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Bioactive metabolites of Cunninghamella, Biodiversity to Biotechnology

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Review Article | DOI: https://doi.org/10.31579/2693-7247/036

Bioactive metabolites of Cunninghamella, Biodiversity to Biotechnology

  • Waill A. Elkhateeb 1*
  • Abdu Ghalib AL Kolaibe 1
  • Ghoson M. Daba 1

1 Chemistry of Natural and Microbial Products Department, Pharmaceutical Industries Division, National Research Centre, Dokki, Giza, 12622, Egypt

*Corresponding Author: Waill A. Elkhateeb, Chemistry of Natural and Microbial Products Department, Pharmaceutical Industries Division, National Research Centre, Dokki, Giza, 12622, Egypt

Citation: Waill A. Elkhateeb, Abdu G. AL Kolaibe, Ghoson M. Daba (2021) Bioactive metabolites of Cunninghamella, Biodiversity to Biotechnology J. Pharmaceutics and Pharmacology Research, 4(3); DOI:10.31579/2693-7247/036

Copyright: © Waill A. Elkhateeb, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 28 March 2021 | Accepted: 19 April 2021 | Published: 24 April 2021

Keywords: cunninghamella; mucorales; bioactive metabolites; biotransformation

Abstract

Cunninghamella is a fungal genus that belongs to family Cunninghamellaceae and has been involved as promising tool in many important mycotechnological applications. Cunninghamella is an endophytic fungus, their secondary metabolites are of potential biological activities especially as antimicrobial agents. The aim of this review is to highlight the description, ecology, and important in medicinal and industrial applications of the genus Cunninghamella in general. Moreover, describing the importance and potentials of this fungus in order to encourage for further studies to search, isolate, and purify already known metabolites. Also, screen for, and discover novel metabolites produced by this potent fungi in order to be involved in additional applications.

Introduction

Fungi play important role in human life such as in agriculture, food industry, medicine, textiles, bioremediation, natural cycling, as bio-fertilizer and in many other ways. Fungi are ubiquitous on earth and represent essential components of many ecosystems where they are involved in many vital processes [1]. Mucorales is the largest order of fungi, it is classified into the subphylum named Mucormycotina [2], that is formed of about 57 genera with 15 families and that comprise about 334 species [3]. Mucorales members are found in soil, water, dung, plants, stored grains, and fungal masses [4, 5]. Many of mucorales members show rapid growth and they colonize and sporulate on a variety of carbohydrate-rich, and terrestrial substrates.

The genus Cunninghamella (Cunninghamellaceae, Mucorales) was established by Matruchot in 1903. The species of this genus are characterized by the formation of the uni-spored sporangia and pedicellate on the vesicle surface [6]. About 14 species are identified in this genus [7, 8]. Thesespecies are usually found in soil, organic substrates, and stored grains, etc. [9, 10]. Some species are reported to cause infection such as human mucormycosis [11, 12], however other species are reported to be very helpful in treating many diseases as well as that can destroy tumors [13]. Based on the morphological characterization, the taxonomy of Cunninghamella has been identified. This include the colony color, shape and size of vesicles, branching pattern of sporophore, sporangiola shape, and the length of the spines [6, 14].

Another study reported that Cunninghamella genus was monographed upon the maximum growth temperatures together with the morphological characteristics [6]. Moreover, other studies have sequenced the internal transcribed spacer (ITS), 28S, and elongation factor 1α gene regions of the accepted taxa and represented the phylogeny to be compatible with Zeng and Chen's taxonomical results [15, 16].

The endophytic fungus, Cunninghamella sp., is considered an enormous source of chemical leads with promising biological activities. Different Cunninghamella species have proved their ability to produce plenty of secondary metabolites including fatty acids (Palmitic acid, oleic acid and stearic acid) in addition to two steroidal compounds; α-amyrin (A4), and β–sitosterol with various biological activities, such as antifungal and antibacterial [17-19]. Cunninghamella species capable to produced different enzymes that can perform both phase I and phase II biotransformations [20].

