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Inhibitory effects of curcumin on sequel of infections and their signaling pathways

a review

Shahcheraghi, Seyed H.a,b; Ayatollahi, Jamshidb; Lotfi, Marziehc

Reviews in Medical Microbiology: April 2019 - Volume 30 - Issue 2 - p 113–121
doi: 10.1097/MRM.0000000000000159
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Curcumin, a bright yellow chemical produced by some plants (turmeric) that are member of the ginger family, is cultivated in tropical regions of Asia. It has many impacts, including antimicrobial, anticarcinogenic, anti-inflammatory, and antioxidant. Different databases such as PubMed, Scopus, Google Scholar, and Web of Science with keywords of ‘Curcumin’, ‘anti-microbial’, ‘anti-fungal’, ‘anti-parasitic’, ‘anti-viral’, ‘Infection’, ‘Pathogen’, ‘anti-bacterial’, and ‘Herbal Drug’ have been considered in this search without publication time limitation. This study reviewed the inhibitory effects of curcumin on infections. Based on these studies, the plant drug of curcumin is a therapeutic effective agent for the advancement of treatment against the types of pathogens including bacteria, viruses, parasites, and fungi. Nevertheless, it seems that be essential for more researches, especially about parasites and fungi that have been performed fewer studies about the effect of curcumin on them. Curcumin exerts its effects on sequel of infections and their agents via influence on signaling pathways, cell cycle, drug synergism, inducing apoptosis and inhibition of virulence factors.

aDepartment of Modern Sciences & Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad

bInfectious Diseases Research Center, Shahid Sadoughi University of Medical Sciences

cDepartment of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Correspondence to Seyed H. Shahcheraghi, Infectious and Tropical Diseases Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Islamic Republic of Iran. Tel: +98 9132531389; e-mail: shahcheraghih@gmail.com

Received 15 July, 2018

Accepted 16 October, 2018

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Introduction

Curcumin, a bright yellow chemical formed by some plants, is a member of the ginger family (Zingiberaceae) that is cultivated in tropical regions of Asia with a chemical formula of [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] gained from the dehydrated rhizomes of Curcuma longa (Fig. 1) [1].

Fig. 1

Fig. 1

It is known as an herbal complementary, cosmetics component, favorable for food, and used as the coloring for food [2]. Its powder is also served in medicinal aims. In the past, it is recognized because of its carminative, inducing, and aromatic characteristics. The component of its turmeric is identified as a household medication for the remedy of pain and swelling created after damage [3]. It has many effects, including antimicrobial, anticarcinogenic, anti-inflammatory, and antioxidant. Its antioxidant characteristics are because of β-diketone, phenolic groups, and methyl that create several impacts as a scavenger of free radicals [4,5]. This component is an antimicrobial main factor appropriate for supplying safe textile. In addition, curcumin in mixture with chitosan and aloe vera can be the main inhibitor for microbial proliferation in wound cotton [3,6]. This material because of biological favorable actions has been obtained the noteworthy attention of researchers the entire of the world. The purpose of the review is investigating curcumin impacts against different bacteria, viruses, fungi, and parasites. Several studies were investigated that more them were performed as in vitro.

Different databases such as PubMed, Scopus, Google Scholar, and Web of Science with keywords of ‘Curcumin’, ‘anti-microbial’, ‘anti-fungal’, ‘anti-parasitic’, ‘anti-viral’, ‘Infection’, ‘Pathogen’, ‘anti-bacterial’, and ‘Herbal Drug’ have been considered in this search without publication time limitation.

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Curcumin effects on bacterial infections

It has been proved that the antioxidant effects of curcumin are significant in diabetic gastroparesis disease [7]. In addition, animal studies have shown that curcumin can eradicate Helicobacter pylori and gastric healing characteristics [8].

The phytochemical agent reduces the hazard of gastric cancer caused by H. pylori through prohibiting DNA damage and oxidative stress [9].

Curcumin decreases the levels of malondialdehyde that is a marker of lipid peroxidation and increases glutation resuscitation [7]. Curcumin can improve considerably the patients’ histological properties via reducing the chronic inflammation. It is verified that curcumin can decrease dyspepsia signs and also can improve the serologic markers related to the gastritis inflammation [9]. The special impacts of curcumin on gastritis can be caused by the prohibiting or decreasing of the creation of gastric acid by prohibiting histamine receptors [10].

