INTRODUCTION:

After diabetes and hypertension, glomerulonephritis, kidney diseases, and nephropathy are the leading causes of chronic kidney disease in the United States and other developed countries¹. The renal cell carcinoma (RCC) accounts for less than 5% of all malignant diseases in adults. The incidence of all stages of this type of cancer has increased in the last 10 years, leading to an increase in mortality. Kidney cancer is not a single tumor, but it is a set of different types of tumors, of which the most common ones are clear cells and papillary chromophobe. Each of the different parts of the nephron is characterized by certain morphological and genetic characteristics^2,3. The molecular pathology of kidney cancer has been widely developed over the past few years, and oncogenetic views have provided a new basis for more accurate classification and more effective systematic treatment. However, in liver cancer, the use of targeted pharmacotherapies in metastatic disease remains incompatible with predictive biomarkers³.

Classification of RCC:

RCC is derived from the renal tubular epithelium. RCC include clear cell, chromophil (papillary), chromophobe, collecting duct, unclassified, sarcomatoid, and small cell⁴. Clear cell RCC: This type of RCC is one of the most common RCCs and often has a mottled appearance which is due to old hemorrhage, necrosis, fibrosis, and ulcers^5-7. Chromophil (papillary): This type of RCC can be easily diagnosed because of its morphologic papillary structure due to necrosis, bleeding, and the presence of foam cells^8,9. Chromophobe RCC: The cytoplasm of this chromophobe carcinoma include many proteins of smooth endoplasmic reticulum, a subset of which has been characterized by eosinophilic cytoplasm (a type of chromophilic-eosinophilic carcinoma)^10,11. Collecting duct: This type of RCC is usually due to carcinoma in the ducts in the central kidney¹². This kidney disorder mainly affects younger people. This carcinoma of collecting duct metastases to the renal corpuscle and may not be seen in the central part of the kidney^13-15. Unclassified RCC: This type of RCC is not classified as any of the known types; these types of tumors are called unclassified. Unclassified RCC represents a proportion of an invasive clinical pathological manifestation in RCC^16,17. Sarcomatoid renal cell carcinoma is a distinct but advanced RCC that, at advanced stages, is seen with other types of RCC^18-21. Bladder Cancer is also one of the most common types of cancers of epithelial cells, the most lethal urinary tract cancer, and the second leading genitourinary cancer that metastases to outside the bladder if not treated early^22-24. Bladder cancer usually begins to develop in the bladder inner membrane. In most cases, bladder cancer is diagnosed early^25,26.

Types of bladder cancer:

In terms of the type of malignant (cancer) cells among the epithelial cells of the urinary tract, three types of cancer may develop^27,28. Transitional cell carcinoma is a type of cancer that occurs in the cells of the innermost layer of the urinary tract in the bladder. Most bladder cancers occur in these resilient cells. Squamous cell carcinoma is a type of cancer that occurs in squamous cells that are thin and flat cells and may be present in the urothelium of the bladder in the urinary tract after long-term infections or inflammation. This cancer is similar to skin cancer under the microscope. Adenocarcinoma is a cancer that occurs in the glandular cells of the bladder. The glandular cells present in the urothelium of the bladder of the urinary tract produce mucus-like substances. Grading of the bladder cancer: The grading of cancer is important for the prediction of the likelihood of cancer recurrence after treatment and the chance of survival for the patients. Bladder tumors can be of two grades: low and high. The grade of non-invasive tumors can be low and high, but all invasive tumors (tumors of stage T1 and higher) are high^29-31.

Symptoms and signs of bladder cancer:

The most common symptom of bladder cancer is the presence of blood in the urine (hematuria) that may be seen with the eye, anemia due to blood loss, bone pain that occurs in the advanced stages of the cancer^32,33, as well as painful urination, namely, dysuria³⁴. Due to the unavoidable side effects of industrial and chemical drugs, the discovery of new drugs that have minimal side effects has drawn much attention. The medicinal plants and natural antioxidants are the appropriate sources to achieve this purpose, especially because they are more compatible with human nature and cause comparatively less side effects. Certainly, the study and information on these plants, which are a constituent of natural resources, is particularly valuable. In many cases, the use of these plants has significant effects on the reduction of complications caused by synthetic drugs or other diseases^35,36. The present review article aims to report the mechanisms of antioxidant and antimicrobial actions of the most important medicinal plants across the world on urinary system disorders. Medicinal plants used to treat common diseases and disorders of the urinary system in the world will be reported as well.

