The aryl hydrocarbon receptor at the forefront of host-microbe interactions in the skin: A perspective on current knowledge gaps and directions for future research and therapeutic applications.

The skin is home to a community of skin microbiota including bacteria, viruses and fungi, which are widely accepted to be of importance for skin homeostasis but also associated with skin diseases. Detailed knowledge on the skin microbiota composition and its changes in a number of skin diseases is available. Yet, specific interactions between microbes and the host skin cells or how they communicate with each other are less well understood. To identify, understand and eventually therapeutically exploit causal relationships of microbial dysbiosis with disease, studies are required that address the receptors and mediators involved in host-microbe interactions. In this perspective article, we provide an outlook on one of such receptors, namely the aryl hydrocarbon receptor (AHR). The AHR is well known for being a ligand-activated transcription factor regulating the proliferation, differentiation and function of many cell types present in the skin. Its targeting by anti-inflammatory therapeutics such as coal tar and Tapinarof is effective in atopic dermatitis and psoriasis. AHR signalling is activated upon binding of wide variety of small chemicals or ligands, including microbiota-derived metabolites. New evidence has emerged pointing towards a key role for epidermal AHR signalling through skin microbiota-derived metabolites. In response, AHR-driven expression of antimicrobial peptides and stratum corneum formation may alter the skin microbiota composition. This a self-perpetuating feedback loop calls for novel therapeutic intervention strategies for which we herein discuss the requirements in future mechanistic studies.

Compositions and antimicrobial properties of binary ZnO-CuO nanocomposites encapsulated calcium and carbon from Calotropis gigantea targeted for skin pathogens.

Calotropis gigantea (C. gigantea) extract with an ecofriendly nanotechnology approach could provide promising antimicrobial activity against skin pathogens. This study investigates the antimicrobial capability of green synthesized binary ZnO-CuO nanocomposites from C. gigantea against non-MDR (Staphylococcus aureus and Escherichia coli) and MDR (Klebsiella pneumoniae, Pseudomonas aeruginosa and methicillin-resistant S. aureus) skin pathogens. Scanning electron microscopy and transmission electron microscopy revealed the size and shape of B3Z1C sample. Results of X-ray powder diffraction, energy-dispersive spectroscopy, FTIR and UV-Vis spectroscopy analyses confirmed the presence of mixed nanoparticles (i.e., zinc oxide, copper oxide, carbon and calcium) and the stabilising phytochemical agents of plant (i.e., phenol and carbonyl). Antimicrobial results showed that carbon and calcium decorated binary ZnO-CuO nanocomposites with compositions of 75 wt% of ZnO and 25 wt% CuO (B3Z1C) was a strong bactericidal agent with the MBC/MIC ratio of ≤ 4 and ≤ 2 for non-MDR and MDR pathogens, respectively. A significant non-MDR zone of inhibitions were observed for BZC by Kirby-Bauer disc-diffusion test. Further time-kill observation revealed significant fourfold reduction in non-MDR pathogen viable count after 12 h study period. Further molecular studies are needed to explain the biocidal mechanism underlying B3Z1C potential.

Looking for NTDs in the skin; an entry door for offering patient centered holistic care.

INTRODUCTION: The majority of neglected tropical diseases (NTDs) have established primary skin manifestations or associated clinical feature. Skin NTDs often result in physical impairment and disfigurement, which can lead to disability. Skin diseases have been proposed as an entry point for integrated NTDs control. However, the magnitude and overlap of skin NTDs is poorly understood. METHODOLOGY: An institution-based cross-sectional study was done using medical records of dermatology patients between July 2017 and June 2018 in a dermatology service in Northeast Ethiopia. A total of 661 patient records were selected using simple random sampling. RESULTS: A total of 656 complete records were included in analysis. Skin NTDs constituted 17.2% (n = 113) of the overall of skin diseases. Of skin NTDS, cutaneous leishmaniasis (n = 40; 35.4%), leprosy (n = 38; 33.6%), and scabies (n = 31; 27.4%) were the most common. Additionally, there were four cases of mycetoma. Of the non NTDs, poverty-related infections such as superficial fungal (n = 118; 21.1%) and bacterial (n = 33; 5.2%) infections were also frequent. Tinea capitis was the most common superficial fungal infections. Impetigo and cellulitis were the predominant bacterial infections. CONCLUSIONS: Skin NTDsand other poverty related skin infections were common at the dermatology service. Dermatological services could act as a good entry point for integrated management of skin NTDs. Future studies should assess how different preventive strategies like contact tracing, early diagnosis and mass drug administration can be integrated.

