Ethnobotanical, Phytochemical, Toxicological, and Pharmacological Properties of Ziziphus lotus (L.) Lam.: A Comprehensive Review.

Ziziphus lotus (L.) Lam. (Rhamnaceae) is a plant species found across the Mediterranean area. This comprehensive overview aims to summarize the botanical description and ethnobotanical uses of Z. lotus and its phytochemical compounds derived with recent updates on its pharmacological and toxicological properties. The data were collected from electronic databases including the Web of Science, PubMed, ScienceDirect, Scopus, SpringerLink, and Google Scholars. It can be seen from the literature that Z. lotus is traditionally used to treat and prevent several diseases including diabetes, digestive problems, urinary tract problems, infectious diseases, cardiovascular disorders, neurological diseases, and dermal problems. The extracts of Z. lotus demonstrated several pharmacological properties in vitro and in vivo such as antidiabetic, anticancer, anti-oxidant, antimicrobials, anti-inflammatory, immunomodulatory, analgesic, anti-proliferative, anti-spasmodic, hepatoprotective, and nephroprotective effects. The phytochemical characterization of Z. lotus extracts revealed the presence of over 181 bioactive compounds including terpenoids, polyphenols, flavonoids, alkaloids, and fatty acids. Toxicity studies on Z. lotus showed that extracts from this plant are safe and free from toxicity. Thus, further research is needed to establish a possible relationship between traditional uses, plant chemistry, and pharmacological properties. Furthermore, Z. lotus is quite promising as a medicinal agent, so further clinical trials should be conducted to prove its efficacy.

Moroccan medicinal plants traditionally used for the treatment of skin diseases: From ethnobotany to clinical trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Skin diseases are among the most common human health affections. A healthy skin promotes a healthy body that can be achieved through modern, allopathic and natural medicines. Therefore, medicinal plants can be a reliable therapy in treating skin diseases in humans through a diverse range of bioactive molecules they contain. AIM OF THE STUDY: This review aims to provide for the first-time scientific evidence related to the dermatological properties of Morocco's medicinal plants and it aims to provide a baseline for the discovery of new drugs having activities against skin issues. METHODS: This review involved an investigation with different search engines for Moroccan ethnobotanical surveys published between 1991 and 2021. The plants used to treat skin diseases have been determined. Information regarding pharmacological effects, phytochemical, and clinical trials related to the plants listed in this review was collected from different scientific databases like PubMed, Science Direct, Google Scholar, Web of Science and Scopus. The data were analyzed and summarized in the review. RESULTS: A total of 401 plants belonging to 86 families mainly represented by Asteraceae, Lamiaceae, Fabaceae, and Apiaceae which have been documented to be in common use by Moroccans for managing skin diseases. Among those plants recorded, the most commonly used are Allium cepa L, Chamaeleon gummifer (L.) Cass and Salvia rosmarinus Schleid. Mill. Leaves were the most commonly used plant part, while powder and decoction were the most common method of traditional drug preparation. 107 of the 401 plants (27%) have undergone pharmacological validation. A total of 44 compounds isolated from 27 plants were investigated to treat different types of skin diseases, and 25 plants have been clinically studied for their activities against skin diseases. CONCLUSION: The beneficial effects of using Moroccan medicinal plants to treat skin diseases, according to traditional practices, have been proven in numerous scientific studies. Therefore, other studies should focus on isolating and identifying specific bioactive compounds from plant extracts, revealing more valuable therapeutic properties. Furthermore, additional reliable clinical trials are needed to confirm their beneficial effect on patients with skin diseases.

Protective Effect of Opuntia dillenii (Ker Gawl.) Haw. Seed Oil on Gentamicin-Induced Nephrotoxicity: A Biochemical and Histological Analysis.

Opuntia dillenii is a medicinal plant with frequent usage in folk medicine to treat many illnesses. The present study aims to investigate the protective effect of Opuntia dillenii seed oil against gentamicin-induced nephrotoxicity in rats. The animals (rats) were randomly divided into three groups (i) the normal control group treated only with distilled water (10 mL/kg), (ii) the gentamicin group treated with distilled water (10 mL/kg) and received an intraperitoneal injection of gentamicin (80 mg/kg), and (iii) the group treated with the Opuntia dillenii seed oil (2 mL/kg) and also received an intraperitoneal injection of gentamicin (80 mg/kg). The rats received their following treatments for 14 consecutive days orally. Serum urea, creatinine, gamma-glutamyl transferase, albumin, and electrolyte levels were quantified as the markers of acute renal and liver failure. Besides, the kidney and liver relative weight, kidney malondialdehydes, and kidney histological analysis were determined. The results have shown that daily pretreatment with Opuntia dillenii seed oil (2 mL/kg) prevented severe alterations of biochemical parameters and disruptions of kidney tissue structures. In addition, the results of the present study showed for the first time that Opuntia dillenii seed oil reduced renal toxicity in gentamicin-induced nephrotoxicity in rats. Therefore, Opuntia dillenii seed oil may represent a new therapeutic avenue to preserve and protect renal function in gentamicin-treated patients.