METHODS:

The information in this review study was obtained from the articles published in databases such as Iran Medex, Irandoc, Institute for Scientific Information, PubMed, Scopus, the Web of Science, Scientific Information Database, Magiran, and Google Scholar using the search words urology, urinary system, urinary system cancer, renal cell carcinoma, renal cell carcinoma classification, bladder cancer and its types, herbal drugs affecting the urinary tract, medicinal plants and bladder cancer, medicinal drugs affecting renal disorders, effects of herbal therapy on renal cell carcinoma in humans and animals, effect of extracts and essential oils of medicinal plants affecting kidney and bladder tissues in mice and humans, and effect of extracts and essential oils of medicinal plants affecting kidney and bladder damage. A total of 110 articles were reviewed.After the preliminary review, 17 articles were found to be eligible to include in final analysis. Relevant articles were included and irrelevant ones were excluded.

RESULTS:

Medicinal plants addressed in this review are effective in the treatment and prevention of diseases and disorders of the urinary system (kidneys, bladders, and urinary tract (Table 1 ).

Based on our review of the articles, a number of plants have been reported to prevent disorders and cancers of urinary system (bladder, kidneys, and urinary tract).including a number of plants used to treat disorders of the urinary tract and prevent renal and bladder diseases such as Equisetum arvense, Cornus mas L., Gynostemma pentaphyllum, Lycium barbarum, Camellia sinensis, Panax ginseng, Liriope muscari, Nigella sativa Linn, Abelmoschus manihot, Astragalus membranaceus, Tripterygium wilfordii, Zingiber zerumbet, Pistacia vera, Terminalia chebula Retz, Paeonia lactiflorapall, Cornus officinalis, Senna auriculata, Terminalia, Chebula, Opuntia megacantha, and Punica granatum. Additional information on medicinal plants is given in Table 1.

The phytochemical studies of these plants have shown that the most important compounds of these plants include total flavonoids and phenolics, steroids, anthocyanin, quercetin, terchebi, luteolin, tannic acid, luteic acid, terflavin B, tannins, chebulinic acid, gallic acid, vanillic acid, oleanolic, ursolic acid, gallic acid, rutin, and saponin.The most important active ingredients and the important flavonoids in these plants are shown in Table 2.

