info@auctorespublishing.com
+1-(302)-520-2644
+1-(302)-520-2644

Nanofluidic Mechanism of Brain Water Metabolism and Its Pharmacological Control

  1. Home
  2. Journals
  3. Pharmaceutics and Pharmacology Research
  4. Archives
Submit Guidelines

Review Article | DOI: https://doi.org/10.31579/2693-7247/094

Nanofluidic Mechanism of Brain Water Metabolism and Its Pharmacological Control

  • Titovets E.

Department of Neurosurgery of Republican Research and Clinical Center of Neurology and Neurosurgery, Minsk, Belarus.

*Corresponding Author: Department of Neurosurgery of Republican Research and Clinical Center of Neurology and Neurosurgery, Minsk, Belarus.

Citation: Titovets E, (2022). Nanofluidic Mechanism of Brain Water Metabolism and Its Pharmacological Control. J Pharmaceutics and Pharmacology Research. 5(8), DOI: 10.31579/2693-7247/094

Copyright: @ 2022 Titovets E, 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: 08 August 2022 | Accepted: 29 September 2022 | Published: 10 October 2022

Keywords: brain water metabolism; diffusion barrier theory; nanofluidic mechanism of brain water metabolism; AQP4-targeted drug therapy

Abstract

Brain water metabolism is involved in realization of a broad spectrum of vitally important physiological functions of the brain. Its disorders in various pathologies often lead to serious complications and death. Finding ways of pharmacological control of brain water metabolism is important to therapy of many conditions in neurology and neurosurgery.  At present, there are the two mutually excluding basic views on brain water metabolism making it a center of theoretical controversy. A conventional approach affirms that the brain nanodimentional extracellular space presents a diffusion barrier to water movement. An interdisciplinary approach suggests that a slip-flow mechanism governs water movement there in the extracellular space that presents an integral part of the brain nanofluidic domain. This review centers on the nanofluidic mechanism of brain water metabolism and the AQP4-targeted drug control of brain water metabolism.  The information presented here might be used in a neurobiological research, development of the AQP4-targeted drug therapy, optimization of intrathecal drug delivery, in a research on the therapy of the brain water metabolism disorders.

Abbreviations:

ISS – the interstitial space; ISF –the interstitial fluid

BBB - the blood-brain barrier

AQP1- aquaporin-1

AQP4- aquaporin-4

Introduction:

The red arrow indicates the direction of the blood flow in the capillary. The dotted blue line with AQP4 present this aquaporin in the astrocyte endfeet membrane enveloping the capillary. The functionally different parts of the capillary are designated as FS (the Filtration Section), OS (the 

Oscillatory Section), and RS (the Reabsorption Section). The blue arrows, with the rate symbols “Jv”, “±Jv”, and –Jv”, indicate the direction of the water flows in the respective sections. The oncotic pressure in the capillary and the interstitial fluid is πC and πISF, respectively. Hydrostatic pressure is pa at the arterial end of the capillary and pv at the venule end. The intracranial pulsatory pressure is f(t). The square brackets indicate the nanofluidic domain.  Note that the schematic is not drawn to scale and does not represent the true ratio between capillary diameter and the capillary length [8] .

Figure 1: Nanofluidic mechanism of brain water metabolism

This interdisciplinary approach opens new fascinating perspectives in elucidating the so far concealed features of the brain water metabolism with important physiological implications. 

Having adopted the nanofluidic approach and employed computer simulation technique, we have studded, in some detail, the brain water metabolism and related issues  [8],[9],[10],  [11],[12],[13],[14],[15].

The nanofluidic model of brain water metabolism is built on the following assumptions: 

the brain nondimensional extracellular space presents a nanofluidic domain where  water movement there governed by the slip-flow mechanism; aquaporin AQP4 ensures kinetic control over water movement between the blood and the brain extracellular space;the overall fluid transfer between the capillary blood and the interstitial fluid is isosmotic;the pulsatory intracranial pressure presents a driving force behind the isosmotic fluid exchange between the capillaries and the interstitial space [8].

A study of brain water metabolism, using a new approach, makes it possible to observe its many features relevant to brain physiology and pathological situations. It has been demonstrated the way AQP4 polarization in the astrocyte endfeet membrane affects the radial water fluxes.  The model made it possible to assess quantitatively the influence of elevated intracranial hydrostatic pressure and elevated venous hydrostatic pressure on the transcapillary water exchange. An interesting feature of the model is that it makes possible to study mass-transfer events in the brain tissue. Thus it has been employed to study tissue oxygenation, transfer of carbon dioxide and glucose. The model might be used to study the effects of pharmacological modulators of AQP4 activity (the BBB permeability). The model demonstrates an intimate connection between brain water metabolisms and heart activity. 

