The Immunomodulatory effects of Zingiber officinale (Ginger):

A Systematic Review

 

Nurul Hikmah Harun*, Mohamad Firdaus Mohamad

School of Biomedicine, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kampus Gong Badak, Gong Badak, 21300 Kuala Nerus, Terengganu Darul Iman, Malaysia.

*Corresponding Author E-mail: nurulhikmah@unisza.edu.my

 

ABSTRACT:

Recently, the available synthetic drugs to treat immune related diseases have been reported to produce many side effects to the consumer. For instance, corticosteroids are used to reduce inflammation during infection but able to cause adverse effects such as bruising, muscle weakness, pathologic fractures, weight gain and sleep disturbances. As an alternative for a safer alternative for preventive and treatment agents with low risk of side effect, Zingiber officinale which is known as ginger or ‘halia’ in Malaysia has a good prospect. It is because this herb is used as traditional medicine among community to treat several ailments, including immune and infectious diseases. Several studies have shown that crude extracts and bioactive components of Z. officinale possessed diverse pharmacological properties such as anticancer, anti-inflammatory, antimicrobial, antioxidant and immunomodulatory. The objective of this research is to find out the effects of Z. officinale on the immunomodulatory activities from the selected previous studies from year 2000 to 2020. Briefly, this study involves 11 randomized controlled trials (RCTs) that determined immunomodulatory activities of Z. officinale. The results of systematic analysis showed that Z. officinale exhibits immunomodulatory activities for both in vitro and in vivo evaluations. However, some limitation should be aware with the detailed reporting on the controls used in the included studies. Future well-designed RCTs with detailed reporting on the controls are required for providing additional data to prove the consequences of Z. officinale on the immunomodulatory as well as safety data of consuming this plant.

 

KEYWORDS: Zingiber officinale, Halia, Ginger, Immunomodulatory, Systematic review.

 

 


INTRODUCTION:

The human immune system is an organisation of cells that responsible to provide protection from infection. The immune system protects the human body by two different types of responses which are innate and acquired immunity1. The innate immunity is a non-specific defence mechanism that provide immediate action or within hours of infection. Meanwhile, the acquired immunity creates immunological memory during the first infection that lead to an enhanced response for the next similar infection2. The innate immune system mainly comprises of physical barriers such as skin and mucous membranes, chemical barriers,

 

antimicrobial peptides, innate cells and oxygen reactive species. Instead of that, innate immunity contains soluble mediator systems such as the complement system, and cytokines3. The major roles of adaptive immune system are to recognise specific “non-self” antigens through pathways of pathogen-based immune effectors to get rid of specific infections. Besides, the acquired immunity creates immunological memory that able to remove a certain pathogen quickly if an infection occurs subsequently2.

 

Immune imbalance able to cause numerous disorders, such as allergies, autoimmune disorders, immunosuppression and acquired immunodeficiency syndrome (AIDS)4-8. Currently, the epidemiological evidence shows the increment pattern of immunological diseases. This problem has led to the development of a specific molecular class, generally termed immunomodulators, which able to improve or suppress the immune response to treat or prevent the immune-mediated diseases9. The immunomodulators have a potential application as immunostimulatory agents for treating infection, immunodeficiency and cancer meanwhile they also useful as immunosuppressive agents in organ transplantation and treat autoimmune diseases9-10. The example of the immunomodulator agent is methotrexate which is a type of disease-modifying anti-rheumatic drug that apply to reduce the growth of the cancer cells and help to treat rheumatoid arthritis by decreasing the activity of immune system11-12.

 