Inventory of Medicinal Plants Used Traditionally to Manage Kidney Diseases in North-Eastern Morocco: Ethnobotanical Fieldwork and Pharmacological Evidence.

Kidney disease is one of the most common health problems and kidney failure can be fatal. It is one of the health disorders associated with extreme pain and discomfort in patients. In developing countries, such as Morocco where socioeconomic and sanitary conditions are precarious, medicinal plants are considered the primary source of medication. In the present work an ethnobotanical survey was conducted in a remote area of North-Eastern Morocco and we focused on (1) establishing a record of medicinal plants used traditionally by local people to treat kidney diseases and (2) correlate the obtained ethnomedical use with well-studied pharmacological evidence. From February 2018 to January2020, information was gathered from 488 informants using semi-structured questionnaires. The data were analyzed using three quantitative indices: The use value (UV), family use value (FUV), and informant consensus factor (ICF). A total of 121 plant species belonging to 57 botanical families were identified to treat kidney diseases. The families most represented were Asteraceae (14 species), followed by Lamiaceae (12 species) and Apiaceae (10 species). The most commonly used plant parts were leaves, followed by the whole plant and they were most commonly prepared by decoction and infusion. The highest value of the (UV) index was attributed to Herniaria hirsuta L. (UV = 0.16), and the highest family use value (FUV) was assigned to Caryophyllaceae with (FUV = 0.163). Regarding the informant consensus factor (ICF), this index's highest values were recorded for kidney stones (ICF = 0.72). The use of 45% of the selected plants were validated based on literature review. This study helped document and preserve crucial traditional plant knowledge of 121 plant species used to treat kidney problems that can be used in the search for new biologically active compounds through more upcoming pharmacological studies.

The Nephroprotective Effect of Zizyphus lotus L. (Desf.) Fruits in a Gentamicin-Induced Acute Kidney Injury Model in Rats: A Biochemical and Histopathological Investigation.

Zizyphus lotus L. (Desf.) (Z. lotus) is a medicinal plant largely distributed all over the Mediterranean basin and is traditionally used by Moroccan people to treat many illnesses, including kidney failure. The nephrotoxicity of gentamicin (GM) has been well documented in humans and animals, although the preventive strategies against it remain to be studied. In this investigation, we explore whether the extract of Zizyphus lotus L. (Desf.) Fruit (ZLF) exhibits a protective effect against renal damage produced by GM. Indeed, twenty-four Wistar rats were separated into four equal groups of six each (♂/♀ = 1). The control group was treated orally with distilled water (10 mL/kg); the GM treated group received distilled water (10 mL/kg) and an intraperitoneal injection of GM (80 mg/kg) 3 h after; and the treated groups received ZLF extract orally at the doses 200 or 400 mg/kg and injected intraperitoneally with the GM. All treatments were given daily for 14 days. At the end of the experiment, the biochemical parameters and the histological observation related the kidney function was explored. ZLF treatment has significantly attenuated the nephrotoxicity induced by the GM. This effect was indicated by its capacity to decrease significantly the serum creatinine, uric acid, urea, alkaline phosphatase, gamma-glutamyl-transpeptidase, albumin, calcium, sodium amounts, water intake, urinary volume, and relative kidney weight. In addition, this effect was also shown by the increase in the creatinine clearance, urinary creatinine, uric acid, and urea levels, weight gain, compared to the rats treated only with the GM. The hemostasis of oxidants/antioxidants has been significantly improved with the treatment of ZLF extract, which was shown by a significant reduction in malondialdehydes levels. Histopathological analysis of renal tissue was correlated with biochemical observation. Chemical analysis by HPLC-DAD showed that the aqueous extract of ZLF is rich in phenolic compounds such as 3-hydroxycinnamic acid, catechin, ferulic acid, gallic acid, hydroxytyrosol, naringenin, p- coumaric Acid, quercetin, rutin, and vanillic acid. In conclusion, ZLF extract improved the nephrotoxicity induced by GM, through the improvement of the biochemical and histological parameters and thus validates its ethnomedicinal use.

Potential Toxicity of Medicinal Plants Inventoried in Northeastern Morocco: An Ethnobotanical Approach.

