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Contents lists available at ScienceDirect

Advances in Integrative Medicine

journal homepage: www.elsevier.com/locate/aimed

Medical hypothesis

Microparticle clearance theory: An update to the potential mechanisms

of action of cupping therapy
Nurudeen Hassana,* , Rizwhan Sulemana , Waheeb Al-Azzanib , Hisham Jaberc, Ali Mahdid
a
ICAHT Centre of Integrative Medicine, 83-85 Rolleston Street, Leicester, England, United Kingdom
b
Trauma and Orthopaedic Surgery, Prince Philip Hospital, Llanelli, Wales, United Kingdom
c
Radiology Department, University Hospital of Wales, Cardiff, Wales, United Kingdom
d
Haematology Department, Royal Gwent Hospital, Newport, Wales, United Kingdom

A R T I C L E I N F O A B S T R A C T

Article history: Cupping therapy is an ancient medical practice that dates back as far as the earliest records of human
Received 30 June 2019 civilisation. Unlike many other ancient therapies, cupping is still widely practised in different parts of the
Received in revised form 26 June 2020 World. The two main forms of cupping; dry cupping and wet-cupping have recently experienced a
Accepted 13 July 2020
resurgence in popularity in the West due, in part, to high profile athletes and celebrities undergoing the
Available online xxx
treatment. Although cupping is widely used by complementary and holistic therapists to treat many
conditions, its mechanisms of action are not fully understood. In this paper, we review the current
Keywords:
theories and mechanisms through which wet-cupping therapy may exert its effects. We also describe, for
Cupping
Wet-cupping therapy
the first time the microparticle clearance theory as a novel mechanism through which wet-cupping
Holistic therapy therapy may exert anti-inflammatory, anti-thrombotic and afford endothelial protection within tissue
Haemodynamics microvasculature. However, further research is required in order to confirm the exact modes of action of
Immunomodulation cupping to inform targeted clinical research in the field.
Microparticles © 2020 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Methodology: literature search . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Current theories and proposed mechanisms of action .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Haemodynamic theory . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Blood detoxification and nitric oxide theory . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Immunomodulation theory . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Microparticle clearance theory (MCT) . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
CRediT authorship contribution statement . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction Chinese Medicine texts [2], and works of the Greek physician, and
‘Father of Western medicine’, Hippocrates [3]. In the United
Cupping is a form of therapy that has been employed Kingdom, like many European countries, cupping was widely used
ubiquitously for millennia by different cultures and civilisations. in combination with venesection until the nineteenth century but
There are references to cupping in records of the civilisations of saw a decline with the introduction of the scientific approach and
antiquity such as the Egyptian Ebbers Papyrus [1], Traditional application of medical statistics to medical science [4,5]. However,
the practice of cupping survived in parts of Western Europe such
as Finland, where it is still practised widely by traditional
* Corresponding author at: Cardiff School of Sport and Health Sciences, Cardiff
therapists [6].
Metropolitan University, Llandaff, Cardiff, CF5 2YB, United Kingdom. In recent years there has been a resurgence in the practice of
E-mail address: nhassan@cardiffmet.ac.uk (N. Hassan). cupping in the West due, in part, to high profile celebrities and

https://doi.org/10.1016/j.aimed.2020.07.001
2212-9588/© 2020 Elsevier Ltd. All rights reserved.

