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Issue 2, Immune enhancement effects and extraction optimization of polysaccharides from Citrus aurantium L. amara Engl. You have access to this article. Please wait while we load your content Something went wrong. Try again? Cited by. Download options Please wait Article type Paper.

Submitted 21 Oct Accepted 30 Dec First published 02 Jan Download Citation. Food Funct. Request permissions. Social activity. Search articles by author Chun-Yan Shen. Li Yang. Jian-Guo Jiang. Naringin also reduced ICAM-1 expression on endothelial cells cultured in high glucose concentrations , an effect associated with reduced phosphorylation of the p38 MAPK.

Inclusion of naringin in the diet of rabbits fed a high cholesterol diet reduced expression of VCAM-1 and MCP-1 in the aortic arch and reduced expression of ICAM-1 on endothelial cells Inclusion of naringin in the diet of mice fed a high cholesterol diet reduced blood levels of sICAM-1 and sE-selectin Dietary naringin lowered serum TNF-α concentration and increased serum adiponectin in mice ref a high fat diet Dietary naringin dose-dependently decreased serum concentrations of TNF-α, IL-6 and CRP and increased adiponectin concentration in diabetic rats fed a high fat diet compared with diabetic control rats In this same study, naringen increased liver and kidney expression of the anti-inflammatory transcription factor peroxisome proliferator activated receptor-γ and of heat shock protein and and decreased liver, kidney, and pancreas expression of NFκB Narirutin and naringin both decreased nitric oxide production by lipopolysaccharide-stimulated macrophages and decreased CRP release from incubated rat aortic vascular ring These data suggest that naringenin and its glycosides naringin and narirutin may have similar anti-inflammatory effects.

Beyond effects supporting immune function and controlling inflammation, bioactives present in citrus fruit juices may have direct anti-viral effects; these have been highlighted in the context of infection with systemic acute respiratory syndrome coronavirus SARS-CoV -2 and the disease that this virus causes, coronavirus disease discovered in COVID Using in silico modelling it was identified that hesperidin can bind with ACE2 and in doing so may make the ACE2-SARS-CoV-2 spike protein structure unstable — Through this action it is proposed that hesperidin could block SARS-CoV-2 from entering host cells and so could prevent the infection.

Hesperidin has also been shown to prevent replication of several viruses including the influenza virus acting through activation of immune-supporting MAPK pathways and in mice it prevented the spread of influenza virus Both hesperidin and hesperetin are able to inhibit key proteases involved in coronavirus replication , As reviewed by Tutunchi naringenin exerts similar actions suggesting it too could inhibit viral entry into host cells and subsequent viral replication.

It includes barrier functions and capabilities for recognition and elimination of pathogens and for immunologic memory. One component of the immune response is inflammation which is designed to create a hostile environment to pathogens.

Generation of oxidative stress is part of the inflammatory response and, in turn, oxidative stress can induce inflammation. Hence, an immune response which is appropriate to the challenge and involves controlled inflammation that is self-resolving is optimal.

Limitation of oxidative stress is one means of controlling inflammation, hence, antioxidants are often also anti-inflammatory. Nutrition is one of many determinants of the immune response 1 , 12 — 16 including the inflammatory component 4 — 6.

Micronutrients vitamins and minerals are especially important for supporting normal immune response 1 , 12 — 16 and plant polyphenols have also emerged as having important roles, not only in helping to control oxidative and inflammatory stress, but also in supporting the activities of the cellular aspects of innate and acquired immunity.

Vitamin C and folate both have roles in sustaining the integrity of immunological barriers including the skin and internal mucosal linings Figure 4 , while vitamin C is an antioxidant and helps to control inflammation Figure 4.

As described earlier, both vitamin C and folate support the function of many types of immune cell including phagocytes, natural killer cells, T-cells, and B-cells Figure 4. The Nutrient Reference Values for vitamin C and folate are 80 mg and μg respectively.

Hesperidin is a glycoside of hesperetin and narirutin and naringin are glycosides of naringenin Figure 3. Hesperidin, hesperetin, naringenin, naringin and narirutin have all been demonstrated to have anti-inflammatory effects, mainly demonstrated in cell culture and some animal studies; all seem to act, at least in part, through inhibiting activation of the pro-inflammatory transcription factor NFκB.