To better investigate of curcumin actions on H. pylori infection, IL-4, IFN-γ, and somatostatin symbolize good molecular markers. IFN-γ levels are increased due to H. pylori[11]. An anti-inflammatory cytokine is IL-4, unidentified to be repressed by H. pylori[12] and somatostatin is a regulator marker required for IL-4-mediated declaration of gastritis related to H. pylori[13]. G cells in the pyloric antrum secrete gastrin hormone and it is the motivation of gastric acid creation and delivers. In H. pylori infection gastrin amount is decreasing. It has been approved that controlling gastric rates may result in modifying and improving gastritis. Considerable impacts of curcumin on the above four factors powerfully prove that curcumin can decrease effects related to H. pylori infection [12]. Curcumin prohibited the matrix metalloproteinases-3, 9 actions as main inflammatory agents in H. pylori infection in-vivo studies and also in cell culture [14].

Normal microflora, coagulase-negative staphylococci (CoNS), that are included Staphylococcus haemolyticus, S. epidermidis, S. hominis, and S. saprophyticus have been identified to be key factors in hospital infections related to elastic tissues especially skin. The considerable enhance in rates of drug resistance among CoNS obtained from skin-related injuries and ulcers are warning. In many clinically separated Staphylococci, multidrug resistance and biofilm creation have been announced and this is an opinion for the improvement of remedial methodologies [15].

One of the most potent antimicrobial curcumin formulations is nanoparticles with Zinc oxide and curcumin combination. Zinc oxide–curcumin nanocomposite was created to enhance the steadiness, bioavailability, and solvability to improve its biological activity. This could be connected to the changed chemical, natural, and physical characteristics of the mentioned nanocomposite in comparison with each of the combinations independently [16]. The low level of curcumin nanoliposomal creation effectively recovered wounds because of its antibacterial characteristics [17].

Urinary system infection is a typical disease of the urinary tract created by aggressive pathogenic organisms of the urinary tract that its result is inflammatory lesions of the urinary system. One of the transmembrane receptor related to the pathogens is Toll-like receptor (TLR) that has a key role in inflammatory reactions [18]. In addition, it has been established that this receptor has importance in the activation of innate immunity system [19] and finally recognition of pathogens [20]. Curcumin can considerably decrease the signs of chronic urinary infections, keep renal tubular action, and also reduce inflammation by inducing the expressions of TLR2 and TLR4 mRNA and via this curative impact has key importance in the remedy of chronic urinary infections [21].

Among the new components of curcumin including indium diacetyl curcumin, indium curcumin, and diacetyl curcumin, indium curcumin had the better impact against several species of bacteria such as Staphylococcus aureus, S. epidermidis, Escherichia coli, and Pseudomonas aeruginosa. Therefore, it can apply as a stronger antibacterial agent toward curcumin [3].

Curcumin repressed cytokinesis of Bacillus subtilis via stimulation of filamentation. It also, without notable effects on the separation and rearrangement of the nucleoids noticeably decreased the cytokinetic Z-ring creation in B. subtilis[22].

The results have shown that eating curcumin during the remedy of infections of S. aureus in combination with antibiotics specially cefixime can be probably very more useful. Curcumin also showed a synergistic impact against methicillin-resistant S. aureus species in a mixture with several antibiotics, including oxacillin, ampicillin, and norfloxacin [23,24].

The act of curcumin as an antibiofilm is a diminution of pathogenicity potency in Caenorhabditis elegans and Arabidopsis thaliana as whole infected models of animal and plant by P. aeruginosa[25].

One of the main virulence factors that are produced by Listeria monocytogenes is the pore-forming toxin listeriolysin O (LLO) that this factor is essential for penetrating organism at the phagosoms and in result transferring to the cytoplasm; therefore, it cannot be identified by the host immune system. Results discovered that curcumin can cause a reduction in LLO-mediated Listeria phagosomal flight and decrease the intracellular bacterial proliferation. This impact of curcumin can inhibit surviving L. monocytogenes in the cytoplasm and also diminish the toxicity and colonization, finally, ease the clearance of L. monocytogenes by macrophages in the cell [26]. Some bacteria, such as Bordetella petrii have been proved that are responsible for different infectious diseases in hosts. Curcumin also inhibits this organism strongly [27].

