Quercetin as a Promising Antiprotozoan Phytochemical: Current Knowledge and Future Research Avenues.

Despite tremendous advances in the prevention and treatment of infectious diseases, only few antiparasitic drugs have been developed to date. Protozoan infections such as malaria, leishmaniasis, and trypanosomiasis continue to exact an enormous toll on public health worldwide, underscoring the need to discover novel antiprotozoan drugs. Recently, there has been an explosion of research into the antiprotozoan properties of quercetin, one of the most abundant flavonoids in the human diet. In this review, we tried to consolidate the current knowledge on the antiprotozoal effects of quercetin and to provide the most fruitful avenues for future research. Quercetin exerts potent antiprotozoan activity against a broad spectrum of pathogens such as Leishmania spp., Trypanosoma spp., Plasmodium spp., Cryptosporidium spp., Trichomonas spp., and Toxoplasma gondii. In addition to its immunomodulatory roles, quercetin disrupts mitochondrial function, induces apoptotic/necrotic cell death, impairs iron uptake, inhibits multiple enzymes involved in fatty acid synthesis and the glycolytic pathways, suppresses the activity of DNA topoisomerases, and downregulates the expression of various heat shock proteins in these pathogens. In vivo studies also show that quercetin is effective in reducing parasitic loads, histopathological damage, and mortality in animals. Future research should focus on designing effective drug delivery systems to increase the oral bioavailability of quercetin. Incorporating quercetin into various nanocarrier systems would be a promising approach to manage localized cutaneous infections. Nevertheless, clinical trials are needed to validate the efficacy of quercetin in treating various protozoan infections.

Antifungal properties of cathelicidin LL-37: current knowledge and future research directions.

The threat of fungal diseases is substantially underestimated worldwide, but they have serious consequences for humans, animals, and plants. Given the limited number of existing antifungal drugs together with the emergence of drug-resistant strains, many researchers have actively sought alternatives or adjuvants to antimycotics. The best way to tackle these issues is to unearth potential antifungal agents with new modes of action. Antimicrobial peptides are being hailed as a promising source of novel antimicrobials since they exhibit rapid and broad-spectrum microbicidal activities with a reduced likelihood of developing drug resistance. Recent years have witnessed an explosion in knowledge on microbicidal activity of LL-37, the sole human cathelicidin. Herein, we provide a summary of the current understanding about antifungal properties of LL-37, with particular emphasis on its molecular mechanisms. We further illustrate fruitful areas for future research. LL-37 is able to inhibit the growth of clinically and agronomically relevant fungi including Aspergillus, Candida, Colletotrichum, Fusarium, Malassezia, Pythium, and Trichophyton. Destruction of the cell wall integrity, membrane permeabilization, induction of oxidative stress, disruption of endoplasmic reticulum homeostasis, formation of autophagy-like structures, alterations in expression of numerous fungal genes, and inhibition of cell cycle progression are the key mechanisms underlying antifungal effects of LL-37. Burgeoning evidence also suggests that LL-37 may act as a potential anti-virulence peptide. It is hoped that this review will not only motivate researchers to conduct more detailed studies in this field, but also inspire further innovations in the design of LL-37-based drugs for the treatment of fungal infections.

Monkeypox Disease with a Focus on the 2022 Outbreak; a Narrative Review.

Monkeypox is a zoonotic disease caused by a double-stranded DNA virus belonging to the genus Orthopoxvirus. Despite being endemic in Central and West Africa, the disease has received relatively little research attention until recent times. As the Coronavirus disease 2019 (COVID-19) pandemic continues to affect the world, the rising number of monkeypox cases in non-endemic countries has further stoked global public health concerns about another pandemic. Unlike previous outbreaks outside Africa, most patients in the present outbreak had no history of travel to the endemic regions. The overwhelming majority of patients were initially identified amongst homosexual men, who had attended large gatherings. Mutations in the coding regions of the viral genome may have resulted in fitness adaptation, enhancement of immune evasion mechanisms, and more efficient transmissibility of the 2022 monkeypox virus. Multiple factors such as diminished cross-protective herd immunity (cessation of smallpox vaccination), deforestation, civil war, refugee displacement, farming, enhanced global interconnectedness, and even climate change may facilitate the unexpected emergence of the disease. In light of the increasing number of cases reported in the present outbreak, healthcare professionals should update their knowledge about monkeypox disease, including its diagnosis, prevention, and clinical management. Herein, we provide an overview of monkeypox, with a focus on the 2022 outbreak, to serve as a primer for clinical practitioners who may encounter the disease in their practice.

