{"id":55636,"date":"2024-03-20T11:08:34","date_gmt":"2024-03-20T11:08:34","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=55636"},"modified":"2024-04-01T19:27:58","modified_gmt":"2024-04-01T19:27:58","slug":"modulation-of-immune-response-from-fibercreme-vco-based-supplementation-in-immunosuppressed-rats","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no1\/modulation-of-immune-response-from-fibercreme-vco-based-supplementation-in-immunosuppressed-rats\/","title":{"rendered":"Modulation of Immune Response from FiberCreme-VCO Based Supplementation in Immunosuppressed Rats"},"content":{"rendered":"\n

Introduction <\/strong><\/p>\n\n\n\n

The global frequency of viral\ninfections has increased during the previous decade. This infection has become\na serious concern in many countries which cause catastrophe in health, social,\neconomic, and financial sectors1<\/sup>. In 2021, there have been\n100,455,529 confirmed cases worldwide, with 2,166,440 deaths recorded2<\/sup>.\nViral infection can result in an immunological response in the host known as\ncytokine storm with overproduction of cytokines. This immune response promotes\ninflammation and fluid accumulation in the lungs which can make respiratory\ndisorder3<\/sup>. Various drug discovery is also being pursued, including\nthe development of therapeutic options such as reuse of existing drugs or\ncombination between drugs and supplements to prevent inflammation4<\/sup>. Viral\ninfection is a self-limiting disease, yet immunomodulation activity in body remains\ncrucial for well-being5<\/sup>. Immunomodulatory dose regimens for viral\ninfections are a preventive strategy which will lower resistance against viral\ninfection affecting human immune system6<\/sup>.<\/p>\n\n\n\n

Previous research has shown that Doxorubicine (Dox) has harmful effects on the rat hematopoietic system, resulting in a decrease in the number of granulocytes, lymphocytes, and monocytes as well as red blood cells (RBCs), white blood cells (WBCs), and WBCs. According to reports, DOX inhibited IL-10 downregulation, lymphocyte proliferation, macrophage capability, phagocytosis activity, and CD8+ cytotoxic T cell production in rats. In spleenocytes from tumor-bearing mice, Dox lowered the production of IL-2 and INF-, as well as lymphocyte proliferation, the CD4+\/CD8+ ratio, and NK cell cytotoxicity7<\/sup>. It also affects the cellular components that trigger immunological responses, leading to immunosuppression with a higher risk of microbial infection and a slower rate of wound healing. Growing interest is being given to the immunomodulatory properties of plants with a broad spectrum of therapeutic properties to develop potential immune-enhancing agents which can be used as components of functional foods, as plant-based therapeutic agents are linked to relatively low toxicities. Silalahi et al. (2018) demonstrated that giving mice VCO  once a day for 7 days with a dose of DOX 4.67 mg\/kg body weight on day 1 and day 4 improved the decrease in TCD4+ and TCD8+ (20.18% and 16.00%) caused by Dox administration. Dox decreases lymphocyte proliferation, suppresses phagocytosis macrophage activity and ability, TCD4+ suppression, and TCD8+ and IL-10 downregulation in Dox-treated animals8<\/sup>.<\/p>\n\n\n\n

FiberCreme is a commercial non-dairy\nfood high in oligosaccharides which are difficult to digest9<\/sup>. Prebiotics\nare nondigestible oligosaccharides (e.g., inulin, oligofructose, isomaltose,\nraffinose, palatinose, and lactose) which can encourage the growth of probiotic\nbacteria such as Lactobacilli<\/em> and Bifidobacteria<\/em>. Prebiotics\naffect local immune system in the gut and systemic immune system. Moreover,\nprebiotics help maintain intestinal permeability and regulate inflammation10<\/sup>.\nDietary oligosaccharides can impact the immune system directly by binding to particular\nsugar receptors on human cells and alter systemic immunological responses11<\/sup>.\nThe elimination of pro-inflammatory cytokines by anti-inflammatory drugs is one\nof intervention mechanisms12<\/sup>. An innovation was created in this\nstudy by replacing vegetable oil in FiberCreme with virgin coconut oil (VCO). Virgin\ncoconut oil is vegetable oil derived from kernel juice of fresh and ripe\ncoconuts (Cocos nucifera<\/em> L.) and has been widely utilized as food\ncomponent in food additive13<\/sup>. Moreover, VCO has high concentration of\nbioactive substances such as tocopherols, sterols, and polyphenols14<\/sup>.\nVirgin coconut oil has ability to disintegrate viral envelope, hinder final\nmaturation stage of viral replication, and prevent viral proteins from\nattaching to the host cell membrane. Furthermore, VCO could decrease C-reactive\nprotein levels to recover from COVID-194<\/sup>.<\/p>\n\n\n\n