A destructive gastrointestinal disease named necrotizing enterocolitis (NEC) infects premature infants. It is recognized by symptoms including leukocytosis and inflammation that can lead to systemic inflammation, intestinal necrosis, and finally death. Howbeit NEC has not a clear pathogenesis; studies have shown a relationship among factors such as hypoxia, formula feeding, and changed bacterial colonization. Curcumin interacts with many effective factors in inflammation [9,28–30]. Cytokines, including IL-1, 6, and 8 by prohibiting activation of TLR4/nuclear factor κ the NECa B (NF-κB) as an important factor in NEC [31]. Inhibition of Janus kinase/activators of transcription signaling pathway in intestinal inflammation models by curcumin declines cell damage and inflammation [31–35].

Curcumin can apply for treatment of intestinal endotoxemia caused by Gram-negative bacteria via increasing LDL receptor expression, finally, detoxification of lipopolysaccharide in the liver [36]. This polyphenolic component also prohibits the growth of several bacterial species, including Salmonella typhimurium[37], Vibrio vulnificus[38], and Neisseria gonorrhea[39,40].

Curcumin anti-inflammatory effect was investigated alone and in mixture with clarithromycin in animal models of inflammation. Although clarithromycin, due to abundant side effects, may not be favorable in the treatment of inflammation, it can be applied in combination with curcumin. This combined treatment will assist to decrease of the immune response against lung infections of Klebsiella pneumonia[41].

Tuberculosis (TB) that is a world problem is caused by Mycobacterium tuberculosis (MTB) and is in the middle of the principal infectious diseases. Curcumin has been lately proved as a useful anti-TB herbal drug. The main virulence factor secreted by the MTB named 19-kDa lipoprotein (P19) powerfully affected macrophages via overexpression of mitogen-activated protein kinases and TLR2. Curcumin and P19 enhance apoptosis of macrophage that is time and dose-dependent [42].

It has been proved that the combination of curcumin and cotrimoxazole decreases the antimicrobial impact of cotrimoxazole in both extraintestinal and intraintestinal parts. Therefore, treatment with curcumin and cotrimoxazole combination may be useful about typhoid fever [37].

Neisseria gonorrhoeae resistance to the drug is an important problem in the present world in particular because of its relationship with high risk of bladder cancer. Vitamin D is an influential and antibacterial factor that is related to N. gonorrhoeae impacts. It induces the innate immunity against bacterial infections, diminishes rates of NF-κB, and transforming growth factor beta (TGF)-β action and also stimulates the creation of LL-37 (cathelicidin) as an antiendotoxin and antibacterial factor. Curcumin also stimulates LL-37 creation through away without the role of vitamin D receptor, prohibiting N. gonorrhoeae-stimulated NF-κB pathway and irritating autophagy. Thus, curcumin and vitamin D combination are beneficial against both usual and drug-resistant N. gonorrhea[43].

Curcumin has an inhibitory effect on the formation of exopolysaccharides, alginate, and biofilm and creation of other factors as virulence agents in several Vibrio species especially Vibrio parahaemolyticus, V. harveyi, and V. vulnificus[44]. Curcumin also prohibits both toxins attaching to human cells and microbial adhesion that are as considerable and principal preserver processes for the reduction of cytotoxicity of V. vulnificus. Curcumin also hampers host cell accumulation and actin in the association, which are the primary characteristics of cell death created by V. vulnificus. In addition, curcumin as an herbal drug reduces translocation of NF-κB stimulated by the V. vulnificus[38].

The investigations show that curcumin is an important anti-Proteus mirabilis and preventing the struvite crystallization related to urinary stone creation. Curcumin also prohibits the action of urease enzyme created by mentioning bacterium, which is the powerful power of struvite crystals. In addition, the pH level of urine enhances slower by curcumin toward without curcumin condition. Consequently, in the present curcumin, urine will be nonsaturated because of struvite construction for a longer period in comparison with without curcumin status [45].

In general, curcumin is a beneficial agent against several important bacteria that have been determined in Fig. 2.

Fig. 2

Fig. 2

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Curumin effect on parasitic infections

Curcumin also has antiparasitic beneficial effects against Leishmania and several species of Plasmodium[2].

The cerebral malaria is the main problem in some parts of the world especially Africa. The plant drug of curcumin can be a potent agent for the advancement of treatment of cerebral malaria in the next researches [46].

