key: cord-0948843-bmw58ikb
authors: Zalegh, Imane; Akssira, Mohamed; Bourhia, Mohammed; Mellouki, Fouad; Rhallabi, Naima; Salamatullah, Ahmad Mohammad; Alkaltham, Mohammed Saeed; Khalil Alyahya, Heba; Mhand, Rajaa Ait
title: A Review on Cistus sp.: Phytochemical and Antimicrobial Activities
date: 2021-06-15
journal: Plants (Basel)
DOI: 10.3390/plants10061214
sha: ce5a068e51f6440c748e4e8c57478627bb772271
doc_id: 948843
cord_uid: bmw58ikb

Resistance to drugs is reaching alarming levels and is placing human health at risk. With the lack of new antimicrobials drugs, infectious diseases are becoming harder to treat. Hence, there is an increasing awareness of active phytochemicals with therapeutic functions. The tremendous research interest on the Cistus L. genus includes numerous plants used in traditional medicine by people living around the Mediterranean Sea, also resulted in some interesting discoveries and written literature. This review aimed at gathering scientific literature about Cistus species, describing phytochemical profiles and the various pharmacological activities. We also extensively reviewed the antimicrobial activities, including antiviral, antiparasitic, antifungal, and antibacterial potentials of Essential Oils (EO), raw extracts as well as isolated compounds. Mechanisms of action along with methods used are also investigated in this review. Considering the findings of the Cistus species extracts, this genus offers an adequate reserve of active phytochemicals since many have been used to create drugs. Therefore, this review work can serve society by providing a global view on Cistus L. sp. regarding pharmacological potentials and their chemical profiles.

Nature is the source of natural remedies widely used by 80% of the world population [1] . In North America, Europe, and other developed regions, over 50% of the population has used traditional medicine at least once [2] .

The World Health Organization (WHO) has a keen interest in documenting medicinal plants used by indigenous people from different parts of the world [3, 4] . The use of plant derivatives as medicinal treatments gained popularity in the late 1990s [5] .

Plants are a biologically and chemically diverse resource. The total plant species estimated on planet Earth is about 25,000 to 500,000 [6] , and more than 10% of them are used for therapeutic purposes [7] . Around 71% of drugs have directly or indirectly been derived from natural products [8] .

The extraordinary advantages of bioactive molecules as a source of biotherapeutics are beyond question [9, 10] . Studies have identified more than 5000 individual phytochemicals, and this number is continuously increasing due to the introduction of new and efficient isolation and characterization techniques [11] [12] [13] [14] . recognized, the preparation method, the temperature used, duration, and the type of water strongly influence phenolic compounds during cooking.

Riehle has proven a significant decrease of different groups of phenolic compounds and flavonoids when brewing the commercially available C. incanus infusions with different water used at various conditions [76] . The profile of phenolic compounds from C. incanus pollen was different between nonhydrolyzed and hydrolyzed. Although the in vivo data about the metabolism of various food sources of phenolic compounds isolated after feeding are contradictory and rare, it is essential to consider data on these compounds and the changes they may undergo once in the human body [77] .

The study of the two Tunisian and Italian teams represented by Marcello Nicoletti and Mariem Ben Jemia, focusing on terpenes, phenols, and glycosides of raw methanolic extract of C. monspeliensis, showed that diterpenes were evident and polyphenols were present in different concentrations. Flavonoids were also reported with isolation of new phenylglucoside,1-(3,5-dihydroxy-2-methylphenyl)ethanone-5-O-β-D-glucopyranoside, named monspelioside, which was identified for the first time from the genus Cistus [70] .

Ben Jemia identified 36 compounds from hexane extracts of C. monspeliensis leaves as a part of the investigation on Tunisian medicinal plants. Top-class was represented by fatty acids and a good amount of hydrocarbons; Vitamin E was also present [41] . The teams have also studied C. libanotis, a complete analysis of the hexane extracts from leaves, and showed 47 constituents. Flavonoids were dominant, followed by fatty acids, monoterpene hydrocarbons, hydrocarbons, oxygenated monoterpenes, diterpenes, sesquiterpenes, oxygenated sesquiterpenes, which were present in a small amount [41] . In contrast, when they focused only on terpenes and phenols constituents, they reported the evidence of diterpenes and flavonoids in methanol extracts [78] . According to the same papers, these diterpenes were rarely reported in C. villosus, dominated by hydrocarbons and Vitamin E and some tannins [69, 71] .

The first investigation on ethanolic extracts of C. laurifolius aerial parts from Spain concluded the isolation of a new diterpene called laurifolic and identification of five glucosides (β-D-glucopyranosiloxyethane, 4-β-D-glucopyranosiloxyacetophenone, reseoside, 1,3-dihydroxy-5-β-D-glucopyranosiloxybenzene, 1-O-methyl-epi-inositol) [55] . Between 2007 and 2012, Erdem Yesilada published two papers about organic extracts of C. laurifolius leaves from Turkey, which reported three flavonoids (3-O-/methylquercetin, 3,7-Odimethylquercetin, and 3,7-O-dimethylkaempferol) [73, 74] . Considering the wide use of the C. laurifolius by the Turkish population, studies on its chemical composition continue. In 2013, another paper was published and reported comparing the chemical profile of aqueous and ethanolic leaves extracts. Results showed higher phenolic contents in ethanolic extract rather than the aqueous one. Flavonoids, chlorogenic acid, gallic and ellagic acid were the most phenolic compounds in C. laurifolius ethanol extract [79] . The aerial parts of C. creticus from the Island of Crete were analyzed by IR, CID-MS, NMR, DEPT. Nine labdane-type diterpenes were found [53] . In 2012, sonication testing was analyzed by GC/FID, and GC/MS concluded the identification of 24 compounds, also dominated by labdane-type diterpenes [51] . To find a correlation between the activities and biomolecules, a team of Micol was carried out on the composition of different extracts of 4 Cistus species abundant in Spanish semi-arid regions. The semiqualitative analysis by RRLC-ESI-TOF-MS of the composition of Cistus clusii Dunal, C. albidus, C. ladaniferus, and C. salviifolius did not reveal a significant difference between the four Cistus extracts. The presence of phenylpropanoid compounds (phenolic acids, falavonoids, and tannins derivatives) in all species should be mentioned; the proportions were varied. Cyclohexane carboxylic acids, gallic acid, glycosylated quercetin, and myricetin were especially abundant in the C. clusii, C. albidus, C. salviifolius extracts. In contrast, labdanoic acid, betuloside, apigenin, kaempferol, and galloylated flavanols were more abundant in those extracts of C. ladaniferus and C. clusii [80] .

All Cistus species produce several compounds with pharmacological properties. The international literature has reported the biological activities of Cistus species, which are widely known in folk and traditional medicine around the Mediterranean basin.

Extracts from C. ladaniferus showed to have an antiaggregant effect by inhibiting the thrombin [81] . Also, an antispasmodic action confirms its traditional use for treating intestinal aches [82] . An evaluation of aqueous extracts against glycemic and lipidemic status in diabetic rats showed a significant reduction in blood glucose levels (similar to those obtained with glibenclamide) and the total cholesterol triglycerides in plasma [83] . A reduction of systemic blood pressure in two animal models of hypertension, and then it has antihypertensive properties [84] . Analgesic and anti-inflammatory purposes were also detected in this species [85] . Two papers have focused on antioxidant activity and revealed excellent effectiveness against peroxyl radicals [41, 55] . Aqueous extracts of C. ladaniferus also have anticarcinogenic compounds, which have cytotoxicity against pancreatic cancer cell lines M220, breast cancer cells MCF7/HER2, and JIMT-1 [86] . The first report about the toxicity of C. ladaniferus was published by El Kabbaoui using male and female mice, reported that a dose of 3 and 5 g/kg produced a 10% to 30% mortality rate (acute toxicity test) [87] .