Numerous studies showed immunomodulation potency from VCO, but still lack of information about combination with FiberCreme. This study aimed to determine the effect of FiberCreme and VCO on immunomodulatory effect in immunosuppressed rat. <\/p>\n\n\n\n

Materials and Methods<\/p>\n\n\n\n

Materials<\/strong><\/p>\n\n\n\n

The key ingredient in this study was FC-VCO which was purchased from PT. Lautan Natural Crimerindo (LNK), Mojokerto, Indonesia. Doxorubicin as immunosuppressive drug and Stimuno\u00ae (PT. Dexa Medica)  as immunomodulator were obtained from Faculty of Pharmacy, Universitas Surabaya, Surabaya, Indonesia. Characterization of FC-VCO showed that it contains protein, fat and ash components (Table 1).<\/p>\n\n\n\n

Table 1: Characterization analysis in FiberCreme-VCO.<\/strong><\/p>\n\n\n\n\n\n\n\n\n
\n

Characteristic<\/strong><\/p>\n<\/td>\n

\n

Content (%)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Protein<\/p>\n<\/td>\n

\n

2.3 \u2013 2.4<\/p>\n<\/td>\n<\/tr>\n

\n

Fat<\/p>\n<\/td>\n

\n

31 \u2013 37<\/p>\n<\/td>\n<\/tr>\n

\n

Ash<\/p>\n<\/td>\n

\n

2.7 \u2013 2.9<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

Animals<\/strong><\/p>\n\n\n\n

This study used 36 male Wistar rats (Rattus norvegicus<\/em>), 10 weeks old and weighing 180-200 g. They were obtained from Integrated Research and Testing Laboratory (LPPT) in Universitas Gajah Mada, Yogyakarta, Indonesia. The animal experimental procedure was authorized by Universitas Surabaya with ethics committee (212\/KE\/XI\/2021). Acclimatization was done for 15 days. Rats were housed in 20 x 30 x 40 cages, three rats of each with free access to food and water ad libitum<\/em>. Room temperature and humidity were set at 22-24\u00b0C and 65-70%, respectively.<\/p>\n\n\n\n

Experimental Design<\/strong><\/p>\n\n\n\n

The\nanimals were separated into six groups after acclimatization. <\/p>\n\n\n\n

Normal Groups : This group used 6 rats that were not stimulated by doxorubicin or FC-VCO and were just given vehicle treatment.<\/p>\n\n\n\n

Negative\nGroups : These groups used 6 mice that were given doxorubicin 4.67 mg\/kg BW\nintraperitoneally on day 1 and 4 and then treated with a vehicle.<\/p>\n\n\n\n

Positive Groups :   This groups used six mice that were administered doxorubicin 4.67 mg\/kg BW intraperitoneally on day 1 and 4 and Stimuno\u00ae orally 0.005 g\/kg BW every day for 14 days.<\/p>\n\n\n\n

FC-VCO Groups : This groups used 18 mice that were given doxorubicin 4.67 mg\/kg BW intraperitoneally on day 1 and 4, then divided into three groups. Three dose levels of FC-VCO were administered to each group: 3 kg\/mg BW, 6 mg\/kg BW, and 9 mg\/kg BW. For 14 days, all FC-VCO treatments were initiated orally each day.<\/p>\n\n\n\n

Sample Collection<\/strong><\/p>\n\n\n\n

The measurement of body weight was done at 12 hours after the last administration of treatment. Afterwards, blood sample was collected from intracardiac under anesthetic conditions with chloroform and the spleen was removed immediately for flow cytometry analysis. The mice were killed, and the spleen was weighed to calculate spleen index (spleen weight (g)\/body weight (g)). Blood serum was collected at 4\u00b0C for 15 minutes at 3000 RPM.<\/p>\n\n\n\n

Analysis of Pro-inflammatory Cytokines<\/strong><\/p>\n\n\n\n

Serum IL-6, TNF-\u03b1 and INF-\u03b3 levels were measured by enzyme-linked immunosorbent assay (ELISA) methods according to protocol standard kit (Nanjing Jiancheng Biotechnology Co., Ltd., Nanjing, China). <\/p>\n\n\n\n

