82]. The antioxidant properties of G. lucidum abolish the activation of the Erk pathway by OS. NADPH oxidase 2 is involved in Erk activation [83], and the inhibition of Erk/mTOR by G. lucidum also prevents NF-κB. mTOR activates NF-κB by phosphorylating the NF-κB p65 subunit, increasing p65 nuclear translocation, and activating gene transcription. With its anti-inflammatory effect, G. lucidum inhibits NF-κB via decreasing inflammatory mediators and cytokines such as TNF or IL-1, and innate immune response effectors activate NF-κB via the IKK complex through IκB protein phosphorylation with subsequent ubiquitination and degradation [84]. Inhibiting mTOR and NF-κB may improve the contractility of the heart, abolish the angiotensin II-induced hypertrophic response of cardiomyocytes [83], and prevent heart failure. A prolonged NF-κB activation promotes heart failure by evoking signals that induce chronic inflammation through the enhancement of cytokines including tumor necrosis factor, IL-1, and IL-6, commencing to endoplasmic reticulum stress responses and cell death [85].

Our results concluded that the antioxidant properties of G. lucidum and the cardioprotection of its polysaccharides may have a direct effect. Its free radical scavenging ability reduces OS and upregulates mTOR via several pathways including Wnt, Erk1/2, and NF-κB/IKK/TOR, thereby improving myocardium contractility (Figure 4). The anti-inflammatory properties may enhance the cAMP/cGMP/mTOR/PPAR pathway and its related protein or/and pathway and mitochondrial function, thus improving myocardium hemostasis. Further study is needed to identify the specific target of GLP in heart tissues.

Abbreviations

ABTS^⋅+:	2,2-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) radical
AOPP:	Advanced oxidation protein products
Bax:	BCL2 associated X, apoptosis regulator
Bcl-xl:	B-cell lymphoma-extra large
BECN1:	Beclin 1
cAMP:	Cyclic adenosine monophosphate
CAT:	Catalase
CCl₄:	Carbon tetrachloride
c-Fos:	A protooncogene
cGMP:	Cyclic guanosine monophosphate
CPT1B and CPT2:	Carnitine palmitoyltransferase 1B and 2
CYP2E1:	Cytochrome P450 2E1
DCM:	Diabetic cardiomyopathy
DM:	Diabetic mellitus
DNA:	Deoxyribonucleic acid
DPPH^⋅:	2,2-diphenylpicrylhydrazyl radical
EMBL:	European Molecular Biology Laboratory
Erk1/2:	Extracellular signal-regulated kinase
GLPs:	Ganoderma lucidum polysaccharides
GPx:	Glutathione peroxidase
GR:	Glutathione reductase
GSH:	Reduced glutathione
GSH-Px:	Glutathione peroxidase
GST:	Glutathione-S-transferase
GTs:	Ganoderma triterpenoids
H₂O₂:	Hydrogen peroxide radicals
HO^⋅:	Hydroxyl radical
IL-6:	Interleukin 6
LC3:	Light chain 3
LPS:	Lipopolysaccharide
MAF1:	Protein negative regulator of RNA polymerase III
MCF-7 cells:	Breast cancer cell line
MDA:	Malondialdehyde level
Mn-SOD:	Manganese-superoxide dismutase
MNU:	N-methyl-N-nitrosourea
MPO:	Myeloperoxidase
mTOR:	Mammalian target of rapamycin
mTORC:	mTOR complex
NF-κB:	Nuclear factor-κB
NO:	Nitrous oxide
NOS:	Nitric oxide synthase
OS:	Oxidative stress
OTP:	Open Targets Platform
PDE:	Phosphodiesterase
PKG:	Protein kinase G
PML:	Promyelocytic leukemia.

Conflicts of Interest

The authors declare no conflict of interest.

Authors’ Contributions

Hongbin Qiu and Shuqiu Wang performed the conceptualization; Fahmi Shaher and Mahfoudh A.M. Abdulghani did the methodology; Hisham AL-ward, Salem Baldi, and Yu Hu participated in the software; Shaobo Zhou, Mahfoudh A.M. Abdulghani, and Weiqun Wang contributed to the validation; Salem Baldi, Fahmi Shaher, and Mahfoudh A.M. Abdulghani performed the formal analysis; Yu Zhang and Yao Wei participated in the investigation; Shuqiu Wang contributed to acquiring resources; Fahmi Shaher helped in the data curation; Fahmi Shaher and Mahfoudh A.M. Abdulghani wrote and prepared the original draft; Shaobo Zhou wrote, reviewed, and edited the manuscript; Mahfoudh A.M. Abdulghani and Fahmi Shaher performed the visualization; Hongbin Qiu supervised the study; Shuqiu Wang did the project administration; Shuqiu Wang helped in funding acquisition. Authorship must be limited to those who have contributed substantially to the work reported.

Acknowledgments

This research was funded by the Jiamusi University, Basic Medicine College team, under grant number JDXKTD-2019002.

Supplementary Materials

Supplementary Table 1: association sore of 309 targets associated with diabetic cardiomyopathy in 30 recorded tissues. Supplementary Table 2: thirty-two tissue organs expressed 309 targets and types of pathways. (Supplementary Materials)

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