The Great Healing Potential Hidden in Plant Preparations of Antioxidant Properties: A Return to Nature?

The application of chemicals in industry and agriculture has contributed to environmental pollution and exposure of living organisms to harmful factors. The development of new pharmaceutical agents enabled successful therapy of various diseases, but their administration may be connected with side effects. Oxidative stress has been found to be involved into etiology of numerous diseases as well as harmful action of drugs and chemicals. For some time, plant origin substances have been studied as potential protective agents alleviating toxicity of various substances and symptoms of diseases. The aim of the current review was to present the diversity of the research performed during the last five years on animal models. The outcomes showed a huge protective potential inherent in plant preparations, including alleviating prooxidative processes, strengthening antioxidant defence, ameliorating immune parameters, and reversing histopathological changes. In many cases, plant origin substances were proved to be comparable or even better than standard drugs. Such findings let us suggest that in the future the plant preparations could make adjuvants or a replacement for pharmaceutical agents. However, the detailed research regarding dose and way of administration as well as the per se effects needs to be performed. In many studies, the last issue was not studied, and in some cases, the deleterious effects have been observed.


Introduction
In the recent centuries, a great change of the conditions of the human life has taken place, due to the development of industry, agriculture, medicine, and pharmacy. The new synthetic substances were applied to protection of crops as well as successful therapy of various diseases. However, except for beneficial influence, consisting in numerous facilitations of human existence and extending human life span, negative effects have also occurred [1,2]. A growing pollution of natural environment, resulting from the industry development, has been observed for many years [3][4][5]. Despite the efforts aiming at alleviating and preventing this phenomenon, it still belongs to the most important problems to be solved by the mankind. The application of plant protection products has made another contribution to environmental contamination [6][7][8][9]. As it is not possible to improve the situation immediately, many people, i.e., industrial workers or farmers are still exposed to harmful substances like heavy metals [4,[10][11][12], organic chemicals (e.g., CCl 4 ) [13,14], or pesticides and plant growth regulators [8,15]. Another problem results from introducing plenty of new pharmaceutical agents. They allowed to relieve suffering of many subject and successive treatment in cases of mortal diseases. However, on the other hand, plenty of side effects have also been observed [16,17]. Analgesic and antipyretic drugs like acetaminophen or aspirin can induce liver and kidney damage [18][19][20][21][22]. The antineoplastic agents can cause severe disturbances like testicular damage [23], nephrotoxic [16,24], cardiotoxic [25,26], and hepatotoxic [27] effects. Antibiotics have also proved to show side effects including liver and kidney damage [28,29]. The widespread practice of using different additives to preserve and improve the taste of food makes another source of toxic action on human organisms [30]. The growing life span is connected with an increase in incidence of neurodegenerative disorders like Parkinson' disease [31] or Alzheimer's disease [32]. Furthermore, in the recent decades, obesity, hyperlipidemia, and connected disturbances have become a significant worldwide problem [33,34].
All the presented facts have made the scientists search for any agents which could exert protective effects against toxic environmental pollutants and chemicals used in industry and agriculture and replace the standard drugs or make beneficial adjuvants. The return to natural products, sometimes used for thousands years in traditional medicine, has become one of the significant directions of this research [35][36][37][38][39]. It could be stated, without any exaggeration, that "a great return to nature" is recently being observed. Plant extracts and plant origin substances per se do not show so many side effects as pharmacological substances. On the other hand, they contain numerous compounds of anti-inflammatory and antioxidative properties like polyphenolic derivatives and flavonoids [40][41][42]. The presented facts prompted large-scale research on possibilities of application of plant preparations as protective agents against toxicity of various substances as well as adjuvants alleviating the symptoms of diseases, obesity, and traumata [6,25,38,[43][44][45][46][47][48][49]. A great quantity of plant species have been investigated, and the obtained results seem to be very promising. Some studies have included the comparison of the investigated materials with standard drugs, and the outcomes suggest that in many cases the replacement would be possible [20,31,35,[50][51][52][53]. However, many questions remain to be solved as to the best way of treatment and the most beneficial dose.
Oxidative stress-the disturbed balance between generation of reactive oxygen species (ROS) and antioxidants' level in an organism-has been found to be involved, less or more, into the etiology of most diseases [54][55][56]. This process involves the generation of ROS, active particles capable of injuring all bioactive compounds-protein, lipids, and nucleic acids in an organism. Lipid peroxidation caused by ROS may lead to damage of membrane lipids. Living organisms developed a wide range of endogenous substances, both enzymatic and low-molecular ones, which can neutralize ROS. Negative effects resulting from stress, exposure to toxic substances, side effects of the standard drugs, or even food supplements have also been proved connected with prooxidative processes and deterioration of antioxidant defence [13,30,40,57,58]. Plant origin preparations, in turn, have been found to exert a strong antioxidant action due to high content of components of antioxidative properties. Numerous studies have revealed their direct influence on oxidative processes by reducing lipid peroxidation or protein carbonylation as well as increase in antioxidant enzymes' activities and low-molecular antioxidant concentrations [34,43,59,60].
Different pathways involved in oxidative and inflammatory processes have been found to be affected in the course of protective action of plant preparations.
The studies have shown the involvement of Nrf2 and Keap1 proteins. Nrf2 is regarded as a key transcription factor mediating the endogenous antioxidant response, and Keap1 is its negative regulator. Under oxidative stress conditions, Nrf2 is released and translocated to the nucleus where it binds to ARE regions in DNA and stimulates antioxidant enzyme gene expression. Both Nrf2 and Keap1 as well proteins regulated by Nrf2, responsible for defence against antioxidant stress like HO-1 and γ-GCS, have been found to be disturbed by harmful factors (cadmium or high-fat diet) and regulated by plant preparations [12,61]. Plant origin substances have been reported to cause upregulation of Nrf2, HO-1, and γ-GCS in both nonexposed and Pbexposed rats [62].
Another pathway connected with oxidative and inflammatory processes which have been proved involved into protective properties of plant preparations is NF-κB pathway. NF-κB is a transcription factor responsible for expression of proinflammatory cytokines [56]. Its activation can be triggered by TLR receptors, belonging to pattern recognition receptors. The inflammation and redox balance have been found to be strongly connected with each other [63]. Interleukins, γ-interferon and tumour necrosis factor, have been found to affect ROS production [64]. The involvement of the LPS-TLR4-NF-κB pathway into protective action of plant materials has been reported [56,65]. Other authors have stated that a protective effect of a plant extract, resulting from antioxidative and anti-inflammatory influence observed in diabetes animal model, could be attributed to inhibition of NF-κB activation [66].
Mitogen-activated protein kinases (MAPK) belong to enzymes which make mediators of various processes occurring in cells like death, proliferation, or differentiation. The MAPK pathway begins from a signal from an extracellular receptor and through a cascade of subsequent protein phosphorylation leads to activation of different proteins including transcription factors (e.g., p53 protein) and finally to the expression of genes. ROS have been proven to be connected with particular steps of the MAPK pathway. There are three kinds of MAPK in mammals: p38 MAPK, ERK1 (extracellular signal-regulated kinase 1), and JNK (c-Jun N-terminal kinase) [64,67]. The studies on plant revealed the influence of the studied plant materials on some elements of the MAPK pathway [42].
The next pathway connected with oxidative stress which has been found affected by plant preparations is the JAK/-STAT pathway. An outside signal, usually being a cytokine, binds to a membrane receptor resulting in its dimerization. The next stage is the activation of JAK which renders possible phosphorylation of receptor, which in turn enables STAT binding and phosphorylation. Activated by phosphorylation STAT is then translocated into the nucleus where it acts as a transcription factor [68]. The relationships between this pathway and ROS have been reported [69]. In the current study, disturbances of oxidative balance as well as bone marrow damage and reduction in pJAK2/JAK2 and pSTAT5a/S-TAT5a, caused by radiation exposure, have been found to be improved by a plant preparation, which made the authors suggest that the studied material can stimulate the JAK2/-STAT5a signal pathway [70].
The aim of the current review is to present the results of the studies performed in the last five years regarding the protective and medicinal properties of plant origin preparations with particular emphasis on their antioxidant action. 2 Oxidative Medicine and Cellular Longevity

