Complex molecules from G. lucidum for cancer treatment

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Introduction

G. lucidum is the dried fruit body of the polypore fungus G. lucidum Karst or Ganoderma sinense. G. lucidum has existed in China for thousands of years and is closely involved in the lives of the Chinese people, often being described as a kind of fairy grass that can cure various diseases.1 In a previous study, the medicinal history, cultivation methods, and species distribution of G. lucidum in China have been described in detail, filling the gaps for future research.2

Modern pharmacological studies have shown that G. lucidum contains a variety of bioactive components, including polysaccharides, nucleosides, furans, sterols, alkaloids, triterpenes, oils, various amino acids and proteins, enzymes, organic germanium, and many trace elements.3 Among them, G. lucidum polysaccharides (GLPs) and G. lucidum triterpenoids (GLTs) are the most important pharmacologically active substances. Recent studies have also highlighted the roles of GLPs in immune regulation and their hypoglycemic, hypolipidemic, anti-oxidant, anti-aging and anti-tumor effects.4 Moreover, GLTs have been found to purify blood and preserve liver function. Various Ganoderma preparations have sedative, anticonvulsant, anti-arrhythmic, anti-hypertensive and anti-tussive effects. In addition, G. lucidum displays anti-coagulant, anti-allergic, and platelet aggregation-inhibiting effects.5 The NIH3T3 cell line was employed to evaluate the cytotoxicity of G. lucidum using the XTT method, and no cytotoxicity related to the administration of G. lucidum was observed.6

G. lucidum is a safe, non-toxic, and widely used traditional Chinese medicine that is highly acknowledged by the world. GLPs and GLTs are the elite ingredients and are favored by researchers because of their high activity in G. lucidum. GLPs and GLTs have also showed remarkable biological effects.7 For example, they have been proven to play an effective role in cancer, neurodegenerative diseases, and diabetes, all of which are currently incurable diseases in humans.8,9 G. lucidum is extremely attractive to researchers, and it provides an in-depth explanation of its therapeutic effects on various cancers. Similarly, Rupeshkumar et al affirmed the magical power of G. lucidum from different angles.10

Currently, radiotherapy and chemotherapy represent the main outlets for cancer treatment in patients, but the side effects are also daunting.11 Maybe, the value of natural products shines exceptionally well. The flock of researchers focused their attention on whether they had the potential to change when combined with radiotherapy and chemotherapy. In a multitude of verification experiments, GLPs and GLTs have been shown to play versatile roles in responding to radiotherapy and chemotherapy, and they can be described as having full allure in future cancer research.12 Therefore, further research on polysaccharides and triterpenes, which are the elite components of G. lucidum, is urgent and valuable.

General Structure

GLPs are composed of three monosaccharide chains, possessing a helical stereo configuration similar to DNA and RNA. Among the more than 200 types of GLPs that have been isolated, in addition to glucose, most of them contain less monosaccharides such as arabinose, xylose, galactose, fucose, mannose, and rhamnose. Liu et al separated and purified GLPs from the fruiting body of G. lucidum, determining that the structure of the repeating unit is β-(1→3)-D-glucan as the main chain and β-(1→6)-D-glucopyranose as the side chain (Figure 1).

Figure 1 Structure of GLP isolated from G. lucidum. Note: Reprinted from Carbohydr Polym, 101, Liu Y, Zhang J, Tang Q, et al. Physicochemical characterization of a high molecular weight bioactive β-D-glucan from the fruiting bodies of Ganoderma lucidum. 968–974, Copyright (2014), with permission from Elsevier.45Abbreviation: Glcp, glucopyrano.

GLTs have 14 types of side chains and 7 types of original nuclei and have many different substituents, such as carboxyl, hydroxyl, ketone, methyl, methoxy, and acetyl groups. GLTs can be divided into C30, C27, and C24, depending on the number of carbon atoms present in the structure, and they can be further divided into classes based on the different functional groups and side chains, including acids, alcohols, aldehydes, and lactones (Figure 2 and Table 1).

Table 1 Species of GLTs

Figure 2 Common nuclei structures of GLTs.