Brain edema brings about an increased intracranial pressure, effects cerebral circulation, causes brain hypoxia and a number of pathophysiological changes leading to severe neurological disorders and death. Cerebral edema occurs in a wide range of pathologies like traumatic brain injury, the stroke, hemorrhages, hydrocephalus, brain tumors,   etc.   The brain edema may also arise from the causes originated outside the brain: postoperative trauma, hemodynamic and hormonal-electrolyte disorders; cardiac, hepatic, renal, respiratory insufficiency; decompensated endocrine pathology, etc. Clinical practice demonstrates that there are still remain unresolved problems about  the correction of the water metabolism disorders [16] , [17]. There are also remain some controversies abbot understanding, at the basic level, the mechanism of the brain water metabolism ` 

This metabolism has been a subject of close attention of researchers and of hot debates. To date, there is remain controversy about the issue. It stands in the way of the development of the effective means of the treatment of the brain water metabolism disorders. 

The role of the choroidal plexus in the brain water metabolism has been scrutinized and subjected to criticism as untenable in the light of the latest basic and clinical research evidence [18] [19]. Acceding to an alternative theory, the main participants in the cerebral water exchange are the capillaries of the whole brain parenchyma, and not the choroidal plexus [20]. 

Water metabolism is associated with the activity of the quantitatively predominant and functionally most important aquaporin AQP4. This aquaporin is expressed in large quantities, as the two-dimensional orthogonal structures, in the plasma membrane of the astrocyte endfeet enveloping the capillaries [21], [22]. AQP4 controls the transfer of water across the BBB. Controlling the water movement between the blood and the interstitial space, it plays an important role in brain physiology, as well as in the development of pathological reactions leading to  edema [23] [24].

AQP4 is viewed a molecular target for drug action directed at correction the disorders of brain water metabolism.  Figure 2 demonstrates the results of AQP4 inhibition on water flow into brain parenchyma.

Figure 2. Aquaporin AQP4 inhibition and water transfer across the BBB into brain parenchyma.

A.No AQP4 inhibition. B. 50% inhibition of AQP4 activity C.  75% inhibition of  AQP4 activity 
1. The total racial water volume transferred over a cardiac cycle. 
2. The racial water volume transferred over the systolic phase of the cardiac cycle. 
3. The racial water volume transferred over the diastolic phase of the cardiac cycle. 

New knowledge makes it possible to outline promising approaches in the treatment of the brain water metabolism disorders [3], [9],[12],[25]. The pharmacological arsenal of medicines currently used to correct disorders of cerebral water metabolism and combat brain edema represents a complex, which includes means of osmotherapy (mannitol, hypertonic sodium chloride solution), diuretics (furosemide, bumetanide) and other drugs with different mechanisms of action (corticosteroids, testosterone, dexamethasone, propofol, piroxicam, acetazolamide, etc.).

The osmotherapy is used to provide an osmotic pressure gradient between blood and the brain fluids and to ensure directed water flow from the brain tissues into the systemic circulation. Diuretics serve the same purpose. 

The success of osmotherapy depends on water permeability of the BBB controlled by AQP4. Numerous studies have shown that the level of expression and the degree of polarization of AQP4 in the BBB structures are labile and depend on many physiological factors. Significant changes in the activity of AQP4 are observed in pathologies  [26]. 

The concept according to which aquaporins present molecular targets for drugs is very attractive and practically important [27], [28], [29], [30] . In view of this, much research has been carried out to study the action of drugs on aquaporin activity. 

The Table shows the effects of some drugs, used in the treatment brain edema and water metabolism disorders, on the activity of aquaporins AQP1 and AQP4.

Table.  Pharmacological modulators of AQP1 and AQP4 activity

Chemical modulators of aquaporins penetrating into the cell produce either an inhibitory or an activating effect on a specific aquaporin. The same aquaporin in different tissues may be involved in implementation of different physiological functions and thus be involved in the appearance of different responses at the organ level. For example, inhibition of AQP1 in the collecting tubes of the kidney results in increased diuresis. On the other hand, AQP1 inhibitors have no effect on water permeability of the BBB. This asks for comprehensive information about drug action on the activity of a respective aquaporin and careful evaluations of their pharmacological effects. 