The Protective Influence of Plant Preparations against
Chemicals Applied in Agriculture. The use of different chemicals in food production has been growing dramatically in the recent years, causing the contamination of the natural environment and increasing thread to human health. Neurotoxicity, hepatotoxicity, reproductive disturbances, and cancerogenesis belong to the negative effects exerted on organisms [6,8,15,71]. Moreover, chemicals of lipophilic character can be accumulated in membranes [9]. Enhanced generation of ROS was proved involved into their harmful influence [6,9,71]. Plant origin materials were revealed to show protective properties not only by strengthening the antioxidant barrier but also by reversing histopathological changes. A wide range of different materials was studied, including simple extracts [2,6,7] as well as commercial products [9,15]. The saponins from Tribulus terrestris, which were reported to possess antiaging action, were found to exert protective effects against rotenoneinduced parkinsonism [15]. The details concerning the above mentioned studies are presented in Table 1.

The Protective Influence of Plant Preparations against
Toxic Effects of Heavy Metals. Environmental pollution with heavy metals makes a great global problem. The most toxic ones are lead, cadmium, and mercury. Even low concentrations can cause severe disturbances of organism, including brain, hepatic, renal, and reproductive damage [10]. As their harmful action is connected with oxidative stress induction, plant extracts showing antioxidant properties were studied as possible protective agents and the obtained results were found to be promising [10,11], although the accumulation of a toxic metal could not be prevented in every case [62].
The ability of plant origin substances proanthocyanidins to prevent lead-induced hepatotoxicity was suggested to be connected with the Nrf2/ARE pathway (as an increase of mRNA expression levels of Nrf2 in the liver of mice administrated with proanthocyanidins and/or lead was observed) as well as with the reduction of endoplasmatic reticulum stress via a decrease in stress-related proteins GRP78 and CHOP [62].
In the experiments concerning the toxicity of mercury, plant extracts relieved the negative effects in the case of both an inorganic form (mercury (II) chloride) and organic one (dimethylmercury); at the same time, the beneficial influence included not only oxidant and immunological parameters but also histopathological changes [4,72,73].
Plant extracts were also found to exert wide protective effects against the third most dangerous heavy metal cadmium, with the results being confirmed by in vitro studies with using murine hepatocytes [3]. Additionally, an animal study showed the involvement of the Nrf2/Keap1 pathway into the protective action of Pyrantha fortuneana extract as the plant material, given both alone and coadministered with cadmium caused a significant increase in expression of Nrf2 and decrease in expression of Keap1 in the kidneys of rats vs. the control and Cd-exposed group, respectively [12].
Apart from lead, mercury, and cadmium the research concerning metals' toxicity included also liver injury caused by iron overload. 70% methanol extract of Drosera burmannii Vahl. showed a distinct, dose-dependent efficacy against iron-induced hepatoxicity. This effect, particularly in case of the highest dose, was comparable with that exerted by a standard drug desirox-an iron chelator. Additionally, the studied extract studied in vitro showed the ability to chelate Fe 2+ ions. Such findings made the authors suggest that the studied preparation might be used as a medicine in cure of iron overload-induced diseases [50].
The details concerning the above-mentioned studies are presented in Table 2.

The Protective Influence of Plant Preparations against
Various Chemicals. Plant origin substances, extracts and their particular fractions, essential oils, and seed powders were found to reverse or alleviate disturbances of organism resulting from exposure to different chemicals. The resent research included various compounds, e.g., hepatotoxic tetrachloromethane (CCl 4 ) used for years as a solvent and now regarded as an environmental pollutant [14], aluminium known for its neurotoxicity [74], aflatoxins produced by toxigenic fungi which made food contaminants [75], and chemicals used in industry and laboratory experiments like thioacetamide [76] or 1-chloro-2,4-dinitrobenzene [77]. Additionally, plant origin substances were proved to decrease mouse mortality resulting from the acute CCl 4 toxicity [78] as well as from Concanavalin A exposure [79]. Furthermore, several studies included the influence of plant materials alone, and generally, no harmful effects were observed [14,54,74,75,78,80,81].
The details of the performed studies are presented in Table 3.

The Protective Influence of Plant Preparations against
Carcinogens. Plant extracts were studied using animal model as for their possible application in tumour therapy due to the presence of anticancer and antioxidant components. The necessity of searching for new agents, suitable for tumour treatment, was challenged by the lack of effective chemotherapy and severe side effects associated with the used medicines. The obtained results seem to be promising as the studied materials alleviated carcinogen-induced oxidative stress as well as disturbances of immunological parameters [47,88,89]. Histolopathological studies confirmed the beneficial effects of the investigated preparations [46,89].
The detailed results of the performed studies are presented in Table 4.

The Protective Influence of Plant Preparations against
Ethanol. Alcohol excessive consumption and addiction leads to different negative effects: liver injuries including steatosis [56,91], brain damage [92], and reproductive system damage [93]. The disturbances of oxidative balance were suggested to be one of the factors underlying alcohol toxicity, which was confirmed by intensification of lipid peroxidation as well as   6 Oxidative Medicine and Cellular Longevity           deterioration of antioxidant barrier, observed in animals exposed to ethanol [44,56,91]. The involvement of oxidant stress into ethanol toxicity was also showed by Phunchago et al. [92] who observed the protective influence of antioxidant vitamin C. The studies presented in the current review proved that plant materials showed a wide range of protective actions including ameliorating of liver markers, oxidative parameters, and alleviation of histopathological changes [56,91,92]. The involvement of LPS-TRL4-NF-κB pathway was also been proved [56,65]. The detailed results of the performed studies are presented in Table 5.
2.6. The Protective Influence of Plant Preparations against Toxic Effects of Antipyretic and Analgesic Drugs. The application of antipyretic and analgesic drugs has been growing rapidly in recent years. Acetaminophen, known also as paracetamol, N-acetyl-p-aminophenol or APAP, a substitute of aspirin, is one of the most often used over-the-counter medicines. However, its application can cause severe hepatotoxicity, and this fact is all the more dangerous because of possible overdose resulting from self-administration [18,22,40,95]. Another side effect, connected with paracetamol application, is nephrotoxicity [22,40]. The harmful action of acetaminophen includes oxidative stress, particularly the depletion of GSH and protein sulfhydryl groups blocking [96]. Several studies revealed the possibility of plant extract application as protective adjuvants, wherein Moringa peregrine, Genista quadriflora, Teucrium polium geyrii, and Cassia surattensis showed the best influence which included not only amelioration of liver damage markers but also improvement of antioxidant parameters and reduction of the lipid peroxidation process [19,20,96].
The details concerning the mentioned investigations are presented in Table 6.