Protective Effects of GLPs and GLTs on Radiotherapy and Chemotherapy

Radiotherapy and chemotherapy directly kill tumor cells and suppress tumor growth, representing the most important treatment options for malignant tumors. However, their side effects are unavoidable and harmful to human health and can lead to decreased gastrointestinal immune function and bone marrow suppression. In recent years, the emergence of natural products derived from traditional Chinese medicine has greatly enriched methods of tumor treatment and has quickly become a research hotspot, gradually evolving into a potential adjuvant therapy for tumor treatment. G. lucidum, which has existed in China for thousands of years, has proved to demonstrate resistance to radiotherapy and chemotherapy side effects. GLPs and GLTs are believed to play a crucial role in resisting radiotherapy and chemotherapy side effects.

The GLP Effects of Radiotherapy and Chemotherapy

Experiments with GLPs in Swiss albino mice showed that β-glucan (BG), a polysaccharide derived from G. lucidum, possessed a certain degree of protection against radiation and could effectively resist radiation-induced damage. In the control group receiving only radiotherapy, 80% of the animals died after receiving radiation for 20 days, while no mice in this group had survived by day 30. Before radiation, the mice were given BG at a dose of 500 μg/kg body weight (bw)/day, and the survival rates on days 20 and 20 were 66% and 33%, respectively. After radiotherapy, mice were given the same dose, but the results showed that the survival rates on days 25 and 30 were 83% and 66%, respectively. These results showed that the survival rate of mice treated with the same dose of BG was significantly higher than that before radiotherapy (P < 0.001), and they confirmed that administering BG at a dose of 500 mg/kg body weight (bw)/day was nontoxic.13

Radiotherapy and chemotherapy are effective methods for treating malignant tumors, but cancer is an expendable disease. As a possible consequence of radiotherapy and chemotherapy, chemotherapy-related fatigue is also an urgent problem to address. In a study on chemotherapy-related fatigue, a weight-loaded swimming test was used to assess the degree of fatigue in rats with A549 lung cancer cells, which showed that, compared to the control group, the duration of weight-loaded swimming in rats with GLPs was longer than that of the control group.14

In an interesting set of binding experiments, the combination of synthetic bismuth sulfide nanoparticles (BiNP) and GLPs presented new prospects in the development of radiotherapies. When combined with radiation, GLP-BiNP achieved a significant inhibitory effect on tumor growth through radio sensitization and immune activity, and mitigated the risk of bismuth nephrotoxicity. For future treatment prospects, this strategy shows huge potential.15 Similarly, the combination of gold nanocomposites and GLPs (GLP-Au) also has broad prospects.16

Paclitaxel (PTX) has become a broad-spectrum first-line chemotherapy drug due to its complex and novel chemical structure, unique biological mechanism of action, and reliable anti-cancer activity. According to research led by Su et al in 2018,17 the combination of G. lucidum spore polysaccharide (SGP) and PTX had incredible effects on tumor treatment. In preliminary studies of PTX in vitro, SGP did not increase the cytotoxicity of PTX. During the 21-day observation, the use of PTX alone in inhibiting tumor growth was effective from day 15, resulting in a reduction in tumor weight (p < 0.05). On the contrary, the inhibitory effect of PTX and SGP combination therapy on tumor growth might have occurred earlier. Additionally, experiments proved that the combined use of PTX and SGP could restore intestinal biological diseases caused by PTX monotherapy, and it helps to inhibit tumor metabolism, thereby inhibiting tumor growth. Another combination therapy of SGP and PTX was proven to ameliorate the intestinal barrier damage caused by PTX. The integrity of the small intestinal barrier of mice induced by PTX can be exceedingly adjusted by SGP. Intestinal injury caused by the use of PTX is closely correlated to the increase in epithelial permeability and the destruction of tight junctions. In view of the side effects of PTX, the combination of PTX and SGP for the protection of the small intestinal barrier damage caused by PTX may be accomplished by promoting the renewal of the intestinal epithelium to enhance the permeability and integrity of the epithelium. The mechanism involved may be related to the suppression of microtubule aggregates to inhibit cell proliferation and apoptosis18 (Figure 3).

Figure 3 A combined therapeutic effect of SGP and PTX. The combination of PTX and SGP can restore the small intestinal barrier damage caused by PTX treatment alone, which helps to inhibit tumor metabolism and ultimately inhibit tumor growth.

