Hyperactivation of P2X7 receptors as a culprit of COVID-19 neuropathology

May combine two claims.

Pro-inflammatory factors are intensely released into the bloodstream, causing the cytokine storm, and reach other organs.

“pro-inflammatory factors are intensely released, the so-called “cytokine storm”, which enter the bloodstream, and reach other organs (Fig. 1A) [9].”

• cites [9] Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020;53:38–42. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Both pro-inflammatory factors and viruses can cross the blood-brain barrier and enter the central nervous system, initiating a neuroinflammatory process.

“both pro-inflammatory factors and viruses can cross the blood–brain barrier (BBB) and enter the central nervous system (CNS), initiating a neuroinflammatory process [10].”

• cites [10] Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich H. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review. JAMA Neurol. 2020;77:1018–27. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

The neuroinflammatory insult could increase susceptibility to neurodegeneration in patients who are not yet suffering from these diseases.

“In addition, the neuroinflammatory insult could increase susceptibility to neurodegeneration in patients who are not yet suffering from these diseases.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Neurotropism of human coronaviruses has been demonstrated in small animals and in autoptic studies of brains infected with SARS-CoV.

“Neurotropism of human coronaviruses has already been demonstrated in small animals and in autoptic studies of brains infected with the severe acute respiratory syndrome coronavirus (SARS-CoV) [11]”

• cites [11] Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202:415–24. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

COVID-19 patients also present impaired taste (10-19.2%), smell (6-21.7%), dysautonomia (4.3-12%), and acute inflammatory demyelinating polyneuropathy (0-16,2%).

“COVID-19 patients also present other nervous system symptoms, such as impaired taste (10–19.2%) and smell (6–21.7%), dysautonomia (4.3–12%), and acute inflammatory demyelinating polyneuropathy (0–16,2%) [22].”

• cites [22] Pezzini A, Padovani A. Lifting the mask on neurological manifestations of COVID-19. Nat Rev Neurol. 2020;16:636–44. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Available data indicate that COVID-19 patients mainly present depressive symptoms (42-65%), anxiety (37-47%), and PTSS (93-96%).

“Although studies on psychiatric symptoms accompanying SARS-CoV-2 illness need further investigation, the available data indicate that COVID-19 patients mainly present depressive symptoms (42–65%), anxiety (37–47%), and PTSS (93–96%).”

• cites [178] Krishnamoorthy Y, Nagarajan R, Saya GK, Menon V. Prevalence of psychological morbidities among general population, healthcare workers and COVID-19 patients amidst the COVID-19 pandemic: a systematic review and meta-analysis. Psychiatry Res. 2020;293:113382. sourceNot checked yet

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• cites [183] Luo M, Guo L, Yu M, Wang H. The psychological and mental impact of coronavirus disease 2019 (COVID-19) on medical staff and general public—a systematic review and meta-analysis. Psychiatry Res. 2020;291:113190. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Reported impaired olfaction could be due to CNS invasion or direct damage of olfactory sensory neurons in the nasal cavity.

“Moreover, reported impaired olfaction could be due to CNS invasion or direct damage of olfactory sensory neurons in the nasal cavity [24].”

• cites [24] Butowt R, Bilinska K. SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection. ACS Chem Neurosci. 2020;11:1200–3. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Both neuroinvasion through the BBB and hyperstimulation of neuroimmune responses observed during COVID-19 infection are mediated by hyperactivation of the P2X7 receptor, possibly through NLRP3 inflammasome stimulation.

“we postulate that both, neuroinvasion through the BBB and hyperstimulation of neuroimmune responses observed during COVID-19 infection, are mediated by hyperactivation of the P2X7 receptor, possibly through NLRP3 inflammasome stimulation.”

• AssumptionRests on an assumption: SARS-CoV-2 infection elevates extracellular ATP levels.

May combine two claims.

Hyperactivation of P2X7 receptors is closely related to inflammatory processes because they are stimulated by ATP released from distressed cells and induce inflammasome activation.

“Hyperactivation of P2X7 receptors is closely related to inflammatory processes since they are stimulated by ATP released from distressed cells and induce inflammasome activation [16–18].”

• cites [16] Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S. The P2X7 receptor in infection and inflammation. Immunity. 2017;47:15–31. sourceNot checked yet

  Not checked in the free run.

• cites [17] Ratajczak MZ, Mack A, Bujko K, Domingues A, Pedziwiatr D, Kucia M, et al. ATP-Nlrp3 inflammasome-complement cascade axis in sterile brain inflammation in psychiatric patients and its impact on stem cell trafficking. Stem Cell Rev Rep. 2019;15:497–505. sourceNot checked yet

  Not checked in the free run.

• cites [18] Ratajczak MZ, Bujko K, Cymer M, Thapa A, Adamiak M, Ratajczak J, et al. The Nlrp3 inflammasome as a “rising star” in studies of normal and malignant hematopoiesis. Leukemia. 2020;34:1512–23. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

These brain pathologies are described as both etiological factors and consequences of psychiatric disorders and neurodegenerative diseases.

“These brain pathologies are described as both etiological factors and consequences of psychiatric disorders and neurodegenerative diseases [15].”

• cites [15] Ferro JM, Caeiro L, Figueira ML. Neuropsychiatric sequelae of stroke. Nat Rev Neurol. 2016;12:269–80. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Activation of P2X7 receptors induced by viral infection leads to molecular alterations (neuroimmune response activation, ROS formation, and glutamate release), behavioral alterations, and mental disorders.

“their activation induced by viral infection leads to molecular (mainly neuroimmune response activation, reactive oxygen species (ROS) formation, and glutamate release) and behavioral alterations [17, 20] as well as to mental disorders [21].”

• cites [17] Ratajczak MZ, Mack A, Bujko K, Domingues A, Pedziwiatr D, Kucia M, et al. ATP-Nlrp3 inflammasome-complement cascade axis in sterile brain inflammation in psychiatric patients and its impact on stem cell trafficking. Stem Cell Rev Rep. 2019;15:497–505. sourceNot checked yet

  Not checked in the free run.

• cites [20] Adinolfi E, Giuliani AL, De Marchi E, Pegoraro A, Orioli E, Di Virgilio F. The P2X7 receptor: a main player in inflammation. Biochem Pharmacol. 2018;151:234–44. sourceNot checked yet

  Not checked in the free run.

• cites [21] Sperlágh B, Illes P. P2X7 receptor: An emerging target in central nervous system diseases. Trends Pharm Sci. 2014;35:537–47. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Image studies and postmortem examination of the brain of COVID-19 patients revealed hemorrhagic lesions accompanied by neuronal injury and neuroinflammation signals.

“Image studies [12, 13] and postmortem examination [14] of the brain of COVID-19 patients also revealed hemorrhagic lesions accompanied by neuronal injury and neuroinflammation signals.”

• cites [12] Politi LS, Salsano E, Grimaldi M. Magnetic resonance imaging alteration of the brain in a patient with coronavirus disease 2019 (COVID-19) and anosmia. JAMA Neurol. 2020;77:1028–9. sourceNot checked yet

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• cites [13] Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology. 2020;296:E119–20. sourceNot checked yet

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• cites [14] Reichard R, Kashani K, Boire N, Constantopoulos E, Guo Y, Lucchinetti C. Neuropathology of COVID-19: a spectrum of vascular and acute disseminated encephalomyelitis (ADEM)-like pathology. Acta Neuropathol. 2020;140:1–6. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In COVID-19 patients presenting at least one neurological symptom, the prevalence of acute stroke (2.9-76.8%), confusion (14.2-65%), and encephalitis (0-27.9%) stands out.

“Noteworthy, in COVID-19 patients presenting at least one neurological symptom, the prevalence of acute stroke (2.9–76.8%), confusion (14.2–65%), and encephalitis (0–27.9%) stands out.”

• cites [22] Pezzini A, Padovani A. Lifting the mask on neurological manifestations of COVID-19. Nat Rev Neurol. 2020;16:636–44. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Patients with COVID-19 are prone to develop neurological disorders, and patients suffering from these conditions are more susceptible to SARS-CoV-2 infection.

“Therefore, it is plausible to suggest that patients with COVID-19 are prone to develop neurological disorders, as well as patients suffering from these conditions are more susceptible to SARS-CoV-2 infection.”

• AssumptionRests on an assumption: BBB permeability is increased in patients with neurodegenerative diseases.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Stress caused by the pandemic situation may also induce depressive symptoms (14.6-48.3%), anxiety (6.33-50.9%), and PTSS (7-53.8%) in the general population.

“Noteworthy, stress caused by the pandemic situation (e.g., social isolation, fear of infection, and financial instability) may also induce depressive symptoms (14.6–48.3%), anxiety (6.33–50.9%), and PTSS (7–53.8%) in the general population.”

• cites [179] Xiong J, Lipsitz O, Nasri F, Lui LMW, Gill H, Phan L, et al. Impact of COVID-19 pandemic on mental health in the general population: a systematic review. J Affect Disord. 2020;277:55–64. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

P2X7 receptors are ATP-gated ion channels widely expressed in the CNS.

“P2X7 receptors are ATP-gated ion channels widely expressed in the CNS [19]”

• cites [19] Sluyter R. The P2X7 receptor. In: Atassi M, editor. Protein reviews. Advances in experimental medicine and biology. Singapore: Springer; 2017. p. 17–53. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

This cascade could lead to COVID-19-associated psychiatric disorders and neurodegenerative diseases.

“This cascade could lead to COVID-19-associated psychiatric disorders and neurodegenerative diseases.”

• AssumptionRests on an assumption: SARS-CoV-2 infection elevates extracellular ATP levels.

Probably not a substantial claim: may not pass S3 (load-bearing).

Neurological manifestations affect between 4.2 and 100% of studied COVID-19 patients.

“As reviewed by Pezzini and Padovani, neurological manifestations affect between 4.2 and 100% of studied patients: dizziness (prevalent in 7.6–46.1%), headache (5.1–77.1%), impaired consciousness (9.5–64.1%), and seizures (1.2–26%) [22].”

• cites [22] Pezzini A, Padovani A. Lifting the mask on neurological manifestations of COVID-19. Nat Rev Neurol. 2020;16:636–44. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

All neurological symptoms together with acute cerebrovascular disorder are correlated with the consequences of strokes or micro-strokes.