The Protective Influence of Plant Preparations against
Toxic Effects of Antibiotics. Not only are antibiotics used for the treatment of Gram-negative bacterial infection, but they also can cause side effects to occur [98,99]. Gentamycin belongs to those which are used in case of strains resistant to other antibiotics, but its application can lead to hepato and nephrotoxicity [28]. The similar properties are shown by an antibiotic polymyxin, whose application was ceased because of its nephrotoxicity, but an increased drug resistance of Gram-negative strains has rendered it being used again [99]. Oxidative stress as well as inflammation processes was suggested to take part in the development of the mentioned negative effects [29,98,99]. Materials obtained from plants containing antioxidant components and affecting immune functions were investigated as to their possible protecting application, and the results seem to be promising although they also pointed to the necessity of taking proper precautions and precise choosing the dose as in some cases the higher dose showed a better influence [29,98], while other authors reported quite opposite results [28].
The details concerning the above mentioned issues are presented in Table 7.

The Protective Influence of Plant Preparations against
Toxic Effects of Anticancer Drugs. Cancer successful therapy is often a great problem because of the side effects of the applied agents which include deterioration of reproductive proficiency [23], nephrotoxicity [16,100], and hepatotoxicity [37] and cardiotoxicity [26]. The results of the studies presented below clearly show that the toxic action of anticancer drugs is strongly connected with the prooxidative processes, deterioration of antioxidant barrier, and histopathological changes. The extracts of different plants, used as spices and drugs in traditional medicine for centuries, were studied for their protective potential [101]. Both simple extracts and particular fractions [25,26] proved their protective properties which included the amelioration of the disturbed oxidant parameters. Antioxidant and antiapoptotic properties of plant extracts were confirmed by in vitro investigations performed on renal tubular epithelia cells [100] and cardiomyocytes [25]. Histopathological changes were also found to be relieved by plant materials [16,23,24,26,102].
The details concerning the above mentioned issues are presented in Table 8.

The Protective Influence of Plant Preparations against
Side Effects of Various Drugs. Many drugs' administration is accompanied with numerous side effects which cause life complication and may negatively influence patients' compliance. These facts prompted the searching for any adjuvants reversing or at least alleviating side effects. Recently, a growing interest in plant origin substances, often those used in traditional medicine, is being observed [104,105]. The studies presented below revealed the effectiveness of plant extracts against toxicity of diverse drugs: psychiatric (lithium carbonate), thyrostatic (Propylthiouracil), and cardiac activity stimulators (Isoproterenol), a contrast medium (Iodixanol), and dermatological medicine (Triamcinolone acetonide). The negative influence of the studied drugs often included deterioration of antioxidant barrier [105,106]. The studied preparations showed beneficial effects, and in vitro studies confirmed their antioxidant potential [104,107].
The details concerning the above mentioned issues are presented in Table 9. Arthritis has recently become a serious, worldwide problem as this disease is related with pain and physical disability, and no effective therapy except for a surgery can be applied [49]. As the risk of it increases with age, the growing spam life contributes to the still enhancing incidence. Plant substances were found to prevent enhancement of the proinflammatory cytokines like IL-1β, IL-6, and TNF-α, involved into osteoarthritis pathogenesis of OA. Additionally, the reduction of metalloproteinases responsible for joint damage as well as upregulation of their inhibitors-TIMPs and extracellular matrix components-was observed [48,49]. Furthermore, plant origin substances were reported to reverse 15 Oxidative Medicine and Cellular Longevity oxidative parameters' disturbances, also taking part in osteoarthritis development [55].
The detailed outcomes of the performed studies are collected in Table 10.

The Protective Effects of Plant Origin Materials in
Cases of Neurodegenerative Disorders. The next type of disorders studied with using an animal model was neurodegenerative diseases. ROS have been reported to be involved in the development of Alzheimer's, Huntington's, and Parkinson's diseases. Extracts obtained from plants used in traditional Chinese and Ayurveda medicine, possessing numerous therapeutic properties and containing antioxidant components, were shown to exert a considerable beneficial influence [31,32,39].
Traumatic brain injury, regarded as a worldwide grave challenge being a cause of many death and disability cases, is considered to need an effective therapy. Water extracts of plant commercial products were revealed to show a beneficial influence on immunological and oxidative parameters [38,60].
Psychiatric disorders like anxiety or depression were also proved to be connected with neurodegenerative disturbances as well as changes of immunological and oxidative parameters which were alleviated by plant extracts [111,112].
The detailed outcomes of the performed studies are collected in Table 11.

The Protective Effects of Plant Origin Materials in
Cases of Animal Menopause Model. In menopausal women, the deficiency of sex hormones can lead to various disturbances of organism. The research concerning hormone replacement therapy showed that it can cause different side effects, so the attention was paid to nonpharmaceutical agents, all the more because plant flavonoids were proved to possess phytoestrogen properties [114]. In the performed studies, plant origin materials improved some elements of lipid profile and oxidative parameters deteriorated by ovariectomy [115]. Bone mineral density in rats was also ameliorated, although this effect became less distinct along with lengthening of the experiment [114]. However, in some cases, the obtained results were not so distinctly beneficial [116].
The details of the performed studies are collected in Table 12.

The Protective Effects of Plant Origin Materials in
Lung Disorders. Plant origin substances were shown to possess some efficacy against lung disorders, and the beneficial effect included the improvement of oxidative and inflammatory parameters, morphological disturbances, and factors controlling extracellular matrix functions and vascular homeostasis [117][118][119].
The details of the performed studies are collected in Table 13.