Another well-known side effect of chemotherapy is myelosuppression. A related study found that GLP could be used as a promoter for myelopoiesis to reduce the effects of myelosuppression induced by chemotherapy, thereby achieving protective effects on chemotherapy. It was recognized that GLPs do not directly stimulate the proliferation of hematopoietic progenitor cells to promote myelopoiesis, rather they indirectly stimulate splenocytes to produce hematopoietic growth factors (HGF), which mainly include granulocyte colony stimulating factor, interleukin-1, and interleukin-6, and stem cell factor19 (Figure 4).

Figure 4 GLP is a promoter of myelopoiesis. GLPs stimulate splenocytes to produce hematopoietic growth factors (HGF), which can act as a promoter of bone marrow production, reduce the bone marrow suppression induced by chemotherapy, and maximize the anti-tumor effect of chemotherapy.

The GLTs Effects of Radiotherapy and Chemotherapy

Smina et al reported that GLTs could strongly mitigate oxidation and scavenge free radicals, and they demonstrated the protective effects of GLTs on DNA and cell membranes after radiation damage using Thiobarbituric acid reactive substances (TBARS), comet assay, and micronucleus assay.20 Another study published by Smina et al revealed the potential therapeutic use of GLTs as an adjuvant in radiation therapy. GLTs were orally administered continuously for 14 days at doses of 50 and 100 mg/kg body weight (bw)/day before exposure of the whole body of Swiss albino mice to radiation. GLTs were shown to reduce the levels of lipid peroxidation and protein oxidation, effectively restore the activities of antioxidant enzymes and glutathione in the liver and brain of irradiated mice, and significantly reduce DNA strand breaks.21 It has also been reported that GLTs could be used as an alternative dietary supplement to prevent cancer-associated colitis.22

In a study using HeLa cells, GLTs and adriamycin displayed a synergistic effect that caused the regulated expression of 14 proteins that play significant roles in cell proliferation, the cell cycle, apoptosis, and oxidative stress. Furthermore, GLTs enhanced the production of reactive oxygen species (ROS) by adriamycin. It was suggested that the synergistic effect between GLTs and adriamycin may be based on the fact that GLTs enhance their sensitivity to chemotherapy by enhancing oxidative stress, DNA damage, and apoptosis23 (Figure 5).

Figure 5 Synergistic effect of GLTs and doxorubicin against chemotherapy sensitivity. The synergistic effect of GLT and adriamycin leads to the expression of multiple proteins, such as eIF5A, 14-3-3 β/α, and Ku80, which play important roles in cell proliferation, cell cycle, apoptosis, and oxidative stress, thereby enhancing the sensitivity to chemotherapy.

Experiments in HL-7702 cells found that GLTs were mainly concentrated in chloroform extracts, which exhibited significant inhibitory malignancy effects of cancer cells and on the repair or protection of normal cells damaged by radiotherapy and chemotherapy. These results showed that GLTs have protective effects against damaged normal cells induced by radiotherapy and chemotherapy.24

Research has shown that mycotherapy can improve the overall response rate during cancer treatment and reduce various chemotherapy-related adverse events. The GLT ganoderic acid A (GAA) was found to enforce QCT-induced apoptosis and Epstein-Barr virus (EBV) lytic reactivation at low concentrations, exhibiting similar biological effects to ganoderic lucidum extracts (GLE) in QCT-mediated antitumor activity. Thus, GAA can be used as a potential food adjunct for the prevention of EBV-associated gastric carcinoma (EBVaGC) development.25 Similarly, ganoderenic acid B (GAB) another type of GLTs could reverse the multidrug resistance of ABCB1-mediated liver cells to adriamycin, vincristine, and PTX, the mechanism of which may be due to the inhibition of ABCB1 transport and the increase in drug accumulation in MDR cells. GAB could also reverse the resistance of ABCB1-overexpressing MCF-7/ADR cells to doxorubicin.26