Considerable research on pharmacological proprieties of C. monspeliensis has been done. One of the first examples of cytotoxic activity of extracts and compounds of this species was studied by Dimas and his colleagues. They have demonstrated the inhibition of myricetin isolated from the hexane aerial parts extract against nine human leukemic cell lines. They also showed that acetylation of this compound enhances the growth inhibition, decreasing from IC 50 50 .1 µM to 38.3 µM. It should be noticed that any paymasters' modification will modify the results [88] . Demetzos showed that a diterpene isolated from hexane extract from leaves of C. monspeliensis does not present any cytotoxic or cytostatic activity against any of the nine cell lines tested [89] . On the other hand, Ben Jemia demonstrated that hexane extract from C. monspeliensis leaves was rich with many compounds, especially fatty acids, hydrocarbons, and Vitamin E. The compounds showed significant cytotoxicity against human breast cancer cells with IC 50 52.44 mg/mL (better than reference drug IC 50 142.36 mg/mL) [41] . Nevertheless, the main limitation of those investigations is the absence of toxicity determination of those extracts. Based on this observation, Vitali studied the acute toxicity using Artemia salina L., and cytotoxicity on normal human prostate cells, of lyophilized aqueous extract from aerials parts of C. monspeliensis. They observed that the toxicity increase after 24 h with a concentration of 5 mg/mL, but the exposure for 48 h to the extract displayed significant growth inhibition from the concentration of 0.1 mg/mL [29] . Demetzos investigated the in vivo anti-inflammatory activity of the ci-clerodane type Diterpene isolated from hexane extract on the back of hairless mice. The topical application did not seem to have any outcome to the skin barrier repair. Compared to Sayah, who found that aerial parts aqueous extract has a potent effect against carrageenan and analgesic reaction at a dose of 500 mg/Kg body weight [85, 89] . This effect may be due to the richness of polyphenolic compounds in the aqueous extract and the lack of epoxide structure in the cis-clerodane molecule. Other researchers reported that methanolic or ethanolic extracts of C. monspeliensis are rich in polyphenolic compounds related to antioxidant activity because they can chelate transition metals and prevent them from participating in metal-catalyzed initiation and hydroperoxide decomposition reactions [78, 90] .

EO's use as a food supplement for neuroprotective proprieties has also been investigated by M.R. Loizzo, aiming acetylcholinesterase (AChE) butyrylcholinesterase (BChE) enzyme. EO of C. monspeliensis does not have any activity against AChE and a slight BChE inhibitory. This observation could be due to the limited amount of compounds that belong to monoterpenes with AChE inhibitory potent such as α-pinene, β-pinene, and α-terpinene. On the other hand, plenty of diterpenes was responsible for the highest lipid peroxidation inhibition [62] . Using in vitro model, Sayah demonstrated the strong effect of aqueous and hydro-methanolic extracts to inhibit α-glucosidase and α-amylase activity (enzymes responsible for the degradation of oligosaccharides into glucose and then increase his level in blood). This inhibition could then be essential in managing blood glucose levels in diabetic patients and preventing type 2 diabetes. The same researchers also established the correlation between total phenolic content, enzyme inhibition, and different antioxidant activities (DPPH, ABTS, FRAP) [91] .

Numerous studies have been conducted to evaluate biologicals proprieties of C. salviifolius compounds. Oxidative stress is an essential factor included in chronic and degenerative diseases and is targeted by researchers. Studies on different extracts of C. salviifolius showed an interesting source of natural antioxidants. A study was done by Fadi Qa'dan using Fremy's salt assay to demonstrate the ability of a purified proanthocyanidin from three fractions to reduce free radicals [92] . Additionally, S.K. El Euch aimed to compare methanolic extract from leaves and flower buds, targeting different antioxidant activity tests (DPPH, ABTS, FRAP), enzyme inhibition (xanthine-oxidase XOD, superoxide dismutase SOD, and AChE), anti-inflammatory and cytotoxic activities. In general, the results revealed that extract's organ origin influenced considerably chemical composition and then biological activities. The highest antioxidant and cytotoxic amounts were observed in flower buds extract, rich with phenolic and flavonoid compounds. On the other hand, leaves extract was rich with tannin compounds and had an inhibitory potent against XOD, SOD, AChE, and anti-inflammatory activity [93] . Another study with aqueous and hydromethanolic aerial parts of Moroccan C. salviifolius by K. Sayah also showed a significant phenolic and flavonoid content and effective antioxidant activities. Still, if IC 50 values of each test were compared, we will find a difference that may be explained by many parameters such as geographical area, organ origin, extraction methods, Etc. Extracts used in this study also exhibited a strong inhibitory toward α-amylase and α-glucosidase, influencing glucose blood levels [91] . To our best knowledge, the survey carried by M.R. Loizzo is the only in literature focused on the antioxidant activity of C. salviifolius EO. EO was able to scavenger DPPH and ABTS radicals to reduce antioxidant compounds on ferric tripyridyltriazine (FRAP assay) and inhibit lipid peroxidation (β-carotene), also inhibit AChE and BChE. IC 50 values reported in this study are much lower compared to those noted with organic extracts. This difference may be attributable to the proportion of different chemical compounds present because EO is a complex mixture of several molecules which can act in synergy or by one or two main components. However, this supports EO's practical use as a food additive and herbal tea because compounds lipophilic could be delivered by the bloodstream to the brain, an area affected by oxidative damage [62] .

Considering the importance of developing pharmaceutical products with lesser side effects for inflammation and pain treatments. The current study proposed by [94] reports the anti-inflammatory and analgesic potent of Moroccan C. salviifolius aqueous extracts, an important reduction of inducing paw edema (97.57%), and significant inhibition of writhes for a dose of 500 mg/Kg of body weight. In a recent paper published by I. Chiocchio, the authors demonstrated for the first time the skin protection effect of C. salviifolius hydro-methanolic extracts [95] . Trials aimed to test the in vitro inhibition of two enzymes which are cosmetic targets (tyrosinase and elastase), showed the inhibition of 51% against elastase and 61% against tyrosinase at a concentration of 50 µg/mL. Also, a correlation was established between inhibition enzymatic potency and the total phenolic and flavonoids content.

Ethnopharmacological data revealed the use of C. albidus flowering top in decoction against respiratory disorders by the North-West of Morocco population [96] . In this regard, a study was carried to support the traditional pharmacopeia in Morocco. A high value of total phenolic content and total flavonoid content was registered from ethanolic extract (TPC 112.48 ± 1.78 mg GAE/g extract; TFC 24.55 ± 0.58 mg QE/g extract).

Those compounds are secondary metabolites that could act as antibacterial responsible for respiratory infections [90] .

The influence of environmental conditions in the production of phenolic compounds is a fact. A study carried on how the medium composition affects both the performance and the antioxidant capacity of C. heterophyllus shoots cultured in vitro. The finding suggested modulation of parameters suited by physical state and chemical composition. Still, a correlation between phenolic compound levels and the antioxidant capacity (evaluated by DPPH assay) in shoots extracts showed the prominent role of defense against oxidative stress [97] .

In contrast, a study carried out with C. clussi on the role of a secondary metabolic pathway in responses to stress such as summer drought, reported the increased syntheses of many phenolic compounds and the maximum efficiency of photosystem II. The induced drought may be due to the compound's action to protect the plant from oxidative damage [98] .

The C. populifolius aqueous extract from Spain have demonstrated for the first time a high polyphenol (especially ellagitannins) content and high antioxidant capacity observed in many analysis, data reported in this study suggests the use of this species in the food industry and biological systems [86] .

Mainly C. crispus was studied by A. Bouyahya's team. It is used as a poultice applied against wounds [96] . It is well known that secondary metabolites are infused by the solvent used for the extraction, thus affecting biological activities. C. cripus methanolic extract showed a higher TPC and TFC, which are the most widely used phenolic substances [99] . Based on our knowledge, there is only one report discussing the ability of C. crispus n-hexane extract to act against tumor cells (embryonal rhabdomyosarcoma cancerous) without affecting normal cells (high selectivity indexes) and remarkable IC 50 value. This finding is interesting, while the absence of correlation between antioxidant and antiproliferative activities supports other targets of phenolic compounds on cancer cell lines [100] .