The Protective Effects of Plant Origin Materials in
Lipid Profile Disturbances. Lipid profile disturbance is associated with severe diseases like diabetes as well as hepatic and cardiovascular disorders [120]. It is rated among the main factors causing disability and death [34]. Factors which were used to induce such a condition were also found to cause intensification of prooxidative processes connected with deterioration of antioxidant defence and DNA damage. Plant preparations proved to display beneficial effects, although only in one case per se influence was studied [120].
The detailed results of the performed studies are collected in Table 14.
2.10.6. The Protective Effects of Plant Origin Materials in Ischaemia/Reperfusion Model. Ischaemia/reperfusion damage is a serious problem which can occur as a consequence of surgery, e.g., transplantation or coronary bypass, and may lead to severe injuries, resulting among other things from increase in ROS generation. Pretreatment with plant materials, obtained from species used in traditional medicine, was found to be effective against prooxidative processes and histopathological changes observed in ischaemia/reperfusion animal model [123][124][125][126].
The detailed results of the performed studies are collected in Table 15.

The Protective Effects of Plant Origin Materials in
Animal Model Diabetes. Plant origin substances were observed to be effective at reversing disturbances observed in the course of diabetes. A wide range of agents was studied, simple extracts, combinations of two extracts as well as an oil, banana pasta or substances separated from plant material. A great variety of species was investigated, including herbs, fruits, or vegetables. Many of them had been known as being useful in different fields of medicine, sometimes from ancient times [66,[127][128][129]. In several studies, biochemical, oxidant, and inflammatory parameters in the blood and organs including the lens, brain, liver, pancreas, kidney, and heart were found considerably improved or restored by different materials [42,57,66,128,129]. Histopathological investigation revealed that plant preparations showed a considerable ability to attenuate pancreas, kidney, and liver damage observed in the animal model of diabetes [127,128,130]. The beneficial influence of plant extracts on the deterioration of sperm quality [131], diabetes-associated cataract, and retinopathy and an ability to suppress MAPK signal transduction [42] and the amyloidogenic pathway [57] were reported. However, there are limitations of these investigations as in most of them the effect of the applied plant substance was not studied.
The detailed results of the performed studies are collected in Table 16.

The Protective Effects of Plant Origin Materials in
Animal Model of Obesity. Plant origin preparations were also investigated as to their potential to prevent pathological processes connected with obesity. This direction seems to be of great importance as obesity and related disturbances, resulting from sedentary lifestyle as well as excessive consumption, are becoming more and more serious world problem [132,133]. Diet-induced obesity was found to be connected with different disturbances of various parameters including liver markers and lipid profile as well as inflammation, lipogenesis, and oxidative balance. The performed research revealed 16 Oxidative Medicine and Cellular Longevity

18
Oxidative Medicine and Cellular Longevity  The protective effect was better for the higher dose.

20
Oxidative Medicine and Cellular Longevity

24
Oxidative Medicine and Cellular Longevity

26
Oxidative Medicine and Cellular Longevity

30
Oxidative Medicine and Cellular Longevity

32
Oxidative Medicine and Cellular Longevity       [61] and the ameliorating effect on lipid status [132,133]. The latter was also confirmed in vitro as the lipolysis-promoting influence in 3T3-L1 cells was observed [61]. In mice fed a high-fat diet, coadministration of Euterpe oleracea extract reversed the changes of lipogenic proteins expression in the liver. Additionally, the investigated preparation increased hepatic expression of ABCG5 and ABCG8 transporters responsible for removing excess of cholesterol by secretion into bile [43].
The detailed results of the performed studies are collected in Table 17.

The Protective Influence of Plant Preparations against
Gastric Ulcer-Inducing Factors. The gastric ulcers are regarded as the most common disease of gastrointestinal tract, but they can be caused by many various factors. Therapy of different disorders with using nonsteroidal antiinflammatory drugs like indomethacin and excessive consumption of alcohol belong to important ones [45,134]. As pharmaceutical agents are not fully effective and their application may also be connected with development of side effects, an alternative ways of treatment became the subject of research. Plant origin substances showed a wide range of beneficial effects, including alleviated or reversed oxidative stress which was found to be involved into gastric ulcer etiology as well as mechanism of indomethacin toxicity [135][136][137].
The detailed results of the performed studies are presented in Table 18.  [36,41,138]. A wide range of diseases: lithiasis, thyroid disorders, retinal degeneration, irritable bowel syndrome, hyperthyroidism, periodontitis, and mammary gland hyperplasia, were studied, pointing to great possibilities "hidden" in plant origin agents.
The details of the performed studies are presented in Table 19.

The Protective Effects of Plant Origin Materials against
Radiation. Plant extracts also showed some efficacy against radiation-induced damage. The research revealed the involvement of JAK-STAT pathway into the mechanism of the protective influence on the hematopoietic system [70]. Animal studies also showed the reversing effect of plant material on the disturbances of antioxidant defence caused by γ-radiation in blood and organs [145,146]. One of the recent in vitro investigations, performed on keratinocyte cells, confirmed the antioxidant action of a plant preparation against UVB radiation, which could contribute to development of new skin protective strategies [147].
The details of the performed studies are presented in Table 20.

The Comparison of Plant Preparations with Standard Drugs and Supplements: The Dependence of Effects on Treatment Way and Doses
The effects of plant origin materials were often investigated in comparison with those shown by standard drugs. The results clearly show that there may be a possibility to replace different medicines with plant preparations which do not cause so many severe side effects, but the detailed research must be performed before the final conclusions can be made. The question of advantage of plant origin extracts over any standard drug is complicated, and a univocal answer is very difficult as in some cases the differences in the influence of the compared agents were strongly dependent on the applied dose [45,135] and studied parameters [115,129].
Hamm et al. [116] found that hops (Humulus lupus L.) flavonoid-rich extract protected against ovariectomyinduced visceral adiposity and increase in liver triglycerides observed in 7-month-old retired breeder C57BL/6 mice. However, particularly in case of the former parameter, the observed effect was not so distinct as that noted in animals receiving 17-β-estradiol. Additionally, hops extract could not prevent the loss of uterus weight caused by the surgery while estrogen showed quite a considerable reversing effect.
Leung et al. compared the effect of black tea extract with that exerted by estrogen in ovariectomized rats. The results were characterized by a considerable diversity. In case of body weight reduction, estradiol's benefit influence was much better. In contrast, aortic cGMP and serum TC and peNOS, NOX2, NOX4, and ROS generation in the aorta were affected in similar or even entirely the same way by both agents. Additionally, in case of serum TG the plant materials proved to possess much better ability to restore the values observed in sham-operated control animals [115].

The Comparison of Crude Extracts and the Particular
Substances Separated from Plant Materials. The plant extract can show better properties than particular compounds administered alone as there may occur some synergistic effects among its components. Such an assumption could be supported by the results reported by He et al. [148] who compared the influence of Paeonia suffruticosa seed extract and 10 compounds (oligostilbenes) isolated from it with using an in vitro IL-1β-induced osteoarthritis model. In the study performed on rabbit chondrocytes, IL-1β caused a significant decrease in viability and 10 studied components used alone showed an improving effect, but the intensity of this effect was markedly different, depending on the structure. However, the application of the extract containing all the oligostilbenes showed the best effect, comparable with that observed for diacerein-a drug of IL-1β-inhibition action, used in osteoarthritis therapy. Such results made the authors suggest the possibility of synergism among the particular oligostilbenes.

