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Brucellosis: Pathophysiology and new promising treatments with medicinal plants and natural antioxidants

Brucellosis is an old, infectious and common zoonosis whose causative agents are Gramnegative bacteria from the Brucella genus. Brucellosis is transmitted through direct contact with infected animals or using unpasteurized dairy products of goats, pigs, camels, sheep, buffalo and cows. Brucellosis is still the most common zoonosis in the world, with most of cases occurring in developing countries. Today, an approach to traditional medicine and medicinal plants, especially with regards to the repeated recommendations of the World Health Organization, is a necessity. One-third of chemical drugs are produced by using plants and there is a high potential to produce more drugs from plants. Medicinal plants are helpful in the management of various conditions, especially bacterial diseases. Although there is not enough scientific evidence regarding the clinical effectiveness of herbal drugs for the treatment of brucellosis, there is strong evidence on the antimicrobial effects of herbal drugs to prevent infection. Therefore, this article seeks to describe the antibacterial effects of some plant-derived essential oils or extracts, so that they can serve as promising choices to develop new anti-Brucella medications, as suitable alternatives to conventional antibiotics for brucellosis, as much as possible, taking into account the benefits of these herbal drugs.


Introduction
Brucellosis is an old, infectious and common zoonosis whose causative agents are Gram-negative bacteria from the Brucella genus. Brucellosis is transmitted through direct contact with infected animals or using unpasteurized dairy products of goats, pigs, camels, sheep, buffalo and cows. People working in slaughterhouses or veterinarians are at high risk of developing the disease. Brucellosis is more common in children than in adults [1,2] Non-specific symptoms of brucellosis include fever, chills, restlessness, headache, fatigue and weakness [3][4][5]. One of the most common symptoms of this disease is bone involvement that is seen in over half of the affected people [6]. The association between Brucella and brucellosis was first discovered by an army surgeon named David Bruce. He isolated bacteria from the spleen of patients in Malta from 1886 to 1887. Brucellosis is still one of the most common zoonosis in the world and more than 500 000 cases each year are diagnosed with the disease, most of whom live in developing countries. The number Brucellosis is an old, infectious and common zoonosis whose causative agents are Gramnegative bacteria from the Brucella genus. Brucellosis is transmitted through direct contact with infected animals or using unpasteurized dairy products of goats, pigs, camels, sheep, buffalo and cows. Brucellosis is still the most common zoonosis in the world, with most of cases occurring in developing countries. Today, an approach to traditional medicine and medicinal plants, especially with regards to the repeated recommendations of the World Health Organization, is a necessity. One-third of chemical drugs are produced by using plants and there is a high potential to produce more drugs from plants. Medicinal plants are helpful in the management of various conditions, especially bacterial diseases. Although there is not enough scientific evidence regarding the clinical effectiveness of herbal drugs for the treatment of brucellosis, there is strong evidence on the antimicrobial effects of herbal drugs to prevent infection. Therefore, this article seeks to describe the antibacterial effects of some plantderived essential oils or extracts, so that they can serve as promising choices to develop new anti-Brucella medications, as suitable alternatives to conventional antibiotics for brucellosis, as much as possible, taking into account the benefits of these herbal drugs.
The disease cycle can be acute, sub-acute or chronic [10]. Four different Brucella species, i.e., Brucella suis (B. suis), Brucella melitensis (B. melitensis), Brucella abortus (B. abortus) and Brucella canis can be pathogenic to humans [11]. Among these species, B. melitensis is the most contagious species, followed by B. abortus and B. suis [9]. Brucella species are intracellular, obligate and Gramnegative coccobacilli and are not able to produce spores [12]. Brucella species have no classic virulence genes encoding capsules, plasmids, pili or exotoxins, and because of factors that cause the bacteria to acquire resistance to phagocytes and increase the proliferation of phagocytic cells, they are relatively less known than other pathogenic bacteria [13].