3.9. Cistus libanotis L. and Cistus villosus L.

Similar to the previous investigation on the Cistus genus, C. libanotis, and C. villosus, we report the leading presence of flavonoid compounds with other phenolic substances in hexane extract without any antiproliferative potent against three different cell lines [41] . However, the same species' methanolic extracts also have a significant amount of phenolic, flavonoid, and tannins content. That could prevent the participation of ions in metalcatalyzed initiation and hydroperoxide decomposition reaction. Indeed, this mechanism has been reported to escape oxidative stress, thus prevent many chronic diseases [78] . Moreover, the EO from Italian C. libanotis had a fraction composed mainly of Monoterpene hydrocarbons, with the most significant antioxidant potent studied by DPPH, ABTS, FRAP, β-carotene bleaching test, AChE, and BChE. Except for C. villosus, which does not have a FRAP activity and low ABTS inhibition [62] .

Investigation on biological activities of C. creticus has started since 1994. Many compounds have been isolated from resin and hexane extract, especially labdane typediterpenes, which exhibited interesting cytostatic and cytotoxic effects against variable human leukemic cell lines with a promising IC 50 suggesting an induction of apoptosis via p-53i independent pathway [89, 97, 101] . Further in vivo use is hindered by their water-insolubility. To overcome that, liposome formulation was used to encapsulate two compounds and compare their activity against human cancer cell lines with the free compounds. It has been proven that encapsulation may have several advantages, but it is also important to signal that it may modify the efficacity (not the same IC 50 ) [102] . Some of those labdane types were also evaluated for their anti-inflammatory activity in vivo on the back of hairless mice. Still, one of the tested compounds has shown a significant contribution to the skin barrier repair compared to the control, which may be due to the lack of the tested molecule's epoxide structure [89] .

Research on biotechnology to produce secondary metabolites has received particular interest. Marijana has successfully established in vitro culture of the shoots and roots of C. creticus, which presented a similarity in secondary metabolites with those found in the native plant, which offers an excellent opportunity for further commercial use while respecting the ecosystem [103] .

The south-Moroccan population has reported leaf decoction in the traditional treatment of diabetes [104] . It has also recently been declared that it had a positive influence on the foraging field containing C. creticus on the quality of goat milk [105] .

Known as C. incanus, Italy's aqueous extract has shown to act as spasmolytic on intestinal and vascular smooth muscle. Its action is concentration-dependently and reversible inhibitory. This finding supports local folk medicine's beneficial effect on diarrhea and digestive disorders [106] . As known, compounds belonging to labdane-type diterpenes were subject to much research and demonstrated their cytostatic and cytotoxic ability. A study aimed to prepare liposomes and incorporate sclareol has shown a notable reduction in human cancer tumor growth rate than free sclareol [107] .

On the other hand, underlining men's life quality impairs because of benign prostatic hypertrophy. The aqueous extract has been active in suppressing the growth of human epithelial prostate cells. This might be used for treatment since they do not reveal significant toxicity [29] . A polyphenol-rich extract from herb C. incanus has increased intracellular oxidative stress in Chinese hamster pulmonary fibroblast cells cultured [108] .

Indeed, many mechanisms were suggested, such as regulation-free radical processes as a signal of the transduction pathway or the pro-oxidant activity of polyphenols and their ability to inhibit and reduce the P-gp protein efflux. An evaluation of oxidant/antioxidant status, estrogenic/anti-estrogenic activity, and gene expression profile in mice fed with Cistus incanus reach bee pollen, revealed a very noticeable health-protective potential and antioxidant activity [77] . Considering the important use of those antioxidants in the human diet, attention has been paid to herbal infusion, which promoted a high content of phenolic substances and strong antioxidant potent.

C. laurifolius is mainly known in Turkish folk medicine to treat various types of pain and disorders. As a part of evaluating this traditional use, numerous studies have been conducted. It has been demonstrated in vivo by many modules the anti-inflammatory effect of leaves extracts against multiple molecules, which play a crucial role in inflammatory and immune response such as IL-1, TNF-α, prostaglandins by inducing inflammation in mice. The results were interesting. Extracts and molecules isolated could exert a strong antinociceptive and anti-inflammatory potent without causing any apparent acute toxicity or damage [109] [110] [111] . The chloroform extract could also exert an analgesic effect by inhibiting tail-flick response rapidly compared with morphine [112] . Another striking point was the in vivo antioxidant activity of extract and compounds isolation, observing possible liver damage and acute toxicity. The potent studied was more than ascorbic acid [113, 114] . Whereas the burden of diabetes and its complications increases, specific attention is given to the utilization of tea leaves from C. laurifolius to explore its potential effect as antidiabetic. It is a possible influence on platelet aggregation and blood coagulation. Results indicated that this species might also benefit diabetic patients [79, 115] .

Upon reviewing the literature on the Cistus genus, it is found that numerous studies have been carried out on multiple features, uses, and valuables activities which we have mentioned above. To our best knowledge, the first review about the Cistus genus has been published by Papaefthimiou. It has summarized an overview of the main Cistus species present in the Mediterranean basin [116] . More recently, Stępień also has published a review paper about the biological properties of Cistus species [117] . Both teams have highlighted mainly the studies showing promising potential on numerous biological applications without showing value details.

As known multidrug-resistant microorganisms have become increasingly problematic, new drugs are essential to tackle this ever-increasing problem. This document's quest was to summarize and update recent scientific investigations to determine anti-infective activities separately (antiviral, antiparasitic, antifungal, antibacterial, and antibiofilm). Also classified antibacterial potency on three levels: a-Effect of EO, b-Effect of isolated compounds, and c-Effect of crude extracts.

Viral infections are life-threatening diseases because of their rapid outbreak. Among the most aggressive viral infections are Ebola, AIDS, influenza, and SARS. For instance, influenza is responsible for over 3 million new severe disease cases and 300,000-500,000 deaths yearly [118] . Alarmingly, the number of patients diagnosed with viral infections is increasing every year. For example, the covid-19 pandemic alone infected about 141 M people and caused 3.1 M deaths (WHO 21/04/2021). Treatment of viral diseases is a great challenge even today because of the virus's adaptation, the emergence of resistant viral pathogens, new viral strains, the high cost and side effects of medicine, and host resistance antiviral drugs [119] .

Herbal drugs have gained much importance due to their easy adaptability, low cost, and fewer side reactions on patients [120] . Most studies related to traditional Cistus specie's uses have been carried out in Greece and Turkey.

Three Cistus have been reportedly studied for their in vitro and in vivo activity against viral pathogens. Different locations, parts of the plant, and solvents have been used to prepare extracts against H7N7, H1N1, H5N1, HIV, Ebola virus, HSV-1, PI-3, and dengue virus (Table 1) .

Dr Pandalis developed a selective extract CYSTUS052 from a distinct variety of C. incanus, with a content of more than 26% of polyphenol. This variety is the main ingredient for several products (Cream, tea, syrup, bio pastilles, decoction, salve, food supplements). This extract has demonstrated the greatest antiviral action against influenza A (H7N7) in in vitro (90% inhibition) but also in vivo model (mice treated with aerosols of Cistus extract were protected from infection). All experiments concluded on the safety of extracts without toxicity or adverse effects on systemic immune response neither epithelial bronchioles cells, suggesting a direct interaction of polymeric polyphenols with viruses before infection leading to the prevention of absorption in the cells [121] . Ehrhardt et al. attempted to demonstrate anti-influenza activity against other subtype strains (H1N1, H7N7, H5N1). Overall results showed the extract's ability to reduce the progeny virus titers of different strains with a dose-dependent response [122] . Following safety analysis, the extract did not show any harmful effect on cells. Moreover, confirmation of the previous hypothesis (reduction of the progeny virus titers) was demonstrated using several experiments to indicate that components of the CYSTUS052 extract can directly be interfering with viral HA to block binding to cellular receptors with an unspecific physical mode of antiviral action (using HRV14 as an example). The model proposed overcame resistance problems by mutations of amino-acid residues.