Plant Preparations as Lipid Profile Regulating Agents -
The Comparison with Standard Drugs. Plan preparations were studied in regard to the possibility of their application 36 Oxidative Medicine and Cellular Longevity

38
Oxidative Medicine and Cellular Longevity         as lipid profile normalizing agents, and the results seem to be auspicious [120][121][122]. Additionally, the researchers performed comparisons with standard drugs. The outcomes showed that the efficacy of plant material needs not be worse than that showed by acknowledged pharmaceutical agents. However, it should be emphasized that the final effects may be different, depending on the applied dose. Veber et al. [34] compared the effects of two doses (125 or 250 mg/kg) of aqueous extract of red cabbage with that showed by fenofibrate, a drug used in therapy of abnormal lipids in the blood, on oxidative stress parameters in rats with hyperlipidemia caused by Triton WR-1339. Although the higher dose proved to possess protective properties generally comparable with the drug, the lower one in some cases showed no efficiency.
Erica multiflora L. leaf methanolic extract (150 or 250 mg/kg) effect was studied in rats with Triton WR-1339induced hyperlipidemia in comparison with fenofibrate taking into account chosen lipid and antioxidant parameters. The higher dose showed comparable or even better protective action than the medicine. In contrast, total DNA damage was alleviated much better by the used drug [120].
Onyenibe et al. [122] investigated the efficiency of two doses of Monodora myristica aqueous extract as a protective agent in case of deterioration of lipid profile and oxidative parameters in hypercholesterolemic rats and compared the obtained results with those noted for a standard drug Questran. The authors found that generally two doses of plant preparation, namely, 100 and 200 mg/kg b.w., showed a better influence.
The effects of lipid-lowering drugs simvastatin and ciprofibrate as well as aqueous extract of Campomanesia adamantium O. Berg root were compared in rats with high-fructose diet-induced hyperlipidemia. The plant material exerted the entirely comparable influence in case of lipid parameters and even better as regards body weight gain lowering [121].

The Comparison of Plant Extracts of Hepatoprotective
Properties with Pharmaceutical Agents. Liu et al. [51] compared the protective action of pretreatment with Sonneratia apetala fruit water extract (100,200, and 400 mg/kg) against hepatic damage caused by acetaminophen in mice with the effect of an acknowledged antidote NAC (N-acetyl-L-cysteine). The scientists observed the protective influence of plant preparation, which was not only comparable but in some cases better-particularly for serum ALT and AST as well as hepatic lipid peroxidation, antioxidant enzymes, TNF-α, and IL-6.
Similarly, the rich polyphenol fractions of methanolic extracts of Genista quadriflora Munby and Teucrium polium geyrii Maire showed a protective effect against hepatoxicity of acetaminophen (APAP) and the comparison with N-acetylcysteine showed their comparable properties with the drug, except for histological changes where Teucrium polium geyrii Maire exerted a better influence than two other studied agents [20].

The Comparison of Plant Extracts with Silymarin, an
Acknowledged Dietary Supplement of Hepatoprotective Properties. Many drugs and chemicals are distinguished by their hepatoxic effects. In view of the increasing environmental pollution as well as more and more common application of different drugs, often over-the-counter ones, the protective agents are highly desirable [18]. Silymarin, a preparation obtained from Silybum marianum L., has been used as a hepatoprotective adjuvant for years. Currently, the attention has been pointed to other plants, often those used since antiquity in traditional medicine [44]. Different hepatotoxicity animal models were used to perform comparison with silymarin.
The possibility of replacing silymarin by an extract of Cassia fistula L. leaves was studied by Kaur et al. [35] in rats exposed to thioacetamide. The studied extract was applied at three doses (50, 100, and 200 mg/kg b.w.), and beneficial effects of the two higher ones were not worse than those observed in rats receiving silymarin.
The similar observations were reported by Fahmi et al. [53] who compared the protective properties of dietary ginger against diethylnitrosamine hepatotoxicity in rats with those showed by silymarin and found that the studied material in the form of ginger powder or essential oil exerted the same or even better beneficial action.
Choi et al. [46] studied the possibility of Centella asiatica leaf ethanol extract (100 or 200 mg/kg) using as a protective agent against dimethylnitrosamine-induced hepatotoxicity in rats. The authors determined different inflammatory cytokines and mediators, liver injury markers, oxidant parameters, and histophological changes. In some cases (liver histology, serum IL-1β, TNF-α, and IL-2), both doses of the extract showed a better action than silymarin. In case of AST, ALP, IL-6, and INF-γ or liver MDA, both agents displayed the similarly significant properties. Furthermore, liver antioxidant enzymes were best ameliorated by the higher dose of plant preparation.
El-Hadary and Ramadan [52] in turn stated that Moringa oleifera leaf extract displayed protective properties against hepatotoxic action of diclofenac sodium. The comparison with silymarin proved that the plant preparation exerted comparable or even better effect.
Ahmad and Zeb [18] in turn compared an effectiveness of silymarin and different doses of water extract of Trifolium repens leaves against acetaminophen-induced hepatoxicity in mice. The authors reported that in case of most studied hematological, serum biochemical, and liver oxidative parameters, the effect of the highest dose was not worse than that shown by silymarin.
However, the comparison of protective action of leaf extract of Solanum surattense with that observed for silymarin in CCl 4 -exposed rats revealed that the latter had entirely better effect regarding liver injury markers and lipid profile in serum as well as lipid peroxidation process in the liver [83].
On the other hand, Dogan and Anuk [44] observed that in ethanol-exposed rats water extract of leaves of Platantus orientalis L. generally showed the protective effects comparable or even better than those observed in silymarin-given animals. Interestingly, in case of some parameters, both silymarin and extracts showed insufficient effectiveness. 43 Oxidative Medicine and Cellular Longevity The possibility of applying a plant extract as an adjuvant which could augment an action of an acknowledged agent was also studied on an example of silymarin. Azim et al. [19] investigated effects of silymarin alone, Moringa peregrina leaf extract alone, and coadministration of those substances in rats subjected to acetaminophen. Generally, as regards plasma liver injury markers and oxidative parameters, the protective influence of all three treatments was found to be practically complete, but in some cases, the combination of both agents exerted the best effect. Interestingly, DNA damage was most markedly alleviated by plant extract alone while silymarin showed the slightest efficacy.
3.5. Immunosuppressive and Anti-Inflammatory Drugs vs. Plant Preparations. Pistacia weinmannifolia root extract was compared regarding anti-inflammatory effects with roflumilast-a drug used in the therapy of lung inflammatory disorders, in mice with pulmonary inflammation induced by cigarette smoke and lipopolysaccharide. The results of the experiment showed that the studied preparation possessed protective properties absolutely comparable with the applied medicine [149].
Sundaram et al. [55] studied the protective effect of guggulipid (an extract from Commiphora whighitii gum resin) against morphology changes, cartilage degradation, and prooxidative processes in rats with experimental arthritis. Along with the evaluation of the plant preparation properties, the authors performed the comparison with a standard nonsteroidal anti-inflammatory drug ibuprofen. The influence of the studied extract proved to be comparable or even much more effective, particularly in cases of hematological and oxidative parameters.
In a study performed on mice subjected to 1-chloro-2,4dinitrobenzene with the aim of inducing atopic dermatitislike skin lesion, the effect of Rumex japonicus Houtt. root extract was compared with the efficacy of a synthetic glucocorticoid dexamethasone. The alleviation of the disease severity caused by the topical application of the plant extract was not much worse (particularly in the case of the higher dose) than that observed in animals treated intraperitoneally with dexamethasone [77].
Kaveh et al. [117] in turn compared the influence of different doses of hydroethanolic extract of Portulaca oleracea with that exerted by dexamethasone in rats with experimental asthma. According the authors, the effect of the highest dose (4 mg/mL in drinking water) was comparable with the drug. However, the lowest dose (1 mg/mL in drinking water) in some cases showed no beneficial influence.
In some cases, the pharmaceutical agents showed a better effect. Sdayria et al. [41] reported that in mice with carrageenan-induced paw edema pretreatment with a nonsteroidal anti-inflammatory drug indomethacin or Euphorbia retusa methanol extract showed comparable effects concerning % edema inhibition, although indomethacin displayed a little better properties. However, in case of oxidant parameters in the liver and paw, the drug exerted more distinct beneficial influence.
In the experiment performed by Jeong et al. [48], a nonsteroidal anti-inflammatory drug celecoxib proved to be much better in reversing the changes of biochemical parameters observed in rats with monosodium iodoacetate-induced osteoarthritis than a water extract of leaves of Morus alba L. Histological examinations confirmed the drug advantage.