There is always a problem to solve concerning a pharmacological modulator reaching its target molecule to produce therapeutic effect. One of the approaches to solve this problem is development of prodrugs. Thus, for this purpose, a prodrug, an acetoxy-methyl derivative of furosemide, has been synthesized that, in the process of bioconversion inside the cell, releases furosemide, an AQP4 antagonist. A similar approach has been used to increase permeability of bumetanide [43].

From the nanofluidic mechanism of the brain water metabolism, there follow some practical recommendations for the treatment of brain edema as far as the BBB water permeability is concerned.  In particular, it is important to employ a pharmacological control of    AQP4 activity in respect to the phases of brain edema. At the early stages, it is reasonable to inhibit AQP4 activity to reduce water flow into the brain and thus preventing further development of edema. The same tactics might be employed for premedication to prevent formation of brain edema, in view of upcoming operation on the brain, etc.

However, in fully developed edema, when there is a problem of removing fluid excess from the brain tissues, the use of AQP4 inhibitors should be avoided. By preventing water outflow, pharmacological inhibitors will negatively affect the effectiveness of osmotherapy, contribute to persistence of edema and negatively reflect upon neurological status of the patient. 

Conclusion:

At present, brain water metabolism has become a center of theoretical controversy.  There are two mutually excluding basic views on the events underlying the workings of brain water metabolism. According to a conventional approach, brain nanodimentional extracellular space presents a diffusion barrier to water movement. Contrary to this theory, an interdisciplinary approach suggests water movement there as a slip-flow process that would result in appearance of water fluxes in the extracellular space. The central argument to support the latter theory is that the extracellular space is an integral part of the brain nanofluidic domain.

The concept of diffusion barrier is incompatible with that of the nanofluidic mechanism of brain water metabolism.   The BBB separates the two water moieties:  that of the blood, governed by convection, and that of the water in the nanodimentional extracellular space, governed by diffusion, according to the diffusion barrier theory. Introducing diffusion is tantamount to making kinetically redundant AQP that otherwise controls water transfer over the BBB. This will be the case because case the limiting step would be shifted from AQP4 to the diffusion barrier of the extracellular space. The diffusion barrier theory makes invisible all those interesting findings in the mechanism of brain water metabolism revealed through the nanofluidic approach.

It should be observed that nanofluidic mechanism of brain water metabolism, contrary to the diffusion barrier theory, opens wide possibilities for developing   the ways of pharmacological control of brain water metabolism.

