Plant-Derived Epi-Nutraceuticals as Potential Broad-Spectrum Anti-Viral Agents.

Although the COVID-19 pandemic appears to be diminishing, the emergence of SARS-CoV-2 variants represents a threat to humans due to their inherent transmissibility, immunological evasion, virulence, and invulnerability to existing therapies. The COVID-19 pandemic affected more than 500 million people and caused over 6 million deaths. Vaccines are essential, but in circumstances in which vaccination is not accessible or in individuals with compromised immune systems, drugs can provide additional protection. Targeting host signaling pathways is recommended due to their genomic stability and resistance barriers. Moreover, targeting host factors allows us to develop compounds that are effective against different viral variants as well as against newly emerging virus strains. In recent years, the globe has experienced climate change, which may contribute to the emergence and spread of infectious diseases through a variety of factors. Warmer temperatures and changing precipitation patterns can increase the geographic range of disease-carrying vectors, increasing the risk of diseases spreading to new areas. Climate change may also affect vector behavior, leading to a longer breeding season and more breeding sites for disease vectors. Climate change may also disrupt ecosystems, bringing humans closer to wildlife that transmits zoonotic diseases. All the above factors may accelerate the emergence of new viral epidemics. Plant-derived products, which have been used in traditional medicine for treating pathological conditions, offer structurally novel therapeutic compounds, including those with anti-viral activity. In addition, plant-derived bioactive substances might serve as the ideal basis for developing sustainable/efficient/cost-effective anti-viral alternatives. Interest in herbal antiviral products has increased. More than 50% of approved drugs originate from herbal sources. Plant-derived compounds offer diverse structures and bioactive molecules that are candidates for new drug development. Combining these therapies with conventional drugs could improve patient outcomes. Epigenetics modifications in the genome can affect gene expression without altering DNA sequences. Host cells can use epigenetic gene regulation as a mechanism to silence incoming viral DNA molecules, while viruses recruit cellular epitranscriptomic (covalent modifications of RNAs) modifiers to increase the translational efficiency and transcript stability of viral transcripts to enhance viral gene expression and replication. Moreover, viruses manipulate host cells' epigenetic machinery to ensure productive viral infections. Environmental factors, such as natural products, may influence epigenetic modifications. In this review, we explore the potential of plant-derived substances as epigenetic modifiers for broad-spectrum anti-viral activity, reviewing their modulation processes and anti-viral effects on DNA and RNA viruses, as well as addressing future research objectives in this rapidly emerging field.

Natural Products Counteracting Cardiotoxicity during Cancer Chemotherapy: The Special Case of Doxorubicin, a Comprehensive Review.

Cardiotoxicity is a frequent undesirable phenomenon observed during oncological treatment that limits the therapeutic dose of antitumor drugs and thus may decrease the effectiveness of cancer eradication. Almost all antitumor drugs exhibit toxic properties towards cardiac muscle. One of the underlying causes of cardiotoxicity is the stimulation of oxidative stress by chemotherapy. This suggests that an appropriately designed diet or dietary supplements based on edible plants rich in antioxidants could decrease the toxicity of antitumor drugs and diminish the risk of cardiac failure. This comprehensive review compares the cardioprotective efficacy of edible plant extracts and foodborne phytochemicals whose beneficial activity was demonstrated in various models in vivo and in vitro. The studies selected for this review concentrated on a therapy frequently applied in cancer, anthracycline antibiotic-doxorubicin-as the oxidative stress- and cardiotoxicity-inducing agent.

Safety of herbal medicine use during chemotherapy in patients with ovarian cancer: a "bedside-to-bench" approach.

In this study, we explored herbal supplements used by patients during chemotherapy and test for herb-drug interactions and response of cancer cells to treatment. Patients with gynecological cancer referred to a complementary and integrative medicine (CIM) service were asked about their use of herbal medicine during chemotherapy. The leading five clinically relevant herbs selected for cytotoxicity analysis included the following: wheatgrass (Triticum aestivum), European mistletoe (Viscum album), ginger (Zingiber officinale), Ephedra (Ephedra campylopoda), and Oriental mistletoe (Viscum cruciatum). Cytotoxicity was examined using XTT assays in cisplatin-sensitive and resistant ovarian cancer cell lines (A2780, A2780CisR), and non-cancer kidney cells (HEK-293). The effect of the selected herbs on carboplatin and paclitaxel cytotoxicity was tested as well. Pro-apoptotic effects were tested using Poly(ADP-ribose) polymerase (PARP) cleavage. Of 98 patients referred to the CIM service, 42 (42.9%) reported using/intending to use herbal products during chemotherapy. European mistletoe and ginger exhibited significant anti-cancer activity in cisplatin-sensitive and resistant ovarian cells. Wheatgrass and ephedra reduced cytotoxicity of carboplatin on cisplatin-sensitive ovarian cancer cells, while ginger, European and Oriental mistletoe increased chemosensitivity in both cancer cell lines. Wheatgrass, European mistletoe, and ginger increased sensitivity to cisplatin-resistant cells treated with carboplatin and paclitaxel. No effect was observed with the addition of any of the herbs on non-cancerous embryonic kidney cells (HEK-293). Herbal medicine use by patients with ovarian cancer may influence anti-cancer activity of chemotherapy. Integrative physicians can provide "bedside-to-bench" guidance on the safety of these products.