Standard Drugs vs. Plant Preparations in Stomach Ulcer
Animal Model. Sattar et al. [137] performed a comparison of protective action of Myristica fragrans extract and sucralfate (a drug used for stomach ulcer treatment) in rats with ethanol-induced gastric ulcers. Although the plant preparation was not so effective with regard to amelioration of total acidity of stomach contents as well as macroscopic evaluation of gastric mucosa, ulcer index, and percentage of protection, its application did not cause serious increase in pH of stomach content as sulfacrate (4.25 vs. 5.0).
On the other hand, Biebersteinia multifida hydromethanolic extract showed a quite comparable or better protective effect than another drug-namely, omeprazole-in cases of gastric ulcers caused by 75% ethanol in rats. This effect included a decrease in ulcer area and number as well as enhancement of total antioxidant capacity in gastric mucosa [134].
Ateufack et al. [150] compared the effect of Piptadeniastrum africanum stem bark aqueous and methanol extracts (125, 250, or 500 mg/kg) in rat gastric ulcer induced by the HCl/ethanol mixture, indomethacin, and acetic acid with that showed by standard drugs (Maalox, Misoprostol, or Ranitidine). Plant extracts, particularly aqueous one when applied in the highest dose, displayed the protective action even better than the investigated drugs in case of animals exposed to HCl/ethanol mixture or indomethacin, but not in those treated with acetic acid.
Rtibi et al. [135] reported that in rats exposed to ethanol, pretreatment with Ceratonia siliqua L. aqueous extract (500, 1000, and 2000 mg/kg b.w.) showed a better or comparable effect with the standard drug famotidine when applied at the highest dose, while the lowest one was found to be either less effective or even ineffective at all.
The interesting results were reported by Chanda et al. [45]. The scientists studied the possibility of using Paederia foetida Linn. leaf methanol extract (100 and 200 mg/kg b.w.) as a gastroprotective agent in rats with gastric ulcers induced by indomethacin-pylorus ligation, alcohol, or water immersion stress. The effects were compared with those obtained for standard drugs ranitidine, sucralfate, and lansoprazole, respectively. As concerns ulcer protection, in the first and third models, there were no distinct differences between the plant material (particularly the higher dose) and the applied drug. In contrast, in the second model, the higher dose of extract showed much better effectiveness than the lower one, but nonetheless not so high as sucralfate.

The Comparison of Plant Preparations with
Cytoprotective Adjuvants Used in Radio and Chemotherapy. The advantage of plant origin substances over drugs was also shown by Dong et al. [70]. Ethanol extract of JXT (a traditional herb obtained from the Spatholobus suberectus Dunn dry rattan) given orally to mice caused a significant improvement of the biochemical parameters previously disturbed by 44 Oxidative Medicine and Cellular Longevity 60 Co γ-radiation, i.e., morphology, bone marrow cell number, and liver lipid peroxidation level as well as activity of antioxidant enzymes. This effect was comparable or better than that exerted by amifostine, an agent applied in cases of radiation syndrome during radiotherapy.

Plant Preparations vs. Drugs and Supplements Applied in
Neurological and Psychiatric Disorders. Pharmaceutical agents used for the treatment of psychiatric and neurodegenerative disorders may cause side effects worsening the condition of patients. Plant preparations, often used for centuries in traditional medicine, have been found to possess anxiolytic and antistress properties, and the comparison with acknowledged drugs and supplements showed their comparable efficacy [17,58]. Plant materials, namely, extracts from two Hypericum species, were studied with regard to their effect on oxidative stress and inflammatory cytokines in an experimental anxiety animal model. The comparison with pure quercetin and a control drug alprazolam was also performed. In most cases, the disturbed brain parameters were positively influenced in a comparable or more distinct way by plant materials than by two other studied substances. It should be emphasized that in some cases the worst effect was observed in animals treated with alprazolam [17].
Almeida et al. [58] compared the protective effect of Clitoria ternatea extract with that shown by cotreatment with dietary supplements choline and docosahexanoic acid against brain oxidative stress caused by separation from mothers in rat pups. During 30-day experiment including the stressing factor and treatments as well as during the subsequent 330-day follow-up, both agents revealed comparable properties regarding the prevention of lipid peroxidation increase and thiol group content depletion.
Chonpathompikunlert et al. [31] compared the neuroprotective effect of Apium graveolens L. extract with that showed by a standard drug Tidomet Plus in an animal model of Parkinson disease. The efficacy of two doses (250 and 375 mg/kg b.w.) proved to be quite comparable (the lower one) or even better (the higher one) with the medicine as regards improvement of behavioral performance, oxidative parameters, and activities of monoamine oxidases A and B.
3.9. Antidiabetic Drugs vs. Plant Preparations. The possibility of plant preparations application in diabetic subjects was also studied. It was prompted by side effects occurring in patients treated by pharmacological agents. The outcomes seem to be promising although in view of the reported results the accurate research is needed to determine mechanism of action and the most beneficial dose [66,127].
Khanra et al. [129] stated that Abroma augusta L. leaf methanol extract (100 or 200 mg/kg) was not so efficient at reversing the serum parameters disturbed in rats by type 2 diabetes course, particularly in the case of the lower dose, as a standard drug glibenclamide. However, in the case of alleviating DNA fragmentation, ATP level, chosen oxidant parameters, and expression of NF-κB in the kidney and heart, the prevalence of the drug was not so distinct.
The comparison of glibenclamide and methanolic extract of Caralluma europaea was performed by Dra et al. [127] on diabetic mice. The higher dose of plant material (500 mg/kg b.w.) was better effective in the reduction of blood glucose than a drug, beginning from the 4 th hour after administration, while a lower one (250 mg/kg b.w.) showed a comparable effect. Additionally, according to the authors, the lower dose showed a more distinct beneficial influence in case of histopathological damage observed in diabetic animals.
The similar results were obtained by Du et al. [66] who compared the protective properties of a standard drug metformin hydrochloride and different doses (100, 250, and 500 mg/kg) of polysaccharide separated from Lycium barbarum in the rat model of diabetes induced by high-fat diet +streptozotocin. Metformin showed a better effect in case of fasting blood glucose and INF-α. As for insulin and ICAM-1, the highest dose of plant origin material proved to possess better ameliorating properties, while serum GPx was more improved by two higher doses.
Balbaa et al. [57] investigated the differences in effects of administration of Nigella sativa seeds oil, standard drugs metformin and glimepiride, and their combinations to diabetic rats. The oil had a better protective action when administrated alone than in combination with metformin or glimepiride against oxidative stress and neuroinflammatory cytokines' increase. When the results of administration of those three agents alone to diabetic rats were compared, the best properties of a plant material were also confirmed.