Treatment Strategies for Infected Wounds.

The treatment of skin wounds is a key research domain owing to the important functional and aesthetic role of this tissue. When the skin is impaired, bacteria can soon infiltrate into underlying tissues which can lead to life-threatening infections. Consequently, effective treatments are necessary to deal with such pathological conditions. Recently, wound dressings loaded with antimicrobial agents have emerged as viable options to reduce wound bacterial colonization and infection, in order to improve the healing process. In this paper, we present an overview of the most prominent antibiotic-embedded wound dressings, as well as the limitations of their use. A promising, but still an underrated group of potential antibacterial agents that can be integrated into wound dressings are natural products, especially essential oils. Some of the most commonly used essential oils against multidrug-resistant microorganisms, such as tea tree, St. John's Wort, lavender and oregano, together with their incorporation into wound dressings are presented. In addition, another natural product that exhibits encouraging antibacterial activity is honey. We highlight recent results of several studies carried out by researchers from different regions of the world on wound dressings impregnated with honey, with a special emphasis on Manuka honey. Finally, we highlight recent advances in using nanoparticles as platforms to increase the effect of pharmaceutical formulations aimed at wound healing. Silver, gold, and zinc nanoparticles alone or functionalized with diverse antimicrobial compounds have been integrated into wound dressings and demonstrated therapeutic effects on wounds.

From Probiotic to Prebiotic Using Thermal Spring Water.

BACKGROUND: La Roche-Posay Thermal Spring Water (LRP-TSW) exhibits both probiotic and prebiotic properties enhancing the diversity of the skin microbiota. METHODS: A review was undertaken to explore the role of LRP-TSW as a topical probiotic and prebiotic therapy in improving the diversity of the skin microbiota and reducing dryness and pruritus in inflammatory skin diseases. RESULTS: The concentration of minerals and non-pathogenic microbes in LRP-TSW may explain its therapeutic benefit when used for inflammatory skin diseases. Clinical studies have shown that topical LRP-TSW treatment results in increases in Gram-negative bacteria with reduction of Gram-positive bacteria, and improvements in skin microbial diversity. At the same time skin condition in atopic dermatitis, psoriasis, and general dryness in otherwise healthy skin, has been shown to improve. CONCLUSIONS: Enhancement of skin microbiota diversity using topical LRP-TSW may offer a valuable option for the treatment and maintenance of inflammatory skin diseases. J Drugs Dermatol. 2018;17(6):657-662.

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Russian traditional medicine in dermatology.

The use of herbal remedies for various medical issues is becoming increasingly commonplace in all fields of medicine, and dermatology is no exception. This review focuses on traditional dermatologic herbal remedies, commonly used in Russia, as the rich array of 11 different plant zones has resulted in a great variety of medicinal plants. Herbal remedies warrant deeper investigation and research, especially due to their active substance content, which may interfere with or reinforce the effect of modern medications, something that medical professionals should be aware of when prescribing treatments. Although there are a great number of traditional herbal treatments in Russia, only the most commonly used and known treatments and applications will be described as an introduction to the field, which has had many books of varying quality written about it. The preparation and application of treatments for vitiligo, pyodermas, parasitic and infectious skin diseases, acne, dermatitides, rosacea, hyperpigmentation, rhytides, psoriasis, and hyperhidrosis are discussed.

Identification of Aspergillus tubingensis in a primary skin infection.