Scientific Name	Family Name	Common Name	Origin of plant	Type affect	The Effects of herbal medicine on Kidney and bladder disorders.	Ref.
Equisetum arvense	Equisetaceae	common horsetail	North America ,Sweden, Finland, and Russia India, and Iran	Ethanolic extract	Ethanol extract of this plant was given to rats for 3 weeks and the concentration of catecholamines and adrenaline and noradrenaline was observed. In physiological conditions, the effect of this plant on reducing the pressure of the bladder and urethra is that the inhibitory effect of EA on bladder activity may be by blocking the release of ATP from bladder epithelial cells. It has been verified that Equisetum Arvense acts as a potent free radical scavenger in antioxidant activity, and this ability may be involved in anti-inflammatory and anti-ATP releases.	38
Cornus mas L.	Cornaceae	Cornelian cherry	Native to Southern Europe and Southwestern Asia.	Methanolic extract	The traditional uses of Cornillian Cherry include kidney stones, urinary tract infections, urinary tract cancer, bleeding and heat fatigue. Due to antioxidant activity, Cornelian cherry has a protective effect on these tissues. Intraperitoneal administration of alcoholic extract of carnival cherry in doses of 50, 200 and 400 mg/kg reduces urea, creatinine and uric acid in tested mice. Methanolic extracts of Cornellian Cherry, 300 and 700 mg/kg, reduced the antioxidant effect of carbon tetrachloride by reducing serum urea, uric acid, and creatine levels. This extract also corrected the glomerular damage affected by carbon tetrachloride.	39
Gynostemma pentaphyllum	jiaogulan	Cucurbitaceae	China, India and Bangladesh to Southeast Asia to Japan and Korea	Aqueous extract	Oral extracts of this plant reduce the production of inflammatory cytokine in the bladder epithelium in response to bacteria. Psoriasin expression increases, Psoriasin (as a chemo-like on neutrophils and stimulates these cells to produce cytokines and chemokines, including IL-6 and IL-8), since psoriasin shows strong activity against E. coli, and it can be said that a higher level of psoriasin causes the elimination of invasive pathogens and, as a result, reduces abnormalities and cancerous cells And the extract of this plant also increases the phosphorylation of ERP kinase MAP in the signal pathway.	40
Lycium barbarum	Solanaceae	red medlar or Murali	Northern China	Ethanolic extract	The extract of this plant causes apoptosis of bladder cancer cells, and the active flavonoids of this plant have inhibitory effects on many of the cancerous cells, including the kidneys and bladders. The extracts of this plant have medicinal biological functions including: nerve protection, antioxidant, anti-aging, cytoprotection and immuno-odulating. Based on the antioxidant activity and anti-apoptosis of this plant, many studies have shown that this plant has an anticancer effect in various tumors (kidney and bladder, and ...) malignant. Studies have shown that the use of extract of this plant in the treatment of renal cell carcinoma (RCC) is very effective.	41
Camellia sinensis	Theaceae	Tea	Native to East Asia, the Indian Subcontinent and Southeast Asia,Europe	Aqueous extract	L-Theanine, a non-proteinaceous amino acid in tea leaves that helps to improve nephropathy, stroke, renal reperfusion injury, kidney disorders and also has antioxidant properties, anti-inflammatory, and relaxing effects. L-Theanine, through its antioxidant and anti-inflammatory activity, improves the induction of overactive bladder induction by stimulating the pre-inflammatory signaling of PKC / ERK / ICAM-1 / IL-33, induction of bladder protrusion and adhesion of leukocytes and their apoptosis In the bladder cancer cell. Epigallocatechin gallate (ECGC) Other green and black tea polyphenols cause intestinal cancer. ECGC suppresses expression of androgens and signaling through several growth factor receptors.	42
Panax Ginseng	Aralioideae	Ginseng	American, Europe, Asia	Aqueous extract	The polysaccharides of this plant have anti-proliferation and anti-metastatic ability in bladder T24 cells. Rg3 ginsenoside is an enzyme linked to the induction of apoptosis in the human bladder transitional cell carcinoma (EJ).	43
Liriope muscari	Asparagaceae	Lily turf	East Asia	Aqueous extract	DT-13 is a saponin monomer from this plant, which has anti-angiogenesis effects in various cancers, including the urinary tract, by decreasing vascular endothelial growth factor (VEGF), C-C chemokine receptor type 5 (CCR5), and hypoxia-inducible factor 1α )HIF-1α(	43
Nigella sativa Linn	Ranunculaceae	nigella	Native to south and southwest Asia.	Aqueous extract	Thymoquinone is an active chemical compound that is a major component of N. sativa grains, has antioxidant properties, free radicals and superoxide anions, also has anti-inflammatory effects, since it inhibits the cyclooxygenase and lipoxygenase-5 pathways. Anti-cancerous and anti-diabetic effects. Anticancer activity (cottage and catheter, etc.) of this plant can be related to the melanin contained in the plant, which can modify the production of cytokines and as The TLR4 ligand has been suggested to also reduce IβBα, break down Caspase 8, and produce IL-8 and IL-6 by signaling NF-β in TLR4-transfected cells and TLR4 expressing cells. Herbal melanin from N. sativa L. is a strong stimulant expressing TLR4 cells; therefore, it may have a potential role in infectious diseases and cancers. Melanin also has antioxidant properties	44
Abelmoschus manihot	Malvaceae	Aibika	Asia: Bhutan, China, India, Indonesia, Malaysia, Nepal	Aqueous extract	Usually used to treat inflammatory diseases in China. AM is used to make a Huangkui capsule that improves kidney inflammation and glomerular damage in a rat with doxorubicin-induced nephropathy by inhibiting the p38 MAPK signaling pathway and expressing the TGFb1 protein. This plant also has anti-fibrous effects.	45