“Together with an acute cerebrovascular disorder, all symptoms are correlated with the consequences of strokes or micro-strokes [23].”

• cites [23] Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145–7. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The stressful situation of healthcare workers may lead to depressive symptoms (12.2-26.3%), anxiety (13-29%), and PTSS (3-20.7%).

“The stressful situation of healthcare workers, specially the fear to infect relatives, may lead to depressive symptoms (12.2–26.3%), anxiety (13–29%), and PTSS (3–20.7%) as well.”

• cites [180] da Silva FCT, Neto MLR. Psychological effects caused by the COVID-19 pandemic in health professionals: a systematic review with meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2021;104:110062. sourceNot checked yet

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• cites [182] de Pablo GS, Vaquerizo-Serrano J, Catalan A, Arango C, Moreno C, Ferre F, et al. Impact of coronavirus syndromes on physical and mental health of health care workers: systematic review and meta-analysis. J Affect Disord. 2020;275:48–57. sourceNot checked yet

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• cites [184] Pappa S, Ntella V, Giannakas T, Giannakoulis VG, Papoutsi E, Katsaounouc P, et al. Prevalence of depression, anxiety, and insomnia among healthcare workers during the COVID-19 pandemic: a systematic review and meta-analysis. Brain Behav Immun. 2020;88:901–7. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

A case report demonstrated the presence of SARS-CoV-2 viral particles in neural tissue and brain capillary endothelium of a Parkinson's disease patient, associated with worsening of neurological symptoms.

“a case report demonstrated the presence of SARS-CoV-2 viral particles in neural tissue and brain capillary endothelium of a Parkinson’s disease patient, which was associated with the worsening of neurological symptoms [28].”

• cites [28] Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol. 2020;92:699–702. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Neuroinvasion potential of SARS-CoV-2 was demonstrated in mice expressing human ACE2 and correlated with increased mortality independent from respiratory infection.

“Neuroinvasion potential of SARS-CoV-2 was demonstrated in mice expressing human ACE2 and correlated with increased mortality independent from respiratory infection [26].”

• cites [26] Song E, Zhang C, Israelow B, Lu-Culligan A, Prado AV, Skriabine S, et al. Neuroinvasion of SARS-CoV-2 in human and mouse brain. 2020. https://doi.org/10.1101/2020.06.25.169946. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

A study detected SARS-CoV-2 in 8 of 21 postmortem brain tissues based on reverse transcriptase polymerase chain reaction.

“a study detected SARS-CoV-2 in 8 of 21 postmortem brain tissues, based on reverse transcriptase polymerase chain reaction [25].”

• cites [25] Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, et al. Multiorgan and renal tropism of SARS-CoV-2 [letter]. N Engl J Med. 2020;383:590–92. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Severe COVID-19 patients commonly develop Acute Respiratory Distress Syndrome, characterized by inflammatory injury to the alveoli-capillary membrane, leading to lung over-permeability and increased pulmonary edema fluid into the airspaces, resulting in lack of respiratory capacity.

“Severe COVID-19 patients commonly develop the Acute Respiratory Distress Syndrome [38], which is characterized by inflammatory injury to the alveoli–capillary membrane, leading to lung over-permeability and increased pulmonary edema fluid into the airspaces, resulting in the lack of respiratory capacity [39].”

• cites [38] Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–2. sourceNot checked yet

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• cites [39] Bhatia M, Zemans RL, Jeyaseelan S. Role of chemokines in the pathogenesis of acute lung injury. Am J Respir Cell Mol Biol. 2012;46:566–72. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Viral infection affects BBB integrity by mechanisms including phosphorylation of tight junction proteins, disruption of the basal lamina or of the actin cytoskeleton, or by invading BBB-epithelial cells and furthermore astrocytes.

“Viral infection also affects BBB integrity by different mechanisms, including phosphorylation of tight junction proteins, disruption of the basal lamina or of the actin cytoskeleton, or by invading BBB-epithelial cells and furthermore astrocytes [10, 31].”

• cites [10] Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich H. Neuropathogenesis and neurologic manifestations of the coronaviruses in the age of coronavirus disease 2019: a review. JAMA Neurol. 2020;77:1018–27. sourceNot checked yet

  Not checked in the free run.

• cites [31] Spindler KR, Hsu TH. Viral disruption of the blood–brain barrier. Trends Microbiol. 2012;20:282–90. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

SARS-CoV, MERS-CoV, and HCoV-OCR43 were able to invade the murine CNS using the transcribrial route, infecting olfactory sensory neurons of the nasal cavity and passing to other neural cells, indicating that SARS-CoV-2 could use the same mechanism.

“In fact, SARS-CoV, MERS-CoV, and HCoV-OCR43 were able to invade the murine CNS using the transcribrial route, infecting olfactory sensory neurons of nasal cavity, and passing to other neural cells, indicating that SARS-CoV-2 could use the same mechanism [24, 35–37].”

• cites [24] Butowt R, Bilinska K. SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection. ACS Chem Neurosci. 2020;11:1200–3. sourceNot checked yet

  Not checked in the free run.

• cites [35] McCray PB, Pewe L, Wohlford-Lenane C, Hickey M, Manzel L, Shi L, et al. Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus. J Virol. 2007;81:813–21. sourceNot checked yet

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• cites [36] Jacomy H, Talbot PJ. Vacuolating encephalitis in mice infected by human coronavirus OC43. Virology. 2003;315:20–33. sourceNot checked yet

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• cites [37] Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, et al. Middle east respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis. 2016;213:712–22. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Human olfactory sensory neurons do not express ACE2 and TMPRSS2 but express CD147 that could allow SARS-CoV-2 neuroinvasion.

“Although current literature data reports that human olfactory sensory neurons do not express these proteins, they express CD147 that could allow SARS-CoV-2 neuroinvasion (Fig. 1) [33, 34].”

• cites [33] Fodoulian L, Tuberosa J, Rossier D, Landis B, Carleton A, Rodriguez I. SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium. 2020. https://doi.org/10.1101/2020.03.31.013268. sourceNot checked yet

  Not checked in the free run.

• cites [34] Brann DH, Tsukahara T, Weinreb C, Lipovsek M, Van den Berge K, Gong B, et al. Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Sci Adv. 2020;6:eabc5801. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Ang II activates AT1R, inducing fibrosis, increased ROS release, vasoconstriction, and gut dysbiosis.

“Ang II activates the AT1R, inducing fibrosis, increased ROS release, vasoconstriction, and gut dysbiosis.”

May combine two claims.

ATP is released into the extracellular milieu upon NLRP3 inflammasome activation, promoting a strong positive feedback loop.

“In addition, ATP is also released into the extracellular milieu upon NLRP3 inflammasome activation, promoting a strong positive feedback loop [44].”

• cites [44] Albalawi F, Lu W, Beckel JM, Lim JC, McCaughey SA, Mitchell CH. The P2X7 receptor primes IL-1beta and the NLRP3 inflammasome in astrocytes exposed to mechanical strain. Front Cell Neurosci. 2017;11:227. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The NLRP3 inflammasome protein complex is usually involved in virus infections and consists of NLRP3 protein, ASC, and pro-caspase-1, and remains inactive in the cytosol in steady-state; upon activation it becomes a multiprotein aggregate.

“The NLRP3 inflammasome protein complex is usually involved in virus infections and consists of NLRP3 protein, apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1, and remains in the cytosol in steady-state conditions in an inactive form.”

• cites [41] Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–89. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

COVID-19-released mediators merge on a common pathway, upregulating the inflammasome, which recognizes pathogen-associated molecular patterns and self-derived danger-associated molecular patterns or alarmines.

“COVID-19-released mediators merge on a common pathway, upregulating cytosolic danger sensing pattern recognition receptor, which is part of a multiprotein complex of the innate immune system that is called inflammasome”

• cites [41] Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477–89. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The cytokine storm induces blood-clot formation and increased capillary permeability, resulting in embolic and hemorrhagic strokes, respectively.

“In addition, the cytokine storm induces blood-clot formation and increased capillary (red) permeability resulting in embolic and hemorrhagic strokes, respectively.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The neuroinflammatory process in the CNS is characterized by microglia hyperactivation, astrocyte stimulation, and demyelination of neurons.

“The result is a neuroinflammatory process characterized by microglia (pink) hyperactivation, astrocyte (green) stimulation, and demyelination (yellow caps) of neurons (blue).”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

ATP activates P2X7 receptors expressed mainly in microglia and astrocytes, resulting in increased Ca2+ influx and glutamate release.

“ATP activates P2X7 receptors (red) expressed mainly in microglia (pink) and astrocytes (green) resulting in increased Ca2+ influx and glutamate (purple circles) release.”

May combine two claims.

Upon inflammasome activation, pro-caspase 1 is cleaved to caspase 1, which converts pro-IL-1β and pro-IL-18 into active forms released from cells; release is facilitated by GSDMD pore channels, which also mediate release of DAMPs including extracellular ATP.

“upon inflammasome protein assembly and activation, pro-caspase 1 protein is cleaved to functional caspase 1, whose main function is the conversion of the inactive and intracellularly stored pro-inflammatory cytokines, pro-IL-1β and pro-IL-18, into their active forms that are released from cells.”

• Also stated in: § Inflammation and CNS-related lethality of COVID-19 · plain

  “In addition to these two cytokines, gasdermin D channels also mediate the release of several biologically active DAMPs or alarmines, including extracellular ATP”

• cites [42] Bertheloot D, Latz E. HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins. Cell Mol Immunol. 2017;14:43–64. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

SARS-CoV-2 may alter brain function by reaching the central nervous system and/or through cytokine storm-mediated effects.

“A SARS-CoV-2 may alter brain function by reaching the central nervous system (described in Fig. 1) and/or through the cytokine storm-mediated effects.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Ang 1-7 binds MasR, protecting against fibrotic formation and presenting antioxidant and vasodilatory effects.

“In contrast, Ang 1–7 binds to Mas receptors (MasR), thus protecting against fibrotic formation, presenting antioxidant and vasodilatory effects.”

May combine two claims.

ACE2 enzyme expressed on the surface of cells is a COVID-19 receptor and is blocked or downregulated after binding of virus or even shed from the cell surface.