OBJECTIVE: Aspergillus section Nigri comprises a group of related species that include Aspergillus niger, A. welwitschiae, A. carbonarius, A. brasiliensis and A. tubingensis. Some of these species are morphologically very similar to A. niger but exhibit different patterns of susceptibility to antifungal agents; such is the case for A. tubingensis. Therefore, when diagnosing aspergillosis, it is important to identify the pathogen at the species level. This study aimed to identify the species of an Aspergillus spp. isolate (MM-82) obtained from a patient with a dermatosis localized to the right leg. MATERIALS AND METHODS: The MM-82 isolate was examined for macro- and microscopic morphology, conidia size and thermotolerance, and a phylogenetic analysis of a benA gene segment was performed for molecular identification. Susceptibility to antifungals was determined using antifungal microdilution according to the methodology of European Society of Clinical Microbiology and Infectious Diseases (EUCAST). RESULTS: Based on its phenotypic characteristics and the phylogenetic analysis of the sequence of a benA gene segment, the MM-82 isolate was identified as A. tubingensis. This fungus did not show resistance to antifungal agents commonly used for treatment. CONCLUSION: This study demonstrated that A. tubingensis can cause skin infection; this constitutes the first report of a case of aspergillosis caused by A. tubingensis in Mexico.

Endosymbiosis and its significance in dermatology.

Proposed at the beginning of the twentieth century to explain the origin of eukaryotic organelles from prokaryotes, endosymbiosis is now medically defined by various interaction patterns between microorganisms and their residing hosts, best exemplified by the bacterial endosymbiont Wolbachia identified in arthropods and filarial nematodes, which can influence normal development, reproduction, survival and transmission of the hosts. Based on the transmission modes, vertical or horizontal, and the function of the endosymbionts, the host-symbiont dependence can be divided into primary or secondary. In dermatology, the role of endosymbionts in skin ectoparasitosis has aroused great interests in the past years. Riesia pediculicola is a primary bacterial endosymbiont in body lice Pediculus humanus, and supplement their hosts with vitamin B, especially pantothenic acid. In cimicosis, the Gram-negative Wolbachia can synthesize biotin and riboflavin, which are crucial for the growth and reproduction of the bedbug Cimex lectularius. In human demodicosis and rosacea, further study is required to prove the pathogenic role of the Gram-negative bacteria Bacillus oleronius or the Gram-positive bacteria Bacillus cereus demonstrated in the Demodex mites. The high infection rate of adult female ticks Ixodes ricinus with the Gram-negative bacteria Midichloria mitochondrii present in the mitochondria in diverse ovarian cells, with the high seroprevalence rate in tick-exposed subjects, raises the possibility that this non-pathogenic endosymbiont may play a role in immune response and successful transmission of the tick-borne pathogen. The anaerobic protozoan Trichomonas vaginalis and bacteria Mycoplasma hominis are two obligate parasites in the urogenital epithelium, with partially overlapping symptoms. Intracellular localization of Mycoplasma hominis can avoid host immune response and penetration of antibiotics, while Trichomonas vaginalis infected with Mycoplasma hominis seems to have a higher cytopathic activity and amoeboid transformation rate. Further study on the biology and pathogenesis of different endosymbionts in dermatological parasitosis will help for the development of new treatment modalities.

La peau : un écosystème microbien: The skin: a microbial ecosystem.

Human hosts a large number of microorganisms that constitute its microbiome and the vast majority of them are very useful and even essentials. The human microbiome is a complex ecosystem where live populations of transient or resident microorganisms. The process of co-development or co-adaptation played a major role in the establishment of indigenous communities and help explain the dominance of positive interactions (commensal, symbiotic or mutualistic) in the human-microorganism relationship. The assimilation of nutrients, production of anti-inflammatory compounds, defense against pathogens, vitamin production or stimulating the immune system are some of the key benefits of the indigenous microorganisms. Understanding the skin microbiome opens new exploratory fields and represents a real challenge for both the academic knowledge and the development of new therapeutic approaches.

Evaluation of the Bacterial Diversity in the Human Tongue Coating Based on Genus-Specific Primers for 16S rRNA Sequencing.

The characteristics of tongue coating are very important symbols for disease diagnosis in traditional Chinese medicine (TCM) theory. As a habitat of oral microbiota, bacteria on the tongue dorsum have been proved to be the cause of many oral diseases. The high-throughput next-generation sequencing (NGS) platforms have been widely applied in the analysis of bacterial 16S rRNA gene. We developed a methodology based on genus-specific multiprimer amplification and ligation-based sequencing for microbiota analysis. In order to validate the efficiency of the approach, we thoroughly analyzed six tongue coating samples from lung cancer patients with different TCM types, and more than 600 genera of bacteria were detected by this platform. The results showed that ligation-based parallel sequencing combined with enzyme digestion and multiamplification could expand the effective length of sequencing reads and could be applied in the microbiota analysis.