Antibiofilm properties of cathelicidin LL-37: an in-depth review.

Notwithstanding ceaseless endeavors toward developing effective antibiofilm chemotherapeutics, biofilm-associated infections continue to be one of the most perplexing challenges confronting medicine today. Endogenous host defense peptides, such as the human cathelicidin LL-37, are being propounded as promising options for treating such infectious diseases. Over the past decennium, LL-37 has duly received tremendous research attention by virtue of its broad-spectrum antimicrobial activity and immunomodulatory properties. No attempt has hitherto been made, as far as we are aware, to comprehensively review the antibiofilm effects of LL-37. Accordingly, the intent in this paper is to provide a fairly all-embracing review of the literature available on the subject. Accumulating evidence suggests that LL-37 is able to prevent biofilm establishment by different bacterial pathogens such as Acinetobacter baumannii, Aggregatibacter actinomycetemcomitans, Bacteroides fragilis, Burkholderia thailandensis, Cutibacterium acnes, Escherichia coli, Francisella tularensis, Helicobacter pylori, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pyogenes. Inhibition of bacterial adhesion, downregulation of biofilm-associated genes, suppression of quorum-sensing pathways, degradation of biofilm matrix, and eradication of biofilm-residing cells are the major mechanisms responsible for antibiofilm properties of LL-37. In terms of its efficacy and safety in vivo, there are still many questions to be answered. Undoubtedly, LL-37 can open up new windows of opportunity to prevent and treat obstinate biofilm-mediated infections.

Synergistic effects of silybin and curcumin on virulence and carbapenemase genes expression in multidrug resistant Klebsiella oxytoca.

OBJECTIVE: Silybin and curcumin have potential antimicrobial effects. This study aimed to evaluate the synergistic antimicrobial effects of silybin and curcumin on virulence and carbapenemase genes expression among multidrug-resistant (MDR) Klebsiella oxytoca. RESULTS: A total of 70 MDR K. oxytoca (carrying blaIMP and blaOXA-48-like genes) were included. The antibiotic susceptibility and biofilm production of isolates were determined. The silybin and curcumin at concentrations 10-500 mg/mL alone and in combination were exposed to bacterial isolates in Mueller Hinton broth medium for 24 h. The expression of blaIMP, blaOXA-48-like, mrkA, pilQ, matB and fimA genes was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). The mean minimum inhibitory concentration (MIC) of curcumin and silybin were 250 mg/mL and 500 mg/mL, respectively. The anti-virulent effect of 100 mg/mL of silybin and curcumin was shown by significant reduction in the expression of fimA (2.1-fold, P < 0.0001) and mrkA (2.1 fold, P < 0.0001) genes. Moreover, these compounds significantly decreased the expression of blaIMP1 (3.2-fold, P < 0.0001) gene. Notably, there was no significant effect on pilQ, matB and blaOXA-48-like genes. The results showed that silybin and curcumin can be candidate as natural way for control the MDR virulent strains of K. oxytoca.

Epidemiology of Dermatophytosis in Tehran, Iran: A Ten-year Retrospective Study.

BACKGROUND: Dermatophytosis still remains a major public health concern worldwide, particularly in developing countries. This study was undertaken to determine the etiological and epidemiological factors of dermatophyte infections in Tehran, Iran. METHODS: A total of 1530 patients clinically suspected of cutaneous fungal infections were examined in two hospitals over a period of 10 years (2010-2020). Samples were analyzed using direct microscopic examination and culture. Data regarding age, gender, and clinical manifestations were also recorded. RESULTS: Out of 1530 cases examined, dermatophytes were detected in 493 (32.2%) patients. Of these patients, 288 (58.4%) were males and 205 (41.6%) were females. The most affected age group was the 25-44 years old (31.6%). Tinea corporis (n=134) was the most prevalent type of ringworm, followed by tinea cruris (n=131), tinea pedis (n=90), tinea manuum (n=65), tinea unguium (n=29), tinea faciei (n=20), tinea capitis (n=18), and tinea barbae (n=2). Both tinea cruris (P<0.001) and tinea pedis (P=0.002) had a significant association with male gender. As for etiological agents, Trichophyton mentagrophytes (29.0%) was the most frequent isolate, followed by Trichophyton tonsurans (25.8%), Trichophyton rubrum (25.3%), Epidermophyton floccosum (6.9%), Trichophyton verrucosum (4.9%), Microsporum audouinii (4.5%), Microsporum canis (2.0%), and Trichophyton violaceum (1.6%). CONCLUSION: Dermatophytes are still the prevailing causes of fungal infection of the skin, hair, and nails in Iran. Further studies with larger samples sizes and inclusion of diverse locations would yield more accurate results.