In addition, existing research shows that the Chinese medicinal herb complex (CCMH: a mixture of citronellol and extracts of G. lucidum, C. pilosula, and A. sinensis) increased the immune cell counts in cancer patients who received the treatment with chemotherapy and/or radiotherapy,27 which suggests that the Chinese medicinal herb has anti-radio-chemotherapy effects. Cao et al confirmed that G. lucidum and the immune system are inextricably linked in cancer treatment. It can activate immune cells, such as T or B lymphocytes, macrophages, and NK cells, and can also promote production of cytokines and antibodies, so as to achieve the purpose of inhibiting the growth of tumor cells.28

Ursolic acid is a naturally synthesized pentacyclic triterpenoid compound that has been widely found in various fruits and vegetables. It has not only demonstrated anti-cancer activities and anti-inflammatory effects but it has also been found to induce apoptosis in several human cancer cell lines. However, there is no clear evidence that there is an explicit limit to the use of ursolic acid in human studies.29 The compounds 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its C28-modified derivative, methyl-ester (CDDO-Me), are two synthetic derivatives of oleanolic acid that have been widely studied for their ability to induce apoptosis and aid in the differentiation of cancer cells. Although some progress has been made in clinical trials, some complications related to heart failure events have been observed.30

Another study demonstrated that Escin, a mixture of triterpenoid saponins extracted from the horse chestnut tree, had anti-cancer effects. However, clinical trial results showed that some patients exhibited diarrhea, dyspnea, dysphagia, and corestenoma, while healthy volunteers did not have similar symptoms.31 Compared to Escin, GLTs play a significant therapeutic role in the treatment of numerous diseases. Among these triterpenes, it has been discovered that GLTs display anti-cancer effects, and most importantly, natural nontoxic effects.

Discussion and Outlook

In the modern treatment of cancer, radiotherapy and chemotherapy are important methods for the treatment of malignant tumors, which have the advantages of killing tumor cells and inhibiting the growth of tumor cells. Specifically, the electron beams, X-rays and radioisotopes show efficacy in most cancers. As a common chemotherapeutic drug, PTX and cisplatin are widely used in the treatment of various cancers through inhibiting cancer cell division, arresting DNA replication process of cancer cells, destroying cancer cell membrane structure, etc. Both radiotherapy and chemotherapy can directly kill cancer cells while simultaneously triggering tumor microenvironment remodeling in which pro-inflammatory signaling pathways are activated and pro-inflammatory mediators are released, thereby recruiting tumor-infiltrating immune cells.

GLPs and GLTs are of the essence of G. lucidum, and have proved to play multi-faceted anti-cancer roles including direct cytotoxicity in tumor cells, antioxidant effect, inhibition of angiogenesis, induction of cell differentiation and immunomodulatory effect (activation of immune host response), etc. Currently, the clinical trials of GLPs and GLTs are under way. Polysaccharide extracts (Ganopoly) stimulate immune responses in advanced stage cancer patients. IL-2, IL-6, IFN-γ and NK cell activity in plasma were increased, while IL-1 and TNF-α were considerably reduced.32–34 Early research on G. lucidum against leukemia indicated that it is an ideal leukemia treatment drug, and its underlying mechanism may be that G. lucidum induces the differentiation of leukemia cells to the mature stage and inhibits their proliferation.35 In various nonrandomized clinical trials of different types of cancer, especially breast cancer, when combined with radiotherapy or chemotherapy, polysaccharide extracts of G. lucidum could be very efficient to reduce the metastasis potential and/or adverse effects, and enhance the effects of chemotherapy and radiotherapy.36–40 Therefore, combination therapy with GLPs/GLTs and radio-chemotherapy is becoming a general trend clinically, which can achieve the goal of increasing efficiency and reducing the side effects caused by drugs (Figure 6).

Figure 6 The synergistic model of GLP and GLTs with chemotherapy and radiotherapy. Combination treatment of GLP/GLTs and chemo-radiotherapy showed synergistic effects in lung cancer, breast cancer and colorectal cancer treatments with ameliorating side effects such as gastrointestinal reactions and myelosuppression.