White-nose syndrome pathology grading in Nearctic and Palearctic bats.

While white-nose syndrome (WNS) has decimated hibernating bat populations in the Nearctic, species from the Palearctic appear to cope better with the fungal skin infection causing WNS. This has encouraged multiple hypotheses on the mechanisms leading to differential survival of species exposed to the same pathogen. To facilitate intercontinental comparisons, we proposed a novel pathogenesis-based grading scheme consistent with WNS diagnosis histopathology criteria. UV light-guided collection was used to obtain single biopsies from Nearctic and Palearctic bat wing membranes non-lethally. The proposed scheme scores eleven grades associated with WNS on histopathology. Given weights reflective of grade severity, the sum of findings from an individual results in weighted cumulative WNS pathology score. The probability of finding fungal skin colonisation and single, multiple or confluent cupping erosions increased with increase in Pseudogymnoascus destructans load. Increasing fungal load mimicked progression of skin infection from epidermal surface colonisation to deep dermal invasion. Similarly, the number of UV-fluorescent lesions increased with increasing weighted cumulative WNS pathology score, demonstrating congruence between WNS-associated tissue damage and extent of UV fluorescence. In a case report, we demonstrated that UV-fluorescence disappears within two weeks of euthermy. Change in fluorescence was coupled with a reduction in weighted cumulative WNS pathology score, whereby both methods lost diagnostic utility. While weighted cumulative WNS pathology scores were greater in the Nearctic than Palearctic, values for Nearctic bats were within the range of those for Palearctic species. Accumulation of wing damage probably influences mortality in affected bats, as demonstrated by a fatal case of Myotis daubentonii with natural WNS infection and healing in Myotis myotis. The proposed semi-quantitative pathology score provided good agreement between experienced raters, showing it to be a powerful and widely applicable tool for defining WNS severity.

Recreational Waterborne Illnesses: Recognition, Treatment, and Prevention.

Illness after recreational water activities can be caused by a variety of agents, including bacteria, viruses, parasites, algae, and even chlorine gas. These illnesses are more common in summer. Waterborne illnesses are underreported because most recreational activity occurs in unsupervised venues or on private property, and participants tend to disperse before illness occurs. Symptoms of waterborne illness are primarily gastrointestinal, but upper respiratory and skin manifestations also occur. Gastrointestinal symptoms are usually self-limited, and supportive treatment may be all that is necessary. However, some infections can cause significant morbidity and mortality. Cryptosporidium and Giardia intestinalis are the most common cause of gastrointestinal illness and have partial chlorine resistance. Respiratory infections are typically mild and self-limited. However, if legionnaires' disease develops and is unrecognized, mortality may be as high as 10%. Cellulitis caused by Vibrio vulnificus can result in serious illness, amputation, and death. Early and appropriate antibiotic treatment is important. Chronically ill and immunocompromised persons are at high risk of infection and should be counseled accordingly.

Preliminary investigations into developing all-D Omiganan for treating Mupirocin-resistant MRSA skin infections.

Staphylococcus aureus is the primary pathogen responsible for the majority of human skin infections, and meticillin-resistant S. aureus (MRSA) currently presents a major clinical concern. The overuse of Mupirocin, the first-line topical antibacterial drug over 30 years, has led to the emergence of Mupirocin-resistant MRSA, creating a clinical concern. The antimicrobial peptide Omiganan was touted to be a promising antibacterial drug candidate due to its rapid membrane-disrupting bactericidal mode of action, entering clinical trials in 2005 as a topical gel to prevent catheter site infections. However, drug development ceased in 2009 due to a lack of efficacy. We postulate this to be due to proteolytic degradation caused by endogenous human skin proteases. Herein, we tested our hypothesis using Omiganan and its all-D enantiomer in a human skin protease stability assay, followed by anti-MRSA activity assay against of a panel of clinical MRSA isolates, a bactericidal/static determination and a time-kill assay to gauge all-D Omiganan's potential for further topical antibacterial drug development.

IN VITRO EFFICACY OF EXTRACTS FROM PLANTS USED BY SMALL-HOLDER FARMERS IN THE TREATMENT OF DERMATOPHILOSIS IN CATTLE.