Since In this interest and based on antiviral potent demonstrated by CYSTUS052, Rebensburg showed the inhibitory potent of aqueous extracts and the polyphenol-enriched fraction of C. incanus against clinical isolation of HIV with multidrug resistance profile, moreover, the potency of these extracts against emerging viruses such Ebola virus and Marburg virus. The inhibition percentages were more than 80% and an EC50 ranging from 5.40 to 15.06 µg/mL. These results have led to further investigation of the mode of action using different systems (EASY-HIT, TOA, GFP-labelled HIV-1 particles) and the observation demonstrating that C. incanus blocks viral particles' attachment to which inhibit viral entry into host cells. In addition, it blocks gp-120 envelope protein in HIV-1 and envelopes glycoproteins of Ebola and Marburg viruses, which prevent these viral proteins from mediating infection. Even after long-term C. incanus treatment (168 days), viruses did not show any resistance. This is presumably attributed to the combination of actives molecules in the extracts compared to treatment with a single-compound antiretroviral drug.

Although these findings were under cell culture conditions and did not identify the individual antiviral agents, it is still believed to have a therapeutic application after extensive investigations, mainly as topical microbicides to prevent STD [123] . Based on the utilization of oleoresin of C. incanus as the main ingredient of "Aliptamuscata" by doctors during epidemics of the medieval period for prevention [124] and to ensure a much investigation of C. incanus antiviral potency, Kuchta has explored the raw extract and fractions of labdanum resin against the dengue virus, leading to severe forms of the disease. Unfortunately, it had a strong cytotoxic effect. Simultaneously, two subfractions of dichloromethane fraction showed the intense anti-dengue activity of 100% with nontoxic concentration (31.25 µg/mL). The chemical composition revealed epi-manoyloxide, 3-hydroxy-manoyloxide, manoyloxide, 3-acetoxy-manoyloxide [125] . The authors have highlighted an interesting point in this study: why water-soluble polyphenols had the greatest antiviral potency? In contrast, in this case, the water-soluble fraction has enhanced viral proliferation, which may be because the aqueous fraction was previously washed with a solvent much more polar.

An initial finding of antiviral potent of C. laurifolius in leaves was reported against HSV-1 and PI-3. No % of inhibition was written. However, the maximum non-toxic concentration measured revealed that hexane fraction had significant activity against PI-3, like the reference drug oseltamivir (32 µg/mL). On the other hand, HSV-1 was less sensitive, with the maximum cytopathogenic effect of 16-32 µg/mL. It is still an interesting finding through the insufficient data since HSV infections are usually severe problems among immunocompromised individuals [126] . 

Each year diseases caused by parasites lead to hundreds of millions of infected people, particularly in tropical and subtropical regions, resulting in one million deaths [127] . At first report about the potential of Cistus against parasites, Fokialakis have demonstrated the significant antileishmanial activity of raw extract of C. monspeliens is and C. creticus [128, 129] . Also, the authors tested pure and semisynthetic compounds from the same species against L. donovani promastigote (causative agent of visceral leishmaniasis). Obviously, among the eight natural compounds from C. monspeliensis, 18-acetoxy-cis-clerod-3-en-15-ol was the most active with an IC 50 value of 3.3 µg/mL, while C. creticus compounds were less sensitive ent-3b-acetoxy-13-epi-manoyl oxide active with an IC 50 value of 17 µg/mL. As far as we could observe, semisynthetic derivatives showed variable responses, ranging from inactivated to more active than the parent compound. As it is commonly acknowledged that the fundamental concepts of activity are about selective toxicity against the target without any toxicity to the host cell, none of all compounds tested in this study was cytotoxic to mammalian cells up to the highest concentration of 47.6 µg/mL.

A recent report by Bouyahya on macerated extracts from C. crispus leaves against three Leishmania species tests at the promastigote stage have demonstrated that among the solvent used, methanol and ethanol, n-hexane showed the best anti-promastigote activity regarding L. major, L. tropica, and L. infantum. Moreover, L. Infantum was the most sensitive IC 50 47.29 µg/mL. Also, it should not be forgotten that all results obtained with C. crispus extracts were lower than the control used (Glucantime ®® IC 50 > 500 µg/mL) [130] . However, no toxicity tests were performed. Unfortunately, there is a high probability that the products that have been classified as active against a particular parasite in vitro are likely to be known toxins to host cells (Table 2 ). The in vivo screen should assess activity against an intracellular stage of parasite development to be genuinely representative for an antiparasitic product suitable for development. Nevertheless, no screening system is perfect because of the lack of correlation between tests in vitro and in vivo in all areas of drug discovery. We cannot emulate the complex situation in vivo.

Even though fungi were the first source of antibacterial agents, they are also responsible for fruits and vegetable diseases, like humans affecting the quality of life, causing pain, discomfort, and psychological symptoms. This concern is more severe with the increase of the resistance phenomena.

In search for antifungal drugs in the Cistus genus, rockrose is also known as C. creticus = C. villosus = C. incanus, was widely investigated. First, by Demetzos et al., in both reports about EO's composition and its effect against C. albicans which had almost the same effect [69, 70] . Comparative MIC analyses of Moroccan and Turkish rockrose against C. glabrata and C. albicans show respectively significant MIC values with methanol extract from Moroccan species 0.19-6.25 mg/mL and 8-32 mg/mL with aqueous extract from Turkish samples. Interestingly the bio-guided extraction (fractionation with increasing polarity solvent) of Bouamama allowed a better activity localization. Butanol fraction and remaining aqueous layer were more active than the raw extract. It also should be noticed that C. glabrata was the most sensitive while C. krusei was the most resistant to extracts [31, 131] . However, the highest anti-candida activity was reported with phenolic extract of C. ladaniferus. MIC was lower 0.05 mg/mL for C. albicans, C. glabrata, and C. parapsilosis [132] . This extract was mainly made of phenolic compounds, which might explain its activity.

Meanwhile, it has been established that EO, aqueous and organic extracts of rockrose are also active against Aspergillus species [131, 133, 134] . Hydro-methanolic extract of C. incanus showed a pretty interesting finding against A. parasiticus since, at a concentration of 0.2 mg/mL, it inhibited the growth in a percentage of 46% and also inhibited the production of Aflatoxin B1 from 72.5% to 90.1% [30] . It is such an outstanding finding considering Aflatoxin's risk and damage to crops and to human health, which is supposed to use these extracts as natural products for biological control. Other studies indicate the potential of extracts derived from rockrose in protection against post-harvest diseases. Ameziane reported activity against P. digitatum, P. italium, G. candidum with mycelial growth inhibition ranging from 27% to 79% using methanol extract. However, they did not test it in vivo against fruits. At the same time, more recently, Talbi demonstrated the tremendous antifungal potential against G. candidum. The extract has inhibited mycelial growth and germination spores at 100%. It has decreased the incidence and severity of sour rote disease respectively to 40% and 32% compared with a control group without causing any phytotoxic effect [135, 136] .

Karim did similar investigations to demonstrate the effectiveness of eight Cistus varying types of extracts. Obviously, for anti-G. citri-aurantii, water was the best extraction solvent, followed by methanol and chloroform. In both studies at a concentration of 5 mg/mL aqueous and methanolic, extracts of C. creticus, C. albidus, C. laurifolius, C. monspeliensis, C. crispus, C. salviifolius, and C. populifolius exhibited a total inhibition of arthrospore germination. However, among all extracts, aqueous ones of C. salviifolius and C. monspeliensis have strongly inhibited the fungi with MIC values low than 0.625 mg/mL.

In comparison, methanolic extracts of the same species had a MIC of 5 mg/mL. Indeed Karim has also uncovered the significant activity of all tested plant extracts to reduce disease incidence and severity [137, 138] .

To the best of our knowledge, little is shown about post-harvest citrus fungal pathogens. These studies have pointed out that Cistus extracts will widen the list of allelopathic plants to G. citri-aurantii growth.