Future directions should focus on the molecular elaboration of GLPs and GLTs in cancer research. It is important to clarify the β-glucan contents in GLPs or SGP, also critical to decipher the structure and biological functions of these β-glucan in GLPs including the immunomodulatory mechanisms. The pharmacodynamics of GLPs in vivo is also important for future clinical translation. In addition, though the elite components of the G. lucidum are GLPs and GLTs, other components such as unsaturated long-chain fatty acids, appear to show the antitumoral activity. Elucidating the antitumor activity of G. lucidum has a great potential in improving human health and curing diseases.

Laminated Glass Market Growth and Industry Perspective, Comprehensive Analysis Forecast To 2027

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The research report published by ResearchMoz on the Laminated Glass Market provides a detailed overview of the demands and consumptions of various products/services associated with the growth dynamics of the market during the forecast period 2021– 2027. The in-depth market estimation of various opportunities in the segments is expressed in volumes and revenues. The insights and analytics on the Laminated Glass Transformation Consulting Services market span several pages. These are covered in numerous sections, including, drivers and restraints, challenges and opportunities, regional segmentation and opportunity assessment, this report on the global Laminated Glass market guarantees a fortune of data on a plenty of development opportunities in the market. The examination incorporates far reaching research by expert analysts. All the development factors influencing the Laminated Glass market across the evaluation time of 2021-2027 have been systematically provided for the report. The exploration endeavors to introduce a gradual evaluation of the important buyers’ propositions targeted by different players and technologies that characterize the microeconomic conditions of the Laminated Glass market.

The new report on the Laminated Glass provides estimations of the size of the global market and share and size of key regional markets during the historical period of 2014 – 2018. The study provides projections of the opportunities and shares, both vis-à-vis value (US$Mn/Bn) and volume volume (n units), of various segments in the Laminated Glass market during the forecast period of 2021 – 2027. The business intelligence study offers readers a granular assessment of key growth dynamics, promising avenues, and the competitive landscape of the Laminated Glass market.

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This report covers leading companies associated in Laminated Glass market:

AGC Glass

Saint-Gobain

Guardian

CSG Holding

Nippon Sheet Glass

Vitro Architectural Glass

Sisecam Group

Fuyao Group

Taiwan Glass

Viridian

Schott

Benxi Yujing Glass

Carey Glass

JE Berkowitz

Lami Glass

Scope of Laminated Glass Market: The Global Laminated Glass Market is valued at million US$ in 2017 and will reach million US$ by the end of 2025, growing at a CAGR of during 2018-2025. This Market Report includes drivers and restraints of the Global Laminated Glass Market and their impact on each region during the forecast period. The report also comprises the study of current issues with consumers and opportunities. It also includes value chain analysis.

Laminated Glass Market Segment by Applications, can be divided into

Construction

Home and Office

Automotive

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Market Segment by Type, covers

PVB

EVA

SGP

Market Segment by Regions, regional analysis covers

● North America (United States, Canada and Mexico)

● Europe (Germany, UK, France, Italy, Russia, Spain and Benelux)

● Asia Pacific (China, Japan, India, Southeast Asia and Australia)

● Latin America (Brazil, Argentina and Colombia)

● Middle East and Africa

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Emerging end-use industries that can propel the market in coming years

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Lucrative opportunities for investments in various end-use industries and regional Laminated Glass markets

Projected CAGR over the forecast period 2021 to 2027

Analysis of historic as well as recent consumer purchasing trends pertaining to global Laminated Glass market

Technological advancements and product innovations with potential to revolutionize the Laminated Glass market

Companies that held leading share in the market during the historic years

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Research debunks myth that COVID vaccination promotes mutations

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A study conducted by researchers at the University of Maryland, USA, has highlighted the importance of coronavirus disease 2019 (COVID-19) vaccination in reducing the frequency of mutations in the delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The study also presents an evolutionary algorithm that can accurately predict new COVID-19 outbreaks. A detailed description of the study is currently available on the medRxiv* preprint server.

Background

Currently, the best possible way to end the COVID-19 pandemic is mass vaccination. However, public distrust and hesitancy to accept COVID-19 vaccines have added an extra level of complicacy in combating the global spread of SARS-CoV-2. Despite proven efficacy against SARS-CoV-2 infections, a large proportion of the global population is still uncertain about the risk-benefit ratio of COVID-19 vaccines.

