RECENT REVIEW ON HERBAL APPROACHES TO REGULATE CANDIDA INFECTIONS

RECENT REVIEW ON HERBAL APPROACHES TO REGULATE CANDIDA INFECTIONS

Mahesh Prasad Singh, Mohit Kumar, Amandeep Singh and Uttam Kumar Mandal *

Department of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University (MRSPTU), Bathinda, Punjab, India.

ABSTRACT: Herbal plants have long been known to have antifungal properties. The medicinal plants are prospective in aquaculture as an alternative to antibiotics and other anti-candida drugs. This article aims to review the reported herbal medicines with their research findings that have an enormous future prospective for the effective treatment of Candida infections. Various species of Candida were classified and their pathogenesis and mechanism of action were highlighted. Mechanisms of action of commonly used synthetic anti-candida drugs were compared to that of the herbal plants. Recent plant-based antifungal activity studies were analyzed. Ten species of candida, namely Candida albicans, Candida glabrata, Candida parapsilosis, Candida krusei, Candida dubliniensis, Candida lusitaniae, Candida guilliermondii, Candida rugosa, Candida zeylanoides and Candida tropicalis were found to be responsible for infection in human. Plant-based natural products were found to produce anti-candida actions based ongermination inhibition and formation of biofilm, cell metabolism, cell wall integrity, cell membrane plasticity, and induction of apoptosis. Around 20 research works were analyzed, and it was found that the majority of the active constituents that produced anti-candida action belonged to the alkaloid, flavonoid, saponin, triterpenoid and anthraquinone class of compounds.

Keywords: Candida infection, Herbal medicine, Antifungal activity, Medicinal plants, Candida albican, In-vivo testing

INTRODUCTION: Approximately 8.7 million eukaryotic species have been found on earth, out of which, 7% are fungi (611,000 species). However, only around 600 species of this number are regarded as human pathogens ¹. Some of the species have mild skin infections, i.e., dermatophytes and Malassezia species, whereas Some other have critical cutaneous infections, i.e., S. schenkii and the rest cause congenital infections, i.e., Candida albicans, Histoplasma capsulatum, C. neoformans and A. fumigatus ².

In USA, Candida species cause hospital non-heritable infections with a fatality rate of 50% ³. Candida is a serious life-threatening pathogen with a major reason of mortality and morbidity, particularly in patients with impaired immune responsiveness ⁴. The major two types of superficial infections in humans caused by C. albicans are mucocutaneous candidiasis, vulvo vaginal candidiasis and dangerous systemic infections (e.g., GIT and genital system) ⁵.

In the case of buccal cavity infection, around 75% of the community is infected by Candida species. The oral Candida infections are known as “oral candidiasis ⁶. C. albicans may be responsible for such infections and may impact the pharynx & the digestive tract of persons with malfunctions of the innate immune system. The disease which is mostly responsible for Oral Candidiasis is HIV ⁷.

Approximately 74% of females suffer once in their life from fungal infection of the vagina ⁸. Major synthetic drugs like 5-flucytosin, amphotericin B and azoles are routinely used to treat Candida infection ⁹. However, these medicines become resistant over time and suffer from serious side effects. Plants are medicines sources for decades. From the earliest, plants have been a prominent source of efficient and safe medicines. Most Countries use plants as remedies, particularly in Asia and Africa. Medicinal plants originating from the desert play a vital role in the modern health service ¹⁰.

Due to their safe, effective, and inexpensive cost, indigenous remedies are renowned amongst the masses of India's urban and rural areas. Several plants have been reported for their important antifungal activities ¹¹. This review exclusively highlights the plants that have been assessed for anti-candida activities with a suggestion for Promoting the use of these plants and the requirements of their extensive analysis and in-vivo testing.