Human trials of hesperidin in people with metabolic syndrome or type-2 diabetes reported reductions in inflammatory markers, including CRP. Hesperidin modified gene expression in white blood cells with significant overlap of the genes modified with those modified by orange juice Thus, citrus fruit juices contain a mix of components that control oxidative stress and inflammation, and support the immune system.

In the context of human trials, orange juice has been most widely explored, although specific trials on immunity are scarce.

Orange juice was shown to limit the post-prandial inflammation induced by a high fat-high carbohydrate meal Consuming orange juice daily for a period of weeks reduced markers of inflammation, including CRP, as confirmed through a recent meta-analysis One human intervention trial with orange juice failed to find effects on markers of innate or acquired immunity 60 ; however this trial studied healthy middle aged men and it may be that groups vulnerable to declines in immune function, such as the elderly, may be a better option for this type of trial.

Despite the findings of the latter study, in general the effects of orange juice, especially with regard to inflammation, are consistent with those of its component bioactives. A newly emerging topic, driven largely by the SARS-CoV-2 pandemic, is whether polyphenols from orange juice have direct anti-viral effects.

Furthermore in vitro studies identify that hesperidin, hesperetin and naringenin can restrict viral replication acting through inhibition of key enzymes involved in this process — Whether these effects occur in infected humans at intakes and circulating concentrations of these bioactives consistent with normal fruit juice consumption is uncertain.

In this context a clinical trial of hesperidin in people newly infected with SARS-CoV-2 has been registered In summary, micronutrients and other bioactives present in citrus fruit juices have established plausible pathways for controlling oxidative stress and inflammation and for supporting innate and acquired immune responses.

Trials in humans demonstrate that orange juice reduces inflammation, while its effects on innate and acquired immunity require further exploration in well-designed trials in appropriate population sub-groups, such as older people. Figure 4 Summary of the effects of orange juice bioactives on different aspects of inflammation and immunity.

Vitamin C and folate support barrier function, T cell mediated immunity and B cell mediated immunity. Vitamin C, folate, hesperidin and its aglycone hesperetin, and narirutin and naringin and their aglycone naringenin all reduce inflammation.

The first draft of the article was prepared by PC. EM provided comment. All authors contributed to the article and approved the submitted version. The University of Southampton received funds from a consortium of orange producers, juice manufacturers and packaging companies based in Europe and Brazil under the umbrella of the European Fruit Juice Association AIJN.

The funders had no influence on the content of the article nor on the decision of where to publish. The 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.

ACE, angiotensin converting enzyme; COVID, coronavirus disease discovered in ; CRP, C-reactive protein; FR4, folate receptor 4; ICAM, intercellular adhesion molecule; IFN, interferon; Ig, immunoglobulin; IL, interleukin; MAMP, microbe-associated molecular pattern; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; SARS-CoV-2, systemic acute respiratory distress syndrome coronavirus 2; TLR, toll-like receptor; TNF, tumour necrosis factor; VCAM, vascular cell adhesion molecule.

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To improve animal well-being, we provided a sanitary environment to prevent disease and proper breeding and management and used appropriate painkillers and anesthetics to reduce pain. The humane endpoints were set by observing body weight change, hair coat, movement and posture of mice and applied in consultation with experimental committee.

When both sings as lack of respiration and faded eye color were observed, the mice were removed from the CO 2 chamber. Aβ 1—42 was dissolved in sterile 0. The respective drugs were given orally p. for 4 weeks Day Based on the results of previous studies, the concentrations of CAE and nobiletin were set 3 , 13 , The passive avoidance test was conducted in all groups for 3 days Days 15—17 and Morris water maze MWM task for 7 days Days 22— The mice were performed by cardiac puncture for exsanguination after carbon dioxide anesthesia at Day 28 and were confirmed the death by observing stop breathing and cardiac dysfunction through CO 2 anesthesia and exsanguination.

The entire experimental schedule is shown in Fig. To determine learning and memory ability, the passive avoidance test was conducted in an acrylic shuttle box with two compartments and a guillotine door in the middle. The box consists of illuminated and non-illuminated compartments with an electric grid floor that allows for electronic shock stimuli.