Antimicrobial resistance patterns, virulence gene profiles, and genetic diversity of Salmonella enterica serotype Enteritidis isolated from patients with gastroenteritis in various Iranian cities.

OBJECTIVES: This study aimed to evaluate antibiotic resistance profiles and presence of virulence genes among Salmonella enterica serovar Enteritidis (S. Enteritidis) isolated from patients with gastroenteritis in various regions of Iran. Moreover, genetic relatedness among the strains was assessed by pulsed-field gel electrophoresis (PFGE). MATERIALS AND METHODS: From April through September 2017, 59 Salmonella strains were isolated from 2116 stool samples. Of these strains, 27 S. Enteritidis were recovered. These strains were subjected to disk diffusion tests, polymerase chain reaction (PCR) for detection of virulence genes (invA, hilA, pefA, rck, stn, ssrA, ssaR, sefA, spvC, sipA, sipC, sopB, sopE, and sopE2), and PFGE. RESULTS: High prevalence of resistance towards cefuroxime (n = 20, 74.1%) and ciprofloxacin (n = 13, 48.2%) were demonstrated. All tested strains possessed invA, hilA, sefA, sipA, sopB, and sopE. The least prevalent virulence gene was rck (n = 6; 22.2%). Based on combinations of virulence genes, 12 virulotypes were observed. The most common virulotype was VP2 (n = 12; 44.4%), harboring all of the virulence genes except for rck. PFGE typing showed only two distinct fingerprints among tested strains. Each fingerprint had completely different virulotypes. Notably, VP4 (harboring all genes except for rck and spvC) was only presented in pulsotype A, while VP2 was confined to pulsotype B. CONCLUSION: S. Enteritidis strains were derived from a limited number of clones, suggesting that it is highly homogenous. Future works should consider combinations of other genotyping methods together with larger sample sizes from more diverse sources.

Evaluation of Fibroblast Viability Seeded on Acellular Human Amniotic Membrane.

BACKGROUND: Investigating the viability and proliferative rates of fibroblast cells on human amniotic membrane (HAM) as a scaffold will be an important subject for further research. The aim of this study was to assess the fibroblast viability seeded on acellular HAM, since foreskin neonatal allogenic fibroblasts seeded on HAM accelerate the wound healing process. METHODS: Fibroblasts were retrieved from the foreskin of a genetically healthy male infant, and we exploited AM of healthy term neonates to prepare the amniotic scaffold for fibroblast transfer. After cell culture, preparation of acellular HAM, and seeding of cells on HAM based on the protocol, different methods including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 4',6-Diamidino-2-phenylindole dihydrochloride (DAPI), and propidium iodide (PI) staining were employed for assessment of fibroblast viability on HAM. RESULTS: Based on the results obtained from the DAPI and PI staining, the percentage of viable cells in the former staining was clearly higher than that of the dead cells in the latter one. The results of DAPI and PI staining were in accordance with the findings of MTT assay, confirming that fibroblasts were viable and even proliferate on HAM. CONCLUSION: Our findings showed the viability of fibroblasts seeded on the acellular HAM using MTT assay, DAPI, and PI staining; however, this study had some limitations. It would be an interesting subject for future research to compare the viability and proliferation rate of fibroblasts seeded on both cellular and acellular HAM.

Melittin as a promising anti-protozoan peptide: current knowledge and future prospects.