In addition to increasing the risk of viral transmission, under-vaccination may affect the rate of viral mutations. On average, the mutation rate of SARS-CoV-2 is 7.23 mutations per viral sample. Mutations that emerged under positive selection pressure, such as vaccine/therapy-induced immunity, are the main driving force of viral evolution. Thus, novel viral variants evolving during the pandemic are likely to develop resistance against vaccines and therapeutics.

In the current study, the scientists have explored the association between vaccine coverage rate and mutation frequency of the SARS-CoV-2 delta variant (B.1.617.2).

For the analysis, they have collected complete genome sequences of SARS-CoV-2 from the Global Initiative on Sharing All Influenza Data (GISAID) database. In total, viral sequences from 20 countries have been included in the analysis.

(A) Correlation between full vaccinated rate [13] and mutation frequency (Mf) from June 20 to July 3 2021 in 20 countries: Australia (AUS), France (FRA), Germany (GER), Indonesia (IDA), India (IND), Ireland (IRL), Israel (ISR), Italy (ITA), Japan (JPN), Mexico (MEX), Netherland (NED), Norway (NOR), Portugal (POR), Singapore (SGP), Spain (ESP), Switzerland (SUI), Sweden (SWE), Turkey (TUR), United States (USA), and UK. Logarithmic regression (solid) line was draw based on 16 countries (pink dots) with a calculated 95% confidence interval (dashed lines). Japan, Switzerland, USA, and Australia are labeled in different colors as outliers. (B and C) Chronology of nucleotide diversity (π) (B) and Tajima D’ value (C) of SARS CoV-2 delta variants in UK (N=27,344, blue), Indian (N=4,451, red), and Australian (N=305, green). Data were plotted every two weeks, and the data only represent the effective population size with more than 3 high quality sequences. The arrows label the epidemiological events of COVID-19 delta variants announced by the World Health Organization (WHO). WHO classified the delta variant as a global variant of interest (VOI) on 4 April 2021, and variants of concern (VOC) on 11 May 2021 [5]. The dashed line in (C) labels the cut-off threshold -2.50 in Tajima D’ test.

Important observations

The analysis revealed that with an increase in vaccination rate, there is a reduction in the frequency of viral mutations. This inverse correlation between vaccination rate and mutation frequency was observed in 16 out of 20 countries.

As an exception, Australia exhibited a very low mutation frequency with a vaccination rate of around 10%. In contrast, a high mutation frequency was observed in the United States, Japan, and Switzerland, despite higher vaccination rates than in Australia. These observations indicate more successful implementation of control measures in Australia than in these countries.

Prediction of new outbreaks

To determine whether vaccine-induced immunity acts as a positive selection pressure to initiate viral evolution, the scientists analyzed genome sequences of the delta variant in the UK, India, and Australia. They performed the Tajima D test to determine whether mutations emerge neutrally or via non-random processes, including directional selection or demographic expansion. Tajima’s D is a statistical test used in population genetics to compare pair-wise genetic diversity and total polymorphism to deduce selection and demographic events.

The findings of the Tajima D test revealed that the delta variants in the UK emerged with rapid clonal expansion. In contrast, the variants in India and Australia mainly emerged with singleton mutations (single nucleotide variants). The values obtained from the Tajima D test were between -2.68 and -2.84 for all the delta variants. These D’ values were equivalent to that calculated from the sequences of B.1.1.7 variant in the UK during the study period. Negative D’ values observed in both the UK and Indian variants throughout the study period indicate more substantial demographic expansion or positive selection.

With further analysis, the scientists observed that new COVID-19 outbreaks occurred in the UK and India 1 – 3 weeks after the reduction of D’ values below -2.50. Based on these findings, they proposed that a D’ value of -2.50 could be used as a threshold to predict new outbreaks.

Study significance

The study reveals that the frequency of viral mutations can be reduced by increasing the rate of full vaccination. In other words, countries with high vaccine coverage are less likely to experience new COVID-19 outbreaks. Thus, public hesitancy to COVID-19 vaccination could potentially lead to the emergence of more pathogenic viral variants and failure to achieve herd immunity.

As recommended by the scientists, mass vaccination, control measure implementation, and continuous genomic surveillance are the most vital strategies to combat the COVID-19 pandemic.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.