Astragalus membranaceus	Fabaceae	Mongolian milkvetch	Asia,China	Aqueous extract	The anti-inflammatory and antioxidant anti-stress properties of this plant have been observed in various cells by the regulation of the nuclear factor [erythroidderived2] -like and the suppression of p38 MAPK (mitogen-activated protein kinase), NF-kB (nuclear factor kB), and receptor-mediated pathways.This plant reduces proteinuria and reduces renal damage in several animal models, also inhibits free radicals and inhibits the synthesis of nitric oxide and also decreases TNF-α (tumor necrosis factor a). The plant also has kidney anti-fibrosis effects by inhibiting the TGFb1 pathway and increasing the degeneration of the extracellular matrix and decreasing nephropathy.	45
Tripterygium wilfordii	Celastraceae	thunder duke vine	Asia,China	Aqueous extract	Triptolide is an active ingredient in this plant, which is widely used to treat glomerulonephritis. It also improves the synthesis of extracellular matrix and inhibits the signaling pathway of TGFb1 / Smad glomerulosclerosis in renal and urinary cancers.	45
Zingiber zerumbet	Zingiberaceae	bitter ginger	Originates from Asia, but can be found in many tropical countries.	Aqueous extract , Hydroalcoholic extract	Extract of this plant can significantly increase plasma glucose and glutathione (GSH) levels and plasma superoxide dismutase (SOD) activity (P <0.05). Nephropathic effects of Z. zerumbet extract have been shown to reduce the severity of kidney damage. Z.zerumbet fresh rhizomes protected against sodium permeation of cipolatin resulted from decreased production of MDA and simultaneous production of GSH.	46
Pistacia vera	Anacardiaceae	pistachio	From Central Asia and the Middle East.	Hydroalcoholic extract	This study shows the nephropathic protective effect of pistachio hydroalcoholic extract, which suggests that pistachio treatment may reduce renal dysfunction and structural damage by reducing oxidative stress and kidney inflammation. Pistachio extract reduced serum creatinine level, urine volume, urine glucose and BUN, and increased creatinine cholesterol in all doses, but the highest change was observed in doses of 100 mg/kg. The nephropathic effects of GA were also confirmed by examination of the tissues of the kidneys.	47
Terminalia chebula Retz	Combretaceae	black- or chebulic myrobalan	South Asia from India and Nepal east to southwest China (Yunnan), and south to Sri Lanka.	Chloroform extract	T. chebula's chloroform extract reduces urinary arrhythmia in glomeruli and leads to an increase in glomerular glomerular pressure. The extract of this plant also inhibits angiotensin-II renal fibrosis, and the extract of this plant inhibits glycosylated products, which inhibits angiotensin II and its receptor, which reduces nephropathy and nephrotoxicity caused by hyperglycemia.	48
Paeonia lactiflorapall	Paeoniaceae	Peony	Asia, Europe and Western North America.	Aqueous extract , Hydroalcoholic extract	Due to increased oxidative stress in diabetic mouse kidneys, the root extract of this plant can prevent kidney damage associated with diabetes against oxidative stress. TGP (extracted from the root of Paeonia lactiflora pal) decreases the proportion of kidney and urine albumens A good marker is a good choice for renal glomerular injury and reduces the high rate of electrolyte excretion of nephropathy and nephrotoxicity of the kidneys.	49
Cornus officinalis	Cornaceae	Cornelian cherry	Asia (china and Korean and Japanese and japan)	Aqueous extract	It has been shown to have a protective effect on diabetic kidney damage. These results indicate that the active ingredient of moroniside in this plant is one of the main components of the protective effect of this plant against nephropathy. It has a protective effect on diabetic kidney damage by controlling hyperglycemia and oxidative stress. This plant reduces the effects of diabetic nephropathy and improves kidney function.	50
Senna auriculata	Fabaceae	matura tea tree	Dry regions of India and Sri Lanka.	Aqueous extract , Hydroalcoholic extract	The findings indicate that the potential mechanism for protection of nephrotica by C. auriculata against renal damage caused by cisplatin and gentamicin can be due to its antioxidant and free radical properties. One of the suggested mechanisms is that by changing the metabolism of arginine and increasing activity of nitric oxide synthase, it acts independently of calcium, C. auriculata is evaluated for antioxidant substances and it eliminates the effects of radical free radical oxide nitrogen. C. auriculata is known as a rich source of flavonoids such as quercetin and ruthenium. Flavonoids of this plant are potent antioxidants.	51
Terminalia chebula	Combretaceae	chebulic myrobalan	South Asia from India and southwest China	Aqueous extract	Showed that T. chebula is more effective than diabetic nephropathy. Diabetic nephropathy is mainly due to excessive urinary albumin excretion, abnormal kidney function, which is expressed by an impairment of serum creatinine.	52
Opuntia megacantha	Cactaceae	culinary	South Africa and South America	Aqueous extract , Hydroalcoholic extract	O. megacantha leaves extract It is an anti-nephrotoxic effect of diabetic patients. Oral administration of leaf extract of this plant shows nephrotoxicity effects on the kidneys, which indicates increased urine creatinine and urea concentrations in diabetic and non diabetic rats.	53
Punica granatum	Lythraceae	pomegranate	Worldwide	Aqueous extract	The effects of pomegranate seeds on oxidative stress markers in the treatment of renal function significantly reduced serum urea. It increases glutathione renal peroxidase-induced diabetes and increases antioxidant activity in the kidneys and the liver, and protects the urinary system against damage to free radicals.	54