A recent Moroccan report about the ethanolic extract from rockrose against P. expansum and P. digitatum: the research was done using agar dilution, and the results revealed the sensitivity of P. digitatum MIC 1 mg/mL while P. expansum was more resistant with MIC of more than 10 mg/mL. Also, the same study has evaluated the effect against unusual fungi such as C. versicolor, G. trabeum, P. placenta, and C. puteana, which is known to be wood decomposition. Most of them presenting a resistance against ethanolic extract. However, they were more sensitive against EO [134] .

According to studies published about EO of C. ladaniferus, firstly, Mrabet have highlighted its activity against various fungi, in which M. racemous, a polluting fungus, was the most sensitive to the EO. The activity observed may be due to the presence of sesquiterpenes compounds [139] . Years later, Upadhyay has published a detailed report about the potent inhibition of the tested EO against A. flavus (MIC 0.6 µL/mL). Its capacity to suppress Aflatoxin B1 production suggests a mode of action based on inhibition of ergosterol biosynthesis (basic sterol of the fungal cell membrane) and enhancement of ions leakage from fungal cells, which leads to fungal growth inhibition. Also, the reduction of methylglyoxal, thus the removal of Aflatoxin B1 biosynthesis. It is also shown that EO was mainly composed of α-asarone, known for its antimicrobial quality but also its toxicity. However, the phytotoxicity investigation has proved EO's safety for seeds used [140] . Tables 3 and 4 summarize the work done on the fungi. 

Following the worldwide epidemiology of bacterial infections, antibiotic resistance has become a global pandemic and one of the most considerable worldwide anxieties. The spread of MDR, XDR, and PDR bacteria suggests that in 2050 the leading cause of death will be antibiotic resistance. World Bank has indicated that the number of deaths will rise to 10 million every year if no action is taken.

The development of new molecules of antibiotics is crucial mainly for the treatment of Gram-negative infections such as EPC (Enterobacterales Producing Carbapenemases), ABIR (Acinetobacter baumannii Imipenem Resistant), and PAIR (Pseudomonas aeruginosa Imipenem Resistant). Also, considering all data about these concerns, to date, several plants have been identified from ethnobotanical information as having valuable properties. Most research into these effects on bacterial infections has been undertaken using EO, aqueous, or organic extracts from purified compounds. Here we analyze the studies about Cistus antibacterial impact by type of extract. First EO followed by isolated compounds and then raw extracts.

Plant EO can be extracted from leaves, fruits, stems, and roots. Cistus EO has shown having a broad antimicrobial spectrum, being antifungal and antibacterial, as demonstrated by Demetzos et al. in its three reports with C. creticus for the first time. EO from leaves and aerial parts shows a similar profile. Their compounds, mainly diterpenes especially manoyl oxide isomers, inhibit the in vitro growth of S. aureus, S. epidermidis, and B. subtilis even at high dilution (1/2000) . Simultaneously, Gram-negative strains represented by E. coli and P. aeruginosa were more resistant to EO's action [69, 70] .

Nevertheless, the oil from C. creticus resin Ladano tested against three Staphylococcus species shows similar activity with MIC value of 2 mg/mL, which was estimated high according to authors compared to the better action of the isolated compound Ent-3βhydroxy-13-epi-manoyl oxide MIC = 0.1 mg/mL. The first time this diterpene was reported in the literature, resin EO was most known for its richness with sesquiterpene [142] . These two-chemical structures (Labdane-type diterpenes and sesquiterpenes) might be called phytoalexin. Citsus plants produce those compounds in response to infections with fungi, bacteria, viruses, and parasites, explaining their effectiveness against microbial strains on in vitro tests.

Following experimental research for antistaphylococcal activity, Guinoiseau [143] demonstrated the potential of C. ladaniferus EO and its efficacy against tested strain, ranging from 0.012 mg/mL for acetate fraction to 0.8 mg/mL for EO in coordination with the inhibition zones. These concentrations were much efficient than those reported with C. creticus EO [142] . Authors have suggested and attempted to introduce these extracts at their MIC and measure the reduction in the number of CFU/mL over 7 h. Results show that alcohol fraction led to 99.9% inhibition in less than one hour; furthermore, they act without cell lysis or drastic cell wall damage. Indeed, the low density of plant oils and their rapid diffusion across cell membranes due to their hydrophobicity might support the non-specific inhibition by disturbing ATPase efficiency or the proton motor force, thus blocking the cell division [143] . This propriety might also offer an alternative delivery route, including transcutaneous delivery after scarification or patch application for burns or skin infections. Even though a screening on agar-diffusion, the available evidence of the effectiveness of C. ladaniferus EO against Gram-positive strains could not be excluded. It has been reported by Viera [144] that this EO has strongly inhibited a Methicillin-resistant S. aureus but also S. pneumoniae. Moreover, these activities include inhibition of E. coli ESBL producer, which more sensitive (20 mm) than the E. coli ATCC 25922 (10 mm). However, a recent study aimed with several EOs C. ladaniferus EO inhibited S. aureus with a high MIC (0.4 mg/mL). These observations raise several questions of parameters influencing activity, which need further research. The phytochemical data indicate the high content in α-pinene, camphene, fenchone, bornyl acetate, and viridiflorol [143, 144] . Despite this, a study carried out the same EO against several strains, including both references and clinical isolates of Gram-negative and positive, did not show any activity except for L. monocytogenes whose diameter of zone inhibition was 19 mm [145] . This may eventually be due to the low volume deposited per disc (3 µL) ( Table 5) .

. 

However, little work has been carried out using purified compounds. Several isolated compounds from Cistus species have definite activity in laboratory trials. In addition to C. creticus, in which Demetzos [142] have provided action against Staphylococcus, the team's investigation continued to isolate other compounds that have antibacterial activity. Years later, they report a novel clerodane diterpene called (+)-19-acetoxy-cis-clerodan-3-ene-15-oic acid from C. monspeliensis leaves extract tested toward Gram-positive and Gram-negative models. The results showed that the smaller concentration of 0.031 mg/mL used induced inhibition of all Staphylococcus growths at this concentration, no inhibition of Gram-negative. When the concentration increases, the compound had a MIC of 0.499 mg/mL against E. coli, K. pneumoniae, P. aeruginosa [147] . Recently, a work published by Móricz [148] was undertaken to investigate and identify antibacterial components from several C. incanus herbal tea. Experiments focused on multi-step extraction to select a fraction that contains flavonoid aglycone.

Additionally, the antibacterial profile of reported components (Apigenin, Kaempferide, Cis-tiliroside/trans-tiliroside, p-coumaric acid-conjugated tiliroside) against B. subtilis and A. fischeri. The determination was done using a simple, rapid, and inexpensive method, namely thin-layer chromatography-direct bioautography (TLC-DB). The bioautograms discovered were corresponding to the total inhibition of both strains. Furthermore, this study has shown the ineffectiveness of the raw extract in comparison to the isolated faction. Indeed, the authors have highlighted the side effect of the usual fractionation protocols whose formation of artifacts may be present. It is generally well known that artifacts lead to loss of activity, the formation of active compounds from inactivating ones, Right away toxic compounds, and the difficulty of reproducing an extraction or purification method. These products and their published activity are recorded in Table 6 . 

Nevertheless, raw extracts and liquid-liquid fractions were widely used to explore the antibacterial potential. S. aureus and E. coli were the most studied strains in all cases. Among the Cistus extracts investigated, ethanolic and its fractions from C. laurifolius exhibited the best inhibition activity against S. aureus (MIC = 0.064 mg/mL) and E. coli (MIC = 0.032 mg/mL) [126] in comparison with other species [31, 86, 99] . A quiet observation about the activity of C. monspeliensis in two studies revealed a difference in MIC while it was about the same strain and same solvent (methanol). Bouamama [131] reports a MIC value of 25 mg/mL while Ben Sassi [149] have found 0.312 mg/mL. However, none of the extracts in this study could inhibit E. coli, reinforcing the suggestion about a difference in regions' chemotype.