Protozoan diseases such as malaria, leishmaniasis, Chagas disease, and sleeping sickness still levy a heavy toll on human lives. Deplorably, only few classes of anti-protozoan drugs have thus far been developed. The problem is further compounded by their intrinsic toxicity, emergence of drug resistance, and the lack of licensed vaccines. Thus, there is a genuine exigency to develop novel anti-protozoan medications. Over the past years, melittin, the major constituent in the venom of European honeybee Apis mellifera, has gathered the attention of researchers due to its potential therapeutic applications. Insofar as we are aware, there has been no review pertinent to anti-protozoan properties of melittin. The present review outlines the current knowledge about anti-protozoan effects of melittin and its underlying mechanisms. The peptide has proven to be efficacious in killing different protozoan parasites such as Leishmania, Plasmodium, Toxoplasma, and Trypanosoma in vitro. Apart from direct membrane-disruptive activity, melittin is capable of destabilizing calcium homeostasis, reducing mitochondrial membrane potential, disorganizing kinetoplast DNA, instigating apoptotic cell death, and induction of autophagy in protozoan pathogens. Emerging evidence suggests that melittin is a promising candidate for future vaccine adjuvants. Transmission-blocking activity of melittin against vector-borne pathogens underscores its potential utility for both transgenic and paratransgenic manipulations. Nevertheless, future research should focus upon investigating anti-microbial activities of melittin, alone or in combination with the current anti-protozoan medications, against a far broader spectrum of protozoan parasites as well as pre-clinical testing of the peptide in animal models.

Emerging and Novel Therapies for Keloids: A compendious review.

Keloids are abnormal fibroproliferative scars with aggressive dermal growth expanding beyond the borders of the original injury. Different therapeutic modalities, such as corticosteroids, surgical excision, topical silicone gel sheeting, laser therapy, cryotherapy, photodynamic therapy and radiotherapy, have been used to treat keloids; however, none of these modalities has proven completely effective. Recently, researchers have devised several promising anti-keloid therapies including anti-hypertensive pharmaceuticals, calcineurin inhibitors, electrical stimulation, mesenchymal stem cell therapy, microneedle physical contact and ribonucleic acid-based therapies. The present review summarises emerging and novel treatments for keloids. PubMed® (National Library of Medicine, Bethesda, Maryland, USA), EMBASE (Elsevier, Amsterdam, Netherlands) and Web of Science (Clarivate Analytics, Philadelphia, Pennsylvania, USA) were searched for relevant literature published between January 1987 to June 2020. A total of 118 articles were included in this review. A deeper understanding of the molecular mechanisms underlying keloid scarring pathogenesis would open further avenues for developing innovative treatments.

Anti-Staphylococcal and cytotoxic activities of the short anti-microbial peptide PVP.

Over the past years, short anti-microbial peptides have drawn growing attention in the research and trade literature because they are usually capable of killing a broad spectrum of pathogens by employing unique mechanisms of action. This study aimed to evaluate the anti-bacterial effects of a previously designed peptide named PVP towards the clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) in vitro. Secondary structure, cytotoxicity, and membrane-permeabilizing effects of the peptide were also assessed. PVP had a tendency to adopt alpha-helical conformation based upon structural predictions and circular dichroism spectroscopy (in 50% trifluoroethanol). The peptide showed MIC values ranging from 1 to 16 µg/mL against 10 strains of MRSA. In contrast to ciprofloxacin and gentamicin, PVP at sub-lethal concentration (1 µg/mL) did not provoke the development of peptide resistance after 14 serial passages. Remarkably, 1 h of exposure to 4 × MBC of PVP (8 µg/mL) was sufficient for total bacterial clearance, whereas 4 × MBC of vancomycin (8 µg/mL) failed to totally eradicate bacterial cells, even after 8 h. PVP showed negligible cytotoxicity against human dermal fibroblasts at concentrations required to kill the MRSA strains. The results of flow cytometric analysis and fluorescence microscopy revealed that PVP caused bacterial membrane permeabilization, eventually culminating in cell death. Owing to the potent anti-bacterial activity, fast bactericidal kinetics, and negligible cytotoxicity, PVP has the potential to be used as a candidate antibiotic for the topical treatment of MRSA infections.

Anti-fungal properties and mechanisms of melittin.