The balance of the human immune system is very important to protect from many diseases13. There are many available drugs which are chemically produced to treat the immune-related and infectious diseases but at the same time able to cause many side effects to the consumer. For example, corticosteroids are used to suppress the inflammation by reducing the activation of several inflammatory mediators during infection and inflammation14-15. The consumption of the drug promotes several side effects that include of bruising, muscle weakness, weight gain, skin changes, sleep disturbances, cataracts, and pathologic fractures16. Natural products contain numerous bioactive constituents and offer variety of pharmacological activities based on the previous studies done17-22. Medicinal plants are part of them that have been shown contain immunomodulatory activities23-29. As an alternative for a safer treatment and prevention as well as its’ low risk of side effects, Zingiber officinale Roscoe is famous among community that is traditionally consumed to boost immunity, to treat fever and and infectious diseases. Z. officinale or known as ginger from Zingiberaceae family and genus of Zingiber, has been a medicinal herbal and spice product for a long times ago. The taxonomy of Z. officinale and picture of Z. officinale are exhibited in Table 1 and Picture 1, respectively. Ginger root has a broad variety of treatments, including headache, colds, nausea, and emesis30. Ginger is an herb that contained numerous bioactive phytochemicals, scented, sparkling and spicy. This plant species is used as a flavouring agent and is now at the top of the list of popular for cold and sore throat treatments. A significant explanation for its use as a medicinal agent is related with its phytochemicals that contain nutritional values and have significant antioxidant effects. Due to this, its active phytochemicals have a good prospect as a potential future drug31.

 

Z. officinale is an herbaceous perennial plant where the rhizome part is used as a spice and folk medicine to treat many illnesses in community32. The herb grows false stems made up of rolled leaves about one meter tall. The family of Zingiberaceae originated form the Maritime Southeast Asia has been linked to have a good property of antimicrobial, antioxidant, anti-inflammatory and anti-cancer. For the centuries, ginger is known as a routine spice that was used by many regions all around the world. The ginger also has been used as traditional medicines to treat common gastrointestinal system ailments and as part of therapeutic procedures for the treatment of many other disorders, such as malignancies33. Ginger contains many natural organic materials (6-gingerol, 6-shogoal and 6-paradol) and its main compounds show a variety of pharmaceutical effects that boost the host's immunity against infectious diseases by enhancing non-specific and specific immunological responses34. However, there are only limited papers that make a systematic compilation of the immunomodulatory activities of the Z. officinale. The pharmacological validation on immunomodulatory of Z. officinale is quite restricted, and several existing review publications on this plant haven't been focused on this activity. Therefore, this study aimed to conduct a systematic assessment of all available data (year 2000 to 2020) to determine the effects of Z. officinale on immunomodulatory activity. Hence, it is also crucial to proof the community statement related with Z. officinale immunomodulatory activity. This review aims to combine the existing literature to offer fundamental knowledge for researchers involved in the confirmation of the traditional claims and immunomodulatory activities of this plant. Hopefully, this study also will provide facts for an idea of advance study to produce a new option for the immunomodulatory agent to prevent and treat immune-related diseases.

 

Table 1. Taxonomy of Zingiber officinale35.  

Classification

Name

Kingdom

Plantae

Division

Magnoliophyta

Class

Liliopsida

Order

Zingiberales

Family

Zingiberaceae

Genus

Zingiber

Species

Zingiber officinale var. Roscoe

 

Figure 1: Picture of Z. officinale36

 

METHODOLOGY:

Systematic review:

Systematic review combines data from several studies on similar research topics to present the findings. This method compiles all relevant research on a specific topic and design. Systematic review is the gold standard for finding, compiling, analysing, and summarising the best available data on a pre-clinical and clinical topics. The findings of systematic reviews provide the most reliable evidence base for developing reliable clinical guidelines (and their recommendations) and clinical decision-making. They follow a structured research process that necessitates the use of rigorous procedures in order to ensure that the results are both credible and relevant to end consumers. As a result, systematic reviews are regarded as the cornerstone of evidence-based medicine37. This systematic review is carried out in accordance with the principles of the Cochrane Collaboration framework.

 

Search strategies and study selection:

From the year 2000 until the year 2020, an electronic search for original papers was done using two selected electronic databases which were PubMed and Science direct. Strategic search terms were ‘Z. officinale’ or ‘ginger’ plus ‘immunomodulatory activities’ or ‘effect of Z. officinale or ginger on immunomodulatory activities’. The papers that were included in the study are previous research that involves the use of the extract or bioactive compound of the Z. officinale which have the immunomodulatory outcomes (in vivo, in vitro or clinical studies). The papers that have not included the above criteria will be excluded38.

 

RESULTS:

Study selection:

The database search done resulted in the discovery of 135 articles. Due to duplication, none of the articles were removed. There were 22 articles included after screening for titles, abstracts, and keywords. Eleven of full-text research articles were reviewed from the screened titles, abstracts, and keywords, and all the papers were included in the systematic review. The flow of study selection for the immunomodulatory activities were presented in Figure 2. All the information of immunomodulatory activities of this plant (model and method used, tested substances, results and tested dose) are summarized in Table 2.