Suppose carrying out a comparison of other species from each Gram class to attempt an extrapolation of activity observed with E. coli and S. aureus, and considering the risk in which such species K. pneumoniae, P. aeruginosa, A. baumannii, E. hireae, and L. monocytogenes may be incriminated (food safety issues, nosocomially acquired infections...). Data analysis of the subsequent studies [86, 143, [149] [150] [151] showed that we could not cluster inhibition activity following bacterial species or Cistus species. The same extract might exert a different effect on strains from the same Gram class, even from the same genus. For example, raw extract of C. monspeliensis demonstrated a significant inhibition against P. aeruginosa (MIC = 0.625 mg/mL) while it did not affect K. pneumoniae [149] , which was sensitive to ethanolic extract from C. laurifolius (MIC = 0.032 mg/mL) [126] . However, if taken independently, L. monocytogenes was more sensitive to ethanolic extract from C. salviifolius (MIC = 0.515 mg/mL) [152] than ethanolic extract from C. crispus (MIC = 8 mg/mL) [99] . Based on these observations and the chemical class differences in each solvent used for extraction, the report of Ustun [126] raises several questions about how a strain presents the same sensitivity profile against all extracts tested (MIC of A. baumannii 0.032 with hexane, chloroform, butanol, ethanol and remaining aqueous extracts).

On the other hand, few studies were done with clinical isolates and resistant strains. According to Ben Sassi [149] , none of the tested extracts was active against isolated bacteria (E. coli, K. penumoniae, E. cloaceae, S. marcescens, A. hyrdophila, S. aureus) except for S. epidermidis and S. saprophyticus. Viapiana [31] have reported the activity of aqueous extract of C. incanus against MRSE (MIC 1 mg/mL) and MRSA (MIC 0.5 mg/mL). Furthermore, this is the only work done against H. pylori and S. pyogenes. This might be due to difficulty maintaining cultures. However, MICs reports were moderate (64 and 8 mg/mL for H. pylori and S. pyogenes, respectively). Nevertheless, there is great hope with this species since C. incanus is widely used as herbal tea.

A short communication published in Natural Product Research reports the potential of ethanolic extract of C. ladaniferus against several strains. Clinical samples of H. pylori were more sensitive than reference strain. Also B. cereus was inhibited at 0.625 mg/mL [153] . Ahlem [154] and Mahmoudi have demonstrated the overall activity of leaves ethanolic extract from C. monspeliensis compared to C. salviifolius. However, the patterns of inhibition varied.

It is not entirely clear why phytochemists and microbiologists have not further researched mycobacteria, even if WHO reports a total of 1.5 million people died from tuberculosis in 2018. Pharmaceutical companies are spending many resources searching for new agents. To our best knowledge, the only report about the antimycobacterial effect with Cistus extracts is from C. albidus, C. salviifolius, and C. monspeliensis by the Iraqui team. Results show complete inhibition of these species against atypical mycobacteria and M. bovis. Even the lack of details and referenced methods to study the activity against this particular strain gives us hope that further research may eventually lead to potential agents [155, 156] .

The very nature of the disease being studied may play a significant role in whether effective natural products will be identified for its treatment. Interestingly, patients reported that the ingestion of tea infusion and aqueous dry extract in the capsule from C. creticus had improved their clinical conditions related to Lyme borreliosis disease. Hence, it was confirmed first by Hutschenreuther [68] whose total stagnation of B. burgdorferi s.s in vitro growth at 0.2% concentration of EO. EO was dominated by labdane-type manoyloxides and carvacrol, while none of the polar extracts has exhibited activity against tested strain. Years later, Rauwald [157] aimed to clarify the anti-Borrelia active component already reported. Bioassay-guided procedure on Crete C. creticus led to the confirmation and isolation of carvacrol and four manoyloxide, in which epi-manoyloxide was the strongest antispirochaetal whose effect was equal to amoxicillin (Table 7) .

A minimal number of studies carried out the anti-adhesive activity of Cistus extracts (Table 8 ). To reinforce the use of C. incanus herbal tea (from Dr. Pandalis) as an appropriate alternative available in everyday life and verify its possible exploitation in dentistry as well. The study of Hanning [158] showed that the impact of cistus-tea on initial oral biofilm using a model. Indeed, the fluorescence microscopy showed a pronounced reduction of initial bacterial colonization due to rinses with cistus-tea. Furthermore, another report in the same field has demonstrated the potential of ethanolic extract from C. ladaniferus against P. aeruginosa marine bacterium, which accelerates the corrosion of 304 L Stainless Steel. The HPLC-Q-TFO-MS analysis revealed many phenolics compounds, which show antibacterial effects and corrosion inhibition [159] . Rinses with cistus-tea rich with polyphenols have reduced initial bacterial colonization (visualized by microscopic fluorescence method) on enamel in situ. Also, enzymes present in the pellicle were conserved and not affected by compounds present in the extract.

[158]

C. ladaniferus Taza, Morocco Leaves Ethanol P. aeruginosa 304 L SS coupons P. aeruginosa accelerates the corrosion rate, while the compounds present in ethanolic extract demonstrate a dual effect: damage in the morphology of bacterial cell membrane and adsorption on a surface. That changes physicochemical proprieties and led to the formation of the non-conducting protective layer, which inhibited the 304 L SS coupon surface's biocorrosion.

[159]

P. aeruginosa: Pseudomonas aeruginosa.

Cistus is a Mediterranean native genus of shrubs belonging to the family Cistaceae. Species of this genus can grow during hot summers and after wildfires. Cistus species are most widespread in the Mediterranean region, whilst some of them are endemic. Cistus plants can grow under slightly different environmental conditions. Most species are very fragrant and sweet-smelling. Studies have reported that Cistus species are riches in polyphenolic compounds. Meanwhile, C. incanus and C. albidus are riche in flavonoids. C. ladaniferus, C. salviifolius, C. laurifolius, C. monspeliensis, and C. libanotis are mainly enriched ellagitannins and flavonoids. Terpenes were identified in C. ladaniferus and C. laurifolius. Diterpenes were reported in C. monspeliensis, C. libanotis, C. villosus, and C. creticus. While sesquiterpenes were detected in C. albidus and C. salviifolius.

Cistus species have long been used as remedies in traditional folk medicines of different populations around the world. The crude extracts and EO of these herbs have been effective against inflammation, would and skin disease, various microbial infections, diabetes, pain, arterial hypertension. Cistus EO is approved by the Food & Drug Administration (FDA) as a food additive and flavoring agent. Due to the increasing interest in natural products and the benefits of Cistus species, EO, labdanum, bee pollen, and tea are owning a significant mark in herbal products. It was reported that C. monspeliensis has the function of promoting energy metabolism pathways in human intestinal epithelial cells. Extracts from C. incanus are used as a dietary supplement to prevent chronic diseases due to their higher and diverse phenolic compounds. These characteristics can be much appreciable for being exploited in the food industry.

Previous summarized works in this review have indicated and confirmed the broad biological potentials of Cistus plant extracts. In in vivo model, Cistus showed anti-influenza, analgesic, anti-inflammatory, and spasmolytic potentials. In the in vitro model, Cistus showed promising effects against HIV, Ebola, Marburg virus, and clinical bacteria.

We can confirm that Cistus can constitute a great source of drug discovery. However, besides all the beneficial attributes of this plant as well investigated above, it is essential to highlight some limitations. Some species belonging to Cistus can exhibit in vivo toxic effects. Moreover, extracts from some Cistus species were reported to be active in vitro only.

The present review sheds light on the antimicrobial activity of Cistus sp. In this sense, we can conclude that this genus has great potential to serve society as it provides promising chemicals to fight such infections. 

The data used to support the findings of this study are available from the corresponding author upon request.