Herbal medicine and its therapeutic applications are widely practiced in northeastern Morocco, and people are knowledgeable about it. Nonetheless, there is a significant knowledge gap regarding their safety. In this study, we reveal the toxic and potential toxic species used as medicines by people in northeastern Morocco in order to compile and document indigenous knowledge of those herbs. Structured and semi-structured interviews were used to collect data, and simple random sampling was used as a sampling technique. Based on this information, species were collected, identified, and herbarium sheets were created. The collected data were analyzed using two quantitative indices: informant consensus factor (ICF) and fidelity level (Fl), as the degree of these indices give an insight into the level of toxicity of a given plant. The results revealed the knowledge of 55 species belonging to 36 families. The most represented families were Apiaceae, Asteraceae, Solanaceae, and Fabaceae. Furthermore, the majority of the species cited were herbs (67%), and the most common toxic parts were seeds, followed by leaves and roots. According to the informant consensus factor, death (0.81%) had the highest agreement, followed by the urological (0.76%) and skin (0.75%) categories. The most significant plants in terms of fidelity level were Solanum sodomaeum L. and Nerium oleander L. for death, Arisarum vulgare O. Targ. Tozz., Mentha spicata L., and Morus alba L. for the digestive category, Petroselinum crispum (Mill.) Fuss. and Citrus x aurantium L. for cardiovascular category, Urtica dioica L. for skin category, Datura stramonium L, and Ephedra altissima Desf. for neurological category, and finally Crocus sativus L. for general and unspecified category. This work highlights a valuable traditional knowledge of poisonous and potential poisonous plants in northeastern Morocco. Further phytochemical and toxicological research is needed to determine the safety of these prized herbs.

An overview on ethnobotanico-pharmacological studies carried out in Morocco, from 1991 to 2015: Systematic review (part 1).

ETHNOPHARMACOLOGICAL RELEVANCE: The full bibliometric records of data retrieved from ethnobotanical field studies carried out in Morocco (1991-2015) was quali-quantitatively analysed. Despite the importance of traditional medicinal uses in Morocco, any comments about the methodologies and approaches adopted by reviewed studies have been undertaken. Include more data about the importance of traditional medicinal uses in Morocco. AIM OF THE STUDY: Three key points were targeted in this review: (i) to contribute to original compilation of medicinal plants traditionally used by people at whole Morocco, by gathering and documenting the current status of these ancestral medical practices, (ii) to provide a novel insight into the relationship between local and biomedical disease concepts in Moroccan society, taking into account health-related beliefs, and their influences on medicinal plant uses, (iii) to figurout the weaknesses and the strengths of the conceptual approches and methods adopted by researchers in ethnobotanical field works. MATERIALS AND METHODS: With the help of a computerized database querying, we conducted an extensive literature search respecting our integration criteria. We performed this bibliographic research by using the following search engines available over the Web: Google Scholar, PUBMED, Sciencedirect, Current Content Connect, SCOPUS, SPRINGER LINK, GLOBAL PLANTS, Cochrane Library and SCIRUS. The scientific names listed in the present paper have been validated according to the "The Plant List" and the African Plants Database in order to standardize ethnobotanical data on an international level. For the analysis of data gathered, quali-quantitative analyses have been performed. RESULTS: A total of 905 medicinal plant species belonging to 116 families and 726 genera have been selected from 63 published articles. The dominant families were ASTERACEAE (111 species) followed by the FABACEAE (77 species), LAMIACEAE (75 species) and APIACEAE (46 species). The plant species listed are used to cure several public ailments. The digestive ailments represented the most important category (494 species) followed by dermatological diseases (407 species), diabetes (315 species) and urinary diseases (277 species). We assigned the importance of the plant species by several measures (including Frequency Cited (FC), Number of Uses (NU), Number of Respondents (NR) and Index of Performance (IP). The ICF (Informant Consensus Factor) calculated was important in all categories of diseases averaging 47%. CONCLUSION: The results obtained, which cover the whole country, delineate the profile of rich wealth of indigenous knowledge on traditional uses of medicinal plants heald by Moroccan society. The total number of 905 plant species listed in this paper, are currently being utilized as medicines and the number is expected to grow as infrastructure allows greater access to unexplored parts of the country. Furthermore, the know how, regarding the plants used, is consistent because the ICF has recorded important values for most diseases treated. Furthermore, in the present paper, we suggested, for authors, some useful recommendations for ethnobotanical field works such as the respect of ethnobotanical standards including checklist of plants with international data base, the deposited voucher specimens, sampling and collection methods.

Anticancer medicinal plants used by Moroccan people: Ethnobotanical, preclinical, phytochemical and clinical evidence.

