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Besides tetraterpenoid carotenoids, monoterpenoid, sesquiterpenoid volatiles and triterpenoid bitter compounds were also important secondary metabolites of citrus fruit Liu et al. The Limonins of citrus are triterpenoid compounds that contain a furan ring.

They are secondary metabolites of some high-oxygen terpenoids. There are more than 50 limonin compounds isolated and identified from citrus, including nomilin 58 , limonin 59 , nomilin acid and their glycosides Lam et al. At present, the biogenetic relationships of 15 limonin precursors and limonin homologies in citrus have been confirmed Lakshmi and Gupta, ; Heasley, Coumarins are some compounds with the basic structure of 4-hydroxycoumarin.

Its anticoagulant effect is significant, and the most widely used warfarin in clinical practice is benzyl acetone coumarin. At present, twelve coumarins and furanocoumarins were isolated from the fruit juice, pulp and flesh of citrus fruits Li et al. Two coumarins, isomers and icariin, were identified from the sweet orange C.

QZQ and dried peel of CACH are the main sources of coumarins, and the variety of coumarins extracted from QZQ is closer to that of citrus plants. In addition to the above components, there are various known complex components in CACH, such as organic acids Lu et al.

Some studies have been reported on the content and types of them. For example, it was found that CACH contains 16 kinds of amino acids, including eight kinds of essential amino acids, and the content of ASP is the highest Zheng et al.

These studies provided an extremely important theoretical basis for the industrial development of CACH, and promoted the further development of its medical and food industry.

The production of CACH is large and the storage is abundant. The ethnomedical applications of CACH has attracted the attention of the scientific community.

It stimulates the trend of in-depth research on various pharmacological mechanisms of CACH. Currently known extracts and isolated compounds have various pharmacological effects, such as anti-inflammatory, antioxidant, antitumor, hypolipidemic and protection on organs.

The specific pharmacological activities are shown in Table 3 and summarized as follows Figure 5. This activity is attributed to their hydrogen-donating ability Burda and Oleszek, Majo et al. Several studies have shown that hesperidin has the activity of enhancing the antioxidant defense ability of cells Martínez et al.

According to the research of Shi et al. Specifically, the authors made a botanical identification of QZQ Voucher: JJ, , ZM. Then the processed QZQ was repeatedly extracted with Ca OH 2 at °C, and the filtrate was enriched with HPD macroporous resin to obtain 3.

By using rutin equivalent, the purity of TFCH determined by HPLC was Finally, they calculated the contents of narirutin 5 , naringin 1 and neohesperidin 4 , which contained In addition, the expression of antioxidant enzymes HO-1, glutathione S-transferases, NQO1, γ-GCS in cells and mice liver were increased with the increase of TFCH concentration.

These results suggest that total flavonoids may be the material basis of antioxidant activity of CACH. However, the specific mechanism of action need to be further confirmed. CACH could be used in the treatment of chronic gastritis and peptic ulcer, these diseases are mainly related to the overexpression of inflammatory factors.

Jiang et al. The specific method was to induce male SD rats with HFD, and then used TFCH treated rats. Wang et al. More specifically, the anti-inflammatory factors IL-4, IL were increased in the lung tissues of mice after treating with TFCH.

Meanwhile authors counted the number of inflammatory cells in bronchoalveolar lavage fluid BALF via Swiss-Giemsa staining. It found that TFCH significantly altered the numbers of total leukocytes, eosinophils, monocytes, neutrophils, and lymphocytes in BALF in a dose-dependent manner, and improved the inflammatory microenvironment of bronchoalveolar cells.

Based on the above findings, this paper summarizes the current studies on the anti-inflammatory mechanism of CACH, as shown in Figure 6. In recent years, the preventive and therapeutic effects of CACH on diabetes and hyperlipidemia received extensive attention and research. Although its mechanism has not been fully elucidated, its hypoglycemic effect may be achieved by increasing glucose consumption, regulating intestinal flora, and improving lipid metabolism.

Early research showed that the intervention of naringin and neohesperidin increased intracellular glucose consumption, a process associated with increased phosphorylation of AMP-activated protein kinase Zhang et al.

According to the literature of Ling et al. The proliferation and metastasis of cancer cells are mediated by many factors. Modern researchs have made the effort on tumor microenvironment, pathogenesis and biomarkers for a long time, but the development of highly specific antitumor drugs is still one of the bottlenecks in this field Mashouri et al.