Exploring an herbal "wonder cure" for cancer: a multidisciplinary approach.

CONTEXT AND OBJECTIVES: The unmonitored use of herbal medicinal remedies by patients with cancer presents a significant challenge to oncology healthcare professionals. We describe an increasingly popular herbal "wonder drug," Ephedra foeminea (Alanda in Arabic), whose use has spread from the Palestinian patient population throughout the Middle East. We conducted a multicentered and multidisciplinary collaborative research effort in order to understand the potential benefits and harms of this popular herbal remedy. METHODS: We conducted an in-depth search of the medical literature, both traditional and modern, for any mention of the clinical use of Alanda for the treatment of cancer. We then tested the remedy, first for toxic ephedra alkaloid components and then for anticancer effects, as well as effects on the cytotoxic activity of chemotherapy agents (cisplatin and carboplatin) on breast cancer cell cultures. RESULTS: We found no mention in the literature, both conventional and traditional, on the use of Alanda for the treatment of cancer. Laboratory testing did not find any toxic components (i.e., ephedra alkaloids) in the preparation. However, in vitro exposure to Alanda led to a reduced cytotoxic effect of chemotherapy on breast cancer cell cultures. CONCLUSIONS: The use of an integrative ethnobotanical, laboratory and clinical research-based approach can be extremely helpful when providing nonjudgmental and evidence-based guidance to patients with cancer, especially on the use of traditional herbal medicine. The effectiveness and safety of these products need to be examined by integrative physicians who are dually trained in both complementary medicine and supportive cancer care.

Sustained proliferation in cancer: Mechanisms and novel therapeutic targets.

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.

The Shaggy Inc Cap medicinal mushroom, Coprinus comatus (O.F.Mull.: Fr.) Pers. (Agaricomycetideae) substances interfere with H2O2 induction of the NF-kappaB pathway through inhibition of Ikappaalpha phosphorylation in MCF7 breast cancer cells.

Breast cancer is the most commonly diagnosed cancer among women. Currently, there is no effective therapy for malignant estrogen-independent breast cancer. In our study, we used hydrogen peroxide, a well-known strong oxidative reagent capable of activating the nuclear factor kappa B (NF-kappaB) transcription factor. The IC50 value of the culinary-medicinal Shaggy Inc Cap mushroom Coprinus comatus culture liquid crude extract on MCF7 cell viability was found to be as low as 76 microg/mL, and the IC50 value of C. comatus ethyl acetate extract was only 32 microg/ mL. Our results also showed that both extracts significantly affected IkappaBalpha phosphorylation in a dose-dependent manner. The effect of ethyl acetate extract was comparable to the effect of curcumin, a known NF-kappaB pathway inhibitor, and seemed to be the most active inhibitor of H2O2-dependent IkappaBalpha phosphorylation. In addition, the data obtained showed that only ethyl acetate extract inhibited the activity of IKK complex, at close to 90% as compared to the control of the untreated sample. These results suggest that C. comatus contains potent compounds capable of inhibiting NF-kappaB function and also possibly acts as an antitumor agent.

Oleic acid is the active component in the mushroom Daedalea gibbosa inhibiting Bcr-Abl kinase autophosphorylation activity.

The hallmark of chronic myeloid leukemia (CML) is the abnormal activity of p210(Bcr-Abl) kinase. Selective kinase inhibitors such as imatinib or nilotinib have been established successfully for the treatment of CML. Despite high rates of clinical response, CML patients can develop resistance to these kinase inhibitors mainly due to point mutations within the Abl kinase domain of the fusion protein. Previously, we reported that a crude extract of the mushroom Daedalea gibbosa inhibited kinase activity of Bcr-Abl kinase. Here we report on the identification of the active component of Daedalea gibbosa, oleic acid, which inhibited Bcr-Abl kinase autophosphorylation in Ba/F3 cells and exhibited anti-CML activity in a BCR/ABL-positive mouse model.

The culinary-medicinal mushroom Coprinus comatus as a natural antiandrogenic modulator.