Analysis of CD4+<\/sup> and CD8+<\/sup> levels<\/strong><\/p>\n\n\n\n

The spleen was extracted, cleaned twice with PBS, and put in a petri dish containing 5 mL of PBS to assess the ratio of CD4+<\/sup> and CD8+ <\/sup>T cells (CD4+<\/sup>\/CD8+). The spleen was washed, crushed, and filtered using a Millipore filter before being placed in a propylene tube and centrifuged at 2500 RPM for 5 min at 4\u00b0C to extract the pellets. Afterwards, 1 mL of PBS was added into the pellets and then homogenized by pipetting. 100 \u03bcL was removed and placed in fresh microtube, followed by the addition of 500 \u03bcL of PBS. The mixture was then centrifuged for 5 minutes at 4\u00b0C at 2500 RPM. Subsequently, 50 \u03bcL of extracellular antibodies (CD4+<\/sup> and CD8+<\/sup>) were added. Furthermore, samples were placed in flowcytometry to analyze the percentage of CD4+<\/sup> and CD8+<\/sup> cells. <\/p>\n\n\n\n

Statistical Analysis <\/strong><\/p>\n\n\n\n

All of data were analyzed with GraphPad Prism software (version 9: San Diego, CA, USA). Shapiro-Wilk test was used to determine normality test. One-way ANOVA test was also used to analyze significancy from FC-VCO treatment. Each group was determined for significancy against normal group and negative group by Tukey test. Significancy value was displayed when p<0.05.<\/p>\n\n\n\n

Results and Discussion<\/strong><\/p>\n\n\n\n

Effects of FiberCreme-VCO on body weight and spleen weight.<\/strong><\/p>\n\n\n\n

The body weight and spleen weight did not show significant difference between negative group and FC-VCO group (Table 2). FiberCreme-VCO did not increase body weight after being induced by doxorubicin, whereas Stimuno\u00ae did lead to body weight gain. In addition, the decrease in spleen weight in the negative group compared to the normal group showed improvement in FC-VCO treatment, although the increase in spleen weight in the FC-VCO group was not significantly different.<\/p>\n\n\n\n

Table 2: Observation of body weight and spleen weight in rats after FiberCreme-VCO induction.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n
\n

Group<\/strong><\/p>\n<\/td>\n

\n

Body Weight (g)<\/strong><\/p>\n<\/td>\n

\n

Spleen Weight (g)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Normal<\/p>\n<\/td>\n

\n

210.67 \u00b1 13.61<\/p>\n<\/td>\n

\n

1.08 \u00b1 0.15<\/p>\n<\/td>\n<\/tr>\n

\n

Negative<\/p>\n<\/td>\n

\n

172 \u00b1 29.51<\/p>\n<\/td>\n

\n

1.03 \u00b1 0.23<\/p>\n<\/td>\n<\/tr>\n

\n

Positive<\/p>\n<\/td>\n

\n

175.33 \u00b1 25.03<\/p>\n<\/td>\n

\n

0.78 \u00b1 0.26<\/p>\n<\/td>\n<\/tr>\n

\n

FC-VCO3<\/p>\n<\/td>\n

\n

176 \u00b1 34.22<\/p>\n<\/td>\n

\n

2.01 \u00b1 1.25<\/p>\n<\/td>\n<\/tr>\n

\n

FC-VCO6<\/p>\n<\/td>\n

\n

168 \u00b1 25.87<\/p>\n<\/td>\n

\n

1.19 \u00b1 0.07<\/p>\n<\/td>\n<\/tr>\n

\n

FC-VCO9<\/p>\n<\/td>\n

\n

173 \u00b1 31.88<\/p>\n<\/td>\n

\n

1.47 \u00b1 0.25<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

Effects of FiberCreme-VCO on CD4+<\/sup> and CD8+<\/sup> percentage.<\/strong><\/p>\n\n\n\n