1. Candida: Candidais a pathogenic fungus. This is generally recognized to cause fungal infection to human ^{12, 13}. This fungusis identified to cause deep tissue and mucosal infections.  Candida also affects the oesophagus, vagina, and GIT, apart from mucosal tissues with mouth. Fungal infection of vagina persists to be a world health hassle to females. Hospitalized patients are commonly having Candidal infections and are not easy to prevent ^{14, 15}. Regarding 50% of juveniles have Candida yeasts in their oral mucosa. Candida infections can widen through the body and become dangerous, particular in patients with impaired immune responsiveness ^{16, 17}. Candida can be divided into two forms, hyphae and yeast forms. The major source of infectious agent i.e. Candida is hyphae ³. Candida species produce biofilms on artificial substances, which aid attachment of the entity to devices and make the organism comparatively resistant to antifungal treatment ¹⁸. Candida biofilms associated with catheter paves the way to infections of bloodstream ¹⁹. Candida-infected catheters, particularly those associated with microbial biofilms, can account for up to 90% of infections among hospitalized patients, making them a leading cause of mortality ²⁰. Candida has different species, and each communicates with the body in different route ²¹. Ten species are described below to highlight their pathogenesis and their mechanism of action.

1.1. Candida albicans: It is called an “expedient” fungus. C. albicans may cause the most common fungal infections in humans ²². Even though Candida albicans is typically not dangerous unchecked it can damage physiological processes ²³.

1.2. Candida glabrata: It is present in the mucous membrane. C. glabrata may cause systemic & mucosal infections ²⁴.

1.3. Candida parapsilosis: It is recognized for the reason of infection amongst newborns and in patients with impaired immune responsiveness ^{25, 26}.

1.4. Candida krusei: It is a threat for persons who get received organ transplants ²⁷.

1.5 Candida dubliniensis: It has been recognized in patients with HIV ²⁸.

1.6. Candida lusitaniae: It is also known as opportunistic yeast; this fungus is found in patients with blood cancer ^{29, 30}. Moreover, this fungus is resistant to the Amphotericin an antifungal drug ³¹.

1.7. Candida guilliermondii: This is a less recognized species. Candida guilliermondii can be hit to persons with low immunity ³².

1.8. Candida rugosa: It is a fungal pathogen ³³. It has been found to be resistant to anti-fungicide drugs ³⁴.

1.9. Candida zeylanoides: The sample of skin, blood and nails are the source of this fungus ^{35, 36}. It has been possibly treated with intravenous (iv) amphotericin therapy ³⁷.

1.10 Candida tropicalis: It is a common class of Candida which is resistant to fluconazole ^{38, 39}.

2. Pathogenesis with Candida species: Three things are concerned for an infection to arise with Candida species: sources, the target of population, and transmission mode. Sources like surfaces and human skin are measured as the most vital sources for Candida infection ⁴⁰. Immuno-compromised patients forever remain at high risk for Candida infection. C. albicansis normally transmitted from mother to newborn baby during childbirth. The unwarranted growth of C. albicansleads to disease symptoms and it arises due to the imbalances – Such as, alter vaginal acidity. The normal human microflora is the classic reservoir of C. albicans ^{41, 42}. Candida contaminations are linked with the formation of biofilm. In fungal infections, biofilms can develop on an assortment of surfaces as well as host tissues and implanted biomaterials, including vascular catheters. Additionally, the systemic infection can be increased by biofilms. The biofilm-forming capability can be encouraged by various factors by C. albicans ⁴³.

3. Complications with Candida Infection: According to earlier research, one-quarter of females who have had one yeast infection will have another within a year. Frequent yeast infections can jeopardize a person's health. Infections can also cause problems in relationships by interfering with normal sexual activity ⁴⁴. Yeast infections are an unpleasant but minor health problem for most people. There aren’t many proofs that vaginal yeast infections might cause pregnancy complications. Pregnant women with yeast infections are more likely to have premature labour and preterm membrane rupture ⁴⁵.

4. Antifungal Agents and Their Mechanism of Actions: There are numerous antifungal agents which are commonly used for Candida infection treatment. The list of conventional used antifungal agents, available dosage forms in the market, and the commonly observed side effects are listed in Table 1. The disruption of the cell membrane, cell division inhibition, and cell wall formation inhibition are common mechanisms of antifungal agents.