Prostate cancer is the most common cancer diagnosed in men. Chemotherapy, androgen ablation, and androgen antagonist treatments have proven to have significant effects in the early stages of prostate cancer, whereas advanced prostate cancer is resilient to such treatments. The androgen receptor (AR), a ligand-dependent transcription factor, is the major drug target of prostate cancer therapy. Transition to the androgen-independent stage involves the activation of signaling pathways, AR gene mutations, and other mechanisms. Higher basidiomycetes mushrooms have been used since ancient times in folk medicine to treat a diversity of diseases, including cancer. The present study evaluates the antiandrogenic activity of different Coprinus comatus strains in their ability to interfere with AR function. The authors found that the most active extract was C comatus strain 734 extracted with hexane (CC734-H). This extract was able to (1) inhibit AR-mediated reporter activity, (2) inhibit the proliferation and viability of the LNCaP cell line, and (3) inhibit the colony formation of the LNCaP cell line, in comparison to the DU-145, PC-3, and MDA-Kb2 cells. In addition, CC734-H was able to reduce AR levels and prostate-specific antigen gene expression in the LNCaP-treated cell line. This study illustrates the potential of the C comatus mushroom as a natural antiandrogenic modulator that could serve in the treatment of prostatic diseases.

Pharmacological values of medicinal mushrooms for prostate cancer therapy: the case of Ganoderma lucidum.

Prostate cancer (PCa) is the most common male malignancy in many Western countries. Primary PCa is hormone dependent and is manageable by hormonal therapy. However, it rapidly develops to hormone-refractory tumors due to the accumulation of mutations in the androgen receptor and/or the acquisition of alternative cellular pathways that support proliferation and inhibit apoptosis of prostate cancer. To date, no effective therapy is available for clinically hormone-insensitive or hormone-refractory stages of prostate cancer.

Androgen receptor-dependent and -independent mechanisms mediate Ganoderma lucidum activities in LNCaP prostate cancer cells.

Ganoderma lucidum (Curt.:Fr.) P. Karst, a medicinal fungus, has been widely used in Asian countries for centuries to prevent or treat a variety of diseases, including cancer. However, the mechanisms responsible for the effects of G. lucidum on cancer cells remain to be elucidated. We have previously shown that ethyl acetate extract of G. lucidum inhibits LNCaP prostate cancer cell viability and proliferation. We also demonstrated that G. lucidum extract decreased androgen receptor transcriptional activity, suppressed levels of secreted prostate-specific antigen, and suppressed androgen receptor protein level. In this study we investigated the mechanisms that underlie the activities of G. lucidum crude extract and its active fraction GLF4 in LNCaP prostate cancer cells. Our data demonstrate that G. lucidum inhibits cell viability by induction of apoptosis through the extrinsic pathway that include activation of caspase-8 and caspase-3 and inhibits cell proliferation by the down-regulation of cyclin D1 expression. Furthermore, G. lucidum crude extract and fraction GLF4 interfere with androgen receptor function via competition with the natural ligand dihydrotestosterone and suppression of androgen receptor/androgen response element complex formation. These results indicate that G. lucidum extracts have profound activity against LNCaP cells that merits further investigation as a potential therapeutic agent for the treatment of prostate cancer.

Fungal substances as modulators of NF-kappaB activation pathway.

MCF7 breast cancer cell line, carrying a luciferase reporter gene under the control of nuclear factor kappa B (NF-kappaB)-responsive promoter, was established and used for the screening of fungal organic extracts for their ability to interfere with the NF-kappaB activation pathway. Twenty-eight crude fungal extracts, out of 242, were found to inhibit NF-kappaB reporter activity by more than 40%. Furthermore, positive extracts were used to evaluate their antiproliferative activity as well as their ability to influence the phosphorylation and degradation levels of IkappaBa. Fungal extracts prepared from Marasmius oreades and Cyathus striatus showed significant inhibitory effects on the NF-kappaB activation pathway. Taken together, our results support the notion of the presence of novel activities that might be utilized as cancer therapeutics.

Medicinal mushroom modulators of molecular targets as cancer therapeutics.

Empirical approaches to discover anticancer drugs and cancer treatments have made limited progress in the past several decades in finding a cure for cancer. The expanded knowledge of the molecular basis of tumorigenesis and metastasis, together with the inherently vast structural diversity of natural compounds found in mushrooms, provided unique opportunities for discovering new drugs that rationally target the abnormal molecular and biochemical signals leading to cancer. This review focuses on mushroom low-molecular-weight secondary metabolites targeting processes such as apoptosis, angiogenesis, metastasis, cell cycle regulation, and signal transduction cascades. Also discussed in this review are high-molecular-weight polysaccharides or polysaccharide-protein complexes from mushrooms that appear to enhance innate and cell-mediated immune responses, exhibit antitumor activities in animals and humans, and demonstrate the anticancer properties of selenium compounds accumulated in mushrooms.