Plant Extract or a Single Substance of Antioxidant
Properties? As beneficial effects of plant preparations were attributed to their antioxidative properties, some researches performed the comparisons with simple substances of acknowledged antioxidant character. The results showed that plant materials could exert a better influence due to the presence of many component which might cooperate with one another.
Jahan et al. [72] studied the possibility of application of Chenopodium album Linn. seed extract as a protective agent against the damage of reproductive functions caused by mercury exposure. They compared the effect of the plant extract with that showed by a known antioxidant vitamin C which was reported to exert beneficial influence on male fertility. Except for plasma cholesterol and triglycerides as well as GST and TBARS in testicular tissue, the benefit influence of the studied plant material was comparable or even better. The similar observations were reported as regards the testicular morphometric parameters.
The comparison of the protective influence of Nigella sativa extract and vitamin E against cisplatin nephrotoxicity was performed by Hosseinian et al. [16]. The cisplatininduced negative changes, i.e., renal damage and thiol group decrease, and lipid peroxidation enhancement in the serum and kidney, were alleviated in a rather comparable way, except for serum thiols, where the prevalence of plant extract was indisputable.
The effects of two Hypericum (H. maculatum and H. perforatum) species extracts on oxidative stress and inflammatory cytokines were studied in an experimental anxiety animal model and compared with pure quercetin. The beneficial influence of plant extracts was mostly comparable and in many cases better, particularly in the case of Hypericum maculatum [17]. Such results could point to synergistic action of various components of extracts, acting as confirmation of the conclusions made by He et al. [148].
3.11. The Action of a Plant Preparation Depending on Its Dose, Time and Form of Treatment 3.11.1. The Relationships between the Dose and the Effects. In many studies, the protective effects of plant extracts and constituents showed a direct dependency on the used dose [15,29,31,56,80,107,117].
However, sometimes, the similar effects were observed for a considerable wide range of the applied doses. Liu et al. [91] studied an effect of various doses (0.0625, 0.125, 0.25, 0.5 g/kg b.w.) of ginseng oligopeptides against ethanol toxicity, and the observed differences were quite slight considering the size of the applied range.
Malik et al. [39] performed a study on animals with Huntington's disease like symptoms and observed practically the same influence of two different doses (100 and 200 mg/kg) of Celastrus paniculatus seed ethanol extract on memory functions, locomotor activity, and oxidative parameters in the brain parts.
The relationships between used doses and an exerted influence were also studied in the experiment concerning the protective properties of water extract of Sonneratia apetala fruit against liver damage caused by acetaminophen exposure in mice. The effects of pretreatment with different doses (100,200 and 400 mg/kg) were very interesting as in the case of some parameters a strong dose dependency was observed (e.g., liver GSH and MDA), while some other ones were affected in the same way, regardless of the applied dose (liver GSH, T-AOC, and TNF-α) [51].
In another study, Wang et al. [119] investigated the protective properties of two doses (4.6 or 14 g/kg b.w.) of aqueous extract of Salvia Miltiorrhiza Bge. f. alba in the monocrotaline-induced animal model of pulmonary hypertension. Various parameters were studied: mean pulmonary artery pressure, right ventricular systolic pressure, pulmonary artery remodelling, plasma vasoactive factors NO, 6-Keto-PGF1α, ET-1, and TXB 2 , and lung TGF-β1, but the observed differences were not as considerable as one could expect taking into account the difference between the applied doses.
The similar observations were reported by El-Hadary and Ramadan [52] who studied two doses of Moringa oleifera leaf extract (150 and 300 mg/kg b.w.) against hepatotoxicity of diclofenac sodium. Both doses displayed protective properties, but again, the difference between them was not so great as one could predict considering their range.
Onyenibe et al. [122] studied the efficacy of two doses of Monodora myristica aqueous extract at preventing impairment of lipid profile and oxidative parameters in hypercholesterolemic rats and generally found no difference between 100 mg/kg b.w. and 200 mg/kg b.w.
Such results point to the necessity of complex research of any possible protective agent with using a wide range of doses. The issue of dependency between the used dose and its effects proved to be additionally complicated as not always a direct relationship was found. The effects of different doses were sometimes divergent as in the experiment performed by Khan et al. [88], who studied the influence of two doses 0.5 g/kg b.w. and 1.0 g/kg b.w. of ajwa dates (Phoenix dactylifera L.) water extract on the biochemical parameters in rats with diethylnitrosamine-induced liver cancer. The lower one in some cases showed even a harmful effect (potentializing the changes caused by the carcinogen), while the higher one showed considerable protective properties. Additionally, the lower dose effect was characterized by a significant diversity as apart from showing the above-mentioned harmful influence, it also exerted a beneficial action, ranging from slight to strong.
In some cases, the higher dose had the worse effect than a lower one. In the study performed by Omole et al. [26], concerning the possible use of pretreatment with kolaviron (a mixture of flavonoids obtained from Garcinia kola seeds, 200 or 400 mg/kg/d) against toxicity of cyclophosphamide, the higher dose proved to be less beneficial, not only exerting less protective properties but also causing a slight increase in lipid peroxidation in the heart tissue.
The similar observations were reported by Apaydin Yildirim et al. [28] who studied the influence of Helichrysum plicatum DC. subsp. plicatum extract (100 or 200 mg/(kg·d) against nephrotoxic as well as hepatotoxic effects of gentamicin in rats. The authors stated that the higher dose showed much less beneficial influence. Additionally, the higher dose exerted some harmful effects, particularly regarding histopahological changes, when administered alone.
In some studies, it would be really very difficult to decide which dose should be chosen for usage. In the experiment performed by Wattanathorn et al. [42], the beneficial influence of the combination of extracts of Mangifera indica L. and Polygonum odoratum L. against diabetes cataract and retinopathy was distinctly showed, but the effect of different doses (2, 10, or 50 mg/kg b.w.) was found to be highly diverse.
Phunchago et al. [92] studied the possible protective effect of Tiliacora triandra water extract against ethanolinduced hippocampus damage in rats. The authors compared three doses: 100, 200, and 400 mg/kg b.w., and found that the middle one showed the best influence in improving some studied parameters while in few cases the worst influence was found for the highest one.
3.11.2. The Relationships between the Period of Treatment and the Effects. The period of the treatment with the studied substances also proved to be a factor of importance. Xu et al. [60] investigated the effect of Rhubarb extract on the oxidative parameters in rats with traumatic brain injury. According to the reported results, the degree of improvement in lipid peroxidation intensity as well as antioxidants levels showed a dependency on the time of experiment. The animals sacrificed after a longer period, starting from surgery and plant material treatment, showed a better amelioration of the studied parameters. Materials and Their Effects. As plant extracts contain many active substances of different solubilities in various solvents, the way of the preparation of the used substances also proved to be an issue of importance.
Malik et al. [39] studied the fractions of Celastrus paniculatus seed ethanol extract, obtained by suspending it in water and sequential partitioning with using petroleum ether, ethyl acetate and n-butanol. These materials were investigated as to their ability to ameliorate the neurotoxic effect of 3-nitropropionic acid by reversing changes of oxidative parameters in striatum and cortex of experimental rats. In the case of improvement of enhanced MDA and nitrites as well as decreased CAT, SOD, and GSH, ethanol extract and aqueous fraction proved to be the most effective; the petroleum ether fraction showed much less efficacy while n-butanol and ethyl acetate ones practically none.