Table 2. Effective material of the herbal plants.

Scientific Name	Effective material	Ref.
Equisetum Arvense	Apigenin luteolin, luteolin-5-O-β-Dglucopyranoside, isoquercetin, apigenin-5-O-glucoside, ursolic acid oleanolic acid	38
Cornus mas L.	Flavonoids, steroids, Anthocyanin, quercetin	39
Gynostemma pentaphyllum	Total flavonoids and phenolics, gallic acid, rutin and quercetin, saponin	40
Lycium barbarum	Flavonoids quercetin 3-O-rutinoside-7-O-glucoside, kaempferol 3-O-rutinoside-7-O-glucoside, rutin, nicotiflorin, isoquercitrin, quercetin, kaempferol damascenone, choline, scopoletin, vanillic acid, salicylic acid, and nicotinic acid , diosgenin, β-sitosterol, and lanosterol	41
Tea	theobromine and theophylline, polyphenols, including flavonoids, epigallocatechin gallate, catechins	42
Ginseng	steroid saponins ,ginsenosides(Saponins Tri pterpenoid), flavonoids, steroids	43
Liriope muscari	Phenolic compounds, namely N-trans-coumaroyltyramine ,N-trans-feruloyltyramine, N-trans-feruloyloctopamine, 5,7-dihydroxy-8-methoxyflavone and (3S)3,5,4'-trihydroxy-7-methoxy-6-methylhomoisoflavanone	43
Nigella sativa Linn	Thymoquinone,thymohydroquinone and thymol, dihydrothymoquinone, p-cymene, carvacrol, α-thujene, α-pinene, β-pinene and trans-anethole.	44
Abelmoschus manihot	Myricetin, cannabiscitrin, myricetin-3-O-beta-D-glucopyranoside, glycerolmonopalmitate, 2, 4-dihydroxy benzoic acid, guanosine, adenosine, maleic acid, heptatriacontanoic acid, 1-triacontanol, tetracosane, β-Sitosterol, and beta-sitosterol-3-O-beta-D-glucoside.	45
Astragalus membranaceus	Polysaccharides , triterpenoids (such as astragalosides, isoflavones (including kumatakenin, calycosin, and formononetin) ,malonates	45
Tripterygium wilfordii	Triterpenes ,pyridine alkaloids , flavonoids, steroids.	45
Zingiber zerumbet	Zerumbone ,alpha-humulene, humulene epoxide II ,caryophyllene oxide ,and camphene .	46
Pistacia vera	Limonene, α-pinene, α-thujene ,α-terpinolene , polyphenols	47
Terminalia chebula Retz	Ellagic acid, 2,4-chebulyl-β-D-glucopyranose, chebulinic acid, gallic acid, ethyl gallate, punicalagin, luteolin, and tannic acid, Chebulic acid, Luteic acid, terflavin B, chebulinic acid	48
Paeonia lactiflorapall	Oleanolic ,ursolic acid	49
Cornus officinalis	Gallotannins ,pentagalloylglucoses, 1,2,3,6-tetragalloylglucose, 1,2,6-trigalloyl-glucose, 1,2,3,4,6-pentagalloyl-glucose and 6-digalloyl-1,2,3-trigalloyl-glucose.	50
Senna auriculata	Pseudosemiglabrin ,(2S)-7,4'-dihydroxyflavan(4β→8)-catechin, and (2S)-7,4'-dihydroxyflavan(4β→8)-gallocatechin	51
Terminalia chebula	Ellagic acid, 2,4-chebulyl-β-D-glucopyranose, chebulinic acid, gallic acid, ethyl gallate, punicalagin, terflavin A, terchebi, luteolin, tannic acid, Chebulic acid is a phenolic acid,Luteic acid,terflavin B, tannins, chebulinic acid.	52
Opuntia monacantha	Gallic acid, vanillic acid , catechins, betalain, betanin, indicaxanthin	53
Punica granatum	Polyphenols, including the hydrolyzable tannins called ellagitannins, ellagic acid and/or gallic acid, delphinidin, cyanidin,pelargonidin glycosides.	54