ETHNOPHARMACOLOGICAL RELEVANCE: Cancer is a major health problem worldwide. Drugs' side effects and high cost of treatment remain the main limitations of conventional therapy. Nowadays, developing new therapeutic strategies is necessary. Therefore, medicinal plants can be used to promote novel, safe, and potent anticancer drugs through their natural compounds. AIM OF THE STUDY: This review aims to provide scientific evidence related to the anticancer activities of medicinal plants used by Moroccan people as well as approving their efficiency as an alternative cancer therapy. METHODS: An ethnopharmacological review approach was conducted by analyzing Moroccan published ethnobotanical surveys from 1991 to 2019 and consulting peer-reviewed articles worldwide to investigate the pharmacological, phytochemical, and clinical effects related to the anticancer activities. Plants with anticancer proprieties were classified into four groups: (a) plants only cited as anticancer, (b) plants pharmacologically investigated, (c) plants with bioactive compounds tested as anticancer, and (d) plants clinically investigated. RESULTS: A total of 103 plant species belonging to 47 botanical families used by Moroccans to treat cancer have been recorded. Aristolochia fontanesii Boiss. & Reut, Marrubium vulgare L., and Allium sativum L. are the most referred species in Morocco. Medicinal plants used for cancer treatment were classified into four groups: 48 species were used traditionally as anticancer (group a), 41 species pharmacologically investigated for their anticancer activities (group b), 32 plants with bioactive compounds tested against cancer (group c), and eight plants were clinically investigated for their anticancer effects (group d). Out of 82 plants' extracts pharmacologically tested (from plants of group b), only 24 ones show a significant cytotoxic effect. A total of seventy-seven compounds are isolated from plants of group (c). However, only six ones were clinically evaluated, and most of them exhibit a beneficial effect on cancerous patients with few side effects. CONCLUSION: Medicinal plants can be a promising candidate for alternative cancer therapy. Nevertheless, it is critical to increasing the clinical trials to confirm their beneficial effect on patients with cancer. Overall, this review can serve as a database for further studies.

Acute and Subacute Toxicity Studies of the Aqueous Extract from Haloxylon scoparium Pomel (Hammada scoparia (Pomel)) by Oral Administration in Rodents.

MATERIALS AND METHODS: Acute toxicity test was performed on Swiss albino mice at a single oral dose of 1-10 g/kg for 14 consecutive days. General behavioral adverse effects, mortality, and latency of mortality were determined. In the subacute study, the Haloxylon scoparium Pomel extract was administered orally at doses of 500, 1000, and 2000 mg/kg daily for 30 days to Wistar rats. Body weight and selected biochemical and hematological parameters were determined at the end of the experiment. Sections of livers and kidneys were removed for histological studies. RESULTS: Acute toxicity study showed that the oral LD50 value of Haloxylon scoparium Pomel extract was 5000 mg/kg. The subacute toxicity study of Haloxylon scoparium Pomel extract at doses 500, 1000, and 2000 mg/kg did not produce any observable symptoms of toxicity and no significant variation in body weight, organ weights, food, and water consumption or mortality in all treated rats. However, the administration of the Haloxylon scoparium Pomel extract to rats at 500 mg/kg and 1000 mg/kg showed a significant decrease in platelets. Moreover, only at the highest dose (2000 mg/kg), the extract caused a significant increase in red blood cells and hemoglobin. Our results showed that subacute treatments with Haloxylon scoparium Pomel extract at doses of 1000 mg/kg and 2000 mg/kg significantly elevated alkaline phosphatase and triglycerides. Histological studies showed that the subacute treatments of rats with Haloxylon scoparium Pomel extracts, at the doses 1000 and 2000 mg/kg, induced some histopathological changes in the livers but a slight changing in kidneys. CONCLUSION: Our results indicated low acute toxicity of the aqueous extract of Haloxylon scoparium Pomel. Furthermore, daily oral administration of Haloxylon scoparium Pomel extract caused some damages to the livers of rats treated with high doses, expressed by an increase in some enzyme activities such as ALP. Regarding the renal function, we did not find remarkable toxicity in the subacute treatment with Haloxylon scoparium Pomel extracts at doses 1000 and 2000 mg/kg. However, further toxicity assessments should be done to ascertain the safety or the toxicity of this valuable plant species "Haloxylon scoparium pomel" in subchronic treatments.

Protective Effect of Zizyphus lotus L. (Desf.) Fruit against CCl4-Induced Acute Liver Injury in Rat.