“The problem with the conversion of Ang II into Ang 1–7 is that the ACE2 enzyme expressed on surface of cells is a COVID-19 receptor and is blocked or downregulated after binding of virus or even shed from the cell surface [43].”

• cites [43] Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19. Hypertens Res. 2020;43:648–54. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Distressed cells release pro-inflammatory cytokines and ATP.

“In a molecular view, the distressed cells release pro-inflammatory cytokines (yellow circles) and ATP (red circles).”

May combine two claims.

The NLRP3 inflammasome is a trigger of the cytokine storm, as seen in COVID-19 patients, that may be induced by P2X7 receptor activation, including in the brain.

“We consider the NLRP3 inflammasome as a trigger of the cytokine storm, as seen in COVID-19 patients, that may be induced by P2X7 receptor activation, including in the brain (Fig. 2).”

• AssumptionRests on an assumption: SARS-CoV-2 infection elevates extracellular ATP levels.

Probably not a substantial claim: may not pass S3 (load-bearing).

The overreaction of the innate immune system against viral infection induces the cytokine storm.

“This overreaction of the innate immune system against viral infection induces the so-called “cytokine storm””

• cites [40] Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res. 2010;20:34–50. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

NLRP3 inflammasome activation during COVID-19 infection is usually triggered by Ang II, which binds to AT1R, leading to vessel contraction and increasing blood pressure.

“Moreover, NLRP3 inflammasome activation during COVID-19 infection is usually triggered by Ang II, which binds to the angiotensin type 1 receptor (AT1R), leading to vessel contraction and increasing blood pressure.”

Probably not a substantial claim: may not pass S4 (based).

NLRP3 inflammasome mediates the activation of caspase-1, which induces the maturation of interleukins by cleaving pro-IL-1β and pro-IL-18 into IL-1β and IL-18.

“NLRP3 inflammasome mediates the activation of caspase-1, which induces the maturation of interleukins (IL) by cleaving pro-IL-1β and pro-IL-18 in IL-1β and IL-18, respectively.”

May combine two claims.

The mature forms of cytokines are secreted, worsening the neuroinflammatory process established.

“The mature forms of cytokines are secreted worsening the neuroinflammatory process established.”

May combine two claims.

SARS-CoV-2-induced systemic inflammatory responses may also result in endothelial damage and consequently increased production of thrombin by inflammatory cytokines during sepsis in a bidirectional way, because inflammation activates coagulation and coagulation augments inflammatory activity.

“SARS-CoV-2-induced systemic inflammatory responses may also result in endothelial damage and consequently increased production of thrombin by inflammatory cytokines during sepsis in a bidirectional way, because inflammation activates coagulation, and coagulation augments inflammatory activity [45].”

• cites [45] Nascimento JHP, Gomes BF, de O, Do Carmo Júnior PR, Petriz JLF, Rizk SI, et al. Covid-19 and hypercoagulable state: a new therapeutic perspective. Arq Bras Cardiol. 2020;114:829–33. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

In microglia, K+ efflux mediated by P2X7 receptor activation may trigger NLRP3 inflammasome assembly and activation through Nek7 binding.

“In microglia, K+ efflux mediated by P2X7 receptor activation may trigger NLRP3 inflammasome assembly and activation through NIMA-related serine/threonine kinase 7 (Nek7) binding.”

May combine two claims.

Recent evidence indicates that the occurrence of psychiatric disorders in patients is linked to "sterile" inflammation of the brain that may be initiated locally by some stressors affecting nervous tissue or occurs due to a systemic inflammation process.

“Recent evidence indicates that the occurrence of psychiatric disorders in patients is linked to “sterile” inflammation of the brain that may be initiated locally by some stressors affecting nervous tissue or occurs due to a systemic inflammation process [17, 46].”

• cites [17] Ratajczak MZ, Mack A, Bujko K, Domingues A, Pedziwiatr D, Kucia M, et al. ATP-Nlrp3 inflammasome-complement cascade axis in sterile brain inflammation in psychiatric patients and its impact on stem cell trafficking. Stem Cell Rev Rep. 2019;15:497–505. sourceNot checked yet

  Not checked in the free run.

• cites [46] Ratajczak MZ, Pedziwiatr D, Cymer M, Kucia M, Kucharska-Mazur J, Samochowiec J. Sterile inflammation of brain, due to activation of innate immunity, as a culprit in psychiatric disorders. Front Psychiatry. 2018;9:60. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Glutamate activates NMDA receptors expressed in nerve terminals, which enable Ca2+-dependent exocytosis of ATP and more glutamate release.

“Glutamate activates NMDA receptors expressed in nerve terminals (blue), which enable Ca2+-dependent exocytosis of ATP and more glutamate release.”

May combine two claims.

Active inflammatory cells expressing specific protease activated receptors (PAR1-4) bind to thrombin, while Toll-like receptor 4 interacts with fibrin.

“In this scenario, active inflammatory cells expressing specific protease activated receptors (PAR1–4) bind to thrombin, while the Toll-like receptor 4 interacts with fibrin.”

• cites [45] Nascimento JHP, Gomes BF, de O, Do Carmo Júnior PR, Petriz JLF, Rizk SI, et al. Covid-19 and hypercoagulable state: a new therapeutic perspective. Arq Bras Cardiol. 2020;114:829–33. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

An auto regenerative loop causes massive release of neurotransmitters, augmenting excitotoxicity and cell death.

“In this way, an auto regenerative loop is formed causing a massive release of these neurotransmitters augmenting excitotoxicity and cell death.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Hyperactivation of the NLRP3 inflammasome and consequent release of cytokines and ATP can occur by different routes.

“The hyperactivation of NPLR3 inflammasome and consequent release of cytokines and ATP can occur by different routes.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Oxidative stress from free radicals includes DNA damage, lipid peroxidation, tyrosine nitration, and excess S-nitrosylation.

“Oxidative stress from free radicals includes DNA damage, lipid peroxidation, tyrosine nitration, and excess S-nitrosylation.”

Probably not a substantial claim: may not pass S4 (based).

SARS-CoV-2 invasion through ACE2, TMPRSS2 or CD147 activates the inflammasome in target cells.

“SARS-CoV-2 invasion through ACE2, TMPRSS2 or CD147 activates the inflammasome in target cells.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

These free radicals can decompose into other reactive species, such as hydroxyl radical and peroxides.

“These free radicals can also decompose into other reactive species, such as hydroxyl radical and peroxides.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

These structural changes can lead to protein misfolding and aggregation, causing neuronal impairment and/or death.

“These structural changes can lead to protein misfolding and aggregation causing neuronal impairment and/or death.”

May combine two claims.

Hyperactivation of these pathways leads to activation of caspase 1, release of mature IL-1β and IL-18, insertion of gasdermin D channels in the cell membrane, and release of DAMPs, which amplify the innate immune response and may lead to cell death by pyroptosis.

“Hyperactivation of these pathways leads to activation of caspase 1, release of mature IL-1β and IL-18, the insertion of gasdermin D channels in the cell membrane and the release of danger-associated molecular pattern molecules (DAMPs), which amplify the innate immune response and may lead to cell death by pyroptosis.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

ATP can also activate MBL and induce this response.

“ATP can also activate MBL and induce this response.”

Probably not a substantial claim: may not pass S4 (based).

NO production mediates neurotoxicity via several mechanisms.

“NO production mediates neurotoxicity via several mechanisms.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

NO also produces reactive nitrogen species and reactive oxygen species (ROS).

“NO also produces reactive nitrogen species and reactive oxygen species (ROS).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Reaction of NO and superoxide ion generates peroxynitrite and peroxynitrous acid.

“Reaction of NO and superoxide ion (O2−, formed by nNOS under low arginine concentrations) generates peroxynitrite (ONOO-) and peroxynitrous acid (ONOOH).”

Probably not a substantial claim: may not pass S4 (based).

NO interacts with the iron-sulfur centers in the mitochondrial electron transport chain, impairing cellular energy production.

“NO interacts with the iron–sulfur centers in the mitochondrial electron transport chain impairing cellular energy production.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Activation of the renin-angiotensin system leads to elevated levels of angiotensin II that binds to the AT1R receptor.

“Activation of the renin–angiotensin system (RAS) leads to elevated levels of angiotensin II (Ang II) that binds to the AT1R receptor.”

Probably not a substantial claim: may not pass S4 (based).

In the postsynaptic neuron, increased [Ca2+]i leads to Ca2+-calmodulin complex formation and consequent nNOS activation.

“In the postsynaptic neuron (blue), increased [Ca2+]i leads to Ca2+-calmodulin (CaM) complex formation and consequent nNOS activation.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Patients, in particular at younger age, are often diagnosed with stroke and cardiovascular complications.

“Supporting these events, patients in particular at younger age are often diagnosed with stroke and cardiovascular complications.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The N proteins of SARS-CoV-2 activate ComC in a mannan binding lectin-dependent manner, producing C3a and C5a anaphylatoxins and forming the non-lytic C5b/C9 membrane attack complex.

“The N proteins of the SARS-CoV-2 virus activate ComC in a mannan binding lectin (MBL)-dependent manner, producing C3a and C5a anaphylatoxins and forming the non-lytic C5b/C9 membrane attack complex (MAC).”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

P2X7 receptor activation by ATP induces K+ influx and inflammasome activation.

“P2X7 receptor activation by ATP induces K+ influx and inflammasome activation.”

May combine two claims.

Consequently, P2X7 receptors are activated, increasing inflammatory responses as well as modulating RAAS-related pathways and BBB permeability.

“Consequently, P2X7 receptors are activated, increasing inflammatory responses as well as modulating RAAS-related pathways and BBB permeability, as we discuss in the following.”

May combine two claims.

During the progress of infection, ATP release may result from the NLRP3 inflammasome response to COVID-19 infection after virus spike protein interaction with ACE2, due to elevated level of Ang II observed in infected patients, or in response to activated ComC mediators.

“During the progress of infection, ATP release may result from the NLRP3 inflammasome response to COVID-19 infection (i) after virus spike protein interaction with the virus entry receptor ACE2, (ii) due to elevated level of Ang II observed in infected patients, or (iii) in response to activated ComC mediators [61].”