Please cite this article in press as: N. Hassan, et al., Microparticle clearance theory: An update to the potential mechanisms of action of cupping
therapy, Adv Integr Med (2020), https://doi.org/10.1016/j.aimed.2020.07.001
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athletes undergoing the treatment. The 2016 Olympics appeared to cupping’, ‘wet cupping therapy’, ‘bloodletting cupping’, ‘dry
mark a watershed moment in the popularisation of cupping cupping’ and ‘hijamah’. The search criteria were full-text scientific
therapy, with many of Olympic athletes sporting the characteristic papers published in English during or prior to March 2020. Only
cupping marks during the competition. full articles discussing and/or supporting the current theories or
The two main forms of cupping are dry-cupping and wet- proposed theories in cupping therapy were included in this review.
cupping (also known as bloodletting cupping). These two forms
have been further categorised on the basis of the type of equipment 3. Current theories and proposed mechanisms of action
employed, the power of suction and other characteristics. For a
detailed review of the different types of cupping and indications Although the exact mechanisms through which WCT exerts its
see [7]. effects remains elusive, several theories that have been proposed
Even though there has been an increasing body of scholarly by researchers in recent years. This section reviews the most
work exploring the effectiveness of cupping therapy in the last widely reported theories prima facie.
decade, cupping therapy is still widely viewed as a pseudoscience
within large parts of the scientific community, in part due to the 3.1. Haemodynamic theory
lack of a coherent scientific understanding of cupping's potential
mechanism of action. This warrants the need to explore its Elsayed et al. [16] proposed a mechanism through which WCT
potential modes of action in order to facilitate targeted high- can clear blood plasma and interstitial fluid of causative
quality research in the field. pathological substances such as excessive iron, ferritin and lysed
In a highly cited systematic review by Cao and colleagues, 135 red blood cells, a theory they termed Taibah theory. In this paper,
randomised controlled trials on cupping published between 1992 we further discuss the proposed haemodynamic effects of WCT in
and 2010 were reviewed. The authors concluded that cupping the context of chronic inflammation–which plays a major role in
appeared to be effective in treating some pain and inflammatory the pathophysiology of a myriad of chronic conditions.
conditions such as herpes zoster, acne, facial paralysis, and cervical During chronic inflammation, the function of tissues is
spondylosis [8]. Though this review provided an insight into how compromised due to the reduced capillary perfusion and
cupping could help with a number of conditions, the work did not accompanying activation of leukocytes [17]. The soluble mediators
discriminate between the different forms of cupping employed in produced by the leukocytes also increases the tissue pressure,
the studies. further compounding the issue. Cupping is understood to cause
In a more focussed review by Rozenfel and Kalichman, the localised hyperaemia as a result of the vasodilation of cutaneous
authors extensively discussed the various theories and applica- capillaries. The vasodilation is driven by the pressure differential
tions of dry cupping in musculoskeletal medicine [9]. Although between the skin and the superficial capillaries [9]. Tham and
extensive, the paper lacked a discussion on potential mechanisms colleagues demonstrated that during cupping, the region of the
of action. This insight was provided to some extent by a seminal highest tensile and compressive stress is at the interface between
