Flavonoids are organic compounds characterized by a range of phenolic structures, which are abundantly present in various natural sources such as fruits, vegetables, cereals, bark, roots, stems, flowers, tea, and wine. The health advantages of these natural substances are renowned, and initiatives are being taken to extract the flavonoids. Apigenin, galangin, hesperetin, kaempferol, myricetin, naringenin, and quercetin are the seven most common compounds belonging to this class. A thorough analysis of bibliographic records from reliable sources including Google Scholar, Web of Science, PubMed, ScienceDirect, MEDLINE, and others was done to learn more about the biological activities of these flavonoids. These flavonoids appear to have promising anti-diabetic, anti-inflammatory, antibacterial, antioxidant, antiviral, cytotoxic, and lipid-lowering activities, according to evidence from in vitro , in vivo , and clinical research. The review contains recent trends, therapeutical interventions, and futuristic aspects of flavonoids to treat several diseases like diabetes, inflammation, bacterial and viral infections, cancers, and cardiovascular diseases. However, this manuscript should be handy in future drug discovery. Despite these encouraging findings, a notable gap exists in clinical research, hindering a comprehensive understanding of the effects of flavonoids at both high and low concentrations on human health. Future investigations should prioritize exploring bioavailability, given the potential for high inter-individual variation. As a starting point for further study on these flavonoids, this review paper may promote identifying and creating innovative therapeutic uses.

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Flavonoids are natural phytochemicals that have therapeutic effects and act in the prevention of several pathologies. These phytochemicals can be found in seeds, grains, tea, coffee, wine, chocolate, cocoa, vegetables and, mainly, in citrus fruits. Neohesperidin, hesperidin and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory and antioxidant potential. Neohesperidin, in the form of neohesperidin dihydrochalcone (NHDC), also has dietary properties as a sweetener. In general, these flavanones have been investigated as a strategy to control bone diseases, such as osteoporosis and osteoarthritis. In this literature review, we compiled studies that investigated the effects of neohesperidin, hesperidin and its aglycone, hesperetin, on bone health. In vitro studies showed that these flavanones exerted an antiosteoclastic and anti- inflammatory effects, inhibiting the expression of osteoclastic markers and reducing the levels of reactive oxygen species, proinflammatory cytokines and matrix metalloproteinase levels. Similarly, such studies favored the osteogenic potential of preosteoblastic cells and induced the overexpression of osteogenic markers. In vivo, these flavanones favored the regeneration of bone defects and minimized inflammation in arthritis- and periodontitis-induced models. Additionally, they exerted a significant anticatabolic effect in ovariectomy models, reducing trabecular bone loss and increasing bone mineral density. Although research should advance to the clinical field, these flavanones may have therapeutic potential for controlling the progression of metabolic, autoimmune or inflammatory bone diseases.

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The most recent outbreak of 2019 novel coronavirus, named as COVID-19, caused pneumonia epidemic in Wuhan with 2121 deaths cases as of February 20th 2020. Identification of effective antiviral agents to combat the novel coronavirus is urgently needed. Citrus fruit peel or wild citrus are rich in flavonoids, and clinically documented for roles in relief of cough and promotion of digestive health. Therefore, citrus fruits are assumed to possess antivirus activities or enhance the host immunity. A previous study found that hesperetin could act as a high potent inhibitor of SARS-CoV 3CLpro. We determined six flavonoid compounds' content in three citrus species by using LC-MS technique. The content of naringin and naringenin was at higher levels in pummelo. Hesperetin and hesperidin were highly accumulated in mandarin and sweet orange. The subsequent in vitro and in vivo experiments indicated that naringin could inhibit the expression of the proinflammatory cytokines (COX-2, iNOS, IL-1β and IL-6) induced by LPS in Raw macrophage cell line, and may restrain cytokine through inhibiting HMGB1 expression in a mouse model. The results revealed that naringin may have a potential application for preventing cytokine storm. We simulated molecular docking to predict the binding affinity of those flavonoids to bind Angiotensin-converting enzyme 2 (ACE 2), which is a receptor of the coronavirus. Consideration of the potential anti-coronavirus and anti-inflammatory activity of flavonoids, the citrus fruit or its derived phytochemicals are promising in the use of prevention and treatment of SARS-CoV-2 infection.

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The emergence of viral pneumonia caused by a novel coronavirus (CoV), known as the 2019 novel coronavirus (2019-nCoV), resulted in a contagious acute respiratory infectious disease in December 2019 in Wuhan, Hubei Province, China. Its alarmingly quick transmission to many countries across the world and a considerable percentage of morbidity and mortality made the World Health Organization recognize it as a pandemic on March 11, 2020. The perceived risk of infection has led many research groups to study COVID-19 from different aspects. In this literature review, the phylogenetics and taxonomy of COVID-19 coronavirus, epidemiology, and respiratory viruses similar to COVID-19 and their mode of action are documented in an approach to understand the behavior of the current virus. Moreover, we suggest targeting the receptors of SARS-CoV and SARS-CoV-2 such as ACE2 and other proteins including 3CLpro and PLpro for improving antiviral activity and immune response against COVID-19 disease. Additionally, since phytochemicals play an essential role in complementary therapies for viral infections, we summarized different bioactive natural products against the mentioned respiratory viruses with a focus on influenza A, SARS-CoV, MERS, and COVID-19.Based on current literature, 130 compounds have antiviral potential, and of these, 94 metabolites demonstrated bioactivity against coronaviruses. Interestingly, these are classified in different groups of natural products, including alkaloids, flavonoids, terpenoids, and others. Most of these compounds comprise flavonoid skeletons. Based on our survey, xanthoangelol E ( 88 ), isolated from Angelica keiskei (Miq.) Koidz showed inhibitory activity against SARS-CoV PLpro with the best IC 50 value of 1.2 μM. Additionally, hispidulin ( 3 ), quercetin ( 6 ), rutin ( 8 ), saikosaponin D ( 36 ), glycyrrhizin ( 47 ), and hesperetin ( 55 ) had remarkable antiviral potential against different viral infections. Among these compounds, quercetin ( 6 ) exhibited antiviral activities against influenza A, SARS-CoV, and COVID-19 and this seems to be a highly promising compound. In addition, our report discusses the obstacles and future perspectives to highlight the importance of developing screening programs to investigate potential natural medicines against COVID-19.

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Citrus originated in Southeast Asia, and it has become one of the most important fruit crops worldwide. Citrus has a long and obscure domestication history due to its clonal propagation, long life cycle, wide sexual compatibility, and complex genetic background. As the genomic information of both wild and cultivated citrus becomes available, their domestication history and underlying traits or genes are becoming clear. This review outlines the genomic features of wild and cultivated species. We propose that the reduction of citric acid is a critical trait for citrus domestication. The genetic model representing the change during domestication may be associated with a regulatory complex known as WD-repeat-MYB-bHLH-WRKY (WMBW), which is involved in acidification and anthocyanin accumulation. The reduction in or loss of anthocyanins may be due to a hitchhiking effect of fruit acidity selection, in which mutation occurs in the common regulator of these two pathways in some domesticated types. Moreover, we have summarized the domestication traits and candidate genes for breeding purposes. This review represents a comprehensive summary of the genes controlling key traits of interest, such as acidity, metabolism, and disease resistance. It also sheds light on recent advances in early flowering from transgenic studies and provides a new perspective for fast breeding of citrus. Our review lays a foundation for future research on fruit acidity, flavor, and disease resistance in citrus.

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