BACKGROUND: Bovine dermatophilosis, an important skin disease of cattle caused by Dermatophilus congolensis, negatively impacts the livelihoods of small-holder farmers in Zimbabwe. This impact is through, morbidity, loss of draught animal power, costs incurred to manage the disease, losses associated with devalued damaged hides and the resultant culling of some of the affected cattle. Due to the inaccessibility of conventional drugs to manage bovine dermatophilosis, farmers have been reported to use local medicinal plants to manage the disease. The aim of the study was to evaluate the in vitro antimicrobial activities of three plants that small-holder farmers in Zimbabwe used to manage bovine dermatophilosis. METHODS: Dried plant materials were ground into powder and extracted individually using, water, 80 % acetone and 80 % methanol. The antimicrobial properties of the plants were evaluated against two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and one Gram-positive (Staphylococcus aureus) reference bacterial strains. They were further evaluated against a field isolate of Dermatophilus congolensis. The assays used were the disc diffusion, minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). RESULTS: Acetone and methanol extracts had superior inhibitory activities than did those of water. Pterocarpus angolensis DC extracts had better inhibitory properties with absolute MIC values of 0.156 - 5 mg/ml, Cissus Quadrangularis L had MIC values in the range 0.156 - 5 mg/ml while that of Catunaregam spinosa Thunb, Terveng was 0.156 - 10 mg/ml. Dermatophilus congolensis was more sensitive to Pterocarpus angolensis DC average MIC = 0.63 mg/ml than to Cissus quadrangularis L average MIC = 1.25 mg/ml and Catunaregam. spinosa Thunb, Terveng average MIC = 2.08 mg/ml. CONCLUSION: These results suggest the potential antibacterial activities of extracts of the three plants and hence farmers are, in a way, justified in using the plants. Better results (lower MIC) could be obtained by extracting and evaluating pure active compounds of the plants.

Antifungal and antioxidant activities of Coleonema album and C. pulchellum against skin diseases.

CONTEXT: Coleonema album (Thunb) Bart. & H. L. Wendl (Rutaceae) has been used in the formulation of skincare products, and the Khoisan people rub it on their skin to add luster. Coleonema pulchellum I. Williams has received less attention in the South African traditional medicine. OBJECTIVE: This study investigates the antifungal and antioxidant activities of C. album and C. pulchellum essential oil (EO) and leaf extracts; and analyzes the chemical components of their EOs. MATERIALS AND METHODS: Antifungal activity of leaf extracts was determined using the microdilution method with griseofulvin and ketoconazole as controls. Antifungal capacity of EO was investigated using the 'Volatile release plate method'. Trichophyton rubrum (ATCC 28188) and T. mentagrophytes (ATCC 9533) mycelia (0.3 cm diameter) were placed on fresh yeast malt agar in Petri dishes with filter paper (impregnated with 20 µL of EO) on the lid for direct exposure to EO volatiles while plates without EO were used as controls. The incubation time was seven days. Antioxidant activities of the leaf extracts were determined. RESULTS: Methanol leaf extract of C. pulchellum inhibited the growth of three fungi tested with MIC values of 195, 391 and 49 µg/mL for Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum gypseum, respectively. Terpenes formed the major components of the EO. The EO from both plants inhibited the growth of T. rubrum in vitro. DISCUSSION AND CONCLUSION: This study revealed the therapeutic value of C. pulchellum. Coleonema album and C. pulchellum should be considered as potential plants for skin ointment from natural origin.

Virulence Inhibitors from Brazilian Peppertree Block Quorum Sensing and Abate Dermonecrosis in Skin Infection Models.

Widespread antibiotic resistance is on the rise and current therapies are becoming increasingly limited in both scope and efficacy. Methicillin-resistant Staphylococcus aureus (MRSA) represents a major contributor to this trend. Quorum sensing controlled virulence factors include secreted toxins responsible for extensive damage to host tissues and evasion of the immune system response; they are major contributors to morbidity and mortality. Investigation of botanical folk medicines for wounds and infections led us to study Schinus terebinthifolia (Brazilian Peppertree) as a potential source of virulence inhibitors. Here, we report the inhibitory activity of a flavone rich extract "430D-F5" against all S. aureus accessory gene regulator (agr) alleles in the absence of growth inhibition. Evidence for this activity is supported by its agr-quenching activity (IC50 2-32 µg mL-1) in transcriptional reporters, direct protein outputs (α-hemolysin and δ-toxin), and an in vivo skin challenge model. Importantly, 430D-F5 was well tolerated by human keratinocytes in cell culture and mouse skin in vivo; it also demonstrated significant reduction in dermonecrosis following skin challenge with a virulent strain of MRSA. This study provides an explanation for the anti-infective activity of peppertree remedies and yields insight into the potential utility of non-biocide virulence inhibitors in treating skin infections.