paper by Lowe [10], where the author presents multiple potential the rim of the cup and skin. They also demonstrated that the
mechanisms through which Haeme-Oxygenase-1 (HO-1) can negative pressure causes the rim of the cup to press against the
mediate therapeutic effects associated with dry cupping. Lowe skin-potentially occluding superficial microcirculation [18]. The
purports that the phagocytic action of macrophages at the site of application and removal of the negative pressure against the
cupping produce HO-1, that in turn, induces antioxidant, anti- cutaneous microvasculature may also induce post-occlusive
inflammatory, anti-proliferative and antinociceptive effects. While hyperaemia in a fashion analogous to skin blood flux observed
further research is required to determine a causal link between the with post-occlusive reactive hyperaemia [19].
described theory and reported physiological effects, a randomised The resultant effect of hyperaemia is increased localised
placebo-controlled trial by Lauche et al. [11] provided evidence for perfusion as characterised by extravasation of blood and ecchy-
the antinociceptive effect of dry cupping. This study demonstrated mosis observed following cupping treatment. Findings from Liu
that dry-cupping was more effective than usual care in improving et al. [20] support this by demonstrating that a single session of
pain and quality of life in fibromyalgia patients. cupping significantly increased blood flow to the site of application
Along with dry-cupping, wet-cupping therapy (WCT) is also up to thirty minutes post-application. In another study by Li et al.
gaining popularity in the West, especially in the field of [21], they used near-infrared spectroscopy to monitor the oxygen
musculoskeletal medicine. WCT has been shown to be effective exchange during cupping and found an increase in the level of
in treating conditions such as hypertension [12], lower back pain oxyhaemoglobin and decrease in deoxyhaemoglobin, suggesting
[13,14] and Neck pain [15]. Unlike dry-cupping, there is a lot of active exchange at the level of the microcirculation during cupping.
variation in the application of WCT among practitioners. However,
WCT principally involves the application of cups on the skin for 3.2. Blood detoxification and nitric oxide theory
2 5 min (dry cupping stage); followed by superficial incisions
using a surgical blade/ scarificator; then replacement of cups at the Studies exploring the blood detoxification effect of WCT have
site for about 5 10 min to extract the localised blood. shown inconclusive results. However, many researchers maintain
Given that WCT appears to exert pleiotropic effects and is that the benefits of WCT is mediated by its ability to ‘filter-out’
employed for multiple indications, this paper focuses on the deleterious components within blood and modulate the release of
current theories and mechanisms of action of WCT by reviewing nitric oxide within the microvasculature. For example, Al-Bedah
peer-reviewed research in the field. Additionally, this paper et al. [22] argue that increased levels of nitric oxide in cupping
presents for the first time, a novel theory by which WCT may blood as reported by Tagil et al. [23], can cause vasodilation,
exert its effect at a cellular and molecular level: Microparticle platelet aggregation and leukocyte adhesion. Previous work by
Clearance Theory. Niasari et al. [24] also demonstrated that WCT selectively
decreased serum levels of low-density lipoprotein, a major risk
2. Methodology: literature search factor of atherosclerosis. In a more recent study by Umar et al. [25],
they also found a significant reduction in systemic levels of heavy
All relevant literature was retrieved through PubMed and metals (aluminium, zinc and cadmium) up to 30 days following a
Google Scholar databases using the following keywords: ‘wet session of WCT.