Many fungal diseases remain poorly addressed by public health authorities, despite posing a substantial threat to humans, animals, and plants. More worryingly, few classes of anti-fungals have been developed to combat fungal infections thus far. These medications also have certain drawbacks in terms of toxicity, spectrum of activity, and pharmacokinetic properties. Hence, there is a dire need for discovery of novel anti-fungal agents. Melittin, the main constituent in the venom of European honeybee Apis mellifera, has attracted considerable attention among researchers owing to its potential therapeutic applications. To our knowledge, there has been no review pertinent to anti-fungal properties of melittin, prompting us to synopsize the results of experimental investigations with a special emphasis upon underlying mechanisms. In this respect, melittin inhibits a broad spectrum of fungal genera including Aspergillus, Botrytis, Candida, Colletotrichum, Fusarium, Malassezia, Neurospora, Penicillium, Saccharomyces, Trichoderma, Trichophyton, and Trichosporon. Melittin hinders fungal growth by several mechanisms such as membrane permeabilization, apoptosis induction by reactive oxygen species-mediated mitochondria/caspase-dependent pathway, inhibition of (1,3)-ß-D-glucan synthase, and alterations in fungal gene expression. Overall, melittin will definitely open up new avenues for various biomedical applications, from medicine to agriculture. KEYPOINTS: • Venom-derived peptides have potential for development of anti-microbial agents. • Many fungal pathogens are susceptible to melittin at micromolar concentrations. • Melittin possesses multi-target mechanism of action against fungal cells.

Associations between climatic parameters and the human salmonellosis in Yazd province, Iran.

Salmonella is one of the most common causes of foodborne disease outbreaks in developing countries. Climatic factors such as temperature, rainfall, and relative humidity can directly increase the growth and spread of these pathogens. Therefore, the aim of this study was to investigate long-term temporal trends and seasonal patterns of Salmonella infections as well as evaluating the effects of demographic and climatic factors on the infection incidence in Yazd province, Iran during 2012-2015. The incidence of Salmonella infections was highest among patients with the age group of ≤5 years and peaked in summer, especially during June. Contrary to expectations, no significant associations were seen between the average monthly temperature, rainfall or humidity and incidence rate (IR) of salmonellosis. Interestingly, atmospheric dust hovering was significantly associated with an increased risk of salmonellosis. Transmission pathways of Salmonella spp. in communities should be considered as a complex ecological process that animal reservoirs, socio-economic factors, and lifestyle behaviors need to be addressed in future studies.

Melittin: a venom-derived peptide with promising anti-viral properties.

Despite tremendous advances in the development of anti-viral therapeutics, viral infections remain a chief culprit accounting for ongoing morbidity and mortality worldwide. Natural products, in particular animal venoms, embody a veritable cornucopia of exotic constituents, suggesting an immensurable source of anti-infective drugs. In this context, melittin, the principal constituent in the venom of the European honeybee Apis mellifera, has been demonstrated to exert anti-cancer, anti-inflammatory, anti-diabetic, anti-infective, and adjuvant properties. To our knowledge, there is no review appertaining to effects of melittin against viruses, prompting us to synopsize experimental investigations on its anti-viral activity throughout the past decades. Accumulating evidence indicates that melittin curbs infectivity of a diverse array of viruses including coxsackievirus, enterovirus, influenza A viruses, human immunodeficiency virus (HIV), herpes simplex virus (HSV), Junín virus (JV), respiratory syncytial virus (RSV), vesicular stomatitis virus (VSV), and tobacco mosaic virus (TMV). However, medication safety, different routes of administrations, and molecular mechanisms behind the anti-viral activity of melittin should be scrutinized in future studies.

An overview on anti-biofilm properties of quercetin against bacterial pathogens.

Bacterial biofilms are multicellular aggregates enclosed in a self-created biopolymer matrix. Biofilm-producing bacteria have become a great public health problem worldwide because biofilms enable these microorganisms to evade several clearance mechanisms produced by host and synthetic sources. Over the past years, different flavonoids including quercetin have engrossed considerable interest among researchers owing to their potential anti-biofilm properties. To our knowledge, there is no review regarding effects of quercetin towards bacterial biofilms, prompting us to summarize experimental evidence on its anti-biofilm properties. Quercetin inhibits biofilm development by a diverse array of bacterial pathogens such as Enterococcus faecalis, Staphylococcus aureus, Streptococcus mutans, Escherichia coli, and Pseudomonas aeruginosa. Prevention of bacterial adhesion, suppression of quorum-sensing pathways, disruption or alteration of plasma membrane, inhibition of efflux pumps, and blocking nucleic acid synthesis have been documented as major anti-biofilm mechanisms of quercetin. Overall, anti-biofilm activity of quercetin can open up new horizons in a wide range of biomedical areas, from food industry to medicine.