A protozoan parasite named Leishmania (leishmania) donovani is an agent of visceral leishmaniasis or kala-azar disease. The limitations of therapy of kala-azar are including high cost, long period of remedy, and side toxic impacts [47]. Curcumin that is one of the health-advancing agents in combination with other drugs, here also has a series of biological effects such as anti-inflammatory and immunomodulation impacts [48] so that, it has been proved that curcumin has an antileishmanial action against Leishmania major[49].

Curcumin effect on social parasites of Eimeria maxima in chick demonstrated that 1% dietary curcumin leads to reduce intestinal lesions and increased weight condition [2].

Mechanism of action of curcumin in the treatment of Chagas heart disease is the prohibition of the pathogenic cyclooxygenase (COX)-2/microsomal isoform of prostaglandin E synthase (mPGES)-1/prostaglandin E (PGE2) and Ca2+/nuclear factor of activated T cells (NFAT)-dependent pathway in myocytes infected by Trypanosoma cruzi that are responsible for cardioprotection and this site due to the limitations in available therapies for Chagas disease, is a valuable therapeutic approach [50].

Curcumin can increase nonopsonic phagocytosis-related to Plasmodium falciparum via overexpression of CD36 on macrophages and monocytes surface part. Expression of CD36 marker and P. falciparum phagocytosis-related to this marker by the curcumin herbal drug is affected by (reactive oxygen species) ROS creation and likely main role of the Nrf2 as an important pathway. The double mechanisms related to curcumin act, including antimalarial and immunomodulatory actions are good reasons that curcumin can suppose as a potential agent and assistant remedy decreasing the danger of recrudescence after common treatment against malaria [51].

One of the main agents of production of intestinal infections by protozoa in many parts of the world is Giardia lamblia. Therefore, the research for finding beneficial therapeutic ways for this parasitic infection is very considerable and valuable. Curcumin in different concentrations can prohibit proliferation of trophozoite in this parasite. Curcumin can also stimulate nuclear staining similar to apoptosis in a condition dependent on dose and time. It also shows a cytotoxic impact in G. lamblia as a prohibitory agent of adherent potency [52].

Curcumin can help to remedy eosinophilia and splenomegaly produced by Schistosoma mansoni. The immune responses, including humoral and cellular, are modulated by curcumin that its result is lessening liver damage and parasite load in acute schistosomiasis [53].

Cryptosporidium parvum is a zoonotic parasite with many characteristics that can be responsible for its resistance to several drugs. Curcumin is one of the herbal drugs that are effective against this parasite and can prohibit its growth with more than 95% efficacy [54]. One of the main mechanisms that have a key role in decreasing infection by Cryptosporidium is the prohibition of arachidonic acid creation [55].

In general, curcumin is a key agent against several main parasites that have been shown in Fig. 3.

Fig. 3

Fig. 3

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Antiviral effects of curcumin

Curcumin and components that are produced from it including allyl-curcumin, reduced type, and tocopheryl-curcumin, have proved 70–85% inhibitory impact in the activation as trans of tat protein of HIV-1 [56].

Curcumin has exhibited the main action as the anti-influenza agent against the types of viruses in the mentioned group such as H1N1, PR8, and H6N1. In some subtypes, including H6N1 and H1N1, the prohibition of the interaction of hemagglutinin factor showed the good impact of curcumin on infection by viral subtypes related to influenza [57].

Two derivatives of curcumin such as gallium and Cu-curcumin altogether curcumin have determined considerable and valuable activities against herpes simplex virus type 1 (HSV-1). They remarkably reduce gene expression of the immediate early and inhibit infection of HSV-1 [58].

Another virus that curcumin has antiviral act against its infection is coxsackie virus. Curcumin performs its action by decreasing expression of coxsackie RNA, virus titer, and viral protein synthesis. In addition, it was proved that curcumin is a protective agent for the cells against mentioning virus by stimulating special cytopathic action and apoptosis [59].

Investigations about the antiviral impact of curcumin on the hepatitis B virus (HBV) showed a reduction in the secretion of viral surface Ag named hepatitis B (HBs) Ag from liver cells. It can also repress the viral particle creation and the level of production of mRNA related to HBV in cells infected by the virus. HBV replication is repressed by curcumin via enhancing the level of p53 important protein by increasing the stability and transcription of genes related to the mentioned protein [60].

Curcumin has also been a potent anti-hepatitis C virus (anti-HCV) agent. It performs this act by reduction of HCV replication and gene expression via repressing the Akt–sterol regulatory element-binding protein (SREBP)-1 pathway that has a key role in this subject. In addition, IFNα altogether curcumin is used as an anti-HCV valuable treatment with the prohibitory act of replication [61,62]. Curcumin can also inhibit HCV entry to the liver cells [63].