In Morocco, "Zizyphus lotus L." is one of the most widely and traditionally used plant species to treat various diseases, including liver disorders. The present study was conducted to evaluate the aqueous extract of Zizyphus lotus L. fruit against carbon tetrachloride- (CCL4-) induced liver damage in Wistar rats. The animals were daily treated with the aqueous extract of Zizyphus lotus L. fruit using two doses separately 200 and 400 mg/kg body weight for 14 days. CCL4 was injected intraperitoneally (1 ml/kg body weight) at two times, 7th and 14th days. At the end of the treatment, rats were sacrificed, and the blood was collected for the assessment of biochemical parameters. Moreover, the body weight as well as liver weight was determined. The injection of CCl4 to the rats induced various alterations such as the increase of relative liver weight, serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, triglycerides, very low-density lipoproteins, total cholesterol (slight increase), creatinine, urea, uric acid, and malondialdehyde. On the contrary, the effects of CCL4 lead to the reduction in serum levels of high-density lipoprotein. However, the daily administration of the aqueous extract of Zizyphus lotus L. fruit to the injected rats with CCL4 restored this abnormal variation in these biochemical parameters to normal values. Based on the results obtained in this study, it seems that the aqueous extract of Zizyphus lotus L. fruit has an hepatoprotective effect against hepatic lesions induced by CCL4 in rats.

Profile on medicinal plants used by the people of North Eastern Morocco: Toxicity concerns.

In the North Eastern region of Morocco, many people are interested in medicinal plants and their uses. However, the rationale for the utilization of medicinal plants has remained largely underestimated with little or no scientific data on plant safety. In this paper we attempt to describe and establish a detailed list of current knowledge in relation to the toxicity of these plants and to evaluate the scientific data concerning the harmful effects of the selected natural products. Our approach consists of collecting published data from literature in specialized journals, books and website related to the toxic plants. This research revealed that 89 plant species, retrieved from 287 plants used as medicine in the North-Eastern region of Morocco, are considered toxic or present some kind of toxicity. Our data determines 55 compounds isolated from the plants which are dominated by five groups of toxic compounds: alkaloids followed by glucosides, terpenoids, protides and phenolics. The present work discusses toxicity-related issues arising from the use of medicinal plants by local people. We conclude that the database considered in this study could serve as an important source of information on the toxicity of medicinal plants used by this society.

Substitution between Aristolochia and Bryonia genus in North-Eastern Morocco: toxicological implications.

ETHNOPHARMACOLOGICAL RELEVANCE: Although acknowledged as toxic herbs, Aristolochia species are still widely used worldwide. The aristolochic acids (AA) they contain can induce the so-called "aristolochic acid nephropathy", leading to renal fibrosis and upper urinary tract cancer. Traditional Moroccan medicine still often uses Aristolochia species under the vernacular name of Bereztem for the treatment of numerous ailments, notably cancer, diabetes or digestive tract disorders. As the botanical identity and renal toxicity of used species remain unexplored, the safety of patients may be threatened. MATERIAL AND METHODS: Ethnopharmacological data were collected from herbalists from the provinces of Oujda and Berkane, located in North-Eastern Morocco. Samples of Bereztem were collected at herbalist shops and checked for their content in AA using TLC and LC-MS methods. The toxicity of crude methanolic extracts of each herb was assessed on a HK-2 cell-based in vitro model by measurement of the cell survival to evaluate cytotoxicity and by assessment of renal-specific toxicity via (i) the evaluation of genes (E-cadherin and α-smooth muscle actin) expression by RT-qPCR; (ii) the quantities of ß-catenin and vimentin by immunofluorescence microscopy; (iii) the secretion of fibronectin; and (iv) the excretion of interleukin-6. RESULTS: The survey indicated that, among 42 herbalists visited, 33 were retailers of Bereztem, which was generally sold as a cancer treatment. Botanical investigations revealed that Aristolochia longa was frequently substituted by Bryonia dioica, which was associated with a higher cytotoxicity. Parameters specific to renal toxicity were also found to be enhanced, as compared to Aristolochia baetica and A. longa: down-regulation of ß-catenin and E-cadherin and up-regulation of vimentin and α-smooth muscle actin, and secretion of fibronectin and interleukin-6. CONCLUSION: In accordance with the Moroccan regulations, the use of so-called Aristolochia species should be discontinued. On one hand, the correctly identified aristolochia contain nephrotoxic aristolochic acids; on the other hand, aristolochia are massively substituted in North-Eastern Morocco and adulterated by a well-known toxic herb, B. dioica. Our data indicate that the bryony renal toxicity may be deleterious in shorter time periods than aristolochia. Reinforced on-site controls are needed to remind herbalists and harvesters that these herbs should be prohibited.