References

  1. Lei, Y, Han, H, Yuan, F, Javeed, A. and Zhao, Y(2017) The brain interstitial system: Anatomy, modeling, in vivo measurement, and applications. Prog Neurobiol, 157: p. 230-246.
    View at Publisher | View at Google Scholar
  2. Simon, M.J. and J.J. Iliff(2016) Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease. Biochim Biophys Acta, 1862(3): p. 442-551.
    View at Publisher | View at Google Scholar
  3. Titovets E.P, S.A.F, Kozich P.V(2019). [Correction of the disorders of the cerebral water metabolism. ](In Russ.). Proceedings of the National Academy of . 16(1): p. 99-107.
    View at Publisher | View at Google Scholar
  4. Nicholson , C.(2007)Modeling Brain Extracellular Space from Diffusion Data. Diffusion Fundamentals, 6: p. 75.1-75.150.
    View at Publisher | View at Google Scholar
  5. Johanson, C.E., et al(2008).Multiplicity of cerebrospinal fluid functions: New challenges in health and disease. Cerebrospinal Fluid Res. 5: p. 10.
    View at Publisher | View at Google Scholar
  6. Bocquet, L(2020). Nanofluidics coming of age. Nat Mater, 19(3): p. 254-256.
    View at Publisher | View at Google Scholar
  7. Abgrall, P, Nguyen,N.-T.( 2009) Nanofluidics., Boston, London: Artech House. 204.
    View at Publisher | View at Google Scholar
  8. Titovets, E(2018). Novel Computational Model of the Brain Water Metabolism: Introducing an Interdisciplinary Approach. J Comp Sys Bio, 3(1): p. 1-11.
    View at Publisher | View at Google Scholar
  9. Titovets, E(2021). [Aquaporins of Humans and Animals. Fundamental and clinical aspects][in Russian. ] (2nd edition revised and expanded). , ., Minsk, Belarus:
    View at Publisher | View at Google Scholar
  10. Titovets, E(2019), Computer Modeling of Convective Mass Transfer of Glucose, Oxygen and Carbon Dioxide in the Neurovascular Unit. J Compl Sys Bio. 4(1): p. 1-8.
    View at Publisher | View at Google Scholar
  11. Titovets, E(2020), Computer Simulations of Brain Oxygenation at the Microvascular Level Validating a New Role of the Arterioles. J Comp Sys Bio, 5(1): p. 1-8.
    View at Publisher | View at Google Scholar
  12. Titovets, E(2019). Nanofluidic Approach to Brain Water Metabolism. ANNR, 2019. 1(2): p. 49-56.
    View at Publisher | View at Google Scholar
  13. Titovets, E(2019). Nanofluidic Approach to Brain Water Metabolism and Related Issues.
    View at Publisher | View at Google Scholar
  14. Titovets, E(2021).Nanofluidic Mechanism and Computational Model of the Brain Water Metabolism. Recent Research Advances in Biology ed. V.A. Tsygankova.Vol 6.Hooghly, IndiaUK, London: BP International.
    View at Publisher | View at Google Scholar
  15. Titovets, E(2020).Nanofluidic Paradigm and Approach to Brain Water Metabolism, in Annual Congress on Advances in Biotechnology. Paris, France.
    View at Publisher | View at Google Scholar
  16. Walcott BP, K.K, Simard JM(2012). Novel treatment targets for cerebral edema. Neurotherapeutics. Jan;9(1)2. 9(1): p. 65-72.
    View at Publisher | View at Google Scholar
  17. Mahajan S, B.H(2016). Cerebral oedema: Pathophysiological mechanisms and experimental therapie. J Neuroanaesthesiol Crit Care. 3: p. Suppl S1:22-38.
    View at Publisher | View at Google Scholar
  18. Orešković, D. and M. Klarica(2014). A new look at cerebrospinal fluid movement. Fluids and Barriers of the CNS. 11: p. 1-16.
    View at Publisher | View at Google Scholar
  19. Orešković D, R.M, .Klarica M(2016). Cerebrospinal fluid secretion by the choroid plexus? Physiol Rev, 96(4): p. 1661-1662.
    View at Publisher | View at Google Scholar
  20. Oreskovic, D., M. Rados, and M. Klarica(2017). New Concepts of Cerebrospinal Fluid Physiology and Development of Hydrocephalus. Pediatr Neurosurg, 52(6): p. 417-425.
    View at Publisher | View at Google Scholar
  21. Wolburg, H, Wolburg-Buchholz, K., Fallier-Becker P, Noell S, Mack A.F(2011), Structure and Functions of Aquaporin-4-Based Orthogonal Arrays of Particles, in International review of cell and molecular biology, K.W. JEON, Editor., Academic Press: New York p. 1-42.
    View at Publisher | View at Google Scholar
  22. Crane, J.M, et al(2008). Aquaporin-4 dynamics in orthogonal arrays in live cells visualized by quantum dot single particle tracking. Mol Biol Cell. 19(8): p. 3369-78.
    View at Publisher | View at Google Scholar
  23. Fukuda, A.M. and J. Badaut(2012). Aquaporin 4: a player in cerebral edema and neuroinflammation. J Neuroinflammation, 9: p. 279.
    View at Publisher | View at Google Scholar
  24. Papadopoulos, M.C.V, A. S(2007), Aquaporin-4 and brain edema. Pediatr Nephrol,. 22(6): p. 778-884.
    View at Publisher | View at Google Scholar
  25. Abbott, N.J, L. Ronnback, and E. Hansson(2006). Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 7(1): p. 41-53.
    View at Publisher | View at Google Scholar
  26. Frydenlund, D.S(2011). Pathophysiological roles of aquaporin-4 in CNS disease Dissertation,: p. 1-65.
    View at Publisher | View at Google Scholar
  27. Tradtrantip, L., et al(2017). Aquaporin-Targeted Therapeutics: State-of-the-Field. Adv Exp Med Biol. 969: p. 239-250.
    View at Publisher | View at Google Scholar
  28. Verkman, A.S, Smith, A. J,Phuan, P. W,Tradtrantip, L,Anderson, M. O(2017), The aquaporin-4 water channel as a potential drug target in neurological disorders. Expert Opin Ther Targets, 21(12): p. 1161-1170.
    View at Publisher | View at Google Scholar
