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The Scientific Rediscovery of an Ancient Chinese Herbal Medicine: Cordyceps sinensis Part I

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Abstract

This review presents Cordyceps sinensis (Berk.) Sacc., a fungus highly valued in China as a tonic food and herbal medicine. The extant records show the continued use of C. sinensis is now centuries old. The major chemical, pharmacological, and toxicological studies on C. sinensis and the various derived, cultured, fermented mycelial products currently in use are reviewed from the English and Chinese literature. Preclinical in vitro and in vivo studies and clinical blinded or open-label trials in to date over 2000 patients are reviewed. These studies show the main activities of the fungus in oxygen-free radical scavenging, antisenescence, endocrine, hypolipidemic, antiatherosclerotic, and sexual function-restorative activities. The safety of the fungus, its effects on the nervous system, glucose metabolism, the respiratory, hepatic, cardiovascular, and immune systems, immunologic disease, inflammatory conditions, cancer, and diseases of the kidney will be reviewed in the second part of this article to be published in the winter issue of this journal.
... Natural Cordyceps sinensis is one of most valued therapeutic agents in traditional Chinese medicine and has a rich history of clinical use in health maintenance, disease amelioration, post-disease and post-surgery recovery, and antiaging therapy [1][2][3]. The Note: "↑" and "↓" indicate an increase or decrease in the AT content, respectively. ...
... As shown in Tables 2-4 and S2 and S3, the transcripts for the repetitive genomic copies of the authentic genes could be identified in the mRNA transcriptome GCQL00000000 for the H. sinensis strain L0106 [51], regardless of the increases, decreases, or bidirectional changes in the AT content and low sequence similarity of the repetitive copies compared with the authentic genes. The authentic genes and repetitive genomic copies likely encode proteins with altered functional specificities, which enhance the adaptability of natural C. sinensis to harsh, high-altitude environments and expand its therapeutic efficacy for disease resistance and treatment, anti-aging, and health preservation [1][2][3]19,43,52,53,71]. Thus, the genetic results of the multilocus analysis and the transcription ability of the repetitive copies further invalidated the pseudogene hypothesis and its root cause of RIP mutagenesis, as proposed by Li et al. [41,42,58]. ...
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Multiple repetitive sequences of authentic genes commonly exist in fungal genomes. AT-biased genotypes of Ophiocordyceps sinensis have been hypothesized as repetitive pseudogenes in the genome of Hirsutella sinensis (GC-biased Genotype #1 of O. sinensis) and are generated through repeat-induced point mutation (RIP), which is charactered by cytosine-to-thymine and guanine-to-adenine transitions, concurrent epigenetic methylation, and dysfunctionality. This multilocus study examined repetitive sequences in the H. sinensis genome and transcriptome using a bioinformatic approach and revealed that 8.2% of the authentic genes had repetitive copies, including various allelic insertions/deletions, transversions, and transitions. The transcripts for the repetitive sequences, regardless of the decreases, increases, or bidirectional changes in the AT content, were identified in the H. sinensis transcriptome, resulting in changes in the secondary protein structure and functional specification. Multiple repetitive internal transcribed spacer (ITS) copies containing multiple insertion/deletion and transversion alleles in the genome of H. sinensis were GC-biased and were theoretically not generated through RIP mutagenesis. The repetitive ITS copies were genetically and phylogenetically distinct from the AT-biased O. sinensis genotypes that possess multiple transition alleles. The sequences of Genotypes #2–17 of O. sinensis, both GC- and AT-biased, were absent from the H. sinensis genome, belong to the interindividual fungi, and differentially occur in different compartments of the natural Cordyceps sinensis insect–fungi complex, which contains >90 fungal species from >37 genera. Metatranscriptomic analyses of natural C. sinensis revealed the transcriptional silencing of 5.8S genes in all C. sinensis-colonizing fungi in natural settings, including H. sinensis and other genotypes of O. sinensis. Thus, AT-biased genotypes of O. sinensis might have evolved through advanced evolutionary mechanisms, not through RIP mutagenesis, in parallel with GC-biased Genotype #1 of H. sinensis from a common genetic ancestor over the long course of evolution.
... These findings underscore the complexity of Chinese cordyceps as a habitat, highlighting the interactions between O. sinensis, the ghost moth, and the host's microbiota, which influence the overall fungal diversity and infection dynamics. Additionally, significant efforts have been made particularly in China to isolate fungi from Chinese cordyceps for anamorph identification (Leung et al., 2009;Zhu et al., 1998). However, O. sinensis may represent the anamorph of Chinese cordyceps although species such as C. multiaxialis and C. nepalensis share nearly identical ITS sequences (Chen et al., 2004;Liu et al., 2001). ...