DISCUSSION:

Most of the plants’ properties are related to antioxidant activity^54,55, which is mainly due to the presence of phenolic compounds^56-60. These phenolic compounds usually have antimicrobial and anticancer activities as well^61-64.

Studies have shown that the use of synthetic and chemical drugs may cause urinary tract and kidney disorders such as glomerular and vascular damage and tubular disorders, such as non-steroidal anti-inflammatory drugs (NSAIDs) and calcineurin inhibitors (CNIs), which may cause glomerular disorders and damage to the activity of renal glomeruli, and cisplatin are likely to affect renal tubules adversely, lead to cytotoxicity, and be associated with damage to these tubules^65-68.

According to studies, medicinal plants produce the most protective effects against renal damage caused by synthetic drugs probably due to the strong antioxidant properties and the presence of many active plant ingredients, including flavonoids and phenolic compounds. Therefore, there is a significant relationship between the components of the polyphenol in the extract and its antioxidant activity^69-73. Different experimental and clinical studies have shown that plants that have antioxidant activity can provide pathological conditions, especially for the treatment and prevention of life-threatening diseases such as diabetes^74-77 cancer^787,79, infection^80,81, and disorders of the urinary system⁸⁰. This property of the above cited medicinal plants may be due to their active ingredients and active flavonoids, such as apigenin, luteolin, isoquercetin, oleanolic acid, steroids, quercetin, total flavonoids and phenolics, gallic acid, rutin, saponin, nicotiflorin, isoquercitrin, kaempferol damascenone, choline, scopoletin, vanillic acid, salicylic acid, nicotinic acid, etc. Therefore, they produce inhibitory effects against many types of the cancer cells, including those in the kidneys and the bladder^53-73.

Medicinal plants have been demonstrated to fight the disorders of the urinary system, the bladder, the kidneys, and the liver as well as various infections in the body due to the presence of antioxidant compounds, bioactive compounds, phenols, flavonoids, and anthocyanins, making it possible to supply herbal drugs in complementary medicine. Therefore, these medicinal plants may be able to deal with these disorders due to containing phenolic compounds and inducing antioxidant and anti-cancer activities, and are most probably a good candidate for herbal drugs ^81-89. Medicinal plants have effects on infectious and noninfectious diseases due to active phytochemicals in them^85-89.

CONCLUSION:

In this study, medicinal plants used for the treatment and prevention of kidney and bladder diseases, urinary tract and urinary system disorders, kidney cancer and bladder cancer, and other disorders of the urinary system were addressed.

AUTHORS’ CONTRIBUTIONS:

All authors searched, studies, reviewed and contributed to the design of the research. All authors reviewed, commented and approved the final draft.

DECLARATION OF CONFLICTING INTERESTS:

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

ETHICAL APPROVAL:

In preparation of this review article we tried to consider all ethical issues.

Funding

No.

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Received on 24.11.2018 Modified on 20.12.2018

Research J. Pharm. and Tech 2019; 12(2):972-980.

DOI: 10.5958/0974-360X.2019.00161.6