The growing use of herbal medicines: Issues relating to adverse reactions and challenges in monitoring safety

Ethnobotanical study of medicinal plants from Ghana; Confirmation of ethnobotanical uses, and review of biological and toxicological studies on medicinal plants used in Apra Hills Sacred Grove

Ethnomedicinal Plants Used by the ethnic Communities of Tinsukia District of Assam

Anti-paralytic medicinal plants-Review

Plant Products as Antimicrobial Agents

Natural products research: Perspectives from a major pharmaceutical company

Antibacterial constituents of the plant family Amaryllidaceae

Natural Products As Sources of New Drugs over the 30 Years from 1981 to 2010

Anti-infective potential of natural products: How to develop a stronger in vitro 'proof-of-concept

Recent Advances in the Chemistry of Bioactive Compounds from Plants and Soil Microbes: A Review

Anticancer attributes of Illicium verum essential oils against colon cancer

Health-Promoting Components of Fruits and Vegetables in the Diet

Phytochemicals: Extraction, Isolation, and Identification of Bioactive Compounds from Plant Extracts

Advances in nanoparticle and microparticle delivery systems for increasing the dispersibility, stability, and bioactivity of phytochemicals

The determination of flavonoid contents in mulberry and their scavenging effects on superoxide radicals

The Antioxidant Activity of Vegetable Extracts I. Flavone Aglycones

Pharmacologically active flavonoids from the anticancer, antioxidant and antimicrobial extracts of Cassia angustifolia Vahl

Plant Science and Human Nutrition: Challenges in Assessing Health-Promoting Properties of Phytochemicals

Dietary inclusion effects of phytochemicals as growth promoters in animal production

Review on potential phytocompounds in drug development for Parkinson disease: A pharmacoinformatic approach

Naturally occurring tyrosinase inhibitors: Mechanism and applications in skin health, cosmetics and agriculture industries

Conservation status of habitats (Directive 92/43 EEC) of coastal and low hill belts in a Mediterranean biodiversity hot spot (Gargano-Italy)

Red List evaluation of the Orchidaceae endemic to Apulia (Italy) and considerations on the application of the IUCN protocol to rare species

Ecological and Plant Community Implication on Essential Oils Composition in Useful Wild Officinal Species: A Pilot Case Study in Apulia (Italy)

Ethnobotanical notes about medicinal and useful plants of the Reventino Massif tradition (Calabria region, Southern Italy)

Exploring Plant-Based Ethnomedicine and Quantitative Ethnopharmacology: Medicinal Plants Utilized by the Population of Jasrota Hill in Western Himalaya

Ecological rather than geographical isolation dominates Quaternary formation of Mediterranean Cistus species

Antiproliferative and cytotoxic activity of extracts from Cistus incanus L. And Cistus monspeliensis L. on human prostate cell lines

Cistus incanus L. extract inhibits Aflatoxin B1 production by Aspergillus parasiticus in macadamia nuts

Cistus incanus L. commercial products as a good source of polyphenols in human diet

Intra-and Interspecific Variation in DNA Content in Cistus (Cistaceae)

Systematics, character evolution, and biogeography of Cistus L. (Cistaceae) based on ITS, trnL-trnF, and matK sequences

Molecular systematics, character evolution, and pollen morphology of Cistus and Halimium (Cistaceae)

Ability of Cistus L. shrubs to promote soil rehabilitation in extensive oak woodlands of Mediterranean areas

Physiological, morphological and anatomical trait variations between winter and summer leaves of Cistus species

Germination and Population Dynamics of Cistus Species in Relation to Fire

Two alleles of rpoB and rpoC1 distinguish an endemic European population from Cistus heterophyllus and its putative hybrid (C. clausonis) with C. albidus

Aromatic plants as a source of important phytochemicals: Vitamins, sugars and fatty acids in Cistus ladanifer, Cupressus lusitanica and Eucalyptus gunnii leaves

Antiproliferative activity of hexane extract from Tunisian Cistus libanotis, Cistus monspeliensis and Cistus villosus

Photosynthetic limitations in response to water stress and recovery in Mediterranean plants with different growth forms

The role of phenology, growth and nutrient retention during leaf fall in the competitive potential of two species of mediterranean shrubs in the context of global climate changes

Population genetic structure of Cistus ladanifer L. (Cistaceae) and genetic differentiation from co-occurring Cistus species

Earlier summer drought affects leaf functioning of the Mediterranean species Cistus monspeliensis L

Essential Oils in Food Preservation, Flavor and Safety

Identification and Effects of Interaction Phytotoxic Compounds from Exudate of Cistus ladanifer Leaves

Plant growth inhibiting flavonoids in exudate of Cistus ladanifer and in associated soils

Simultaneous LC-DAD and LC-MS Determination of Ellagitannins, Flavonoid Glycosides, and Acyl-Glycosyl Flavonoids in Cistus salvifolius L. Leaves

A systematic study of the polyphenolic composition of aqueous extracts deriving from several Cistus genus species: Evolutionary relationship

Diversity and divergence in Cistus salvifolius (L.) populations from contrasting habitats

Chemotaxonomie der Pflanzen: Eine Ubersicht uber die Verbreitung und die Systematische Bedeutung der Pflanzenstoffe

A rearranged labdane: Salmantic acid from Cistus laurifolius

Diterpenoid and other components of Cistus laurifolius

A New Labdane-Type Diterpene and Other Compounds from the Leaves of Cistus incanus ssp. creticus

Natural Metabolites of ent-13-epi-Manoyl Oxide and Other Cytotoxic Diterpenes from the Resin "LADANO" of Cistus creticus

Ring a functionalized Neo-clerodane diterpenoids from Cistus populifolius

Classics in Spectroscopy: Isolation and Structure Elucidation of Natural Products

Diterpene esters of malonic acid from the resin 'Ladano' of Cistus creticus

Diurnal and seasonal variation of the essential oil labdanes and clerodanes from Cistus monspeliensis L. leaves

Tundis, R. Chemistry and functional properties in prevention of neurodegenerative disorders of five Cistus species essential oils

Ibn Mansour, A. Composition of the Essential Oils of Cistus ladaniferus and C. monspeliensis from Morocco

Variabilité de la Composition des Huiles Essentielles et Intérêt de la Notion de Chémotype en Aromathérapie

Characterization of the Portuguese-Grown Cistus ladanifer Essential Oil

Comparison of essential oil composition of two varieties of Cistus ladanifer

Simultaneous distillation-extraction of high-value volatile compounds from Cistus ladanifer L

Growth inhibiting activity of volatile oil from Cistus creticus L. against Borrelia burgdorferi s.s. in vitro

Composition and Antimicrobial Activity of the Essential oil of Cistus criticus L

Composition and Antimicrobial Activity of the Essential Oil of Cistus criticus subsp. eriocephalus

Morphological, chemical and genetic differentiation of two subspecies of Cistus creticus L. (C. creticus subsp. eriocephalus and C. creticus subsp. corsicus)

Essential oil composition of Cistus albidus leaves

In vivo volatiles emission and essential oils from different organs and pollen of Cistus albidus from Caprione

Detailed analysis of the essential oil from Cistus albidus L. by combination of GC/RI, GC/MS and 13C-NMR spectroscopy

A comparative study of the essential oils of Cistus salviifolius in several populations of Crete (Greece)

Phenolic compounds in Cistus incanus herbal infusions-Antioxidant capacity and thermal stability during the brewing process

Antioxidant effects of flavonoid from Croatian Cystus incanus L. rich bee pollen

Antioxidant activity and chemical composition of three Tunisian Cistus: Cistus monspeliensis Cistus villosus and Cistus libanotis

In vivo and in vitro antidiabetic effect of Cistus laurifolius L. and detection of major phenolic compounds by UPLC-TOF-MS analysis

Diversity and host range of foliar fungal endophytes: Are tropical leaves biodiversity hotspots? Ecology

Platelet anti-aggregant property of some Moroccan medicinal plants

Relaxant effect of aqueous extract of Cistus ladaniferus on rodent intestinal contractions

Evaluation of hypoglycemic and hypolipidemic activities of aqueous extract of Cistus ladaniferus in streptozotocin-induced diabetic rats

Antihypertensive and endothelium-dependent vasodilator effects of aqueous extract of Cistus ladaniferus

In Vivo Anti-Inflammatory and Analgesic Effects of Aqueous Extract of Cistus ladanifer L. From Morocco

Cistaceae aqueous extracts containing ellagitannins show antioxidant and antimicrobial capacity, and cytotoxic activity against human cancer cells