 

Figure 2: Flow diagram of study selection for immunomodulatory activities38.

 


Table 2. Immunomodulatory activities of crude extracts, bioactive fractions and compounds derived from Zingiber officinale

No.

Tested substances

Model used

Tested dose

Results (using tested substances)

References

1.

Lipophilic extract

Human peripheral blood mononuclear cells (PBMCs)

6-gingerol: 2.75 mg

6-shogaol: 0.75 mg

↑ mRNA expression (PPM1B and RORA).

↓ gene expression (ALDOA, DEFA1/DEFA3, PRDX2, PRDX3 and SDCBP).

39

 

 

2.

Aqueous extract of whole plant

Proximal colon and ileum of new-born pups of Wistar albino rats induced with necrotizing enterocolitis.

1000 mg/kg/day

↓ levels of TNF-α, IL-1β and IL-6.

↑ antioxidant system.

 

40

 

3.

Ginger crude aqueous extract and

[6]-gingerol

In-vitro: PBMCs carrying hydatic cyst (cystic echinococcosis)

 

Ginger extract: 1, 10 and 100 mg/mL

[6]-gingerol: 100 mg/mL

Ginger extract:

1mg/mL: kill 51.80% parasite after 24 hours of culture.

100mg/mL: kill 89.72% parasite after 24 hours of culture.

[6]-gingerol:

100mg/mL: ↓ cell viability and nitric oxide (NO) production.

41

 

4.

Aqueous extract

Heparinized blood of broiler chicks

5g/kg diet daily for 21 days

↑ phagocytic cells capacity to engulf Candida albicans yeast particles.

↓ NO production.

42

 

5.

Ethanol and aqueous extracts

BALB/c mice (male) 6–8 weeks old

Ethanol extract: 500 mg/kg aqueous extract: 720 mg/kg

Both extracts:

↓ inflammatory cell infiltration around the airways.

↓ elevated levels of IL-4 and IL-5 in lung and BALF.

43

 

6.

[6]-gingerol

Female C57BL/6 mice (8 weeks) induced experimental autoimmune encephalomyelitis (EAE)

10mg/kg

↓ inflammatory cell infiltration from the peripheral blood into the central nervous system.

↓ neuroinflammation and demyelination.

44

 

7.

Dried, ground of fresh herbs

Spleen cells of C57 mice

0.15mg/mL

↓ thymidine incorporation in alloantigen activated lymphocytes by 56.2%.

↓ thymidine incorporation in mitogen-activated lymphocytes by 68.9%.

45

 

8.

Ethanol extract

Cardiac muscle tissue of male Wistar rats, weighing 250±30g.

100, 200 and 400mg/kg

↓ inflammatory cells in a dose-dependent manner.

46

 

9.

[6]-gingerol

CD4+ and CD8+ T cells of female C57BL/6 (6–8 weeks of age) and Thy1.1+ mice infected with H37Rv

[6]-Gingerol:

10 mg/kg

↑ host protective Th1 and Th17.

↑ IFN-γ and IL-17 expression.

Activation of p38 MAPK signalling pathway.

47

 

10.

Zingerone (ZGR)

Serum and portion of the liver male C57BL/6 mice (aged 6 weeks, weighing 27 g) exposed to lipopolysaccharides (LPS)

0.18mg/kg, 0.36mg/kg and 0.72 mg/kg

0.72 mg/kg: 

↓ TLR4 expression.

↓MyD88-dependent signalling.

↓ MAPK activation.

↓ expression of inflammatory genes in LPS-induced hepatic failure.

48

 

11.

[6]-gingerol

Tissue colon of male C57BL/6 mice aged seven to eight weeks old, macrophages (RAW 264.7) and bone marrow-derived macrophages (BMDMs) cells.

20mg/kg

↓ serum IL-1β expression in septic mice.

↓ LPS/ATP-induced HMGB1, activate caspase-1p20 and mature IL-1β secretion in both RAW264.7 and BMDMs cells.

↓ NLRP3 inflammasome by inhibiting phosphorylation of MAPK.

49

 

The characteristic of included studies for systematic review of the immunomodulatory related outcomes. (↑= increase, ↓=decrease).