Secondary metabolites differ from primary nutrients in that they are not essential for growth, but they play a vital role in the survival and adaptation of producing organisms in nature [21]. The genus Cunninghamella contains species of importance in medical mycology and in biotechnological processes. Cunninghamella is a filamentous fungus found in soil and plant material, particularly at Mediterranean and subtropical zones. Cunninghamellabertholletiae, Cunninghamellaelegans and Cunninghamellaechinulata are the most common species. Cunninghamella colonies are rapidly growing, full mature in 4 days, colony shape is cottony and white to tannish-grey in color. Cunninghamellaelegans produces purely gray colonies. [22, 23].

The genus Cunninghamella description and ecology

Colonies fast growing, completely filling the plate on Czapek’s, malte extract, or potato dextrose agar, after 3-5 days of incubation at 25°C, floccose, up to 3 cm high, white to dark grey; mycelium non septate, often becoming septate without order in age; hyphae broad up to thick. Sporangiophores (Conidiophores) erect, branched in verticillate or irregular, each branch terminating in globose, obovoid pyriform to clavate vesicle furnished with small sporangioles (Conidia) bearing denticles, usually sporangiophores swollen at point of attachment of lateral branches; sporangioles arising from denticles synchronously (Figure, 1, 2). 1-Spored globose, ovoid or elliptical, smooth verrucose or echinulate, hyaline mostly heterothallic. Zygospores globose to somewhat flattened, dark brown, tuberculate, suspensors equal. When mature colonies greyish white; terminal vesicles up to 40 um in diameter, sporangioles smooth, species is Cunninghamella elegans. When mature colonies pale grey, terminal vesicles up to 50 um in diameter, sporangioles echinulate, species is Cunninghamella echinulata. Cunninghamella echinulata most common and is worldwide distribution [24-26].

Figure 1. Cunninghamella different species with different shapes on different media (cited in: www.thunderhouse4-yuri.blogspot.comand https://www.natur.cuni.cz).
Figure 2. Cunninghamella elegans with smooth globose conidia isolated and identified by Dr. Waill Elkhateeb (Photographs was taken by Dr. Waill A. Elkhateeb, Locality: National Research Center of Egypt). 

Cunninghamella secondary metabolites and their biological activities

Various fungi produce many secondary metabolites that have diverse molecular structure [27]. Several phytochemical groups have been isolated from fungi, these include alkaloids, carbohydrates, fatty acid, phenolic compound, polyketides, and terpenes [28]. Nowadays, over 90,000 species of fungi have been identified [29], nevertheless, not all these fungi have been fully studied for their potential biological and chemical properties [30, 31]. Cunninghamella is a fungal genus that belongs to family Cunninghamellaceae. This family may exist in soil, plant and animal material, and Brazil nuts, etc. [32]. Members of this genus are characterized by possessing cytochrome P-450 monooxygenase systems similar to those found in mammals [33]. Thus, they have been applied to many drugs where they act in a manner that similar to those of mammalian enzyme systems [34]. For this reason, Cunninghamella species have been applied as biotransformation media, because of its capacity to convert different molecules to valuable medicinal substances [35]. 

Among the objectives of the recent European Union legislation governing the testing and evaluation of chemicals, REACH (Regulation, Evaluation, Authorisation and Restriction of Chemicals), is to minimize depending on animals in testing experiments. Since some microorganisms including the actinomycetes bacteria and Cunninghamella fungi are able to metabolize different xenobiotic compounds in a way which is analogous to that of mammals [22, 23], [36, 37]. These microorganisms have been considered as potent models of mammalian metabolism [38], even though many concerns are found about their predictive value (8). However, some microorganisms are very crucial in the generation of useful quantities of drug metabolic intermediates [39].

Various Cunninghamella species have shown different biological activities. For example, Cunninghamella echinulata has been reported to biotransform the drug “loratadine” to its active metabolite “desloratadine” and which was proved to be more potent (about four times that of loratadine) when consumed at low doses. Desloratadine is a potent antihistaminic drug that has showed its efficacy in allergic disease [40, 41]. Also, Cunninghamella elegans ATCC 9245, showed its ability to biotransform doxepin which is a tricyclic antidepressant drug [42]. Interestingly, previous studies revealed diverse pathways for Cunninghamella blakesleana AS 3. 153 to metabolize verapamil, in a way similar to humans that is why this species could be a useful model for studying mammalian drug metabolism system [43].