Please cite this article in press as: N. Hassan, et al., Microparticle clearance theory: An update to the potential mechanisms of action of cupping
therapy, Adv Integr Med (2020), https://doi.org/10.1016/j.aimed.2020.07.001
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Taken together, these studies suggest that WCT may have blood molecular patterns (DAMPS) [32]. However, EMPs have been
detoxification effects and stimulate the release of nitric oxide. associated with systemic inflammatory conditions [33–35].
However, it is still unclear whether these observations are due to EMPs have also been shown to be involved in pro-inflammatory
artefacts arising from the cupping process and therefore more priming of the immune system following transfusion [36],
studies in the form of controlled randomised control trials should which may contribute to conditions such as transfusion-
be undertaken to confirm these effects. associated lung injury. Microparticles derived from platelets,
endothelial cells and leukocytes have also been associated with
3.3. Immunomodulation theory disease processes [see 32]. In a study that underscores the
deleterious effects of microparticles, Danesh et al. [37]
In a study published over a decade ago by Ahmed et al. [26], demonstrated that granulocyte-derived EVs potently activated
they demonstrated that WCT significantly increased levels of the monocytes ex-vivo and were linked to increased risk of mortality
anti-inflammatory cytokine, Interleukin-4 (IL-4) in patients with among intensive care patients.
rheumatoid arthritis. Since their early work, other lines of evidence Within the microcirculation, normal haemodynamic param-
have emerged to suggest that cupping can improve conditions eters cause segregation of blood components, with red blood
characterised by immune system dysregulation such as psoriasis cells flowing through the middle of the blood vessel. Other
[27] and asthma [see 8]. smaller components and particles flow near the interface of the
More recently, Liu et al. [28] observed a significant difference blood vessel walls and can interact more readily with the
between the protein profiles of fluid isolates from cupping blisters endothelial cells [38]. Within the blood vessels, microparticles
in comparison to burn blisters. Using a 2D-PAGE proteomics can initiate and promote disease processes through activation of
approach they observed higher levels of proteins involved in inflammatory signals and immune cells [39]. This can, in turn,
immune responses, oxidative stress and metabolic-related pro- decrease endothelial nitric oxide bioavailability [see 40] and
cesses within the cupping group. Although this study gives an activate the coagulation cascade [41], potentially leading to in
insight into the acute cellular response of the tissues following situ thrombosis.
cupping, it is still unclear whether the observed immune response Given the effects of cupping to the local tissue microvasculature
exerts beneficial physiological effects downstream of the cupping as reviewed in Section 3.1, we herein propose that the process of
site. Additionally, it is not understood whether the physiological WCT could effectively cause the clearance of microparticles at the
effects of cupping therapy are mediated through a mechanism of local site of application in a fashion akin to apheresis. Apheresis is
hormesis in a similar fashion to reactive oxygen species (ROS) and an extracorporeal method of separating blood components based
exercise [29]. on their physical properties. Given that apheresis has been shown
Although the cellular and molecular mediators that facilitate to reduce circulating microparticles in patients with familial
the immune-modulatory effects of cupping remains to be fully hypercholesterolemia [42], we hypothesise that cupping may
elucidated, Lowe proposed that cupping causes a shift in induce similar effects.
macrophage polarisation from a pro-inflammatory (M1) pheno- The clearance of microparticles from the local microcirculation
type to an immune-regulatory (M2) phenotype [10]. Given that may reduce disease pathophysiology by targeting the major
the polarisation of certain M2 macrophage subtypes is disease drivers such as chronic inflammation and endothelial
modulated by the bioavailability of IL-4, this is in congruence dysfunction. A mechanistic model of how WCT can potentially
with the findings from Ahmed et al. [26], who reported an exert beneficial physiolgical effects through microparticle clear-
increase in IL-4 levels following WCT. This is further supported ance is presented in Fig. 1
by recent work by Zhang et al. [30] who demonstrated an Microparticles play a major role in the pathogenesis of many
increase in anti-inflammatory lipids and the concomitant inflammatory disorders and have been shown to activate immune
decrease in pro-inflammatory lipids in a mouse model following cells through the activation of NF-kB [43]. The clearance of
cupping therapy. They also showed that the addition of the microparticles by WCT could reduce the downstream activation of
upregulated lipids attenuated IL-6 induced inflammation in inflammatory signals.
cultured macrophages. Microparticles have been shown to promote endothelial
Collectively, these studies suggest that cupping potentially dysfunction through inactivation of endothelial nitric oxide
exerts immunomodulatory effects at the local site of cupping that synthase [44]. Therefore, Cupping-mediated clearance of micro-
may have systemic effects. However, further research is required to particles may afford a protective effect to the tissue vasculature.
unravel the exact mechanism(s) through which cupping exerts Additionally, modulation of the hydrodynamic forces by negative
these proposed immunomodulatory effects. pressure during WCT could potentially increase the shear stress at
the interface of endothelial lining-which causes eNOS activation
4. Microparticle clearance theory (MCT) and release of nitric oxide [45,46]. The bioavailable nitric oxide
(NO) can induce vasodilation and can act as a scavenger of free
Microparticles (also referred to as microvesicles) form part of a radicals in the tissue vasculature, further attenuating disease-
class of submicron (100 1000 nm) membrane-bound vesicles causing effects.
collectively called extracellular vesicles (EVs). These vesicles are Another dimension that remains to be explored is the link
released by different cell types in response to a patho-/physiologi- between the reported anti-nociceptive effects of cupping and
cal stimulus [31]. In this paper, we present for the first time, a microparticles. WCT has been shown to exert analgesic effects
putative mechanism through which cupping may exert beneficial [47,48]. Some researchers have proposed that these effects are
physiological effects by modulating the bioavailability and tissue mediated through β-endorphin [49], however, the mechanism
distribution of microparticles. through which WCT mediates these effects remains to be fully
Red blood cell or Erythrocyte microparticles (EMPs) are the elucidated.
most widely studied class of microparticles. The release of Given that microparticles are known to mediate nociception
microparticles from erythrocytes is a protective mechanism [50], we propose that another mechanism through which cupping
that occurs with the ageing of erythrocytes to prevent the may exert its analgesic effects is through the clearance of
activation of the immune system through danger-associated microparticles from tissues.