The O-polysaccharide chain on the lipopolysaccharide layer plays an important role in pathogenicity of the bacteria. The O-polysaccharide chain of Brucella prevents complement accumulation on bacterial surfaces [14,15]. This is done by preventing the C1q access to the external surface of the targeted proteins; and a study led to the hypothesis that the size of the O chain acts as a protective factor against the complement system [16]. Brucella lipopolysaccharide protects the bacteria against antibacterial cationic peptides in addition to blocking the pathway for activation of the complement. It has been shown that brucellosis is resistant to a large variety of peptides such as defensin NP-2, lactoferrin, cecropines lysozyme, bactenecin-derived peptides, defensin-like antibiotic polymyxin B, as well as lysosomal compounds produced from polymorphonuclear leukocytes [17,18]. By controlling the adenine and guanine monophosphate systems, the bacteria prevent the integration of phagolysosomes, the release of myeloproxidase, and production of tumor necrosis factor (TNF), and thus cause the disease [19].
Brucella can survive inside certain macrophages in certain ways. It protects itself against the host immune system in certain ways such as stopping macrophage apoptosis, suppressing T1 specific immune responses and inhibiting TNF-毩 production [20][21][22]. Brucella should prevent Th1 polarization in order to protect itself against the activation of macrophages and the production of cytotoxic T cells.
Polarization of the immune system is accomplished by cytokines that are rapidly produced by infected macrophages. Therefore, stopping the expression of cytokines such as TNF is one of the methods of the pathogens to fight the immune system [20,23]. Investigation of B.
suis-infected monocytes revealed that the expression of the A1 gene, which is one of the genes of the bcl-2 family, increases in these cells, and contributes to the survival of the cells and, consequently, resistance to apoptosis. B. suis-infected cells are also resistant to the signaling of Fas ligand or apoptosis-inducing interferon gamma, which protects the host cell against different cytotoxic processes of the immune system [17].
Brucellosis is a systemic disease with a wide range of clinical symptoms so that it can be asymptomatic or cause lifethreatening symptoms [24,25]. Symptoms include headache, fever, sweating, weight loss and back pain; and the most commonly observed symptoms due to the disease are meningitis, dizziness, hepatomegaly, hypoesthesia and splenomegaly [26]. Due to the specific characteristics of the bacterium, Brucella is one of the most important causes of fever of unknown origin [27,28]. This disease can involve various organs in the body. Bone involvement is the most commonly observed involvement in half of the people with brucellosis [29,30]. The mortality rate from brucellosis is less than 1% and the most common cause of death is heart involvement.
Brucellosis also causes certain disorders such as endocarditis, pericarditis, myocarditis, and inflammation of the walls of the veins and arteries [31,32].
Nervous system disorders occur in 10% of patients and can lead to meningoencephalitis, myelitis, cerebellar involvement, cranial nerve palsy, stroke, spinal cord atrophy, chronic and acute meningitis, polyradiculoneuropathy and paraplegia. Neurological disorders, especially in the white matter, are due to immune responses to bacteria [33][34][35]. It can also affect the genitourinary system. Genital tract infections include testicular and epididymal inflammation, renal and testicular abscesses, prostate inflammation, glomerulonephritis and calcified nodules, which are observed in 2%-20% of the patients.
The cause of epididymal inflammation is the presence of various sugars similar to erythritol in the epididymis, because bacteria need this sugar for growth [36,37]. In addition to the aforementioned disorders, this disease also causes a lot of hematologic disorders, including lymphocytosis, leukopenia, leukocytosis, thrombocytopenia, increased erythrocyte sedimentation rate and anemia; hematologic disorders are caused by hemophagocytosis, microgranuloma and hyperplasm [38]. Liver is another organ that can be involved in brucellosis. Hepatomegaly and splenomegaly have been reported in 63% and 56% of patients, respectively. Cirrhosis of the liver, hepatic parenchymal necrosis and hyperplasia of Kupffer cells are also some of the studied liver involvements [39,40].
Each year more than 500 000 people acquire brucellosis and most of them live in the Mediterranean region, the west and central Asia, certain parts of Africa and Latin America [4], as well as some Asian countries including Syria, Iraq, Iran [41] and Mongolia [42]. The overall prevalence has been reported to be high but the prevalence in China and South Korea is low [43]. However, the disease remains endemic in some areas of the two countries [44]. Brucellosis is more common in men due to their greater activity than women and children [45].
Brucellosis is an important disease in the Sub Saharan countries and has been reported in almost all African countries [46].
There is strong evidence on the antimicrobial effects of herbal drugs to prevent infection. Furthermore, oxidative stress and inflammation are involved in a lot of diseases [47][48][49] A total of 155 articles were retrieved articles from databases.
After analysis, 28 articles were deleted for the following reasons: repeatability and old age of publication of articles (16), lack of summaries (5) and lack of access to their full text (7). In the end, 127 articles directly affect the effect of herbs and their derivatives on the control of Brucella bacteria were selected for the study of cytological overview.