The test was performed on 3 consecutive days at h intervals. On the first day Day 15 , the animals were allowed to explore the non-illuminated compartment for 2 min and then transferred back to the illuminated compartment. They were then allowed to access the illuminated and non-illuminated compartment freely for 60 sec.

If the mice moved to the non-illuminated compartment, they were immediately removed and trained to adapt to the illuminated compartment. After the end of adaptation the time, on the second day, the mice moved between the two compartments for sec, but when they entered the non-illuminated compartment, the guillotine door automatically closed and a scrambled shock was given for 2 sec.

On the last day of the test, Day 17, the mice were placed in the illuminated compartment and the time taken for them to move to the non-illuminated compartment after the door opened was measured.

On Day 22, the mice were tested using the MWM task. A circular water pool was divided into quadrants; the platform was randomly located within one quadrant. The mice were trained to find the platform for 60 sec. When the mice reached the platform, they were allowed to remain on the platform for 30 sec; if they could not find the platform within 60 sec, they were guided and placed on it for 30 sec to learn the extra maze cues.

All animals performed two trials per day and the position of the platform in the circular pool was randomly changed. The task consisted of 2 days of training; 4 days of acquisition, during which the time to find the platform was recorded; and 1 day of probe trial.

For the probe trial, the platform was removed and the animals were allowed to search it for 1 min. The number of crossings by the mice in the quadrant with the removed platform was measured on Day At the end of the experiment, the mice were sacrificed, and the cortex and hippocampus were dissected from the brain.

Both tissues were rapidly homogenized and sonicated in 0. AchE activity was determined using commercial assay kits Abnova; cat.

KA, Taiwan according to the manufacturer's instructions. The activity was calculated as the optical density OD at nm and represented as OD values per milligram of protein. The dissected cortex and hippocampus tissues were lysed in radioimmunoprecipitation assay buffer containing 50 mM Tris-HCl pH 7.

The supernatant was collected, and the protein concentration was calculated by bicinchoninic acid protein assay kit Thermo, USA. The membranes were blocked with commercial blocking buffer Thermo, USA for 1 h at room temperature and washed thrice with Tris-buffered saline containing 0.

After washing, the membrane was incubated at 4°C overnight with the following appropriate antibodies: B-cell lymphoma 2 Bcl-2 -associated X protein Bax; ,; cat. The membranes were again washed thrice and enhanced using chemi-luminescence reagents.

The protein bands on the membrane were detected by a chemi-luminometer ATTO, Japan. Densitometry was performed using the Image-Pro Plus soft-ware version 6. Data are expressed as the mean ± standard error and were analyzed with SPSS Statistics Different treatment groups were compared using one-way analysis of variance followed by multiple comparisons using Dunnett's post hoc test using Origin 7.

The composition in CAE were investigated the chromatographic profiles of a standard on HPLC analysis. The optimized CAE was used in all subsequent experiments. The mice did not show any change in body weight during the experiment, but hair coat showed rough condition.

Response to weak stimuli decreased and activity ability also decreased. Also, the mice was sitting on the floor with a curved posture was observed and through these symptoms, the humane endpoint was set. The animals were sacrificed by meeting the defined endpoint.

The effect of CAE and nobiletin on the Aβ 1—induced memory impairment was measured using a passive avoidance task. The step-through latency of the Aβ 1—only treated group was significantly shortened compared to the control group Fig.

However, the reduced step latency with Aβ 1—42 was restored by the administration of CAE and nobiletin. Effect of nobiletin and CAE on step-through latency in passive avoidance test in Aβ 1—42 induced memory impairment.

The data are presented as mean ± standard error of the mean. Aβ, amyloid β; CAE, Citrus aurantium extract. The efficacy of CAE and nobiletin in protection from the spatial memory impairment via Aβ 1—42 injection was further confirmed.

The escape latency assessment was performed twice a day. During the test period, escape latency decreased slightly in the second trial compare to the first trial in all experimental groups Fig.

No difference was observed in the escape latency for 4 days in the amnesic mice, which were treated with Aβ 1— By contrast, the control group showed significantly decreased escape latency in two trials over 4 days Fig. It is well-established that Aβ 1—42 induces memory loss and increases the escape latency.