Acute and sub-chronic toxicity studies of the aqueous extract from leaves of Cistus ladaniferus L. in mice and rats

Biological activity of myricetin and its derivatives against human leukemic cell lines in vitro

Cytotoxic and Anti-Inflammatory Activity of Labdane and cis-Clerodane Type Diterpenes

Determination of Phenol Content and Antibacterial Activity of Five Medicinal Plants Ethanolic Extracts from North-West of Morocco

Antioxidant Activity and Inhibitory Potential of Cistus salviifolius (L.) and Cistus monspeliensis (L.) Aerial Parts Extracts against Key Enzymes Linked to Hyperglycemia

Antioxidant oligomeric proanthocyanidins from Cistus salvifolius

Chemical composition, biological and cytotoxic activities of Cistus salviifolius flower buds and leaves extracts

In vivo anti-inflammatory and analgesic activities of Cistus salviifolius (L.) and Cistus monspeliensis (L.) aqueous extracts

Screening of a hundred plant extracts as tyrosinase and elastase inhibitors, two enzymatic targets of cosmetic interest

Indigenous knowledge of the use of medicinal plants in the North-West of Morocco and their biological activities

Antioxidant Capacity as a Marker for Assessing the In Vitro Performance of the Endangered Cistus heterophyllus

Drought-induced changes in flavonoids and other low molecular weight antioxidants in Cistus clusii grown under Mediterranean field conditions

In vitro antiproliferative activity of selected medicinal plants from the North-West of Morocco on several cancer cell lines

Cytotoxic Activity of Labdane Type Diterpenes Against Human Leukemic Cell Lines in vitro

Labdane-type diterpenes: Thermal effects on phospholipid bilayers, incorporation into liposomes and biological activity

Cytotoxic activity of ethanol extracts of in vitro grown Cistus creticus subsp. creticus L. on human cancer cell lines

Ethnobotanical survey of medicinal plants used in the traditional treatment of diabetes in Chtouka Ait Baha and Tiznit

Relationships among nutritive value of selected forages, diet composition and milk quality in goats grazing in a Mediterranean woody rangeland

Cistus incanus and Cistus monspeliensis inhibit the contractile response in isolated rat smooth muscle

Cytotoxic and antitumor activity of liposomeincorporated sclareol against cancer cell lines and human colon cancer xenografts

Conditions of prooxidant activity of cistus and pomegranate polyphenols in v79 cell cultures

Inhibitory effects of Turkish folk remedies on inflammatory cytokines: Interleukin-1α, interleukin-1β and tumor necrosis factor α

Prostaglandin inhibitory and antioxidant components of Cistus laurifolius, a Turkish medicinal plant

Flavonoids with anti-inflammatory and antinociceptive activity from Cistus laurifolius L. leaves through bioassay-guided procedures

Analgesic Activity of Cistus laurifolius in Mice

Effect of Cistus laurifolius L. leaf extracts and flavonoids on acetaminophen-induced hepatotoxicity in mice

Anticholinesterase and antioxidant effects of the ethanol extract, ethanol fractions and isolated flavonoids from Cistus laurifolius L. leaves. Food Chem

Inhibitory Effect of Traditional Turkish Folk Medicines on Aldose Reductase (AR) and Hematological Activity, and on AR Inhibitory Activity of Quercetin-3-O-methyl Ether Isolated from Cistus laurifolius L

A model for exploring labdane-type diterpenes' biosynthesis and a natural source of high value products with biological, aromatic, and pharmacological properties

Biological properties of Cistus species

Current antiviral drugs and their analysis in biological materials-Part II: Antivirals against hepatitis and HIV viruses

Antiviral activity of Plantago major extracts and related compounds in vitro

Antiviral activity of leaves extracts of Marrubium alysson L

CYSTUS052, a polyphenol-rich plant extract, exerts anti-influenza virus activity in mice

A polyphenol rich plant extract, CYSTUS052, exerts anti influenza virus activity in cell culture without toxic side effects or the tendency to induce viral resistance

Potent in vitro antiviral activity of Cistus incanus extract against HIV and Filoviruses targets viral envelope proteins

What caused the Black Death?

The old pharmaceutical oleoresin labdanum of Cistus creticus L. exerts pronounced in vitro anti-dengue virus activity

Bioactivities of ethanolic extract and its fractions of Cistus laurifolius L. (Cistaceae) and Salvia wiedemannii Boiss. (Lamiaceae) species

Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study

Evaluation of the antimalarial and antileishmanial activity of plants from the Greek island of Crete

Antileishmanial Activity of Natural Diterpenes from Cistus sp. and Semisynthetic Derivatives Thereof

Antileishmanial potential of medicinal plant extracts from the North-West of Morocco. Beni-Suef Univ

Antimicrobial activities of the leaf extracts of two Moroccan Cistus L. species

Antifungal activity and detailed chemical characterization of Cistus ladanifer phenolic extracts

Super foods and Super herbs: Antioxidant and Antifungal Activity

Chemical composition, antioxidant, antimicrobial and antifungal activity of Moroccan Cistus creticus leaves

Antifungal activity of Moroccan plants against citrus fruit pathogens

Antifungal activity of some Moroccan plants against Geotrichum candidum, the causal agent of postharvest citrus sour rot

Use of Cistus aqueous extracts as botanical fungicides in the control of Citrus sour rot

Antifungal properties of organic extracts of eight Cistus L. species against postharvest citrus sour rot

Effect of Moroccan Cistus ladaniferus L. (rockrose) extracts on the growth of four fungi

Cistus ladanifer L. essential oil as a plant based preservative against molds infesting oil seeds, aflatoxin B1 secretion, oxidative deterioration and methylglyoxal biosynthesis

Comparison of antioxidant and antimicrobial activities of two cultivated Cistus species from Tunisia

Chemical Analysis and Antimicrobial Activity of the Resin Ladano, of its Essential Oil and of the Isolated Compounds

Primary Mode of Action of Cistus ladaniferus L. Essential Oil Active Fractions on Staphylococcus aureus Strain

Chemical Composition, Antibacterial, Antibiofilm and Synergistic Properties of Essential Oils from Eucalyptus globulus Labill. and Seven Mediterranean Aromatic Plants

Antibacterial activity of essential oils from Cistus ladaniferus L. and Lavandula stoechas L

Screening essential oils for their antimicrobial activities against the foodborne pathogenic bacteria Escherichia coli and Staphylococcus aureus

Structure elucidation and conformational properties of a novel bioactive clerodane diterpene using a combination of high field NMR spectroscopy, computational analysis and X-ray diffraction

Antibacterial potential of the Cistus incanus L. phenolics as studied with use of thin-layer chromatography combined with direct bioautography and in situ hydrolysis

Investigation of Some Medicinal Plants from Tunisia for Antimicrobial Activities

Correlation between the antibacterial activity and the composition of extracts derived from various Spanish Cistus species

Antibacterial activities of the crude ethanol extracts of medicinal plants against Listeria monocytogenes and some other pathogenic strains

Screening of antimicrobial activity of Cistus ladanifer and Arbutus unedo extracts

Antibacterial and Antifungal Activities of Ethanol Extracts of Halimium halimifolium, Cistus salviifolius and Cistus monspeliensis

Évaluation de l'effet antimycobactérien de plantes du centre-nord du Maroc

Activité antimycobactérienne des extraits de deux espèces marocaines du genre Cistus

Labdanum and Labdanes of Cistus creticus and C. ladanifer: Anti-Borrelia activity and its phytochemical profiling

Effects of Cistus-tea on bacterial colonization and enzyme activities of the in situ pellicle

Mitigation of microbiologically influenced corrosion of 304L stainless steel in the presence of Pseudomonas aeruginosa by Cistus ladanifer leaves extract

Antibacterial activities of the methanol extracts of Cinnamomum cassia Cistus monspeliensis and three other medicinal plants against multi-drug resistant Gram-negative bacteria

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through research group no (RG-1441-360).

The authors declare no conflict of interest.Plants 2021, 10, 1214