Progressing cervical carcinoma is created by high-risk human papillomaviruses (HPVs) through the expression of key oncoproteins including of E6 and E7. Curcumin exhibited a valuable the prohibitory act against the expression of mentioned oncoproteins in HPV-18 and HPV-16 that are two major greatly oncogenic human papilloma viruses [64].

The main factor of adult T-cell leukemia is oncogenesis by a virus named human T-cell leukemia virus type 1 that is significantly associated with another factor called the activator protein 1. Curcumin is an effective inhibitory agent on DNA binding and transcription of activator protein 1 in T cells infected by the human T-lymphotropic virus (HTLV)-1 and via this effect can be a beneficial remedial agent [65].

Infection of both Zika and chikungunya viruses can be controlled by curcumin effect. It has been proved that these infections respond to treatment with rates of up to 5 μmol/l curcumin [66].

Antihuman cytomegalovirus action of curcumin has been demonstrated. Here, the effect of curcumin is similar to geldanamycin as an antiviral drug that its aim is the heat shock protein 90 [67].

The mechanism of curcumin impact on the viral hemorrhagic septicemia virus (VHSV) infection is the repression of entry of the virus via alteration of the F-actin/G-actin proportion by decreasing expression of heat shock cognate 71 that controls VHSV infection in the primary phases [68].

The agent of hand, foot, and mouth disease (HFMD) in children is human enterovirus 71 (EV71). The prevalence of HFMD especially in wide parts from Asia-Pacific for long times has converted it to a serious problem, and lack of vaccine and antiviral drugs have severed this subject. Curcumin can decrease the activity of proteasomes that is enhanced by HFMD infection. In addition, the assembling of key proteins such as p53 and p21 is enhanced by curcumin in cells infected with EV71 [69].

Respiratory syncytial virus (RSV) is another virus that can create severe bronchitis and lower respiratory tract disease in young children and infants. Curcumin as a beneficial herbal component hampers the replication process of RSV [70–73].

One of the family members of arboviruses is Rift Valley fever virus (RVFV) that is considered as an important agent, an appearing infectious virus, and finally a pathogenic virus in agriculture. Curcumin is a potent agent with prohibitory effect on the replication of the mentioned virus via influence on the cell cycle and its suppressing. Curcumin also showed its usefulness as an important herbal drug against ZH501 that is the completely virulent version of RVFV [72].

Briefly, curcumin can be used as a drug against several viral infections that have been stated in Table 1.

Table 1

Table 1

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Antifungal effects related to curcumin

Lessening creation of ergosterol leads to assembling biosynthetic primary materials effective in the production of ergosterol, which results in cell death by creating of ROS. Diminution in the secretion of proteinase enzyme and changing characteristics of related to membrane-ATPase action are other probable vital parameters for antifungal acts of curcumin [73].

Curcumin can also apply as an important antifungal drug that is effective against two fungi named Helminthosporium oryzae and Fusarium solani that are members of the family of phytophagous fungi [74].

Curcumin herbal drug has exhibited considerable and better impact against Paracoccidioides brasiliensis toward fluconazole. It also has a prohibitory activity against Cryptococcus neoformans and Cryptococcus dubliniensis[75].

It has been proved that curcumin has a special anti-Candida effect against several various species of Candida such as some strains of resistance to fluconazole and clinical species of C. albicans, C. tropicalis, C. krusei, C. guilliermondii, and C. glabrata[76].

The application of curcumin altogether light demonstrated to be an effective and useful way for development of the antifungal treatments against yeasts with planktonic shapes [77].

Curcumin can regulate the efflux related to transporters of several drugs of the ATP-binding cassette (ABC) of C. albicans, and has a synergistic effect with definite usual antifungal drugs, including itraconazole, ketoconazole, and miconazole [78,79].

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Conclusion

Curcumin is a therapeutic beneficial agent for the advancement of treatment against the types of pathogens, including bacteria, viruses, parasites, and fungi. In general, it exerts its effects via influence on signaling pathways, cell cycle, drug synergism, inducing apoptosis and inhibition of virulence factors. Nevertheless, it seems that be essential for more researches, especially about parasites and fungi that have been done fewer studies about the effect of curcumin on them.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

antifungal; antimicrobial; antiparasitic; antiviral; curcumin

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