The use of diet to treat cancer has been a new research direction in recent years. From the perspective of regulating the cancer metabolic microenvironment, the method of antitumor is to find out the active molecules of food, which can specifically target metabolic pathway.

As mentioned above, CACH contains abundant flavonoids, including neohesperidin 4 and PMFs Interestingly, Interestingly, early studies have shown that neohesperidin has neuroprotective activity Hwang and Yen, ; Martínez et al.

Duan et al. According to the literatures in the database, it is found that the anti-tumor activity of CACH is related to intervening cell cycle and inhibiting proliferation.

The targets and toxicological datas in this process still need to be further explored. More and more in-depth research on antitumor activity may be one of the future directions and trends. As a fructus aurantii of Chinese herbals, QZQ has the characteristics of multi-target, multi-pathway, synergistic effect, non-toxicity, which are great value for the development of new drugs.

Although it will change the types and content of active components after the TCM processing of CACH into QZQ, literatures shown that both of them have significant protection effect on organs, such as respiratory system protection, intestinal adjustment, hepatoprotective activity, etc.

In these aspects, QZQ has direct or indirect regulatory effect on lung, stomach and other organs, which is not particularly different from the traditional effect of conventional fructus aurantii. The specific research contents are summarized as follows.

Previous studies have found CACH has protective effects on some liver disease models. The main disease models were nonalcoholic fatty liver disease NAFLD and liver fibrosis in these studies.

The main pathological feature of NAFLD is diffuse hepatic fatty lesion, the disease spectrum includes simple fatty liver, steatohepatitis, and hepatic sclerosis, and some patients may even develop liver cancer Yu et al.

Sufficient data indicate the prevention and treatment activities of CACH on liver diseases are mainly achieved through anti-inflammatory, antioxidant and intestinal microflora regulation. For example, NF-κB, the key protein in the mechanisms of regulating liver inflammation in NAFLD, has been widely studied.

TFCH was extracted and prepared by Jiang et al. TFCH improves the inflammatory environment of the liver by inhibiting the phosphorylation of IκBα to block the disintegration process of NF-κB, thereby inhibiting the synthesis and release of inflammatory factors. The results were also confirmed in positive drug group Polyene phosphatidycholine capsule group, In addition, Shi et al.

Unfortunately, the intermolecular regulatory role of these mechanisms has not been clearly elucidated.

Airway inflammation is the most common pathological feature of respiratory diseases. Allergic asthma is one of the typical diseases of respiratory system caused by chronic inflammation. It is triggered by some external factors, leading to infiltration of immune and inflammatory cells and accumulation in the airway.

Wheezing, shortness of breath, chest tightness and bronchoconstriction are the diagnostic characteristics of it in clinic Humbert et al. The flavonoids extract of CACH could alleviate local irritation by inhibiting the synthesis and release of inflammatory factors in airway smooth muscle.

It provides a potential therapeutic strategy for allergic asthma. Liu et al. Therefore, the deterioration of airway inflammation was inhibited, and airway pathology and hyperresponsiveness were improved. Relevant studies on the regulation of QZQ on respiratory system are important to the industrial development of CACH.

They prove that the local folk prescriptions in Changshan are meaningful, and also provide scientific basis for the rational use of QZQ. Intestinal adverse reactions caused by drugs are very common and have been paid more and more attention by pharmaceutical industry.

Reasonable intervention of intestinal microenvironment is of great significance to guide rational drug use in clinic. Chen et al. Authors induced intestinal injury in SD rats via continuous irrigation stomach with diclofenac 7. Meanwhile, administration of PTFC attenuated the decrease in intestinal tight junction protein expression and was associated with intestinal mucosal barrier repair in the NSAID-induced small intestine injury model.

He et al. It could significantly increased the relative abundances of Bacteroidaceae and Christensenellaceae. Furthermore, PTFC reduced the content of toxic bile acids and increased the ratio of secondary to primary bile acids. Rutaceae plants have a long medicinal history. They are widely used in many traditional Chinese medicine prescriptions and have been widely recognized in the clinical practice of TCM.

Citrus fruits are grown in tropical, subtropical and temperate regions of the Earth. In recent years, they have become more and more popular in the World, and their rich bioactive substances have made a significant contribution to global human health.

Daily consumption of citrus fruits is one of the ideal dietary approaches to prevent diseases, which is related to the intervention of inflammatory production, antigen presentation, antioxidant defense mechanisms and intestinal microbiota.

QZQ is the dry and immature fruit of CACH, a hybridization of Citrus grandis Osbeck and C. It has the function of promoting blood circulation and is used in TCM clinical treatment.