• cites [61] Ratajczak MZ, Kucia M. SARS-CoV-2 infection and overactivation of Nlrp3 inflammasome as a trigger of cytokine “storm” and risk factor for damage of hematopoietic stem cells. Leukemia. 2020;34:1726–9. sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

The P2X7 receptor is a trimeric ionotropic receptor with low affinity for ATP (EC50 around 0.3-1.8 mM) and, under prolonged stimulation, can form pores allowing the passage of large hydrophilic molecules.

“The P2X7 receptor is a trimeric ionotropic receptor that belongs to the P2X family of purinergic receptors, presenting low affinity for ATP (EC50 around 0.3–1.8 mM) and, under prolonged stimulation, can form pores allowing the passage of large hydrophilic molecules [62–64].”

• cites [62] Chessell IP, Michel AD, Humphrey PPA. Properties of the pore-forming P2X7 purinoceptor in mouse NTW8 microglial cells. Br J Pharm. 1997;121:1429–37. sourceNot checked yet

  Not checked in the free run.

• cites [63] Chessell IP, Michel AD, Humphrey PPA. Effects of antagonists at the human recombinant P2X7 receptor. Br J Pharm. 1998;124:1314–20. sourceNot checked yet

  Not checked in the free run.

• cites [64] Di Virgilio F, Schmalzing G, Markwardt F. The elusive P2X7 macropore. Trends Cell Biol. 2018;28:392–404. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The P2X7 receptor is widely expressed through the body, including in immune, lung, and CNS cells, mainly microglia and oligodendrocytes.

“The P2X7 receptor is widely expressed through the body [47], including in immune [48], lung [49], and CNS cells, mainly microglia and oligodendrocytes [50–52], whereas its expression in neurons and astrocytes is still under discussion [50, 51, 53–60].”

• cites [47] Burnstock G, Kennedy C. P2X receptors in health and disease. In: Advances in pharmacology, vol. 61. Academic Press Inc; 2011. p. 333–72. sourceNot checked yet

  Not checked in the free run.

• cites [48] Janks L, Sprague RS, Egan TM. ATP-gated P2X7 receptors require chloride channels to promote inflammation in human macrophages. J Immunol. 2019;202:883–98. sourceNot checked yet

  Not checked in the free run.

• cites [49] Chen Z, Jin N, Narasaraju T, Chen J, McFarland LR, Scott M, et al. Identification of two novel markers for alveolar epithelial type I and II cells. Biochem Biophys Res Commun. 2004;319:774–80. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Pathological increase of AngII-AT1R-mediated activation of NLRP3 inflammasome may initiate psychosis.

“In agreement, pathological increase of AngII-AT1R-mediated activation of NLRP3 inflammasome may initiate psychosis.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Clinical data describe correlations between systemic chronic inflammatory processes and psychiatric disorders.

“Moreover, clinical data describe correlations between systemic chronic inflammatory processes and psychiatric disorders.”

May combine two claims.

Several inflammatory mediators and markers are detected in the peripheral blood of patients with psychiatric and neurodegenerative disorders, which could worsen prognoses for COVID-19 outcome.

“This is supported by the observation that several inflammatory mediators and markers are detected in the peripheral blood of patients with psychiatric and neurodegenerative disorders [17, 46], which could worsen prognoses for COVID-19 outcome.”

• cites [17] Ratajczak MZ, Mack A, Bujko K, Domingues A, Pedziwiatr D, Kucia M, et al. ATP-Nlrp3 inflammasome-complement cascade axis in sterile brain inflammation in psychiatric patients and its impact on stem cell trafficking. Stem Cell Rev Rep. 2019;15:497–505. sourceNot checked yet

  Not checked in the free run.

• cites [46] Ratajczak MZ, Pedziwiatr D, Cymer M, Kucia M, Kucharska-Mazur J, Samochowiec J. Sterile inflammation of brain, due to activation of innate immunity, as a culprit in psychiatric disorders. Front Psychiatry. 2018;9:60. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Bioactive inflammatory mediators released during the cytokine storm, such as extracellular ATP, affect the CNS and may lead to its impairment, mainly through P2X7 receptor activation.

“We believe that bioactive inflammatory mediators released during the cytokine storm, such as extracellular ATP, affect the CNS and may lead to its impairment, mainly through P2X7 receptor activation, as we discuss in the following.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Some reported anti-inflammatory treatment strategies ameliorate neurodegeneration.

“This may also explain, why some reported anti-inflammatory treatment strategies ameliorate neurodegeneration [17, 46].”

• cites [17] Ratajczak MZ, Mack A, Bujko K, Domingues A, Pedziwiatr D, Kucia M, et al. ATP-Nlrp3 inflammasome-complement cascade axis in sterile brain inflammation in psychiatric patients and its impact on stem cell trafficking. Stem Cell Rev Rep. 2019;15:497–505. sourceNot checked yet

  Not checked in the free run.

• cites [46] Ratajczak MZ, Pedziwiatr D, Cymer M, Kucia M, Kucharska-Mazur J, Samochowiec J. Sterile inflammation of brain, due to activation of innate immunity, as a culprit in psychiatric disorders. Front Psychiatry. 2018;9:60. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In a disease state such as infection or brain disease, extracellular ATP levels largely increase and activate P2X7 receptors.

“Conversely, in a disease state as infection or brain disease, extracellular ATP levels largely increase and activate P2X7 receptors [68–70].”

• cites [68] Pellegatti P, Raffaghello L, Bianchi G, Piccardi F, Pistoia V, Di Virgilio F. Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS ONE. 2008;3:e2599. sourceNot checked yet

  Not checked in the free run.

• cites [69] Wilhelm K, Ganesan J, Grimm M, Beilhack A, Krempl CD, Sorichter S, et al. Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R. Nat Med. 2010;16:1434–9. sourceNot checked yet

  Not checked in the free run.

• cites [70] Barberà‐Cremades M, Baroja-Mazo A, Gomez AI, Machado F, Di Virgilio F, Pelegrín P. P2X7 receptor‐stimulation causes fever via PGE2 and IL‐1β release. FASEB J. 2012;26:2951–62. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ATP may act as a DAMP, which activates the nuclear transcription factor NF-κB, resulting in expression upregulation of pro-IL-1β and pro-IL-18 and the NLRP3 protein.

“In these circumstances, ATP may act as DAMP, which activates the nuclear transcription factor NF-κB resulting in expression upregulation of pro-IL-1β and pro-IL-18 and the NLRP3 protein [16, 71].”

• cites [16] Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S. The P2X7 receptor in infection and inflammation. Immunity. 2017;47:15–31. sourceNot checked yet

  Not checked in the free run.

• cites [71] Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016;13:148–59. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Pore formation results in enhanced release of ATP and establishes a positive feedback in pathological conditions.

“Consequently, pore formation results in enhanced release of ATP and establishes a positive feedback in pathological conditions.”

May combine two claims.

Consequently, there is an activation of caspase-1 and maturation of IL-1β and IL-18, resulting in pro-inflammatory cytokine release.

“Consequently, there is an activation of caspase-1 and maturation of IL-1β and IL-18, resulting in pro-inflammatory cytokine release [16, 20, 52, 71, 73].”

• cites [16] Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S. The P2X7 receptor in infection and inflammation. Immunity. 2017;47:15–31. sourceNot checked yet

  Not checked in the free run.

• cites [20] Adinolfi E, Giuliani AL, De Marchi E, Pegoraro A, Orioli E, Di Virgilio F. The P2X7 receptor: a main player in inflammation. Biochem Pharmacol. 2018;151:234–44. sourceNot checked yet

  Not checked in the free run.

• cites [52] He Y, Taylor N, Fourgeaud L, Bhattacharya A. The role of microglial P2X7: modulation of cell death and cytokine release. J Neuroinflammation. 2017;14:135. sourceNot checked yet

  Not checked in the free run.

• cites [71] Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016;13:148–59. sourceNot checked yet

  Not checked in the free run.

• cites [73] Bhattacharya A, Jones DNC. Emerging role of the P2X7-NLRP3-IL1β pathway in mood disorders. Psychoneuroendocrinology. 2018;98:95–100. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

P2X7 receptor activation is associated with numerous cellular functions, such as plasma membrane blebbing, phosphatidylserine exposure in the membrane, formation of ROS, interleukin secretion, cell death and proliferation.

“Consequently, P2X7 receptor activation is associated with numerous cellular functions, as plasma membrane blebbing, phosphatidylserine exposure in the membrane, formation of ROS, interleukin secretion, cell death and proliferation [65, 66].”

• cites [65] Kopp R, Krautloher A, Ramírez-Fernández A, Nicke A. P2X7 interactions and signaling—making head or tail of it. Front Mol Neurosci. 2019;12:1–25. sourceNot checked yet

  Not checked in the free run.

• cites [66] Sluyter R, Stokes L. Significance of p2x7 receptor variants to human health and disease. Recent Pat DNA Gene Seq. 2011;5:41–54. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Activation of P2X7 receptor elicits rapid K+ efflux as well as Ca2+ and Na+ influx, resulting in the stimulation of several intracellular intermediators.

“Activation of P2X7 receptor elicits rapid K+ efflux as well as Ca2+ and Na+ influx, resulting in the stimulation of several intracellular intermediators, as PLC, PLA2, PKC, MAPK, PI3K, ERK1/2 and p38, among others [65].”

• cites [65] Kopp R, Krautloher A, Ramírez-Fernández A, Nicke A. P2X7 interactions and signaling—making head or tail of it. Front Mol Neurosci. 2019;12:1–25. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

P2X7 receptor modulates acute and chronic infection, inflammatory diseases, sepsis, neuropathic pain, and T-cell activation.

“It was already reported its capacity to modulate acute and chronic infection [81, 82], inflammatory diseases [82], sepsis [83, 84], neuropathic pain [85], and T-cell activation [86].”

• cites [81] Morandini A, Savio L, Coutinho-Silva R. The role of p2x7 receptor in infectious inflammatory diseases and the influence of ectonucleotidases. Biomed J. 2014;37:169–77. sourceNot checked yet

  Not checked in the free run.

• cites [82] Savio LEB, Mello P de A, da Silva CG, Coutinho-Silva R. The P2X7 receptor in inflammatory diseases: angel or demon? Front Pharmacol. 2018;9:1–31. sourceNot checked yet

  Not checked in the free run.