Please cite this article in press as: N. Hassan, et al., Microparticle clearance theory: An update to the potential mechanisms of action of cupping
therapy, Adv Integr Med (2020), https://doi.org/10.1016/j.aimed.2020.07.001
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4 N. Hassan et al. / Advances in Integrative Medicine xxx (2019) xxx–xxx

Fig. 1. Mechanistic model of Microparticle Clearance Theory. Effect of circulating microparticles on inflammation, thrombosis and endothelial dysfunction and proposed
‘clearance’ effect of cupping therapy at a cellular level.

5. Conclusion [3] P. Mehta, V. Dhapte, Cupping therapy: a prudent remedy for a plethora of
medical ailments, J. Tradit. Complement. Med. 5 (3) (2015) 127–134.
[4] J.L. Turk, E. Allen, Bleeding and cupping, Ann. R. Coll. Surg. Engl. 65 (2) (1983)
Cupping is an ancient medical practice that has seen a 128–131.
resurgence in popularity in recent years. However, the exact [5] M.I. Sajid, Hijama therapy (wet cupping) - its potential use to complement
mechanisms through which it exerts its effects are not fully British healthcare in practice, understanding, evidence and regulation,
Complement. Ther. Clin. Pract. 23 (2016) 9–13.
understood. Consequently, there is a need to elucidate the modes [6] T. Vaskilampi, O. Hanninen, Cupping as an indigenous treatment of pain
of action of cupping in the light of modern medical science. In this syndromes in the Finnish culture and social context, Soc. Sci. Med. 16 (21)
paper, a range of current putative mechanisms through which (1982) 1893–1901.
[7] T.S. Aboushanab, S. AlSanad, Cupping therapy: an overview from a modern
cupping therapy may mediate its health-promoting effects have medicine perspective, J. Acupunct. Meridian Stud. S2005-2901 (17) (2018)
been reviewed. This paper also presents, for the first time, a novel 30202–30204.
theory through which cupping may exert its pleiotropic effects: [8] H. Cao, et al., Clinical research evidence of cupping therapy in China: a
systematic literature review, BMC Complement. Altern. Med. 10 (2010) 70.
microparticle clearance theory. Notwithstanding, further basic
[9] E. Rozenfeld, L. Kalichman, New is the well-forgotten old: the use of dry
scientific and clinical research is required in order to confirm the cupping in musculoskeletal medicine, J. Bodyw. Mov. Ther. 20 (1) (2016) 173–
proposed theories through which cupping may be exerting its 178.
effects. [10] D.T. Lowe, Cupping therapy: an analysis of the effects of suction on skin and the
possible influence on human health, Complement. Ther. Clin. Pract. 29 (2017)
162–168.
[11] R. Lauche, et al., Efficacy of cupping therapy in patients with the fibromyalgia
CRediT authorship contribution statement syndrome-a randomised placebo controlled trial, Sci. Rep. 6 (2016) 37316.
[12] N.A. Aleyeidi, et al., Effects of wet-cupping on blood pressure in hypertensive
Nurudeen Hassan: Conceptualization, Writing - original draft. patients: a randomized controlled trial, J. Integr. Med. 13 (6) (2015) 391–399.
[13] A. Al-Bedah, et al., The use of wet cupping for persistent nonspecific low back
Rizwhan Suleman: Writing - review & editing. Waheeb Al- pain: randomized controlled clinical trial, J. Altern. Complement. Med. 21 (8)
Azzani: Writing - review & editing. Hisham Jaber: Writing - review (2015) 504–508.
& editing. Ali Mahdi: Writing - review & editing. [14] K. Farhadi, et al., The effectiveness of wet-cupping for nonspecific low back
pain in Iran: a randomized controlled trial, Complement. Ther. Med. 17 (1)
(2009) 9–15.
Declaration of Competing Interest [15] R. Lauche, et al., The effect of traditional cupping on pain and mechanical
thresholds in patients with chronic nonspecific neck pain: a randomised
controlled pilot study, Evid. Complement. Alternat. Med. 2012 (2012) p.
None.
429718.
[16] S.M. El Sayed, et al., Percutaneous excretion of iron and ferritin (through Al-
hijamah) as a novel treatment for iron overload in beta-thalassemia major,
References hemochromatosis and sideroblastic anemia, Med. Hypotheses 83 (2) (2014)
238–246.
[1] J.C. Nickel, Management of urinary tract infections: historical perspective and [17] D.N. Granger, E. Senchenkova, Integrated Systems Physiology-From Cell to
current strategies: part 1–before antibiotics, J. Urol. 173 (1) (2005) 21–26. Function, in Inflammation and the Microcirculation, Morgan & Claypool Life
[2] H. Cao, X. Li, J. Liu, An updated review of the efficacy of cupping therapy, PLoS Science. Copyright (c) 2010 by Morgan & Claypool Life Sciences, San Rafael
One 7 (2) (2012) p. e31793. (CA), 2010.