Treatment effects of lysozyme-shelled microbubbles and ultrasound in inflammatory skin disease.

Acne vulgaris is the most common skin disorder, and is caused by Propionibacterium acnes (P. acnes) and can induce inflammation. Antibiotic therapy often needs to be administered for long durations in acne therapy, which results in extensive antibiotic exposure. The present study investigated a new treatment model for evaluating the antibacterial effects of lysozyme (LY)-shelled microbubbles (MBs) and ultrasound (US)-mediated LY-shelled MBs cavitation against P. acnes both in vitro and in vivo, with the aims of reducing the dose and treatment duration and improving the prognosis of acne vulgaris. In terms of the in vitro treatment efficacy, the growth of P. acnes was inhibited by 86.08 ± 2.99% in the LY-shelled MBs group and by 57.74 ± 3.09% in the LY solution group. For US power densities of 1, 2, and 3 W/cm2 in the LY-shelled MBs group, the growth of P. acnes was inhibited by 95.79 ± 3.30%, 97.99 ± 1.16%, and 98.69 ± 1.13%, respectively. The in vivo results showed that the recovery rate on day 13 was higher in the US group with LY-shelled MBs (97.8 ± 19.8%) than in the LY-shelled MBs group (90.3 ± 23.3%). Our results show that combined treatments of US and LY-shelled MBs can significantly reduce the treatment duration and inhibit P.-acnes-induced inflammatory skin diseases.

Evaluation of wound healing property of Caesalpinia mimosoides Lam.

ETHNOPHARMACOLOGICAL RELEVANCE: Caesalpinia mimosoides Lam. is one of the important traditional folk medicinal plants in the treatment of skin diseases and wounds used by healers of Uttara Kannada district of Karnataka state (India). However scientific validation of documented traditional knowledge related to medicinal plants is an important path in current scenario to fulfill the increasing demand of herbal medicine. AIM OF THE STUDY: The study was carried out to evaluate the claimed uses of Caesalpinia mimosoides using antimicrobial, wound healing and antioxidant activities followed by detection of possible active bio-constituents. MATERIALS AND METHODS: Extracts prepared by hot percolation method were subjected to preliminary phytochemical analysis followed by antimicrobial activity using MIC assay. In vivo wound healing activity was evaluated by circular excision and linear incision wound models. The extract with significant antimicrobial and wound healing activity was investigated for antioxidant capacity using DPPH, nitric oxide, antilipid peroxidation and total antioxidant activity methods. Total phenolic and flavonoid contents were also determined by Folin-Ciocalteu, Swain and Hillis methods. Possible bio-active constituents were identified by GC-MS technique. RP-UFLC-DAD analysis was carried out to quantify ethyl gallate and gallic acid in the plant extract. RESULTS: Preliminary phytochemical analysis showed positive results for ethanol and aqueous extracts for all the chemical constituents. The ethanol extract proved potent antimicrobial activity against both bacterial and fungal skin pathogens compared to other extracts. The efficacy of topical application of potent ethanol extract and traditionally used aqueous extracts was evidenced by the complete re-epithelization of the epidermal layer with increased percentage of wound contraction in a shorter period. However, aqueous extract failed to perform a consistent effect in the histopathological assessment. Ethanol extract showed effective scavenging activity against DPPH and nitric oxide free radicals with an expressive amount of phenolic and moderate concentration of flavonoid contents. Ethyl gallate and gallic acid were found to be the probable bio-active compounds evidenced by GCMS and RP-UFLC-DAD analysis. CONCLUSION: The study revealed the significant antimicrobial, wound healing and antioxidant activities of tender parts of C. mimosoides and proved the traditional folklore knowledge.