TABLE 1: LIST OF COMMONLY USED ANTIFUNGAL AGENTS AND THEIR COMMERCIAL PREPARATIONS

4.1. Cell Membrane Disruption: The membrane of cell interruption by attacking ergosterol occurs by ant fungicide agents. Ergosterol is same to mammal cholesterol ⁴⁶.

4.2. Inhibition of Cell Division: Division of cell is influenced by nucleoside antifungal agents ⁴⁷.

4.3. Inhibition of Cell Wall Formation: Interference of fungal cell layer synthesis has not been as better and efficient as penicillin’s and beta-lactam antibiotics oppose the bacteria ⁴⁸.

5. Herbal Medicine as a Boom for Treatment of Candida Infections: Herbal medicine has developed to be a thing of global impact, both therapeutic and economical. Although the tradition of these herbal drugs has amplified, their worth, safety and effectiveness are serious concerns in industrialized and developing countries. Herbal preparation is receiving growing patient conformity as they are devoid of typical adverse effects of allopathic medicines ^{49, 50}. Plants have been well-acknowledged for decades as a foremost basis of medicines since age. Several countries still utilize them as main preparations, mostly in Africa and Asia ⁵¹.

Herbal plants have been a rich resource of effective and harmless medicines from the earliest times. Due to their safe, effective, and inexpensive nature, indigenous remedies are admired among the people of both urban and rural areas in India ⁵².

5.1 Mechanism of Action of Anti-candida natural Products: The anti-Candida mechanisms of action began by plant-based natural products can involve germination, inhibition, and formation of biofilm, metabolism of the cell, the integrity of cell wall, the plasticity of the cell membrane, or may engage induction of programmed cell death given in Fig. 1. They are further elaborated on in the following section:

FIG. 1: MECHANISM OF ANTI-CANDIDA NATURAL PRODUCTS

Inhibition of Formation of Candida Biofilm and Transition to Hypha form: The switch of Candida from yeast to hyphae is mainly followed by the resistant formation of biofilm. Candida biofilms are hard to remove and are linked with resistance against many existing antifungals. Thyme oil is a chief element of Thymol, which can interfere with the metabolic activity of biofilm and the formation of biofilm grown-up ⁵³.

Inhibition of Candida Germ Tube Formation: Among yeast and hyphal cells, GTF is a transitional stage which is an essential stage for Candida malignancy activity. GTF promotes fungal adhesion to inflamed tissues as well as penetration. C is inhibited by oregano essential oil. When compared to other essential oils, albicans are the most potent. The lipophilicity of essential oils and their interaction with the Candida cell wall cause alterations and damage to fungal cell structural and enzymatic elements, including adenosine triphosphate (ATP) ⁵⁴.

Candida Cell Membrane Alteration: Terpenes can alter Candida cell permeability by getting entrapped between the fatty acyl chains of membrane lipid bilayers, altering lipid packing and, as a result, membrane shape and function ⁵⁵.

Candida Mitochondrial Respiratory Chain Interference: The respiration process in mitochondria is accompanied by the production of a large amount of ROS. ROS can injure proteins of cells, lipids, and DNA. HsAFP1 shows apoptic action against C. albicans ⁵⁶.

Inhibition of Candida Adherence: The anti-adherent activity of C. albicans illustrated by the oil of R. officinalis. The bioactivity of R. officinalis is connected with its main chemical constituents, inclusive of limonene, cineole, and cymene ⁵⁷.

Induction of Candida Apoptosis: Baicalein flavonoid shows potent activity as opposed to fluconazole-resistant C. albicans. C. albicans mainly inhibits by Baicalein by apoptosis Silibinin, extracted can cause Candida apoptosis through mitochondrial Ca²⁺ signaling interference. Ca²⁺ signaling plays a vital role in physiological processes and is associated with stress responses in fungi ⁵⁸.

Interference with Candida Cell Metabolism: Allicin has a high anti-Candida effect, mostly through inhibiting thiol-containing amino acids and proteins, interfering with cell metabolism ⁵⁹.