Please cite this article in press as: N. Hassan, et al., Microparticle clearance theory: An update to the potential mechanisms of action of cupping
therapy, Adv Integr Med (2020), https://doi.org/10.1016/j.aimed.2020.07.001
G Model
AIMED 249 No. of Pages 5

N. Hassan et al. / Advances in Integrative Medicine xxx (2019) xxx–xxx 5

[18] L.M. Tham, H.P. Lee, C. Lu, Cupping: from a biomechanical perspective, J. [35] F.D. George, Microparticles in vascular diseases, Thromb. Res. 122 (Suppl 1)
Biomech. 39 (12) (2006) 2183–2193. (2008) S55–9.
[19] M. Roustit, J.L. Cracowski, Assessment of endothelial and neurovascular [36] M.W. Kent, et al., The pro-inflammatory potential of microparticles in red
function in human skin microcirculation, Trends Pharmacol. Sci. 34 (7) (2013) blood cell units, Transfus. Med. 24 (3) (2014) 176–181.
373–384. [37] A. Danesh, et al., Granulocyte-derived extracellular vesicles activate
[20] W. Liu, et al., Effects of cupping on blood flow under skin of back in healthy monocytes and are associated with mortality in intensive care unit
human, World J. Acupunct. - Moxibustion 23 (3) (2013) 50–52. patients, Front. Immunol. 9 (2018) 956.
[21] T. Li, et al., Significant and sustaining elevation of blood oxygen induced by [38] Y. Li, et al., Cell and nanoparticle transport in tumour microvasculature: the
Chinese cupping therapy as assessed by near-infrared spectroscopy, Biomed. role of size, shape and surface functionality of nanoparticles, Interface Focus 6
Opt. Express 8 (1) (2017) 223–229. (1) (2016) p. 20150086.
[22] A.M.N. Al-Bedah, et al., The medical perspective of cupping therapy: effects [39] A.M. Curtis, et al., p38 mitogen-activated protein kinase targets the production
and mechanisms of action, J. Tradit. Complement. Med. (2019). of proinflammatory endothelial microparticles, J. Thromb. Haemost. 7 (4)
[23] S.M. Tagil, et al., Wet-cupping removes oxidants and decreases oxidative (2009) 701–709.
stress, Complement. Ther. Med. 22 (6) (2014) 1032–1036. [40] A.S. Said, S.C. Rogers, A. Doctor, Physiologic impact of circulating RBC
[24] M. Niasari, F. Kosari, A. Ahmadi, The effect of wet cupping on serum lipid microparticles upon blood-vascular interactions, Front. Physiol. 8 (2017) 1120.
concentrations of clinically healthy young men: a randomized controlled trial, [41] O. Rubin, et al., Red blood cell-derived microparticles isolated from blood units
J. Altern. Complement. Med. 13 (1) (2007) 79–82. initiate and propagate thrombin generation, Transfusion 53 (8) (2013) 1744–1754.
[25] N.K. Umar, et al., The effects of wet cupping therapy on the blood levels of some [42] K.D. Connolly, et al., Lipoprotein-apheresis reduces circulating microparticles
heavy metals: a pilot study, J. Acupunct. Meridian Stud. (2018). in individuals with familial hypercholesterolemia, J. Lipid Res. 55 (10) (2014)
[26] S.M. Ahmed, N.H. Madbouly, S.S. Maklad, E.A. Abu-Shady, Immunomodulatory 2064–2072.