Similarly, the escape latency in mice administered nobiletin significantly decreased for 4 days compared to the Aβ 1—only injected group. Effect of nobiletin and CAE on Aβ 1—42 induced memory impairment in the Morris water maze. The escape latency of A Trial 1 and B Trial 2, and the mean of C Trial 1 and Trial 2 during the training sessions for 4 days.

The effect of CAE and nobiletin treatment on the swim distance to locate the platform in the MWM task is shown in Table I. The control group mice were able to swiftly locate the platform and reached the platform during the training session.

However, the Aβ 1—treated group had difficulty learning to locate the platform. The swim distance was significantly increased compared to that of the control group. The mice in the nobiletin-treated group were also able to find the platform easily with a short swim distance, especially on Day Effect of nobiletin and CAE on the distance swum by Aβ 1—42 treated mice to find the platform in the water maze task.

To evaluate the spatial memory of the mice, the number of crossings to the platform was measured in the probe trial on Day As shown in Fig. These results show that these drugs enhance spatial cognition, learning, and memory functions against Aβ 1—induced memory impairment.

Effect of nobiletin and CAE on the number of crossing in a probe trail on Day To investigate the neuroprotective effect of CAE and nobiletin on brain tissue, AchE activity was measured in the cortex and hippocampus Table II.

The AchE activity in the Aβ 1—treatment group was significantly increased compared to that in control group. Similarly, the AchE activity in the nobiletin treatment group also decreased significantly by The effect of CAE and nobiletin on the Bcl-2 family and caspase pathway was investigated in the cortex and hippocampus.

In contrast, Bcl-2 protein expression was higher in the control group than in the Aβ 1—only treated group in the cortex and hippocampus.

A similar protein expression pattern was observed in the cortex. Effect of nobiletin and CAE on protein expression in A hippocampal and B cortex tissues. The expression was detected by western blot analysis.

Bax, Bcl-2 and cleaved caspase-3 protein levels were normalized by separate control β-actin, respectively. Aβ, amyloid β; CAE, Citrus aurantium extract; Nob, Nobiletin. The present study is the first report to evaluate the neuroprotective effects in Aβ 1—induced memory impairment animal model and not the transgenic or senescence accelerated mouse model.

Our results showed that the Aβ 1—injection resulted in severe performance deficits in the passive avoidance and Morris water task as well as neurodegeneration in the mice brain that was evident from increased AchE activity in the hippocampus and cortex.

In this study, we treated the amnesic mice with CAE and nobiletin and confirmed the anti-amnesic effect by regulating of apoptotic signaling. Aβ plays a major role in the development of AD, particularly the neurotoxic Aβ 1—42 The direct injection of Aβ 1—42 in the rodent brain has been used to cause apparent memory deficits, and Aβ-exposed rats have shown hippocampus-dependent spatial learning dysfunction in long and short-term tasks 4.

Also, the brains of AD patients demonstrated a high Aβ level compared with normal aged brain samples The deposition of Aβ in the cortex and hippocampus, which are responsible for learning and memory performance, resulted in neuronal apoptosis 21 , To examine the protective effect of CAE and nobiletin, we performed the passive avoidance and MWM tasks to investigate learning and memory function.

The passive avoidance task is a method that is used to measure the escape time from the space that induces pain and fear by electronic shock in rodents It is commonly used to confirm the memory function, and we found in this study that CAE and nobiletin administration significantly increased the step-through latency to similar levels, a phenomenon that was reduced by the Aβ 1—42 injection.

The MWM is an assessment method to evaluate hippocampal-dependent learning abilities and cognitive deficits in rodents. The animals were trained to learn spatial working information at the learning stage and assisted to build future memory These results are consistent with those of previous studies that show Aβ-induced memory deficits in an MWM task than those in the saline group As a result of two trials for 4 days on the MWM task, CAE treatment reduced escape latency in the second trial compared to the first trial, and escape time decreased over training days.

The nobiletin administration group showed similar escape latency for 4 days in the first trial, and the escape latency decreased rapidly on Day 26 in the second trial. Although the pattern of escape latency of the CAE and nobiletin group was slightly different, the mean escape latency was decreased to a similar pattern.