Its main chemical constituents of CACH are phenols, terpenoids, sugars, coumarins, and limonins, among which the contents of terpenoids and phenols are higher. As a fructus aurantii of Chinese herbals, CACH shows a variety of significant pharmacological activities, such as anti-inflammatory, antioxidant, antitumor and hypolycemic activities, which provide a certain pharmacological basis for its clinical application.

Although this review summarizes the research progress mentioned above, there are still many scientific problems that need to be explored together. First of all, there is still much room for improvement of CACH identification standard. Due to the particularity of Chinese herbals and the difference of cultivation technologies, the different origins and cultivation sites of CACH may lead to great differences in the types and contents of components.

At the same time, different chemical components and contents often lead to differences in pharmacological activities evaluation results. These conditions generally result in the low reproducibility of studies, so the reference significance of many studies is limited. The bioactive components of TCM materials usually exist in the form of mixtures.

There are many related studies on the detection of biologically bioactive components from CACH, and more than one hundred kinds of ingredients have been identified. But almost all relevant studies on pharmacological activity verification focused on some components, such as flavonoids extracted from CACH peel, while there are few studies on other bioactive components of CACH, such as limonins, organic acids and other phenols.

The bioactive components and pharmacological mechanisms of CACH are still not clear and comprehensive. It is more common that researchers focus too much on the results.

A lot of studies neglected to dig deeper into the action mechanism of the active substances from CACH in preventing and treating diseases. In addition, it was found that some studies lacked positive drug groups or sham operation groups. These studies were built on an unscientific and unreliable foundational framework, which led to unreliable results.

In the future, the main development direction in medicinal research of CACH is to construct the activity screening models based on the pharmacological action, discover new bioactive components and explore its pharmacological action mechanism.

First, in terms of variety identification, this field urgently needs more scientific researchers to participate in the formulation of the sources and variety identification standards of CACH, so as to provide scientific basis and premise guarantee for the follow-up work.

Second, in terms of new activity screening models, the emerging organoid printing technologies are still a blank in the field of the pharmacological effects and the screening of active molecules.

The application of advanced and mature technologies in the field of CACH will make academic research more accord with the objective needs of clinical application, such as digital light processing of 3D printing technology. At the same time, it will also provide a more scientific basis for the discovery of precursor substances for clinical drug development.

Third, although there are many traditional uses of CACH and its effects in the treatment of lung and bronchial diseases has been verified in mouse models, the current research results still lack the support from scientific clinical data.

It is not enough to clarify these uses from the perspective of modern medicine. Therefore, it is necessary to obtain its toxicology and pharmacokinetics data, so as to provide a safe basis for clinical research and product development of CACH. In conclusion, the review summarized the basic background, chemical composition, pharmacological activity, development bottleneck and future direction of CACH.

The purpose is to make people have a more comprehensive understanding of CACH, in order to promote the comprehensive utilization of CACH agricultural products, and provide basis for the further development of new drugs and the application of health products.

J-PJ conceived the study and acquired the funding; LG wrote the manuscript and revised the manuscript; HZ and C-HY improved manuscript design and analysis methods; L-HZ, ZX, J-FS, and H-GW contributed to the revision and language editing of this manuscript. All authors agreed the submission of this manuscript, and agreed to be accountable for all aspects of this work.

We appreciate the great support from the institute of Chinese materia medica, Zhejiang University of Technology and The First Affiliated Hospital of Zhejiang Chinese Medical University Zhejiang Provincial Hospital of Traditional Chinese Medicine.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Similar to grapefruit, citrus aurantium interacts with the medications that are metabolized by the enzyme complex called cytochrome P Citrus aurantium should be avoided in the following conditions:. Log in Register.

Don't have an account yet? Register now! Remember Me. Citrus Aurantium: Also known as bitter orange , Seville orange , zhi chi , and chongcao , citrus aurantium is a member of citrus trees and its fruits and leaves have been used for medicinal and athletic purposes.

The peels of bitter orange contain synephrine, octopamine, tyramine, hordenine, N-methyltyramine, volatile oils , and carotenoids. Athletic Benefits of Citrus Aurantium: Since ephedrine has been banned in sports, synephrine — containing citrus aurantium may be a good alternative.

The potential athletic benefits are as follows: May improve athletic performance by acting as a mild stimulant. Promotes mental clarity. Helps promote athletic agility. Useful in weight loss by decreasing appetite and increasing basal metabolic rate BMR.