effects of blood letting cupping therapy in patients with rheumatoid arthritis, [43] Y. Wang, et al., Dysfunctional endothelial-derived microparticles promote
Egypt. J. Immunol. 12 (2) (2005) 39–51. inflammatory macrophage formation via NF-small ka, CyrillicB and IL-1beta
[27] I.A. Malik, S. Akhter, M.A. Kamal, Treatment of psoriasis by using Hijamah: a signal pathways, J. Cell. Mol. Med. (2018).
case report, Saudi J. Biol. Sci. 22 (1) (2015) 117–121. [44] Z.B. Lin, et al., Endothelial microparticles are increased in congenital heart
[28] Z. Liu, et al., Is cupping blister harmful?-A proteomical analysis of blister fluid diseases and contribute to endothelial dysfunction, J. Transl. Med.15 (1) (2017) 4.
induced by cupping therapy and scald, Complement. Ther. Med. 36 (2018) 25–29. [45] B. Yang, V. Rizzo, Shear stress activates eNOS at the endothelial apical surface
[29] Z. Radak, K. Ishihara, E. Tekus, C. Varga, A. Posa, L. Balogh, I. Boldogh, E. Koltai, through beta1 containing integrins and caveolae, Cell. Mol. Bioeng. 6 (3) (2013)
Exercise, oxidants, and antioxidants change the shape of the bell-shaped 346–354.
hormesis curve, Redox. Biol. 12 (August) (2017) 285–290. [46] Y.S. Li, J.H. Haga, S. Chien, Molecular basis of the effects of shear stress on
[30] Q. Zhang, et al., Anti- versus pro-inflammatory metabololipidome upon vascular endothelial cells, J. Biomech. 38 (10) (2005) 1949–1971.
cupping treatment, Cell. Physiol. Biochem. 45 (4) (2018) 1377–1389. [47] H. Tian, et al., Impacts of bleeding and cupping therapy on serum P substance in
[31] E. Dey-Hazra, et al., Detection of circulating microparticles by flow cytometry: patients of postherpetic neuralgia, Zhongguo Zhen Jiu 33 (8) (2013) 678–681.
influence of centrifugation, filtration of buffer, and freezing, Vasc. Health Risk [48] X.W. Meng, et al., Wet cupping therapy improves local blood perfusion and
Manag. 6 (2010) 1125–1133. analgesic effects in patients with nerve-root type cervical spondylosis, Chin. J.
[32] F. Cognasse, et al., The role of microparticles in inflammation and transfusion: Integr. Med. 24 (11) (2018) 830–834.
a concise review, Transfus. Apher. Sci. 53 (2) (2015) 159–167. [49] I. Subadi, et al., Pain relief with wet cupping therapy in rats is mediated by heat
[33] M. Diamant, et al., Cellular microparticles: new players in the field of vascular shock protein 70 and ss-endorphin, Iran. J. Med. Sci. 42 (4) (2017) 384–391.
disease? Eur. J. Clin. Invest. 34 (6) (2004) 392–401. [50] R. Simeoli, et al., Exosomal cargo including microRNA regulates sensory
[34] A.T. Nurden, Platelets, inflammation and tissue regeneration, Thromb. neuron to macrophage communication after nerve trauma, Nat. Commun. 8
Haemost. 105 (Suppl 1) (2011) S13–33. (1) (2017) 1778.

Please cite this article in press as: N. Hassan, et al., Microparticle clearance theory: An update to the potential mechanisms of action of cupping
therapy, Adv Integr Med (2020), https://doi.org/10.1016/j.aimed.2020.07.001