• cites [83] Martínez-García J, Martínez-Banaclocha H, Angosto-Bazarra D, De Torre-Minguela C, Baroja-Mazo A, Alarcón-Vila C, et al. P2X7 receptor induces mitochondrial failure in monocytes and compromises NLRP3 inflammasome activation during sepsis. Nat Commun. 2019;10:1–14. sourceNot checked yet

  Not checked in the free run.

• cites [84] Savio LEB, Juste Andrade MG, de Andrade Mello P, Teixeira Santana P, Cristina Abreu Moreira-Souza A, Kolling J, et al. P2X7 receptor signaling contributes to sepsis-associated brain dysfunction. Mol Neurobiol. 2017;54:6459–70. sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The role of P2X7 receptor as a modulator of inflammatory response is well-established.

“In fact, the role of P2X7 receptor as a modulator of inflammatory response is well-established [16, 70].”

• cites [16] Di Virgilio F, Dal Ben D, Sarti AC, Giuliani AL, Falzoni S. The P2X7 receptor in infection and inflammation. Immunity. 2017;47:15–31. sourceNot checked yet

  Not checked in the free run.

• cites [70] Barberà‐Cremades M, Baroja-Mazo A, Gomez AI, Machado F, Di Virgilio F, Pelegrín P. P2X7 receptor‐stimulation causes fever via PGE2 and IL‐1β release. FASEB J. 2012;26:2951–62. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

P2X7 receptor activation increases neuroinflammatory responses, which have been associated with neurodegenerative diseases, psychiatric disorders and stroke.

“Remarkably, P2X7 receptor activation increases neuroinflammatory responses, which have been associated with neurodegenerative diseases, psychiatric disorders and stroke [21, 92–95], as further discussed.”

• cites [21] Sperlágh B, Illes P. P2X7 receptor: An emerging target in central nervous system diseases. Trends Pharm Sci. 2014;35:537–47. sourceNot checked yet

  Not checked in the free run.

• cites [92] Cheffer A, Castillo AR, Corrêa-Velloso JC, Gonçalves MCB, Naaldijk Y, Nascimento IC, et al. Purinergic system in psychiatric diseases. Mol Psychiatry. 2018;23:94–106. sourceNot checked yet

  Not checked in the free run.

• cites [93] Bhattacharya A, Biber K. The microglial ATP-gated ion channel P2X7 as a CNS drug target. Glia. 2016;64:1772–87. sourceNot checked yet

  Not checked in the free run.

• cites [94] Burnstock G. Purinergic signalling and neurological diseases: an update. CNS Neurol Disord - Drug Targets. 2017;16:257–65. sourceNot checked yet

  Not checked in the free run.

• cites [95] Andrejew R, Oliveira-Giacomelli Á, Ribeiro DE, Glaser T, Arnaud-Sampaio VF, Lameu C, et al. The P2X7 receptor: central hub of brain diseases. Front Mol Neurosci. 2020;13:124. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Patients infected with SARS-CoV-2 present elevated levels of IL-6, IL-10, IL-1β, INF-γ, CCL2, TNF-α, CXCL10, CCL7, IL-1 receptor antagonist and IL-2 receptor, supposedly associated with disease severity.

“Patients infected with SARS-CoV-2 present elevated levels of IL-6, IL-10, IL-1β, INF-γ, CCL2, TNF-α, CXCL10, CCL7, IL-1 receptor antagonist and IL-2 receptor, supposedly associated with disease severity [9, 98–105].”

• cites [9] Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020;53:38–42. sourceNot checked yet

  Not checked in the free run.

• cites [98] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. sourceNot checked yet

  Not checked in the free run.

• cites [99] Yang Y, Shen C, Li J, Yuan J, Wei J, Huang F, et al. Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19. J Allergy Clin Immunol. 2020;146:119–27. sourceNot checked yet

  Not checked in the free run.

• cites [100] Pedersen SF, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest. 2020;130:2202–5. sourceNot checked yet

  Not checked in the free run.

• cites [101] Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–9. sourceNot checked yet

  Not checked in the free run.

• cites [102] Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients With COVID-19 in Wuhan, China. Clin Infect Dis. 2020;71:762–8. sourceNot checked yet

  Not checked in the free run.

• cites [103] Gao Y, Li T, Han M, Li X, Wu D, Xu Y, et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol. 2020;92:791–6. sourceNot checked yet

  Not checked in the free run.

• cites [104] Liu T, Zhang J, Yang Y, Ma H, Li Z, Zhang J, et al. The role of interleukin-6 in monitoring severe case of coronavirus disease 2019. EMBO Mol Med. 2020;12:e12421. sourceNot checked yet

  Not checked in the free run.

• cites [105] Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. 2020;71:769–77. sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Cytokine storms have been reported in several viral infections, including SARS-CoV-2.

“Cytokine storms have been reported in several viral infections [96], including SARS-CoV-2 [9, 97].”

• cites [96] Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76:16–32. sourceNot checked yet

  Not checked in the free run.

• cites [9] Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, et al. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020;53:38–42. sourceNot checked yet

  Not checked in the free run.

• cites [97] Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm” in COVID-19. J Infect. 2020;80:607–13. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

P2X7 receptor expression deletion appears to be beneficial in acute lung injury, asthma, lung inflammation, and fibrosis.

“In addition, P2X7 receptor expression deletion appears to be beneficial in case of acute lung injury, asthma, lung inflammation, and fibrosis [87–91].”

• cites [87] Galam L, Rajan A, Failla A, Soundararajan R, Lockey RF, Kolliputi N. Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression. Am J Physiol - Lung Cell Mol Physiol. 2016;310:572–81. sourceNot checked yet

  Not checked in the free run.

• cites [88] Duan L, Hu Ghuang, Li Yjin, Zhang Cliang, Jiang M. P2X7 receptor is involved in lung injuries induced by ischemia-reperfusion in pulmonary arterial hypertension rats. Mol Immunol. 2018;101:409–18. sourceNot checked yet

  Not checked in the free run.

• cites [89] Riteau N, Gasse P, Fauconnier L, Gombault A, Couegnat M, Fick L, et al. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am J Respir Crit Care Med. 2010;182:774–83. sourceNot checked yet

  Not checked in the free run.

• cites [90] Wang S, Zhao J, Wang H, Liang Y, Yang N, Huang Y. Blockage of P2X7 attenuates acute lung injury in mice by inhibiting NLRP3 inflammasome. Int Immunopharmacol. 2015;27:38–45. sourceNot checked yet

  Not checked in the free run.

• cites [91] Li R, Wang J, Li R, Zhu F, Xu W, Zha G, et al. ATP/P2X7-NLRP3 axis of dendritic cells participates in the regulation of airway inflammation and hyper-responsiveness in asthma by mediating HMGB1 expression and secretion. Exp Cell Res. 2018;366:1–15. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

RAAS mediates key events of COVID-19, including viral entry in the cell, inflammation, and lung fibrosis.

“RAAS mediates key events of the disease, including viral entry in the cell [112, 113], inflammation, and lung fibrosis [114].”

• cites [112] Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46:586–90. sourceNot checked yet

  Not checked in the free run.

• cites [113] Pillat MM, Krüger A, Guimarães LMF, Lameu C, de Souza EE, Wrenger C, et al. Insights in chloroquine action: perspectives and implications in Malaria and COVID-19. Cytom Part A. 2020;97:872–81. sourceNot checked yet

  Not checked in the free run.

• cites [114] Wang J, Chen L, Chen B, Meliton A, Liu SQ, Shi Y, et al. Chronic activation of the renin-angiotensin system induces lung fibrosis. Sci Rep. 2015;5:15561. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S1 (asserted).

P2X7 receptor activation is involved in the cytokine storm and associated lung and brain inflammation caused by SARS-CoV-2 infection.

“Therefore, we hypothesize that the P2X7 receptor activation is involved in the cytokine storm and associated lung and brain inflammation caused by SARS-CoV-2 infection.”

Probably not a substantial claim: may not pass S3 (load-bearing).

P2X7 receptor facilitates virion release from HIV-infected macrophages in an exocytosis-dependent way.

“Controversially to the above-cited beneficial P2X7 receptor-mediated viral elimination, this receptor was described to even facilitate virion release from HIV-infected macrophages in an exocytosis-dependent way [109].”

• cites [109] Graziano F, Desdouits M, Garzetti L, Podini P, Alfano M, Rubartelli A, et al. Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages. Proc Natl Acad Sci U S A. 2015;112:E3265–73. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

P2X7 receptor activation exacerbated inflammation, enhanced tissue damage, increased mortality, and worsened lung pathology in studies with influenza A virus and adenovirus.

“Moreover, P2X7 receptor activation exacerbated inflammation, enhanced tissue damage, increased mortality, and worsened lung pathology involving P2X7 receptor expression or activation, such as observed in several other studies with e.g., influenza A virus [110] and adenovirus [111].”

• cites [110] Leyva-Grado VH, Ermler ME, Schotsaert M, Gonzalez MG, Gillespie V, Lim JK, et al. Contribution of the purinergic receptor P2X7 to development of lung immunopathology during influenza virus infection. MBio. 2017;8:1–15. sourceNot checked yet

  Not checked in the free run.

• cites [111] Lee BH, Hwang DM, Palaniyar N, Grinstein S, Philpott DJ, Hu J. Activation of P2X(7) receptor by ATP plays an important role in regulating inflammatory responses during acute viral infection. PLoS ONE. 2012;7:e35812. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The P2X7 receptor participates in viral infections, exerting mostly pro-inflammatory roles, is important for pathogen elimination, but its activation may be detrimental to the host due to induction of exacerbated inflammatory responses.

“The P2X7 receptor, as a central player in inflammation, participates in viral infections. Exerting mostly pro-inflammatory roles [20], the P2X7 receptor is important for pathogen elimination [108], but on the other hand, its activation may be detrimental to the host due to the induction of exacerbated inflammatory responses.”

• cites [20] Adinolfi E, Giuliani AL, De Marchi E, Pegoraro A, Orioli E, Di Virgilio F. The P2X7 receptor: a main player in inflammation. Biochem Pharmacol. 2018;151:234–44. sourceNot checked yet

  Not checked in the free run.

• cites [108] Zhang C, He H, Wang L, Zhang N, Huang H, Xiong Q, et al. Virus-triggered ATP release limits viral replication through facilitating IFN-β production in a P2X7-dependent manner. J Immunol. 2017;199:1372–81. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

The P2X7 receptor triggers pathways related to the functioning of the RAAS, which is importantly implicated in COVID-19 pathology.