The CD4+<\/sup> percentage significantly decreased after doxorubicin induction compared to normal group. Administration of Stimuno\u00ae and FC-VCO aimed to stimulate CD4+<\/sup> percentage (Figure 1). The findings of this study revealed that the CD4+ percentage in the Stimuno\u00ae therapy group was higher than in the control group, with a significant difference (p<0.05). FC-VCO at 6 mg\/kg BW had a higher percentage CD4+ than the control group. However, as compared to the negative group, FC-VCO at 3 mg\/kg BW and 9 mg\/kg BW did not demonstrate a significantly different increase in percentage CD4+ (p>0.05). The CD8+<\/sup> percentage from spleen was also measured in this study. Negative group showed elevated percentage than normal group but not significantly different (p>0.05). Furthermore, Stimuno\u00ae and FC-VCO therapy also not significantly (p>0.05) increasing CD8+<\/sup> percentage than negative group. The ratio between CD4+<\/sup> and CD8+<\/sup> percentage were checked to understand the correlation with the treatment given. The value yielded by negative group was found to be lower than normal group yet still not significant (p>0.05). Furthermore, Stimuno\u00ae and FC-VCO with dose 6 mg\/kg BW possessed higher ratio than negative group. However, the result was also found to be not significant (p>0.05) too<\/s>. The Foxp3 percentage after doxorubicin induction was also display lower value than normal group eventhough not significant (p>0.05) (Figure 2). A combination of Stimuno\u00ae and FC-VCO treatment was used to increase Foxp3 in spleen cells. Both could increase Foxp3 percentage although not significantly (p>0.05) than negative group (Figure 3). <\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 1: CD4+ and CD8+ double staining analysis by flow cytometry. A: Normal group, B: Negative group, C: Positive group, D: FC-VCO3 group, E: FC-VCO6 group, F: FC-VCO7 group. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\nFigure 2: Foxp3 staining analysis by flow cytometry. A: Normal group, B: Negative group, C: Positive group, D: FC-VCO3 group, E: FC-VCO6 group, F: FC-VCO7 group. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n\n
\"\"<\/td>\nFigure 3: CD4+<\/sup> and CD8+<\/sup> percentage after inducing by doxorubicin for 14 days. A: CD4+<\/sup> percentage, B: CD8+<\/sup> percentage, C: Ration of CD4+<\/sup> and CD8+<\/sup>, D: Foxp3 percentage. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Effects of FiberCreme-VCO on pro-inflammatory cytokines.<\/strong><\/p>\n\n\n\n

Pro-inflammatory cytokines in this study were important to measure the suitability of FC-VCO as immunomodulator. TNF-\u03b1 levels from negative group showed higher value than normal group. However, this increasing was not significant (p>0.05) (Figure 4). Inducing with Stimuno\u00ae and FC-VCO treatment has elevated the value higher than negative group albeit not significantly (p>0.05). The IFN-\u03b3 levels of negative group displayed significantly lower value than normal group (p<0.05). Positive and FC-VCO9 groups displayed significantly elevated (p<0.05) IFN-\u03b3 levels than negative group. Meanwhile, FC-VCO3 and FC-VCO6 groups did not show a significant increase (p>0.05) than negative group.  Measurement of IL-6 levels displayed decreasing value in positive group when compared to normal group, but also not significant (p>0.05). Inducing with Stimuno\u00ae could significantly increase (p<0.05) IL-6 levels than negative group. Moreover, FC-VCO treatment could elevate IL-6 levels higher than negative group, although insignificantly (p>0.05).<\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 4: pro-inflammatory cytokine levels after inducing by doxorubicin for 14 days. A: TNF-\u03b1 levels; B: IFN- \u03b3 levels; IL-6 levels.<\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

Immunomodulators\nare substances which assist in regulating immune system15<\/sup>. Doxorubicin\nis one of the chemotherapy agents to treat various cancers including breast,\npulmonary, prostate, skeletal, and bone. However, long-term use of doxorubicin\nleads to immunosuppression. Doxorubicin has non-selective effect on cell\nformation that are actively dividing such as bone marrow, lymphocytes, hair,\nand various organ toxicities16,7<\/sup>. Adding FC-VCO as a treatment could\nincrease body and spleen weight due to nutrition from FC-VCO such as protein would\nelevate regeneration rate in cells. Numerous studies have shown that decreased\nT cell proliferation affect in low cytokine levels such as TNF-\u03b1, IFN-\u03b3, IL-2 and\nIL-12. Immune enhancers have recently been developed as components of\nfunctional meals by immunomodulatory activities from natural foods or food\nadditive17,18<\/sup>. The\nfindings of this study provide preclinical evidence of the promising effects of\nFC-VCO on Dox-induced immune system modulation in rats, further supporting the\npotential utility of FC-VCO as an immune-enhancing functional food agent. These\nresults could be attributed to the ability of FC-VCO to reverse Dox-induced\nchanges in the parameters of body weight, spleen weight, inflammatory response,\nand T cell balance.<\/p>\n\n\n\n