 


DISCUSSION:

The preliminary study who identified that various compound from the lipophilic extract significantly increase the mRNA expression of RORA and PPM1B and decrease of PRDX2, ALDOA, PRDX3, DEFA1/DEFA3 and SDCBP gene expression in the human PBMCs. All of these genes involve in the reduction of inflammation39. In a study conducted by40, the aqueous extract of whole ginger (1000mg/kg/day) able to decrease the levels of IL-1β, TNF-α and IL-6. The reduction of IL-1β, TNF-α and IL-6 causes reduced of inflammation in albino rat with necrotizing enterocolitis. Besides, the aqueous extract treatment able to stimulate the functioning of the antioxidant system of the albino rat. 

 

The other study showed that ginger crude extract and [6]-gingerol at concentration of 1 to 100mg/mL significantly kill 89.72% of Echinococcus granulosus after 24 hours of culture and also reduce the cell viability and NO secretion of human PBMCs in a dose-dependent manner. Furthermore, numerous in vivo investigations were also conducted to investigate the immunomodulatory properties of the ginger41. Meanwhile, the previous study which used heparinized blood of broiler chicks as a model presented that the aqueous extract of ginger at dose (5g/kg diet daily for 21 days) able to inhibit C. albicans. This study presented significant increase of the phagocytic cells capacity to engulf C. albicans yeast particle and also decrease the NO production42.

 

In addition, the study done by43 stated that ethanol and aqueous extracts decrease the inflammatory cell infiltration around the airways and also decrease the elevated levels of IL-4 and IL-5 in lung and BALF of BALB/c mice when compared to methylprednisolone as a control group. The other in vivo investigation revealed that [6]-gingerol in phosphate-buffered saline (PBS) at dose of 10mg/kg decrease the inflammatory cell infiltration from the peripheral blood into the central nervous system and decrease the neuroinflammation and demyelination44.

 

Moreover, the in vitro study by45 who were using spleen cells of C57 mice as a model discovered that the dried, ground fresh ginger (0.15mg/mL) decrease the thymidine incorporation in alloantigen activated lymphocyte to 56.2% and also decrease the thymidine incorporation in mitogen-activated lymphocytes to 68.9 %. The other study conducted also mentioned that ethanol extract at concentration of 100 to 400mg/kg decreased the inflammatory cells in a dose-dependent manner in the cardiac muscle tissue of male Wistar rats compared to the control group of metformin (200 mg/kg)46. The other study also showed that the [6]-gingerol at concentration of 10 mg/kg increases the host protective T helper 1 (Th1) and T helper 17 (Th17), as well as IFN-γ and IL-17 expression and also activate the p38 MAPK signalling pathway mice47.

 

Furthermore, zingerone (ZGR) in 0.5% Dimethyl sulfoxide (DMSO) at dose of 0.72mg/kg inhibits the toll-like receptor 4 (TLR-4) protein expression, myeloid differentiation primary response gene 88 (MyD88)-dependant signalling, mitogen-activated protein kinase (MAPK) activation and expression of inflammatory gene in lipopolysaccharide (LPS)-induced liver failure of C57BL/6 mice48. The TLR-4 protein expression involves in the immune cell activation, hence the ZGR plays a hepatoprotective effects to prevent overexpression of TLR-4. Based on the previous report, 20mg/kg of [6]-gingerol decreased the serum IL-1β expression in septic mice, reduce the LPS/ATP-induced HMGB1, activated the caspase-1p20 and mature IL-1β secretion in both RAW 264.7 and BMDMs cells and also decreased the NLRP3 inflammasome by inhibiting phosphorylation of MAPK49.

 

CONCLUSION:

In a nutshell, the overall findings revealed that the Z. officinale extracts and bioactive compounds have the immunomodulatory activities. The outcomes of the studies which compiled in this review suggest that Z. officinale has the possibility to be applied as future immunomodulator agent for the development of novel plant-based pharmaceuticals to cure or prevent immune-related diseases.

 

CONFLICTS OF INTEREST:

The authors report no financial or any other conflicts of interest in this work.

 

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Received on 07.12.2021           Modified on 12.02.2022

Accepted on 21.03.2022         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(8):3776-3781.

DOI: 10.52711/0974-360X.2022.00634