Plants used in treating brucellosis
The use of medicinal plants has increased among adults and children in recent years, so that approximately 4 per every 10 Americans use alternative therapies such as medicinal plants [50].
More than one-third of chemical drugs are produced from plants and there is a high potential to produce more effective drugs from them. Medicinal plants are used to treat various diseases such as rheumatic disorders, acquired immune deficiency syndrome, cancer, depression and bacterial diseases [51,52]. Due to low resistance to high temperatures and the carcinogenicity of some of the synthetic compounds, today, attention has been drawn to the use of natural antioxidants. Hence, a list of the most important medicinal plants which are effective against Brucella and have the potential to use as anti-Brucella remedies are presented (Table1).

Alhagi camelorum (A. camelorum)
A. camelorum is a perennial shrub with a relatively deep creeping root and is used as a traditional drug for diuresis or to remove kidney stones and pain [53]. The aqueous extract of the plant at 500 mg/mL caused an minimum inhibitory concentration (MIC) of 27 mm within 48 h under 37°曟 [54].

Allium sativum (A. sativum)
A. sativum grows around the world depending on seasonal changes, however, its production is limited by the region and the type of weather. The plant is cultivated in autumn and is harvested in the summer [55]. Shapoury

Arctium lappa (A. lappa)
A. lappa, a herbaceous plant with large leaves and long root, is used orally as a medicine. In a study, the effect of A. lappa extracts on B.

Berberis integerrima
Berberis integerrima is a deciduous shrub that reaches a height of 5 m, has egg-shaped leaves, yellow flowers and bark and red fruits, growing in the Middle East and central Asia [58].

Caraway (Carum carvi L.)
Carum carvi is an andromonoecious plant that occurs in many countries in Europe, Asia and Africa, and is traditionally used to produce oil and also is used for pharmaceutical purposes [60].    limon on B. abortus 544 were investigated. The inhibitory effect of 1% essential oil of the bark of Cinnamomum verum persisted after 24-144 h following infection [68]. This plant is an evergreen plant belonging to the Lauraceae family, has anti-allergic and antipyretic properties, and grows in the tropical regions of Africa and Asia [69].
Mentha piperita is a perennial plant and native to Europe, northern America and Canada, has a variety of colors, with fragrant leaves and can grow up to 30-90 cm [70]. It was observed to reduce bacterial growth within 4-144 h. C. limon is a tree of 3-6 m, and its 1% essential oil is able to inhibit bacterial growth within 48-96 hours [68].
Origanum majorana is a perennial and resistant plant that grows wildly in Egypt, eastern Mediterranean region, and northern Europe with mulching materials. The 1% essential oil of its leaf, along with 0.1% essential oil of cinnamon, was able to reduce bacterial growth within 24-144 h [71]. The 1% essential oil of Myristica fragrans, an evergreen that is native to tropical region such as Indonesia, along with C. limon, produces a synergistic effect to inhibit B. abortus 544 [68].

Lavandula pubescens (L. pubescens)
In a study, the effect of raw extracts of L. pubescens aerial parts, which has almost oval leaves and is found mostly in the Middle  N. sativa in white cheese in freezer [(2 ± 5)°曟]. In that study, N. sativa oil and seed were found to be able to inhibit B. melitensis, and the oil produced a more potent effect. After two days, cheese with 1% of seed (1% of the total cheese content), cheese with 0.3% oil (percentage of total cheese content) were able to reduce B. melitensis growth [75].

Oliveria decumbens
Oliveria decumbens occurs in south and southwest Iran, is endemic in Iran and is traditionally used to treat diarrhea and fever [76]. The

Origanum syriacum (O. syriacum) and Thymus syriacus (T. syriacus)
T. syriacus is used as a herbal tea and spice, and to treat cough and respiratory disorders, and grows in the eastern Mediterranean region [78,79]. O. syriacum can grow up to 90 cm in vast regions of the eastern Mediterranean region, southern Turkey, Syria and Cyprus, and is used in Syria to treat respiratory and digestive disorders [79].
The essential oil of T. syriacus aerial parts at 50 mg/mL caused a moderate growth inhibition zone (22.6 mm in diameter), while the O. syriacum essential oil was able to cause a growth inhibition zone of 16.2 mm in diameter [80].