  29. Yool, A.J., E.A. Brown, and G.A. Flynn(2010). Roles for novel pharmacological blockers of aquaporins in the treatment of brain oedema and cancer. Clin Exp Pharmacol Physiol, 37(4): p. 403-419.
    View at Publisher | View at Google Scholar
  30. Papadopoulos, M.C. and A.S. Verkman(2008). Potential utility of aquaporin modulators for therapy of brain disorders. Prog Brain Res,. 170: p. 589-601.
    View at Publisher | View at Google Scholar
  31. Gu, F, et al(2003). Testosterone up-regulates aquaporin-4 expression in cultured astrocytes. J Neurosci Res, 72(6): p. 709-815.
    View at Publisher | View at Google Scholar
  32. Voigtlaender, J, B. Heindl, and B.F. Becker(2002), Transmembrane water influx via aquaporin-1 is inhibited by barbiturates and propofol in red blood cells. Naunyn Schmiedebergs Arch Pharmacol, 366(3): p. 209-317.
    View at Publisher | View at Google Scholar
  33. Ding Z, Z.J, Xu J, Sheng G, Huang G(2013). Propofol administration modulates AQP-4 expression and brain edema after traumatic brain injury. Cell Biochem Biophys., 67(2): p. 615-722.
    View at Publisher | View at Google Scholar
  34. Zheng, Y.Y, et al(2009). Propofol pretreatment attenuates aquaporin-4 over-expression and alleviates cerebral edema after transient focal brain ischemia reperfusion in rats. Anesth Analg, 2008. 107(6): p.16.
    View at Publisher | View at Google Scholar
  35. Gu, Y.T, H. Zhang, and Y.X. Xue(2007). Dexamethasone treatment modulates aquaporin-4 expression after intracerebral hemorrhage in rats. Neurosci Lett, 413(2): p. 126-231.
    View at Publisher | View at Google Scholar
  36. Bhattacharya, P, et al(2013). Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents. PLoS One, 8(9): p. e73481.
    View at Publisher | View at Google Scholar
  37. Tanimura, Y, Y. Hiroaki, and Y. Fujiyoshi(2009). Acetazolamide reversibly inhibits water conduction by aquaporin-4. J Struct Biol. 166(1): p. 16-21.
    View at Publisher | View at Google Scholar
  38. Gao, J, Wang, X,Chang, Y,Zhang, J,Song, Q.,Yu, H(2006). Acetazolamide inhibits osmotic water permeability by interaction with aquaporin-1. Anal Biochem, 350(2): p. 165-270.
    View at Publisher | View at Google Scholar
  39. Migliati, E., et al(2009). Inhibition of aquaporin-1 and aquaporin-4 water permeability by a derivative of the loop diuretic bumetanide acting at an internal pore-occluding binding site. Mol Pharmacol, 76(1): p. 105-212.
    View at Publisher | View at Google Scholar
  40. Dorward, H.S, et al(2016). Pharmacological blockade of aquaporin-1 water channel by AqB013 restricts migration and invasiveness of colon cancer cells and prevents endothelial tube formation in vitro. J Exp Clin Cancer Res. 35: p. 36.
    View at Publisher | View at Google Scholar
  41. Yool, A.J, et al(2013). AqF026 is a pharmacologic agonist of the water channel aquaporin-1. J Am Soc Nephrol, 24(7): p. 1045-1152.
    View at Publisher | View at Google Scholar
  42. Stoenoiu, M.S(2003). Corticosteroids Induce Expression of Aquaporin-1 and Increase Transcellular Water Transport in Rat Peritoneum. Journal of the American Society of Nephrology, 14(3): p. 555-565.
    View at Publisher | View at Google Scholar
  43. Soveral, G, Casini, A(2017). Aquaporin modulators: a patent review (2010-2015). Expert Opin Ther Pat, 27(1): p. 49-62.
    View at Publisher | View at Google Scholar

Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.

img

Virginia E. Koenig

Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.

img

Delcio G Silva Junior

Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.

img

Ziemlé Clément Méda

Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.

img

Mina Sherif Soliman Georgy

We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.

img

Layla Shojaie

The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.

img

Sing-yung Wu

Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.

img

Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

img

Katarzyna Byczkowska

Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.

img

Anthony Kodzo-Grey Venyo

Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.

img

Pedro Marques Gomes

Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.

img

Bernard Terkimbi Utoo

This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.

img

Prof Sherif W Mansour

Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

img

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.

img

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.

img

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.

img

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.

img

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.

img

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!

img

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".

img

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.

img

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.

img

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.

img

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.

img

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.

img

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.

img

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”.

img

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.

img

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.

img

Khurram Arshad