Previous\nresearch has shown that medium-chain fatty acids in VCO improve phagocytic\nactivity19<\/sup>. In this study, immunosuppression could be reversed by\nFC-VCO which specifically reduced splenocyte cell proliferation, cytokine and cytotoxic\nT cell lymphocyte (CTL) activity, CD4+<\/sup> percentage, CD8+<\/sup>\npercentage, and CD4\/CD8 ratio20<\/sup>.  The cytokines produced by diverse immune cells\nare crucial for immunological responses like host defense against bacterial\ninfection, cell survival, and control of inflammation. Cell function is\ndetermined by cytokines which are crucial in the humoral immune response21<\/sup>.\nEnhancement in proliferation of lymphocytes, neutrophils, CD8+<\/sup>\ncells, and CD4+<\/sup> cells were exhibited by FC-VCO\u2019s immunostimulatory\nimpact, especially from VCO and isomalto-oligosaccharides (IMOSs) in FC-VCO22<\/sup>.  <\/p>\n\n\n\n

T cells are classified into two primary subsets;\nhelper T cells, and killer T cells, which express CD4+<\/sup> and CD8+<\/sup>,\nrespectively. Helper T cells are recognized as cytokine makers, whereas killer\nT cells exhibit cytotoxicity to infections. Depending on the cytokines that\nthey express, helper T cells are further divided into Th1 and Th2 subtypes.\nWhen necessary, Th1 cytokines activate additional immune cells, including\nneutrophils, lymphocytes, and macrophages. Th1-type cytokines cause\nproinflammatory responses by releasing Th1 cytokines such as IL-2, IFN-\u03b3, and\nTNF-\u03b1. IFN-\u03b3 regulates macrophages, which are secreted by immune cells such T\ncells, macrophages, and NK cells. It is also identified as a Th1 T cell\nrepresentative marker. Th1 and Th2 cells actively interact in an optimal immune\nsystem to produce balance through a complimentary connection. Our findings\nreveal that FC-VCO at dose 9 mg\/kgBW supplementation increased the expression\nof Th1 cytokines IFN-\u03b3, showing that FC-VCO has a strong immune-boosting\nimpact. The isomalto-oligosaccharide content of FC-VCO may be the mechanism\nunderlying the involvement of IFN, a cytokine released by Th cells that has the\nability to influence the immune system 23,24<\/sup>.<\/p>\n\n\n\n

Isomalto-oligosaccharides\nas one of commercially prebiotic sub-stances, are created by enzymatic\nconversion of starch. Moreover, IMOSs are generally utilized as functionalized\nfood in Asia and are made of \u03b1(1-6)- and \u03b1(1-4)-linked glucose oligomers which\nenhance gut microbiota and encourage the growth of \u2018good bacteria\u2019. Prebiotics\ncan be used to modulate immune system in both humans and animals. Improving\nimmune function in prebiotic-treated hosts is primarily due to increasing in\npopulation of beneficial bacteria and their products in gut. The gut microbiota\nplays major role in the immune system of host25,26,27<\/sup>.  <\/p>\n\n\n\n

Treatment with FC-VCO restored IFN-\u03b3 along with improvement in CD4+<\/sup> levels in immunosuppressed splenocyte model induced by doxorubicin. The cytokine is crucial for growth and maintenance of T regulatory (Treg) cells as well as activation-induced cell death, which regulates non-essential immune responses. These results collectively imply that FC-VCO contribute to stimulate of<\/s> humoral and cell-mediated immune responses and boosts immunostimulatory activity by protecting immune cells from doxorubicin-induced damage. Therefore, FC-VCO has the potential to be used as a functional food alternative to boost immunity, particularly for immunosuppressed patients.<\/p>\n\n\n\n

Conclusions<\/strong><\/p>\n\n\n\n

In conclusion, FC-VCO at dose 9 mg\/kgBW\nsupplementation increased the expression of Th1 cytokines IFN-\u03b3 (p<0.05)\nalong with increased CD4+<\/sup> levels (p<0.05) in immunosuppressed\nsplenocyte model caused by doxorubicin, showing that FC-VCO has a strong\nimmune-boosting impact and has the potential to\nbe used as a functional food alternative to boost immunity.<\/p>\n\n\n\n

Acknowledgments<\/strong><\/p>\n\n\n\n

Thanks\nto Ministry of Education, Culture, Research and Technology for writing of the\narticle (e.g. providing advice on the language, editing, or proofreading the\narticle).<\/p>\n\n\n\n

Competing Interests<\/strong><\/p>\n\n\n\n

There is no competing interest between author<\/p>\n\n\n\n

Funding<\/strong> Source <\/strong><\/p>\n\n\n\n

This research was funded by Indonesian Ministry of Research, Technology and Higher Education under the Matching Fund grant (068\/ST-Lit\/LPPM-01\/FT\/MF\/IX\/2021),<\/p>\n\n\n\n

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