Treatment of Pretreatment?
The way of treatment, i.e., pre or post, in some cases was shown to be a crucial factor influencing the observed effect to a considerable degree. Afsar et al. [23] studied the effects of ethyl acetate fraction of Acacia hydaspica methanol extract against cisplatin toxicity and observed that the protective influence observed in the case of posttreatment started concomitantly with cisplatin and continued for five days was decidedly less distinct than that of 15-day pretreatment combined with posttreatment.
On the other hand, some authors did not report any differences between the mentioned two ways. Khattab et al. [146] did not observe any differences between pre-and posttreatment with Borago officinal L. seed oil in rats exposed to γ-radiation.
The similar effects were observed by Nasri et al. [109] in rats subjected to a contrast medium iodixanol and 70% ethanol green tea extract. The plant agent alleviated iodixanol-induced histopathological kidney changes, but no significant differences between pre-and posttreatment were observed.
Hosseinian et al. [16] studied the possible protective effect against cisplatin nephrotoxicity of Nigella sativa extract (100 and 200 mg/kg) using the design, whereby two ways of administration were applied-pretreatment alone or with the addition of posttreatment. The outcomes were really interesting. In case of renal SH groups and tissue damage as well as serum SH groups and MDA plant material proved to possess beneficial effect, regardless of the way of administration.

The Effects of Plant Preparations Per Se
The fact that generally effects of plant preparations per se were observed occasionally makes the considerable limitation of the studies presented in the current review. Only a few scientists reported observations considering any influence of the studied materials. Sheweita et al., for instance, investigated the effects of application of essential oils of Foeniculum vulgare (fennel) Miller seeds, Cuminum cyminum L. (cumin) seeds, and Syzygium aromaticum L. (clove) flower and reported that the used oils themselves caused several beneficial effects like decrease in liver TBARS as well as enhancement of liver antioxidants [101].
El-Kashlan et al. [143] found the decrease in lipid peroxidation as well as reinforcement of antioxidant defence in rats receiving commercial date palm pollen.
El-Rahman et al. [110] reported alleviation of prooxidative processes as well as the increase in antioxidants in rats given Saussurea lappa root extract.
Furthermore, the beneficial influence of plant preparations included not only improvement in biochemical parameters. Sheng et al. [33] reported that, apart from positive effect on body and adipose tissue weight and insulin sensitivity, liver, and kidney functions, addition of mulberry leaves powder to diet also caused amelioration of microbiota community structure in gut of obese mice.
Balbaa et al. [57] investigated the differences in the effects of administration of Nigella sativa seeds oil, antidiabetic drugs metformin and glimepiride, and their combinations to rats. In some cases, the plant oil per se showed the least or no negative effect in nondiabetic rats when compared to medicines. The reduction of brain β-amyloid-42 as well as the increase in antioxidants' level was observed. On the other hand, brain lipid peroxidation was found to be enhanced.
However, some authors reported the negative effects of plant preparations on experimental animal organisms.
In one of the recently published articles, Nahdi et al. [151] observed that leaf Hypericum humifusum aqueous (200 or 400 mg/kg b.w.) and methanolic (10 or 20 mg/kg b.w.) extracts, given to rats, induced histopathological changes as well as impaired biochemical parameters including an increase in WBC, liver MDA, plasma ALT, AST, and LDH. Additionally, activities of hepatic antioxidant enzymes CAT and SOD were markedly decreased vs. control with no treatment. Interestingly, in case of the aqueous extract, the worse effect was exerted by the lower dose while the methanolic one was found to be more harmful when given in the higher dose.

Conclusions
The outcomes of the studies presented in the current review showed a huge potential inherent in plant preparations. They were revealed to reverse or alleviate toxicity of different factors, side effects of drugs, and symptoms of various diseases. In many cases, they were proved to be comparable or better than standard drugs which let us suggest that in future the plant origin substances could make a replacement for pharmaceutical agents. However, the presented above results of some experiments point to the fact that the proper precautions must be undertaken before applying any plant material. The detailed research regarding the per se effects, dose, and way of administration needs to be performed. Sex hormone-binding globulin SOD: Superoxide dismutase SPF: Specific pathogen free Srebf1: Sterol regulatory element-binding transcription factor 1 SREBP-1c: Sterol-regulatory-element binding protein-1c STAT: Signal transducer and activator of transcription T: Testosterone T-AOC: Total antioxidant capacity TAS: Total antioxidant status TBARS: Thiobarbituric acid reactive substances TC: Total cholesterol TG: Triglycerides TGF-β: Transforming growth factor beta tHcy: Total homocysteine TIMP: Tissue inhibitor of metalloproteinases TLC: Total leukocytic count TLR: Tall-like receptor TNF-α: Tumor necrosis factor alpha TOS: Total oxidant status TP: Total protein TSH: Thyroid-stimulating hormone TXA 2 : Thromboxane A2 TXB 2 : Thromboxane B2 UA: Uric acid UDPGT: UDP-glucuronosyl transferase VEGF: Vascular endothelial growth factor VLDL: Very low-density lipoprotein VLDL-c: Very low-density lipoprotein cholesterol WBC: White blood cells XO: Xanthine oxidase Zn: Zinc.