“Importantly, the P2X7 receptor triggers pathways related to the functioning of the RAAS, importantly implicated in COVID-19 pathology.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Protective roles of P2X7 receptor activation have been described against vesicular stomatitis virus, Newcastle disease virus, murine leukemia virus and HSV virus infections.

“Protective roles of P2X7 receptor activation have been described, for instance, against vesicular stomatitis virus, Newcastle disease virus, murine leukemia virus and HSV virus infections [108].”

• cites [108] Zhang C, He H, Wang L, Zhang N, Huang H, Xiong Q, et al. Virus-triggered ATP release limits viral replication through facilitating IFN-β production in a P2X7-dependent manner. J Immunol. 2017;199:1372–81. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

P2X7 receptor activation may be involved in the cytokine storm observed in COVID-19 by stimulating NLRP3 inflammasome, overshooting inflammation with extensive cytokine release, affecting coagulation and leading to diffuse lung edema and infiltration by immune cells and inflammatory cytokines.

“Considering the P2X7 receptor role in inflammation, its activation may be involved in the cytokine storm observed in COVID-19 by stimulating NLRP3 inflammasome, overshooting inflammation with extensive cytokine release, affecting coagulation and leading to diffuse lung edema and infiltration by immune cells and inflammatory cytokines [106].”

• cites [106] Di Virgilio F, Tang Y, Sarti AC, Rossato M. A rationale for targeting the P2X7 receptor in Coronavirus disease 19 (Covid-19). Br J Pharmacol. 2020;177:4990–94. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

P2X7 receptor knockout mice submitted to a model of lung fibrosis revealed reduced infiltration of inflammatory cells, cytokine release, apoptosis, and fibrosis, while P2X7 receptor agonists increased these deleterious processes.

“In addition, P2X7 receptor knockout mice submitted to a model of lung fibrosis revealed reduced infiltration of inflammatory cells, cytokine release, apoptosis, and fibrosis, while P2X7 receptor agonists increased these deleterious processes [88, 107].”

• cites [88] Duan L, Hu Ghuang, Li Yjin, Zhang Cliang, Jiang M. P2X7 receptor is involved in lung injuries induced by ischemia-reperfusion in pulmonary arterial hypertension rats. Mol Immunol. 2018;101:409–18. sourceNot checked yet

  Not checked in the free run.

• cites [107] Monção-Ribeiro LC, Faffe DS, Santana PT, Vieira FS, da Graça CLAL, Marques-da-Silva C, et al. P2X7 receptor modulates inflammatory and functional pulmonary changes induced by silica. PLoS ONE. 2014;9:e110185. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

The pressor axis of RAAS is based on Ang II actions through the activation of AT1R.

“The pressor axis of RAAS bases on Ang II actions through the activation of AT1R.”

May combine two claims.

Consequently, Ang 1,7 that would exert beneficial effects against CNS damage and neurological deficits is not formed, prevailing Ang II actions mediated by the AT1R promoting fibrosis, lung injury, and neuroinflammation.

“Consequently, Ang 1,7 that would exert beneficial effects against CNS damage and neurological deficits [115] is not formed, prevailing Ang II actions mediated by the AT1R promoting fibrosis, lung injury, and importantly neuroinflammation [115].”

• cites [115] Gironacci MM, Vicario A, Cerezo G, Silva MG. The depressor axis of the renin-angiotensin system and brain disorders: A translational approach. Clin Sci. 2018;132:1021–38. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Components of the depressor axis correlate to enhanced cognition and cell survival in the brain, orchestrating antioxidant and anti-inflammatory responses.

“Briefly, components of the depressor axis correlate to enhanced cognition and cell survival in the brain, orchestrating antioxidant, and anti-inflammatory responses.”

• cites [115] Gironacci MM, Vicario A, Cerezo G, Silva MG. The depressor axis of the renin-angiotensin system and brain disorders: A translational approach. Clin Sci. 2018;132:1021–38. sourceNot checked yet

  Not checked in the free run.

• cites [117] Jackson L, Eldahshan W, Fagan SC, Ergul A. Within the brain: the renin angiotensin system. Int J Mol Sci. 2018;19:876. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Inhibition of the P2X7 receptor might decrease pathological traits mediated by the RAAS pressor axis and protect against brain and lung injury in COVID-19 patients.

“Since the P2X7 receptor is also involved in lung damage [87–89], neurodegenerative and psychiatric disorders [92, 95, 118], the hypothesis is reasonable that inhibition of this receptor might decrease pathological traits mediated by the RAAS pressor axis and protect against brain and lung injury in COVID-19 patients.”

• cites [87] Galam L, Rajan A, Failla A, Soundararajan R, Lockey RF, Kolliputi N. Deletion of P2X7 attenuates hyperoxia-induced acute lung injury via inflammasome suppression. Am J Physiol - Lung Cell Mol Physiol. 2016;310:572–81. sourceNot checked yet

  Not checked in the free run.

• cites [88] Duan L, Hu Ghuang, Li Yjin, Zhang Cliang, Jiang M. P2X7 receptor is involved in lung injuries induced by ischemia-reperfusion in pulmonary arterial hypertension rats. Mol Immunol. 2018;101:409–18. sourceNot checked yet

  Not checked in the free run.

• cites [89] Riteau N, Gasse P, Fauconnier L, Gombault A, Couegnat M, Fick L, et al. Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis. Am J Respir Crit Care Med. 2010;182:774–83. sourceNot checked yet

  Not checked in the free run.

• cites [92] Cheffer A, Castillo AR, Corrêa-Velloso JC, Gonçalves MCB, Naaldijk Y, Nascimento IC, et al. Purinergic system in psychiatric diseases. Mol Psychiatry. 2018;23:94–106. sourceNot checked yet

  Not checked in the free run.

• cites [95] Andrejew R, Oliveira-Giacomelli Á, Ribeiro DE, Glaser T, Arnaud-Sampaio VF, Lameu C, et al. The P2X7 receptor: central hub of brain diseases. Front Mol Neurosci. 2020;13:124. sourceNot checked yet

  Not checked in the free run.

• cites [118] Ribeiro DE, Roncalho AL, Glaser T, Ulrich H, Wegener G, Joca S. P2X7 receptor signaling in stress and depression. Int J Mol Sci. 2019;20:2778. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In rats with diabetic nephropathy, P2X7 receptor expression decreased ACE activity and Ang II levels, which might increase ACE2 expression and counteract SARS-CoV-2-induced inflammatory exacerbation.

“Furthermore, in rats with diabetic nephropathy, P2X7 receptor expression decreased ACE activity and Ang II levels [120], which might increase ACE2 expression [43] and counteract SARS-CoV-2-induced inflammatory exacerbation.”

• cites [120] Nascimento M, Punaro GR, Serralha RS, Lima DY, Mouro MG, Oliveira LCG, et al. Inhibition of the P2X7 receptor improves renal function via renin-angiotensin system and nitric oxide on diabetic nephropathy in rats. Life Sci. 2020;251:117640. sourceNot checked yet

  Not checked in the free run.

• cites [43] Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19. Hypertens Res. 2020;43:648–54. sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

The balance between the pressor and depressor axis of RAAS is implicated in neurodegenerative and psychiatric disorders.

“In fact, the balance between the pressor and depressor axis of RAAS is implicated in neurodegenerative and psychiatric disorders, as carefully reviewed elsewhere [115, 117].”

• cites [115] Gironacci MM, Vicario A, Cerezo G, Silva MG. The depressor axis of the renin-angiotensin system and brain disorders: A translational approach. Clin Sci. 2018;132:1021–38. sourceNot checked yet

  Not checked in the free run.

• cites [117] Jackson L, Eldahshan W, Fagan SC, Ergul A. Within the brain: the renin angiotensin system. Int J Mol Sci. 2018;19:876. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ACE2 serves as a SARS-CoV-2 entry route in human cells, but as this enzyme is internalized following virus binding, its enzyme function is lost.

“ACE2, independent from its enzymatic activity, serves as SARS-CoV-2 entry route in human cells, but as this enzyme is internalized following virus binding, its enzyme function is lost [6, 116].”

• cites [6] Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020;11:1620. sourceNot checked yet

  Not checked in the free run.

• cites [116] Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res. 2020;126:1456–74. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ACE cleaves angiotensin I into Ang II, and Ang II levels are counterbalanced by the depressor axis that degrades Ang II into Ang 1,7 through ACE2 activity; Ang 1,7 activates MasR.

“ACE is responsible for the cleavage of angiotensin I into Ang II, and Ang II levels are counterbalanced by the depressor axis that degrades Ang II into Ang 1,7 through ACE2 activity. Finally, Ang 1,7 activates MasR [115].”

• cites [115] Gironacci MM, Vicario A, Cerezo G, Silva MG. The depressor axis of the renin-angiotensin system and brain disorders: A translational approach. Clin Sci. 2018;132:1021–38. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Both intracerebral hemorrhage and clots are responsible for the primary stroke in the brain.

“Both intracerebral hemorrhage, against which the P2X7 receptor antagonist protects [124], and clots are responsible for the primary stroke in the brain [128].”

• cites [124] Zhao H, Zhang X, Dai Z, Feng Y, Li Q, Zhang JH, et al. P2X7 receptor suppression preserves blood–brain barrier through inhibiting RhoA activation after experimental intracerebral hemorrhage in rats. Sci Rep. 2016;6:23286. sourceNot checked yet

  Not checked in the free run.

• cites [128] Avula A, Nalleballe K, Narula N, Sapozhnikov S, Dandu V, Toom S, et al. COVID-19 presenting as stroke. Brain Behav Immun. 2020;87:115–9. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

SARS-CoV-2 infection can disrupt the BBB by directly infecting and killing endothelial cells, as well as by triggering P2X7 receptor signaling.

“In this way, SARS-CoV-2 infection can disrupt the BBB by directly infecting and killing endothelial cells, as well as by triggering P2X7 receptor signaling.”

May combine two claims.

Blockade of P2X7 receptors might prevent inflammatory exacerbation both through its direct actions in inflammasome assembly and through RAAS modulation, avoiding deleterious actions of RAAS in several tissues, including the lung and the brain.