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Entomopathogenic fungi (EPF) represent a specialized group of microorganisms which are distinguished by their ability to infect and kill arthropods. Ophiocordyceps sinensis, a well-known and highly valued EPF species, infects the soil-dwelling larvae of Thitarodes/Hepialus (ghost moths) on the Tibetan Plateau. After the mummification of ghost moth larvae, the fungus-insect parasite complex with a fruiting body is known as Chinese cordyceps. This complex is highly esteemed as one of the most valuable traditional Asian medicines. Notably, the ghost moth larvae can survive several months after infection with O. sinensis, which makes it an exceptional model for gaining insight into the complex mechanisms in the production of Chinese cordyceps. In this review we discussed the interactions of important EPF with some key insects. Specifically, we summarized the mechanisms of EPF's mode of entry and action, uncovering the intriguing processes behind their pathogenicity. We further discussed the influence of fungal toxins on insect physiology and development, revealing the multifaceted effects that result in host mortality. Moreover, we summarized the interaction of EPF with insect's microbiota, revealing the complex dynamics that impact the pathogenic process. However, our primary focus remains on the interaction of O. sinensis with the ghost moth. Such understandings will further improve our knowledge of this complex interplay between O. sinensis and ghost moth, ultimately contributing to the improvement of Chinese cordyceps production.
... Boesi (2003), Winkler (2005Winkler ( , 2008 and Lama (2007) explains that Yartsa Gunbu income provides cash for health care, education and transportation and "spore" money for entrepreneurial activities. It also opened access to bank loans for rural Tibetans thereby leading to an empowerment of marginal communities even though it also causes challenges like Community disputes over grazing rights, access to caterpillar fungus resources etc. Zhu, JS and Jones, K. (1998) pointed out that Cordyceps sinensis has been used as a tonic for longevity, endurance, and vitality for thousands of years by the Chinese as Cordyceps has a wide-range of uses including immune system stimulation, reducing cholesterol levels and the treatment of Asthma, Arrhythmia and Cancer and also Cordyceps has become very popular in sports nutrition due to its ability to increase physical endurance and its use by Olympic athletes, also the high Adenosine content in Cordyceps also helps to prevent blood Platelet aggregation. Shimizu, D. (1994) stated that "in the West, Cordyceps only recently received attention after Chinese female runners established several world long-distance records (1500 to 10,000 meters) within a short period of time in 1993 since the athletes' coach attributed their success in part to a special Cordyceps-containing diet that enhanced their physical performance and endurance". ...
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Cordyceps has been a resource in the Bhutanese traditional medicine for many years and in the recent years, Cordyceps has become one of the most expensive mushrooms in the world fetching up to US7200toUS 7200 to US 10900 per kilo gram. The Royal Government of Bhutan legalized the harvesting of Cordyceps in the year 2004 and now it is legally harvested throughout the alpine areas of Bhutan. This research intends to study on the sustainability and future prospects of Cordyceps sinensis business in Bhutan. The research mainly focuses on finding out the aspects of Cordyceps business faced by the Cordyceps harvesters and collectors like opportunities, threats, harvesting/collection, selling, existing and future market scenarios of Cordyceps. The research also intends to study about the contribution of Cordyceps business towards the socio-economic development of the Cordyceps harvesters/collectors as a whole thereby assessing the comfortable level of the Cordyceps collectors of Sephu Gewog with the present system of Cordyceps business and the Government’s policies towards it. Keywords: Cordyceps, Mushroom, Harvesters, Medicine, Opportunities, Threats, Marketing, Sustainability, Socio-economic, Government
... However, its applications in oriental medicine range from its simple use in the case of back pain to consumption in the case of cardiovascular, kidney, liver and lung diseases (e.g., from asthma to tuberculosis) [37]. Its action mechanism aims to enhance the response of the immune system and its use, even in combination with conventional therapies, seems to lead to a recovery of physiological oxygen-free radical scavenging, in addition to its antisenescence and antiatherosclerotic effects [38]. It is also regularly used as an adjuvant in cancer therapy, in combination with conventional pharmacological treatment [39]. ...