Peganum harmala L.
Peganum harmala is a perennial and flowering bush, and grows up to 30-100 cm. The plant spreads in northern Africa, the Mediterranean region, the Middle East, Pakistan, India and Iran [81]. The effects of the extracts of the seed, leaf, flower and root of the plant within    [86][87][88]. The whole dried root of Radix paeoniae is used as a traditional drug in China to treat blood stasis syndrome and to reduce pharygeal pain and pharyngitis [89]. and its MICs for the 16M, 293, 183, and 4611 species were 18, 14, 18 and 16 mm, respectively [90].
Different parts of the G. chinensis are used to treat various diseases in traditional Chinese medicine [91]. The MICs of the G. chinensis on species 16M, 293, 183 and 4611 were 39, 32, 33 and 40 mm, respectively [90]. Cortex phellodendrim, known as Huangbai, is used as a herbal drug in several regions of China and to treat diseases such as diarrhea and cancer [87].

Teucrium polium
Teucrium polium is found in abundance and is used as a traditional drug in Iran. The plant has pink to white flowers [95].

Vitex pseudo-negundo
Vitex pseudo-negundo is found in different regions of the world from the Mediterranean region to central Asia and is used in Iran as a herbal drug [97]. Among the plants mentioned, Z. multiflora exhibited the strongest effect. Lamiaceae is a highly valuable medicinal plant and is found in large quantities in Iran, Pakistan and Afghanistan [98]. This plant is locally called Saatar, has small, egg-shaped and almost rounded leaves with a large number of small flowers [89,99]. and 0.5 g/mL were 9, 10, 11, 15, 9 mm and 11, 11, 13, 15, 9 mm

Conclusion
Perhaps the oldest human medicines for the treatment of undulant fever that still retain their place in modern medicine are herbal syriacum. Carvacrol is a monoterpenoid phenol with a tangy taste.
Carvacrol is produced by the plant's aerial organs, and is stored in the subcuticular storage cavity [111]. The antibacterial action mechanism of carvacrol involves eliminating the membrane integrity, proton and potassium outflow from the cell by increasing the permeability of the membrane and changing pH gradient in the cells [112]. This substance can also depolarize the membrane by using its hydroxyl groups [113].
According to studies on the toxicity of this substance, the Caco-2 cells did not get damage in the short-term exposure to carvacrol [114].
Also, carvacrol has no significant effect on lymphocytes and indices of blood growth [115]. In addition, thymol is the main compound of plants such as Z. multiflora, Oliveria decumbens, Sylvia hortensis, N.
cataria and T. syriacus. Thymol is the main identified phenol in the essential oils of the plants belonging to the Lamiaceae family [116].
Thymol is the product of p-cymene hydroxylation and p-cymene is the product of毭-terpinene aromatization [117,118]. The essential oils rich in thymol are used in the food industry as a flavoring and preservative agent [119]. Thymol has also been used as an insectrepellent and for medical purposes from ancient times [120,121]. It has a phenolic hydroxyl in different sites on the phenol ring and, by virtue of its hydrophilicity, dissolves and destroys the organisms, and also can lead to the depolarization of the bacterial membrane.
Thymol produces no destructive effect on Caco-2 cells in the short term [114]. The main compound of some plants such as A. lappa, Q.
brantii, G. chinensis, sumac and A. camelorum is tannin. Tannins are water-soluble polyphenols which can be detected in higher herbaceous and woody plants and are divided into two groups: Hydrolysable and non-hydrolysable. They are found in many foodstuffs such as tea, cocoa seed and grapes [122,123]. Because of the presence of hydroxyl groups, they are able to bind to proteins and other macromolecules [124]. Tannins destroy bacteria through various mechanisms, including inhibition of bacterial enzymes through the formation of a complex with them, exerting destructive effect on the membrane of the organism, forming complex with iron ion, depriving the organism of its essential nutrients, and affecting the metabolism of the bacteria directly by inhibiting oxidative phosphorylation [125]. Other plants that have effective ingredients, such as berberine, possess many pharmaceutical and biological properties, such as anti-inflammatory, anti-tumor, viral, and bacterial, and stop bacterial growth by inhibiting DNA and protein synthesis, while causing very low toxicity [126,127]. Therefore, the active ingredients of the herbal drugs can be used to make the best use of them. However, it is noteworthy that herbal remedies have different compounds that may lead to synergistic effects by inducing different mechanisms in the living organism and may be more effective than the constituents isolated from them.

Recommendations
More clinical, controlled trials using extracts and other products are needed to determine the efficacy and risks of plant products in the treatment of brucellosis, as well as to examine the long-term safety and tolerability of plant medicines used in food supplements.