“Conciliating all these findings, we highlight that the blockade of P2X7 receptors might prevent inflammatory exacerbation both, through its direct actions in inflammasome assembly and through RAAS modulation, avoiding deleterious actions of RAAS in several tissues, including the lung and the brain.”

May combine two claims.

Endothelial cells express high levels of ACE2, which is the main mediator of SARS-CoV-2 infection.

“Endothelial cells express high levels of ACE2, which is the main mediator of SARS-CoV-2 infection.”

Classified as probably not a substantial claim. May combine two claims.

Endothelial cells comprise the BBB and are highly selective in filtering the content that is available to neurons.

“Endothelial cells comprise the BBB and are highly selective in consequently filtering the content that is available to neurons [121].”

• cites [121] Daneman R, Prat A. The blood–brain barrier. Cold Spring Harb Perspect Biol. 2015;7:a020412. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The opening of P2X7 receptor channels leads to IL-1β production mainly through NLRP3 inflammasome activation, thus contributing to the disruption of the BBB.

“The opening of P2X7 receptor channels leads to IL-1β production mainly through NLRP3 inflammasome activation [123], thus contributing to the disruption of the BBB.”

• cites [123] Giuliani AL, Sarti AC, Falzoni S, Di Virgilio F. The P2X7 receptor-interleukin-1 liaison. Front Pharm. 2017;8:123. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ATP acts as a DAMP and activates the P2X7 receptor, which is largely expressed by endothelial cells and astrocytes/microglial cells, releasing pro-inflammatory cytokines and amplifying the immune response.

“As previously mentioned, ATP acts as a DAMP and activates the P2X7 receptor, which is largely expressed by endothelial cells and astrocytes/microglial cells, releasing pro-inflammatory cytokines and amplifying the immune response [122].”

• cites [122] Yang F, Zhao K, Zhang X, Zhang J, Xu B. ATP induces disruption of tight junction proteins via IL-1 beta-dependent MMP-9 activation of human blood–brain barrier in vitro. Neural Plast. 2016;2016:8928530.Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Diverse hospitals reported increasing levels of patients affected by stroke during SARS-CoV-2 infection.

“Diverse hospitals reported increasing levels of patients affected by stroke during SARS-CoV-2 infection [129, 130].”

• cites [129] Khot UN, Reimer AP, Brown A, Hustey FM, Hussain MS, Kapadia SR, et al. Impact of COVID-19 pandemic on critical care transfers for ST-elevation myocardial infarction, stroke, and aortic emergencies. Circ Cardiovasc Qual Outcomes. 2020;13:e006938. sourceNot checked yet

  Not checked in the free run.

• cites [130] Wang H, Tang X, Fan H, Luo Y, Song Y, Xu Y, et al. Potential mechanisms of hemorrhagic stroke in elderly COVID-19 patients. Aging. 2020;12:10022–34. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Pathological inflammation may be induced by P2X7 receptor activation, and its antagonism has been proposed as a therapeutic approach for COVID-19 treatment.

“Pathological inflammation may be induced by P2X7 receptor activation, and its antagonism has been proposed as a therapeutic approach for COVID-19 treatment [106].”

• cites [106] Di Virgilio F, Tang Y, Sarti AC, Rossato M. A rationale for targeting the P2X7 receptor in Coronavirus disease 19 (Covid-19). Br J Pharmacol. 2020;177:4990–94. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

The cytokine storm induced by viral infection could stimulate neuroinflammation and neuronal death, facilitating the development of these diseases.

“Since the CNS immune response is also modulated by peripheral components [137], we hypothesized that the cytokine storm induced by viral infection could stimulate neuroinflammation and neuronal death, facilitating the development of these diseases (Fig. 2B).”

• cites [137] Sankowski R, Mader S, Valdés-Ferrer SI. Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci. 2015;9:98. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The role of the P2X7 receptor in neuroinflammatory processes in neuropsychiatric and neurodegenerative diseases is widely studied.

“The role of the P2X7 receptor in neuroinflammatory processes in neuropsychiatric and neurodegenerative diseases is widely studied [95, 118].”

• cites [95] Andrejew R, Oliveira-Giacomelli Á, Ribeiro DE, Glaser T, Arnaud-Sampaio VF, Lameu C, et al. The P2X7 receptor: central hub of brain diseases. Front Mol Neurosci. 2020;13:124. sourceNot checked yet

  Not checked in the free run.

• cites [118] Ribeiro DE, Roncalho AL, Glaser T, Ulrich H, Wegener G, Joca S. P2X7 receptor signaling in stress and depression. Int J Mol Sci. 2019;20:2778. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Inflammation is mediated by cytokines, chemokines, ROS and other bioactive molecules.

“As already mentioned, inflammation is mediated by cytokines, chemokines, ROS and other bioactive molecules.”

May combine two claims.

The virus can access the brain through the blood stream and infect BBB cells, as observed for other viruses.

“Further, the virus can access the brain through the blood stream and infect BBB cells, as observed for other viruses [131].”

• cites [131] Keep RF, Zhou N, Xiang J, Andjelkovic AV, Hua Y, Xi G. Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage. Fluids Barriers CNS. 2014;11:1–13. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

COVID-19 patients are suffering acute cerebrovascular disorder and other correlated neurological symptoms as consequences of stroke or micro-strokes.

“COVID-19 patients are suffering acute cerebrovascular disorder and other correlated neurological symptoms as consequences of stroke or micro-strokes [24].”

• cites [24] Butowt R, Bilinska K. SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection. ACS Chem Neurosci. 2020;11:1200–3. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Neuroinflammation is closely related to neurodegenerative diseases, such as Huntington's, Alzheimer's and Parkinson's disease, and neuropsychiatric disorders, such as major depressive disorder, bipolar disorder and anxiety.

“In fact, neuroinflammation is closely related to neurodegenerative diseases, as Huntington’s [133], Alzheimer’s [134] and Parkinson’s disease [135] and neuropsychiatric disorders, such as major depressive disorder, bipolar disorder and anxiety [136].”

• cites [133] Lois C, González I, Izquierdo-García D, Zürcher NR, Wilkens P, Loggia ML, et al. Neuroinflammation in Huntington’s disease: new Insights with 11C-PBR28 PET/MRI. ACS Chem Neurosci. 2018;9:2563–71. sourceNot checked yet

  Not checked in the free run.

• cites [134] Heneka MT, O’Banion MK, Terwel D, Kummer MP. Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm. 2010;117:919–47. sourceNot checked yet

  Not checked in the free run.

• cites [135] Troncoso-Escudero P, Parra A, Nassif M, Vidal RL. Outside in: unraveling the role of neuroinflammation in the progression of Parkinson’s disease. Front Neurol. 2018;9:860. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

These molecules act like DAMPs, signaling astro- and microgliosis.

“These molecules act like DAMPs, signaling astro- and microgliosis.”

May combine two claims.

The first immune response to an insult in the nervous system is the activation of microglial cells of the M2 phenotype, which is involved in anti-inflammatory mechanisms for defense and injury repair.

“The first immune response to an insult in the nervous system is the activation of microglial cells of the M2 phenotype, which is involved in anti-inflammatory mechanisms for defense and injury repair [132].”

• cites [132] Tang Y, Le W. Differential Roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol. 2016;53:1181–94. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Experimental evidence supports that viral infection may evoke neuronal death, encephalopathy, myelin destruction and juvenile Parkinson's disease development; however, these studies did not include coronaviruses.

“Experimental evidence supports that viral infection may evoke neuronal death, encephalopathy, myelin destruction and juvenile Parkinson’s disease development; however, these studies did not include coronaviruses [140].”

• cites [140] Zhou L, Miranda-Saksena M, Saksena NK. Viruses and neurodegeneration. Virol J. 2013;10:1–17. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Klok and colleagues observed disturbing increases in the incidence of thrombotic complications in critically ill intensive care unit patients as high as 31% and recommended pharmacological prophylaxis against thrombosis.

“Klok and colleagues observed disturbing increases in the incidence of thrombotic complications in critically ill intensive care unit patients as high as 31% and recommended pharmacological prophylaxis against thrombosis [24].”

• cites [24] Butowt R, Bilinska K. SARS-CoV-2: olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection. ACS Chem Neurosci. 2020;11:1200–3. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In neurodegenerative diseases, cell death is accompanied by neuroinflammatory processes and massive ATP release.

“In neurodegenerative diseases, cell death is accompanied by neuroinflammatory processes and massive ATP release [138].”

• cites [138] Oliveira-Giacomelli Á, Naaldijk Y, Sardá-Arroyo L, Gonçalves MCB, Corrêa-Velloso J, Pillat MM, et al. Purinergic receptors in neurological diseases with motor symptoms: targets for therapy. Front Pharm. 2018;9:325. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In animal models for neurodegeneration, P2X7 receptor antagonism exerted beneficial anti-inflammatory effects, indicating that P2X7 receptor activation and subsequent neuroinflammation is tightly related to neurodegeneration worsening.

“In animal models for neurodegeneration P2X7 receptor antagonism exerted beneficial anti-inflammatory effects [138, 139], indicating that P2X7 receptor activation and subsequent neuroinflammation is tightly related to neurodegeneration worsening.”

• cites [138] Oliveira-Giacomelli Á, Naaldijk Y, Sardá-Arroyo L, Gonçalves MCB, Corrêa-Velloso J, Pillat MM, et al. Purinergic receptors in neurological diseases with motor symptoms: targets for therapy. Front Pharm. 2018;9:325. sourceNot checked yet

  Not checked in the free run.

• cites [139] Oliveira-Giacomelli Á, Albino CM, de Souza HDN, Corrêa-Velloso J, de Jesus Santos AP, Baranova J, et al. P2Y6 and P2X7 receptor antagonism exerts neuroprotective/ neuroregenerative effects in an animal model of Parkinson’s disease. Front Cell Neurosci. 2019;13:476. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Both ways can lead to increased inflammation due to hypoxia, increased acidification and release of DAMPs at the niche of the injury, disrupting the BBB and damaging the CNS and, thus, leading to the development of neuropsychiatric disorders.

“Both ways can lead to increased inflammation due to hypoxia, increased acidification and release of DAMPs at the niche of the injury, disrupting the BBB and damaging the CNS and, thus, leading to the development of neuropsychiatric disorders.”