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Breast cancer (BC) is the most commonly diagnosed tumor, remaining one of the leading causes of morbidity and mortality in females worldwide, with the highest rates in Western countries. Among metastatic BC (MBC), triple-negative breast cancer (TNBC) is characterized by the lack of expression of specific receptors, and differs from other subgroups of BC for its increased growth and fast spreading, with reduced treatment possibilities and a worse outcome. Actually, MBC patients are extremely prone to metastasis and consequent relapses, which affect distant target organs (e.g., brain, lung, bone and liver). Hence, the comprehension of biological mechanisms underlying the BC metastatization process is a key requirement to conceive/set up innovative medicinal strategies, with the goal to achieve long-lasting therapeutic efficacy, reducing adverse effects, and also ameliorating Quality of Life (QoL). Bioactive metabolites isolated from medicinal mushrooms (MMs) used as a supportive treatment, combined with conventional oncology, have recently gained wide interest. In fact, mounting evidence has revealed their peculiar promising immunomodulatory, anti-inflammatory and anticancer activities, even though these effects have to be further clarified. Among the group of most promising MMs are Lentinula edodes, Grifola frondosa, Ganoderma lucidum, Ophiocordyceps sinensis and Agaricus blazei, which are already employed in conventional cancer protocols in Asia and China. Recently, a growing number of studies have focused on the pharmacology and feasibility of MM-derived bioactive compounds as a novel valuable approach to propose an effective adjuvant therapy for MBC patients’ management. In this review, we summarized the current state of knowledge on the abovementioned MM-derived bioactive compounds and their therapeutic potential in clinical settings.
... Cordyceps have been used for over 2000 years in Chinese medicine to cure numerous infectious diseases (Zhou et al., 2009). The basis for considering Cordyceps and allies in oriental medicine is the belief, as well as clinical trials, that O. sinensis enhances sexual function in men and women (Zhu et al., 1998). From 1980 onwards, scientific perceptions were applied with advanced methodology to validate the traditional claims on Cordyceps (Holliday and Cleaver, 2008). ...
Chapter
Cordyceps and allied species are versatile ascomycetous macrofungi well known for their medicinal and nutritional attributes. Literature about nutritional, medicinal, and biological properties and applications is available for Cordyceps and related species. Cordyceps is the second most commercially popular macrofungi in China, Japan, and Korea owing to its therapeutic versatility. The Himalayan range of the Indian subcontinent is one of the prime ecoregions for their occurrence and distribution. In the recent past, reports on the existence of Cordyceps and related species have been available from the Western Ghats and southwest ecosystems of India. There seem to be Himalayan and Western Ghat Cordyceps that have evolved concurrently in high-altitude cold and high-altitude warm ecoregions, respectively. Cordyceps and allies are physiologically versatile in their association (bipartite and tripartite) with plants and insects. This review emphasizes the occurrence, distribution, diversity, and significance of Cordyceps and related species in India. Keywords Distribution, Ecology, Entomopathogen, Himalayas, Medicinal mushrooms, Scrub jungles, Western Ghats
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Sexual reproduction in ascomycetes is controlled by the mating-type (MAT) locus. (Pseudo)homothallic reproduction has been hypothesized on the basis of genetic data from Hirsutella sinensis (Genotype #1 of Ophiocordyceps sinensis). However, the differential occurrence and differential transcription of mating-type genes in the MAT1-1 and MAT1-2 idiomorphs were found in the genome and transcriptome assemblies of H. sinensis, and the introns of the MAT1-2-1 transcript were alternatively spliced with an unspliced intron I that contains stop codons. These findings reveal that O. sinensis reproduction is controlled at the genetic, transcriptional, and coupled transcriptional-translational levels. This study revealed that mutant mating proteins could potentially have various secondary structures. Differential occurrence and transcription of the a-/α-pheromone receptor genes were also found in H. sinensis. The data were inconsistent with self-fertilization under (pseudo)homothallism but suggest the self-sterility of H. sinensis and the requirement of mating partners to achieve O. sinensis sexual outcrossing under heterothallism or hybridization. Although consistent occurrence and transcription of the mating-type genes of both the MAT1-1 and MAT1-2 idiomorphs have been reported in natural and cultivated Cordyceps sinensis insect-fungi complexes, the mutant MAT1-1-1 and α-pheromone receptor transcripts in natural C. sinensis result in N-terminal or middle-truncated proteins with significantly altered overall hydrophobicity and secondary structures of the proteins, suggesting heterogeneous fungal source(s) of the proteins and hybridization reproduction because of the co-occurrence of multiple genomically independent genotypes of O. sinensis and >90 fungal species in natural C. sinensis.
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