Interference with Candida Cell wall Integrity: During Candida cell growth and morphogenesis and in the face of extrinsic stresses that generate cell wall stress, cell wall integrity is critical. Several natural compounds have been demonstrated to interfere with the integrity of Candida cell walls ⁶⁰.

6. Reported Research Works on Plant-Based Antifungal Activity: A glimpse of recent plant-based antifungal activity studies is presented in Table 2. Some of them are highlighted below. Plants Cassia occidentalis and Oxalis corniculata were indexed for skin disease treatment caused by fungi ⁶¹. Wrightiatintoriawas indexed as externally use in the treatment of vaginal candidiasis ⁶². The stem bark of Bauhinia variegata Linn. was reported as antibacterial and antifungal ⁶³.

TABLE 2: LIST OF INVESTIGATED PLANTS FOR ANTI-CANDIDA ACTIVITY

A variety of medicinal belongings have been accredited to this plant in the traditional system of Indian medicine ⁸². Numerous anthraquinones have been secluded from the seeds of C. tora. Sennosides have been well recognized for their medicinal significance. C. tora extract has been used as a treatment for a variety of skin diseases, rheumatic disease and as laxatives. C. tora leaves extract has been originated from acquiring major anti-inflammatory and hepatoprotective activity. The seeds of C. tora have been used in Chinese medicine as diuretic agents, antiasthma, aperient, and better visual activity ^{83, 84}. Ajania is a genus of flowering plants from the daisy family. The genus is resident in temperate Asia, primarily in Russia and China. Ajania fruticulosa (Ledeb.) Poljak (Asteraceae), circulated primarily in the northwestern part of China, has long been used as traditional Chinese medicine to treat appendicitis, emphysema, tuberculosis, and skin disease ^{85, 86}. Traditionally used herbals for treatment of Candida in various parts of the world are shown in Table 3.

TABLE 3: TRADITIONALLY USED HERBAL PLANTS FOR THE MANAGEMENT OF CANDIDA INFECTION

7. Future Aspects: The effects of the herbals can be synergizing by combining with probiotics, probiotics are well known for their beneficial effect to host when used in adequate amount. Probiotics work by their antifungal property, which is essential for anti-candida activity. Various researchers have already done research work by combining the probiotic stain with herbal drugs, but at present, no marketed formulation is available in probiotic with herbal drugs for the treatment of candida infections. There are many active moieties in herbals that have potent effects that can be used for different research purposes. The potential effects of these herbals in combination with probiotics should be assessed at an in-vivo level for maximum assurance about the plant's effect

CONCLUSION: As concluding remarks, several natural products obtained from plant sources have been tested for anti-Candida activities. These herbal products can target actual cause of the biological activities of Candida, including cell membrane plasticity, the integrity of cell wall, induction of programmed cell death, metabolism of the cell, host cell and respiratory chain adherence, germination, and formation of biofilm. Natural items' anti-Candida activities have been compared to controls, but only a handful have been studied in vivo, and none have ever been used therapeutically as anti-Candida. On the other hand, while some of these ingredients, such as ginger, garlic, probiotics, cinnamon, and peppermint, are available in pharmacies for different medical purposes, they have never been used as antifungals. Because Candida is a serious resistant fungus, there is an urgent need for new anti-Candida drugs; therefore, promoting some of the selected herbal medicines for clinical testing will be advantageous.

Funding: This review work was not supported by funding bodies in the public, private, or not-for-profit sectors.

ACKNOWLEDGEMENT: We thank the Department of Pharmaceutical Sciences & Technology, Maharaja Ranjit Singh Punjab Technical University (MRSPTU), Bathinda, India, for providing the necessary infrastructure.

CONFLICTS OF INTEREST: The authors state that they have no financial or other conflicts of interest.

Supplementary Material: Not applicable.

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     How to cite this article:

     Singh MP, Kumar M, Singh A and Mandal UK: Recent review on herbal approaches to regulate Candida infections. Int J Pharm Sci & Res 2022; 13(7): 2621-30. doi: 10.13040/IJPSR.0975-8232.13(7). 2621-30.

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