Probably not a substantial claim: may not pass S3 (load-bearing).

COVID-19 related psychiatric symptoms have been largely described during and after the occurrence of other respiratory pandemics, such as MERS and SARS.

“Moreover, COVID-19 related psychiatric symptoms (including anger, anxiety, suicidal ideas, hallucinations, insomnia, impaired memory, poor concentration, time disorientation, fear/panic, pressured speech, mood alterations, pessimistic thinking, crying spell and persecutory ideas) have been largely described during and after the occurrence of other respiratory pandemics, such as MERS [151] and SARS”

• cites [151] Kim HC, Yoo SY, Lee BH, Lee SH, Shin HS. Psychiatric findings in suspected and confirmed middle east respiratory syndrome patients quarantined in hospital: a retrospective chart analysis. Psychiatry Investig. 2018;15:355–60. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Olfactory impairment is an early predictor of Parkinson's disease development due to α-synuclein aggregation in the olfactory bulb.

“It is worthwhile noting that olfactory impairment is an early predictor of Parkinson’s disease development due to α-synuclein aggregation in the olfactory bulb [142].”

• cites [142] Rey NL, Wesson DW, Brundin P. The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. Neurobiol Dis. 2018;109:226–48. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Dysregulated stress and neuroinflammatory responses might cause hypothalamic-pituitary-adrenal (HPA) axis dysfunction.

“Dysregulated stress and neuroinflammatory responses might cause hypothalamic–pituitary–adrenal (HPA) axis dysfunction.”

May combine two claims.

α-synuclein induces mitochondrial dysfunction and microglial activation caused by P2X7 receptor stimulation.

“Although these symptoms might not be disease-related, studies show that α-synuclein induces mitochondrial dysfunction and microglial activation caused by P2X7 receptor stimulation [143, 144].”

• cites [143] Wilkaniec A, Gąssowska M, Czapski GA, Cieślik M, Sulkowski G, Adamczyk A. P2X7 receptor-pannexin 1 interaction mediates extracellular alpha-synuclein-induced ATP release in neuroblastoma SH-SY5Y cells. Purinergic Signal. 2017;13:347–61. sourceNot checked yet

  Not checked in the free run.

• cites [144] Jiang T, Hoekstra J, Heng X, Kang W, Ding J, Liu J, et al. P2X7 receptor is critical in α-synuclein-mediated microglial NADPH oxidase activation. Neurobiol Aging. 2015;36:2304–18. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Murine coronavirus is used to induce encephalitis in mice with prominent demyelination and axonal damage.

“In fact, murine coronavirus is used to induce encephalitis in mice with prominent demyelination and axonal damage.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Alterations in the HPA axis have been linked to mood diseases, and HPA activation has been connected with suicide.

“Alterations in the HPA axis have been linked to mood diseases, and HPA activation has been connected with suicide.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A study with 714 patients with COVID-19 found a prevalence of self-reported post-traumatic stress disorder symptoms in 96.2% of them.

“As mentioned, a study with 714 patients with COVID-19 found a prevalence of self-reported post-traumatic stress disorder symptoms in 96.2% of them [149].”

• cites [149] Bo HX, Li W, Yang Y, Wang Y, Zhang Q, Cheung T, et al. Posttraumatic stress symptoms and attitude toward crisis mental health services among clinically stable patients with COVID-19 in China. Psychological Medicine. 2020;1-9. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Okusaga et al. connected seropositivity for human coronavirus strain L63 with mood disorders and suicide attempts.

“Further indication for psychiatric implications of coronaviruses infections came from a study of Okusaga et al. [160], who connected seropositivity for human coronavirus strain L63 with mood disorders and suicide attempts.”

• cites [160] Okusaga O, Yolken RH, Langenberg P, Lapidus M, Arling TA, Dickerson FB, et al. Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts. J Affect Disord. 2011;130:220–5. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Anosmia is one of the neurological symptoms reported by SARS-CoV-2 patients.

“Curiously, anosmia is one of the neurological symptoms reported by SARS-CoV-2 patients.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The P2X7 receptor antagonist JNJ-54175446 is undergoing clinical trials with treatment-resistant depressive patients.

“Noteworthy, the P2X7 receptor antagonist JNJ-54175446 is undergoing clinical trials with treatment-resistant depressive patients (EudraCT number 2018-001884-21 at www.clinicaltrialsregister.eu).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Another study with 114 patients reported that 34.7% of patients presented anxiety symptoms, while 28.5% of them displayed depression symptoms.

“Another study with 114 patients reported that 34.7% of patients presented anxiety symptoms, while 28.5% of them displayed depression symptoms [150].”

• cites [150] Kong X, Zheng K, Tang M, Kong F, Zhou J, Diao L, et al. Prevalence and Factors Associated with Depression and Anxiety of Hospitalized Patients with COVID-19. 2020. https://doi.org/10.1101/2020.03.24.20043075. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The cytokine storm and cell death induced by SARS-CoV-2 infection results in P2X7 receptor-mediated neuroinflammation, leading to the development of neuropsychiatry disorders.

“In this context, we propose that the cytokine storm and cell death induced by SARS-CoV-2 infection results in P2X7 receptor-mediated neuroinflammation, leading to the development of neuropsychiatry disorders.”

Classified as probably not a substantial claim. May combine two claims.

Neuroinflammation and increased levels of ATP are observed in neuropsychiatry disorders, supposedly correlated with P2X7 receptor activation.

“Neuroinflammation and increased levels of ATP are observed in neuropsychiatry disorders, supposedly correlated with P2X7 receptor activation [118, 145].”

• cites [118] Ribeiro DE, Roncalho AL, Glaser T, Ulrich H, Wegener G, Joca S. P2X7 receptor signaling in stress and depression. Int J Mol Sci. 2019;20:2778. sourceNot checked yet

  Not checked in the free run.

• cites [145] Deussing JM, Arzt E. P2X7 receptor: a potential therapeutic target for depression? Trends Mol Med. 2018;24:736–47. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Based on observed pathophysiology and disease progression, murine coronavirus has been proposed as an animal model of multiple sclerosis.

“Based on observed pathophysiology and disease progression, this has been proposed as an animal model of multiple sclerosis [141].”

• cites [141] Lee S, Nedumaran B, Hypolite J, Caldwell B, Rudolph MC, Malykhina AP. Differential neurodegenerative phenotypes are associated with heterogeneous voiding dysfunction in a coronavirus-induced model of multiple sclerosis. Sci Rep. 2019;9:1–11. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The COVID-19 entry receptor ACE2 activates RAAS for neuroinflammation and VEGF synthesis by Ang II binding to AT1R.

“The COVID-19 entry receptor ACE2 activates RAAS for neuroinflammation and VEGF synthesis by Ang II binding to AT1R (reviewed in ref. [167]).”

• cites [167] Yin XX, Zheng XR, Peng W, Wu ML, Mao XY. Vascular endothelial growth factor (VEGF) as a vital target for brain inflammation during the COVID-19 outbreak. ACS Chem Neurosci. 2020;11:1704–5. sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

Mood disorder patients might be more prone to severe COVID-19 disease development.

“Noteworthy, such mechanism would explain the possible propensity for the development of mood disorders triggered by COVID-19 infection as well as raise the hypothesis that mood disorder patients might be more prone to severe COVID-19 disease development.”

May combine two claims.

The main mechanism involved in this scenario is neuroinflammation, a critical process in psychiatric and neurodegenerative disease development.

“The main mechanism involved in this scenario is neuroinflammation, a critical process in psychiatric and neurodegenerative disease development.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

SARS-CoV-2 infection induces a cytokine storm that could trigger and/or worsen neuroinflammatory processes.

“SARS-CoV-2 infection induces a cytokine storm that could trigger and/or worse neuroinflammatory processes.”

Probably not a substantial claim: may not pass S4 (based).

Several lines of evidence have raised the possibility of neuroinvasion by SARS-CoV-2, which may cause short- or long-term impairment of the CNS.

“Several lines of evidence have raised the possibility of neuroinvasion by SARS-CoV-2 (Fig. 1), which may cause short- or long-term impairment of the CNS.”

May combine two claims.

Increasing VEGF concentrations recruit inflammatory cells into the brain and sustain neuroinflammation, and have been named as target for COVID-19 treatment.

“Finally, increasing VEGF concentrations, which recruit inflammatory cells into the brain and sustain neuroinflammation, have been named as target for COVID-19 treatment [167].”

• cites [167] Yin XX, Zheng XR, Peng W, Wu ML, Mao XY. Vascular endothelial growth factor (VEGF) as a vital target for brain inflammation during the COVID-19 outbreak. ACS Chem Neurosci. 2020;11:1704–5. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These patients already carry augmented inflammation patterns, such as systemic inflammation, or suffer from a cytokine storm and show enhanced P2X7 receptor expression.

“These patients already carry augmented inflammation patterns, such as systemic inflammation, or suffer from a cytokine storm [166] and show enhanced P2X7 receptor expression, as previously discussed.”

• cites [166] Fleshner M, Frank M, Maier SF. Danger signals and inflammasomes: stress-evoked sterile inflammation in mood disorders. Neuropsychopharmacology. 2017;42:36–45. sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Gene knockout or pharmacological inhibition of P2X7 receptors induced antidepressant-like behavior in mice exposed to stress, accompanied by HPA axis restoration.

“Noteworthy, gene knockout or pharmacological inhibition of P2X7 receptors induced antidepressant-like behavior in mice exposed to stress, accompanied by HPA axis restoration [163, 164].”

• cites [163] Farooq RK, Tanti A, Ainouche S, Roger S, Belzung C, Camus V. A P2X7 receptor antagonist reverses behavioural alterations, microglial activation and neuroendocrine dysregulation in an unpredictable chronic mild stress (UCMS) model of depression in mice. Psychoneuroendocrinology. 2018;97:120–30. sourceNot checked yet

  Not checked in the free run.

• cites [164] Csölle C, Andó RD, Kittel A, Gölöncsér F, Baranyi M, Soproni K, et al. The absence of P2X7 receptors (P2rx7) on non-haematopoietic cells leads to selective alteration in mood-related behaviour with dysregulated gene expression and stress reactivity in mice. Int J Neuropsychopharmacol. 2013;16:213–33. sourceNot checked yet

  Not checked in the free run.