This species also showed its importance in treatment of cancer. Some studies reported that the potential of employing Cunninghamella species to transform many xenobiotic compounds in an analogous way similar to mammals. Cunninghamella species were able to biotransform the anti-cancer drug flutamide into four fluorometabolites. Among the produced metabolites, the most predominant one was the 2-hydroxyflutamide which is known to be a major pharmacologically active compound in mammals. Cunninghamella species also play an important role in inflammation treatment. They can biotransform flurbiprofen “the fluorinated anti-inflammatory drug”, where, mono- and dihydroxylated metabolites were detected by gas chromatography-mass spectrometry (GC-MS) and fluorine-19 nuclear magnetic resonance spectroscopy (19FNMR). 4′-hydroxyflurbiprofen was proved to be the major metabolite being converted by both microbial and mammalian systems [44]. 

The antimicrobial activities of Cunninghamella blakesleeana ethanol extract has been examined against different Gram-positive and Gram-negative bacteria, as well as other fungi. Some of the isolated compounds showed their ability to inhibit the growth of some microorganisms. The maximum antimicrobial activity of Cunninghamella blakesleeana alcohol extract was reported against Staphylococcus aureus this was followed by Streptococcus pyogenes. On the other side, the maximum antimicrobial activity was reported against for both Candida albicans and Pseudomonas aeruginosa [17]. Cunninghamella blakesleeana has been also reported to produce many fatty acids. About ten of them were detected. Stearic acid was the major fatty acid isolated from C. blakesleeana (74.61%), palmitic acid was considered the second high percentage (10.35%), however, docosanoic acid showed the least percentage (0.01%) [17]. These lipids can be applied in various industries such as essential oils, natural food colors, spice, and oleoresins. Also they can be used in cosmetics and medicinal uses [45]. Additionally, Cunninghamella elegans showed its capacity to produce polysaccharides when the fungus was grown on corn steep liquor and cassava wastewater. The obtained chitin and chitosan showed deacetylation degrees of 40.98 and 88.24%, and a crystalline index of 35.80% and 23.82%, respectively. The produced chitin and chitosan are found to be non-irritating since they do not promote vascular change such as vasoconstriction, haemorrhage, and coagulation [46]. 

Recently, more effort has been directed towards the production of fungal chitin and chitosan as an alternative source of biopolymers in order to overcome the undesirable side effects of the traditional extraction methods of these polysaccharides [47, 48]. Additionally, the microbial chitin and chitosan have more consistent quality and homogenous characteristics [49, 50]. Chitin and chitosan extracted from mycelial biomass of C. elegans were able to remove various metals such as copper, lead, and iron from their aqueous solutions, where chitosan (1% w/v) showed the highest capacity for copper biosorption (75%). While chitin (1% w/v) showed the maximum capacity to remove iron metal (56%), both experiment were conducted at pH 4 and 2.0 mM metals concentration [51].

Moreover, the dye biosorption potential of has been proven to be very effective, where it was found to remove some industrial dyes such as R80 and B214. Dye and toxic metals biosorption with fungal biomasses are considered important alternatives to other traditional wastewater treatment techniques that aim to reuse water. Fungal biomasses have the advantages of being cheaper, easier in operation and insensitive to toxic pollutants [52]. Also, Cunninghamellaelegans showed its ability to remove toxic metals, where it was able to grow in the presence of large amount of toxic copper [53]. Cunninghamella blakesleeana, Cunninghamella homothallica, and Cunninghamella elegans to show their ability to grow in the presence of different metals such as cadmium, cobalt, and chromium [54]. These results indicate that Cunninghamella species can offer a new natural way for bioremediation of toxic industrial wastes such as dyes as well as other toxic metals.

Conclusion

The application of microbial models has gained a great attention as a complementary tool to study drugs metabolism. Microorganisms may be employed as an efficient and valuable alternative to animals or even synthetic chemistry to study many drug derivatives. The expression of the cytochromes P450 in heterologous systems (such as fungi) has been successfully employed as a tool for investigating the metabolism of a wide variety of drugs. Among these fungi species is Cunninghamella species that can find a great application as a reliable alternative to in vitro models to study various drugs metabolism. Cunninghamella species have been reported to produce some metabolites such as polysaccharides and fatty acids, that show valuable applications. Moreover, Cunninghamella species can be employed as a powerful bioremediation tool to get rid of many harmful industrial dyes as well as toxic metals.

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner

My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.

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Lin-Show Chin

My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.

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Sonila Qirko

My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.

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Luiz Sellmann