This means that CAE and nobiletin administration showed significant decreases in escape latency, improvement in cognitive performance, and amelioration of the memory deficits. Furthermore, to investigate the neuroprotective effect of CAE and nobiletin, we examined the changes in the Ach system in the hippocampus and cortex.

Ach is an essential enzyme that maintains the normal function of the nervous system and is hydrolyzed by AchE. In addition, Aβ deposition is increased in the presence of AchE, and AchE activity in AD is related to Aβ deposition Therefore, it is important to reduce the level of AchE, which is used as a marker for the cholinergic nervous system.

Here we found that AchE activity in the cortex was similar to that of CAE and nobiletin. However, nobiletin administration showed significantly lower AchE activity than CAE administration in the hippocampus.

CAE and nobiletin administration benefits on the cholinergic neurotransmission by decreasing AchE activities in the cortex and hippocampus. AchE can also be used as a marker of apoptosis. AchE expression or activity is increased when the cells undergo apoptosis, and enhanced AchE expression levels are detected in the brain of focal cerebral ischemic rats 26 , AchE is usually present in the cytoplasm and moves to the nucleus before nuclear morphological changes occur.

It then accelerates chromatin condensation and fragmentation by modulating nuclear components Therefore, AchE can be detected on the fragmented nuclei of apoptotic cells, and increased AchE activity implies the occurrence of cell death Apoptosis is triggered via two major pathways: The mitochondrial intrinsic pathway and the death receptor-mediated extrinsic pathway.

In this study, we focused on the mitochondrial pathway, which is regulated by Bcl-2 family and caspases Bcl-2 is a known anti-apoptotic protein, while Bax is a pro-apoptotic protein that promotes apoptosis. These two proteins are the major factors responsible for cell death regulation.

The Bcl-2 and Bax ratio determines whether a cell undergoes or escapes apoptosis 23 , In our study, the Aβ 1—42 injection group had increased Bax and cleaved caspase-3 protein expressions compared with the control group, while Bcl-2 protein levels were increased in the control group and reduced in the Aβ 1—treated group.

CAE treatment significantly decreased the Bax and cleaved caspase-3 protein expression levels and simultaneously increased Bcl-2 protein expression in the hippocampus and cortex. Likewise, the treatments also increased the expression ratio of Bcl-2 to Bax in the cortex and hippocampus.

On the other hand, Bcl-2 protein expression in the nobiletin administration group was increased to a level similar to that of the control group. Bax and cleaved caspase-3 protein expressions in the cortex were significantly inhibited by nobiletin treatment, while the Bcl-2 protein level was significantly enhanced compared the control group.

In conclusion, our results indicate that the administration of CAE and nobiletin had a similar neuroprotective effect against Aβ-induced cognitive impairment through reduction of AchE activity and anti-apoptotic activity and regulating the Bcl-2 family and caspase pathway in the cortex and hippocampus.

Our results provide evidence of the dietary intake of CAE or nobiletin as a valuable functional food since it has the ability to reduce cognitive impairment and memory dysfunction. However, to confirm the neuroprotective effects of CAE and nobiletin, we have to confirm the morphological change of brain tissues in further study.

However, it can also have some serious side effects. These include increased risk of bleeding, liver damage, and allergic reactions. It can also interact with certain medications, such as blood thinners, and can cause dangerous interactions. It is important to speak with a doctor before taking any dietary supplement, including Neoeriocitrin, to ensure it is safe for you to take.

Vitamin C tablets, Neoeriocitrin capsules, Neoeriocitrin powder, Neoeriocitrin chewable tablets, Neoeriocitrin liquid drops. Neoeriocitrin is not a dietary supplement that is regulated across the world.

However, it is regulated in some countries, such as the United States, where it is classified as a dietary ingredient and is subject to the regulations of the Dietary Supplement Health and Education Act DSHEA. In other countries, such as the European Union, Neoeriocitrin is not regulated as a dietary supplement, but is instead regulated as a food additive.

Tags: Vitamins. Get the most up-to-date information about Neoeriocitrin with SGS Digicomply. Stay informed about current regulations, incident monitoring, risk prevention, scientific insights, mentions in the media, and relevant updates. Smart GPT-like search, customizable dashboard, and comprehensive guides tailored to your specific area, product, and target market.

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